List of Abbreviations
AIADs – Autoinflammatory diseases
AH – Arterial hypertension
ALT – Alanine aminotransferase
AST – Aspartate aminotransferase
ANA – Antinuclear antibodies
ANCA – Antineutrophil cytoplasmic antibodies
ACPA – Antibodies to cyclic citrullinated peptide
BD – Behçet's disease
VAS – Visual Analogue Scale
IBD – Inflammatory bowel disease
bDMARDs – Genetically engineered biological drugs (interleukin inhibitors L04AC, tumor necrosis factor alpha inhibitors L04AB)
GCs – Glucocorticosteroids
HPS – Hemophagocytic syndrome
DNA – Deoxyribonucleic acid
GI – Gastrointestinal tract
PFS – Protracted febrile myalgia
IL – Interleukin
CT – Computed tomography
CPK – Creatine phosphokinase
PT – Physiotherapy
ICD – International Statistical Classification of Diseases and Related Health Problems
MRI – Magnetic resonance imaging
NSAIDs – Non-steroidal anti-inflammatory and antirheumatic drugs
ARI – Acute respiratory infection
HSP – Henoch-Schönlein purpura
PET – Positron emission tomography
RDS – Respiratory distress syndrome
MS – Multiple sclerosis
RF – Rheumatoid factor
RP – Radiopharmaceutical
SAA – Serum amyloid A
ESR – Erythrocyte sedimentation rate
CRP – C-reactive protein
sJIA – Systemic juvenile idiopathic arthritis (systemic-onset juvenile arthritis)
FMF – Familial Mediterranean fever
Ultrasound – Ultrasound examination
PAN – Polyarteritis nodosa
FC – Functional class
TNF – Tumor necrosis factor
CRF – Chronic renal failure
CMV – Cytomegalovirus
EGD – Esophagogastroduodenoscopy
ECG – Electrocardiography
EchoCG – Echocardiography
JA – Juvenile arthritis
JAS – Juvenile ankylosing spondyloarthritis
CINCA – Chronic infantile neurologic, cutaneous and articular syndrome
EUROFEVER – International registry for study of autoinflammatory diseases established within PRINTO
FCAS – Familial cold autoinflammatory syndrome
FMF – Familial Mediterranean fever
HLA-B27 – Human leukocyte antigen B27
Ig G, M, A – Immunoglobulin G, M, A
HIDS/MKD – Hyperimmunoglobulinemia D syndrome / Mevalonate kinase deficiency
MWS – Muckle-Wells syndrome
PFAPA – PFAPA syndrome (Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis)
Per os – By mouth, orally
Scl-70 – Non-histone chromosomal protein Scl-70, which is the enzyme topoisomerase I with a molecular weight of 70 kDa
Th – T helper lymphocytes
TRAPS – Tumor necrosis factor receptor-associated periodic syndrome
Note legend
…** – medicinal product included in the List of Vital and Essential Drugs for medical use
…# – 'information on the method of administration and dosage of the medicinal product, duration of its administration with references to clinical trials of efficacy and safety of the applied dosing regimen for this disease or references to relevant literature sources if the thesis-recommendation refers to a medicinal product for medical use used not in accordance with the indications for use and contraindications, methods of administration and doses contained in the instructions for use of the medicinal product' (off-label).
Terms and Definitions
Autoinflammatory syndromes – a group of hereditary monogenic diseases characterized by unprovoked attacks of inflammation and manifested by fever and clinical symptoms resembling rheumatic ones (arthritis, rashes, serositis, CNS involvement, etc.) in the absence of autoimmune and infectious causes.
Antineutrophil cytoplasmic antibodies (ANCA, Eng. – ANCA) – autoantibodies against neutrophil cytoplasm components. Found in so-called ANCA-associated diseases, including ANCA-associated vasculitis.
Antinuclear factor (ANF) – autoantibodies directed against soluble components of the cell nucleus (ribonucleoproteins), forming a whole family (over 200 varieties) of antinuclear antibodies (ANA).
Anti-cyclic citrullinated peptide antibodies (anti-CCP, synonyms – anti-CCP antibodies, anti-CCP) – a heterogeneous group of IgG autoantibodies that recognize antigenic determinants of filaggrin and other proteins containing the atypical amino acid citrulline.
Anti-Scl-70 antibodies – anti-scleroderma antibodies to the non-histone chromosomal protein Scl-70, which is the enzyme topoisomerase I with a molecular weight of 70 kDa, antibodies to topoisomerase I.
Genetically engineered biological drugs (bDMARDs) – a group of medicinal products of biological origin, including monoclonal antibodies (chimeric, humanized, fully human) and recombinant proteins (usually including human IgG Fc fragment) obtained by genetic engineering methods, characterized by a selective effect on certain mechanisms of chronic inflammation development, specifically suppressing the immunoinflammatory process and slowing down the progression of joint destruction.
Idiopathic [idiopathicus; idio- + Greek pathos suffering, disease] – arising without apparent causes, characterized by unclear origin.
Interleukins (IL) – a group of cytokines that mediate the activation and interaction of immunocompetent cells in the immune response and regulate myelopoiesis and erythropoiesis.
Class I major histocompatibility complex molecules (A, B, C) – present peptides from the cytoplasm on the cell surface (including viral peptides, if present). These peptides are fragments of proteins degraded in proteasomes. The peptide length averages about 9 amino acids. Foreign antigens attract killer T cells (also called CD8-positive or cytotoxic T cells), which destroy the antigen-bearing cell. Molecules of this class are present on the surface of all cell types except erythrocytes and trophoblast cells.
Class II major histocompatibility complex molecules (DP, DM, DOA, DOB, DQ, DR) – present antigens from the extracellular space to T lymphocytes. Some antigens stimulate T-helper division, which then stimulate B cells to produce antibodies against this antigen. Molecules of this class are located on the surface of antigen-presenting cells: dendritic cells, macrophages, B lymphocytes. Class III major histocompatibility complex molecules encode components of the complement system, proteins present in the blood.
Rheumatoid factor (RF) – autoantibodies that react as an autoantigen with own immunoglobulins G modified under the influence of some agent (e.g., a virus).
Nonsteroidal anti-inflammatory drugs (NSAIDs) – a group of medicinal products with analgesic, antipyretic, and anti-inflammatory effects. They are subdivided into selective (s-NSAIDs) and non-selective (ns-NSAIDs) inhibitors of the cyclooxygenase enzyme.
Uveitis – an inflammatory disease of the middle coat of the eye (uvea).
Anterior uveitis (iridocyclitis) is an inflammatory lesion of the anterior segments of the uveal tract.
Enthesitis is inflammation of the entheses, the specific sites where tendons and ligaments attach to bone.
Juvenile ankylosing spondylitis (JAS) is a chronic inflammatory disease from the group of spondyloarthritides, characterized by mandatory involvement of the sacroiliac joints and/or spine with the potential outcome of ankylosis, with frequent involvement of entheses and peripheral joints in the pathological process.
Juvenile [Lat. Juvenīlis – young, youthful] – characteristic of youth; young, juvenile.
HLA (Human Leukocyte Antigens) – human leukocyte antigens, or the human tissue compatibility system – a group of histocompatibility antigens, the major histocompatibility complex in humans.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Familial Mediterranean Fever (FMF) is a hereditary monogenic autoinflammatory disease (AID) with an autosomal recessive inheritance pattern, prevalent mainly among certain ethnic groups, manifested by periodically occurring unprovoked fever attacks and accompanied by severe abdominal and/or chest pain and other symptoms, combined with a significant increase in acute-phase reactant levels (ESR, CRP, SAA) within 12–72 hours [1–5].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Familial Mediterranean Fever is caused by mutations in the MEFV gene located on the short arm of chromosome 16 (16p13.3) and is inherited in an autosomal recessive manner. The MEFV gene is expressed predominantly in granulocytes, consists of 10 exons regulating the sequence of 781 amino acid residues. Normally, it encodes a protein called pyrin or marenostrin, which is expressed by circulating neutrophils. Pyrin belongs to the family of transcription factors, is detected in the cytoplasm of myeloid cells, participates in the regulation of the expression of the proinflammatory cytokine IL-1, and ensures a reduction in the inflammatory response, likely by inhibiting neutrophil activation and chemotaxis. Gene mutations lead to the synthesis of defective pyrin molecules; it is hypothesized that minor, unknown triggers of the inflammatory response that are normally controlled by intact pyrin are not suppressed because pyrin is defective. Clinical consequences include spontaneous episodes of predominantly neutrophilic inflammation in the abdominal cavity as well as in other locations.
The most common mutation is M694V (replacement of methionine with valine) – found in 80% of examined patients with periodic disease, associated with a severe disease course and a high risk of developing amyloidosis.
To date, 244 variants of MEFV gene mutations are known.
Since FMF is an autosomal recessive disease, its development requires the carriage of 2 pathogenic mutations on paired chromosomes: identical ones (homozygosity) or different ones (compound heterozygosity). However, the disease can also develop in carriers of a single pathogenic mutation (heterozygotes). The proportion of heterozygotes among FMF patients in various populations ranges from 16.5% to 33.8%. In approximately 10% of patients with a confirmed FMF diagnosis, MEFV gene mutations are not detected at all. Most known pathogenic mutations are localized in exon 10 of the gene. A number of mutations are localized in exons 2, 3, 5, 9. The most common mutations are p.M680I, p.M694V, p.M694I, pK695R, pV726A, pA744S and pR761H. Mutations differ in expressivity (pathogenicity). The most expressive mutation, which determines the severity of the course and a high risk of an adverse outcome, is the p.M694V mutation. A number of mutations have uncertain significance. Homozygosity for the mutation p.E148Q, which is most common in the European region, can be found both in patients with clinically overt FMF and in healthy individuals [4–9].
1.3 Epidemiology of the Disease or Condition
FMF is the most common monogenic autoinflammatory disease (AID) in the world. More than 100 thousand FMF patients are registered worldwide. FMF is most frequently found among four ethnic groups: Sephardic Jews (non-Ashkenazi/North African Jews), Arabs, Turks, and Armenians. The carrier frequency of mutant alleles in these populations is 1:5 – 1:16, 1:56, 1:5, and 1:7, respectively. Less frequently, the disease can occur in representatives of other ethnic groups: peoples of the South Caucasus (Azeris, Georgians) and the North Caucasus, peoples of Southern Europe (Italians, Greeks, Spaniards, etc.), and peoples of the Balkan Peninsula. Cases of FMF have been described in Japanese individuals, the indigenous population of India, Roma, and other peoples. There is a description of the disease in Russian patients. Due to this, the ethnic factor is not decisive in making a diagnosis [3,5,10–12].
1.4 Features of Coding the Disease or Condition
In ICD-10, Familial Mediterranean Fever is coded in the section "Endocrine, nutritional and metabolic diseases" (E00-E90) as Hereditary familial amyloidosis without neuropathy / Familial Mediterranean fever (E85.0).
1.5 Classification of the disease or condition
In the modern classification of monogenic (hereditary) and multifactorial AIDs, FMF is presented under the heading "periodic recurrent fevers" [13].
There is no universally accepted classification of the disease. In most countries, various criteria for establishing an FMF diagnosis are used.
1.5.1. Diagnostic criteria for familial Mediterranean fever
Several variants of diagnostic criteria have been developed to establish a diagnosis of familial Mediterranean fever (Tables 1–5) [14–17].
Table 1. FMF Diagnostic Criteria (Tel Hashomer) [14,15].
Major criteria | Minor criteria |
Episodes of fever + serositis (peritonitis, pleuritis, synovitis) | Recurrent fever attacks |
AA amyloidosis in the absence of any other predisposing disease | Erysipelas-like erythema on the skin |
Therapeutic response to colchicine | Presence of FMF among first-degree relatives |
1. A definite FMF diagnosis requires the presence of 2 major or 1 major and 2 minor criteria. 2. A probable diagnosis requires the presence of 1 major and 1 minor criterion. | |
Table 2. Turkish Pediatric FMF Criteria [16].
Criterion | Definition |
Fever | Axillary temperature 38.0 °C, duration 6–72 hours, at least 3 episodes. |
Abdominal pain | Duration 6–72 hours, at least 3 episodes. |
Chest pain | Duration 6–72 hours, at least 3 episodes. |
Arthritis | Duration 6–72 hours, at least 3 episodes, oligoarthritis. |
Presence of patients with FMF in the family | |
To establish a diagnosis, the presence of 2 out of 5 criteria is required. | |
Table 3. Clinical diagnostic/classification criteria for FMF (EUROFEVER) [18].
Presence of the feature | Points |
Duration of episodes <2 days | 9 |
Chest pain | 13 |
Abdominal pain | 9 |
Origin from Eastern Mediterranean ethnic groups* | 22 |
Origin from Northern Mediterranean ethnic groups** | 7 |
Absence of the feature | Points |
Aphthous stomatitis | 9 |
Urticarial rash | 15 |
Cervical lymphadenopathy | 10 |
Duration of episodes >6 days | 13 |
Cut-off value | > 60 |
*Eastern Mediterranean ethnic groups: Turks, Armenians, non-Ashkenazi Jews, Arabs. **Northern Mediterranean ethnic groups: Italians, Spaniards, Greeks. | |
The evaluated clinical signs must be associated with a typical FMF attack (application of these criteria is possible only after excluding intercurrent infections and comorbid conditions).
Criteria are evaluated by summing points for the presence or absence of a clinical sign; the threshold for diagnosing FMF is a total score greater than or equal to 60 points.
Table 4. New Eurofever/PRINTO classification criteria for FMF in the presence of molecular genetic testing [17].
Presence of a confirming genotype* of the MEFV gene and at least one of the following criteria: |
Duration of episodes – 1–3 days Arthritis Chest pain Abdominal pain |
OR presence of a non-confirming genotype†‡ of the MEFV gene and at least 2 of the following criteria: |
Duration of episodes – 1–3 days Arthritis Chest pain Abdominal pain |
A patient with a confirmed increase in acute-phase reactants (ESR, or CRP, or SAA) clearly correlating with the clinical manifestations of the attack (1), (2) with careful exclusion of potential masking diseases (oncological, infectious, autoimmune, and other congenital immune response anomalies), with a disease history duration of at least 6 months, can be regarded as a patient with hereditary periodic fever. *Pathogenic or likely pathogenic variants (heterozygous in autosomal dominant inheritance of the disease; homozygous or biallelic compound heterozygous variants in trans (a genotype with two different mutant alleles at the same locus in autosomal recessive inheritance of the disease). †Variants of uncertain significance (VUS). Benign or likely benign variants are excluded. ‡Compound heterozygous variants in trans in case of detecting one pathogenic variant of the MEFV gene and one variant of uncertain significance, or a biallelic variant of uncertain significance (VUS), or heterozygosity in case of detecting one pathogenic variant of the MEF gene. |
Table 5. Eurofever/PRINTO clinical classification criteria for FMF [17]*
At least 6 of 9 criteria: |
Presence |
Eastern Mediterranean ethnicity Duration of episodes 1–3 days Chest pain Abdominal pain Arthritis |
Absence of |
Aphthous stomatitis Urticarial rash Maculopapular rash Painful lymph nodes |
*These criteria can be used as a potential tool to refer a patient with suspected FMF for molecular genetic testing or as classification criteria in cases where genetic testing is not feasible.
In the Russian Federation, the FMF classification developed by Arutyunyan V.M. and Akopyan G.S. is used (Table 6) [1].
Table 6. Classification of FMF (Problem Commission of the M. Heratsi Yerevan State Medical University) [1]
By clinical form: |
1. Abdominal form 2. Thoracic form 3. Mixed form |
By additional clinical manifestations: |
1. Renal syndrome 2. Articular syndrome 3. Neurological syndrome 4. Endocrinopathic syndrome 5. Cutaneous syndrome |
By course: |
1. Frequent attacks (2 times a month or more) 2. Moderate frequency attacks; 3. Rare attacks (2 times a year or less) |
By disease activity: |
1. Exacerbation stage 2. Relative remission 3. Remission (no attacks for 1 year) |
1.6 Clinical presentation of the disease or condition
Any form of FMF is characterized by: a chronic, relapsing course, a severe condition during attacks and a sensation of complete health during remissions of varying duration; stereotyped attacks that differ only in severity and duration (most commonly 1–4 days) and leave no prominent anatomical changes; consistency of nonspecific shifts in laboratory tests.
FMF is characterized by: recurrent episodes of fever and peritonitis, sometimes with pleuritis, pericarditis, rash, arthritis, myalgia. In the majority of patients, FMF presents as the abdominal, or less commonly, thoracic or mixed form. Very rarely, recurrent aseptic Mollaret's meningitis or cerebrovascular accidents develop. FMF may be associated with other immune-mediated diseases: polyarteritis nodosa, hemorrhagic vasculitis (Henoch-Schönlein purpura), Behçet's disease, juvenile arthritis, inflammatory bowel disease, multiple sclerosis, uveitis. A risk factor for this combination is a mutation in the MEFV gene — M694V [19–22].
FMF may also present with isolated sacroiliitis, which differs in its characteristics from juvenile spondyloarthritis (higher inflammatory markers, rarer spinal involvement and enthesitis, and detection of HLA-B27) and juvenile spondyloarthritis [23,24]
With a prolonged uncompensated course of the disease, signs of renal failure may appear due to the development of AA amyloidosis.
Renal involvement in FMF goes through several stages:
· Preclinical stage: amyloid is present in the medullary zone and along the straight vessels of the pyramids, with developing edema and foci of sclerosis. This stage lasts 3–5 years.
· Proteinuric (albuminuric) stage — amyloid appears in the mesangium, capillary loops, pyramids, and renal cortex, as well as in blood vessels. Sclerosis and nephron atrophy, hyperemia, and lymphostasis develop. The kidneys are enlarged and dense, dull, grayish-pink. Proteinuria is moderately pronounced initially, may temporarily be transient, decrease and increase, and then becomes persistent (stage of intermittent proteinuria). Proteinuria at this stage can be selective and non-selective. The duration of this stage is 10–13 years.
· Nephrotic (edematous, edematous-hypotonic) stage — amyloid-lipoid nephrosis. Amyloid is deposited in all parts of the nephron. Sclerosis and amyloidosis of the medulla develop, while the cortical layer shows no marked sclerotic changes. The kidneys are enlarged in size, dense (large greasy kidney). Clinically, this stage manifests as classic nephrotic syndrome with all its features: massive proteinuria (more than 3–5 grams per day), hypoproteinemia with hypoalbuminemia, hypercholesterolemia, lipiduria with edema up to the degree of anasarca. The urinary sediment contains hyaline casts, and as proteinuria increases, granular casts, micro- and macrohematuria, and leukocyturia without pyelonephritis. The duration of this stage is up to 6 years.
· Uremic (terminal, azotemic) stage — amyloid "contracted kidney". The kidney is reduced in size, dense, with scars. Chronic kidney disease develops, which differs little from CKD in other chronic kidney diseases. It is believed that, unlike glomerulonephritis, in which CKD proceeds with polyuria and may be accompanied by a decrease in edema, in amyloidosis azotemia develops against the background of low blood pressure and nephrotic syndrome [25,26].
CKD goes through several stages in its development:
· Latent stage: clinical manifestations may be completely absent. Changes may be detected incidentally during examination. Sometimes the patient may note increased fatigue or general weakness.
· Compensated stage: general weakness and fatigue during routine physical exertion are more frequent; the amount of urine excreted (polyuria) increases to more than 2 liters per day; frequent nighttime urination (nocturia) is bothersome; edema appears on the face and around the eyes.
· Intermittent stage: pronounced weakness and constant drowsiness develop; nausea, vomiting, dry mouth and dry skin, decreased appetite, bitter taste in the mouth, prominent facial edema, muscle twitching in the legs (restless legs syndrome), elevated blood pressure, subcutaneous hemorrhages, nosebleeds, and anemia associated with impaired hematopoiesis in renal tissue appear; frequent respiratory infections occur.
· Terminal (decompensated) stage: weight loss and decreased body temperature, loss of appetite, acetone breath, diarrhea, vomiting, sharp mood swings, distinct urine odor from the patient, shortness of breath, edema syndrome, severe anemia and blood clotting disorders (hemorrhages) are noted; with significant impairment, coma may occur; pneumonia develops.
Classification and stratification of CKD stages by GFR level are presented in Tables 7 and 8.
Table 7. Classification and stratification of CKD stages by GFR level [27].
Designation of CKD stages | Characteristics of global renal function | GFR level, mL/min/1.73 m² |
|---|---|---|
C1 | High or optimal | >90 |
C2 | Mildly decreased | 60-89 |
C3a | Mildly to moderately decreased | 45-59 |
C3b | Moderately to severely decreased | 30-44 |
C4 | Severely decreased | 15-29 |
C5 | End-stage renal disease | <15 |
Table 8. Grades of albuminuria (mg/day) [27].
A1 | A2 | A3 | A4 |
|---|---|---|---|
Optimal or increased | High | Very high | Nephrotic |
<10-29 | 30-299 | 300-1999* | ≥2000** |
Note: * — corresponds to daily proteinuria ≥0.5 g; ** — corresponds to daily proteinuria ≥3.5 g.
2. Diagnostics, medical indications and contraindications for diagnostic methods
2.1 Evaluation of patients with suspected familial Mediterranean fever
2.1 Complaints and Anamnesis
Taking a history of complaints is recommended for all patients to identify the clinical features of FMF [1–4,10,11,28–30].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Comments: patients and their parents may complain of: recurrent rises in body temperature up to 38–40°C, accompanied by abdominal pain ranging from moderate to severe (an "acute abdomen" picture), sometimes accompanied by diarrhea, and/or chest pain aggravated by inspiration; skin rashes; swelling, pain, and restricted movement in the joints; intense muscle pain, in some cases leading to immobility; swelling and pain in the scrotum in boys; headache, photophobia, lacrimation, sleep disturbance, tinnitus; edema on the face, legs, arms, abdominal wall, sacrum, and genital area.
It is also necessary to evaluate complaints characteristic of other autoimmune diseases that may be associated with FMF (JA, JSpA, IBD, uveitis, PAN, Henoch-Schönlein purpura, multiple sclerosis, uveitis).
Taking a family history is recommended for all patients to identify similar cases of the disease in relatives [1–5,10,11,28–30].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Comments: when taking a family history, it is necessary to determine the presence/absence of consanguineous marriage in the patient's parents, the presence of confirmed FMF or a similar clinical picture in relatives, and belonging to an ethnic group with an increased risk of developing FMF.
It is recommended to analyze the history of the disease in all patients in order to identify the specific features of the pathological process [1–5,10,11,28–31].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Comments: it is necessary to determine the age of disease onset, what preceded the appearance of the first symptoms and subsequent attacks, whether periodicity of episodes was noted, persistence of symptoms during the interictal period, as well as all results of examinations performed since the manifestation of the disease. Familial Mediterranean fever typically debuts in childhood, most often before 10 years of age (75% of patients). In a small proportion of patients, onset is possible in the first year of life. Intervals between attacks range from several days to several years, with an interval of 3–5 weeks being the most typical.
It is recommended to analyze the presence of prodrome ("aura") before the development of an attack in all patients in order to identify characteristic signs of FMF [28,29].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Comments: the prodrome preceding a FMF attack is characterized by weakness, abdominal discomfort, irritability, dizziness, and sometimes vomiting.
It is recommended to analyze the specific features of the attack in all patients in order to identify characteristic signs of FMF [2,1,3–5,28–30].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Comments: a FMF attack is characterized by: recurrent fever up to 38–40°C; abdominal pain; chest pain aggravated by inspiration; pain in the knee, ankle, or hip joints lasting 7–10 days; myalgia during fever; skin rash; edema; headache.
2.2 Physical Examination
It is recommended to perform thermometry in all patients in order to assess the severity and character of the fever [1–5,10,11,32,33].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: a FMF attack is characterized by recurrent fever up to 38–40°C; abdominal pain; chest pain aggravated by inspiration; pain in the knee, ankle, or hip joints lasting 7–10 days; myalgia during fever; skin rash; edema; headache.
It is recommended to assess the general condition of all patients for subsequent dynamic monitoring [1–5,10,11,30,32,33].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: during an attack, the condition of children is moderate to severe. Often the child cries from pain in the abdomen, chest, joints, and muscles, cannot turn over in bed, and exhibits stiffness and weakness. In the interictal period, the condition of children is satisfactory.
It is recommended to examine the skin and mucous membranes in all patients to detect rashes, signs of vasculitis, and mucosal lesions [1–5,10,11,21,30,32,33].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: characteristic erysipelas-like erythema may develop: a red, painful, hot patch, usually located on the lateral surface of the ankle joint and foot. When FMF is combined with Henoch-Schönlein purpura, a hemorrhagic rash (petechiae, ecchymoses) may develop; when combined with polyarteritis nodosa, localized angioedema, livedo reticularis/racemosa, necrosis, and gangrene may occur; when combined with systemic JIA, a macular, maculopapular, or linear rash, most pronounced at the peak of fever, may appear; with Crohn's disease – stomatitis, erythema nodosum; with Behçet's disease – erythema nodosum, papulopustular lesions, folliculitis, oral and genital ulcers.
It is recommended to perform an inspection and palpation of lymph nodes in all patients to identify pathological changes [1–5,10,11,30–34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in the majority of patients with FMF, lymph nodes are not enlarged. When FMF is combined with systemic JIA or vasculitis, generalized lymphadenopathy may be detected.
It is recommended to analyze complaints, perform inspection, percussion, and palpation of the cardiovascular system in all patients to identify physical signs of its involvement [34–36].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: pericarditis develops in ≤ 1% of patients with FMF and is accompanied by dyspnea, chest pain aggravated in the supine position and radiating to the back, shoulders, and neck. Percussion may reveal widening of relative cardiac dullness; auscultation reveals muffled heart sounds, a systolic murmur at the mitral valve projection point, tachycardia, and less commonly bradycardia; rarely, a pericardial friction rub. When FMF is combined with ankylosing spondylitis, aortitis with aortic regurgitation may develop, accompanied by a systolic murmur at its projection point; when combined with systemic JIA, myopericarditis may occur.
When FMF is combined with polyarteritis nodosa (PAN) at the peak of polyarteritis nodosa activity, almost all patients exhibit cardiac syndrome. Coronary arteritis up to myocardial infarction, myocarditis, and less commonly pericarditis and valvular regurgitation develop. Examination reveals cardiomegaly, and auscultation reveals muffled heart sounds, tachycardia, and an organic murmur over the mitral and/or aortic valves.
PAN is characterized by arterial hypertension (AH) syndrome caused by ischemia of the renal juxtaglomerular apparatus with disruption of the renin-angiotensin-aldosterone system. The severity of the children's condition and the seriousness of the prognosis are due to persistently elevated blood pressure, ranging from 140/90 – 180/120 mm Hg, and sometimes reaching 220/110 – 240/170 mm Hg. During the active period of the disease, children with AH syndrome frequently experience cerebrovascular disorders. As the process progresses, AH becomes malignant, signs of cerebral edema appear, chronic renal failure sometimes develops, and cerebral hemorrhage and renal rupture are possible.
It is recommended to analyze complaints, perform inspection, percussion, and palpation of the respiratory system in all patients to identify physical signs of its involvement [21,30–34].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: pleurisy develops in 30% of patients with FMF and may manifest with chest pain, signs of respiratory failure: dyspnea, retraction of compliant areas of the chest, epigastric region, and rib attachment sites of the diaphragm; cyanosis. Lung percussion may determine: normal or hyperresonant percussion sound, dullness in the posterior-inferior lung regions; auscultation reveals a pleural friction rub and decreased breath sounds in the posterior-inferior lung regions.
When FMF is combined with bronchial asthma, patients may experience episodes of bronchial obstruction, expiratory dyspnea, and auscultation reveals wheezing and moist rales in young children, and wheezing in adolescents.
When FMF is combined with polyarteritis nodosa/Henoch-Schönlein purpura, or Behçet's disease with pulmonary involvement, mixed-type dyspnea, cough with scant sputum, bronchospasm (in PAN), hemoptysis, chest pain, progressive respiratory failure, hyperresonant percussion sound with areas of dullness, and crepitant rales on auscultation may be observed.
It is recommended to analyze complaints, perform inspection, percussion, and palpation of the digestive system in all patients to identify physical signs of its involvement [37–40].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: fever in patients with FMF is usually accompanied by symptoms of peritonitis. Abdominal pain (typically starting in one quadrant and spreading throughout the abdomen) is observed in approximately 95% of patients and can vary in severity from attack to attack. Examination of the child at the peak of an attack reveals decreased bowel sounds, abdominal distension, tension of the anterior abdominal wall muscles, and peritoneal irritation signs that cannot be distinguished from internal organ perforation.
When amyloidosis develops, examination reveals abdominal distension, and percussion and palpation reveal hepatosplenomegaly.
During the interictal period, palpation may reveal tenderness in the epigastric region and the projection point of the duodenum and pancreas. The use of a large amount of antipyretics and NSAIDs may lead to the development of inflammatory lesions in the upper gastrointestinal tract (GIT).
Complaints of frequent loose stools with mucus and/or blood and/or greenish discoloration, pain in the ileocecal region, and abdominal bloating suggest inflammatory bowel disease (IBD).
When FMF is combined with Behçet's disease or PAN, abdominal pain, nausea, vomiting, diarrhea, and gastrointestinal bleeding are observed.
It is recommended to analyze complaints, perform inspection and palpation of joints in all patients to detect active arthritis [1–5,10,11,22–24,30–34,41].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: Arthritis develops in 25% of patients with systemic lupus erythematosus (SLE) and is characterized by a sterile synovial effusion; it predominantly affects the knee, ankle, and hip joints, but may also involve the shoulders, temporomandibular, or sternoclavicular joints. The involvement is typically mono- or oligoarticular. In approximately 75% of SLE patients, joint attacks occur suddenly and can be triggered by minor trauma or exertion, such as prolonged walking. SLE arthritis is characterized by involvement of one of the large joints of the lower extremity, accompanied by a febrile fever of ≥39°C. These manifestations peak within 24–48 hours and subsequently resolve gradually in the majority of patients. Protracted episodes of arthritis are observed in about 5% of cases. Unlike other manifestations of SLE, joint syndrome may persist during periods between attacks.
SLE may be associated with polyarticular, oligoarticular, systemic juvenile arthritis (sJIA), and enthesitis-related arthritis.
Oligoarticular JIA presents with an asymmetric joint syndrome with predominant involvement of the lower extremity joints, whereas polyarthritis presents with a symmetric joint syndrome.
Spondyloarthritis should be suspected in SLE patients with oligoarthritis, inflammatory back pain, and enthesopathies who are older than 6 years of age.
Joint syndrome in JIA is typically asymmetric. Peripheral joints are affected in 82% of patients, upper extremity joints in 16%, and distal joints are affected more frequently than proximal ones. Oligoarthritis develops in 75% of patients and polyarthritis in 25%. Characteristic features include involvement of one or both knee joints, ankle joints, small joints of the feet and toes; development of tarsitis accompanied by pain, stiffness, and functional impairment; involvement of the 1st metatarsophalangeal joint with the formation of hallus valgus. The shoulder, temporomandibular, and sternoclavicular joints are frequently involved, hip joints rarely, and small joints of the hands extremely rarely. Pain in the sternoclavicular and acromioclavicular joints combined with clavicular pain can lead to impaired chest wall excursion. When SLE is associated with Behçet's disease, arthralgia and/or non-deforming oligoarthritis may be observed; with polyarteritis nodosa, pain in large and small joints; and swelling in the area of large joints with symmetric involvement without the development of permanent deformity.
It is recommended to assess the range of passive and active joint motion in all patients with arthralgia/arthritis to detect functional impairment [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: if there is no joint pain at the normal range of motion, it is necessary to assess the appearance of pain (protective muscle guarding, resistance) at the maximum range of motion.
The range of motion is evaluated as follows:
o Cervical spine. Ask the patient to: throw the head back (normal extension is 50–60°), touch the chin to the sternum (normal flexion is 45°), turn the head to the right and left (normal rotation is 60–80°), and touch the head to the right and left shoulder (lateral flexion is 40°).
o Temporomandibular joints. Ask the patient to: open the mouth, protrude and re-retract the mandible, and perform side-to-side lateral movements of the mandible.
o Shoulder joints. Ask the patient to: raise the arms laterally and upward, reach the right and left ear behind the head, reach the right and left scapula with the opposite hand from behind, take off a shirt or t-shirt independently, and comb the hair.
o Elbow joints. Ask the patient to: place the hands on the shoulders (normal flexion angle is no more than 20°), straighten the arm at the elbow joint (normal is at least 180°), and check pronation and supination (normal is 90°).
o Wrist joints. Check: dorsiflexion (normal is 70°) and palmar flexion (normal is 90°).
o Small joints of the hands. Ask the patient to: make a tight fist, take off socks and tights independently, and button and unbutton clothes. Normally, the fingers easily touch the palm.
o Hip joints: check abduction (at least 140°), adduction (the thighs and knees should touch the chest), and external and internal rotation (normal is at least 40–45°).
o Internal rotation test in the hip joints. The child lies supine with the hips and knees flexed at 90°. Keeping the knees together, the lower legs are rotated outward.
o In almost all hip joint disorders, internal rotation is impaired first.
o Knee joints. Ask the patient to: flex the legs at the knees (should touch the heel to the buttocks), sit on the knees and lower the buttocks onto the heels, extend the knee joints (180° angle), and squat.
o Check for the patellar tap (ballotment) sign.
o The lower extremities are flexed at the knee joints. Normally, the heels touch the buttocks without difficulty. The lower extremities are maximally extended at the knee joints with the child in the supine position.
o Foot and ankle joints. Check: dorsiflexion (normal angle is 45°), plantar flexion (normal angle is 20°), supination (inward rotation of the foot is 30°), and pronation (outward rotation of the foot is 20°). Ask the patient to: stand on tiptoe and walk, and stand on heels and walk (normally the child should do this without difficulty). Observe for asymmetry when moving the ankles in different directions. Noticeable limitation of flexion is usually detected without difficulty, even in the absence of visible joint swelling.
It is recommended to examine the joints of the axial skeleton in all patients to identify pathological changes [23,24].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: The joints of the axial skeleton are involved in the late stages of the disease. In children with sacroiliitis, pain may occur with direct pressure on one or both sacroiliac joints or on the pelvis. Swelling in the sacral region may also be detected. Spinal involvement reveals flattening of the lumbar lordosis, increased thoracic kyphosis, an increased distance from the head to the wall during diagnostic tests, disappearance of the physiological curves of the spine, and rigidity in its various segments. Involvement of the thoracic spine can lead to restricted chest wall excursion. In the late stages of the disease, typically in adulthood, the "supplicant's posture" develops.
Sacroiliitis rarely develops in Behçet's disease.
It is recommended to evaluate spinal mobility and chest wall excursion in all patients with oligoarthritis, asymmetric polyarthritis, and/or inflammatory back pain to detect pathological changes [24].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: Evaluation of functional tests: Schober, Ott, Tomayer, Zatsepin, Forestier tests, and the chin-to-sternum test.
Assessment of tenderness along the spinous processes of the spine and at paraspinal points.
Zatsepin's sign: tenderness upon pressure at the attachment site of the 10th–12th ribs to the vertebrae due to an inflammatory process in the costovertebral articulations.
Forestier's sign: used to determine posture type. The patient stands with their back to the wall, touching it with the heels, torso, and head. Normally, the heels, shoulder blades, and occiput should touch the wall. In patients with ankylosing spondylitis and Forestier's disease, contact at any point will be absent due to the development of kyphosis.
Determination of cervical spine mobility. Measure 8 cm upward from C7 and make a mark. The patient is then asked to bend the head down as much as possible, and the distance is measured again. In healthy individuals, it increases by 3 cm. When the cervical spine is affected, this distance increases insignificantly or does not change at all. The test is uninformative in patients with ankylosing spondylitis and a short neck.
Chin-to-sternum test: a healthy person easily touches the sternum with the chin. When the cervical spine is affected, a distance remains between the chin and the sternum upon maximal forward flexion of the head.
Ott's test: used to determine thoracic spine mobility. Measure 30 cm downward from C7 and make a mark. The distance between these points is then measured again when the subject bends forward as far as possible. In healthy individuals, this distance increases by 4–5 cm, whereas in patients with ankylosing spondylitis, it remains practically unchanged.
Determination of restricted respiratory excursions of the chest: used to detect pathological processes in the costovertebral joints. Measurements are taken with a tape measure at the level of the 4th rib. Normally, the difference in chest circumference between maximal inhalation and exhalation is 6–8 cm. With the development of costovertebral joint ankylosis, this difference decreases to 1–2 cm. The test is uninformative in the presence of pulmonary emphysema.
Schober's test: used to detect restricted lumbar spine mobility. Measure 10 cm upward from L5 and make a mark. Upon maximal forward flexion in healthy individuals, this distance increases by 4–5 cm, whereas in lumbar spine involvement, it remains practically unchanged.
Schober's test – for assessing overall spinal mobility. It is determined by measuring in centimeters the distance from the 3rd finger of outstretched hands to the floor during maximum forward flexion. This normal distance is "0" and increases when spinal flexion is restricted. exclusion of juvenile arthritis, bone tuberculosis, osteomyelitis, benign and malignant tumors, and bone metastases.
It is recommended for all patients with oligoarthritis, asymmetric polyarthritis, and/or complaints of inflammatory back pain to determine the presence of enthesitis in order to establish a diagnosis [24].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: enthesitis (inflammatory changes at the sites of attachment of ligaments, tendons, and fascia to bones) is a pathognomonic sign of enthesitis-related arthritis, allowing for differential diagnosis with other variants of JIA. Enthesitis is typical for ERA and develops more frequently than in AS. It manifests as severe pain and marked functional joint impairment, and is often the child's most serious complaint.
Physical examination reveals pronounced local tenderness in the patellar region (at 10, 14, and 18 o'clock), the tibial tuberosity; at the insertion site of the Achilles tendon and plantar aponeurosis into the calcaneal tuberosity; the plantar aponeurosis to the base of the fifth metatarsal bone; in the region of the metatarsal heads; greater trochanters of the femurs; anterior superior iliac spine; pubic symphysis; ischial tuberosity, and rarely in the upper extremities. The development of dactylitis is possible.
It is recommended to evaluate gait in all patients with arthralgia/arthritis to identify the nature of its impairment [30, 42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: gait is generally impaired when FMF is combined with JIA. Gait patterns in joint involvement:
o with rapid transfer of body weight from the affected leg to the healthy one (involvement of the knee and hip joints, feet). The patient steps on the whole foot or toe (heel involvement),
o "waddling" gait (bilateral hip joint involvement).
Observation of gait during walking and running: limping in a patient is an important diagnostic clue for identifying pain or stiffness. Limping and gait abnormalities are most pronounced in children with JIA in the morning hours due to morning stiffness. When examining the patient in the afternoon, limping may be absent, and gait disturbance is minimal or not apparent.
When FMF is combined with MS, gait and balance disturbances (up to the inability to walk independently), static and dynamic ataxia may be detected.
It is recommended to analyze complaints, perform an examination and palpation of the muscular system in all patients to identify the nature of its involvement [1–5, 10, 11, 31–34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: carriers of the p.M694V mutation may develop protracted febrile myalgia (PFM) – an FMF-associated vasculitis characterized by prolonged, severe (sometimes disabling) muscle pain (1 month or more) accompanied by febrile fever, which may be combined with abdominal pain, diarrhea, and normal CK values.
When FMF is combined with JIA, muscle atrophy proximal to the affected joint and muscle contractures are detected; with MS, muscle weakness and spasticity.
When FMF is combined with Behçet's disease, myopathy and myositis are detected; with PAN, pronounced myalgias predominantly in the calf muscles.
It is recommended to analyze complaints, perform an examination and palpation of the urogenital system in all patients to identify the nature of its involvement [1–5, 10, 11, 22, 30–34].
LoR CGoE 4Level of Recommendation C (Level of Evidence – 4)
Comments: male patients may develop pain, swelling, and redness of the scrotum; in rare cases, non-amyloid renal involvement (nephritis) develops, which may manifest as nephrotic syndrome (edema, decreased diuresis, proteinuria, hyperlipidemia, hypoalbuminemia, dysproteinemia); with the development/progression of renal amyloidosis, oliguria may occur; edema of the face and lower extremities appears, up to anasarca.
When FMF is combined with Behçet's disease, ulcers may be detected on the genitalia.
When FMF is combined with MS, patients may complain of urinary retention, imperative urges combined with difficulty emptying the bladder.
It is recommended for all patients with frequent attacks and prolonged inflammatory changes in the joints to rule out diseases that can present with similar clinical symptoms before prescribing pathogenetic therapy [43].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: diseases that should be excluded during diagnosis: malignant neoplasms (neuroblastoma, solid tumors, hemoblastosis, lymphoproliferative diseases); other autoinflammatory syndromes; IBD; rheumatic diseases (systemic lupus erythematosus, dermatopolymyositis, polyarteritis nodosa, Kawasaki disease, sarcoidosis, Castleman disease); immunodeficiency states; infectious diseases (acute inflammatory response, tuberculosis, bacterial endocarditis, acute rheumatic fever, yersiniosis, salmonellosis, cat-scratch disease, toxoplasmosis, Lyme disease, leishmaniasis, acute intermittent porphyria, hereditary angioedema with abdominal attacks, recurrent pancreatitis, mycoplasma infection, cytomegalovirus infection, Epstein-Barr virus infection, etc.).
