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
AOSD – Adult-onset Still's disease
VAS – Visual analogue scale
IBD – Inflammatory bowel disease
BBDs – Biologic Disease-Modifying Antirheumatic Drugs (interleukin inhibitors L04AC)
GCs – Glucocorticoids (H02AB)
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 – Nonsteroidal anti-inflammatory and antirheumatic drugs (M01A)
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
SS – Schnitzler syndrome
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 – Electrocardiogram
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 syndrome
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
…** – medication included in the List of Vital and Essential Drugs for medical use
…# – "information on the method of administration, dose, and duration of use of the medicinal product, including references to clinical trials of the efficacy and safety of the applied dosing regimen for the given disease, or references to relevant literature sources if the recommendation thesis refers to a medicinal product used for medical application off-label (not in accordance with the indications for use, contraindications, methods of administration, and doses contained in the instructions for medical use)".
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.
Major histocompatibility complex class I 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 average peptide length is 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.
Major histocompatibility complex class II molecules (DP, DM, DOA, DOB, DQ, DR) – present antigens from the extracellular space to T lymphocytes. Some antigens stimulate the division of T helper cells, which then stimulate B cells to produce antibodies against that antigen. Molecules of this class are located on the surface of antigen-presenting cells: dendritic cells, macrophages, B lymphocytes. Major histocompatibility complex class III molecules encode components of the complement system, proteins present in the blood.
Rheumatoid factor (RF) – autoantibodies that react as autoantigens 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 – inflammation of entheses, at the specific site where tendons and ligaments attach to bone.
Juvenile ankylosing spondylitis (JAS) – a chronic inflammatory disease from the group of spondyloarthritides, characterized by mandatory involvement of the sacroiliac joints and/or spine with potential progression to 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
Cryopyrin-Associated Periodic Syndromes (CAPS) are monogenic (hereditary) autoinflammatory diseases (AIDs) characterized by a chronic relapsing course, fever, recurring urticaria-like skin rashes, ocular disorders (conjunctivitis, uveitis), a wide spectrum of joint involvement ranging from arthralgia to persistent arthritis, involvement of the central and peripheral nervous system, development of sensorineural hearing loss, amyloidosis (in 20-40% of patients), renal failure, and potential mortality. These diseases are almost always accompanied by elevated acute-phase reactants (ESR, CRP, SAA), while autoantibodies (RF, ANA, etc.) are absent [1–5].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
CAPS are inherited in an autosomal dominant manner and are transmitted by an affected parent carrying an abnormal gene copy (every human has 2 copies of all genes). The risk of transmitting the mutated gene copy and the disease from an affected carrier parent is 50%.
CAPS are caused by a mutation in the NLRP3 gene (also known as CIAS1, NALP3, PYPAF1, CATERPILLER1.1), which is located on the long arm of chromosome 1 and encodes the cryopyrin protein.
Cryopyrin belongs to the family of intracellular NOD-like receptors (NLRs), containing a pyrin domain, a nucleotide-binding domain (NBS), and a leucine-rich repeat (LRR) domain. It consists of 1034 amino acid residues with a molecular weight of 117.9 kDa. It forms molecular oligomers as a chain of a small number of identical subunits and binds to the ASC adapter protein.
Cryopyrin plays a key role in the development of a genetically determined inflammatory response. When activated, it is capable of binding to other proteins to form a large molecular complex—the inflammasome—in macrophages and neutrophils.
The inflammasome is a multi-protein oligomeric complex involved in the activation of the inflammatory response, including NLRP3 (cryopyrin), the ASC auxiliary protein (apoptosis-associated speck-like protein containing a CARD), and procaspase-1; it promotes the production of pro-inflammatory cytokines (IL-1β and IL-18); it stimulates pyroptosis, a specific type of programmed cell death; and normally provides defense against foreign microorganisms (bacteria and viruses).
Mutations in the NLRP3 gene lead to uncontrolled activation of the NLRP3 inflammasome, increased expression of IL-1β, and the development of the clinical picture of an autoinflammatory disease.
The development of clinical manifestations of the disease (fever, rash, and others) and pathological changes in laboratory parameters (leukocytosis, elevated C-reactive protein, ESR, SAA) are associated with the overproduction of the pro-inflammatory cytokine IL-1β.
A mutation in the NLRP3 gene is detected in 60% of patients with CAPS, 50–70% with MWS, and 65–75% with CINCA/NOMID. Familial cases of the disease have been described. The majority of CINCA/NOMID cases are sporadic [2,3,5].
1.3 Epidemiology of the Disease or Condition
Data on the prevalence of CAPS worldwide vary and are often unreliable due to low physician awareness and underdiagnosis. The prevalence of CAPS varies depending on the variant and region of residence, but overall is 1–3 cases per 1,000,000. According to the EUROFEVER registry data from 32 countries, approximately 150 patients with CAPS are registered worldwide. In the USA, the prevalence of CAPS is about 1:1,000,000, although formal studies have not been conducted, and the likely number of undiagnosed cases, especially MWS, may be higher. In France, the incidence of MWS is 1:360,000. The age of onset for FCAS and CINCA/NOMID is very early (practically from birth), while MWS can debut in childhood or adulthood, developing in older children and adolescents in 2/3 of cases. Boys and girls are affected with equal frequency. Flares are directly related to cold exposure in FCAS. Cold may act as a trigger for inflammatory episodes in MWS, but such a correlation is less frequently observed. CINCA/NOMID debuts and progresses independently of triggering factors [2,3,5,6].
1.4 Features of Coding the Disease or Condition
D89.8 Other specified disorders involving the immune mechanism, not elsewhere classified
1.5 Classification of the disease or condition
In the modern classification of monogenic (hereditary) and multifactorial AIDs, CAPS are presented under the heading "systemic inflammation with urticarial rash" [7].
1.5.1 New Eurofever/PRINTO classification criteria for CAPS in the presence of molecular genetic testing
New Eurofever/PRINTO classification criteria for CAPS in the presence of molecular genetic testing are presented in Table 1.
Table 1. Eurofever/PRINTO classification criteria for CAPS in the presence of molecular genetic testing [8,9].
Presence of a confirmatory NLRP3 genotype* and at least one of the criteria listed below: |
|---|
|
OR in the absence of a confirmatory NLRP3 genotype†, the presence of at least two of the criteria listed below: |
Urticarial rash Redness of the eyes (conjunctivitis, episcleritis, uveitis) Sensorineural hearing loss |
A patient with a confirmed elevation of acute-phase inflammatory markers (ESR, or CRP, or SAA) clearly correlating with the clinical manifestations of the disease, with a thorough exclusion of potential masking conditions (oncological, infectious, autoimmune, and other congenital immune response anomalies), and a disease history duration of at least 6 months, may 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-position (a genotype with two different mutant alleles at the same locus – in autosomal recessive inheritance of the disease. †Variants of uncertain clinical significance (VUS). Benign or likely benign variants are excluded. |
1.5.2 Eurofever/PRINTO clinical classification criteria for CAPS*
The diagnosis of CAPS is established based on a combination of anamnestic and clinical data, laboratory test results (biochemical and molecular genetic analysis). Diagnostic criteria for CAPS are presented in Table 2.
Table 2. Eurofever/PRINTO clinical classification criteria for CAPS*[10].
Mandatory criterion | Additional criteria |
|---|---|
elevated inflammatory markers (CRP/SAA) | urticaria-like rash episodes triggered by cold or stress sensorineural hearing loss musculoskeletal symptoms (arthralgia/arthritis/myalgia) chronic aseptic meningitis skeletal abnormalities (epiphyseal overgrowth/frontal bossing) |
A CAPS diagnosis is established if the obligatory criterion is present in combination with ≥ 2 of the 6 additional criteria. | |
*These criteria can be used as a potential tool for referring a patient with suspected CAPS for molecular genetic testing, or as classification criteria if genetic testing is not feasible.
1.6 Clinical presentation of the disease or condition
CAPS are represented by three variants that differ in severity, prognosis, and the nature of developing complications:
Familial Cold Autoinflammatory Syndrome / Familial Cold Urticaria (FCAS / FCU);
Muckle-Wells Syndrome (MWS);
Chronic Infantile Onset Neurologic Cutaneous Articular / Neonatal Onset Multisystem Inflammatory Disease (CINCA / NOMID).
Currently, they are regarded as clinical variants of a single disease with varying manifestation severity, degree of pathological process severity, and outcomes. FCAS is quite rare, often has a benign course, and does not lead to serious life-threatening conditions. MWS and CINCA/NOMID are the most severe in terms of manifestations, outcomes, and prognosis [1–5].
All three variants of CAPS represent different clinical variants of the disease course with a clinical picture of varying severity: from mild to severe.
Common symptoms include fever, urticaria-like rash, musculoskeletal system involvement, central and peripheral nervous system involvement, ocular involvement, development of renal amyloidosis (in 20–40% of patients), and renal failure [3,6,11]. A fatal outcome is possible.
1.6.1 Clinical presentation of familial cold autoinflammatory syndrome
Familial Cold Autoinflammatory Syndrome (FCAS) manifests as urticarial rashes and fever occurring upon exposure to cold.
In 95% of cases, the disease debuts in the first 6 months of life, often noted from birth. The disease manifests as episodes of fever, urticaria-type rash, and arthralgia triggered by exposure to cold, wind, or abrupt temperature changes. Fever typically does not reach high values. Additionally, fever episodes may be accompanied by conjunctivitis, sweating, somnolence, headache, excruciating thirst, and nausea. Symptoms appear 1–2 hours after cold exposure, peak at 6–8 hours from onset, and disappear within 24 hours. Episodes occur more frequently during the cold season. Cases of amyloidosis in FCAS are exceptionally rare (2–4%).
1.6.2 Clinical presentation of Muckle-Wells syndrome
Muckle-Wells Syndrome (MWS) is intermediate in severity among CAPS and is characterized by recurrent episodes of fever and urticarial rash accompanied by symptoms of joint and eye involvement [1,12–14].
Disease onset is possible in both childhood and adulthood. The rash is urticaria-like, predominantly non-pruritic, generalized, affecting almost all parts of the body: extremities, trunk, face. Rashes can be maculopapular or erythematous. Sizes range from pinpoint (2–5 mm) to large-spotted (5–6 cm) or confluent. The rash may be transient or constantly present. It can be provoked by cold and persists for a long time. Myalgia, arthralgia/arthritis, most commonly oligoarthritis, occur in patients. Joint changes are transient with regression and complete restoration of configuration and function. Articular syndrome varies from short episodes of arthralgia to recurrent arthritis of large joints. Frequent symptoms of the attack include conjunctivitis, episcleritis, or iridocyclitis. Uveitis may develop. The duration of the attack is from 1 to 3 days. The disease may present as recurring episodes, although sometimes it persists long-term. Focal neurological symptoms are not described. Headaches are noted in some patients. Sensorineural hearing loss develops in 50–70% of patients, usually in adolescence or young adults.
A frequent complication of MWS is renal AA amyloidosis (in 20–40% of patients) [1,11,13,14].
1.6.3 Clinical presentation of CINCA/NOMID syndrome
CINCA/NOMID syndrome is the most severe form of CAPS; the disease debuts at an early age, and in some patients is present from birth [1,11,13,14].
With an early onset, prematurity and immaturity are characteristic; 33–55% of patients have low birth weight. Prolonged fever episodes, in some cases continuous; growth and physical development retardation (in 70% of patients). Migratory persistent urticarial or maculopapular rashes. In 2/3 of patients, arthralgia or "migratory" arthritis is observed. In a third of patients, joint changes are polyarticular, persistent, forming symmetrical hypertrophic arthropathy predominantly of large joints (knee, ankle, wrist, elbow), accompanied by clubbing-like deformation and contracture development. The underlying mechanisms include accelerated growth of metaphyses and epiphyses of long tubular bones, rapid ossification of ossification centers, and cartilage proliferation. Hypertrophic arthropathy often develops before 3 years of age.
Eye involvement is observed in 90% of patients. Anterior uveitis is diagnosed in 50% of them, and posterior uveitis in 20%. 80% of patients have optic nerve involvement: edema, inflammation, atrophy. 25% of patients show progressive visual impairment, leading to blindness in 50% of patients.
Chronic aseptic meningitis is diagnosed in 90% of patients. Its clinical manifestations include headaches, vomiting, excitability, irritability, and epileptic seizures. Chronic elevation of intracranial pressure, hydrocephalus, cerebral cortex atrophy, and delayed mental development and higher cognitive functions (in 70%) are characteristic. 75% of patients develop sensorineural hearing loss. Patients with CINCA/NOMID have hearing impairments from an early age, sometimes from birth [15,16].
AA amyloidosis is the main complication and cause of death in patients; it develops in 20% of patients by the age of 20 [2,3,6,11].
With a prolonged uncompensated disease course, signs of renal failure may appear due to the development of AA amyloidosis [17–20]. Renal involvement goes through several stages (Table 3).
Classification and staging of CKD stages by GFR level are presented in Tables 4 and 5.
Table 3. Stages of amyloid renal involvement and chronic kidney disease.
Stages of amyloid renal involvement | ||
|---|---|---|
Stage | Clinical features | Duration |
Preclinical stage | 3–5 years | |
Proteinuric (albuminuric) stage | 10–13 years | |
Nephrotic (edematous, edematous-hypotonic) stage | Classical nephrotic syndrome with all its features | up to 6 years |
Uremic (terminal, azotemic) stage – amyloid | Chronic kidney disease with features similar to CKD from other chronic renal diseases. «Shrunken kidney» | |
Stages of chronic renal failure | ||
Grade | Clinical signs | |
Latent stage | No clinical signs in most cases | |
Compensated stage | General weakness, fatigue during routine physical activity; urine output (polyuria) exceeding 2 liters per day; increased nocturnal urination (nocturia); facial edema, swelling around the eyes. | |
Intermittent stage | Pronounced weakness, constant drowsiness; nausea, vomiting; dry mouth and dry skin; decreased appetite; bitter taste in the mouth; prominent facial edema; muscle twitches in the legs (restless legs syndrome); elevated blood pressure; subcutaneous hemorrhages, nosebleeds, anemia associated with hematopoietic dysfunction in the renal tissue; frequent respiratory infections. | |
Terminal (decompensated) stage | Weight loss and body temperature drop; loss of appetite; acetone breath; diarrhea, vomiting; sharp mood swings; distinct urine odor from the patient; shortness of breath; edema syndrome; severe anemia and coagulation disorders (bleeding); coma in cases of significant impairment; inflammatory pneumonia | |
Table 4. Classification and stratification of CKD stages by GFR level [21].
CKD stage designation | 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 5. Grades of albuminuria (mg/day) [21].
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
Evaluation of patients with suspected cryopyrin-associated periodic syndromes
2.1 Complaints and Anamnesis
It is recommended to perform diagnostics, including differential diagnostics, in all patients with suspected cryopyrin-associated periodic syndromes in an inpatient setting providing medical care to children with rheumatic diseases in order to establish a diagnosis [1,5,11,13-15,22].
(LoE 5, GoR C)
It is recommended to take the medical history and assess complaints in all patients with suspected CAPS in order to identify the clinical features of CAPS [1,5,11,13-15,22].
(LoE 5, GoR C)
Comments: patients/parents may complain of fatigue, weakness; fever/chills; lymph node enlargement, urticaria-type rash, joint pain, muscle pain; joint swelling and restricted movement; headache; abdominal pain; eye redness; oral ulcers; hearing impairment; developmental delay.
When taking the medical history and assessing complaints, it is necessary to pay attention to the presence of a burdened family history (similar cases of the disease in siblings); the presence of relatives with a history of fever episodes, urticaria-like rash, joint pain or arthritis, hearing loss, renal pathology, and death from renal failure.
It is recommended to take a general medical history and assess complaints in all patients in order to identify the features of the pathological process course [11,13,22].
(LoE 5, GoR C)
Comments: it is necessary to determine the age of disease onset, what preceded the appearance of the first symptoms and subsequent attacks, the features of the disease course (nature of fever, rash, presence of musculoskeletal system involvement, ocular involvement, hearing loss, psychomotor/physical development disorders); whether periodicity of episodes was noted, persistence of symptoms during the interictal period; and to analyze the results of all examinations performed since the manifestation of the disease.
2.2 Physical Examination
It is recommended to perform general thermometry in all patients to assess the severity and nature of the fever [11,13,22].
(LoE 5, GoR C)
Comments: FCAS is characterized by fever attacks triggered by exposure to cold, wind, or sudden temperature changes; fever usually does not reach high values; Muckle-Wells syndrome presents with recurrent fever episodes; CINCA/NOMID syndrome is characterized by prolonged episodes of febrile fever, which are continuous in some cases.
It is recommended to assess the general condition in all patients for subsequent dynamic monitoring [11,13,22].
(LoE 5, GoR C)
Comments: the condition of children can be moderate or severe depending on the course of the disease, the degree of musculoskeletal system and/or internal organ involvement, and renal failure.
It is recommended to perform a therapeutic visual inspection and a visual examination of the oral cavity pathology in all patients to detect rashes and mucosal lesions [11,13,22].
(LoE 5, GoR C)
Comments: FCAS is characterized by a urticaria-like rash induced by cold exposure, often daily; Muckle-Wells syndrome presents with a urticaria-like rash that intensifies during attacks; CINCA/NOMID syndrome features a persistently present urticaria-like rash that intensifies during attacks. The rash may be maculopapular or erythematous, ranging in size from pinpoint (2–5 mm) to large macules (5–6 cm) or confluent lesions, with or without pruritus, generally widespread, and localized on almost all areas of the trunk and face. The rash may be transient or constantly present. Erosions and ulcers may be detected on the oral mucosa.
It is recommended to perform a therapeutic palpation in all patients to detect peripheral lymphadenopathy [11,13,22].
(LoE 5, GoR C)
Comments: enlargement of inguinal and cervical lymph nodes up to 2–3 cm in diameter is detected in patients with CINCA/NOMID syndrome, less frequently in Muckle-Wells syndrome, and is practically absent in FCAS. The lymph nodes are typically mobile, painless, not fused to each other or to the underlying tissues, and have a soft-to-firm or elastic consistency.
It is recommended to take medical history and assess complaints, perform visual inspection, percussion, and palpation regarding heart and pericardial pathology in all patients to identify physical signs of its involvement [11,13,22].
(LoE 5, GoR C)
Comments: the cardiovascular system in patients with CAPS is generally not affected. In severe cases, pericarditis may develop.
It is recommended to take medical history and assess complaints, perform visual inspection, percussion, and palpation regarding lung and bronchial diseases in all patients to identify physical signs of their involvement [11,13,22].
(LoE 5, GoR C)
Comments: the respiratory system in patients with CAPS is generally not affected. In severe cases, pneumonitis and/or pleuritis may develop.
It is recommended to take medical history and assess complaints, perform visual inspection, percussion, and palpation regarding diseases of the liver, biliary tract, pancreas, esophagus, stomach, duodenum, small intestine, and large intestine in all patients to identify physical signs of their involvement [11,13,22].
(LoE 5, GoR C)
Comments: patients with Muckle-Wells syndrome and CINCA/NOMID may complain of abdominal pain; upon examination, hepatomegaly and/or splenomegaly are detected in some cases.
When amyloidosis develops, examination reveals abdominal enlargement, while percussion and palpation reveal enlargement of the liver and spleen.
Palpation may reveal tenderness in the epigastrium and the projection points of the duodenum and pancreas. The use of large amounts of antipyretics and NSAIDs may lead to inflammatory lesions of the upper gastrointestinal tract (GI).
Complaints of frequent loose stools with mucus and/or blood, and/or green discoloration, pain in the ileocecal region, and abdominal bloating make inflammatory bowel disease (IBD) suspected.
It is recommended to take medical history and assess complaints regarding joint pathology, perform visual examination and palpation of the joints in all patients to detect active arthritis [11,13,22].
(LoE 5, GoR C)
Comments: in FCAS, arthralgia without external changes and functional impairments and myalgia are most commonly observed; in Muckle-Wells syndrome, joint changes are transient with regression and complete restoration of configuration and function. The articular syndrome varies from short episodes of arthralgia to recurrent arthritis of large joints.
Smoothing of contours, detiguration, effusion, tenderness, and restricted movement in the ankle, wrist, and less commonly small hand joints may also be detected. Two-thirds of patients with CINCA/NOMID present with arthralgia or migratory arthritis. In one-third, joint changes are polyarticular and persistent, leading to symmetrical hypertrophic arthropathy predominantly affecting large joints (knee, ankle, wrist, elbow), accompanied by clubbing-like deformation and contractures. The development is based on accelerated growth of metaphyses and epiphyses of long tubular bones, rapid ossification of ossification centers, and cartilage proliferation. Hypertrophic arthropathy often develops before the age of 3 years.
It is recommended to determine the range of motion in all joints: measuring the passive range of motion of a single joint in a single plane and measuring the active range of motion of a single joint in a single plane in all patients with arthralgia/arthritis to identify functional impairment [4,23].
(LoE 5, GoR C)
Comments: if there is no pain in the joints at a normal range of motion, it is necessary to assess the appearance of pain (protective muscle tension, resistance) at the maximum range of motion.
The range of motion is evaluated as follows:
- Cervical spine. Ask the patient to: tilt the head backward (normal extension is 50-60°), touch the chest with the chin (normal flexion is 45°), turn the head to the right and left (normal rotation is 60-80°), touch the right and left shoulder with the head (lateral flexion is 40°).
- Temporomandibular joints. Ask the patient to: open the mouth, protrude and re-retract the mandible, perform lateral side-to-side movements of the mandible.
- Shoulder joints. Ask the patient to: raise the arms laterally upwards, reach the right and left ear over the back of the head, reach the right and left scapula with the opposite hand from behind, independently take off a shirt or t-shirt, comb the hair.
- Elbow joints. Ask the patient to: place hands on the shoulders (normal flexion angle is no more than 20°), extend the arm at the elbow joint (normal is at least 180°), check pronation and supination (normal is 90°).
- Wrist joints. Check: dorsiflexion (normal is 70°), palmar flexion (normal is 90°).
- Small joints of the hands. Ask the patient to: make a tight fist, independently put off and put on socks and tights, button and unbutton clothes. Normally, the fingers easily touch the palm.
- Hip joints: check abduction (at least 140°), adduction (the thighs and knees should touch the chest), external and internal rotation (normal is at least 40-45°).
- Test for internal rotation in the hip joints. The child lies on their back with hips and knees flexed at a 90° angle. Keeping the knees together, the lower legs are turned outward.
- In almost all hip joint diseases, internal rotation is affected first.
- Knee joints. Ask the patient to: flex the legs at the knee joints (the heel should touch the buttocks), sit on the knees and lower the buttocks onto the heels, extend the knee joints (180° angle), squat.
- Check the patellar tapotement (ballottement) sign.
- The lower limbs are flexed at the knee joints. Usually, heels touch the buttocks without difficulty. The lower limbs are maximally extended at the knee joints with the child in the supine position.
- Foot joints, ankle joints. Check: dorsiflexion (normal angle is 45°), plantar extension (normal angle is 20°), supination (inward turning of the foot is 30°), pronation (outward turning of the foot is 20°). Ask the patient to: stand on tiptoes and walk, stand on heels and walk (the child should do this without difficulty). Observe asymmetry when moving the ankles in different directions. Noticeable restriction of flexion is usually detected without difficulty, even in the absence of visible joint swelling.
It is recommended to evaluate the gait in all patients with arthralgia/arthritis to identify the nature of its disturbance [4,23].
(LoE 5, GoR C)
Comments: gait is typically impaired when CAPS is combined with JIA. Gait patterns in joint involvement:
- with rapid transfer of body weight from the affected leg to the healthy one (involvement of knee, hip joints, and feet). The patient steps on the entire foot or toes (heel involvement),
- "waddling" gait (bilateral hip joint involvement).
Observation of gait during walking and running: a patient's limp is an important diagnostic clue for identifying pain or stiffness. Limping and gait abnormalities are most pronounced in children, usually in the morning hours due to morning stiffness. Upon examination of the patient in the afternoon, there may be no limp, and gait abnormalities may be minimal or absent.
It is recommended to collect anamnesis and complaints in muscle diseases, collect anamnesis and complaints in bone system pathology, perform a visual examination of the muscles and skeletal system, and palpate the muscles and skeletal system to determine the nature of the lesion [11, 13, 22].
(LoE 5, GoR C)
Comments: myalgia is observed in all variants of CAPS.
It is recommended to collect anamnesis and complaints, perform a visual inspection, percussion, and palpation in case of pathology of the kidneys and urinary system in all patients to identify the nature of the lesion [11, 13, 17, 20, 22, 24].
(LoE 5, GoR C)
Comments: progressive renal amyloidosis manifests as nephrotic syndrome (edema, decreased diuresis).
It is recommended to exclude diseases that may present with similar clinical symptoms in all patients before prescribing pathogenetic therapy [4, 11, 13, 22, 23, 25, 25–27].
(LoE 5, GoR C)
Comments: diseases that should be excluded during diagnosis:
- malignant neoplasms (neuroblastoma, solid tumors, hemoblastoses, 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, mycoplasma infection, cytomegalovirus infection, Epstein-Barr virus infection, etc.).
2.3 Laboratory Diagnostics
It is recommended to perform a complete blood count (including erythrocyte sedimentation rate, red blood cell count, leukocyte count, platelet count, differential leukocyte count [leukocyte formula], and hemoglobin level) in all patients to assess disease activity and detect pathological changes [11, 13, 22, 28–34].
(Level of Evidence 3, Grade of Recommendation C)
Comments: in FCAS, elevated levels of acute-phase reactants (ESR, leukocyte count, platelet count) are observed during attacks; there is no inflammatory activity between attacks; in Muckle-Wells syndrome and CINCA/NOMID, elevated levels of acute-phase inflammatory markers may be detected throughout the entire course of the disease.
Single-, bi-, or pancytopenia may develop due to the toxic effect of nonsteroidal anti-inflammatory drugs, as well as upon the development of secondary macrophage activation syndrome (MAS).
The complete blood count findings are not specific for CAPS; therefore, diagnostic and differential diagnostic workup must continue. First and foremost, hemoblastoses, lymphoproliferative, and oncological diseases must be excluded.
It is recommended to perform a coagulogram (screening hemostasis test) determining prothrombin index, antithrombin III activity in blood, plasminogen level in blood, fibrinogen level in blood, D-dimer concentration in blood, soluble fibrin monomer complex level in blood, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time in blood, and von Willebrand factor activity and properties in blood in all patients to assess the state of the hemostatic system [35–38].
(LoE 5, GoR C)
Comments: an elevated blood fibrinogen concentration is observed during the active period of the disease; along with elevated D-dimer, soluble fibrin monomer complexes, and von Willebrand factor. When macrophage activation syndrome (MAS) develops, there is prolongation of prothrombin time in blood or plasma, thrombin time, and activated partial thromboplastin time, along with a decrease in the prothrombin index and blood fibrinogen concentration.
It is recommended to perform thrombelastography in patients with signs of vasculitis to assess the severity of hemostatic disorders and the risk of thrombosis and bleeding [35–37, 39–43].
(LEL 4, GRC C)
It is recommended to perform a routine biochemical blood test (including total protein, albumin, total bilirubin, free and conjugated bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, low-density lipoprotein cholesterol, sodium, potassium, total calcium, lactate dehydrogenase activity, aspartate aminotransferase activity, alanine aminotransferase activity, gamma-glutamyltransferase activity, alkaline phosphatase activity, serum iron, creatine kinase activity, pancreatic amylase activity, and lipase activity) in all patients to detect pathological changes [2, 4, 11, 13, 22, 28–31, 34, 44, 45].
(LoE 5, GoR C)
Comments: elevated serum concentrations of ferritin, triglycerides, direct bilirubin, along with increased blood ALT, AST, and LDH activity, may be observed in secondary/primary hemophagocytic lymphohistiocytosis (HLH), as well as drug-induced toxicity, oncological diseases, hemoblastosis, lymphoproliferative disorders, or sepsis, which provides grounds for further differential diagnosis.
Elevated blood levels of CK, LDH, ALT, and AST indicate the development of inflammatory myopathy.
Elevated total protein concentration is observed in amyloidosis; decreased albumin and total protein concentrations, dysproteinemia, and elevated cholesterol concentration occur in nephrotic syndrome; elevated serum potassium, urea, uric acid, creatinine, and decreased glomerular filtration rate indicate renal failure secondary to amyloidosis.
It is recommended to measure blood immunoglobulin levels in all patients to assess immune status and rule out primary immunodeficiency [2, 4, 27, 44].
(Level of Evidence 3, Grade of Recommendation C)
Comments: in CAPS, blood immunoglobulin M and G concentrations are within normal limits or elevated.
It is recommended to test for antinuclear antibodies and anti-DNA antibodies, rheumatoid factor (RF) in blood, markers of ANCA-associated vasculitis (PR3 [c-ANCA], MPO [p-ANCA]), anticentromere antibodies, anti-RNA antibodies, antibodies to cyclic citrullinated peptide (anti-CCP), antinuclear antibodies to Sm antigen, antibodies to Scl-70, complement C3 fraction, and complement C4 fraction in all patients to rule out primary immunodeficiency and to confirm or rule out other rheumatic diseases [2, 4, 27, 44].
(Level of Evidence 3, Grade of Recommendation C)
Comments: in CAPS, complement C3 and C4 fraction concentrations are within normal limits or elevated; in FCAS, serum CRP concentration is elevated during an attack; in Muckle-Wells syndrome and CINCA/NOMID, it is elevated throughout the entire disease. Concentrations of antinuclear antibodies, anti-DNA antibodies, RF, ANCA, anticentromere antibodies, anti-RNA antibodies, anti-CCP, anti-Sm antibodies, and anti-Scl-70 antibodies are not elevated.
It is recommended to determine anti-streptolysin-O in blood serum in all patients to rule out or confirm group A beta-hemolytic streptococcus infection [2, 4, 44, 46].
(Level of Evidence 3, Grade of Recommendation C)
Comments: an elevated serum anti-streptolysin-O level indicates acute or chronic streptococcal infection, which can trigger a CAPS attack.
It is recommended to measure serum C-reactive protein in all patients to determine disease activity [2, 4, 27].
(LoE 5, GoR C)
Comments: in FCAS, serum CRP level is elevated during an attack; in Muckle-Wells syndrome and CINCA/NOMID, it is elevated throughout the entire disease.
It is recommended to determine ABO blood groups, subgroups and other minor blood groups (A-1, A-2, D, Cc, E, Kell, Duffy), and Rhesus antigen D (Rh factor) in all patients prior to invasive procedures (esophagogastroduodenoscopy, colonoscopy with biopsy, bone marrow puncture for cytologic preparation, cytologic examination of bone marrow trephine biopsy imprints, bone biopsy) [4, 44, 47–49].
(LoE 5, GoR C)
It is recommended to perform a general (clinical) urinalysis, determine urinary albumin, and measure 24-hour urinary protein to rule out renal diseases, other rheumatic and non-rheumatic conditions, and iatrogenic complications, as well as to detect early symptoms of secondary renal amyloidosis [11, 13, 22, 33, 50].
(LoE 5, GoR C)
Comments: micro- or macrohematuria may be a consequence of the toxic effect of NSAIDs and methotrexate on the kidneys.
Proteinuria is detected during the development of amyloidosis and may be its first symptom. Initially, proteinuria is moderate, transient for a period, fluctuating, and then becomes persistent (intermittent proteinuria stage); it can be selective and non-selective.
As amyloidosis progresses, the nephrotic stage develops with massive proteinuria (more than 3–5 grams per day) and lipiduria; hyaline casts, and granular casts as proteinuria increases, appear in the urinary sediment, and micro- and macrohematuria or leukocyturia may occur in the absence of pyelonephritis.
It is recommended to perform a comprehensive assessment of renal function in patients with clinical/laboratory signs of kidney damage to determine the severity of impairment [17–19,21,22].
(LEL 4, GRC C)
Comments: the Schwartz formula is used to calculate the glomerular filtration rate. The normal glomerular filtration rate in children aged 2 to 18 years is 90–130 mL/min/1.73 m2. A decrease in the glomerular filtration rate in patients with uncontrolled CAPS may indicate the development of secondary renal amyloidosis.
It is recommended to perform a set of diagnostic tests to evaluate the severity of renal failure in patients with clinical/laboratory signs of nephrotic syndrome/renal failure [17–19,21,22].
(LEL 4, GRC C)
It is recommended to perform molecular genetic testing—a panel of tests for the diagnosis of cryopyrin-associated periodic syndromes in all patients to confirm the diagnosis and rule out other autoinflammatory diseases [11,13,22,51,52].
(LEL 4, GRC C)
Comments: mutations are detected in the NLRP3 gene responsible for familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (CINCA/NOMID), as well as in genes responsible for tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and familial Mediterranean fever (FMF).
It is recommended to determine the HLA-B27 antigen by flow cytometry in all patients with clinical manifestations of CAPS for differential diagnosis with spondyloarthropathies [4].
(LoE 5, GoR C)
Comments: the presence of HLA-B27 does not rule out the diagnosis of CAPS.
It is recommended to measure blood procalcitonin levels in all patients to rule out sepsis [53–55].
(LEL 4, GRC C)
Comments: blood procalcitonin levels are elevated in sepsis. In CAPS without infectious complications, they remain within reference ranges.
It is recommended to perform lymphocyte subset analysis in all patients to detect/rule out immunodeficiency states and assess disease activity [4,56,57].
(LoE 5, GoR C)
It is recommended to perform a focal tuberculin test (Mantoff test, test with tuberculosis recombinant allergen in standard dilution**) and/or determination of interferon-gamma release level to Mycobacterium tuberculosis complex antigens in blood for all patients in order to detect/exclude infection with Mycobacterium tuberculosis [34,50,58,59].
(LEL 4, GRC C)
It is recommended to determine antibodies of classes A, M, G (IgA, IgM, IgG) to Chlamydia psittaci in the blood; determine antibodies to Chlamydophila pneumoniae 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 of all patients to rule out an infectious process that may present with a clinical picture similar to CAPS [2,4].
(LoE 5, GoR C)
It is recommended to determine antibodies to Salmonella enterica in the blood, determine antibodies to Salmonella typhi in the blood, determine classes M, G antibodies (IgM, IgG) to Yersinia pseudotuberculosis in the blood, determine antibodies to Yersinia enterocolitica serovars in the blood of all patients to rule out an infectious process that may present with a clinical picture similar to CAPS [2,4,60].
(LoE 5, GoR C)
It is recommended to determine classes M, G antibodies (IgM, IgG) to Shigella boydii in the blood, determine classes M, G antibodies (IgM, IgG) to Shigella dysenteriae in the blood, determine classes M, G antibodies (IgM, IgG) to Shigella sonnei in the blood, determine classes M, G antibodies (IgM, IgG) to Shigella flexneri in the blood of all patients to detect/rule out an infectious process that may present with a clinical picture similar to CAPS [2,4,60–63].
(LoE 5, GoR C)
It is recommended to detect deoxyribonucleic acid (DNA) of tick-borne borreliosis agents of the Borrelia burgdorferi sensu lato group in the blood by PCR; determine class M antibodies (IgM) to tick-borne borreliosis agents of the Borrelia burgdorferi sensu lato group in the blood; determine class G antibodies (IgG) to tick-borne borreliosis agents of the Borrelia burgdorferi sensu lato group in the blood, determine total antibodies to tick-borne borreliosis agents of the Borrelia burgdorferi sensu lato group in the blood in patients with a history of visiting a forest, living in tick-endemic areas, or a tick bite, in order to rule out borreliosis [34,64,65].
(LoE 5, GoR C)
It is recommended to detect Epstein-Barr virus (Epstein-Barr virus) DNA by quantitative PCR in peripheral and cord blood, detect Epstein-Barr virus (Epstein-Barr virus) DNA in oropharyngeal swabs by qualitative PCR, detect Epstein-Barr virus (Epstein-Barr virus) DNA in urine by qualitative PCR in all patients to detect/rule out diseases caused by herpesviruses [2,4,34,50,66–70].
(LoE 5, GoR C)
It is recommended to detect cytomegalovirus (Cytomegalovirus) DNA by quantitative PCR in peripheral and cord blood, detect cytomegalovirus (Cytomegalovirus) DNA in oropharyngeal swabs by qualitative PCR, detect cytomegalovirus (Cytomegalovirus) DNA in urine by qualitative PCR in all patients to detect/rule out diseases caused by herpesviruses [2,4,34,50,66,70–73].
(LoE 5, GoR C)
It is recommended to detect herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA by quantitative PCR in the blood, detect herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in oropharyngeal swabs by qualitative PCR, detect herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in urine by qualitative PCR in all patients to detect/rule out diseases caused by herpesviruses [2,4,34,50,66,74–78].
(LoE 5, GoR C)
It is recommended to determine classes M, G antibodies (IgM, IgG) to cytomegalovirus (Cytomegalovirus) in the blood of all patients to detect/rule out active cytomegalovirus infection [2,4,34,50,66,72,79–81].
(LoE 5, GoR C)
It is recommended to determine classes M, G antibodies (IgM, IgG) to Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients to detect/rule out diseases caused by Epstein-Barr virus [2,4,34,50,66–70].
(LoE 5, GoR C)
It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients to detect/rule out diseases caused by Epstein-Barr virus [2,4,34,50,66–70].
(LoE 5, GoR C)
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 to detect/rule out diseases caused by Epstein-Barr virus [2,4,34,50,66–70].
(LoE 5, GoR C)
It is recommended to determine antibodies to herpes simplex virus (Herpes simplex virus) in the blood of all patients to detect/rule out diseases caused by herpes simplex virus [2,4,34,50,66,74–76,78,82].
(LoE 5, GoR C)
It is recommended to perform molecular biological testing of blood for Toxoplasma gondii in patients with a history of animal contact to rule out toxoplasmosis [83].
(LoE 5, GoR C)
It is recommended to perform molecular biological testing of blood for hepatitis C virus (Hepatitis C virus) and molecular biological testing of blood for hepatitis B virus (Hepatitis B virus) in patients with clinical and laboratory signs of hepatitis for differential diagnosis [84–86].
(LoE 5, GoR C)
Comments: in patients with CAPS, hepatitis may develop due to unregulated use of NSAIDs and can also be a sign of secondary hemophagocytic syndrome.
It is recommended to determine antibodies to hepatitis B surface antigen (HBsAg) (Hepatitis B virus) and antibodies to hepatitis C virus (Hepatitis C virus) in the blood of patients with clinical and laboratory signs of hepatitis for differential diagnosis [84–86].
(LoE 5, GoR C)
It is recommended to determine antibodies class M, G (IgM, IgG) to human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV 1) in the blood, and antibodies class M, G (IgM, IgG) to human immunodeficiency virus HIV-2 (Human immunodeficiency virus HIV 2) in the blood for patients with signs of immunodeficiency to detect/exclude HIV infection [87,88].
(LoE 5, GoR C)
It is recommended to determine antibodies to Leishmania (Leishmania) in the blood in patients with a history of staying in endemic areas to exclude leishmaniasis [34,89–91].
(LEL 4, GRC C)
It is recommended to perform microbiological (culture) examination of mucus from the tonsils and posterior pharyngeal wall for aerobic and facultatively anaerobic microorganisms in all patients to exclude nasopharyngeal contamination by pathogenic and opportunistic flora [34,50,66].
(LoE 5, GoR C)
It is recommended to perform microbiological (culture) blood test for sterility, and microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms in all patients to detect/exclude an acute inflammatory response (sepsis) and bacteremia [66].
(LoE 5, GoR C)
It is recommended to test the level of fecal calprotectin in all patients to exclude IBD [92–94].
(LoE 5, GoR C)
2.4 Instrumental Diagnostics
It is recommended to perform a comprehensive ultrasound examination (ultrasound) of internal organs (including a comprehensive ultrasound examination of the abdominal organs, and kidney ultrasound) in all patients to detect/exclude pathological changes [13].
(LoE 5, GoR C)
Comments: the study may reveal signs of peritonitis, kidney damage, enlargement of mesenteric lymph nodes, liver and/or spleen, assess intestinal motility, and exclude conditions presenting with "acute abdomen" symptoms (urolithiasis, acute cholecystitis, pancreatitis, appendicitis, intestinal obstruction, perforation, gynecological pathology).
It is recommended to perform echocardiography (EchoCG) in all patients with clinical signs of CAPS for differential diagnosis with acute rheumatic fever, sJIA, Kawasaki disease, infective endocarditis, and other autoinflammatory diseases (recurrent pericarditis) [2,4,11,13,22,66,95].
