Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (Other specified disorders involving the immune mechanism, not elsewhere classified): clinical guidelines

Applies tochildren2026 editionD89.8

Clinical guidelines of the Russian Ministry of Health, pediatric. 2026 edition, ICD-10 code: D89.8. This page features a shortened version by WhiteCoat Pro and the full official text.

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Brief for Practice

WhiteCoat Pro editorial summary of the guideline text, 2026 edition. Each point links to the original section — verify with it before prescribing.

TRAPS is an inherited autosomal dominant periodic fever syndrome associated with heterozygous variants in the TNFRSF1A gene. This guideline focuses on disease recognition, ruling out infectious, oncological, and rheumatic mimickers, treating inflammation, and preventing amyloidosis and hemophagocytic syndrome.

Key points

The typical phenotype includes recurrent fever attacks, migratory painful rash, myalgia, abdominal or chest pain due to serositis, arthralgia, conjunctivitis, and periorbital edema; symptoms and inflammatory markers sometimes persist between attacks. → in text
In the presence of a confirmed pathogenic or likely pathogenic TNFRSF1A variant, a single criterion is sufficient to classify TRAPS: attacks lasting ≥7 days, myalgia, migratory rash, periorbital edema, or affected relatives. If the genotype is unconfirmed, at least two of these criteria are required, and benign variants must be excluded. → in text
Eurofever/PRINTO clinical criteria assign 2 points for fever lasting ≥7 days, 1 point each for fever lasting 5–6 days, migratory rash, periorbital edema, myalgia, family history, as well as for the absence of aphthous stomatitis and pharyngotonsillitis; the diagnostic threshold is ≥5 points. → in text
Without treatment, amyloidosis is reported in 15–25% of patients; elevated blood AA-protein levels indicate amyloid deposition. Proteinuria is detected upon the development of amyloidosis and may be its first symptom. → in text
Before initiating targeted therapy, it is necessary to rule out infections, tumors and hemoblastoses, other autoinflammatory and rheumatic diseases, immunodeficiencies, and inflammatory bowel disease. → in text
Canakinumab is the primary agent for targeted therapy in systemic inflammation or organ involvement, ESR >30 mm/h, CRP >20 mg/L or >4 upper limits of normal, and ≥3 attacks over 9–12 months. → in text
In a patient with TRAPS and fever, secondary hemophagocytic syndrome should be actively sought: its early markers include lymphadenopathy, erythrocytes <4.34 million/µL, platelets <208 thousand/µL, chlorides <101.9 mmol/L, and LDH >412 U/L. → in text

Diagnostics

Take the history: age of onset, duration and periodicity of attacks, intercritical symptoms, triggers, nature of the rash and pain, involvement of eyes, joints, heart, lungs, abdomen, and kidneys; separately inquire about family history of fever, rash, arthritis, and renal failure. → in text
Perform a physical examination including thermometry, assessment of general status, skin and mucous membranes, lymph nodes, heart and lungs, abdomen, joints, muscles, and urinary system; in case of arthralgia or arthritis, determine range of motion and evaluate gait. → in text
Assess inflammatory activity and potential complications: complete blood count, CRP, ESR, biochemical parameters, coagulogram, urinalysis, albumin and protein in 24-hour urine; calculate GFR if signs of renal involvement are present. → in text
Perform differential diagnosis: procalcitonin and microbiological tests to rule out sepsis, tests for tuberculosis and infections, immunological assays, fecal calprotectin to exclude IBD; in atypical presentations, screen for other autoinflammatory syndromes. → in text
Confirm TRAPS by molecular genetic testing of TNFRSF1A; partial or complete gene analysis is performed, most commonly evaluating exons 2–4. If attack duration is up to 7 days or atypical features are present, genes for other monogenic autoinflammatory diseases are tested. → in text
Perform ultrasound of the abdominal cavity and kidneys, echocardiography, and ECG; in case of abdominal syndrome, rule out acute surgical pathology, and for arthritis, use joint ultrasound and, as indicated, radiography, CT, or MRI. → in text
If hemophagocytic syndrome is suspected, determine ferritin, platelets, AST, triglycerides, and fibrinogen: diagnostic criteria include ferritin >684 ng/mL plus any 2 features: platelets ≤180×10⁹/L, AST >48 U/L, triglycerides >1.75 mmol/L, fibrinogen ≤3.60 g/L. → in text

Treatment

Prior to establishing a diagnosis and during the diagnostic workup, only NSAIDs are used to relieve fever and pain; NSAID monotherapy should not be continued for more than 1 month. Potential drugs include diclofenac, nimesulide, meloxicam, or ibuprofen at doses per instructions. → in text
Until the complete diagnostic workup is finished and oncological and hemato-oncological diseases are excluded, glucocorticoids, colchicine, or biologic therapies are not prescribed. In established TRAPS with severe pain, persistent febrile/hectic fever, pericarditis, or pleuritis, methylprednisolone 10–30 mg/kg intravenously for 3 days (if necessary, 5 days), or prednisolone or methylprednisolone 0.5–1 mg/kg/day orally may be used. → in text
Canakinumab is used in children older than 2 years: for a weight of 7.5–40 kg, 2 mg/kg subcutaneously once every 4 weeks; for weight >40 kg, 150 mg subcutaneously once every 4 weeks. If there is no effect after 7 days, a second injection is administered at the same dose; after a complete response, the maintenance dose is 4 mg/kg or 300 mg once every 4 weeks, respectively. → in text
In case of inefficacy or intolerance to canakinumab, etanercept 0.4 mg/kg subcutaneously twice a week or 0.8 mg/kg once a week is an option. In children with active chronic arthritis or a combination of TRAPS and juvenile arthritis who fail or are intolerant to canakinumab and etanercept, tocilizumab 8 mg/kg intravenously once every 2 weeks or 162 mg subcutaneously once a week is used. → in text
In a benign course with rare attacks and moderate laboratory activity, colchicine is an option: 0.5 mg/day up to 5 years, 0.5–1.0 mg/day at 5–10 years, 1.0–1.5 mg/day over 10 years; if inflammation persists, the dose is increased by 0.5 or 0.6 mg/day, not exceeding 2 mg/kg/day (Note: standard max is 2 mg/day). → in text
In TRAPS complicated by hemophagocytic syndrome, glucocorticoids are used in combination with cyclosporine and normal human immunoglobulin. Pulse therapy: methylprednisolone 20–30 mg/kg intravenously or dexamethasone 10–20 mg/m²/day intravenously; cyclosporine 3–5 mg/kg/day, immunoglobulin 1–2 g/kg per course over 2 days. → in text
Response to HPS treatment is evaluated every 48 hours: cessation of fever, reduction in spleen size, platelets ≥100×10⁹/L, normalization of fibrinogen, and a 25% decrease in ferritin. If activity increases in the first 48 hours, anakinra 5–10 mg/kg/day intravenously in 2 divided doses is added for 3–10 days, or longer if necessary. → in text
AIDAI is evaluated 3 months after starting or adjusting therapy and every 6 months thereafter; ADDI is evaluated once a year. → in text

When to refer and how to monitor

A patient with suspected TRAPS is referred to a rheumatology inpatient department for diagnosis, differential workup, and initiation of targeted therapy. → in text
In active TRAPS, hospitalization is necessary for examination and adjustment of ineffective therapy; discharge is possible after stabilization, resolution of fever and other systemic manifestations, reduction of joint activity, and a trend toward normalization of laboratory parameters. → in text
In active hemophagocytic syndrome, hospitalization is mandatory; discharge occurs after the clinical and laboratory signs of HPS resolve and TRAPS activity is absent. → in text
Disease flare or complication, concomitant illness, adverse effect, or persistent intolerance to biologics or colchicine require urgent hospitalization in the rheumatology department that initiated targeted therapy. → in text
If pneumonia is suspected, generalized herpetic infection, CMV or Epstein-Barr virus infection, as well as in case of a severe allergic reaction, emergency hospitalization is required. → in text

Frequently asked questions

Which signs most strongly indicate TRAPS?

Fever attacks lasting ≥7 days, myalgia, migratory rash, periorbital edema, and family history of the disease are most characteristic. A Eurofever/PRINTO clinical score of ≥5 allows for the classification of TRAPS. → in text

How is the diagnosis of TRAPS confirmed?

Molecular genetic testing of TNFRSF1A is performed, and infections, tumors, immunodeficiencies, other autoinflammatory, and rheumatic diseases are excluded. → in text

What is the first-line targeted therapy?

The primary agent for inducing remission is canakinumab in cases of systemic inflammation, organ manifestations, elevated ESR/CRP, and frequent attacks. For children older than 2 years, the standard initial regimen is 2 mg/kg or 150 mg subcutaneously once every 4 weeks depending on body weight. → in text

When should hemophagocytic syndrome be suspected?

Diagnostic threshold: ferritin >684 ng/mL plus any 2 of 4 criteria — platelets ≤180×10⁹/L, AST >48 U/L, triglycerides >1.75 mmol/L, fibrinogen ≤3.60 g/L. → in text

How to monitor the risk of amyloidosis?

Urinalysis, urinary albumin, and urinary protein are evaluated regularly; proteinuria may be the first sign of amyloidosis. If clinical or laboratory signs of renal involvement are present, a comprehensive study of renal function is performed. → in text

Status: Applied · approved by the Scientific and Practical Council of the Russian Ministry of Health
Database ID: 759, revision 2 (ID 759_2)
Publication date: September 24, 2026
Age category: children
ICD-10 codes: D89.8
Specialties: Medical Genetics Rheumatology Pediatrics
Developers: Association of Medical Geneticists
Association of Pediatric Rheumatologists
Official text: Russian Ministry of Health Rubricator — 759_2

Shortened clinical guidelines: Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) (Other specified disorders involving the immune mechanism, not elsewhere classified)

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All abbreviated guidelines: 290

Beginning of abbreviated version — open

Autoinflammatory syndromes are a group of hereditary monogenic disorders characterized by unprovoked episodes of inflammation (fever, arthritis, rash, serositis, CNS involvement) in the absence of autoimmune or infectious causes.

ANCA are autoantibodies against neutrophil cytoplasm, a marker of ANCA-associated vasculitis.

ANA are autoantibodies against cell nucleus components (a family of over 200 antinuclear antibodies).

ACPA (anti-CCP) are IgG autoantibodies to citrulline-containing proteins (filaggrin, etc.).

Anti-Scl-70 antibodies are antiscleroderma antibodies against topoisomerase I (70 kDa).

Biological DMARDs (bDMARDs) are biological medicinal products (monoclonal antibodies, recombinant proteins) that selectively suppress the mechanisms of chronic inflammation.

Idiopathic means arising from no apparent cause.

Interleukins (IL) are cytokines that mediate the activation of immunocompetent cells and regulate myeloid and erythropoiesis.

MHC class I (A, B, C) present peptides from the cytoplasm (including viral ones) on the cell surface, attracting cytotoxic T cells (CD8+). Found on all nucleated cells except erythrocytes and trophoblast.

MHC class II (DP, DM, DOA, DOB, DQ, DR) present extracellular antigens to T lymphocytes; found on dendritic cells, macrophages, and B lymphocytes. MHC class III encodes complement system proteins.

Rheumatoid factor (RF) are autoantibodies directed against modified IgG.

NSAIDs are drugs with analgesic, antipyretic, and anti-inflammatory effects; subdivided into selective (s-NSAIDs) and non-selective (ns-NSAIDs) COX inhibitors.

Uveitis is inflammation of the uveal tract of the eye.

Anterior uveitis (iridocyclitis) is inflammation of the anterior segments of the uveal tract.

Juvenile means pertaining to youth or young age.

HLA are human leukocyte antigens, the human major histocompatibility complex.

TRAPS (Tumor Necrosis Factor Receptor-Associated Periodic Syndrome) is a hereditary monogenic periodic fever syndrome caused by a mutation in the TNFRSF1A gene encoding the type I TNF receptor. It manifests as recurring episodes of fever of varying duration, painful rashes, intense abdominal and chest pain, ocular involvement, etc.

An autosomal dominant disease caused by a heterozygous mutation in the TNFRSF1A gene (short arm of chromosome 12) encoding the type I TNF receptor (55 kDa).

The pathogenesis is heterogeneous and depends on the mutation type. The most pathogenic mutations (cysteine substitution in the CRD domains of the extracellular part of TNFR1, e.g., C88Y) disrupt disulfide bonds. Common variants R92Q and P46L result in a milder phenotype and occur even in healthy individuals.

Mutations impair the binding of TNFR1 to the TNF ligand and receptor shedding from the cell surface. The accumulation of misfolded receptors activates NF-κB and MAPK pathways, increases the production of reactive oxygen species, and causes hyperproduction of IL-1β, IL-6, TNF, and chemokines. IL-1 likely acts as a pro-inflammatory mediator operating downstream of TNF.

The exact frequency has not been established; the disease is orphan, with a prevalence of 1:1,000,000. In populations of Northern European descent, it is 1:100,000. It occurs in all ethnic groups with equal frequency. According to the Eurofever/Eurotraps registry (2013), there are 158 patients (105 adults, 53 children).

ICD-10: Class III "Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism", code D89.8 "Other specified disorders involving the immune mechanism, not elsewhere classified".

TRAPS belongs to the category "Periodic fever syndromes" in the classification of monogenic and multifactorial autoinflammatory diseases.

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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

AOSD – Adult-onset Still's disease

VAS – Visual analogue scale

IBD – Inflammatory bowel disease

bDMARDs – Biological disease-modifying antirheumatic drugs (interleukin inhibitors (L04AC), tumor necrosis factor alpha inhibitors (L04AB))

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

PET – Positron emission tomography

RDS – Respiratory distress syndrome

RF – Rheumatoid factor

RP – Radiopharmaceutical (V08)

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

FC – Functional class

TNF – Tumor necrosis factor

CRF – Chronic renal failure

CMV – Cytomegalovirus

EGD – Esophagogastroduodenoscopy

ECG – Electrocardiogram

EchoCG – Echocardiography

JA – Juvenile arthritis

ASC – Apoptosis-associated speck-like protein

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, indicating references to clinical trials of the efficacy and safety of the applied dosing regimen for this disease, or references to relevant literature sources if the recommendation thesis refers to a medicinal product used 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, predominantly monogenic diseases characterized by unprovoked episodes of inflammation and manifested by fever and clinical symptoms resembling rheumatic conditions (arthritis, rashes, serositis, central nervous system 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.

Biological disease-modifying antirheumatic drugs (bDMARDs) – a group of drugs of biological origin, including monoclonal antibodies (chimeric, humanized, fully human) and recombinant proteins (usually including the Fc fragment of human IgG) obtained using genetic engineering methods, characterized by a selective action 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).

Non-steroidal anti-inflammatory and antirheumatic 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.

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

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) – a hereditary monogenic periodic fever syndrome caused by a mutation in the tumor necrosis factor (TNF) receptor type I gene TNFRSF1A and manifested by periodic episodes of fever of varying duration, painful rashes, intense abdominal and chest pain, eye damage, etc. [1–7].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The disease is characterized by an autosomal dominant inheritance pattern and is caused by a heterozygous mutation in the TNFRSF1A gene located on the short arm of chromosome 12 and encoding the TNF receptor type I (55 kDa).

The pathogenesis of TRAPS is complex and involves multiple non-mutually exclusive mechanisms. It is possible that some of these mechanisms are mutation-specific, which explains the heterogeneity of pathological processes and clinical manifestations associated with TRAPS. The most pathogenic mutations lead to the replacement of a cysteine residue with another amino acid in the cysteine-rich domains (CRD) of the extracellular part of TNF receptor 1 (TNFR1), resulting in the disappearance of disulfide bonds, as in the C88Y mutation. More common mutation variants, such as R92Q and P46L, are usually associated with milder clinical phenotypes and can also be detected in clinically healthy individuals [2–4,8].

The binding of TNF to TNFR1 leads to the activation of a signaling pathway that regulates the expression of proinflammatory cytokine genes. Mutations affect the structure of the extracellular domain and impair its ability to bind the TNF ligand. Mutated receptors lose the ability to shed from the cell surface and generate soluble TNFR1 proteins. Accumulations of misfolded TNF receptor particles stimulate the NF-κB signaling pathway; excessive activation of mitogen-activated protein kinase (MAPK), increased production of reactive oxygen species, and hyperproduction of IL-1β, IL-6, TNF, and chemokines develop [9].

The molecular link between TRAPS syndrome and IL-1 is unclear: the pathogenesis for each mutation may differ, but IL-1 likely acts as a proinflammatory mediator downstream of TNF.

1.3 Epidemiology of the Disease or Condition

The incidence of TRAPS has not been precisely established. The disease is orphan, and according to some data, the prevalence is 1 : 1,000,000 [6,10].

Nevertheless, this rare disease occurs in populations of Northern European descent with a prevalence of 1/100,000. TRAPS is not limited to any single ethnic group and is actually found with similar frequency in several other ethnicities. According to the international Eurofever/Eurotraps registry, the number of TRAPS patients in 2013 was 158 (105 adults and 53 children) [2,4,6,10].

1.4 Features of Coding the Disease or Condition

In accordance with the current classification, TRAPS belongs to Class III of ICD-10 «Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism» with ICD-10 code 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 autoinflammatory diseases, TRAPS is listed under the category «Periodic fever syndromes» [11].

1.5.1 New Eurofever/PRINTO classification criteria for TRAPS in the presence of molecular genetic testing

New Eurofever/PRINTO classification criteria for TRAPS in the presence of molecular genetic testing are presented in Table 1.

Table 1. Eurofever/PRINTO classification criteria for TRAPS in the presence of molecular genetic testing [12]

A diagnosis of TRAPS is established in the presence of a confirmed TNFRSF1A genotype* and at least one of the criteria listed below:
Duration of attacks ≥ 7 days Myalgia Migratory rash Periorbital edema Family history of the disease
OR in the absence of a confirming TNFRSF1A genotype† and the presence of at least two of the criteria listed below:
Duration of attacks ≥ 7 days Myalgia Migratory rash Periorbital edema Family history of the disease
A patient with a documented elevation of acute-phase inflammatory reactants (ESR, or CRP, or SAA) clearly correlating with the clinical manifestations of an attack (1), (2), after a thorough exclusion of potential confounding diseases (oncological, infectious, autoimmune, and other congenital immune response disorders), with a disease history duration of at least 6 months, can be regarded as having a hereditary periodic fever. *Pathogenic or likely pathogenic variants (heterozygous in autosomal dominant inheritance); †Variants of uncertain significance (VUS). Benign or likely benign variants are excluded.

1.5.2 Eurofever/PRINTO clinical classification criteria for TRAPS*

Clinical classification criteria (Table 2) are assessed by summing points in the presence or absence of a clinical feature; the threshold score for establishing a diagnosis is greater than or equal to 5 points.

Table 2. Eurofever/PRINTO clinical classification criteria for TRAPS [12]

Presence of:
Fever ≥ 7 days	2 points
Fever 5–6 days	1 point
Migratory rash	1 point
Periorbital edema	1 point
Myalgia	1 point
Family history of the disease	1 point
Absence of:
Aphthous stomatitis	1 point
Pharyngotonsillitis	1 point

*These criteria can be used as a potential tool for referring a patient with suspected TRAPS for molecular genetic testing or as classification criteria in cases where genetic testing is unavailable.

1.6 Clinical presentation of the disease or condition

Most patients develop the disease in childhood (median age 4 years), although adult-onset cases also occur. Most patients experience periodic fever attacks accompanied by serositis (abdominal and/or chest pain), myalgia with or without a typical migratory rash, sometimes annular lesions, periorbital edema, conjunctivitis, arthralgia and arthritis, and elevated ESR and CRP levels. In some patients, symptoms and acute-phase markers are prolonged and persist between attacks.

TRAPS attacks can be triggered by emotional and physical stress, infections, trauma, hormonal shifts, fatigue, or vaccination. However, in most cases, the triggering factor remains unknown.

During attacks, painless skin lesions may develop on the trunk or extremities and may migrate distally, manifesting as periodic episodes of prolonged fever, painful rashes, intense abdominal and chest pain, eye involvement, etc. These episodes occur either spontaneously or after minor triggers (stress, infection, physical exercise, etc.). Skin manifestations may include erythema, edematous plaques, and urticaria. Eye involvement may present as conjunctivitis, periorbital edema (a very specific feature), or uveitis [1–7].

Serous inflammation (pleuritis, peritonitis) is quite common. Abdominal pain and arthralgia are frequent symptoms.

The most common clinical manifestations of TRAPS include: fever (96%), abdominal pain (70%), myalgia (69%), arthralgia (69%), erythematous rash (60%), acute conjunctivitis (37%), and periorbital edema (28%).

Secondary amyloidosis with renal and hepatic manifestations may develop over time. The incidence of untreated amyloidosis is 15–25%.

The highest risk of developing amyloidosis is observed in patients with pathogenic variants affecting cysteine residues or carriers of the p.T79M (T50M) variant, due to longer attacks and more pronounced inflammation.

High blood levels of AA protein serve as an indicator of amyloid deposition [13].

Proteinuria and renal failure develop in 80–90% of patients with amyloidosis, whereas amyloid deposition in the thyroid gland, myocardium, liver, and spleen is less common. Amyloid renal involvement goes through several stages in its development (Table 3).

Table 3. Stages of amyloid renal involvement and chronic kidney disease.

Stages of amyloid renal involvement
Grade	Clinical signs	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 kidney disease
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

Classification and staging of CKD stages by GFR level are presented in Tables 4 and 5.

Table 4. Classification and staging of CKD stages by GFR level [14].

Designation of CKD stages	Characteristics of global renal function	GFR level, mL/min/1.73 m²
C1	High or optimal	> 90
C2	Mildly decreased	60-89
C3a	Mildly to moderately decreased	45-59
C3b	Moderately to severely decreased	30-44
C4	Severely decreased	15-29
C5	End-stage renal disease	< 15

Table 5. Albuminuria grades (mg/day) [14].

A1	A2	A3	A4
Optimal or increased	High	Very high	Nephrotic
< 10-29	30-299	300-1999*	≥ 2000**

Note: * – corresponds to 24-hour proteinuria ≥ 0.5 g;

** – corresponds to 24-hour proteinuria ≥ 3.5 g.

Patients with TRAPS have an increased risk of developing atherosclerosis and acute myocardial infarction.

Clinical signs strongly predictive of TRAPS are presented in Table 6 [15].

Table 6. Clinical signs for predicting TRAPS [15].

General and organ-specific manifestations	Clinical features of TRAPS allowing for high-confidence prognosis
Family history	Family history (score 7)
Duration of fever / attack	> 6 days (score 19)
Skin involvement	Typical migratory rash (score 18)
Musculoskeletal involvement	Myalgia (score 6)
Gastrointestinal involvement	Absence of vomiting, absence of aphthous stomatitis
Ocular involvement	Periorbital edema (score 21)
Respiratory involvement	Absent
Central nervous system involvement	Absent
Genitourinary system involvement	Absent
Cardiovascular system involvement	Absent
Lymphatic system involvement	Absent
Renal involvement	Absent
Autonomic nervous system	Absent

It has been proven that certain clinical conditions are closely associated with TRAPS. These features were evaluated according to the strength of manifestation. A score of ≥ 43 strongly indicates TRAPS [4,15].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Evaluation of patients with suspected tumor necrosis factor receptor-associated periodic syndrome

2.1 Complaints and Anamnesis

It is recommended to perform diagnostic procedures, including differential diagnosis, in all patients with suspected tumor necrosis factor receptor-associated periodic syndrome in an inpatient setting providing medical care to children with rheumatic diseases in order to establish a diagnosis [5,16].

(LoE 5, GoR C)

It is recommended to take medical history and ascertain complaints in all patients to identify clinical features of TRAPS [1,2,12,17].

(LoE 3, GoR B)

Comments: patients/parents may complain of fatigue, asthenia, malaise, weakness; fever/chills; annular skin rash and/or migratory painful spots, usually not accompanied by itching; joint pain, muscle pain; joint swelling and restricted movement; headache; abdominal pain accompanied by nausea and/or vomiting; swelling, redness of the eyes.

When taking medical history and ascertaining complaints, it is necessary to pay attention to a burdened family history (similar cases of the disease in siblings); presence of relatives with a history of fever episodes, skin rashes; joint pain or arthritis, kidney pathology, and death from renal failure.

It is recommended to analyze the hereditary history in all patients to identify similar cases of the disease in relatives [1,2,12,17].

(LoE 3, GoR B)

It is recommended to take a general medical history and ascertain complaints in all patients to identify the specific course of the pathological process [1,2,12,17].

(LoE 3, GoR B)

Comments: it is necessary to determine the age of disease onset, what preceded the appearance of the first symptoms and subsequent attacks, features of the disease course (nature of fever, rash, presence of musculoskeletal and ocular involvement; which symptoms appeared and in what sequence, how they were interrelated); whether periodicity of episodes was noted, persistence of symptoms during the intercritical period; and to analyze the results of all examinations performed since the manifestation of the disease. Whether exclusion of infectious, allergic, immunodeficiency, oncohematological and other tumor diseases was performed (whether bone marrow puncture was performed), rheumatic diseases, whether antibacterial and antihistamine drugs were used (which ones, dose, duration of administration, effect of their use). Whether glucocorticoids were used (dose, duration of administration, effect of their use), immunosuppressants (which one, dose, duration of administration, effect of their use), biological disease-modifying antirheumatic drugs (bDMARDs) (which one, dose, duration of administration, effect of their use).

2.2 Physical Examination

It is recommended to perform general thermometry in all patients to assess the severity and nature of fever [1,2,12,17].

(LoE 3, GoR B)

Comments: fever is the most frequent symptom of TRAPS, observed in almost all patients; it is febrile in nature (38–40 °C), the attack lasts from 7 to 21 days with intervals ranging from 2 weeks to 21 days, sometimes less frequently.

It is recommended to assess the general condition in all patients for subsequent dynamic monitoring [1,2,12,17].

(LoE 3, GoR B)

Comments: at the peak of fever, the general condition of children ranges from moderately severe to severe; a forced bed position is possible due to concomitant abdominal pain; malaise, weakness, and fatigue are noted. In the intercritical period, the patient is active, capable of working, and sometimes feels malaise, fatigue, and weakness despite normal temperature.

It is recommended to perform a general visual examination in all patients to identify rash and mucosal lesions [1,2,12,17].

(LoE 3, GoR B)

Comments: TRAPS is characterized by an annular rash with scalloped borders, presenting as painful erythema migrating within a day, usually without itching, localized on the limbs, trunk, face; the rash may also be maculopapular, urticarial, or erysipelas-like.

Mucosal involvement manifests as erythematous/exudative pharyngitis, aphthous stomatitis.

It is recommended to perform general palpation in all patients to detect peripheral lymphadenopathy [1,2,12,17].

(LoE 3, GoR B)

Comments: in patients with TRAPS, lymph nodes are usually not enlarged. However, in some cases, enlargement of isolated groups of lymph nodes or generalized lymphadenopathy develops. Lymph nodes are mobile, not fused to each other and underlying tissues, soft-elastic or dense-elastic in consistency, painless, though in some cases painful upon palpation.

It is recommended to take history and ascertain complaints, perform visual inspection, percussion, and palpation for heart and pericardial pathology in all patients to identify physical signs of its involvement [1,2,18–22].

(LEL 4, GRC C)

Comments: pericarditis may develop in TRAPS. Patients may complain of chest pain, epigastric pain, and a feeling of air hunger. Percussion reveals widening of the boundaries of relative cardiac dullness; auscultation reveals muffled heart sounds and a pericardial friction rub.

It is recommended to take history and ascertain complaints, perform visual inspection, percussion, and palpation for lung and bronchial diseases in all patients to identify physical signs of their involvement [1,2,18–20,22].

(LEL 4, GRC C)

Comments: pleurisy and/or pneumonitis, and rarely pneumonia, may develop in TRAPS. Patients may complain of persistent cough, chest pain, and a feeling of air hunger. Percussion reveals a mosaic percussion sound; auscultation reveals weakened breath sounds, fine moist/crepitant rales, and pleural friction rub.

It is recommended to take history and ascertain complaints, perform visual inspection, percussion, and palpation for 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 [1,2,12,17].

(LoE 3, GoR B)

Comments: TRAPS may present with: abdominal pain (in more than 70% of patients), diarrhea, constipation, nausea, hepatosplenomegaly, serous peritonitis, and gastrointestinal bleeding.

Severe abdominal pain with all symptoms of an acute abdomen occurs during an attack. It is necessary to evaluate peritoneal irritation signs (Shchetkin-Blumberg sign, Sitkovsky sign, Rovsing sign, etc.) and muscle defense.

Hepatosplenomegaly develops in some patients with TRAPS during an attack, as well as upon the development of amyloidosis.

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 the development of inflammatory lesions in the upper gastrointestinal tract (GIT).

If there are complaints of abdominal pain; nausea, abdominal distension; frequent episodes of vomiting, including those with blood impurities, frequent loose stools with mucus and/or blood, and/or green discoloration, gastrointestinal amyloidosis should be suspected, and inflammatory bowel disease (IBD) must be ruled out.

It is recommended to take history and ascertain complaints regarding joint pathology, perform visual joint examination and joint palpation in all patients to identify active arthritis [1,2,12,17].

(LoE 3, GoR B)

Comments: TRAPS is most commonly characterized by arthralgia and myalgia, and less frequently by mono-, oligo-, or polyarthritis, fasciitis, myositis, and bone pain.

It is recommended to determine the range of motion in all joints: determining the range of passive motion of a single joint in one plane, determining the range of active motion of a single joint in one plane in all patients with arthralgia/arthritis to identify functional impairment [1,2,5,16,18–20,23].

(LEL 4, GRC 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:

o Cervical spine. Ask the patient to: throw the head back (normal extension is 50–60°), touch the sternum 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 (normal lateral flexion is 40°).

o Temporomandibular joints. Ask the patient to: open the mouth, protrude and re-retract the mandible, perform side-to-side lateral movements of the mandible.

o Shoulder joints. Ask the patient to: raise the arms up through the sides, touch the right and left ear from behind the head, reach the right and left scapula with the opposite hand from behind, independently take off a shirt or T-shirt, and comb their hair.

o Elbow joints. Ask the patient to: place the 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°).

o Wrist joints. Check: dorsiflexion (normal is 70°), palmar flexion (normal is 90°).

o Small joints of the hands. Ask the patient to: make a fist (the fist should be tight), independently put on and take off socks and tights, button and unbutton clothes. Normally, the fingers easily touch the palm.

o Hip joints: check abduction (at least 140°), adduction (the patient should be able to touch the chest with thighs and knees), external and internal rotation (normal is at least 40–45°).

o Test for internal rotation of the hip joints. The child lies supine with hips and knees flexed at a 90° angle. Keeping the knees together, the lower legs are rotated outward.

o In almost all diseases of the hip joints, internal rotation is the first to be impaired.

o Knee joints. Ask the patient to: flex the legs at the knee joints (the heel should touch the buttocks), kneel down and lower the buttocks onto the heels, extend the knee joints (normal angle is 180°), squat down.

o Check the patellar tapotement (ballotment) test.

o 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.

o Joints of the feet and ankles. Check: dorsiflexion (normal angle is 45°), plantar extension (normal angle is 20°), supination (inward rotation of the foot is 30°), pronation (outward rotation of the foot is 20°). Ask the patient to: stand on tiptoes and walk, stand on heels and walk (normally the child should do this without difficulty). Observe asymmetry when moving the ankles in different directions. Marked limitation of flexion is usually detected without difficulty, even in the absence of visible joint swelling.

It is recommended to assess gait in all patients with arthralgia/arthritis in order to identify the nature of its impairment [1,5,16].

(LoE 5, GoR C)

Comments: gait is generally impaired when persistent arthritis or severe arthralgia develops. Gait patterns in joint involvement include:

o with a rapid transfer of body weight from the affected leg to the healthy one (involvement of the knee, hip joints, and feet). The patient steps on the whole foot or toe (heel involvement),

o "waddling" gait (bilateral involvement of the hip joints).

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 take the medical history and ascertain complaints for muscle diseases, take the medical history and ascertain complaints for bone system pathology, perform a visual examination of the muscles and bone system, and palpate the muscles and bone system in all patients to identify the nature of their involvement [1,2,12,17].

(LoE 3, GoR B)

Comments: myalgia is observed in TRAPS.

It is recommended to take the medical history and ascertain complaints, perform a visual inspection, percussion, and palpation regarding pathology of the kidneys and urinary system in all patients to identify the nature of their involvement [1,5,16].

(LoE 5, GoR C)

Comments: scrotal pain may develop in boys; progressive renal amyloidosis manifests as nephrotic syndrome (edema, decreased urine output).

It is recommended to exclude diseases that may present with similar clinical symptoms in all patients before prescribing pathogenetic therapy [18–20,24–26].

(LoE 5, GoR C)

Comments: diseases to be excluded during diagnosis: malignancies (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 (clinical) blood count with differential (including erythrocyte sedimentation rate determination, blood erythrocyte count, blood leukocyte count, blood platelet count, differential leukocyte count (leukocyte formula), and blood total hemoglobin level) in all patients to assess disease activity and identify pathological changes [18–20,23,27,28].

