Juvenile Arthritis: Clinical Guidelines

List of Abbreviations

ACR – American College of Rheumatology

ACR pedi – American College of Rheumatology Pediatric Criteria

ALT – Alanine aminotransferase

ANA – Antinuclear antibody

ANCA – Antineutrophil cytoplasmic antibodies

AS – ankylosing spondylitis

AST – Aspartate aminotransferase

ACPA – Antibodies to cyclic citrullinated peptide

VAS – Visual Analog Scale

IBD – Inflammatory bowel disease

IVIG – Normal human immunoglobulin** (ATC code: J06BA – normal human immunoglobulins)

bDMARDs – Biologic disease-modifying antirheumatic drugs (ATC codes: L04AB – tumor necrosis factor alpha (TNF-alpha) inhibitors, L01XC – monoclonal antibodies, L04AC – interleukin inhibitors)

GCs – Glucocorticoids

GGT – Gamma-glutamyl transferase

HPS – Hemophagocytic syndrome

DNA – Deoxyribonucleic acid

GI – Gastrointestinal tract

IL – Interleukin

JAK inhibitor – Janus-associated kinase (JAK) inhibitor

CT – Computed tomography

CK – Creatine kinase

PT – Physiotherapy

LDH – Lactate dehydrogenase

PT – Physiotherapy

ICD – International Statistical Classification of Diseases and Related Health Problems

MRI – Magnetic resonance imaging

NSAIDs – Non-steroidal anti-inflammatory and antirheumatic drugs (ATC code M01A)

AKI – Acute kidney injury

ARI – Acute respiratory infection

PET – Positron emission tomography

RDS – Respiratory distress syndrome

RF – Rheumatoid factor

RP – Radiopharmaceutical (ATC code V09: Diagnostic radiopharmaceuticals, V10: Therapeutic radiopharmaceuticals)

ESR – Erythrocyte sedimentation rate

CRP – C-reactive protein

MPS – Mononuclear phagocyte system

sJIA – Systemic juvenile idiopathic arthritis

sJIA – Systemic juvenile idiopathic arthritis (systemic-onset juvenile arthritis)

LoE – level of evidence

Ultrasound – Ultrasound examination

Grade of Recommendation (GoR) – level of recommendation persuasiveness

FC – Functional class

TNF – Tumor necrosis factor

CMV – Cytomegalovirus

ALP – alkaline phosphatase

EGD – Esophagogastroduodenoscopy

ECG – Electrocardiography

EchoCG – Echocardiography

JA – Juvenile arthritis

CINCA – Chronic infantile neurologic, cutaneous and articular syndrome

FCAS – Familial cold autoinflammatory syndrome

FMF – Familial Mediterranean fever

HLA-B27 – Human leukocyte antigen B27

Ig G, M, A – Immunoglobulin G, M, A

ILAR – International League of Associations for Rheumatology

MKD – Mevalonate kinase deficiency

MWS – Muckle-Wells syndrome

PAPA – PAPA syndrome (Pyogenic sterile arthritis, pyoderma gangrenosum, and acne)

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

Clarification of notes

…^** – medication included in the List of Vital and Essential Drugs for medical use

…^# – "information on the method of administration, dose, and duration of use of the medicinal product, including references to clinical trials of the efficacy and safety of the applied dosing regimen for the given disease, or references to relevant literature sources if the recommendation thesis refers to a medicinal product used for medical application off-label (not in accordance with the indications for use, contraindications, methods of administration, and doses contained in the instructions for medical use)".

Terms and Definitions

Juvenile [Lat. Juvenīlis – young, youthful] – characteristic of youth; young, adolescent.

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.

Antinuclear factor (ANF) – autoantibodies directed against soluble components of the cell nucleus (ribonucleoproteins), forming a whole family (over 200 varieties) of antinuclear antibodies (ANA).

Rheumatoid factor (RF) – autoantibodies that react as an autoantigen with the subject's own immunoglobulins G modified under the influence of an agent (e.g., a virus)

Antineutrophil cytoplasmic antibodies (ANCA, Eng. – ANCA) – autoantibodies to components of the neutrophil cytoplasm. Found in so-called ANCA-associated diseases, including ANCA-associated vasculitis.

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.

HLA (Human Leukocyte Antigens) – human leukocyte antigens, or the human tissue compatibility system – a group of histocompatibility antigens, the major histocompatibility complex in humans.

Class I major histocompatibility complex molecules (A, B, C) – present peptides from the cytoplasm on the cell surface (including viral peptides, if present). These peptides are fragments of proteins degraded in proteasomes. The peptide length averages about 9 amino acids. Foreign antigens attract killer T cells (also called CD8-positive or cytotoxic T cells), which destroy the antigen-bearing cell. Molecules of this class are present on the surface of all cell types except erythrocytes and trophoblast cells.

Class II major histocompatibility complex molecules (DP, DM, DOA, DOB, DQ, DR) – present antigens from the extracellular space to T lymphocytes. Some antigens stimulate the division of T helpers, which then stimulate B cells to produce antibodies against this antigen. Molecules of this class are located on the surface of antigen-presenting cells: dendritic cells, macrophages, B lymphocytes. Class III major histocompatibility complex molecules encode components of the complement system and blood proteins.

Ankylosing spondylitis (AS) – a chronic inflammatory disease from the group of spondyloarthritides, characterized by obligatory involvement of the sacroiliac joints and/or spine with potential progression to ankylosis, with frequent involvement of entheses and peripheral joints in the pathological process

Uveitis – an inflammatory disease of the middle coat of the eye (uvea).

Anterior uveitis (iridocyclitis) is an inflammatory lesion of the anterior segments of the uveal tract.

Enthesitis is inflammation of the entheses, the specific sites where tendons and ligaments attach to bone.

Reiter's syndrome is a disease characterized by inflammatory lesions of the urogenital tract, joints, and eyes. Reiter's syndrome belongs to the group of reactive arthritides—non-suppurative "sterile" inflammatory diseases of the musculoskeletal system triggered by an extra-articular infection, primarily of the urogenital or intestinal tract.

Nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs) (ATC code M01A) – a group of medicinal products possessing analgesic, antipyretic, and anti-inflammatory effects. They are subdivided into selective (s-NSAIDs) and non-selective (ns-NSAIDs) inhibitors of the cyclooxygenase enzyme.

Biologic disease-modifying antirheumatic drugs (bDMARDs) (ATC code L04AB – tumor necrosis factor alpha (TNF-alpha) inhibitors, L01XC – monoclonal antibodies, L04AC – interleukin inhibitors) – a group of medicinal products 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 effect on specific mechanisms of chronic inflammation development, specifically suppressing the immunoinflammatory process and slowing down the progression of joint destruction.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Juvenile arthritis (syn.: juvenile arthritis (JA), juvenile idiopathic arthritis (JIA)) is an arthritis of unknown cause lasting more than 6 weeks, developing in children aged 16 years or younger with the exclusion of other joint pathologies [1].

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

Juvenile arthritis is a genetically determined, multifactorial disease.