(LoE 5, GoR C)
Comments: myocarditis reveals left ventricular (LV) dilation, decreased left ventricular ejection fraction, hypokinesia of the LV posterior wall and/or interventricular septum, aortitis, signs of relative mitral, aortic and/or tricuspid valve regurgitation, and increased pulmonary artery pressure. Myocarditis is not typical for CAPS. The endocardium and valve apparatus in CAPS are generally unaffected. Pericarditis is characterized by separation of pericardial leaves and free fluid in the pericardial cavity; it is rare in CAPS.
In infective endocarditis, valvular vegetations are detected; in Kawasaki disease, coronaritis and coronary artery aneurysms are found.
It is recommended to perform an electrocardiogram in all patients to detect/exclude pathological changes [45].
(LEL 4, GRC C)
Comments: if myocarditis is present, signs of left and/or right heart overload are detected. In most cases, pericarditis is not accompanied by decreased QRS voltage, ST-segment elevation, or T-wave inversion on the ECG.
It is recommended to perform a joint ultrasound in patients with active arthritis to assess the severity of joint effusion, the state of the synovial membrane, and cartilage [23,45].
(LEL 4, GRC C)
Comments: in CAPS, there are signs of synovitis and an increased amount of synovial fluid. Thickening (proliferation) of the synovial membrane, cartilage fibrillation, and cartilage erosions are not typical for CAPS; if present, juvenile arthritis should be excluded.
It is recommended to perform radiography of the temporomandibular joint and/or radiography of intervertebral articulations, and/or radiography of the elbow joint, and/or radiography of the wrist joint, and/or radiography of the knee joint, and/or radiography of the shoulder joint, and/or radiography of the hip joint, and/or radiography of the ankle joint, and/or radiography of the acromioclavicular articulation, and/or radiography of the sternoclavicular articulation, and/or radiography of the hand, and/or radiography of the foot in two projections, or computed tomography of the joint with or without anesthesia (including early postoperative management) in patients with active arthritis to detect/exclude pathological changes [22,23,96–99].
(LEL 4, GRC C)
Comments: juvenile arthritis, bone tuberculosis, osteomyelitis, benign and malignant tumors, and bone metastases are excluded.
Arthritis in FCAS and Muckle-Wells syndrome is non-destructive. Periarticular osteoporosis may be detected.
In JIA, the following are revealed: 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 necrosis, subluxations, fractures, osteophytes, calcinates, etc. Patients with CINCA/NOMID exhibit hypertrophy of the epiphyses of long tubular bones and remodeling of the epiphyseal bone tissue.
It is recommended to perform magnetic resonance imaging of joints (single joint) with contrast enhancement, with or without anesthesia (including early postoperative management), in patients with active arthritis to exclude traumatic injury of the tendon-ligament apparatus, menisci, tumors, purulent (septic) arthritis, and JIA [22,23,96–99].
(LEL 4, GRC C)
It is recommended to perform plain abdominal radiography in patients with abdominal syndrome to exclude intestinal obstruction and perforation of a hollow abdominal organ [23].
(LoE 5, GoR C)
Comments: in hollow organ perforation, plain abdominal radiography reveals free air; in intestinal obstruction, it reveals fluid levels in the intestinal loops.
It is recommended to perform esophagogastroduodenoscopy with or without anesthesia (including early postoperative management) in all patients to exclude inflammatory, erosive, and ulcerative processes [45,94,100,101].
(LEL 4, GRC C)
Comments: specific erosive/ulcerative lesions are not typical for CAPS; they may be a manifestation of inflammatory gastropathy (associated with Helicobacter pylori or not), Crohn's disease involving the upper GI tract, or amyloidosis.
A pathomorphological (biopsy/surgical specimen) examination is required to establish the diagnosis.
It is recommended to perform a microbiological (culture) study of Helicobacter pylori gastric mucosal biopsies (Helicobacter pylori) in patients with inflammatory, erosive, and/or ulcerative changes according to esophagogastroduodenoscopy to exclude GI pathology associated with Helicobacter pylori [45,94,100,101].
(LEL 4, GRC C)
It is recommended to perform esophageal biopsy via endoscopy, gastric biopsy via endoscopy, duodenal biopsy via endoscopy, and jejunal biopsy via endoscopy with or without anesthesia (including early postoperative management), along with pathomorphological examination of the biopsy (surgical) material of the esophagus, stomach, duodenum, and jejunum in patients with inflammatory, erosive, and/or ulcerative mucosal changes according to esophagogastroduodenoscopy to exclude inflammatory bowel diseases [45,94,100,101].
(LEL 4, GRC C)
It is recommended to perform colonoscopy with anesthesia (including early postoperative management) in all patients to exclude IBD and amyloidosis [45,94,100,101].
(LEL 4, GRC C)
Comments: erosive/ulcerative lesions of the intestinal mucosa can develop in IBD and amyloidosis. Pathomorphological examination of the biopsy (surgical) material is required to establish a diagnosis.
It is recommended to perform a biopsy of the large intestine via endoscopy with pathomorphological examination of the large intestinal biopsy (surgical) material in patients who show inflammatory, erosive, and/or ulcerative changes in the large intestine according to colonoscopy to exclude IBD and amyloidosis [45,94,100,101].
(LEL 4, GRC C)
Comments: erosive/ulcerative lesions of the intestinal mucosa can develop in IBD and amyloidosis. Pathomorphological examination of the biopsy (surgical) material is required to establish a diagnosis.
It is recommended to perform magnetic resonance enterography (MR enterography, hydro-MRI) with contrast enhancement, with or without anesthesia (including early postoperative management), in patients with clinical signs of inflammatory bowel diseases and/or elevated fecal calprotectin levels in the absence of changes on esophagogastroduodenoscopy and colonoscopy to exclude contraindications for capsule video endoscopy of the small intestine (to exclude/confirm small bowel strictures or when these conditions are suspected) [102–105].
(Level of Evidence 1, Grade of Recommendation B)
Comments: video capsule small bowel endoscopy is contraindicated in the presence of small bowel strictures.
It is recommended to perform video capsule small bowel endoscopy in patients with clinical signs of inflammatory bowel disease and/or elevated fecal calprotectin levels when esophagogastroduodenoscopy and colonoscopy show no abnormalities, in order to exclude Crohn's disease with isolated small bowel involvement [93].
(LoE 5, GoR C)
It is recommended to perform computed tomography of the chest organs with or without anesthesia support (including early postoperative management) in all patients to detect pleurisy, exclude/confirm pneumonia, oncological/oncohematological/lymphoproliferative diseases, tuberculosis, sarcoidosis, or granulomatous vasculitis [45,59,106].
(LEL 4, GRC C)
It is recommended to perform contrast-enhanced magnetic resonance imaging of the brain, contrast-enhanced magnetic resonance imaging of the abdominal organs, contrast-enhanced magnetic resonance imaging of the retroperitoneal space, and contrast-enhanced magnetic resonance imaging of the pelvic organs with or without anesthesia support (including early postoperative management) in all patients to identify/exclude oncological/oncohematological/lymphoproliferative diseases, tuberculosis, or abscesses [45,59,106].
(LEL 4, GRC C)
Comments: exclude oncological/oncohematological/lymphoproliferative diseases, tuberculosis of intra-abdominal lymph nodes, and purulent inflammation in the abdominal cavity and small pelvis.
The development of secondary amyloidosis is manifested by hepatosplenomegaly and typical renal changes.
It is recommended to perform computed tomography of the brain, contrast-enhanced computed tomography of the abdominal organs, and contrast-enhanced computed tomography of the retroperitoneal space with intravenous bolus contrast, with or without anesthesia support (including early postoperative management), in patients with contraindications to MRI, in order to exclude internal organ involvement in CAPS and to identify/exclude oncological/oncohematological/lymphoproliferative diseases, tuberculosis, or abscesses [45,59,106].
(LEL 4, GRC C)
It is recommended to perform contrast-enhanced magnetic resonance imaging of the brain and contrast-enhanced magnetic resonance imaging of the spinal cord (one segment) with or without anesthesia support (including early postoperative management) in patients with symptoms of CNS involvement to identify/exclude pathological changes [16,107].
(LEL 4, GRC C)
It is recommended to perform a lumbar puncture with anesthesia support (including early postoperative management), including microscopic examination, cell count in a counting chamber (determination of cytosis), examination of the physical properties of the cerebrospinal fluid, and serological examination, in patients with symptoms of CNS involvement to identify/exclude pathological changes [16,107].
(LEL 4, GRC C)
Comments: performed in patients with neurological manifestations (headaches, recurrent meningitis or meningoencephalitis, seizures, etc.) and in patients with suspected CINCA/NOMID syndrome to rule out an infectious origin of neurological disorders (meningococcal infection, viral meningitis, etc.).
It is recommended to perform a kidney biopsy with anesthesia 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 the presence of proteinuria > 500 mg per day, in the absence of contraindications, to perform differential diagnosis of secondary amyloidosis from other diseases presenting with kidney involvement [24].
(LoE 5, GoR C)
Comments: contraindications for kidney biopsy include: thrombocytopenia, coagulopathy, use of heparin-group drugs, and hemodialysis dependence. Performing a kidney biopsy in the presence of contraindications is associated with a high risk of bleeding, hematoma formation, and infection. In the preclinical stage: amyloid is present in the intermediate zone and along the straight vessels of the medullary pyramids; edema and foci of sclerosis develop. In the proteinuric (albuminuric) stage, amyloid appears in the mesangium, capillary loops, pyramids, glomerular cortex, and vessels; sclerosis and atrophy of nephrons, hyperemia, and lymphostasis develop. The kidneys are enlarged, dense, dull, and grayish-pink.
In the nephrotic (edematous, edematous-hypotonic) stage, amyloid-lipoid nephrosis develops. Amyloid is deposited in all parts of the nephron. Sclerosis and amyloidosis of the medulla develop, while the cortical layer shows no pronounced sclerotic changes. The kidneys are enlarged and dense (large white kidney).
In the uremic (terminal, azotemic) stage, an amyloid "contracted kidney" is formed. The kidney is reduced in size, dense, with scars.
It is recommended to obtain a bone marrow cytologic specimen via puncture and a bone marrow histologic specimen with anesthesia support (including early postoperative management), along with cytologic examination of a bone marrow smear (myelogram) and pathomorphological examination of the bone marrow biopsy (surgical) material using immunohistochemical methods, in all patients to exclude oncological/oncohematological/lymphoproliferative diseases and metastatic bone marrow involvement [11,13,22,66].
(LoE 5, GoR C)
Comments: if glucocorticoids or immunosuppressants are used, the test is performed no earlier than 2 weeks after their discontinuation.
It is recommended to perform a lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) with anesthesia support (including early postoperative management), including cytologic examination of the lymph node tissue preparation and pathomorphological examination of the biopsy (surgical) material, in patients with pronounced enlargement of peripheral and/or intrathoracic and/or intra-abdominal lymph nodes at the diagnostic stage prior to pathogenetic therapy, in order to exclude hemoblastoses, lymphoproliferative diseases, and metastatic lymph node involvement [108].
(LEL 4, GRC C)
Comments: if glucocorticoids or immunosuppressants are used, the test is performed no earlier than 2 weeks after their discontinuation.
It is recommended to perform a pelvic bone trephine biopsy with anesthesia support (including early postoperative management), including pathomorphological examination of the 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 with an atypical course of CAPS during the diagnostic workup, in order to exclude oncological/oncohematological/lymphoproliferative diseases and metastatic bone marrow involvement [106,108–111].
(LoE 5, GoR C)
Comments: if glucocorticoids or immunosuppressants are used, the test is performed no earlier than 2 weeks after their discontinuation.
It is recommended to perform a bone biopsy with anesthesia support (including early postoperative management) and pathomorphological examination of the bone biopsy (surgical) material in patients with bone destruction foci that are atypical for CAPS, in order to exclude malignant and benign bone tumors, metastatic bone lesions, and multifocal osteomyelitis [106,108–111].
(LoE 5, GoR C)
Comments: bone tissue destruction is not characteristic of CAPS. Destruction foci are characteristic of multifocal osteomyelitis, malignant neoplasms, and hemoblastoses, which can present with episodes of febrile fever accompanied by pain in the abdomen, chest, joints, and bones. A bone biopsy is necessary to perform differential diagnosis.
It is recommended to perform multi-position bone scintigraphy with or without anesthesia support (including early postoperative management) in patients with bone destruction foci atypical for CAPS to exclude malignant and benign bone tumors and metastatic bone lesions [106,109].
(LoE 5, GoR C)
Comments: bone tissue destruction is not characteristic of CAPS. Destruction foci are characteristic of multifocal osteomyelitis, malignant neoplasms, and hemoblastoses, which can present with episodes of febrile fever accompanied by pain in the abdomen, chest, joints, and bones. A bone biopsy is necessary to perform differential diagnosis.
It is recommended to perform positron emission tomography combined with computed tomography (PET-CT) using tumor-seeking radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)) with contrast enhancement, and, if necessary, whole-body positron emission tomography with tumor-seeking radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)) with or without anesthesia support (including early postoperative management), for patients with severe arthralgia, myalgia, ossalgia, bone destructive changes, subcutaneous adipose tissue infiltrates, lesions in parenchymal organs, brain, or spinal cord, to detect/rule out oncological/oncohematological lymphoproliferative diseases [106, 108–111].
(LEL 2, GRR C)
Comments: PET-CT is performed in patients with severe arthralgia, myalgia, ossalgia, destructive bone changes, subcutaneous adipose tissue infiltrates, lesions in parenchymal organs, brain, or spinal cord to rule out oncological/oncohematological/lymphoproliferative diseases.
2.5 Other Procedures
It is recommended to perform an initial consultation (examination, assessment) by a pediatric surgeon for all patients with abdominal and thoracic symptoms to rule out acute surgical pathology [2, 4, 11, 13, 22, 23].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (examination, assessment) by a gastroenterologist for all patients with abdominal symptoms to address further management and rule out other diseases [2, 4, 11, 13, 22, 23].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (examination, assessment) by a pediatric oncologist for patients with suspected oncological or oncohematological disease based on examination results, in order to rule them out [66, 106–109, 112].
(LoE 5, GoR C)
Comments: performed based on the results of examinations (computed tomography of the chest cavity organs; magnetic resonance imaging of the brain with contrast enhancement, magnetic resonance imaging of the abdominal organs with intravenous contrast enhancement, magnetic resonance imaging of the retroperitoneal space with intravenous contrast enhancement, magnetic resonance imaging of the pelvic organs with intravenous contrast enhancement; cytological examination of 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; positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)) with contrast enhancement, whole-body positron emission tomography using tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)); multi-position bone scintigraphy; pathomorphological examination of bone marrow biopsy (surgical) material (trephine biopsy) using immunohistochemical methods, bone biopsy with pathomorphological examination of bone tissue biopsy (surgical) material.
It is recommended to perform an initial consultation (examination, assessment) by an obstetrician-gynecologist for all female patients with abdominal symptoms to determine the need for further examination and rule out gynecological conditions [2, 4, 11, 13, 22, 23].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (examination, assessment) by a nephrologist for patients with urinalysis abnormalities and/or nephrotic syndrome/renal failure to address further examination and identify/rule out nephrological pathology/renal amyloidosis [11, 13, 17, 20, 22, 24, 113].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (examination, assessment) by a neurologist for patients with symptoms of central and peripheral nervous system involvement and patients with thoracic symptoms to identify/rule out pathological changes [16, 107].
(LEL 4, GRC C)
Comments: An FCAS attack may be accompanied by drowsiness and headache; children with Muckle-Wells syndrome may complain of headaches. Chronic aseptic meningitis is diagnosed in 90% of patients with CINCA/NOMID syndrome. Its clinical manifestations include headaches, vomiting, excitability, irritability, and epileptic seizures. Chronic elevation of intracranial pressure, hydrocephalus, cerebral cortical atrophy, and delayed mental and higher cognitive development (in 70%) are characteristic.
It is recommended to perform an initial consultation (examination, assessment) by a phthisiatrician for patients with positive focal tuberculin skin tests and/or elevated blood interferon-gamma levels specific to Mycobacterium tuberculosis complex antigens and/or infiltrative pulmonary lesions, in order to rule out tuberculosis [34, 50, 58, 59].
(LEL 4, GRC C)
It is recommended to perform an initial consultation (examination, assessment) by an orthopedic traumatologist for patients with acute arthritis, mass and destructive lesions, as well as bone deformities atypical for CAPS, in order to rule out septic arthritis, osteomyelitis, and other surgical pathology [2, 4, 11, 13, 22, 23].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (examination, assessment) by an otorhinolaryngologist for all patients to detect foci of acute ENT infections [2, 4, 11, 114].
(LEL 4, GRC C)
It is recommended to perform an initial consultation (examination, assessment) by an otoneurologist/audiologist for all patients to detect sensorineural hearing loss [15, 16, 114].
(LEL 4, GRC C)
Comments: Sensorineural hearing loss develops in 50–70% of patients with Muckle-Wells syndrome, typically in adolescence or young adulthood; and in 75% of patients with CINCA/NOMID syndrome from an early age, sometimes from birth.
It is recommended to perform an initial consultation (examination, assessment) by an ophthalmologist, including mandatory biomicroscopy of ocular media, for all patients to detect ocular involvement [16, 115].
(LEL 4, GRC C)
Comments: Conjunctivitis, episcleritis, or iridocyclitis are observed in Muckle-Wells syndrome. Uveitis may develop. Ocular involvement develops in 90% of patients with CINCA/NOMID syndrome: anterior uveitis is diagnosed in 50%, posterior uveitis in 20%, and optic nerve involvement (edema, inflammation, atrophy) in 80%. Progressive vision loss is noted in 25% of patients, leading to blindness in 50% of patients.
It is recommended to perform an initial consultation (examination, assessment) by a pediatric dentist for patients with clinical indications to rule out acute oral cavity pathology [2, 4].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (examination, assessment) by a geneticist for patients who are found to have NLRP3 gene mutations based on molecular genetic testing, in order to determine their pathogenicity [11, 13, 22].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (assessment) by an anesthesiologist-resuscitologist for patients scheduled for examinations under anesthesia to assess their condition [47, 48, 116–118].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (assessment) by an anesthesiologist-resuscitologist for critically ill patients to address the question of transfer to the intensive care unit [47, 48, 116–118].
(LoE 5, GoR C)
It is recommended to provide 24-hour monitoring by an anesthesiologist-resuscitologist for all critically ill patients (multiple organ dysfunction syndrome, macrophage activation syndrome) to provide care in the intensive care unit setting [47, 48, 116–118].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (testing, assessment) by a medical psychologist for all patients older than 1 year and all parents (regardless of the child's age) 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 physicians and medical staff to achieve disease remission; to promote social psychological adaptation; and to develop an individual psychological rehabilitation program for the patient and their parents [119–121].
(LEL 4, GRC C)
Evaluation of patients with cryopyrin-associated periodic syndromes with suspected macrophage activation syndrome
Secondary macrophage activation syndrome (sMAS) is a complication of systemic juvenile idiopathic arthritis, a life-threatening hyperinflammatory syndrome representing the culmination of a severe, uncontrolled reaction characterized by hypercytokinemia with a marked yet ineffective immune response. It is a consequence of the innate or acquired inability of the immune system to cope with a trigger—most commonly an infectious agent [122–129].
Secondary MAS is triggered by viruses (cytomegalovirus, Epstein-Barr virus, herpesviruses, etc.), medications (NSAIDs, gold preparations, sulfasalazine**, etc.). Secondary MAS results from excessive activation and expansion of mononuclear phagocyte system (MPS) cells and T lymphocytes, manifested by cytopenia, systemic inflammatory response, and liver and spleen injury. 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 biological blood and lymph filter that removes tumor cells, virus-infected cells, microorganisms, toxins, various metabolites, and circulating immune complexes. Histiocytes (syn.: macrophages) also perform antigen-presenting functions [122–129].
It is not always possible to establish a diagnosis of sMAS because its clinical and laboratory manifestations may mimic a flare of systemic JIA or an infectious process [122–129].
Complaints and anamnesis
see section 2.1.1.
Physical examination
It is recommended to perform diagnostic evaluations, including differential diagnosis, in all patients with suspected MAS within an inpatient setting that provides medical care to children with rheumatic diseases [4, 23].
(LoE 5, GoR C)
It is recommended to perform general thermometry in all patients to assess the severity and pattern of fever [130].
(LoE 5, GoR C)
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 perform an overall health assessment in all patients for ongoing monitoring purposes [130].
(LoE 5, GoR C)
Comments: the course of secondary HPS ranges from mild, with minimal symptom severity, to severe. In severe uncontrolled HPS, impaired consciousness and coma may develop, and a fatal outcome is possible.
It is recommended to perform a visual therapeutic examination in all patients in order to detect pathological changes [130].
(LoE 5, GoR C)
Comments: the frequency of skin manifestations in HPS ranges from 6 to 65%. Skin involvement may present as generalized maculopapular rash, erythroderma, edema, panniculitis, morbilliform rash, and purpura. Some manifestations are similar to those of Kawasaki disease.
Pathological and anatomical examination of skin biopsy (surgical) material reveals lymphohistiocytic infiltration of the dermis with phenomena of hemophagocytosis.
It is recommended to perform a therapeutic palpation in all patients in order to detect peripheral lymphadenopathy [130].
(LoE 5, GoR C)
Comments: with the development of HPS, lymph node size significantly increases and generalized lymphadenopathy develops.
It is recommended to take medical history and assess complaints, perform visual examination, percussion, and auscultation regarding heart and pericardial pathology in all patients in order to detect pathological changes [130].
(LoE 5, GoR C)
Comments: progressive sHPS leads to microangiopathy with thrombosis, which can be accompanied by arrhythmias and, in some cases, myocardial infarction. Acute heart failure is one of the consequences of small vessel thrombosis, microvascular dysfunction, or stress-induced cardiomyopathy.
Signs of cardiovascular complications in sHPS include pain in the heart region, behind the sternum, in the chest, epigastric pain radiating to the back, left shoulder, or neck, cough, shortness of breath worsening in a supine position, and progressive cyanosis.
Physical examination may reveal enhanced cardiac pulsation, expansion of the boundaries of relative cardiac dullness, arrhythmias, and pathological murmurs over the projection areas of heart valves. As sHPS progresses, heart failure typically develops.
It is recommended to take medical history and assess complaints, perform visual examination, percussion, and auscultation regarding lung and bronchial diseases in all patients in order to detect pathological changes in the respiratory system [130].
(LoE 5, GoR C)
Comments: sHPS may be complicated by acute respiratory distress syndrome due to microangiopathy with pulmonary vessel thrombosis. Lung 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.
Examination may reveal dyspnea, cyanosis, patchy percussion sound, decreased breath sounds, crepitant rales, and moist rales of various calibers, predominantly fine-bubbling.
It is recommended to take medical history and assess complaints, perform visual examination, percussion, and palpation regarding diseases of the liver and biliary tract, pancreas, esophagus, stomach, duodenum, small intestine, and large intestine in all patients in order to detect pathological changes [130].
(LoE 5, GoR C)
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.
It is recommended to take medical history and assess complaints, perform visual examination, percussion, and palpation regarding kidney and urinary tract diseases in all patients in order to detect physical signs of damage [130].
(LoE 5, GoR C)
Comments: renal involvement in sHPS manifests as impaired filtration of nitrogenous bases, increasing azotemia, and the development of acute kidney injury.
Laboratory diagnostic tests
It is recommended to perform a complete blood count (including erythrocyte sedimentation rate determination, erythrocyte count, leukocyte count, platelet count, differential leukocyte count (leukogram), and total hemoglobin level) in all patients in order to detect pathological changes characteristic of HPS [124,126,127,130–134].
(LoE 5, GoR C)
Comments: thrombocytopenia, leukopenia, erythropenia, and a decreased ESR are observed in HPS.
It is recommended to perform a coagulogram (screening hemostasis test) including determination of prothrombin index, blood antithrombin III activity, blood plasminogen level, blood fibrinogen level, blood D-dimer concentration, blood soluble fibrin monomer complexes, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time, blood protein C level, blood protein S activity, and von Willebrand factor activity and properties in all patients to assess the state of the hemostatic system [35–37,135,136].
(LEL 4, GRC C)
Comments: in HFS, 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 risk of thrombosis and bleeding [35–37,135,137].
(LoE 5, GoR C)
It is recommended to determine blood heparin levels in all patients receiving heparin group drugs to assess the severity of hemostatic disorders and the risk of thrombosis/bleeding [35–37,41,42,135,137–139].
(LoE 5, GoR C)
It is recommended to perform a general general-medical blood chemistry panel (determination of total blood protein, blood albumin, total blood bilirubin, free and conjugated blood bilirubin, blood creatinine, blood urea, blood uric acid, blood glucose, blood ferritin, blood triglycerides, blood cholesterol, blood sodium, blood potassium, total blood calcium, blood lactate dehydrogenase activity, blood aspartate aminotransferase activity, blood alanine aminotransferase activity, blood gamma-glutamyltransferase activity, blood alkaline phosphatase activity, serum iron, blood creatine kinase activity, blood pancreatic amylase activity, blood lipase activity) to detect pathological changes characteristic of HFS [124,126,127,130–134].
(LoE 5, GoR C)
Comments: HFS is characterized by elevated serum levels of ferritin, triglycerides, ALT, AST, LDH, hyponatremia, hypochloremia, and hypoalbuminemia.
As multiple organ dysfunction progresses, hyperbilirubinemia, elevated creatinine, uric acid, and urea levels may be observed.
It is recommended to determine serum C-reactive protein levels in all patients to assess disease activity [124,126,127,130–134].
(LEL 4, GRC C)
Comments: with the development of HFS serum CRP levels increase significantly.
It is recommended to perform microbiological (culture) blood test for sterility, microbiological (culture) test of tonsillar and posterior pharyngeal swabs for aerobic and facultatively anaerobic microorganisms, microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms, microbiological (culture) stool test for aerobic and facultatively anaerobic microorganisms with antimicrobial susceptibility testing in all patients to detect active bacterial and/or fungal infection as a triggering factor for sHFS [4,126,127,133,140–144].
(LoE 5, GoR C)
It is recommended to determine classes A, M, G antibodies (IgA, IgM, IgG) to Chlamydia psittaci; antibodies to Chlamydia trachomatis; antibodies to Chlamydophila pneumoniae in blood; and classes M, G antibodies (IgM, IgG) in blood to Mycoplasma pneumoniae in all patients to detect/exclude active mycoplasma and/or chlamydial infection as a triggering factor for sHFS [2,4,34,126,133,140,142,143].
(LoE 5, GoR C)
It is recommended to detect Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR when interstitial, focal, and/or infiltrative lung changes are detected on chest computed tomography to identify/exclude active mycoplasma infection as a triggering factor for sHFS [80,127,141,142,145–148].
(LoE 5, GoR C)
It is recommended to determine Epstein-Barr virus DNA by PCR in peripheral and cord blood (quantitative assay), Epstein-Barr virus DNA in oropharyngeal swabs by PCR (qualitative assay), and Epstein-Barr virus DNA in urine by PCR (qualitative assay) in all patients to detect/exclude active herpesvirus infection as a triggering factor for sHFS [4,67,67–70,80,127,141,142,149].
(LEL 4, GRC C)
It is recommended to determine Cytomegalovirus DNA by PCR in peripheral and cord blood (quantitative assay), Cytomegalovirus DNA in oropharyngeal swabs by PCR (qualitative assay), and Cytomegalovirus DNA in urine by PCR (qualitative assay) in all patients to detect/exclude active herpesvirus infection as a triggering factor for sHFS [4,70,72,73,79,80,126,127,133,141,142,149,150].
(LEL 4, GRC C)
It is recommended to determine Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in blood by PCR (quantitative assay), determine Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in oropharyngeal swabs by PCR (qualitative assay), and determine Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in urine by PCR (qualitative assay) in all patients to detect/rule out an active herpetic infection as a trigger factor of sHLH [4,70,74,79,80,126,141,142,151,152].
(LEL 4, GRC C)
It is recommended to determine class M and G antibodies (IgM, IgG) to Cytomegalovirus (Cytomegalovirus) in blood in all patients to detect/rule out an active cytomegalovirus infection as a trigger factor of sHLH [73,80,126,133].
(LoE 5, GoR C)
It is recommended to determine class M and G antibodies (IgM, IgG) to Epstein-Barr virus (Epstein-Barr virus) in blood in all patients to detect/rule out an active Epstein-Barr virus infection as a trigger factor of sHLH [68,72,126,133,141,142,150].
(LEL 4, GRC C)
It is recommended to determine antibodies to Epstein-Barr virus capsid antigen (VCA) (Epstein-Barr virus) in blood in all patients to detect/rule out an active Epstein-Barr virus infection as a trigger factor of sHLH [68,72,126,133,141,142,150].
(LEL 4, GRC C)
It is recommended to determine class G antibodies (IgG) to Epstein-Barr virus early antigens (EA) (Epstein-Barr virus) in blood in all patients to detect/rule out an active Epstein-Barr virus infection as a trigger factor of sHLH [68,72,126,133,141,142,150].
(LEL 4, GRC C)
It is recommended to determine antibodies to Herpes simplex virus (Herpes simplex virus) in blood in all patients to detect/rule out an active herpetic infection as a trigger factor of sHLH [74,76,126,133,141].
(LEL 4, GRC C)
It is recommended to perform microbiological (culture) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms using automated seeding with antimicrobial susceptibility testing of microorganisms in the presence of interstitial, focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of lung lesion [126,133,153,154].
(LEL 4, GRC C)
It is recommended to determine Epstein-Barr virus (Epstein-Barr virus) DNA in sputum and bronchoalveolar lavage fluid by PCR in the presence of interstitial, focal, and/or infiltrative lung changes according to chest computed tomography to detect/rule out an active Epstein-Barr virus infection as a trigger factor of sHLH [125,126,153–156].
(LEL 4, GRC C)
It is recommended to determine Cytomegalovirus (Cytomegalovirus) DNA in sputum and bronchoalveolar lavage fluid by PCR in the presence of interstitial, focal, and/or infiltrative lung changes according to chest computed tomography to detect/rule out an active cytomegalovirus infection as a trigger factor of sHLH [125,126,153–156].
(LEL 4, GRC C)
It is recommended to determine Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, and bronchoalveolar lavage fluid by PCR (quantitative assay) in the presence of interstitial, focal, and/or infiltrative lung changes according to chest computed tomography to detect/rule out an active Pneumocystis infection as a trigger factor of sHLH [126,141,150,157–162].
(LEL 4, GRC C)
It is recommended to determine class M and G antibodies to Pneumocystis jirovecii in blood in the presence of interstitial, focal, and/or infiltrative lung changes according to chest computed tomography to detect/rule out an active Pneumocystis infection as a trigger factor of sHLH [126,127,141,159,163,164].
(LoE 5, GoR C)
It is recommended to perform microbiological (culture) examination of bronchoalveolar lavage fluid for Pneumocystis cysts (Pneumocystis carinii) in the presence of interstitial, focal, and/or infiltrative lung changes according to chest computed tomography to detect/rule out an active Pneumocystis infection as a trigger factor of sHLH [126,133,141,150,156–162,165,166].
(LEL 4, GRC C)
It is recommended to perform microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeast and mold) in the presence of interstitial, focal, and/or infiltrative lung changes according to chest computed tomography to detect/rule out mycosis as a trigger factor of sHLH [133,141,153,160,167,168].
(LEL 4, GRC C)
It is recommended to determine the mannan antigen of fungi of the genus Candida albicans and the galactomannan antigen of fungi of the genus Aspergillus (Aspergillus spp.) in blood serum by enzyme-linked immunosorbent assay (ELISA) when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to computed tomography of the chest organs in order to detect/rule out aspergillosis as a triggering factor for sHLH [133,141,153,160,167,168].
(LEL 4, GRC C)
It is recommended to determine the mannan antigen of fungi of the genus Candida albicans and the galactomannan antigen of fungi of the genus Aspergillus (Aspergillus spp.) in bronchoalveolar lavage fluid by enzyme-linked immunosorbent assay (ELISA) when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to computed tomography of the chest organs in order to detect/rule out aspergillosis as a triggering factor for sHLH [133,141,153,160,167,168].
(LEL 4, GRC C)
It is recommended to test blood procalcitonin levels in all patients in order to rule out sepsis [36,53,55,126,133].
(LE D, GRC C) [40,103,105,180,188]
Comments: an elevated procalcitonin level should raise suspicion of a superimposed infection and the development of sepsis.
It is recommended to perform a complete (clinical) urinalysis, determine urinary albumin, and measure daily urinary protein in all patients in order to diagnose and assess the severity of renal failure [125,126,131,132,169].
(LoE 5, GoR C)
Comments: Tubular necrosis is the predominant form of renal injury in acute kidney injury associated with sHLH (sHLH-AKI). However, histopathological changes may also include interstitial inflammation, glomerular abnormalities, microlesions, and thrombotic microangiopathy. Patients with sHLH-AKI typically present with oliguria, azotemia, and nephrotic syndrome. Urinalysis reveals varying degrees of proteinuria, macroscopic and microscopic hematuria, and cylindruria.
Instrumental diagnostic tests
It is recommended to perform a comprehensive ultrasound examination of internal organs (including comprehensive abdominal ultrasound, renal ultrasound) in all patients in order to detect progressive enlargement of the liver and spleen, as well as intra-abdominal lymph nodes [4,23,126,133,170,171].
(LoE 5, GoR C)
It is recommended to perform echocardiography in all patients in order to assess cardiac status [4,23,126,132,133].
(LoE 5, GoR C)
It is recommended to record an electrocardiogram in all patients in order to evaluate cardiac function [4,23,126,133,172].
(LoE 5, GoR C)
It is recommended to perform computed tomography of the chest organs with or without anesthetic management (including early postoperative care) in all patients in order to detect/rule out lung injury [4,23,126,133,170].
(LoE 5, GoR C)
Comments: HLH can be complicated by hemorrhagic alveolitis, alveolar and interstitial pulmonary edema resembling respiratory distress syndrome (RDS).
It is recommended to perform brain magnetic resonance imaging with or without anesthetic management (including early postoperative care) in patients with neurological symptoms in order to detect brain injury [4,23,126,133,170,173].
(LoE 5, GoR C)
Comments: HLH may manifest with ischemic/hemorrhagic strokes, well-defined demyelinating lesions, and posterior reversible encephalopathy syndrome (PRES).
It is recommended to perform magnetic resonance imaging of the abdominal cavity, retroperitoneal space, and pelvic organs with or without anesthetic management (including early postoperative care) in patients who develop multiple organ dysfunction syndrome, in order to detect organomegaly, free fluid in the abdominal and pelvic cavities, and to assess the state of the liver, kidney, and splenic parenchyma [4,23,126,131,133,174].
(LoE 5, GoR C)
It is recommended to obtain a bone marrow cytological specimen via puncture with anesthetic management (including early postoperative care) and a bone marrow histological specimen with cytological examination of the bone marrow smear (myelogram) and pathomorphological examination of the bone marrow biopsy (surgical) material in all patients in order to identify differentiated macrophages phagocytosing hematopoietic cells [4,23,123,126,133,175–177].
(LoE 5, GoR C)
Comments: bone marrow aplasia may develop in severe HFS.
Other diagnostic examinations
It is recommended to perform an initial neurological examination and consultation for patients with neurological symptoms to assess the state of the central and peripheral nervous system [4,23,126,133].
(LoE 5, GoR C)
Comments: 30–35% of patients develop symptoms of central nervous system involvement: seizures, meningism, decreased 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 levels), and hemophagocytic cells.
Peripheral neuropathy and marked generalized weakness, disproportionate to the degree of anemia, are also encountered.
It is recommended to perform an initial ophthalmological examination and consultation for patients with hemorrhagic syndrome to assess the state of the ocular media and membranes, optic nerve, retina, and fundus [4,23,126,133,178–180].
(LoE 5, GoR C)
Comments: patients with hemophagocytic syndrome (HPS) may exhibit retinal hemorrhages, optic neuritis, and uveal infiltration.
It is recommended to perform an initial consultation (assessment) by an anesthesiologist-resuscitologist for patients scheduled for examinations under anesthesia to assess their condition [47, 48, 116–118].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (assessment) by an anesthesiologist-resuscitologist for critically ill patients to address the question of transfer to the intensive care unit [47, 48, 116–118].
(LoE 5, GoR C)
It is recommended to provide 24-hour monitoring by an anesthesiologist-resuscitologist for all critically ill patients (multiple organ dysfunction syndrome, macrophage activation syndrome) to provide care in the intensive care unit setting [47, 48, 116–118].
(LoE 5, GoR C)
Criteria for diagnosing secondary hemophagocytic syndrome in patients with cryopyrin-associated periodic syndromes.
A. Ravelli et al. criteria [181]
Serum ferritin concentration > 684 ng/ml and 2 of the following:
blood platelet count ≤ 180 x 109/l;
serum AST concentration > 48 IU/L;
serum triglyceride concentration > 1.75 mmol/l;
blood fibrinogen concentration ≤ 3.60 g/l.
Personalized diagnostic algorithm for secondary hemophagocytic syndrome
All patients with a confirmed diagnosis of cryopyrin-associated periodic syndrome presenting with febrile fever require:
Evaluation of the following clinical parameters:
fever, rash, hepatosplenomegaly, lymphadenopathy, myalgia, hemorrhagic syndrome, central nervous system involvement (seizures, paresthesias, confusion, cranial or peripheral neuropathy), renal, pulmonary, and cardiac involvement.
Evaluation of the results of the following tests:
laboratory tests: hemoglobin level, absolute count of red blood cells, white blood cells, neutrophils, lymphocytes, and platelets, ESR, ALT, AST, GGT, LDH activity, concentration of creatinine, urea, CRP, ferritin, triglycerides, procalcitonin, total protein and serum albumin, blood electrolyte composition (sodium, potassium, chlorides, iron), glomerular filtration rate (in case of worsening azotemia), blood clotting profile (Quick's prothrombin time, thrombin time, prothrombin time, INR, aPTT, D-dimer, fibrinogen, fibrin monomer, von Willebrand factor, protein S, protein C);
instrumental tests – ECG, echocardiography, ultrasound of the abdominal organs, kidneys, chest CT, brain and abdominal MRI;
microbiological tests of blood, urine, nasopharyngeal mucus, intestinal discharge;
molecular biological PCR testing to determine DNA of viruses from the Herpesviridae family (cytomegalovirus, Epstein-Barr virus, herpes simplex virus types 1 and 2). After analyzing the clinical data and test results described above, patients must be verified for the diagnosis of sHPS according to the criteria of A. Ravelli et al. from 2016 (see section 2.3) and immunosuppressive therapy should be initiated in accordance with the treatment algorithm for cryopyrin-associated periodic syndrome complicated by hemophagocytic syndrome (see section 3.1.2).
Monitoring of early markers for sHPS development[182]:
All patients require monitoring for early markers of secondary HPS development:
Early clinical markers of secondary HPS:
lymphadenopathy
Early instrumental markers of secondary HPS:
decrease in red blood cell count < 4.34 million/µL
decrease in blood platelet count < 208 thousand/µl
decrease in blood chloride concentration < 101.9 mmol/l
increase in serum LDH activity > 412 IU/l
If early markers of sHPS development are detected, immunosuppressive therapy must be initiated in accordance with the treatment algorithm for cryopyrin-associated syndrome complicated by hemophagocytic syndrome (see section 3.1.2).
Evaluation of patients with a confirmed diagnosis of cryopyrin-associated periodic syndromes in the active disease stage for the purpose of prescribing/adjusting therapy
It is recommended to perform an evaluation prior to prescribing/adjusting therapy in all patients with a confirmed diagnosis of CAPS in the active stage, in a hospital setting providing care for children with rheumatic diseases, for the purpose of prescribing/adjusting therapy [1,2,4,183].
(LoE 5, GoR C)
Complaints and anamnesis
see section 2.1.1.
Physical examination
see section 2.1.2.
Laboratory diagnostic tests
It is recommended to perform a complete blood count (including erythrocyte sedimentation rate determination, red blood cell count, white blood cell count, platelet count, differential leukocyte count (leukocyte formula), and total hemoglobin level) in all patients prior to prescribing/adjusting therapy to determine disease activity and potential adverse effects of NSAIDs and/or immunosuppressants, and/or biological DMARDs (interleukin inhibitors) [11,13,22,28–34].
(LEL 4, GRC C)
Comments: leukocytosis, moderate thrombocytosis, and elevated ESR are detected. In HPS, leukopenia and/or thrombocytopenia, and/or erythropenia, and possibly decreased ESR may occur. Normal leukocyte and platelet counts in patients with fever may indicate ongoing HPS. Single-, double-, or triple-line cytopenia can also be an adverse effect of NSAID and/or biological DMARD (interleukin inhibitor) therapy.