2.3 Laboratory Diagnostics
It is recommended to perform a complete (clinical) blood count for all patients to assess disease activity and identify pathological changes [44].
GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)
Comments: during an active FMF attack, the following are detected: leukocytosis with a left neutrophil shift, elevated erythrocyte sedimentation rate (ESR), and possible thrombocytosis.
Similar inflammatory changes in complete (clinical) blood count parameters are observed during the active course of JIA, ERA, polyarteritis nodosa, and Behçet's disease. However, unlike FMF, laboratory parameters generally normalize only when GCs and/or immunosuppressants, and/or bDMARDs are prescribed.
Single-, bi-, or pancytopenia may develop due to the toxic effect of nonsteroidal anti-inflammatory drugs, as well as the development of secondary hemophagocytic syndrome (HPS), which is rarely observed in patients with FMF.
During the interictal period, complete (clinical) blood count parameters correspond to reference values.
The picture of the clinical blood count is not specific for FMF; therefore, the diagnostic and differential diagnostic search must continue. First of all, it is necessary to exclude hemoblastosis, lymphoproliferative, and oncological diseases.
It is recommended to study the coagulogram (exploratory hemostasis study) with determination of prothrombin index, antithrombin III activity; plasminogen and fibrinogen levels, D-dimer concentration, soluble fibrin monomer complex levels in the blood, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time in blood, and von Willebrand factor in all patients to assess the state of the hemostatic system [45–50].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: during an FMF attack, an increase in blood fibrinogen concentration is observed; when FMF is combined with polyarteritis nodosa, sJIA – an increase in D-dimer concentration, blood soluble fibrin monomer complex levels, and von Willebrand factor. With the development of HPS – prolongation of prothrombin time in blood or plasma, thrombin time, activated partial thromboplastin time, a decrease in the prothrombin index and blood fibrinogen concentration.
Hypercoagulation-type changes in the coagulogram are also characteristic of PAN, Behçet's disease, and Henoch-Schönlein purpura.
It is recommended to perform a general general-medical blood chemistry analysis with determination of the levels of total protein, albumin, total bilirubin, free (unconjugated) and bound (conjugated) bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, potassium, sodium, total calcium in the blood; activity of LDH, creatine kinase, AST, ALT, GGT, amylase, blood ALP, and serum iron in all patients to identify pathological changes [51–56].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: an increase in the concentration of ferritin, triglycerides, total bilirubin due to the direct fraction of blood serum, activity of ALT, AST, blood LDH may be observed in secondary/primary HPS, as well as toxic drug effects, oncological disease, hemoblastosis, lymphoproliferative disease, sepsis, which is the basis for continuing the differential diagnosis.
An increase in the activity of CK, LDH, ALT, and AST in the blood indicates the development of inflammatory myopathy.
An elevated total protein concentration is observed in the development of amyloidosis; a decreased albumin and total protein concentration, along with an elevated cholesterol concentration, are observed in nephrotic syndrome; elevated urea and serum creatinine concentrations, as well as a decreased glomerular filtration rate, are observed in renal failure due to amyloidosis.
Determination of blood immunoglobulin levels, anti-nuclear and anti-DNA antibodies in blood serum, rheumatoid factor (RF), anti-neutrophil cytoplasmic antibodies (ANCA), anti-centromere antibodies, anti-RNA antibodies, anti-cyclic citrullinated peptide (anti-CCP) antibodies in blood, anti-Sm nuclear antibodies, anti-Scl-70 antibodies, and C3 and C4 complement fractions is recommended for all patients in order to rule out primary immunodeficiency and to confirm or rule out other rheumatic diseases [30,57–59].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in systemic juvenile idiopathic arthritis (sJIA), serum immunoglobulin M and G levels and C3 and C4 complement fractions are within normal limits or elevated. The concentrations of anti-nuclear and anti-DNA antibodies, RF, ANCA, anti-centromere antibodies, anti-RNA antibodies, anti-CCP, anti-Sm nuclear antibodies, and anti-Scl-70 antibodies are not elevated. RF and/or anti-CCP may be detected when sJIA is combined with seropositive juvenile arthritis, and ANCA with polyarteritis nodosa.
If urticarial rashes persist, testing for anti-C1q antibodies is necessary to rule out hypocomplementemic urticarial vasculitis.
Determination of serum antistreptolysin-O (ASO) levels is recommended for all patients to rule out or confirm Group A beta-hemolytic streptococcal infection [60].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: an elevated serum antistreptolysin-O level indicates acute or chronic streptococcal infection, which can trigger a flare of sJIA.
Determination of serum C-reactive protein (CRP) levels is recommended for all patients to assess disease activity [57–59].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: serum CRP levels are significantly elevated during active sJIA, as well as in active juvenile arthritis, polyarteritis nodosa, and Behçet's disease.
Determination of the HLA-B27 antigen by flow cytometry is recommended for all patients to confirm or rule out genetic predisposition to spondyloarthropathies [61].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: in some cases, an association with HLA-B27 may be present.
Routine urinalysis, Nechiporenko urine test, and quantitative measurement of albumin and protein in 24-hour urine are recommended for all patients to rule out kidney diseases, other rheumatic and non-rheumatic conditions, and iatrogenic complications, as well as to detect early signs of secondary renal amyloidosis [44,62].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: in the development of amyloidosis, the following are detected: proteinuria, lipiduria, hyaline casts in the urine sediment, and granular casts as proteinuria progresses; micro- and macroscopic hematuria and leukocyturia are possible in the absence of pyelonephritis. Renal involvement may develop when sJIA is combined with polyarteritis nodosa, Henoch-Schönlein purpura, or Behçet's disease, presenting with characteristic abnormalities in routine urinalysis (hematuria, proteinuria, cylindruria).
A comprehensive renal function panel is recommended to determine the degree of impairment in patients with clinical or laboratory signs of renal involvement [1,2,5,11,63–65].
GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)
Comments: the glomerular filtration rate is calculated using the Schwartz formula. Normally, the glomerular filtration rate in children aged 2 to 18 years is 90–130 mL/min/1.73 m². A decreased glomerular filtration rate in patients with uncontrolled sJIA may indicate the development of secondary renal amyloidosis.
A comprehensive diagnostic workup to assess the severity of renal failure is recommended for patients with clinical or laboratory signs of nephrotic syndrome or renal failure [1,2,5,11,27,51].
Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)
Molecular genetic testing—a panel for the diagnosis of cryopyrin-associated periodic syndromes—is recommended for all patients to confirm sJIA and rule out other autoinflammatory diseases [43,66–68].
GCR BLOE 3Grade of Recommendation B (Level of Evidence 3)
Comments: partial or complete gene analysis is performed to detect mutations in the MEFV gene. Molecular genetic testing of the MEFV gene to confirm the diagnosis of sJIA should be performed in all patients presenting with fever and a suspected diagnosis. The vast majority of mutations are localized in exon 10. Some pathogenic mutations are located in exons 2, 3, 5, and 9. Whole-gene analysis is preferred, though testing can be limited to exon 10 ("hot spot") alone. Mutation screening in genes responsible for other monogenic autoinflammatory diseases should be performed in cases of fever lasting more than 4 days accompanied by urticaria-like rash, conjunctivitis, scleritis, sensorineural hearing loss, aphthous stomatitis, cervical lymphadenopathy, and other symptoms that do not fit the typical presentation of sJIA. Testing targets genes responsible for tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID/CINCA).
Blood procalcitonin testing is recommended for all patients to rule out sepsis [69].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: in sepsis, blood procalcitonin levels are elevated. In sJIA without infectious complications, they remain within reference ranges.
Peripheral blood immunophenotyping to determine major lymphocyte subpopulations is recommended for all patients to rule out primary or secondary immunodeficiency [58,70].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Tuberculin skin testing (Mantoux test, or test with recombinant tuberculosis allergen in standard dilution) and blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens are recommended for all patients to rule out mycobacterial infection [30,68].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Determination of blood IgA, IgM, and IgG antibodies to Chlamydia psittaci; blood IgM antibodies to Chlamydia trachomatis; blood IgG antibodies to Chlamydia trachomatis; and blood IgM and IgG antibodies to Mycoplasma pneumoniae is recommended for all patients to rule out an infectious process that may mimic the clinical presentation of sJIA [30,68,71].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Determination of blood antibodies to Salmonella enterica and blood IgM and IgG antibodies to Yersinia pseudotuberculosis is recommended for all patients to rule out an infectious process that may mimic the clinical presentation of sJIA [30,68,71].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
PCR detection of Borrelia burgdorferi sensu lato complex DNA in blood; determination of blood IgM antibodies to Borrelia burgdorferi sensu lato complex; determination of blood IgG antibodies to Borrelia burgdorferi sensu lato complex; and determination of total antibodies to Borrelia burgdorferi sensu lato complex in blood are recommended for patients with a history of forest visits, residing in tick-endemic areas, or a tick bite, in order to rule out borreliosis [68,72,73].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Quantitative PCR assay for Epstein-Barr virus, Cytomegalovirus, and Herpes simplex virus types 1 and 2 DNA in peripheral blood (quantitative study), saliva, and urine is recommended for all patients to rule out infections caused by the herpesvirus family [30,68,74].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Molecular biological blood testing for Toxoplasma gondii is recommended for patients with a history of animal contact to rule out toxoplasmosis [75].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Determination of blood antibodies to Leishmania is recommended for patients with a history of travel to endemic areas to rule out leishmaniasis [68,76].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Microbiological (culture) analysis of tonsillar and posterior pharyngeal swabs for aerobic and facultatively anaerobic microorganisms is recommended for all patients to rule out colonization of the nasopharynx by pathogenic and opportunistic flora [30,68].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Microbiological (culture) blood and urine test for sterility is recommended for all patients to rule out acute inflammatory response (sepsis) and bacteremia [77,78].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Fecal calprotectin testing is recommended for all patients to rule out IBD [79,80].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
A set of tests for the diagnosis of acute hepatic porphyria is recommended for patients whose urine color during an attack ranges from pink to dark brown, or darkens later upon exposure to daylight or simply over time [81].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: Acute intermittent porphyria should be suspected if the patient presents with the triad of symptoms: abdominal pain; vomiting, which usually accompanies the pain syndrome and in some cases is intractable; prolonged constipation accompanied by abdominal distension and a picture of pseudo-intestinal obstruction; as well as symmetrical flaccid peripheral paralysis, muscle atrophy, and epileptic seizures.
In acute intermittent hepatic porphyria, urine analysis reveals a quantitative increase in porphyrin precursors (delta-aminolevulinic acid and porphobilinogen) to more than 100 mg per day (normal 1–2 mg) and uroporphyrin, sometimes reaching several mg per day (normal 0–15 mg). During remission periods, uroporphyrin may be absent in the urine, whereas porphobilinogen continues to be excreted despite a quantitative decrease.
A set of tests is recommended for patients with urticarial rashes to diagnose hereditary angioedema (complement system defects) [82,83].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: Hereditary angioedema should be suspected in patients who develop edema of the skin and subcutaneous tissue on the hands, feet, and sometimes the face and neck. In more severe cases, edematous phenomena occur on the mucous membranes of the oral cavity, larynx, and pharynx.
2.4 Instrumental Diagnostics
Comprehensive ultrasound examination (ultrasound) of internal organs is recommended for all patients to detect/rule out pathological changes [1,2,4,5,30,31,33,34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: Examination during an attack makes it possible to detect signs of peritonitis, kidney damage, enlargement of mesenteric lymph nodes, liver and/or spleen, assess intestinal motility, and rule out other pathologies presenting with "acute abdomen" symptoms (urolithiasis, acute cholecystitis, pancreatitis, appendicitis, intestinal obstruction, perforation, gynecological pathology).
Signs of glomerulonephritis may be detected when CAPS is combined with PAN, Henoch-Schönlein purpura; incomplete bladder emptying when combined with MS. When CAPS is combined with PAN, liver and/or spleen infarcts, signs of pancreatitis, pancreatic necrosis, ultrasound signs of kidney infarction, perirenal hematoma, and impaired renal blood flow with peripheral depletion and impaired differentiation of renal layers may be detected.
Echocardiography (EchoCG) is recommended for all patients to detect/rule out pathological changes [36].
Recommendation Grade BEvidence Level 3Level of Clinical Recommendation B (Level of Evidence – 3)
Comments: Examination during an attack makes it possible to detect signs of pericarditis: separation of pericardial leaflets, presence of free fluid in the pericardial cavity, and to rule out/confirm myocardial and heart valve involvement. The myocardium, endocarditis, and valve apparatus are not involved in CAPS.
When CAPS is combined with sJIA and PAN, signs of myocarditis and/or pericarditis may be detected; with PAN, lesions of the mitral and/or aortic valves, coronaritis, cardiac dysfunction, pulmonary hypertension, and myocardial hypertrophy.
When combined with sJIA – aortitis (involvement of the ascending aorta, predominantly its root); involvement of the aortic valve cusps with the development of its insufficiency; involvement of the membranous part of the interventricular septum, aortic regurgitation; when combined with Behçet's disease – pericarditis, atrial or ventricular thrombosis.
ECG recording is recommended for all patients to detect/rule out pathological changes [36].
GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)
Comments: in the presence of myocarditis, signs of left and/or right heart overload are detected. In most cases, pericarditis is not accompanied by a decrease in QRS voltage, ST-segment elevation, or T-wave inversion on the ECG.
When CAPS is combined with sJIA with involvement of the membranous part of the interventricular septum, signs of atrioventricular and intraventricular conduction disturbances, conduction block may be detected; when combined with PAN, Behçet's disease – signs of coronary blood flow disorders, symptoms of conduction system disorders, signs of pulmonary hypertension or myocardial hypertrophy; abnormalities characteristic of myocardial ischemia/infarction.
Ultrasound examination of affected joints is recommended for patients with arthralgia/arthritis to assess the severity of effusion in the joint cavity, the state of the synovial membrane and cartilage [2,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in CAPS, signs of synovitis, increased amount of synovial fluid. Thickening (proliferation) of the synovial membrane, fibrillation of cartilage, and cartilage erosions are not characteristic of CAPS; if they are detected, juvenile arthritis must be ruled out.
CT scan of the affected joints using anesthesia management (including early postoperative management) is indicated for patients with monoarthritis or involvement of two joints to detect/rule out pathological changes [5,11,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: Juvenile arthritis, bone tuberculosis, osteomyelitis, benign and malignant tumors, and bone metastases are ruled out.
Arthritis in CAPS is non-destructive. Periarticular osteoporosis may be detected.
In juvenile arthritis, the following are detected: osteoporosis, destructive changes in bone structures, changes in the joint space, integrity of the articular surfaces of the bones forming the joint, presence of erosions, uzeration of articular surfaces, cysts, foci of bone tissue necrosis, subluxations, fractures, osteophytes, calcifications, etc.
Magnetic resonance imaging (MRI) of the affected joints with anesthesia management (including early postoperative management) as indicated with intravenous contrast is recommended for all patients with mono- or oligoarthritis to rule out traumatic injury to the musculotendinous and ligamentous apparatus, menisci, tumors, purulent (septic) arthritis, and juvenile arthritis [84,85].
LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)
Plain abdominal radiography is recommended for all patients with abdominal syndrome to rule out intestinal obstruction and perforation of a hollow abdominal viscus [85,86].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: in hollow organ perforation, free air is detected on the plain abdominal radiograph; in intestinal obstruction, fluid levels in intestinal loops.
Esophagogastroduodenoscopy (EGD) with biopsy of the esophagus/stomach/duodenum/jejunum using anesthesia management (including early postoperative management) as indicated and pathomorphological examination of the biopsy (surgical) specimen with determination of Helicobacter pylori is recommended for all patients with abdominal syndrome to detect/rule out pathological changes in the upper GI tract [30,34,38–40].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: Specific erosive/ulcerative lesions are not characteristic of CAPS; they may be a manifestation of inflammatory gastropathy, whether associated with Helicobacter pylori or not; Crohn's disease with upper GI tract involvement; Behçet's disease (neutrophilic phlebitis); amyloidosis.
Morphological examination is required to establish the diagnosis.
Colonoscopy with biopsy using anesthesia management (including early postoperative management) and pathomorphological examination of the large intestine biopsy (surgical) specimen is recommended for all patients with abdominal syndrome to rule out IBD and amyloidosis [30,34,38–40].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: Erosive/ulcerative lesions of the intestinal mucosa may develop when CAPS is combined with IBD; PAN, Henoch-Schönlein purpura, Behçet's disease.
Morphological examination is required to establish the diagnosis.
Video capsule small bowel endoscopy is recommended for patients with clinical signs of IBD and/or significantly elevated fecal calprotectin in the absence of changes according to EGD and colonoscopy data to rule out IBD with isolated small bowel involvement [87].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
CT scan of the chest organs using anesthesia management (including early postoperative management) as indicated is recommended for all patients to detect pleurisy, rule out/confirm pneumonia, oncological/oncohematological/lymphoproliferative diseases, tuberculosis, sarcoidosis, and granulomatous vasculitis [30,85].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: in CSS, aseptic pleuritis may develop; chest computed tomography can reveal a small effusion in the costophrenic angle, which typically resolves within 48 hours. Lung parenchyma involvement is not characteristic of CSS.
When CSS is combined with GPA, Behçet's disease, or Henoch-Schönlein purpura, pleuritis, pneumonitis, eosinophilic pulmonary infiltrates (in GPA), hemorrhagic alveolitis, pulmonary embolism, and pulmonary infarction may develop; in secondary HPS, acute respiratory distress syndrome and pulmonary infarction may occur.
In case of aneurysm rupture in GPA, pulmonary hemorrhage may develop.
MRI of the abdominal cavity, retroperitoneal space, and pelvis with intravenous contrast enhancement, including anesthetic management (and early postoperative care), is recommended for all patients as indicated to detect/exclude pathology [30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: oncological / oncohematological / lymphoproliferative diseases, tuberculosis of intra-abdominal lymph nodes, purulent inflammation in the abdominal cavity and pelvic organs are excluded .
When secondary amyloidosis develops, hepatosplenomegaly and typical renal changes are detected.
When CSS is combined with GPA, Behçet's disease, Henoch-Schönlein purpura, or secondary HPS, mesenteric thrombosis and intestinal infarction; thrombosis of abdominal/retroperitoneal arteries/veins; and infarctions of abdominal and retroperitoneal parenchymal organs may develop.
Brain and spinal cord MRI with intravenous contrast enhancement, including anesthetic management (and early postoperative care), is recommended for all patients as indicated to detect/exclude pathological changes [30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: mass lesions, inflammatory and infectious processes, strokes, and posterior reversible encephalopathy syndrome are excluded.
When CSS is combined with GPA, Behçet's disease, Henoch-Schönlein purpura, or HPS, hemorrhagic/ischemic strokes may develop; when combined with MS, T2-weighted MRI reveals characteristic MS-hyperintense lesions measuring 3 mm or more, ovoid in shape, often confluent, corresponding to areas of demyelination in the brain. The most typical localization of lesions is periventricular, in the corpus callosum with characteristic extension from the corpus callosum into the white matter ("Dawson's fingers"), as well as in the brainstem, cerebellum, spinal cord, and optic nerves. An important diagnostic feature of MS is "dissemination in space"—the detection of hyperintense lesions in multiple CNS zones simultaneously.
Lumbar puncture with anesthetic management (including early postoperative care), microscopic examination, cell counting in a counting chamber (determination of pleocytosis), analysis of the physical properties of cerebrospinal fluid, and serological testing is recommended for all patients with symptoms of CNS involvement to confirm/exclude pathological changes [88].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: performed in patients with neurological manifestations (headaches, recurrent meningitis or meningoencephalitis, seizures, etc.) to rule out an infectious origin of neurological disorders (meningococcal infection, viral meningitis, etc.).
Mollaret's "benign" recurrent meningitis is characterized by cerebrospinal fluid pleocytosis with large endothelial cells, neutrophilic granulocytes, and lymphocytes.
When CSS is combined with MS, oligoclonal antibodies to myelin proteins and an elevated level of immunoglobulin G in the cerebrospinal fluid compared to blood serum are detected in the cerebrospinal fluid. Oligoclonal antibodies are found in 90–95% of patients with definite MS, and once appeared, they persist in the cerebrospinal fluid for life.
Kidney biopsy with anesthetic management (including early postoperative care) and pathomorphological examination of the renal biopsy (surgical) specimen is recommended for patients with clinical/laboratory/ultrasound signs of renal involvement and/or renal failure, and/or in the presence of proteinuria >500 mg/day for the differential diagnosis of secondary amyloidosis with other diseases accompanied by renal involvement [1,2,5,11,25,66].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Bone marrow aspiration (cytological preparation) and bone marrow trephine biopsy (histological preparation) with anesthetic management (including early postoperative care), accompanied by cytological examination of bone marrow smears (myelogram) and immunohistochemical pathomorphological examination of the bone marrow biopsy (surgical) material, are recommended for all patients to rule out oncological/oncohematological/lymphoproliferative diseases/metastatic bone marrow involvement [60].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: if GCS or immunosuppressants are used, the test should be performed no earlier than 2 weeks after their withdrawal.
Lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) with anesthetic management (including early postoperative care), cytological examination of the tissue preparation, and pathomorphological examination of the biopsy (surgical) material is recommended for all patients with marked enlargement of peripheral and/or intrathoracic and/or intra-abdominal lymph nodes at the diagnostic stage prior to pathogenetic therapy to rule out hemoblastoses, lymphoproliferative diseases, and metastatic lymph node involvement [89–91].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: if GCS or immunosuppressants are used, the test should be performed no earlier than 2 weeks after their withdrawal.
Pelvic bone trephine biopsy with anesthetic management (including early postoperative care), pathomorphological examination of the bone marrow biopsy (surgical) material using immunohistochemical methods, cytological examination of trephine biopsy imprints, immunocytochemical examination of trephine biopsy imprints, and immunophenotyping of hematopoietic progenitor cells in the bone marrow is recommended in atypical cases of CSS during the evaluation stage, prior to prescribing GCS, #Colchicum autumnale seed extract/colchicine and/or immunosuppressants, and/or biologic agents to rule out oncological/oncohematological/lymphoproliferative diseases/metastatic bone marrow involvement [89,91,92].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: if GCS or immunosuppressants are used, the test should be performed no earlier than 2 weeks after their withdrawal.
Bone biopsy with anesthetic management (including early postoperative care) and pathomorphological examination of the bone biopsy (surgical) material is recommended for patients with bone destruction foci that are atypical for CSS to rule out malignant and benign tumors, metastatic bone lesions, and multifocal osteomyelitis [60].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: bone destruction is not characteristic of CSS. Destructive foci are characteristic of multifocal osteomyelitis, malignancies, and hemoblastoses, which may present with episodes of febrile fever accompanied by pain in the abdomen, chest, joints, and bones. Bone biopsy is necessary for differential diagnosis.
Multi-position bone scintigraphy with anesthetic management (including early postoperative care) is recommended as indicated for patients with bone destruction foci atypical for CSS to rule out malignant and benign bone tumors and metastatic bone lesions [60].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: bone destruction is not characteristic of CSS. Destructive foci are characteristic of multifocal osteomyelitis, malignancies, and hemoblastoses, which may present with episodes of febrile fever accompanied by pain in the abdomen, chest, joints, and bones. Multi-position bone scintigraphy is necessary for differential diagnosis and detection of pathological radiopharmaceutical uptake.
Positron emission tomography (PET) combined with CT using tumorotropic radiopharmaceuticals with contrast enhancement, or whole-body PET with tumorotropic radiopharmaceuticals if necessary, with anesthetic management (including early postoperative care) is recommended when indicated to rule out oncological diseases [89,90,93,94].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Comments: PET-CT is performed in patients with pronounced arthralgia, myalgia, ossalgia, bone destructive changes, subcutaneous adipose tissue infiltrates, and foci in parenchymal organs, the brain, or spinal cord to rule out oncological/oncohematological/lymphoproliferative diseases.
2.5 Other Procedures
An initial consultation (examination) by a pediatric surgeon is recommended for all patients with abdominal and thoracic symptoms to rule out acute surgical pathology [1,2,4,5,11,30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination) by a gastroenterologist is recommended for all patients with abdominal symptoms to determine the need for further evaluation and to rule out other diseases [1,2,4,5,11,30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination) by a pediatric oncologist is recommended for patients in whom oncological or oncohematological diseases are suspected based on evaluation results, in order to rule them out [89–91].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: carried out based on the results of evaluation (CT of the chest organs; MRI of the brain, abdominal organs, retroperitoneal space, and pelvis with intravenous contrast; cytological examination of a bone marrow smear (myelogram); pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods; cytological and immunocytochemical examination of bone marrow trephine biopsy imprints; immunophenotyping of hematopoietic progenitor cells in the bone marrow; cytological examination of lymph node tissue preparation and pathomorphological examination of lymph node biopsy (surgical) material; PET combined with CT using tumorotropic radiopharmaceuticals with contrast; whole-body PET with tumorotropic radiopharmaceuticals).
An initial consultation (examination) by an obstetrician-gynecologist is recommended for all female patients with abdominal symptoms to determine the need for further evaluation and to rule out gynecological diseases [1–5,11,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination) by a pediatric urologist-andrologist is recommended for all male patients with abdominal symptoms and/or inflammatory changes in the scrotum to determine the need for further evaluation and to rule out urological and andrological diseases [1–5,8,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination) by a nephrologist is recommended for patients with abnormal urinalysis results and/or nephrotic syndrome/renal failure to determine the need for further evaluation and to detect/rule out nephrological pathology/renal amyloidosis [1,3–5,11,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination) by a neurologist is recommended for patients with symptoms of central and peripheral nervous system involvement and patients with thoracic symptoms to detect/rule out pathological changes [1,3–5,10,11,30,32,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in rare cases, patients with FMF develop "benign" recurrent Mollaret's serous meningitis. Patients may experience: recurrent episodes of headache, nuchal rigidity, meningism; epileptiform seizures, speech and motor coordination disorders, diplopia, anisocoria, and rarely coma. The attack lasts from 1–3 days to several weeks.
When FMF is combined with multiple sclerosis (MS) the following may be observed: eye movement disorders leading to double vision; incomplete vision loss accompanied by pain with eye movements, paresthesia or decreased tactile and pain sensitivity starting in the fingertips and subsequently spreading, Lhermitte's sign (electric shock sensation down the spine radiating to the legs or arms when flexing the neck); acute transverse myelitis with the development of lower spastic paraparesis, sensory impairment (according to the level of the lesion), and pelvic dysfunction; symptoms of cerebellar involvement and its connections may manifest as gait and balance disorders, static and dynamic ataxia, dysmetria, hypermetria, asynergia, intention tremor, imprecise performance of coordination tests; scandent speech, megalographia, generalized tremor resembling severe hyperkinesia; facial myokymia, dysarthria, akinesia, and epileptic seizures. Examination reveals hyperactive deep tendon and periosteal reflexes, and pathological signs (Babinski sign appears among the first).
When FMF is combined with Behçet's disease, epileptiform seizures; parenchymatous inflammatory meningoencephalitis; non-parenchymatous lesions associated with vascular involvement; or mixed parenchymatous and non-parenchymatous lesions may develop.
The parenchymatous type of lesion is characterized by multifocal/diffuse involvement of the brainstem/spinal cord/cerebellum; asymptomatic ("silent") involvement/optic neuropathy; subacute development of brainstem symptoms with/without other manifestations; cerebral hemisphere/spinal cord lesion syndrome/pyramidal insufficiency; behavioral disorders; headache; ophthalmoplegia, and sphincter dysfunction.
The non-parenchymatous type of lesion is characterized by cerebral venous sinus thrombosis (intracranial hypertension); development of cerebral artery aneurysms; extracranial artery dissection; acute meningeal syndrome; headache and visual disturbances associated with intracranial hypertension due to cerebral venous sinus thrombosis. It can also manifest as acute cerebrovascular accident due to arterial thrombosis, aneurysm rupture, or dissection, although these changes are rare.
Peripheral nervous system involvement in the combination of FMF with Behçet's disease is characterized by the development of peripheral neuropathy or multiple mononeuropathies.
Chronic anxiety-depressive spectrum disorders (chronic depression, recurrent depressive disorder, generalized anxiety disorder), stress-related disorders, and cognitive impairments (memory and attention deficits) may also develop, occurring in 30–88% of patients with Behçet's disease.
An initial consultation (examination) by a phthisiatrician is recommended for patients with positive focal tuberculin skin tests and/or elevated blood interferon-gamma levels against Mycobacterium tuberculosis complex antigens and/or infiltrative lung lesions to rule out tuberculosis [1,5,30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination) by a trauma orthopedic surgeon is recommended for patients with acute arthritis, mass-forming and destructive lesions, as well as bone deformities not typical of FMF, to rule out septic arthritis, osteomyelitis, and other surgical pathologies [11,30,42,60].
GCR C LEL 4 Grade of Recommendation C (Level of Evidence – 4)
An initial consultation (examination) by an otorhinolaryngologist is recommended for all patients to detect foci of acute ENT infection [1,3,5,11,30,31].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
An initial consultation (examination) by an ophthalmologist is recommended with mandatory biomicroscopy of the ocular media for all patients to detect visual organ involvement [2,3,5,11,30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: when FMF is combined with oligoarticular/polyarticular juvenile arthritis, the development of unilateral or bilateral anterior uveitis (iritis, iridocyclitis, hypopyon, scleritis, episcleritis, keratitis, rarely conjunctivitis) is possible. In most cases, uveitis is characterized by a subacute or chronic course.
When FMF is combined with juvenile spondyloarthritis (JSpA), the development of acute unilateral or bilateral anterior uveitis is possible.
When FMF is combined with Behçet's disease, the development of anterior/posterior uveitis/panuveitis/retinal vasculitis is possible.
Posterior uveitis is characterized by periarteritis and periphlebitis with occlusive retinal vasculitis, retinitis, and vitreous involvement with hemorrhages, optic neuritis, peripapillary edema, and rarely choroiditis. Involvement is usually bilateral.
Manifestations of uveitis: sensations of "fog before the eyes", periorbital pain, photophobia, lacrimation, pericorneal injection. Complications of uveitis: macular edema and degeneration, cataract, posterior synechiae, peripheral anterior synechiae, secondary glaucoma, iris deformation and/or atrophy, retinal or optic nerve atrophy, partial retinal vein occlusion, iritis or neovascularization and retinal detachment, extraocular muscle palsy.
An initial consultation (examination) by a pediatric dentist is recommended for patients with clinical indications to rule out acute oral cavity pathology [30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination) by an audiologist-otorhinolaryngologist is recommended for all patients to confirm/rule out the presence of hearing loss [2,3,5,11,30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination) by a geneticist is recommended for patients in whom molecular genetic testing reveals mutations in the MEFV gene to determine their pathogenicity [2,3,5,11,30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients older than 1 year and all parents (regardless of the child's age) undergo an initial appointment (testing, consultation) with a medical psychologist in order to harmonize the development of the child's personality in the context of a severe chronic disease and optimize parent-child relationships; to increase treatment adherence and cooperation with the physician and medical staff to achieve disease remission; and to achieve social psychological adaptation and develop an individual psychological rehabilitation program for the patient and their parents [95].
Level of Recommendations CLevel of Evidence 4Level of Recommendations C (Level of Evidence – 4)
2.2. Evaluation of patients with familial Mediterranean fever with suspected hemophagocytic syndrome
HPS is a dangerous hyperinflammatory syndrome representing the outcome of a severe uncontrolled reaction characterized by hypercytokinemia with a significant yet ineffective immune response. It is a consequence of the innate or acquired inability of the immune system to cope with the trigger—most commonly an infectious agent [96].
HPS is triggered by viruses (cytomegalovirus, Epstein-Barr virus, herpes virus, etc.), medicinal products (NSAIDs, gold preparations, sulfasalazine**, etc.).
HPS is a consequence of excessive activation and expansion of mononuclear phagocyte system (MPS) cells and T lymphocytes, which manifests as cytopenia, systemic inflammatory reaction, and damage to the liver and spleen. The cells comprising the MPS form a single differentiation lineage, including bone marrow progenitor cells, as well as a pool of monocytes and macrophages. Overall, the MPS functions as a specific biological filter of blood and lymph that removes tumor cells, virus-infected cells, microorganisms, toxins, various metabolites, and circulating immune complexes. Histiocytes (syn. macrophages) also perform antigen-presenting functions.
In patients with familial Mediterranean fever, HPS develops less frequently than in sJIA and other systemic autoinflammatory diseases, which is likely due to the protective effect of mutations in the MEFV gene [97].
2.2.1. Physical examination in suspected hemophagocytic lymphohistiocytosis
It is recommended to perform diagnostic procedures, including differential diagnosis, in a rheumatology inpatient setting for all patients with suspected hemophagocytic syndrome [30, 42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to continuously monitor body temperature (thermometry) in all patients to assess the severity and pattern of fever [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: fever (constant or non-remitting) is one of the main clinical symptoms of HPS. It is invariably resistant to anti-infective treatment. At the same time, normalization of body temperature as a result of immunosuppressive therapy serves as one of the signs supporting a diagnosis of HPS.
It is recommended to assess the general condition of all patients for the purpose of its further monitoring [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the course of secondary HPS varies from mild, with minimal symptom severity, to severe. In severe uncontrolled HPS, impaired consciousness, coma, and fatal outcomes may develop.
It is recommended to examine the skin in all patients to detect pathological changes [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the frequency of cutaneous manifestations in HPS ranges from 6 to 65%. Skin lesions may present as a generalized maculopapular rash, erythroderma, edema, panniculitis, morbilliform rash, and purpura. Some manifestations are similar to those seen in Kawasaki disease.
Pathological examination of skin biopsy (surgical) material reveals lymphohistiocytic infiltration of the dermis with evidence of hemophagocytosis.
It is recommended to examine the lymph nodes in all patients to detect pathological changes [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments with the development of HPS, the size of lymph nodes significantly increases, and generalized lymphadenopathy develops.
It is recommended to analyze complaints, perform examination, percussion, and palpation of the cardiovascular system in all patients to detect pathological changes [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: as HPS progresses, heart failure develops as part of multiple organ dysfunction syndrome.
It is recommended to analyze complaints, perform examination, percussion, and palpation of the respiratory system in all patients to detect pathological changes [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: pulmonary involvement in HPS can also vary in severity, up to the development of severe respiratory failure requiring mechanical ventilation.
Patient mortality in pulmonary involvement is up to 88%.
Increasing respiratory failure is an alarming sign indicating inadequate control of HPS or the addition of a superinfection.
It is recommended to analyze complaints, perform examination, percussion, and palpation of the digestive system in all patients to detect pathological changes [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: liver involvement occurs in the vast majority of patients with HPS, ranging from an asymptomatic course with blood test abnormalities to the development of hepatic encephalopathy, severe hypocoagulation, and edematous-ascitic syndrome. Spontaneous development of hepatic veno-occlusive disease has been described.
The degree of splenic enlargement varies from marked to moderate, with splenomegaly detected only during instrumental examinations.
2.2.2. Laboratory diagnostic tests in suspected hemophagocytic lymphohistiocytosis
It is recommended to perform a complete blood count (CBC) with differential in all patients to detect pathological changes characteristic of HPS [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: thrombocytopenia, leukopenia, erythropenia develop in HPS, and the erythrocyte sedimentation rate (ESR) decreases.
It is recommended to perform a coagulogram (exploratory hemostasis assay) determining prothrombin index, antithrombin III activity; plasminogen and fibrinogen levels, D-dimer concentration, soluble fibrin monomer complex levels in blood, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time in blood, and von Willebrand factor [45–50, 100].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in HPS, the levels of D-dimer and fibrin degradation products increase (an early preclinical sign), while the fibrinogen level decreases.
It is recommended to perform thromboelastography in all patients to assess the severity of hemostatic disorders and the degree of risk for thrombosis and bleeding [45, 47, 48, 100, 101].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in HPS, thromboelastography reveals signs of hypercoagulation, and hypocoagulation upon consumption coagulopathy development. Thromboelastography data are necessary to determine anticoagulant therapy tactics and monitor its efficacy.
It is recommended to perform a general clinical blood chemistry panel determining the levels of total protein, albumin, total bilirubin, free (unconjugated) and conjugated bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, potassium, sodium, total calcium in blood; activities of LDH, creatine kinase, AST, ALT, GGT, amylase, blood ALP, and serum iron in order to detect pathological changes characteristic of HPS [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: HPS is characterized by elevated serum levels of ferritin, triglycerides, ALT, AST, and LDH. Serum C-reactive protein (CRP) levels also rise.
It is recommended to measure blood procalcitonin levels in all patients to rule out sepsis [78, 102].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: an elevated procalcitonin level should raise suspicion of a superimposed infection and the development of sepsis.
2.2.3. Instrumental diagnostic tests in suspected hemophagocytic lymphohistiocytosis
It is recommended to perform comprehensive ultrasound of internal organs in all patients to detect increases in the size of the liver and spleen, as well as intra-abdominal lymph nodes [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform echocardiography in all patients to assess cardiac status [30, 98, 99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to record an ECG in all patients to assess cardiac function [30, 42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform chest CT in all patients to detect/rule out pulmonary involvement, with anesthetic support (including early postoperative management) as indicated [30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: HPS may be complicated by hemorrhagic alveolitis, alveolar and interstitial pulmonary edema resembling acute respiratory distress syndrome (ARDS).
It is recommended to perform brain MRI with anesthetic support (including early postoperative management) as indicated in patients with neurological symptoms to detect pathological changes [30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: HPS may reveal ischemic/hemorrhagic strokes, well-defined demyelinating lesions, and posterior reversible encephalopathy syndrome (PRES).
It is recommended to perform a comprehensive ultrasound of the abdominal organs and/or MRI of the abdominal cavity, retroperitoneal space, and pelvis with anesthesia support (including early postoperative management) according to indications in the event of multiple organ dysfunction syndrome, in order to detect organomegaly, free fluid in the abdominal cavity and small pelvis, and to assess the condition of the liver, kidney, and spleen parenchyma [30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to obtain a bone marrow cytologic preparation by puncture with anesthesia support (including early postoperative management) and a bone marrow histologic preparation with cytologic examination of the bone marrow smear (myelogram), along with pathoanatomical examination of the bone marrow biopsy (surgical) material, in order to identify differentiated macrophages phagocytosing hematopoietic cells [30,98,99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: bone marrow aplasia may develop in severe HFS.
2.2.4. Other diagnostic tests in suspected hemophagocytic lymphohistiocytosis
It is recommended that all patients with neurological symptoms undergo a repeat examination (consultation, evaluation) by a neurologist in order to assess the state of the central and peripheral nervous system [30,98,99].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in 30–35% of patients, symptoms of CNS involvement develop: seizures, meningism, altered level of consciousness, cranial nerve palsy, psychomotor agitation, ataxia, hypotonia, irritability.
In half of the patients with neuropsychiatric symptoms, cerebrospinal fluid analysis reveals pleocytosis, hyperproteinorachia (elevated CSF protein), and hemophagocytic cells.
Peripheral neuropathy and marked generalized weakness, disproportionate to the degree of anemia, are also encountered.
It is recommended that all patients with hemorrhagic syndrome undergo a repeat examination (consultation, evaluation) by an ophthalmologist in order to assess the condition of the ocular media, membranes, optic nerve, retina, and fundus [30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: patients with HFS may exhibit retinal hemorrhages, optic neuritis, and choroidal infiltration.
2.2.5. Criteria for diagnosing secondary hemophagocytic syndrome in patients with familial Mediterranean fever.
Serum ferritin concentration >684 ng/mL and 2 of the following:
- blood platelet count ≤180 × 10⁹/L;
- serum AST concentration >48 IU/L;
- serum triglyceride concentration >1.75 mmol/L;
- blood fibrinogen concentration ≤3.60 g/L.
2.3 Evaluation of patients with a confirmed diagnosis of familial Mediterranean fever in the active disease stage for the purpose of prescribing/adjusting therapy
It is recommended to conduct the evaluation in a rheumatology inpatient setting in order to prescribe/adjust therapy for all patients with a confirmed diagnosis of FMF in the active stage [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
For complaints and anamnesis, see section 2.1.1.
For physical examination, see section 2.1.2.
2.3.1 Laboratory diagnostic tests
It is recommended to perform a complete blood count (CBC) with differential for all patients prior to prescribing/adjusting therapy in order to determine disease activity and potential adverse effects of NSAIDs and/or immunosuppressants, and/or biological DMARDs [30,44].
GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)
Comments: leukocytosis, moderate thrombocytosis, and elevated ESR are observed. In HFS, leukopenia and/or thrombocytopenia and/or erythropenia occur, and ESR may be decreased. A normal leukocyte and platelet count in patients with fever may indicate ongoing HFS. Single-, double-, or trilineage cytopenia may also be an adverse manifestation of treatment with NSAIDs and/or #Autumn crocus seed extract/colchicine and/or biological DMARDs, and/or immunosuppressants.