(LEL 4, GRC C)

Comments: in TRAPS, an increase in acute-phase reactants (ESR, leukocyte count, platelet count) is observed during attacks; between attacks, inflammatory activity is either absent or laboratory parameters are elevated, but not to the same extent as during an attack.

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 picture is not specific for TRAPS; therefore, diagnostic and differential diagnostic search must continue. First of all, hemoblastoses, lymphoproliferative, and oncological diseases must be excluded.

It is recommended to perform a coagulogram (screening hemostasis test) with determination of prothrombin index, antithrombin III activity in the blood, blood plasminogen level, blood fibrinogen level, blood D-dimer concentration, soluble fibrin monomer complex level 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 to assess the state of the hemostatic system [29–32].

(LoE 5, GoR C)

Comments: during the active period of the disease, there is an increase in blood fibrinogen concentration, D-dimer, blood soluble fibrin monomer complexes, and von Willebrand factor. With the development of MAS, 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 [29–31,33–37].

(LEL 4, GRC C)

It is recommended to perform a general routine biochemical blood test (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 Ringer's/potassium, total blood calcium, blood lactate dehydrogenase activity, aspartate aminotransferase activity, alanine aminotransferase activity, gamma-glutamyl transferase activity, alkaline phosphatase activity, serum iron, blood creatine kinase activity, pancreatic amylase activity, lipase activity) in all patients to detect pathological changes [2,18–20,23,27,38,39].

(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 determine the levels of antinuclear antibodies and anti-DNA antibodies, blood rheumatoid factor (RF), markers of ANCA-associated vasculitis: PR3 (c-ANCA), MPO (p-ANCA), anti-centromere antibodies, anti-RNA antibodies, anti-cyclic citrullinated peptide (anti-CCP) antibodies; antinuclear antibodies to Sm antigen, anti-Scl-70 antibodies, complement C3 fraction, and complement C4 fraction in all patients to rule out primary immunodeficiency and to confirm or exclude other rheumatic diseases [2,4,5,16,20,23,32,40].

(LoE 5, GoR C)

Comments: in TRAPS, blood immunoglobulin M and G levels, as well as complement C3 and C4 fractions, are within the normal range or elevated. Antibodies to nuclear antigens and DNA; RF, ANCA, anti-centromere antibodies, anti-RNA antibodies, anti-CCP; antinuclear antibodies to Sm antigen, and anti-Scl-70 antibodies are not elevated. If urticarial rashes persist, anti-C1q antibodies are determined to rule out hypocomplementemic urticarial vasculitis.

It is recommended to measure blood immunoglobulin levels in all patients to assess immune status and rule out primary immunodeficiency [32,41].

(LoE 3, GoR B)

Comments: blood immunoglobulin levels in TRAPS generally correspond to reference values.

It is recommended to determine serum antistreptolysin-O in all patients to rule out or confirm infection with group A beta-hemolytic streptococcus [32,41].

(LoE 3, GoR B)

Comments: an elevated serum antistreptolysin-O level indicates acute or chronic streptococcal infection, which may trigger a TRAPS attack.

It is recommended to measure serum C-reactive protein in all patients to determine disease activity [2,4,5,20,23,28,32].

(LEL 4, GRC C)

Comments: in TRAPS, serum C-reactive protein is elevated during a flare; it may also remain elevated during remission, though not to the same extent as during an attack.

It is recommended to determine AB0 blood groups, subgroups and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy, and Rh blood group D antigen (Rh factor) in all patients prior to invasive procedures (esophagogastroduodenoscopy, colonoscopy with biopsy, bone marrow aspiration, cytological examination of bone marrow trephine biopsy imprints, bone biopsy) [5,41–44].

(LoE 5, GoR C)

It is recommended to perform a general (clinical) urinalysis, determine urinary albumin, and measure 24-hour urinary protein in all patients to monitor renal function [2,18–20,23,27,32,38,39,45].

(LoE 5, GoR C)

Comments: micro- or macrohematuria may be a consequence of the nephrotoxic effects of NSAIDs.

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 as proteinuria increases, granular casts are detected in the urine sediment, with possible micro- and macrohematuria, and leukocyturia in the absence of pyelonephritis.

It is recommended to perform a complex of renal function tests in patients with clinical/laboratory signs of kidney damage in order to determine the degree of its impairment [2,14,16,18–20,23].

(LoE 5, GoR C)

Comments: the glomerular filtration rate is calculated using the Schwartz formula. Normally, the glomerular filtration rate in children aged 2 to 18 years is 90–130 mL/min/1.73 m². A decrease in the glomerular filtration rate in patients with uncontrolled TRAPS may indicate the development of secondary renal amyloidosis.

It is recommended to perform a complex of tests for the diagnosis and assessment of the severity of renal failure in patients with clinical/laboratory signs of nephrotic syndrome/renal failure in order to determine the extent of damage [2,14,16,18–20,23].

(LoE 5, GoR C)

It is recommended to perform molecular genetic testing—a complex of tests for the diagnosis of cryopyrin-associated periodic syndromes and other autoinflammatory diseases in all patients to confirm TRAPS and exclude other autoinflammatory diseases [18–20,23,16,46,47].

(LEL 4, GRC C)

Comments: partial or complete gene analysis is performed to detect mutations in the TNFRSF1A gene. Mutations are most frequently found in exons 2, 3, and 4.

The search for mutations in genes of other monogenic autoinflammatory diseases should be carried out when the duration of attacks is up to 7 days, with a specific ethnicity, urticaria-like rash, high intensity of abdominal syndrome, sensorineural hearing loss, aphthous stomatitis, cervical lymphadenopathy, and other symptoms that do not fit the typical picture of TRAPS.

Mutations in the NLRP3 gene responsible for the development of familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disease (CINCA/NOMID), as well as in genes responsible for mevalonate kinase deficiency (MKD) and familial Mediterranean fever (FMF), are identified.

It is recommended to determine the HLA-B27 antigen by flow cytometry in patients with clinical manifestations of TRAPS for differential diagnosis with spondyloarthropathies according to indications [16,23,48–51].

(LEL 4, GRC C)

Comments: the presence of HLA-B27 is not an exclusion criterion for the diagnosis of TRAPS.

It is recommended to test blood procalcitonin levels in all patients to exclude sepsis [45,52–56].

(Level of Evidence 1, Grade of Recommendation B)

Comments: in sepsis, blood procalcitonin levels are elevated. In TRAPS without infectious complications, they are within reference ranges.

It is recommended to study lymphocyte populations in all patients to rule out primary/secondary immunodeficiency [57,58].

(LEL 4, GRC C)

It is recommended to perform a focal reaction test with tuberculin (Mantoux test, test with recombinant tuberculosis allergen in standard dilution) and/or to test interferon-gamma release in response to Mycobacterium tuberculosis complex antigens in blood in all patients to rule out infection with Mycobacterium tuberculosis [40,45,59,60].

(LEL 4, GRC C)

It is recommended to determine the blood levels of class A, M, and G antibodies (IgA, IgM, IgG) to Chlamydia psittaci; antibodies to Chlamydophila pneumoniae; class M antibodies (IgM) to Chlamydia trachomatis; class G antibodies (IgG) to Chlamydia trachomatis; and class M and G antibodies (IgM, IgG) to Mycoplasma pneumoniae in all patients to rule out an infectious process that may present with a clinical picture similar to TRAPS [4,5,40,61–63].

(LoE 5, GoR C)

It is recommended to determine blood antibodies to Salmonella enterica, antibodies to Salmonella typhi, class M and G antibodies (IgM, IgG) to Yersinia pseudotuberculosis, and antibodies to Yersinia enterocolitica serovars in all patients to rule out an infectious process that may present with a clinical picture similar to TRAPS [4,5,40,61–63].

(LoE 5, GoR C)

It is recommended to determine blood class M and G antibodies (IgM, IgG) to Shigella boydii, class M and G antibodies (IgM, IgG) to Shigella dysenteriae, class M and G antibodies (IgM, IgG) to Shigella sonnei, and class M and G antibodies (IgM, IgG) to Shigella flexneri in all patients to detect/rule out an infectious process that may present with a clinical picture similar to TRAPS [4,5,62,64–66].

(LoE 5, GoR C)

It is recommended to perform PCR detection of Borrelia burgdorferi sensu lato group tick-borne borreliosis causative agents DNA in the blood; determine class M antibodies (IgM) to Borrelia burgdorferi sensu lato group tick-borne borreliosis causative agents in the blood; determine class G antibodies (IgG) to Borrelia burgdorferi sensu lato group tick-borne borreliosis causative agents in the blood; and determine total antibodies to Borrelia burgdorferi sensu lato group tick-borne borreliosis causative agents in patients with a history of visiting forests, living in tick-endemic areas, or tick bites, in order to rule out borreliosis [67–69].

(LoE 5, GoR C)

It is recommended to perform quantitative PCR detection of Epstein-Barr virus DNA in peripheral and cord blood, qualitative PCR detection of Epstein-Barr virus DNA in oropharyngeal swabs, and qualitative PCR detection of Epstein-Barr virus DNA in urine in all patients to detect/rule out herpesvirus infections [4,5,40,45,63,70–73].

(LoE 5, GoR C)

It is recommended to perform quantitative PCR detection of Cytomegalovirus DNA in peripheral and cord blood, qualitative PCR detection of Cytomegalovirus DNA in oropharyngeal swabs, and qualitative PCR detection of Cytomegalovirus DNA in urine in all patients to detect/rule out herpesvirus infections [4,5,40,45,63,73–76].

(LoE 5, GoR C)

It is recommended to perform quantitative PCR detection of Herpes simplex virus types 1, 2 DNA in the blood, qualitative PCR detection of Herpes simplex virus types 1, 2 DNA in oropharyngeal swabs, and qualitative PCR detection of Herpes simplex virus types 1, 2 DNA in urine in all patients to detect/rule out herpesvirus infections [4,5,40,45,63,77–81].

(LoE 5, GoR C)

It is recommended to determine blood class M and G antibodies (IgM, IgG) to Cytomegalovirus in all patients to detect/rule out active cytomegalovirus infection [4,5,40,45,63,75,82–84].

(LoE 5, GoR C)

It is recommended to determine blood class M and G antibodies (IgM, IgG) to Epstein-Barr virus in all patients to detect/rule out Epstein-Barr virus infection [4,5,40,45,63,70–73].

(LoE 5, GoR C)

It is recommended to determine blood antibodies to the viral capsid antigen (VCA) of Epstein-Barr virus in all patients to detect/rule out Epstein-Barr virus infection [4,5,40,45,63,70–73].

(LoE 5, GoR C)

It is recommended to determine blood class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus in all patients to detect/rule out Epstein-Barr virus infection [4,5,40,45,63,70–73].

(LoE 5, GoR C)

It is recommended to determine blood antibodies to Herpes simplex virus in all patients to detect/rule out herpes simplex virus infection [4,5,40,45,63,77–79,81,85].

(LoE 5, GoR C)

It is recommended to perform molecular biological testing of blood for Hepatitis C virus and Hepatitis B virus in patients with clinical and laboratory signs of hepatitis for differential diagnosis [86–88].

(LoE 5, GoR C)

Comments: in patients with TRAPS, hepatitis may develop secondary to uncontrolled NSAID use or may be a sign of secondary hemophagocytic lymphohistiocytosis.

It is recommended to determine blood hepatitis B surface antigen (HBsAg) (Hepatitis B virus) and antibodies to Hepatitis C virus in patients with clinical and laboratory signs of hepatitis for differential diagnosis [86–88].

(LoE 5, GoR C)

It is recommended to determine blood class M and G antibodies (IgM, IgG) to Human immunodeficiency virus HIV 1 and class M and G antibodies (IgM, IgG) to Human immunodeficiency virus HIV 2 in patients with signs of immunodeficiency to detect/rule out HIV infection [89,90].

(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 and leishmaniasis [91].

(LoE 5, GoR C)

It is recommended to determine blood antibodies to Leishmania in patients with a history of animal contact to rule out leishmaniasis [40,92–94].

(LoE 3, GoR B)

It is recommended to perform microbiological (culture) examination of tonsillar and posterior pharyngeal wall mucus for aerobic and facultatively anaerobic microorganisms in all patients to rule out nasopharyngeal colonization by pathogenic and opportunistic flora [40,45,63].

(LoE 5, GoR C)

It is recommended to perform microbiological (culture) blood testing for sterility and microbiological (culture) urine testing for aerobic and facultatively anaerobic opportunistic microorganisms in all patients to detect/rule out acute inflammatory response (sepsis) and bacteremia [45,52,53].

(LoE 5, GoR C)

It is recommended to measure fecal calprotectin levels in all patients to rule out inflammatory bowel disease [95–97].

(Level of Evidence 1, Grade of Recommendation B)

2.4 Instrumental Diagnostics

It is recommended to perform comprehensive ultrasound examination of internal organs (including comprehensive abdominal ultrasound and renal ultrasound) in all patients to detect/rule out pathological changes [2].

(LoE 5, GoR C)

Comments: the examination may reveal signs of peritonitis, renal involvement, enlargement of mesenteric lymph nodes, liver, and/or spleen, assess bowel motility, and rule out 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 TRAPS to detect cardiac involvement, perform differential diagnosis with acute rheumatic fever, systemic juvenile idiopathic arthritis, Kawasaki disease, infective endocarditis, and other autoinflammatory diseases (recurrent pericarditis) [2,18–20,23,50,98].

(LEL 4, GRC C)

Comments: myocarditis manifests with left ventricular (LV) dilation, decreased left ventricular ejection fraction, hypokinesia of the posterior LV wall and/or interventricular septum, aortitis, signs of relative mitral, aortic, and/or tricuspid valve regurgitation, and elevated pulmonary artery pressure. Myocarditis is not typical for TRAPS. The endocarditis and valve apparatus are generally unaffected in TRAPS. Pericarditis is characterized by separation of the pericardial leaflets and the presence of free fluid in the pericardial cavity.

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/rule out pathological changes [19].

(LoE 5, GoR 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 an ultrasound examination of the joint in patients with active arthritis to assess the severity of joint effusion, the state of the synovial membrane, and cartilage [2,16,20,23,51,99].

(LoE 5, GoR C)

Comments: in TRAPS, signs of synovitis and increased synovial fluid volume are detected. Thickening (proliferation) of the synovial membrane, cartilage fibrillation, and cartilage erosions are possible. However, these changes are more often observed in juvenile arthritis.

It is recommended to perform X-ray imaging of the temporomandibular joint and/or X-ray imaging of the intervertebral joints, and/or X-ray imaging of the elbow joint, and/or X-ray imaging of the wrist joint, and/or X-ray imaging of the knee joint, and/or X-ray imaging of the shoulder joint, and/or X-ray imaging of the hip joint, and/or X-ray imaging of the ankle joint, and/or X-ray imaging of the acromioclavicular joint, and/or X-ray imaging of the sternoclavicular joint, and/or X-ray imaging of the hand and/or X-ray imaging 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/rule out pathological changes [2,16,20,23,51,59,99].

(LoE 5, GoR C)

Comments: juvenile arthritis, bone tuberculosis, osteomyelitis, benign and malignant tumors, and bone metastases are ruled out.

In juvenile arthritis, the following are detected: osteoporosis, destructive changes in bone structures, alterations in the joint space, integrity of the articular surfaces of the bones forming the joint, presence of erosions, uesuration of articular surfaces, cysts, foci of bone necrosis, subluxations, fractures, osteophytes, calcifications, etc.

It is recommended to perform contrast-enhanced magnetic resonance imaging of joints (single joint) with or without anesthesia (including early postoperative management) in patients with active arthritis to rule out traumatic injuries of the tendon-ligament apparatus, menisci, tumors, purulent (septic) arthritis, and juvenile arthritis [2,16,20,23,51,59,99].

(LoE 5, GoR C)

It is recommended to perform a plain abdominal X-ray in all patients with abdominal syndrome to rule out intestinal obstruction and perforation of a hollow abdominal viscus [1,2,17–20].

(LoE 5, GoR C)

Comments: in hollow organ perforation, free air is detected on plain abdominal radiographs; in intestinal obstruction, fluid levels in intestinal loops are observed.

It is recommended to perform esophagogastroduodenoscopy with or without anesthesia (including early postoperative management) in all patients to rule out inflammatory as well as erosive and ulcerative processes [13,96,100–102].

(LoE 5, GoR C)

Comments: specific erosive/ulcerative lesions are not typical for TRAPS; they may be a manifestation of inflammatory gastropathy (whether associated with Helicobacter pylori or not), Crohn's disease involving the upper gastrointestinal tract, or amyloidosis.

A pathomorphological (biopsy/surgical specimen) examination is required to establish the diagnosis.

It is recommended to perform a microbiological (culture) examination of gastric mucosa biopsies for Helicobacter pylori (Helicobacter pylori) in patients with inflammatory and/or erosive and/or ulcerative changes according to esophagogastroduodenoscopy data, to rule out Helicobacter pylori-associated gastrointestinal pathology [13,96,100–102].

(LEL 4, GRC C)

It is recommended to perform endoscopic esophageal biopsy, endoscopic gastric biopsy, endoscopic duodenal biopsy, and endoscopic jejunal biopsy with or without anesthesia (including early postoperative management), accompanied by pathomorphological examination of the biopsy (surgical) material of the esophagus, stomach, duodenum, and jejunum, in patients with inflammatory and/or erosive and/or ulcerative mucosal changes according to esophagogastroduodenoscopy data, to rule out inflammatory bowel diseases [13,96,100–102].

(LEL 4, GRC C)

It is recommended to perform colonoscopy with anesthesia (including early postoperative management) in all patients to rule out inflammatory bowel disease and amyloidosis [13,96,103,104].

(LEL 4, GRC C)

Comments: erosive/ulcerative lesions of the intestinal mucosa can develop in inflammatory bowel disease and amyloidosis. A pathomorphological examination of the biopsy (surgical) material is required to establish the diagnosis.

It is recommended to perform an endoscopic biopsy of the large intestine with pathomorphological examination of the large intestine biopsy (surgical) material in patients who show inflammatory and/or erosive and/or ulcerative changes in the large intestine according to colonoscopy data, to rule out inflammatory bowel disease and amyloidosis [13,96,103,104].

(LEL 4, GRC C)

It is recommended to perform contrast-enhanced magnetic resonance enterography (MR enterography, hydro-MRI) 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 changes on esophagogastroduodenoscopy and colonoscopy, to rule out contraindications for capsule endoscopy of the small intestine (to rule out/confirm small bowel strictures or when such conditions are suspected) [105–108].

(Level of Evidence 1, Grade of Recommendation B)

Comments: if small bowel strictures are present, capsule endoscopy of the small intestine is contraindicated.

It is recommended to perform capsule endoscopy of the small intestine in patients with clinical signs of inflammatory bowel disease and/or significantly elevated fecal calprotectin in the absence of changes on esophagogastroduodenoscopy and colonoscopy, to rule out inflammatory bowel disease with isolated small bowel involvement [95].

(LoE 5, GoR C)

It is recommended to perform computed tomography of the chest cavity with or without anesthesia (including early postoperative management) in all patients to detect pleurisy, rule out/confirm pneumonia, oncological/oncohematological/lymphoproliferative diseases, tuberculosis, sarcoidosis, and granulomatous vasculitis [18–20,61,62,109,110].

(LoE 5, GoR C)

It is recommended to perform contrast-enhanced magnetic resonance imaging of the brain, intravenous contrast-enhanced magnetic resonance imaging of the abdominal cavity, intravenous contrast-enhanced magnetic resonance imaging of the retroperitoneal space, and intravenous contrast-enhanced magnetic resonance imaging of the pelvic organs with or without anesthesia (including early postoperative management) in all patients to detect/rule out pathology [60,104,109–112].

(LoE 5, GoR C)

Comments: oncological/oncohematological/lymphoproliferative diseases, tuberculosis of intra-abdominal lymph nodes, and purulent inflammation in the abdominal cavity and small pelvis are ruled out.

The development of secondary amyloidosis is manifested by hepatosplenomegaly and typical renal changes.

It is recommended to perform 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 support (including early postoperative management), in patients with contraindications to MRI in order to rule out internal organ involvement in TRAPS, and to detect/rule out oncological/onco-hematological/lymphoproliferative diseases, tuberculosis, and abscesses [60,104,109–112].

(LoE 5, GoR C)

It is recommended to perform contrast-enhanced magnetic resonance imaging of the brain, 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 in order to detect/rule out pathological changes [23,113].

(LoE 5, GoR C)

Comments: space-occupying lesions, inflammatory and infectious processes, strokes, and posterior reversible encephalopathy syndrome are ruled out.

It is recommended to perform a lumbar puncture with anesthesia support (including early postoperative management), including microscopic examination, cell counting in a counting chamber (determination of cytosis), examination of the physical properties of the cerebrospinal fluid, and serological examination, in all patients with symptoms of CNS involvement in order to confirm/rule out pathological changes [23].

(LoE 5, GoR C)

Comments: performed in patients with neurological manifestations (headaches, seizures) to rule out the infectious origin of neurological disorders (meningococcal infection, viral meningitis, etc.), as well as to rule out aseptic meningitis in CAPS and systemic lupus erythematosus.

It is recommended to perform a kidney biopsy with anesthesia support (including early postoperative management) and pathomorphological examination of the renal biopsy (surgical) specimen in patients with clinical/laboratory/ultrasound signs of renal involvement and/or renal failure, and/or in the presence of proteinuria > 500 mg per day in order to perform differential diagnosis of secondary amyloidosis from other diseases accompanied by renal involvement, provided there are no contraindications [2,114,115].

(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 intermediary zone and along the straight vessels of the pyramids, and edema and areas of sclerosis develop. In the proteinuric (albuminuric) stage, amyloid appears in the mesangium, capillary loops, pyramids, and cortical layer of the glomeruli, as well as in blood vessels. Sclerosis and atrophy of nephrons, hyperemia, and lymphostasis develop. The kidneys are enlarged, dense, and have a dull grayish-pink color.

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, and scarred.

It is recommended to obtain a bone marrow cytologic preparation by puncture and a bone marrow histologic preparation with anesthesia support (including early postoperative management), 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 in order to rule out oncological/oncohematological/lymphoproliferative diseases/metastatic bone marrow involvement [2,23,63].

(LoE 5, GoR C)

Comments: in cases where GCs or immunosuppressants are used, the test should be 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), with cytologic examination of the lymph node tissue preparation and pathomorphological examination of the biopsy (surgical) material, in patients with marked enlargement of peripheral and/or intrathoracic and/or intra-abdominal lymph nodes at the diagnostic stage prior to prescribing pathogenetic therapy, in order to rule out hemoblastoses, lymphoproliferative diseases, and metastatic lymph node involvement [63,109,116–118].

(LEL 4, GRC C)

Comments: in cases where GCs or immunosuppressants are used, the test should be 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 prior to prescribing GCs, ^#Colchicum autumnale seed extract/colchicine, and/or an immunosuppressant, and/or a biological DMARD in patients with atypical TRAPS presentation during the workup stage, in order to rule out oncological/oncohematological/lymphoproliferative diseases/metastatic bone marrow involvement [110,117,118].

(LEL 4, GRC C)

Comments: in cases where GCs or immunosuppressants are used, the test should be 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 TRAPS in order to rule out malignant and benign tumors and metastatic bone lesions [63,109,110,117,118].

(LEL 4, GRC C)

Comments: bone destruction is not typical for TRAPS. Destruction foci are characteristic of multifocal osteomyelitis, malignant neoplasms, and hemoblastoses, which can manifest with episodes of febrile fever accompanied by pain in the abdomen, chest, joints, and bones. Bone biopsy is required for 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 that are atypical for TRAPS in order to rule out malignant and benign bone tumors and metastatic bone lesions [109,110,117,118].

(LoE 5, GoR C)

It is recommended to perform positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)) with contrast enhancement, or if necessary, whole-body positron emission tomography with tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)), with or without anesthesia support (including early postoperative management), in patients with severe arthralgia, myalgia, ossalgia, bone destruction changes, subcutaneous adipose tissue infiltrates, or lesions in parenchymal organs, the brain, or the spinal cord, in order to detect/rule out oncological/onco-hematological/lymphoproliferative diseases [63,109,110,116,119–121].

(LEL 2, GRR C)

Comments: PET-CT is performed in patients with severe arthralgia, myalgia, ossalgia, bone destruction changes, subcutaneous adipose tissue infiltrates, or lesions in parenchymal organs, the brain, or the spinal cord in order to rule out oncological/onco-hematological/lymphoproliferative diseases.

2.5 Other Procedures

It is recommended to perform an initial consultation (examination, assessment) by a pediatric surgeon in patients with abdominal symptoms in order to rule out acute surgical pathology [2,4,5,16,18–20,23,63].

(LoE 5, GoR C)

It is recommended to perform an initial consultation (examination, assessment) by a gastroenterologist in all patients with abdominal symptoms in order to determine further management and rule out other diseases [2,4,5,16,18–20,23,63].

(LoE 5, GoR C)

It is recommended to perform an initial consultation (examination, assessment) by a pediatric oncologist in patients suspected of having an oncological or onco-hematological disease based on examination results, in order to rule them out [2,4,5,16,18–20,23,63,109,110].

(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 examination (inspection, consultation) by a pediatric urologist-andrologist for all male patients with abdominal symptoms, pain syndrome, and inflammatory changes in the gonadal region to address the issue of further examination [2,4,5,16,18–20,23,63].

(LoE 5, GoR C)

It is recommended to perform an initial examination (inspection, consultation) by an obstetrician-gynecologist for all female patients with abdominal symptoms, pain syndrome in the gonadal region to address the issue of further examination and rule out gynecological diseases [2,4,5,16,18–20,23,63].

(LoE 5, GoR C)

It is recommended to perform an initial examination (inspection, consultation) by a nephrologist for patients with abnormalities in urinalysis and/or with nephrotic syndrome/renal failure to address the issue of further examination and to detect/rule out nephrological pathology/renal amyloidosis [2,14,39,114,115,122,123].

(LoE 5, GoR C)

It is recommended to perform an initial examination (inspection, consultation) by a neurologist for patients with symptoms of central and peripheral nervous system involvement and patients with thoracic symptoms to detect/rule out pathological changes [2,4,5,18–20,23,113].

(LoE 5, GoR C)

Comments: a TRAPS attack may be accompanied by drowsiness, headache, and seizures.

It is recommended to perform an initial examination (inspection, consultation) by a phthisiatrician for patients with positive focal tuberculin skin tests and/or an elevated level of interferon-gamma to Mycobacterium tuberculosis complex antigens in the blood and/or infiltrative foci in the lungs to rule out tuberculosis [40,45,59,60].

(LEL 4, GRC C)

It is recommended to perform an initial examination (inspection, consultation) by an orthopedic traumatologist for patients with acute arthritis, volumetric and destructive changes, as well as bone deformities not typical for TRAPS to rule out septic arthritis, osteomyelitis, and other surgical pathologies [2,4,5,16,18–20,23,63].

(LoE 5, GoR C)

It is recommended to perform an initial examination (inspection, consultation) by an otorhinolaryngologist for all patients to detect foci of acute ENT infection [2,4,5,18–20,23,40,45,63].

(LEL 4, GRC C)

It is recommended to perform an initial examination (inspection, consultation) by a pediatric otorhinolaryngologist-audiologist for all patients to detect sensorineural hearing loss [2,4,5,18–20,63,124].

(LoE 5, GoR C)

Comments: sensorineural hearing loss is not characteristic of TRAPS; if detected, cryopyrin-associated periodic syndromes must be ruled out.

It is recommended to perform an initial ophthalmological examination (inspection, consultation) with mandatory ocular biomicroscopy for all patients to detect visual organ involvement [2,4,5,18–20,63,124].

(LoE 5, GoR C)

Comments: conjunctivitis, periorbital edema, periorbital pain, and in some cases uveitis are observed in TRAPS.

It is recommended to perform an examination (inspection, consultation) by a pediatric dentist for patients with clinical indications to rule out acute oral cavity pathology [2,4,5,18–20,63,124].

(LoE 5, GoR C)

It is recommended to perform an initial examination (inspection, consultation) by a geneticist for patients in whom molecular genetic testing reveals mutations in the TNFRSF1A gene to determine their pathogenicity [2,4,5,18–20,63,124].

(LoE 5, GoR C)

It is recommended to conduct an initial medical psychology assessment (testing, consultation) 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 under conditions of severe chronic illness and optimize parent-child relationships; to increase treatment adherence and cooperation with the physician and medical staff to achieve disease remission; to achieve social psychological adaptation; and to develop an individual psychological rehabilitation program for the patient and their parents [125–127].

(Level of Evidence 3, Grade of Recommendation C)

It is recommended to conduct an initial examination (consultation) by an anesthesiologist-resuscitologist for patients scheduled for examinations under general anesthesia to assess their condition [42,43,128–130].

(LoE 5, GoR C)

It is recommended to conduct an initial examination (consultation) by an anesthesiologist-resuscitologist for patients in severe condition to address the issue of transfer to the intensive care unit [42,43,128–130].

(LoE 5, GoR C)

It is recommended to provide 24-hour monitoring by an anesthesiologist-resuscitologist for all patients in critical condition (multiple organ dysfunction syndrome, hemophagocytic syndrome) to provide care in the intensive care unit [42,43,128–130].

(LoE 5, GoR C)

Evaluation of patients with periodic fever syndrome caused by a mutation of the tumor necrosis factor receptor type 1 gene with suspected hemophagocytic syndrome

Secondary hemophagocytic syndrome (sHPS) is a complication of TRAPS, a dangerous hyperinflammatory syndrome, representing the endpoint of a severe uncontrolled reaction characterized by hypercytokinemia with a significant yet ineffective immune response. This is a consequence of the innate or acquired inability of the immune system to cope with the trigger—most commonly an infectious agent [119,131–137].

Secondary HPS is triggered by viruses (cytomegalovirus, Epstein-Barr virus, herpesviruses, etc.), medications (NSAIDs, gold preparations, sulfasalazine**, etc.). Secondary HPS is the result of excessive activation and expansion of mononuclear phagocyte system (MPS) cells and T-lymphocytes, manifested by cytopenia, systemic inflammatory response, and liver and spleen damage. The cells comprising the MPS form a single differentiation lineage, including bone marrow progenitor cells as well as a pool of monocytes and macrophages. The MPS as a whole acts as a specific biological filter for blood and lymph, removing tumor cells, virus-infected cells, microorganisms, toxins, various metabolites, and circulating immune complexes. Histiocytes (syn.: macrophages) also perform antigen-presenting functions [119,131–137].

It is not always possible to establish a diagnosis of sHPS because its clinical and laboratory manifestations may resemble a TRAPS flare, as well as an infectious process [119,131–137].

Physical examination

It is recommended to perform diagnostics, including differential diagnostics, in all patients with suspected HPS in an inpatient setting providing medical care to children with rheumatic diseases [5,16].

(LoE 5, GoR C)

It is recommended to perform general thermometry in all patients to assess the severity and pattern of fever [138].

(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 assess the general condition of all patients for its subsequent monitoring [138].

(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 general visual inspection in all patients to identify pathological changes [138].

(LoE 5, GoR C)

Comments: the frequency of cutaneous manifestations in HPS ranges from 6 to 65%. Skin involvement may present as a generalized maculopapular rash, erythroderma, edema, panniculitis, morbilliform rash, and purpura. Some manifestations are similar to those in 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 to detect peripheral lymphadenopathy [138].

(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 complaints, perform visual inspection, percussion, and auscultation for heart and pericardial pathology in all patients to identify pathological changes [138].

(LoE 5, GoR C)

Comments: progressive sHPS leads to microangiopathy with thrombosis, which may be accompanied by arrhythmias and, in some cases, myocardial infarction. One of the consequences of microvascular thrombosis, microvascular dysfunction, or stress-induced cardiomyopathy is acute heart failure.

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 complaints, perform visual inspection, percussion, and auscultation for lung and bronchial diseases in all patients to identify pathological changes in the respiratory system [138].

(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 complaints, perform visual inspection, percussion, and palpation for diseases of the liver, biliary tract, pancreas, esophagus, stomach, duodenum, small intestine, and large intestine in all patients to detect pathological changes [138].

(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.

Laboratory diagnostic tests

It is recommended to perform a complete blood count (including erythrocyte sedimentation rate, red blood cell count, white blood cell count, platelet count, differential leukocyte count (leukocyte formula), and total hemoglobin level) in all patients to identify pathological changes characteristic of HPS [133,135,136,138–142].

(LoE 5, GoR C)

Comments: HPS is characterized by thrombocytopenia, leukopenia, erythropenia, and a decreased ESR.

It is recommended to perform a coagulogram (exploratory hemostasis evaluation) including prothrombin index, antithrombin III activity, plasminogen level, fibrinogen level, D-dimer concentration, soluble fibrin monomer complexes, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, thrombin time, protein C level, protein S activity, and von Willebrand factor activity and properties in all patients to assess the state of the hemostatic system [29–31,143,144].

(LEL 4, GRC C)

Comments: HPS is characterized by elevated levels of D-dimer and fibrin degradation products (an early preclinical sign), and a decreased fibrinogen level.

It is recommended to perform thromboelastography in all patients to assess the severity of hemostatic disorders and the risk of thrombosis and bleeding [29–31,143,145].