It is recommended to perform a coagulogram (screening hemostasis test) determining prothrombin index, blood antithrombin III activity, blood plasminogen level, blood fibrinogen level, blood 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 activity and properties in patients with HPS and/or signs of vasculitis, and/or receiving heparin-group drugs prior to prescribing/adjusting therapy to assess the hemostatic system and determine the need for correction [35–38,135,136].
(LEL 4, GRC C)
Comments: hypocoagulation and consumption coagulopathy develop in HPS; elevated fibrin degradation products serve as an early preclinical sign.
It is recommended to perform thrombelastography in patients with HPS and/or signs of vasculitis, and/or receiving heparin-group drugs prior to prescribing/adjusting therapy to determine the strategy for anticoagulant therapy [35–37,135,137].
(LoE 5, GoR C)
It is recommended to test blood heparin levels in patients with HPS and/or signs of vasculitis, and/or receiving heparin-group drugs prior to prescribing/adjusting anticoagulant therapy to assess its efficacy [35–37,41,42,135,137,138].
(LoE 5, GoR C)
It is recommended to perform a general general-medical blood chemistry panel (total protein, albumin, total bilirubin, free and conjugated bilirubin, creatinine, urea, uric acid, glucose, ferritin, triglycerides, cholesterol, potassium, sodium, total calcium, lactate dehydrogenase activity, creatine kinase activity, aspartate aminotransferase activity, alanine aminotransferase activity, gamma-glutamyltransferase activity, amylase activity, alkaline phosphatase activity, serum iron) in all patients to assess disease activity and liver, kidney, and pancreatic function [2,4,11,13,22,28–31,34,44,45].
(LEL 4, GRC C)
Comments: elevated triglycerides, ferritin, LDH, AST, and ALT levels indicate the development of HPS; elevated 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 triglycerides can be an adverse effect of NSAID and/or biological DMARD, and/or glucocorticoid therapy. Elevated creatinine, urea, uric acid, and potassium are signs of renal failure development.
It is recommended to test blood procalcitonin levels in patients with fever prior to prescribing/adjusting therapy to rule out a septic process [53–55].
(LoE 5, GoR C)
Comments: procalcitonin levels rise during bacterial infection and acute inflammatory response.
It is recommended to test serum C-reactive protein levels in all patients prior to prescribing/adjusting therapy to determine disease activity [2,4,27,44,128,184].
(Level of Evidence 3, Grade of Recommendation C)
Comments: serum CRP levels are significantly elevated in the active stage of CAPS, as well as during the development of HPS and/or concurrent bacterial infection.
It is recommended to determine serum antistreptolysin-O to identify/exclude group A beta-hemolytic streptococcal infection [2,4,44,46].
(LEL 4, GRC C)
Comments: elevated serum antistreptolysin-O levels indicate acute or chronic streptococcal infection, the exacerbation of which can trigger CAPS attacks.
It is recommended to test blood immunoglobulin levels in all patients prior to prescribing/adjusting therapy to rule out a primary/secondary immunodeficiency state [2,4,27,44,56].
(LEL 4, GRC C)
Comments: blood immunoglobulin levels in CAPS generally fall within reference ranges; decreased immunoglobulin levels indicate the development of an immunodeficiency state.
It is recommended to study lymphocyte subsets in patients who frequently suffer from viral, purulent bacterial, or opportunistic infections, prior to prescribing/adjusting therapy to rule out immunodeficiency resulting from glucocorticoid and/or biological DMARD treatment [4,56,57].
(LoE 5, GoR C)
It is recommended to determine AB0 blood groups, minor subgroups and antigens (A-1, A-2, D, Cc, E, Kell, Duffy), and Rhesus factor (D antigen) in all patients prior to invasive procedures (esophagogastroduodenoscopy, colonoscopy with biopsy, bone marrow aspiration for cytology, bone marrow trephine biopsy imprint cytology, bone biopsy) [4,44,47–49].
(LoE 5, GoR C)
It is recommended to perform a focal tuberculin skin test (Mantoux test, test with recombinant tuberculosis allergen in standard dilution**) and/or blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens in all patients prior to prescribing/adjusting therapy in order to rule out mycobacterial tuberculosis infection [59,185–189].
(LoE 5, GoR C)
It is recommended to determine blood antibodies to Salmonella enterica, blood antibodies to Salmonella typhi, blood IgM and IgG antibodies to Yersinia pseudotuberculosis, and blood antibodies to serovars of Yersinia enterocolitica in patients with abdominal syndrome prior to prescribing/adjusting therapy to rule out intestinal group bacterial infection [2,4,60].
(LoE 5, GoR C)
It is recommended to determine blood IgA, IgM, and IgG antibodies to Chlamydia psittaci, blood antibodies to Chlamydophila pneumoniae, blood IgG antibodies to Chlamydia trachomatis, and blood IgM and IgG antibodies to Mycoplasma pneumoniae in all patients prior to prescribing/adjusting therapy to rule out mycoplasma and chlamydial infection [2,4].
(LoE 5, GoR C)
It is recommended to determine blood IgM and IgG antibodies to Shigella boydii, blood IgM and IgG antibodies to Shigella dysenteriae, blood IgM and IgG antibodies to Shigella sonnei, and blood IgM and IgG antibodies to Shigella flexneri in patients with abdominal syndrome prior to prescribing/adjusting therapy to rule out intestinal group bacterial infection [2,4,60–63].
(LoE 5, GoR C)
It is recommended to perform quantitative PCR determination of Epstein-Barr virus DNA in peripheral and cord blood, qualitative PCR determination of Epstein-Barr virus DNA in oropharyngeal swabs, and qualitative PCR determination of Epstein-Barr virus DNA in urine in all patients prior to prescribing/adjusting therapy to confirm/exclude active Epstein-Barr virus infection and determine the need for etiotropic therapy [2,4,34,50,66,107].
(LoE 5, GoR C)
It is recommended to perform quantitative PCR determination of Cytomegalovirus DNA in peripheral and cord blood, qualitative PCR determination of Cytomegalovirus DNA in oropharyngeal swabs, and qualitative PCR determination of Cytomegalovirus DNA in urine in all patients prior to prescribing/adjusting therapy to confirm/exclude active cytomegalovirus infection and determine the need for etiotropic therapy [2,4,34,50,66,107].
(LoE 5, GoR C)
It is recommended to perform quantitative PCR determination of Herpes simplex virus types 1, 2 DNA in blood, qualitative PCR determination of Herpes simplex virus types 1, 2 DNA in oropharyngeal swabs, and qualitative PCR determination of Herpes simplex virus types 1, 2 DNA in urine in all patients prior to prescribing/adjusting therapy to confirm/exclude active herpetic infection and determine the need for etiotropic therapy [2,4,34,50,66,107].
(LoE 5, GoR C)
It is recommended to perform a complete (clinical) urinalysis, determine urine albumin, and quantify 24-hour urine protein prior to prescribing/adjusting therapy in all patients to assess the condition of the urinary system [11,13,22,33,50].
(LoE 5, GoR C)
Comments: micro- and macrohematuria may result from the toxic effect of NSAIDs on the kidneys; in the development of amyloidosis, the following are detected: proteinuria ≥ 500 mg/day, lipiduria, hyaline casts in the urinary sediment, and granular casts as proteinuria progresses; micro- and macrohematuria, and leukocyturia are possible in the absence of pyelonephritis.
It is recommended to perform a panel of renal function tests in patients with clinical/laboratory signs of kidney damage prior to prescribing/adjusting therapy to determine the degree of renal impairment [18,19,21,22,24].
(LEL 4, GRC C)
It is recommended to perform a panel of tests for the diagnosis and severity assessment of renal failure in patients with clinical/laboratory signs of nephrotic syndrome/renal failure prior to prescribing/adjusting therapy to clarify the severity of renal failure [18,19,21,22,24].
(LEL 4, GRC C)
It is recommended to perform microbiological (culture) examination of tonsillar and posterior pharyngeal wall mucus for aerobic and facultatively anaerobic microorganisms prior to prescribing/adjusting therapy to rule out nasopharyngeal contamination by aerobic and facultatively anaerobic microorganisms [4,23,66].
(LoE 5, GoR C)
It is recommended to perform microbiological (culture) blood test for sterility and microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms in patients with febrile and hectic fever prior to prescribing/adjusting therapy to rule out sepsis [50,54,55,80,158–161,190,191].
(LoE 5, GoR C)
It is recommended to perform microbiological (culture) examination of bronchoalveolar lavage fluid for Pneumocystis carinii cysts in patients with signs of pneumonia on chest computed tomography to confirm/exclude pneumocystis etiology of pneumonia and determine the need for etiotropic therapy [159,162–164,166,192–195].
(LEL 4, GRC C)
It is recommended to perform quantitative PCR determination of Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, and bronchoalveolar lavage fluid in patients with signs of pneumonia on chest computed tomography to confirm/exclude pneumocystis etiology of pneumonia and determine the need for etiotropic therapy [159,162–164,166,192–196].
(LEL 4, GRC C)
It is recommended to perform microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeasts and molds) in patients with signs of pneumonia on chest computed tomography to identify the etiology of pneumonia and determine the need for etiotropic therapy [50,54,55,80,158–161,190,191].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to perform microbiological (culture) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms in patients with signs of pneumonia on chest computed tomography to identify the etiology of pneumonia and determine the need for etiotropic therapy [50,54,55,80,158–161,190,191].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to determine antibodies to Aspergillus spp. in the blood of patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to identify the etiology of pneumonia and determine the need for etiotropic therapy [50,54,55,80,158–161,190,191].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to determine mannan and galactomannan in lavage fluid and blood in patients with signs of pneumonia on chest computed tomography to identify the etiology of pneumonia and determine the need for etiotropic therapy [80,190,197–201].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to perform PCR determination of Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid in patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to identify the etiology of pneumonia and determine the need for etiotropic therapy [80,190,197–201].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to perform PCR determination of Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid in patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to identify the etiology of pneumonia and determine the need for etiotropic therapy [80,190,197–202].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to determine Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG) DNA with species differentiation in sputum or bronchoalveolar lavage fluid by PCR in patients with interstitial, focal, and/or infiltrative changes in the lungs detected by chest computed tomography to identify the etiology of pneumonia and determine the appropriate etiotropic therapy [80,185,186,190,197–209].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to determine class M and G antibodies (IgM, IgG) to Cytomegalovirus in the blood of patients with interstitial, focal, and/or infiltrative changes in the lungs detected by chest computed tomography to identify the etiology of pneumonia and determine the appropriate etiotropic therapy [2,4,34,50,66,72,79–81,107,202,210].
(LoE 5, GoR C)
It is recommended to determine class M and G antibodies (IgM, IgG) to Epstein-Barr virus in the blood of patients with interstitial, focal, and/or infiltrative changes in the lungs detected by chest computed tomography to identify the etiology of pneumonia and determine the appropriate etiotropic therapy [2,4,34,50,66–69,80,107,203,211].
(LEL 4, GRC C)
It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus in the blood of patients with interstitial, focal, and/or infiltrative changes in the lungs detected by chest computed tomography to identify the etiology of pneumonia and determine the appropriate etiotropic therapy [2,4,34,50,66–69,80,107,203,211].
(LEL 4, GRC C)
It is recommended to determine class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus in the blood of patients with interstitial, focal, and/or infiltrative changes in the lungs detected by chest computed tomography to identify the etiology of pneumonia and determine the appropriate etiotropic therapy [2,4,34,50,66–69,80,107,203,211].
(LEL 4, GRC C)
It is recommended to determine antibodies to Herpes simplex virus in the blood of patients with interstitial, focal, and/or infiltrative changes in the lungs detected by chest computed tomography to identify the etiology of pneumonia and determine the appropriate etiotropic therapy [2,4,34,50,66,74–76,78,82,107,212].
(LoE 5, GoR C)
It is recommended to perform a fecal calprotectin test in patients who develop clinical manifestations of IBD (diarrhea, abdominal pain, blood/mucus in stool) prior to prescribing or adjusting therapy in order to rule out IBD [92–94].
(Level of Evidence 1, Grade of Recommendation B)
Instrumental diagnostic tests
It is recommended to perform a comprehensive ultrasound examination of internal organs (including comprehensive abdominal ultrasound and renal ultrasound) in all patients prior to prescribing or adjusting therapy to assess the state of the liver, spleen, kidneys, intestinal motility, and pancreas [4,11,13,22,66].
(LoE 5, GoR C)
Comments: the development of amyloidosis manifests as hepatosplenomegaly, heterogeneous structure of parenchymal organs, and large lardaceous kidney.
It is recommended to perform echocardiography in all patients prior to prescribing or adjusting therapy to detect or rule out pathological changes [2,4,11,13,22,66,95].
(LoE 5, GoR C)
Comments: myocardial involvement, development of diastolic dysfunction, exhaustion of ventricular diastolic reserve, and a tendency toward pulmonary hypertension due to microvascular dysfunction are possible.
It is recommended to perform an electrocardiogram in all patients prior to prescribing or adjusting therapy in order to detect or rule out pathological changes [2,4,45].
(LoE 5, GoR C)
Comments: in most cases, pericarditis in CAPS is not accompanied by low 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 arterial hypertension prior to prescribing or adjusting therapy to develop a treatment strategy [213].
(LoE 3, GoR B)
It is recommended to perform Holter ECG monitoring in patients with arrhythmia or pathological electrocardiographic changes prior to prescribing or adjusting therapy to detect or rule out pathological changes [214].
(LoE 5, GoR C)
It is recommended to perform joint ultrasound in patients with active arthritis prior to prescribing or adjusting therapy to assess the condition of the synovial membrane and cartilage and to detect joint effusion [2,4,23,45].
(LoE 5, GoR C)
It is recommended to perform esophagogastroduodenoscopy with or without anesthesia (including early postoperative management) in patients with dyspepsia, patients receiving NSAIDs for more than 1 month, glucocorticoids, and/or biologic agents, as well as in patients with a disease duration of more than 5 years and/or presence of proteinuria > 500 mg/day, prior to prescribing or adjusting therapy, to rule out inflammatory, erosive, and ulcerative processes [45,94,100,101].
(LEL 4, GRC C)
Comments: it is necessary to rule out upper gastrointestinal inflammatory diseases associated with Helicobacter pylori and/or the use of NSAIDs and/or glucocorticoids (GC), as well as amyloidosis.
It is recommended to perform a microbiological (culture) study of Helicobacter pylori gastric mucosal biopsies (Helicobacter pylori) in patients with inflammatory, erosive, and/or ulcerative changes according to esophagogastroduodenoscopy to exclude GI pathology associated with Helicobacter pylori [45,94,100,101].
(LEL 4, GRC C)
It is recommended to perform esophageal biopsy via endoscopy, gastric biopsy via endoscopy, duodenal biopsy via endoscopy, and jejunal biopsy via endoscopy with or without anesthesia (including early postoperative management), along with pathomorphological examination of the biopsy (surgical) material of the esophagus, stomach, duodenum, and jejunum in patients with inflammatory, erosive, and/or ulcerative mucosal changes according to esophagogastroduodenoscopy to exclude inflammatory bowel diseases [45,94,100,101].
(LEL 4, GRC C)
It is recommended to perform colonoscopy with anesthesia (including early postoperative management) in patients with abdominal syndrome prior to prescribing or adjusting therapy to detect or rule out comorbid bowel diseases and amyloidosis [45,94,100,101].
(LEL 4, GRC C)
Comments: this procedure is performed upon the appearance of intestinal symptoms atypical for CAPS (prolonged diarrhea, abdominal pain, presence of blood and pus in the stool) to rule out IBD, as well as in cases with a disease duration of more than 5 years and/or presence of proteinuria > 500 mg/day.
It is recommended to perform endoscopic colon biopsy with pathomorphological examination of the biopsy (surgical) material of the colon in patients who have inflammatory, erosive, and/or ulcerative changes in the large intestine according to colonoscopy, in order to detect or rule out comorbid bowel diseases and amyloidosis [45,94,100,101].
(LEL 4, GRC C)
It is recommended to perform a kidney biopsy with anesthesia (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen in patients with clinical, laboratory, or ultrasound signs of renal involvement and/or renal failure, and/or presence of proteinuria > 500 mg/day, prior to prescribing or adjusting therapy, to detect or rule out amyloidosis in the absence of contraindications [24].
(LoE 5, GoR C)
Comments: contraindications for kidney biopsy include: thrombocytopenia, coagulopathy, use of heparin-group drugs, and hemodialysis dependence. Performing a kidney biopsy in the presence of contraindications is associated with a high risk of bleeding, hematoma formation, and infection.
It is recommended to perform radiography of the temporomandibular joint and/or intervertebral joints, and/or elbow joint, and/or wrist joint, and/or knee joint, and/or shoulder joint, and/or hip joint, and/or ankle joint, and/or acromioclavicular joint, and/or sternoclavicular joint, and/or hand, and/or foot in two projections, or joint computed tomography with or without anesthesia (including early postoperative management), in patients with active arthritis prior to prescribing or adjusting antirheumatic therapy, to determine the aggressiveness of the disease course and the efficacy of antirheumatic therapy [22,23,96–99].
(LEL 4, GRC C)
It is recommended to perform contrast-enhanced magnetic resonance imaging of a joint (single joint) with or without anesthesia (including early postoperative management) in patients with active arthritis prior to prescribing or adjusting antirheumatic therapy to assess the degree of synovial proliferation (pannus), cartilage damage, bone marrow edema, early manifestations of avascular osteonecrosis, and Baker's cysts [22,23,96–99].
(LEL 4, GRC C)
It is recommended to perform contrast-enhanced brain magnetic resonance imaging with or without anesthesia (including early postoperative management) in patients with neurological symptoms prior to prescribing or adjusting therapy to detect complications and comorbidities [16,107].
(LEL 4, GRC C)
Comments: this is performed in patients with CINCA/NOMID and MWS, as well as those receiving biologic therapy with central nervous system manifestations (headaches, recurrent meningitis, or meningoencephalitis) to verify brain changes (cerebral cortex atrophy, signs of hydrocephalus) and assess the dynamics of changes.
It is recommended to perform a lumbar puncture with anesthetic management (including early postoperative care), microscopic examination, cell counting in a counting chamber (determination of CSF cell count), examination of the physical properties of cerebrospinal fluid, and serological examination in all patients with symptoms of CNS involvement before prescribing/adjusting therapy to exclude/confirm pathological changes [11,13,16,22].
(LEL 4, GRC C)
Comments: performed in patients with neurological manifestations (headaches, recurrent meningitis or meningoencephalitis, seizures, etc.) and in patients with suspected CINCA/NOMID syndrome to rule out an infectious origin of neurological disorders (meningococcal infection, viral meningitis, etc.).
It is recommended to perform computed tomography of the chest organs with or without anesthetic management (including early postoperative care) in all patients before prescribing/adjusting therapy to detect/exclude pathological changes [59,107].
(LEL 4, GRC C)
Comments: focal, lobar, or interstitial pneumonia and pulmonary tuberculosis must be ruled out.
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 with anesthetic management (including early postoperative care) in patients with pulmonary involvement before prescribing/adjusting antirheumatic therapy to obtain bronchoalveolar lavage fluid and perform its analysis [190,191,197–200].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to perform X-ray densitometry in patients receiving or who have received GCs to detect osteopenia/osteoporosis and develop treatment tactics [215,216].
(LoE 5, GoR C)
Other diagnostic examinations
Specialist consultations aimed at diagnosing and treating manifestations of the underlying disease, comorbidities, and/or complications.
It is recommended to perform an initial examination (inspection, consultation) by a trauma and orthopedic surgeon in patients with functional joint insufficiency to address the need for orthopedic correction [2,4,13,22,23].
(LoE 5, GoR C)
It is recommended to perform an initial examination (inspection, consultation) by an otorhinolaryngologist in all patients before prescribing/adjusting therapy to identify foci of chronic ENT infection and address the need for sanitization [114].
(LEL 4, GRC C)
It is recommended to perform an initial examination (inspection, consultation) by an audiologist-otorhinolaryngologist in all patients before prescribing/adjusting therapy to perform an audiogram, detect/exclude sensorineural hearing loss, and determine the degree of hearing impairment [22,114].
(LEL 4, GRC C)
It is recommended to perform an initial examination (inspection, consultation) by a pediatric dentist in all patients before prescribing/adjusting therapy to determine the condition of the oral cavity and the need for its sanitization [2,4].
(LoE 5, GoR C)
It is recommended to perform an initial examination (inspection, consultation) by an ophthalmologist with mandatory ocular biomicroscopy in all patients to detect/exclude uveitis and its complications, as well as complicated steroid cataract, before prescribing/adjusting therapy [11,13,16,22,115].
(LEL 4, GRC C)
Comments: local therapy is prescribed to patients with uveitis and complicated steroid cataract.
It is recommended to perform an initial examination (inspection, consultation) by a pediatric cardiologist in patients with cardiac arrhythmias and/or arterial hypertension to address the issue of cardiotropic and/or antihypertensive therapy before prescribing/adjusting treatment [22].
(LoE 5, GoR C)
It is recommended to perform an initial examination (inspection, consultation) by a phthisiatrician in patients with positive results of a focal tuberculin skin test and/or intradermal test with tuberculosis allergen, and/or an elevated blood level of interferon-gamma to Mycobacterium tuberculosis complex antigens, and/or focal, infiltrative changes in the lungs before prescribing/adjusting antirheumatic therapy to address the issue of chemoprophylaxis or anti-tuberculosis chemotherapy [59].
(LEL 4, GRC C)
It is recommended to perform an initial examination (inspection, consultation) by a pediatric endocrinologist in patients with endocrine pathology to develop tactics for further examination and treatment [22].
(LoE 5, GoR C)
It is recommended to perform an initial examination (inspection, consultation) by a neurologist in patients with neurological symptoms to address the issue of therapy [16].
(LEL 4, GRC C)
It is recommended to perform an initial examination (inspection, consultation) by a nephrologist in patients with nephrotic syndrome, changes in general clinical blood biochemistry, and general urinalysis typical of the development of amyloidosis/renal failure to determine treatment tactics [11,13,17,20,22,24,113].
(LoE 5, GoR C)
It is recommended to perform an initial examination (inspection, consultation) by a dietitian in all patients with nutritional disorders to develop an individual dietary program [4,23,217,218].
(LoE 5, GoR C)
It is recommended to perform an initial examination (consultation) by an anesthesiologist-resuscitator in patients scheduled for procedures under anesthesia in order to assess their condition [47,48,116–118].
(LoE 5, GoR C)
It is recommended to perform an initial consultation (assessment) by an anesthesiologist-resuscitologist for critically ill patients to address the question of transfer to the intensive care unit [47, 48, 116–118].
(LoE 5, GoR C)
It is recommended to provide 24-hour monitoring by an anesthesiologist-resuscitologist for all critically ill patients (multiple organ dysfunction syndrome, macrophage activation syndrome) to provide care in the intensive care unit setting [47, 48, 116–118].
(LoE 5, GoR C)
It is recommended to perform an initial psychological examination (testing, consultation) by a medical psychologist in all patients older than 1 year and all parents (regardless of the child's age) with the aim of harmonizing the development of the child's personality in the context of a severe chronic disease and optimizing parent-child relationships; increasing treatment adherence and cooperation with the doctor and medical staff to achieve disease remission; psychological adaptation in society; and developing an individual psychological rehabilitation program for the patient and their parents [119–121].
(LEL 4, GRC C)
It is recommended to perform a follow-up examination (inspection, consultation) by an otorhinolaryngologist in all patients after the sanitization of foci of chronic infection to monitor its efficacy [22].
(LoE 5, GoR C)
It is recommended to perform a follow-up examination (inspection, consultation) by a pediatric dentist in patients after the sanitization of foci of chronic oral infection to monitor its efficacy [2,4].
(LoE 5, GoR C)
It is recommended to perform a follow-up examination (inspection, consultation) by an ophthalmologist with mandatory ocular biomicroscopy in all patients with identified pathology to monitor treatment efficacy and address the issue of surgical treatment in an ophthalmology inpatient setting [11,13,16,22,115].
(LEL 4, GRC C)
It is recommended to perform a follow-up examination (inspection, consultation) by a pediatric cardiologist in patients with cardiac arrhythmias and/or arterial hypertension to monitor the efficacy of cardiotropic and/or antihypertensive therapy [22].
(LoE 5, GoR C)
It is recommended to perform a follow-up examination (inspection, consultation) by a pediatric endocrinologist in patients with endocrine pathology to monitor treatment efficacy [22].
(LoE 5, GoR C)
It is recommended to perform a follow-up examination (inspection, consultation) by a dietitian in all patients with nutritional disorders to monitor compliance with the individual dietary program and recommendations on eating behavior in an outpatient setting [4,23,217,218].
(LoE 5, GoR C)
It is recommended to perform a follow-up examination (inspection, consultation) by a neurologist in patients with neurological symptoms and psychotic reactions to monitor treatment efficacy [16].
(LEL 4, GRC C)
It is recommended to perform a follow-up examination (inspection, consultation) by a nephrologist in patients with nephrotic syndrome, changes in general clinical blood biochemistry, and general urinalysis typical of the development of amyloidosis/renal failure to monitor treatment efficacy [11,13,17,20,22,24,113].
(LoE 5, GoR C)
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 establishment/confirmation of the CAPS diagnosis, in an inpatient setting providing medical care to children with rheumatic diseases [4,11,13,22,23].
(LoE 5, GoR C)
3.1 Conservative Treatment
It is recommended to prescribe only NSAIDs (M01A) in patients with an unconfirmed CAPS diagnosis at the diagnostic stage to relieve fever and pain syndrome [4,11,22,222–225].
(LoE 5, GoR C)
It is recommended to prescribe NSAIDs (M01A) in patients with a confirmed CAPS diagnosis to relieve fever and pain syndrome [4,11,22,222,223,225].
(LoE 5, GoR C)
Comments: NSAIDs (M01A) are prescribed in the following dosages:
- diclofenac** (M01AB) in accordance with the drug's instructions for use, or
- nimesulide (M01AX) in accordance with the drug's instructions for use, or
- meloxicam (M01AC) in accordance with the drug's instructions for use, or
- ibuprofen** (M01AE01) in accordance with the drug's instructions for use#.
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, over 15 years of age as tablets; intramuscular injection is approved from 18 years of age.
Ibuprofen** (M01AE01) is used in children over 3 months of age as a suspension and over 6 years of age as tablets; the interval between doses is 6–8 hours.
Monotherapy with NSAIDs lasting more than 1 month is not recommended for any patients.
It is not recommended to prescribe GCs (H02AB) orally and/or intravenously, and/or targeted biological therapies (TBAs) before completing a full laboratory and instrumental workup, ruling out oncological and onco-hematological diseases, and establishing a diagnosis of CAPS [11,13,25,34,223].
(LoE 5, GoR C)
Comments: the use of GCs and TBAs (canakinumab**) in oncological and onco-hematological diseases mimicking CAPS will significantly complicate subsequent diagnosis verification, as they have a pronounced immunosuppressive effect and mask the clinical and morphological presentation of malignant neoplasms.
It is recommended to perform pulse therapy #with methylprednisolone** (H02AB) at a dose of 10-30 mg/kg/administration intravenously for 3, and if necessary 5 consecutive days, in patients with a confirmed CAPS diagnosis at the workup stage in the presence of severe pain syndrome and/or life-threatening systemic manifestations (persistent febrile or hectic fever, and/or pericarditis, and/or pleuritis) to achieve a rapid anti-inflammatory effect [5,12,23,219].
(LoE 5, GoR C)
It is recommended to prescribe #prednisolone** (H02AB) or #methylprednisolone** (H02AB) orally at a dose of 1 mg/kg/day for patients with an established diagnosis of CAPS during the evaluation stage, in the presence of severe pain syndrome and/or life-threatening systemic manifestations (persistent febrile or hectic fever, and/or pericarditis, and/or pleuritis), or for patients with a refractory course of CAPS in order to achieve a rapid anti-inflammatory effect [4,11,22,226,227].
(LoE 5, GoR C)
It is recommended to prescribe the interleukin-1 beta (IL-1β) inhibitor canakinumab** (L04AC) or the interleukin-1 (IL-1α and IL-1β) inhibitor anakinra** (L04AC03) as the main pathogenetic therapy for all patients with an established diagnosis of CAPS who have signs of a systemic inflammatory response (fever, rash, etc.), organ involvement (hearing loss, eye pathology, CNS or joint changes), elevated ESR above 30 mm/h (by Panchenkov), CRP above 20 mg/L, or more than 4 times the upper limit of normal at the time of examination or within a month prior to it, in order to induce remission of CAPS [22,228–233].
(LoE 3, GoR B)
It is recommended to prescribe canakinumab** (L04AC) to patients older than 2 years in accordance with the instructions for medical use of the medicinal product in order to maintain remission of CAPS [22,228–237].
(Level of Evidence 3, Grade of Recommendation C)
Comments: treatment with canakinumab** (L04AC) is carried out for life. Administration of the drug can be performed in inpatient and outpatient settings.
Monitoring of therapy includes relief of systemic manifestations (fever, rash, pain syndrome), absence of organ involvement (hearing loss, ocular manifestations, amyloid organ damage), and laboratory activity (ESR, CRP within normal values).
Monitoring of treatment efficacy – see Appendix A3, G1–G3.
It is recommended to administer maintenance therapy with canakinumab** (L04AC) to patients older than 2 years in accordance with the instructions for medical use of the medicinal product in order to maintain remission of CAPS [22,228–237].
(Level of Evidence 3, Grade of Recommendation C)
Comments: the clinical effect is the relief of fever, rash, and the decrease/normalization of acute-phase inflammatory markers (ESR, CRP, white blood cell count).
Monitoring of treatment efficacy – see Appendix A3, G1–G3.
It is recommended to administer a second injection of canakinumab** (L04AC) to patients older than 2 years if the clinical effect is not achieved 7 days after the first injection of canakinumab** (L04AC) in accordance with the instructions for medical use of the medicinal product in order to induce remission of CAPS [22,228–237].
(LoE 5, GoR C)
Comments: the clinical effect is the relief of fever, rash, and the decrease/normalization of acute-phase inflammatory markers (ESR, CRP, white blood cell count).
Monitoring of treatment efficacy – see Appendix A3, G1–G3.
It is recommended to administer maintenance therapy with canakinumab** (L04AC) to patients older than 2 years if the clinical effect is achieved 7 days after the second injection of canakinumab** (L04AC) in accordance with the instructions for medical use of the medicinal product in order to maintain remission of CAPS [22,228–237].
(LoE 5, GoR C)
Comments: the clinical effect is the relief of fever, rash, and the decrease/normalization of acute-phase inflammatory markers (ESR, CRP, white blood cell count).
Monitoring of treatment efficacy – see Appendix A3, G1–G3.
It is recommended to administer a third injection of canakinumab** (L04AC) to patients older than 4 years if the clinical effect is not achieved 7 days after the second injection of canakinumab** (L04AC) in accordance with the instructions for medical use of the medicinal product in order to induce remission of CAPS [22,228–237].
(LoE 5, GoR C)
Comments: the clinical effect is the relief of fever, rash, and the decrease/normalization of acute-phase inflammatory markers (ESR, CRP, white blood cell count).
Monitoring of treatment efficacy – see Appendix A3, G1–G3.
It is recommended to administer maintenance therapy with canakinumab** (L04AC) subcutaneously to patients older than 4 years upon achieving a complete clinical response 7 days after the third injection of canakinumab** (L04AC) in accordance with the instructions for medical use of the medicinal product in order to maintain remission of CAPS [22,228–237].
(LEL 4, GRC C)
Comments: the clinical effect is the relief of fever, rash, and the decrease/normalization of acute-phase inflammatory markers (ESR, CRP, white blood cell count).
Monitoring of treatment efficacy – see Appendix A3, G1–G3.
It is recommended to prescribe anakinra** (L04AC03) to patients older than 8 months with a body weight ≥ 10 kg at 1–2 mg/kg/day subcutaneously in order to induce remission of CAPS [11,13,22,238].
(LoE 3, GoR B)
Monitoring of treatment efficacy – see Appendix A3, G1–G3.
It is recommended to administer maintenance therapy with anakinra** (L04AC03) to patients older than 8 months with a body weight ≥ 10 kg at 1–2 mg/kg/day subcutaneously upon achieving a clinical effect in order to maintain remission of CAPS [11,13,22,238].
(LoE 3, GoR B)
Comments: the clinical effect is the relief of fever, rash, joint pain, and headache, decrease/normalization of acute-phase inflammatory markers (ESR, CRP, white blood cell count) and frequency of exacerbations.
Monitoring of treatment efficacy – see Appendix A3, G1–G3.
It is recommended to increase the dose of anakinra** (L04AC03) to 3–4 mg/kg/day, if necessary, with a subsequent increase to a maximum dose of 8 mg/kg/day subcutaneously in case of failure to achieve clinical effect or in severe CAPS (MWS and CINCA/NOMID) in order to induce remission of CAPS [11,13,22,238].
(LoE 3, GoR B)
It is recommended to evaluate the Autoinflammatory Disease Activity Index (AIDAI) (Appendix G1) and the MWS-DAS index (Appendix G2) in all patients with a diagnosis of CAPS in order to assess the efficacy of therapy [239].
(Level of Evidence 3, Grade of Recommendation C)
Comments: performed in all patients in active and inactive stages of the disease. All disease symptoms over the last month are assessed as yes or no (1/0) and their severity (1 – minimal, 2 – moderate, 3 – severe). More than 9 active manifestations are assessed as disease activity.
It is recommended to evaluate the damage index (ADDI) in all patients with a diagnosis of CAPS in order to assess treatment efficacy and the aggressive course of the disease (Appendix G3) [5,11,22,240].
(LoE 5, GoR C)
Comments: performed in all patients in active and inactive stages of the disease.
Monitoring of treatment efficacy – see Appendix G1-G3.
3.1.2 Treatment of hemophagocytic syndrome in patients with cryopyrin-associated periodic syndromes
It is recommended to prescribe and administer therapy in a hospital setting providing medical care to children with rheumatic diseases after diagnostics, including differential diagnostics, and establishing/confirming the diagnosis of CAPS with hemophagocytic syndrome in all patients in order to ensure the prevention and timely relief of severe complications [4,11,13,22,23].
(LoE 5, GoR C)
It is recommended to prescribe targeted etiotropic therapy with systemic antibacterial drugs (J01) and/or systemic antifungal drugs (J02A), and/or systemic antiviral drugs (J05) in patients with a known infectious etiological factor in order to halt the activation of the innate immune system [4,126,133,141].
(LoE 5, GoR C)
It is recommended to prescribe GCs (H02AB) in combination with #cyclosporine** (L04AD) and #normal human immunoglobulin** (J06BA) in all patients in order to relieve HPS [126,131,133,134,241–243].
(LoE 5, GoR C)
It is recommended to administer 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 order to relieve HPS [123,126,130,133,175,242,244–248].
(LoE 5, GoR C)
It is recommended to gradually taper the dose of intravenous GCs after the resolution of clinical and laboratory signs of MAS according to the following regimens:
- #dexamethasone** (H02AB) starting from a dose of 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;
- #methylprednisolone** starting at a dose of 20–30 mg/kg/administration for 3–5 days, tapering the dose by 25% every 2–3 days to prevent withdrawal syndrome [4,133,243,245,249–251].
(LoE 5, GoR C)
It is recommended to prescribe #cyclosporine** at a dose of 3–5 mg/kg/day intravenously or orally to all patients in order to relieve HPS [126,131,133,242,243,245,247,251,252].
(LEL 4, GRC C)
It is recommended to prescribe #normal human immunoglobulin** (J06BA) at a dose of 1–2 g/kg/course over 2 days intravenously to all patients in order to achieve an immunosuppressive effect and relieve HPS [133,243,247,251,253,254].
(LoE 5, GoR C)
Comments: administration of the full course dose of #normal human immunoglobulin** is carried out via continuous prolonged infusion as a single dose to ensure blockade of IgG Fc receptors on phagocytic cells; suppression of T-lymphocyte proliferation and immunoglobulin production; interaction with the complement system; blockade of cytokine activation and action; and blockade of adhesion molecule expression on endothelial cells.
It is recommended to evaluate the efficacy of the applied HPS treatment regimen in accordance with the criteria for achieving a therapeutic response (resolution of fever, reduction in spleen size, increase in blood platelet count ≥ 100 × 109/L, normalization of blood fibrinogen levels, reduction in serum ferritin concentration by 25%) every 48 hours in order to decide on continuing/changing the induction therapy regimen [126,133].
(LoE 5, GoR C)
It is recommended to prescribe #anakinra** (L04AC) at a dose of 5–10 mg/kg/day intravenously in 2 doses for 3–10 days, or longer if necessary, upon escalation of HPS activity during the first 48 hours of GC therapy in combination with #cyclosporine** (L04AD) and #normal human immunoglobulin** (J06BA) in order to relieve HPS [126,133,255–260].
(LEL 4, GRC C)
It is recommended, in case of inefficacy of the combination of #anakinra** (L04AC) with GCs, #cyclosporine** (L04AD), and #normal human immunoglobulin** (J06BA), to additionally prescribe:
- #ruxolitinib** orally
o for children weighing up to 10 kg – 2.5 mg x 2 times/day;
o for children weighing from 10 to 25 kg – 5 mg x 2 times/day;
o in children weighing > 25 kg – 10 mg × 2 times/day.
(LEL 4, GRC C)
- or #tofacitinib** (L04AA) orally at a dose of 10 mg × 2 times/day in order to relieve HPS [133,261,262].
(LEL 4, GRC C)
It is recommended to prescribe #prednisolone** at a dose of 1-2 mg/kg orally or #methylprednisolone** (H02AB) at a dose equivalent to prednisolone, in case of inefficacy of combination therapy for HLH or HLH reactivation during reduction/withdrawal of intravenous GCs, in order to relieve HLH [126, 131, 133, 247].
(LEL 4, GRC C)
It is recommended to prescribe #acyclovir** (J05AB) to children aged < 1 year at a dose of 10 mg/kg/administration intravenously every 8 hours; to children aged ≥ 1 year at a dose of 500 mg/m2 intravenously every 8 hours in the event of Herpes zoster infection in order to suppress the triggering factor of HLH [263–267].
(LoE 5, GoR C)
It is recommended to prescribe #acyclovir** (J05AB) at a dose of 5-10 mg/kg/administration intravenously every 8 hours for 7-10 days upon confirmation of an active infection caused by Herpes simplex virus in order to suppress the triggering factor of HLH [77, 265].
(LoE 5, GoR C)
Comments: treatment is carried out until complete resolution of the herpetic infection.
It is recommended to prescribe #ganciclovir** (J05AB) at a dose of 6 mg/kg/administration intravenously every 12 hours for 14-21 days upon confirmation of active cytomegalovirus infection in order to suppress the triggering factor of HLH [71, 268–270].
(LoE 5, GoR C)
It is recommended to prescribe #ganciclovir** (J05AB) at a dose of 10 mg/kg/administration intravenously every 12 hours for 14-21 days upon confirmation of active Epstein-Barr virus infection in order to suppress the triggering factor of HLH [271, 272].
(LoE 5, GoR C)
It is recommended to prescribe #ganciclovir** (J05AB) at a dose of 10 mg/kg/administration intravenously every 12 hours for 14-21 days upon confirmation of active Epstein-Barr virus infection in order to suppress the triggering factor of HLH [3, 7, 395].
(LoE 5, GoR C)
It is recommended to prescribe #rituximab** as a first-line biologic DMARD in combination with #cyclosporine**, #normal human immunoglobulin** and #co-trimoxazole** in active Epstein-Barr virus infection in order to suppress viral replication in B-lymphocytes and relieve HLH [247, 273].
(LoE 5, GoR C)
Comments: regimens of administration:
- #rituximab** (L01XC) – at a dose of 375 mg/m2/week intravenously for 1-4 consecutive weeks [247, 273];
- #cyclosporine** (L04AD) – 3-5 mg/kg/day [247, 273];
- #normal human immunoglobulin** (J06BA) – 1-2 g/kg/course over 2 days [247, 273];
- #co-trimoxazole** (JO1EE) – for the dosing regimen and doses of #co-trimoxazole** (JO1EE), see below [162,193].
It is recommended to prescribe #rituximab** (L01XC) in combination with #co-trimoxazole** (J01EE) 5 mg/kg based on trimethoprim orally 3 times a week or daily for the prevention of Pneumocystis pneumonia in accordance with international guidelines [274–281].
(LoE 5, GoR C)
It is recommended to prescribe antithrombotic agents (B01A), including heparin-group drugs (B01B), antiplatelet agents other than 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 in order to prevent thrombotic complications and relieve coagulopathy [35–37, 55, 126, 138, 282–284].