It is recommended to perform a coagulogram (screening hemostasis test) determining prothrombin index, antithrombin III activity, plasminogen and fibrinogen levels, D-dimer concentration, soluble fibrin monomer complexes in the blood, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time, and von Willebrand factor in all patients before prescribing/adjusting therapy to assess the hemostatic system and address the need for its correction [45–50,100].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform thromboelastography in patients with HFS prior to prescribing/adjusting therapy in order to determine the tactics of anticoagulant therapy [45,47,48,100,101].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in HFS, thromboelastography reveals signs of hypercoagulability, or hypocoagulability if consumption coagulopathy develops. Thromboelastography data are necessary to assess the state of the hemostatic system and monitor the efficacy of anticoagulant therapy.
It is recommended to perform a routine biochemical blood test determining the levels of total protein, albumin, total bilirubin, free (unconjugated) and bound (conjugated) bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, potassium, sodium, total calcium in the blood; the activity of LDH, creatine kinase, AST, ALT, GGT, amylase, ALP, and serum iron in all patients prior to prescribing/adjusting therapy in order to assess disease activity and the functional state of the liver, kidneys, and pancreas [11,44,51–56].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: elevated levels of triglycerides, ferritin, and LDH, AST, and ALT activity indicate the development of HFS; elevated levels of creatinine and/or urea, and/or ALT, AST, and/or amylase, and/or GGT, and/or ALP, and/or K, and/or total bilirubin, and/or glucose, and/or cholesterol, and/or triglycerides may be an adverse manifestation of treatment with NSAIDs and/or #Autumn crocus seed extract/colchicine and/or biological DMARDs, and/or GCS. Elevated levels of creatinine, urea, uric acid, and potassium are signs of renal failure development.
It is recommended to determine blood procalcitonin levels in all patients with fever prior to prescribing/adjusting therapy in order to rule out a septic process [69].
GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)
Comments: procalcitonin levels rise in the presence of a bacterial infection and acute inflammatory response.
It is recommended to determine blood immunoglobulin levels in all patients prior to prescribing/adjusting therapy in order to rule out a primary/secondary immunodeficiency state [57–59].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Comments: blood immunoglobulin levels in FMF generally fall within reference ranges.
It is recommended to determine serum CRP levels in all patients prior to prescribing/adjusting therapy in order to assess disease activity [57–59].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Comments: serum CRP levels are significantly elevated in the active stage of FMF, as well as when FMF is combined with other rheumatic diseases and/or complicated by a bacterial infection.
It is recommended to determine serum antistreptolysin-O to detect/exclude group A β-hemolytic streptococcus infection [60].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: an elevated serum antistreptolysin-O level indicates acute or chronic streptococcal infection, an exacerbation of which may trigger FMF attacks.
It is recommended to perform peripheral blood immunophenotyping to determine lymphocyte subpopulation composition (main subsets) in patients prone to frequent viral, pyogenic bacterial, and opportunistic infections, prior to prescribing/adjusting therapy in order to rule out immunodeficiency developed as a result of treatment with GCS and/or #Autumn crocus seed extract/colchicine, and/or biological DMARDs [58,70].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
It is recommended to perform a focal tuberculin test (Manttu test, test with recombinant tuberculosis allergen in standard dilution) and test blood interferon-gamma levels against Mycobacterium tuberculosis complex antigens in all patients prior to prescribing/adjusting therapy in order to rule out Mycobacterium tuberculosis infection [30,103,104].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine antibodies to Salmonella enterica in the blood, and IgM and IgG antibodies to Yersinia pseudotuberculosis in the blood of all patients prior to prescribing/adjusting therapy in order to rule out intestinal bacterial infections [30,68].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine IgA, IgM, and IgG antibodies to Chlamydia psittaci in the blood; IgM antibodies to Chlamydia trachomatis in the blood; IgG antibodies to Chlamydia trachomatis in the blood; and IgM and IgG antibodies to Mycoplasma pneumoniae in the blood of all patients prior to prescribing/adjusting therapy in order to rule out mycoplasma and chlamydial infections [30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine the DNA of Epstein-Barr virus (Epstein-Barr virus), Cytomegalovirus, Herpes simplex virus types 1 and 2 by PCR in peripheral blood (quantitative assay), saliva, and urine in all patients before prescribing/adjusting therapy to laboratory confirm/exclude active Epstein-Barr and/or cytomegalovirus, and/or herpetic infection [30,68,74].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform a general (clinical) urine test, Nechyporenko urine test, and determine albumin and total protein in a 24-hour urine collection in all patients before prescribing/adjusting therapy to assess the condition of the urinary system [44,62].
LoR BLoE 4Level of Recommendation B (Level of Evidence – 4)
Comments: micro- or macrohematuria may be a consequence of the toxic effect of NSAIDs on the kidneys; when amyloidosis develops, the following are detected: proteinuria ≥500 mg/day, lipiduria, hyaline casts in the urinary sediment, and, as proteinuria increases, granular casts; micro- and macrohematuria, and leukocyturia are possible in the absence of pyelonephritis.
It is recommended to perform a set of renal function tests in patients with clinical/laboratory signs of kidney damage before prescribing/adjusting therapy to identify the severity of their impairment [1,2,5,11,27,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform a set of tests to diagnose and assess the severity of renal failure in patients with clinical/laboratory signs of nephrotic syndrome/renal failure before prescribing/adjusting therapy [1,2,5,11,27,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform microbiological (culture) testing of mucus from the tonsils and posterior pharyngeal wall for aerobic and facultatively anaerobic microorganisms in all patients before prescribing/adjusting therapy to rule out nasopharyngeal contamination by aerobic and facultatively anaerobic microorganisms [30,68].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform microbiological (culture) testing of bronchoalveolar lavage fluid for fungi (yeasts and molds) in all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia and decide on etiotropic therapy [103–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to perform microbiological (culture) testing of lavage fluid for aerobic and facultatively anaerobic microorganisms in all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia and decide on etiotropic therapy [103–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine antibodies to Aspergillus spp. in the blood of all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia and decide on etiotropic therapy [181-186].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine mannan and galactomannan in lavage fluid and blood in all patients with signs of pneumonia according to chest CT scans to identify the etiology of pneumonia and decide on etiotropic therapy [106–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR in all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia and decide on etiotropic therapy [106–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR in all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia and decide on etiotropic therapy [105–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG) DNA with species differentiation in sputum and bronchoalveolar lavage fluid by PCR in all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia and decide on etiotropic therapy [103–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine class M and G antibodies (IgM, IgG) to Cytomegalovirus in the blood of all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine class M and G antibodies (IgM, IgG) to Epstein-Barr virus in the blood of all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus in the blood of all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus in the blood of all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia and decide on etiotropic therapy [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine antibodies to Herpes simplex virus in the blood of all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT scans to identify the etiological factor of pneumonia and decide on etiotropic therapy [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform microbiological (culture) blood and urine tests for sterility in patients with febrile and hectic fever before prescribing/adjusting therapy to rule out sepsis [77,78].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine the fecal calprotectin level in patients who develop clinical manifestations of IBD (diarrhea, abdominal pain, blood/mucus in stool) before prescribing/adjusting therapy to rule them out [79].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
2.3.2 Instrumental diagnostic tests
It is recommended to perform a comprehensive ultrasound of internal organs in all patients before prescribing/adjusting therapy to assess the condition of the liver, spleen, kidneys, bowel motility, and pancreas [1,2,4,5,30,31,33,34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the development of amyloidosis reveals hepatosplenomegaly, heterogeneity of the structure of parenchymal organs, and a large lardaceous kidney.
It is recommended to perform an echocardiogram in all patients before prescribing/adjusting therapy to detect/exclude pathological changes [35,36].
GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)
Comments: myocardial damage is possible, along with the development of diastolic dysfunction, depletion of ventricular diastolic reserve, and a tendency toward pulmonary hypertension due to microvascular dysfunction.
It is recommended to perform an ECG in all patients before prescribing/adjusting therapy to assess and detect/exclude pathological changes [35].
GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)
Comments: pericarditis in systemic sclerosis is in most cases not accompanied by low QRS voltage, ST-segment elevation, or T-wave inversion on the ECG.
It is recommended to perform 24-hour ambulatory blood pressure monitoring in patients with hypertension before prescribing/adjusting therapy to determine the grade of arterial hypertension [1,2,4,5,30,31,33,34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform Holter ECG monitoring in patients with arrhythmias or pathological changes on the electrocardiogram before prescribing/adjusting therapy to develop a treatment strategy [1,2,4,5,30,31,33,34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform ultrasound of affected joints in all patients with active arthritis before prescribing/adjusting therapy to assess the condition of the synovial membrane and cartilage and to detect joint effusion [2,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform a CT scan of affected joints with anesthetic support (including early postoperative management) before prescribing/adjusting therapy, according to indications, to detect/exclude pathological changes [5,11,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform magnetic resonance imaging (MRI) of affected joints with anesthetic support (including early postoperative management) before prescribing/adjusting therapy, according to indications, with intravenous contrast enhancement to assess the condition of the synovial membrane and cartilage and to detect joint effusion [84,85].
LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)
It is recommended to perform esophagogastroduodenoscopy (EGD) with biopsy under anesthesia (including early postoperative management) as indicated, with pathomorphological examination of the biopsy (surgical) specimen in patients with dyspeptic symptoms, patients receiving NSAIDs and/or GCS, and/or biologic agents, as well as when the disease duration exceeds 5 years and/or in the presence of proteinuria >500 mg per day prior to prescribing/adjusting therapy, in order to rule out inflammatory gastropathies and amyloidosis [39,40].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: It is necessary to rule out inflammatory diseases of the upper gastrointestinal tract associated with Helicobacter pylori and/or the use of NSAIDs and/or glucocorticosteroids (GCS), as well as amyloidosis.
It is recommended to perform colonoscopy with biopsy under anesthesia (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen in patients with abdominal syndrome prior to prescribing/adjusting therapy in order to detect/rule out complications of systemic connective tissue diseases and concomitant bowel diseases, as well as amyloidosis [37,39,40].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: performed upon the appearance of intestinal symptoms atypical for systemic connective tissue diseases (prolonged diarrhea, abdominal pain, blood and pus admixture in stool) to rule out IBD, as well as in disease duration exceeding 5 years and/or in the presence of proteinuria >500 mg per day.
It is recommended to perform a kidney biopsy under anesthesia (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen in patients with chronic kidney disease/signs of renal failure prior to prescribing/adjusting therapy in order to detect/rule out amyloidosis [25,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform chest CT under anesthesia (including early postoperative management) as indicated in all patients prior to prescribing/adjusting therapy in order to detect/rule out pathological changes [85,86].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: it is necessary to exclude focal, lobar, or interstitial pneumonia, and pulmonary tuberculosis.
Interstitial pneumonia should be suspected in the presence of low-grade/high-grade fever, dry cough/cough with a scant amount of sputum, crepitations/weakened breath sounds upon auscultation, and dyspnea.
It is recommended to perform bronchoscopy under anesthesia (including early postoperative management) in all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT [85,86,103–107,112].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
2.3.3. Other diagnostic tests
Specialist consultations for the purpose of diagnosis and treatment of manifestations of the underlying disease, comorbidities, and/o complications.
It is recommended that patients with joint functional impairment undergo an initial consultation (examination) by an orthopedic trauma surgeon to determine the need for orthopedic correction [1,3,5,10,30,60].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients undergo an initial consultation (examination) by an otolaryngologist prior to prescribing/adjusting therapy in order to identify foci of chronic ENT infection and address the issue of sanitization [1,5,10,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to sanitize foci of chronic ENT infection in all patients prior to prescribing/adjusting therapy in order to reduce the risk of infectious complications under conditions of pathogenetic therapy [1,5,10,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A follow-up consultation (examination) by an otolaryngologist is performed in all patients after the sanitization of foci of chronic infection to monitor its effectiveness [1,5,10,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients undergo an initial consultation (examination) by a pediatric dentist prior to prescribing/adjusting therapy to assess the oral cavity status and the need for its sanitization [30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to sanitize the oral cavity in patients with foci of chronic infection prior to prescribing/adjusting therapy in order to reduce the risk of infectious complications under conditions of pathogenetic therapy [30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A follow-up consultation (examination) by a pediatric dentist is performed in all patients after the sanitization of foci of chronic oral infection to monitor its effectiveness [30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients undergo an initial consultation (examination) by an ophthalmologist with mandatory biomicroscopy of the eye prior to prescribing/adjusting therapy in order to detect/rule out visual organ involvement and determine treatment tactics [1,5,10,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: local therapy is prescribed to patients with uveitis and complicated steroid cataract.
It is recommended that all patients with identified pathology undergo a follow-up consultation (examination) by an ophthalmologist with mandatory biomicroscopy of the eye to monitor treatment efficacy and address the issue of surgical treatment in an ophthalmology department [1,5,10,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with cardiac rhythm disorders and/or arterial hypertension undergo an initial consultation (examination) by a pediatric cardiologist prior to prescribing/adjusting therapy to address the need for cardiotropic and/or antihypertensive therapy [35].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
It is recommended that patients with cardiac rhythm disorders and/or arterial hypertension undergo a follow-up consultation (examination) by a pediatric cardiologist to monitor the efficacy of cardiotropic and/or antihypertensive therapy [35].
GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)
It is recommended that patients with endocrine pathology undergo an initial consultation (examination) by a pediatric endocrinologist prior to prescribing/adjusting therapy to develop further examination and treatment tactics [1,3,5,11,30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with endocrine pathology undergo a follow-up consultation (examination) by a pediatric endocrinologist to monitor treatment efficacy [1,3,5,11,30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients with nutritional disorders undergo an initial consultation (examination) by a dietician prior to prescribing/adjusting therapy to develop an individualized dietary program [30,31,113,114].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended that all patients with nutritional disorders undergo a follow-up consultation (examination) by a dietician to monitor compliance with the individualized dietary program and dietary behavior recommendations in an outpatient setting [30,31,113,114].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended that patients with neurological symptoms undergo an initial consultation (examination) by a neurologist prior to prescribing/adjusting therapy to address the management strategy [1,3–5,10,11,30,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with neurological symptoms or psychotic reactions undergo a follow-up consultation (examination) by a neurologist to monitor treatment efficacy [1,3–5,10,11,30,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with nephrotic syndrome, changes in routine general blood biochemistry, and general urinalysis typical for the development of amyloidosis/renal failure undergo an initial consultation (examination) by a nephrologist prior to prescribing/adjusting therapy to decide on treatment tactics [1,3–5,10,11,25,30,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with nephrotic syndrome, changes in routine general blood biochemistry, and general urinalysis typical for the development of amyloidosis/renal failure undergo a follow-up consultation (examination) by a nephrologist to monitor treatment efficacy [1,4,5,10,11,25,30,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Monitoring of efficacy – see Appendices A3, G3-8, G10.
It is recommended that male patients with inflammatory changes of the scrotum undergo an initial consultation (examination) by a pediatric urologist-andrologist prior to prescribing/adjusting therapy to decide on treatment tactics [1–5,8,11].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that male patients with inflammatory changes of the scrotum undergo a follow-up consultation (examination) by a pediatric urologist-andrologist to monitor treatment efficacy [1–5,8,11].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with positive focal tuberculin skin test results and/or elevated blood interferon-gamma levels in response to Mycobacterium tuberculosis complex antigens and/or focal, infiltrative changes in the lungs undergo an initial consultation (examination) by a phthisiatrician prior to prescribing/adjusting therapy to decide on chemoprophylaxis or anti-tuberculosis chemotherapy [1,5,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients older than 1 year and all parents (regardless of the child's age) undergo an initial consultation (testing, examination) by a medical psychologist in order to harmonize the formation of the child's personality in the context of a severe chronic disease and optimize parent-child relationships; increase adherence to treatment and cooperation with the physician and medical staff to achieve disease remission; achieve psychological adaptation in society; and develop an individualized psychological rehabilitation program for the patient and their parents [95].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended that all patients older than 1 year and all parents undergo a follow-up assessment (testing, consultation) with a medical psychologist after completion of the psychological rehabilitation program to evaluate its efficacy [95].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended that all patients with functional impairment after disease activity has decreased undergo an initial examination (consultation) by a physical therapy physician to develop a program of physical therapy procedures within the medical rehabilitation program [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with functional impairment after disease activity has decreased undergo an initial examination (consultation) by an exercise therapy (ET) physician to develop a medical rehabilitation program [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients with functional impairment undergo medical rehabilitation after disease activity has decreased [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients with functional impairment undergo a follow-up examination (consultation) by a physical therapy physician after completion of the physical therapy program within the medical rehabilitation program to evaluate its efficacy [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients with functional impairment undergo a follow-up examination (consultation) by an exercise therapy physician after completion of the medical rehabilitation program to evaluate its efficacy [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
It is recommended to prescribe pathogenetic therapy to all patients after diagnostics, including differential diagnostics, and establishing/confirming the diagnosis of FMF in a rheumatology inpatient setting [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
3.1. Conservative management
It is recommended to prescribe NSAIDs (M01A) alone in patients with an unconfirmed diagnosis of FMF for the relief of fever and pain syndrome during the work-up stage [117,118].
GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)
It is recommended to prescribe NSAIDs for the relief of fever and pain syndrome in patients with a confirmed diagnosis of FMF (M01A) [30,117,118].
GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)
It is recommended to prescribe #diclofenac** (M01AB) to children older than 6 years at a dose of 0.5–3 mg/kg/day or nimesulide (M01AX) to children older than 2 years at a dose of 1.5 mg/kg in 2–3 divided doses (no more than 5 mg/kg/day), to children older than 12 years at a dose of 3–5 mg/kg/day, or #meloxicam (M01AC) to children older than 2 years at a dose of 0.125 mg/kg/day, to children older than 15 years at a dose of 7.5–15 mg/day, or ibuprofen** (M01AE01) to children older than 3 months at up to 30 mg/kg/day in 3–4 divided doses to achieve an anti-inflammatory, analgesic, and antipyretic effect [30,117–123].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: NSAIDs (M01A) are prescribed in the following dosages:
Diclofenac** (M01AB) is used in children from 6 years of age in tablets and suppositories; intramuscular injections are approved from 18 years of age.
Nimesulide (M01AX) is used in children from 2 years of age as a suspension, and over 12 years of age as tablets.
Meloxicam (M01AC) is used in children from 2 years of age as a suspension and over 15 years of age as tablets; intramuscular injections are approved from 18 years of age.
Ibuprofen** (M01AE01) is used in children over 3 months of age as a suspension, over 6 years of age in tablets; the intervals between doses are 6–8 hours.
#Diclofenac** (M01AB), nimesulide (M01AX), and #meloxicam (M01AC) off-label are prescribed by decision of a medical commission, after obtaining informed consent from parents and children older than 15 years.
It is not recommended to prescribe GCS (H02AB) orally and/or intravenously, and/or intra-articularly, and/or immunosuppressants, and/or biologic disease-modifying antirheumatic drugs (bDMARDs) until a complete laboratory and instrumental work-up is completed, oncological and onco-hematological diseases are ruled out, and the diagnosis of FMF is established [67,68,124].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the use of #Colchicum autumnale seed extract/colchicine, GCS, immunosuppressants (sulfasalazine**, #methotrexate**), bDMARDs (#canakinumab** or #tocilizumab**, or adalimumab**, or etanercept**) in oncological and onco-hematological diseases presenting under the mask of FMF significantly complicates subsequent verification of the diagnosis, as they have a pronounced immunosuppressive effect and mask the clinical and morphological picture of malignant neoplasms.
It is recommended to administer pulse therapy with #methylprednisolone** (H02AB) at a dose of 10–30 mg/kg/administration intravenously for 3 days, or 5 consecutive days if necessary, to patients with a confirmed diagnosis of FMF at the work-up stage, in case of severe pain syndrome and/ulatory life-threatening systemic manifestations (persistent febrile or hectic fever and/or pericarditis, and/or pleuritis, and/or peritonitis), and/or protracted febrile myalgia (PFM) to achieve a rapid anti-inflammatory effect [5,30,51,125–129].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: pulse therapy with #methylprednisolone** (H02AB) is prescribed by decision of a medical commission, after obtaining informed consent from parents and children older than 15 years.
It is recommended to prescribe #prednisolone** (H02AB) or #methylprednisolone** (H02AB) orally at a dose of 1 mg/kg/day to patients with protracted febrile myalgia to achieve an anti-inflammatory effect [5,30,51,128–131].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to administer intra-articular GCS (H02AB), #betamethasone** (H02AB) or triamcinolone, no more than once every 4 months in case of arthritis flare as concomitant therapy to achieve a rapid anti-inflammatory effect [30].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: indications for intra-articular GCS administration include severe pain syndrome in monoarthritis or oligoarthritis.
#Triamcinolone is used for intra-articular injections in children older than 12 years up to 10 mg of the drug.
#Betamethasone** (H02AB) is used for intra-articular injections in children from 3 years of age up to 4 mg of the drug.
When using #betamethasone** (H02AB) or #triamcinolone off-label, they are prescribed by decision of a medical commission, after obtaining informed consent from parents and children older than 15 years.
It is recommended to prescribe #Colchicum autumnale seed extract/colchicine as permanent therapy to patients with typical FMF attacks, homozygosity, compound heterozygosity, or heterozygosity for MEFV gene mutations to reduce attack frequency/induce FMF remission [51,132–134].
GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)
It is recommended to prescribe #Colchicum autumnale seed extract/colchicine at a starting daily dose of 0.5 mg/day in children under 5 years, 0.5–1.0 mg/day in children 5–10 years, and 1.0–1.5 mg/day in children older than 10 years [51,132–134].
LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)
Comments: the daily dose of #Colchicum autumnale seed extract/colchicine may be taken at once or divided into 2 or more doses depending on tolerability and patient preference.
It is recommended to increase the dose of #Colchicum autumnale seed extract/colchicine by 0.5 or 0.6 mg per day if inflammatory activity persists despite compliance with the recommended starting dose, with careful monitoring of side effects, to reduce attack frequency/induce FMF remission [51,132–134].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the daily dose (0.5 or 0.6 mg) is chosen depending on the available dosage form of the drug; inflammatory activity is determined by ongoing attacks or elevated acute-phase markers of inflammation between attacks.
If attacks persist at >1 attack per month for ≥3 months, the issue of prescribing bDMARDs is considered.
#Colchicum autumnale seed extract/colchicine is prescribed in combination with NSAIDs during an FMF attack.
#Colchicum autumnale seed extract/colchicine is prescribed for vital indications, by decision of a medical commission, after obtaining informed consent from parents and children older than 15 years.
Monitoring of therapy efficacy – see Appendices A3, G3–G8
It is recommended to prescribe #Colchicum autumnale seed extract/colchicine as permanent therapy to patients with chronic joint involvement dominating the clinical picture, and homozygosity or compound heterozygosity for MEFV gene mutations to induce FMF remission [51,132,134].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: for dosing regimen, see above.
#Colchicum autumnale seed extract/colchicine is prescribed in combination with an immunosuppressant (see below).
Monitoring of therapy efficacy – see Appendices A3, G1–G10
It is recommended to prescribe #Colchicum autumnale seed extract/colchicine as permanent therapy to patients with protracted febrile myalgia to reduce attack frequency/induce FMF remission [51,132,134].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: for dosing regimen, see above.
#Colchicum autumnale seed extract/colchicine is prescribed in combination with GCS at the time of an attack at a dose of 1 mg/kg (see above).
Monitoring of therapy efficacy – see Appendices A3, G3–G8
It is recommended to prescribe #Colchicum autumnale seed extract/colchicine as permanent therapy to relatives of FMF patients who are asymptomatic but have persistently elevated acute-phase inflammatory markers/proteinuria, and homozygosity or compound heterozygosity for MEFV gene mutations to reduce inflammatory activity [132].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: for dosing regimen, see above.
Monitoring of therapy efficacy – see Appendices A3, G3–G8
It is not recommended to exceed the dose of #Colchicum autumnale seed extract/colchicine >2.0 mg/day to prevent adverse events [51,132–135].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Comments: exceeding the maximum recommended dose does not lead to a significant increase in the severity and frequency of achieving the effect, but substantially increases the risks of adverse events (hypertransaminasemia, myopathy, cytopenia, etc.), including severe ones.
Prescription of #Colchicum autumnale seed extract / colchicine or altering its dose for the relief of an FMF attack is not recommended [51,135].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: #Colchicum autumnale seed extract / colchicine does not relieve an FMF attack, and increasing its dose at the time of the attack is clinically inappropriate.
Prescription of the interleukin-1β (IL-1β) inhibitor #canakinumab** or the interleukin-1α and IL-1β inhibitor anakinra** is recommended for compliant patients with colchicine-resistant FMF who have >1 attack per month while receiving the maximum tolerated dose of #Colchicum autumnale seed extract / colchicine for ≥3 months [135–138].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Prescription of the interleukin-1β (IL-1β) inhibitor #canakinumab** (L04AC) or the interleukin-1α and IL-1β inhibitor anakinra** (L04AC03) is recommended for colchicine-resistant patients with typical FMF attacks, homozygosity, compound heterozygosity, or heterozygosity for MEFV gene mutations in order to reduce attack frequency / achieve FMF remission [135–138].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: #canakinumab** (L04AC) is prescribed to patients with established colchicine resistance (see Appendix G3) when step-up dose titration of #Colchicum autumnale seed extract / colchicine up to the maximum is ineffective.
Monitoring of therapy efficacy – see Appendices A3, G3–G8
Prescription of the interleukin-1β (IL-1β) inhibitor #canakinumab** (L04AC) or the interleukin-1α and IL-1β inhibitor anakinra** (L04AC03) is recommended for patients with severe, infrequent FMF attacks and an increased risk of secondary amyloidosis in order to reduce attack frequency / achieve FMF remission and prevent the development of amyloidosis [135–138].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Monitoring of therapy efficacy – see Appendices A3, G3–G8
Prescription of the interleukin-1β (IL-1β) inhibitor #canakinumab** (L04AC) or the interleukin-1α and IL-1β inhibitor anakinra** (L04AC03) is recommended for colchicine-resistant patients with chronic joint involvement as a dominant clinical feature, and with homozygosity or compound heterozygosity for MEFV gene mutations in order to reduce attack frequency / achieve FMF remission [135,136].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: #canakinumab** (L04AC) or anakinra** (L04AC03) are prescribed when #Colchicum autumnale seed extract / colchicine in an adequate dose combined with NSAIDs and an immunosuppressant is ineffective.
Monitoring of therapy efficacy – see Appendices A3, G1–G10
Prescription of the interleukin-1β (IL-1β) inhibitor #canakinumab** (L04AC) or the interleukin-1α and IL-1β inhibitor anakinra (L04AC03) is recommended for colchicine-resistant patients with protracted febrile myalgia in order to relieve it [135,136,139].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: # canakinumab** (L04AC08) or anakinra** (L04AC03) are prescribed when #Colchicum autumnale seed extract / colchicine in an adequate dose combined with GCs at the time of an attack is ineffective.
For monitoring of treatment efficacy, see Appendices A3, G3–8
Prescription of #canakinumab** (L04AC) is recommended for children with a body weight of ≥7.5 ≤40 kg at a dose of 2 mg/kg once every 4 weeks, subcutaneously; > 40 kg at a dose of 150 mg once every 4 weeks subcutaneously in combination with #Colchicum autumnale seed extract / colchicine at the maximum tolerated dose in order to induce FMF remission [136,138].
GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)
Comments: #canakinumab** (L04AC) is prescribed to patients with established colchicine resistance. Colchicine-resistant patients are defined as fully compliant patients who have >1 attack per month while receiving the maximum tolerated dose of #Colchicum autumnale seed extract / colchicine for ≥3 months. Before classifying a patient as colchicine-resistant, compliance must be verified. #Canakinumab** (L04AC) may be prescribed to patients with severe, infrequent FMF attacks and an increased risk of secondary amyloidosis.
Administration of #canakinumab** (L04AC) can be performed in outpatient and inpatient settings.
In children under 2 years of age, #canakinumab** (L04AC) is prescribed for vital indications, by decision of a medical commission, after obtaining informed consent from the parents.
Upon achieving a clinical effect 7 days after the #canakinumab** (L04AC) injection, it is recommended to administer maintenance therapy with #canakinumab** (L04AC) at a dose of 2 mg/kg once every 4 weeks subcutaneously in patients with a body weight of ≤40 kg, and at a dose of 150 mg once every 4 weeks subcutaneously in patients with a body weight of >40 kg, in order to maintain FMF remission [138].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: clinical effect is defined as the cessation of the attack: relief of fever, abdominal and/or chest pain, and other FMF symptoms, reduction/normalization of acute-phase inflammatory markers (ESR, CRP, blood leukocyte count).
If no clinical effect is achieved 7 days after the #canakinumab** (L04AC) injection, a second injection of #canakinumab** (L04AC) is recommended at a dose of 2 mg/kg subcutaneously for patients with a body weight of ≤40 kg, and at a dose of 150 mg subcutaneously for patients with a body weight of >40 kg, in order to induce FMF remission [138].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: failure to achieve a clinical effect is defined as the persistence of fever, abdominal and/or chest pain, and other FMF symptoms, and persistence/increase of acute-phase inflammatory markers (ESR, CRP, blood leukocyte count).
Upon achieving a full clinical effect after the second #canakinumab** (L04AC) injection, maintenance therapy with #canakinumab** (L04AC) is recommended at a dose of 4 mg/kg once every 4 weeks subcutaneously for patients with a body weight of ≤40 kg, and at a dose of 300 mg once every 4 weeks subcutaneously for patients with a body weight of >40 kg, in order to maintain FMF remission [138].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Monitoring of therapy efficacy – see Appendices A3, G1–G10
Prescription of anakinra** (L04AC03) is recommended for patients with a body weight of less than 50 kg at a dose of 1–2 mg/kg/day, and for patients with a body weight of ≥50 kg at a dose of 100 mg/day subcutaneously in order to reduce attack frequency / achieve FMF remission [133,135–138].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Monitoring of therapy efficacy – see Appendices A3, G1–G10
Upon achieving a clinical effect within one month, maintenance therapy with anakinra** (L04AC03) is recommended at a dose of 1–2 mg/kg/day for patients with a body weight of less than 50 kg, and at a dose of 100 mg/day subcutaneously for patients with a body weight of ≥50 kg, in order to maintain FMF remission [133,135–138].
GCR BLOE 3Grade of Recommendation B (Level of Evidence 3)
In case of an insufficient therapeutic response, increasing the dose of anakinra** (L04AC03) up to 4 mg/kg/day subcutaneously is recommended in order to induce remission [136].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Prescription of #methotrexate** (L01BA) at a dose of 15 mg/m2/week subcutaneously or #sulfasalazine** (A07EC) at a dose of 30–40 mg/kg orally in 2 divided doses is recommended for FMF patients with chronic joint involvement as a dominant clinical feature, and with homozygosity or compound heterozygosity for MEFV gene mutations when #Colchicum autumnale seed extract / colchicine at the maximum tolerated dose is ineffective, as well as in cases of FMF combined with JIA, in order to induce arthritis remission [131,136,140–148].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: #methotrexate** (L01BA) is prescribed by decision of a medical commission, after obtaining informed consent from parents and children over 15 years of age.
#Sulfasalazine** (A07EC) is prescribed by decision of a medical commission, after obtaining informed consent from parents and children over 15 years of age.
The choice of drug is made by a rheumatologist based on the clinical features and the course of the articular syndrome.
At any stage of treatment, if intolerance and/or inefficacy of #sulfasalazine** (A07EC) or #methotrexate** (L01BA) develops, switching between the drugs is permissible.
Monitoring of therapy efficacy – see Appendices A3, G1–G10
Increasing the dose of #methotrexate** (L01BA) >15 mg/m2/week (not exceeding 25 mg/week) is not recommended for patients with active chronic arthritis and/or FMF combined with JIA in order to prevent adverse events [131,136,140,142–145,147–149].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Comments: increasing the dose of #methotrexate** (L01BA) is not associated with additional therapeutic benefits.
Prescription of folic acid** (B03BB) at a dose of 1 mg daily or 2.5 mg once a week orally during #methotrexate** (L01BA) therapy is recommended to prevent adverse effects of #methotrexate** (L01BA) [147,150,151].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
In case of #canakinumab** (L04AC) inefficacy, the prescription of #tocilizumab** (L04AC) at a dose of 8 mg/kg/infusion intravenously once every 2 weeks or at a dose of 162 mg subcutaneously once a week in combination with #Colchicum autumnale seed extract / colchicine and/or #methotrexate** (L01BA (if intolerant)), and/or #sulfasalazine** (A07EC) (if tolerated) is recommended for patients with active chronic arthritis and/or FMF combined with JIA in order to induce remission of systemic FMF manifestations [136,137,152–157].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: #tocilizumab** (L04AC) is prescribed for vital indications, by decision of a medical commission, after obtaining informed consent from parents and children over 15 years of age.
Monitoring of therapy efficacy – see Appendices A3, G1–G10
It is recommended in case of intolerance to #canakinumab** (L04AC) to switch to #tocilizumab** (L04AC) at a dose of 8 mg/kg/administration intravenously every 2 weeks or at a dose of 162 mg subcutaneously once a week in combination with #Colchicum autumnale seed extract/colchicine and/or #methotrexate** (L01BA) (in case of its intolerance), and/or #sulfasalazine** (A07EC) (in case of its tolerability) in patients with active chronic arthritis and/or combination of FMF with JIA in order to maintain/induce FMF remission [136,137,152–157].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: #tocilizumab** (L04AC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children older than 15 years.
Monitoring of therapy efficacy – see Appendices A3, G1–G10
It is recommended in case of intolerance to #Colchicum autumnale seed extract /colchicine to perform monotherapy with #tocilizumab** (L04AC) at a dose of 8 mg/kg/administration intravenously every 2 weeks or at a dose of 162 mg subcutaneously once a week or in combination with #methotrexate** (L01BA) (in case of its tolerability) or #sulfasalazine** (A07EC) (in case of its tolerability) in patients with active chronic arthritis and/or combination of FMF with JIA in order to induce remission of systemic manifestations of FMF [136,137,152–157].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: #tocilizumab** (L04AC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children older than 15 years.
Monitoring of therapy efficacy – see Appendices A3, G1–G10
It is recommended to switch to tumor necrosis factor alpha (TNF-alpha) inhibitors** (L04AB) in patients with active chronic arthritis dominating the clinical picture and/or combination of FMF with JIA, homozygosity or compound heterozygosity for MEFV gene mutations when #Colchicum autumnale seed extract/colchicine in combination with #methotrexate** (L01BA) or #sulfasalazine** (A07EC) is ineffective, in order to induce arthritis remission [30,129,136,137,141,146,149,158].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: TNF-alpha inhibitors** (L04AB) are prescribed only to patients with chronic arthritis that dominates the clinical picture and does not respond to therapy with #Colchicum autumnale seed extract/colchicine in combination with #methotrexate** (L01BA) at a dose of 15 mg/m² once a week subcutaneously or #sulfasalazine** (A07EC) at a dose of 30-40 mg/kg/day.
#Adalimumab** (L04AB), #etanercept** (L04AB), #golimumab** (L04AB) are prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children older than 15 years.
Monitoring of therapy efficacy – see Appendices A3, G1–G10
It is recommended to prescribe tumor necrosis factor alpha (TNF-alpha) inhibitors #adalimumab** (L04AB) to children with a body weight from 10 to 30 kg – 20 mg once every 2 weeks; >30 kg – 40 mg once every 2 weeks, or #etanercept** (L04AB) 0.4 mg/kg/administration subcutaneously twice a week or 0.8 mg/kg/administration once a week in combination with #Colchicum autumnale seed extract/colchicine at the maximum tolerated dose, with #methotrexate** (L01BA) (in case of its tolerability) at a dose of 15 mg/m² once a week subcutaneously or with #sulfasalazine** (A07EC) at a dose of 30-40 mg/kg/day orally [30,129,136,137,141,146,149,158–164].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: TNF-alpha inhibitors** (L04AB) are prescribed only to patients with chronic arthritis that dominates the clinical picture and does not respond to therapy with #Colchicum autumnale seed extract/colchicine in combination with #methotrexate** (L01BA) at a dose of 15 mg/m² once a week subcutaneously or #sulfasalazine** (A07EC) at a dose of 30-40 mg/kg/day, or combination of FMF with JIA.
In case of intolerance to #Colchicum autumnale seed extract/colchicine, TNF-alpha inhibitors are used in combination with #methotrexate** (in case of its tolerability) or #sulfasalazine** (in case of its tolerability).
#Adalimumab** (L04AB), #etanercept** (L04AB), #golimumab** (L04AB) are prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children older than 15 years.
Monitoring of treatment efficacy – see Appendices G1–G10
It is recommended to evaluate the efficacy of pathogenetic therapy according to FMF50, Autoionic Disease Activity Index (AIDAI) 3 months after the initiation of therapy and then every 6 months; disease severity according to the International Severe Systemic Autoinflammatory Disease Score (ISSF) for FMF – once every 6 months, damage index (ADDI) – once a year [133,165–167].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: in severe variants of the disease and persistence of even minimal activity on colchicine therapy, patients are considered as candidates for the prescription of biological DMARDs.
Monitoring of therapy efficacy – see Appendices G4-G8.
3.1.1. Basic principles of treatment for familial Mediterranean fever
The basis of FMF treatment is the long-term use of #Colchicum autumnale seed extract/colchicine at an adequate dose. #Colchicum autumnale seed extract/colchicine should be prescribed immediately as soon as the diagnosis of FMF is established in all patients. The drug is effective in 90% of patients.
Despite satisfactory tolerability of #Colchicum autumnale seed extract/colchicine, adverse events of therapy may develop, especially when exceeding recommended doses, which requires regular clinical and laboratory monitoring of patients receiving colchicine.
5–10% of patients do not tolerate therapy with #Colchicum autumnale seed extract/colchicine.
In patients with colchicine resistance and intolerance to #Colchicum autumnale seed extract/colchicine, the use of interleukin-1 beta (IL-1β) inhibitor #canakinumab** is effective. Patients receiving #canakinumab** should continue to receive #Colchicum autumnale seed extract/colchicine at the maximum tolerated dose.
Long-term outcomes directly depend on phenotype severity, genotype characteristics (homozygosity for p.M694V and α/α SAA1), delay in diagnosis and initiation of effective therapy, and adequacy of #Colchicum autumnale seed extract/colchicine dosing.
It has also been shown that colchicine therapy significantly improves health-related quality of life [4,51,132].
3.1.2. Treatment of hemophagocytic lymphohistiocytosis in patients with familial Mediterranean fever
It is recommended to prescribe therapy to all patients after diagnosis, including differential diagnosis, and establishment/confirmation of the diagnosis of FMF with hemophagocytic syndrome, in a rheumatology inpatient setting [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform pulse therapy with #methylprednisolone** (H02AB) at a dose of 20–30 mg/kg/administration intravenously or prescribe #dexamethasone** (H02AB) at a dose of 10–20 mg/m²/day intravenously in combination (or without) with oral prednisolone** (H02AB) 1-2 mg/kg/day, #cyclosporine** (L04AD) at a dose of 5-7 mg/kg/day orally or intravenously in order to control macrophage activation syndrome [42,98,168–172].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: #dexamethasone** (H02AB) and #cyclosporine** (L04AD) are prescribed on vital indications by decision of the medical commission, after obtaining informed consent from parents and children older than 15 years.
It is recommended to gradually reduce the dose of #dexamethasone** (H02AB) after relief of clinical and laboratory signs of macrophage activation syndrome according to the following regimen: 10-20 mg/m²/day for 1-2 weeks, at a dose of 5-10 mg/m²/day for 3-4 weeks, at a dose of 2.5-5 mg/m²/day for 5-6 weeks, at a dose of 1.25-2.5 mg/m²/day for 7-8 weeks [168,172].
LoR CGoE 4Level of Recommendation C (Level of Evidence – 4)
Comments: #dexamethasone** (H02AB) is prescribed on vital indications by decision of the medical commission, after obtaining informed consent from parents and children older than 15 years.
It is recommended to prescribe #canakinumab** (L04AC) subcutaneously at a dose of 4 mg/kg/administration once every 4 weeks in order to control macrophage activation syndrome [173].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: #canakinumab**(L04AC) is prescribed in combination with GCS and #cyclosporine**(L04AD) at a dose of 5 mg/kg/day.
#Canakinumab**(L04AC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children older than 15 years.
It is recommended to prescribe #normal human immunoglobulin** (J06BA) at a dose of 2 g/kg intravenously to achieve an immunosuppressive effect [98,170,172,174–177].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: administration of the total course dose of immunoglobulin is carried out by continuous prolonged infusion as a single dose to ensure blocking of IgG Fc receptors on phagocytic cells; suppression of T-lymphocyte proliferation and immunoglobulin production; interaction with the complement system; blocking of cytokine activation and action; blocking of adhesion molecule expression on endothelial cells.
#Normal human immunoglobulin** is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children older than 15 years.
It is recommended to prescribe antithrombotic agents (B01A): heparin group drugs (B01B), antiplatelet agents excluding heparin (B01AC), antifibrinolytic agents (B02A), direct factor Xa inhibitors (B01AF) in the presence of hypercoagulation and vascular endothelial damage according to coagulogram and thromboelastogram data, upon the development of coagulopathy and disseminated intravascular coagulation according to coagulogram (exploratory hemostasis test) and thromboelastography in accordance with international guidelines [45, 47, 48].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: antithrombotic agents (B01A) off-label for age are prescribed by decision of the medical committee, after obtaining informed consent from parents and children over 15 years of age.