(LoE 5, GoR C)

It is recommended to measure blood heparin levels in all patients receiving heparin group drugs to assess the severity of hemostatic disorders and the risk of thrombosis/bleeding [29–31,35,36,143,145–147].

(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, uric acid, glucose, ferritin, triglycerides, 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) to identify pathological changes characteristic of HPS [133,135,136,138–142].

(LoE 5, GoR C)

Comments: HPS is characterized by elevated serum levels of ferritin, triglycerides, ALT, AST, and LDH, as well as hyponatremia, hypochloremia, and hypoalbuminemia.

As multiple organ dysfunction progresses, hyperbilirubinemia, elevated creatinine, uric acid, and urea levels may be observed.

It is recommended to measure serum C-reactive protein in all patients to determine disease activity [133,135,136,138–142].

(LEL 4, GRC C)

Comments: serum CRP levels increase significantly with the development of HPS.

It is recommended to perform microbiological (culture) blood test for sterility, microbiological (culture) examination of tonsil and posterior pharyngeal wall mucus for aerobic and facultatively anaerobic microorganisms, microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms, and 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 sHPS [5,135,136,141,148–152].

(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) to Mycoplasma pneumoniae in blood in all patients to detect/exclude active mycoplasma and/or chlamydial infection as a triggering factor for sHPS [4,5,40,135,141,148,150,151].

(LoE 5, GoR C)

It is recommended to detect Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR when interstitial and/or focal, and/or infiltrative lung changes are detected on chest computed tomography to identify/exclude active mycoplasma infection as a triggering factor for sHPS [83,136,149,150,153–156].

(LoE 5, GoR C)

It is recommended to detect Epstein-Barr virus (Epstein-Barr virus) DNA in peripheral and umbilical cord blood by quantitative PCR, Epstein-Barr virus (Epstein-Barr virus) DNA in oropharyngeal mucosal swabs by qualitative PCR, and Epstein-Barr virus (Epstein-Barr virus) DNA in urine by qualitative PCR in all patients to identify/exclude active herpesvirus infection as a triggering factor for sHPS [5,70,70–73,83,136,149,150,157].

(LEL 4, GRC C)

It is recommended to perform quantitative PCR to determine Cytomegalovirus DNA in peripheral and cord blood, qualitative PCR to determine Cytomegalovirus DNA in oropharyngeal swabs, and qualitative PCR to determine Cytomegalovirus DNA in urine in all patients to identify or rule out an active herpesvirus infection as a triggering factor for sHLH [5,73,75,76,82,83,135,136,141,149,150,157,158].

(LEL 4, GRC C)

It is recommended to perform quantitative PCR to determine Herpes simplex virus types 1, 2 DNA in blood, qualitative PCR to determine Herpes simplex virus types 1, 2 DNA in oropharyngeal swabs, and qualitative PCR to determine Herpes simplex virus types 1, 2 DNA in urine in all patients to identify or rule out an active herpesvirus infection as a triggering factor for sHLH [5,73,77,82,83,135,149,150,159,160].

(LEL 4, GRC C)

It is recommended to determine IgM and IgG antibodies to Cytomegalovirus in the blood of all patients to identify or rule out an active cytomegalovirus infection as a triggering factor for sHLH [76,83,135,141].

(LoE 5, GoR C)

It is recommended to determine IgM and IgG antibodies to Epstein-Barr virus in the blood of all patients to identify or rule out an active Epstein-Barr virus infection as a triggering factor for sHLH [71,75,135,141,149,150,158].

(LEL 4, GRC C)

It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus in the blood of all patients to identify or rule out an active Epstein-Barr virus infection as a triggering factor for sHLH [71,75,135,141,149,150,158].

(LEL 4, GRC C)

It is recommended to determine IgG antibodies to early antigens (EA) of Epstein-Barr virus in the blood of all patients to identify or rule out an active Epstein-Barr virus infection as a triggering factor for sHLH [71,75,135,141,149,150,158].

(LEL 4, GRC C)

It is recommended to determine antibodies to Herpes simplex virus in the blood of all patients to identify or rule out an active herpesvirus infection as a triggering factor for sHLH [77,79,135,141,149].

(LEL 4, GRC C)

It is recommended to perform microbiological (culture) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms using automated inoculation with antimicrobial susceptibility testing when interstitial, focal, and/or infiltrative lung changes are detected on chest computed tomography, in order to identify the etiological factor of pulmonary involvement [135,141,161,162].

(LEL 4, GRC C)

It is recommended to determine Epstein-Barr virus DNA in sputum and bronchoalveolar lavage fluid by PCR when interstitial, focal, and/or infiltrative lung changes are detected on chest computed tomography, in order to identify or rule out an active Epstein-Barr virus infection as a triggering factor for sHLH [134,135,161–164].

(LEL 4, GRC C)

It is recommended to determine Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR when interstitial, focal, and/or infiltrative lung changes are detected on chest computed tomography, in order to identify or rule out an active cytomegalovirus infection as a triggering factor for sHLH [134,135,161–164].

(LEL 4, GRC C)

It is recommended to perform quantitative PCR to determine Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, and bronchoalveolar lavage fluid when interstitial, focal, and/or infiltrative lung changes are detected on chest computed tomography, in order to identify or rule out an active Pneumocystis infection as a triggering factor for sHLH [135,149,158,165–170].

(LEL 4, GRC C)

It is recommended to determine IgM and IgG antibodies to Pneumocystis jirovecii in the blood when interstitial, focal, and/or infiltrative lung changes are detected on chest computed tomography, in order to identify or rule out an active Pneumocystis infection as a triggering factor for sHLH [135,136,149,167,171,172].

(LoE 5, GoR C)

It is recommended to perform microbiological (culture) examination of bronchoalveolar lavage fluid for Pneumocystis cysts (Pneumocystis carinii) when interstitial, focal, and/or infiltrative lung changes are detected on chest computed tomography, in order to identify or rule out an active Pneumocystis infection as a triggering factor for sHLH [135,141,149,158,164–170,173,174].

(LEL 4, GRC C)

It is recommended to perform microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeasts and molds) when interstitial, focal, and/or infiltrative lung changes are detected on chest computed tomography, in order to identify or rule out a mycosis as a triggering factor for sHLH [141,149,161,168,175,176].

(LEL 4, GRC C)

It is recommended to determine Candida albicans mannan antigen and Aspergillus spp. galactomannan antigen in blood serum by enzyme-linked immunosorbent assay (ELISA) when interstitial, focal, and/or infiltrative lung changes are detected on chest computed tomography, in order to identify or rule out aspergillosis as a triggering factor for sHLH [141,149,161,168,175,176].

(LEL 4, GRC C)

It is recommended to determine Candida albicans mannan antigen and Aspergillus spp. galactomannan antigen in bronchoalveolar lavage fluid by enzyme-linked immunosorbent assay (ELISA) when interstitial, focal, and/or infiltrative lung changes are detected on chest computed tomography, in order to identify or rule out aspergillosis as a triggering factor for sHLH [141,149,161,168,175,176].

(LEL 4, GRC C)

It is recommended to measure blood procalcitonin levels in all patients to rule out sepsis [30,53–56,135,141].

(Level of Evidence 1, Grade of Recommendation B)

Comments: an elevated procalcitonin level should raise suspicion of secondary infection and sepsis development.

It is recommended to perform a complete urinalysis, determine urine albumin, and quantify 24-hour urine protein in all patients for the diagnosis and assessment of renal failure severity [134,135,139,140,177].

(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 findings may also include interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Patients with sHLH-AKI typically present with oliguria, azotemia, and nephrotic syndrome. Urinalysis reveals varying degrees of proteinuria, macro- and microhematuria, and cylindruria.

Instrumental diagnostic tests

It is recommended to perform a comprehensive ultrasound examination of internal organs (including a comprehensive abdominal ultrasound and renal ultrasound) in all patients to detect hepatosplenomegaly and enlarged intra-abdominal lymph nodes [5,16,135,141,178,179].

(LEL 4, GRC C)

It is recommended to perform echocardiography in all patients to assess cardiac status [5,16,135,140,141].

(LEL 4, GRC C)

It is recommended to perform an electrocardiogram in all patients to assess cardiac function [5,16,135,141,180].

(LoE 5, GoR C)

It is recommended to perform chest computed tomography with or without anesthesia support (including early postoperative management) in all patients to identify or rule out pulmonary involvement [5,16,135,141,178].

(LEL 4, GRC 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 anesthesia support (including early postoperative management) in patients with neurological symptoms to detect brain involvement [5,16,135,141,178,181].

(LEL 4, GRC 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 (MRI) of the abdominal cavity, MRI of the retroperitoneal space, and MRI of the pelvic organs with or without anesthesia/sedation support (including early postoperative management) in the event of multiorgan failure in all patients to detect organomegaly, free fluid in the abdominal and pelvic cavities, and to assess the state of the liver, kidney, and splenic parenchyma [5,16,135,139,141,182].

(LoE 5, GoR C)

It is recommended to obtain a bone marrow cytological preparation by puncture using anesthesia/sedation support (including early postoperative management) and a bone marrow histological preparation with cytological examination of a bone marrow smear (myelogram) and pathomorphological examination of bone marrow biopsy (surgical) material in all patients to identify differentiated macrophages phagocytosing hematopoietic cells [5,16,132,135,141,183–185].

(LoE 5, GoR C)

Comments: bone marrow aplasia may develop in severe HFS.

Other diagnostic examinations

It is recommended that patients with neurological symptoms undergo an initial consultation (examination) by a neurologist to assess the state of the central and peripheral nervous system [5,16,135,141].

(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 that patients with hemorrhagic syndrome undergo an initial consultation (examination) by an ophthalmologist to assess the media and membranes of the eye, optic nerve, retina, and fundus [5,16,135,141,186–188].

(LoE 5, GoR C)

Comments: patients with hemophagocytic syndrome (HPS) may exhibit retinal hemorrhages, optic neuritis, and uveal infiltration.

(LoE 5, GoR C)

Criteria for diagnosing secondary hemophagocytic syndrome in patients with periodic fever syndrome associated with a mutation in the tumor necrosis factor receptor type 1 gene.

A. Ravelli et al. criteria [189]

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 periodic fever syndrome associated with a tumor necrosis factor receptor type 1 gene mutation, in the presence of 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 tests by PCR with determination of 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 verify the diagnosis of secondary HPS according to the criteria of A. Ravelli et al. from 2016 (see section 2.3) and initiate immunosuppressive therapy in accordance with the treatment algorithm for periodic fever syndrome associated with a tumor necrosis factor receptor type 1 gene mutation (see section 3.1.2).

Monitoring of early markers of secondary HPS development [190]:

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 blood 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 secondary HPS development are identified, immunosuppressive therapy must be initiated in accordance with the treatment algorithm for periodic fever syndrome associated with a tumor necrosis factor receptor type 1 gene mutation with hemophagocytic syndrome (see section 3.1.2).

Evaluation of patients with a confirmed diagnosis of periodic fever syndrome associated with a tumor necrosis factor receptor type 1 gene mutation during 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 TRAPS in the active stage, in a hospital setting providing care for children with rheumatic diseases [5,16].

(LoE 5, GoR C)

Complaints and anamnesis

see section 2.1.

Physical examination

see section 2.2.

Laboratory diagnostic tests

It is recommended to perform a complete blood count (CBC) with differential (erythrocyte sedimentation rate determination, blood erythrocyte level determination, blood leukocyte level determination, blood platelet level determination, differential leukocyte count (leukocyte formula), blood total hemoglobin level determination) in all patients before prescribing/adjusting therapy to determine disease activity, adverse effects of NSAIDs and/or immunosuppressants, and/or biologic DMARDs [2,4,5,16,18–20,23,27].

(LoE 5, GoR C)

Comments: leukocytosis, thrombocytosis, normochromic anemia, and elevated ESR are detected. In HPS, leukopenia and/or thrombocytopenia, and/or anemia are observed, and ESR may be decreased. A normal leukocyte and platelet count in patients with fever may indicate ongoing HPS. Single-, bi-, or pancytopenia may also be an adverse manifestation of NSAID and/or biologic DMARD therapy.

It is recommended to perform a coagulogram (screening hemostasis test) determining the prothrombin index, blood antithrombin III activity; blood plasminogen level and 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 blood von Willebrand factor activity and properties in patients with HPS and/or signs of vasculitis and/or receiving heparin group drugs before prescribing/adjusting therapy to assess the state of the hemostatic system and decide on its correction [29–32,143].

(LoE 5, GoR C)

Comments: hypercoagulation and elevated fibrinogen levels are characteristic of TRAPS.

In HPS, hypocoagulation and consumption coagulopathy develop; an increase in fibrin degradation products is 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 before prescribing/adjusting pathogenetic therapy to determine the anticoagulant therapy strategy [29–31,143,145].

(Level of Evidence 3, Grade of Recommendation C)

It is recommended to test the blood heparin level in patients with HPS and/or signs of vasculitis and/or receiving heparin group drugs before prescribing/adjusting anticoagulant therapy to assess its efficacy [29–31,35,36,143,145,146].

(LoE 5, GoR C)

It is recommended to perform a routine general biochemical blood test (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 potassium, blood sodium, total blood calcium; blood lactate dehydrogenase activity, blood creatine kinase activity, blood aspartate aminotransferase activity, blood alanine aminotransferase activity, blood gamma-glutamyl transferase activity, blood amylase activity, blood alkaline phosphatase activity, serum iron) to assess disease activity and the functional state of the liver, kidneys, and pancreas [2,4,5,16,18–20,23,27].

(LoE 5, GoR C)

Comments: elevated blood levels of triglycerides, ferritin, and LDH, AST, and ALT activity indicate the development of macrophage activation syndrome (MAS); 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/or triglycerides in the blood may be an adverse manifestation of NSAID, biologic therapy, and/or GC therapy. An increase in blood levels of creatinine, urea, uric acid, and potassium is a sign of renal failure development.

It is recommended to test blood procalcitonin levels in all patients with fever before prescribing or adjusting therapy to rule out a septic process [52–56].

(Level of Evidence 1, Grade of Recommendation B)

Comments: blood procalcitonin levels increase with bacterial infection and acute inflammatory response.

It is recommended to measure blood immunoglobulin levels in all patients before prescribing or adjusting therapy to rule out a primary/secondary immunodeficiency state [32,41].

(LoE 3, GoR B)

Comments: blood immunoglobulin levels in TRAPS generally fall within reference ranges.

It is recommended to determine antistreptolysin-O in blood serum in all patients before prescribing or adjusting therapy to rule out/confirm infection with group A beta-hemolytic streptococcus [32,41].

(LoE 3, GoR B)

Comments: an elevated serum antistreptolysin-O level indicates acute or chronic streptococcal infection, which may trigger a TRAPS attack.

It is recommended to test blood serum C-reactive protein levels in all patients before prescribing or adjusting therapy to determine disease activity [2,4,5,16,28,32].

(LEL 4, GRC C)

Comments: in TRAPS, serum CRP levels are elevated during an attack; they may also be elevated during the intercritical period, but not to the same extent as during an attack.

It is recommended to perform lymphocyte subset profiling in patients with frequent viral or purulent bacterial infections, including opportunistic ones, before prescribing or adjusting therapy to rule out immunodeficiency developed as a result of GC and/or biologic treatment [57,58].

(LEL 4, GRC C)

(LoE 5, GoR C)

It is recommended to perform a tuberculin skin test (Mantoux test, or test with recombinant tuberculosis allergen in standard dilution**) and/or blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens in all patients before prescribing or adjusting therapy to rule out tuberculosis infection [40,59,60,191,192].

(LoE 5, GoR C)

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 before prescribing or adjusting therapy to rule out intestinal bacterial infection [4,5,16].

(LoE 5, GoR C)

It is recommended to determine IgA, IgM, and IgG antibodies to Chlamydia psittaci in the blood; antibodies to Chlamydophila pneumoniae in the blood; IgM antibodies to Chlamydia trachomatis in the blood; IgG antibodies to Chlamydia trachomatis in the blood; and IgM and IgG antibodies to Mycoplasma pneumoniae in the blood before prescribing or adjusting therapy to rule out mycoplasma and chlamydial infection [4,5,16].

(LoE 5, GoR C)

It is recommended to determine IgM and IgG antibodies to Shigella boydii in the blood, IgM and IgG antibodies to Shigella dysenteriae in the blood, IgM and IgG antibodies to Shigella sonnei in the blood, and IgM and IgG antibodies to Shigella flexneri in the blood in patients with abdominal syndrome before prescribing or adjusting therapy to rule out intestinal bacterial infection [4,5,64–66,193].

(LoE 5, GoR C)

It is recommended to perform quantitative PCR testing for Epstein-Barr virus DNA in peripheral and cord blood, qualitative PCR testing for Epstein-Barr virus DNA in oropharyngeal swabs, and qualitative PCR testing for Epstein-Barr virus DNA in urine in all patients before prescribing or adjusting therapy to laboratory confirm/exclude active Epstein-Barr virus infection and address the issue of etiotropic therapy [5,70,70–73,83,136,149,150,157].

(LEL 4, GRC C)

It is recommended to perform quantitative PCR testing for Cytomegalovirus DNA in peripheral and cord blood, qualitative PCR testing for Cytomegalovirus DNA in oropharyngeal swabs, and qualitative PCR testing for Cytomegalovirus DNA in urine in all patients before prescribing or adjusting therapy to laboratory confirm/exclude active cytomegalovirus infection and address the issue of etiotropic therapy [5,73,75,76,82,83,135,136,141,149,150,157,158].

(LEL 4, GRC C)

It is recommended to perform quantitative PCR testing for Herpes simplex virus types 1, 2 DNA in the blood, qualitative PCR testing for Herpes simplex virus types 1, 2 DNA in oropharyngeal swabs, and qualitative PCR testing for Herpes simplex virus types 1, 2 DNA in urine in all patients before prescribing or adjusting therapy to laboratory confirm/exclude active herpesvirus infection and address the issue of etiotropic therapy [5,73,77,82,83,135,149,150,159,160].

(LEL 4, GRC C)

It is recommended to perform a general urinalysis, determine urine albumin, and quantify 24-hour urine protein in all patients before prescribing or adjusting therapy to confirm/exclude renal involvement [2,18–20,23,27,32,38,39,45].

(LoE 5, GoR C)

Comments: micro- or macrohematuria may result from the nephrotoxic effect of NSAIDs; when amyloidosis develops, 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 comprehensive assessment of renal function in patients with clinical/laboratory signs of kidney damage before prescribing or adjusting pathogenetic therapy to determine the severity of impairment [2,14,16,18–20,23,194].

(LEL 4, GRC C)

It is recommended to perform a comprehensive diagnostic workup to assess the severity of renal failure in patients with clinical/laboratory signs of nephrotic syndrome/renal failure before prescribing or adjusting pathogenetic therapy to clarify the presence and extent of renal involvement [2,14,16,18–20,23,194].

(LEL 4, GRC C)

It is recommended to perform microbiological (culture) examination of tonsillar and posterior pharyngeal mucus for aerobic and facultatively anaerobic microorganisms before prescribing or adjusting therapy to rule out nasopharyngeal contamination by aerobic and facultatively anaerobic microorganisms [40,45,63].

(LoE 5, GoR C)

It is recommended to perform microbiological (culture) blood test for sterility, microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic pathogens in patients with febrile and hectic fever prior to prescribing/adjusting therapy to rule out sepsis [40,45,53,53,63,118].

(LoE 5, GoR C)

It is recommended to determine Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, or bronchoalveolar lavage fluid by PCR (quantitative assay) in patients with signs of pneumonia based on chest computed tomography to confirm/rule out pneumocystis etiology of pneumonia and to decide on etiotropic therapy [167,170–172,174,195–199].

(LEL 4, GRC C)

It is recommended to perform microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeast and mold) in patients with interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [83,191,192,200–205].

(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 interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [83,191,192,200–205].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to determine antibodies to Aspergillus spp. in blood in patients with interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [181-186].

(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 according to chest computed tomography to identify the etiology of pneumonia and decide on etiotropic therapy [200–205].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to determine Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR in patients with interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [200–205].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to determine Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR in patients with interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [83,200–205].

(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 and bronchoalveolar lavage fluid by PCR in patients with interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [83,191,192,200–205].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to determine class M and G antibodies (IgM, IgG) to Cytomegalovirus in blood in patients with interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of pneumonia [4,5,40,45,63,75,82–84,206–208].

(LoE 5, GoR C)

It is recommended to determine class M and G antibodies (IgM, IgG) to Epstein-Barr virus in blood in patients with interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of pneumonia [4,5,40,45,63,70–72,83,206,209,210].

(LoE 5, GoR C)

It is recommended to determine antibodies to viral capsid antigen (VCA) of Epstein-Barr virus in blood in patients with interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of pneumonia [4,5,40,45,63,70–72,83,206,209,210].

(LoE 5, GoR C)

It is recommended to determine class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus in blood in patients with interstitial and/or focal, and/or infiltrative lung changes according to chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [4,5,40,45,63,70–72,83,206,209,210].

(LoE 5, GoR 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 to identify the etiological factor of pneumonia and decide on etiotropic therapy [5,83].

(LoE 5, GoR C)

It is recommended to test stool for calprotectin in patients who develop clinical manifestations of IBD (diarrhea, abdominal pain, blood/mucus in stool) prior to prescribing/adjusting pathogenetic therapy to rule it out [95–97].

(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/adjusting therapy to assess the state of the liver, spleen, kidneys, bowel motility, and pancreas [2,18–20,23,27].

(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/adjusting therapy to detect/exclude pathological changes [2,18–20,23,50,98].

(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/adjusting therapy to detect/exclude pathological changes [2,18–20,23,98].

(LoE 5, GoR C)

Comments: pericarditis in TRAPS is in most cases 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 hypertension prior to prescribing/adjusting pathogenetic therapy to determine its severity [211].

(LoE 3, GoR B)

It is recommended to perform Holter ECG monitoring in patients with arrhythmias or ECG abnormalities prior to prescribing/adjusting pathogenetic therapy to determine the nature of the arrhythmia [212].

(LoE 5, GoR C)

It is recommended to perform joint ultrasound in patients with active arthritis prior to prescribing/adjusting pathogenetic therapy to assess the condition of the synovial membrane and cartilage and to detect joint effusion [2,16,20,99].

(LoE 5, GoR C)

It is recommended to perform temporomandibular joint X-ray and/or spinal articulation X-ray, and/or elbow X-ray, and/or wrist X-ray, and/or knee X-ray, and/or shoulder X-ray, and/or hip X-ray, and/or ankle X-ray, and/or acromioclavicular joint X-ray, and/or sternoclavicular joint X-ray, and/or hand X-ray, and/or foot X-ray 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 [2,16,20,51,59,99].

(LoE 5, GoR C)

It is recommended to perform magnetic resonance imaging (MRI) of the joints (one joint) with contrast enhancement, with or without anesthesia/sedation (including early postoperative management), in patients with active arthritis prior to prescribing/adjusting antirheumatic therapy, in order to assess the condition of the synovial membrane and cartilage and to detect joint effusion [2,16,20,51,59,99].

(LoE 5, GoR C)

It is recommended to perform esophagogastroduodenoscopy (EGD) with or without anesthesia/sedation (including early postoperative management) in patients with dyspeptic symptoms, patients receiving NSAIDs for more than 1 month and/or GCs, and/or biologic DMARDs, as well as in those with a disease duration of more than 5 years and/or the presence of proteinuria > 500 mg/day prior to prescribing/adjusting pathogenetic therapy, in order to rule out inflammatory gastropathies and amyloidosis [102,104,213].

(LEL 4, GRC C)

Comments: it is necessary to rule out inflammatory diseases of the upper gastrointestinal tract associated with Helicobacter pylori and/or the use of NSAIDs and/or glucocorticoids (GCs), as well as amyloidosis.

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 data, in order to rule out gastrointestinal pathology associated with Helicobacter pylori [102,104,213].

(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/sedation (including early postoperative management), accompanied by pathomorphological (biopsy/surgical) examination of the esophagus, stomach, duodenum, and jejunum in patients presenting with inflammatory and/or erosive, and/or ulcerative mucosal changes according to esophagogastroduodenoscopy, in order to rule out inflammatory bowel diseases [102,104,213].

(LEL 4, GRC C)

It is recommended to perform colonoscopy with anesthesia/sedation (including early postoperative management) in patients with abdominal syndrome prior to prescribing/adjusting therapy, in order to detect/rule out concomitant bowel diseases and amyloidosis [102,104,213].

(LEL 4, GRC C)

Comments: this is performed when atypical bowel symptoms for TRAPS appear (prolonged diarrhea, abdominal pain, blood and mucus in the stool) to rule out IBD, as well as in cases of disease duration exceeding 5 years and/or the presence of proteinuria > 500 mg/day.

It is recommended to perform a large intestine biopsy via endoscopy with pathomorphological examination of the large intestine biopsy (surgical) material in patients who show inflammatory and/or erosive and/or ulcerative changes in the large bowel according to colonoscopy, in order to detect/rule out concomitant bowel diseases and amyloidosis [102,104,213].

(LEL 4, GRC C)

It is recommended to perform a kidney biopsy with anesthesia/sedation (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen in patients with chronic kidney disease/signs of renal failure prior to prescribing/adjusting pathogenetic therapy, in order to detect/rule out amyloidosis in the absence of contraindications [2,14,18,18,20,39,114,115,122,123].

(LoE 5, GoR C)

It is recommended to perform brain magnetic resonance imaging (MRI) with contrast enhancement, with or without anesthesia/sedation (including early postoperative management), in patients with neurological symptoms prior to prescribing/adjusting therapy, in order to detect complications and comorbid conditions [113].

(LoE 5, GoR C)

Comments: this is performed in patients with clinical CNS manifestations (headaches, seizures) to verify brain changes and assess the dynamics of changes.

It is recommended to perform a lumbar puncture with anesthesia/sedation (including early postoperative management), microscopic examination, cell counting in a counting chamber (determination of cytosis), assessment of physical properties of the cerebrospinal fluid, and serological testing in patients with symptoms of CNS involvement prior to prescribing/adjusting therapy, in order to rule out/confirm pathological changes [2,4,5].

(LoE 5, GoR C)

Comments: this is performed in patients with neurological manifestations (headaches, seizures) to rule out an infectious etiology of neurological disorders (meningococcal infection, viral meningitis, etc.).

It is recommended to perform computed tomography (CT) of the chest organs with or without anesthesia/sedation (including early postoperative management) in all patients prior to prescribing/adjusting therapy, in order to detect/rule out pathological changes [18–20,61,63,109,110].

(LoE 5, GoR C)

Comments: focal, lobar, or interstitial pneumonia and pulmonary tuberculosis must be ruled out.

Interstitial pneumonia should be suspected upon the appearance of low-grade/high-grade fever, dry cough / cough with a scanty amount of sputum, crepitations / weakened breath sounds on auscultation, and dyspnea.

It is recommended to perform bronchoscopy with anesthesia/sedation (including early postoperative management) in patients when interstitial and/or focal, and/or infiltrative changes in the lungs are detected on chest computed tomography [200,201].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to perform X-ray densitometry in patients currently or previously receiving glucocorticoids (GCs), in order to detect osteopenia/osteoporosis and develop a therapeutic management strategy [214,215].

(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 conduct an initial appointment (examination, consultation) with an orthopedic traumatologist in patients with functional joint insufficiency, in order to address the need for orthopedic correction [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to conduct an initial appointment (examination, consultation) with an otorhinolaryngologist in all patients prior to prescribing/adjusting therapy, in order to identify foci of chronic ENT infection and decide on sanitation [2,4,5,40].

(LEL 4, GRC C)

It is recommended to conduct an initial appointment (examination, consultation) with a pediatric dentist in patients with foci of chronic infection prior to prescribing/adjusting therapy, in order to assess the condition of the oral cavity and determine the need for its sanitation [2,4,5,16].

(LoE 5, GoR C)

It is recommended to conduct an initial appointment (examination, consultation) with an ophthalmologist with mandatory biomicroscopy of the eye in all patients prior to prescribing/adjusting therapy, in order to detect/rule out uveitis and its complications, as well as complicated steroid cataract [2,4,5,16].

(LoE 5, GoR C)

Comments: local therapy is prescribed to patients with uveitis and complicated steroid cataract.

It is recommended to conduct an initial appointment (examination, consultation) with a pediatric cardiologist in patients with cardiac dysfunction and/or arterial hypertension prior to prescribing/adjusting therapy, in order to decide on cardiotropic and/or antihypertensive therapy [2,4,5,16].

(LoE 5, GoR C)

It is recommended to conduct an initial appointment (examination, consultation) with a phthisiatrician in patients with positive results from a focal tuberculin skin test and/or elevated blood interferon-gamma levels specific to Mycobacterium tuberculosis complex antigens, and/or focal or infiltrative pulmonary changes prior to prescribing/adjusting pathogenetic therapy, in order to decide on chemoprophylaxis or anti-tuberculosis chemotherapy [40,45,59,60,191,192].

(LEL 4, GRC C)

It is recommended to conduct an initial appointment (examination, consultation) with a pediatric endocrinologist in patients with endocrinological pathology prior to prescribing/adjusting therapy, in order to develop a strategy for further examination and treatment [2,4,5,16].

(LoE 5, GoR C)

It is recommended to conduct an initial appointment (examination, consultation) with a dietitian in all patients with nutritional disorders prior to prescribing/adjusting therapy, in order to develop an individualized dietary program [4,5,16,216–219].

(LoE 5, GoR C)

It is recommended to conduct an initial appointment (examination, consultation) with a neurologist in patients with neurological symptoms prior to prescribing/adjusting therapy, in order to decide on therapeutic management [2,4,5,16,18–20].

(LoE 5, GoR C)

It is recommended to conduct an initial appointment (examination, consultation) with a nephrologist in patients with nephrotic syndrome, alterations in general general-clinical blood chemistry tests, or routine urinalysis typical of the development of amyloidosis/renal failure prior to prescribing/adjusting therapy, in order to determine treatment tactics [2,14,114,115,122,123,220].

(LoE 5, GoR C)

(Level of Evidence 3, Grade of Recommendation C)

It is recommended to perform a follow-up appointment (examination, consultation) with anotorhinolaryngologist for all patients after the sanation of foci of chronic infection in order to monitor its therapeutic efficacy and prevent the development of infectious complications under conditions of pathogenetic treatment [2,4,5,16,18–20,23,40,63].

(LoE 5, GoR C)

It is recommended to perform a follow-up appointment (examination, consultation) with a pediatric dentist for all patients after the sanation of foci of chronic oral infection in order to monitor its therapeutic efficacy [2,4,5,16].

(LoE 5, GoR C)

It is recommended to perform a follow-up appointment (examination, consultation) with an ophthalmologist with mandatory biomicroscopy of the eye for all patients with identified pathology in order to monitor therapy efficacy and to address the issue of surgical treatment in an ophthalmological inpatient setting [2,4,5,16].

(LoE 5, GoR C)

It is recommended to perform a follow-up appointment (examination, consultation) with a pediatric cardiologist for patients with cardiac rhythm disorders and/or arterial hypertension in order to monitor the efficacy of cardiotropic and/or antihypertensive therapy [2,4,5,16].

(LoE 5, GoR C)

It is recommended to perform a follow-up appointment (examination, consultation) with a pediatric endocrinologist for patients with endocrinological pathology in order to monitor therapy efficacy [2,4,5,16].

(LoE 5, GoR C)

It is recommended to perform a follow-up appointment (examination, consultation) with a nutritionist for all patients with nutritional disorders in order to monitor compliance with the individualized dietary program and dietary behavior recommendations in an outpatient setting [4,5,16,216–219].

(LoE 5, GoR C)

It is recommended to perform a follow-up appointment (examination, consultation) with a neurologist for patients with neurological symptoms or psychotic reactions in order to monitor therapy efficacy [2,4,5,16,18–20].

(LoE 5, GoR C)

It is recommended to perform a follow-up appointment (examination, consultation) with a nephrologist for patients with nephrotic syndrome, changes in general clinical blood chemistry tests, or general urinalysis typical of the development of amyloidosis/renal failure in order to monitor therapy efficacy [2,14,114,115,122,123,220].

(LoE 5, GoR C)

Monitoring of efficacy – see Appendices.

(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 TRAPS diagnosis, in an inpatient setting providing medical care to children with rheumatic diseases [5,16].

(LoE 5, GoR C)

3.1 Conservative Treatment

It is recommended to prescribe only NSAIDs (M01A) to patients with an unconfirmed TRAPS diagnosis during the examination stage to relieve fever and pain syndrome [5,9,16,23,63,224–226].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to prescribe NSAIDs (M01A) to patients with a confirmed TRAPS diagnosis to relieve fever and pain syndrome [5,9,16,23,63,224–229].

(LEL 4, GRC 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 intra-articularly, and/or ^#colchicine / autumn crocus seed extract, and/or genetically engineered biologic drugs (GEBDs) until the completion of a full laboratory and instrumental examination, exclusion of oncological and oncohematological diseases, and establishment of the TRAPS diagnosis [9,16,23,25,38,40,61,63].

(LEL 4, GRC C)

Comments: the use of GCs, GEBDs, ^#colchicine / autumn crocus seed extract in oncological and oncohematological diseases mimicking TRAPS significantly complicates subsequent diagnosis verification, as they possess pronounced immunosuppressive effects and mask the clinical and morphological presentation of malignant neoplasms.