(LoE 5, GoR C)
It is recommended to perform blood transfusion in the event of consumption coagulopathy or bleeding in order to restore balance in the hemostatic system [35, 285, 286].
(LoE 5, GoR C)
Comments: in the event of consumption coagulopathy, blood transfusion and blood products (B05A) are administered: red blood cells, platelets, blood plasma, albumin, blood coagulation factor VII, human blood coagulation factor VIII, etc., in accordance with indications.
It is recommended to prescribe the colony-stimulating factor #filgrastim** (L03AA) at a dose of 5-10 mcg/kg/day subcutaneously for 3-5 days (longer if necessary) when the absolute neutrophil count drops to ≤ 1.0 × 109/L in order to restore blood neutrophil counts and prevent infectious complications [4, 287, 288].
(LoE 5, GoR C)
It is recommended to prescribe empiric systemic antibacterial therapy (J01) active against gram-positive, gram-negative, and anaerobic flora, and/or systemic antifungal drugs (J02A), and/or systemic antiviral drugs (J05) in the event of sepsis/infectious complication prior to confirmation of the etiological factor in order to arrest/prevent the progression of the infectious process [34, 36, 54, 55, 126, 289–293].
(LoE 5, GoR C)
It is recommended to prescribe targeted therapy according to microbial susceptibility upon confirmation of the etiological factor of sepsis/infectious complication, depending on the clinical situation, with systemic antibacterial drugs (J01) (combinations of penicillins, including combinations with beta-lactamase inhibitors (J01CR) and/or 4th-generation cephalosporins (J01DE), and/or carbapenems (J01DH), and/or other antibacterial drugs (J01XX), and/or glycopeptide antibiotics (J01XA), and/or other aminoglycosides (J01GB)) with or without systemic antifungal drugs (J02A) and/or systemic antiviral drugs (J05) in order to resolve sepsis/infectious complications [34, 36, 54, 55, 126, 289–293].
(LoE 5, GoR C)
It is recommended to continue HLH treatment until the criteria for the inactive stage are achieved (absence of fever, splenomegaly, cytopenia (Hb ≥ 90 g/L, platelets ≥ 100 × 109/L, neutrophils ≥ 0.5 × 109/L), blood triglyceride level < 3 mmol/L or < 265 mg/dL, ferritin ≤ 500 µg/L, normalization of cerebrospinal fluid parameters (in CNS involvement)) in order to prevent the development of multiorgan failure and fatal outcome [294].
(LoE 5, GoR C)
3.2 Surgical Treatment
It is recommended to consider surgical treatment for patients with severe hearing impairment [11, 15, 16, 22, 295].
(LEL 4, GRC C)
Comments: performed after consultation with an otorhinolaryngologist-audiologist.
It is recommended to perform joint arthroplasty with anesthetic management (including early postoperative management) in children with stage 3-4 secondary coxarthrosis, taking into account age restrictions [4, 23].
(LoE 5, GoR C)
3.3 Non-pharmacological treatment
It is recommended to provide maintenance hemodialysis to patients with amyloidosis and end-stage chronic kidney disease [17].
(LoE 5, GoR C)
It is recommended to consume foods with an increased content of calcium and vitamin D for the prevention of osteoporosis in patients receiving GCs [23].
(LoE 5, GoR C)
It is recommended to use braces, splints, and insoles in patients with chronic arthritis, joint deformities, and lower limb growth disturbances in order to correct orthopedic disorders [2, 4, 23].
(LoE 5, GoR C)
Comments: for static orthoses, intermittent immobilization is necessary – they should be worn or put on during free time and must be removed during the day to stimulate the muscular system during physical exercises, activities, occupational therapy, and personal hygiene. In case of pronounced osteoporosis in the thoracic and lumbar spine, a corset or posture corrector 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 to all patients with functional impairment after disease activity reduction in order to restore functional capacity [119, 120].
(LoE 5, GoR C)
It is recommended to conduct an initial appointment (testing, consultation) with a medical psychologist for all patients older than 1 year and all parents (regardless of the child's age) in order to develop an individual psychological rehabilitation program for the patient and their parents to harmonize the development of the child's personality under conditions of a severe chronic disease and optimize parent-child relationships; to increase treatment adherence and cooperation with the physician and medical personnel to achieve disease remission; and to achieve psychological adaptation in society [119–121].
(LEL 4, GRC C)
It is recommended to conduct a follow-up appointment (testing, consultation) with a medical psychologist for all patients older than 1 year and all parents after completion of the psychological rehabilitation program in order to evaluate its effectiveness [119–121].
(LEL 4, GRC C)
It is recommended to conduct an initial examination (consultation) with a physical therapist for all patients with functional impairment after disease activity reduction in order to develop a physiotherapy program as part of the medical rehabilitation program [119, 120].
(LoE 5, GoR C)
It is recommended to conduct an initial appointment (examination, consultation) with a medical exercise therapy physician for patients with functional impairment after disease activity reduction in order to develop a medical rehabilitation program [119, 120].
(LoE 5, GoR C)
It is recommended to conduct a follow-up examination (consultation) with a physical therapist for all patients with functional impairment after completion of the physiotherapy program as part of the medical rehabilitation program in order to evaluate its effectiveness [119, 120].
(LoE 5, GoR C)
It is recommended to conduct a follow-up appointment (examination, consultation) with a medical exercise therapy physician for all patients with functional impairment after completion of the medical rehabilitation program in order to evaluate its effectiveness [119, 120].
(LoE 5, GoR C)
It is recommended to provide medical rehabilitation services to patients with systemic connective tissue diseases, inflammatory arthropathies, and spondyloarthropathies in order to restore functional capacity [119, 120].
(LoE 5, GoR C)
Comments: performed in all patients with musculoskeletal system disorders; 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, for the week, for the entire period of rehabilitation; the motor regime, individual boundaries of the intensity of applied interventions on a patient with functional impairments are determined; an individual exercise therapy program is developed; rehabilitation methods are determined: medications, kinesiotherapy, mechanotherapy, including therapeutic mechanotherapy in water, physiotherapy, robotics, exoskeletons, information technologies, psychological correction, occupational therapy; forms of medical rehabilitation are selected at various stages of its application, in various periods of the course of the disease (individual, group session, session using telemedical technologies); counseling of legal representatives of children in need of medical rehabilitation is carried out, along with teaching them rehabilitation techniques approved for home use and care skills for severely ill children.
It is recommended to perform physiotherapy in all patients with joint involvement, muscle atrophy, and steroid myopathy once remission is achieved [119, 120].
(LoE 5, GoR C)
Comments: a plan is being developed, the goal and objectives of applying physiotherapy in a patient with CAPS are formulated during the implementation of an individual rehabilitation program; physiotherapy methods—high-frequency electric field therapy, magnetotherapy, polarized light therapy, mechanotherapy, thermal therapy, and sanatorium-resort treatment (climatotherapy, balneotherapy, peloidotherapy)—are selected depending on the various periods of the disease course.
It is recommended to conduct a psychological rehabilitation school for patients with CAPS and their relatives [119–121].
(LEL 4, GRC C)
Comments: medical rehabilitation is necessarily combined with the psychological rehabilitation of children and their parents; an individual program of 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, taking into account the clinical presentation, personality traits, psychotherapeutic hypothesis, psychotherapeutic targets; methods of psychological intervention (psychotherapy, psychological counseling, psychological correction, and psychological rehabilitation) are selected; types of psychotherapy (dynamic, cognitive-behavioral, existential-humanistic, psychotherapy using non-mainstream modalities—art therapy, body-oriented psychotherapy, psychodrama, suggestive psychotherapy, etc.); forms of psychotherapy (individual, family-couple, group, natural environment psychotherapy, milieu therapy).
It is recommended to conduct the "School for Children with Rheumatic Diseases and Their Parents" [4,296].
(LoE 5, GoR C)
Comments: the objective of WhiteCoat Pro is to inform parents and children about the features, pathogenesis, clinical presentation, treatment, mechanisms of drug action, their efficacy, potential side effects; methods of medical and psychological rehabilitation, disease outcomes; vaccination, prevention of exacerbations, complications, and adverse effects of antirheumatic drugs. Training in methods for monitoring drug efficacy and safety using standard rheumatological scales and questionnaires.
5. Prevention and Dispensary Observation
5.1 Prevention
Primary prevention consists of genetic forecasting for the birth of a child with CAPS.
It is recommended that parents have a follow-up appointment (examination, consultation) with a medical geneticist after the diagnosis is established in a child, for the purpose of genetic counseling regarding the recurrence risk of CAPS in future children within this family [11,13,22].
(LoE 5, GoR C)
Comment: families with children suffering from CAPS are advised to undergo genetic counseling to assess the genetic risk. The inheritance pattern of CAPS is autosomal dominant, and the disease can be transmitted from an affected family member to their children; the recurrence risk is estimated at 50% and is independent of sex. However, it should be noted that most cases are sporadic, and there may be no other affected individuals in the family. According to literature data, up to 40% of patients with clinical manifestations may not exhibit mutations when using direct sequencing methods, which can be due to both mosaicism and the presence of mutations in other genes, including currently unknown ones. Therefore, the absence of mutations does not completely rule out the diagnosis.
Prenatal diagnosis is possible if the genotype has been established and is performed using molecular genetic or biochemical methods by analyzing DNA extracted from a chorionic villus biopsy at 9–11 weeks of pregnancy. However, given the possibilities of disease management and the varying severity of clinical forms, all risks and prognoses must be discussed in detail with the family.
It is recommended to implement the prevention of complications and exacerbations of CAPS, as well as adverse effects of targeted therapy, in all patients in order to prevent the development of severe consequences [11,13,22].
(LoE 5, GoR C)
Comments: to prevent exacerbations and complications of CAPS, long-term maintenance therapy is carried out under the continuous monitoring of clinical and laboratory indicators of disease activity, tailored to the individual characteristics of the patient and the variant of the disease, with its correction if necessary; a protective regimen is ensured (psycho-emotional and physical loads are limited; during the exacerbation period, children are homeschooled and attend school during the inactive disease phase/remission; contacts are limited to reduce the risk of infectious diseases); insolation, trips to regions with high levels of insolation, and UV therapy are excluded; sunscreens must be used, wearing clothing that maximally covers the skin and wide-brimmed hats is recommended; hypothermia is prevented; an individual approach to vaccination is developed; the use of live vaccines and immunomodulators is excluded.
To reduce the risk of side effects from antirheumatic drugs, regular monitoring of clinical and laboratory safety parameters is carried out; the use of medicinal products that increase the toxicity of GCs, immunosuppressants, and bDMARDs is excluded. Dispensary follow-up is recommended: a physical examination by a specialist (pediatrician, rheumatologist, allergist-immunologist, etc.) who is monitoring the patient, including musculoskeletal and neurological manifestations, child growth and development once every 6 months. Ophthalmologic examination (with slit-lamp biomicroscopy) once every 3 months, or more frequently if necessary. Audiogram once a year. MRI, radiography of the femoral and tibial bones, knee joints (patellae), brain MRI, lumbar punctures (pressure, cell count, protein level in cerebrospinal fluid) in patients with CINCA/NOMID once a year. Cognitive testing in severe patients. Assessment of the impact on quality of life and social adaptation. Assessment of disease activity using the AIDAI and MWS-DAS indices, and damage index (ADDI) once a year. Monitoring the efficacy and safety of interleukin inhibitor therapy (canakinumab**): complete blood count and urinalysis (proteinuria), general clinical biochemical blood test (ALT, AST, creatinine, total protein), and serum C-reactive protein level measurement once every 3 months. Individual approach to vaccination — vaccination of children should be carried out only during a period of complete disease remission, with its prolonged maintenance for at least one year, according to an individual schedule, excluding live vaccines.
It is not recommended to administer live and live-attenuated vaccines concurrently with bDMARD therapy in patients receiving bDMARDs, in order to avoid disease exacerbation [297,298].
(LoE 5, GoR C)
Comments: the safety of such a combination has not been established. Exacerbation of CAPS or hemophagocytic lymphohistiocytosis (HLH) may develop. There are no data on the secondary transmission of infection from patients immunized with live vaccines to patients receiving bDMARDs.
It is recommended to conduct pre-exposure prophylaxis for novel coronavirus infection in patients aged 12 years and older weighing at least 40 kg, prior to prescribing or at any stage of bDMARD therapy combined with or without GCs, by means of passive immunization with antiviral monoclonal antibody preparations (J06BD) to avoid disease exacerbation [299].
(LoE 5, GoR C)
It is recommended to administer pneumococcal polysaccharide conjugate vaccine (adsorbed)** containing capsular polysaccharides of 13 pneumococcal serotypes to all CAPS patients prior to prescribing or at any stage of bDMARD therapy combined with or without GCs (except for #rituximab**) for the prevention of pneumococcal infection, improvement of treatment adherence, and prevention of exacerbations in accordance with international guidelines [297,298].
(LoE 5, GoR C)
Comments: vaccination with the 13-valent pneumococcal polysaccharide conjugate vaccine in patients receiving canakinumab** is performed 2 weeks before the planned injection or 2 weeks after; in patients for whom #rituximab** is planned to be prescribed, it is performed before the first infusion to prevent infectious complications, improve treatment adherence, and prevent CAPS exacerbations.
5.2 Follow-up examination of patients with cryopyrin-associated periodic syndrome in an inpatient/day hospital setting that initiated the prescription of bDMARDs/immunosuppressants
The examination is carried out once every 3–6 months: 3 months after therapy initiation; 6 months after therapy initiation; and subsequently every 6 months to detect disease complications, comorbid pathology, and to monitor the efficacy and safety of therapy.
For complaints and anamnesis, see section 2.1.1
For physical examination, see section 2.1.2
It is recommended to evaluate treatment efficacy and the safety of antirheumatic therapy in all patients with a confirmed diagnosis of CAPS in an inpatient setting providing medical care to children with rheumatic diseases, 3 months after therapy initiation; 6 months after therapy initiation; and subsequently every 6 months to address the issue of continuing/modifying therapy [1,2,4].
(LoE 5, GoR C)
It is recommended to perform a complete blood count (CBC) with differential (including erythrocyte sedimentation rate [ESR], red blood cell count, white blood cell count, platelet count, leukocyte differential, and total hemoglobin level) in all patients to assess disease activity and monitor the safety of pathogenetic therapy [11,13,22].
(LoE 5, GoR C)
Comments: Complete blood count parameters should be within the normal range. Single-, bi-, or pancytopenia may, among other things, be an adverse manifestation of treatment with canakinumab**/anakinra**.
It is recommended to discontinue canakinumab**/anakinra** injections (for 7 days) in all patients if the platelet count decreases to ≤ 150 > 100 × 109/L or the neutrophil count decreases to < 1.5 ≥ 1.0 × 109/L on the complete blood count, in order to manage adverse events associated with the therapy [2,4,13,22,23].
(LoE 5, GoR C)
Comments: Previously prescribed oral glucocorticoids should be continued. Repeat the complete blood count in 1 week.
It is recommended to withdraw canakinumab**/anakinra** injections in all patients if the absolute neutrophil count drops below < 1.0 × 109/L and/or the platelet count drops below < 100 × 109/L on the complete blood count, to prevent the progression of cytopenia [2,4,13,22,23].
(LoE 5, GoR C)
Comments: Previously prescribed oral glucocorticoids should be continued. Repeat the complete blood count in 1 week.
It is recommended to prescribe the colony-stimulating factor #filgrastim** (L03AA) at a dose of 5–10 mcg/kg/day subcutaneously for leukopenia with an absolute neutrophil count ≤ 1.0 × 109/L for 3–5 days (or longer if necessary) to normalize leukocyte and neutrophil counts [23,288,292,300,301].
(LEL 4, GRC C)
It is recommended to prescribe the colony-stimulating factor #filgrastim** (L03AA) at a dose of 5–10 mcg/kg/day subcutaneously combined with systemic antibacterial drugs (J01) intravenously for febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count ≤ 1.0 × 109/L to normalize leukocyte and neutrophil counts [23,288,292,300,301].
(LEL 4, GRC C)
Comments: Treatment with #filgrastim** (L03AA) is administered for 3–5 days (or longer if necessary) until complete normalization of leukocyte and neutrophil counts.
It is recommended to continue treatment with systemic antibacterial drugs (J01) in all patients with febrile neutropenia (neutropenia accompanied by fever) to resolve febrile fever and normalize the leukocyte formula according to the complete blood count [23,288,292,300,301].
(LoE 5, GoR C)
It is recommended to resume treatment with canakinumab**/anakinra** at the same dose in all patients after neutrophil recovery to ≥ 1.5 × 109/L according to the complete blood count, with the goal of maintaining CAPS remission [4,23].
(LoE 5, GoR C)
It is recommended to adjust canakinumab**/anakinra** therapy in all patients if there are recurrent episodes of decreased blood cell counts on the complete blood count, in order to manage adverse events associated with the therapy [4,23].
(LoE 5, GoR C)
It is recommended to prescribe fluconazole** intravenously at 3–12 mg/kg/day, depending on the severity and duration of induced neutropenia, in patients with neutropenia to prevent fungal infections resulting from treatment with canakinumab**/anakinra** and/or #rituximab** [1,2,4,302].
(LoE 5, GoR C)
It is recommended to perform a general clinical biochemical blood test (including total protein, albumin, total bilirubin, free and conjugated bilirubin, creatinine, urea, glucose, ferritin, sodium, potassium, total calcium, lactate dehydrogenase [LDH], aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transferase [GGT], alkaline phosphatase [ALP], and serum iron) to monitor disease activity, liver, kidney, and pancreatic function, and electrolyte balance during therapy with canakinumab**/anakinra** [4,22,23].
(LoE 5, GoR C)
Comments: Elevated creatinine and/or urea, and/or uric acid, and/or bilirubin, and/or potassium, and/or cholesterol; elevated LDH and/or ALT, and/or AST, and/or GGT, and/or ALP, and/or amylase activity may be an adverse manifestation of treatment with canakinumab**/anakinra**.
A gradual 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.
It is recommended to temporarily discontinue canakinumab**/anakinra** therapy in all patients if serum ALT or AST levels increase to ≥ 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 parameters exceed the upper limit of normal [4,23].
(LoE 5, GoR C)
Comments: Previously prescribed oral GCs should be continued. Repeat the general clinical blood chemistry panel in a week.
It is recommended to resume canakinumab**/anakinra** therapy in all patients at the same dose after normalization of the general biochemical blood test parameters, with the goal of maintaining CAPS remission [4,23].
(LoE 5, GoR C)
It is recommended to adjust canakinumab**/anakinra** therapy in all patients if there are recurrent episodes of elevated biochemical parameters, in order to manage adverse events associated with therapy [4,23].
(LoE 5, GoR C)
It is recommended to measure serum C-reactive protein (CRP) levels in all patients to monitor disease activity [2,11,13,22,23,27,44,106,128].
(Level of Evidence 3, Grade of Recommendation C)
Comments: An elevated serum C-reactive protein level indicates CAPS activity and/or secondary infection, and/or the development of macrophage activation syndrome (MAS).
It is recommended to measure blood immunoglobulin levels in all patients to rule out immunodeficiency developing during treatment with canakinumab**/anakinra** combined with or without glucocorticoids [4,23,303–305].
(LoE 5, GoR C)
It is recommended to prescribe #normal human immunoglobulin** (J06BA) at 400 mg/kg, and if an adequate immunoglobulin level of 500 mg/kg is not achieved, at least once every 2–4 weeks until blood immunoglobulin levels normalize, in the event of decreased blood immunoglobulin levels, for the purpose of correcting blood immunoglobulin levels and preventing infectious complications in the setting of immunodeficiency developing during immunosuppressive and/or genetically engineered biological therapy [4,23,303–307].
(LoE 5, GoR C)
It is recommended to determine antistreptolysin-O (ASO) in serum to detect or rule out group A beta-hemolytic streptococcal infection [2,11,13,22,23,44].
(Level of Evidence 3, Grade of Recommendation C)
Comments: An elevated serum antistreptolysin-O level indicates acute or chronic streptococcal infection, the exacerbation of which can trigger a CAPS flare.
It is recommended to measure blood procalcitonin levels in patients with fever for the differential diagnosis of the etiology of the fever [53–55].
(LoE 5, GoR C)
Comments: An elevated blood procalcitonin level indicates an infectious origin of the fever.
It is recommended to perform a comprehensive panel of diagnostic tests to rule out sepsis: complete blood count (CBC) with differential, general biochemical blood test, serum C-reactive protein (CRP) level testing, microbiological (culture) blood test for sterility, microbiological (culture) examination of mucus from the tonsils and posterior pharyngeal wall for aerobic and facultatively anaerobic microorganisms, microbiological (culture) urine test for bacterial pathogens using automated culture methods with antimicrobial susceptibility testing, microbiological (culture) test of anal discharge, thromboelastography, coagulogram (screening hemostasis test); computed tomography (CT) of the chest organs, comprehensive ultrasound examination of the abdominal organs, ultrasound examination of the kidneys, echocardiography, magnetic resonance imaging (MRI) of the abdominal organs, magnetic resonance imaging of the pelvic organs, and magnetic resonance imaging of the retroperitoneal space) in accordance with clinical guidelines for the treatment of sepsis in children for patients with febrile or hectic fever, leukocytosis/leukopenia, thrombocytopenia, elevated serum C-reactive protein and serum procalcitonin levels not associated with CAPS activity, in order to rule out sepsis [34,54,55,66,128,137,293,308].
(Level of Evidence 3, Grade of Recommendation C)
Comments: performed in patients with febrile, hectic fever, leukocytosis/leukopenia, thrombocytopenia, elevated serum C-reactive protein and procalcitonin levels unrelated to CAPS activity.
It is recommended to initiate empirical antibacterial therapy upon the development of sepsis, followed subsequently, depending on the clinical situation, by the intravenous administration of systemic antibacterial drugs (J01) active against Gram-positive, Gram-negative, and anaerobic flora (combinations of penicillins, including combinations with beta-lactamase inhibitors (J01CR) and/or 4th-generation cephalosporins (J01DE), and/or carbapenems (J01DH), and/or other antibacterial drugs (J01XX), and/or glycopeptide antibiotics (J01XA), and/or other aminoglycosides (J01GB), and/or macrolides (J01FA)) combined with or without systemic antifungal drugs (J02A) according to microbiological sensitivity data, combined with #normal human immunoglobulin** (J06BA) at a dose of 400 mg/kg/course (5 days) in accordance with clinical guidelines for the treatment of sepsis in children [34,36,54,55,66,290,293,309,310].
(LoE 5, GoR C)
Comments: when sepsis develops, the administration of biological DMARDs is discontinued for the entire duration of antibiotic therapy. Previously prescribed oral GCs should be continued. If CAPS activity increases, pulse therapy with #methylprednisolone** (see above) is performed and/or oral GCs are prescribed (dose increased) (see CAPS treatment).
It is recommended to discontinue canakinumab**/anakinra** injections for the entire duration of antibiotic therapy, continue previously prescribed oral GCs, and perform pulse therapy with #methylprednisolone** when disease activity increases in patients with CAPS presenting with bacterial complications/sepsis [4,23].
(LoE 5, GoR C)
It is recommended to resume therapy with canakinumab**/anakinra** no earlier than one week after the complete resolution of clinical and laboratory signs of the infectious complication/sepsis and the completion of antibacterial therapy in all patients in order to maintain CAPS remission [4,23].
(LoE 5, GoR C)
It is recommended to perform a coagulogram (screening hemostasis test) with determination of prothrombin index, blood antithrombin III activity; blood plasminogen level and blood fibrinogen level, blood D-dimer concentration, blood soluble fibrin monomer complex levels, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time in blood, and blood von Willebrand factor activity and properties in patients with febrile fever/sepsis/HPS to assess the state of the hemostatic system [35–37,135,136].
(LoE 5, GoR C)
Comments: sepsis and HPS are characterized by hypercoagulation followed by hypocoagulation (disseminated intravascular coagulation [DIC] syndrome).
It is recommended to perform thromboelastography in patients with febrile fever/sepsis/HPS/signs of thrombosis and hypocoagulation to determine the tactics of anticoagulant therapy [35–37,135,137].
(LEL 4, GRC C)
It is recommended to prescribe/adjust therapy with antithrombotic agents (B01A), including heparin group drugs (B01B), antiplatelet agents excluding heparin (B01AC), antifibrinolytic agents (B02A), direct factor Xa inhibitors (B01AF) upon the development of coagulopathy or disseminated intravascular coagulation according to coagulogram data (screening hemostasis test) and thromboelastography in order to correct the hemostatic system [35–37,40,41,137].
(LoE 5, GoR C)
It is recommended to perform lymphocyte subset testing in patients frequently suffering from viral, purulent bacterial infections, including opportunistic infections, in order to identify the subpopulation composition of lymphocytes (main subsets) [4,23,56].
(LoE 5, GoR C)
Comments: a decrease in the level of T and/or B lymphocyte subpopulations and/or natural killers indicates the development of secondary immunodeficiency under conditions of treatment with canakinumab**/anakinra** combined with (or without) GCs.
It is recommended to determine Epstein-Barr virus (Epstein-Barr virus) DNA by PCR in peripheral and cord blood (quantitative test), determine Epstein-Barr virus (Epstein-Barr virus) DNA in oropharyngeal mucosal swabs by PCR (qualitative test), and determine Epstein-Barr virus (Epstein-Barr virus) DNA by PCR (qualitative test) in urine in patients receiving canakinumab**/anakinra** combined with (or without) GCs, presenting with clinical manifestations of herpetic infection, or in patients with interstitial pneumonia, in order to detect active herpetic infection as an infectious complication developing under immunosuppressive therapy and/or biological DMARDs combined with (or without) GCs [2,4,34,50,66–69,107,211].
(LoE 5, GoR C)
It is recommended to determine cytomegalovirus (Cytomegalovirus) DNA by PCR in peripheral and cord blood (quantitative test), determine cytomegalovirus (Cytomegalovirus) DNA in oropharyngeal mucosal swabs by PCR (qualitative test), and determine cytomegalovirus (Cytomegalovirus) DNA by PCR (qualitative test) in urine in patients receiving canakinumab**/anakinra** combined with (or without) GCs, presenting with clinical manifestations of herpetic infection, or in patients with interstitial pneumonia, in order to detect active herpetic infection as an infectious complication developing under immunosuppressive therapy and/or biological DMARDs combined with (or without) GCs [2,4,34,50,66,71–73,107].
(LoE 5, GoR C)
It is recommended to determine herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA by PCR in blood (quantitative test), determine herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA by PCR in oropharyngeal mucosal swabs (qualitative test), and determine herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA by PCR (qualitative test) in urine in patients receiving canakinumab**/anakinra** combined with (or without) GCs, presenting with clinical manifestations of herpetic infection, or in patients with interstitial pneumonia, in order to detect active herpetic infection as an infectious complication developing under immunosuppressive therapy and/or biological DMARDs combined with (or without) GCs [2,4,34,50,66,74,76,77,107,266].
(LoE 5, GoR C)
It is recommended to determine class M and G antibodies (IgM, IgG) to cytomegalovirus (Cytomegalovirus) in blood in patients receiving canakinumab**/anakinra** combined with (or without) GCs, presenting with clinical manifestations of herpetic infection, or in patients with interstitial pneumonia, in order to detect active herpetic infection as an infectious complication developing under immunosuppressive therapy and/or biological DMARDs combined with (or without) GCs [2,4,34,50,66,71–73,107,202].
(LoE 5, GoR C)
It is recommended to determine class M and G antibodies (IgM, IgG) to Epstein-Barr virus (Epstein-Barr virus) in blood in patients receiving canakinumab**/anakinra** combined with (or without) GCs, presenting with clinical manifestations of herpetic infection, or in patients with interstitial pneumonia, in order to detect active herpetic infection as an infectious complication developing under immunosuppressive therapy and/or biological DMARDs combined with (or without) GCs [2,4,34,50,66–69,107,211].
(LoE 5, GoR C)
It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of patients receiving canakinumab**/anakinra** with or without GCS, presenting with clinical manifestations of herpetic infection, or patients with interstitial pneumonia, in order to detect active herpetic infection as an infectious complication developed during treatment with immunosuppressants and/or biologic DMARDs with or without GCS [2,4,34,50,66–69,107,211].
(LoE 5, GoR C)
It is recommended to determine immunoglobulin G (IgG) antibodies to early antigens (EA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of patients receiving canakinumab**/anakinra** with or without GCS, presenting with clinical manifestations of herpetic infection, or patients with interstitial pneumonia, in order to detect active herpetic infection as an infectious complication developed during treatment with immunosuppressants and/or biologic DMARDs with or without GCS [2,4,34,50,66–69,107,211].
(LoE 5, GoR C)
It is recommended to determine antibodies to herpes simplex virus (Herpes simplex virus) in the blood of patients receiving canakinumab**/anakinra** with or without GCS, presenting with clinical manifestations of herpetic infection, or patients with interstitial pneumonia, in order to detect active herpetic infection as an infectious complication developed during treatment with immunosuppressants and/or biologic DMARDs with or without GCS [2,4,34,50,66,74–76,78,82,107,212].
(LoE 5, GoR C)
It is recommended to prescribe #acyclovir** (JO5AB)
— at a dose of 200 mg orally per day in 5 divided doses (no more than 1000 mg/day) in children older than 2 years or at a dose of 5–10 mg/kg/injection intravenously every 8 hours in case of localized herpetic infection;
— 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 in case of Herpes zoster development in accordance with clinical guidelines for the management of herpesvirus infections in children, including immunocompromised patients [265,274,311–314].
(LEL 4, GRC C)
Comments: injections of canakinumab**/anakinra** are 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** (JO5AB) at a dose of 6 mg/kg/injection intravenously every 12 hours upon the development of cytomegalovirus infection, or #ganciclovir** (JO5AB) at a dose of 10 mg/kg/injection intravenously every 12 hours upon the development of Epstein-Barr virus infection in accordance with clinical guidelines for the management of immunocompromised children [81,210,313,315,316].
(LoE 2, GoR B)
It is recommended to temporarily withdraw canakinumab**/anakinra** therapy in all patients who develop an infection, for the duration of antiviral therapy caused by herpesviruses [4,23].
(LoE 5, GoR C)
It is recommended to resume canakinumab**/anakinra** therapy 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 [4,23].
(LoE 5, GoR C)
It is recommended to screen for the presence/absence of tuberculosis (tuberculin skin test, recombinant tuberculosis allergen test in standard dilution**, and/or blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens, computed tomography of the chest organs) in all patients receiving canakinumab**/anakinra** with or without GCS, at least twice a year [80,185,186].
(LoE 5, GoR C)
It is recommended to discontinue canakinumab**/anakinra** therapy in all patients with a positive intradermal tuberculin skin test (papule > 5 mm) and/or elevated interferon-gamma levels and/or lung and/or intrathoracic lymph node lesions [23,80,185,186].
(LoE 5, GoR C)
Comments: Previously prescribed oral GCs should be continued.
It is recommended that all patients with a positive intradermal tuberculin skin test (papule > 5 mm) and/or elevated interferon-gamma levels and/or lung and/or intrathoracic lymph node lesions undergo an initial examination (examination, consultation) by a phthisiatrician [23,59,80,185,186].
(LEL 4, GRC C)
It is recommended to prescribe oral GCS to all patients during a CAPS flare for the duration of specific antituberculosis therapy in order to maintain CAPS remission [23,80,185,186].
(LoE 5, GoR C)
Comments: the issue of resuming canakinumab therapy is addressed after the completion of specific chemotherapy and consultation with a phthisiatrician.
It is recommended to continue canakinumab**/anakinra** treatment and oral administration of previously prescribed GCS under the supervision of a rheumatologist, general (clinical) and biochemical general practitioner blood tests in patients with tuberculosis infection without focus during specific antituberculosis chemotherapy [23,185,186].
(LoE 5, GoR C)
Comments: the issue of continuing biologic DMARD therapy is decided on an individual basis.
It is recommended to resume canakinumab**/anakinra** therapy in all patients after the completion of specific antituberculosis therapy and consultation with a phthisiatrician [23,80,185,186].
(LoE 5, GoR C)
Comments: the issue of continuing biologic DMARD therapy is decided on an individual basis.
It is recommended to determine antibodies to Salmonella enterica in the blood, antibodies to Salmonella typhi in the blood, IgM and IgG antibodies to Yersinia pseudotuberculosis in the blood, and antibodies to Yersinia enterocolitica serovars in the blood in patients with abdominal syndrome to detect intestinal bacterial infection developed during treatment with canakinumab**/anakinra** with or without GCS [80,317–324].
(LoE 5, GoR C)
It is recommended to administer etiotropic therapy upon detection of IgA and IgM antibodies in a diagnostic titer, as well as high-titer IgG antibodies to Yersinia pseudotuberculosis, Yersinia enterocolitica serovars, Salmonella enterica, and Salmonella typhi in the blood, in accordance with clinical guidelines for the diagnosis and treatment of intestinal infections in children [80,317–324].
(LoE 5, GoR C)
Comments: administration of canakinumab**/anakinra** is discontinued for the entire period of antibiotic therapy. Previously prescribed oral GCS should be continued.
Treatment with canakinumab**/anakinra** is resumed no earlier than 1 week after the decrease in laboratory markers of infection and completion of antibacterial therapy.
It is recommended to determine IgA, IgM, and IgG antibodies to Chlamydia psittaci in the blood; antibodies to Chlamydia trachomatis in the blood; antibodies to Chlamydophila pneumoniae in the blood; and IgM and IgG antibodies to Mycoplasma pneumoniae in the blood in patients with interstitial pneumonia to detect mycoplasma and chlamydial infection developed during treatment with canakinumab**/anakinra** with or without GCS [4,23,319–325].
(LoE 5, GoR C)
It is recommended to administer etiotropic therapy upon detection of IgA and IgM antibodies in a diagnostic titer, as well as high-titer IgG antibodies to Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, and Chlamydophila pneumoniae in the blood in all patients receiving canakinumab**/anakinra** with or without GCS, in accordance with clinical guidelines for the diagnosis and treatment of mycoplasma and chlamydial infection in children [4,23].
(LoE 5, GoR C)
Comments: administration of canakinumab**/anakinra** is discontinued for the entire period of antibiotic therapy. Previously prescribed oral GCS should be continued.
Treatment with canakinumab/anakinra is resumed no earlier than 1 week after the decrease in laboratory markers of infection and 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 developed during treatment with canakinumab**/anakinra** with or without GCS [4,23,320–324].
(LoE 5, GoR C)
Comments: if nasopharyngeal contamination with pathogenic and/or opportunistic microorganisms is detected, an otorhinolaryngologist consultation is required to address the need for sanitization.
In the absence of clinical manifestations, therapy with canakinumab**/anakinra** with or without GCS is not discontinued.
In the presence of inflammatory changes in the nasopharynx, antibacterial therapy is administered. Injections of canakinumab**/anakinra** are discontinued for the duration of antiviral therapy. Previously prescribed oral glucocorticoids should be continued. Treatment with canakinumab** 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 that a general (clinical) urinalysis be performed in all patients to assess renal function [11,13,22,33,50].
(LoE 5, GoR C)
It is recommended to determine urine albumin and 24-hour urine protein in patients with clinical/laboratory signs of nephrotic syndrome and/or renal failure, and/or a disease duration of more than 5 years to determine the degree of renal impairment [11,13,22,33,50].
(LoE 5, GoR C)
Comments: the presence of proteinuria > 500 mg/day may indicate the development of secondary renal amyloidosis.
It is recommended to perform a complex of renal function tests and diagnostic tests to assess 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 to determine the degree of renal impairment [11,13,22,33,50].
(LEL 4, GRC C)
It is recommended to perform a renal biopsy with anesthetic management (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 a disease duration of more than 5 years, and/or in the presence of proteinuria > 500 mg per day to detect/rule out renal amyloidosis in the absence of contraindications [24].
(LoE 5, GoR C)
Comments: contraindications for kidney biopsy include: thrombocytopenia, coagulopathy, use of heparin-group drugs, and hemodialysis dependence. Performing a kidney biopsy in the presence of contraindications is associated with a high risk of bleeding, hematoma formation, and infection.
It is recommended to perform an electrocardiography in all patients to monitor cardiac function [11,13,22,45].
(LEL 4, GRC C)
Comments: performed in all patients. In patients with CAPS remission, no pathological changes are detected on ECG.
It is recommended to perform 24-hour Holter ECG monitoring in patients with arrhythmia or pathological changes on electrocardiography to detect arrhythmias [214].
(LoE 5, GoR C)
Comments: performed in patients with arrhythmias and pathological electrocardiographic findings.
It is recommended to perform 24-hour ambulatory blood pressure monitoring in patients with arterial hypertension to identify deviations in blood pressure from normal values and to develop an antihypertensive therapy strategy [213].
(LoE 3, GoR B)
It is recommended to perform a comprehensive ultrasound examination of internal organs (including a comprehensive ultrasound of the abdominal organs and an ultrasound of the kidneys) in all patients to identify/rule out pathological changes [4,11,13,22,23].
(LoE 5, GoR C)
Comments: performed in all patients. Includes ultrasound of the abdominal organs (comprehensive) and ultrasound of the kidneys. Examination may reveal: mild hepatomegaly, biliary dyskinesia, reactive changes in the pancreas, thickening of the gallbladder wall, and thickening of the walls of the stomach and intestines. All changes may be associated with adverse drug reactions.
When amyloidosis develops, ultrasound signs of amyloid deposition in the kidneys are observed (large pale kidney, decreased renal blood flow, shrunken amyloid kidney).
It is recommended to perform echocardiography in all patients to monitor cardiac function and detect myocardial, pericardial, and endocardial lesions [2,4].
(LoE 5, GoR C)
Comments: performed in all patients. In patients with CAPS remission, no pathological changes are detected on echocardiography.
Long-standing disease may lead to ventricular myocardial diastolic dysfunction and signs of pulmonary hypertension.
It is recommended to perform esophagogastroduodenoscopy with or without anesthetic management (including early postoperative management) in patients with dyspeptic symptoms, patients receiving NSAIDs for more than 1 month and/or glucocorticoids, and/or biologic DMARDs, as well as in those with a disease duration of more than 5 years, to rule out upper gastrointestinal inflammatory diseases associated with the underlying disease and/or Helicobacter pylori and/or the use of NSAIDs and/or glucocorticoids [45,94,100,101,326,327].
(LEL 4, GRC C)
It is recommended to perform a microbiological (culture) examination of gastric mucosa biopsy specimens for Helicobacter pylori in patients with inflammatory, and/or erosive, and/or ulcerative changes according to esophagogastroduodenoscopy in order to rule out Helicobacter pylori-associated GI pathology [45,94,100,101,326,327].
(LEL 4, GRC C)
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 by esophagogastroduodenoscopy, in accordance with clinical guidelines for the treatment of inflammatory gastropathy and gastroesophageal reflux disease in children and international guidelines [45,94,100,101,326,327].
(LoE 5, GoR C)
Comments: during anti-inflammatory therapy, treatment with canakinumab and previously prescribed GCs should be continued.
It is recommended to perform eradication therapy prescribing proton pump inhibitors (A02BC), systemic antibacterial drugs (J01), and bismuth tripotassium dicitrate** at a dose of 8 mg/kg/day in 1-2 doses (for patients aged 4 to 8 years) for 4-8 weeks, at a dose of 120 mg 2 times/day (for patients aged 8 to 12 years), or at a dose of 120 mg 4 times/day or 240 mg 2 times/day (for patients older than 12 years) for inflammatory gastropathy, erosive and/or ulcerative processes in the stomach and/or duodenum associated with Helicobacter pylori, in accordance with clinical guidelines [45,94,100,101,326,327].
(LoE 5, GoR C)
It is recommended to temporarily discontinue canakinumab**/anakinra** therapy in all patients during eradication therapy [4,23].
(LoE 5, GoR C)
Comments: previously prescribed GCs should be continued. Resumption of canakinumab** treatment is carried out after the completion of eradication therapy.
It is recommended to perform colonoscopy with anesthesia support (including early postoperative management) in patients with abdominal syndrome to detect/rule out CAPS complications and concomitant bowel diseases [45,94].
(LEL 4, GRC C)
Comments: this procedure is performed upon the appearance of intestinal symptoms atypical for CAPS (prolonged diarrhea, abdominal pain, presence of blood and pus in the stool) to rule out IBD, as well as in cases with a disease duration of more than 5 years and/or presence of proteinuria > 500 mg/day.
It is recommended to perform large intestine biopsy via endoscopy with pathomorphological examination of the large intestine biopsy (surgical) material in patients who show inflammatory, erosive, and/or ulcerative changes in the large intestine according to colonoscopy, in order to detect/rule out CAPS complications and concomitant bowel diseases [45,94].