It is recommended to perform transfusions of blood and blood products (B05A) upon the development of consumption coagulopathy or bleeding [47].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: upon the development of consumption coagulopathy, transfusions of red blood cell mass, fresh frozen plasma, cryoprecipitate, etc., are performed in accordance with indications.
It is recommended to prescribe #rituximab** (L01XC) as a first-line biological disease-modifying antirheumatic drug (bDMARD) in patients with hemophagocytic syndrome (HPS) and active Epstein-Barr virus infection at a dose of 375 mg/m² per week intravenously once a week for 4 consecutive weeks in combination with #cyclosporine** (L04AD) 5–7 mg/kg/day and #normal human immunoglobulin** (J06BA) 1–2 g/kg to suppress virus replication in B-lymphocytes and arrest HPS [42, 98, 168–172, 178].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: #rituximab** (L01XC) is prescribed for life-saving indications, by decision of the medical committee, after obtaining informed consent from parents/patients over 15 years of age.
#Rituximab** (L01XC) is prescribed in combination with #cyclosporine** and #normal human immunoglobulin** (J06BA).
It is recommended to prescribe #rituximab** (L01XC) in combination with #co-trimoxazole** (J01EE) at a dose of 5 mg/kg based on trimethoprim orally 3 times a week or daily for the prevention of Pneumocystis pneumonia in accordance with international guidelines [179–187].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended, in the event of concurrent infection and development of sepsis accompanied by an elevated blood procalcitonin level, to prescribe empirical antibiotic therapy initially, followed by systemic antibacterial drugs (J01) active against gram-positive, gram-negative, and anaerobic flora (penicillin combinations, including combinations with beta-lactamase inhibitors (J01CR); 4th-generation cephalosporins (J01DE); carbapenems (J01DH); other antibacterial agents (J01XX); glycopeptide antibiotics (J01XA); other aminoglycosides (J01GB); in combination with systemic antifungal agents (J02A)) based on microbial susceptibility in accordance with clinical guidelines for the treatment of sepsis in children [78].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: systemic antibacterial drugs (J01) off-label for age are prescribed by decision of the medical committee, after obtaining informed consent from parents and children over 15 years of age.
It is recommended to evaluate the efficacy of HPS treatment after 2–4 weeks to decide on the continuation of induction therapy or switching the treatment regimen [188].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: criteria for achieving a therapeutic response include: resolution of fever, reduction in spleen size, increase in blood platelet count ≥100 × 10⁹/L, normalization of blood fibrinogen level, and a 25% decrease in serum ferritin concentration.
Upon achieving a response, it is advisable to continue therapy until the inactive disease stage is reached.
It is recommended to treat HPS until the inactive stage is achieved [188].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: criteria for the inactive stage of HPS include: absence of fever, splenomegaly, cytopenia (Hb ≥90 g/L, platelets ≥100 × 10⁹/L, neutrophils ≥0.5 × 10⁹/L), decrease in serum triglyceride concentration <3 mmol/L or <265 mg/dL, ferritin ≤500 µg/L, normalization of cerebrospinal fluid parameters (in central nervous system involvement), and a decrease in sCD25 if performed.
After HPS resolution, it is recommended to administer therapy in accordance with clinical guidelines (see above).
3.2. Surgical treatment
It is recommended to perform joint replacement surgery with anesthetic support (including early postoperative management) in children with stage 3–4 secondary coxarthrosis, taking into account age restrictions [30, 42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
3.3. Non-pharmacological treatment
It is recommended to perform maintenance hemodialysis in patients with amyloidosis and end-stage chronic kidney disease [5].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to consume a diet with a high content of calcium and vitamin D for the prevention of osteoporosis in patients receiving glucocorticoids [30, 42, 113, 114].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Splints, orthoses, insoles, and lightweight removable appliances are recommended for the correction of orthopedic disorders in patients with chronic arthritis, joint deformities, and lower limb growth impairment [30, 42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: for static orthoses, intermittency of immobilization is necessary – they should be worn or put on outside of classes and must be removed during the day to stimulate the muscular system during physical exercises, studies, occupational therapy, and personal hygiene. In case of pronounced osteoporosis in the thoracic and lumbar spine, a corset or reclinator should be worn; in case of cervical spine joint involvement, a cervical collar (soft, rigid) should be worn.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
It is recommended to provide medical rehabilitation services to patients with systemic connective tissue disorders, inflammatory arthropathies, and spondylopathies to restore their functional capacity [115, 116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: performed in all patients with chronic arthritis; an individual rehabilitation program is developed; goals and objectives of rehabilitation measures are formulated based on the rehabilitation diagnosis and rehabilitation potential for the day, week, and the entire rehabilitation period; the motor regime and individual intensity limits of interventions applied to the patient with functional impairments are determined; an individual exercise therapy program is developed; rehabilitation methods are selected: medications, kinesiotherapy, mechanotherapy (including aquatic therapeutic mechanotherapy), physiotherapy, robotics, exoskeletons, information technologies, psychological correction, occupational therapy; forms of medical rehabilitation are chosen at various stages of its application and during different periods of the disease course (individual, group sessions, sessions using telemedicine technologies); legal representatives of children in need of medical rehabilitation are consulted and trained in home-approved rehabilitation methods and care skills for severely ill children
Physiotherapy is recommended for all patients with joint involvement, muscle atrophy, and steroid myopathy once remission is achieved [115, 116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: a plan is developed, and the goal and objectives of physiotherapy for a patient with systemic connective tissue diseases during the implementation of the individual rehabilitation program are formulated; physiotherapy methods—high-frequency electric field therapy, magnetotherapy, polarized light therapy, mechanotherapy, thermotherapy, and spa treatment (climatotherapy, balneotherapy, pelotherapy)—are selected depending on the various periods of the disease course.
A psychological rehabilitation school is recommended for patients with systemic connective tissue diseases and their relatives [95].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: medical rehabilitation is necessarily combined with the psychological rehabilitation of children and their parents; an individual psychological rehabilitation and psychotherapeutic program is developed taking into account the clinical picture of the disease, identified psychological and psychosocial mechanisms of the mental disorder, personal characteristics, psychotherapeutic hypothesis, and psychotherapeutic targets; methods of psychological intervention (psychotherapy, psychological counseling, psychological correction, and psychological rehabilitation) are selected; types of psychotherapy include dynamic, cognitive-behavioral, existential-humanistic, and non-mainstream modalities—art therapy, body-oriented psychotherapy, psychodrama, suggestive psychotherapy, etc.; forms of psychotherapy include individual, family-couples, group, natural environment-based, and milieu therapy.
5. Prevention and Dispensary Observation
5.1. Prevention
Primary prevention consists of genetic counseling for the birth of a child with a systemic connective tissue disease.
A repeat appointment (examination, consultation) with a geneticist is recommended for parents after a child is diagnosed, for genetic counseling regarding the recurrence risk of systemic connective tissue diseases in subsequent children in the family [2, 3, 5, 11, 30, 31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comment: Systemic autoinflammatory diseases are usually inherited in an autosomal recessive manner, in which both parents of an affected individual with two pathogenic MEFV variants are healthy heterozygous carriers. However, in populations with a high carrier rate and/or high rate of consanguineous marriages, it is possible that one or both parents carry two pathogenic variants and are affected.
Autosomal dominant inheritance of systemic autoinflammatory diseases has also been reported, where heterozygous carriers of pathogenic variants in the MEFV gene exhibited both mild and severe disease courses.
Thus, it is advisable to consider molecular genetic testing of the proband's parents to determine their genetic status. If both parents are heterozygotes, the risk for siblings to inherit two pathogenic variants is 25%.
In families with FMF patients, prenatal and preimplantation genetic diagnosis can be performed. For this, parents need to consult specialized diagnostic laboratories and medical centers.
Prenatal diagnosis is carried out using molecular genetic or biochemical methods by analyzing DNA extracted from a chorionic villus biopsy at 9–11 weeks of gestation.
Primary prevention also includes monitoring family members of patients with confirmed FMF, with careful surveillance for the onset of symptoms and the dynamics of inflammatory activity markers (ESR, CRP, SAA) in asymptomatic individuals, performing genetic testing for MEFV gene mutations if necessary.
Prevention of FMF complications and flares, as well as adverse effects of targeted therapy, is recommended [11,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: to prevent flares and complications of FMF, long-term maintenance therapy is administered under the constant monitoring of clinical and laboratory disease activity indicators, tailored to the patient's individual characteristics and disease variant, with subsequent adjustment if necessary; a protective regimen is ensured (psychosocial and physical stress are limited; during a flare, children are homeschooled and attend school only during inactive disease/remission; contacts are limited to reduce the risk of infectious diseases; the use of live vaccines and immunomodulators is excluded).
To reduce the risk of adverse effects from targeted drugs, regular monitoring of clinical and laboratory safety parameters is performed; the use of medications that increase the toxicity of glucocorticoids, #colchicine (Colchicum autumnale seeds extract), immunosuppressants, and bDMARDs is excluded.
It is not recommended for patients receiving bDMARDs to be immunized with live and live-attenuated vaccines concurrently with therapy with #colchicine (Colchicum autumnale seeds extract) and/or bDMARDs, and/or an immunosuppressant [30,189].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the safety of such a combination has not been established. An FMF flare may develop. There are no data on the secondary transmission of infection from patients immunized with live vaccines to patients receiving bDMARDs.
5.2. Follow-up (dispensary observation) of patients with familial Mediterranean fever in an inpatient / day-hospital setting that initiated the targeted therapy prescription
The examination is performed every 3–6 months: at 3 and 6 months after therapy initiation; thereafter every 6 months to monitor the efficacy and safety of therapy, detect disease complications and comorbid conditions,
For complaints and anamnesis, see section 2.1.1.
For physical examination, see section 2.1.2.
A comprehensive (clinical) blood count is recommended for all patients to assess disease activity and monitor the safety of targeted drugs [11,44].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: complete blood count parameters should be within the normal range. Single-, bi-, or pancytopenia may be, among other things, an undesirable manifestation of treatment with #colchicine (Colchicum autumnale seeds extract), and/or bDMARDs, and/or an immunosuppressant.
Leukopenia and agranulocytosis most frequently develop with the use of #colchicine (Colchicum autumnale seeds extract), #sulfasalazine**, #tocilizumab**, and less frequently with #canakinumab**, TNF-alpha inhibitors, and #methotrexate**.
Aplastic anemia may develop during treatment with #colchicine (Colchicum autumnale seeds extract).
Overdose of #colchicine (Colchicum autumnale seeds extract) may cause severe bone marrow suppression with leukopenia, thrombocytopenia, and coagulopathy.
Thrombocytopenia may develop during long-term treatment with #colchicine (Colchicum autumnale seeds extract), as well as any bDMARD or immunosuppressant.
A 50% dose reduction of #colchicine (Colchicum autumnale seeds extract), withholding of a bDMARD injection/infusion, and/or withholding of #methotrexate** or #sulfasalazine** (for 7 days) is recommended for all patients when the platelet count drops to ≤150 >100 × 10⁹/L, or the neutrophil count drops to <1.5 ≥1.0 × 10⁹/L in a complete blood count, to prevent the progression of cytopenia [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: previously prescribed oral glucocorticoids should be continued.
Repeat the complete blood count in one week. If there is evidence of recurrent episodes of blood cell count decrease, address the issue of adjusting therapy with #colchicine (Colchicum autumnale seeds extract) and/or bDMARDs, and/or an immunosuppressant.
Discontinuation of #colchicine (Colchicum autumnale seeds extract) and/or an immunosuppressant and/or a bDMARD is recommended for all patients if the absolute neutrophil count drops to <1.0 × 10⁹/L and/or the platelet count drops to <100 × 10⁹/L in a complete blood count, to prevent the progression of cytopenia [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: previously prescribed oral glucocorticoids should be continued.
Repeat the complete blood count in one week.
The administration of the granulocyte colony-stimulating factor #filgrastim** (L03AA) at a dose of 5–10 mcg/kg/day subcutaneously is recommended for leukopenia with an absolute neutrophil count ≤1.0 × 10⁹/L for 3–5 days (or longer if necessary) until complete normalization of leukocyte and neutrophil counts [42,190,191].
LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)
Comments: in children aged <1 year, #filgrastim** (L03AA) is prescribed by decision of a medical commission, after obtaining informed parental consent.
The administration of the granulocyte colony-stimulating factor #filgrastim** (L03AA) at 5–10 mcg/kg/day subcutaneously combined with systemic antibacterial drugs (J01) intravenously is recommended in febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count ≤1.0 × 10⁹/L [42,190,191].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: in children aged <1 year, #filgrastim** (L03AA) is prescribed by decision of a medical commission, after obtaining informed parental consent.
Treatment with #filgrastim** (L03AA) is carried out for 3–5 days (or longer if necessary) until complete normalization of leukocyte and neutrophil counts.
Continuation of systemic antibacterial therapy (J01) is recommended for all patients with febrile neutropenia (neutropenia accompanied by fever) until the resolution of febrile fever and normalization of the leukocyte formula according to the complete blood count [42,190,191].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Resumption of treatment with #colchicine (Colchicum autumnale seeds extract) and/or an immunosuppressant, and/or a bDMARD at the same dose is recommended for all patients after the recovery of the neutrophil count to ≥1.5 × 10⁹/L according to the complete blood count, to maintain FMF remission [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Therapy adjustment involving #colchicine (Colchicum autumnale seeds extract) and/or an immunosuppressant, and/or a bDMARD is recommended for all patients in case of recurrent episodes of decreased blood cell counts in the complete blood count, to control adverse events associated with therapy [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A general biochemical blood test is recommended, determining total protein, albumin, total bilirubin, free (unconjugated) and conjugated bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, potassium, sodium, total calcium; activity of LDH, creatine kinase, AST, ALT, GGT, amylase, alkaline phosphatase; serum iron, and vitamin B12, to monitor disease activity, liver, kidney, and pancreatic function, and electrolyte balance during therapy with #colchicine (Colchicum autumnale seeds extract) and/or bDMARDs, and/or an immunosuppressant [1,2,5,11,42,44,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: an increase in creatinine and/or urea, and/or uric acid, and/or total bilirubin, free (unconjugated) and/or conjugated bilirubin, and/or potassium, and/or cholesterol, and/or triglycerides; an increase in the activity of LDH and/or ALT, and/or AST, and/or GGT, and/or alkaline phosphatase, and/or amylase may be an undesirable manifestation of treatment with #colchicine (Colchicum autumnale seeds extract) and/or bDMARDs, and/or an immunosuppressant.
Vitamin B12 deficiency may result from the toxic effect of #colchicine (Colchicum autumnale seeds extract).
A progressive increase in creatinine, urea, uric acid, potassium, cholesterol, and a decrease in total protein and serum albumin may indicate the development of renal failure secondary to amyloidosis.
A rapid increase in blood serum creatinine, urea, uric acid, and potassium levels combined with oligo- or anuria may indicate the development of acute kidney injury due to overdose of #Colchicum autumnale seed extract / colchicine.
Temporary discontinuation of #Colchicum autumnale seed extract / colchicine and/or immunosuppressive agent, and/or biologic DMARD is recommended for all patients if serum ALT or AST levels increase ≥ 1.5 times the upper limit of normal and/or total bilirubin, free (unconjugated) and/or conjugated bilirubin, and/or urea, and/or creatinine, and/or uric acid, and/or other biochemical parameter(s) exceed the upper limit of normal [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: previously prescribed oral GCS therapy should be continued. Repeat routine blood biochemistry in one week.
Resumption of therapy with #Colchicum autumnale seed extract / colchicine and/or immunosuppressive agent, and/or biologic DMARD at the same dose is recommended for all patients after normalization of routine blood biochemistry parameters in order to maintain TLS remission [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Adjustment of therapy with #Colchicum autumnale seed extract / colchicine and/or immunosuppressive agent, and/or biologic DMARD is recommended for all patients in the event of recurrent episodes of elevated biochemical parameter(s) in order to control adverse events during therapy [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Determination of blood immunoglobulin levels, anti-nuclear antibodies (ANA) and anti-DNA antibodies; serum CRP and procalcitonin is recommended for all patients to monitor disease activity, adverse events of TNF-alpha inhibitor therapy, and acute inflammatory response during treatment with #Colchicum autumnale seed extract / colchicine and/or biologic DMARDs, and/or immunosuppressive agents [57–59,69,192].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in the inactive disease stage / remission, the levels of all serum inflammatory markers (CRP, procalcitonin, ferritin) as well as blood immunoglobulins are within the reference range. Decreased immunoglobulin levels occur in secondary immunodeficiency states. Increased titers of anti-nuclear antibodies and/or anti-double-stranded DNA antibodies are observed during treatment with TNF-alpha inhibitors and indicate the development of lupus-like syndrome.
If lupus-like syndrome develops, TNF-alpha inhibitors are discontinued and the patient is switched to a biologic DMARD with a different mechanism of action.
An increasing CRP level may indicate an exacerbation of the disease and/or an infectious complication, while elevated serum CRP and procalcitonin levels indicate an acute inflammatory response (sepsis).
If infectious complications develop, antibacterial therapy is prescribed.
When prescribing antibacterial therapy, the administration of #Colchicum autumnale seed extract / colchicine and/or biologic DMARDs, and/or the injection/administration of immunosuppressants is skipped. Previously prescribed oral GCS therapy should be continued. Treatment with #Colchicum autumnale seed extract / colchicine and/or biologic DMARDs, and/or immunosuppressive agents is resumed at the same dose after completion of antibacterial therapy.
In patients receiving #Colchicum autumnale seed extract / colchicine and/or biologic DMARDs, and/or immunosuppressive agents who present with decreased blood immunoglobulin levels, it is recommended to administer #normal human immunoglobulin** (J06BA) at a dose of 400 mg/kg, or 500 mg/kg if an adequate immunoglobulin level is not achieved, to correct blood immunoglobulin levels and prevent infectious complications [193].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
All patients with fever are recommended to undergo a set of examinations to rule out sepsis (complete blood count, routine blood biochemistry, serum CRP, blood procalcitonin, blood microbiological (culture) test for sterility, microbiological (culture) test of tonsillar and posterior pharyngeal wall mucus for aerobic and facultative anaerobic microorganisms, urine microbiological (culture) test for bacterial pathogens using automated inoculation, antimicrobial susceptibility testing, thromboelastography, coagulogram (screening hemostasis test); chest CT, complex abdominal ultrasound, renal ultrasound, echocardiography, MRI of the abdomen, pelvis, and retroperitoneal space) in accordance with clinical guidelines for the treatment of sepsis in children [45,47,48,68,78,78,101,102,194,195].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: performed in patients with febrile or hectic fever, leukocytosis/leukopenia, thrombocytopenia, and elevated serum CRP and procalcitonin levels not related to AOSD activity.
In the event of sepsis, it is recommended to initiate empirical antibacterial therapy, followed by intravenous systemic antibacterial agents (J01) targeting gram-positive, gram-negative, and anaerobic flora (combinations of penicillins, including beta-lactamase inhibitor combinations (J01CR); 4th generation cephalosporins (J01DE); carbapenems (J01DH); other antibacterials (J01XX); glycopeptide antibiotics (J01XA); other aminoglycosides (J01GB); macrolides (J01GB)) combined with systemic antifungals (J02A) according to microbiological susceptibility, along with #normal human immunoglobulin (J06BA) at a dose of 400 mg/kg/course in accordance with clinical guidelines for the treatment of sepsis in children [78,196].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: off-label systemic antibacterial agents (J01) are prescribed by decision of the medical board, after obtaining informed consent from parents and children over 15 years of age.
Upon the development of sepsis, the administration of #Colchicum autumnale seed extract / colchicine and/or biologic DMARDs, and/or immunosuppressant injections/administration are discontinued for the entire duration of antibiotic treatment. Previously prescribed oral GCS therapy should be continued.
With increasing AOSD activity, pulse therapy with #methylprednisolone (see above) is performed and/or the dose of oral GCS is increased (see above). Treatment with #Colchicum autumnale seed extract / colchicine and/or biologic DMARD, and/or immunosuppressive agent is resumed no earlier than 1 week after complete resolution of clinical and laboratory signs of sepsis and completion of antibacterial therapy.
Resumption of therapy with #Colchicum autumnale seed extract / colchicine and/or immunosuppressive agent, and/or biologic DMARD no earlier than one week after complete resolution of clinical and laboratory signs of sepsis and completion of antibiotic therapy is recommended for all patients to maintain AOSD remission [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Assessment of hemostasis (screening hemostasis test) with determination of prothrombin index, antithrombin III activity, plasminogen and fibrinogen levels, D-dimer concentration, soluble fibrin monomer complexes in blood, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time, and von Willebrand factor in blood is recommended for patients with sepsis and HPS in order to evaluate the hemostatic system [45–48].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: sepsis and HPS are characterized by hypercoagulation followed by hypocoagulation (disseminated intravascular coagulation [DIC] syndrome).
The development of coagulopathy is characteristic of #Colchicum autumnale seed extract / colchicine overdose.
Thromboelastography is recommended for patients with HPS, sepsis, and signs of thrombosis and hypocoagulation to determine the management strategy for anticoagulant therapy [101].
Leveled of Evidence CLevel of Data Reliability 2Level of evidence C (level of data reliability – 2)
Prescription of antithrombotic agents (B01A): heparin group drugs (B01B), antiplatelet agents excluding heparin (B01AC), antifibrinolytics (B02A), direct factor Xa inhibitors (B01AF) is recommended in cases of coagulopathy or disseminated intravascular coagulation based on coagulogram (screening hemostasis test) and thromboelastogram data [45,47,48].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: off-label antithrombotic agents (B01A) are prescribed on vital indications, by decision of the medical board, after obtaining informed consent from parents and children over 15 years of age.
Blood transfusions and blood products (B05A) are recommended in accordance with international guidelines when consumption coagulopathy / bleeding develops [47].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
All patients with a history of frequent viral and purulent bacterial infections, including opportunistic infections, are recommended to undergo peripheral blood immunophenotyping to determine the subpopulation composition of lymphocytes (main subsets) [58,70].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: a decrease in the level of T- and/or B-lymphocyte subpopulations, and/or natural killer cells indicates the development of a secondary immunodeficiency state during treatment with #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants.
It is recommended to determine DNA of Epstein-Barr virus (Epstein-Barr virus), cytomegalovirus (Cytomegalovirus), and herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) by PCR in peripheral blood (quantitative assay), saliva, and urine in all patients receiving #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS, presenting with clinical manifestations of herpesvirus infection / interstitial pneumonia to detect activeherpetic infection as an infectious complication developed during treatment with #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine class M and G antibodies (IgM, IgG) to cytomegalovirus (Cytomegalovirus) in the blood of all patients receiving #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS, presenting with clinical manifestations of herpesvirus infection to detect/rule out active cytomegalovirus infection as an infectious complication developed during treatment with #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine class M and G antibodies (IgM, IgG) to Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients receiving Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS, presenting with clinical manifestations of herpesvirus infection, to detect/rule out active Epstein-Barr virus infection as an infectious complication developed during treatment with #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients receiving Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS, presenting with clinical manifestations of herpesvirus infection, to detect/rule out active Epstein-Barr virus infection as an infectious complication developed during treatment with #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients receiving Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS, presenting with clinical manifestations of herpesvirus infection, to detect/rule out active Epstein-Barr virus infection as an infectious complication developed during treatment with #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine antibodies to Herpes simplex (Herpes simplex) in the blood of all patients receiving #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS, presenting with clinical manifestations of herpesvirus infection, to detect/rule out active herpetic infection as an infectious complication during treatment with #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to prescribe #acyclovir** (J05AB) at a dose of 200 mg per day orally in 5 doses (no more than 1000 mg/day) in children older than 2 years or at a dose of 5–10 mg/kg/administration intravenously every 8 hours in case of localized herpetic infection; #acyclovir** at a dose of 10 mg/kg/administration intravenously every 8 hours in children aged <1 year; at a dose of 500 mg/m² intravenously every 8 hours in children aged ≥1 year in case of Herpes zoster development, in accordance with clinical guidelines for the treatment of herpesvirus infections in children, including immunocompromised patients [179,187,197–200].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: #acyclovir** (J05AB) in children aged <3 years is prescribed for life-saving indications, by decision of the medical commission, after obtaining informed consent from the parents.
Administration of #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or injection/administration of immunosuppressants is discontinued during antiviral therapy. Previously prescribed oral GCS should be continued. Treatment with acyclovir** is carried out for 7–10 days until the complete disappearance of herpetic rashes.
It is recommended to prescribe #ganciclovir** (J05AB) at a dose of 6 mg/kg/administration intravenously every 12 hours in case of cytomegalovirus infection or #ganciclovir** (J05AB) at a dose of 10 mg/kg/administration intravenously every 12 hours in case of Epstein-Barr virus infection in accordance with clinical guidelines for the treatment of immunocompromised children [179,187,200–202].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: #ganciclovir** (J05AB) in children aged <12 years is prescribed for life-saving indications, by decision of the medical commission, after obtaining informed consent from the parents.
It is recommended to temporarily discontinue #Colchicum autumnale seed extract/colchicine and/or immunosuppressants, and/or biologic DMARDs in all patients upon the development of herpesvirus infection [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: administration of #Colchicum autumnale seed extract/colchicine and/or immunosuppressants, and/or biologic DMARDs is discontinued during antiviral therapy. Previously prescribed oral GCS should be continued.
It is recommended to resume therapy with #Colchicum autumnale seed extract/colchicine and/or immunosuppressants, and/or biologic DMARDs in all patients no earlier than 1 week after the complete resolution of clinical and laboratory signs of infection and the completion of antiviral therapy [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to screen for the presence/absence of tuberculosis (tuberculin skin test, recombinant tuberculosis allergen test in standard dilution, blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens, chest CT) in all patients receiving #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS, at least twice a year [103,104,112,203,204].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to discontinue #Colchicum autumnale seed extract/colchicine and/or immunosuppressants, and/or biologic DMARDs in all patients with a positive tuberculin skin test (papule >5 mm) and/or elevated interferon-gamma levels, and/or lung lesions, and/or intrathoracic lymphadenopathy [103,104,112,203,204].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: previously prescribed oral GCS therapy should be continued.
An initial examination (visit, consultation) by a phthisiatrician is recommended for all patients with a positive tuberculin skin test (papule >5 mm) and/or elevated interferon-gamma levels and/or lung lesions and/or intrathoracic lymph node involvement [103,104,112,203,204].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Oral GCS are recommended for all patients upon exacerbation of systemic connective tissue disease for the duration of specific anti-tuberculosis therapy [103,104].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the issue of resuming therapy with #Colchicum autumnale seed extract/colchicine and selecting biological agents and/or immunosuppressants is resolved after completion of specific chemotherapy and consultation with a phthisiatrician.
It is recommended to resume therapy with #Colchicum autumnale seed extract/colchicine and/or immunosuppressants, and/or biologic DMARDs in all patients after completion of specific antituberculosis therapy and consultation with a phthisiatrician [103,104].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the question of continuing biological therapy is decided on an individual basis.
It is recommended to determine antibodies to Salmonella enterica (Salmonella enterica) in the blood; determination of class M and G antibodies (IgM, IgG) to Yersinia pseudotuberculosis (Yersinia pseudotuberculosis) in the blood to detect intestinal bacterial infection developed during treatment with #Colchicum autumnale seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants combined (or not) with GCS [205].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to performetiotropic therapy if diagnostic titers of IgA and M antibodies, as well as high titers of IgG antibodies to Yersinia pseudotuberculosis, Yersinia enterocolitica serovars, and Salmonella enterica are detected in the blood of all patients receiving immunosuppressants and/or biological DMARDs combined with or without GCs, in accordance with the clinical guidelines for the diagnosis and treatment of intestinal infections in children [205].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: administration of #Colchicum autumnale seed extract/colchicine and/or administration of biological DMARDs, and/or injections/administration of immunosuppressants are discontinued for the entire period of antibiotic therapy. Previously prescribed oral GCs should be continued.
Treatment with #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or immunosuppressants is resumed no earlier than 1 week after the decrease in laboratory markers of infection and the completion of antibacterial therapy.
It is recommended to determine the antibodies of classes A, M, G (IgA, IgM, IgG) to Chlamydia psittaci in the blood; determine class M antibodies (IgM) to Chlamydia trachomatis in the blood; determine class G antibodies (IgG) to Chlamydia trachomatis in the blood; determine classes M, G antibodies (IgM, IgG) to Mycoplasma pneumoniae in the blood in all patients to detect mycoplasma and chlamydia infection that has developed during treatment with #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or immunosuppressants combined with or without GCs [30,42,71].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform etiotropic therapy if diagnostic titers of IgA and M antibodies, as well as high titers of IgG antibodies to Mycoplasma pneumoniae, Chlamydia trachomatis, C. psittaci are detected in the blood of all patients receiving #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or immunosuppressants combined with or without GCs, in accordance with the clinical guidelines for the diagnosis and treatment of mycoplasma and chlamydia infections in children [30,42,71].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: administration of #Colchicum autumnale seed extract/colchicine and/or administration of biological DMARDs, and/or injections/administration of immunosuppressants are discontinued for the entire period of antibiotic therapy. Previously prescribed oral GCs should be continued.
Treatment with #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or immunosuppressants is resumed no earlier than 1 week after the decrease in laboratory markers of infection and the completion of antibacterial therapy.
It is recommended to perform a microbiological (culture) examination of mucus from the tonsils and posterior pharyngeal wall in all patients to detect nasopharyngeal contamination by pathogenic or opportunistic microorganisms that has developed during treatment with #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or immunosuppressants combined with or without GCs [30,42,71].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: if nasopharyngeal contamination by pathogenic and/or opportunistic microorganisms is detected, an otorhinolaryngologist consultation is performed to address the issue of sanitation.
In the absence of clinical manifestations, therapy with #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or immunosuppressants is not discontinued.
In the presence of inflammatory changes in the nasopharynx, antibacterial therapy is performed. Administration of #Colchicum autumnale seed extract/colchicine and/or administration of biological DMARDs, and/or injections/administration of immunosuppressants are discontinued for the duration of antiviral therapy. Previously prescribed oral GCs should be continued. Treatment with #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or immunosuppressants is resumed no earlier than 1 week after the complete resolution of clinical and laboratory signs of infection and the completion of antiviral therapy.
It is recommended to perform a general (clinical) urinalysis, Nechyporenko urine test, and determination of albumin and total protein in daily urine [1,3–5,11,44,51,62].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: the presence of isolated microhematuria may be an adverse event of treatment with #Colchicum autumnale seed extract/colchicine and/or #methotrexate**.
If microhematuria develops, #Colchicum autumnale seed extract/colchicine and/or #methotrexate** are discontinued. Administration of biological DMARDs should be continued.
Treatment with #Colchicum autumnale seed extract/colchicine and/or #methotrexate** is resumed after the resolution of hematuria. The dose of #Colchicum autumnale seed extract/colchicine and/or #methotrexate** is reduced by half. In case of a recurrent episode of hematuria, #Colchicum autumnale seed extract/colchicine and/or #methotrexate** are discontinued and therapy is adjusted.
The presence of proteinuria >500 mg/day may indicate the development of secondary renal amyloidosis.
It is recommended to perform a set of studies on renal function and a set of studies for the diagnosis and assessment of the severity of renal failure in patients with clinical/laboratory signs of nephrotic syndrome and/or renal failure, and/or a disease duration of more than 5 years, and/or in the presence of proteinuria >500 mg per day in order to determine the severity of renal damage [1,2,5,11,27,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform a kidney biopsy with anesthetic support (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen in patients with clinical/laboratory/ultrasound signs of renal involvement and/or renal failure, and/or in the presence of proteinuria >500 mg per day in order to detect/exclude renal amyloidosis [66].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to perform an ECG to monitor the state of cardiac function [2,18–21].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: performed in all patients. In patients with FMF remission, pathological changes on ECG are not detected.
In case of overdose of #Colchicum autumnale seed extract/colchicine, a decrease in myocardial contractility and S-T segment elevation are possible.
It is recommended to perform Holter ECG monitoring to detect arrhythmias [206].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: performed in patients with arrhythmias and pathological changes on electrocardiography.
It is recommended to perform 24-hour ambulatory blood pressure monitoring in patients with arterial hypertension to detect deviations of blood pressure from the norm and develop a hypotensive therapy strategy [207].
GCR C LEL 4 Grade of Recommendation C (Level of Evidence – 4)
It is recommended to perform a comprehensive ultrasound of internal organs to detect/exclude pathological changes [1,2,4,5,30,31,33,34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: performed in all patients. Includes ultrasound of the abdominal organs and kidneys. The examination may reveal: minor hepatomegaly, biliary dyskinesia, reactive changes in the pancreas, thickening of the gallbladder wall, thickening of the stomach and intestinal walls. All changes may be associated with adverse drug reactions.
When amyloidosis develops, ultrasound signs of amyloid deposition in the kidneys are detected (large white kidney, depletion of renal blood flow, amyloid shrunken kidney).
It is recommended to perform Echocardiography in all patients to monitor cardiac function and detect myocardial, pericardial, and endocardial lesions [35,36].
GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)
Comments: performed in all patients. In patients with FMF remission, pathological changes on Echocardiography are not detected.
With a long-term course of the disease, the development of diastolic dysfunction and signs of pulmonary hypertension are possible.
It is recommended to perform EGD with gastric/duodenal biopsy using anesthetic support (including early postoperative management) according to indications with determination of Helicobacter pylori in all patients with dyspeptic symptoms, patients receiving NSAIDs and/or GCs, and/or immunosuppressants, and/or biological DMARDs, as well as to monitor the effectiveness of previously conducted therapy for inflammatory gastropathies [37–40,208,209].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: dyspeptic disorders (decreased appetite, diarrhea, nausea, vomiting, abdominal pain, malabsorption syndrome) may develop in case of overdose of #Colchicum autumnale seed extract/colchicine.
If dyspeptic disorders develop, a differential diagnosis with inflammatory gastropathies must be performed. #Colchicum autumnale seed extract/colchicine should be discontinued. Once inflammatory gastropathies are excluded, resume administration of #Colchicum autumnale seed extract/colchicine after dyspeptic symptoms resolve. Reduce the dose of #Colchicum autumnale seed extract/colchicine by half. In case of intolerance to #Colchicum autumnale seed extract/colchicine, address the issue of therapy adjustment.
It is recommended to prescribe medications for the treatment of gastric and duodenal ulcers and gastroesophageal reflux disease (A02B) when reflux disease and/or inflammatory gastropathy, erosive and/or ulcerative processes in the esophagus and/or stomach, and/or duodenum are detected according to EGD data in accordance with international guidelines [209].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: for the duration of anti-inflammatory therapy, the administration of #colchicine / autumn crocus extract seeds and/or the administration of biological DMARDs, and/or injections/administration of immunosuppressants are suspended; previously prescribed systemic glucocorticoids should be continued.
Resumption of treatment with #colchicine / autumn crocus extract seeds and/or biological DMARDs, and/or immunosuppressants is carried out after the end of anti-inflammatory therapy.
It is recommended to perform eradication therapy with the prescription of proton pump inhibitors (A02BC), systemic antibacterial drugs (J01), and bismuth tripotassium dicitrate** for inflammatory gastropathy, erosive and/or ulcerative processes in the stomach and/or duodenum associated with Helicobacter pylori, in accordance with clinical guidelines with the aim of eliminating H. pylori contamination of the gastric and/or duodenal mucosa to provide conditions for the healing of ulcers and other mucosal lesions [210].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: eradication therapy outside of age indications is prescribed by decision of the medical commission after obtaining informed consent from parents and children aged ≥15 years.
Temporary discontinuation of #colchicine / autumn crocus extract seeds and/or immunosuppressants, and/or biological DMARDs is recommended for all patients during eradication therapy [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the administration of previously prescribed systemic glucocorticoids should be continued. Resumption of treatment with #colchicine / autumn crocus extract seeds and/or immunosuppressants, and/or biological DMARDs is carried out after the end of eradication therapy.
It is recommended to perform colonoscopy with biopsy using anesthetic management (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen in patients with abdominal syndrome in order to detect/rule out complications of systemic juvenile idiopathic arthritis and concomitant bowel diseases [37,39,40].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: performed upon the appearance of intestinal symptoms atypical for systemic connective tissue diseases (prolonged diarrhea, abdominal pain, blood and pus admixture in stool) to rule out IBD, as well as in disease duration exceeding 5 years and/or in the presence of proteinuria >500 mg per day.
It is recommended to perform MRI of the affected joints in patients with chronic arthritis using anesthetic management (including early postoperative management) according to indications in order to monitor therapy efficacy [5,11,30,84,85].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to perform CT of the chest organs in all patients using anesthetic management (including early postoperative management) according to indications in order to rule out pneumonia and tuberculosis [85,86,112].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: when treated with biological DMARDs, especially in combination with immunosuppressants and systemic glucocorticoids, pneumonia may develop (interstitial, focal, lobar, multi-segmental).
Interstitial pneumonia develops during the use of #canakinumab**, tocilizumab**, rarely – during treatment with TNF-alpha inhibitors.
Interstitial pneumonia should be suspected upon the appearance of low-grade/high-grade fever, dry cough/cough with scant sputum/dyspnea, and crackles/decreased breath sounds on auscultation.
Focal or lobar pneumonia more often develops during the use of #tocilizumab**, TNF-alpha inhibitors, less often – #canakinumab**.
Pneumonia developing under treatment with #tocilizumab**, less often TNF-alpha inhibitors, is characterized by low-grade fever or its complete absence, a meager clinical picture, and no increase in acute-phase inflammation markers: ESR, blood leukocyte count, and serum CRP level.
Focal pneumonia should be suspected if dry/wet cough or throat clearing appears.
Infiltrative changes in the lungs may develop in case of overdose of #colchicine / autumn crocus extract seeds.
It is recommended to perform bronchoscopy under anesthesia (including early postoperative management) in all patients if interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest CT [85,86,103–107,112].
LoR CGoE 1Level of Recommendation C (Level of Evidence – 1)
It is recommended to perform microbiological (cultural) examination of bronchoalveolar lavage fluid for fungi (yeasts and molds) in all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia and decide on etiotropic therapy [103–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to perform microbiological (cultural) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms in all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia and decide on etiotropic therapy [103–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine antibodies to fungi of the genus Aspergillus (Aspergillus spp.) in the blood of all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia and decide on etiotropic therapy [106–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine mannan and galactomannan in lavage fluid and blood in all patients with signs of pneumonia according to chest CT data in order to identify the etiology of pneumonia and decide on etiotropic therapy [106–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR in all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia and decide on etiotropic therapy [106–111].
GCR BLoE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine cytomegalovirus (Cytomegalovirus) DNA in sputum and bronchoalveolar lavage fluid by PCR in all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia and decide on etiotropic therapy [105–111].
GCR BLoE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG) DNA with species differentiation in sputum and bronchoalveolar lavage fluid by PCR in all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia and decide on etiotropic therapy [103–111].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended to determine classes M and G antibodies (IgM, IgG) to cytomegalovirus (Cytomegalovirus) in the blood of all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine classes M and G antibodies (IgM, IgG) to Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine class G antibodies (IgG) to early proteins (EA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia and decide on etiotropic therapy [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to determine antibodies to herpes simplex virus (Herpes simplex) in the blood of all patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest CT data in order to identify the etiological factor of pneumonia and decide on etiotropic therapy [30,105].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended, prior to identifying the etiological factor of pneumonia, to prescribe empirical antibiotic therapy with #cotrimoxazole** (J01EE) in combination with systemic antibacterial drugs (J01) active against gram-positive, gram-negative, and anaerobic flora (penicillin combinations, including beta-lactamase inhibitor combinations (J01CR); 4th-generation cephalosporins (J01DE); carbapenems (J01DH), other antibacterial drugs (J01X)) combined with systemic antifungal drugs (J02A) in accordance with the recommendations for the treatment of pneumonia in immunocompromised children [179,211].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: systemic antibacterial drugs (J01) used off-label regarding age are prescribed by decision of the medical commission after obtaining informed consent from parents and children older than 15 years.
Administration of #Colchicum autumnale seed extract/colchicine and/or administration of biological disease-modifying antirheumatic drugs (bDMARDs), and/or injections/administration of immunosuppressants are discontinued during antibacterial therapy. Previously prescribed oral GCS should be continued. If signs of respiratory failure develop, the patient is transferred to the intensive care unit.
Treatment with #Colchicum autumnale seed extract/colchicine and/or bDMARDs, and/or immunosuppressants is resumed no earlier than 1 week after the complete resolution of pneumonia according to laboratory findings, follow-up chest CT with anesthetic support (including early postoperative management) as indicated, and completion of antibacterial therapy; prescription/adjustment of therapy is carried out after the resolution of clinical, radiological, and laboratory signs of interstitial pneumonia.
Temporary withdrawal of therapy with #Colchicum autumnale seed extract/colchicine and/or immunosuppressants, and/or bDMARDs is recommended for all patients with suspected/developed pneumonia [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: treatment with #Colchicum autumnale seed extract/colchicine and/or immunosuppressants, and/or bDMARDs is discontinued during antibacterial therapy. Previously prescribed oral GCS should be continued.