It is recommended to administer pulse therapy with ^#methylprednisolone** (H02AB) at a dose of 10–30 mg/kg/administration intravenously for 3, and if necessary, 5 consecutive days to patients with a confirmed TRAPS diagnosis at the examination stage, in the presence of severe pain syndrome or life-threatening systemic manifestations (persistent febrile or hectic fever and/or pericarditis and/or pleuritis), in order to achieve a rapid anti-inflammatory effect [5,9,23,38,61,230–233].

(LoE 5, GoR C)

It is recommended to prescribe ^#prednisolone** (H02AB) or ^#methylprednisolone** (H02AB) orally at a dose of 0.5–1 mg/kg per day to patients with a confirmed TRAPS diagnosis at the examination 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) in order to achieve a rapid anti-inflammatory effect [5,9,23,38,61,230,234].

(LEL 4, GRC C)

It is recommended to prescribe the interleukin-1 beta (IL-1β) inhibitor canakinumab** (L04AC) as the primary pathogenetic therapy for the induction of remission in all patients with a confirmed TRAPS diagnosis who have signs of a systemic inflammatory response (fever, rash, etc.), organ dysfunction (eye pathology, gastrointestinal tract changes, joint involvement), ESR greater than 30 mm/h (by Panchenkov), CRP greater than 20 mg/L or greater than 4 upper limits of normal at the time of examination or within the preceding month, with an attack frequency of ≥ 3 per 9–12 months of disease course, in order to induce TRAPS remission [20,23,235,236].

(LoE 2, GoR B)

It is recommended to prescribe canakinumab** (L04AC) to children older than 2 years with a weight of ≥ 7.5 and ≤ 40 kg at a dose of 2 mg/kg subcutaneously once every 4 weeks; > 40 kg at a dose of 150 mg subcutaneously once every 4 weeks in order to induce TRAPS remission [20,23,235,236].

(LoE 2, GoR B)

Comments: treatment with ^#canakinumab** (L04AC) is carried out for life. Administration of the drug can be performed in inpatient and outpatient settings.

Therapy monitoring includes the resolution of systemic manifestations (fever, rash, pain syndrome), absence of organ involvement (damage to organs of vision, cardiovascular system, respiratory system, gastrointestinal tract, joints), normalization of laboratory activity parameters (ESR, CRP, blood leukocyte and platelet counts), AIDAI score < 9, PGA and PPGA = 0/10.

Monitoring of therapy efficacy – see Appendix A3, G1–G2.

It is recommended to administer maintenance therapy with canakinumab** (L04AC) to children older than 2 years with a body weight ≤ 40 kg at a dose of 2 mg/kg subcutaneously once every 4 weeks, and to children with a body weight > 40 kg at a dose of 150 mg subcutaneously once every 4 weeks, upon achieving a clinical effect 7 days after the canakinumab** (L04AC) injection, in order to maintain TRAPS remission [237].

(LEL 4, GRC C)

Comments: clinical effect is defined as the termination of an attack: relief of fever, abdominal and/or chest pain, and other TRAPS symptoms, along with reduction/normalization of acute-phase inflammatory markers (ESR, CRP, blood leukocyte count).

It is recommended to administer a second injection of canakinumab** (L04AC) to children older than 2 years with a body weight ≤ 40 kg at a dose of 2 mg/kg subcutaneously, and to children with a body weight > 40 kg at 150 mg subcutaneously, if the clinical effect is not achieved 7 days after the canakinumab** (L04AC) injection, in order to induce TRAPS remission [237].

(LEL 4, GRC C)

Comments: lack of clinical effect is defined as the persistence of fever, abdominal and/or chest pain, and other TRAPS symptoms, as well as persistent/increasing acute-phase inflammatory markers (ESR, CRP, blood leukocyte count).

It is recommended to administer maintenance therapy with canakinumab** (L04AC) to children older than 2 years with a body weight ≤ 40 kg at a dose of 4 mg/kg subcutaneously once every 4 weeks, and to children with a body weight > 40 kg at a dose of 300 mg subcutaneously once every 4 weeks, upon achieving a full clinical effect 7 days after the second subcutaneous injection of canakinumab** (L04AC), in order to maintain TRAPS remission [236,237].

(LoE 2, GoR B)

Comments: clinical effect is defined as the relief of fever and rash, and the reduction/normalization of acute-phase inflammatory markers (ESR, CRP, blood leukocyte count).

Monitoring of therapy efficacy – see Appendix A3, G1–G2.

It is recommended to prescribe the TNF inhibitor ^#etanercept** (L04AB01) as a second-line pathogenetic therapy at a dose of 0.4 mg/kg twice a week or 0.8 mg/kg once a week subcutaneously in case of inefficacy/intolerance of canakinumab** with the aim of inducing TRAPS remission [20,23,27,38,238].

(LoE 5, GoR C)

Comments: therapy monitoring includes the resolution of systemic manifestations (fever, rash, pain syndrome), absence of organ involvement (eye, cardiovascular, respiratory, gastrointestinal, joint involvement), normalization of laboratory markers of activity (ESR, CRP, blood leukocyte and platelet counts), AIDAI score < 9, PGA and PPGA = 0/10.

It is recommended to prescribe ^#tocilizumab** (L04AC) at a dose of 8 mg/kg/administration intravenously once every 2 weeks or at a dose of 162 mg subcutaneously once a week; to children with active chronic arthritis and/or combination of TRAPS with JIA in case of inefficacy of canakinumab** (L04AC) and ^#etanercept**(L04AC) with the aim of maintaining/inducing TRAPS remission [239–241].

(LEL 4, GRC C)

It is recommended to switch to ^#tocilizumab** (L04AC) at a dose of 8 mg/kg/administration intravenously once every 2 weeks or at a dose of 162 mg subcutaneously once a week; to children with active chronic arthritis and/or combination of TRAPS with JIA in case of intolerance to canakinumab** (L04AC) and ^#etanercept**(L04AC) with the aim of maintaining/inducing TRAPS remission [239–241].

(LEL 4, GRC C)

Comments: switching to ^#tocilizumab** (L04AC) can occur at any stage of treatment upon the development of intolerance to canakinumab** (L04AC) and ^#etanercept** (L04AC).

It is recommended to prescribe ^#Colchicum autumnale seed extract/colchicine in a benign course of the disease (rare attacks, moderate laboratory activity, low-penetrance mutation, etc.) with the aim of inducing TRAPS remission [38,242,243].

(LoE 5, GoR C)

It is recommended to prescribe ^#Colchicum autumnale seed extract/colchicine at a starting daily dose of 0.5 mg/day in children under 5 years, 0.5–1.0 mg/day in children aged 5–10 years, and 1.0–1.5 mg/day in children over 10 years with the aim of inducing TRAPS remission [38,242,243].

(LoE 5, GoR C)

Comments: the daily dose of ^#Colchicum autumnale seed extract/colchicine can be taken all at once or divided into 2 or more doses depending on tolerability and patient preference.

It is recommended to increase the dose of ^#Colchicum autumnale seed extract/colchicine by 0.5 or 0.6 mg per day if inflammatory activity persists despite adherence to the recommended starting dose, with careful monitoring of side effects, with the aim of inducing TRAPS remission [38,242,243].

(LoE 5, GoR C)

Comments: the daily dose (0.5 or 0.6 mg) is chosen depending on the available dosage form of the drug; inflammatory activity is determined by ongoing attacks or elevated acute-phase inflammatory markers between attacks.

It is not recommended to exceed the dose of ^#Colchicum autumnale seed extract/colchicine > 2.0 mg/day in order to prevent the development of adverse events [38,242,243].

(LoE 5, GoR C)

Comments: exceeding the maximum recommended dose does not lead to a significant increase in the severity and frequency of achieving the effect, but substantially increases the risks of adverse events (hypertransaminasemia, myopathy, cytopenia, etc.), including severe ones.

It is recommended to determine the Autoimmune Disease Activity Index (AIDAI) in all patients diagnosed with TRAPS to assess treatment efficacy [2,17,23,244].

(Level of Evidence 3, Grade of Recommendation C)

Comments: performed in all patients in active and inactive stages of the disease. All symptoms of the disease over the past month are assessed as "yes" or "no" (1/0) and their severity (1 – mild, 2 – moderate, 3 – severe). More than 9 active manifestations are assessed as disease activity.

Monitoring of therapy efficacy – see Appendix A3, G1–G2.

It is recommended to assess the Autoinflammatory Disease Damage Index (ADDI) in all patients diagnosed with TRAPS to evaluate treatment efficacy and disease course aggressiveness (Appendix G2) [2,23,245].

(LoE 5, GoR C)

Comments: performed in all patients in active and inactive stages of the disease.

Monitoring of therapy efficacy – see Appendix A3, G1–G2.

3.1.1 Treatment of hemophagocytic syndrome in patients with periodic fever syndrome caused by a mutation in the tumor necrosis factor receptor type I gene

It is recommended to prescribe and administer therapy to all patients after diagnostics, including differential diagnostics, and establishment/confirmation of the diagnosis of TRAPS with hemophagocytic syndrome in a hospital setting providing medical care to children with rheumatic diseases, with the aim of ensuring the prevention and timely relief of severe complications [5,16,23,32,246].

(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 with the aim of halting the activation of the innate immune system [5,135,141,149].

(LoE 5, GoR C)

It is recommended to prescribe GCs (H02AB) in combination with ^#cyclosporine** (L04AD) and ^#normal human immunoglobulin** (J06BA) to all patients with the aim of halting macrophage activation syndrome (MAS) [135,139,141,142,247–249].

(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 with the aim of halting MAS [132,135,138,141,183,248,250–254].

(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 from a dose of 20–30 mg/kg/administration for 3–5 days, tapering the dose by 25% once every 2–3 days with the aim of preventing withdrawal syndrome [5,141,249,251,255–257].

(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 with the aim of halting MAS [135,139,141,248,249,251,253,257,258].

(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 with the aim of achieving an immunosuppressive effect and halting MAS [141,249,253,257,259,260].

(LoE 5, GoR C)

Comments: administration of the full course dose of ^#normal human immunoglobulin** is carried out by continuous prolonged infusion administered at once 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 MAS 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 level, decrease in serum ferritin concentration by 25%) every 48 hours with the aim of deciding on the continuation/modification of the induction therapy regimen [135,141].

(LoE 5, GoR C)

It is recommended to prescribe ^#anakinra** (L04AC) at a dose of 5–10 mg/kg/day intravenously in 2 administrations for 3–10 days, longer if necessary, in case of increasing MAS activity in the first 48 hours of GC therapy in combination with ^#cyclosporine** (L04AD) and ^#normal human immunoglobulin** (J06BA) with the aim of halting MAS [135,141,261–266].

(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 in children weighing 10 to 25 kg — 5 mg × 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 with the aim of halting MAS [141,267,268].

(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 combined MAS therapy or MAS reactivation during the tapering/withdrawal of intravenous GCs with the aim of halting MAS [135,139,141,253].

(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 to suppress the triggering factor of macrophage activation syndrome (MAS) [269–273].

(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 active Herpes simplex virus infection to suppress the triggering factor of MAS [80, 271].

(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 to suppress the triggering factor of MAS [74, 274–276].

(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 to suppress the triggering factor of MAS [277, 278].

(LoE 5, GoR C)

It is recommended to prescribe ^#rituximab** as a first-line biological disease-modifying antirheumatic drug (bDMARD) in combination with ^#ciclosporin**, ^#normal human immunoglobulin**, and ^#co-trimoxazole** in active Epstein-Barr virus infection to suppress viral replication in B-lymphocytes and relieve MAS [253, 279].

(LoE 5, GoR C)

Comments: administration regimens:

- ^#rituximab** (L01XC) – at a dose of 375 mg/m²/week intravenously for 1–4 consecutive weeks [253, 279];

- ^#ciclosporin** (L04AD) – 3–5 mg/kg/day [253, 279];

- ^#normal human immunoglobulin** (J06BA) – 1–2 g/kg/course over 2 days [253, 279];

- ^#co-trimoxazole** (J01EE) – for the administration schedule and doses of #co-trimoxazole** (J01EE), see below [170, 196].

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 [280–287].

(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, to prevent thrombotic complications and relieve coagulopathy [29–31, 53, 135, 146, 288–290].

(LoE 5, GoR C)

It is recommended to perform blood transfusion in the development of consumption coagulopathy and bleeding to restore balance in the hemostatic system [29, 291, 292].

(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 decreases to ≤ 1.0 × 10⁹/L to restore the blood neutrophil count and prevent infectious complications [5, 293, 294].

(LoE 5, GoR C)

It is recommended to prescribe empirical 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 etiological confirmation, to relieve/prevent the progression of the infectious process [30, 40, 52, 53, 135, 295–299].

(LoE 5, GoR C)

It is recommended to prescribe targeted therapy based on 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)), combined with or without systemic antifungal drugs (J02A) and/or systemic antiviral drugs (J05), to relieve sepsis/infectious complications [30, 40, 52, 53, 135, 295–299].

(LoE 5, GoR C)

It is recommended to continue MAS treatment until 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 case of CNS involvement)) to prevent multiple organ failure and death [300].

(LoE 5, GoR C)

3.2 Surgical Treatment

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, 5, 16].

(LoE 5, GoR C)

3.3 Non-pharmacological treatment

It is recommended to perform maintenance hemodialysis in patients with amyloidosis and end-stage renal disease (ESRD) [114].

(LoE 5, GoR C)

It is recommended to consume a diet with an increased content of calcium and vitamin D for the prevention of osteoporosis in patients receiving glucocorticoids [4, 5, 16].

(LoE 5, GoR C)

It is recommended to use splints, casts, and insoles in patients with chronic arthritis, joint deformities, and lower limb growth impairment for the correction of orthopedic disorders [4, 5, 16].

(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 decreases, with the aim of restoring functional activity [125, 301].

(LoE 5, GoR C)

It is recommended that all patients older than 1 year and all parents (regardless of the child's age) undergo an initial appointment (testing, consultation) with a medical psychologist to develop an individual psychological rehabilitation program for the patient and their parents in order to harmonize the development of the child's personality in the context of a severe chronic disease and optimize parent-child relationships; increase treatment adherence and cooperation with the physician and medical staff to achieve disease remission; and achieve psychological social adaptation [2, 4, 5, 125, 220, 301, 302].

(LEL 4, GRC C)

It is recommended that all patients older than 1 year and all parents undergo a follow-up appointment (testing, consultation) with a medical psychologist upon completion of the psychological rehabilitation program to assess its effectiveness [2, 4, 5, 125, 220, 301, 302].

(LEL 4, GRC C)

It is recommended that all patients with functional impairment undergo an initial examination (consultation) by a physical therapist after disease activity decreases, in order to develop a physiotherapy program as part of the medical rehabilitation program [125, 301].

(LoE 5, GoR C)

It is recommended that patients with functional impairment undergo an initial appointment (examination, consultation) with a physical therapy physician after disease activity decreases, in order to develop a medical rehabilitation program [125, 301].

(LoE 5, GoR C)

It is recommended to provide medical rehabilitation services to patients with systemic connective tissue diseases, inflammatory arthropathies, and spondylopathies to restore their functional capacity [125, 301, 302].

(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 damage, muscle atrophy, and steroid myopathy upon achieving remission [125,301,302].

(LoE 5, GoR C)

Comments: a plan is developed, the goal and objectives of using physiotherapy in a patient with TRAPS are formulated during the implementation of the individual rehabilitation program; physiotherapy methods: high-frequency electric field therapy, magnetotherapy, polarized light therapy, mechanotherapy, thermal therapy, and spa-resort treatment (climatotherapy, balneotherapy, peloidotherapy) are chosen depending on various periods of the course of the disease.

It is recommended to perform a follow-up examination (consultation) by a physical therapy physician in all patients with functional impairment after completion of the physiotherapy procedures program as part of the medical rehabilitation program to assess its efficacy [125,301].

(LoE 5, GoR C)

It is recommended to perform a follow-up visit (examination, consultation) by an exercise therapy physician in all patients with functional impairment after completion of the medical rehabilitation program to assess its efficacy [125,301].

(LoE 5, GoR C)

It is recommended to conduct a psychological rehabilitation school for patients with TRAPS and their relatives [125,126,301,302].

(LoE 5, GoR 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, clinical features, personality traits, psychotherapeutic hypothesis, psychotherapeutic targets; methods of psychological intervention (psychotherapy, psychological counseling, psychological correction, and psychological rehabilitation) are chosen; types of psychotherapy (dynamic, cognitive-behavioral, existential-humanistic, secondary modalities of psychotherapy — art therapy, body-oriented psychotherapy, psychodrama, suggestive psychotherapy, etc.); forms of psychotherapy (individual, family-marital, group, natural environment psychotherapy, milieu therapy).

It is recommended to conduct the "School for Children with Rheumatic Diseases and Their Parents" [5,303].

(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 counseling and prognosis for the birth of a child with TRAPS.

It is recommended to have a follow-up visit (examination, consultation) with a medical geneticist for parents after establishing the diagnosis in a child for the purpose of medical genetic counseling regarding the genetic risk of having children with TRAPS in this family [2,18–20,23,124].

(LoE 5, GoR C)

Comment: families with children suffering from TRAPS are recommended to undergo medical genetic counseling in order to assess the genetic risk. The inheritance pattern of TRAPS is autosomal dominant, and the disease can be transmitted from an affected family member to their children; the genetic risk is estimated at 50% and is independent of sex. However, it should be noted that the majority of cases are sporadic, and there may be no other affected individuals in the family. Families of patients with TRAPS, as well as children and adults, are recommended to undergo medical genetic counseling to determine the genetic risk.

As with other autosomal dominant disorders, a patient with TRAPS has a 50% risk of having a child with each pregnancy. In families where one of the spouses has TRAPS, prenatal and preimplantation genetic testing is available. To do this, parents need to contact specialized diagnostic laboratories and medical centers. Prenatal diagnosis is carried out using molecular genetic or biochemical methods by analyzing DNA extracted from chorionic villus biopsy samples at 9–11 weeks of gestation. However, taking into account the possibilities of disease management and the presence of clinical forms varying in severity, all risks and prognoses should be discussed with the family in detail.

Primary prevention includes genetic testing of family members of patients with confirmed TRAPS, and careful monitoring for the onset of symptoms and laboratory activity (ESR, CRP) in asymptomatic individuals.

It is recommended to carry out prevention of TRAPS complications and exacerbations, as well as adverse effects of pathogenetic therapy [2,18–20,23,124].

(LoE 5, GoR C)

Comments: dispensary follow-up (clinical observation) is recommended: physical examination by a specialist (pediatrician, rheumatologist, allergist-immunologist, etc.) overseeing the patient, assessing general health, musculoskeletal and neurological manifestations, child growth and development; the impact of the disease on quality of life and social adaptation; disease activity using the AIDAI scores every 3 months, and the damage index (ADDI) once a year. An individualized approach to vaccination (vaccination of children should be carried out only during a period of complete disease remission, lasting for at least 1 year, according to an individualized schedule, excluding live vaccines).

It is not recommended to administer live and live-attenuated vaccines simultaneously with therapy using #Colchicum autumnale seed extract / colchicine and/or bDMARDs [304].

(LoE 5, GoR C)

Comments: the safety of immunization with live and live-attenuated vaccines in patients with TRAPS has not been established. An exacerbation of TRAPS or macrophage activation syndrome (MAS) 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 perform pre-exposure prophylaxis for novel coronavirus infection in patients aged 12 years and older weighing at least 40 kg, prior to initiating or at any stage of therapy with ^#Colchicum autumnale seed extract / colchicine and/or bDMARDs, with or without GCs, by means of passive immunization with antiviral monoclonal antibody preparations (J06BD) [305].

(LoE 5, GoR C)

It is recommended to vaccinate all patients with TRAPS using 13-valent pneumococcal conjugate vaccine** containing capsular polysaccharides of 13 pneumococcal serotypes, prior to initiating or at any stage of therapy with ^#Colchicum autumnale seed extract / colchicine and/or bDMARDs, with or without GCs (excluding ^#rituximab**), for the prevention of pneumococcal infection, improving treatment adherence, and preventing flares in accordance with international guidelines [306,307].

(LoE 5, GoR C)

Comments: vaccination with the 13-valent pneumococcal conjugate vaccine in patients receiving canakinumab** is performed 2 weeks before the planned injection or 2 weeks after; in patients scheduled to receive ^#rituximab** — before the first infusion for the prevention of infectious complications, improving treatment adherence, and preventing TRAPS flares.

5.2 Inpatient / day-hospital follow-up examination of patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) who initiated pathogenetic therapy

The examination is carried out every 3–6 months: 3 months after the initiation of therapy; 6 months after the initiation of therapy; then every 6 months, in order to identify disease complications, comorbid conditions, and to monitor the efficacy and safety of therapy.

Complaints and anamnesis

see section 2.1.1.

Physical examination

see section 2.1.2.

It is recommended to evaluate the treatment efficacy and safety of antirheumatic therapy in all patients with an established diagnosis of TRAPS in an inpatient setting providing medical care to children with rheumatic diseases, 3 months after the initiation of therapy; 6 months after the initiation of therapy; then every 6 months, in order to decide on the continuation/modification of therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to perform a complete blood count (including erythrocyte sedimentation rate determination, erythrocyte count, leukocyte count, platelet count, leukocyte differential count, and total hemoglobin level determination) in all patients to assess disease activity and monitor the safety of pathogenetic drugs [2,18–20,23,124].

(LoE 5, GoR C)

Comments: Complete blood count parameters should be within normal limits. Single-, double-, or triple-lineage cytopenia may be, among other things, an adverse manifestation of treatment with bDMARDs (canakinumab**, ^#etanercept**, ^#tocilizumab**), as well as ^#Colchicum autumnale seed extract / colchicine (if used).

It is recommended to omit bDMARD injections/infusions and/or ^#Colchicum autumnale seed extract / colchicine intake (if used) for 7 days in all patients with a platelet count reduction of ≤ 150 > 100 × 10⁹/L or a neutrophil count reduction of < 1.5 ≥ 1.0 × 10⁹/L in the complete blood count, in order to manage adverse events associated with the therapy [2,4,5,16,23].

(LoE 5, GoR C)

Comments: Previously prescribed oral GCs should be continued.

Repeat the complete blood count in a week. If there are data on recurrent episodes of decreased blood cell counts, address the issue of modifying bDMARD therapy and/or ^#Colchicum autumnale seed extract / colchicine (if used).

It is recommended to discontinue bDMARD injections/infusions and/or ^#Colchicum autumnale seed extract / colchicine (if used) in all patients if the absolute neutrophil count drops below < 1.0 × 10⁹/L and/or the platelet count drops below < 100 × 10⁹/L in the complete blood count, in order to prevent the progression of cytopenia [2,4,5,16,23].

(LoE 5, GoR C)

Comments: Previously prescribed oral GCs should be continued. Repeat the complete blood count in a week.

It is recommended to administer the colony-stimulating factor ^#filgrastim** (L03AA) at a dose of 5–10 mcg/kg/day subcutaneously for leukopenia with an absolute neutrophil count of ≤ 1.0 × 10⁹/L for 3–5 days (or longer if necessary) to normalize the leukocyte and neutrophil counts [16,294,308,309].

(LEL 4, GRC C)

It is recommended to administer the colony-stimulating factor ^#filgrastim** (L03AA) at a dose of 5–10 mcg/kg/day subcutaneously in combination with systemic antibacterial drugs (J01) intravenously for febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count of ≤ 1.0 × 10⁹/L to normalize leukocyte and neutrophil counts [16,294,308,309].

(LEL 4, GRC C)

Comments: When the neutrophil count drops to ≤ 1.0 × 10⁹/L, bDMARD injections/infusions are discontinued, as well as ^#Colchicum autumnale seed extract / colchicine (if used). Previously prescribed oral GCs should be continued.

Treatment with ^#filgrastim** (L03AA) is carried out 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 complete blood count data [16,294,308,309].

(LEL 4, GRC C)

It is recommended to resume bDMARD injections/infusions and/or ^#Colchicum autumnale seed extract / colchicine intake (if used) at the same dose in all patients after neutrophil recovery to ≥ 1.5 × 10⁹/L according to complete blood count data, in order to maintain TRAPS remission [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to adjust bDMARD therapy and/or ^#Colchicum autumnale seed extract / colchicine (if used) in all patients if there are data on recurrent episodes of decreased blood cell counts in the complete blood count, in order to manage adverse events associated with therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to administer fluconazole** (J02AC01) intravenously at a dose of 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 ^#Colchicum autumnale seed extract / colchicine and/or an immunosuppressant, and/or a bDMARD [4,5,19,310].

(LoE 5, GoR C)

It is recommended to perform a general clinical blood chemistry panel (including determination of total blood protein, blood albumin, total blood bilirubin, free and conjugated blood 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) to monitor disease activity, liver, kidney, and pancreatic function, and electrolyte balance during therapy with ^#Colchicum autumnale seed extract / colchicine (if used) and/or bDMARDs [2,18–20,23,124].

(LoE 5, GoR C)

Comments: An increase in creatinine and/or urea, and/or uric acid, and/or total bilirubin, free (unconjugated) and/or conjugated bilirubin, and/or K, and/or cholesterol, and/or triglycerides; LDH and/or ALT, and/or AST, and/or GGT, and/or ALP, and/or blood amylase activity may be an adverse manifestation of treatment with bDMARDs and ^#Colchicum autumnale seed extract / colchicine (if used). A gradual increase in creatinine, urea, uric acid, potassium, cholesterol, and a decrease in total blood protein and albumin may indicate the development of renal failure secondary to amyloidosis. A rapid rise in blood creatinine, urea, uric acid, and potassium combined with oliguria or anuria may indicate the development of acute renal failure due to overdose of Colchicum autumnale seed extract / colchicine.

It is recommended to temporarily discontinue bDMARD injections/infusions and/or ^#Colchicum autumnale seed extract / colchicine (if used) in all patients if blood ALT or AST activity increases ≥ 1.5 times the upper limit of normal and/or if total bilirubin, free (unconjugated) and/or conjugated bilirubin, urea, creatinine, uric acid, and/or other biochemical parameter(s) exceed the upper limit of normal [4,5,16,23].

(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 bDMARD therapy and/or ^#Colchicum autumnale seed extract / colchicine (if used) in all patients at the same dose after normalization of general clinical blood chemistry parameters, in order to maintain TRAPS remission [4,5,16,23].

(LoE 5, GoR C)

It is recommended to adjust bDMARD therapy and/or ^#Colchicum autumnale seed extract / colchicine (if used) in all patients if there are data on recurrent elevations of biochemical parameter(s), in order to manage adverse events associated with therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to determine the blood immunoglobulin levels in all patients to detect secondary immunodeficiency during treatment with bDMARDs and ^#Colchicum autumnale seed extract / colchicine combined (or not) with GCs [4,5,16].

(LoE 5, GoR C)

It is recommended to prescribe ^#normal human immunoglobulin** (J06BA) at 400 mg/kg, and if an adequate 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, for the purpose of correcting blood immunoglobulin levels and preventing infectious complications in patients developing an immunodeficiency state during immunosuppressive and/or biological therapy [5,16,311–315].

(LoE 5, GoR C)

It is recommended to determine the levels of antinuclear antibodies and anti-DNA antibodies in patients receiving TNF-alpha inhibitors to detect lupus-like syndrome [2,4,5,16,23].

(LoE 5, GoR C)

Comments: in case of lupus-like syndrome development, the TNF-alpha inhibitor is discontinued.

It is recommended to test the serum C-reactive protein level to monitor disease activity and/or the onset of infectious complications during treatment with bDMARDs and ^#Colchicum autumnale seed extract / colchicine combined (or not) with GCs [4,5,16,23].

(LoE 5, GoR C)

Comments: in the case of an inactive disease stage/remission, in the absence of infectious complications, the serum C-reactive protein level corresponds to reference values.

An increase in serum C-reactive protein levels may indicate the development of a disease exacerbation and/or an infectious complication; an increase in serum C-reactive protein and blood procalcitonin levels indicates the development of an acute inflammatory response (sepsis).

It is recommended to determine blood procalcitonin levels in patients with fever to detect/exclude an acute inflammatory response (sepsis) during treatment with bDMARDs and ^#Colchicum autumnale seed extract/colchicine combined (or not) with GCs [4,16,5,54–56].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to perform a comprehensive set of tests to rule out sepsis (complete blood count with differential, general biochemical blood test, serum C-reactive protein test, blood culture for sterility, microbiological culture of mucus from the tonsils and posterior pharyngeal wall for aerobic and facultative anaerobic microorganisms, urine culture for bacterial pathogens using automated seeding with determination of antimicrobial susceptibility, microbiological culture of anal discharge, thromboelastography, coagulogram (screening hemostasis test); computed tomography of the thoracic organs, comprehensive abdominal ultrasound, kidney ultrasound, echocardiography, magnetic resonance imaging of the abdominal cavity, 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, hectic fever, leukocytosis/leukopenia, thrombocytopenia, elevated serum C-reactive protein and procalcitonin levels not associated with TRAPS activity, in order to exclude sepsis [29,30,40,53,53,54,63,145,316,317].

(LEL 4, GRC C)

Comments: performed in patients with febrile, hectic fever, leukocytosis/leukopenia, thrombocytopenia, elevated CRP and serum procalcitonin levels not associated with TRAPS activity.

It is recommended to prescribe initial empirical antibacterial therapy followed, depending on the clinical situation, by intravenous systemic antibacterial drugs (J01) targeting 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 (J01XX), and/or glycopeptide antibiotics (J01XA), and/or other aminoglycosides (J01GB), and/or macrolides (J01FA)) with or without systemic antifungals (J02A) according to microbial susceptibility, combined with ^#normal human immunoglobulin** (J06BA) at a dose of 400 mg/kg/course (5 days) for patients who develop sepsis, in accordance with clinical guidelines for the treatment of sepsis in children [52,53,229].

(LoE 5, GoR C)

It is recommended to temporarily discontinue biologic DMARD therapy and/or ^#Colchicum autumnale seeds extract/colchicine (if used), continue previously prescribed oral GCs, and administer ^#methylprednisolone** pulse therapy upon increased disease activity in TRAPS patients with bacterial complications/sepsis [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to resume biologic DMARD therapy and/or ^#Colchicum autumnale seeds extract/colchicine (if used) no earlier than one week after complete resolution of clinical and laboratory signs of sepsis and completion of antibacterial therapy in all patients to maintain TRAPS remission [2,4,5,16,23].

(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, blood fibrinogen level, blood D-dimer concentration, blood soluble fibrin monomer complexes, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, blood thrombin time, and von Willebrand factor activity and properties in patients with febrile fever/sepsis/HPS to assess the hemostatic system status [29–32,143].

(LEL 4, GRC 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 / HFS / signs of thrombosis and hypocoagulation to determine the tactics of anticoagulant therapy [29–31,143,145].

(Level of Evidence 3, Grade of Recommendation 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 (exploratory hemostasis study) and thromboelastography to correct the hemostatic system [29–31,143].

(LEL 4, GRC C)

It is recommended to perform blood transfusion in the development of consumption coagulopathy and bleeding to restore balance in the hemostatic system [29, 291, 292].

(LoE 5, GoR C)

It is recommended to study lymphocyte populations in patients frequently suffering from viral, purulent bacterial infections, including opportunistic infections, to identify the subpopulation composition of lymphocytes (main ones) [58,240,318].

(LEL 4, GRC C)

Comments: a decrease in the level of T and/or B lymphocyte subpopulations and/or natural killers indicates the development of a secondary immunodeficiency state during treatment with bDMARDs and Colchicum autumnale seed extract/colchicine in combination (or without) with GCs.

It is recommended to determine Epstein-Barr virus (Epstein-Barr virus) DNA by PCR in peripheral and cord blood, quantitative study, to determine Epstein-Barr virus (Epstein-Barr virus) DNA in oropharyngeal mucosa swabs by PCR, qualitative study, to determine Epstein-Barr virus (Epstein-Barr virus) DNA by PCR qualitative study in urine in patients receiving bDMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if used) in combination (or without) with GCs, with clinical manifestations of herpetic infection, in patients with interstitial pneumonia to detect active herpetic infection as an infectious complication developed during treatment with ^#Colchicum autumnale seed extract/colchicine and/or bDMARDs, and/or immunosuppressant in combination (or without) with GCs [4,5,40,45,63,70–72,206,210].

(LoE 5, GoR C)

It is recommended to determine Cytomegalovirus (Cytomegalovirus) DNA by PCR in peripheral and cord blood (quantitative assay), Cytomegalovirus (Cytomegalovirus) DNA in oropharyngeal swabs by PCR (qualitative assay), and Cytomegalovirus (Cytomegalovirus) DNA in urine by PCR (qualitative assay) in patients receiving biologic DMARDs (bDMARDs) and/or ^#autumn crocus seed extract/colchicine (if applicable) combined with or without GCs, presenting with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia, in order to detect active herpetic infection as an infectious complication developed during treatment with ^#autumn crocus seed extract/colchicine and/or bDMARDs, and/or immunosuppressants combined with or without GCs [4,5,40,45,63,74–76,206].