(LEL 4, GRC C)
Comments: this procedure is performed upon the appearance of intestinal symptoms atypical for CAPS (prolonged diarrhea, abdominal pain, presence of blood and pus in the stool) to rule out IBD, as well as in cases with a disease duration of more than 5 years and/or presence of proteinuria > 500 mg/day.
It is recommended to perform magnetic resonance imaging of joints (single joint) with or without anesthesia support (including early postoperative management) in patients with active arthritis to monitor treatment efficacy [23].
(LoE 5, GoR C)
It is recommended to perform computed tomography of the chest organs in all patients, with or without anesthesia support (including early postoperative management), at least once every 6 months to rule out pneumonia and tuberculosis [59,107,185,186].
(LoE 5, GoR C)
Comments: when treating with canakinumab**, especially in combination with GCs, pneumonia (interstitial, focal, lobar, polysegmental) may develop.
Interstitial pneumonia should be suspected if low-grade/high-grade fever, dry cough/cough with a small amount of sputum, dyspnea, crackles/decreased breath sounds on auscultation appear.
Pneumonia developing during biologic therapy is characterized by low-grade fever or its complete absence, sparse clinical presentation, and no increase in acute-phase inflammatory markers: ESR, blood leukocyte count, and serum CRP level.
Focal pneumonia should be suspected if dry/wet cough or throat clearing appears.
It is recommended to perform bronchoscopy with anesthesia support (including early postoperative management) in patients when interstitial, focal, and/or infiltrative changes in the lungs are detected by chest computed tomography, to assess the condition of the bronchial tree mucosa and obtain bronchoalveolar lavage for further examination [190,197–201].
(LE 1, GR C)
It is recommended to perform microbiological (culture) examination of bronchoalveolar lavage fluid for Pneumocystis carinii cysts in patients with signs of pneumonia on chest computed tomography to confirm/exclude pneumocystis etiology of pneumonia and determine the need for etiotropic therapy [159,162–164,166,192–195].
(LEL 4, GRC C)
It is recommended to perform quantitative PCR determination of Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, and bronchoalveolar lavage fluid in patients with signs of pneumonia on chest computed tomography to confirm/exclude pneumocystis etiology of pneumonia and determine the need for etiotropic therapy [159,162–164,166,192–196].
(LEL 4, GRC C)
It is recommended to determine class M and G antibodies to Pneumocystis jirovecii in the blood of patients with signs of pneumonia according to chest computed tomography to identify the etiology of pneumonia and decide on etiotropic therapy [159,162–164,166,192–196].
(LEL 4, GRC C)
It is recommended to perform microbiological (culture) examination of sputum for fungi (yeast and mold) in patients with signs of pneumonia according to chest computed tomography to identify the etiology of pneumonia and decide on etiotropic therapy [50,54,55,80,158–161,190,191].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to perform microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeasts and molds) in patients with signs of pneumonia on chest computed tomography to identify the etiology of pneumonia and determine the need for etiotropic therapy [50,54,55,80,158–161,190,191].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to perform microbiological (culture) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms in patients with signs of pneumonia on chest computed tomography to identify the etiology of pneumonia and determine the need for etiotropic therapy [50,54,55,80,158–161,190,191].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to determine antibodies to Aspergillus spp. in the blood of patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to identify the etiology of pneumonia and determine the need for etiotropic therapy [50,54,55,80,158–161,190,191].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to determine mannan and galactomannan in lavage fluid and blood in all patients with signs of pneumonia according to chest computed tomography in order to identify the etiology of pneumonia and resolve the issue of etiotropic therapy [80, 190, 197–201].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to detect Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR in all patients with interstitial and/or focal and/or infiltrative lung changes according to chest computed tomography in order to identify the etiology of pneumonia and resolve the issue of etiotropic therapy [80, 190, 197–201].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to detect Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR in all patients with interstitial and/or focal and/or infiltrative lung changes according to chest computed tomography in order to identify the etiology of pneumonia and resolve the issue of etiotropic therapy [80, 190, 197–202].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to determine Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG) DNA with species differentiation in sputum or bronchoalveolar lavage fluid by PCR in patients with interstitial, focal, and/or infiltrative changes in the lungs detected by chest computed tomography to identify the etiology of pneumonia and determine the appropriate etiotropic therapy [80,185,186,190,197–209].
(Level of Evidence 1, Grade of Recommendation B)
It is recommended to determine classes M and G antibodies (IgM, IgG) to Cytomegalovirus in blood in all patients with interstitial and/or focal and/or infiltrative lung changes according to chest computed tomography in order to identify the etiological factor of pneumonia [80, 190, 197–201].
(LoE 5, GoR C)
It is recommended to determine classes M and G antibodies (IgM, IgG) to Epstein-Barr virus in blood in all patients with interstitial and/or focal and/or infiltrative lung changes according to chest computed tomography in order to identify the etiological factor of pneumonia [80, 190, 197–201].
(LoE 5, GoR C)
It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus in blood in all patients with interstitial and/or focal and/or infiltrative lung changes according to chest computed tomography in order to identify the etiological factor of pneumonia [4, 80, 190, 197–201, 211, 328].
(LEL 4, GRC C)
It is recommended to determine class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus in blood in all patients with interstitial and/or focal and/or infiltrative lung changes according to chest computed tomography in order to identify the etiological factor of pneumonia and resolve the issue of etiotropic therapy [4, 80, 190, 197–201, 211, 328].
(LEL 4, GRC C)
It is recommended to determine antibodies to Herpes simplex virus in blood in all patients with interstitial and/or focal and/or infiltrative lung changes according to chest computed tomography in order to identify the etiological factor of pneumonia and resolve the issue of etiotropic therapy [4, 80, 107, 190, 197–201, 212].
(LoE 5, GoR C)
It is recommended to prescribe empirical antibiotic therapy: #cotrimoxazole** (J01EE) in combination with systemic antibacterial drugs (J01) affecting gram-positive, gram-negative, and anaerobic flora (penicillin combinations, including beta-lactamase inhibitor combinations (J01CR) and/or 4th generation cephalosporins (J01DE), and/or carbapenems (J01DH), and/or other antibacterial drugs (J01X)) combined with systemic antifungals (J02A) prior to identifying the etiological factor of interstitial pneumonia, depending on the clinical situation, in accordance with the guidelines for the treatment of pneumonia in immunocompromised children [54, 55, 162, 281, 293, 320–324, 329, 329].
(LoE 5, GoR C)
It is recommended to administer intravenous glucocorticoids, #cotrimoxazole** (J01EE) at a dose of 3.75–5.0 mg/kg body weight/administration (15–20 mg/kg/day) (calculated for trimethoprim) intravenously every 8 hours for moderately severe Pneumocystis pneumonia, or at a dose of 3.75–5.0 mg/kg body weight/administration (15–20 mg/kg/day) (calculated for trimethoprim) intravenously every 6–8 hours for severe Pneumocystis pneumonia, in accordance with international guidelines for the treatment of immunocompromised children [5, 281, 329, 330].
(LoE 5, GoR C)
It is recommended to administer #voriconazole** at a dose of 6 mg/kg per administration intravenously every 12 hours for the first 24 hours and 4 mg/kg starting from the second day, in accordance with international guidelines for the treatment of immunocompromised children, when galactomannan is detected in lavage fluid and/or blood and/or antibodies to Aspergillus spp. are detected in blood [281, 331].
(LoE 5, GoR C)
It is recommended to administer fluconazole** intravenously at a dose of 6–12 mg/kg/day in accordance with international guidelines for the treatment of immunocompromised children when mannan is detected in lavage fluid and/or blood [281, 302].
(LoE 5, GoR C)
It is recommended to prescribe systemic antibacterial drugs (J01) affecting 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 antifungals (J02A) in focal, lobar, or polysegmental pneumonia in accordance with the clinical guidelines for the treatment of pneumonia in immunocompromised children [54, 55, 162, 281, 293, 320–324, 329, 329].
(LoE 5, GoR C)
It is recommended to temporarily discontinue canakinumab**/anakinra** therapy while continuing previously prescribed oral glucocorticoids in all patients with suspected/developing pneumonia [4, 23].
(LoE 5, GoR C)
It is recommended to resume canakinumab**/anakinra** therapy in all patients no earlier than 1 week after complete resolution of pneumonia according to laboratory studies and follow-up chest computed tomography, with or without anesthesia support (including early postoperative management) [4, 23].
(LoE 5, GoR C)
Comments: therapy is prescribed/adjusted after clinical, radiological, and laboratory signs of interstitial pneumonia have resolved.
It is recommended to perform radiography of the temporomandibular joint and/or intervertebral joints, and/or elbow joint, and/or wrist joint, and/or knee joint, and/or shoulder joint, and/or hip joint, and/or ankle joint, and/or acromioclavicular joint, and/or sternoclavicular joint, and/or hand, and/or foot in two projections, or joint computed tomography with or without anesthesia support (including early postoperative management) in all patients with active arthritis in order to determine the degree of osteocartilaginous destruction [97, 98].
(LEL 4, GRC C)
Comments: performed no more than once every 12 months.
It is recommended to perform X-ray densitometry in all patients receiving or who have received glucocorticoids in order to detect osteopenia/osteoporosis in accordance with clinical guidelines for the diagnosis and treatment of secondary osteoporosis in children [215, 216].
(LoE 5, GoR C)
It is recommended to prescribe calcium preparations (A12A) and vitamin D and its analogues (A11CC) to patients with osteopenia/osteoporosis in accordance with clinical guidelines for the diagnosis and treatment of secondary osteoporosis in children [215, 216].
(LoE 5, GoR C)
It is recommended to prescribe:
— #pamidronic acid in patients < 1 year at a dose of 0.5 mg/kg i.v. every 2 months, in patients aged 1–2 years at a dose of 0.25–0.5 mg/kg/day i.v. for 3 days every 3 months, in patients aged 2–3 years at a dose of 0.375–0.75 mg/kg/day i.v. for 3 days every 3 months, in patients older than 3 years at a dose of 0.5–1 mg/kg/day i.v. for 3 days every 4 months (maximum dose 60 mg/administration),
— or #alendronate** at a dose of 1–2 mg/kg/week orally; in patients with body weight < 40 kg at a dose of 5 mg/day or 35 mg/week; in 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 i.v. every 6–12 months (maximum dose 4 mg),
— or #ibandronic acid** at a dose of 3 mg/administration i.v. once every 3 months or at a dose of 150 mg orally once a month in patients with osteoporosis for the treatment of osteoporosis [215, 216, 332–334].
(LoE 5, GoR C)
It is recommended to perform a lumbar puncture with anesthetic management (including early postoperative care), microscopic examination, cell counting in a counting chamber (determination of cell count), analysis of the physical properties of the cerebrospinal fluid, and serological testing in all patients with symptoms of CNS involvement in order to rule out/confirm pathological changes [12,13,22].
(LoE 5, GoR C)
Comments: performed in patients with CAPS presenting with CNS symptoms (headaches, recurrent meningitis, or meningoencephalitis) who are receiving bDMARDs to monitor treatment tolerance and detect complications.
It is recommended to perform brain magnetic resonance imaging with anesthetic management (including early postoperative care) or without it in patients with signs of CNS involvement at least once a year to assess the dynamics of changes [52].
(LEL 4, GRC C)
It is recommended that all patients undergo an initial ENT consultation (examination) to identify foci of chronic infection in the ENT organs and determine the feasibility of their sanitation to prevent infectious complications during treatment with canakinumab**/anakinra** combined with (or without) GCs, in order to evaluate the efficacy of ENT organ sanitation in patients who have undergone it [74].
(LEL 4, GRC C)
It is recommended that all patients undergo an initial consultation (examination) with an audiologist-otorhinolaryngologist to detect/exclude hearing loss and assess the degree of hearing impairment [74].
(LEL 4, GRC C)
It is recommended that all patients undergo an initial ophthalmological consultation (examination) with mandatory slit-lamp biomicroscopy of the eye to detect pathological changes [16].
(LEL 4, GRC C)
Comments: in patients with uveitis and its complications, as well as complicated steroid cataract, treatment efficacy is monitored and the need for surgical treatment is determined.
It is recommended that patients with cardiac involvement and/or arterial hypertension undergo an initial pediatric cardiologist consultation (examination) to decide on the administration of cardiotropic and/or antihypertensive therapy [2,4].
(LoE 5, GoR C)
It is recommended that an initial phthisiatrician consultation (examination) be performed in all patients with positive results of a focal tuberculin skin test and/or intradermal test with tuberculosis allergen, and/or elevated blood interferon-gamma levels in response to Mycobacterium tuberculosis complex antigens, and/or focal, infiltrative changes in the lungs, in order to decide on chemoprophylaxis or antituberculosis chemotherapy [59].
(LEL 4, GRC C)
It is recommended that patients with endocrine pathology, including those receiving GCs, undergo an initial pediatric endocrinologist consultation (examination) to monitor treatment efficacy [4,23].
(LoE 5, GoR C)
It is recommended that patients with underweight, amyotrophy, osteopenia/osteoporosis, constitutional obesity, Cushing's syndrome, and steroid-induced diabetes undergo an initial nutritionist consultation (examination) to develop an individualized dietary program and dietary behavior recommendations in an outpatient setting [335,336].
(LEL 4, GRC C)
It is recommended that patients with functional joint insufficiency, impaired longitudinal bone growth, subluxations, or back pain undergo an initial orthopedic trauma surgeon consultation (examination), as well as to address the feasibility of reconstructive surgery and joint replacement [2,4,11,13,22,23].
(LoE 5, GoR C)
It is recommended that patients with kidney involvement undergo an initial nephrologist consultation (examination) to decide on treatment strategy [11,17,20,22,24,113].
(LoE 5, GoR C)
It is recommended that patients with kidney involvement undergo a follow-up nephrologist consultation (examination) to evaluate the efficacy of the therapy administered [13].
(LoE 5, GoR C)
It is recommended that patients with neurological symptoms, psychomotor developmental delay, or psychotic reactions undergo an initial neurologist consultation (examination) to decide on treatment strategy [11,16,22,107].
(LoE 5, GoR C)
It is recommended that patients with neurological symptoms, psychomotor developmental delay, or psychotic reactions undergo a follow-up neurologist consultation (examination) to evaluate the efficacy of the therapy administered [11,16,22,107].
(LoE 5, GoR C)
It is recommended that all patients starting from the age of 1 year and their parents (regardless of the child's age) undergo an initial consultation (testing) 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 improve treatment adherence and cooperation with the physician and medical staff to achieve disease remission and social psychological adaptation [119–121].
(LEL 4, GRC C)
It is recommended to evaluate the efficacy of targeted therapy using the Autoinflammatory Disease Activity Index (AIDAI) and the MWS-DAS index 3 months after initiation/adjustment of therapy and subsequently every 6 months; and the Damage Index for Autoinflammatory Diseases (ADDI) once a year [337].
(LoE 5, GoR C)
Comments: performed in all patients in active and inactive disease stages. All disease symptoms over the past month are scored as "yes" or "no" (1/0) along with their severity (1 – mild, 2 – moderate, 3 – severe). More than 9 active manifestations indicate active disease.
Monitoring of treatment efficacy – see Appendices G1-G3
It is recommended to adjust targeted therapy in all patients in case of inefficacy and/or intolerance to canakinumab**/anakinra** within the rheumatology department that initiated the targeted therapy [2,4,11,13,22,23].
(LoE 5, GoR C)
5.2.1 Vigilance for malignancy in patients with cryopyrin-associated periodic syndromes receiving bDMARD therapy combined with (or without) GCs
Considering that oncologic/oncohematologic/lymphoproliferative diseases may be among the adverse effects of bDMARD therapy, vigilance for malignancy must be maintained at any stage of examination/treatment (in an inpatient setting and during follow-up monitoring).
If an oncologic/oncohematologic/lymphoproliferative disease is suspected, the therapy should be immediately discontinued, and the patient must be hospitalized for appropriate evaluation.
It is recommended to maintain clinical vigilance for malignancy due to the potential development of oncological/oncohematological/lymphoproliferative diseases during therapy with canakinumab**/anakinra** at any stage of treatment [99–103,300,329–331].
(LEL 4, GRC C)
It is recommended to immediately discontinue bDMARDs and hospitalize the patient if an oncological/oncohematological/lymphoproliferative disease is suspected, in order to perform appropriate diagnostic workup [99–103,300,329–331].
(LEL 4, GRC C)
It is recommended to obtain a bone marrow cytologic specimen with anesthetic management (including early postoperative care) via aspiration, as well as 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, in patients receiving bDMARDs with an atypical disease course, in order to rule out oncological/oncohematological/lymphoproliferative diseases/metastatic bone marrow involvement [106,108–111,308,338–340].
(LEL 4, GRC C)
It is recommended to perform a lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) with anesthetic management (including early postoperative care), accompanied by cytologic examination of the lymph node tissue preparation and pathomorphological examination of the lymph node biopsy (surgical) material, in patients with marked enlargement of peripheral and/or intrathoracic and/or intra-abdominal lymph nodes who are receiving bDMARDs with an atypical disease course, in order to rule out oncological/oncohematological/lymphoproliferative diseases/metastatic lymph node involvement [106,108–111,308,338–340].
(LEL 4, GRC C)
It is recommended to perform contrast-enhanced magnetic resonance imaging of the brain, contrast-enhanced magnetic resonance imaging of the abdominal organs, contrast-enhanced magnetic resonance imaging of the retroperitoneal space, and contrast-enhanced magnetic resonance imaging of the pelvic organs, with or without anesthesia (including early postoperative management), in patients receiving biological therapy with an atypical disease course in order to rule out oncological/oncohematological/lymphoproliferative diseases [106,108–111,308,338–340].
(LEL 4, GRC C)
It is recommended to perform contrast-enhanced computed tomography of the chest organs with intravenous bolus injection with anesthetic management (including early postoperative care) or without it, in patients receiving bDMARDs with an atypical disease course, in order to rule out pulmonary metastases/mediastinal organ involvement in oncological/oncohematological/lymphoproliferative diseases [106,108–111,308,338–340].
(LEL 4, GRC C)
It is recommended to perform magnetic resonance imaging of bone tissue (one region) and magnetic resonance imaging of joints (one joint) with or without anesthetic care (including early postoperative management) with intravenous contrast enhancement in patients receiving biologic DMARDs with an atypical disease course in order to rule out oncological/oncohematological diseases [106, 108–111, 308, 338–340].
(LEL 4, GRC C)
It is recommended to perform computed tomography of the bone and computed tomography of the joint with or without anesthetic care (including early postoperative management) in patients receiving biologic DMARDs who have bone destruction foci that are atypical for CAPS, in order to rule out oncological/oncohematological diseases [106, 108–111, 308, 338–340].
(LEL 4, GRC C)
It is recommended to perform positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)) with contrast enhancement, and if necessary, whole-body positron emission tomography with tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)) with or without anesthetic care (including early postoperative management) in patients receiving an immunosuppressant and/or biologic DMARDs who present with severe arthralgia, myalgia, ossalgia, destructive bone changes, subcutaneous adipose tissue infiltrates, or lesions in parenchymal organs, the brain, or the spinal cord, in order to rule out oncological/oncohematological/lymphoproliferative diseases [106, 108–110, 341].
(LEL 4, GRC C)
It is recommended to perform multi-position bone scintigraphy with or without anesthetic care (including early postoperative management) in patients receiving biologic DMARDs who have bone destruction foci atypical for CAPS, in order to rule out malignant neoplasms/metastatic bone lesions [106, 108–110, 341].
(LEL 4, GRC C)
It is recommended to perform CT-guided trephine bone biopsy of the pelvis with anesthetic care (including early postoperative management), including pathomorphological examination of 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 biologic DMARDs with an atypical disease course, in order to rule out hemoblastoses/lymphoproliferative diseases/metastatic bone marrow involvement [106, 108–111, 308, 338–340].
(LEL 4, GRC C)
It is recommended to perform a bone biopsy with anesthetic care (including early postoperative management), including pathomorphological examination of the bone biopsy (surgical) material in patients receiving biologic DMARDs who have bone destruction foci atypical for CAPS, in order to rule out malignant neoplasms/metastatic bone lesions [106, 108–111, 308, 338–340].
(LEL 4, GRC C)
It is recommended to conduct an initial consultation (examination) by a pediatric oncologist for patients in whom an oncological/oncohematological/lymphoproliferative disease or metastatic lesion is suspected or detected based on examination results, in order to decide on transferring the child to a specialized medical facility for further examination and treatment [106, 108–111, 308, 338–340].
(LEL 4, GRC C)
5.3 Follow-up examination within the framework of dispensary monitoring in outpatient settings
Complaints and anamnesis
see section 2.1.1.
Physical examination
see section 2.1.2.
It is recommended to provide dispensary monitoring for patients with CAPS consisting of an initial consultation (examination) by a rheumatologist, evaluating the efficacy and safety of therapy at least once a year after therapy initiation/adjustment and after achieving disease remission [2, 4, 11, 13, 22, 23].
(LoE 5, GoR C)
It is recommended to provide dispensary monitoring for patients with CAPS consisting of a follow-up consultation (examination) by a rheumatologist, evaluating the efficacy and safety of therapy at least once a month after therapy initiation/adjustment and at least once every 3 months after achieving disease remission; assessing the need for referral for unplanned hospitalization to the inpatient rheumatology department that initiated therapy with canakinumab**/anakinra** at any stage of treatment in the event of exacerbations/complications, comorbid conditions, complications/side effects/persistent intolerance to therapy; issuing a referral for planned hospitalization to the inpatient rheumatology department that initiated therapy with canakinumab**/anakinra** at 3 and 6 months after prescription/adjustment of therapy and every 6 months thereafter; and conducting a remote consultation with the rheumatologist of the inpatient department that initiated therapy for all patients who develop any signs of treatment failure and/or intolerance [2, 4, 11, 13, 22, 23].
(LoE 5, GoR C)
Comments: the rheumatologist assesses the patient's general condition, presence of systemic manifestations, and activity of joint syndrome; analyzes the efficacy and safety of pathogenetic therapy using generally accepted questionnaires and scales (see Appendices G1-G3); 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 canakinumab**/anakinra** combined with (or without) glucocorticoids; how infections manifest under pathogenetic therapy; what actions parents should take if infections and adverse events of antirheumatic drugs develop; and collaborates with medical specialists as well as the rheumatologist of the inpatient rheumatology department, including remotely.
It is recommended to evaluate the efficacy of pathogenetic therapy using the Autoinflammatory Disease Activity Index (AIDAI) and MWS-DAS 3 months after the start/adjustment of therapy and every 6 months thereafter, and the Damage Index (ADDI) once a year [5, 11, 22, 239, 342].
(LoE 5, GoR C)
Comments: performed in all patients in active and inactive disease stages. All disease symptoms over the past month are assessed as "yes" or "no" (1/0) along with their severity (1 – minimal, 2 – moderate, 3 – severe). More than 9 active manifestations indicate disease activity.
In case of secondary treatment failure, an urgent consultation with an inpatient rheumatologist is performed (including remotely).
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).
It is recommended that all patients undergo a consultation (examination) by a pediatrician to ensure continuity of care and referral for medical and social expertise [1, 2, 4].
(LoE 5, GoR C)
It is recommended that patients with cryopyrin-associated periodic syndromes undergo a dispensary consultation (examination) by a pediatrician or district pediatrician in the absence of a local rheumatologist at least once a month after therapy initiation/adjustment and at least once every 3 months after achieving disease remission, in order to organize dispensary monitoring and evaluate therapy efficacy and safety [1, 2, 4].
(LoE 5, GoR C)
Comments: in accordance with the procedure for dispensary monitoring of children with rheumatic diseases, if a pediatric rheumatologist is not available at the patient's place of residence, dispensary monitoring is carried out by the district pediatrician, pediatrician, or general practitioner (family physician) of the medical organization.
It is recommended to immediately discontinue the administration of canakinumab**/anakinra** if an allergic reaction develops [23, 343, 344].
(LoE 5, GoR C)
Comments: an allergic reaction can occur at any stage of treatment with canakinumab**.
If a severe allergic reaction develops, emergency hospitalization is indicated.
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, following a consultation (including a telemedicine consultation).
It is recommended to prescribe systemic antihistamines and/or glucocorticoids if an allergic reaction develops to the administration of canakinumab**/anakinra** [334].
(LEL 4, GRC C)
Comments: the choice of drug and its route of administration depend on the severity of the allergic reaction.
It is recommended to conduct a consultation (examination, including remote) by a rheumatologist from the inpatient department that initiated therapy, in the event of an allergic reaction to the intake and/or administration of canakinumab**/anakinra**, in order to decide on the need for therapy adjustment and the appropriate setting for it [4, 23].
(LoE 5, GoR C)
It is recommended to perform emergency hospitalization in the event of an allergic reaction to the administration of canakinumab**/anakinra** in order to decide on the need for therapy adjustment [4, 23].
(LoE 5, GoR C)
It is recommended to perform a complete blood count (erythrocyte sedimentation rate determination, blood erythrocyte count, blood leukocyte count, blood platelet count, differential leukocyte count (leukocyte formula), blood total hemoglobin determination) in all patients at least once every 2–4 weeks to monitor disease activity and the adverse effects of canakinumab**/anakinra** on the bone marrow [11, 13, 22, 23].
(LoE 5, GoR C)
It is recommended to discontinue the immunosuppressant and/or biologic DMARD, and continue the previously prescribed oral GCs if the platelet count drops to ≤ 150 > 100 × 109/L or the neutrophil count drops to < 1.5 ≥ 1.0 × 109/L according to the complete blood count with differential, in order to prevent infectious complications [4,23].
(LoE 5, GoR C)
Comments: Previously prescribed oral GCs should be continued. Repeat the complete blood count in a week.
It is recommended to resume treatment with canakinumab**/anakinra** at the same dose in all patients after complete recovery of complete blood count parameters to maintain CAPS remission [4,23].
(LoE 5, GoR C)
It is recommended to prescribe the colony-stimulating factor #filgrastim** (L03AA) at a dose of 5–10 mcg/kg/day subcutaneously for 3–5 days (or longer if necessary) when the leukocyte count drops with an absolute neutrophil count ≤ 1.0 × 109/L for 3–5 days (or longer if necessary) to normalize blood leukocyte counts [23,288,300,301].
(LEL 4, GRC C)
It is recommended to prescribe the colony-stimulating factor #filgrastim** (L03AA) at a dose of 5–10 mcg/kg/day subcutaneously, arrange urgent hospitalization to a local inpatient facility, and administer intravenous systemic antibacterial drugs (J01) upon the development of febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count < 1.0 × 109/L to normalize blood leukocyte counts and prevent infectious complications [23,288,300,301].
(LEL 4, GRC C)
Comments: Previously prescribed oral GCs should be continued.
It is recommended to prescribe fluconazole** 3–12 mg/kg/day, depending on the severity and duration of induced neutropenia, orally to patients with neutropenia for the prevention of fungal infections resulting from treatment with immunosuppressants and/or biologic DMARDs [23,288,300–302].
(LoE 5, GoR C)
It is recommended to resume therapy with canakinumab**/anakinra** at the previous dose after normalization of complete blood count parameters and an increase in blood neutrophils to ≥ 1.5 × 109/L to prevent an increase in disease activity / maintain remission of CAPS [23,288,300,301].
(LoE 5, GoR C)
It is recommended that all patients undergo an appointment (examination, consultation, including remote) with the inpatient rheumatologist who initiated the therapy upon a repeated episode of decreased neutrophil count, development of febrile neutropenia, and/or decreased blood platelet count according to the complete blood count, in order to decide on the need for therapy adjustment and the setting in which it should be administered [4,23].
(LoE 5, GoR C)
It is recommended to perform a general biochemical blood test (testing blood levels of total protein, albumin, total bilirubin, free and conjugated bilirubin, creatinine, urea, glucose, potassium, sodium, total calcium; lactate dehydrogenase activity, aspartate aminotransferase activity, alanine aminotransferase activity, gamma-glutamyl transferase activity, alkaline phosphatase activity, serum iron) in all patients at least once every 2–4 weeks to monitor disease activity, liver, kidney, and pancreatic function, and electrolyte balance during pathogenetic therapy [11,13,22,23].
(LoE 5, GoR C)
Comments: if blood ferritin levels increase to ≥ 684 ng/mL, along with elevated triglycerides, ALT, AST, and LDH activity combined with bicytopenia, macrophage activation syndrome (MAS) should be suspected and the child should be urgently referred for hospitalization in a rheumatology inpatient department.
It is recommended to temporarily discontinue canakinumab**/anakinra** therapy and continue previously prescribed oral GCs in all patients if serum ALT and AST levels increase to ≥ 1.5 times the upper limit of normal and/or other biochemical parameters exceed the upper limit of normal [4,23].
(LoE 5, GoR C)
It is recommended to resume canakinumab**/anakinra** therapy in all patients after normalization of the biochemical parameter(s) to prevent increased disease activity / maintain remission of CAPS [4,23].
(LoE 5, GoR C)
It is recommended to have an appointment (examination, consultation, including remote) with the inpatient rheumatologist who initiated therapy, in the presence of data on repeated episodes of increased biochemical parameter(s), to determine the need for therapy adjustment and the setting in which it should be administered [4,23].
(LoE 5, GoR C)
It is recommended to test serum C-reactive protein levels at least once every 3 months to monitor disease activity [11,13,22,27,33,66].
(LoE 5, GoR C)
Comments: if serum C-reactive protein levels increase, an appointment (examination, consultation, including remote) with the inpatient rheumatologist who initiated therapy is performed.
The decision regarding the need to adjust therapy and the setting in which it should be administered is made by the inpatient rheumatologist who initiated the therapy, based on the results of an appointment (examination, consultation, including remote) with the inpatient rheumatologist who initiated the therapy.
It is recommended to test blood immunoglobulin levels at least once every 3 months in all patients to detect/exclude an immunodeficiency state developing during treatment with canakinumab**/anakinra** combined with GCs (or without them) [11,13,22,27,33,66].
(LoE 5, GoR C)
Comments: a decrease in blood immunoglobulin levels occurs in secondary immunodeficiency states.
It is recommended to temporarily discontinue canakinumab**/anakinra** therapy and continue previously prescribed oral GCs in all patients upon a decrease in blood immunoglobulins to prevent infectious complications [4,23].
(LoE 5, GoR C)
It is recommended to have an appointment (examination, consultation, including remote) with the inpatient rheumatologist who initiated therapy upon a decrease in blood immunoglobulins, to decide on the need for therapy adjustment and the setting in which it should be administered [4,23].
(LoE 5, GoR C)
Comments: the decision on the need for therapy adjustment and the setting in which it should be administered is made by the hospital rheumatologist who initiated the therapy, following a consultation (including telemedical).
It is recommended to hospitalize all patients with decreased blood immunoglobulin levels for replacement therapy with #normal human immunoglobulin** [4,23].
(LoE 5, GoR C)
It is recommended to determine anti-streptolysin-O in blood serum to detect/exclude infection with group A beta-hemolytic streptococcus at least once every 3 months [4,23].
(LoE 5, GoR C)
It is recommended to maintain vigilance regarding the possible development of infectious diseases in patients with CAPS receiving canakinumab**/anakinra** combined with GCs (or without them) [23,343].
(LoE 5, GoR C)
It is recommended to temporarily discontinue canakinumab**/anakinra** therapy and continue previously prescribed oral GCs in all patients when signs of an infectious complication appear [4,23].
(LoE 5, GoR C)
It is recommended that all patients have an appointment (examination, consultation, including remote) with the inpatient rheumatologist who initiated therapy when signs of an infectious complication appear, to decide on the need for therapy adjustment and the setting in which it should be administered [4,23].
(LoE 5, GoR C)
It is recommended to urgently hospitalize patients in case of suspected/developed pneumonia [5,24].
(LoE 5, GoR C)
Comments: pneumonia should be suspected upon the onset of low-grade/febrile fever, dry/productive cough or minor cough and/or low-grade/febrile fever not associated with an exacerbation of the underlying disease, and/or dyspnea/shortness of breath, and/or crepitations/decreased breath sounds upon auscultation.
It is recommended to temporarily discontinue canakinumab**/anakinra** therapy while continuing previously prescribed oral glucocorticoids in all patients with suspected/developing pneumonia [4, 23].
(LoE 5, GoR C)
It is recommended that all patients have an appointment (examination, consultation, including remote) with the inpatient rheumatologist who initiated therapy in case of suspected/developed pneumonia, to decide on the need for therapy adjustment and the setting in which it should be administered [4,23].
(LoE 5, GoR C)
It is recommended to resume canakinumab**/anakinra** in all patients no earlier than 1 week after complete resolution of pneumonia according to laboratory tests, follow-up chest computed tomography (with or without anesthesia support, including early postoperative management), and completion of antibacterial therapy [4,23].
(LoE 5, GoR C)
It is recommended to prescribe #acyclovir** (J05AB) at a dose of 200 mg orally 5 times a day for children older than 2 years (not exceeding 1000 mg/day) in accordance with clinical guidelines for the treatment of herpesvirus infections in children, including immunocompromised patients, upon the development of localized herpetic infection [274,281,312,314].
(LoE 5, GoR C)
It is recommended to temporarily discontinue canakinumab**/anakinra** therapy and continue previously prescribed oral GCs upon the development of herpesvirus infection [4,23].
(LoE 5, GoR C)
It is recommended to hospitalize all patients with generalized herpetic infection / suspected cytomegalovirus or Epstein-Barr virus infection [4,23].
(LoE 5, GoR C)
Comments: an appointment (examination, consultation, including remote ones) is conducted with the inpatient rheumatologist who initiated the therapy, to resolve the issue of further patient management.
It is recommended to resume canakinumab**/anakinra** therapy 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 [4,23].
(LoE 5, GoR C)
It is recommended to monitor the efficacy of canakinumab**/anakinra** in all patients to timely address the issue of "switching" to a biologic DMARD with a different mechanism of action in order to achieve disease remission, prevent complications, and curb the progression of patient disability [343].
(LEL 4, GRC C)
Comments: monitoring the efficacy of anti-inflammatory and antirheumatic drugs is carried out at least once a month, with special attention paid to the development of secondary inefficacy. Secondary inefficacy of biologic DMARDs manifests as a "waning" effect and increasing disease activity at any stage of treatment. If secondary inefficacy develops, an urgent appointment (examination, consultation, including remote ones) with the inpatient rheumatologist who initiated the therapy is performed.
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).
It is recommended to monitor the tolerability of canakinumab**/anakinra** in all patients to prevent severe toxic complications, timely discontinue the drug, and "switch" to a biologic DMARD with a different mechanism of action [343].
(LEL 4, GRC C)
Comments: intolerance to biologic DMARDs and/or immunosuppressants can develop at any stage of treatment. If intolerance develops, regardless of its severity, the biologic DMARD and/or immunosuppressant is discontinued. Previously prescribed oral GCs should be continued.
It is recommended that all patients undergo an appointment (examination, consultation, including remote ones) with the inpatient rheumatologist who initiated the therapy upon the development of any signs of inefficacy and/or intolerance to biologic DMARDs to resolve the need for therapy adjustment and the setting in which it should be administered [4,23].
(LoE 5, GoR C)
It is recommended to vaccinate children only during disease remission lasting for at least 6 months, according to an individual schedule, excluding live vaccines [297].
(LoE 5, GoR C)
It is recommended to perform a focal tuberculin test (Mantoux test, recombinant tuberculosis allergen test in standard dilution**) in all patients at least once every 6 months (more frequently if clinically indicated) to rule out Mycobacterium tuberculosis infection during pathogenetic therapy [58,59,343].
(LEL 4, GRC C)
It is recommended to perform a general (clinical) urinalysis in all patients at least once a month to monitor renal function [34].
(LoE 5, GoR C)
Comments: the onset of proteinuria > 500 mg per day may indicate the development of amyloidosis.
It is recommended to perform an electrocardiogram in all patients at least once every 3 months as part of dispensary follow-up to monitor the cardiovascular system [4,23].
(LoE 5, GoR C)
It is recommended to perform a comprehensive abdominal ultrasound, echocardiography, and renal ultrasound in all patients at least once every 6 months as part of dispensary follow-up to monitor disease activity and adverse events of pathogenetic therapy [4,23].
(LoE 5, GoR C)
It is recommended that patients with ENT disorders have an initial appointment (examination, consultation) with an otorhinolaryngologist no later than 7 days after hospital discharge to detect foci of chronic ENT infections and address their sanitization, as well as to diagnose acute ENT infections that have developed under pathogenetic therapy [4,23].
(LoE 5, GoR C)
It is recommended to have a follow-up appointment (examination, consultation) with an otorhinolaryngologist based on medical indications, at least once every 6 months, to monitor the condition of ENT organs, early detection of pathology, its treatment, and the prevention of infectious complications during antirheumatic therapy [4,23].
(LoE 5, GoR C)
It is recommended to have an initial appointment (examination, consultation) with a pediatric cardiologist based on medical indications to develop an individual therapy program based on the recommendations of the inpatient pediatric cardiologist [4,23].
(LoE 5, GoR C)
It is recommended to have a follow-up appointment (examination, consultation) with a pediatric cardiologist based on medical indications to monitor the efficacy of the individual therapy program developed on the recommendations of the inpatient pediatric cardiologist [4,23].
(LoE 5, GoR C)
It is recommended that all patients have an initial appointment (examination, consultation) with a pediatric dentist within 1 month after hospital discharge to detect foci of chronic oral cavity infections and address their sanitization, as well as to diagnose acute oral cavity infections that have developed under pathogenetic therapy [4,23].
(LoE 5, GoR C)
It is recommended to have a follow-up appointment (examination, consultation) with a pediatric dentist based on medical indications for the early detection of oral cavity pathology, its treatment, and the prevention of infectious complications during antirheumatic therapy [4,23].
(LoE 5, GoR C)
It is recommended to have an initial ophthalmologist appointment (examination, consultation) (with ocular biomicroscopy no later than 7 days after hospital discharge in the presence of ophthalmological pathology) to develop an individual treatment program based on the recommendations of the inpatient ophthalmologist [4,22,23].
(LoE 5, GoR C)
It is recommended to have a follow-up ophthalmologist appointment (examination, consultation) (at least once every 3 months) with mandatory ocular biomicroscopy for all patients with ophthalmological pathology based on individual indications to monitor treatment efficacy and adjust it if necessary [4,22,23].
(LEL 4, GRC C)
It is recommended to have an initial nephrologist appointment (examination, consultation) no later than 7 days after hospital discharge in the presence of kidney damage to develop an individual treatment program based on the recommendations of the inpatient rheumatologist and nephrologist [11,13,17,20,22,24,113].
(LoE 5, GoR C)
It is recommended to have a follow-up nephrologist appointment (examination, consultation) for patients with kidney damage at least once every 3 months as part of dispensary follow-up to monitor therapy efficacy [11,13,17,20,22,24,113].
(LoE 5, GoR C)
It is recommended to have an initial dietitian appointment (examination, consultation) based on medical indications to develop an individual dietary program [4,23].
(LoE 5, GoR C)
It is recommended to have a follow-up dietitian appointment (examination, consultation) based on individual indications to monitor/adjust the individual dietary program [4,23].
(LoE 5, GoR C)
It is recommended to have an initial phthisiatrician appointment (examination, consultation) (in the presence of a positive focal test and/or intradermal test with a tuberculosis allergen/tuberculin, and/or infiltrative lesions in the lungs) to resolve the issue of chemoprophylaxis or anti-tuberculosis therapy [59].
(LEL 4, GRC C)
Comments: the decision on the need to adjust therapy and the setting in which it should be carried out is made by the inpatient rheumatologist who initiated the therapy, based on the results of the consultation (including remote).
It is recommended to have an appointment (examination, consultation, including remote ones) with the inpatient rheumatologist who initiated the therapy for patients with a positive intradermal tuberculin test to resolve the issue of whether canakinumab**/anakinra** therapy can be continued [4,23].
(LoE 5, GoR C)
It is recommended to have a follow-up phthisiatrician appointment (examination, consultation) for patients with a positive focal tuberculin test and/or intradermal tuberculosis allergen test, and/or elevated blood interferon-gamma levels to Mycobacterium tuberculosis complex antigens, and/or focal or infiltrative changes in the lungs to monitor/adjust chemoprophylaxis or anti-tuberculosis chemotherapy [59].
(LEL 4, GRC C)
Comments: the decision on the need to adjust therapy and the setting in which it should be carried out is made by the inpatient rheumatologist who initiated the therapy, based on the results of the consultation (including remote).