Trigger factors for the development of JA include: Epstein-Barr virus, parvovirus B, rubella virus, hepatitis B virus, bacteria Salmonella spp., Shigella spp., Campylobacter spp., S. pyogenes, B. henselae, M. pneumoniae, Chlamydophila pneumoniae, trauma, sun exposure, psychological trauma.

A risk factor for the development of the disease is maternal smoking during pregnancy, which increases the likelihood of immune imbalance during fetal development [2].

Juvenile arthritis is a disease with an immunoaggressive pathogenesis. A foreign antigen is engulfed and processed by antigen-presenting cells (dendritic cells, macrophages, B lymphocytes, etc.), which, in turn, present it (or information about it) to T lymphocytes. The interaction of the antigen-presenting cell with CD4+ lymphocytes stimulates their synthesis of corresponding cytokines. Interleukin 2 (IL-2), produced upon Th1 activation, interacts with specific IL-2 receptors, which causes clonal expansion of T lymphocytes and stimulates the growth of B lymphocytes. The latter leads to massive synthesis of immunoglobulin (Ig) G by plasma cells, increases the activity of natural killer (NK) cells, and activates macrophages. IL-4, synthesized by Th2 cells, causes the activation of the humoral immune response (manifested by increasing antibody synthesis), stimulation of eosinophils and mast cells, as well as the development of allergic reactions. Activated cells (macrophages, T and B lymphocytes, etc.) synthesize pro-inflammatory cytokines IL-1, IL-6, IL-8, IL-17, tumor necrosis factor alpha (TNF-α), etc. The hyperproduction of pro-inflammatory cytokines underlies neoangiogenesis; damage to the synovial membrane of the joint, cartilage (and subsequently bone), as well as the development of systemic manifestations of the disease and the transformation of acute immune inflammation (characteristic of the early stage of juvenile arthritis) into chronic inflammation with the development of pannus and irreversible destruction of joint structures [1,2].

Juvenile ankylosing spondylitis is a specific form of JA, associated in 90% of patients with HLA-B27, which is encoded by the gene of the same name [4–6]. HLA-B27 encodes a class I major histocompatibility complex (MHC) molecule involved in antigen processing and presentation. It is hypothesized that HLA-B27 drives the pathogenesis of spondyloarthropathies through three mechanisms: (1) presentation of a yet unidentified arthritogenic peptide that triggers lymphocyte activation, (2) dimerization on the surface of antigen-presenting cells, causing CD4 lymphocyte activation, or (3) induction of endoplasmic reticulum stress leading to the secretion of IL-23 and IL-17 cytokines, which subsequently also activate T helper 17 (Th17) cells [4–6].

Innate immune cells play an important role in the pathogenesis of juvenile ankylosing spondylitis (JAS). In patients with spondyloarthritis, macrophages infiltrate the synovial membrane of affected joints, where they produce pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα) [7]. Additionally, some patients with JAS exhibit clinically overt or subclinical inflammation of the intestinal mucosa due to the activation of gamma/delta T lymphocytes (γδ T cells) or type 3 innate lymphoid cells (ILC3), as well as Th17 cells, which produce IL-17 and IL-23 cytokines. The synovial fluid of patients with JAS shows a predominance of type 1 T helper cells [8].

Although the role of B lymphocytes is not obvious in the classical understanding of spondyloarthritis pathogenesis, some studies show that autoantibodies against CD74 (macrophage migration inhibitory factor (MIF) receptor) may be present in the blood serum of patients with JAS [9]. Many current studies are investigating the role of gut microbiome alterations in the development of spondyloarthritis, as children with JAS exhibit decreased gut microbiome diversity and impaired tryptophan metabolism. However, attempts to normalize the gut microbiome using probiotics do not help reduce disease activity in children with JAS [10].

1.3 Epidemiology of the Disease or Condition

Juvenile arthritis is one of the most frequent and disabling rheumatic diseases occurring in children. The incidence of JA ranges from 1.6 to 23 cases per 100,000 children under 16 years of age. The prevalence of JA in various countries ranges from 3.8 to 400 cases per 100,000 children [11–13].

Pauciarticular (oligoarticular) juvenile arthritis (JA) accounts for 50 to 80% of JIA cases in North America and Europe, 25% in Eastern India, 26% among the Native American population of North America, and 31% in other ethnic groups. The peak incidence occurs at 1-2 years of age. Some children develop the disease after the age of 2. However, in these cases, there is a high probability of developing other conditions—enthesitis-related arthritis, juvenile ankylosing spondylitis, psoriatic arthritis, or polyarthritis. In North America and Europe, oligoarthritis predominantly affects girls, with a female-to-male ratio of 3:1. In children with uveitis, the female-to-male ratio is higher, ranging from 5:1 to 6.6:1. In Asia, oligoarthritis is more common in boys, and uveitis develops rarely [1, 3, 11].

The incidence of seronegative polyarthritis is 1-4 per 100,000, and the prevalence is 21-37 per 100,000 children. Polyarthritis accounts for 20% of JIA cases. Seronegative polyarthritis can debut between the ages of 0 and 18 years. The first peak of incidence occurs at 1-3 years of age, and the second occurs during adolescence. Girls are affected 4 times more often than boys. The female-to-male ratio for early-onset disease is 3:1, and in adolescence, it is 10:1 [1, 3, 11].

In the European population, approximately 15% of patients with polyarthritis test positive for rheumatoid factor (RF). Seropositive JA accounts for approximately 3% of JIA cases. The frequency of seropositive polyarthritis ranges from 51% in Canadian First Nations children; 17% in Eastern India; 14% in African Americans; 12.5% in Japan; 0.2-0.5% in Europe; and 1% in the USA. The approximate incidence is 0.3-0.5 per 100,000 patient-years, and the prevalence is 0-6.7 per 100,000 children in Europe. The average age of onset is 9-11 years (range 1.5-15 years). Girls are significantly more affected than boys. The female-to-male ratio ranges from 4:1 to 13:1 [13].

Due to discrepancies in the definition and classification criteria of juvenile ankylosing spondylitis (JAS), data on the true prevalence of the disease are lacking. In studies conducted in the USA and Canada, the incidence rate of JAS ranges from 2.1 to 24.0 cases per 100,000 population. The relative frequency of JAS among children with JIA varies from 10% to 37.4% in different populations. From 30% to 50% of Mexican, Indian, and some Asian patients develop JAS before the age of 16 [14].

As of 2023, the prevalence of JA in children under 18 years of age in the Russian Federation reached 100.3 per 100,000 children, and the primary incidence was 21.2 per 100,000. Among adolescents, these figures were 168.6 per 100,000 children and 38.3 per 100,000 children, respectively; among children under 14 years of age, they were 87.2 per 100,000 children and 17.9 per 100,000 children.

Girls are more frequently affected. Mortality ranges between 0.5-1% [3].