(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 assay), Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in oropharyngeal swabs by PCR (qualitative assay), and Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in urine by PCR (qualitative assay) in patients receiving bDMARDs and/or ^#autumn crocus seed extract/colchicine (if applicable) combined with or without GCs, presenting with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia, in order to detect active herpetic infection as an infectious complication developed during treatment with ^#autumn crocus seed extract/colchicine and/or bDMARDs, and/or immunosuppressants combined with or without GCs [4,5,40,45,63,77,79,80,206,272].

(LoE 5, GoR C)

It is recommended to determine IgM and IgG antibodies to Cytomegalovirus (Cytomegalovirus) in the blood of all patients receiving bDMARDs and/or ^#autumn crocus seed extract/colchicine (if applicable) combined with or without GCs, presenting with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia, in order to detect/exclude active cytomegalovirus infection as an infectious complication developed during treatment with ^#autumn crocus seed extract/colchicine and/or bDMARDs, and/or immunosuppressants combined with or without GCs [5,83].

(LoE 5, GoR C)

It is recommended to determine IgM and IgG antibodies to Epstein-Barr virus (Epstein-Barr virus) in the blood of all patients receiving bDMARDs and/or ^#autumn crocus seed extract/colchicine (if applicable) combined with or without GCs, presenting with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia, in order to detect/exclude active Epstein-Barr virus infection as an infectious complication developed during treatment with ^#autumn crocus seed extract/colchicine and/or bDMARDs, and/or immunosuppressants combined with or without GCs [5,83].

(LoE 5, GoR C)

It is recommended to determine antibodies to Epstein-Barr virus capsid antigen (VCA) (Epstein-Barr virus) in the blood of all patients receiving bDMARDs and/or ^#autumn crocus seed extract/colchicine (if applicable) combined with or without GCs, presenting with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia, in order to detect/exclude active Epstein-Barr virus infection as an infectious complication developed during treatment with ^#autumn crocus seed extract/colchicine and/or bDMARDs, and/or immunosuppressants combined with or without GCs [5,83].

(LoE 5, GoR C)

It is recommended to determine IgG antibodies to Epstein-Barr virus early antigens (EA) (Epstein-Barr virus) in the blood of all patients receiving bDMARDs and/or ^#autumn crocus seed extract/colchicine (if applicable) combined with or without GCs, presenting with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia, in order to detect/exclude active Epstein-Barr virus infection as an infectious complication developed during treatment with ^#autumn crocus seed extract/colchicine and/or bDMARDs, and/or immunosuppressants combined with or without GCs [5,83].

(LoE 5, GoR C)

It is recommended to determine antibodies to Herpes simplex virus (Herpes simplex) in the blood of all patients receiving bDMARDs and/or ^#autumn crocus seed extract/colchicine (if applicable) combined with or without GCs, presenting with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia, in order to detect/exclude active herpetic infection as an infectious complication under treatment with ^#autumn crocus seed extract/colchicine and/or bDMARDs, and/or immunosuppressants combined with or without GCs [5,83].

(LoE 5, GoR C)

It is recommended to prescribe:

— ^#acyclovir** (J05AB) at a dose of 200 mg daily orally in 5 divided doses (not exceeding 1000 mg/day) in children older than 2 years, or at a dose of 5–10 mg/kg/injection intravenously every 8 hours upon development of localized herpetic infection;

— prescribing ^#acyclovir** at a dose of 10 mg/kg/injection intravenously every 8 hours in children aged < 1 year; at a dose of 500 mg/m²intravenously every 8 hours in children aged ≥ 1 year upon development of Herpes zoster in accordance with clinical guidelines for the treatment of herpesvirus infections in children, including immunocompromised patients [280,319–322].

(LoE 5, GoR C)

Comments: bDMARD injections/infusions and administration of ^#autumn crocus seed extract/colchicine (if applicable) are suspended during antiviral therapy. Previously prescribed oral GCs should be continued. Treatment with ^#acyclovir** is carried out for 7–10 days until complete disappearance of herpetic rashes.

It is recommended to prescribe ^#ganciclovir** (J05AB) at a dose of 6 mg/kg/injection intravenously every 12 hours upon development of cytomegalovirus infection, or ganciclovir** (J05AB) at a dose of 10 mg/kg/injection intravenously every 12 hours upon development of Epstein-Barr virus infection, in accordance with clinical guidelines for the treatment of immunocompromised children [84,208,280,322–324].

(LoE 5, GoR C)

It is recommended to temporarily discontinue bDMARD therapy and/or administration of ^#autumn crocus seed extract/colchicine (if applicable) in all patients upon development of infection, for the duration of antiviral therapy caused by herpesviruses [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to resume bDMARD therapy and/or ^#autumn crocus seed extract/colchicine (if applicable) in all patients no earlier than 1 week after complete resolution of clinical and laboratory signs of infection and completion of antiviral therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to screen for tuberculosis (tuberculin skin test, recombinant tuberculosis allergen test in standard dilution** and/or blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens, chest computed tomography) in all patients receiving bDMARDs and/or ^#autumn crocus seed extract/colchicine (if applicable) combined with or without GCs, at least twice a year [60,191,192,325].

(LoE 5, GoR C)

It is recommended to discontinue bDMARD therapy and/or ^#autumn crocus seed extract/colchicine (if applicable) 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 [60,191,192].

(LoE 5, GoR C)

Comments: Previously prescribed oral GCs should be continued.

It is recommended to conduct an initial visit (examination, consultation) with a phthisiatrician for 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 [60,191,192].

(LoE 5, GoR C)

Comments: bronchoscopy and determination of Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG) DNA with species differentiation in sputum are performed. If a tuberculous infection without a focal lesion is detected, specific anti-tuberculosis chemotherapy is administered for 3 months (prescribed by a phthisiatrician).

It is recommended to prescribe oral GCs to all patients during a TRAPS flare for the duration of specific anti-tuberculosis therapy [4,5,16,60,191,192].

(LoE 5, GoR C)

Comments: the issue of resuming bDMARD therapy and/or ^#autumn crocus seed extract/colchicine (if applicable) is resolved after completion of specific chemotherapy and consultation with a phthisiatrician.

It is recommended to resume biologic DMARD (bDMARD) therapy and/or ^#colchicine / meadow saffron seeds extract (if used) in all patients after completing specific antituberculosis therapy and consulting a phthisiotherapist [60,191,192].

(LoE 5, GoR C)

Comments: the question of continuing biological therapy is decided on an individual basis.

It is recommended to determine antibodies to Salmonella enterica in the blood, determine antibodies to Salmonella typhi in the blood, determine class M and G antibodies (IgM, IgG) to Yersinia pseudotuberculosis in the blood, and determine antibodies to serovars of Yersinia enterocolitica in the blood in patients with abdominal syndrome in order to detect infection with enteric bacteria developed during treatment with targeted biologic disease-modifying antirheumatic drugs (tBDMARDs) and/or ^#Colchicum autumnale seed extract / colchicine (if used) in combination (or without) with GCs [326,327].

(LoE 5, GoR C)

It is recommended to administer targeted therapy in patients receiving bDMARDs and/or ^#colchicine / meadow saffron seeds extract (if used) combined with or without GCs who have IgA and IgM antibodies at diagnostic titers, or high titers of IgG antibodies to Yersinia pseudotuberculosis, Yersinia enterocolitica, Salmonella enterica, or Salmonella typhi in blood, in accordance with clinical guidelines for the diagnosis and treatment of intestinal infections in children [326,327].

(LoE 5, GoR C)

Comments: bDMARD injections/infusions and administration of ^#colchicine / meadow saffron seeds extract (if used) are suspended for the entire duration of antibiotic therapy. Previously prescribed oral GCs should be continued.

Treatment with bDMARDs and ^#colchicine / meadow saffron seeds extract (if used) should be resumed no earlier than 1 week after the normalization of laboratory markers of infection and completion of antibiotic therapy.

It is recommended to test blood for IgA, IgM, and IgG antibodies to Chlamydia psittaci, antibodies to Chlamydia trachomatis, antibodies to Chlamydophila pneumoniae, and IgM and IgG antibodies to Mycoplasma pneumoniae in patients with interstitial pneumonia to detect mycoplasma and chlamydial infection developed during treatment with bDMARDs and/or ^#colchicine / meadow saffron seeds extract (if used) combined with or without GCs [2,4,5,16,62,328].

(LoE 5, GoR C)

It is recommended to administer targeted therapy in all patients receiving bDMARDs and ^#colchicine / meadow saffron seeds extract (if used) combined with or without GCs who test positive for IgA and IgM antibodies at diagnostic titers, or high titers of IgG antibodies to Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, or Chlamydophila pneumoniae in blood, in accordance with clinical guidelines for the diagnosis and treatment of mycoplasma and chlamydial infections in children [2,4,5,16,62,328].

(LoE 5, GoR C)

Treatment with bDMARDs and ^#colchicine / meadow saffron seeds extract should be resumed no earlier than 1 week after the normalization of laboratory markers of infection and completion of antibiotic therapy.

It is recommended to perform a microbiological (culture) swab of the tonsils and posterior pharyngeal wall in all patients to detect nasopharyngeal contamination by pathogenic or opportunistic microorganisms developed during treatment with bDMARDs and ^#colchicine / meadow saffron seeds extract combined with or without GCs [2,4,5,16,23].

(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 bDMARDs and ^#colchicine / meadow saffron seeds extract (if used) combined with or without GCs is not discontinued.

If inflammatory changes in the nasopharynx are present, antibacterial therapy is administered. bDMARD injections/infusions and administration of ^#colchicine / meadow saffron seeds extract (if used) are suspended for the duration of antiviral therapy. Previously prescribed oral GCs should be continued. Treatment with bDMARDs and ^#colchicine / meadow saffron seeds extract is resumed no earlier than 1 week after complete resolution of clinical and laboratory signs of infection and completion of antiviral therapy.

It is recommended to perform a routine urinalysis in all patients to monitor renal function [2,16,23].

(LoE 5, GoR C)

Comments: proteinuria > 500 mg/day may indicate the development of secondary renal amyloidosis.

It is recommended to measure urinary albumin and 24-hour urinary protein in patients with clinical/laboratory signs of nephrotic syndrome and/or renal failure, and/or disease duration exceeding 5 years to assess the severity of renal involvement [2,16,23].

(LoE 5, GoR C)

Comments: proteinuria > 500 mg/day may indicate the development of secondary renal amyloidosis.

It is recommended to perform a comprehensive assessment of renal function and diagnostic tests for renal failure severity in patients with clinical/laboratory signs of nephrotic syndrome and/or renal failure, disease duration exceeding 5 years, and/or proteinuria > 500 mg/day to determine the extent of renal damage [114,115,122,123,194].

(LEL 4, GRC C)

It is recommended to perform a kidney biopsy under anesthesia (including early postoperative management) with pathomorphological examination of the biopsy specimen in patients with clinical/laboratory/ultrasound signs of renal involvement and/or renal failure, and/or proteinuria > 500 mg/day to detect or exclude renal amyloidosis in the absence of contraindications [114].

(LoE 5, GoR C)

It is recommended to perform an electrocardiogram (ECG) in all patients to monitor cardiac function [2,4,5,16,23].

(LoE 5, GoR C)

Comments: patients with TRAPS in remission show no pathological ECG changes.

It is recommended to perform Holter ECG monitoring in patients with arrhythmias or pathological ECG findings to detect arrhythmias [212].

(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 detect blood pressure abnormalities and develop an antihypertensive treatment strategy [211].

(Level of Evidence 3, Grade of Recommendation C)

It is recommended to perform a comprehensive ultrasound examination of internal organs (including comprehensive abdominal ultrasound and renal ultrasound) to detect or exclude pathological changes [2,4,5,16,39].

(LoE 5, GoR C)

Comments: performed in all patients. Includes ultrasound of the abdominal organs and kidneys. Findings may include mild hepatomegaly, biliary dyskinesia, reactive changes in the pancreas, gallbladder wall thickening, and thickening of the gastric and intestinal walls. All changes may be related to drug adverse events.

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, or endocardial lesions [2,18,19,23,39,124,126].

(LoE 5, GoR C)

Comments: performed in all patients. Patients with TRAPS in remission show no pathological echocardiographic changes.

Long-standing disease may lead to ventricular myocardial diastolic dysfunction and signs of pulmonary hypertension.

It is recommended to perform esophagogastroduodenoscopy with or without anesthesia (including early postoperative management) in patients with dyspeptic symptoms, patients receiving NSAIDs for more than 1 month and/or GCs, and/or biologic agents, as well as when the disease duration is more than 5 years, in order to rule out inflammatory diseases of the upper gastrointestinal tract associated with the underlying disease and/or with Helicobacter pylori and/or with the use of NSAIDs and/or GCs, and to monitor the efficacy of previously administered therapy for inflammatory gastropathies [13,96,100–102].

(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 gastrointestinal pathology associated with Helicobacter pylori [13,96,100–102].

(LEL 4, GRC C)

It is recommended to prescribe drugs for the treatment of gastric and duodenal ulcer and gastroesophageal reflux disease (A02B) upon detection of reflux disease and/or inflammatory gastropathy, erosive and/or ulcerative processes in the esophagus and/or stomach, and/or duodenum according to esophagogastroduodenoscopy, in accordance with clinical guidelines for the treatment of inflammatory gastropathy and gastroesophageal reflux disease in children in accordance with international guidelines [13,96,100–102].

(LEL 4, GRC C)

Comments: during anti-inflammatory therapy, treatment with biologic agents and ^#colchicine / autumn crocus seed extract (if used), as well as previously prescribed GCs, should be continued.

It is recommended to perform eradication therapy with the prescription of proton pump inhibitors (A02BC), systemic antibacterial drugs (J01), 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 twice daily (for patients aged 8 to 12 years), or at a dose of 120 mg 4 times daily or 240 mg twice daily (for patients older than 12 years) in inflammatory gastropathy, erosive and/or ulcerative processes in the stomach and/or duodenum associated with Helicobacter pylori, in accordance with clinical guidelines [102].

(LoE 5, GoR C)

It is recommended to temporarily discontinue biologic therapy and/or the intake of ^#colchicine / autumn crocus seed extract (if used) in all patients during eradication therapy [2,4,5,16,23].

(LoE 5, GoR C)

Comments: previously prescribed GCs should be continued. Resumption of biologic therapy and/or intake of ^#colchicine / autumn crocus seed extract (if used) is carried out after the completion of eradication therapy.

It is recommended to perform colonoscopy with anesthesia (including early postoperative management) in patients with abdominal syndrome to identify/exclude TRAPS complications and concomitant bowel diseases [96].

(LoE 5, GoR C)

It is recommended to perform a colon biopsy using endoscopy and pathomorphological examination of the colonic biopsy (surgical) material in patients who show inflammatory and/or erosive and/or ulcerative changes in the large intestine according to colonoscopy, in order to identify/exclude TRAPS complications and concomitant bowel diseases [96].

(LoE 5, GoR C)

It is recommended to perform magnetic resonance imaging of joints (single joint) with or without anesthesia (including early postoperative management) in patients with active arthritis to monitor therapy efficacy [2,16,20,23,51,59,99].

(LoE 5, GoR C)

It is recommended to perform computed tomography of the chest organs with or without anesthesia (including early postoperative management) in all patients at least once every 6 months to rule out pneumonia and tuberculosis [18–20,61,63,109,110].

(LoE 5, GoR C)

Comments: pneumonia (interstitial, focal, lobar, polysegmental) may develop during treatment with biologic agents, especially in combination with ^#colchicine / autumn crocus seed extract (if used) and/or GCs.

Interstitial pneumonia should be suspected upon the appearance of low-grade/high-grade fever, dry cough / cough with a small amount of sputum, crepitations / weakened breath sounds on auscultation.

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 (including early postoperative management) in patients with interstitial and/or focal, and/or infiltrative lung changes detected by chest computed tomography to assess the condition of the bronchial mucosal tree and obtain bronchoalveolar lavage for further examination [59,83,191,192,200,201,329,330].

(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 according to chest computed tomography to confirm/exclude pneumocystis etiology of pneumonia and decide on etiotropic therapy [167,170–172,174,195–198].

(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 [167,170–172,174,195–199].

(LEL 4, GRC C)

It is recommended to perform microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeasts and molds) in patients with interstitial and/or focal, and/or infiltrative lung changes detected by chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [83,191,192,200–205].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to determine antibodies to fungi of the genus Aspergillus (Aspergillus spp.) in the blood of patients with interstitial and/or focal, and/or infiltrative lung changes detected by chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [200–205].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to determine Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR in patients with interstitial and/or focal, and/or infiltrative lung changes detected by chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [200–205].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to determine Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR in all patients with interstitial and/or focal, and/or infiltrative lung changes detected by chest computed tomography to identify the etiological factor of pneumonia and decide on etiotropic therapy [83,200–205].

(Level of Evidence 1, Grade of Recommendation B)

It is recommended to determine class M, G antibodies (IgM, IgG) to Cytomegalovirus in the blood of all patients with interstitial and/or focal, and/or infiltrative lung changes detected by chest computed tomography to identify the etiological factor of pneumonia [5,83].

(LoE 5, GoR C)

It is recommended to determine class M, G antibodies (IgM, IgG) to Epstein-Barr virus in the blood of all patients with interstitial and/or focal, and/or infiltrative lung changes detected by chest computed tomography to identify the etiological factor of pneumonia [5,83].

(LoE 5, GoR C)

It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus in the blood of all patients with interstitial and/or focal, and/or infiltrative lung changes detected by chest computed tomography to identify the etiological factor of pneumonia [5,83].

(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 when interstitial and/or focal, and/or infiltrative lung changes are detected on chest computed tomography in order to identify the etiological factor of pneumonia and decide on etiotropic therapy [5,83].

(LoE 5, GoR C)

It is recommended to determine antibodies to Herpes simplex virus in the blood of all patients when interstitial and/or focal, and/or infiltrative lung changes are detected on chest computed tomography in order to identify the etiological factor of pneumonia and decide on etiotropic therapy [5,83].

(LoE 5, GoR C)

It is recommended to prescribe empirical antibiotic therapy with ^#co-trimoxazole** (J01EE) in combination with systemic antibacterial drugs (J01) active against Gram-positive, Gram-negative, and anaerobic flora (penicillin combinations, including combinations with beta-lactamase inhibitors (J01CR); 4th-generation cephalosporins (J01DE); carbapenems (J01DH), other antibacterial drugs (J01X)) combined with systemic antifungals (J02A) prior to identifying the etiological factor of interstitial pneumonia to prevent the progression of lung damage in accordance with international guidelines for the treatment of pneumonia in immunocompromised children [331].

(LoE 5, GoR C)

It is recommended to administer intravenous GCs, ^#co-trimoxazole** (J01EE) at a dose of 3.75–5.0 mg/kg body weight/administration (15–20 mg/kg/day) (calculated as trimethoprim) intravenously every 8 hours in moderate Pneumocystis pneumonia, or at a dose of 3.75–5.0 mg/kg body weight/administration (15–20 mg/kg/day) (calculated as trimethoprim) intravenously every 6–8 hours in severe Pneumocystis pneumonia to prevent the progression of lung damage in accordance with international guidelines for the treatment of pneumonia in immunocompromised children [280,287,331,332].

(LoE 5, GoR C)

It is recommended to prescribe ^#voriconazole** (J02AC03) 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, upon detection of galactomannan in lavage fluid and/or blood, and/or antibodies to Aspergillus spp. fungi in the blood [287,333].

(LoE 5, GoR C)

It is recommended to prescribe fluconazole** (J02AC01) intravenously at a dose of 6–12 mg/kg/day upon detection of mannan in lavage fluid and/or blood, in accordance with international guidelines for the treatment of immunocompromised children [287,310].

(LoE 5, GoR C)

It is recommended to temporarily discontinue injections/infusions of targeted biologic DMARDs and/or intake of ^#Autumn crocus seed extract/colchicine (if used) in all patients with suspected/developed pneumonia [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to resume injections/infusions of targeted biologic DMARDs and/or intake of ^#Autumn crocus seed extract/colchicine (if used) in all patients no earlier than 1 week after complete resolution of pneumonia based on laboratory tests and follow-up chest computed tomography, with or without anesthesia support (including early postoperative management) [2,4,5,16,23].

(LoE 5, GoR C)

Comments: therapy is prescribed/adjusted after clinical, radiological, and laboratory signs of interstitial pneumonia have resolved.

It is recommended to prescribe systemic antibacterial drugs (J01) active against Gram-positive, Gram-negative, and anaerobic flora (penicillin combinations, including combinations with beta-lactamase inhibitors (J01CR); 4th-generation cephalosporins (J01DE); carbapenems (J01DH), other antibacterial drugs (J01X)) combined with systemic antifungals (J02A) in focal, lobar, or polysegmental pneumonia, in accordance with clinical guidelines for the treatment of pneumonia in immunocompromised children [331].

(LoE 5, GoR C)

It is recommended to perform X-ray imaging 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 computed tomography of the joint, with or without anesthesia support (including early postoperative management), in all patients with active arthritis to determine the degree of osseous and cartilaginous destruction [2,16,20,23,51,99].

(LoE 5, GoR 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 GCs to detect osteopenia/osteoporosis, in accordance with clinical guidelines for the diagnosis and treatment of secondary osteoporosis in children [214,215,323].

(LoE 5, GoR C)

It is recommended to prescribe calcium supplements (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 [214,215].

(LoE 5, GoR C)

It is recommended to prescribe bisphosphonates (M05BA) in combination with calcium supplements and vitamin D and its analogues (A11CC) to patients with osteoporosis in accordance with clinical guidelines for the diagnosis and treatment of secondary osteoporosis in children [214,215,323].

(LoE 5, GoR C)

It is recommended to prescribe:

o ^#pamidronic acid to patients < 1 year at a dose of 0.5 mg/kg IV every 2 months, patients aged 1–2 years at a dose of 0.25–0.5 mg/kg/day IV for 3 days every 3 months, patients aged 2–3 years at a dose of 0.375–0.75 mg/kg/day IV for 3 days every 3 months, 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);

o or ^#alendronate sodium** at a dose of 1–2 mg/kg/week orally, to patients with body weight < 40 kg at a dose of 5 mg/day or 35 mg/week, to patients with body weight > 40 kg at a dose of 10 mg/day or 70 mg/week (maximum dose 70 mg/week);

o or ^#zoledronic acid** at a dose of 0.0125–0.05 mg/kg per administration IV every 6–12 months (maximum dose 4 mg);

o or ^#ibandronic acid** at a dose of 3 mg per administration IV once every 3 months or 150 mg orally once a month in patients with osteoporosis for the treatment of osteoporosis [214,215,323,334,335].

(LoE 5, GoR C)

It is recommended to perform brain magnetic resonance imaging, with or without anesthesia support (including early postoperative management), in patients with signs of CNS involvement to identify pathological changes [113].

(LoE 5, GoR C)

It is recommended that all patients undergo an initial examination (inspection, consultation) by an otorhinolaryngologist to detect chronic infection foci in ENT organs and decide on their sanitation for the prevention of infectious complications during treatment with targeted biologic DMARDScombined (or not) with GCs, in order to evaluate the efficacy of ENT sanitation in patients who have undergone it [2,4,5,18–20,23,40,45,63].

(LEL 4, GRC C)

It is recommended that all patients undergo an initial examination (inspection, consultation) by an ophthalmologist with mandatory ocular biomicroscopy to detect pathological changes [2,4,5,16,23].

(LoE 5, GoR 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 examination (inspection, consultation) by a pediatric cardiologist to decide on cardiotropic and/or antihypertensive therapy [2,18–20,23,63,336].

(LoE 5, GoR C)

It is recommended that all 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 lung changes, undergo an initial examination (inspection, consultation) by a phthisiatrician to decide on chemoprophylaxis or anti-tuberculosis chemotherapy [59,60].

(LEL 4, GRC C)

It is recommended that patients with endocrinological pathology undergo an initial examination (inspection, consultation) by a pediatric endocrinologist to monitor treatment efficacy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to perform an initial consultation (examination, inspection) by a nutritionist for patients with underweight, amyotrophy, osteopenia/osteoporosis, constitutional obesity, Cushing's syndrome, and steroid diabetes to develop an individual dietary program and recommendations for eating behavior in an outpatient setting [4,5,16,216–219].

(LoE 3, GoR B)

It is recommended to perform an initial consultation (examination, inspection) by an orthopedic traumatologist for patients with joint functional insufficiency, impaired longitudinal bone growth, subluxations, and back pain to resolve the issue of reconstructive surgery and joint replacement [2,4,5,16,18–20,23,63].

(LoE 5, GoR C)

It is recommended to perform an initial consultation (examination, inspection) by a nephrologist for patients with renal damage to resolve the issue of therapy management [2,14,114,115,122,123,337].

(LEL 4, GRC C)

It is recommended to perform a follow-up consultation (examination, inspection) by a nephrologist for patients with renal damage to evaluate the efficacy of the therapy administered [2,14,114,115,122,123,337].

(LEL 4, GRC C)

It is recommended to perform an initial consultation (examination, inspection) by a neurologist for patients with neurological symptoms and psychotic reactions to resolve the issue of therapy management [2,4,5,18–20,23,113].

(LoE 5, GoR C)

It is recommended to perform a follow-up consultation (examination, inspection) by a neurologist for patients with neurological symptoms and psychotic reactions to evaluate the efficacy of the therapy administered [2,4,5,18–20,23,113].

(LoE 5, GoR C)

It is recommended to perform an initial consultation (testing, counseling) by a medical psychologist for all patients aged 1 year and older and their parents (regardless of the child's age) to harmonize the process of child personality development in the context of a severe chronic disease and optimize child-parent relationships; to increase treatment adherence and cooperation with the physician and medical staff to achieve disease remission; and to achieve psychological adaptation in society [125–127].

(LoE 3, GoR B)

(LoE 5, GoR C)

It is recommended to evaluate the efficacy of targeted therapy using the Autoinflammatory Disease Activity Index (AIDAI) 3 months after the initiation/adjustment of therapy and subsequently every 6 months, and the Autoinflammatory Disease Damage Index (ADDI) once a year [2,17,20,23,244].

(Level of Evidence 3, Grade of Recommendation 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 active disease.

For monitoring treatment efficacy, see Appendices A3, G1-G2.

5.2.1 Vigilance for malignancy in patients with periodic fever syndrome caused by a tumor necrosis factor receptor type 1 gene mutation receiving biologic disease-modifying antirheumatic drugs (bDMARDs) combined with (or without) glucocorticoids (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 vigilance for malignancy due to the potential development of oncologic/oncohematologic/lymphoproliferative diseases during therapy with bDMARDs and/or ^#Colchicum autumnale seed extract / colchicine (if used) combined with ( or without) GCs at any stage of treatment [99–103,300,329–331].

(LEL 4, GRC C)

It is recommended to immediately discontinue bDMARDs and/or ^#Colchicum autumnale seed extract / colchicine (if used) and hospitalize the patient if an oncologic/oncohematologic/lymphoproliferative disease is suspected to perform appropriate evaluation [99–103,300,329–331].

(LEL 4, GRC C)

It is recommended to obtain a bone marrow cytological specimen using anesthesia (including early postoperative management) via puncture and a bone marrow histological specimen with bone marrow smear cytological examination (myelogram), and pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods in patients receiving bDMARDs and/or ^#Colchicum autumnale seed extract / colchicine (if used) combined with (or without) GCs, presenting with an atypical disease course, to rule out oncologic/oncohematologic/lymphoproliferative diseases / bone marrow metastatic involvement [109,110,116–118,338–341].

(LEL 4, GRC C)

It is recommended to perform a lymph node biopsy (peripheral, or intra-abdominal / intrathoracic as indicated) using anesthesia (including early postoperative management) with cytological examination of the lymph node tissue specimen 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 and/or ^#Colchicum autumnale seed extract / colchicine (if used) combined with (or without) GCs and have an atypical disease course, to rule out oncologic/oncohematologic/lymphoproliferative diseases / lymph node metastatic involvement [109,110,116–118,338–341].

(LEL 4, GRC C)

It is recommended to perform contrast-enhanced brain magnetic resonance imaging (MRI), contrast-enhanced abdominal MRI, contrast-enhanced retroperitoneal MRI, and contrast-enhanced pelvic MRI with or without anesthesia (including early postoperative management) in patients receiving bDMARDs and/or ^#Colchicum autumnale seed extract / colchicine (if used) combined with (or without) GCswith an atypical disease course, to rule out oncologic/oncohematologic/lymphoproliferative diseases [109,110,116–118,338–341].

(LEL 4, GRC C)

It is recommended to perform contrast-enhanced computed tomography (CT) of the chest with intravenous bolus injection, with or without anesthesia (including early postoperative management), in patients receiving bDMARDs and/or ^#Colchicum autumnale seed extract / colchicine (if used) combined with (or without) GCs with an atypical disease course, to rule out lung metastases / mediastinal organ involvement in oncologic/oncohematologic/lymphoproliferative diseases [109,110,116–118,338–341].

(LEL 4, GRC C)

It is recommended to perform contrast-enhanced magnetic resonance imaging of bone tissue (one region) and magnetic resonance imaging of joints (one joint), with or without anesthesia (including early postoperative management), in patients receiving bDMARDs and/or ^#Colchicum autumnale seed extract / colchicine (if used) combined with (or without) GCs, with an atypical disease course, to rule out oncologic/oncohematologic diseases [109,110,116–118,338–341].

(LEL 4, GRC C)

It is recommended to perform bone computed tomography and joint computed tomography, with or without anesthesia (including early postoperative management), in patients receiving bDMARDs and/or ^#Colchicum autumnale seed extract / colchicine (if used) combined with (or without) GCs, who have bone destruction foci atypical for TRAPS, to rule out oncologic/oncohematologic diseases [109,110,116–118,338–341].

(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, or, if necessary, whole-body positron emission tomography with tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)), with or without anesthesia (including early postoperative management), in patients receiving bDMARDs and/or ^#Colchicum autumnale seed extract / colchicine (if used) combined with (or without) GCs who present with severe arthralgia, myalgia, ossalgia, bone destructive changes, subcutaneous adipose tissue infiltrates, or lesions in parenchymal organs, the brain, or the spinal cord, to rule out oncologic/oncohematologic/lymphoproliferative diseases [109,110,116,117,342].

(LEL 4, GRC C)

It is recommended to perform multi-position bone scintigraphy with or without anesthetic management (including early postoperative management) in patients receiving bDMARDs and/or ^#colchicine / Colchicum autumnale seeds extract (if used) in combination with GCs (or without), who have bone destruction lesions atypical for TRAPS, in order to rule out malignancies/metastatic bone disease [109,110,116,117,342].

(LEL 4, GRC C)

It is recommended to perform CT-guided iliac bone trephine biopsy with anesthetic management (including early postoperative management), followed by pathomorphological examination of the bone marrow biopsy (surgical) material using immunohistochemical methods; cytological examination of bone marrow trephine biopsy imprints; immunocytochemical examination of bone marrow trephine biopsy imprints; and immunophenotyping of bone marrow hematopoietic progenitor cells in patients receiving bDMARDs and/or ^#colchicine / Colchicum autumnale seeds extract (if used) in combination with GCs (or without), who present with an atypical disease course, in order to rule out hemoblastoses/lymphoproliferative disorders/metastatic bone marrow involvement [109,110,116–118,338–341].

(LEL 4, GRC C)

It is recommended to perform bone biopsy with anesthetic management (including early postoperative management), followed by pathomorphological examination of the bone biopsy (surgical) material in patients receiving bDMARDs and/or ^#colchicine / Colchicum autumnale seeds extract (if used) in combination with GCs (or without), who have bone destruction lesions atypical for TRAPS, in order to rule out malignancies/metastatic bone disease [109,110,116–118,338–341].

(LEL 4, GRC C)

It is recommended that patients in whom oncological/oncohematological/lymphoproliferative disease or metastatic involvement is suspected/detected based on examination results undergo an initial consultation (examination) by a pediatric oncologist to decide on transferring the child to a specialized institution for further evaluation and treatment [109,110,116–118,338–341].

(LEL 4, GRC C)

5.3 Follow-up examination within the framework of dispensary observation of patients with periodic fever syndrome associated with a mutation in the type I tumor necrosis factor receptor gene in outpatient settings

It is recommended to provide dispensary observation for TRAPS patients – an initial consultation (examination) by a rheumatologist with evaluation of therapy efficacy and safety at least once a year following the initiation/adjustment of therapy and after achieving disease remission [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to provide dispensary observation for TRAPS patients – a follow-up consultation (examination) by a rheumatologist (evaluating treatment efficacy and safety at least once every 1 month after initiating or adjusting therapy and at least once every 3 months after achieving disease remission; assessing the need for referral for unplanned hospitalization to the rheumatology department of the inpatient facility that initiated therapy with a biological DMARD and/or immunosuppressant at any stage of treatment in the event of exacerbation and/or complications, comorbid conditions, complications and/or adverse effects, and/or persistent treatment intolerance; issuing referrals for planned hospitalization to the rheumatology department of the inpatient facility that initiated therapy with a biological DMARD and/or immunosuppressant at 3 months and 6 months after prescribing and/or adjusting therapy and every 6 months thereafter; and conducting remote consultations with a rheumatologist from the inpatient facility that initiated therapy for all patients who develop any signs of treatment inefficacy and/or intolerance) [2,4,5,16,23].