Resumption of therapy with #Colchicum autumnale seed extract/colchicine and/or immunosuppressants and/or bDMARDs is recommended for all patients no earlier than 1 week after the complete resolution of pneumonia according to laboratory findings, follow-up chest CT with anesthetic support (including early postoperative management) as indicated, and completion of antibacterial therapy [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: prescription/adjustment of therapy is carried out after the resolution of clinical, radiological, and laboratory signs of interstitial pneumonia.
In the event of Pneumocystis jirovecii pneumonia, it is recommended to prescribe intravenous GCS and #co-trimoxazole** (J01EE) at a dose of 3.75–5.0 mg/kg body weight/administration (15–20 mg/kg/day) (calculated as trimethoprim) intravenously every 6 hours in accordance with international guidelines for the management of immunocompromised children [179,187,212].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: #co-trimoxazole** (J01EE) for off-label age use is prescribed by decision of the medical commission after obtaining informed consent from the parents.
Administration of #Colchicum autumnale seed extract/colchicine and/or administration of biological disease-modifying antirheumatic drugs (bDMARDs), and/or injections/administration of immunosuppressants are discontinued during antibacterial therapy. Previously prescribed oral GCS should be continued. If signs of respiratory failure develop, the patient is transferred to the intensive care unit.
Treatment with #Colchicum autumnale seed extract/colchicine and/or bDMARDs, and/or immunosuppressants is resumed no earlier than 1 week after the complete resolution of pneumonia according to laboratory findings, follow-up chest CT with anesthetic support (including early postoperative management) as indicated, and completion of antibacterial therapy; prescription/adjustment of therapy is carried out after the resolution of clinical, radiological, and laboratory signs of interstitial pneumonia.
It is recommended to prescribe systemic antibacterial drugs (J01) active against gram-positive, gram-negative, and anaerobic flora (penicillin combinations, including beta-lactamase inhibitor combinations (J01CR); 4th generation cephalosporins (J01DE); carbapenems (J01DH), other antibacterial drugs (J01X)) in combination with systemic antifungal drugs (J02A) in the event of focal, lobar, or multislice (multisegmental) pneumonia in accordance with the clinical guidelines for the management of pneumonia in immunocompromised children [211].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: systemic antibacterial drugs (J01) for off-label age use are prescribed for vital indications, by decision of the medical commission, after obtaining informed consent from the parents and permission from the local ethics committee of the medical organization.
Administration of #Colchicum autumnale seed extract/colchicine and/or administration of bDMARDs, and/or injections/administration of immunosuppressants are discontinued during antibacterial therapy. Previously prescribed oral GCS should be continued. Treatment #with Colchicum autumnale seed extract/colchicine and/or bDMARDs, and/or immunosuppressants is resumed no earlier than 1 week after the complete resolution of pneumonia according to laboratory findings, follow-up chest CT with anesthetic support (including early postoperative management) and completion of antibacterial therapy.
X-ray/CT of joints with anesthetic support (including early postoperative management) as indicated is recommended for patients with active chronic arthritis to determine the degree of osteocartilaginous destruction [5,11,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: performed no more than once every 12 months.
X-ray densitometry is recommended for all patients receiving or having received GCS to detect osteopenia/osteoporosis in accordance with the clinical guidelines for the diagnosis and treatment of secondary osteoporosis in children [213,214].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Prescription of calcium preparations, vitamin D, and its analogues is recommended for patients with osteopenia/osteoporosis [213,214].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Prescription of bisphosphonates (M05BA) in combination with calcium preparations, vitamin D, and its analogues (A11CC) is recommended for patients with osteoporosis in accordance with the clinical guidelines for the diagnosis and treatment of secondary osteoporosis in children [201,213,214].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to prescribe #pamidronic acid to patients <1 year of age at a dose of 0.5 mg/kg IV every 2 months; to patients aged 1–2 years at a dose of 0.25–0.5 mg/kg/day IV for 3 days every 3 months; to patients aged 2–3 years at a dose of 0.375–0.75 mg/kg/day IV for 3 days every 3 months; to patients older than 3 years at a dose of 0.5–1 mg/kg/day IV for 3 days every 4 months (maximum dose 60 mg/administration), or #alendronic acid** at a dose of 1–2 mg/kg/week orally (for patients with body weight <40 kg at a dose of 5 mg/day or 35 mg/week; for patients with body weight >40 kg at a dose of 10 mg/day or 70 mg/week [maximum dose 70 mg/week]), or #zoledronic acid** at a dose of 0.0125–0.05 mg/kg/administration IV every 6–12 months (maximum dose 4 mg), or #ibandronic acid** at a dose of 3 mg/administration IV once every 3 months or at a dose of 150 mg orally once a month for the treatment of osteoporosis [201,213–216].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: bisphosphonates (M05BA) are prescribed for vital indications, by decision of the medical commission, after obtaining informed consent from parents and children aged ≥15 years.
Lumbar puncture with anesthetic support (including early postoperative management), microscopic examination, cell counting in a counting chamber (determination of CSF pleocytosis), examination of physical properties of the cerebrospinal fluid, and serological examination are recommended for all patients with symptoms of CNS involvement to exclude/confirm pathological changes [78,88].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: performed in patients with systemic-onset juvenile idiopathic arthritis with CNS manifestations (headaches, recurrent meningitis, or meningoencephalitis) who are receiving bDMARDs to monitor treatment tolerance and identify its complications.
Magnetic resonance imaging of the brain with anesthetic support (including early postoperative management) as indicated is recommended for patients with signs of CNS involvement at least once a year to assess the dynamics of changes [30,85].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Initial otorhinolaryngologist examination (inspection, consultation) is recommended for all patients to detect foci of chronic ENT infection and address the issue of their sanitation for the prevention of infectious complications during treatment with #Colchicum autumnale seed extract/colchicine and/or bDMARDs, and/or immunosuppressants in combination (or without) with GCS to assess the effectiveness of ENT organ sanitation in patients who have undergone it [1,3,5,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Initial pediatric dentist examination (inspection, consultation) is recommended for all patients receiving #Colchicum autumnale seed extract/colchicine and/or bDMARDs, and/or immunosuppressants in combination (or without) with GCS to determine the condition of the oral cavity, address the issue of its sanitation, or assess its effectiveness [30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in case of overdose of #Colchicum autumnale seed extract/colchicine, oral pain may develop. If this symptom appears, #Colchicum autumnale seed extract/colchicine must be discontinued.
Resume administration of #Colchicum autumnale seed extract/colchicine after pain relief. Reduce the dose of #Colchicum autumnale seed extract/colchicine by half. In case of a recurrent episode of oral pain, discontinue colchicine and address the issue of therapy adjustment.
Initial ophthalmologist examination (inspection, consultation) with mandatory biomicroscopy of the eye is recommended for all patients to detect pathological changes [2,3,5,11,30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in patients with uveitis and its complications, as well as complicated steroid cataract, the effectiveness of therapy is monitored and the issue of the need for surgical treatment is resolved.
It is recommended that patients with heart involvement and/or arterial hypertension undergo an initial appointment (examination, consultation) by a pediatric cardiologist to address the issue of cardiotropic and/or antihypertensive therapy [36].
GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)
It is recommended that all patients with positive results of a focal tuberculin skin test and/or elevated blood levels of interferon-gamma in response to Mycobacterium tuberculosis complex antigens and/or focal or infiltrative lung changes undergo an initial appointment (examination, consultation) by a phthisiologist to decide on chemoprophylaxis or anti-tuberculosis chemotherapy [112,203].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended that patients with endocrinological pathology undergo an initial appointment (examination, consultation) by a pediatric endocrinologist to monitor treatment efficacy [2,3,5,11,30,31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with underweight, amyotrophy, osteopenia/osteoporosis, constitutional obesity, Cushing's syndrome, and steroid diabetes undergo an initial appointment (examination, consultation) by a dietician to develop an individual dietary program and recommendations on eating behavior in outpatient settings [11,30,31,113,114].
GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)
It is recommended that patients with joint functional insufficiency, impaired longitudinal bone growth, subluxations, and back pain undergo an initial appointment (examination, consultation) by an orthopedic trauma surgeon to address the issue of reconstructive surgery and joint replacement [1,3,5,10,30,60].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended that patients with kidney involvement undergo an initial appointment (examination, consultation) by a nephrologist to decide on therapy [1,3–5,11,32,51].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended that patients with kidney involvement undergo a follow-up appointment (examination, consultation) by a nephrologist to assess the effectiveness of the therapy administered [1,3–5,11,32,51].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended that patients with neurological symptoms and psychotic reactions undergo an initial appointment (examination, consultation) by a neurologist to decide on therapy [1,3–5,10,11,32,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: treatment with autumn crocus seed extract/colchicine may lead to depression, peripheral neuritis, and neuropathy; overdosage may cause seizures, ascending paralysis, and respiratory depression.
If neurological symptoms develop and other causes are ruled out, autumn crocus seed extract/colchicine must be discontinued and the issue of adjusting the therapy should be addressed (see above).
It is recommended that patients with neurological symptoms and psychotic reactions undergo a follow-up appointment (examination, consultation) by a neurologist to assess the effectiveness of the therapy administered [1,3–5,10,11,32,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients aged 1 year and older and their parents (regardless of the child's age) undergo an initial appointment (testing, consultation) with a medical psychologist to harmonize the process of child personality development in the context of a severe chronic disease and optimize parent-child relationships; to increase treatment adherence and cooperation with the physician and medical staff to achieve disease remission; and to achieve psychological adaptation in society [95].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended that patients with functional insufficiency undergo an initial examination (consultation) by a physical therapy doctor to develop a program of physiotherapeutic procedures as part of a medical rehabilitation program [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients undergo a follow-up examination (consultation) by a physical therapy doctor after completing a program of physiotherapeutic procedures as part of the medical rehabilitation program to assess its effectiveness [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with functional insufficiency undergo an initial appointment (examination, consultation) by a physical therapy (exercise therapy) doctor to develop an exercise therapy complex as part of the medical rehabilitation program [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to conduct medical rehabilitation for all patients with functional insufficiency in order to restore functional capacity [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that all patients with functional impairment undergo a follow-up examination (consultation) by an exercise therapy physician after completion of the medical rehabilitation program to evaluate its efficacy [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to evaluate the effectiveness of pathogenetic therapy according to FMF50 and the Autoinflammatory Disease Activity Index (AIDAI) 3 months after the initiation/adjustment of therapy and every 6 months thereafter; disease severity according to the International Severity Scoring System for FMF (ISSF) — once every 6 months, and the damage index (ADDI) — once a year [133,165–167].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
For monitoring treatment efficacy, see Appendices G4–G8
5.3. Dispensary follow-up of patients with familial Mediterranean fever in outpatient and polyclinic settings
Dispensary follow-up of patients with FMF is recommended — an initial appointment (examination, consultation) by a rheumatologist with an assessment of the efficacy and safety of therapy at least once a year after the initiation/adjustment of therapy and after achieving disease remission [1,3–5,11,32,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Dispensary follow-up of patients with FMF is recommended — a follow-up appointment (examination, consultation) by a rheumatologist with an assessment of the efficacy and safety of therapy at least once a month after the initiation/adjustment of therapy and at least once every 3 months after achieving disease remission [1,3–5,11,32,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the rheumatologist examines the patient at least once a month, assesses their general condition, the presence of systemic manifestations, and the activity of articular syndrome; analyzes the efficacy and safety of pathogenetic therapy using standard questionnaires and scales (see Appendices G1–G5); analyzes the results of laboratory and instrumental examinations; conducts health education work with the patient and their parents (legal representatives), explaining the need for treatment adherence and psychological and medical rehabilitation; explains what adverse events may develop during treatment with autumn crocus seed extract/colchicine, biologic DMARDs, GCs, and immunosuppressants; how infections proceed under conditions of FMF pathogenetic therapy; what actions parents should take if infections and adverse events of antirheumatic drugs develop; and interacts with medical specialists as well as the rheumatologist of the inpatient rheumatology department, including remotely.
For monitoring treatment efficacy, see Appendices A3, G1–G11
It is recommended to immediately discontinue autumn crocus seed extract/colchicine and/or the administration of biologic DMARDs, and/or immunosuppressant injections/administration in the event of an allergic reaction [42,204].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: an allergic reaction can occur at any stage of treatment with autumn crocus seed extract/colchicine and/or biologic DMARDs, and/or an immunosuppressant.
If a severe allergic reaction develops, emergency hospitalization is indicated.
It is recommended to consult a inpatient rheumatologist (including remotely) who initiated the prescription of therapy in the event of an allergic reaction to autumn crocus seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants, in order to decide on the need for therapy correction and the setting in which it should be carried out [42,204].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Emergency hospitalization is recommended in the event of an allergic reaction to autumn crocus seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants in order to decide on the need for therapy correction [42,204].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to prescribe antihistamines and/or GCs in the event of an allergic reaction to autumn crocus seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants [204,217,218].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: the choice of drug and its route of administration depend on the severity of the allergic reaction.
It is recommended to perform a complete blood count (CBC) for all patients at least once every 2–4 weeks to monitor disease activity and side effects of pathogenetic drugs on the bone marrow [42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to halve the dose of autumn crocus seed extract/colchicine, discontinue biologic DMARD injections/infusions and/or #methotrexate** injections/administration or #sulfasalazine** intake (for 7 days) in all patients if the platelet count drops to ≤150 >100 × 109/l or the neutrophil count drops to <1.5 ≥1.0 × 109/l in the complete blood count, in order to control adverse events during therapy [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: previously prescribed oral glucocorticoids should be continued.
Repeat the complete blood count in a week.
It is recommended to discontinue autumn crocus seed extract/colchicine and/or the immunosuppressant and/or biologic DMARD in all patients if the absolute neutrophil count drops to <1.0 × 109/l and/or the platelet count drops to <100 × 109/l in the complete blood count, in order to control adverse events during therapy [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: previously prescribed oral glucocorticoids should be continued.
Repeat the complete blood count in a week.
It is recommended to resume therapy with #Colchicum autumnale seed extract/colchicine and/or an immunosuppressant and/or a biological DMARD at the same dose in all patients after complete recovery of complete blood count parameters in order to maintain remission of systemic autoinflammatory diseases [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: previously prescribed oral glucocorticoids should be continued.
Repeat the complete blood count in one week.
Consultation with a inpatient rheumatologist (including remote consultation) who initiated the therapy is recommended for all patients presenting with a repeated episode of decreased blood neutrophil and/or platelet count to determine the need for therapy adjustment and the setting in which it should be performed [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Administration of granulocyte colony-stimulating factor #filgrastim** (L03AA) at a dose of 5–10 mcg/kg/day subcutaneously is recommended for decreased white blood cell count with an absolute neutrophil count <1.0 × 10⁹/L for 3–5 days (longer if necessary) [42,190,191].
GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)
Comments: in children aged <1 year, filgrastim** (L03AA) is prescribed by decision of a medical commission after obtaining informed parental consent.
Neutropenia more frequently develops during treatment with #Colchicum autumnale seed extract/colchicine, #sulfasalazine**, #tocilizumab**, and less frequently with #methotrexate**, #canakinumab**, and TNF-alpha inhibitors.
Previously prescribed oral GCS therapy should be continued.
Administration of granulocyte colony-stimulating factor #filgrastim** (L03AA) at a dose of 5–10 mcg/kg/day subcutaneously in combination with broad-spectrum intravenous antibiotics (J01) is recommended in febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count ≤1.0 × 10⁹/L [42,190,191].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: in children aged <1 year, filgrastim** (L03AA) is prescribed by decision of a medical commission after obtaining informed parental consent.
Previously prescribed oral GCS therapy should be continued.
Resumption of therapy with #Colchicum autumnale seed extract/colchicine and/or an immunosuppressant and/or a biological DMARD is recommended for all patients after normalization of complete blood count parameters [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Consultation with an inpatient rheumatologist (including remote consultation) who initiated the therapy is recommended for all patients presenting with a repeated episode of decreased neutrophil count, development of febrile neutropenia, and/or decreased blood platelet count according to the complete blood count to determine the need for therapy adjustment and the setting in which it should be performed [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Routine general biochemical blood testing is recommended for all patients, determining the levels of total protein, albumin, total bilirubin, free (unconjugated) and conjugated bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, potassium, sodium, total calcium; activity of LDH, creatine kinase, AST, ALT, GGT, amylase, alkaline phosphatase, and serum iron at least once every 2–4 weeks to monitor disease activity, liver, kidney, and pancreatic function, and electrolyte balance during pathogenetic therapy [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: if serum ferritin levels are ≥684 ng/mL, along with elevated triglycerides, ALT, AST, and LDH activity in combination with bicytopenia, the development of hemophagocytic lymphohistiocytosis should be suspected and the child must be urgently referred for hospitalization in a rheumatology department.
Temporary discontinuation of therapy with #Colchicum autumnale seed extract/colchicine and/or an immunosuppressant and/or a biological DMARD is recommended for all patients if serum ALT or AST levels increase to ≥1.5 times the upper limit of normal and/or other biochemical parameters exceed the upper limit of normal [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: previously prescribed oral GCS therapy should be continued. Repeat routine blood biochemistry in one week.
Resumption of therapy with #Colchicum autumnale seed extract/colchicine and/or an immunosuppressant and/or a biological DMARD at the same dose is recommended for all patients after normalization of routine biochemical blood test parameters [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Consultation with an inpatient rheumatologist (including remote consultation) who initiated the therapy is recommended for all patients with recurrent episodes of elevated biochemical parameter(s) to determine the need for therapy adjustment and the setting in which it should be performed [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to be alert to the potential development of infectious diseases in patients with systemic autoinflammatory diseases receiving #Colchicum autumnale seed extract/colchicine combined with a biological DMARD and/or an immunosuppressant, with or without GCS [157].
GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)
Comments: Therapy with #Colchicum autumnale seed extract/colchicine, biological DMARDs, and immunosuppressants is discontinued. Previously prescribed oral GCS therapy should be continued. An in-person visit (examination, consultation) (including remote) with an inpatient rheumatologist is performed to determine further therapeutic tactics.
Temporary discontinuation of therapy with #Colchicum autumnale seed extract/colchicine and/or an immunosuppressant and/or a biological DMARD is recommended for all patients upon the appearance of signs of an infectious complication [30,42,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: previously prescribed oral GCS therapy should be continued.
Consultation with an inpatient rheumatologist (including remote consultation) who initiated the therapy is recommended for all patients upon the appearance of signs of an infectious complication to determine the need for therapy adjustment and the setting in which it should be performed [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Monitoring the efficacy of #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or immunosuppressants is recommended in order to timely address switching to an immunosuppressant and/or biological DMARD with a different mechanism of action to achieve disease remission, prevent complications, and reduce the progression of patient disability [42,190,191].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Evaluation of pathogenetic therapy efficacy is recommended using FMF50 and the Auto-Inflammatory Diseases Activity Index (AIDAI) at 3 months after initiation/adjustment of therapy, at 6 months, and every 6 months thereafter; disease severity using the International Severity Score for FMF (ISSF) for systemic autoinflammatory diseases – once every 6 months, and the damage index (ADDI) – once a year [165–167,219].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: the disease activity index (AIDAI) is determined for all patients to identify active disease periods (Appendix G5). All symptoms of the disease over the past month are assessed as "yes" or "no" (1/0) along with their severity (1 – minimal, 2 – moderate, 3 – severe). The presence of more than 9 active manifestations indicates active disease. The International Autoinflammatory Disease Severity Score is determined for all patients every 6 months to evaluate the efficacy of ongoing therapy (Appendix G6, G7). The disease is considered severe with a score >6, moderately severe with a score of 3–5, and mild with a score <2.
The damage index (ADDI) is evaluated in all patients at least once a year (Appendix G8).
Monitoring the efficacy of #Colchicum autumnale seed extract/colchicine and/or biological DMARDs and/or according to FMF50 (Appendix G4) is performed at 3 months after initiation/adjustment of therapy, at 6 months, and every 6 months thereafter.
Secondary inefficacy of #Colchicum autumnale seed extract/colchicine and/or biological DMARDs and/or immunosuppressants manifests as a "waning" of the effect, increasing disease activity, more frequent/severe attacks, appearance of new symptoms, and onset/progression of arthritis activity, and may develop at any stage of treatment. If secondary inefficacy develops, an urgent consultation with an inpatient rheumatologist (including remote) is conducted.
The decision regarding the need for therapy adjustment and the setting in which it should be performed is made by the inpatient rheumatologist who initiated the therapy based on the consultation results (including remote).
Vaccination of children is recommended only during a period of disease remission persisting for at least 6 months, according to an individualized schedule, excluding live vaccines [189].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Monitoring the tolerability of #Colchicum autumnale seed extract/colchicine and/or biological DMARDs and/or immunosuppressants is recommended for all patients to prevent severe toxic complications, enable timely drug discontinuation, and switch to an immunosuppressant and/or biological DMARD with a different mechanism of action [204].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: intolerance to #Colchicum autumnale seed extract/colchicine/biological DMARDs/immunosuppressants may develop at any stage of treatment. If intolerance develops, regardless of severity, colchicine and/or biological DMARDs, and/or immunosuppressants are discontinued. Previously prescribed oral GCS therapy should be continued.
It is recommended to consult a hospital rheumatologist (including remotely) who initiated the therapy for all patients who develop any signs of intolerance to #Autumn crocus seed extract/colchicine and/or an immunosuppressant, and/or bDMARDs to decide on the need for therapy adjustment and the setting in which it should be carried out [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Emergency hospitalization is recommended if pneumonia is suspected or develops [42,88].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: interstitial pneumonia may rarely develop during treatment with #Autumn crocus seed extract/colchicine, #canakinumab**, #tocilizumab**, and extremely rarely during treatment with TNF-alpha inhibitors.
Pneumonia should be suspected if the patient presents with low-grade/high-grade fever, dry/productive cough or throat clearing, and/or low-grade/high-grade fever unrelated to an exacerbation of the underlying disease, and/or shortness of breath/difficulty breathing, and/or crackles/decreased breath sounds upon auscultation.
If pneumonia is suspected or develops, administration of #Autumn crocus seed extract/colchicine, bDMARD infusions/injections, and immunosuppressant injections/administration should be discontinued. Previously prescribed oral GCS therapy should be continued.
The child is urgently hospitalized in the rheumatology department for diagnosis and treatment (see above).
The decision on the need to adjust therapy and the setting in which it should be carried out is made by the inpatient rheumatologist of the hospital that initiated the therapy prescription, based on the results of a consultation (including telemedicine).
It is recommended to prescribe #acyclovir** (J05AB) at a dose of 200 mg orally per day in 5 divided doses for children older than 2 years (maximum 1000 mg/day) in case of local herpes infection, in accordance with clinical guidelines for the treatment of herpesvirus infections in children, including immunocompromised patients [179,187,200].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in children aged <3 years, #acyclovir** (J05AB) is prescribed by decision of a medical commission, after obtaining informed consent from the parents.
Temporary discontinuation of therapy with #Autumn crocus seed extract/colchicine and/or an immunosuppressant, and/or bDMARDs is recommended for all patients who develop a herpes virus infection [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: administration of #Autumn crocus seed extract/colchicine and/or an immunosuppressant, and/or bDMARDs is discontinued for the duration of antiviral therapy. Previously prescribed oral GCS therapy should be continued.
Hospitalization is recommended for all patients with generalized herpetic infection/suspected cytomegalovirus/Epstein-Barr virus infection [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: a consultation with the hospital rheumatologist (including remotely) who initiated the therapy is performed to decide on the further management of the patient.
Resumption of therapy with #Autumn crocus seed extract/colchicine and/or an immunosuppressant, and/or bDMARDs is recommended for all patients no earlier than 1 week after the complete resolution of clinical and laboratory signs of infection and the completion of antiviral therapy [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Determination of antinuclear antibodies (ANA) and anti-dsDNA antibodies is recommended for all patients receiving TNF-alpha inhibitors at least once every 3 months to monitor therapy safety [30,42,192].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: serum levels of ANA and anti-dsDNA antibodies increase in patients receiving TNF-alpha inhibitors (most commonly adalimumab**) when an adverse event—a lupus-like reaction—develops.
Temporary discontinuation of TNF-alpha inhibitor therapy is recommended for all patients with elevated serum levels of ANA and anti-dsDNA antibodies [30,42,192].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: previously prescribed GCS therapy should be continued
It is recommended to consult a hospital rheumatologist (including remotely) who initiated the therapy for all patients with elevated serum levels of ANA and anti-dsDNA antibodies to decide on the need for therapy adjustment and the setting in which it should be carried out [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Determination of serum CRP levels is recommended at least once every 3 months to monitor disease activity [30,42,51,57–59].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Comments: serum CRP levels increase with the development of an infectious complication and/or exacerbation of the underlying disease. In this case, the child is urgently hospitalized in a rheumatology department for diagnosis and treatment.
Determination of blood immunoglobulin levels is recommended for all patients at least once every 3 months to detect immunodeficiency developing during treatment with #Autumn crocus seed extract/colchicine and/or an immunosuppressant, and/or bDMARDs [30,42,51,57–59].
GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)
Temporary discontinuation of therapy with #Autumn crocus seed extract/colchicine and/or an immunosuppressant, and/or bDMARDs is recommended for all patients with decreased blood immunoglobulin levels [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: previously prescribed GCS therapy should be continued
It is recommended to consult a hospital rheumatologist (including remotely) who initiated the therapy for all patients with decreased blood immunoglobulin levels to decide on the need for therapy adjustment and the setting in which it should be carried out [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Hospitalization is recommended for all patients with decreased blood immunoglobulin levels for replacement therapy with normal human immunoglobulin [30,42,193].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Administration of #normal human immunoglobulin** (J06BA) at a dose of 400 mg/kg is recommended, or 500 mg/kg if an adequate immunoglobulin level is not achieved, to correct blood immunoglobulin levels and prevent infectious complications [30,42,193].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Focal tuberculin skin testing (Mantoux test, recombinant tuberculosis allergen test in standard dilution) is recommended for all patients at least once every 6 months (more frequently if indicated) to rule out Mycobacterium tuberculosis infection during antirheumatic therapy [112,203,204].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
General clinical urinalysis is recommended for all patients at least once a month to monitor renal function [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: microhematuria and, rarely, macrohematuria develop as adverse events of #methotrexate** treatment. The appearance of proteinuria >500 mg/day may indicate the development of amyloidosis.
The decision on the need for therapy adjustment and the setting in which it should be carried out is made by the hospital rheumatologist who initiated the therapy, based on the results of the consultation (including teleconsultation).
Temporary discontinuation of methotrexate therapy is recommended for all patients who develop hematuria [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: previously prescribed GCS therapy should be continued.
It is recommended to consult a hospital rheumatologist (including remotely) who initiated the therapy for all patients who develop hematuria to decide on the need for therapy adjustment and the setting in which it should be carried out [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Electrocardiography (ECG) is recommended for all patients at least once every 3 months as part of routine follow-up to monitor the cardiovascular system [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Abdominal and renal ultrasound (comprehensive) is recommended for all patients at least once every 6 months as part of routine follow-up to monitor disease activity and adverse events of antirheumatic therapy [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Echocardiography (Echo-CG) is recommended for all patients at least once every 6 months as part of routine follow-up to monitor disease activity and adverse events of pathogenetic therapy [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial outpatient appointment (examination, consultation) with an otorhinolaryngologist is recommended for all patients within 2 weeks after hospital discharge to detect foci of chronic ENT infection and decide on their sanitization, as well as to diagnose acute ENT infections that developed during antirheumatic therapy [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A follow-up appointment (examination, consultation) with an otorhinolaryngologist is recommended for patients requiring sanitization of chronic infection foci and treatment of acute ENT infections to prevent infectious complications during antirheumatic therapy [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A routine dispensary appointment (examination, consultation) with an otorhinolaryngologist is recommended for all patients with juvenile systemic sclerosis at least once every 3 months as part of follow-up to monitor the condition of ENT organs, early detection of pathology, and its treatment to prevent infectious complications during antirheumatic therapy [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial appointment (examination, consultation) with a pediatric cardiologist is recommended within 2 weeks after hospital discharge for patients with cardiac dysfunction and/or arterial hypertension to develop an individual program of cardiotropic and/or antihypertensive therapy based on the recommendations of the hospital pediatric cardiologist [2,33–36,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An appointment (examination, consultation) with a pediatric cardiologist is recommended for patients with cardiac dysfunction and/or arterial hypertension to monitor treatment efficacy and adjust it if necessary [2,33–36,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A routine dispensary appointment (examination, consultation) with a pediatric cardiologist is recommended for patients with cardiac dysfunction and/or arterial hypertension to monitor the efficacy of the individual cardiotropic and/or antihypertensive therapy program based on the recommendations of the hospital pediatric cardiologist [2,33–36,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination, inspection) with a pediatric dentist is recommended for all patients with FMF within 1 month after discharge from the hospital to identify foci of chronic oral infection, resolve the issue of their sanitation, and diagnose acute oral infection that has developed under anti-rheumatic therapy [30,31,42].
Level CLevel 5Level of recommendation evidence C (level of data reliability – 5)
A follow-up consultation (examination, inspection) with a pediatric dentist is recommended for patients who require sanitation of foci of chronic infection and treatment of acute oral infection, with the aim of preventing infectious complications under anti-rheumatic therapy [30,31,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A dispensary consultation (examination, inspection) with a pediatric dentist is recommended for all patients with FMF at least once every 3 months as part of follow-up care to monitor the condition of the oral cavity, early detection of pathology, and its treatment to prevent the development of infectious complications under anti-rheumatic therapy [30,31,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination, inspection) with an ophthalmologist with mandatory eye biomicroscopy is recommended for all patients with FMF within 1 month after discharge from the hospital with identified visual impairment in order to develop an individual treatment program based on the recommendations of the inpatient ophthalmologist [1,5,10,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A follow-up consultation (examination, inspection) with an ophthalmologist with mandatory eye biomicroscopy is recommended for all patients with visual impairment based on individual indications to monitor treatment efficacy and correct it if necessary [1,5,10,30].
Level CLevel 5Level of recommendation evidence C (level of data reliability – 5)
A dispensary consultation (examination, inspection) with an ophthalmologist with mandatory eye biomicroscopy is recommended for all patients at least once every 6 months as part of follow-up care to monitor the condition of the visual system [1,5,10,30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with kidney involvement undergo an initial appointment (examination, consultation) by a nephrologist to decide on therapy [1,3–5,11,32,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients with kidney involvement undergo a follow-up appointment (examination, consultation) by a nephrologist to assess the effectiveness of the therapy administered [1,3–5,11,32,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A dispensary consultation (examination, inspection) with a nephrologist is recommended as part of follow-up care for patients with renal involvement at least once a month to assess the efficacy of ongoing therapy [1,3–5,11,32,51].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination, inspection) with a nutritionist is recommended within 2 weeks after hospital discharge for patients with underweight, amyotrophy, osteopenia/osteoporosis, constitutional obesity and Cushing's syndrome, steroid diabetes, amyloidosis/CKD to develop an individual dietary program [11,30,31,113,114].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
A follow-up consultation (examination, inspection) with a nutritionist is recommended for all patients with underweight, amyotrophy, osteopenia/osteoporosis, constitutional obesity and Cushing's syndrome, steroid diabetes, amyloidosis/CKD to monitor/correct the individual dietary program [11,30,31,113,114].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
An initial consultation (examination, inspection) with a phthisiotherapist is recommended for patients with positive results of a focal tuberculin skin test and/or focal, infiltrative changes in the lungs to address the issue of chemoprophylaxis or anti-tuberculosis chemotherapy [112,203].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
A follow-up consultation (examination, inspection) with a phthisiotherapist is recommended for all patients with positive results of a focal tuberculin skin test and/or focal, infiltrative changes in the lungs to monitor/correct chemotherapy/chemoprophylaxis [30,42,103,104,203].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
A consultation with the inpatient rheumatologist (including remote consultation) who initiated the therapy is recommended for all patients with a positive intradermal tuberculin test and/or focal, infiltrative changes in the lungs to decide on the need to adjust therapy and the conditions under which it should be administered [30,42,103,104,203].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination, inspection) with a pediatric endocrinologist is recommended within 2 weeks after hospital discharge for all patients with endocrine pathology to prescribe an individual program recommended by the inpatient pediatric endocrinologist [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A dispensary consultation (examination, inspection) with a pediatric endocrinologist is recommended for all patients with endocrine pathology to monitor/correct the individual program recommended by the inpatient pediatric endocrinologist [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination, inspection) with an orthopedic traumatologist is recommended within 2 weeks after hospital discharge for patients with joint functional insufficiency, impaired longitudinal bone growth, subluxations, back pain after hospital discharge to address the need for orthopedic correction [1,3,5,10,30,60,89].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
A follow-up consultation (examination, inspection) with an orthopedic traumatologist is recommended to monitor the efficacy of/correct the orthopedic treatment [1,3,5,10,30,60,89].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
A dispensary consultation (examination, inspection) with an orthopedic traumatologist is recommended for all patients with functional insufficiency at least once every 3 months as part of follow-up care to detect functional disorders and monitor orthopedic correction [1,3,5,10,30,60,89].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
An initial session (testing, consultation) with a medical psychologist is recommended within 2 weeks after hospital discharge for all patients older than 1 year and all parents (regardless of the child's age) to develop a psychological rehabilitation program for the patient and their parents [95].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
A follow-up session (testing, consultation) with a medical psychologist is recommended for all patients older than 1 year and all parents (regardless of the child's age) after completion of the psychological rehabilitation program to assess its efficacy [95].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
A dispensary session (testing, consultation) with a medical psychologist is recommended for all patients older than 1 year and all parents (regardless of the child's age) at least once every 3 months as part of follow-up care for testing the psychological state of patients and their parents [95].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
An initial consultation (examination, inspection) with a physical therapy doctor is recommended within 2 weeks after hospital discharge for patients with impaired joint function to develop a program of physiotherapeutic procedures as part of the medical rehabilitation program [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
An initial consultation (examination, inspection) with an exercise therapy doctor is recommended within 2 weeks after hospital discharge for all patients with functional insufficiency to develop a medical rehabilitation program based on the recommendations of the inpatient exercise therapy doctor [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Implementation of a medical rehabilitation program is recommended for all patients with functional insufficiency [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A follow-up consultation (examination, inspection) with a physical therapy doctor is recommended for all patients with functional insufficiency to monitor the efficacy of the medical rehabilitation program [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A follow-up consultation (examination, inspection) with an exercise therapy doctor is recommended for all patients with functional insufficiency to monitor the efficacy of the medical rehabilitation program [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
A dispensary consultation (examination, inspection) with an exercise therapy doctor is recommended for all patients with functional insufficiency to monitor the efficacy of/correct the medical rehabilitation program [115,116].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: carried out at least once every 3 months as part of follow-up care.
Planned hospitalization in the rheumatology department of the hospital that initiated the prescription of #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or an immunosuppressant is recommended for all patients to monitor the efficacy and safety of therapy [30,42].
Comments: planned efficacy monitoring is performed 3 and 6 months after the initiation of therapy and further every 6 months to monitor the efficacy and safety of pathogenetic therapy.
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Unplanned hospitalization in the rheumatology department of the hospital that initiated the prescription of #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or an immunosuppressant is recommended for examination and therapy adjustment at any stage of treatment in the event of exacerbation/complications of FMF, comorbidities, complications/side effects/persistent intolerance to #Colchicum autumnale seed extract/colchicine and/or biological DMARDs, and/or an immunosuppressant [30,42].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
5.4. Oncological vigilance in patients with familial Mediterranean fever receiving biological DMARDs/immunosuppressants
Considering that oncological/oncohematological/lymphoproliferative diseases are among the adverse effects of biological DMARD therapy, it is necessary to maintain oncological vigilance at any stage of examination/treatment (in-hospital and during follow-up care).
If an oncological, oncohematological, or lymphoproliferative disease is suspected, #Autumn_crocus_seed_extract/colchicine and/or immunosuppressants/bDMARDs should be discontinued immediately, and the patient must be hospitalized for appropriate diagnostic workup.
It is recommended to obtain a bone marrow cytological preparation with anesthesia (including early postoperative management) via aspiration, as well as a bone marrow histological preparation with cytological examination of the bone marrow smear (myelogram) and pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods, in patients receiving #Autumn_crocus_ seed_extract/colchicine and/or immunosuppressants, and/or bDMARDs who present with an atypical disease course, in order to rule out oncological, oncohematological, or lymphoproliferative diseases or metastatic bone marrow involvement [91].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to perform a lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) with anesthesia (including early postoperative management), along with cytological examination of the lymph node tissue preparation and pathomorphological examination of the lymph node biopsy (surgical) material, in patients with marked enlargement of peripheral, intrathoracic, and/or intra-abdominal lymph nodes receiving #Autumn_crocus_seed_extract/colchicine and/or immunosuppressants, and/or bDMARDs with an atypical disease course, in order to rule out oncological, oncohematological, or lymphoproliferative diseases or metastatic lymph node involvement [91].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to perform contrast-enhanced MRI of the brain, abdominal cavity, retroperitoneal space, and pelvis with anesthesia (including early postoperative management) as indicated, in patients receiving #Autumn_crocus_seed_extract/colchicine and/or immunosuppressants, and/or bDMARDs with an atypical disease course, in order to rule out oncological, oncohematological, or lymphoproliferative diseases [91].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to perform contrast-enhanced chest CT with anesthesia (including early postoperative management) as indicated, in patients receiving #Autumn_crocus_seed_extract/colchicine and/or immunosuppressants, and/or bDMARDs with an atypical disease course, in order to rule out pulmonary metastases or mediastinal involvement in oncological, oncohematological, or lymphoproliferative diseases [91].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to perform contrast-enhanced MRI of bone tissue and joints with anesthesia (including early postoperative management) as indicated, in patients receiving #Autumn_crocus_seed_extract/colchicine and/or immunosuppressants, and/or bDMARDs with an atypical disease course, in order to rule out oncological or oncohematological diseases [91].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to perform contrast-enhanced CT of bones and affected joints with anesthesia (including early postoperative management) as indicated, in patients receiving #Autumn_crocus_seed_extract/colchicine and/or immunosuppressants, and/or bDMARDs who have bone destruction foci atypical for FMF, in order to rule out oncological or oncohematological diseases [91].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to perform PET-CT with tumor-tropic radiopharmaceuticals with contrast enhancement, or whole-body PET with tumor-tropic radiopharmaceuticals using anesthesia (including early postoperative management) as indicated, in patients receiving #Autumn_crocus_seed_extract/colchicine and/or immunosuppressants, and/or bDMARDs who present with severe arthralgia, myalgia, ossalgia, bone destruction lesions, subcutaneous adipose tissue infiltrates, or lesions in parenchymal organs, the brain, or spinal cord, in order to rule out oncological, oncohematological, or lymphoproliferative diseases [90].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
It is recommended to perform multi-position bone scintigraphy with anesthesia (including early postoperative management) as indicated, in patients receiving #Autumn_crocus_seed_extract/colchicine and/or immunosuppressants, and/or bDMARDs who have bone destruction foci atypical for FMF, in order to rule out malignancies or metastatic bone lesions [60].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform CT-guided pelvic bone trephine biopsy with anesthesia (including early postoperative management), including pathomorphological examination of the bone marrow biopsy (surgical) material using immunohistochemical methods; cytological examination of bone marrow trephine biopsy imprints; immunocytochemical examination of bone marrow trephine biopsy imprints; and immunophenotyping of hematopoietic progenitor cells in the bone marrow, in patients receiving #Autumn_crocus_seed_extract/colchicine and/or immunosuppressants, and/or bDMARDs with an atypical disease course, in order to rule out hemoblastoses, lymphoproliferative diseases, or metastatic bone marrow involvement [90–92,220].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform a bone biopsy with anesthesia (including early postoperative management) and pathomorphological examination of the bone biopsy (surgical) material in patients receiving #Autumn_crocus_seed_extract/colchicine and/or immunosuppressants, and/or bDMARDs who have bone destruction foci atypical for FMF, in order to rule out malignancies or metastatic bone lesions [90–92,220].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended that patients in whom diagnostic findings suggest or reveal an oncological, oncohematological, or lymphoproliferative disease, or metastatic involvement, undergo an initial consultation and examination by a pediatric oncologist to determine the need for transferring the child to a specialized institution for further workup and treatment [91].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
6. Organization of Medical Care
6.1. Indications for hospital admission and discharge of patients.
Suspicion of familial Mediterranean fever.
Diagnosis, including differential diagnosis, and administration of pathogenetic therapy for all patients are carried out in an inpatient rheumatology department.
Indications for discharge
Completion of diagnostic workup; establishing the diagnosis of FMF.
Initiation of pathogenetic therapy.
Absence of side effects or intolerance.
Stabilization of the condition during drug therapy: relief of fever and other systemic manifestations, reduction in the activity of joint syndrome.
Pronounced trend toward normalization / normalization of laboratory markers of activity.
Established diagnosis of familial Mediterranean fever, active stage.
Examination and adjustment of therapy in case of its ineffectiveness are performed for all patients in an inpatient rheumatology department.
Indications for discharge
Completion of examination.
Adjustment of therapy.
Absence of adverse effects or drug intolerance. Stabilization of the condition under pharmacological therapy: resolution of fever, other systemic manifestations, and decrease in joint syndrome activity.