Uveitis is primarily an adult disease; children account for approximately 5-10%. According to a study conducted in Finland, the overall incidence of uveitis in the pediatric population was 4.3 per 100,000 person-years, and the prevalence was 27.9 per 100,000. The combination of uveitis and JA occurs in 15-67% of patients. Uveitis may precede the development of arthritis in 3-7% of cases. Uveitis developing against the background of joint syndrome is detected in 11.6-30.0% of children, on average 1.8 years after the onset of articular syndrome. The maximum frequency of uveitis development is observed when JA debuts at the age of 1-2 years (47%); when arthritis manifests at the age of >7 years, uveitis develops in <10% of cases. Manifestation of JA-associated uveitis is possible at any age [15–17].

1.4 Features of Coding the Disease or Condition

In the ICD, juvenile arthritis is coded under the section "Diseases of the musculoskeletal system and connective tissue (M00-M99)".

M08.0 – Juvenile (rheumatoid) arthritis (RF+).

M08.1 – Juvenile ankylosing spondylitis.

M08.3 – Juvenile (seronegative) polyarthritis.

M08.4 – Pauciarticular juvenile arthritis.

In accordance with ICD-10, the diagnosis is established as "Juvenile rheumatoid arthritis", or "Juvenile arthritis with active/inactive arthritis (oligo-/polyarthritis)", or "Juvenile ankylosing spondylitis". When formulating the diagnosis, the following data must be indicated:

— degree of disease activity (0-3) with/without therapy, absence/presence of functional impairment of varying severity (functional class [FC] 1–4);

— radiographic stage (1–4), absence/presence of disease progression; absence/presence of disease flares (number of flares per year);

— need for therapy adjustment, possibility of achieving remission only with immunosuppressive therapy using drugs from several (2 or more) pharmacotherapeutic groups (excluding nonsteroidal anti-inflammatory drugs [NSAIDs]), including biological disease-modifying antirheumatic drugs (bDMARDs);

— presence of disease complications, complications resulting from ongoing pharmacotherapy.

Examples of diagnoses:

1. Pauciarticular juvenile arthritis (M08.4) with mild joint function impairment; radiological stage I, no disease progression; with or without exacerbations (no more than 1 time per year), 0 or I degree of inflammatory activity during therapy; FC I; absence of adverse effects from ongoing drug therapy (NSAIDs).

2. Seronegative juvenile polyarthritis (M08.3) with moderate joint function impairment (FC II); radiological stage II; progressive disease course: exacerbations 2-4 times a year, persistent grade I or II inflammatory activity during immunosuppressive therapy; need for therapy adjustment, possibility of achieving remission only with immunosuppressive therapy using drugs from multiple (2 or more) pharmacotherapeutic groups (excluding NSAIDs), including bDMARDs; presence of complications from the disease and ongoing medical therapy.

3. Seronegative juvenile polyarthritis (M08.3) with severe impairment of statodynamic function due to joint involvement; radiological stage II or III, progressive disease course; frequent prolonged exacerbations (more than 4 times a year), FC II or III; persistent grade 2 or 3 inflammatory activity during immunosuppressive therapy; possibility of achieving remission only with immunosuppressive therapy using drugs from multiple (2 or more) pharmacotherapeutic groups (excluding NSAIDs), including bDMARDs; presence of complications from the disease and ongoing medical therapy.

4. Seropositive juvenile rheumatoid arthritis (M08.0) with severe impairment of statodynamic functions due to joint involvement; radiological stage III or IV; rapidly progressive disease course; grade 3 inflammatory activity; FC III or IV; low efficacy or resistance to ongoing immunosuppressive therapy with drugs from multiple pharmacotherapeutic groups (2 or more, including bDMARDs); presence of irreversible complications from the disease and ongoing medical therapy.

5. Juvenile ankylosing spondylitis (M08.1) with no or mild joint function impairment; radiological stage I, no disease progression; with or without exacerbations (no more than 1 time per year), 0 or I degree of inflammatory activity during therapy; FC I; absence of adverse effects from ongoing drug therapy (NSAIDs).

6. Juvenile ankylosing spondylitis (M08.1) with severe impairment of statodynamic function due to joint involvement; radiological stage II or III, progressive disease course; frequent prolonged exacerbations (more than 4 times a year), FC II or III; persistent grade 2 or 3 inflammatory activity during immunosuppressive therapy; possibility of achieving remission only with immunosuppressive therapy using drugs from multiple (2 or more) pharmacotherapeutic groups (excluding NSAIDs), including bDMARDs; presence of complications from the disease and ongoing medical therapy.

1.5 Classification of the disease or condition

In addition to ICD-10 coding, the International League of Associations for Rheumatology (ILAR) has developed a classification of juvenile idiopathic arthritis (JIA), according to which the following categories of JIA without systemic features correspond to ICD-10 [18]:

• Oligoarthritis – M08.4 – Pauciarticular juvenile arthritis.

  • persistent oligoarthritis

  • extended oligoarthritis

• RF-negative polyarthritis – M08.3 – Juvenile (seronegative) polyarthritis.

• RF-positive polyarthritis M08.0 – Juvenile (rheumatoid) arthritis (RF+).

• Enthesitis-related arthritis – M08.1 – Juvenile ankylosing spondylitis.

1.6 Clinical presentation of the disease or condition

The primary clinical manifestation of all variants of JA is arthritis.

M08.4 – Pauciarticular juvenile arthritis (oligoarticular JIA)

Definition. Arthritis involving 1-4 joints during the first 6 months of the disease [18].

There are 2 subcategories:

1. Oligoarticular persistent: arthritis involving 1-4 joints throughout the entire disease course.

2. Oligoarticular extended: involvement of 5 or more joints after 6 months of the disease.

Exclusion criteria:

1) psoriasis in the child or a first-degree relative;

2) arthritis associated with the HLA-B27 antigen in boys older than 6 years;

3) ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis in the presence of inflammatory bowel disease, Reiter's syndrome, or anterior uveitis in first-degree relatives;

4) presence of rheumatoid factor in at least two tests within 3 months;

5) presence of systemic arthritis.

M08.3 – Juvenile (juvenile) polyarthritis (seronegative) (polyarticular JIA, RF-negative (seronegative)

Definition. Arthritis involving 5 or more joints during the first 6 months of the disease, with a negative RF test [18].

Exclusion criteria:

1) psoriasis in the child or a first-degree relative;

2) arthritis associated with HLA-B27 antigen in boys older than 6 years;

3) ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis in the presence of inflammatory bowel disease, Reiter's syndrome, anterior uveitis in first-degree relatives;

4) presence of rheumatoid factor in at least two tests within 3 mo.;

5) presence of systemic arthritis.

M08.0 – Juvenile (juvenile) rheumatoid arthritis (RF+) (polyarticular JIA, RF-positive (seropositive)

Definition. Arthritis involving 5 or more joints during the first 6 months of the disease, associated with a positive RF in two tests within 3 months [18].

Exclusion criteria:

1) psoriasis in the child or first-degree relatives;

2) arthritis associated with HLA-B27 in boys older than 6 years;

3) ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis in the presence of inflammatory bowel disease, Reiter's syndrome, anterior uveitis in first-degree relatives;

4) presence of systemic arthritis.