(LoE 5, GoR C)

Comments: the rheumatologist assesses the patient's general condition, presence of systemic manifestations, and joint syndrome activity; analyzes the efficacy and safety of targeted therapy using standard questionnaires and scales (see Appendices A3, G1-G2); 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 bDMARDs combined with ^#colchicine / Colchicum autumnale seeds extract with or without GCs; how infections manifest under targeted therapy; what actions parents should take if infections and adverse events of antirheumatic drugs develop; and interacts with medical specialists as well as the rheumatologist of the inpatient rheumatology department, including remotely.

It is recommended to evaluate the efficacy of targeted therapy using the Autoinflammatory Disease Activity Index (AIDAI) in all patients 3 months after therapy initiation/adjustment and every 6 months thereafter, and to assess the damage index (ADDI) once a year [2,17,20,23,244].

(LoE 5, GoR C)

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 a referral for medical and social expertise [4,5,19].

(LoE 5, GoR C)

It is recommended that patients with TRAPS undergo dispensary follow-up examinations (evaluations, consultations) by a pediatrician or a district pediatrician at least once a month following the initiation or adjustment of therapy, and at least once every 3 months after achieving disease remission, if a pediatric rheumatologist is not available locally, in order to organize dispensary monitoring and to assess the efficacy and safety of therapy [4,5,19].

(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 bDMARDs and the intake of ^#Colchicum autumnale seed extract / colchicine (if used) in the event of an allergic reaction [16,325,343].

(LEL 4, GRC C)

Comments: an allergic reaction may occur at any stage of bDMARD treatment.

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 GCs if an allergic reaction develops to the administration of bDMARDs and/or the intake of ^#Colchicum autumnale seed extract / colchicine (if used) [16,325,343].

(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 that the patient undergo a consultation (including telemedicine) with the inpatient rheumatologist who initiated the therapy, in the event of an allergic reaction to ^#Colchicum autumnale seed extract / colchicine and/or the administration of bDMARDs, in order to decide whether therapy adjustment is necessary and determine the setting in which it should be performed [16,325].

(LEL 4, GRC C)

It is recommended to arrange emergency hospitalization in the event of an allergic reaction to ^#Colchicum autumnale seed extract / colchicine and/or the administration of bDMARDs, in order to decide on the need for therapy adjustment [16,325].

(LoE 5, GoR C)

It is recommended to perform a complete blood count (including erythrocyte sedimentation rate, red blood cell count, white blood cell count, platelet count, differential leukocyte count (leukocyte formula), and total hemoglobin level) for all patients at least once every 2–4 weeks to monitor disease activity and adverse effects of bDMARDs on the bone marrow [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to temporarily discontinue bDMARD therapy and/or ^#Colchicum autumnale seed extract / colchicine (if used) for 7 days in all patients when the complete blood count shows a platelet count of ≤ 150 > 100 × 10⁹/L or a neutrophil count of < 1.5 ≥ 1.0 × 10³/L, in order to manage adverse events associated with the therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to discontinue balTID and/or ^#Colchicum autumnale seed extract/colchicine (if used) when the absolute neutrophil count drops below < 1.0 × 10⁹/L and/or the platelet count drops below < 100 × 10⁹/L in a complete blood count, in order to manage adverse events associated with the therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to resume treatment with bDMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if applicable) at the same dose in all patients after complete recovery of complete blood count parameters in order to maintain TRAPS remission [2,4,5,16,23].

(LoE 5, GoR C)

Comments: Previously prescribed oral GCs should be continued. Repeat the complete blood count in a week.

It is recommended to 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 leukocyte counts decrease with an absolute neutrophil count < 1.0 × 10⁹/L, in order to normalize blood leukocyte counts [16,294,308,309].

(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, perform urgent hospitalization to a local hospital, and prescribe systemic antibacterial drugs (J01) intravenously upon the development of febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count < 1.0 × 10⁹/L, in order to normalize blood leukocyte counts and prevent infectious complications [16,294,308,309].

(LEL 4, GRC C)

It is recommended to prescribe fluconazole** (J02AC01) at a dose of 3–12 mg/kg/day orally, depending on the severity and duration of induced neutropenia, in patients with neutropenia to prevent fungal infections resulting from immunosuppressive therapy and/or bDMARDs [16,294,308–310].

(LoE 5, GoR C)

It is recommended to resume bDMARD injections/infusions and/or ^#Colchicum autumnale seed extract/colchicine administration (if applicable) in all patients after the neutrophil count recovers to ≥ 1.5 × 10⁹/L according to complete blood count data [16,294,308,309].

(LoE 5, GoR C)

It is recommended for all patients to have an appointment (examination, consultation, including telemedical) with the hospital rheumatologist who initiated the therapy, in the event of a recurrent episode of decreased neutrophil count, development of febrile neutropenia, and/or decreased blood platelet count according to complete blood count data, to determine the need for therapy adjustment and the setting in which it should be administered [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to perform a routine general biochemical blood test (including 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, and serum iron) at least once every 2–4 weeks to monitor disease activity, liver, kidney, and pancreatic function, and electrolyte balance during pathogenetic therapy [2,4,5,16,23].

(LoE 5, GoR C)

Comments: if blood ferritin levels are ≥ 684 ng/mL, along with elevated triglycerides, ALT, AST, and LDH levels combined with bicytopenia, hemophagocytic lymphohistiocytosis should be suspected, and the child must be urgently referred for hospitalization in the inpatient rheumatology department.

It is recommended to temporarily discontinue bDMARD therapy and/or ^#Colchicum autumnale seed extract/colchicine (if applicable) in all patients if serum ALT or AST levels increase to ≥ 1.5 times the upper limit of normal and/or other biochemical parameters exceed the upper limit of normal [2,4,5,16,23].

(LoE 5, GoR C)

Comments: Previously prescribed oral GCs should be continued.

It is recommended to resume bDMARD therapy and/or ^#Colchicum autumnale seed extract/colchicine (if applicable) in all patients at the same dose after normalization of routine biochemical blood test parameters [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to have an appointment (examination, consultation, including telemedical) with the hospital rheumatologist who initiated the therapy, if there is evidence of repeated episodes of elevated biochemical parameter(s), to determine the need for therapy adjustment and the setting in which it should be administered [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to test serum C-reactive protein levels in all patients at least once every 3 months to monitor disease activity [4,5,16,23].

(LoE 5, GoR C)

Comments: serum C-reactive protein levels increase during infectious complications and exacerbations of the underlying disease. In such cases, the child is urgently hospitalized in a rheumatology department for diagnosis and treatment.

It is recommended to test blood immunoglobulin levels in all patients at least once every 3 months to detect immune deficiency developing during treatment with bDMARDs and ^#Colchicum autumnale seed extract/colchicine combined with (or without) GCs [4,5,16].

(LoE 5, GoR C)

It is recommended to temporarily discontinue bDMARD therapy and/or ^#Colchicum autumnale seed extract/colchicine (if applicable) in all patients if blood immunoglobulins decrease, in order to prevent infectious complications [2,4,5,16,23].

(LoE 5, GoR C)

Comments: previously prescribed GCs should be continued.

It is recommended to have an appointment (examination, consultation, including telemedical) with the hospital rheumatologist who initiated the therapy, in case of decreased blood immunoglobulins, to determine the need for therapy adjustment and the setting in which it should be administered [2,4,5,16,23].

(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** [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to determine anti-nuclear and anti-DNA antibody levels in all patients receiving TNF-alpha inhibitors at least once every 3 months to monitor therapy safety [5,16,344].

(LEL 4, GRC C)

Comments: serum anti-nuclear and anti-DNA antibody levels increase in patients receiving TNF-alpha inhibitors upon the development of an adverse event—a lupus-like reaction.

It is recommended to temporarily discontinue TNF-alpha inhibitor therapy in all patients if serum anti-nuclear and anti-DNA antibody levels increase [5,16,344].

(LEL 4, GRC C)

Comments: previously prescribed GCs should be continued.

It is recommended to have an appointment (examination, consultation, including telemedical) with the hospital rheumatologist who initiated the therapy for all patients with increased serum anti-nuclear and anti-DNA antibody levels, to determine the need for therapy adjustment and the setting in which it should be administered [5,16].

(LoE 5, GoR C)

It is recommended to determine antistreptolysin-O in serum at least once every 3 months to detect/exclude Group A beta-hemolytic streptococcal infection [5,16].

(LoE 5, GoR C)

It is recommended to remain vigilant regarding the potential development of infectious diseases in patients receiving bDMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if applicable) combined with (or without) GCs [2,16,18–20,23].

(LoE 5, GoR C)

It is recommended to temporarily discontinue bDMARD therapy and/or ^#Colchicum autumnale seed extract/colchicine (if applicable) and continue previously prescribed oral GCs in all patients upon the appearance of signs of an infectious complication [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended for all patients to have an appointment (examination, consultation, including telemedical) with the hospital rheumatologist who initiated the therapy, upon the appearance of signs of an infectious complication, to determine the need for therapy adjustment and the setting in which it should be administered [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to urgently hospitalize patients if pneumonia is suspected or developed [2,4,5,16,23].

(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 bDMARD therapy and/or ^#Colchicum autumnale seeds extract/colchicine (if used) in all patients with suspected/developing pneumonia [2,4,5,16,23].

(LoE 5, GoR C)

Comments: Previously prescribed oral GCs should be continued.

It is recommended for all patients with suspected/developed pneumonia to have a consultation (examination, assessment, including remote) by the inpatient rheumatologist who initiated the therapy, in order to decide on the need for therapy adjustment and the setting in which it should be managed [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to resume bDMARD therapy and/or ^#Colchicum autumnale seeds extract/colchicine (if used) 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 antibiotic therapy [2,4,5,16,23].

(LoE 5, GoR C)

Comments: therapy is prescribed/adjusted after clinical, radiological, and laboratory signs of interstitial pneumonia have resolved.

It is recommended to prescribe ^#acyclovir** (J05AB) at a dose of 200 mg daily orally in 5 divided doses for children over 2 years of age (not exceeding 1000 mg/day) until the complete disappearance of herpetic eruptions in patients who develop a localized herpetic infection, in accordance with clinical guidelines for the treatment of herpesvirus infections in children, including immunocompromised patients [280,287,319,322].

(LoE 5, GoR C)

It is recommended to temporarily discontinue bDMARD therapy and/or ^#Colchicum autumnale seeds extract/colchicine (if used) in all patients while continuing previously prescribed oral GCs if herpesvirus, cytomegalovirus, and/or Epstein-Barr virus infection generalization is suspected or develops, as well as upon the development of Herpes zoster in all patients for the duration of antiviral therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to hospitalize the patient in the inpatient facility in case of generalized herpetic infection / suspected cytomegalovirus or Epstein-Barr virus infection [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to monitor the efficacy of bDMARDs and/or ^#Colchicum autumnale seeds extract/colchicine (if used) in order to timely address the issue of "switching" to an immunosuppressant and/or a bDMARD with a different mechanism of action to achieve disease remission, prevent the development of disease complications, and progression of patient disability [16,294,309].

(LoE 5, GoR C)

Comments: monitoring the efficacy of anti-inflammatory and antirheumatic drugs is performed at least once a month, with special attention paid to the development of secondary inefficacy. Secondary inefficacy of bDMARDs manifests as a "waning" effect and increasing disease activity at any stage of treatment. If secondary inefficacy develops, an urgent consultation (examination, assessment, including remote) by the inpatient rheumatologist who initiated the therapy is performed.

It is recommended to monitor the tolerability of bDMARDs and ^#Colchicum autumnale seeds extract/colchicine (if used) in all patients to prevent the development of severe toxic complications and allow timely drug discontinuation [325].

(LEL 4, GRC C)

Comments: intolerance to bDMARDs and ^#Colchicum autumnale seeds extract/colchicine (if used) may develop at any stage of treatment. If intolerance develops, regardless of its severity, colchicine and/or bDMARDs, and/or the immunosuppressant should be discontinued. Previously prescribed oral GCs should be continued.

It is recommended to conduct an in-patient rheumatologist appointment (examination, consultation, including remote) who initiated the therapy for all patients who develop any signs of inefficacy and/or intolerance to ^#Colchicum autumnale seeds extract/colchicine and/or immunosuppressant and/or bDMARD to address the need for therapy adjustment and the setting in which it should be performed [5,16].

(LoE 5, GoR C)

It is recommended to perform a focal tuberculin skin test (Mantoux test, test with recombinant tuberculosis allergen in standard dilution) in all patients at least once every 6 months (more frequently if indicated) to rule out Mycobacterium tuberculosis infection during anti-rheumatic therapy [40,59,60,191,192].

(LoE 5, GoR C)

It is recommended to perform a general (clinical) urinalysis in all patients at least once a month to monitor renal function [2,16,18–20,23].

(LoE 5, GoR C)

Comments: the onset of proteinuria > 500 mg per day may indicate the development of amyloidosis.

It is recommended to vaccinate children only during disease remission lasting for at least 6 months, according to an individual schedule, excluding live vaccines [304].

(LoE 5, GoR C)

It is recommended to perform an electrocardiogram for all patients at least once every 3 months as part of follow-up care to monitor the state of the cardiovascular system [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to perform a comprehensive ultrasound examination of the abdominal organs and an ultrasound examination of the kidneys for all patients at least once every 6 months as part of follow-up care to monitor disease activity and adverse events of pathogenetic therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to perform echocardiography for all patients at least once every 6 months as part of follow-up care to monitor disease activity and adverse events of pathogenetic therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to conduct an initial consultation (examination) with an otorhinolaryngologist for patients with ENT pathology no later than 7 days after hospital discharge to identify foci of chronic ENT infection and address the issue of their sanitation, as well as to diagnose acute ENT infections that have developed against the background of pathogenetic therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to conduct a follow-up consultation (examination) with an otorhinolaryngologist according to 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 [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to conduct an initial consultation (examination) with a pediatric cardiologist according to medical indications in order to develop an individual therapy program based on the recommendations of the inpatient pediatric cardiologist [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to conduct a follow-up consultation (examination) with a pediatric cardiologist according to medical indications to monitor the effectiveness of the individual therapy program developed on the basis of the recommendations of the inpatient pediatric cardiologist [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to conduct an initial consultation (examination) with a pediatric dentist for all patients within 1 month after hospital discharge to identify foci of chronic oral infection and address the issue of their sanitation, as well as to diagnose acute oral infections that have developed against the background of pathogenetic therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to conduct a follow-up consultation (examination) with a pediatric dentist according to medical indications for the early detection of oral pathology, its treatment, and the prevention of infectious complications during antirheumatic therapy [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to conduct an initial consultation (examination) with an ophthalmologist (including biomicroscopy of the eye 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 [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to conduct a follow-up consultation (examination) with an ophthalmologist (at least once every 3 months) with mandatory biomicroscopy of the eye for all patients with ophthalmological pathology according to individual indications to monitor treatment efficacy and adjust it if necessary [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to conduct a consultation (examination) with a nephrologist no later than 7 days after hospital discharge in the presence of renal impairment to develop an individual treatment program based on the recommendations of the inpatient rheumatologist and nephrologist [2,14,114,115,122,123,337].

(LEL 4, GRC C)

It is recommended to conduct a consultation (examination) with a nephrologist for patients with renal impairment at least once every 3 months as part of follow-up care to monitor treatment efficacy [2,14,114,115,122,123,337].

(LEL 4, GRC C)

It is recommended to perform an initial dietary consultation (examination) based on medical indications in order to develop an individual dietary program [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to perform a follow-up dietary consultation (examination) based on individual indications in order to monitor/adjust the individual dietary program [217,218].

(LoE 5, GoR C)

It is recommended to consult a phthisiatrician (in the presence of a positive focal test and/or intradermal test with a tuberculosis allergen with tuberculin, and/or with infiltrative foci in the lungs) to resolve the issue of chemoprophylaxis or antituberculosis therapy [40,45,59,60].

(LEL 4, GRC C)

It is recommended to perform a follow-up consultation with a phthisiatrician for patients with a positive focal tuberculin test and/or intradermal test with a tuberculosis allergen, and/or an elevated blood interferon-gamma level to Mycobacterium tuberculosis complex antigens, and/or focal or infiltrative changes in the lungs in order to monitor/adjust chemoprophylaxis or antituberculosis chemotherapy [60,191,192].

(LoE 5, GoR C)

It is recommended to conduct a consultation (examination, including remote) with the inpatient rheumatologist who initiated the therapy for patients with a positive intradermal tuberculin test to decide on the possibility of continuing therapy [60,191,192].

(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 perform an initial pediatric endocrinologist consultation (examination) based on medical indications in order to prescribe the individual program recommended by the inpatient pediatric endocrinologist [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to perform a follow-up pediatric endocrinologist consultation (examination) based on medical indications in order to monitor/adjust the individual program recommended by the inpatient pediatric endocrinologist [23,345–347].

(LEL 4, GRC C)

It is recommended to perform an initial orthopedic trauma consultation (examination) based on medical indications to resolve the issue of the need for orthopedic correction [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to perform a follow-up orthopedic trauma consultation (examination) based on medical indications to monitor the efficacy/adjust orthopedic correction [2,4,5,16,23].

(LoE 5, GoR C)

It is recommended to perform an initial medical psychologist consultation (testing, consultation) based on medical indications to develop a psychological rehabilitation program for the patient and their parents [2,4,5,125,220,301,302].

(LoE 5, GoR C)

It is recommended to perform a follow-up medical psychologist consultation (testing, consultation) based on medical indications after completion of the psychological rehabilitation program to assess its efficacy [2,4,5,125,220,301,302].

(LoE 5, GoR C)

It is recommended to schedule a planned hospitalization in the rheumatology department of the hospital that initiated the prescription of genetically engineered biologic drugs and #colchicine / autumn crocus seed extract for all patients in order to monitor the efficacy and safety of therapy [2,4,5,16,23].

(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 monitoring efficacy, see Appendix G1-G2.

It is recommended to conduct a consultation (examination, including remote) with the inpatient rheumatologist who initiated the therapy for all patients who develop adverse events from therapy / infectious complications / intolerance to genetically engineered biologic drugs and/or #colchicine / autumn crocus seed extract (if used) in order to resolve the issue of adjusting the therapy and the setting in which it should be carried out [5,16].

(LoE 5, GoR C)

It is recommended to perform an unplanned hospitalization in the rheumatology department of the hospital that initiated the prescription of genetically engineered biologic drugs and #colchicine / autumn crocus seed extract at any stage of treatment in the event of exacerbation/complications of TRAPS, comorbid conditions, complications/side effects/persistent intolerance to genetically engineered biologic drugs, for examination and therapy adjustment [2,4,5,16,23].

(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 TRAPS who develops exacerbation/complications of the disease, comorbid conditions, complications/side effects/persistent intolerance to genetically engineered biologic drugs and/or ^#colchicine / autumn crocus seed extract (if used), must be urgently hospitalized in the rheumatology department of the hospital that initiated the pathogenetic therapy for examination and therapy adjustment at any stage of treatment.

6.1.1 Suspected periodic fever syndrome associated with a mutation in the tumor necrosis factor receptor type I gene

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

o Completion of examination.

o Prescription of pathogenetic therapy.

o Absence of side effects or drug intolerance.

o Stabilization of condition with drug therapy: relief of fever, other systemic manifestations, and reduction in articular syndrome activity.

o Marked trend toward normalization / normalization of laboratory activity parameters.

6.1.2 Established diagnosis of periodic fever syndrome associated with a mutation in the tumor necrosis factor receptor type I gene, 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

o Completion of examination.

o Prescription/adjustment of pathogenetic therapy.

o Absence of side effects or drug intolerance.

o Stabilization of condition with drug therapy: relief of fever, other systemic manifestations, and reduction in articular syndrome activity.

o Marked trend toward normalization / normalization of laboratory activity parameters of TRAPS.

6.1.3 Established diagnosis of periodic fever syndrome associated with a mutation in the tumor necrosis factor receptor type I gene 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

o Completion of examination.

o Prescription of pathogenetic therapy for hemophagocytic syndrome.

o Absence of side effects or drug intolerance.

o Resolution of clinical and laboratory signs of hemophagocytic syndrome.

o Absence of clinical and laboratory signs of TRAPS activity.

6.1.4 Examination and therapy adjustment upon development of complications/intolerance to medical treatment are carried out in the rheumatology department of a hospital

a) Indications for discharge:

o Completion of examination.

o Resolution of side effects.

o Therapy adjustment.

o Absence of side effects or drug intolerance.

o Absence of signs of disease activity.

6.1.5 Established diagnosis of periodic fever syndrome associated with a mutation in the tumor necrosis factor receptor type I gene in remission stage

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

o Completion of examination.

o Absence of side effects or drug intolerance.

o Absence of signs of TRAPS activity.

A patient with an established diagnosis of TRAPS who develops exacerbation/complications of the disease, comorbid conditions, complications/side effects/persistent intolerance to genetically engineered biologic drugs and/or ^#colchicine / autumn crocus seed extract must be urgently hospitalized in the rheumatology department of the hospital that initiated the pathogenetic therapy for examination and therapy adjustment at any stage of treatment.

Indications for anti-rheumatic therapy in patients with TRAPS, including genetically engineered biologic drugs ( intramuscular and subcutaneous administration of medications) in a medical organization (pediatric rheumatology department in a 24-hour hospital and/or day hospital; treatment room of a primary care medical 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:

prescribing and (or) replacement of genetically engineered biological drugs and (or) selective immunosuppressants with or without glucocorticoid pulse therapy, and (or) immunosuppressants, and (or) high-dose normal human immunoglobulin in patients with periodic fever syndrome caused by a tumor necrosis factor receptor type 1 gene mutation with high/moderate inflammatory activity and (or) resistance to ongoing medical treatment.

6.2 Regulatory and legal documents governing the provision of medical care to children with periodic fever syndrome caused by a tumor necrosis factor receptor type 1 gene mutation

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

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 Declaring a Person 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. 374n dated July 26, 2024: Quantitative rating system for 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.

If a child with TRAPS is not provided with pathogenetic medications in a timely manner, there is a high probability of developing an exacerbation/increased disease activity, amyloidosis, renal failure, progression of joint damage, and functional disability in the patient.

Decree of the President of the Russian Federation No. 16 of January 5, 2021, on the establishment of the Circle of Добро (Circle of Kindness) Foundation for Support of Children with Severe Life-Threatening and Chronic Diseases, Including Rare (Orphan) Diseases.

7.1 Outcomes and prognosis

The incidence of amyloidosis is 25%. Outcomes and prognosis depend on timely diagnosis and prescription of targeted therapy with IL-1 inhibitors [4,5,11,20].

Control of inflammation implies the relief of main TRAPS-associated symptoms, normalization of inflammatory markers, and the absence of progression of organ damage. Before the introduction of modern bDMARDs, most patients with TRAPS used high doses of GCs to control symptoms during inflammatory attacks, making them heavily dependent on them.

There are no exact epidemiological data on the frequency of side effects from such treatment, but it is quite likely that the complications were significant. In addition, the response to GC therapy decreased over time without adequate control over activity in 15–25% of patients with highly penetrant mutations who are at risk for amyloidosis, renal or liver failure, and death [4,5,11,20].

According to Eurofever/Eurotraps registries, the proportion of such patients has decreased to 10% in recent years, but there is no reliable information on what fraction of them received bDMARDs [4,5,11,20].

Key points:

GCs are effective as symptomatic therapy in TRAPS, but their use does not prevent the development of amyloidosis and is limited by long-term complications.
Patients with low-penetrance mutations may respond to colchicine and have a better response to treatment with the TNF inhibitor etanercept.
Interleukin-1 (IL-1) inhibitors are the drugs of choice in patients with TRAPS with high-penetrance mutations and active disease.
A response to therapy is observed in 90% of patients.
Monitoring of infections and major adverse events is necessary.

Long-term outcomes of TRAPS depend directly on the severity of the phenotype and the timing of initiation of effective therapy. It has also been shown that IL-1 therapy significantly improves health-related quality of life [4,5,11,20].

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of medical care

Organizational and technical conditions for the provision of medical care.

Type of medical care	Primary specialized health care / Specialized medical care
Conditions of medical care	Outpatient / Inpatient / Day hospital
Form of medical care	Elective

Table 1. Criteria for assessing the quality of initial diagnosis to establish the diagnosis of tumor necrosis factor receptor type 1-associated periodic fever syndrome

№	Quality criteria	Performance assessment (yes/no)
1	Diagnosis, including differential diagnosis, has been performed in a hospital setting providing medical care to children with rheumatic diseases for all patients with suspected tumor necrosis factor receptor type 1-associated periodic syndrome	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	Coagulation testing (exploratory hemostasis screening) has been performed, 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, blood thrombin time, and von Willebrand factor activity and properties	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	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
7	A study of immunoglobulin levels in blood was 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	ABO blood group typing, determination of minor blood subgroups A-1, A-2, D, Cc, E, Kell, Duffy, and Rhesus D antigen (Rh factor) determination performed in all patients prior to invasive procedures (esophagogastroduodenoscopy, colonoscopy with biopsy, bone marrow puncture for cytological specimen acquisition, bone marrow trephine biopsy imprint cytological examination, bone biopsy)	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—a comprehensive panel for the diagnosis of cryopyrin-associated periodic syndromes and other autoinflammatory diseases—has been performed	yes/no
15	HLA-B27 antigen determination by flow cytometry has been performed in patients with clinical manifestations of TRAPS	yes/no
16	Blood procalcitonin level testing	yes/no
17	Focal tuberculin testing (Mantoux test, test with recombinant tuberculosis allergen in standard dilution) and/or blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens has been performed	yes/no
18	Determination of classes A, M, G antibodies (IgA, IgM, IgG) to Chlamydia psittaci in blood; antibodies to Chlamydophila pneumoniae in blood; class M antibodies (IgM) to Chlamydia trachomatis in blood; class G antibodies (IgG) to Chlamydia trachomatis in blood; and classes M, G antibodies (IgM, IgG) to Mycoplasma pneumoniae in blood has been 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 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
21	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
22	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
23	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
24	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 have been performed	yes/no
25	Antibodies of classes M, G (IgM, IgG) to Cytomegalovirus in blood testing	yes/no
26	Antibodies of classes M, G (IgM, IgG) to Epstein-Barr virus in blood testing	yes/no
27	Antibodies to Epstein-Barr virus (Epstein-Barr virus) capsid antigen (VCA) in blood testing	yes/no
28	Class G antibodies (IgG) to Epstein-Barr virus (Epstein-Barr virus) early antigens (EA) in blood testing	yes/no
29	Antibodies to Herpes simplex virus in blood testing	yes/no
30	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
31	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
32	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
33	Molecular biological blood testing for Toxoplasma gondii has been performed in patients with a history of animal contact	yes/no
34	Determination of antibodies to Leischmania in blood has been performed in patients with a history of animal contact	yes/no
35	Microbiological (culture) examination of tonsillar and posterior pharyngeal wall mucus for aerobic and facultatively anaerobic microorganisms performed	yes/no
36	Microbiological (culture) blood test for sterility, microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms performed	yes/no
37	Fecal calprotectin level testing was performed	yes/no
38	Comprehensive ultrasound examination of internal organs (including comprehensive abdominal ultrasound and renal ultrasound) has been performed	yes/no
39	Echocardiography performed	yes/no
40	Electrocardiogram recording performed	yes/no
41	Joint ultrasound has been performed in patients with active arthritis	yes/no
42	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
43	Magnetic resonance imaging of joints (single joint) with contrast enhancement, with or without anesthesia support (including early postoperative management), has been performed in patients with active arthritis	yes/no
44	Plain abdominal X-ray imaging has been performed in all patients with abdominal syndrome	yes/no
45	Esophagogastroduodenoscopy with or without anesthesia support (including early postoperative management) has been performed	yes/no
46	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
47	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
48	Performed colonoscopy with anesthetic management (including early postoperative management)	yes/no
49	Performed endoscopic biopsy of the large intestine with pathomorphological examination of the biopsy (surgical) material from the large intestine in patients with inflammatory, erosive, and/or ulcerative changes in the large intestine detected by colonoscopy	yes/no
50	Performed contrast-enhanced magnetic resonance imaging of the small intestine (MR enterography, hydro-MRI) with or without anesthetic management (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
51	Performed capsule endoscopy of the small intestine in patients with clinical signs of IBD and/or significantly elevated fecal calprotectin levels in the absence of abnormalities on esophagogastroduodenoscopy and colonoscopy	yes/no
52	Performed computed tomography of the chest organs with or without anesthetic management (including early postoperative management)	yes/no
53	Performed contrast-enhanced magnetic resonance imaging of the brain, contrast-enhanced magnetic resonance imaging of the abdominal organs with intravenous contrast, contrast-enhanced magnetic resonance imaging of the retroperitoneal space with intravenous contrast, and contrast-enhanced magnetic resonance imaging of the pelvic organs with intravenous contrast with or without anesthetic management (including early postoperative management)	yes/no
54	Performed computed tomography of the brain, computed tomography of the abdominal organs with intravenous bolus contrast enhancement, and computed tomography of the retroperitoneal space with intravenous bolus contrast enhancement with or without anesthetic management (including early postoperative management) in patients with contraindications to MRI	yes/no
55	Performed contrast-enhanced magnetic resonance imaging of the brain and contrast-enhanced magnetic resonance imaging of the spinal cord (one segment) with or without anesthetic management (including early postoperative management) in patients with symptoms of central nervous system involvement	yes/no
56	Performed lumbar puncture with anesthetic management (including early postoperative management), including microscopic examination, cell counting in a counting chamber (determination of cytosis), assessment of physical properties of the cerebrospinal fluid, and serological examination in all patients with symptoms of central nervous system involvement	yes/no
57	Performed kidney biopsy with anesthetic management (including early postoperative management) and pathomorphological examination of the renal biopsy (surgical) specimen in patients with clinical/laboratory/ultrasound signs of renal involvement and/or renal failure, and/or in the presence of proteinuria > 500 mg per day in the absence of contraindications	yes/no
58	Performed bone marrow aspiration to obtain a cytological bone marrow preparation and histological bone marrow preparation with anesthetic management (including early postoperative management), including cytological examination of the bone marrow smear (myelogram) and immunohistochemical pathomorphological examination of the bone marrow biopsy (surgical) material	yes/no
59	Performed lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) with anesthetic management (including early postoperative management), including cytological examination of the lymph node tissue preparation and pathomorphological examination of the biopsy (surgical) material in patients with marked enlargement of peripheral, intrathoracic, and/or intra-abdominal lymph nodes during the diagnostic stage prior to initiating pathogenetic therapy	yes/no
60	Performed pelvic bone trephine biopsy with anesthetic management (including early postoperative management), including immunohistochemical pathomorphological examination of the bone marrow biopsy (surgical) material; 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 prior to prescribing glucocorticoids, ^#colchicine / autumn crocus seed extract, and/or an immunosuppressant, and/or a biological agent in patients with atypical TRAPS presentation during the evaluation stage	yes/no
61	Performed bone biopsy with anesthetic management (including early postoperative management) and pathomorphological examination of the bone biopsy (surgical) material in patients with bone destruction foci atypical for TRAPS	yes/no
62	Performed multi-site bone scintigraphy with or without anesthetic management (including early postoperative management) in patients with bone destruction foci atypical for TRAPS	yes/no
63	Performed positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)) with contrast enhancement, or whole-body positron emission tomography with tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)) as needed, with or without anesthetic management (including early postoperative management) in patients with severe arthralgia, myalgia, ossalgia, bone destruction changes, subcutaneous adipose tissue infiltrates, or lesions in parenchymal organs, the brain, or the spinal cord	yes/no
64	Performed initial examination (inspection, consultation) by a pediatric surgeon in patients with abdominal symptoms	yes/no
65	Initial consultation (examination) by a gastroenterologist was performed in all patients with abdominal symptoms	yes/no
66	Initial consultation (examination) by a pediatric oncologist was performed in patients with suspected oncological or oncohematological diseases based on examination results	yes/no
67	Performed initial examination (inspection, consultation) by a pediatric urologist-andrologist in all male patients with abdominal symptoms, pain syndrome, and inflammatory changes in the gonadal region	yes/no
68	Performed initial examination (inspection, consultation) by an obstetrician-gynecologist in all female patients with abdominal symptoms and pain syndrome in the gonadal region	yes/no
69	Performed initial examination (inspection, consultation) by a nephrologist in patients with abnormal urinalysis results 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	Performed initial examination (inspection, consultation) by a phthisiatrician in patients with positive focal tuberculin skin tests and/or elevated blood interferon-gamma levels in response to Mycobacterium tuberculosis complex antigens and/or infiltrative pulmonary foci	yes/no
72	Performed initial examination (inspection, consultation) by an orthopedic traumatologist in patients with acute arthritis, space-occupying and destructive lesions, and bone deformities atypical for TRAPS	yes/no
73	Initial appointment (examination, consultation) by anotorhinolaryngologist was completed.	yes/no
74	Performed examination (inspection, consultation) by an otolaryngologist-audiologist	yes/no
75	Initial ophthalmologist consultation (examination) with mandatory ocular biomicroscopy was performed	yes/no
76	Performed examination (inspection, consultation) by a pediatric dentist in patients with clinical indications	yes/no
77	Performed initial examination (inspection, consultation) by a geneticist in patients with mutations in the TNFRSF1A gene identified by molecular genetic testing	yes/no
78	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
79	Performed initial examination (consultation) by an anesthesiologist-resuscitologist in patients scheduled for procedures under general anesthesia	yes/no
80	Performed initial examination (consultation) by an anesthesiologist-resuscitologist in critically ill patients	yes/no
81	Performed 24-hour monitoring by an anesthesiologist-resuscitologist for all critically ill patients (multiple organ dysfunction syndrome, hemophagocytic syndrome)	yes/no