Pronounced trend toward normalization / normalization of laboratory markers of activity.
Established diagnosis of familial Mediterranean fever with active hemophagocytic syndrome.
Diagnostics, including differential diagnostics, and prescription of therapy for all patients are performed in an inpatient rheumatology department.
Indications for discharge
Established diagnosis of familial Mediterranean fever. Completion of diagnostic workup.
Prescription of therapy.
Absence of side effects or drug intolerance.
Stabilization of the condition during drug therapy: relief of fever and other systemic manifestations, reduction in the activity of joint syndrome.
Relief of clinical and laboratory signs of hemophagocytic syndrome.
Pronounced trend toward normalization / normalization of laboratory markers of FMF activity.
Examination and adjustment of therapy upon the development of complications/intolerance to drug treatment are performed in an inpatient rheumatology department.
Indications for discharge
Completion of examination.
Relief of side effects.
Adjustment of therapy.
Absence of side effects or drug intolerance.
Absence of signs of disease activity.
Established diagnosis of familial Mediterranean fever in remission stage.
Monitoring of the efficacy and safety of pathogenetic therapy is carried out in an inpatient rheumatology department 3 months after therapy initiation, 6 months after therapy initiation, and subsequently every 6–12 months.
Indications for discharge
Absence of FMF attacks for 3–6 months or longer.
Remission of joint syndrome for 3–6 months or longer.
Absence of adverse events or drug intolerance.
A patient with an established diagnosis of FMF who develops a disease exacerbation, complications, comorbidities, or complications/adverse effects/persistent intolerance to #Autumn_crocus_seed_extract/colchicine and/or bDMARDs, and/or immunosuppressants must be urgently hospitalized in the inpatient rheumatology department that initiated pathogenetic therapy, for evaluation and treatment adjustment at any stage of care.
6.2. Regulatory and legal documents governing the provision of medical care to children with familial Mediterranean fever.
Order of the Ministry of Health of the Russian Federation No. 700n dated October 7, 2015, "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education" (registered with the Ministry of Justice of the Russian Federation on November 12, 2015, No. 39696). Order of the Ministry of Health of the Russian Federation No. 707n dated October 8, 2015, "On Approval of Qualification Requirements for Medical and Pharmaceutical Personnel with Higher Education in the Field of Study 'Healthcare and Medical Sciences'." Registered with the Ministry of Justice of the Russian Federation on October 23, 2015, Registration No. 39438.
Order of the Ministry of Health of the Russian Federation No. 441n dated October 25, 2012, “On approval of the Procedure for Providing Medical Care to Children with Rheumatology Profiles” (as amended on February 21, 2020).
Order of the Ministry of Health of the Russian Federation No. 917n dated November 15, 2012, "On approval of the Procedure for providing medical care to patients with congenital and (or) hereditary diseases." Registered with the Ministry of Justice of the Russian Federation on December 21, 2012. Registration No. 26301.
Order of the Ministry of Health of the Russian Federation No. 878n dated October 23, 2019, "On approval of the Procedure for organizing medical rehabilitation for children," registered with the Ministry of Justice of the Russian Federation on December 23, 2019, registration No. 56954.
Government Decree No. 403 dated April 26, 2012, "On the procedure for maintaining the federal register of persons suffering from life-threatening and chronic progressive rare (orphan) diseases leading to a reduction in the life expectancy of citizens or their disability, and its regional segment."
Order of the Ministry of Health of the Russian Federation No. 231n dated March 19, 2021 (registered with the Ministry of Justice of the Russian Federation on July 29, 2021, No. 64445) "On approval of the Procedure for monitoring the volume, timing, quality, and conditions of providing medical care under compulsory medical insurance to insured persons, as well as its financial provision."
Order of the Ministry of Health of the Russian Federation No. 108n dated February 28, 2019 (as amended on September 3, 2021) "On approval of the Rules of Compulsory Medical Insurance" (Registered with the Ministry of Justice of the Russian Federation on May 17, 2019, No. 54643).
Order of the Ministry of Health of the Russian Federation No. 696n dated July 1, 2021, "On amendments to the Rules of Compulsory Medical Insurance approved by Order of the Ministry of Health of the Russian Federation No. 108n of February 28, 2019."
Amendment 14.1 to Article 37. Organization of Medical Care of Federal Law No. 323-FZ of November 21, 2011 (as amended on June 11, 2022, with amendments of July 13, 2022) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" (with amendments and additions, effective June 29, 2022): "It is permitted to include in standards of medical care for children and clinical guidelines a medicinal product registered in the territory of the Russian Federation used in accordance with indications (characteristics) of the medicinal product not specified in its instructions for use, provided that such medicinal product complies with the requirements established by the Government of the Russian Federation. The list of diseases or conditions (groups of diseases or conditions) for which the use of a medicinal product in accordance with the indications (characteristics) of the medicinal product not specified in its instructions for use is permitted shall be established by the Government of the Russian Federation."
Order of the Government of the Russian Federation No. 1180-r dated May 16, 2022 "List of diseases or conditions (groups of diseases or conditions) in which the use of a medicinal product is permitted in accordance with the indications (characteristics) of the medicinal product not specified in the instructions for its use."
7. Additional Information
It is recommended to refer children to the ITU bureau (Bureau of Medical and Social Expertise) to obtain the status of "disabled child" [42].
The diagnosis when referring to the MSE is established in accordance with the recommendations (see section 1.5).
The assignment of the "disabled child" status to children is carried out in accordance with the following regulatory legal documents:
Decree of the Government of the Russian Federation No. 95 dated February 20, 2016 "On the procedure and conditions for recognizing a person as disabled" (as amended by Decrees of the Government of the Russian Federation dated 07.04.2008 No. 247, dated 30.12.2009 No. 1121, dated 06.02.2012 No. 89, dated 16.04.2012 No. 318, dated 04.09.2012 No. 882, dated 06.08.2015 No. 805, dated 10.08.2016 No. 772, dated 24.01.2018 No. 60, dated 29.03.2018 No. 339, dated 21.06.2018 No. 709, dated 22.03.2019 No. 304, dated 16.05.2019 No. 607, dated 04.06.2019 No. 715, dated 27.06.2019 No. 823, dated 14.11.2019 No. 1454).
Order of the Ministry of Labor and Social Protection of the RF No. 585n dated August 27, 2019 "On Classifications and Criteria Used in Carrying Out Medical and Social Expertise of Citizens by Federal State Institutions of Medical and Social Expertise"
In accordance with subparagraph 5.2.105 of the Regulations on the Ministry of Labor and Social Protection of the Russian Federation, approved by Decree of the Government of the Russian Federation No. 610 of June 19, 2012 (Collected Legislation of the Russian Federation, 2012, No. 26, art. 3528; 2013, No. 22, art. 2809; No. 36, art. 4578; No. 37, art. 4703; No. 45, art. 5822; No. 46, art. 5952; 2014, No. 21, art. 2710; No. 26, art. 3577; No. 29, art. 4160; No. 32, art. 4499; No. 36, art. 4868; 2015, No. 2, art. 491; No. 6, art. 963; No. 16, art. 2384; 2016, No. 2, art. 325; No. 4, art. 534; No. 23, art. 3322; No. 28, art. 4741; No. 29, art. 4812; No. 43, art. 6038; No. 47, art. 6659; 2017, No. 1, art. 187; No. 7, art. 1093; No. 17, art. 2581; No. 22, art. 3149; No. 28, art. 4167; 2018, No. 10, art. 1494; No. 24, art. 3530; No. 36, art. 5634; No. 46, art. 7052; No. 49, art. 7600; No. 53, art. 8678; 2019, No. 1, art. 31; No. 5, art. 408; No. 21, art. 2563)
Appendix No. 2 to the classifications and criteria used in the implementation of medical and social expertise by federal state institutions of medical and social expertise, approved by Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019.
Quantitative system for assessing the severity of persistent impairments of bodily functions in children under 18 years of age caused by diseases, consequences of injuries, or defects (in percentages, in relation to the clinical and functional characteristics of persistent impairments of human body functions).
If the "disabled child" status is granted, the child and their parents will be entitled to a number of social services; preferential travel; benefits for medical devices, instruments, and medications; benefits for admission to secondary and higher educational institutions; free travel for the child and an accompanying adult to the place of treatment (sanatorium, resort) and back; an annual sanatorium-treatment voucher for the child and the accompanying adult.
In the case of untimely provision of pathogenetic drugs to a child with FMF, there is a high probability of developing an exacerbation/increase in disease activity, the development of amyloidosis, renal failure, progression of joint damage, and functional impairment of the patient.
Decree of the President of the Russian Federation No. 16 of January 5, 2021, on the establishment of the Circle of Добро (Circle of Kindness) Foundation for Support of Children with Severe Life-Threatening and Chronic Diseases, Including Rare (Orphan) Diseases.
7.1 Outcomes and prognosis
The prognosis of the disease is serious in patients with an untimely diagnosis, without colchicine therapy in adequate doses, and in the absence of compliance.
The risk of developing amyloidosis (most often renal) is 25–70% (depending on the population), which leads to chronic renal failure and death of the patient.
The risk of amyloidosis is maximal in patients presenting with arthritis, homozygosity for the p.M694V mutation, and the α/α genotype of the SAA1 gene. With timely diagnosis and simultaneous prescription of #Colchicum autumnale seed extract/colchicine in an adequate dose with its subsequent adjustment, the risk of amyloidosis is <1%.
Goals of therapy: control of inflammation—suppression of FMF attacks with normalization of inflammatory markers and absence of progression of organ damage. Against the background of therapy with #Colchicum autumnale seed extract/colchicine, cessation of FMF attacks is achieved in 90–95% of patients. About 5–10% of children do not tolerate therapy with #Colchicum autumnale seed extract/colchicine. In the treatment of such patients, the use of the interleukin-1β (IL-1β) inhibitor #canakinumab** or the interleukin-1 (IL-1β and α) inhibitor anakinra** is effective. Patients prescribed #canakinumab** or anakinra** must receive colchicine at the maximum tolerated dose.
The second most frequent complication of FMF is adhesive disease with the development of adhesive intestinal obstruction. The risk of adhesive disease is associated with a severe course of the disease, homozygosity for the p.M694V mutation, late diagnosis and delay in prescribing #Colchicum autumnale seed extract/colchicine, and unjustified abdominal surgical interventions.
The incidence of adhesive disease in the Armenian pediatric population is 3%.
Criteria for Evaluating the Quality of Medical Care
Organizational and technical conditions for the provision of medical care.
Type of medical care | Primary specialized health care / Specialized medical care |
|---|---|
Conditions of medical care | Outpatient / Inpatient / Day hospital |
Form of medical care | Elective |
Table 1. Criteria for assessing the quality of primary diagnostics for establishing the diagnosis of familial Mediterranean fever
№ | Quality criteria | Level of evidence |
|---|---|---|
1 | A complete blood count (differential) was performed | C |
2 | General clinical blood chemistry analysis performed with determination of total protein, albumin, total bilirubin, free (unconjugated) and conjugated bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, potassium, sodium, total calcium in blood; activity of LDH, creatine kinase, AST, ALT, GGT, amylase, blood ALP, serum iron | C |
3 | Coagulogram performed (exploratory study of the hemostasis system with determination of prothrombin index, antithrombin III activity; plasminogen and fibrinogen level, D-dimer concentration, level of soluble fibrin monomer complexes in blood, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time in blood, von Willebrand factor) | C |
4 | Determination of blood immunoglobulins, antibodies to cell nucleus antigens and DNA in blood serum; RF, antibodies to neutrophil cytoplasm (ANCA), anticentromere antibodies in blood, antibodies to RNA, antibodies to cyclic citrullinated peptide (anti-CCP) in blood; antibodies to Sm antigen; to SLc70, level of C3, C4 complement fractions in blood | C |
5 | Determination of antistreptolysin-O level in blood serum | C |
6 | Determination of blood serum CRP level | C |
7 | Determination of HLA antigens (HLA-B27 antigen) | C |
8 | General (clinical) urine analysis, Nechiporenko urine test, Nechiporenko urine test, determination of albumin and protein amount in 24-hour urine | C |
9 | A set of kidney function tests was performed in patients with clinical/laboratory signs of kidney damage | C |
10 | A set of tests for the diagnosis and severity assessment of renal failure was performed in patients with clinical/laboratory signs of nephrotic syndrome/renal failure | C |
11 | Molecular genetic testing was performed – a panel of tests for the diagnosis of cryopyrin-associated periodic syndromes | C |
12 | Blood procalcitonin level testing | C |
13 | Peripheral blood immunophenotyping was performed to determine the lymphocyte subpopulations (major) | C |
14 | A focal tuberculin skin test (Mantoux test, recombinant tuberculosis allergen test at standard dilution) and blood interferon-gamma assay for Mycobacterium tuberculosis complex antigens were performed | C |
15 | Determination of antibodies to Salmonella enterica in blood; determination of IgM, IgG classes antibodies to Yersinia pseudotuberculosis in blood were performed | C |
16 | Determination of antibodies to Mycoplasma pneumoniae, Chlamydia trachomatis, and Chlamydia psittaci in blood was performed | C |
17 | Quantitative PCR determination of Epstein-Barr virus (Epstein-Barr virus), cytomegalovirus (Cytomegalovirus), and herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in peripheral blood, saliva, and urine was performed | C |
18 | Molecular biological blood testing for Toxoplasma gondii was performed in patients with a history of animal contact | C |
19 | Determination of antibodies to Leishmania in blood was performed in patients | C |
20 | Microbiological (culture) examination of tonsillar and posterior pharyngeal wall mucus for aerobic and facultatively anaerobic microorganisms performed | C |
21 | Microbiological (culture) blood and urine tests for sterility were performed | C |
22 | A set of tests for the diagnosis of acute hepatic porphyria was performed in patients who present during an attack with urine colored pink to dark brown, or which darkens subsequently upon exposure to daylight or simply over time | C |
23 | A set of tests was performed in patients with urticarial rashes for the diagnosis of hereditary angioedema (complement system defects) | C |
24 | Fecal calprotectin level testing was performed | C |
25 | Echocardiography was performed | C |
26 | ECG recording was performed | C |
27 | Ultrasound of affected joints was performed | C |
28 | Comprehensive ultrasound of internal organs was performed | C |
29 | Plain abdominal radiography was performed in all patients with abdominal syndrome to rule out intestinal obstruction and perforation of a hollow abdominal viscus | C |
30 | CT of affected joints with anesthetic care (including early postoperative management) was performed as indicated | C |
31 | MRI with intravenous contrast of affected joints with anesthetic care (including early postoperative management) was performed as indicated | C |
32 | EGD with biopsy of the esophagus, stomach, duodenum, and jejunum with anesthetic care (including early postoperative management), determination of Helicobacter pylori, and pathomorphological examination of the biopsy (surgical) specimen of the esophagus, stomach, duodenum, and small intestine was performed | C |
33 | Colonoscopy with biopsy using anesthetic care (including early postoperative management) and pathomorphological examination of the large intestine biopsy (surgical) specimen was performed | C |
34 | Video capsule endoscopy of the small intestine was performed in patients with clinical signs of IBD and/or significantly elevated fecal calprotectin in the absence of findings on EGD and colonoscopy | C |
35 | Chest CT with anesthetic care (including early postoperative management) was performed as indicated | C |
36 | MRI of the brain, abdominal organs, retroperitoneum, and pelvis with intravenous contrast and anesthetic care (including early postoperative management) was performed as indicated | C |
37 | Lumbar puncture with anesthetic care (including early postoperative management), microscopic examination, cell counting in a counting chamber (cytosis determination), physical properties of cerebrospinal fluid, and serological examination was performed in all patients with CNS symptoms | C |
38 | Kidney biopsy with anesthetic care (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen was performed in patients with clinical/laboratory/ultrasound signs of kidney damage and/or renal failure, and/or in the presence of proteinuria >500 mg/day | C |
39 | Lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) with anesthetic care (including early postoperative management), cytological examination of the lymph node tissue preparation, and pathomorphological examination of the biopsy (surgical) material was performed in all patients with marked enlargement of peripheral, intrathoracic, and/or intra-abdominal lymph nodes | C |
40 | PET-CT combined with tumor-tropic radiopharmaceuticals with contrast, and whole-body PET with tumor-tropic radiopharmaceuticals if necessary, was performed with anesthetic care (including early postoperative management) as indicated in patients with severe arthralgia, myalgia, ossalgia, bone destruction, subcutaneous fat infiltrates, and lesions in parenchymal organs, the brain, or the spinal cord | C |
41 | Multi-position bone scintigraphy with anesthetic care was performed as indicated in patients with bone destruction lesions atypical for systemic connective tissue diseases | C |
42 | Bone marrow aspiration (cytological preparation) and bone marrow trephine biopsy (histological preparation) with anesthetic care (including early postoperative management), cytological examination of the bone marrow smear (myelogram), and immunohistochemical pathomorphological examination of the bone marrow biopsy (surgical) material were performed | C |
43 | Pelvic bone trephine biopsy with anesthetic care (including early postoperative management), immunohistochemical pathomorphological examination of the bone marrow biopsy (surgical) material, cytological examination of trephine biopsy imprints, immunocytochemical examination of trephine biopsy imprints, and hematopoietic progenitor cell immunophenotyping in the bone marrow was performed in patients with an atypical course of systemic connective tissue diseases | C |
44 | Bone biopsy with anesthetic care (including early postoperative management) and pathomorphological examination of the bone biopsy (surgical) material was performed in patients with space-occupying and destructive lesions, as well as bone deformations atypical for systemic connective tissue diseases | C |
45 | Initial consultation (examination) by a pediatric oncologist was performed in patients with suspected oncological or oncohematological diseases based on examination results | C |
46 | Initial consultation (examination) by a pediatric surgeon was performed in all patients with abdominal and thoracic symptoms | C |
47 | Initial consultation (examination) by a gastroenterologist was performed in all patients with abdominal symptoms | C |
48 | Initial consultation (examination) by an orthopedic traumatologist was performed in patients with space-occupying and destructive lesions, as well as bone deformations atypical for systemic connective tissue diseases | C |
49 | Initial consultation (examination) by an obstetrician-gynecologist was performed in all female patients with abdominal symptoms | C |
50 | Initial consultation (examination) by a pediatric urologist-andrologist was performed in all male patients with abdominal symptoms and/or inflammatory changes of the scrotum | C |
51 | Initial nephrologist consultation (examination) is recommended for patients with abnormal urinalysis and/or nephrotic syndrome/renal failure | C |
52 | Initial appointment (examination, consultation) by anotorhinolaryngologist was completed. | C |
53 | Initial appointment (examination, consultation) with an ophthalmologist was performed | C |
54 | Initial consultation (examination) by a pediatric dentist was performed | C |
55 | Initial consultation (examination) by a neurologist was performed in patients with neurological symptoms | C |
56 | Initial consultation (examination) by a phthisiatrician was performed in patients with positive intradermal tuberculin tests and/or elevated blood interferon-gamma levels against Mycobacterium tuberculosis complex antigens and/or infiltrative lung lesions | C |
57 | Initial consultation (examination) by an otorhinolaryngologist-audiologist was performed | C |
58 | Initial consultation (examination) by a geneticist was performed in patients who were found to have MEFV gene mutations upon molecular genetic testing | C |
59 | Initial consultation (testing, examination) by a medical psychologist was performed in all patients aged 1 year and older and all parents (regardless of the child's age) | C |
Table 2. Diagnostic quality criteria for hemophagocytic lymphohistiocytosis
№ | Quality criteria | Level of evidence |
|---|---|---|
1 | Diagnosis, including differential diagnosis, was performed in all patients with suspected hemophagocytic syndrome in the inpatient rheumatology department | C |
2 | A complete blood count (differential) was performed | C |
3 | General clinical blood chemistry analysis performed with determination of total protein, albumin, total bilirubin, free (unconjugated) and conjugated bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, potassium, sodium, total calcium in blood; activity of LDH, creatine kinase, AST, ALT, GGT, amylase, blood ALP, serum iron | C |
4 | A coagulogram (screening hemostasis test) was performed, including the determination of prothrombin index, antithrombin III activity, plasminogen and fibrinogen levels, D-dimer concentration, soluble fibrin monomer complexes in the blood, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time in the blood, and von Willebrand factor | C |
5 | Thromboelastography was performed in patients with signs of thrombosis and hypocoagulation | C |
6 | Blood procalcitonin level testing | C |
7 | Comprehensive ultrasound of internal organs was performed | C |
8 | Echocardiography was performed | C |
9 | ECG recording was performed | C |
10 | Chest CT with anesthetic care (including early postoperative management) was performed as indicated | C |
11 | Brain MRI with anesthetic management (including early postoperative care) was performed as indicated in patients with neurological symptoms | C |
12 | Ultrasound and/or MRI of the abdominal cavity, retroperitoneal space, and pelvis with anesthetic management (including early postoperative care) were performed as indicated | C |
13 | A follow-up consultation (examination) by a neurologist was performed in patients with neurological symptoms | C |
14 | A follow-up consultation (examination) by an ophthalmologist was performed, assessing the state of the ocular media and membranes, optic nerve, retina, and fundus in patients with hemorrhagic syndrome | C |
Table 3. Quality assessment criteria for the evaluation of patients with a confirmed diagnosis of familial Mediterranean fever prior to the prescription/adjustment of pathogenetic therapy
№ | Quality criteria | Level of evidence |
|---|---|---|
1 | Evaluation prior to the prescription/adjustment of antirheumatic therapy was performed in all patients with an established diagnosis of FMF in the active stage within a rheumatology inpatient setting. | C |
2 | A complete blood count (differential) was performed | C |
3 | General clinical blood chemistry analysis performed with determination of total protein, albumin, total bilirubin, free (unconjugated) and conjugated bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, potassium, sodium, total calcium in blood; activity of LDH, creatine kinase, AST, ALT, GGT, amylase, blood ALP, serum iron | C |
4 | A coagulogram (screening hemostasis test) was performed, including the determination of prothrombin index, antithrombin III activity, plasminogen and fibrinogen levels, D-dimer concentration, soluble fibrin monomer complexes in the blood, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time in the blood, and von Willebrand factor | C |
5 | Determination of blood immunoglobulin levels was performed | C |
6 | Antistreptolysin-O blood serum test | C |
7 | Determination of blood serum CRP level | C |
8 | Complete (clinical) urinalysis, Nechiporenko urine test, and determination of albumin and total protein in 24-hour urine were performed | C |
9 | A set of kidney function tests was performed in patients with clinical/laboratory signs of kidney damage | C |
10 | A set of tests for the diagnosis and assessment of the severity of renal failure was performed in patients with clinical/laboratory signs of nephrotic syndrome/renal failure | C |
11 | Blood procalcitonin level measurement was performed in all patients with fever | C |
12 | Peripheral blood immunophenotyping to determine the subpopulation composition of lymphocytes (main subsets) was performed in patients frequently suffering from viral, purulent bacterial infections, including opportunistic ones | C |
13 | A focal tuberculin skin test (Mantoux test, recombinant tuberculosis allergen test at standard dilution) and blood interferon-gamma assay for Mycobacterium tuberculosis complex antigens were performed | C |
14 | Determination of antibodies to Salmonella enterica in the blood; determination of IgM and IgG antibodies to Yersinia pseudotuberculosis in the blood were performed | C |
15 | Determination of antibodies to Mycoplasma pneumoniae, Chlamydia trachomatis, and Chlamydia psittaci in the blood was performed | C |
16 | Quantitative PCR determination of Epstein-Barr virus (Epstein-Barr virus), cytomegalovirus (Cytomegalovirus), and herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in peripheral blood, saliva, and urine was performed | C |
17 | Microbiological (culture) examination of tonsillar and posterior pharyngeal swabs for aerobic and facultatively anaerobic microorganisms was performed | C |
18 | Microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeasts and molds) was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
19 | Microbiological (culture) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
20 | Antibodies to Aspergillus spp. in the blood were determined in all patients upon detection of interstitial and/or focal and/or infiltrative changes in the lungs according to chest CT data | C |
21 | Determination of mannan and galactomannan in lavage fluid and blood was performed in all patients with signs of pneumonia on chest CT | C |
22 | Detection of Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
23 | Detection of Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
24 | Detection of Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG) DNA with species differentiation in sputum and bronchoalveolar lavage fluid by PCR was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
25 | Determination of antibodies to the capsid antigen (VCA) of Epstein-Barr virus in the blood was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
26 | Determination of IgG antibodies to early antigens (EA) of Epstein-Barr virus in the blood was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
27 | Microbiological (culture) blood and urine tests for sterility were performed in patients with febrile and hectic fever | C |
28 | Fecal calprotectin level testing was performed in patients with clinical manifestations of IBD | C |
29 | Echocardiography was performed | C |
30 | ECG recording was performed | C |
31 | Holter ECG monitoring was performed in patients with arrhythmia or pathological electrocardiographic findings | C |
32 | Ambulatory blood pressure monitoring was performed in patients with arterial hypertension | C |
33 | Ultrasound of affected joints was performed in patients with active arthritis | C |
34 | Comprehensive ultrasound of internal organs was performed | C |
35 | X-ray/CT of affected joints with anesthetic management (including early postoperative care) was performed as indicated | C |
36 | Chest CT was performed | C |
37 | Bronchoscopy with anesthetic management (including early postoperative care) was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
38 | MRI of affected joints with intravenous contrast and anesthetic management (including early postoperative care) was performed as indicated | A |
39 | EGD with biopsy, anesthetic management (including early postoperative care) as indicated, and pathomorphological examination of the biopsy (surgical) specimen was performed in patients with dyspeptic symptoms, patients receiving NSAIDs, GCS, and/or biologic agents, as well as those with a disease duration of more than 5 years and/or proteinuria >500 mg/day | C |
40 | Colonoscopy with biopsy, anesthetic management (including early postoperative care), and pathomorphological examination of the biopsy (surgical) specimen was performed in patients with abdominal syndrome / atypical intestinal symptoms for FMF (prolonged diarrhea, abdominal pain, blood and pus admixture in stool) / disease duration of more than 5 years / proteinuria >500 mg/day. | C |
41 | Kidney biopsy with anesthetic care (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen was performed in patients with clinical/laboratory/ultrasound signs of kidney damage and/or renal failure, and/or in the presence of proteinuria >500 mg/day | C |
42 | An initial consultation (examination) by an orthopedic traumatologist was performed in patients with functional joint impairment | C |
43 | An initial consultation (examination) by an otorhinolaryngologist was performed in all patients | C |
44 | Sanation of chronic ENT infection foci was performed in all patients prior to the prescription/adjustment of therapy | C |
45 | A follow-up consultation (examination) by an otorhinolaryngologist was performed in all patients following the sanation of chronic ENT infection foci | C |
46 | An initial consultation (examination) by an ophthalmologist with mandatory biomicroscopy of the eye was performed in all patients | C |
47 | A follow-up consultation (examination) by an ophthalmologist with mandatory biomicroscopy of the eye was performed in all patients with uveitis and/or complicated steroid cataract | |
48 | An initial consultation (examination) by a pediatric cardiologist was performed in patients with cardiac dysfunction and/or arterial hypertension | C |
49 | A follow-up consultation (examination) by a pediatric cardiologist was performed in patients with cardiac dysfunction and/or arterial hypertension | C |
50 | Initial consultation (examination) by a neurologist was performed in patients with neurological symptoms | C |
51 | A follow-up consultation (examination) by a neurologist was performed in patients with neurological symptoms | C |
52 | An initial consultation (examination) by a nephrologist was performed in patients with nephrotic syndrome, abnormalities in routine general blood biochemistry or urinalysis typical of the development of amyloidosis/renal failure | C |
553 | A follow-up consultation (examination) by a nephrologist was performed in patients with nephrotic syndrome, abnormalities in routine general blood biochemistry or urinalysis typical of the development of amyloidosis/renal failure | C |
54 | An initial consultation (examination) by a pediatric urologist-andrologist was performed in male patients with inflammatory changes of the scrotum | C |
55 | A follow-up consultation (examination) by a pediatric urologist-andrologist was performed in male patients with inflammatory changes of the scrotum | C |
56 | Initial examination (consultation) by a dietitian was performed for all patients with nutritional disorders | C |
57 | Follow-up examination (consultation) by a dietitian was performed for all patients with nutritional disorders | C |
58 | Initial examination (consultation) by a pediatric endocrinologist was performed for patients with endocrinological pathology | C |
59 | Follow-up examination (consultation) by a pediatric endocrinologist was performed for patients with endocrinological pathology | C |
60 | Initial examination (consultation) by a pediatric dentist was performed for patients | C |
61 | Initial examination (consultation) by a pediatric dentist was performed for all patients with foci of chronic infection | C |
62 | Oral sanitation was performed in patients with foci of chronic infection prior to prescribing/adjusting therapy | C |
63 | Follow-up examination (consultation) by a pediatric dentist was performed for all patients following sanitation of oral foci of chronic infection | C |
64 | Initial examination (consultation) by a phthisiatrician was performed for patients with positive results of a focal tuberculin skin test and/or elevated blood interferon-gamma levels specific to Mycobacterium tuberculosis complex antigens and/or focal or infiltrative changes in the lungs | C |
65 | Initial examination (testing, consultation) by a medical psychologist was performed for all patients older than 1 year and all parents (regardless of the child's age) | C |
66 | A psychological rehabilitation program was completed for all patients older than 1 year and all parents (regardless of the child's age) | C |
67 | Follow-up examination (testing, consultation) by a medical psychologist was performed for all patients older than 1 year and all parents (regardless of the child's age) upon completion of the psychological rehabilitation program | C |
68 | Initial examination (consultation) by a physical therapy doctor was performed for all patients with functional impairment after disease activity reduction | C |
69 | A program of physiotherapeutic procedures was performed for all patients with functional impairment as part of the medical rehabilitation program after disease activity reduction | C |
70 | Initial examination (consultation) by an exercise therapy doctor was performed for all patients with functional impairment after disease activity reduction | C |
71 | A medical rehabilitation program was completed for all patients with functional impairment after disease activity reduction | C |
72 | Follow-up examination (consultation) by a physical therapy doctor was performed for all patients with functional impairment upon completion of the physiotherapeutic procedures program within the medical rehabilitation program | C |
73 | Follow-up examination (consultation) by an exercise therapy doctor was performed for all patients with functional impairment upon completion of the medical rehabilitation program | C |
Table 4. Criteria for assessing the quality of treatment for familial Mediterranean fever
№ | Quality criteria | Level of evidence |
|---|---|---|
1 | Pathogenetic therapy was prescribed to all patients after diagnostics, including differential diagnostics, and establishment/confirmation of FMF diagnosis in the inpatient rheumatology department | C |
2 | Only NSAIDs were prescribed to patients with an unconfirmed FMF diagnosis at the evaluation stage | C |
3 | NSAIDs were prescribed to relieve fever and pain syndrome in patients with a confirmed FMF diagnosis | C |
4 | Diclofenac was prescribed to children older than 6 years at a dose of 0.5–3 mg/kg/day, or nimesulide to children older than 2 years at a dose of 1.5 mg/kg in 2–3 divided doses (not exceeding 5 mg/kg/day), or to children older than 12 years at a dose of 3–5 mg/kg/day, or meloxicam to children older than 2 years at a dose of 0.125 mg/kg/day and to children older than 15 years at a dose of 7.5–15 mg/day, or ibuprofen to children older than 3 months at up to 30 mg/kg/day in 3–4 divided doses | C |
5 | GCS were prescribed to patients with a confirmed FMF diagnosis at the evaluation stage in case of pronounced pain syndrome, life-threatening systemic manifestations (persistent febrile or hectic fever and/or pericarditis, and/or pleuritis, and/or peritonitis), and/or prolonged febrile myalgia | C |
6 | Systemic GCS were prescribed: methylprednisolone pulse therapy at a dose of 10–30 mg/kg/administration for 3, and if necessary, 5 consecutive days | C |
7 | Oral prednisolone or methylprednisolone was prescribed at a dose of 1 mg/kg/day for prolonged febrile myalgia | C |
8 | Intra-articular administration of betamethasone or triamcinolone GCS was performed no more than once every 4 months in case of arthritis exacerbation | C |
9 | Colchicum autumnale seed extract/colchicine, oral/intravenous/intra-articular GCS, and/or immunosuppressants, and/or bDMARDs were prescribed after ruling out oncological/oncohematological/proliferative diseases | C |
10 | Colchicum autumnale seed extract/colchicine was prescribed by decision of the medical commission after obtaining informed consent from parents and children over 15 years of age | C |
11 | Colchicum autumnale seed extract/colchicine was prescribed as maintenance therapy to patients with typical FMF attacks, homozygosity, compound heterozygosity, or heterozygosity for MEFV gene mutations | C |
12 | Colchicum autumnale seed extract/colchicine was prescribed at a starting daily dose of 0.5 mg/day for children under 5 years, 0.5–1.0 mg/day for 5–10 years, and 1.0–1.5 mg/day for older than 10 years | C |
13 | The daily dose of Colchicum autumnale seed extract/colchicine was increased by 0.5 or 0.6 mg (not exceeding 2.0 mg/day) in case of persistent attacks and/or inflammatory activity, with careful monitoring for side effects | C |
14 | Colchicum autumnale seed extract/colchicine was prescribed as maintenance therapy to patients with chronic joint involvement dominating the clinical picture, with homozygosity or compound heterozygosity for MEFV gene mutations | C |
15 | Colchicum autumnale seed extract/colchicine was prescribed as maintenance therapy to relative patients of FMF patients without clinical manifestations who have persistently elevated acute-phase markers of inflammation/proteinuria, and homozygosity or compound heterozygosity for MEFV gene mutations | C |
16 | Evaluation of the efficacy of Colchicum autumnale seed extract/colchicine was performed using FMF50 and the AutoVascular/Autoinflammatory Disease Activity Index (AIDAI) 3 months after starting therapy and every 6 months thereafter; disease severity was evaluated using the International Severity Score for FMF (ISSF) once every 6 months, and the damage index (ADDI) once a year | C |
17 | Interleukin-1β (IL-1β) inhibitor canakinumab or interleukin-1α and IL-1β inhibitor anakinra was prescribed to compliant patients with colchicine-resistant FMF having >1 attack per month, receiving the maximally tolerated dose of Colchicum autumnale seed extract/colchicine for ≥3 months | C |
18 | Interleukin-1β (IL-1β) inhibitor canakinumab or interleukin-1α and IL-1β inhibitor anakinra was prescribed to colchicine-resistant patients with typical FMF attacks, homozygosity, compound heterozygosity, or heterozygosity for MEFV gene mutations | B |
19 | Interleukin-1β (IL-1β) inhibitor canakinumab or interleukin-1α and IL-1β inhibitor anakinra was prescribed to patients with severe rare FMF attacks and an elevated risk of secondary amyloidosis | C |
20 | Interleukin-1β (IL-1β) inhibitor canakinumab or interleukin-1α and IL-1β inhibitor anakinra was prescribed to colchicine-resistant patients with chronic joint involvement dominating the clinical picture, and homozygosity or compound heterozygosity for MEFV gene mutations | B |
21 | Canakinumab was prescribed to children with a weight of ≥7.5 to ≤40 kg at a dose of 2 mg/kg subcutaneously once every 4 weeks; >40 kg at a dose of 150 mg subcutaneously once every 4 weeks in combination with the maximally tolerated dose of Colchicum autumnale seed extract/colchicine | C |
22 | Maintenance therapy with canakinumab was administered at a dose of 2 mg/kg subcutaneously once every 4 weeks to patients with a body weight of ≤40 kg, and at a dose of 150 mg subcutaneously once every 4 weeks to patients with a body weight of >40 kg upon achieving a clinical effect 7 days after the first canakinumab injection | C |
23 | A second injection of canakinumab was administered at a dose of 2 mg/kg subcutaneously to patients with a body weight of ≤40 kg, and at a dose of 150 mg subcutaneously to patients with a body weight of >40 kg if the clinical effect was not achieved 7 days after the first canakinumab injection | C |
24 | Maintenance therapy with canakinumab was administered at a dose of 4 mg/kg subcutaneously once every 4 weeks to patients with a body weight of ≤40 kg, and at a dose of 300 mg subcutaneously once every 4 weeks to patients with a body weight of >40 kg upon achieving a full clinical effect after the second injection of canakinumab | C |
25 | Anakinra was prescribed to patients with a body weight of less than 50 kg at a dose of 1–2 mg/kg/day, and to patients with a body weight of ≥50 kg at a dose of 100 mg/day subcutaneously | C |
26 | Maintenance therapy with anakinra was administered to patients with a body weight of less than 50 kg at a dose of 1–2 mg/kg/day, and to patients with a body weight of ≥50 kg at a dose of 100 mg/day subcutaneously | C |
27 | The anakinra dose was increased up to 4 mg/kg/day in case of an insufficient response to therapy | C |
28 | It is recommended to prescribe methotrexate at a dose of 10–15 mg/m²/week subcutaneously or sulfasalazine at a dose of 30–40 mg/kg orally in 2 divided doses to patients with FMF and chronic joint involvement dominating the clinical picture, homozygosity or compound heterozygosity for MEFV gene mutations, as well as FMF combined with JIA, in combination with Colchicum autumnale seed extract/colchicine at the maximum tolerated dose | C |
29 | The dose of methotrexate was not increased >15 mg/m²/week (not exceeding 25 mg/week) in patients with FMF and active chronic arthritis and FMF combined with JIA | C |
30 | Subcutaneous administration of methotrexate was performed in patients with active chronic arthritis and FMF combined with JIA | C |
31 | Folic acid was prescribed at a dose of 1 mg/day daily or 2.5 mg/day once a week orally during methotrexate therapy in patients receiving methotrexate | C |
32 | Sulfasalazine was prescribed at a dose of 30–40 mg/kg/day orally in two divided doses to patients with chronic joint involvement dominating the clinical picture, FMF combined with JIA, and homozygosity or compound heterozygosity for MEFV gene mutations in case of inefficacy of methotrexate at a dose of 15 mg/m²/week in combination with Colchicum autumnale seed extract/colchicine at the maximum tolerated dose | C |
33 | Sulfasalazine was prescribed at a dose of 30–40 mg/kg/day orally in two divided doses in combination with Colchicum autumnale seed extract/colchicine at the maximum tolerated dose in patients with chronic joint involvement dominating the clinical picture, FMF combined with JIA, and homozygosity or compound heterozygosity for MEFV gene mutations in case of intolerance to methotrexate at a dose of 15 mg/m²/week | C |
34 | Methotrexate was prescribed at a dose of 15 mg/m²/week in case of inefficacy of sulfasalazine at a dose of 30–40 mg/kg/day as a first-line drug in combination with Colchicum autumnale seed extract/colchicine at the maximum tolerated dose in patients with chronic joint involvement dominating the clinical picture, FMF combined with JIA, and homozygosity or compound heterozygosity for MEFV gene mutations | C |
35 | Methotrexate was prescribed at a dose of 15 mg/m²/week in case of intolerance to sulfasalazine at a dose of 30–40 mg/kg/day as a first-line drug in combination with Colchicum autumnale seed extract/colchicine at the maximum tolerated dose in patients with chronic joint involvement dominating the clinical picture, FMF combined with JIA, and homozygosity or compound heterozygosity for MEFV gene mutations | C |
36 | In case of inefficacy of canakinumab/anakinra, tocilizumab was prescribed at a dose of 8 mg/kg/administration intravenously once every 2 weeks or at a dose of 162 mg subcutaneously once a week in combination with Colchicum autumnale seed extract/colchicine and/or methotrexate (in case of its intolerance), and/or sulfasalazine (in case of its tolerability) in patients with chronic arthritis and FMF combined with JIA | C |
37 | In case of intolerance to canakinumab/anakinra, switching to tocilizumab was performed at a dose of 8 mg/kg/administration intravenously once every 2 weeks or at a dose of 162 mg subcutaneously once a week in combination with Colchicum autumnale seed extract/colchicine and/or methotrexate (in case of its intolerance), and/or sulfasalazine (in case of its tolerability) in patients with chronic arthritis and FMF combined with JIA | C |
38 | In case of intolerance to Colchicum autumnale seed extract/colchicine, monotherapy with tocilizumab was performed at a dose of 8 mg/kg/administration intravenously once every 2 weeks or at a dose of 162 mg subcutaneously once a week, or in combination with methotrexate (in case of its tolerability) or sulfasalazine (in case of its tolerability) in patients with chronic arthritis and FMF combined with JIA | C |
39 | Switching to tumor necrosis factor alpha (TNF-alpha) inhibitors was performed in patients with chronic arthritis dominating the clinical picture, FMF combined with JIA, and homozygosity or compound heterozygosity for MEFV gene mutations in case of inefficacy of Colchicum autumnale seed extract/colchicine in combination with methotrexate or sulfasalazine | C |
40 | Tumor necrosis factor alpha (TNF-alpha) inhibitors were prescribed: adalimumab for children with a body weight of 10 to 30 kg — 20 mg once every 2 weeks; >30 kg — 40 mg once every 2 weeks, or etanercept 0.4 mg/kg/administration subcutaneously twice a week or 0.8 mg/kg/administration once a week in combination with Colchicum autumnale seed extract/colchicine at the maximum tolerated dose, with methotrexate (in case of its tolerability) at a dose of 15 mg/m² once a week subcutaneously, or with sulfasalazine at a dose of 30–40 mg/kg/day orally | C |