Polyarticular RF-positive variant is essentially identical to adult RF+ rheumatoid arthritis in its clinical phenotype, laboratory, and immunogenetic parameters. Both diseases can develop within the same family [1, 4].

M08.1 – Juvenile ankylosing spondylitis (enthesitis-related arthritis)

Definition. this is arthritis and enthesitis, or arthritis or enthesitis combined with at least 2 of the following features [18]:.

Exclusion criteria:

1) psoriasis in the child or a first-degree relative;

2) presence of systemic arthritis.

General manifestations. Fever is typically low-grade (subfebrile). In some cases, an acute onset may be observed, resembling the onset and course of systemic-onset juvenile arthritis with high fever, maculopapular rash, severe intoxication, arthralgia, and myalgia [1]. In most patients, periodic arthralgia, myalgia, and peripheral joint stiffness develop along with enthesitis, predominantly affecting the knee, ankle, and foot joints. Spinal involvement (spondylitis) and sacroiliac joint involvement (sacroiliitis) typically occur as the disease progresses [19, 20].

Peripheral arthritis. Peripheral arthritis in juvenile ankylosing spondylitis (JAS) is characterized by asymmetric involvement primarily of the large joints of the lower extremities—knees, hips, and ankles. Typically, asymmetric oligoarthritis develops, but polyarthritis involving the small joints of the feet, toes, and sternoclavicular joints can also occur [20, 21]. Unlike other JIA subtypes, hip involvement in JAS is relatively frequent [22], whereas small joint involvement of the hands is rare [1].

Enthesitis. Enthesitis is inflammation of the enthesis, which is the site of attachment of a ligament, tendon, or joint capsule to bone. It is characterized by pain and swelling, predominantly in the knee, foot, or heel region. The presence of enthesitis helps differentiate JAS from other JIA subtypes. However, entheseal tenderness can also occur in other rheumatic diseases, including other JIA subtypes, and even in healthy children [23]. In addition, Osgood-Schlatter disease and fibromyalgia should be excluded, as these conditions also present with similar symptoms [24].

Axial skeleton involvement. Involvement of the spine and sacroiliac joints is relatively rare at the onset of JAS, but may develop several years after disease onset [25]. Axial skeleton involvement is frequently asymptomatic [26–28], but may also manifest as pain, particularly in the lower back and buttocks, or stiffness and reduced spinal mobility. Prolonged periods of physical inactivity can exacerbate these symptoms. Physical examination may reveal tenderness upon palpation of the sacroiliac joints, pain upon flexion, abduction, and external rotation of the hip (Patrick's test or FABER test), and limited lumbar spine mobility in the sagittal plane during forward bending (Schober's test). Cervical spine involvement also occurs [29].

Uveitis associated with juvenile arthritis.

Uveitis most frequently develops in pauciarticular juvenile arthritis, seronegative polyarthritis, and juvenile ankylosing spondylitis. Uveitis in patients with poly- and pauciarticular arthritis is typically characterized by an asymptomatic, chronic course, with diagnosis often established only when the child experiences significant visual acuity loss. Uveitis developing in JAS is characterized by an acute course with lacrimation, photophobia, eye pain and redness, vision impairment, and headache.

Risk factors for the development of uveitis in JIA patients include: mono/oligoarthritis; age at onset of joint syndrome under 4 years (according to some data, up to 6 years); female sex (75–80%); circulating antinuclear antibodies (ANA) (detected in 66–92% of cases in JIA with uveitis, vs. 30–42% without uveitis); HLA phenotype (HLA-B27, HLA-DR5, HLA-DRB1*13); antihistone antibodies; elevated ESR [16, 17, 30, 31].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Evaluation of patients with suspected juvenile arthritis

2.1 Complaints and Anamnesis

Comments: complaints in oligo- or polyarthritis include: morning stiffness or joint stiffness developing after periods of inactivity, lasting from several minutes to several hours; pain and/or swelling, and/or restricted joint movement, gait abnormalities; fever, typically up to subfebrile levels, weakness, fatigue, and rapid exhaustion [1, 4, 32]. In JAS, complaints include pain in the buttocks, groin, thighs, heels, around the shoulder joints, and less frequently (in approximately 24% of patients) pain, stiffness, or functional limitation in the lumbosacral spine or sacroiliac joints. Pain may resolve spontaneously, complicating early diagnosis. Axial skeleton involvement at disease onset is less frequent in children than in adults with AS: the onset of JAS may be gradual (sometimes acute) and characterized by intermittent muscle, joint, and ligament pain, stiffness, or inflammatory changes predominantly in peripheral joints. Arthritis is typically combined with enthesitis in one or more locations: most commonly in the knee or foot region. The disease may also debut with isolated hip joint involvement. Symptoms of spinal involvement are usually absent at onset in adolescents but may appear during the course of the disease [1, 3, 4].

Uveitis is characteristic of all JIA variants and may be acute, subacute, or chronic (indolent or relapsing). Chronic uveitis develops in approximately 15% of patients with RF- polyarthritis and 20% with oligoarthritis [1, 2, 6]; children typically have no complaints, and uveitis develops insidiously, being detected only when visual acuity decreases and pupillary deformation appears. In JAS, acute uveitis develops in the majority of cases, accompanied by eye irritation, ocular pain, decreased and/or blurred vision, floating spots before the eyes, eye redness, photophobia, and lacrimation.

Based on localization, uveitis can be anterior (iritis, anterior cyclitis, iridocyclitis) – inflammation of the iris and/or ciliary body; peripheral (posterior cyclitis) involving the ciliary body and the peripheral parts of the choroid; posterior (choroiditis, chorioretinitis) – inflammation of the choroid. In some cases, panuveitis may develop.

Depending on the number of affected eyes – unilateral and bilateral [1, 2, 6, 7, 11].

Comments: screening for urogenital and other infections (chlamydial, mycoplasmal, cytomegalovirus, herpetic, Epstein-Barr virus, etc.) that may be triggers for juvenile arthritis (JA) in a child, before and during pregnancy. Data on the course of previous pregnancies. It is necessary to ascertain whether intrauterine fetal death, chronic habitual miscarriage, premature birth, primary or secondary infertility occurred. All these pathologies can be a consequence of intrauterine fetal infection, in particular viral and bacterial infection. Data on the course of the present pregnancy (harmful occupational or environmental factors the mother was exposed to during pregnancy, gestosis in the first and second halves of pregnancy, threatened miscarriage in early and late stages, anemia of pregnancy, diseases suffered during pregnancy). Data on the course of childbirth (timeliness of labor, duration of the water-free interval, duration of the first and second stages of labor, nature of the amniotic fluid, timeliness of placental separation and its quality).