It is recommended to have an initial pediatric endocrinologist appointment (examination, consultation) based on medical indications to prescribe an individual program recommended by the inpatient pediatric endocrinologist [4,23].
(LoE 5, GoR C)
It is recommended to have a follow-up pediatric endocrinologist appointment (examination, consultation) based on medical indications to monitor/adjust the individual program recommended by the inpatient pediatric endocrinologist [4,22,23].
(LoE 5, GoR C)
It is recommended to have an initial trauma and orthopedic surgeon appointment (examination, consultation) based on medical indications to address the need for orthopedic correction [4,23].
(LoE 5, GoR C)
It is recommended to have a follow-up trauma and orthopedic surgeon appointment (examination, consultation) based on medical indications to monitor the efficacy of / adjust orthopedic correction [4,23].
(LoE 5, GoR C)
It is recommended to have an initial medical psychologist appointment (testing, consultation) based on medical indications to develop a psychological rehabilitation program for the patient and their parents [119–121].
(LEL 4, GRC C)
It is recommended to conduct a follow-up appointment (testing, consultation) with a medical psychologist for medical indications after completion of the psychological rehabilitation program in order to evaluate its effectiveness [119–121].
(LEL 4, GRC C)
It is recommended to plan an inpatient admission to the rheumatology department of the hospital that initiated the prescription of targeted synthetic/biological DMARDs for all patients in order to monitor the efficacy and safety of therapy [4, 23].
(LoE 5, GoR C)
Comments: planned monitoring of efficacy is performed 3 and 6 months after the initiation of therapy and subsequently every 6 months to monitor the efficacy and safety of pathogenetic therapy.
For efficacy monitoring, see Appendix G1–G3.
It is recommended to conduct an appointment (examination, consultation, including telemedicine) with a rheumatologist at the hospital that initiated the therapy for all patients who develop adverse therapy events/infectious complications/intolerance to canakinumab**/anakinra** in order to decide on therapy adjustment and the setting in which to administer it [4, 23].
(LoE 5, GoR C)
It is recommended to arrange an unscheduled inpatient admission as clinically indicated to the rheumatology department of the hospital that initiated the prescription of targeted synthetic/biological DMARDs for evaluation and therapy adjustment at any stage of treatment in the event of CAPS flare/complications, comorbid conditions, complications/side effects/persistent intolerance to canakinumab**/anakinra** [4, 23].
(LoE 5, GoR C)
6. Organization of Medical Care
6.1 Indications for hospitalization and discharge of patients
A patient with an established diagnosis of CAPS who develops a disease flare/complications, comorbid conditions, complications/side effects, or persistent intolerance to canakinumab**/anakinra** must be urgently hospitalized in the rheumatology department of the hospital that initiated pathogenetic therapy for evaluation and treatment adjustment at any stage of treatment.
6.1.1 Suspected cryopyrin-associated periodic syndromes
a) Indications for hospitalization
For diagnostic procedures, including differential diagnosis, and prescription of pathogenetic therapy for all patients in the rheumatology department of a hospital.
б) Indications for discharge
Completion of examination.
Initiation of pathogenetic 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.
Pronounced trend toward normalization / normalization of laboratory markers of activity.
6.1.2 Established diagnosis of cryopyrin-associated periodic syndrome, active stage
a) Indications for hospitalization
For examination and therapy adjustment in case of inefficacy in all patients in the rheumatology department of a hospital.
б) Indications for discharge
Completion of examination.
Prescription/adjustment of pathogenetic 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.
Pronounced trend toward normalization/normalization of laboratory parameters of CAPS activity.
6.1.3 Established diagnosis of cryopyrin-associated periodic syndrome with active hemophagocytic syndrome
a) Indications for hospitalization
For diagnostic procedures, including differential diagnosis, and prescription of therapy for all patients in the rheumatology department of a hospital.
б) Indications for discharge
Completion of examination.
Prescription of pathogenetic therapy for hemophagocytic syndrome.
Absence of side effects or drug intolerance.
Resolution of clinical and laboratory signs of hemophagocytic syndrome.
Absence of clinical and laboratory signs of CAPS activity.
6.1.4 Established diagnosis of cryopyrin-associated periodic syndrome in remission
a) Indications for hospitalization
To monitor the efficacy and safety of pathogenetic therapy in the rheumatology department of a hospital 3 months after therapy initiation; 6 months after therapy initiation; thereafter every 6–12 months.
б) Indications for discharge
Completion of examination.
Absence of side effects or drug intolerance.
Absence of signs of CAPS activity.
Absence of clinical and laboratory signs of hemophagocytic syndrome.
A patient with an established diagnosis of CAPS who develops a disease flare/complications, comorbid conditions, complications/side effects, or persistent intolerance to targeted synthetic/biological DMARDs/immunosuppressants must be urgently hospitalized in the rheumatology department of the hospital that initiated the targeted synthetic/biological DMARDs/immunosuppressants for evaluation and treatment adjustment at any stage of treatment.
Indications for administering anti-rheumatic therapy, including targeted synthetic and biological DMARDs (intramuscular and subcutaneous administration), to patients with CAPS in a medical organization (pediatric rheumatology department in an inpatient and/or day care setting; treatment room of a primary healthcare organization; treatment room of a paramedic-midwife station in the absence of a pediatric rheumatology office):
inability to independently administer genetically engineered biologic drugs (intramuscular and subcutaneous administration of medications) at home by parents (legal representatives) and/or the patient over 15 years of age due to low compliance and lack of drug administration skills.
Indications for consultation with a federal-subordinate medical organization, including via telemedicine technologies:
prescription and/or substitution of targeted synthetic and biological DMARDs and/or selective immunosuppressants, with or without glucocorticoid pulse therapy, and/or immunosuppressants, and/or high-dose normal human immunoglobulin in patients with cryopyrin-associated periodic syndromes of high/moderate inflammatory activity and/en/or resistance to ongoing drug therapy.
6.2 Regulatory and legal documents governing the provision of medical care to children with cryopyrin-associated periodic syndromes
Order of the Ministry of Health of the Russian Federation No. 700n dated October 7, 2015 (as amended on December 9, 2019) "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, Registration No. 39696).
Order of the Ministry of Health of the Russian Federation No. 206n dated May 2, 2023 "On Approval of Qualification Requirements for Medical and Pharmaceutical Workers with Higher Education" (Registered with the Ministry of Justice of the Russian Federation on June 1, 2023, Registration No. 73677).
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 in the Profile 'Rheumatology'" (as amended on February 21, 2020).
Order of the Ministry of Health of the Russian Federation No. 274n dated April 21, 2022 “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 July 13, 2022, registration No. 69251).
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 of Children" (Registered with the Ministry of Justice of the Russian Federation on December 23, 2019, Registration No. 56954).
Order of the Ministry of Health of the Russian Federation No. 231n dated March 19, 2021 (as amended on February 21, 2022) "On Approval of the Procedure for Monitoring the Volume, Timing, Quality, and Conditions of Provision of Medical Care under Compulsory Medical Insurance to Insured Persons, as well as its Financial Provision" (Registered with the Ministry of Justice of the Russian Federation on May 13, 2021, No. 63410).
Order of the Russian Ministry of Health No. 108n dated February 28, 2019 (as amended on December 13, 2022) "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. 789n dated December 13, 2022 "On Amendments to the Rules of Compulsory Medical Insurance Approved by Order of the Ministry of Health of the Russian Federation No. 108n dated February 28, 2019" (Registered with the Ministry of Justice of the Russian Federation on December 30, 2022, Registration No. 71905).
Cl. 14.1 of Article 37. Organization of Medical Care of Federal Law No. 323-FZ dated November 21, 2011 (as amended on June 11, 2022, with rev. dated July 13, 2022) "On the Fundamentals of Health Protection of Citizens in the Russian Federation" (with rev. and add., entered into force on June 29, 2022): "Standards of medical care for children and clinical guidelines may include medicinal products registered in the territory of the Russian Federation and used in accordance with indications (characteristics) of the medicinal product not specified in its instructions for use, provided that such a 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 indications (characteristics) not specified in its instructions for use is permitted shall be established by the Government of the Russian Federation."
Cl. 15 of Article 37. Organization of Medical Care of Federal Law No. 323-FZ dated November 21, 2011 (as amended on June 11, 2022, with rev. dated July 13, 2022) "On the Fundamentals of Health Protection of Citizens in the Russian Federation" (with rev. and add., entered into force on June 29, 2022): "The prescription and use of medicinal products, medical devices, and specialized medical nutrition products not included in the relevant standard of medical care or not provided for by the relevant clinical guideline are permitted in the presence of medical indications (individual intolerance, life-threatening conditions) by decision of the medical commission. The effect of this requirement may be modified for medical organizations of the private healthcare system participating in an experimental legal regime in the field of digital innovations in accordance with the program of the experimental legal regime in the field of digital innovations approved in accordance with Federal Law No. 258-FZ dated July 31, 2020 'On Experimental Legal Regimes in the Field of Digital Innovations in the Russian Federation'."
Decree 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 in Accordance with Indications (Characteristics) of the Medicinal Product Not Specified in Its Instructions for Use Is Permitted".
Resolution of the Government of the Russian Federation No. 1799 dated October 27, 2023 "On Approval of Requirements for 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, the Inclusion of Which Is Permitted in Standards of Medical Care for Children and Clinical Guidelines".
Order of the Ministry of Health of the Russian Federation No. 1008n dated September 23, 2020 "On Approval of the Procedure for Providing Patients with Medical Nutrition" (Registered with the Ministry of Justice of the Russian Federation on September 30, 2020, registration No. 60137).
Order of the Ministry of Health of the Russian Federation No. 203n dated April 14, 2025 "On Approval of Criteria for Assessing the Quality of Medical Care" (Registered on May 28, 2025, No. 82382).
7. Additional Information
It is recommended to refer children to the medical and social expertise bureau to obtain the "disabled child" status [23].
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. 588 dated April 5, 2022 (as amended on March 12, 2024) "On Recognition of a Person as Disabled" (as amended by Decrees of the Government of the Russian Federation No. 2121 dated November 23, 2022, No. 77 dated January 24, 2023, No. 1887 dated November 10, 2023, No. 2003 dated November 28, 2023, No. 289 dated April 12, 2024).
Order of the Ministry of Labor and Social Protection of the Russian Federation No. 374n dated July 26, 2024, "On Approval of Classifications and Criteria Used in Carrying out Medical and Social Expertise of Citizens by Federal Medical and Social Expertise Institutions."
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 dated June 19, 2012 (Collected Legislation of the Russian Federation, 2012, No. 26, item 3528; 2013, No. 22, item 2809; No. 36, item 4578; No. 37, item 4703; No. 45, item 5822; No. 46, item 5952; 2014, No. 21, item 2710; No. 26, item 3577; No. 29, item 4160; No. 32, item 4499; No. 36, item 4868; 2015, No. 2, item 491; No. 6, item 963; No. 16, item 2384; 2016, No. 2, item 325; No. 4, item 534; No. 23, item 3322; No. 28, item 4741; No. 29, item 4812; No. 43, item 6038; No. 47, item 6659; 2017, No. 1, item 187; No. 7, item 1093; No. 17, item 2581; No. 22, item 3149; No. 28, item 4167; 2018, No. 10, item 1494; No. 24, item 3530; No. 36, item 5634; No. 46, item 7052; No. 49, item 7600; No. 53, item 8678; 2019, No. 1, item 31; No. 5, item 408; No. 21, item 2563).
Appendix No. 2 to the classifications and criteria used in carrying out 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. 26, 2024, No. 374n. Quantitative system for assessing the severity of persistent dysfunctions of a child's body under the age of 18 years caused by diseases, consequences of injuries, or defects (in percentages, in relation to the clinical and functional characteristics of persistent human body dysfunctions).
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 event of untimely provision of pathogenetic drugs to a child with CAPS, there is a high probability of disease exacerbation/increased disease activity, development of amyloidosis, renal failure, progression of joint damage, and patient functional disability.
7.1 Outcomes and prognosis
The most favorable prognosis is observed in patients with FCAS. Organ damage does not develop, and the risk of amyloidosis is 3%. Patients with MWS have 2 phases of disease development: systemic and organ inflammation (in childhood) and organ damage (adult phenotype) [11,13,22,23].
Initiation of treatment in the first phase prevents the development of organ damage such as deafness and renal amyloidosis. Deafness develops in adolescence and young adulthood in 50–70% of patients with MWS. The risk of amyloidosis (predominantly renal) is 20–40%, leading to renal failure and death. The most severe prognosis is in patients with CINCA/NOMID. Mortality in adolescence is 20%. Severe arthropathy occurs in 50% of patients, deafness in 75%, blindness, and neurological disorders (hydrocephalic syndrome, physical and mental developmental delay, cognitive decline) in 70%. The incidence of amyloidosis is 25%. Outcomes and prognosis depend on timely diagnosis and prescription of targeted therapy with IL-1 inhibitors [11,13,22,23,345–347].
Control of inflammation entails the relief of core CAPS-associated symptoms, normalization of inflammatory markers, and absence of progression of organ damage. With canakinumab**/anakinra** therapy over 24 months of treatment, complete remission is achieved in 78%. Ten percent with severe disease experience exacerbations; dose escalation and shortening the administration interval lead to remission in 24%. Mild-to-moderate adverse events during therapy develop in 66% of patients (common infections), and severe infections in 10% [2,5].
Key points:
IL-1 inhibitors are the most effective treatment in patients with CAPS. Young patients and those with a severe phenotype require higher doses to control activity.
Ninety percent of patients show a response to therapy.
Monitoring of infections and major adverse events is necessary.
Long-term outcomes directly depend on the severity of the phenotype and the delay in initiating effective therapy. It has also been demonstrated that IL-1 therapy significantly improves health-related quality of life [5,346,347].
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. Quality assessment criteria for primary diagnosis to establish the diagnosis of cryopyrin-associated periodic syndromes
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1 | Diagnosis, including differential diagnosis, was performed in all patients with suspected cryopyrin-associated periodic syndromes in an inpatient setting providing medical care to children with rheumatic diseases | yes/no |
2 | A detailed general (clinical) blood test was performed (study of erythrocyte sedimentation rate, study of red blood cell level in blood, study of white blood cell level in blood, study of platelet level in blood, differential leukocyte count (leukocyte formula), study of total hemoglobin level in blood) | yes/no |
3 | Coagulogram (exploratory hemostasis assay) was performed with determination of prothrombin index, blood antithrombin III activity, blood plasminogen level, blood fibrinogen level, blood D-dimer concentration, blood soluble fibrin monomer complexes, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time in blood, and von Willebrand factor activity and properties in blood | yes/no |
4 | Thromboelastography has been performed in patients with signs of vasculitis | yes/no |
5 | General clinical blood biochemistry has been performed (determination of total blood protein, blood albumin, total blood bilirubin, free and conjugated blood bilirubin, blood creatinine, blood urea, blood uric acid, blood glucose, blood ferritin, blood triglycerides, blood cholesterol, low-density lipoprotein cholesterol, blood sodium, blood potassium, total blood calcium, blood lactate dehydrogenase activity, aspartate aminotransferase activity, alanine aminotransferase activity, gamma-glutamyltransferase activity, alkaline phosphatase activity, serum iron, creatine kinase activity, pancreatic amylase activity, lipase activity) | yes/no |
6 | A study of immunoglobulin levels in blood was performed | yes/no |
7 | Determination of autoantibodies to cell nuclei and DNA antigens, rheumatoid factor (RF) in blood, markers of ANCA-associated vasculitis: PR3 (c-ANCA), MPO (p-ANCA), anticentromere antibodies in blood, anti-RNA antibodies in blood, anti-cyclic citrullinated peptide (anti-CCP) antibodies in blood (ACPA); antinuclear antibodies to Sm antigen, antibodies to Scl-70, complement component C3 level, complement component C4 level has been performed | yes/no |
8 | Antistreptolysin-O blood serum test | yes/no |
9 | A study of the C-reactive protein level in blood serum was performed | yes/no |
10 | Determination of main ABO blood groups, subgroups, and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy, and Rhesus D antigen (Rh factor) was performed | yes/no |
11 | General (clinical) urinalysis, urinary albumin determination, and 24-hour urinary protein quantification have been performed | yes/no |
12 | A set of kidney function tests was performed in patients with clinical/laboratory signs of kidney damage | yes/no |
13 | A comprehensive diagnostic evaluation to assess the severity of renal failure has been performed in patients with clinical/laboratory signs of nephrotic syndrome/renal failure | yes/no |
14 | Molecular genetic testing was performed – a panel of tests for the diagnosis of cryopyrin-associated periodic syndromes | yes/no |
15 | HLA-B27 antigen determination by flow cytometry was performed | yes/no |
16 | Blood procalcitonin level testing | yes/no |
17 | Lymphocyte subset analysis was performed | yes/no |
18 | Focal tuberculin test (Mantoux test, test with recombinant tuberculosis allergen in standard dilution**) and/or blood interferon-gamma assay for Mycobacterium tuberculosis complex antigens was performed | yes/no |
19 | Antibodies to Salmonella enterica in blood, antibodies to Salmonella typhi in blood, antibodies of classes M, G (IgM, IgG) to Yersinia pseudotuberculosis in blood, antibodies to Yersinia enterocolitica serovars in blood testing | yes/no |
20 | Determination of class A, M, G antibodies (IgA, IgM, IgG) to Chlamydia psittaci in the blood; determination of antibodies to Chlamydophila pneumoniae in the blood; determination of class G antibodies (IgG) to Chlamydia trachomatis in the blood; determination of class M and G antibodies (IgM, IgG) to Mycoplasma pneumoniae in the blood | yes/no |
21 | Determination of classes M, G antibodies (IgM, IgG) to Shigella boydii in blood, classes M, G antibodies (IgM, IgG) to Shigella dysenteriae in blood, classes M, G antibodies (IgM, IgG) to Shigella sonnei in blood, and classes M, G antibodies (IgM, IgG) to Shigella flexneri in blood has been performed | yes/no |
22 | PCR detection of deoxyribonucleic acid (DNA) of tick-borne borreliosis pathogens of the Borrelia burgdorferi sensu lato group in blood; determination of class M antibodies (IgM) to tick-borne borreliosis pathogens of the Borrelia burgdorferi sensu lato group in blood; determination of class G antibodies (IgG) to tick-borne borreliosis pathogens of the Borrelia burgdorferi sensu lato group in blood; and determination of total antibodies to tick-borne borreliosis pathogens of the Borrelia burgdorferi sensu lato group in blood have been performed in patients with an anamnestic history of visiting a forest, residing in tick-endemic areas, or suffering a tick bite | yes/no |
23 | Quantitative PCR detection of Epstein-Barr virus (Epstein-Barr virus) DNA in peripheral and cord blood, qualitative PCR detection of Epstein-Barr virus (Epstein-Barr virus) DNA in oropharyngeal swabs, and qualitative PCR detection of Epstein-Barr virus (Epstein-Barr virus) DNA in urine have been performed | yes/no |
24 | Quantitative PCR detection of cytomegalovirus (Cytomegalovirus) DNA in peripheral and cord blood, qualitative PCR detection of cytomegalovirus (Cytomegalovirus) DNA in oropharyngeal swabs, and qualitative PCR detection of cytomegalovirus (Cytomegalovirus) DNA in urine have been performed | yes/no |
25 | Quantitative PCR detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in blood, qualitative PCR detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in oropharyngeal swabs, and qualitative PCR detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in urine were performed | yes/no |
26 | Antibodies of classes M, G (IgM, IgG) to Cytomegalovirus in blood testing | yes/no |
27 | Antibodies of classes M, G (IgM, IgG) to Epstein-Barr virus in blood testing | yes/no |
28 | Antibodies to Epstein-Barr virus (Epstein-Barr virus) capsid antigen (VCA) in blood testing | yes/no |
29 | Class G antibodies (IgG) to Epstein-Barr virus (Epstein-Barr virus) early antigens (EA) in blood testing | yes/no |
30 | Antibodies to Herpes simplex virus in blood testing | yes/no |
31 | Molecular biological blood testing for Toxoplasma gondii was performed in patients with a history of animal contact | yes/no |
32 | Molecular biological blood testing for hepatitis C virus (Hepatitis C virus) and hepatitis B virus (Hepatitis B virus) has been performed in patients with clinical and laboratory signs of hepatitis | yes/no |
33 | Determination of hepatitis B virus (Hepatitis B virus) surface antigen (HBsAg) and antibodies to hepatitis C virus (Hepatitis C virus) in blood has been performed in patients with clinical and laboratory signs of hepatitis | yes/no |
34 | Antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV 1) in blood, antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-2 (Human immunodeficiency virus HIV 2) in blood testing for patients with signs of immunodeficiency | yes/no |
35 | Determination of antibodies to (Leischmania) in the blood in patients with a history of animal contact to rule out leishmaniasis | yes/no |
36 | Microbiological (culture) examination of tonsillar and posterior pharyngeal wall mucus for aerobic and facultatively anaerobic microorganisms performed | yes/no |
37 | Microbiological (culture) blood test for sterility, microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms performed | yes/no |
38 | Fecal calprotectin level testing was performed | yes/no |
39 | Comprehensive ultrasound examination (ultrasound) of internal organs (includes comprehensive abdominal ultrasound, renal ultrasound) | yes/no |
40 | Echocardiography performed | yes/no |
41 | Electrocardiogram recording performed | yes/no |
42 | Joint ultrasound has been performed in patients with active arthritis | yes/no |
43 | X-ray imaging of the temporomandibular joint and/or intervertebral articulations, and/or elbow joint, and/or wrist joint, and/or knee joint, and/or shoulder joint, and/or hip joint, and/or ankle joint, and/or acromioclavicular articulation, and/or sternoclavicular articulation, and/or hand, and/or foot in two projections, or computed tomography of the joint with or without anesthesia support (including early postoperative management), has been performed in patients with active arthritis | yes/no |
44 | Magnetic resonance imaging of joints (single joint) with contrast enhancement, with or without anesthesia (including early postoperative management), in patients with active arthritis | yes/no |
45 | Plain abdominal radiography in all patients with abdominal syndrome | yes/no |
46 | Esophagogastroduodenoscopy with or without anesthesia (including early postoperative management) performed | yes/no |
47 | Microbiological (cultural) examination of gastric mucosa biopsy specimens for Helicobacter pylori has been performed in patients with inflammatory, erosive, and/or ulcerative changes detected by esophagogastroduodenoscopy | yes/no |
48 | Performed endoscopic biopsy of the esophagus, endoscopic biopsy of the stomach, endoscopic biopsy of the duodenum, and endoscopic biopsy of the jejunum with or without anesthetic management (including early postoperative management), followed by pathomorphological examination of the biopsy (surgical) material from the esophagus, stomach, duodenum, and jejunum in patients presenting with inflammatory, erosive, and/or ulcerative mucosal changes according to esophagogastroduodenoscopy findings | yes/no |
49 | Colonoscopy with anesthesia (including early postoperative management) | yes/no |
50 | Colon biopsy via endoscopy with pathomorphological examination of the colonic biopsy (surgical) specimen in patients with inflammatory, erosive, and/or ulcerative changes in the colon detected by colonoscopy | yes/no |
51 | Magnetic resonance enterography (MR enterography, hydro-MRI) with contrast enhancement, with or without anesthesia (including early postoperative management), in patients with clinical signs of inflammatory bowel disease and/or elevated fecal calprotectin levels in the absence of abnormalities on esophagogastroduodenoscopy and colonoscopy | yes/no |
52 | Video capsule endoscopy of the small intestine in patients with clinical signs of inflammatory bowel disease and/or elevated fecal calprotectin levels in the absence of abnormalities on esophagogastroduodenoscopy and colonoscopy | yes/no |
53 | Performed computed tomography of the chest organs with or without anesthetic care (including early postoperative management) | yes/no |
54 | Performed contrast-enhanced magnetic resonance imaging of the brain, contrast-enhanced magnetic resonance imaging of the abdominal organs, contrast-enhanced magnetic resonance imaging of the retroperitoneal space, and contrast-enhanced magnetic resonance imaging of the pelvic organs with or without anesthetic care (including early postoperative management) | yes/no |
55 | Computed tomography of the brain, computed tomography of the abdominal organs with intravenous bolus contrast enhancement, computed tomography of the retroperitoneal space with intravenous bolus contrast enhancement, with or without anesthesia (including early postoperative management), in patients with contraindications to MRI | yes/no |
56 | Magnetic resonance imaging of the spinal cord with contrast enhancement (one spinal segment) with or without anesthesia (including early postoperative management) in patients with symptoms of CNS involvement | yes/no |
57 | Lumbar puncture with anesthetic care (including early postoperative management) with microscopic examination, cell counting in a counting chamber (determination of cytosis), examination of physical properties of cerebrospinal fluid, and serological examination performed in patients with symptoms of central nervous system involvement | yes/no |
58 | Renal biopsy with anesthesia (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 proteinuria > 500 mg/day in the absence of contraindications | yes/no |
59 | 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 | yes/no |
60 | 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 | yes/no |
61 | Pelvic bone trephine biopsy with anesthesia (including early postoperative management) and 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; immunophenotyping of hematopoietic progenitor cells in the bone marrow in patients with an atypical course of CAPS | yes/no |
62 | Bone biopsy with anesthesia (including early postoperative management) and pathomorphological examination of the bone biopsy (surgical) material in patients with space-occupying and destructive lesions, as well as bone deformities atypical for CAPS | yes/no |
63 | Multiposition bone scintigraphy with or without anesthesia (including early postoperative management) in patients with bone destruction foci atypical for CAPS | yes/no |
64 | Positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)) with contrast enhancement, if necessary, whole-body positron emission tomography using tumor-tropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)), with or without anesthesia (including early postoperative management), in patients with severe arthralgia, myalgia, ossalgia, bone destructive changes, subcutaneous adipose tissue infiltrates, and lesions in parenchymal organs, brain, or spinal cord | yes/no |
65 | Initial consultation (examination) by a pediatric surgeon was performed in all patients with abdominal and thoracic symptoms | yes/no |
66 | Initial consultation (examination) by a gastroenterologist was performed in all patients with abdominal symptoms | yes/no |
67 | Initial consultation (examination) by a pediatric oncologist was performed in patients with suspected oncological or oncohematological diseases based on examination results | yes/no |
68 | Initial consultation (examination) by an obstetrician-gynecologist was performed in all female patients with abdominal symptoms | yes/no |
69 | Initial nephrologist consultation (examination) is recommended for patients with abnormal urinalysis and/or nephrotic syndrome/renal failure | yes/no |
70 | Performed initial examination (inspection, consultation) by a neurologist in patients with symptoms of central and peripheral nervous system involvement and in patients with thoracic symptoms | yes/no |
71 | 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 | yes/no |
72 | Initial consultation (examination) by an orthopedic traumatologist in patients with acute arthritis, space-occupying and destructive lesions, as well as bone deformities atypical for CAPS | yes/no |
73 | Initial appointment (examination, consultation) by anotorhinolaryngologist was completed. | yes/no |
74 | Initial consultation (examination) by an otorhinolaryngologist-audiologist was performed | yes/no |
75 | Initial appointment (examination, consultation) with an ophthalmologist was performed | yes/no |
76 | Initial consultation (examination) by a pediatric dentist | yes/no |
77 | Initial appointment (examination, consultation) by a medical geneticist performed | yes/no |
78 | Performed initial examination (consultation) by an anesthesiologist-resuscitologist in patients scheduled for procedures under general anesthesia | yes/no |
79 | Performed initial examination (consultation) by an anesthesiologist-resuscitologist in critically ill patients | yes/no |
80 | Performed 24-hour monitoring by an anesthesiologist-resuscitologist for all critically ill patients (multiple organ dysfunction syndrome, hemophagocytic syndrome) | yes/no |
81 | 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) | yes/no |
Table 2. Criteria for assessing the quality of diagnosis of hemophagocytic syndrome
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1 | Diagnosis, including differential diagnosis, in all patients with suspected hemophagocytic syndrome in an inpatient setting providing medical care to children with rheumatic diseases | yes/no |
2 | A detailed general (clinical) blood test was performed (study of erythrocyte sedimentation rate, study of red blood cell level in blood, study of white blood cell level in blood, study of platelet level in blood, differential leukocyte count (leukocyte formula), study of total hemoglobin level in blood) | yes/no |
3 | A coagulogram (exploratory hemostasis evaluation) was performed, including the determination of prothrombin index, blood antithrombin III activity, blood plasminogen level, blood fibrinogen level, blood D-dimer concentration, blood soluble fibrin monomer complexes, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time, blood protein C level, blood protein S activity, and blood von Willebrand factor activity and properties | yes/no |
4 | Performed thromboelastography | yes/no |
5 | Blood heparin level was measured in all patients receiving heparin group drugs | yes/no |
6 | General general-clinical biochemical blood test was performed (determination of total blood protein, blood albumin, total blood bilirubin, free and conjugated blood bilirubin, blood creatinine, blood urea, blood uric acid, blood glucose, blood ferritin, blood triglycerides, blood cholesterol, blood sodium, blood potassium, total blood calcium, blood lactate dehydrogenase activity, blood aspartate aminotransferase activity, blood alanine aminotransferase activity, blood gamma-glutamyltransferase activity, blood alkaline phosphatase activity, serum iron, blood creatine kinase activity, pancreatic amylase activity, and lipase activity) | yes/no |
7 | A study of the C-reactive protein level in blood serum was performed | yes/no |
8 | Microbiological (cultural) blood test for sterility, microbiological (cultural) test of tonsillar and posterior pharyngeal swabs for aerobic and facultatively anaerobic microorganisms, microbiological (cultural) urine test for aerobic and facultatively anaerobic opportunistic pathogens, and microbiological (cultural) stool test for aerobic and facultatively anaerobic microorganisms with antimicrobial susceptibility testing were performed | yes/no |
9 | Determination of classes A, M, G antibodies (IgA, IgM, IgG) to Chlamydia psittaci; determination of antibodies to Chlamydia trachomatis; determination of antibodies to Chlamydophila pneumoniae in blood; determination of classes M, G antibodies (IgM, IgG) to Mycoplasma pneumoniae in blood were performed | yes/no |
10 | Detection of Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR was performed upon detection of interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography | yes/no |
11 | Determination of Epstein-Barr virus (Epstein-Barr virus) DNA by PCR in peripheral and cord blood (quantitative assay), determination of Epstein-Barr virus (Epstein-Barr virus) DNA in oropharyngeal swabs by PCR (qualitative assay), determination of Epstein-Barr virus (Epstein-Barr virus) DNA by PCR (qualitative assay) in urine | yes/no |
12 | Cytomegalovirus (Cytomegalovirus) DNA PCR assay in peripheral and cord blood (quantitative), Cytomegalovirus (Cytomegalovirus) DNA PCR assay in oropharyngeal swabs (qualitative), Cytomegalovirus (Cytomegalovirus) DNA PCR assay in urine (qualitative) | yes/no |
13 | Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA PCR blood assay (quantitative), Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA PCR oropharyngeal swab assay (qualitative), Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA PCR urine assay (qualitative) | yes/no |
14 | Antibodies of classes M, G (IgM, IgG) to Cytomegalovirus in blood testing | yes/no |
15 | Antibodies of classes M, G (IgM, IgG) to Epstein-Barr virus in blood testing | yes/no |
16 | Antibodies to Epstein-Barr virus (Epstein-Barr virus) capsid antigen (VCA) in blood testing | yes/no |
17 | Class G antibodies (IgG) to Epstein-Barr virus (Epstein-Barr virus) early antigens (EA) in blood testing | yes/no |
18 | Antibodies to Herpes simplex virus in blood testing | yes/no |
19 | Microbiological (cultural) test of lavage fluid for aerobic and facultatively anaerobic microorganisms using automated seeding with antimicrobial susceptibility testing was performed upon detection of interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography | yes/no |
20 | Detection of Epstein-Barr virus DNA in sputum and bronchoalveolar lavage fluid by PCR was performed upon detection of interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography | yes/no |
21 | Detection of Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR was performed upon detection of interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography | yes/no |
22 | Quantitative detection of Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, and bronchoalveolar lavage fluid by PCR was performed upon detection of interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography | yes/no |
23 | Determination of class M and G antibodies to Pneumocystis jirovecii in blood was performed upon detection of interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography | yes/no |
24 | Microbiological (cultural) examination of bronchoalveolar lavage fluid for Pneumocystis cysts (Pneumocystis carinii) upon detection of interstitial, focal, and/or infiltrative changes in the lungs according to chest computed tomography | yes/no |
25 | Microbiological (cultural) test of bronchoalveolar lavage fluid for fungi (yeast and mycelial) was performed upon detection of interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography | yes/no |
26 | Determination of mannan antigen of fungi of the genus Candida albicans and galactomannan antigen of fungi of the genus Aspergillus (Aspergillus spp.) in blood serum by enzyme-linked immunosorbent assay upon detection of interstitial, focal, and/or infiltrative changes in the lungs according to chest computed tomography | yes/no |
27 | Determination of mannan antigen of Candida albicans and galactomannan antigen of Aspergillus spp. in bronchoalveolar lavage fluid by ELISA was performed upon detection of interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography | yes/no |
28 | Blood procalcitonin level testing | yes/no |
29 | General (clinical) urinalysis, urinary albumin determination, and 24-hour urinary protein quantification have been performed | yes/no |
30 | Comprehensive ultrasound examination of internal organs was performed (including comprehensive abdominal ultrasound, renal ultrasound) | yes/no |
31 | Echocardiography performed | yes/no |
32 | Electrocardiogram recording performed | yes/no |
33 | Performed computed tomography of the chest organs with or without anesthetic care (including early postoperative management) | yes/no |
34 | Magnetic resonance imaging of the brain with or without anesthesia support (including early postoperative management) was performed in patients with neurological symptoms | yes/no |
35 | Magnetic resonance imaging of the abdominal cavity, retroperitoneal space, and pelvic organs with or without anesthesia support (including early postoperative management) was performed in patients who developed multiorgan failure | yes/no |
36 | Obtaining a bone marrow cytologic preparation by puncture with anesthesia support (including early postoperative management) and a bone marrow histologic preparation with bone marrow smear cytologic examination (myelogram) and pathomorphological examination of bone marrow biopsy (surgical) material was performed | yes/no |
37 | Initial consultation (examination) by a neurologist was performed in patients with neurological symptoms | yes/no |
38 | Initial examination (consultation) by an anesthesiologist-resuscitologist was performed for patients scheduled for procedures under general anesthesia | yes/no |
39 | Initial examination (consultation) by an anesthesiologist-resuscitologist was performed for patients in severe/critical condition | yes/no |
40 | Daily monitoring by an anesthesiologist-resuscitologist was performed for patients with pancytopenia, single-organ and multiorgan failure, and CNS damage | yes/no |
41 | Initial visit (examination, consultation) by an ophthalmologist was performed for patients with hemorrhagic syndrome | yes/no |
Table 3. Criteria for assessing the quality of examination of patients with an established diagnosis of cryopyrin-associated periodic syndrome prior to the initiation/adjustment of pathogenetic therapy
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1 | Examination prior to the initiation/adjustment of therapy in all patients with an established diagnosis of CAPS, active stage, in an inpatient setting providing care to children with rheumatic diseases | yes/no |
2 | A detailed general (clinical) blood test was performed (study of erythrocyte sedimentation rate, study of red blood cell level in blood, study of white blood cell level in blood, study of platelet level in blood, differential leukocyte count (leukocyte formula), study of total hemoglobin level in blood) | yes/no |
3 | Coagulogram (screening hemostasis test) including prothrombin index, antithrombin III activity in the blood, plasminogen level in the blood, fibrinogen level in the blood, D-dimer concentration in the blood, 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 activity and properties in patients with HPS and/or signs of vasculitis, and/or receiving heparin group drugs | yes/no |
4 | Thromboelastography in patients with HPS, signs of vasculitis, and/or receiving heparin group drugs | yes/no |
5 | Blood heparin level testing was performed in patients with MAS and/or signs of vasculitis and/or receiving heparin group drugs | yes/no |
6 | General clinical biochemical blood analysis was performed (total blood protein assay, blood albumin assay, total blood bilirubin assay, free and conjugated blood bilirubin assay, blood creatinine assay, blood urea assay, blood uric acid assay, blood glucose assay, blood ferritin assay, blood triglycerides assay, blood cholesterol assay, blood potassium assay, blood sodium assay, total blood calcium assay; blood lactate dehydrogenase activity determination, blood creatine kinase activity determination, blood aspartate aminotransferase activity determination, blood alanine aminotransferase activity determination, blood gamma-glutamyl transferase activity determination, blood amylase activity determination, blood alkaline phosphatase activity determination, serum iron assay) | yes/no |
7 | Determination of blood procalcitonin levels in all patients with fever | yes/no |
8 | Determination of C-reactive protein level in blood serum | yes/no |
9 | Determination of antistreptolysin-O level in blood serum | yes/no |
10 | A study of immunoglobulin levels in blood was performed | yes/no |
11 | Lymphocyte subset analysis in patients with a history of frequent viral or purulent bacterial infections, including opportunistic ones | yes/no |
12 | Determination of ABO blood groups, subgroup and minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy, Rhesus D antigen (Rh factor), and coagulogram (screening hemostasis test) prior to invasive procedures (esophagogastroduodenoscopy, colonoscopy with biopsy, bone marrow aspiration for cytological preparation, cytological examination of bone marrow trephine biopsy imprints, bone biopsy) | yes/no |
13 | Focal tuberculin test (Mantoux test, test with recombinant tuberculosis allergen in standard dilution**) and/or blood interferon-gamma assay for Mycobacterium tuberculosis complex antigens was performed | yes/no |
14 | Blood antibody testing for Salmonella enterica, blood antibody testing for Salmonella typhi, blood class M and G antibody (IgM, IgG) testing for Yersinia pseudotuberculosis, and blood antibody testing for Yersinia enterocolitica serovars were performed in patients with abdominal syndrome | yes/no |
15 | Determination of class A, M, G antibodies (IgA, IgM, IgG) to Chlamydia psittaci in the blood; determination of antibodies to Chlamydophila pneumoniae in the blood; determination of class G antibodies (IgG) to Chlamydia trachomatis in the blood; determination of class M and G antibodies (IgM, IgG) to Mycoplasma pneumoniae in the blood | yes/no |
16 | Blood class M and G antibody (IgM, IgG) testing for Shigella boydii, blood class M and G antibody (IgM, IgG) testing for Shigella dysenteriae, blood class M and G antibody (IgM, IgG) testing for Shigella sonnei, and blood class M and G antibody (IgM, IgG) testing for Shigella flexneri were performed in patients with abdominal syndrome | yes/no |
17 | Quantitative PCR detection of Epstein-Barr virus (Epstein-Barr virus) DNA in peripheral and cord blood, qualitative PCR detection of Epstein-Barr virus (Epstein-Barr virus) DNA in oropharyngeal swabs, and qualitative PCR detection of Epstein-Barr virus (Epstein-Barr virus) DNA in urine have been performed | yes/no |
18 | Quantitative PCR detection of cytomegalovirus (Cytomegalovirus) DNA in peripheral and cord blood, qualitative PCR detection of cytomegalovirus (Cytomegalovirus) DNA in oropharyngeal swabs, and qualitative PCR detection of cytomegalovirus (Cytomegalovirus) DNA in urine have been performed | yes/no |
19 | Quantitative PCR detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in blood, qualitative PCR detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in oropharyngeal swabs, and qualitative PCR detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in urine were performed | yes/no |
20 | General (clinical) urinalysis, urinary albumin determination, and 24-hour urinary protein quantification have been performed | yes/no |
21 | A set of kidney function tests was performed in patients with clinical/laboratory signs of kidney damage | yes/no |
22 | A comprehensive diagnostic evaluation to assess the severity of renal failure has been performed in patients with clinical/laboratory signs of nephrotic syndrome/renal failure | yes/no |
23 | Microbiological (culture) examination of tonsillar and posterior pharyngeal swabs for aerobic and facultatively anaerobic microorganisms was performed | yes/no |
24 | Microbiological (cultural) blood test for sterility, and microbiological (cultural) urine test for aerobic and facultatively anaerobic opportunistic microorganisms were performed in patients with febrile and hectic fever | yes/no |
25 | Performed microbiological (culture) examination of bronchoalveolar lavage fluid for pneumocystis cysts (Pneumocystis carinii) in patients with signs of pneumonia according to chest computed tomography | yes/no |
26 | Performed quantitative PCR detection of Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, or bronchoalveolar lavage fluid in patients with signs of pneumonia according to chest computed tomography | yes/no |
27 | Microbiological (cultural) examination of bronchoalveolar lavage fluid for fungi (yeast and mold) in patients with signs of pneumonia according to chest computed tomography | yes/no |
28 | Microbiological (cultural) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms in patients with signs of pneumonia according to chest computed tomography | yes/no |
29 | Antibodies to Aspergillus spp. in the blood were determined in patients with interstitial, focal, and/or infiltrative lung changes detected by chest computed tomography | yes/no |