Table 2. Criteria for assessing the quality of diagnosis of hemophagocytic syndrome

№	Quality criteria	Performance assessment (yes/no)
1	Diagnostics, including differential diagnostics, were performed for all patients with suspected HFS 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	Epstein-Barr virus (Epstein - Barr virus) DNA PCR assay in peripheral and cord blood (quantitative), Epstein-Barr virus (Epstein - Barr virus) DNA PCR assay in oropharyngeal swabs (qualitative), Epstein-Barr virus (Epstein - Barr virus) DNA PCR assay in urine (qualitative)	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) test of bronchoalveolar lavage fluid for Pneumocystis carinii cysts was performed upon detection of interstitial and/or focal, and/or infiltrative lung changes 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 Candida albicans and galactomannan antigen of Aspergillus spp. in blood serum by ELISA was performed upon detection of interstitial and/or focal, and/or infiltrative lung changes 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 evaluating the quality of examination of patients with an established diagnosis of periodic fever syndrome associated with a tumor necrosis factor receptor type 1 gene mutation prior to prescribing/adjusting pathogenetic therapy

№	Quality criteria	Performance assessment (yes/no)
1	Examination prior to prescribing/adjusting antirheumatic therapy was performed for all patients with an established diagnosis of periodic fever syndrome associated with a tumor necrosis factor receptor type 1 gene mutation in the active stage 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 study) 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 in blood, and blood von Willebrand factor activity and properties in patients with macrophage activation syndrome (MAS) and/or signs of vasculitis, and/or receiving heparin group drugs	yes/no
4	Thromboelastography was performed in patients with MAS and/or 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	Blood procalcitonin level measurement was performed in all patients with fever	yes/no
8	A study of immunoglobulin levels in blood was performed	yes/no
9	Antistreptolysin-O blood serum test	yes/no
10	A study of the C-reactive protein level in blood serum was performed	yes/no
11	Lymphocyte subset analysis was performed in patients with frequent viral and purulent bacterial infections, including opportunistic ones, prior to therapy initiation/adjustment	yes/no
12	ABO blood group typing, determination of minor blood subgroups A-1, A-2, D, Cc, E, Kell, Duffy, and Rhesus D antigen (Rh factor) determination performed in all patients prior to invasive procedures (esophagogastroduodenoscopy, colonoscopy with biopsy, bone marrow puncture for cytological specimen acquisition, bone marrow trephine biopsy imprint cytological examination, bone biopsy)	yes/no
13	A tuberculin skin 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	Blood class A, M, and G antibody (IgA, IgM, IgG) testing for Chlamydia psittaci; antibody testing for Chlamydophila pneumoniae; blood class M antibody (IgM) testing for Chlamydia trachomatis; blood class G antibody (IgG) testing for Chlamydia trachomatis; and blood class M and G antibody (IgM, IgG) testing for Mycoplasma pneumoniae were performed	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 wall mucus for aerobic and facultatively anaerobic microorganisms 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	Quantitative PCR detection of Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, or bronchoalveolar lavage fluid was performed in patients with signs of pneumonia according to chest computed tomography	yes/no
26	Microbiological (cultural) examination of bronchoalveolar lavage fluid for fungi (yeast and mold) was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography	yes/no
27	Microbiological (cultural) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography	yes/no
28	Blood antibody testing for fungi of the genus Aspergillus (Aspergillus spp.) was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography	yes/no
29	Mannan and galactomannan testing in lavage fluid and blood was performed in patients with signs of pneumonia according to chest computed tomography	yes/no
30	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
31	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
32	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
33	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
34	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
35	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
36	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
37	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
38	Fecal calprotectin level testing was performed in patients who developed clinical manifestations of IBD (diarrhea, abdominal pain, blood/mucus in stool)	yes/no
39	Comprehensive ultrasound examination of internal organs was performed (includes comprehensive abdominal ultrasound, renal ultrasound)	yes/no
40	Echocardiography performed	yes/no
41	Electrocardiogram recording performed	yes/no
42	Ambulatory blood pressure monitoring was performed in patients with arterial hypertension	yes/no
43	Holter ECG monitoring was performed in patients with arrhythmia or pathological electrocardiographic findings	yes/no
44	Joint ultrasound has been performed in patients with active arthritis	yes/no
45	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
46	Magnetic resonance imaging of joints (single joint) with contrast enhancement, with or without anesthesia (including early postoperative management), was performed in patients with active arthritis	yes/no
47	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
48	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
49	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
50	Colonoscopy with anesthetic care performed (including early postoperative management for patients with abdominal syndrome)	yes/no
51	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
52	Kidney biopsy with anesthetic care (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen performed in patients with chronic kidney disease/signs of renal failure in the absence of contraindications	yes/no
53	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
54	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
55	Performed computed tomography of the chest organs with or without anesthetic care (including early postoperative management)	yes/no
56	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
57	X-ray densitometry performed in patients receiving or previously receiving glucocorticoids	yes/no
58	Initial appointment (examination, consultation) by an orthopedic traumatologist performed in patients with functional joint insufficiency	yes/no
59	Initial appointment (examination, consultation) by anotorhinolaryngologist was completed.	yes/no
60	Initial appointment (examination, consultation) by a pediatric dentist performed in patients with foci of chronic infection	yes/no
61	Initial ophthalmologist consultation (examination) with mandatory ocular biomicroscopy was performed	yes/no
62	An initial consultation (examination) by a pediatric cardiologist was performed in patients with cardiac dysfunction and/or arterial hypertension	yes/no
63	Initial appointment (examination, consultation) by a phthisiatrician performed in patients with positive results of a focal tuberculin skin test and/or elevated blood interferon-gamma level to Mycobacterium tuberculosis complex antigens, and/or focal or infiltrative pulmonary changes	yes/no
64	Initial examination (consultation) by a pediatric endocrinologist was performed for patients with endocrinological pathology	yes/no
65	Initial examination (consultation) by a dietitian was performed for all patients with nutritional disorders	yes/no
66	Initial consultation (examination) by a neurologist was performed in patients with neurological symptoms	yes/no
67	Initial 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
68	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
69	Follow-up appointment (examination, consultation) by an otorhinolaryngologist	yes/no
70	Follow-up appointment (examination, consultation) by a pediatric dentist performed in all patients after sanitation of oral foci of chronic infection	yes/no
71	Follow-up appointment (examination, consultation) by an ophthalmologist with mandatory ocular biomicroscopy performed in all patients with identified pathology	yes/no
72	A follow-up consultation (examination) by a pediatric cardiologist was performed in patients with cardiac dysfunction and/or arterial hypertension	yes/no
73	Follow-up examination (consultation) by a dietitian was performed for all patients with nutritional disorders	yes/no
74	Follow-up appointment (examination, consultation) by a neurologist performed in patients with neurological symptoms and psychotic reactions	yes/no
75	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
76	Performed initial examination (consultation) by an anesthesiologist-resuscitologist in patients scheduled for procedures under general anesthesia	yes/no
77	Performed initial examination (consultation) by an anesthesiologist-resuscitologist in critically ill patients	yes/no
78	Performed 24-hour monitoring by an anesthesiologist-resuscitologist for all critically ill patients (multiple organ dysfunction syndrome, hemophagocytic syndrome)	yes/no

Table 4. Quality evaluation criteria for the treatment of periodic fever syndrome associated with a tumor necrosis factor receptor type 1 gene mutation

№	Quality criteria	Performance assessment (yes/no)
1	Pathogenetic therapy prescribed to all patients following diagnostics, including differential diagnostics, and establishment/confirmation of the TRAPS diagnosis in an inpatient setting providing medical care to children with rheumatic diseases	yes/no
2	Only NSAIDs prescribed to patients with an unconfirmed TRAPS diagnosis during the evaluation phase	yes/no
3	NSAIDs prescribed to patients with a confirmed TRAPS diagnosis	yes/no
4	Oral and/or intravenous and/or intra-articular glucocorticoids and/or ^#Colchicum autumnale seed extract/colchicine, and/or biological DMARDs (bDMARDs) NOT prescribed prior to the completion of a full laboratory and instrumental workup, exclusion of oncological and oncohematological diseases, and establishment of the TRAPS diagnosis	yes/no
5	Pulse therapy with ^#methylprednisolone** at a dose of 10–30 mg/kg/administration intravenously for 3, or if necessary 5 consecutive days, performed in patients with a confirmed TRAPS diagnosis at the evaluation stage, presenting with severe pain syndrome and life-threatening systemic manifestations (persistent febrile or hectic fever and/or pericarditis, and/or pleurisy)	yes/no
6	Prescription of ^#prednisolone or ^#methylprednisolone orally at a dose of 0.5–1 mg/kg/day in patients with a confirmed TRAPS diagnosis during the evaluation stage, presenting with severe pain syndrome and/or life-threatening systemic manifestations (persistent febrile or hectic fever and/or pericarditis, and/or pleurisy)	yes/no
7	Prescription of the interleukin-1β (IL-1β) inhibitor canakinumab** as the primary pathogenetic therapy for remission induction in all patients with a confirmed TRAPS diagnosis who present with signs of systemic inflammatory response (fever, rash, etc.), organ involvement (ocular pathology, gastrointestinal or joint changes), ESR elevation > 30 mm/h (by Panchenkov), CRP > 20 mg/L or > 4 times the upper limit of normal at evaluation or within the preceding month, with an attack frequency ≥ 3 per 9–12 months of disease course	yes/no
8	Prescription of canakinumab** to children older than 2 years with a body weight ≥ 7.5 and ≤ 40 kg at a dose of 2 mg/kg subcutaneously once every 4 weeks; > 40 kg at a dose of 150 mg subcutaneously once every 4 weeks	yes/no
9	Maintenance therapy with canakinumab administered to children older than 2 years with a body weight ≤ 40 kg at a dose of 2 mg/kg subcutaneously once every 4 weeks, and to children with a body weight > 40 kg at a dose of 150 mg subcutaneously once every 4 weeks upon achieving a clinical effect 7 days after the canakinumab injection	yes/no
10	Second injection of canakinumab administered to children older than 2 years with a body weight ≤ 40 kg at a dose of 2 mg/kg subcutaneously, and to children with a body weight > 40 kg at a dose of 150 mg subcutaneously if the clinical effect is not achieved 7 days after the canakinumab injection	yes/no
11	Administration to children older than 2 years with a body weight ≤ 40 kg at a dose of 4 mg/kg subcutaneously once every 4 weeks, and to children with a body weight > 40 kg at a dose of 300 mg subcutaneously once every 4 weeks upon achieving a complete clinical effect 7 days after the second canakinumab** injection	yes/no
12	Prescription of the TNF inhibitor ^#etanercept as second-line pathogenetic therapy at a dose of 0.4 mg/kg twice a week or 0.8 mg/kg once a week subcutaneously in case of inefficacy/intolerance of canakinumab	yes/no
13	Prescription of ^#tocilizumab at a dose of 8 mg/kg/administration intravenously once every 2 weeks or 162 mg subcutaneously once a week in children with active chronic arthritis and/or combination of TRAPS with juvenile idiopathic arthritis when canakinumab and ^#etanercept** are ineffective	yes/no
14	Switching to ^#tocilizumab at a dose of 8 mg/kg/administration intravenously once every 2 weeks or 162 mg subcutaneously once a week in children with active chronic arthritis and/or combination of TRAPS with juvenile idiopathic arthritis in case of intolerance to canakinumab and ^#etanercept**	yes/no
15	Prescription of ^#Colchicum autumnale seed extract/colchicine in a benign disease course (infrequent attacks, moderate laboratory activity, low-penetrance mutation, etc.)	yes/no
16	Prescription of ^#Colchicum autumnale seed extract/colchicine at a starting daily dose of 0.5 mg/day for children under 5 years, 0.5–1.0 mg/day for 5–10 years, and 1.0–1.5 mg/day for over 10 years	yes/no
17	Increase in the daily dose of ^#Colchicum autumnale seed extract/colchicine by 0.5 or 0.6 mg per day if inflammatory activity persists despite adherence to the recommended initial dose and careful monitoring for side effects	yes/no
18	Exceeding the dose of ^#Colchicum autumnale seed extract/colchicine > 2.0 mg/day NOT performed	yes/no
19	Determination of the Autoinflammatory Diseases Activity Index (AIDAI) and Autoinflammatory Disease Damage Index (ADDI) performed to assess therapy efficacy	yes/no
20	Assessment of the Damage Index (ADDI) performed to evaluate therapy efficacy	yes/no

Table 5. Quality evaluation criteria for the treatment of hemophagocytic lymphohistiocytosis in patients with periodic fever syndrome associated with a tumor necrosis factor receptor type 1 gene mutation

№	Quality criteria	Performance assessment (yes/no)
1	Prescription and administration of therapy performed in all patients following diagnostics, including differential diagnostics, and establishment/confirmation of the TRAPS diagnosis with hemophagocytic syndrome in an inpatient setting providing medical care to children with rheumatic diseases	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 dose reduction of intravenous GCs was performed after resolution of clinical and laboratory signs of HPS according to the following regimens: ^#dexamethasone from an initial 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 from an initial dose of 20-30 mg/kg/administration for 3-5 days with dose reduction by 25% once 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 prescribed at a dose of 1–2 mg/kg orally or ^#methylprednisolone at an equivalent dose to prednisolone, in case of combination therapy failure in HLH or HLH reactivation during the tapering/withdrawal of intravenous corticosteroids	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/m²intravenously 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. Criteria for assessing the quality of dispensary observation of patients with periodic fever syndrome caused by a mutation of the tumor necrosis factor receptor type I gene in an inpatient/day hospital setting that initiated pathogenetic therapy

№	Quality criteria	Performance assessment (yes/no)
1	Assessment of treatment efficacy and safety of antirheumatic therapy performed for all patients with an established diagnosis of TRAPS in an inpatient facility providing medical care to children with rheumatic diseases, at 3 months after therapy initiation, at 6 months after therapy initiation, 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	Biologic DMARD injections/infusions and/or ^#Colchicum autumnale seed extract/colchicine (if used) omitted for 7 days in all patients when platelets drop to ≤ 150 and > 100 × 10⁹/L, or neutrophils drop to < 1.5 and ≥ 1.0 × 10⁹/L in the complete blood count	yes/no
4	Biologic DMARD injections/infusions and/or ^#Colchicum autumnale seed extract/colchicine (if used) discontinued in all patients when the absolute neutrophil count drops to < 1.0 × 10⁹/L and/or platelet count drops to < 100 × 10⁹/L in the complete blood count	yes/no
5	Colony-stimulating factor ^#filgrastim** prescribed at a dose of 5–10 mcg/kg/day subcutaneously for leukopenia with an absolute neutrophil count of ≤ 1.0 × 10⁹/L for 3–5 days (or longer if necessary)	yes/no
6	Colony-stimulating factor ^#filgrastim** prescribed at a dose of 5–10 mcg/kg/day subcutaneously in combination with intravenous systemic antibacterial drugs for febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count of ≤ 1.0 × 10⁹/L	yes/no
7	Continuation of treatment with systemic antibacterial drugs performed in all patients with febrile neutropenia (neutropenia accompanied by fever)	yes/no
8	Resumption of biologic DMARD injection/infusion and/or ^#Colchicum autumnale seed extract/colchicine (if used) at the same dose in all patients after recovery of the neutrophil count to ≥ 1.5 × 10⁹/L according to the complete blood count	yes/no
9	Adjustment of biologic DMARD therapy and/or ^#Colchicum autumnale seed extract/colchicine (if used) performed in all patients in the presence of data on recurrent episodes of decreased blood cell counts in the complete blood count	yes/no
10	Fluconazole** prescribed intravenously at a dose of 3–12 mg/kg/day depending on the severity and duration of induced neutropenia in 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 biologic DMARD injections/infusions and/or ^#Colchicum autumnale seed extract/colchicine (if used) was performed in all patients upon an increase in blood ALT and AST activity ≥ 1.5 times the upper limit of normal and/or an increase in total bilirubin, free (unconjugated) and/or conjugated bilirubin, and/or blood urea, and/or creatinine, and/or uric acid, and/or other biochemical parameter(s) above the upper limit of normal	yes/no
13	Resumption of biologic DMARD therapy and/or ^#Colchicum autumnale seed extract/colchicine (if used) at the same dose was performed in all patients after normalization of general biochemical blood test parameters	yes/no
14	Correction of biologic DMARD therapy and/or ^#Colchicum autumnale seed extract/colchicine (if used) was performed in all patients in the presence of data on repeated episodes of elevation of biochemical parameter(s)	yes/no
15	A study of immunoglobulin levels in blood was performed	yes/no
16	Administration of ^#normal human immunoglobulin** at 400 mg/kg was performed; 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 case of decreased blood immunoglobulin levels	yes/no
17	Determination of antibodies to cell nuclear antigens and DNA was performed in patients receiving TNF-alpha inhibitors	yes/no
18	A study of the C-reactive protein level in blood serum was performed	yes/no
19	Procalcitonin level blood testing was performed in patients with fever	yes/no
20	A set of studies to rule out sepsis (complete blood count with differential, general biochemical blood test, serum C-reactive protein level test, blood culture for sterility, microbiological [culture] examination of tonsils and posterior pharyngeal wall mucus for aerobic and facultatively anaerobic microorganisms, urine microbiological [culture] examination for bacterial pathogens using automated inoculation with antimicrobial susceptibility testing, microbiological [culture] examination of anal discharge, thromboelastography, coagulography [exploratory hemostasis assessment]; computed tomography of the chest cavity, comprehensive abdominal ultrasound, renal ultrasound, echocardiography, abdominal MRI, pelvic MRI, and retroperitoneal MRI) was performed in accordance with clinical guidelines for the treatment of sepsis in children for patients with febrile/hectic fever, leukocytosis/leukopenia, thrombocytopenia, elevated serum C-reactive protein and serum procalcitonin levels not related to TRAPS activity	yes/no
21	Administration was performed first of empirical antibacterial therapy, and subsequently, depending on the clinical situation, intravenous systemic antibacterial drugs affecting Gram-positive, Gram-negative, and anaerobic flora (combinations of penicillins, 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) combined with or without systemic antifungal drugs according to microbial susceptibility, in combination with ^#normal human immunoglobulin** at a dose of 400 mg/kg/course (5 days) in patients who develop sepsis	yes/no
22	Temporary discontinuation of biologic DMARD therapy and/or administration of ^#Colchicum autumnale seed extract/colchicine (if used) was performed, continuing previously prescribed oral GCs, with ^#methylprednisolone** pulse therapy upon increased activity in TRAPS patients with bacterial complications/sepsis	yes/no
23	Resumption of biologic DMARD therapy and/or ^#Colchicum autumnale seed extract/colchicine (if used) was performed no earlier than one week after complete resolution of clinical and laboratory signs of sepsis and completion of antibacterial therapy in all patients	yes/no
24	Administration of biologic DMARDs and/or Colchicum autumnale seed extract/colchicine (if used) was performed no earlier than 1 week after complete resolution of clinical and laboratory signs of sepsis and completion of antibacterial therapy	yes/no
25	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
26	Thromboelastography was performed in patients with febrile fever/sepsis/MAS/signs of thrombosis and hypocoagulation	yes/no
27	Administration/adjustment of antithrombotic therapy, including heparin-group drugs, non-heparin antiplatelet agents, antifibrinolytic agents, and direct factor Xa inhibitors, was performed upon development of coagulopathy or disseminated intravascular coagulation according to coagulography (exploratory hemostasis assessment) and thromboelastography data	yes/no
28	Blood transfusion was performed upon development of consumption coagulopathy or bleeding	yes/no
29	Lymphocyte subset testing was performed in patients frequently afflicted with viral or purulent bacterial infections, including opportunistic infections	yes/no
30	Determination of Epstein-Barr virus (Epstein-Barr virus), Cytomegalovirus (Cytomegalovirus), and Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA by PCR in peripheral blood (quantitative test), saliva, and urine was performed in patients with clinical manifestations of herpesvirus infection/interstitial pneumonia	yes/no
31	Determination of Epstein-Barr virus (Epstein-Barr virus) DNA by PCR in peripheral and cord blood (quantitative test), determination of Epstein-Barr virus (Epstein-Barr virus) DNA in oropharyngeal mucosal swabs by PCR (qualitative test), and determination of Epstein-Barr virus (Epstein-Barr virus) DNA by PCR (qualitative test) in urine were performed in patients receiving biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if used) combined with (or without) GCs, with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia	yes/no
32	Determination of Cytomegalovirus (Cytomegalovirus) DNA by PCR in peripheral and cord blood (quantitative test), determination of Cytomegalovirus (Cytomegalovirus) DNA in oropharyngeal mucosal swabs by PCR (qualitative test), and determination of Cytomegalovirus (Cytomegalovirus) DNA by PCR (qualitative test) in urine were performed in patients receiving biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if used) combined with (or without) GCs, with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia	yes/no
33	Determination of Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA by PCR in blood (quantitative test), determination of Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in oropharyngeal mucosal swabs by PCR (qualitative test), and determination of Herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA by PCR (qualitative test) in urine were performed in patients receiving biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if used) combined with (or without) GCs, with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia	yes/no
34	Determination of IgM and IgG antibodies to Cytomegalovirus (Cytomegalovirus) in blood was performed in all patients receiving biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if used) combined with (or without) GCs, with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia	yes/no
35	Determination of IgM and IgG antibodies to Epstein-Barr virus (Epstein-Barr virus) in blood was performed in all patients receiving biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if used) combined with (or without) GCs, with clinical manifestations of herpetic infection, and in patients with interstitial pneumonia	yes/no
36	Determination of antibodies to the capsid antigen (VCA) of Epstein-Barr virus (Epstein-Barr virus) in the blood has been performed for all patients receiving biological disease-modifying antirheumatic drugs (bDMARDs) and/or ^#colchicine / autumn crocus seed extract (if applicable), combined with glucocorticoids (GCs) or without them, presenting with clinical manifestations of herpetic infection, and for patients with interstitial pneumonia	yes/no
37	Determination of class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus (Epstein-Barr virus) in the blood has been performed for all patients receiving bDMARDs and/or ^#colchicine / autumn crocus seed extract (if applicable), combined with GCs or without them, presenting with clinical manifestations of herpetic infection, and for patients with interstitial pneumonia	yes/no
38	Determination of antibodies to Herpes simplex virus in the blood has been performed for all patients receiving bDMARDs and/or ^#colchicine / autumn crocus seed extract (if applicable), combined with GCs or without them, presenting with clinical manifestations of herpetic infection, and for patients with interstitial pneumonia	yes/no
39	Prescription has been made: ^#acyclovir (JO5AB) at a dose of 200 mg/day orally 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 upon development of localized herpetic infection; prescription of ^#acyclovir at a dose of 10 mg/kg/injection intravenously every 8 hours in children aged < 1 year; at a dose of 500 mg/m²intravenously every 8 hours in children aged ≥ 1 year upon development of Herpes zoster	yes/no
40	Prescription of ^#ganciclovir at a dose of 6 mg/kg/injection intravenously every 12 hours upon development of cytomegalovirus infection, or ganciclovir at a dose of 10 mg/kg/injection intravenously every 12 hours upon development of Epstein-Barr virus infection has been made	yes/no
41	Temporary discontinuation of bDMARD therapy and/or ^#colchicine / autumn crocus seed extract intake (if applicable) has been performed for all patients upon development of infection, for the duration of antiviral therapy caused by herpesviruses	yes/no
42	Resumption of bDMARD therapy and/or ^#colchicine / autumn crocus seed extract intake (if applicable) has been performed for all patients no earlier than 1 week after complete resolution of clinical and laboratory signs of infection and completion of antiviral therapy	yes/no
43	Screening for the presence/absence of tuberculosis (tuberculin skin test, test with recombinant tuberculosis allergen in standard dilution*, and/or blood interferon-gamma release assay for Mycobacterium tuberculosis complex* antigens, chest computed tomography) has been performed for all patients receiving bDMARDs and/or ^#colchicine / autumn crocus seed extract (if applicable), combined with GCs or without them, at least 2 times a year	yes/no
44	Discontinuation of bDMARD therapy and/or ^#colchicine / autumn crocus seed extract intake (if applicable) has been performed for all patients with a detected positive tuberculin skin test (papule > 5 mm) and/hagen/or elevated interferon-gamma levels and/or lung and/or intrathoracic lymph node lesions	yes/no
45	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
46	Prescription of oral GCs has been performed for all patients upon development of a TRAPS flare for the duration of specific antituberculous therapy	yes/no
47	Resumption of bDMARD therapy and/or ^#colchicine / autumn crocus seed extract intake (if applicable) has been performed for all patients after completion of specific antituberculous therapy and consultation with a phthisiatrician	yes/no
48	Determination of antibodies to Salmonella enterica in the blood, determination of antibodies to Salmonella typhi in the blood, determination of IgM and IgG class antibodies to Yersinia pseudotuberculosis in the blood, and determination of antibodies to serovars of Yersinia enterocolitica in the blood have been performed for patients with abdominal syndrome	yes/no
49	Etiotropic therapy has been administered upon detection of IgA and IgM antibodies in diagnostic titer, as well as high-titer IgG antibodies to Yersinia pseudotuberculosis, Yersinia enterocolitica serovars, Salmonella enterica, and Salmonella typhi in the blood of all patients receiving bDMARDs and/or ^#colchicine / autumn crocus seed extract (if applicable), combined with GCs or without them	yes/no
50	Determination of IgA, IgM, and IgG class antibodies to Chlamydia psittaci in the blood; determination of antibodies to Chlamydia trachomatis in the blood; determination of antibodies to Chlamydophila pneumoniae in the blood; determination of IgM and IgG class antibodies to Mycoplasma pneumoniae in the blood have been performed for patients with interstitial pneumonia	yes/no
51	Etiotropic therapy has been administered upon detection of IgA and IgM antibodies in diagnostic titer, as well as high-titer IgG antibodies to Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, and Chlamydophila pneumoniae in the blood of all patients receiving bDMARDs and ^#colchicine / autumn crocus seed extract (if applicable), combined with GCs or without them, in accordance with clinical guidelines for the diagnosis and treatment of mycoplasmal and chlamydial infection in children	yes/no
52	Microbiological (culture) examination of mucus from the tonsils and posterior pharyngeal wall has been performed	yes/no
53	A general (clinical) urinalysis was performed	yes/no
54	Determination of urine albumin and daily urinary protein excretion has been performed for patients with clinical/laboratory signs of nephrotic syndrome and/or renal failure, and/or disease duration of more than 5 years	yes/no
55	A set of renal function tests and diagnostic studies for assessing the severity of renal failure has been performed for patients with clinical/laboratory signs of nephrotic syndrome and/or renal failure, and/or disease duration of more than 5 years, and/or in the presence of proteinuria > 500 mg/day	yes/no
56	Renal biopsy with anesthetic support (including early postoperative management) and pathomorphological examination of the biopsy (surgical) specimen has been performed for patients with clinical/laboratory/ultrasound signs of renal damage and/or renal failure, and/or in the presence of proteinuria > 500 mg/day in the absence of contraindications	yes/no
57	Electrocardiogram recording performed	yes/no
58	Holter ECG monitoring was performed in patients with arrhythmia or pathological electrocardiographic findings	yes/no
59	Ambulatory blood pressure monitoring was performed in patients with arterial hypertension	yes/no
60	Complex ultrasound examination of internal organs (including complex abdominal ultrasound and renal ultrasound) has been performed	yes/no
61	Echocardiography performed	yes/no
62	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
63	Microbiological (culture) examination of gastric mucosal biopsy specimens for Helicobacter pylori has been performed for patients with inflammatory, erosive, and/or ulcerative changes according to esophagogastroduodenoscopy	yes/no
64	Prescription of medications for the treatment of gastric and duodenal ulcer disease and gastroesophageal reflux disease has been made upon detection of reflux disease and/or inflammatory gastropathy, erosive and/or ulcerative processes in the esophagus and/or stomach and/or duodenum	yes/no
65	Eradication therapy has been administered, including proton pump inhibitors (A02BC), systemic antibacterial drugs, 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 twice daily (for patients aged 8 to 12 years), at a dose of 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
66	Temporary discontinuation of bDMARD therapy and/or Colchicum autumnale (autumn crocus) seed extract/colchicine (if used) performed in all patients during eradication therapy	yes/no
67	Colonoscopy with anesthetic support (including early postoperative management) has been performed for patients with abdominal syndrome	yes/no
68	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
69	Performed magnetic resonance imaging of joints (one joint) with or without anesthetic management (including early postoperative care) in patients with active arthritis	yes/no
70	Performed computed tomography of the chest organs with or without anesthetic management (including early postoperative care) at least once every 6 months	yes/no
71	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
72	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
73	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
74	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
75	Performed microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeast and mold) in all patients when interstitial, focal, and/or infiltrative changes in the lungs are detected by chest computed tomography	yes/no
76	Microbiological (cultural) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms was performed in patients with interstitial and/or focal and/or infiltrative lung changes detected by chest computed tomography	yes/no
77	Performed determination of antibodies to fungi of the genus Aspergillus (Aspergillus spp.) in the blood of patients when interstitial, focal, and/or infiltrative changes in the lungs are detected by chest computed tomography	yes/no
78	Mannan and galactomannan testing in lavage fluid and blood was performed in patients with signs of pneumonia according to chest computed tomography	yes/no
79	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
80	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
81	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
82	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
83	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
84	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
85	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
86	Performed determination of antibodies to herpes simplex virus (Herpes simplex) in the blood of all patients when interstitial, focal, and/or infiltrative changes in the lungs are detected by chest computed tomography	yes/no
87	Administered empirical antibacterial therapy with ^#co-trimoxazole** in combination with systemic antibacterial drugs active against gram-positive, gram-negative, and anaerobic flora (penicillin combinations, including beta-lactamase inhibitor combinations; 4th-generation cephalosporins; carbapenems, other antibacterial drugs) combined with systemic antifungals until the etiologic factor of interstitial pneumonia is identified	yes/no
88	Administered intravenous corticosteroids and ^#co-trimoxazole** at a dose of 3.75–5.0 mg/kg body weight/administration (15–20 mg/kg/day) (calculated as trimethoprim) intravenously every 8 hours for moderate Pneumocystis pneumonia, or at a dose of 3.75–5.0 mg/kg body weight/administration (15–20 mg/kg/day) (calculated as trimethoprim) intravenously every 6–8 hours for severe Pneumocystis pneumonia	yes/no
89	Administered ^#voriconazole** at a dose of 6 mg/kg/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 upon detection of galactomannan in lavage fluid and/or blood, and/or antibodies to Aspergillus fungi (Aspergillus spp.) in the blood	yes/no
90	Administered fluconazole** intravenously at a dose of 6–12 mg/kg/day upon detection of mannan in lavage fluid and/or blood in accordance with international guidelines for the treatment of immunocompromised children	yes/no
91	Temporarily suspended injections/infusions of targeted biologic therapies and/or meadow saffron seed extract/colchicine intake (if used) in all patients with suspected/developing pneumonia	yes/no
92	Resumed injections/infusions of targeted biologic therapies and/or intake of ^#meadow saffron seed extract/colchicine (if used) in all patients no earlier than 1 week after complete resolution of pneumonia according to laboratory tests and follow-up chest computed tomography with or without anesthetic management (including early postoperative care)	yes/no
93	Administered systemic antibacterial drugs active against gram-positive, gram-negative, and anaerobic flora (penicillin combinations, including beta-lactamase inhibitor combinations; 4th-generation cephalosporins; carbapenems, other antibacterial drugs) combined with systemic antifungals in the event of focal, lobar, or multislot/multisegmental pneumonia	yes/no
94	Performed 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 anesthetic management (including early postoperative care) in all patients with active arthritis	yes/no
95	Performed X-ray densitometry in all patients receiving or previously receiving corticosteroids	yes/no
96	Administered calcium and vitamin D supplements and their analogues to patients with osteopenia/osteoporosis	yes/no
97	Administered bisphosphonates combined with calcium and vitamin D supplements and their analogues to patients with osteoporosis	yes/no
98	Administered: ^#pamidronate acid in patients < 1 year at a dose of 0.5 mg/kg IV every 2 months; patients aged 1–2 years at 0.25–0.5 mg/kg/day IV for 3 days every 3 months; patients aged 2–3 years at 0.375–0.75 mg/kg/day IV for 3 days every 3 months; patients older than 3 years at 0.5–1 mg/kg/day IV for 3 days every 4 months (maximum dose 60 mg/administration), or ^#alendronate acid at a dose of 1–2 mg/kg/week orally (patients with body weight < 40 kg at 5 mg/day or 35 mg/week; patients with body weight > 40 kg at 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 to patients with osteoporosis	yes/no
99	Performed brain magnetic resonance imaging with or without anesthetic management (including early postoperative care) in patients with signs of central nervous system involvement	yes/no
100	Performed an initial appointment (examination, consultation) with an otolaryngologist for all patients to identify foci of chronic ENT infection and address their sanitation for the prevention of infectious complications during treatment with targeted biologic therapies combined with or without corticosteroids	yes/no
101	Initial ophthalmologist consultation (examination) with mandatory ocular biomicroscopy was performed	yes/no
102	Performed an initial appointment (examination, consultation) with a pediatric cardiologist in patients with cardiac involvement and/or arterial hypertension	yes/no
103	Performed an initial appointment (examination, consultation) with a phthisiatrician for all patients with positive results of a focal tuberculin skin test and/or elevated interferon-gamma levels in response to Mycobacterium tuberculosis complex antigens in the blood and/or focal, infiltrative changes in the lungs	yes/no
104	Initial examination (consultation) by a pediatric endocrinologist was performed for patients with endocrinological pathology	yes/no
105	Initial dietitian consultation (examination) was performed in patients with underweight, amyotrophy, osteopenia/osteoporosis, constitutional obesity and Cushing's syndrome, or steroid diabetes	yes/no
106	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
107	Performed an initial appointment (examination, consultation) with a nephrologist in patients with renal involvement	yes/no
108	Performed a follow-up appointment (examination, consultation) with a nephrologist in patients with renal involvement	yes/no
109	Initial neurologist consultation (examination) was performed in patients with neurological symptoms or psychotic reactions	yes/no
110	Follow-up appointment (examination, consultation) by a neurologist performed in patients with neurological symptoms and psychotic reactions	yes/no
112	Performed initial examination (testing, consultation) by a medical psychologist in all patients aged 1 year and older and their parents (regardless of the child's age)	yes/no
113	Performed initial examination (consultation) by an anesthesiologist-resuscitologist in patients scheduled for procedures under general anesthesia	yes/no
114	Performed initial examination (consultation) by an anesthesiologist-resuscitologist in critically ill patients	yes/no
115	Performed 24-hour monitoring by an anesthesiologist-resuscitologist for all critically ill patients (multiple organ dysfunction syndrome, hemophagocytic syndrome)	yes/no
116	Performed evaluation of pathogenetic therapy efficacy using the Autoimmune Disease Activity Index (AIDAI) 3 months after therapy initiation/adjustment and every 6 months thereafter, and the Damage Index (ADDI) once a year	yes/no
117	Oncological vigilance was observed due to the possible development of oncological/onco-hematological/lymphoproliferative diseases during therapy with biologic DMARDs (bDMARDs) and/or Colchicum autumnale seed extract/colchicine (if used), in combination (or not) with GCs, at any stage of treatment	yes/no
118	Performed immediate discontinuation of bDMARDs and ^#Colchicum autumnale seed extract/colchicine (if used) and/or hospitalization of the patient upon suspicion of an oncological/hemato-oncological/lymphoproliferative disease	yes/no
119	Bone marrow cytological preparation was obtained using anesthesia support (including early postoperative management) via puncture, along with a bone marrow histological preparation with cytological examination of the bone marrow smear (myelogram) and pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods, performed in patients receiving bal/targeted synthetic DMARDs and/or ^#Colchicum autumnale seeds extract/colchicine (if used) combined with or without GCs, who present with an atypical disease course	yes/no
120	Lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) was performed using anesthesia support (including early postoperative management), with cytological examination of the lymph node tissue preparation and pathomorphological examination of the lymph node biopsy (surgical) material, in patients with marked enlargement of peripheral and/or intrathoracic, and/or intra-abdominal lymph nodes receiving bal/targeted synthetic DMARDs and/or ^#Colchicum autumnale seeds extract/colchicine (if used) combined with or without GCs, who present with an atypical disease course	yes/no
121	Brain MRI with contrast enhancement, abdominal MRI with intravenous contrast enhancement, retroperitoneal MRI with intravenous contrast enhancement, and pelvic MRI with intravenous contrast enhancement were performed with or without anesthesia support (including early postoperative management) in patients receiving bal/targeted synthetic DMARDs and/or ^#Colchicum autumnale seeds extract/colchicine (if used) combined with or without GCswith an atypical disease course	yes/no
122	Chest CT with intravenous bolus contrast enhancement was performed with or without anesthesia support (including early postoperative management) in patients receiving bal/targeted synthetic DMARDs and/or ^#Colchicum autumnale seeds extract/colchicine (if used) combined with or without GCs with an atypical disease course	yes/no
123	Bone MRI (one region) and joint MRI (one joint) with intravenous contrast enhancement were performed with or without anesthesia support (including early postoperative management) in patients receiving bal/targeted synthetic DMARDs and/or ^#Colchicum autumnale seeds extract/colchicine (if used) combined with or without GCs, with an atypical disease course	yes/no
124	Bone CT and joint CT were performed with or without anesthesia support (including early postoperative management) in patients receiving bal/targeted synthetic DMARDs and/or ^#Colchicum autumnale seeds extract/colchicine (if used) combined with or without GCs, presenting with bone destruction foci atypical for TRAPS	yes/no
125	Performed positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)), with contrast enhancement when necessary, or whole-body positron emission tomography using tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)) with or without anesthesia support (including early postoperative management) in patients receiving bDMARDs and/or ^#Безвременника осеннего семян экстракт/колхицин (в случае его применения) в сочетании (или без) с ГК with pronounced arthralgia, myalgia, ossalgia, bone destructive changes, subcutaneous fat infiltrates, and foci in parenchymal organs, the brain, or spinal cord	yes/no
126	Multi-position bone scintigraphy was performed with or without anesthesia support (including early postoperative management) in patients receiving bal/targeted synthetic DMARDs and/or ^#Colchicum autumnale seeds extract/colchicine (if used) combined with or without GCs, presenting with bone destruction foci atypical for TRAPS	yes/no
127	CT-guided iliac bone trephine biopsy was performed using anesthesia support (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 bal/targeted synthetic DMARDs and/or ^#Colchicum autumnale seeds extract/colchicine (if used) combined with or without GCs, with an atypical disease course	yes/no
128	Bone biopsy was performed using anesthesia support (including early postoperative management), with pathomorphological examination of the bone biopsy (surgical) material in patients receiving bal/targeted synthetic DMARDs and/or ^#Colchicum autumnale seeds extract/colchicine (if used) combined with or without GCs, presenting with bone destruction foci atypical for TRAPS	yes/no
129	Performed an initial consultation (examination) by a pediatric oncologist for patients in whom examination results suggest/detect an oncological/hemato-oncological/lymphoproliferative disease or metastatic lesions	yes/no
130	No vaccination with live or live-attenuated vaccines was performed in patients receiving bDMARDs	yes/no
131	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
132	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
133	Performed an initial consultation (examination) by a physical therapy physician for patients with functional impairment after a decrease in disease activity	yes/no
134	Performed an initial consultation (examination) by an exercise therapy (kinesiotherapy) physician for patients with functional impairment after a decrease in disease activity	yes/no
135	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
136	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
137	Immunization with live and live-attenuated vaccines was not performed in patients receiving biologic disease-modifying antirheumatic drugs (bDMARDs)	yes/no
138	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
139	Performed vaccination with an adsorbed polysaccharide conjugated pneumococcal vaccine containing 13 pneumococcal capsular serotypes in all patients with TRAPS, prior to prescribing or at any stage of therapy with ^#Colchicum autumnale seed extract/colchicine and/or bDMARDs combined with GCs or without (except for ^#rituximab)	yes/no