Comments: special attention should be paid to clinical manifestations of infections: conjunctivitis, omphalitis, balanitis, balanoposthitis, infected adhesions of the foreskin (in boys), cystitis, vulvovaginitis, vulvitis, asymptomatic leukocyturia, dysuric symptoms, cystitis (in girls), frequent otitis media, bronchitis, pneumonia, presence of herpetic eruptions on the face, frequent ARIs, intestinal infections. It is necessary to pay attention to the presence of allergic reactions, as well as reactions to vaccinations, presence of pets or birds in the household.

Comments: it is necessary to determine whether the patient has first- or second-degree relatives suffering from the following diseases: rheumatoid arthritis, acute rheumatic fever, systemic lupus erythematosus, dermatomyositis, scleroderma, etc., Reiter's disease, Bekhterev's disease (ankylosing spondylitis), Crohn's disease, ulcerative colitis, psoriasis, uveitis.

Comments: evaluate the nature of the onset (acute or subacute, with or without eye involvement). It is necessary to find out what preceded the development of the disease (trauma, acute respiratory infection, bacterial infection, vaccination, insolation, psychological trauma, urogenital or intestinal infection, conjunctivitis, bronchopulmonary infection, otitis media), whether the patient received antibacterial drugs and/or glucocorticoid hormones: which ones, what their dose and duration of administration were.

The onset of seronegative polyarthritis can be acute, but is more often subacute, with the gradual involvement of new joints in the process.

The onset of juvenile ankylosing spondylitis (JAS) can be acute or subacute, with or without involvement of the joints, spine, and eyes.

2.2 Physical Examination

Comments: An increase in body temperature is not typical for JA without systemic manifestations. However, fever may be observed in polyarticular JA, especially in seropositive JA and JAS. The temperature is usually subfebrile, rarely febrile.

Comments: the general condition is usually moderate, sometimes severe, and satisfactory during periods of remission. Patients often report morning stiffness, which can last for several hours; children cannot walk or take care of themselves. In patients with polyarthritis, an increase in pain syndrome in the joints and muscles may be observed at the peak of fever. When body temperature drops, well-being normalizes, and the child becomes active.

Comments: rashes are not typical for JA without systemic manifestations. Rheumatoid nodules may be detected. They form most frequently in seropositive polyarthritis (in 30% of patients), and less frequently in RF-negative polyarthritis (in less than 1% of patients).

Nodules are usually localized distally to the olecranon and other bony prominences, in pressure areas. Rheumatoid nodules are mobile and painless upon palpation, but pressure may cause pain. Rheumatoid nodules are factors of unfavorable prognosis in patients with RF-positive polyarthritis. Sometimes nodules are the result of methotrexate** (MT) treatment. In this case, they are multiple, develop in a short time, are localized on the hands, and quickly disappear upon discontinuation of MT treatment.

Rheumatoid nodules must be differentiated from subcutaneous nodules in acute rheumatic fever, which are smaller in size and are not associated with chronic arthritis.

Cutaneous vasculitis is a very rare manifestation of JA without systemic manifestations and most commonly develops in older children with RF-positive polyarthritis.

Comments: lymphadenopathy is not typical for JA without systemic manifestations, but may be observed in RF-negative JA. Lymph nodes are generally mobile, painless, not fused to each other or to the underlying tissues, and have a soft-elastic or dense-elastic consistency.

Comments: heart involvement develops extremely rarely in oligoarticular and RF-negative polyarthritis. In RF-positive polyarthritis, the aortic valve may be affected, though rarely. Aortic regurgitation develops, and acute heart failure is possible. As a rule, cardiac involvement manifests 4–17 years after the onset of RF-positive polyarthritis, but pathological heart murmurs may be auscultated as early as one year after the disease onset.

Cardiovascular system involvement in JAS is rare; the following develop: aortitis (involvement of the ascending aorta, predominantly its root); involvement of the aortic valve cusps with the development of its insufficiency; involvement of the membranous part of the interventricular septum with impaired atrioventricular and intraventricular conduction. Aortic regurgitation and conduction block develop in approximately 5% of patients on average 15 years after the disease onset. In rare cases, heart disease precedes the development of sacroiliitis. In case of aortic valve involvement, murmurs may be heard on auscultation.

Comments: in some cases, the child may complain of a cough, difficulty breathing, or shortness of breath. Lung involvement in children with oligoarthritis and RF-negative polyarthritis is rare. In RF-positive polyarthritis, pulmonary involvement is also a rare manifestation, but can occur in two variants: lymphoid interstitial pneumonitis or bronchiolitis obliterans. Pulmonary involvement may develop in childhood, adolescence, or adulthood 10–20 years after the onset of JA. Visually upon patient examination, signs of pulmonary involvement may not be detected; in some cases, respiratory failure develops, manifested by shortness of breath, retraction of compliant areas of the chest, the epigastric region, and areas of diaphragmatic attachment to the costal margin, as well as cyanosis. Percussion sound may be normal, with a hyperresonant (box) shade; with dullness in the posterior-inferior lung regions; auscultation may reveal moist and crepitant rales of various calibers, pleural friction rub, and decreased breath sounds in the posterior-inferior lung regions.

In JAS, lung parenchyma involvement is observed rarely. Pulmonary apex fibrosis may be observed.

Comments: patients with juvenile arthritis (JA) frequently complain of epigastric pain and dyspeptic symptoms. Periumbilical pain may be associated with mesenteric lymphadenopathy. Physical examination may reveal weight loss, coated tongue, abdominal distension; abdominal percussion may show hepatomegaly and splenomegaly (hepatomegaly and splenomegaly in JA without systemic manifestations are rare, more commonly seen in RF-positive polyarthritis). Significant splenomegaly accompanied by neutropenia and infections is characteristic of Felty's syndrome, which develops very rarely in children. Progressive hepatomegaly is characteristic of secondary amyloidosis. Palpation may reveal epigastric tenderness at projection points of the gallbladder, duodenum, and pancreas, hepatomegaly and splenomegaly; in case of intestinal involvement, tenderness in the ileocecal region and along the colon.

Most children with JA develop upper gastrointestinal (GI) tract inflammation associated with NSAID use.

Comments: joints must be examined for swelling. Skin temperature over the joints should be assessed, followed by the temperature difference between symmetrical skin areas.

In RF-negative polyarthritis, the knees, wrists, ankles, and small joints of the hands and feet are most frequently affected both at disease onset and throughout its course. The 2nd and 3rd metacarpophalangeal and proximal interphalangeal joints are most commonly involved. Distal interphalangeal joints are rarely affected in children at disease onset. Temporomandibular joints are significantly more often affected in RF-negative polyarthritis than in RF-positive polyarthritis. A "bird-like" jaw develops. The cervical spine is rarely affected at the onset of RF-negative polyarthritis, but as the disease progresses, limitation of movement (extension) in the cervical spine is observed. In late stages, ankylosis of the apophyseal joints of the 2nd and 3rd vertebrae may develop. In the polyarticular RF-negative variant of JA, the number of affected joints is smaller, and the nature of the articular syndrome is more asymmetrical than in the seropositive variant of the disease; the wrists and small joints of the hands are less frequently affected; hip joints are involved at onset in 20% of patients; destructive changes progress in them as the disease progresses. In polyarticular RF-negative JA, growth impairment is more pronounced than in seropositive polyarthritis. In some patients with RF-negative polyarthritis, joint effusion and synovial hypertrophy are absent, while joint contractures progress in these patients, accompanied by elevated laboratory markers of inflammation. This type of polyarthritis is termed "dry synovitis".