41 | Assessment of the efficacy of pathogenetic therapy according to FMF50 and the AutoVascular/Autoinflammatory Disease Activity Index (AIDAI) was performed 3 months after the start of therapy and every 6 months thereafter; disease severity according to the International Severity Scoring System for FMF (ISSF) was assessed once every 6 months, and the damage index (ADDI) once a year | C |
Table 5. Quality assessment criteria for the treatment of familial Mediterranean fever complicated by hemophagocytic syndrome
№ | Quality criteria | Level of Evidence |
|---|---|---|
1 | Therapy was prescribed to all patients after diagnostics, including differential diagnostics, and establishment/confirmation of the diagnosis of FMF with hemophagocytic syndrome in the setting of an inpatient rheumatology department | C |
2 | Pulse therapy with methylprednisolone at a dose of 20–30 mg/kg/administration / dexamethasone at a dose of 10–20 mg/m²/day intravenously was prescribed | C |
3 | Prednisolone was prescribed orally at a dose of 1–2 mg/kg | C |
4 | Cyclosporine was prescribed at a dose of 5–7 mg/kg/day orally/intravenously | C |
5 | Canakinumab was prescribed subcutaneously at a dose of 4 mg/kg/administration once every 4 weeks | C |
6 | Normal human immunoglobulin was prescribed at a dose of 1–2 g/kg intravenously as a single dose | C |
7 | Antithrombotic agents were prescribed in the presence of hypercoagulation and vascular endothelial damage according to coagulogram and thromboelastogram data, and upon the development of coagulopathy and disseminated intravascular coagulation according to coagulogram and thromboelastogram data | C |
8 | Blood and/or blood product transfusions were performed in the case of consumption coagulopathy according to coagulogram/thromboelastography data or hemorrhage | C |
9 | Systemic antibacterial drugs affecting gram-positive, gram-negative, and anaerobic flora in combination with antifungal drugs were prescribed in the case of moderate or severe neutropenia / acute inflammatory response accompanied by an elevated blood procalcitonin level, even without a focus of infection confirmed by bacteriological and/or serological methods | C |
10 | The dose of intravenous dexamethasone was reduced after the relief of clinical and laboratory signs of HPS according to the schedule: 10–20 mg/m²/day for 1–2 weeks, 5–10 mg/m²/day for 3–4 weeks, 2.5–5 mg/m²/day for 5–6 weeks, 1.25–2.5 mg/m²/day for 7–8 weeks | C |
11 | Rituximab was prescribed at 375 mg/m² per week intravenously once a week for 2–4 consecutive weeks in combination with cyclosporine at 5–7 mg/kg/day and normal human immunoglobulin at a dose of 1–2 g/kg in patients with HPS and active Epstein-Barr virus infection | C |
12 | Rituximab was prescribed in combination with co-trimoxazole at a dose of 5 mg/kg orally 3 times a week for the prevention of Pneumocystis jirovecii pneumonia | C |
13 | Rituximab was prescribed as a life-saving measure, by decision of the medical commission, after obtaining informed consent from the parents/patients older than 15 years | C |
14 | Evaluation of the efficacy of HPS treatment was performed after 2–4 weeks to decide on the continuation of induction therapy or changing the treatment regimen | C |
15 | Treatment of HPS was performed until an inactive stage was achieved | C |
Table 6. Quality assessment criteria for follow-up (dispensary observation) of patients with familial Mediterranean fever in a hospital / day hospital setting that initiated pathogenetic therapy
№ | Quality criteria | Level of evidence |
|---|---|---|
1 | Hospitalization in the rheumatology department was performed 3 months after initiating therapy; 6 months after initiating therapy; and every 6 months thereafter | C |
2 | Immunization with live and live-attenuated vaccines was not performed in patients receiving biologic disease-modifying antirheumatic drugs (bDMARDs) | C |
3 | A complete blood count (differential) was performed | C |
4 | Reduction of the dose of Colchicum autumnale seed extract/colchicine by half; discontinuation of bDMARD injections/infusions and/or methotrexate injections/administration, or sulfasalazine administration (for 7 days) was performed when the platelet count dropped to ≤150 >100 × 10⁹/L and/or the neutrophil count to <1.5 ≥1.0 × 10⁹/L | C |
5 | Resumption of treatment with Colchicum autumnale seed extract/colchicine at the same dose and/or bDMARDs and/or immunosuppressants was performed after complete recovery of the platelet/neutrophil count | C |
6 | Discontinuation of Colchicum autumnale seed extract/colchicine and/or immunosuppressants and/or bDMARDs was performed when the absolute neutrophil count decreased to <1.0 × 10⁹/L and/or the platelet count to <100 × 10⁹/L | C |
7 | Granulocyte colony-stimulating factor (filgrastim) was prescribed at a dose of 5–10 mcg/kg/day subcutaneously for 3–5 days (longer if necessary) in the event of leukopenia with an absolute neutrophil count ≤1.0 × 10⁹/L | C |
8 | Administered granulocyte colony-stimulating factor (filgrastim) at 5–10 mcg/kg/day subcutaneously for 3–5 days (or longer if necessary) in combination with broad-spectrum intravenous antibiotics for febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count of < 1.0 × 10⁹/L | C |
9 | Administered antibiotic treatment until normalization of the complete blood count with differential and resolution of fever | C |
10 | Prescribed *Colchicum autumnale* seed extract / colchicine and/or an immunosuppressant, and/or a biological DMARD upon normalization of complete blood count parameters | C |
11 | Adjusted therapy with *Colchicum autumnale* seed extract / colchicine and/or an immunosuppressant, and/or a biological DMARD in cases of recurrent episodes of leukopenia/thrombocytopenia | C |
12 | Performed a general routine biochemical blood test to determine the levels of total protein, albumin, total bilirubin, free (unconjugated) and conjugated bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, potassium, sodium, and total calcium in the blood; activity of LDH, creatine kinase, AST, ALT, GGT, amylase, and alkaline phosphatase in the blood; serum iron, and vitamin B12 | C |
13 | Temporarily discontinued *Colchicum autumnale* seed extract / colchicine and/or an immunosuppressant, and/or a biological DMARD in all patients if serum ALT or AST levels increase to ≥ 1.5 times the upper limit of normal and/or if bilirubin, urea, creatinine, uric acid, and/or other biochemical parameter(s) rise above the upper limit of normal | C |
14 | Prescribed *Colchicum autumnale* seed extract / colchicine and/or an immunosuppressant, and/or a biological DMARD upon normalization of biochemical parameters | C |
15 | Adjusted therapy with *Colchicum autumnale* seed extract / colchicine and/or an immunosuppressant, and/or a biological DMARD in all patients with a history of recurrent episodes of elevated biochemical parameter(s) | C |
16 | Determined blood immunoglobulin levels, autoantibodies to nuclear antigens and DNA, as well as serum CRP and procalcitonin levels | C |
17 | Administered normal human immunoglobulin at a dose of 400 mg/kg to patients experiencing a decrease in blood immunoglobulin levels while receiving *Colchicum autumnale* seed extract / colchicine, and/or a biological DMARD, and/or an immunosuppressant, or at a dose of 500 mg/kg if adequate immunoglobulin levels are not achieved | C |
18 | Performed a comprehensive workup to rule out sepsis (complete blood count with differential, general routine biochemical blood test, serum CRP level, blood procalcitonin level, blood culture for sterility, microbiological (cultural) swab of the tonsils and posterior pharyngeal wall for aerobic and facultatively anaerobic microorganisms, urine microbiological (cultural) culture for bacterial pathogens using automated seeding with antimicrobial susceptibility testing, thromboelastography, coagulogram; MRI of the abdominal cavity, pelvis, and retroperitoneal space) in patients with febrile or hectic fever, leukocytosis/leukopenia, thrombocytopenia, and elevated serum CRP and procalcitonin levels not related to the activity of systemic connective tissue diseases | C |
19 | Administered normal human immunoglobulin at a dose of 400 mg/kg and empirical systemic antibacterial therapy, followed by adjustment of antibacterial therapy based on microbial susceptibility upon the development of infectious complications | C |
20 | Prescribed *Colchicum autumnale* seed extract / colchicine and/or an immunosuppressant, and/or a biological DMARD no earlier than 1 week after the complete resolution of clinical and laboratory signs of sepsis and the completion of antibiotic therapy | C |
21 | Performed a coagulogram (exploratory hemostasis evaluation) including prothrombin index, antithrombin III activity; plasminogen and fibrinogen levels, D-dimer concentration, soluble fibrin monomer complexes in the blood, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time, and von Willebrand factor in the blood | C |
22 | Performed thromboelastography in patients with macrophage activation syndrome, sepsis, and signs of thrombosis and hypocoagulation | C |
23 | Administered blood and blood product transfusions upon the development of consumption coagulopathy or bleeding | C |
24 | Administered antithrombotic agents upon the development of disseminated intravascular coagulation (DIC) syndrome | C |
25 | Complete (clinical) urinalysis, Nechiporenko urine test, and determination of albumin and total protein in 24-hour urine were performed | C |
26 | Performed a comprehensive renal function assessment and a panel of diagnostic tests to evaluate the severity of renal failure in patients with clinical/laboratory signs of nephrotic syndrome/renal failure/disease duration > 5 years/presence of proteinuria > 500 mg/day for the purpose of diagnosing and assessing the degree of renal damage | C |
27 | Performed peripheral blood immunophenotyping to identify major lymphocyte subpopulations in all patients with frequent viral or purulent bacterial infections, including opportunistic infections | C |
28 | A focal tuberculin skin test (Mantoux test, recombinant tuberculosis allergen test at standard dilution) and blood interferon-gamma assay for Mycobacterium tuberculosis complex antigens were performed | C |
29 | Consulted a phthisiatrician upon detecting a positive focal tuberculin skin test (papula > 5 mm) and/or elevated interferon-gamma levels, and/or a response to recombinant tuberculosis allergen in standard dilution, and/or lung and/or intrathoracic lymph node lesions | C |
30 | Discontinued *Colchicum autumnale* seed extract / colchicine and/or a biological DMARD, and/or an immunosuppressant in the presence of pulmonary lesions and/or intrathoracic lymph node involvement | C |
31 | Administered oral glucocorticosteroids during a flare of systemic connective tissue disease while undergoing specific chemotherapy | C |
32 | Prescribed or switched *Colchicum autumnale* seed extract / an immunosuppressant, and/or a biological DMARD after completing the course of specific chemotherapy | C |
33 | Continued treatment with *Colchicum autumnale* seed extract / colchicine and/or an immunosuppressant, and/or a biological DMARD along with previously prescribed oral glucocorticosteroids under the supervision of a rheumatologist, complete blood count, and general routine biochemical blood tests during specific anti-tuberculosis chemotherapy in patients with tuberculosis infection without an active focus | C |
34 | Determined blood classes A, M, G antibodies (IgA, IgM, IgG) to Chlamydia psittaci; class M antibodies (IgM) to Chlamydia trachomatis in the blood; class G antibodies (IgG) to Chlamydia trachomatis in the blood; classes M, G antibodies (IgM, IgG) to Mycoplasma pneumoniae in the blood for all patients | C |
35 | Administered etiotropic therapy upon detecting diagnostic titers of classes A and M antibodies, as well as high titers of class G antibodies to Mycoplasma pneumoniae, Chlamydia trachomatis, C. psittaci in patients receiving *Colchicum autumnale* seed extract / colchicine and/or a biological DMARD, and/or an immunosuppressant combined with or without glucocorticosteroids | C |
36 | Determination of antibodies to Salmonella enterica in blood; determination of IgM, IgG classes antibodies to Yersinia pseudotuberculosis in blood were performed | C |
37 | Administered etiotropic therapy upon detecting diagnostic titers of classes A and M antibodies, as well as high titers of class G antibodies to Yersinia pseudotuberculosis, Yersinia enterocolitica serovars, and Salmonella enterica in the blood | C |
38 | Determined DNA of Epstein-Barr virus, Cytomegalovirus, and Herpes simplex virus types 1 and 2 by PCR in peripheral blood (quantitative assay), saliva, and urine in patients receiving *Colchicum autumnale* seed extract / colchicine and/or a biological DMARD, and/or an immunosuppressant combined with or without glucocorticosteroids who present with clinical manifestations of herpesvirus infection | C |
39 | It is recommended to determine blood classes M, G antibodies (IgM, IgG) to Cytomegalovirus in all patients receiving *Colchicum autumnale* seed extract / colchicine and/or a biological DMARD, and/or an immunosuppressant combined with or without glucocorticosteroids who present with clinical manifestations of herpesvirus infection | C |
40 | It is recommended to determine blood classes M, G antibodies (IgM, IgG) to Epstein-Barr virus in all patients receiving *Colchicum autumnale* seed extract / colchicine and/or a biological DMARD, and/or an immunosuppressant combined with or without glucocorticosteroids who present with clinical manifestations of herpesvirus infection | C |
41 | It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus in the blood of all patients receiving *Colchicum autumnale* seed extract / colchicine and/or a biological DMARD, and/or an immunosuppressant combined with or without glucocorticosteroids who present with clinical manifestations of herpesvirus infection | C |
42 | It is recommended to determine class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients receiving *Colchicum autumnale* seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants in combination with (or without) GCS who present with clinical symptoms of herpesvirus infection | C |
43 | It is recommended to determine antibodies to herpes simplex virus (Herpes simplex) in the blood of all patients receiving *Colchicum autumnale* seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants in combination with (or without) GCS who present with clinical symptoms of herpesvirus infection | C |
44 | receiving *Colchicum autumnale* seed extract/colchicine and/or biologic DMARDs, and/or immunosuppressants in combination with (or without) GCS who present with clinical symptoms of herpesvirus infection | |
45 | Acyclovir was administered at a dose of 200 mg per day orally in 5 divided doses (maximum 1000 mg/day) in children older than 2 years, or at a dose of 5-10 mg/kg/injection intravenously every 8 hours upon the development of local herpesvirus infection | C |
46 | Acyclovir was administered at a dose of 10 mg/kg/injection intravenously every 8 hours in children aged <1 year; at a dose of 500 mg/m² intravenously every 8 hours in children aged ≥1 year upon the development of Herpes zoster | C |
47 | Ganciclovir was administered at 6 mg/kg/injection intravenously every 12 hours for 14–21 days upon the development of cytomegalovirus infection, or ganciclovir (J05AB) at a dose of 10 mg/kg/injection intravenously every 12 hours upon the development of Epstein-Barr virus infection | C |
48 | Withdrawal of *Colchicum autumnale* seed extract/colchicine and/or immunosuppressants, and/or biologic DMARDs was performed upon the development of herpesvirus infection | C |
49 | Administration of *Colchicum autumnale* seed extract/colchicine and/or immunosuppressants, and/or biologic DMARDs was performed no earlier than 1 week after the completion of antiviral therapy | C |
50 | Echocardiography was performed | C |
51 | ECG recording was performed | C |
52 | Holter ECG monitoring was performed in patients with arrhythmias | C |
53 | Ambulatory blood pressure monitoring was performed in patients with arterial hypertension | C |
54 | Comprehensive ultrasound of internal organs was performed | C |
55 | EGD with gastric/duodenal biopsy under anesthesia (including early postoperative management) was performed as indicated with Helicobacter pylori testing | C |
56 | Drugs for the treatment of peptic ulcer disease and gastroesophageal reflux disease were prescribed upon detection of reflux disease and/or inflammatory gastropathy, erosive and/or ulcerative lesions in the esophagus and/or stomach, and/or duodenum according to EGD data | C |
57 | Eradication therapy was prescribed upon detection of Helicobacter pylori | C |
58 | Withdrawal of *Colchicum autumnale* seed extract/colchicine and/or immunosuppressants, and/or biologic DMARDs was performed for the duration of eradication therapy | C |
59 | Colonoscopy under anesthesia (including early postoperative management) with pathomorphological examination of the biopsy (surgical) specimen was performed in patients with intestinal symptoms atypical for systemic autoinflammatory diseases (protracted diarrhea, abdominal pain, blood and pus admixture in stool) / disease duration > 5 years / proteinuria > 500 mg/day | C |
60 | Joint X-ray/CT under anesthesia (including early postoperative management) was performed as indicated in patients with active chronic arthritis | C |
61 | Chest CT was performed in all patients | C |
62 | Determination of class M and G antibodies (IgM, IgG) to cytomegalovirus (Cytomegalovirus) in the blood was performed in all patients upon detection of interstitial and/or focal, and/or infiltrative lung changes on chest CT | C |
63 | Determination of class M and G antibodies (IgM, IgG) to Epstein-Barr virus (Epstein-Barr virus) in the blood was performed in all patients upon detection of interstitial and/or focal, and/or infiltrative lung changes on chest CT | C |
64 | Determination of antibodies to the capsid antigen (VCA) of Epstein-Barr virus in the blood was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
65 | Determination of class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus (Epstein-Barr virus) in the blood was performed in all patients upon detection of interstitial and/or focal, and/or infiltrative lung changes on chest CT | C |
66 | Determination of antibodies to herpes simplex virus (Herpes simplex) in the blood was performed in all patients upon detection of interstitial and/or focal, and/or infiltrative lung changes on chest CT | C |
67 | Bronchoscopy under anesthesia (including early postoperative management) was performed in all patients upon detection of interstitial and/or focal, and/or infiltrative lung changes on chest CT | C |
68 | Microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeasts and molds) was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
69 | Microbiological (culture) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
70 | Antibodies to Aspergillus spp. in the blood were determined in all patients upon detection of interstitial and/or focal and/or infiltrative changes in the lungs according to chest CT data | C |
71 | Mannan and galactomannan levels in lavage fluid and blood were determined in all patients upon detection of interstitial and/or focal, and/or infiltrative lung changes on chest CT | C |
72 | Detection of Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
73 | Detection of Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
74 | Detection of Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG) DNA with species differentiation in sputum and bronchoalveolar lavage fluid by PCR was performed in all patients with interstitial, focal, and/or infiltrative lung changes detected by chest CT | C |
75 | Immediate withdrawal of *Colchicum autumnale* seed extract/colchicine and/or immunosuppressants, and/or biologic DMARDs was performed upon suspected/developed pneumonia | C |
76 | Empirical antibacterial therapy with co-trimoxazole combined with systemic antibacterial drugs targeting gram-positive, gram-negative, and anaerobic flora, along with systemic antifungal drugs, was prescribed prior to identifying the etiological factor of interstitial pneumonia | C |
77 | Intravenous GCS and co-trimoxazole at 3.75–5.0 mg/kg body weight/injection (calculated by trimethoprim) intravenously every 6 hours were prescribed upon the development of *Pneumocystis* pneumonia | C |
78 | Systemic antibacterial drugs targeting gram-positive, gram-negative, and anaerobic flora, combined with systemic antifungal drugs, were prescribed upon the development of focal or lobar pneumonia | C |
79 | Administration of *Colchicum autumnale* seed extract/colchicine and/or immunosuppressants, and/or biologic DMARDs was performed no earlier than 1 week after complete resolution of pneumonia according to laboratory tests, follow-up chest CT under anesthesia (including early postoperative management) as indicated, and completion of antibacterial therapy | C |
80 | Brain MRI under anesthesia (including early postoperative management) was performed as indicated in patients with signs of CNS involvement | C |
81 | Lumbar puncture under anesthesia (including early postoperative management) with microscopic examination, cell counting in a counting chamber (cytosis determination), physical property analysis of cerebrospinal fluid, and serological testing was performed in patients with symptoms of CNS involvement | C |
82 | X-ray densitometry was performed in patients currently or previously receiving GCS | C |
83 | Bisphosphonates combined with calcium preparations, vitamin D, and its analogues were prescribed to patients with osteoporosis | C |
84 | Pamidronate was administered in patients <1 year at 0.5 mg/kg IV every 2 months; in patients aged 1–2 years at 0.25–0.5 mg/kg/day IV for 3 days every 3 months; in patients aged 2–3 years at 0.375–0.75 mg/kg/day IV for 3 days every 3 months; in patients older than 3 years at 0.5–1 mg/kg/day IV for 3 days every 4 months (maximum dose 60 mg/injection), or alendronate at 1–2 mg/kg/week orally (in patients with body weight <40 kg at 5 mg/day or 35 mg/week; in patients with body weight >40 kg at 10 mg/day or 70 mg/week [maximum dose 70 mg/week]), or zoledronic acid at 0.0125–0.05 mg/kg/injection IV every 6–12 months (maximum dose 4 mg), or ibandronate at 3 mg/injection IV once every 3 months or 150 mg orally once a month | C |
85 | MRI of affected joints under anesthesia (including early postoperative management) was performed as indicated | C |
86 | Kidney biopsy under anesthesia (including early postoperative management) with pathomorphological examination of the biopsy (surgical) specimen was performed in patients with a disease duration of more than 5 years / proteinuria > 500 mg/day / chronic kidney disease / signs of renal failure | C |
87 | Initial appointment (examination, consultation) by anotorhinolaryngologist was completed. | C |
88 | Initial consultation (examination) by a pediatric dentist was performed | C |
89 | Initial nephrologist consultation (examination) was performed in patients with renal involvement | C |
90 | Follow-up nephrologist consultation (examination) was performed in patients with renal involvement | C |
91 | Initial ophthalmologist consultation (examination) with mandatory ocular biomicroscopy was performed | C |
92 | An initial consultation (examination) by a pediatric cardiologist was performed in patients with cardiac dysfunction and/or arterial hypertension | C |
93 | Initial pediatric endocrinologist consultation (examination) was performed in patients with endocrine pathology | C |
94 | Initial dietitian consultation (examination) was performed in patients with underweight, amyotrophy, osteopenia/osteoporosis, constitutional obesity and Cushing's syndrome, or steroid diabetes | C |
95 | Initial orthopedic traumatologist consultation (examination) was performed in patients with functional joint insufficiency, impaired longitudinal bone growth, subluxations, or back pain | C |
96 | Initial neurologist consultation (examination) was performed in patients with neurological symptoms or psychotic reactions | C |
97 | Initial examination (testing, consultation) by a medical psychologist was performed for all patients older than 1 year and all parents regardless of the child's age | C |
98 | Initial examination (evaluation, consultation) by a physical therapy physician was performed for patients with functional impairment | C |
99 | Initial examination (evaluation, consultation) by an exercise therapy physician was performed for patients with functional impairment | C |
100 | A medical rehabilitation program was completed for all patients with functional impairment | C |
101 | Follow-up examination (evaluation, consultation) by a physical therapy physician was performed for patients after completing the course of physical therapy procedures within the medical rehabilitation program | C |
102 | Follow-up examination (consultation) by an exercise therapy doctor was performed for all patients with functional impairment upon completion of the medical rehabilitation program | C |
103 | Adjustment of pathogenetic therapy was performed in the inpatient rheumatology department that initiated pathogenetic therapy, in cases of ineffectiveness and/or intolerance to Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a biological DMARD (bDMARD) | C |
104 | Immediate discontinuation of Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a bDMARD was performed upon suspicion of an oncological/onco-hematological/lymphoproliferative disease | C |
105 | Acquisition of a bone marrow cytologic specimen via puncture with anesthetic support (including early postoperative management) and a bone marrow histologic specimen with cytologic examination of the bone marrow smear (myelogram), and pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods was performed in patients receiving Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a bDMARD, with an atypical disease course | C |
106 | Lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) with anesthetic support (including early postoperative management), cytologic examination of the lymph node tissue specimen, and pathomorphological examination of the lymph node biopsy (surgical) material was performed in patients receiving Colchicum autumnale seed extract/colchicine and/oр an immunosuppressant, and/or a bDMARD with an atypical disease course accompanied by marked enlargement of peripheral and/or intrathoracic, and/or intra-abdominal lymph nodes | C |
107 | Chest CT with intravenous contrast and anesthetic support (including early postoperative management) was performed as indicated in patients receiving Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a bDMARD with an atypical disease course | C |
108 | PET/CT with tumor-tropic radiopharmaceuticals and contrast enhancement, or whole-body PET with tumor-tropic radiopharmaceuticals using anesthetic support (including early postoperative management) as indicated, was performed in patients receiving Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a bDMARD who present with pronounced arthralgia, myalgia, ossalgia, bone destructive changes, infiltrates in subcutaneous adipose tissue, or lesions in parenchymal organs, the brain, or the spinal cord | C |
109 | Multi-position bone scintigraphy using anesthetic support (including early postoperative management) was performed as indicated in patients receiving Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a bDMARD with atypical bone destruction foci not typical of familial Mediterranean fever | C |
110 | Pelvic bone trephine biopsy using anesthetic support (including early postoperative management) under CT guidance was performed with pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods; cytologic examination of bone marrow trephine biopsy imprints; immunocytochemical examination of bone marrow trephine biopsy imprints; and immunophenotyping of hematopoietic progenitor cells in the bone marrow in patients receiving Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a bDMARD with an atypical disease course | C |
111 | Bone biopsy using anesthetic support (including early postoperative management) with pathomorphological examination of the bone biopsy (surgical) material was performed in patients receiving Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a bDMARD with bone destruction foci not typical of familial Mediterranean fever, | C |
112 | Initial examination (evaluation, consultation) by a pediatric oncologist was performed for patients in whom an oncological/onco-hematological/lymphoproliferative disease or metastatic lesion was suspected/detected based on examination results | C |
Table 7. Quality assessment criteria for dispensary monitoring of patients with familial Mediterranean fever in outpatient settings
№ | Quality criteria | Level of evidence |
|---|---|---|
1 | Dispensary monitoring of patients with FMF was performed, including an initial examination (evaluation, consultation) by a rheumatologist with assessment of therapy efficacy and safety at least once a year after therapy initiation/adjustment | C |
2 | Dispensary monitoring of patients with FMF was performed, including a follow-up examination (evaluation, consultation) by a rheumatologist with assessment of therapy efficacy and safety at least once a month after therapy initiation/adjustment and at least once every 3 months after achieving disease remission | C |
3 | Vaccination of children was performed exclusively during disease remission, provided it has been maintained for at least 6 months, according to an individual schedule, excluding live vaccines | C |
4 | Evaluation of pathogenetic therapy efficacy was performed using FMF50 and the Autoinflammatory Disease Activity Index (AIDAI) 3 months after treatment initiation and every 6 months thereafter; disease severity was evaluated using the International Severity Score for FMF (ISSF) every 6 months, and the Autoinflammatory Disease Damage Index (ADDI) once a year | C |
5 | Immediate discontinuation of Colchicum autumnale seed extract/colchicine, administration of a bDMARD, and/or injections/administration of an immunosuppressant were performed in the event of an allergic reaction | C |
6 | Prescription of antihistamines and/or glucocorticosteroids was performed upon the development of an allergic reaction to Colchicum autumnale seed extract/colchicine and/or administration of a bDMARD and/or an immunosuppressant | |
7 | Consultation with an inpatient rheumatologist (including remote consultation) was performed upon the development of an allergic reaction to Colchicum autumnale seed extract/colchicine and/or administration of a bDMARD and/or an immunosuppressant | C |
8 | Urgent hospital admission was performed in the event of an allergic reaction to Colchicum autumnale seed extract/colchicine and/or administration of a bDMARD and/or an immunosuppressant | C |
9 | Complete blood count (CBC) with differential was performed at least once every 2–4 weeks | C |
10 | Reduction of the dose of Colchicum autumnale seed extract/colchicine by half; discontinuation of bDMARD injections/infusions and/or methotrexate injections/administration, or sulfasalazine administration (for 7 days) was performed when the platelet count dropped to ≤150 >100 × 10⁹/L and/or the neutrophil count to <1.5 ≥1.0 × 10⁹/L | C |
11 | Resumption of treatment with Colchicum autumnale seed extract/colchicine at the same dose and/or a bDMARD and/or an immunosuppressant was performed after complete recovery of platelet/neutrophil counts | C |
12 | Discontinuation of Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a bDMARD was performed when the absolute neutrophil count (ANC) dropped below <1.0 × 10⁹/L and/or the platelet count dropped below <100 × 10⁹/L | C |
13 | Granulocyte colony-stimulating factor (filgrastim) was prescribed at a dose of 5–10 mcg/kg/day subcutaneously for 3–5 days (longer if necessary) in the event of leukopenia with an absolute neutrophil count ≤1.0 × 10⁹/L | C |
14 | Administration of the granulocyte colony-stimulating factor filgrastim (L03AA) at a dose of 5–10 mcg/kg/day subcutaneously was performed in cases of decreased leukocyte levels with an absolute neutrophil count <1.0 × 10⁹/L | C |
15 | Administration of the granulocyte colony-stimulating factor filgrastim at 5–10 mcg/kg/day subcutaneously for 3–5 days (or longer if necessary) combined with intravenous broad-spectrum antibiotics was performed in febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count <1.0 × 10⁹/L | C |
16 | Prescribed *Colchicum autumnale* seed extract / colchicine and/or an immunosuppressant, and/or a biological DMARD upon normalization of complete blood count parameters | C |
17 | Consultation with an inpatient rheumatologist (including remote consultation) was performed in the event of a recurrent episode of decreased blood neutrophil and/or platelet counts | C |
18 | Routine biochemical blood analysis was performed at least once every 2–4 weeks | C |
19 | Discontinuation of Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a bDMARD was performed if serum ALT or AST levels increased to ≥ 1.5 times the upper limit of normal and/or other biochemical parameters exceeded the upper limit of normal | C |
20 | Prescription of Colchicum autumnale seed extract/colchicine and/or an immunosuppressant, and/or a bDMARD was performed upon normalization of the routine biochemical blood test parameter(s) | C |
21 | Consultation with an inpatient rheumatologist (including remote consultation) was performed in the event of a recurrent episode of elevated routine biochemical blood test parameter(s) | C |
22 | Discontinuation of Colchicum autumnale seed extract/colchicine and/or a bDMARD, and/or an immunosuppressant was performed upon the appearance of signs of an infectious complication | C |
23 | Consultation with an inpatient rheumatologist (including remote consultation) was performed upon the appearance of signs of an infectious complication | C |
24 | Discontinuation of Colchicum autumnale seed extract/colchicine and/or a bDMARD, and/or an immunosuppressant was performed upon suspicion/development of pneumonia | C |
25 | Hospital admission of the patient was performed upon suspicion/development of pneumonia | C |
26 | The autumn crocus seed extract/colchicine and/or immunosuppressant, and/or biologic DMARD was discontinued upon the development of herpetic infection | C |
27 | Acyclovir was prescribed at a dose of 200 mg daily orally in 5 divided doses for children aged over 2 years (not exceeding 1000 mg/day) upon the development of localized herpetic infection | C |
28 | Autumn crocus seed extract/colchicine and/or biologic DMARD, and/or immunosuppressant was prescribed after complete resolution of clinical and laboratory signs of infection and completion of antiviral therapy | C |
29 | Inpatient hospitalization was performed upon generalization of herpetic infection / suspected cytomegalovirus or Epstein-Barr virus infection | C |
30 | Anti-nuclear antibody (ANA) and anti-DNA antibody testing was performed in all patients receiving TNF-alpha inhibitors at least once every 3 months | C |
31 | Blood immunoglobulin levels and serum CRP were determined at least once every 3 months | C |
32 | Autumn crocus seed extract and/or biologic DMARD, and/or immunosuppressant was discontinued upon a decrease in blood immunoglobulin levels | C |
33 | Consultation with a inpatient rheumatologist (including remote consultation) was performed upon a decrease in blood immunoglobulin levels | C |
34 | Inpatient hospitalization was performed for human normal immunoglobulin replacement therapy upon a decrease in blood immunoglobulin levels | C |
35 | The TNF-alpha inhibitor was discontinued upon an increase in serum anti-nuclear antibodies (ANA) and anti-DNA antibodies | C |
36 | Consultation with an inpatient rheumatologist (including remote consultation) was performed upon an increase in anti-nuclear antibodies (ANA) and anti-DNA antibodies | C |
37 | Focal tuberculin testing (Mantoux test, or recombinant tuberculosis allergen in standard dilution) was performed at least once every 6 months | C |
38 | Complete urinalysis was performed at least once a month | C |
39 | Methotrexate was discontinued upon the appearance of hematuria | C |
40 | Consultation with an inpatient rheumatologist (including remote consultation) was performed upon the appearance of hematuria | C |
41 | Autumn crocus seed extract/colchicine and/or immunosuppressant, and/or biologic DMARD was discontinued upon the development of any signs of intolerance | C |
42 | Consultation with an inpatient rheumatologist (including remote consultation) was performed upon the development of any signs of intolerance to autumn crocus seed extract/colchicine and/or immunosuppressant, and/or biologic DMARD | C |
43 | ECG recording was performed at least once every 3 months | C |
44 | Abdominal and renal ultrasound was performed in all patients at least once every 6 months | C |
45 | Echocardiography was performed in all patients at least once every 6 months. | C |
46 | An initial otorhinolaryngologist consultation (examination) was performed within 2 weeks after hospital discharge to diagnose acute ENT infections and determine treatment management | C |
47 | A follow-up otorhinolaryngologist consultation (examination) was performed for the sanitation of chronic infection foci and treatment of acute ENT infections | C |
48 | A routine dispensary otorhinolaryngologist consultation (examination) was performed at least once every 3 months as part of follow-up care to monitor the condition of the ENT organs | C |
49 | An initial pediatric dentist consultation (examination) was performed within 1 month after hospital discharge to diagnose acute oral cavity infections and determine treatment management | C |
50 | A follow-up pediatric dentist consultation (examination) was performed for patients requiring sanitation of chronic infection foci and treatment of acute oral cavity infections, to prevent infectious complications during anti-rheumatic therapy | C |
51 | A routine dispensary pediatric dentist consultation (examination) was performed for all patients at least once every 3 months as part of follow-up care to monitor the oral cavity, for early detection of pathology and its treatment to prevent infectious complications during anti-rheumatic therapy | C |
52 | An initial nephrologist consultation (examination) was performed for patients with renal involvement to develop an individualized therapy program based on the recommendations of the inpatient nephrologist | C |
53 | A follow-up nephrologist consultation (examination) is recommended for patients with renal involvement | |
54 | A dispensary nephrologist consultation (examination) is recommended as part of follow-up care for patients with renal involvement to monitor the efficacy of the individualized therapy program based on the recommendations of the inpatient nephrologist | |
55 | An initial pediatric cardiologist consultation (examination) was performed for patients with cardiac dysfunction and/or arterial hypertension to develop an individualized cardiotropic and/or antihypertensive therapy program based on the recommendations of the inpatient pediatric cardiologist | C |
56 | A dispensary pediatric cardiologist consultation (examination) was performed for patients with cardiac dysfunction and/or arterial hypertension to monitor the efficacy of the individualized cardiotropic and/or antihypertensive therapy program based on the recommendations of the inpatient pediatric cardiologist | C |
57 | An initial ophthalmologist consultation (examination) with mandatory biomicroscopy was performed within 1 month after hospital discharge for patients with visual system pathology to develop an individualized treatment program based on the recommendations of the inpatient ophthalmologist | C |
58 | A follow-up ophthalmologist consultation (examination) with mandatory biomicroscopy was performed to monitor treatment efficacy and adjust therapy if necessary. | C |
59 | A dispensary ophthalmologist consultation (examination) with mandatory eye biomicroscopy was performed at least once every 6 months | C |
60 | An initial dietitian consultation (examination) was performed for patients with underweight, amyotrophy, osteopenia/osteoporosis, constitutional obesity, Cushing's syndrome, and steroid-induced diabetes to develop an individualized dietary program within 2 weeks after discharge | C |
61 | A follow-up dietitian consultation (examination) was performed to monitor/adjust the individualized dietary program | C |
62 | An initial phthisiatrician consultation (examination) was performed for patients with positive focal tuberculin test results and/or elevated titers and/or focal, infiltrative pulmonary changes to address the issue of chemoprophylaxis or anti-tuberculosis chemotherapy | C |
63 | Consultation with a rheumatology department physician was performed for a patient with a positive intradermal tuberculin test to address the possibility of continuing treatment with autumn crocus seed extract/colchicine and/or immunosuppressant, and/or biologic DMARD | C |
64 | An initial phthisiatrician consultation (examination) was performed for patients with positive focal tuberculin test results and/or focal, infiltrative pulmonary changes to address the issue of chemoprophylaxis or anti-tuberculosis chemotherapy | C |
65 | An initial pediatric endocrinologist consultation (examination) was performed within 2 weeks after hospital discharge for all patients with endocrine pathology to implement an individualized program recommended by the inpatient pediatric endocrinologist | C |
66 | A dispensary pediatric endocrinologist consultation (examination) was performed for patients with endocrine pathology to monitor/adjust the individualized therapy program recommended by the inpatient pediatric endocrinologist | C |
67 | An initial orthopedic trauma consultation (examination) was performed for patients with functional impairment, impaired longitudinal bone growth, subluxations, and back pain within 2 weeks after hospital discharge | C |
68 | A dispensary orthopedic trauma consultation (examination) was performed at least once every 3 months as part of follow-up care to detect functional disorders and monitor orthopedic correction | C |
69 | An initial medical psychologist consultation (testing, examination) was performed within 2 weeks after hospital discharge to develop a psychological rehabilitation program for all children older than 1 year and all parents (regardless of the child's age) | C |
70 | A follow-up medical psychologist consultation (testing, examination) was performed for all children older than 1 year and all parents (regardless of the child's age) after completing the psychological rehabilitation program to assess its efficacy | C |
71 | A dispensary medical psychologist consultation (testing, examination) was performed at least once every 3 months as part of follow-up care to test the psychological state of all children older than 1 year and all parents (regardless of the child's age) | C |
72 | An initial physical therapist consultation (examination, consultation) was performed for patients with functional impairment after hospital discharge to develop a physiotherapy program as part of the medical rehabilitation program within 2 weeks after hospital discharge | C |
73 | Performed initial medical examination (inspection, consultation) by a physical therapy physician for patients with functional impairment after discharge from the inpatient facility to develop an individual physical therapy program as part of the medical rehabilitation program within 2 weeks after discharge from the inpatient facility | C |
74 | Completed the medical rehabilitation program | C |
75 | Performed a follow-up medical examination (inspection, consultation) by a physical therapist to monitor the effectiveness of the individual rehabilitation program | C |
76 | Performed a follow-up medical examination (inspection, consultation) by a physical therapy physician to monitor the effectiveness of the individual rehabilitation program | C |
77 | Performed a routine dispensary medical examination (inspection, consultation) by a physical therapy physician at least once every 3 months as part of the health check-up (dispensary profiling) | C |
78 | Performed urgent referral to the inpatient rheumatology department that initiated the prescription of colchicine (Colchicum autumnale seed extract) and/or bDMARDs/targeted synthetic DMARDs, and/or immunosuppressants, for all patients with a diagnosed FMF upon development of disease exacerbation/complications, comorbid conditions, complications/side effects/persistent intolerance to colchicine (Colchicum autumnale seed extract) and/or immunosuppressants, and/or bDMARDs/targeted synthetic DMARDs for evaluation and treatment adjustment at any stage of therapy | C |
79 | Performed referral for planned hospitalization to the inpatient rheumatology department that initiated therapy with colchicine (Colchicum autumnale seed extract) and/or immunosuppressants, and/or bDMARDs/targeted synthetic DMARDs, for all patients 3 months after initiating therapy; 6 months after initiating therapy, and thereafter every 6 months to monitor the efficacy and safety of pathogenetic therapy | C |
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Ahmadinejad Z, Mansori S, Ziaee V, et al. Periodic Fever: a review on clinical, management and guideline for Iranian patients - part I. Iran J Pediatr 2014;24:1–13.
Chien YL, Huang FL, Huang CM, Chen PY. Clinical approach to fever of unknown origin in children. J Microbiol Immunol Infect. Dec 2017;50(6):893–8.
El-Nawawy A, El-Kinany H, Hamdy El-Sayed M, Boshra N. Intravenous Polyclonal Immunoglobulin Administration to Sepsis Syndrome Patients: A Prospective Study in a Pediatric Intensive Care Unit. J Trop Pediatr. Oct 1 2005;51(5):271–8.
Gülez N, Makay B, Sözeri B. Long-term effectiveness and safety of canakinumab in pediatric familial Mediterranean fever patients. Mod Rheumatol. Jan 2 2020;30(1):166–71.
Rao S, Abzug MJ, Carosone-Link P, Peterson T, Child J, Siparksy G, et al. Intravenous Acyclovir and Renal Dysfunction in Children: A Matched Case Control Study. J Pediatr. Jun 2015;166(6):1462-1468.e4.
Whitley RJ. Herpes simplex virus in children. Curr Treat Options Neurol. May 2002;4(3):231–7.
Antiviral Drugs in Children and Adolescents. Pediatr Infect Dis. Jul 16 2020;1(3):123–8.
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Adler SP, Marshall B. Cytomegalovirus Infections. :11.
Aksenova VA, Baryshnikov LA, Klevno NI, et al. New opportunities for screening and diagnosis of various manifestations of tuberculosis infection in children and adolescents in Russia. Current Pediatrics. 2011;10:16–22.
Koç R, Sönmez HE, Çakan M, Karadağ ŞG, Tanatar A, Çakmak F, et al. Drug reactions in children with rheumatic diseases receiving parenteral therapies: 9 years’ experience of a tertiary pediatric rheumatology center. Rheumatol Int. May 2020;40(5):771–6.