Table 7. Criteria for assessing the quality of dispensary follow-up for patients with periodic fever syndrome associated with a mutation in the tumor necrosis factor receptor type 1 gene in outpatient settings

№	Quality criteria	Performance assessment (yes/no)
1	Performed dispensary follow-up of patients with TRAPS — initial rheumatologist consultation (examination) including evaluation of therapy efficacy and safety at least once a year following therapy initiation/adjustment and after achieving disease remission	yes/no
2	Dispensing follow-up of patients with TRAPS was performed – follow-up appointment (examination, consultation) by a rheumatologist (with assessment of treatment efficacy and safety at least once every 1 month after initiation or adjustment of therapy and at least once every 3 months after achieving disease remission, assessment of the need for referral for unplanned hospitalization to the rheumatology department of the inpatient facility that initiated therapy with a genetically engineered biological product and/or immunosuppressant at any stage of treatment upon development of a flare and/or complications, concomitant diseases, complications and/or side effects, and/or persistent intolerance to therapy, and referral for elective hospitalization to the rheumatology department of the inpatient facility that initiated therapy with a genetically engineered biological product and/or immunosuppressant at 3 months and 6 months after prescribing and/or adjusting therapy and subsequently every 6 months, and conducting a remote consultation with a rheumatologist of the inpatient facility that initiated the prescription of therapy for all patients upon development of any signs of inefficacy and/or intolerance to treatment)	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	A dispensary appointment (examination, consultation) by a pediatrician or a district pediatrician was performed for patients with TRAPS in the absence of a rheumatologist at their place of residence at least once a month after initiation/adjustment of therapy and at least once every 3 months after achieving disease remission	yes/no
6	Immediate discontinuation of GEBP administration, and intake of ^#Colchicum autumnale seed extract/colchicine (if used) was performed in the event of an allergic reaction	yes/no
7	Prescription of systemic antihistamines and/or GCs was performed upon the development of an allergic reaction to the administration of GEBPs and/or intake of ^#Colchicum autumnale seed extract/colchicine (if used)	yes/no
8	An appointment (examination, consultation, including remote) by a rheumatologist of the inpatient facility that initiated the prescription of therapy was performed upon the development of an allergic reaction to the intake of ^#Colchicum autumnale seed extract/colchicine and/or administration of GEBPs	yes/no
9	Emergency hospitalization was performed due to the development of an allergic reaction to ^#Colchicum autumnale seed extract/colchicine and/or administration of biologic agents (bDMARDs)	yes/no
10	A complete blood count (CBC) with differential was performed (erythrocyte sedimentation rate test, red blood cell count, white blood cell count, platelet count, differential leukocyte count (leukocyte formula), total hemoglobin level test in blood) for all patients at least once every 2–4 weeks	yes/no
11	Temporary discontinuation of GEBP therapy and/or ^#Colchicum autumnale seed extract/colchicine (if used) for 7 days was performed for all patients when the platelet count dropped to ≤ 150 > 100 × 10⁹/L, and the neutrophil count dropped to < 1.5 ≥ 1.0 × 10⁹/L in the complete blood count	yes/no
12	Discontinuation of GEBPs and/or intake of ^#Colchicum autumnale seed extract/colchicine (if used) was performed when the absolute neutrophil count dropped to < 1.0 × 10⁹/L and/or the platelet count dropped to < 100 × 10⁹/L in the complete blood count	yes/no
13	Resumption of GEBP treatment and/ or intake of ^#Colchicum autumnale seed extract/colchicine (if used) at the same dose was performed for all patients after complete recovery of complete blood count parameters	yes/no
14	Prescription of the colony-stimulating factor ^#filgrastim** at a dose of 5–10 mcg/kg/day subcutaneously for 3–5 days (if necessary, longer) was performed when white blood cell levels dropped with an absolute neutrophil count < 1.0 × 10⁹/L	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, and prescription of systemic antibacterial drugs (J01) intravenously were performed upon the development of febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count < 1.0 × 10⁹/L	yes/no
16	Prescription of fluconazole** at a dose of 3–12 mg/kg/day, depending on the severity and duration of induced neutropenia, orally was performed for patients with neutropenia	yes/no
17	Resumption of GEBP injection/infusion and/or intake of ^#Colchicum autumnale seed extract/colchicine (if used) was performed for all patients after the recovery of the neutrophil count to ≥ 1.5 × 10⁹/L according to complete blood count data	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 clinical blood chemistry analysis (total protein level test, albumin level test, total bilirubin level test, free and conjugated bilirubin level test, creatinine level test, urea level test, glucose level test, potassium level test, sodium level test, total calcium level test; lactate dehydrogenase activity assay, aspartate aminotransferase activity assay, alanine aminotransferase activity assay, gamma-glutamyltransferase activity assay, alkaline phosphatase activity assay, serum iron level test) was performed at least once every 2–4 weeks	yes/no
20	Temporary discontinuation of GEBP therapy and/or ^#Colchicum autumnale seed extract/colchicine (if used) was performed for all patients when serum ALT and AST levels increased to ≥ 1.5 times the upper limit of normal and/or other biochemical parameters exceeded the upper limit of normal	yes/no
21	Resumption of GEBP therapy and/or ^#Colchicum autumnale seed extract/colchicine (if used) was performed for all patients at the same dose after normalization of general clinical blood chemistry parameters	yes/no
22	An appointment (examination, consultation, including remote) by a rheumatologist of the inpatient facility, that initiated the prescription of therapy was performed in the presence of data on repeated episodes of elevated 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 test was performed for all patients at least once every 3 months	yes/no
25	Temporary discontinuation of GEBP therapy and/or ^#Colchicum autumnale seed extract/colchicine (if used) was performed for all patients upon a decrease in blood immunoglobulins	yes/no
26	An appointment (examination, consultation, including remote) by a rheumatologist of the inpatient facility that initiated the prescription of therapy was performed upon a decrease in 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 anti-nuclear and anti-DNA antibodies was performed for all patients receiving TNF-alpha inhibitors at least once every 3 months	yes/no
29	Temporary discontinuation of TNF-alpha inhibitor therapy was performed for all patients upon an increase in serum anti-nuclear and anti-DNA antibodies	yes/no
30	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 an increase in serum anti-nuclear and anti-DNA antibodies	yes/no
31	Determination of antistreptolysin-O in blood serum was performed at least once every 3 months	yes/no
32	Vigilance regarding the potential development of infectious diseases was maintained in patients receiving GEBPs and/or ^#Colchicum autumnale seed extract/colchicine in combination (or without) with GCs	yes/no
33	Temporary discontinuation of GEBP therapy and/or ^#Colchicum autumnale seed extract/colchicine (if used) with continuation of previously prescribed oral GCs was performed for all patients upon the appearance of signs of an infectious complication	yes/no
34	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 the appearance of signs of an infectious complication	yes/no
35	Emergency hospitalization to an inpatient facility was performed upon suspicion/development of pneumonia	yes/no
36	Temporary discontinuation of biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if used) was performed in all patients with suspected/developing pneumonia	yes/no
37	An initial or follow-up examination (evaluation, consultation, including remote) by the inpatient rheumatologist who initiated the therapy was performed for all patients with suspected/developing pneumonia	yes/no
38	Resumption of biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine therapy (if used) was performed in all patients no earlier than 1 week after complete resolution of pneumonia according to laboratory tests, follow-up computed tomography of the chest with or without anesthetic support (including early postoperative management), and completion of antibacterial therapy	yes/no
39	Prescription of ^#acyclovir** at a dose of 200 mg per day orally in 5 divided doses was administered to children older than 2 years (not exceeding 1000 mg/day) until complete disappearance of herpetic eruptions in patients who developed localized herpetic infection	yes/no
40	Temporary discontinuation of biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if used) was performed in all patients, with continuation of previously prescribed oral glucocorticoids, upon suspicion/development of generalized herpetic and/or cytomegalovirus and/or Epstein-Barr virus infection, as well as upon development of Herpes zoster	yes/no
41	Hospitalization to an inpatient facility was performed in cases of generalized herpetic infection / suspected cytomegalovirus / Epstein-Barr virus infection	yes/no
42	Resumption of biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine therapy (if used) was performed 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
43	Monitoring of the efficacy of biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if used) was performed in order to timely address the issue of "switching" to an immunosuppressant and/or a biologic DMARD with a different mechanism of action	yes/no
44	Monitoring of the tolerability of biologic DMARDs and ^#Colchicum autumnale seed extract/colchicine (if used) was performed	yes/no
45	An initial or follow-up examination (evaluation, consultation, including remote) by the inpatient rheumatologist who initiated the therapy was performed in all patients upon development of any signs of inefficacy and/or intolerance to ^#Colchicum autumnale seed extract/colchicine and/or the immunosuppressant, and/or biologic DMARDs	yes/no
46	A focal tuberculin skin test (Mantoux test, recombinant tuberculosis allergen test in standard dilution) was performed in all patients at least once every 6 months (more frequently if indicated)	yes/no
47	A general (clinical) urinalysis was performed	yes/no
48	Vaccination of children was performed only during disease remission, provided it persists for at least 6 months, according to an individual schedule, excluding live vaccines	yes/no
49	Electrocardiogram recording performed	yes/no
50	Abdominal ultrasound (comprehensive) and renal ultrasound were performed in all patients at least once every 6 months	yes/no
51	Echocardiography was performed	yes/no
52	An initial examination (evaluation, consultation) by an otorhinolaryngologist was performed for patients with ENT pathology no later than 7 days after discharge from the hospital	yes/no
53	A follow-up examination (evaluation, consultation) by an otorhinolaryngologist was performed according to medical indications, at least once every 6 months	yes/no
54	An initial examination (evaluation, consultation) by a pediatric cardiologist was performed according to medical indications	yes/no
55	A follow-up examination (evaluation, consultation) by a pediatric cardiologist was performed according to medical indications	yes/no
56	An initial examination (evaluation, consultation) by a pediatric dentist was performed in all patients within 1 month after discharge from the hospital	yes/no
57	A follow-up examination (evaluation, consultation) by a pediatric dentist was performed according to medical indications	yes/no
58	An initial examination (evaluation, consultation) by an ophthalmologist is recommended (with biomicroscopy of the eye no later than 7 days after hospital discharge if ophthalmological pathology is present)	yes/no
59	A follow-up examination (evaluation, consultation) by an ophthalmologist is recommended (at least once every 3 months) with mandatory biomicroscopy of the eye	yes/no
60	An examination (evaluation, consultation) by a nephrologist was performed no later than 7 days after hospital discharge in the presence of renal involvement	yes/no
61	An examination (evaluation, consultation) by a nephrologist was performed in patients with renal involvement at least once every 3 months as part of dispensary follow-up	yes/no
62	An initial examination (evaluation, consultation) by a dietitian was performed according to medical indications	yes/no
63	A follow-up examination (evaluation, consultation) by a dietitian was performed according to individual indications	yes/no
64	An examination (evaluation, 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 infiltrative foci in the lungs)	yes/no
65	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
66	An examination (evaluation, consultation, including remote) by the inpatient rheumatologist who initiated the therapy was performed in patients with a positive intradermal tuberculin test	yes/no
67	An initial examination (evaluation, consultation) by a pediatric endocrinologist was performed according to medical indications	yes/no
68	A follow-up examination (evaluation, consultation) by a pediatric endocrinologist was performed according to medical indications	yes/no
69	An initial examination (evaluation, consultation) by an orthopedic traumatologist was performed according to medical indications	yes/no
70	A follow-up examination (evaluation, consultation) by an orthopedic traumatologist was performed according to medical indications	yes/no
71	An initial examination (testing, consultation) by a medical psychologist was performed according to medical indications	yes/no
72	A follow-up examination (testing, consultation) by a medical psychologist was performed according to medical indications	yes/no
73	Planned hospitalization in the rheumatology department of the hospital that initiated the prescription of biologic DMARDs and ^#Colchicum autumnale seed extract/colchicine was performed	yes/no
74	An examination (evaluation, consultation, including remote) by the inpatient rheumatologist who initiated the therapy was performed in all patients who developed adverse events from therapy / infectious complications / intolerance to biologic DMARDs and/or ^#Colchicum autumnale seed extract/colchicine (if used)	yes/no
75	Unplanned hospitalization in the rheumatology department of the hospital that initiated the prescription of biologic DMARDs and ^#Colchicum autumnale seed extract/colchicine was performed at any stage of treatment upon the development of exacerbation / complications of TRAPS, comorbid conditions, complications / side effects / persistent intolerance to biologic DMARDs	yes/no

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Ishak GE, Khoury NJ, Birjawi GA, et al. Imaging findings of familial Mediterranean fever. Clin Imaging. 2006;30:153–9. doi: 10.1016/j.clinimag.2005.07.002
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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., PhD, Senior Research Fellow
Kriulina T.Yu., Junior Research Fellow

Working Group of the Association of Medical Geneticists:

Kutsev S.I., MD, Professor, Corresponding Member of the Russian Academy of Sciences
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

Pediatricians
Pediatric rheumatologists of pediatric rheumatology departments
Pediatric rheumatologists of pediatric rheumatology offices in outpatient clinics
Pediatric nephrologists of pediatric nephrology departments
Pediatric nephrologists of outpatient pediatric clinics
Medical geneticists
Pediatric surgeons
Allergists-immunologists
Medical psychologists
Medical students
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

o External peer review.

o Internal peer 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. Levels of Evidence (LoE) grading scale 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. Levels of Evidence (LoE) grading scale 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 grading levels of clinical persuasiveness of recommendations (LCPR) 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

Timeframe for monitoring the efficacy of TRAPS therapy

№	International Nonproprietary Name (INN) of the medicinal product	Timing of therapeutic efficacy monitoring¹
1.	Canakinumab**	3 months after initiation of treatment. Thereafter, every 6 months.
2.	Etanercept**	3 months after initiation of treatment. Thereafter, every 6 months.
3.	Tocilizumab**	3 months after initiation of treatment. Thereafter, every 6 months.

¹Therapy adjustment is performed at any stage of treatment in case of inefficacy and/or lack of safety

Appendix B. Physician Action Algorithms

Diagram 1

Appendix B. Algorithms of physician actions — Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (Other specified disorders involving the immune mechanism, not elsewhere classified)

Regimen 2

Regimen 3

Diagram 4

Diagram 5

Regimen 6

Regimen 7

Appendix C. Patient Information

What is tumor necrosis factor receptor type 1-associated periodic fever syndrome (TRAPS)?

TRAPS is a rare hereditary genetic disorder characterized by recurring episodes of fever, muscle and joint pain, joint swelling, abdominal pain, headache, and skin rash. The frequency of TRAPS flares ranges from once every few weeks to once every few years. The duration of attacks is from 7 to 20 days. Symptoms can vary from patient to patient. In later stages of the disease, renal impairment may occur. Such cases can be observed among members of the same family.

How common is this disease?

TRAPS is considered a rare disease with a prevalence of 1 in 1,000,000 individuals and is the second most common hereditary periodic fever syndrome after familial Mediterranean fever. The overwhelming majority of patients are of European descent, but an increasing number of cases are found in other ethnic groups. More than 1,000 cases of TRAPS have been diagnosed worldwide. The disease affects both sexes equally and typically begins in childhood, although adult-onset patients have also been described.

What are the causes of the disease?

TRAPS is a disorder caused by a mutation in the TNFRSF1A gene. TRAPS is characterized by atypical immune activation. This occurs due to abnormalities in the tumor necrosis factor receptor gene, which is involved in the inflammatory response. The exact mechanism by which the mutated gene alters the inflammatory response is still not established. Triggers for a disease attack may include infections, trauma, or psychological stress. There is no evidence that the time of year or climate affects the course of the disease.

The diagnosis of TRAPS is established based on the clinical presentation and confirmed by genetic testing.

Is this disease hereditary?

TRAPS is inherited in an autosomal dominant manner. This means that the disease is transmitted by a parent who has the condition and carries an abnormal copy of the TNFRSF1A gene. Parents can also be carriers of the mutation without showing any signs of the disease. Since every person has 2 copies of all our genes, the risk of transmitting the mutated copy of the TNFRSF1A gene from a carrier parent, and therefore the risk of passing the disease to each child, is 50%. It should be noted that not all mutant gene carriers, even in families with recurrent cases of TRAPS, develop clinical symptoms of the disease. However, the probability of a TRAPS diagnosis increases if a close relative has the condition or is a carrier of the altered gene. De novo (new) mutations can also occur; in these cases, neither parent has the disease or carries a mutation in the TNFRSF1A gene, but the gene abnormality arises at conception. In such cases, the risk of TRAPS developing in another child is sporadic.

Is this disease infectious?

TRAPS is not an infectious disease. This condition can only develop in individuals with genetic abnormalities.

What are the main symptoms?

The main symptoms are recurrent fever episodes that typically last two to three weeks, but occasionally may last for a longer or shorter duration. These episodes are accompanied by chills and intense pain in the trunk and upper extremities. A typical rash is red, painful, and reflects inflammation of the underlying skin and muscle tissue. At the onset of an attack, most patients experience deep, spasmodic muscle pain that gradually increases in intensity and begins to migrate to other parts of the limbs, followed by the appearance of a rash. The rash may also be annular with laced edges. Patients frequently report abdominal pain of varying severity, accompanied by nausea and vomiting. Characteristic features of TRAPS include inflammation of the membrane covering the front of the eye (conjunctivitis) or swelling around the eyes, although this symptom can also be observed in other conditions. Chest pain caused by inflammation of the pleura (the membrane surrounding the lungs) or pericardium (the membrane surrounding the heart) has also been described. Complaints of scrotal pain are likewise characteristic. Arthralgia in large joints frequently occurs, while arthritis (asymmetric mono- or oligoarthritis of large joints) and tendonitis are rare (isolated cases). The type and duration of symptoms and disease flares vary significantly among different patients.

In some patients, particularly in adulthood, the disease follows a fluctuating, subchronic course characterized by flare-ups of abdominal pain, joint and muscle pain, ocular manifestations with or without fever, and persistently elevated laboratory inflammatory markers. TRAPS persists throughout life, but episodes become milder and less frequent with age. Amyloidosis is the most severe long-term complication of TRAPS, observed in 10–15% of patients. Amyloidosis is caused by the accumulation in tissues of a circulating substance produced during inflammation, known as serum amyloid A. The deposition of amyloid A in the kidneys leads to heavy urinary protein loss and progressive renal failure. The risk of amyloidosis depends on the mutation type: carriage of pathogenic alleles resulting in the substitution of a cysteine residue in the gene product protein molecule carries the highest risk.

Does the disease manifest identically in all children?

The manifestations of TRAPS vary from patient to patient in terms of the duration of each attack and the length of symptom-free periods. The combination of main symptoms is also variable. These differences are presumably partly due to genetic factors.

2. DIAGNOSIS AND TREATMENT

How is this disease diagnosed?

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.

An experienced physician will suspect TRAPS syndrome based on clinical symptoms identified during a physical examination and family history. Genetic testing to detect a mutation in the TNFRSF1A gene is performed for a definitive diagnosis in specialized genetic laboratories. Laboratory evaluation includes determining the levels of acute-phase markers of the disease: erythrocyte sedimentation rate, serum C-reactive protein, and serum amyloid A (SAA), which are significantly elevated. These tests are periodically repeated when the child is symptom-free to monitor whether these parameters have returned to normal. A complete clinical urinalysis also aims to detect the presence of protein and red blood cells. Temporary changes are possible during attacks. In patients with amyloidosis, high levels of protein in the urine are persistently present.

Can this disease be treated or cured?

A complete cure is impossible because TRAPS is a genetic disease. TRAPS is a lifelong condition, although the intensity of fever episodes may decrease with age, and a more pronounced chronic and fluctuating course may be observed. Unfortunately, these changes do not prevent the potential development of amyloidosis.

What are the treatment methods?

To date, there is no treatment that can prevent or cure this disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) (ATC code M01A) help alleviate symptoms. High doses of glucocorticoids (ATC code H02AB) are often effective, but continuous use of these drugs can lead to serious side effects.

Currently, the most effective treatment for TRAPS is the use of biologic agents (ATC code L04A) – IL-1 inhibitors (canakinumab** (L04AC), ^#anakinra** (L04AC03)). In the Russian Federation, canakinumab** (L04AC) is approved for the indication of TRAPS. Several studies have shown that this drug effectively controls inflammatory manifestations of TRAPS when administered via subcutaneous injection once every 4 weeks. 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 lifelong.

Specific blockade of the inflammatory cytokine TNF using a soluble TNF receptor (^#etanercept** (L04AB)) is also an effective treatment in some patients, allowing for the prevention of fever attacks. However, secondary inefficacy frequently develops during the course of treatment. Monoclonal antibody-based drugs targeting TNFα (^#infliximab** (L04AB), ^#adalimumab** (L04AB), etc.) are ineffective and not indicated for use in this disease. The use of anti-TNF monoclonal antibodies has been shown to sometimes provoke disease flares. In some cases, the use of colchicine is possible. Therapy with methotrexate, azathioprine, and other immunosuppressive drugs is ineffective.

Nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs) (ATC code M01A)

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 (ATC code: H02AB)

Glucocorticoids are the most effective available anti-inflammatory drugs, but their use is limited by the fact that their long-term use is accompanied by a number of serious adverse events, including osteoporosis and growth retardation. Nevertheless, the advantage of glucocorticoids is that they can be used to treat systemic symptoms that do not respond to other therapies, in life-threatening systemic complications, and as a "bridging" treatment during the acute phase of the disease while waiting for the effect of biologic therapy.

Other treatment methods

Rehabilitation

Rehabilitation is an important component of treatment. It includes appropriate exercises and, when indicated, the use of joint splints to hold joints in a comfortable position to prevent pain, stiffness, muscle contractures, and joint deformities. Rehabilitation should begin early and be performed routinely to improve or maintain joint and muscle function.

What is the long-term prognosis of the disease?

The long-term prognosis of TRAPS depends on the course of the disease, inflammatory activity during and, especially, between attacks, and the type of genetic mutation. Quality of life may be affected by recurrent episodes of fever and other manifestations. The long-term prognosis can be affected by the development of amyloidosis and renal impairment. Treatment with IL-1 blockers significantly improves the prognosis in TRAPS.

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.

What are the main side effects of treatment?

The medications used in the treatment of TRAPS 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 these drugs.

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 that determine the timing for initiating 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.

3. DAILY LIFE

How can the disease affect the child and the family's daily life?

The unpredictable nature of TRAPS episodes means it is difficult to determine the impact it may have on daily life. Some patients experience flares every six weeks, while others may be free of fever attacks for many years, allowing them to live full lives. Frequent and prolonged attacks disrupt normal family life and can affect the work of the parents or the patient. There is often a significant delay in establishing the correct diagnosis, which leads to parental anxiety and sometimes unnecessary medical procedures. The disease cannot be cured, but much can be done to reduce its impact on daily life. It is important to establish strong and trusting relationships with the medical specialists managing TRAPS, as this will significantly improve well-being and overall quality of life.

What about school?

Frequent attacks cause problems with school attendance. With effective treatment, missed school days become less frequent. Continuing education is of great importance for children with chronic illnesses. Teachers should be informed about the disease and what to do if an attack begins at school. 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 be academically successful, but also so they are accepted and recognized by their peers and adults. Future integration into the professional world is essential for the young patient and is one of the goals of comprehensive care for chronically ill patients.

What about sports?

Sports are an important aspect of any child's daily life. One of the goals of therapy is to allow children to lead as normal a life as possible and feel no different from their peers. Sports and physical activity are encouraged, but the type of physical exertion should be selected individually, such as yoga and light exercises, which are easier to perform regularly. However, physical activity must be restricted or rest ensured during the acute phase.

What about diet?

No specific dietary recommendations can be given. In general, the child should follow a balanced, age-appropriate diet. A healthy, well-balanced diet containing adequate amounts of protein, calcium, and vitamins is recommended for a growing child.

Can climate affect the course of the disease?

No, it cannot.

Can a child be vaccinated?

The child can and should be vaccinated; however, the attending physician must be informed of the condition before the child is vaccinated so that appropriate guidance can be provided on an individual basis. Live vaccines are not recommended.

What about sex life, pregnancy, and contraception?

So far, there is no information on this issue in the literature. Patients with TRAPS syndrome can have a normal sex life and have their own children. However, they should be aware of a 50% probability that the disease will be transmitted to their child. Patients should be offered genetic counseling to discuss this aspect with their children and family members. It is advisable, as with other autoinflammatory diseases, to plan pregnancy thoughtfully, as this will allow for early adjustment of treatment, taking into account the potential adverse effects of biological drugs on the fetus.

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):

Appendix G1 - G... Rating scales, questionnaires — Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (Other specified disorders involving the immune mechanism, not elsewhere classified)

Each line corresponds to a day of the month; the diary is completed throughout the flare period. Symptoms are rated as present (1) or absent (0); a separate diary must be used for each month. If no flare occurred during the month, the diary is left blank; only symptoms related to the autoinflammatory disease are recorded.

Key (interpretation):

A total AIDAI score < 9 points allows separating inactive patients from active patients (with a total score ≥ 9 points).

Appendix G2. Auto-Inflammatory 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	½/3
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 one organ; generalized, affecting more than one organ. Renal insufficiency: 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, abnormalities not resulting in visual impairment; moderate, abnormalities resulting in 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 less than -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 older than 18 years: 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 spinal compression fracture and/or pathological bone fractures confirmed by imaging studies, which may include bone densitometry. The presence of isolated decreased bone mineral density is not sufficient for the diagnosis of osteoporosis.

Proteinuria: persistent urine protein-to-creatinine ratio > 20 mg/mmol in the first morning urine; and/or 24-hour urine protein excretion > 0.3 g/24 h or urine albumin-to-creatinine ratio > 15 mg/mmol.

Delayed puberty: Tanner stage below -2 SD for age or below the 3rd percentile for age, or any Tanner stage following pharmacological induction 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.

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