In the polyarticular RF-positive variant of JA, large and small joints of the upper and lower extremities, the cervical spine, and the temporomandibular joints are affected. Symmetrical arthritis is typical, involving the metacarpophalangeal and interphalangeal joints, wrist joints, small joints of the feet, and proximal interphalangeal joints of the feet. Unlike RF-negative polyarthritis, micrognathia does not develop in the RF-positive variant when temporomandibular joints are affected due to later onset. Functional impairment and deformities develop very rapidly in the wrists: ulnar deviation of the wrist and metacarpophalangeal joints, boutonnière and swan-neck deformities in the fingers. Deformities in the lower limb joints also develop: hallus valgus (hallux valgus) – deformity of the first metatarsophalangeal joints, tuning-fork deformities, etc.

In oligoarthritis, the first 6 months of the disease are characterized by inflammatory changes in 4 or fewer joints. The child has no systemic manifestations, except for chronic uveitis. Lower extremity joints are predominantly affected – knees (in 89%), ankles (in 36%), small joints of the fingers and toes (in 6%). Elbow, hip, wrist, and temporomandibular joints are affected in 3% of patients. Monoarthritis with knee joint involvement develops in 50%. Joints in oligoarthritis are typically swollen, warm, but not very painful, and are never red.

In juvenile ankylosing spondylitis (JAS), the articular syndrome is typically asymmetrical. Peripheral joints are affected in 82% of patients, upper extremity joints in 16%, and distal joints are affected more often than proximal ones. Oligoarthritis develops in 75% of patients, and polyarthritis in 25%. Characteristic features include involvement of one or both knee joints, ankle joints, small joints of the feet and toes; development of tarsitis accompanied by pain, stiffness, and functional impairment; involvement of the 1st metatarsophalangeal joint with the formation of hallux valgus. Shoulders, temporomandibular, and sternoclavicular joints are frequently involved, hips are rarely involved, and small joints of the hands are extremely rarely involved. Pain in the sternoclavicular and acromioclavicular joints combined with clavicular pain may lead to impaired chest excursion.

Comments: in JAS, axial skeleton joints are involved in the late stages of the disease. In children with sacroiliitis, pain may occur with direct pressure on one or both sacroiliac joints, or on the pelvis. Swelling in the sacral region may also be detected.

Spinal involvement reveals flattening of the lumbar lordosis, increased thoracic kyphosis, an increased distance from the head to the wall during diagnostic tests, disappearance of physiological spinal curves, and rigidity in its various segments.

Involvement of the thoracic spine can lead to restricted chest excursion. In late stages of the disease, typically in adulthood, a "beggar's posture" develops.

Perform functional assessments including Tomayer, Ott, Schober, Zatsepin, Forestier tests, and the chin-to-chest test. Assess tenderness along the spinous processes of the spine and at paraspinal points.

Zatsepin's sign is tenderness upon pressure at the attachment site of the X–XII ribs to the vertebrae due to an inflammatory process in the costovertebral articulations.

Forestier's sign is assessed to determine posture type. The patient stands with their back to the wall, touching it with their heels, torso, and head. Normally, the heels, shoulder blades, and occiput should touch the wall. In patients with ankylosing spondylitis and Forestier's disease, contact at some point will be absent due to the development of kyphosis.

Determination of mobility in the cervical spine. Measure 8 cm upward from CVII and make a mark. Then ask the patient to bend their head down as far as possible and measure this distance again. In healthy individuals, it increases by 3 cm.

In case of cervical spine involvement, this distance increases insignificantly or does not change at all. In patients with ankylosing spondylitis and a short neck, the test is uninformative.

Chin-chest test: a healthy person easily touches the sternum with their chin. With cervical spine involvement, a distance remains between the chin and the sternum when the head is maximally flexed forward.

Ott's test is performed to determine mobility in the thoracic spine. Measure 30 cm downward from CVII and make a mark. Then the distance between the indicated points is measured again when the subject bends forward maximally. In healthy people, this distance increases by 4–5 cm, whereas in patients with ankylosing spondylitis, it remains practically unchanged.

Determination of restricted respiratory chest excursion to detect pathological processes in the costovertebral joints. Measurements are taken with a tape measure at the level of the 4th rib. Normally, the difference in chest circumference between maximum inspiration and expiration is 6–8 cm. With the development of costovertebral joint ankylosis, this difference decreases to 1–2 cm. In the presence of pulmonary emphysema, the test is uninformative.

Schober's test is performed to detect restricted mobility in the lumbar spine. Measure 10 cm upward from LV and make a mark. With maximal forward flexion in healthy individuals, this distance increases by 4–5 cm, whereas with lumbar spine involvement, it remains practically unchanged.

Schober's test is performed to assess overall spinal mobility. It is determined by measuring in centimeters the distance from the third (III) finger of outstretched hands to the floor during maximum forward bending. This distance is normally equal to "0" and increases when spinal flexion is limited.

Comments: if joints are painless at a normal range of motion, it is necessary to assess for the onset of pain (protective muscle spasm, resistance) at the maximum range of motion.

Assess the range of motion:

— Cervical spine. Ask the patient to: throw the head back (normal extension is 50–60°), touch the chin to the sternum (normal flexion is 45°), turn the head to the right and left (normal rotation is 60–80°), and tilt the head toward the right and left shoulder (normal lateral flexion is 40°).

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

— Shoulder joints. Ask the patient to: raise the arms sideways and up, reach the right and left ear over the back of the head, reach the right and left scapula with the opposite hand from behind, independently take off a shirt or t-shirt, and comb their hair.

— 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°), and check pronation and supination (normal is 90°).

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

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

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

— Internal rotation test in the hip joints. The child lies supine with the hips and knees flexed at a 90° angle. Keeping the knees together, the lower legs are rotated outward.

— In almost all hip joint diseases, internal rotation is the first to be affected.

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

— Check for the patellar tap (ballotment) sign.

— The lower extremities are flexed at the knee joints. Usually, the heels touch the buttocks without difficulty. The lower extremities are maximally extended at the knee joints while the child is in the supine position.

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

Comments: gait variants:

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

- "waddling" gait (bilateral hip joint involvement).

Observation of gait during walking and running: limping in a patient is an important diagnostic clue for identifying pain or stiffness. Limping and gait abnormalities are most pronounced in children with JIA in the morning hours due to morning stiffness. When examining the patient in the afternoon, limping may be absent, and gait disturbance is minimal or not apparent.

Comments: enthesitis (inflammatory changes at the sites of attachment of ligaments, tendons, and fascia to bones) is a pathognomonic sign of enthesitis-related arthritis, allowing for differential diagnosis with other variants of juvenile idiopathic arthritis (JIA).