Bockemühl J, Roggentin P. Enterale Yersiniosen: Klinische Bedeutung, Epidemiologie, Diagnostik und Prävention. Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz [Internet]. Jul 2004 [cited 2022 Oct 2];47(7). Available from: http://link.springer.com/10.1007/s00103-004-0865-9
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Appendix A1. Working Group Composition
These clinical guidelines were developed by professional associations: the Association of Pediatric Rheumatologists and the Association of Medical Geneticists.
Approved by the working group of the Association of Pediatric Rheumatologists and the Association of Medical Geneticists.
Working Group of the Association of Pediatric Rheumatologists:
1. Alekseeva E.I., MD, PhD, Professor, Corresponding Member of the RAS
2. Shilgrot I.Yu., Candidate of Medical Sciences
3. Salugina S.O., MD, PhD
4. Dvoryakovskaya T.M., MD, PhD
5. Fedorov E.S., Candidate of Medical Sciences
6. Surkov A.G., Candidate of Medical Sciences
7. Kostik M.M., MD, PhD
8. Nikishina I.P., Candidate of Medical Sciences
9. Ushakova S.A., MD, PhD, Professor
10. Ulyanova E.A., Candidate of Medical Sciences
11. Glazyrina G.A., Candidate of Medical Sciences
12. Zholobova E.S., MD, PhD, Professor
13. Sudareva O.O., Candidate of Medical Sciences
14. Igisheva L.N., MD, PhD, Associate Professor
15. Ligostaeva E.A., Candidate of Medical Sciences
16. Malievsky V.A., MD, PhD, Professor
17. Kriulin I.A., Junior Researcher
18. Kriulina T.Yu., Clinical Postgraduate Student
Working Group of the Association of Medical Geneticists:
1. Kutsev S.I., MD, PhD, Professor, Corresponding Member of the RAS
2. Zakharova E.Yu., MD, PhD
3. Polyakov A.V., Doctor of Biological Sciences
Conflict of interest: the working group members declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target Audience
Pediatricians
Pediatric rheumatologists of pediatric rheumatology departments
Pediatric rheumatologists of pediatric rheumatology offices in outpatient clinics
Pediatric nephrologists of pediatric nephrology departments
Pediatric nephrologists of outpatient pediatric clinics
Medical geneticists
Pediatric surgeons
Immunologists
Medical psychologists
Medical students
Residents
Methods used for collecting/selecting evidence: electronic database search.
Description of methods used for assessing the quality and strength of evidence: the evidence base for the recommendations includes publications from the Cochrane Library, EMBASE, MEDLINE, and PubMed databases. The search depth is 5 years.
Methods used for assessing the quality and strength of evidence:
expert consensus;
assessment of significance in accordance with the rating scheme.
Methods used for analyzing evidence:
reviews of published meta-analyses;
systematic reviews with evidence tables.
Description of methods used for analyzing evidence
When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations.
To minimize potential bias, each study was evaluated independently. Any discrepancies in evaluations were discussed by the full panel of authors. If a consensus could not be reached, an independent expert was involved.
Evidence tables: compiled by the authors of the clinical guidelines.
Methods used for formulating recommendations: expert consensus.
Economic analysis
Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.
Recommendation validation method
External expert review.
Internal expert review.
Description of the recommendation validation method
The draft of these recommendations was reviewed by independent experts who were primarily asked to comment on how comprehensible the interpretation of the evidence underlying the recommendations is.
Feedback was obtained from primary care pediatric rheumatologists regarding the clarity and practical relevance of the proposed recommendations as a daily clinical tool.
All comments received from experts were carefully systematized and discussed by the authors of the recommendations. Each point was discussed individually.
Consultation and peer review
The draft recommendations were reviewed by independent experts who evaluated the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.
Author Contributions
For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.
The clinical guidelines were developed based on a systematic literature review of Medline (Pubmed version), Embase (Dialog version), and Cochrane Library databases from 1992 to 2021, utilizing established protocols of current international clinical guidelines for the diagnosis, treatment, and management of patients with rheumatic diseases.
Because systemic sclerosis-like disorders are rare hereditary conditions, large cohort and randomized controlled trials are precluded; therefore, diagnostic and therapeutic protocols rely solely on expert case studies published over the past two decades.
Key recommendations
Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
1 | Systematic reviews of reference-controlled studies or systematic reviews of randomized clinical trials with meta-analysis |
2 | Individual reference-controlled studies, individual randomized clinical trials, and systematic reviews of studies of any design other than randomized clinical trials with meta-analysis |
3 | Studies without consecutive reference control, studies with a reference method not independent of the evaluated method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports |
5 | Rationale based solely on mechanism of action or expert opinion |
Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definitions |
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design other than RCTs with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Rationale based solely on the mechanism of action of the intervention (preclinical studies) or expert opinion |
Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
A | Strong recommendation (all evaluated efficacy criteria (outcomes) are important, all studies have high or satisfactory methodological quality, and their conclusions regarding the outcomes of interest are consistent) |
B | Conditional recommendation (not all evaluated efficacy criteria (outcomes) are important, not all studies have high or satisfactory methodological quality, and/or their conclusions regarding the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all evaluated efficacy criteria (outcomes) are unimportant, all studies have low methodological quality, and their conclusions regarding the outcomes of interest are inconsistent) |
Appendix A3. Reference Materials
№ | International Nonproprietary Name (INN) of the medicinal product | Timing of therapeutic efficacy monitoring¹ |
|---|---|---|
1 | Colchicum autumnale seed extract /colchicine | At 3 and 6 months from the start of treatment. Thereafter — every 6 months |
2 | Methotrexate** | At 3 and 6 months from the start of treatment. Thereafter — every 6 months |
3 | Sulfasalazine** | At 3 and 6 months from the start of treatment. Thereafter — every 6 months |
4 | Canakinumab** | At 3 and 6 months from the start of treatment. Thereafter — every 6 months |
5 | Anakinra** | At 3 and 6 months from the start of treatment. Thereafter — every 6 months |
6 | Tocilizumab** | At 3 and 6 months from the start of treatment. Thereafter — every 6 months |
7 | Adalimumab** | At 3 and 6 months from the start of treatment. Thereafter — every 6 months |
8 | Etanercept** | At 3 and 6 months from the start of treatment. Thereafter — every 6 months |
9 | Golimumab** | At 3 and 6 months from the start of treatment. Thereafter — every 6 months |
¹ — Therapy adjustment is carried out at any stage of treatment if it is ineffective and/or unsafe.
Appendix B. Physician Action Algorithms
Diagram 1
Diagram 2
Diagram 3
Diagram 4
Diagram 5
Diagram 6
Diagram 7
Appendix C. Patient Information
What is Familial Mediterranean Fever?
Familial Mediterranean Fever (FMF) is a genetic disorder that is inherited. Patients suffer from recurrent attacks of fever accompanied by abdominal or chest pain, or joint pain and swelling. The disease most frequently affects individuals of Mediterranean and Middle Eastern descent, particularly Armenians, Jews (especially Sephardic Jews), Turks, and Arabs.
In the Russian Federation, the majority of patients belong to Armenian and Azerbaijani ethnic groups and the peoples of the North Caucasus. At the same time, FMF can occur, albeit rarely, in patients of any nationality.
How common is this disease?
The prevalence of the disease in high-risk populations is about 1–3 per 1,000. In other ethnic groups, this disease is rare. Nevertheless, since the discovery of the responsible gene, this disease has been diagnosed more frequently, even among populations in which it was considered very rare, such as Italians, Greeks, and Americans.
In approximately 90% of patients, the first FMF attacks begin before the age of 20. In more than half of the patients, the disease manifests during the first decade of life. Boys are affected slightly more often than girls (1.3 : 1).
What are the causes of the disease?
FMF is a genetic disorder. The gene responsible for it is called MEFV. It affects a protein that plays a role in the natural resolution of inflammation. If this gene carries a mutation, as occurs in FMF, such regulation cannot function properly, and patients experience fever attacks.
Is this disease hereditary?
This disease is inherited mainly in an autosomal recessive manner, which means that the parents usually do not exhibit symptoms of the disease. This type of transmission means that for a person to have FMF, both copies of the MEFV gene that a person possesses (one from the mother and the other from the father) must be mutant; thus, both parents are carriers (a carrier has only one mutant copy of the gene, but not the disease).
If the disease is present in a large family, it is likely to be found in a sibling, cousin, uncle, or distant relative. However, as observed in a small percentage of cases, if one of the parents has FMF and the other is a carrier of the mutant gene, there is a 50% probability that their child will inherit the disease. In a small fraction of patients, one or even both copies of the gene turn out to be normal.
Why did my child get this disease? Can this disease be prevented?
Your child has the disease because they are a carrier of the mutant genes that cause FMF.
Is this disease infectious?
No.
What are the main symptoms?
The main symptom of the disease is a periodic increase in body temperature accompanied by pain in the abdomen, chest, or joints. Abdominal pain attacks are the most common, observed in approximately 90% of patients.
Chest pain attacks are noted in 20–40%, and joint pain in 50–60% of patients.
As a rule, children complain of attacks of a specific type, such as recurrent abdominal pain and fever. Nevertheless, some patients experience attacks of various types — separately or in combination.
These attacks are self-limiting in nature (meaning they resolve without treatment) and last from one to four days. The patient's well-being fully recovers by the end of the attack, and they feel well between attacks. Some attacks can be so painful that the patient or family seeks medical attention. Severe abdominal pain attacks can mimic acute appendicitis, and therefore some patients may undergo unnecessary abdominal surgeries, such as appendectomy.
Nevertheless, some attacks, even in the same patient, may be mild enough to be mistaken for a minor upset stomach. This is one of the reasons why FMF is difficult to recognize in a patient. When a child has abdominal pain, they usually experience constipation, but once the pain subsides, softer stools appear.
A child may have a very high fever during one attack and a moderate temperature elevation during another. Chest pain typically affects only one side and can be so severe that the patient is unable to breathe deeply enough. This resolves within a few days.
Typically, only one joint is affected during an attack (monoarthritis). This is usually the ankle or knee joint. The joint can be so swollen and painful that the child cannot walk. In about a third of patients, the skin over the affected joint becomes red. Attacks affecting the joints may last slightly longer than other types of attacks: it can take anywhere from four days to two weeks before the pain completely subsides.
In some children, the only symptom of the disease may be recurrent joint pain and swelling, which is misdiagnosed as acute rheumatic fever or juvenile idiopathic arthritis. In 5–10% of cases, joint involvement becomes chronic and can lead to joint damage.
In some cases, a characteristic FMF skin rash appears, known as "erysipelas-like erythema". As a rule, it is observed on the lower extremities and in the area of the joints. Some children may complain of leg pain.
Rarer forms of attacks include recurrent pericarditis (inflammation of the outer lining of the heart), myositis (muscle inflammation), meningitis (inflammation of the membranes of the brain and spinal cord), and periorchitis (inflammation of the tissues surrounding the testis).
What are the possible complications?
Children with FMF are more likely to develop certain other diseases characterized by inflammation of blood vessels (vasculitis), such as Henoch-Schönlein purpura and polyarteritis nodosa. The most severe complication of FMF in the absence of treatment is the development of amyloidosis.
Amyloid is a specific protein that is deposited in certain organs, such as the kidneys, intestines, skin, and heart, and causes a gradual decline in function, especially of the kidneys. Amyloidosis is not specific to FMF; it is a complication that also develops in other chronic inflammatory diseases if they are not treated properly.
Proteins in the urine can be a key to diagnosis. The detection of amyloid in the intestine or kidneys confirms the diagnosis. Children who receive the proper dose of colchicine are protected from the risk of developing this life-threatening complication.
Does the disease manifest identically in all children?
The disease manifests differently in different children. Furthermore, the type, duration, and severity of attacks can vary each time, even in the same child.
Does the disease differ in children compared to adults?
In general, the manifestations of FMF in children are similar to those observed in adults. However, certain features of the disease, such as arthritis (joint inflammation) and myositis, are more common in childhood. The frequency of attacks generally decreases with age. Periorchitis is detected more often in boys than in adult men. The risk of amyloidosis is higher among untreated patients whose disease began at an early age.
DIAGNOSIS AND TREATMENT
How is this disease diagnosed?
As a rule, the following approach is used for diagnosis:
Clinical suspicion: reasons to suspect FMF arise only after the child has experienced at least three attacks. It is necessary to review a detailed history of ethnic origin, as well as to find out if there are relatives with similar complaints or renal failure.
Parents should be asked to give a detailed description of previous attacks.
Follow-up: a child with suspected FMF should be under careful observation before a definitive diagnosis is made. During this observation period, the patient should, if possible, visit the doctor during an attack for a thorough physical examination and blood tests to assess the presence of inflammation. Typically, these tests become positive during an attack and return to normal or near-normal levels after the attack subsides.
Classification criteria have been developed to help recognize FMF. For various reasons, it is not always possible to observe a child during an attack. Therefore, parents are asked to keep a diary and describe what is happening. They can also use a local laboratory for blood tests.
Response to colchicine intake: children whose clinical examination and laboratory test results strongly suggest a diagnosis of FMF receive colchicine for approximately six months, after which symptoms are reassessed. In the case of FMF, attacks either stop completely or decrease in number, severity, and duration. Only after these steps are completed can a patient be diagnosed with FMF and prescribed lifelong colchicine use.
Because FMF affects a number of different body systems, various specialists may be involved in the diagnosis and treatment of FMF, including physicians (pediatricians, rheumatologists, nephrologists, gastroenterologists).
Genetic testing: recently, it has become possible to perform genetic testing in patients to identify the presence of mutations thought to be responsible for the development of FMF.
A clinical diagnosis of FMF is confirmed if the patient is found to be a carrier of 2 mutant genes, one from each parent. However, the mutations described so far are detected in 70-80% of FMF patients. This means that there are FMF patients with a single mutation or even without any mutation; therefore, the diagnosis of FMF still relies on clinical evaluation. Genetic testing is not available at every medical center.
Fever and abdominal pain are very common complaints in children. Therefore, it is sometimes not so easy to diagnose FMF even in high-risk groups. It may take several years before FMF is recognized. This diagnostic delay should be minimized because untreated patients are at high risk of amyloidosis.
There is a number of other diseases characterized by periodic fever attacks and bouts of abdominal and joint pain. Some of these diseases are also genetic and share certain clinical features, but each has its own distinct clinical and laboratory characteristics.
What is the significance of the tests?
Laboratory tests are very important in diagnosing FMF. Tests such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, complete blood count (CBC), and fibrinogen are important during an attack (within a maximum of 24–48 hours after the onset of the attack) to assess the degree of inflammation. These tests are repeated when the child's symptoms resolve to check whether the analyzed parameters have returned to normal. In about one-third of patients, test results return to normal levels. In the remaining two-thirds, levels drop significantly but remain above the upper limit of normal.
A small amount of blood is also required for genetic testing. Children who are on lifelong colchicine therapy must undergo regular blood and urine tests twice a year to monitor their condition.
Urinalysis is also aimed at detecting the presence of protein and red blood cells in the urine. Temporary changes may occur during attacks, but a persistent increase in urine protein levels may indicate amyloidosis. The physician may then perform a rectal or kidney biopsy.
A rectal biopsy involves taking a very small piece of tissue from the rectum, which is very easy to perform. If the rectal biopsy shows no amyloid, a kidney biopsy is needed to confirm the diagnosis. For a kidney biopsy, the child must spend a night in the hospital. The biopsy tissues are stained and then examined for amyloid deposits.
Can this disease be treated / cured?
FMF cannot be cured, but it can be controlled through lifelong use of colchicine. Thus, periodic attacks can be prevented or reduced, and the development of amyloidosis can be prevented. If the patient stops taking the medication, attacks and the risk of developing amyloidosis will return.
What are the treatment methods?
Treatment for FMF is simple, inexpensive, and not associated with any serious side effects if the medication is taken in the correct dose. Today, the natural product colchicine is the drug of choice for the prophylactic treatment of FMF. Once diagnosed, the child must take the medication for the rest of their life. If the medication is taken correctly, attacks disappear in about 60% of patients, a partial effect is achieved in 30%, and in 5-10% of patients the treatment is ineffective. This therapy not only controls attacks but also eliminates the risk of developing amyloidosis. Therefore, it is essential that doctors repeatedly explain to parents and the patient how important it is to take this medication in the prescribed dose. Strict adherence to medical recommendations is very crucial. With strict adherence to these recommendations, the child can live a normal life and the disease will not affect their life expectancy. Parents should not change the dose of the medication without consulting a physician.
The dose of colchicine should not be increased during an already active attack, as such an increase is ineffective. An important objective is the prevention of attacks.
In patients resistant to colchicine, biological agents are used.
What are the side effects of drug therapy?
It is not easy to accept that a child must take pills at all times. Parents often worry about potential side effects of colchicine. This drug is safe; it causes only minor side effects that usually resolve when the dose is reduced. The most common side effect is diarrhea. Some children are unable to adhere to the prescribed dose due to frequent watery stools. In such cases, the dose should be reduced until it is well tolerated by the child, and then slowly increased again in small steps to the appropriate dose. Dietary lactose content may also be reduced for 3 weeks, and gastrointestinal symptoms often disappear.
Other side effects include nausea, vomiting, and abdominal cramps. In rare cases, the drug may cause muscle weakness. Peripheral blood cell counts (white and red blood cells and platelets) may sometimes decrease, but these parameters recover upon dose reduction.
How long should treatment last?
FMF requires lifelong prophylactic treatment.
What about alternative or complementary therapy?
There is no known complementary therapy for FMF.
What periodic check-ups are necessary?
Children undergoing treatment must have blood and urine tests at least twice a year.
How long will the disease last?
FMF is a lifelong condition.
What is the long-term prognosis of the disease (expected outcome and course)?
With proper lifelong use of colchicine, children with FMF live normal lives. In case of delayed diagnosis or non-compliance with the treatment regimen, there is a risk of developing amyloidosis, in which case the prognosis is poor. Children who develop amyloidosis may require a kidney transplant.
Growth retardation is not a significant problem in FMF. In some children, growth recovery during puberty occurs only after colchicine treatment.
Is a complete cure possible?
No, because it is a genetic disease. However, lifelong colchicine therapy gives the patient the opportunity to live a normal life, without restrictions and without the risk of developing amyloidosis.
DAILY LIFE
How can the disease affect the child and the family's daily life?
The child and their family face significant problems even before the disease is diagnosed. The child requires frequent consultations due to severe abdominal, chest, or joint pain. Some children undergo unnecessary surgery due to misdiagnosis. Once the diagnosis is made, the goal of treatment should be to enable both the child and their parents to live an almost normal life. FMF patients require long-term regular treatment, so disruptions in the colchicine regimen may occur. Failure to adhere to the medication regimen can put the patient at risk of developing amyloidosis.
A significant issue is the psychological burden of lifelong treatment. Psychological support and educational programs can be of great help to patients and their parents.
School
Frequent attacks cause serious problems with school attendance, and colchicine treatment helps to reduce this problem.
Informing teachers about the disease can be useful, in particular so they know how to act in the event of an attack.
Sports and physical activity
Patients with FMF who receive lifelong colchicine can engage in any sport of their choice. The only issue may be prolonged bouts of joint inflammation, which can lead to restricted movement in the affected joints.
Diet
There are no special dietary recommendations.
Can a child be vaccinated?
A child can and should be vaccinated; however, the attending physician must be informed of the condition before vaccination so that appropriate individualized recommendations can be provided. Live vaccines are contraindicated.
What about sex life, pregnancy, and contraception?
FMF patients may experience fertility issues prior to colchicine treatment, but once colchicine is prescribed, this problem resolves. At the doses used for treatment, a decrease in sperm count is very rare. Female patients should not stop taking colchicine during pregnancy or breastfeeding.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Appendix G1. Evaluation of Therapy Efficacy
Russian title: Childhood Health Assessment Questionnaire
Original title (if applicable): Childhood Health Assessment Questionnaire (CHAQ)
Source (official developer website, validation publication): Kuzmina, N. N., Nikishina, I. P., Shaikov, A. V., Ruperta, N., Shelepina, T. A., & Salugina, S. O. (2002). Russian adapted version of questionnaires for assessing the quality of life and health status of children with juvenile chronic arthritis. Scientific and Practical Rheumatology, (1), 40-44.
Type (underline): - questionnaire
Childhood Health Assessment Questionnaire (CHAQ) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
In this section, we want to obtain information on how your child's illness affects their ability to cope with daily life. You may write any comments on the back of this page. When answering the questions, you should check the one response that best reflects the child's physical abilities (average condition throughout the day) OVER THE PAST WEEK. CONSIDER ONLY THOSE PROBLEMS THAT ARE CAUSED BY THE ILLNESS. If the child is unable to perform any function due to age, use the term "Not applicable". For example, if your child has difficulty performing certain functions or cannot perform them at all due to age, but this is not related to their illness, use the term "NOT applicable". | ||||||||||
Without difficulty | With some difficulty | With much difficulty | Unable to do | Not applicable | ||||||
1. DRESSING AND GROOMING | ||||||||||
Are you able/Is your child able to: | ||||||||||
- Dress, including tying shoelaces and buttoning up? | | | | | | |||||
- Shampoo hair? | | | | | | |||||
- Take off socks? | | | | | | |||||
- Cut toenails? | | | | | | |||||
2. ARISING | ||||||||||
Are you able/Is your child able to: | ||||||||||
- Stand up from a low armchair or the floor? | | | | | | |||||
- Get in and out of bed or get up from a crib? | | | | | | |||||
3. EATING | ||||||||||
Are you able/Is your child able to: | ||||||||||
- Cut a piece of meat? | | | | | | |||||
- Lift a cup or glass to the mouth? | | | | | | |||||
- Open a new cereal box? | | | | | | |||||
4. WALKING | ||||||||||
Are you able/Is your child able to: | ||||||||||
- Walk outdoors on flat ground? | | | | | | |||||
- Climb 5 steps? | | | | | | |||||
Indicate what DEVICES AND AIDS your child uses when performing the specified functions: | ||||||||||
- Cane | | - Dressing aids (button hook, zipper pull, long-handled shoehorn, etc.) | | |||||||
- Walker | | - Built-up or special pencil | | |||||||
- Crutches | | - Special or raised chair | | |||||||
- Wheelchair | | - Other (Please specify: ________________________) | | |||||||
Indicate for which daily activities your child requires DUE TO ILLNESS the help of another person: | ||||||||||
- Dressing and Grooming | | - Eating | | |||||||
- Arising | | - Walking | | |||||||
Without difficulty | With some difficulty | With much difficulty | Unable to do | Not applicable | ||||||
5. HYGIENE | ||||||||||
Are you able/Is your child able to: | ||||||||||
- Wash and dry entire body? | | | | | | |||||
- Get in and out of the tub? | | | | | | |||||
- Sit down and get up from the toilet or potty? | | | | | | |||||
- Brush teeth? | | | | | | |||||
- Comb hair? | | | | | | |||||
6. REACH | ||||||||||
Are you able/Is your child able to: | ||||||||||
- Reach and get down a heavy object from head level (large toy, books)? | | | | | | |||||
- Bend down and pick up clothing or a piece of paper from the floor? | | | | | | |||||
- Put on a sweater over the head? | | | | | | |||||
- Turn neck to look back? | | | | | | |||||
7. GRIPPING | ||||||||||
Are you able/Is your child able to: | ||||||||||
- Write with a pen/pencil? | | | | | | |||||
- Open a car door? | | | | | | |||||
- Open a previously opened jar? | | | | | | |||||
- Open and close a water faucet? | | | | | | |||||
- Open a door after turning the doorknob? | | | | | | |||||
8. ACTIVITIES | ||||||||||
Are you able/Is your child able to: | ||||||||||
- Run errands outside the home, go shopping? | | | | | | |||||
- Get in and out of a car, a child car seat, a school bus? | | | | | | |||||
- Ride a bicycle? | | | | | | |||||
- Do household chores (wash dishes, take out the trash, vacuum, do yard work, make the bed and tidy the room)? | | | | | | |||||
- Run and play? | | | | | | |||||
Indicate the DEVICES needed by the child when performing the following activities: | ||||||||||
- Raised toilet seat | | - Special bathroom grab bar | | |||||||
- Special bath seat | | - Long-handled devices to reach things? | | |||||||
- Can opener (if the jar is already open) | | - Long-handled bathing sponge/brush? | | |||||||
Indicate the daily activities in which the child NEEDS additional help from others DUE TO ILLNESS: | ||||||||||
- Hygiene | | - Gripping and opening objects | | |||||||
- Reaching for items | | - Running errands and housework | | |||||||
9. PAIN: In addition, we would like to clarify whether your child's illness is accompanied by pain or not? If "YES", rate the pain your child has experienced OVER THE PAST WEEK? Rate your child's pain by marking it on a special line | ||||||||||
No pain 0 100 Very severe pain | ||||||||||
FINAL ASSESSMENT: Considering all the negative aspects of the illness, give an overall assessment of your child's health status by marking it on a special line: Very good 0 ______________________________________________________________________ 100 Very poor | ||||||||||
1990 ã Original version Singh G et al. 1999 ã Cross-cultural adapted version Kuzmina N, Shaikov A et al for PRINTO
Appendix G2. Visual Analog Scale (VAS)
Russian title: Visual Analog Scale (VAS)
Original title (if available): Visual Analog Scale for Pain (VAS Pain)
Source (official developer website, validation publication): Hawker G.A., Mian S., Kendzerska T., French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken) 2011;63(Suppl 11):S240–52
Type (underline): - assessment scale
Content (template), key (interpretation): The patient's condition is assessed based on the subjective rating by the patient themselves or their parents and the disease activity assessed by the physician.
The following are performed:
a) general health status assessment based on the subjective rating of the patient or their parents using a 100 mm VAS in scores.
"0" scores correspond to very good health, "100" scores to very poor health. The child or parent marks a point on the line corresponding to their perception of health status. Then, using a ruler, the distance between the selected point and "0" is measured. The resulting value is measured in mm (scores) from 0 to 100.
b) physician's global assessment of disease activity using a 100 mm VAS (points), where "0" is no activity, and "100" is the highest disease activity.
The physician marks a point on the line corresponding to their assessment of the health status. Then, using a ruler, the distance between the selected point and "0" is measured. The resulting value is measured in mm (scores) from 0 to 100.
Appendix G3. Treatment adherence scale for familial Mediterranean fever.
Medication adherence scale in familial mediterranean fever (MASIF)
Russian title:
Treatment adherence scale for familial Mediterranean fever
Original title (if any): Medication adherence scale in familial Mediterranean fever (MASIF)
Source (official developers' website, validation publication): Yesilkaya S, Acıkel C, Eren Fidanci B, Sozeri B, Aktay Ayaz N, Akıncı N, Ozcelik G, Kavukcu S, Aydogan U, Ozenc S, Emre S, Donmez O, Yuksel S, Delibas A, Berdelli A, Poyrazoglu H, Saldir M, Cakar N, Peru H, Bakkaloglu S, Tabel Y, Sari O, Polat A, Basbozkurt G, Unsal E, Gok F, Kasapcopur O, Ozen S, Demirkaya E, FMF Arthritis Vasculitis and Orphan disease Research in Paediatric Rheumatology (FAVOR). Developing of a new scale for assessing the adherence to colchicine’s treatment in pediatric patients with FMF. Pediatr Rheumatol. 2013;11 Suppl 2:P194.
Type (underline): - assessment scale
Content (template):
N | Question | Score* |
|---|---|---|
1 | I know about my illness and know that my treatment will continue for a long time | |
2 | Sometimes I forget to take my medications | |
3 | I rely on the treatment prescribed by my doctor for my illness | |
4 | I refrain from taking other medications for my illness, except those prescribed by my doctor | |
5 | Taking medications constantly affects my daily life | |
6 | When I am away from home (on vacation, traveling, etc.), I forget to take my medication | |
7 | I wish this illness could be cured without medications. | |
8 | Sometimes I do not take my medications on time because of my daily routine | |
9 | I think the course of my illness will improve if I take my medication regularly | |
10 | I am aware of the side effects of the medication prescribed for my illness. | |
11 | I need to be persuaded to take my medications regularly, for a long time. | |
12 | I am afraid that constant medication intake may lead to other diseases. | |
13 | If I stop taking my medication, my disease may flare up | |
14 | I cannot get used to taking medication regularly | |
15 | When I realize I forgot to take my medication, I take it even if delayed, but I do not skip a dose. | |
16 | When I stop taking the medication, my symptoms may worsen. | |
17 | I am tired of constantly taking medication | |
18 | I find it quite difficult to take medication in multiple doses throughout the day |
Participants answer each question on a Likert scale (1 – strongly agree, 2 – agree, 3 – do not know, 4 – disagree, 5 – strongly disagree). The total score ranges from 18 to 90.
Key (interpretation):
On this scale, a high score indicates good treatment adherence. The generally accepted cut-off value is 60 points.
A score greater than 60 indicates "good treatment adherence" and a score of less than 60 indicates "poor treatment adherence".
Appendix G4. Assessment of Treatment Response in Familial Mediterranean Fever by FMF50
Russian title: Assessment of treatment response in familial Mediterranean fever using the FMF50 score.
Original title (if any): FMF50
Source (official developer website, validation publication): Ozen S, Demirkaya E, Duzova A, Erdogan O, Erken E, Gul A, Kasapcopur O, Kasifoglu T, Kisacik B, Ozdogan H, Tunca M, Acikel C. FMF50: a score for assessing outcome in familial Mediterranean fever. Ann Rheum Dis. 2014;73(5):897–901.
Type (underline): - assessment scale
Content (template):
1. | Percentage change in attack frequency during treatment |
|---|---|
2. | Percentage change in attack duration during treatment |
3. | Patient's / parent's global assessment of disease severity (10 cm VAS) |
4. | Physician's global assessment of disease severity (10 cm VAS) |
5. | Percentage change in arthritis attacks during treatment |
6. | Percentage change in CRP, ESR, or SAA levels during treatment |
Key (interpretation):
A 50% response is defined as at least a 50% improvement in at least five of the six criteria with no worsening in any of them.
Appendix G5. Autoinflammatory Disease Activity Index (AIDAI)
Russian title: Auto-Inflammatory Diseases Activity Index
Original title (if any): Auto-Inflammatory Diseases Activity Index (AIDAI)
Source (official developer website, validation publication): Piram M, et al. Ann Rheum Dis. 2014;73:2168-73.
Type (underline): - index
Each line corresponds to a day of the month; the diary is completed throughout the flare period. Symptoms are rated as present (1) or absent (0); a separate diary must be used for each month. If no flare occurred during the month, the diary is left blank; only symptoms related to the autoinflammatory disease are recorded.
Key (interpretation):
A total AIDAI score <9 points allows for distinguishing inactive patients from active patients (with a total score ≥9 points).
Appendix G6. International Severity Scoring System for Familial Mediterranean Fever
Russian title: International Severity Scoring System for Familial Mediterranean Fever
Original title (if any): none
Source (official developer website, validation publication): Demirkaya E, Acikel C, Gul A, Gattorno M, Ben-Chetrit E, Ozdogan H, Hashkes P, Polat A, Livneh A, Ozen S. PReS-FINAL-2328 Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF). Ann Rheum Dis 2016 Jun;75(6):1051-6. doi: 10.1136/annrheumdis-2015-208671. Epub 2016 Jan 28.
Type (underline): - rating scale
Criterion | Points | |
|---|---|---|
1. | Chronic consequences (including amyloidosis, growth retardation, anemia, splenomegaly) | 1 |
2. | Organ dysfunction (nephrotic proteinuria) | 1 |
3. | Organ failure (focal, renal, etc.) | 1 |
4a. | Attack frequency (average number of attacks 1 to 2 per month) | 1 |
4b. | Attack frequency (average number of attacks >2 per month) | 1 |
5. | Elevated acute-phase reactants (CRP, SAA, ESR, fibrinogen) during the intercritical period, 2 weeks after the last attack (at least twice with a 1-month interval) | 1 |
6. | Involvement of more than two sites during a single acute attack (pericarditis, pleuritis, peritonitis, synovitis, elevated liver enzymes, scrotal involvement, vaginitis, myalgia, etc.) | 1 |
7. | More than two different types of attacks during the disease course (isolated fever, pericarditis, pleuritis, peritonitis, synovitis, elevated liver enzymes, scrotal involvement, vaginitis, myalgia, etc.) | 1 |
8. | Attack duration (>72 hours in at least three attacks per year) | 1 |
9. | Exertional leg pain (pain after standing and/or exercise, excluding other causes) | 1 |
Key (interpretation):
Severity is assessed by summing the scores for each parameter.
Result: 3–5 points – "mild", 6–8 – "moderate", and ≥9 – "severe disease".
Appendix G7. Assessment of familial Mediterranean fever severity according to Pras et al.
Russian title: Assessment of familial Mediterranean fever severity according to Pras et al.
Original title (if any): none
Source (official developer website, validation publication): Pras E, Livneh A, Balow Jr JE, Pras E, Kastner DL, Pras M, Langevitz P. Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet. 1998;75(2):216–9.
Type (underline): - index
Parameter | Value | Score |
|---|---|---|
Age of onset (years) | >31 | 0 |
21-31 | 1 | |
11-20 | 2 | |
6-10 | 3 | |
<6 | 4 | |
Number of attacks per month | <1 | 1 |
1-2 | 2 | |
>2 | 3 | |
Arthritis | acute | 2 |
chronic | 3 | |
Erysipelas-like erythema | 2 | |
Amyloidosis | 3 | |
Colchicum autumnale seed extract / colchicine dose (mg/day) | 1 | 1 |
1,5 | 2 | |
2 | 3 | |
>2 | 4 |
Key (interpretation):
Severity is assessed by summing the scores for each parameter.
Result: 3–5 points – "mild", 6–8 – "moderate", and ≥9 – "severe disease".
Appendix G8. Autoinflammatory Disease Damage Index (ADDI)
Russian title: Autoinflammatory Disease Damage Index
Original title (if any): Autoinflammatory Disease Damage Index
Source (official developer website, validation publication): TER HAAR NM, van DELFT ALJ, ANNINK KV et al.: In silico validation of the Autoinflammatory Disease Damage Index. Ann Rheum Dis 2018; 77: 1599-605.
Type (underline): - index
Affected systems | *Severity | **Score |
|---|---|---|
Reproductive system: | Maximum 2 | |
Reproductive dysfunction/infertility | 2 | |
Amenorrhea | 1 | |
Renal component/amyloidosis | Maximum 6 | |
Amyloidosis | Localized/Generalized | 2/3 |
Proteinuria | 1 | |
Renal impairment | Moderate/Severe | 2/3 |
Developmental abnormalities | Maximum 3 | |
Growth retardation | 2 | |
Delayed puberty | 1 | |
Serositis | Maximum 1 | |
Serosal scarring | 1 | |
Neurological | Maximum 6 | |
Developmental delay | 2 | |
Cognitive impairment | 3 | |
Increased intracranial pressure | 2 | |
Central nervous system involvement | 3 | |
Hearing | Maximum 2 | |
Hearing loss | Moderate/Severe | ½ |
Vision | Maximum 3 | |
Ocular involvement | Mild/Moderate/Severe | 1/2/3 |
Musculoskeletal system | Maximum 4 | |
Joint mobility restriction | 2 | |
Bone deformation | 2 | |
Osteoporosis | 1 | |
Bone/muscle pain | 1 | |
The total ADDI score is determined as the sum of 8 categories (maximum 27) | ||
*Severity: the score depends on the severity of damage. Amyloidosis: localized, involving a single organ; generalized, involving more than one organ. Renal impairment: moderate, GFR between 15 and 60 ml/min/1.73 m²; severe, GFR <15 ml/min/1.73 m², dialysis, or transplantation. Hearing loss: moderate, hearing impairment not requiring hearing aids or cochlear implants; severe, hearing impairment requiring hearing aids or cochlear implants. Ocular involvement: mild, impairment not resulting in visual impairment; moderate, impairment resulting in visual impairment; severe, practical blindness.
**Score assigned according to system damage. For systems with a severity scale, the lowest score value corresponds to mild manifestations, and the highest value corresponds to severe manifestations. The score for each category is capped at a maximum value.
Glossary of Terms:
Amenorrhea: primary amenorrhea is the absence of menarche by age 16 or the absence of menarche within 5 years after thelarche in females. Secondary amenorrhea is the absence of menstruation for 6 consecutive months or more in females who previously menstruated.
Amyloidosis: symptomatic amyloidosis confirmed by Congo red staining of tissue sections or serum amyloid P (SAP) scintigraphy.
Bone deformation: bone deformation or hypertrophy confirmed clinically and/or by imaging studies.
Central nervous system involvement: focal neurological deficit (gross and/or minor sensorimotor), generalized deficit (e.g., memory, behavior), seizures, and spinal cord symptoms. Neuropsychiatric disorders unrelated to the disease should not be scored.
Cognitive impairment: need for special education due to cognitive impairment, or an IQ <70 according to neuropsychological assessment or equivalent systems.
Developmental delay: failure to achieve developmental milestones, including language/speech, motor, social/emotional, and cognitive milestones.
Increased intracranial pressure: signs and/or symptoms of increased intracranial pressure confirmed by appropriate methods.
Growth retardation: defined as the presence of at least two of the following three features:
- Height below the 3rd percentile or -2 standard deviations (SD) for age
- Growth velocity below the 3rd percentile or -2 SD for age
- Crossing of at least 2 percentile lines (5th, 10th, 25th, 50th, 75th, 90th, 95th) on the growth chart
For patients older than 18 years: pathologically short stature (e.g., below the 3rd percentile or -2 standard deviations for the normal population).
Hearing loss: sensorineural hearing loss confirmed by audiometry or other age-appropriate methodology, or the need for hearing aids or a cochlear implant.
Infertility: a disorder of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse, not due to known abnormalities in a healthy partner.
Joint mobility restriction: fixed limitation in the normal range of joint motion affecting function, with or without destructive arthropathy or avascular necrosis.
Musculoskeletal pain: non-inflammatory musculoskeletal pain impairing daily activities.
Ocular damage: damage to the eyes (e.g., optic atrophy, increased intraocular pressure, or cataract) confirmed by an ophthalmologist, with or without visual impairment.
Osteoporosis: decreased bone mineral density with spinal collapse and/or pathological fractures confirmed by imaging methods, which may include bone densitometry. Requires evidence of both decreased bone density and fragility; "low bone density" alone is insufficient.
Proteinuria: persistent urine protein-to-creatinine ratio >20 mg/mmol in the first morning urine sample; and/or 24-hour urinary protein excretion >0.3 g/24 h, or urine albumin-to-creatinine ratio >15 mg/mmol.
Delayed puberty: Tanner stage below -2 SD for age or below the 3rd percentile for age, or any Tanner stage following pharmacological induction.
Renal impairment: glomerular filtration rate (GFR) <60 ml/min/1.73 m², dialysis, or transplantation.
Serosal scarring: symptomatic adhesions or fibrosis involving the pericardium, pleura, peritoneum, and/or retroperitoneum, confirmed by imaging, endoscopy, or surgery.
Appendix G9. Criteria for Inactive Disease Stage / Remission
Russian title: Criteria for clinical inactive disease / remission, (C. Wallace et al., 2011)
Original title (if available): Criteria for clinical inactive disease (CID)
Source (official developer website, validation publication): Wallace C. A. et al. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis //Arthritis care & research. – 2011. – Vol. 63. – No. 7. – pp. 929-936.
Content (template), key (interpretation):
1. Absence of joints with active arthritis
2. Absence of fever, rash, serositis, splenomegaly, or generalized lymphadenopathy
3. Absence of active uveitis
4. Normal ESR and/or CRP levels
5. Absence of disease activity by physician global assessment (using VAS);
6. Morning stiffness duration of less than 15 minutes.
To establish the absence of disease activity (inactive disease state), the patient must meet all of the listed criteria.
Pharmacological clinical remission is established when the disease is in an inactive state while on medication therapy for 6 consecutive months.
Non-pharmacological clinical remission is established when the disease is in an inactive state for 12 consecutive months without anti-rheumatic drugs.
The "Remission duration" indicator is expressed in months elapsed since the onset of the inactive phase of the disease.
Appendix G10. 71-Joint Disease Activity Score (JADAS71)
Name in Russian: Disease Activity Index in 71 Joints; Juvenile Arthritis Disease Activity Score (JADAS71)
Original title (if applicable): Juvenile Arthritis Disease Activity Score (JADAS71)
Source (official developer website, validation publication): Consolaro A. et al. Development and validation of a composite disease activity score for juvenile idiopathic arthritis //Arthritis Care & Research: Official Journal of the American College of Rheumatology. – 2009. – Vol. 61. – No. 5. – P. 658-666.
Type (underline): index
Content (template):
Number of joints with active arthritis
Physician global assessment of disease activity on a 100 mm VAS; 0 – minimum activity, 10 cm – maximum activity, where centimeters are equated to points
Parent/patient global assessment of health status on a 100 mm VAS; 0 cm – very good health, 10 cm – very poor health, where centimeters are equated to points
Erythrocyte sedimentation rate. To construct the 0 to 10 scale, the following formula was used: (ESR - 20)/10. A value of less than 20 mm/h is scored as 0 points, and greater than 120 mm/h as 10 points.
Key (interpretation):
The final JADAS71 index is calculated as the sum of all components (0–101).
An index of JADAS71 <1 point corresponds to the stage of inactive disease.