30 | Mannan and galactomannan testing in lavage fluid and blood was performed in patients with signs of pneumonia according to chest computed tomography | yes/no |
31 | PCR detection of Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography | yes/no |
32 | PCR detection of cytomegalovirus (Cytomegalovirus) DNA in sputum and bronchoalveolar lavage fluid was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography | yes/no |
33 | PCR detection of Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG) DNA with species differentiation in sputum and bronchoalveolar lavage fluid was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography | yes/no |
34 | Blood class M and G antibody (IgM, IgG) testing for cytomegalovirus (Cytomegalovirus) was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography | yes/no |
35 | Blood class M and G antibody (IgM, IgG) testing for Epstein-Barr virus (Epstein-Barr virus) was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography | yes/no |
36 | Blood antibody testing against Epstein-Barr virus (Epstein-Barr virus) capsid antigen (VCA) was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography | yes/no |
37 | Blood class G antibody (IgG) testing against Epstein-Barr virus (Epstein-Barr virus) early antigens (EA) was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography | yes/no |
38 | Antibodies to Herpes simplex virus in the blood were determined in patients with interstitial, focal, and/or infiltrative lung changes detected by chest computed tomography | yes/no |
39 | Fecal calprotectin level testing was performed in patients with clinical manifestations of IBD (diarrhea, abdominal pain, blood/mucus in stool) | yes/no |
40 | Comprehensive ultrasound examination of internal organs was performed (includes comprehensive abdominal ultrasound, renal ultrasound) | yes/no |
41 | Echocardiography performed | yes/no |
42 | Electrocardiogram recording performed | yes/no |
43 | Holter ECG monitoring was performed in patients with arrhythmia or pathological electrocardiographic findings | yes/no |
44 | Ambulatory blood pressure monitoring was performed in patients with arterial hypertension | yes/no |
45 | Joint ultrasound has been performed in patients with active arthritis | yes/no |
46 | Esophagogastroduodenoscopy with or without anesthesia (including early postoperative management) was performed in patients with dyspeptic symptoms, patients receiving NSAIDs for more than 1 month and/or GCs, and/or biologic agents (targeted synthetic and biologic DMARDs), as well as in those with a disease duration of more than 5 years and/or presence of proteinuria > 500 mg/day | yes/no |
47 | Microbiological (cultural) examination of gastric mucosa biopsy specimens for Helicobacter pylori has been performed in patients with inflammatory, erosive, and/or ulcerative changes detected by esophagogastroduodenoscopy | yes/no |
48 | Endoscopic biopsy of the esophagus, endoscopic biopsy of the stomach, endoscopic biopsy of the duodenum, endoscopic biopsy of the jejunum with or without anesthetic management (including early postoperative management), combined with pathomorphological examination of the esophageal biopsy (surgical) material, pathomorphological examination of the gastric biopsy (surgical) material, pathomorphological examination of the duodenal biopsy (surgical) material, and pathomorphological examination of the jejunal material were performed in patients with inflammatory, erosive, and/or ulcerative changes of the mucous membrane according to esophagogastroduodenoscopy | yes/no |
49 | Colonoscopy with anesthetic support (including early postoperative management) has been performed for patients with abdominal syndrome | yes/no |
50 | Colonic biopsy using endoscopy and pathomorphological examination of the colonic biopsy (surgical) material performed in patients with inflammatory and/or erosive and/or ulcerative changes in the colon according to colonoscopy data | yes/no |
51 | Kidney biopsy with anesthetic management (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 with proteinuria > 500 mg/day in the absence of contraindications | yes/no |
52 | X-ray of the temporomandibular joint and/or X-ray of the intervertebral joints, and/or X-ray of the elbow joint, and/or X-ray of the wrist joint, and/or X-ray of the knee joint, and/or X-ray of the shoulder joint, and/or X-ray of the hip joint, and/or X-ray of the ankle joint, and/or X-ray of the acromioclavicular joint, and/or X-ray of the sternoclavicular joint, and/or X-ray of the hand, and/or X-ray of the foot in two projections, or joint computed tomography with or without anesthetic management (including early postoperative management), was performed in patients with active arthritis prior to prescribing/adjusting antirheumatic therapy | yes/no |
53 | Magnetic resonance imaging of joints (single joint) with contrast enhancement, with or without anesthesia (including early postoperative management), in patients with active arthritis | yes/no |
54 | Brain magnetic resonance imaging with contrast enhancement using anesthetic care (including early postoperative management) or without it performed in patients with neurological symptoms | yes/no |
55 | Lumbar puncture with anesthetic management (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 symptoms of CNS involvement | yes/no |
56 | Performed computed tomography of the chest organs with or without anesthetic care (including early postoperative management) | yes/no |
57 | Bronchoscopy with anesthetic management (including early postoperative management) was performed in patients with lung involvement | yes/no |
58 | X-ray densitometry performed in patients receiving or previously receiving glucocorticoids | yes/no |
59 | An initial consultation (examination) by an orthopedic traumatologist was performed in patients with functional joint impairment | yes/no |
60 | Initial appointment (examination, consultation) by anotorhinolaryngologist was completed. | yes/no |
61 | Initial appointment (examination, consultation) by a pediatric otorhinolaryngologist-audiologist | yes/no |
62 | Initial appointment (examination, consultation) by a pediatric dentist | yes/no |
63 | Initial ophthalmologist consultation (examination) with mandatory ocular biomicroscopy was performed | yes/no |
64 | An initial consultation (examination) by a pediatric cardiologist was performed in patients with cardiac dysfunction and/or arterial hypertension | yes/no |
65 | 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 | yes/no |
66 | Initial examination (consultation) by a pediatric endocrinologist was performed for patients with endocrinological pathology | yes/no |
67 | Initial consultation (examination) by a neurologist was performed in patients with neurological symptoms | yes/no |
68 | 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 | yes/no |
69 | Initial examination (consultation) by a dietitian was performed for all patients with nutritional disorders | yes/no |
70 | Follow-up examination (consultation) by a dietitian was performed for all patients with nutritional disorders | yes/no |
71 | Initial examination (consultation) by an anesthesiologist-resuscitologist was performed for patients scheduled for procedures under general anesthesia | yes/no |
72 | Initial examination (consultation) by an anesthesiologist-resuscitologist was performed for patients in severe/critical condition | yes/no |
73 | 24-hour monitoring by an anesthesiologist-intensivist was performed for patients in critical condition (multiple organ failure, HFS) | yes/no |
74 | 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) | yes/no |
75 | Follow-up appointment (examination, consultation) by an otorhinolaryngologist | yes/no |
76 | Follow-up appointment (examination, consultation) by a pediatric dentist performed in all patients after sanitation of oral foci of chronic infection | yes/no |
77 | Follow-up appointment (examination, consultation) by an ophthalmologist with mandatory ocular biomicroscopy | yes/no |
78 | A follow-up consultation (examination) by a pediatric cardiologist was performed in patients with cardiac dysfunction and/or arterial hypertension | yes/no |
79 | Follow-up examination (consultation) by a pediatric endocrinologist was performed for patients with endocrinological pathology | yes/no |
80 | Follow-up examination (consultation) by a dietitian was performed for all patients with nutritional disorders | yes/no |
81 | Follow-up appointment (examination, consultation) by a neurologist performed in patients with neurological symptoms and psychotic reactions | yes/no |
82 | Follow-up appointment (examination, consultation) by a nephrologist performed in patients with nephrotic syndrome, changes in general clinical blood biochemistry and urinalysis typical for the development of amyloidosis/renal failure | yes/no |
Table 4. Quality criteria for evaluating the treatment of cryopyrin-associated periodic syndromes
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1 | Pathogenetic therapy was prescribed in a rheumatology inpatient department for all patients following diagnostics, including differential diagnostics, and establishment/confirmation of the CAPS diagnosis | yes/no |
2 | Only NSAIDs were prescribed to patients with an unconfirmed CAPS diagnosis during the diagnostic workup phase | yes/no |
3 | NSAIDs were prescribed for the relief of fever and pain in patients with a confirmed CAPS diagnosis | yes/no |
4 | Oral and/or intravenous GCs and/or biological DMARDs (bDMARDs) were not prescribed until the complete laboratory and instrumental workup was finished, oncological and hemato-oncological diseases were ruled out, and a CAPS diagnosis was established | yes/no |
5 | Pulse therapy with #methylprednisolone** at a dose of 10–30 mg/kg/administration intravenously for 3, and if necessary 5 consecutive days, was performed in patients with an established CAPS diagnosis at the diagnostic stage who presented with severe pain and/or life-threatening systemic manifestations (persistent febrile or hectic fever and/or pericarditis, and/or pleuritis) | yes/no |
6 | #Prednisolone** or #methylprednisolone** was prescribed orally at a dose of 1 mg/kg/day in patients with an established CAPS diagnosis at the diagnostic stage who had severe pain and/or life-threatening systemic manifestations (persistent febrile or hectic fever and/or pericarditis, and/or pleuritis), or in patients with refractory CAPS | yes/no |
7 | Canakinumab**, an interleukin-1β (IL-1β) inhibitor, or anakinra**, an interleukin-1α and IL-1β inhibitor, was prescribed as the primary pathogenetic therapy for all patients with a confirmed CAPS diagnosis who exhibited signs of systemic inflammatory response (fever, rash, etc.), organ impairment (hearing loss, eye pathology, CNS or joint changes), ESR > 30 mm/h (by Panchenkov), CRP > 20 mg/L, or > 4 times the upper limit of normal at the time of examination or within the preceding month | yes/no |
8 | Canakinumab** was prescribed to patients older than 2 years in accordance with the drug's prescribing information | yes/no |
9 | Maintenance therapy with canakinumab** was administered to patients older than 2 years in accordance with the drug's prescribing information | yes/no |
10 | A second injection of canakinumab was administered to patients older than 2 years if the clinical effect was not achieved 7 days after the first injection of canakinumab**, in accordance with the drug's prescribing information | yes/no |
11 | Maintenance therapy with canakinumab was administered to patients older than 2 years upon achieving a clinical effect 7 days after the second injection of canakinumab**, in accordance with the drug's prescribing information | yes/no |
12 | A third injection of canakinumab was administered to patients older than 4 years if the clinical effect was not achieved 7 days after the second injection of canakinumab**, in accordance with the drug's prescribing information | yes/no |
13 | Maintenance therapy with canakinumab was administered subcutaneously to patients older than 4 years upon achieving a complete clinical response 7 days after the third injection of canakinumab**, in accordance with the drug's prescribing information | yes/no |
14 | Anakinra** was prescribed to patients older than 8 months with a body weight ≥ 10 kg at a dose of 1–2 mg/kg/day subcutaneously | yes/no |
15 | Maintenance therapy with anakinra at 1–2 mg/kg/day subcutaneously was administered to patients older than 8 months with a body weight ≥ 10 kg upon achieving a clinical effect | yes/no |
16 | The anakinra dose was increased to 3–4 mg/kg/day, if necessary, with subsequent titration up to a maximum dose of 8 mg/kg/day subcutaneously if the clinical effect was not achieved or in severe cases of CAPS (MWS and CINCA/NOMID) | yes/no |
17 | The Autoinflammatory Disease Activity Index (AIDAI) and the MWS Disease Activity Score (MWS-DAS) were evaluated | yes/no |
18 | The Autoinflammatory Disease Damage Index (ADDI) was evaluated | yes/no |
Table 5. Quality criteria for evaluating the treatment of hemophagocytic syndrome in patients with cryopyrin-associated periodic syndromes
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1 | Therapy was prescribed and administered in a hospital setting providing medical care to children with rheumatic diseases for all patients after completing diagnostics, including differential diagnostics, and establishing/confirming a diagnosis of CAPS with hemophagocytic syndrome | yes/no |
2 | Prescription of targeted etiotropic therapy with systemic antibacterial and/or systemic antifungal and/or systemic antiviral drugs performed in patients with a known infectious etiological factor | yes/no |
3 | Corticosteroids administered in combination with #cyclosporine** and #normal human immunoglobulin** | yes/no |
4 | Pulse therapy administered with #methylprednisolone** at a dose of 20–30 mg/kg/administration intravenously, or #dexamethasone** prescribed at a dose of 10–20 mg/m²/day intravenously | yes/no |
5 | A gradual tapering of intravenous GCs was performed after the resolution of clinical and laboratory signs of HPS according to the following regimens: #dexamethasone** starting at a dose of 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; #methylprednisolone** starting at a dose of 20-30 mg/kg/administration for 3-5 days with a 25% dose reduction every 2-3 days | yes/no |
6 | #Cyclosporine** prescribed at a dose of 3–5 mg/kg/day intravenously or orally | yes/no |
7 | #Normal human immunoglobulin** prescribed at a dose of 1–2 g/kg/course over 2 days | yes/no |
8 | Assessment of the efficacy of the HLH treatment regimen performed in accordance with the criteria for achieving a therapeutic response (cessation of fever, reduction in spleen size, increase in blood platelet count ≥ 100 × 109/L, normalization of blood fibrinogen levels, and a 25% decrease in serum ferritin concentration) every 48 hours | yes/no |
9 | #Anakinra** prescribed at 5–10 mg/kg/day intravenously in 2 divided doses for 3–10 days, or longer if necessary upon increasing HLH activity during the first 48 hours of corticosteroid therapy combined with #cyclosporine** and #normal human immunoglobulin** | yes/no |
10 | Additional administration of #ruxolitinib** orally in children weighing up to 10 kg at 2.5 mg twice daily; children weighing 10 to 25 kg at 5 mg twice daily; children weighing > 25 kg at 10 mg twice daily, or #tofacitinib** orally at a dose of 10 mg twice daily in case of failure of the combination of #anakinra** with corticosteroids, #cyclosporine** and #normal human immunoglobulin** | yes/no |
11 | #Prednisolone** at a dose of 1–2 mg/kg orally or #methylprednisolone** at a dose equivalent to prednisolone was prescribed when combination therapy for HFS failed or when HFS reactivated during the tapering/withdrawal of intravenous GCs | yes/no |
12 | #Acyclovir** prescribed to children aged < 1 year at a dose of 10 mg/kg/administration intravenously every 8 hours; to children aged ≥ 1 year at a dose of 500 mg/m2 intravenously every 8 hours upon the development of Herpes zoster | yes/no |
13 | #Acyclovir** prescribed at a dose of 5–10 mg/kg/administration intravenously every 8 hours for 7–10 days upon the development of herpetic infection caused by Herpes simplex virus | yes/no |
14 | #Ganciclovir** prescribed at a dose of 6 mg/kg/administration intravenously every 12 hours for 14–21 days upon confirmation of active cytomegalovirus infection | yes/no |
15 | #Ganciclovir** prescribed at a dose of 10 mg/kg/administration intravenously every 12 hours for 14–21 days upon confirmation of active Epstein-Barr virus infection | yes/no |
16 | #Rituximab** prescribed as a first-line biologic DMARD in combination with #cyclosporine**, #normal human immunoglobulin**, and #cotrimoxazole** in active Epstein-Barr virus infection | yes/no |
17 | #Rituximab** prescribed in combination with #co-trimoxazole** 5 mg/kg based on trimethoprim orally 3 times a week or daily | yes/no |
18 | Antithrombotic agents administered, including heparin group drugs or direct factor Xa inhibitors; antiplatelet agents (excluding heparin); antifibrinolytic agents in the presence of hypercoagulation or the development of coagulopathy | yes/no |
19 | Blood transfusion performed upon the development of consumption coagulopathy or bleeding | yes/no |
20 | Colony-stimulating factor #filgrastim** prescribed at a dose of 5–10 mcg/kg/day subcutaneously for 3–5 days (or longer if necessary) when the absolute neutrophil count drops to ≤ 1.0 × 109/L | yes/no |
21 | Empirical antibacterial therapy with systemic agents active against Gram-positive, Gram-negative, and anaerobic flora, and/or systemic antifungal agents, and/or systemic antiviral agents administered upon the development of sepsis/infectious complications prior to the confirmation of the etiological factor | yes/no |
22 | Targeted therapy prescribed according to microbial susceptibility using systemic antibacterial drugs (combinations of penicillins, including combinations with beta-lactamase inhibitors and/or 4th-generation cephalosporins, and/or carbapenems, and/or other antibacterial drugs, and/or glycopeptide antibiotics, and/or other aminoglycosides) with or without systemic antifungal and/or systemic antiviral drugs upon confirmation of the etiological factor of sepsis/infectious complication | yes/no |
23 | Treatment of HLH performed until an inactive stage is reached (absence of fever, splenomegaly, cytopenia [Hb ≥ 90 g/L, platelets ≥ 100 × 109/L, neutrophils ≥ 0.5 × 109/L], blood triglyceride level < 3 mmol/L or < 265 mg/dL, ferritin ≤ 500 µg/L, and normalization of cerebrospinal fluid parameters in CNS involvement) | yes/no |
Table 6. Quality criteria for follow-up outpatient/day-hospital monitoring of patients with cryopyrin-associated periodic syndromes in the inpatient/day-hospital facility that initiated pathogenetic therapy
№ | Quality criteria | Performance assessment (yes/no) | |
|---|---|---|---|
1 | Treatment efficacy and the safety of antirheumatic therapy were evaluated in all patients with a confirmed diagnosis of CAPS in a rheumatology inpatient setting 3 months after starting therapy, 6 months after starting therapy, and every 6 months thereafter | yes/no | |
2 | A detailed general (clinical) blood test was performed (study of erythrocyte sedimentation rate, study of red blood cell level in blood, study of white blood cell level in blood, study of platelet level in blood, differential leukocyte count (leukocyte formula), study of total hemoglobin level in blood) | yes/no | |
3 | Discontinuation of canakinumab**/anakinra** injections (within 7 days) performed when platelet count drops to ≤ 150 > 100 × 109/L, and neutrophil count to < 1.5 ≥ 1.0 × 109/L on a complete blood count | yes/no | |
4 | Suspension of canakinumab**/anakinra** injections performed when absolute neutrophil count drops to < 1.0 × 109/L and/or platelet count to < 100 × 109/L on a complete blood count | yes/no | |
5 | Administration of the colony-stimulating factor #filgrastim** at a dose of 5–10 mcg/kg/day subcutaneously performed for leukopenia with an absolute neutrophil count ≤ 1.0 × 109/L for 3–5 days (longer if necessary) | yes/no | |
6 | Administration of the colony-stimulating factor #filgrastim** at a dose of 5–10 mcg/kg/day subcutaneously in combination with systemic antibacterial drugs (J01) intravenously performed for febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count ≤ 1.0 × 109/L | yes/no | |
7 | Continuation of treatment with systemic antibacterial drugs (J01) performed for all patients with febrile neutropenia (neutropenia accompanied by fever) | yes/no | |
8 | Resumption of treatment with canakinumab**/anakinra** at the same dose performed for all patients after recovery of the neutrophil count to ≥ 1.5 × 109/L according to complete blood count data | yes/no | |
9 | Adjustment of canakinumab**/anakinra** therapy performed for all patients in case of recurrent episodes of blood cell count decrease on complete blood count | yes/no | |
10 | Administration of fluconazole** intravenously at 3–12 mg/kg/day depending on the severity and duration of induced neutropenia performed for patients with neutropenia | yes/no | |
11 | General general-purpose clinical biochemistry blood analysis performed (testing for total blood protein, blood albumin, total blood bilirubin, free and conjugated bilirubin, blood creatinine, blood urea, blood glucose, blood ferritin, blood sodium, blood potassium, total blood calcium, blood lactate dehydrogenase activity, aspartate aminotransferase activity, alanine aminotransferase activity, gamma-glutamyl transferase activity, alkaline phosphatase activity, and serum iron levels) | yes/no | |
12 | Temporary discontinuation of canakinumab**/anakinra** therapy performed for all patients when serum ALT or AST levels increase to ≥ 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) rise above the upper limit of normal | yes/no | |
13 | Resumption of canakinumab**/anakinra** therapy at the same dose performed for all patients after normalization of routine biochemical blood test parameter(s) | yes/no | |
14 | Adjustment of canakinumab**/anakinra** therapy performed for all patients in case of recurrent episodes of elevated biochemical parameter(s) | yes/no | |
15 | A study of the C-reactive protein level in blood serum was performed | yes/no | |
16 | A study of immunoglobulin levels in blood was performed | yes/no | |
17 | Administration of #normal human immunoglobulin** at 400 mg/kg performed, and if a sufficient immunoglobulin level is not achieved, at 500 mg/kg at least once every 2–4 weeks until blood immunoglobulin levels normalize, in case of decreased blood immunoglobulin levels | yes/no | |
18 | Antistreptolysin-O blood serum test | yes/no | |
19 | Procalcitonin serum level testing performed for patients with fever | yes/no | |
20 | A comprehensive diagnostic workup to rule out sepsis performed for patients with febrile or hectic fever, leukocytosis/leukopenia, thrombocytopenia, elevated serum C-reactive protein, and serum procalcitonin not related to CAPS activity: (comprehensive complete blood count, routine biochemical blood test, serum C-reactive protein testing, blood culture for sterility, microbiological culture of tonsil and posterior pharyngeal swabs for aerobic and facultative anaerobic microorganisms, urine microbiological culture for bacterial pathogens using automated inoculation, anal swab microbiological culture with determination of microorganism susceptibility to antimicrobial chemotherapeutic drugs, thromboelastography, coagulogram [screening hemostasis test]; chest computed tomography, comprehensive abdominal ultrasound, renal ultrasound, echocardiography, abdominal magnetic resonance imaging, pelvic magnetic resonance imaging, retroperitoneal magnetic resonance imaging) | yes/no | |
21 | Initial empirical antibacterial therapy followed, depending on the clinical situation, by intravenous systemic antibacterial drugs targeting Gram-positive, Gram-negative, and anaerobic flora (penicillin combinations including beta-lactamase inhibitor combinations and/or 4th-generation cephalosporins, and/or carbapenems, and/or other antibacterial drugs, and/or glycopeptide antibiotics, and/or other aminoglycosides, and/or macrolides) with or without systemic antifungal drugs according to microbial susceptibility, combined with #normal human immunoglobulin** at a dose of 400 mg/kg/course (5 days) performed upon the development of sepsis | yes/no | |
22 | Discontinuation of canakinumab**/anakinra** injection for the entire duration of antibiotic treatment, continuation of previously prescribed oral glucocorticoids, and pulse therapy with #methylprednisolone** performed upon activity increase in CAPS patients with bacterial complications/sepsis | yes/no | |
23 | Resumption of canakinumab**/anakinra** therapy performed no earlier than one week after complete resolution of clinical and laboratory signs of the infectious complication/sepsis and completion of antibacterial therapy | yes/no | |
24 | Coagulography (exploratory hemostasis assessment) was performed with determination of prothrombin index, blood antithrombin III activity; blood plasminogen level test and blood fibrinogen level test, blood D-dimer concentration determination, blood soluble fibrin monomer complex level test, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time in blood, and von Willebrand factor activity and properties test in patients with febrile fever/sepsis/MAS | yes/no | |
25 | Thromboelastography performed for patients with febrile fever/sepsis/macrophage activation syndrome/signs of thrombosis and hypocoagulation | yes/no | |
26 | Administration/adjustment of antithrombotic therapy (B01A), including heparin group drugs (B01B), antiplatelet agents excluding heparin (B01AC), antifibrinolytic agents (B02A), and direct factor Xa inhibitors (B01AF), performed upon the development of coagulopathy or disseminated intravascular coagulation according to coagulogram (screening hemostasis test) and thromboelastography | yes/no | |
27 | Lymphocyte subset testing was performed in patients frequently afflicted with viral or purulent bacterial infections, including opportunistic infections | yes/no | |
28 | Quantitative PCR detection of Epstein-Barr virus (Epstein-Barr virus) DNA in peripheral and cord blood, qualitative PCR detection of Epstein-Barr virus (Epstein-Barr virus) DNA in oropharyngeal swabs, and qualitative PCR detection of Epstein-Barr virus (Epstein-Barr virus) DNA in urine performed for patients receiving canakinumab**/anakinra** with or without glucocorticoids, presenting with clinical manifestations of herpetic infection, or having interstitial pneumonia | yes/no | |
29 | Quantitative PCR detection of cytomegalovirus (Cytomegalovirus) DNA in peripheral and cord blood, qualitative PCR detection of cytomegalovirus (Cytomegalovirus) DNA in oropharyngeal swabs, and qualitative PCR detection of cytomegalovirus (Cytomegalovirus) DNA in urine performed for patients receiving canakinumab**/anakinra** with or without glucocorticoids, presenting with clinical manifestations of herpetic infection, or having interstitial pneumonia | yes/no | |
30 | Quantitative PCR detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in blood, qualitative PCR detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in oropharyngeal swabs, and qualitative PCR detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in urine performed for patients receiving canakinumab**/anakinra** with or without glucocorticoids, presenting with clinical manifestations of herpetic infection, or having interstitial pneumonia | yes/no | |
31 | Detection of IgM and IgG antibodies to cytomegalovirus (Cytomegalovirus) in blood performed for patients receiving canakinumab**/anakinra** with or without glucocorticoids, presenting with clinical manifestations of herpetic infection, or having interstitial pneumonia | yes/no | |
32 | Detection of IgM and IgG antibodies to Epstein-Barr virus (Epstein-Barr virus) in blood performed for patients receiving canakinumab**/anakinra** with or without glucocorticoids, presenting with clinical manifestations of herpetic infection, or having interstitial pneumonia | yes/no | |
33 | Detection of antibodies to Epstein-Barr virus (Epstein-Barr virus) capsid antigen (VCA) in blood performed for patients receiving canakinumab**/anakinra** with or without glucocorticoids, presenting with clinical manifestations of herpetic infection, or having interstitial pneumonia | yes/no | |
34 | Detection of IgG antibodies to Epstein-Barr virus (Epstein-Barr virus) early antigens (EA) in blood performed for patients receiving canakinumab**/anakinra** with or without glucocorticoids, presenting with clinical manifestations of herpetic infection, or having interstitial pneumonia | yes/no | |
35 | Antibodies to Herpes simplex virus in the blood were measured in patients receiving canakinumab**/anakinra** with or without GCs, presenting with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia | yes/no | |
36 | #Acyclovir** was prescribed at a dose of 200 mg orally 5 times daily (max. 1000 mg/day) in children aged > 2 years, or at 5-10 mg/kg/dose intravenously every 8 hours upon development of local herpetic infection; #acyclovir** was prescribed at 10 mg/kg/dose intravenously every 8 hours in children aged < 1 year; and at 500 mg/m2 intravenously every 8 hours in children aged ≥ 1 year upon development of Herpes zoster | yes/no | |
37 | #Ganciclovir** was prescribed at a dose of 6 mg/kg/dose intravenously every 12 hours for 14-21 days upon development of cytomegalovirus infection, or #ganciclovir** at 10 mg/kg/dose intravenously every 12 hours for 14-21 days upon development of Epstein-Barr virus infection | yes/no | |
38 | Therapy with canakinumab**/anakinra** was temporarily discontinued in all patients upon development of infection, for the duration of herpes virus-specific antiviral therapy | yes/no | |
39 | Therapy with canakinumab**/anakinra** was resumed in all patients no earlier than 1 week after complete resolution of clinical and laboratory signs of infection and completion of antiviral therapy | yes/no | |
40 | Screening for tuberculosis (tuberculin skin test, recombinant tuberculosis allergen test in standard dilution**, blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens, chest computed tomography) was performed in all patients receiving canakinumab**/anakinra** with or without GCs at least twice a year | yes/no | |
41 | Therapy with canakinumab**/anakinra** was discontinued in all patients with a positive tuberculin skin test (papule > 5 mm) and/or elevated interferon-gamma levels and/or lung and/or intrathoracic lymph node lesions | yes/no | |
42 | Initial appointment (examination, consultation) by a phthisiatrician has been performed for all patients with a detected positive tuberculin skin test (papule > 5 mm) and/or elevated interferon-gamma levels and/or lung and/or intrathoracic lymph node lesions | yes/no | |
43 | Oral GCs were prescribed to all patients upon development of a CAPS flare for the duration of specific anti-tuberculosis therapy | yes/no | |
44 | Treatment with canakinumab**/anakinra** and previously prescribed oral GCs were continued under the supervision of a rheumatologist, complete blood count, and standard biochemical blood tests in patients with tuberculosis infection without a focus, for the duration of specific anti-tuberculosis chemotherapy | yes/no | |
45 | Therapy with canakinumab**/anakinra** was resumed in all patients after completion of specific anti-tuberculosis therapy and consultation with a phthisiatrician | yes/no | |
46 | Blood antibody testing for Salmonella enterica, blood antibody testing for Salmonella typhi, blood class M and G antibody (IgM, IgG) testing for Yersinia pseudotuberculosis, and blood antibody testing for Yersinia enterocolitica serovars were performed in patients with abdominal syndrome | yes/no | |
47 | Etiotropic therapy was administered upon detection of class A and M antibodies in diagnostic titers, as well as high titers of class G antibodies to Yersinia pseudotuberculosis, Yersinia enterocolitica serovars, Salmonella enterica, and Salmonella typhi in the blood | yes/no | |
48 | Determination of class A, M, G antibodies (IgA, IgM, IgG) to Chlamydia psittaci in the blood; determination of antibodies to Chlamydia trachomatis in the blood; determination of antibodies to Chlamydophila pneumoniae in the blood; and determination of class M, G antibodies (IgM, IgG) to Mycoplasma pneumoniae in the blood were performed in patients with interstitial pneumonia | yes/no | |
49 | Etiotropic therapy was administered upon detection of class A and M antibodies in diagnostic titers, as well as high titers of class G antibodies to Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, and Chlamydophila pneumoniae in the blood | yes/no | |
50 | Microbiological (culture) examination of mucus from the tonsils and posterior pharyngeal wall has been performed | yes/no | |
51 | A general (clinical) urinalysis was performed | yes/no | |
52 | Urinary albumin and 24-hour urine protein were measured in patients with clinical/laboratory signs of nephrotic syndrome and/or renal failure, and/or disease duration of more than 5 years | yes/no | |
53 | A comprehensive renal function assessment and diagnostic workup to evaluate the severity of renal failure were performed in patients with clinical/laboratory signs of nephrotic syndrome/renal failure/disease duration > 5 years/presence of proteinuria > 500 mg/day | yes/no | |
54 | Renal biopsy with anesthetic support (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen was performed in patients with clinical/laboratory/ultrasound signs of renal involvement and/or renal failure, and/or disease duration > 5 years, and/or presence of proteinuria > 500 mg/day in the absence of contraindications | yes/no | |
55 | Electrocardiogram recording performed | yes/no | |
56 | Holter ECG monitoring was performed in patients with arrhythmias and pathological electrocardiographic changes | yes/no | |
57 | Ambulatory blood pressure monitoring was performed in patients with arterial hypertension | yes/no | |
58 | A comprehensive ultrasound examination of internal organs (including comprehensive abdominal ultrasound and renal ultrasound) was performed | yes/no | |
59 | Echocardiography performed | yes/no | |
60 | Esophagogastroduodenoscopy with or without anesthetic support (including early postoperative management) has been performed for patients with dyspeptic symptoms, patients receiving NSAIDs for more than 1 month and/or GCs and/or bDMARDs, as well as in case of disease duration of more than 5 years | yes/no | |
61 | Microbiological (cultural) examination of gastric mucosa biopsy specimens for Helicobacter pylori has been performed in patients with inflammatory, erosive, and/or ulcerative changes detected by esophagogastroduodenoscopy | yes/no | |
62 | Drugs for the treatment of gastric and duodenal ulcers 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 esophagogastroduodenoscopy data | yes/no | |
63 | Eradication therapy was administered including proton pump inhibitors, systemic antibacterial drugs, and bismuth subcitrate potassium** at a dose of 8 mg/kg/day in 1-2 doses (for patients aged 4 to 8 years) for 4-8 weeks, at 120 mg twice daily (for patients aged 8 to 12 years), or at 120 mg 4 times daily or 240 mg twice daily (for patients older than 12 years) in case of inflammatory gastropathy, erosive and/or ulcerative processes in the stomach and/or duodenum associated with Helicobacter pylori | yes/no | |
64 | Therapy with canakinumab**/anakinra** was temporarily discontinued in all patients for the duration of eradication therapy | yes/no | |
65 | Colonoscopy with anesthetic support (including early postoperative management) has been performed for patients with abdominal syndrome | yes/no | |
66 | Colon biopsy via endoscopy with pathomorphological examination of the colonic biopsy (surgical) material was performed in patients with identified inflammatory and/or erosive and/or ulcerative changes in the colon | yes/no | |
67 | Performed magnetic resonance imaging of joints (one joint) with or without anesthetic management (including early postoperative care) in patients with active arthritis | yes/no | |
68 | Chest computed tomography was performed in all patients with or without anesthetic support (including early postoperative management) | yes/no | |
69 | Bronchoscopy with anesthetic care (including early postoperative management) performed in patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected according to chest computed tomography data | yes/no | |
70 | Performed microbiological (culture) examination of bronchoalveolar lavage fluid for pneumocystis cysts (Pneumocystis carinii) in patients with signs of pneumonia according to chest computed tomography | yes/no | |
71 | Performed quantitative PCR detection of Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, or bronchoalveolar lavage fluid in patients with signs of pneumonia according to chest computed tomography | yes/no | |
72 | Performed determination of class M and G antibodies to Pneumocystis jirovecii in the blood of patients with signs of pneumonia according to chest computed tomography | yes/no | |
73 | Microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeasts and molds) was performed in patients with signs of pneumonia according to chest computed tomography | yes/no | |
74 | Microbiological (cultural) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms in patients with signs of pneumonia according to chest computed tomography | yes/no | |
75 | Antibodies to fungi of the genus Aspergillus spp. in the blood were measured in patients with interstitial and/or focal and/or infiltrative lung changes according to chest computed tomography | yes/no | |
76 | Mannan and galactomannan were measured in lavage fluid and blood in all patients with signs of pneumonia according to chest computed tomography | yes/no | |
77 | Detection of Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR was performed in all patients with interstitial and/or focal and/or infiltrative lung changes according to chest computed tomography | yes/no | |
78 | Detection of Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR was performed in all patients with interstitial and/or focal and/or infiltrative lung changes according to chest computed tomography | yes/no | |
79 | PCR detection of Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG) DNA with species differentiation in sputum and bronchoalveolar lavage fluid was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography | yes/no | |
80 | Performed determination of class M and G antibodies (IgM, IgG) to cytomegalovirus (Cytomegalovirus) in the blood of all patients when interstitial, focal, and/or infiltrative changes in the lungs are detected by chest computed tomography | yes/no | |
81 | Performed determination of class M and G antibodies (IgM, IgG) to Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients when interstitial, focal, and/or infiltrative changes in the lungs are detected by chest computed tomography | yes/no | |
82 | Performed determination of antibodies to the capsid antigen (VCA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients when interstitial, focal, and/or infiltrative changes in the lungs are detected by chest computed tomography | yes/no | |
83 | Performed determination of class G antibodies (IgG) to early proteins (EA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients when interstitial, focal, and/or infiltrative changes in the lungs are detected by chest computed tomography | yes/no | |
84 | Blood antibody testing for herpes simplex virus (Herpes simplex) was performed in all patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography | yes/no | |
85 | Empirical antibacterial therapy was prescribed: #co-trimoxazole** in combination with systemic antibacterial drugs targeting Gram-positive, Gram-negative, and anaerobic flora (penicillin combinations, including beta-lactamase inhibitor combinations, and/or 4th-generation cephalosporins, and/or carbapenems, and/or other antibacterial drugs) combined with systemic antifungals until the etiological factor of interstitial pneumonia is identified, depending on the clinical situation | yes/no | |
86 | Intravenous GCs and #co-trimoxazole** at 3.75-5.0 mg/kg body weight/dose (15-20 mg/kg/day) (calculated as trimethoprim) intravenously every 8 hours were prescribed upon development of moderate Pneumocystis pneumonia, or at 3.75-5.0 mg/kg body weight/dose (15-20 mg/kg/day) (calculated as trimethoprim) intravenously every 6-8 hours upon development of severe Pneumocystis pneumonia | yes/no | |
87 | Prescribed #voriconazole** at a dose of 6 mg/kg intravenously every 12 hours for the first 24 hours and 4 mg/kg starting from day 2, in accordance with international guidelines for the management of immunocompromised children upon detection of galactomannan in lavage fluid and/or blood, and/or antibodies to Aspergillus spp. in blood | yes/no | |
88 | Prescribed fluconazole** intravenously at a dose of 6–12 mg/kg/day in accordance with international guidelines for the management of immunocompromised children upon detection of mannan in lavage fluid and/or blood | yes/no | |
89 | Prescribed systemic antibacterial agents active against Gram-positive, Gram-negative, and anaerobic flora (combinations of penicillins, including beta-lactamase inhibitor combinations; 4th-generation cephalosporins; carbapenems, and other antibacterials combined with systemic antifungals) upon the development of focal, lobar, or multisegmental pneumonia | yes/no | |
90 | Temporary discontinuation of canakinumab**/anakinra** therapy, with continuation of previously prescribed oral GCs in all patients with suspected/developing pneumonia | yes/no | |
91 | Resumption of therapy with canakinumab**/anakinra** was performed in all patients no earlier than 1 week after complete resolution of pneumonia according to laboratory tests and follow-up chest CT, with or without anesthesia (including early postoperative management) | yes/no | |
92 | Performed radiography of the temporomandibular joint and/or intervertebral joints, and/or elbow joint, and/or wrist joint, and/or knee joint, and/or shoulder joint, and/or hip joint, and/or ankle joint, and/or acromioclavicular joint, and/or sternoclavicular joint, and/or hand, and/or foot in two projections, or joint computed tomography, with or without anesthesia support (including early postoperative management), in all patients with active arthritis | yes/no | |
93 | Performed X-ray densitometry in all patients receiving or previously receiving corticosteroids | yes/no | |
94 | Administered calcium and vitamin D supplements and their analogues to patients with osteopenia/osteoporosis | yes/no | |
95 | Prescribed: #pamidronic acid in patients < 1 year at a dose of 0.5 mg/kg IV every 2 months; in patients aged 1–2 years at a dose of 0.25–0.5 mg/kg/day IV for 3 days every 3 months; in patients aged 2–3 years at a dose of 0.375–0.75 mg/kg/day IV for 3 days every 3 months; in 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 (in patients with body weight < 40 kg at a dose of 5 mg/day or 35 mg/week; in 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 150 mg orally once a month in patients with osteoporosis | yes/no | |
96 | Lumbar puncture with anesthetic management (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 symptoms of CNS involvement | yes/no | |
97 | Performed brain MRI with or without anesthesia support (including early postoperative management) in patients with signs of CNS involvement at least once a year | yes/no | |
98 | Initial appointment (examination, consultation) by anotorhinolaryngologist was completed. | yes/no | |
99 | Initial appointment (examination, consultation) by a pediatric otorhinolaryngologist-audiologist | yes/no | |
100 | Initial ophthalmologist consultation (examination) with mandatory ocular biomicroscopy was performed | yes/no | |
101 | Performed an initial appointment (examination, consultation) with a pediatric cardiologist in patients with cardiac involvement and/or arterial hypertension | yes/no | |
102 | Performed initial examination (consultation) by a phthisiatrician in all patients with positive results of a focal tuberculin skin test and/or intradermal test with a tuberculosis allergen, and/or elevated blood interferon-gamma levels in response to Mycobacterium tuberculosis complex antigens, and/or focal or infiltrative changes in the lungs | yes/no | |
103 | Initial pediatric endocrinologist consultation (examination) was performed in patients with endocrine pathology | yes/no | |
104 | Initial dietitian consultation (examination) was performed in patients with underweight, amyotrophy, osteopenia/osteoporosis, constitutional obesity and Cushing's syndrome, or steroid diabetes | yes/no | |
105 | Performed an initial appointment (examination, consultation) with a pediatric orthopedic trauma surgeon in patients with joint functional insufficiency, longitudinal bone growth disorders, subluxations, or back pain | yes/no | |
106 | Initial nephrologist consultation (examination) was performed in patients with renal involvement | yes/no | |
107 | Follow-up nephrologist consultation (examination) was performed in patients with renal involvement | yes/no | |
108 | Performed initial examination (consultation) by a neurologist in patients with neurological symptoms, psychotic reactions, or psychomotor developmental delay | yes/no | |
109 | Performed follow-up examination (consultation) by a neurologist in patients with neurological symptoms, psychotic reactions, or psychomotor developmental delay | yes/no | |
110 | Evaluated the efficacy of pathogenetic therapy using the Autoinflammatory Disease Activity Index (AIDAI) and MWS-DAS 3 months after initiation/adjustment of therapy and every 6 months thereafter; the Damage Index (ADDI) is evaluated once a year | yes/no | |
111 | Adjusted pathogenetic therapy in all patients who developed inefficacy and/or intolerance to canakinumab**/anakinra** within the rheumatology department that initiated the pathogenetic therapy | yes/no | |
112 | Provided medical rehabilitation for all patients with functional impairment after disease activity reduction | yes/no | |
113 | 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 | yes/no | |
114 | Performed a follow-up consultation (testing, counseling) by a medical psychologist for all patients older than 1 year and all parents after completing the psychological rehabilitation program | yes/no | |
115 | Performed an initial consultation (examination) by a physical therapy physician for patients with functional impairment after a decrease in disease activity | yes/no | |
116 | Performed an initial consultation (examination) by an exercise therapy (kinesiotherapy) physician for patients with functional impairment after a decrease in disease activity | yes/no | |
117 | Performed a follow-up consultation (examination) by a physical therapy physician for all patients with functional impairment upon completion of the physiotherapy procedures program within the medical rehabilitation program | yes/no | |
118 | Performed a follow-up consultation (examination) by an exercise therapy physician for all patients with functional impairment upon completion of the medical rehabilitation program | yes/no | |
119 | No vaccination with live or live-attenuated vaccines was performed in patients receiving bDMARDs | yes/no | |