Enthesitis is typical for enthesitis-related JIA and develops more frequently than in ankylosing spondylitis. It manifests as severe pain and marked functional insufficiency of the joints and is often the child's most serious complaint. On examination, pronounced local tenderness is determined in the area of the patella (at 10, 14, and 18 o'clock), the tibial tuberosity; at the attachment sites of the Achilles tendon and plantar aponeurosis to the calcaneal tuberosity; the plantar aponeurosis to the base of the fifth metatarsal bone; in the area of the metatarsal heads; greater trochanters of the femurs; anterior superior iliac spine; pubic symphysis; ischial tuberosity, and rarely in the upper extremities. Dactylitis may also develop.

Comments: JIA is characterized by weakness of the muscles around the affected joints, atrophy and shortening of muscles and tendons, which leads to the development of flexion contractures in the joints. RF-negative polyarthritis is characterized by the development of total amyotrophy, especially when the disease debuts under the age of 3 years. Nonspecific myositis may also develop in JIA, accompanied by muscle weakness, muscle edema, pain, and an increase in the blood concentration of muscle breakdown enzymes. In the presence of active arthritis, muscle atrophy develops proximally to the affected joint.

In juvenile enthesitis-related arthritis, a myopathic syndrome may develop, which manifests as decreased muscle strength, spontaneous and palpation pain in the muscles, and weakness.

Comments: diseases that must be ruled out in the case of monoarthritis development: enthesitis-related arthritis, psoriatic arthritis, septic arthritis, oncological diseases, leukemia, neuroblastoma, hemophilia, trauma, familial Mediterranean fever and other periodic fevers; pigmented villonodular synovitis, sarcoidosis. Diseases that should be ruled out when diagnosing oligoarthritis, polyarthritis, and enthesitis-related JIA: acute rheumatic fever, reactive arthritis (following infections; yersiniosis, shigellosis, salmonellosis, chlamydiosis, toxoplasmosis, toxocariasis), septic arthritis, systemic lupus erythematosus, mixed connective tissue disease, systemic sclerosis, juvenile dermatomyositis, hemorrhagic vasculitis (Henoch-Schönlein purpura), chronic nonspecific ulcerative colitis, Crohn's disease, tuberculosis, Lyme disease (systemic tick-borne borreliosis), viral arthritis (herpes simplex, cytomegalovirus infection, hepatitis B and C), hypertrophic osteoarthropathy (Pierre Marie-Bamberger syndrome), hemophilia, leukemias, neoplastic processes, neuroblastoma, sarcoma, osteoid osteoma, benign and malignant tumors of joints and soft tissues, hypothyroidism, autoinflammatory syndromes.

2.3 Laboratory Diagnostics

Comments: in oligoarthritis, peripheral blood parameters typically show no changes, though ESR may be elevated while hemoglobin level, leukocyte count, and platelet count remain within normal limits; in polyarthritis, a normal or moderately elevated leukocyte count with a neutrophilic left shift, elevated ESR, and rarely hypochromic anemia or thrombocytosis may be observed. The clinical blood count picture is not specific for juvenile arthritis; therefore, the differential diagnostic workup must continue. First and foremost, hemoblastoses, lymphoproliferative, and oncological diseases must be ruled out.

In enthesitis-related JIA, findings typically include a normal or moderately elevated leukocyte count with a neutrophilic left shift, elevated ESR (up to 100 mm/h, occasionally higher), rarely hypochromic anemia, and rarely thrombocytosis (>500×10⁹/L). The clinical blood count picture is not specific for enthesitis-related JIA; therefore, the differential diagnostic workup must continue.

Comments: juvenile arthritis is characterized by changes in the hemostatic system of a hypercoagulable nature.

• It is recommended to perform thromboelastography in patients with signs of vasculitis to assess the severity of disorders in the hemostatic system [46,47,50,51,56–59]. (LeD 5, GR C)

• It is recommended to determine the main blood groups by the AB0 system, subgroups and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy, and to determine the D antigen of the Rhesus system (rhesus factor) in all patients before invasive procedures (esophagogastroduodenoscopy, colonoscopy with biopsy, bone marrow aspiration cytology, bone marrow trephine biopsy imprint cytology, bone biopsy) in order to ensure the possibility of blood transfusion if indicated during or after the procedure [1,3,60–63]. (LeveL of Evidence 5, Grade of Recommendation C)

Comments: Blood typing is performed for every patient when indicated for an invasive procedure.

Comments: elevated levels of ferritin, triglycerides, ALT, AST, LDH, GGT, and hyponatremia may be observed in secondary hemophagocytic lymphohistiocytosis (HLH), as well as drug toxicity, oncological disease, hemoblastosis, lymphoproliferative disease, other rheumatic diseases, and sepsis, which warrants further differential diagnosis.

Comments: in most patients with oligoarticular juvenile arthritis (JA), serum CRP levels are within reference ranges, whereas in polyarthritis RF+, RF-, and juvenile ankylosing spondylitis, they are generally elevated.

Comments: rheumatoid factor is significantly elevated in RF+ polyarthritis. High titers of IgM RF are typically detected, and IgA RF may also be present. Detection of IgA RF alone or combined with IgM RF is associated with high disease activity, marked functional impairment, joint space narrowing, and articular surface erosion. The frequency of anti-CCP detection is 57-90% in patients with RF+ polyarthritis and 17% in those with RF- polyarthritis. As in adults, anti-CCP is associated with the DR4 antigen and the development of erosions. Antinuclear antibodies (ANA) are detected in 50% of patients with RF- polyarthritis, typically in low titers of 1:80 to 1:640. The presence of ANA in RF- polyarthritis is associated with early disease onset, more frequently in girls, the development of asymmetric arthritis, and a high risk of uveitis. In RF+ polyarthritis, ANA is detected in 80% of patients. In oligoarthritis, ANA is detected in 65-85% of patients, primarily in girls with uveitis. Complement levels are normal or elevated.

In juvenile ankylosing spondylitis, RF is negative. ANA is detected more frequently than in the general population of JA patients.

The levels of anti-nuclear and anti-DNA antibodies; ANCA, anti-centromere antibodies, anti-RNA antibodies; antinuclear antibodies to Sm antigen, and anti-Scl-70 antibodies are not elevated.

Comments: serum immunoglobulin levels in JA may be elevated in the presence of high autoantibody titers.

Comments: an elevated serum antistreptolysin-O level indicates acute or chronic streptococcal infection and does not rule out the presence of JA.

Comments: the HLA-B27 antigen is detected in 90% of children with juvenile ankylosing spondylitis. Determination of HLA-B27 serves as a risk marker rather than a diagnostic test.

Comments: mutations in genes responsible for familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID/CINCA) are assessed.