120 | Performed pre-exposure prophylaxis for novel coronavirus infection in patients aged 12 years and older with a body weight of at least 40 kg, prior to prescribing or at any stage of therapy with bDMARDs combined with GCs or without, via passive immunization with antiviral monoclonal antibody drugs | yes/no | |
121 | Administered pneumococcal polysaccharide conjugate adsorbed vaccine** containing capsular polysaccharides of 13 pneumococcal serotypes to all patients with CAPS prior to prescribing or at any stage of biologic disease-modifying antirheumatic drug (bDMARD) therapy, combined with or without GCs (excluding #rituximab**) | yes/no | |
122 | Maintained high oncological vigilance due to the potential development of oncological/onco-hematological/lymphoproliferative diseases during canakinumab**/anakinra** therapy at any stage of treatment | yes/no | |
123 | Immediate discontinuation of the immunosuppressant and/or bDMARD and hospitalization of the patient upon suspicion of an oncological/onco-hematological/lymphoproliferative disease | yes/no | |
124 | Obtained a bone marrow cytological specimen via puncture with anesthesia support (including early postoperative management) and a bone marrow histological specimen with cytological examination of bone marrow smear (myelogram), alongside pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods in patients receiving an immunosuppressant and/or bDMARD with an atypical disease course | yes/no | |
125 | Performed lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) with anesthesia support (including early postoperative management), including cytological examination of tissue preparation and pathomorphological examination of biopsy (surgical) material of the lymph node in patients with marked enlargement of peripheral, intrathoracic, and/or intra-abdominal lymph nodes receiving an immunosuppressant and/or bDMARD with an atypical disease course | yes/no | |
126 | Performed contrast-enhanced brain MRI, intravenous contrast-enhanced abdominal MRI, intravenous contrast-enhanced retroperitoneal MRI, and intravenous contrast-enhanced pelvic MRI with or without anesthesia support (including early postoperative management) in patients receiving an immunosuppressant and/or bDMARD with an atypical disease course | yes/no | |
127 | Performed intravenous bolus contrast-enhanced chest computed tomography with or without anesthesia support (including early postoperative management) in patients receiving an immunosuppressant and/or bDMARD with an atypical disease course | yes/no | |
128 | Performed intravenous contrast-enhanced bone MRI (one region) and joint MRI (one joint) with or without anesthesia support (including early postoperative management) in patients receiving an immunosuppressant and/or bDMARD with an atypical disease course | yes/no | |
129 | Performed bone computed tomography and joint computed tomography with or without anesthesia support (including early postoperative management) in patients receiving an immunosuppressant and/or bDMARD who have bone destruction foci atypical for CAPS | yes/no | |
130 | Performed positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals (diagnostic radiopharmaceuticals), with contrast enhancement if necessary; whole-body positron emission tomography with tumor-tropic radiopharmaceuticals with or without anesthesia support (including early postoperative management) in patients receiving an immunosuppressant and/or bDMARD who present with severe arthralgia, myalgia, ossalgia, bone destruction, subcutaneous fat infiltrates, or lesions in parenchymal organs, the brain, or spinal cord | yes/no | |
131 | Performed multi-positional bone scintigraphy with or without anesthesia support (including early postoperative management) in patients receiving an immunosuppressant and/or bDMARD who have bone destruction foci atypical for CAPS | yes/no | |
132 | CT-guided pelvic bone trephine biopsy with anesthetic management (including early postoperative management), with pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods; cytological examination of bone marrow trephine biopsy imprints; immunocytochemical examination of bone marrow trephine biopsy imprints; immunophenotyping of bone marrow hematopoietic progenitor cells in patients receiving an immunosuppressant and/or biologic DMARD with an atypical disease course | yes/no | |
133 | Bone biopsy with anesthetic management (including early postoperative management), with pathomorphological examination of bone tissue biopsy (surgical) material in patients receiving an immunosuppressant and/or biologic DMARD, with bone destruction lesions uncharacteristic of CAPS | yes/no | |
134 | Initial appointment (examination, consultation) by a pediatric oncologist for patients with suspected/confirmed oncological/onco-hematological/lymphoproliferative disease or metastatic lesion based on examination results | yes/no | |
Table 7. Criteria for evaluating the quality of clinical follow-up (dispensary observation) of patients with cryopyrin-associated periodic syndromes in an outpatient setting
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1 | Clinical follow-up (dispensary observation) of patients with CAPS performed — initial appointment (examination, consultation) by a rheumatologist with evaluation of therapy efficacy and safety at least once a year after therapy initiation/adjustment and after achieving disease remission | yes/no |
2 | Clinical follow-up (dispensary observation) of patients with CAPS performed — follow-up appointment (examination, consultation) by a rheumatologist with evaluation 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, assessing the need for referral for unscheduled hospitalization to the inpatient rheumatology department that initiated therapy with canakinumab**/anakinra** at any stage of treatment upon development of exacerbation/complications, comorbid conditions, complications/side effects/persistent intolerance to therapy, and with referral for scheduled hospitalization to the inpatient rheumatology department that initiated therapy with canakinumab**/anakinra** at 3 and 6 months after prescription/adjustment of therapy and subsequently every 6 months, and conducting a telemedical consultation with a rheumatologist from the inpatient department that initiated therapy for all patients upon development of any signs of inefficacy and/or intolerance to therapy) | yes/no |
3 | Assessment of the efficacy of pathogenetic therapy was performed using the MWS-DAS index and the Autoinflammatory Disease Activity Index (AIDAI) every 3 months after the start of therapy and subsequently every 6 months; and the Autoimmune Damage Index (ADDI) once a year | yes/no |
4 | A pediatrician's appointment (examination, consultation) was performed | yes/no |
5 | Dispensary appointment (examination, consultation) by a pediatrician or district pediatrician performed for patients with cryopyrin-associated periodic syndromes in the absence of a rheumatologist at the place of residence, at least once a month after therapy initiation/adjustment and at least once every 3 months after achieving disease remission | yes/no |
6 | Immediate discontinuation of canakinumab**/anakinra** administration performed in the event of an allergic reaction | yes/no |
7 | Prescription of systemic antihistamines and/or GCs performed upon development of an allergic reaction to canakinumab**/anakinra** administration | yes/no |
8 | Appointment (examination, consultation, including telemedical) by a rheumatologist of the inpatient department that initiated therapy performed upon development of an allergic reaction to the intake and/or administration of canakinumab**/anakinra** | yes/no |
9 | Emergency hospitalization performed upon development of an allergic reaction to canakinumab**/anakinra** administration | yes/no |
10 | Complete (clinical) blood count performed (erythrocyte sedimentation rate determination, blood erythrocyte count, blood leukocyte count, blood platelet count, differential leukocyte count (leukocyte formula), blood total hemoglobin level determination) at least once every 2–4 weeks | yes/no |
11 | Discontinuation of the immunosuppressant and/or biologic DMARD, continuation of previously prescribed oral GCs performed when the platelet count is ≤ 150 > 100 × 109/L, and neutrophil count is < 1.5 ≥ 1.0 × 109/L according to the complete (clinical) blood count | yes/no |
12 | Resumption of treatment with canakinumab**/anakinra** at the same dose performed for all patients after complete recovery of complete (clinical) blood count parameters | yes/no |
13 | Discontinuation of canakinumab performed when the absolute neutrophil count is < 1.0 × 109/L and/or platelet count is < 100 × 109/L | yes/no |
14 | Administration of the colony-stimulating factor #filgrastim** at a dose of 5–10 mcg/kg/day subcutaneously for 3–5 days (longer if necessary) performed in case of decreased leukocyte count with an absolute neutrophil count ≤ 1.0 × 109/L for 3–5 days (longer if necessary) | yes/no |
15 | Prescription of the colony-stimulating factor #filgrastim** at a dose of 5–10 mcg/kg/day subcutaneously, urgent hospitalization to the local inpatient facility, prescription of systemic antibacterial drugs intravenously performed upon development of febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count < 1.0 × 109/L | yes/no |
16 | Prescription of fluconazole** 3–12 mg/kg/day, depending on the severity and duration of induced neutropenia, orally performed for patients with neutropenia | yes/no |
17 | Resumption of canakinumab**/anakinra** therapy at the previous dose performed after normalization of complete (clinical) blood count parameters and an increase in blood neutrophil count ≥ 1.5 × 109/L | yes/no |
18 | An appointment (examination, consultation, including remote) by a rheumatologist of the inpatient facility that initiated the prescription of therapy, was performed for all patients upon a repeated episode of decreased neutrophil count, development of febrile neutropenia, and/or decreased blood platelet count according to complete blood count data | yes/no |
19 | General general-clinical blood biochemistry test performed (determination of total blood protein level, blood albumin level, total blood bilirubin level, free and conjugated bilirubin levels, blood creatinine level, blood urea level, blood glucose level, blood potassium level, blood sodium level, total blood calcium level; blood lactate dehydrogenase activity, aspartate aminotransferase activity, alanine aminotransferase activity, gamma-glutamyltransferase activity, alkaline phosphatase activity, serum iron level) for all patients at least once every 2–4 weeks | yes/no |
20 | Temporary suspension of canakinumab**/anakinra** therapy, continuation of previously prescribed oral GCs performed for all patients when serum ALT and AST levels are ≥ 1.5 times above the upper limit of normal and/or other biochemical parameters are above the upper limit of normal | yes/no |
21 | Resumption of canakinumab**/anakinra** therapy performed for all patients after normalization of the biochemical parameter(s) | yes/no |
22 | Appointment (examination, consultation, including telemedical) by a rheumatologist of the inpatient department that initiated therapy performed in the presence of data on repeated episodes of elevation of biochemical parameter(s) | yes/no |
23 | Serum C-reactive protein level test was performed at least once every 3 months | yes/no |
24 | Blood immunoglobulin level testing performed at least once every 3 months | yes/no |
25 | Temporary suspension of canakinumab**/anakinra** therapy, continuation of previously prescribed oral GCs performed for all patients in case of decreased blood immunoglobulins | yes/no |
26 | Appointment (examination, consultation, including telemedical) by a rheumatologist of the inpatient department that initiated therapy performed in case of decreased blood immunoglobulins | yes/no |
27 | Hospitalization to an inpatient facility was performed for all patients with decreased blood immunoglobulin levels | yes/no |
28 | Determination of antistreptolysin-O in blood serum aimed at detecting/excluding group A β-hemolytic streptococcus infection performed at least once every 3 months | yes/no |
29 | Temporary suspension of canakinumab**/anakinra** therapy, continuation of previously prescribed oral GCs performed for all patients upon the appearance of signs of an infectious complication | yes/no |
30 | Appointment (examination, consultation, including telemedical) by a rheumatologist of the inpatient department that initiated therapy performed for all patients upon the appearance of signs of an infectious complication | yes/no |
31 | Emergency hospitalization to an inpatient facility performed upon suspected/developed pneumonia | yes/no |
32 | Temporary discontinuation of canakinumab**/anakinra** therapy, with continuation of previously prescribed oral GCs in all patients with suspected/developing pneumonia | yes/no |
33 | Resumption of canakinumab**/anakinra** performed for all patients no earlier than 1 week after complete resolution of pneumonia according to laboratory data, follow-up chest computed tomography with or without anesthetic management (including early postoperative management), and completion of antibacterial therapy | yes/no |
34 | Prescription of #acyclovir** (J05AB) at a dose of 200 mg orally 5 times a day to children over 2 years of age (not exceeding 1000 mg/day) in accordance with clinical guidelines for the treatment of herpesvirus infections in children, including immunocompromised ones, performed upon development of local herpes infection | yes/no |
35 | Temporary suspension of canakinumab**/anakinra** therapy, continuation of previously prescribed oral GCs performed upon development of an infection caused by herpesviruses | yes/no |
36 | Hospitalization was performed for all patients with generalized herpetic infection / suspected cytomegalovirus / Epstein-Barr virus infection | yes/no |
37 | Therapy with canakinumab**/anakinra** was resumed in all patients no earlier than 1 week after the complete resolution of clinical and laboratory signs of infection and completion of antiviral therapy | yes/no |
38 | Monitoring of canakinumab**/anakinra** efficacy was performed | yes/no |
39 | Monitoring of canakinumab**/anakinra** tolerability was performed | yes/no |
40 | An initial or follow-up examination (consultation, including remote) by the hospital rheumatologist who initiated the therapy was performed for all patients who developed any signs of biologic DMARD failure and/or intolerance | yes/no |
41 | 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 | yes/no |
42 | Focal tuberculin skin testing (Mantoo test, recombinant tuberculosis allergen test in standard dilution**) was performed in all patients at least once every 6 months (more frequently if clinically indicated) | yes/no |
43 | Complete urinalysis was performed at least once a month | yes/no |
44 | Electrocardiography was performed at least once every 3 months | yes/no |
45 | Abdominal ultrasound (comprehensive), echocardiography, and kidney ultrasound were performed in all patients at least once every 6 months | yes/no |
46 | An initial examination (consultation) by an otorhinolaryngologist was performed in patients with ENT pathology no later than 7 days after discharge from the hospital | yes/no |
47 | A follow-up examination (consultation) by an otorhinolaryngologist was performed according to medical indications, at least once every 6 months | yes/no |
48 | An initial examination (consultation) by a pediatric cardiologist was performed according to medical indications | yes/no |
49 | A follow-up examination (consultation) by a pediatric cardiologist was performed according to medical indications | yes/no |
50 | An initial examination (consultation) by a pediatric dentist was performed in all patients within 1 month after discharge from the hospital | yes/no |
51 | A follow-up examination (consultation) by a pediatric dentist was performed according to medical indications | yes/no |
52 | An initial examination (consultation) by an ophthalmologist with mandatory eye biomicroscopy was performed no later than 7 days after hospital discharge in patients with ophthalmological pathology | yes/no |
53 | A follow-up examination (consultation) by an ophthalmologist (at least once every 3 months) with mandatory eye biomicroscopy was performed in all patients with ophthalmological pathology based on individual indications. | yes/no |
54 | An initial examination (consultation) by a nephrologist was performed no later than 7 days after hospital discharge in the presence of renal impairment | yes/no |
55 | A follow-up examination (consultation) by a nephrologist is recommended for patients with renal impairment at least once every 3 months | yes/no |
56 | An initial examination (consultation) by a dietitian was performed according to medical indications | yes/no |
57 | A follow-up examination (consultation) by a dietitian was performed based on individual indications | yes/no |
58 | An initial examination (consultation) by a phthisiatrician was performed (in the presence of a positive focal test and/or intradermal test with tuberculosis allergen with tuberculin, and/or with infiltrative lesions in the lungs) | yes/no |
59 | An examination (consultation, including remote) by the hospital rheumatologist who initiated the therapy was performed in patients with a positive intradermal tuberculin test | yes/no |
60 | A follow-up examination (evaluation, consultation) by a phthisiatrician was performed in patients with a positive focal tuberculin test and/or intradermal test with tuberculosis allergen, and/or an elevated blood interferon-gamma level to Mycobacterium tuberculosis complex antigens, and/or focal, infiltrative changes in the lungs | yes/no |
61 | An initial examination (consultation) by a pediatric endocrinologist was performed according to medical indications | yes/no |
62 | A follow-up examination (consultation) by a pediatric endocrinologist was performed according to medical indications | yes/no |
63 | An initial examination (consultation) by a pediatric orthopedist-traumatologist was performed according to medical indications | yes/no |
64 | A follow-up examination (consultation) by a pediatric orthopedist-traumatologist was performed according to medical indications | yes/no |
65 | An initial examination (testing, consultation) by a medical psychologist was performed according to medical indications | yes/no |
66 | A follow-up examination (testing, consultation) by a medical psychologist was performed according to medical indications | yes/no |
67 | Elective hospitalization was performed in the rheumatology department of the hospital that initiated the biologic DMARD therapy | yes/no |
68 | Emergency hospitalization was performed as indicated in the rheumatology department of the hospital that initiated the biologic DMARD therapy for examination and therapy adjustment at any stage of treatment in case of exacerbation/complications of CAPS, comorbid conditions, complications/side effects/persistent intolerance to canakinumab**/anakinra** | yes/no |
69 | An examination (consultation, including remote) by the hospital rheumatologist who initiated the therapy was performed for all patients who developed adverse events of therapy / infectious complications / intolerance to canakinumab**/anakinra** | yes/no |
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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:
Alekseeva E.I., MD, Professor, Corresponding Member of the Russian Academy of Sciences
Salugina S.O., MD
Shilgrot I.Yu., PhD
Dvoryakovskaya T.M., MD
Fedorov E.S., PhD
Kostik M.M., MD
Nikishina I.P., PhD
Ushakova S.A., MD, Professor
Ulyanova E.A., PhD
Glazyrina G.A., PhD
Zholobova E.S., MD, Professor
Sudareva O.O., PhD
Igisheva L.N., MD, Associate Professor
Ligostaeva E.A., PhD
Malievsky V.A., MD, Professor
Kriulin I.A., Senior Researcher
Kriulina T.Yu., Junior Research Fellow
Working Group of the Association of Medical Geneticists:
Kutsev S.I., MD, Professor, Corresponding Member of the RAS
Zakharova E.Yu., MD
Polyakov A.V., DSc
Conflict of interest: the working group members declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target Audience
1. Pediatricians
2. Rheumatologists of pediatric rheumatology departments
3. Rheumatologists of pediatric rheumatology offices in out-patient clinics
4. Nephrologists of pediatric nephrology departments
5. Nephrologists of pediatric out-patient clinics
6. Medical geneticists
7. Pediatric surgeons
8. Allergists-immunologists
10. Medical psychologists
11. Medical university students
12. Residents
Description of methods used to formulate the guidelines
To gather/select evidence, a systematic search and selection of publications on the issues reflected in these guidelines was performed in the PubMed, Google Scholar, Cochrane Library, EMBASE, and eLibrary bibliographic databases. In case of zero results from the systematic search and selection of publications in the specified databases, an additional search was conducted using the Yandex and Google search engines. Disagreements regarding the inclusion of publications were resolved by involving a third investigator. The search depth was unlimited.
The guidelines were developed through a consensus of expert working group members based on the results of the literature review, taking into account the benefit-risk ratio for patients, the clinical and epidemiological characteristics of the Russian patient population, as well as the organization of medical care in the Russian Federation, in accordance with the scales for grading levels of evidence and grades of recommendation. If consensus could not be reached, an independent expert was involved.
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
A preliminary version of these guidelines was reviewed by independent experts. Primary care pediatric rheumatologists provided comments regarding the clarity and importance of the proposed recommendations as a tool for daily practice. All comments received from experts were carefully systematized and discussed by the guideline authors. Each item was discussed individually.
Authors
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.
Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)
LoE | Definition |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except 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 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Scale for evaluating the levels of убедительности рекомендаций (LoR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Appendix A3. Reference Materials
№ | International Nonproprietary Name (INN) of the medicinal product | Timing of therapeutic efficacy monitoring¹ |
|---|---|---|
1 | Canakinumab** | 3 months after the start of treatment. Thereafter, every 6 months |
2 | Anakinra** | 3 months after the start of treatment. Thereafter, every 6 months |
¹ Therapy adjustment is performed at any stage of treatment if it is ineffective and/or unsafe
Appendix B. Physician Action Algorithms
Diagram 1
Diagram 5
Appendix C. Patient Information
What are cryopyrin-associated periodic syndromes (CAPS)?
Cryopyrin-associated periodic syndromes (CAPS) are a group of rare autoinflammatory diseases that include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurologic cutaneous and articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID). These syndromes were originally described as separate nosological entities despite several clinical similarities: patients frequently present with symptoms such as fever, urticaria-like skin rash, and varying degrees of joint involvement associated with systemic inflammation. Most patients have symptoms from birth, although FCAS and MWS can manifest in both childhood and adulthood.
These three conditions represent a spectrum of severity: FCAS is the mildest disease, CINCA/NOMID is the most severe, and patients with MWS have an intermediate phenotype.
Molecular studies of these pathologies have demonstrated mutations in the same gene across all three diseases (1,2 from patient information). The first and primary symptom of all CAPS is a skin rash. As a rule, it is the first to be noticed in infancy. Its intensity varies among individual patients and depends on disease activity. In addition to the rash, all variants of CAPS have their own additional symptoms.
How common is this disease?
CAPS is a very rare disease affecting only a few people per million, but it is highly likely that this estimate is underestimated. CAPS occurs worldwide.
Why does the disease occur?
CAPS diseases are genetic in nature. The gene responsible for these 3 nosological entities (FCAS, MWS, CINCA/NOMID) is called NLRP3 and encodes a protein called cryopyrin. This protein plays a key role in the development of the body's inflammatory response. Impairments in this gene lead to an increased function of the specified protein (so-called gain-of-function) and enhanced inflammatory responses. These enhanced inflammatory responses cause the clinical symptoms observed in CAPS.
Mutations can be pathogenic, significant (high-penetrance), and of uncertain significance, causing an incomplete and less severe disease picture. Additional genetic and environmental factors may also influence disease severity and symptoms.
Is this disease hereditary?
CAPS are inherited in an autosomal dominant manner. This means that the disease is transmitted by a parent who has the disease and carries an abnormal copy of the NLRP3 gene. Parents may also be carriers of the mutation without showing signs of the disease. Since every person has 2 copies of all our genes, the risk of transmitting the mutated copy of the NLRP3 gene from a parent who is a carrier, and thus the risk of transmitting the disease to each child, is 50%. De novo (new) mutations can also occur; in these cases, neither parent has the disease nor carries a mutation in the NLRP3 gene, but the NLRP3 gene defect appears at conception. In such cases, the risk of developing CAPS in another child is sporadic.
Is this disease infectious?
Diseases belonging to the CAPS group are not infectious.
What are the main symptoms?
The rash is a key symptom in all three diseases and is typically the first to be noted. Regardless of which specific syndrome has developed in the patient, it shares the same characteristics: it is a migratory maculopapular rash (urticarial-like) that is generally not pruritic. The intensity of the skin rash may vary from patient to patient and depending on disease activity.
FCAS, formerly known as "familial cold urticaria", is characterized by recurrent short episodes of fever, rash, and joint pain triggered by exposure to low temperatures. Other frequently reported symptoms include conjunctivitis and muscle pain. Symptoms typically appear 1-2 hours after general exposure to low temperatures or a significant temperature change, and the duration of attacks is usually short (less than 24 hours). These attacks are self-limiting in nature (meaning they resolve without treatment). Patients often report a pattern of feeling well in the morning after a warm night, but then worsening later the same day due to cold exposure. An early onset of the disease is common: at birth or within the first 6 months of life. Signs of inflammation in the blood are observed during inflammatory episodes. The quality of life of patients with FCAS may vary depending on the frequency and intensity of symptoms. However, long-term complications such as deafness and amyloidosis are generally absent.
MWS is characterized by recurrent episodes of fever and a predominantly urticarial rash, accompanied by inflammation of the joints and eyes (conjunctivitis, uveitis). Chronic fatigue is very common.
Triggering factors are generally not identified, and cold exposure is rarely a factor precipitating an attack. The disease course varies from more typical recurrent inflammatory attacks to more persistent symptoms. Initial symptoms appear early in life, but cases of the disease developing in older children and even adults have also been described.
Deafness is frequent (in approximately 75% of cases) and typically begins in adolescence or early adulthood. Amyloidosis is the most serious complication of MWS. It develops in adulthood in approximately 25% of cases. The cause of this complication is the deposition of amyloid—a special protein associated with inflammation—in certain organs (e.g., kidneys, intestines, skin, or heart). These deposits gradually lead to the loss of organ function, especially renal function; it manifests as proteinuria (elevated protein levels in the urine) and subsequent renal impairment. Amyloidosis is not specific to CAPS; it is a complication that also develops in other chronic inflammatory diseases.
In CINCA/NOMID, symptoms are the most severe in this disease spectrum. The rash is typically the first sign; it appears at birth or in early childhood. One-third of patients may be born prematurely or be small for gestational age. Fever may be transient, and in some cases, it persists constantly. Patients frequently complain of fatigue.
Bone and joint inflammation varies in severity; in approximately two-thirds of patients, joint manifestations are limited to pain or transient swelling during a disease flare. However, in one third of cases, severe and disabling joint damage develops as a result of cartilage overgrowth. These arthropathies can cause significant joint deformations accompanied by pain and restricted range of motion. The knees, ankles, wrists, and elbows are most frequently and symmetrically affected. Radiographic changes in the form of hypertrophic arthropathy are characteristic, and when present, usually develop at an early age (under 3 years).
Central nervous system (CNS) abnormalities are present in almost all patients and are caused by chronic aseptic meningitis (non-infectious inflammation of the membrane surrounding the brain and spinal cord). This chronic inflammation leads to a sustained increase in intracranial pressure. Symptoms associated with this condition vary in intensity and include chronic headaches, occasional vomiting, irritability in infants, and papilledema, which can be detected by funduscopy (a specialized ophthalmologic examination). From time to time, severely ill patients experience epileptic seizures (convulsions), cognitive impairment, and delayed psychomotor and speech development.
The eyes may also be affected in this disease. Inflammation can occur in the anterior and/or posterior segments of the eye (anterior and posterior uveitis, optic neuropathy). Ocular manifestations can progress and lead to vision loss in adulthood (blindness). Sensorineural hearing loss is common and usually develops early in the disease course. Amyloidosis is detected with age in 25% of patients. Growth and pubertal delay may be observed as a consequence of chronic inflammation. Signs of inflammation in the blood are present persistently in most cases. Thorough examination of CAPS patients typically reveals overlapping clinical symptoms. Patients with MWS may exhibit symptoms characteristic of FCAS, such as cold sensitivity (i.e., an increased frequency of attacks in winter), or mild CNS symptoms such as frequent headaches or asymptomatic papilledema, which are typical of CINCA/NOMID patients.
Does the disease manifest identically in all children?
There is an extremely high variability in disease severity among patients with CAPS. FCAS is a mild disease with a good long-term prognosis. MWS is a more serious condition as it can lead to hearing loss and amyloidosis. CINCA/NOMID is the most severe form. Within this group, variability also exists depending on the severity of neurological involvement and joint involvement. Members of the same family suffering from CAPS may exhibit different symptoms and varying degrees of severity.
2. DIAGNOSIS AND TREATMENT
What examinations are necessary?
At the time of diagnosis, conditions with similar clinical presentations (infectious diseases, allergic conditions, acute and chronic osteomyelitis, inflammatory bowel disease, other rheumatic diseases, etc.) must be ruled out. To this end, a comprehensive evaluation is performed, including a set of laboratory and instrumental studies determined by your rheumatologist in accordance with clinical guidelines.
The diagnosis is established based on the medical history, clinical symptoms, laboratory findings, and the results of additional instrumental examinations (ophthalmological examination with a slit lamp, radiological, audiological examination of hearing, and analysis of cerebrospinal fluid if necessary via lumbar puncture). Laboratory evaluation includes determining the levels of acute-phase inflammatory markers: ESR, C-reactive protein (CRP), and serum amyloid A (SAA), which are significantly elevated. A family history and the presence of similar symptoms in relatives are also important to consider. Genetic testing to identify a mutation in the NLRP3 gene is performed to definitively confirm the diagnosis.
What treatments are available?
Recent studies on the genetics and pathophysiology of CAPS show that in this group of diseases, a potent inflammatory cytokine (protein), IL-1β, is produced in excess and plays a major role in the pathogenesis of the disease. Currently, several agents that inhibit IL-1β (IL-1 blockers) are available. The first drug used in the treatment of these conditions was anakinra. It has been demonstrated that this drug provides rapid and effective relief of inflammation, rash, fever, pain, and fatigue across all CAPS disorders.
This treatment also effectively improves ocular and neurological disorders. Under certain conditions, the drug can reduce hearing loss and control amyloidosis. Unfortunately, this medication is not effective for hypertrophic arthropathy. The required doses depend on disease severity. Treatment should be initiated at an early age, before chronic inflammation leads to irreversible organ damage such as hearing loss or amyloidosis. This requires daily subcutaneous injections. Injection site reactions are frequently observed, but they tend to resolve over time.
Canakinumab is another IL-1-suppressing agent. It is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with CAPS aged 4 years and older. Several studies have shown that this drug effectively controls the inflammatory manifestations of CAPS when administered via subcutaneous injection once every 4–8 weeks, depending on severity. Canakinumab is approved in the Russian Federation for the treatment of patients with CAPS. Given the genetic nature of the disease, it can be assumed that pharmacological IL-1 blockade must be maintained for a long time, if not for life.
Nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs)
NSAIDs are agents for symptomatic anti-inflammatory and antipyretic (temperature-lowering) treatment; "symptomatic" means they are incapable of inducing disease remission and only relieve inflammation-related symptoms. The most commonly used are diclofenac, nimesulide, meloxicam, ibuprofen, and paracetamol. NSAIDs are generally well tolerated by children. Side effects include gastric discomfort, which is more common in adults than in children. Occasionally, one NSAID may be effective when another is insufficiently effective. Combining different NSAIDs is not indicated. The optimal effect on joint inflammation is observed a few weeks after starting treatment.
Glucocorticoids
Glucocorticoids are the most effective available anti-inflammatory drugs, but their use is limited by the fact that long-term administration is accompanied by a number of serious adverse effects, including osteoporosis and growth retardation. Nevertheless, the advantage of glucocorticoids is that they can be used to treat systemic symptoms that are refractory to other therapies, in life-threatening systemic complications, and as a "bridging" therapy during the acute phase of the disease while awaiting the onset of action of second-line agents.
Other treatment methods
Rehabilitation
Rehabilitation is an important component of treatment. It includes appropriate exercises. Rehabilitation should be initiated early and performed routinely to improve or preserve joint and muscle function.
What are the main side effects of treatment?
Drugs used in the treatment of CAPS are generally well tolerated. Gastric intolerance—the most common side effect of NSAIDs (which is precisely why they must be taken with food)—is less frequently observed in children than in adults. NSAIDs may cause an elevation in certain liver enzymes in the blood, but this is a rare occurrence with their use.
Long-term use of high-dose GCs is accompanied by a number of significant side effects. These include growth retardation and osteoporosis. High doses of GCs cause a marked increase in appetite, which in turn can lead to obesity. Therefore, it is important to encourage children to eat foods that can satisfy their appetite without increasing calorie intake.
Biologic agents are generally well tolerated, at least in the first years of treatment. Patients must be closely monitored for the potential development of infections or other adverse events. However, it is important to understand that the experience with medications used for the treatment of CAPS is limited in quantity and duration (biological drugs have only been available since 2000).
When should treatment be started?
Currently, there are domestic, international, and national guidelines available to assist physicians and families in choosing treatment. Treatment should be prescribed immediately after the diagnosis is established.
How long should treatment be continued?
Treatment is long-term. Its duration is determined by the attending physician based on the patient's condition.
Can this disease be treated or cured?
Highly effective treatments are currently available for patients with CAPS. However, CAPS disorders cannot be cured as they are genetic diseases. Nevertheless, thanks to significant progress in understanding these disorders, promising new therapeutic agents for CAPS are now available and are currently being studied to determine their long-term efficacy.
What is the long-term prognosis of the disease?
The long-term prognosis of FCAS is favorable, but quality of life can be affected by recurrent fever episodes. In MWS, the long-term prognosis can be impacted by the development of amyloidosis and renal impairment. Hearing loss is also a significant long-term complication. In patients with CINCA/NOMID, growth potential may be impaired during the course of the disease. In CINCA/NOMID, the long-term prognosis depends on the severity of neurological, neurosensory, and joint lesions, as well as the timing of therapy initiation. Hypertrophic arthropathies can lead to severe disability. Premature death cannot be ruled out in severe patients. Treatment with IL-1 blockers significantly improves the prognosis in CAPS.
What about complementary or alternative therapies?
There are many complementary and alternative therapies, and this can be confusing for patients and their families. Carefully consider the risks and benefits of such treatments, as their efficacy is not proven and they can be costly in terms of time, burden on the child, and financial expense. If you wish to explore complementary and alternative treatment options, please discuss these choices with your pediatric rheumatologist. Some treatments may interact with conventional medications. Most physicians will not object to alternative treatments provided you follow medical recommendations. It is very important not to stop taking prescribed medications. When medications, such as GCs, are necessary to keep the disease under control, stopping them can be very dangerous if the disease is still in its active phase. Please discuss any concerns you have about the prescribed medication with your child's doctor.
3. DAILY LIFE
How can the disease affect the child and the family's daily life?
Quality of life can be affected by recurrent episodes of fever. There is often a significant delay in establishing the correct diagnosis, which causes anxiety for parents and sometimes leads to unnecessary medical procedures.
What about school?
For children with chronic diseases, continuing their education is of paramount importance. There are several factors that can cause school attendance issues, and therefore it is important to explain the child's potential needs to teachers. Parents and teachers should do everything in their power to enable the child to participate in school activities normally, not only so the child can succeed academically, but also to be accepted and recognized among peers and adults. Future integration into the professional world is essential for the young patient and is one of the overarching goals of comprehensive care for chronically ill patients.
What about sports?
Sports and physical activities are an important aspect of any child's daily life. One of the goals of therapy is to allow children to live as normal a life as possible and feel no different from their peers. Therefore, the child may engage in any activities they can handle. However, during an acute phase, physical exertion must be limited or adequate rest must be ensured.
What about diet?
In general, the child should follow a balanced, age-appropriate diet. A healthy, well-balanced diet with adequate protein, calcium, and vitamins is recommended for a growing child.
Can climate affect the course of the disease?
Symptoms may be triggered by low temperatures or exposure to cold.
Can a child be vaccinated?
The child can and should be vaccinated; however, the attending physician must be informed of the condition prior to vaccination so that appropriate individualized recommendations can be provided. Live vaccines are not recommended.
What about sex life, pregnancy, and contraception?
To date, literature on this subject is lacking. As with other autoinflammatory diseases, it is advisable to plan pregnancy thoughtfully, as this allows for timely adjustment of treatment in advance, taking into account potential adverse effects of biological agents on the fetus. A genetic counseling consultation is recommended before planning pregnancy.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Appendix G1. Auto-Inflammatory Disease Activity Index (AIDAI)
Russian title: Auto-Inflammatory Diseases Activity Index.
Original title (if applicable): 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.
Purpose: assessment of disease activity.
Content (template):
Key (interpretation):
A total AIDAI score < 9 points allows separating inactive patients from active patients (with a total score ≥ 9 points).
Appendix G2. CAPS Activity Index (DAS-MWS)
Russian title: CAPS Activity Score (DAS-MWS).
Original title (if applicable): CAPS Activity Score (DAS-MWS).
Source (official developer website, validation publication): 1. Kuemmerle-Deschner J.B., Ozen S., Tyrrell P.N. et al. Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS) Ann Rheum Dis 2017;76:942-947. doi: 10.1136/annrheumdis-2016-209686
2. Piram M., Koné-Paut I. Lachmann H.J. et al. on the behalf of EUROFEVER, EUROTRAPS and the Paediatric Rheumatology International Trials Organisation (PRINTO) networks Validation of the Auto-Inflammatory Diseases Activity Index (AIDAI) for hereditary recurrent fever syndromes. Ann Rheum Dis 2014;73:2168–2173. doi:10.1136/annrheumdis-2013-203666
3. Terreri M. T., Bernardo W. M., Len C. A. et al. Guidelines for the management and treatment of periodic fever syndromes: Cryopyrin-associated periodic syndromes (cryopyrinopathies – CAPS). Rev Bras Reumatol Engl Ed. 2016; 56,1: 44-51.
Type (underline): index.
Purpose: assessment of disease activity.
Content (template):
Includes 10 aspects, 9 of which reflect organ and system involvement:
fever
headache
ocular involvement
hearing impairment
oral ulcers
abdominal pain
renal disease
musculoskeletal symptoms
rash
PGAS (Patient Global Assessment Score) – patient's global assessment of activity on a VAS scale.
Key (interpretation): each symptom is scored according to the MWS-DAS index as 0 – no symptoms, 1 – mild symptoms, 2 – severe symptoms for each disease activity parameter.
A DAS-MWS score < 10 points reflects a mild course, while ≥ 10 points indicates high activity and a severe course of MWS.
Predictors of poor prognosis:
Severe MWS (DAS-MWS ≥ 10 points)
Female sex
Hearing loss
Musculoskeletal manifestations
PGAS (Physician Global Assessment Score), PMS (Patient Mood Score), PPS (Patient Performance Score)
Decreased hemoglobin level
Elevated ESR
Appendix G3. Autoinflammatory Disease Damage Index (ADDI)
Original title (if applicable): 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.
Purpose: assessment of disease activity.
Content (template):
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) | ||
Notes:
*Severity: score depends on the severity of damage.
Amyloidosis: localized, affecting a single organ; extensive, affecting more than one organ. Renal failure: 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 a hearing aid or cochlear implant; severe, hearing impairment requiring a hearing aid or cochlear implant. Ocular involvement: mild, impairments not leading to visual impairment; moderate, impairments leading to visual impairment; severe, practical blindness.
**Score assigned according to system damage. For systems where a severity scale exists, the lowest score corresponds to mild manifestations, and the highest score to severe manifestations. The score for each category is capped at a maximum value.
Glossary of terms:
Amenorrhea: Primary amenorrhea: absence of menarche by age 16 years or absence of menarche within 5 years after thelarche in women. Secondary amenorrhea: absence of menstruation for 6 consecutive months or more in women 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), general deficit (e.g., memory, behavior), seizures, and spinal cord symptoms. Neuropsychiatric disorders not related to the disease should not be assessed.
Cognitive impairment: need for special education due to impaired cognitive functions or IQ < 70 according to neuropsychological assessment or other 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 2 of the following 3 features:
- Height below the 3rd percentile or below - 2 standard deviations (SD) for age.
- Growth velocity over the last 6 months below the 3rd percentile or less than -2 SD for age.
- Crossing of at least 2 centiles (5%, 10%, 25%, 50%, 75%, 90%, 95%) on the growth chart.
For patients over 18 years of age: pathologically short stature (e.g., below the 3rd percentile or - 2 SD 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 disease of the reproductive system defined by the inability to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse, not due to known disorders 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: visual system damage (e.g., optic atrophy, increased intraocular pressure, or cataract) confirmed by an ophthalmologist, with or without visual impairment.
Osteoporosis: decreased bone mineral density combined with a vertebral compression fracture and/or pathological bone fractures confirmed by imaging studies, which may include bone densitometry. The presence of isolated low bone mineral density is not sufficient to diagnose «osteoporosis».
Proteinuria: persistent urine protein-to-creatinine ratio > 20 mg/mmol in the first morning urine sample; and/or daily protein excretion > 0.3 g/24 h or urine albumin-to-creatinine ratio > 15 mg/mmol.
Pubertal delay: Tanner stage below - 2 SD for age or below the 3rd percentile for age, or any Tanner stage following pharmacological induction of puberty.
Renal impairment: glomerular filtration rate (GFR) < 60 mL/min/1.73 m2, dialysis, or transplantation.
Serosal scarring: symptomatic adhesions or fibrosis affecting the pericardium, pleura, peritoneum, and/or retroperitoneal space, confirmed by imaging, endoscopy, or surgery.