• It is recommended to test lymphocyte subsets in patients who frequently suffer from viral, purulent bacterial infections, including opportunistic infections, to rule out immunodeficiency states [83–85]. (Level of Evidence 3, Grade of Recommendation B)

• It is recommended to perform a focal tuberculin test (Mantoux test, test with recombinant tuberculosis allergen in standard dilution**) and test blood interferon-gamma to Mycobacterium tuberculosis complex antigens in all patients to detect/rule out Mycobacterium tuberculosis infection [3,32,86–94]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to determine blood antibodies of classes A, M, G (IgA, IgM, IgG) to Chlamydia psittaci; blood antibodies to Chlamydophila pneumoniae; blood class G (IgG) antibodies to Chlamydia trachomatis; and blood antibodies of classes M, G (IgM, IgG) to Mycoplasma pneumoniae in all patients to rule out an infectious process that may present with clinical features similar to JA [1,3,32,81,95–99]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to determine blood antibodies to Salmonella enterica; blood antibodies to Salmonella typhi; blood antibodies of classes M, G (IgM, IgG) to Yersinia pseudotuberculosis; and blood antibodies to Yersinia enterocolitica serovars in all patients to rule out an infectious process that may present with a clinical picture similar to JA [1,3,32,95,96,100–108]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to determine blood antibodies of classes M, G (IgM, IgG) to Shigella boydii; blood antibodies of classes M, G (IgM, IgG) to Shigella dysenteriae; blood antibodies of classes M, G (IgM, IgG) to Shigella sonnei; and blood antibodies of classes M, G (IgM, IgG) to Shigella flexneri in all patients to identify/rule out an infectious process that may present with clinical features similar to JA [95,96]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to determine deoxyribonucleic acid (DNA) of Borrelia burgdorferi sensu lato group ixodid tick-borne borreliosis agents in the blood by PCR; determine class M antibodies (IgM) to Borrelia burgdorferi sensu lato group ixodid tick-borne borreliosis agents in the blood; determine class G antibodies (IgG) to Borrelia burgdorferi sensu lato group ixodid tick-borne borreliosis agents in the blood, and determine total antibodies to Borrelia burgdorferi sensu lato group ixodid tick-borne borreliosis agents in the blood in patients with an anamnestic history of visiting forests, living in areas endemic for tick habitation, or a tick bite, in order to rule out borreliosis [3, 32, 109–111]. (LEL 5, GOR C)

• It is recommended to determine Epstein-Barr virus DNA in peripheral and cord blood by PCR (quantitative assay), Epstein-Barr virus DNA in oropharyngeal mucosal swabs by PCR (qualitative assay), and Epstein-Barr virus DNA in urine by PCR (qualitative assay) in patients with fever in order to detect/rule out diseases and active Epstein-Barr virus infection [1, 3, 32, 81, 112–118].

• It is recommended to determine Cytomegalovirus DNA in peripheral and cord blood by PCR (quantitative assay), Cytomegalovirus DNA in oropharyngeal mucosal swabs by PCR (qualitative assay), and Cytomegalovirus DNA in urine by PCR (qualitative assay) in patients with fever in order to detect/rule out active cytomegalovirus infection [1, 3, 32, 115, 116, 119–122]. (LEL 4, GOR C)

• It is recommended to determine Herpes simplex virus types 1 and 2 DNA in blood by PCR (quantitative assay), Herpes simplex virus types 1 and 2 DNA in oropharyngeal swabs by PCR (qualitative assay), and Herpes simplex virus types 1 and 2 DNA in urine by PCR (qualitative assay) in patients with clinical signs of active herpetic infection and/or fever in order to detect/rule out active herpetic infection [1, 3, 32, 115, 116, 119, 123]. (LEL 4, GOR C)

• It is recommended to determine class M and G antibodies (IgM, IgG) to Cytomegalovirus in the blood of patients with fever in order to detect/rule out active cytomegalovirus infection [1, 112, 115, 119, 121, 122, 124, 125]. (LEL 4, GOR C)

• It is recommended to determine class M and G antibodies (IgM, IgG) to Epstein-Barr virus in the blood of patients with fever in order to detect/rule out active Epstein-Barr virus infection [3, 32, 113, 115, 119, 126]. (LEL 4, GOR C)

• It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus in the blood of patients with fever in order to detect/rule out Epstein-Barr virus-associated diseases [3, 32, 113, 126]. (LEL 5, GOR C)

• It is recommended to determine class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus in the blood of patients with fever in order to detect/rule out diseases and active Epstein-Barr virus infection [3, 32, 113, 126]. (LEL 5, GOR C)

• It is recommended to determine antibodies to Herpes simplex virus in the blood of patients with clinical signs of herpetic infection and/or fever in order to detect/rule out active herpetic infection [1, 3, 32, 81, 115, 119, 127–130]. (LEL 5, GOR C)

• It is recommended to perform molecular biological testing of blood for Toxoplasma gondii in patients with a history of animal contact in order to rule out toxoplasmosis [131–135]. (LEL 3, GOR B)

• It is recommended to determine antibodies to Leishmania in the blood of patients with a history of travel or residence in endemic areas in order to rule out leishmaniasis [136–140]. (LEL 3, GOR B)

• It is recommended to perform molecular biological testing of blood for Hepatitis C virus and molecular biological testing of blood for Hepatitis B virus in patients with clinical and laboratory signs of hepatitis for differential diagnosis [3, 32, 141–145]. (LEL 5, GOR C)

Comments: juvenile arthritis may be complicated by autoimmune hepatitis or NSAID-induced hepatitis, and hepatitis can also be a sign of secondary hemophagocytic lymphohistiocytosis accompanied by cytolysis.

Comments: juvenile arthritis may be complicated by autoimmune hepatitis or hemophagocytic lymphohistiocytosis accompanied by cytolysis.

• It is recommended to determine class M and G antibodies (IgM, IgG) to human immunodeficiency virus type 1 (HIV-1) in the blood, and class M and G antibodies (IgM, IgG) to human immunodeficiency virus type 2 (HIV-2) in the blood of patients with clinical and laboratory signs of immunodeficiency in order to detect/rule out HIV infection [32, 146–149]. (LEL 5, GOR C)

• It is recommended to test blood procalcitonin levels in patients with fever in order to rule out sepsis [3, 32, 150–153]. (LEL 3, GOR C)

Comments: blood procalcitonin levels are elevated during an acute inflammatory response. In juvenile arthritis without infectious complications, they remain within reference ranges.

• It is recommended to perform blood culture for sterility, and urine microbiological (culture) testing for aerobic and facultatively anaerobic opportunistic microorganisms in patients with fever in order to rule out sepsis and urinary tract infection [1, 3, 32, 81, 95, 150, 151, 154–156]. (LEL 4, GOR C)

• It is recommended to perform microbiological (culture) testing of tonsillar and posterior pharyngeal wall mucus for aerobic and facultatively anaerobic microorganisms in all patients in order to rule out nasopharyngeal contamination with pathogenic and opportunistic flora [1, 3, 32, 81, 150, 151, 157, 158]. (LEL 5, GOR C)

• It is recommended to perform a routine urinalysis and urine microscopy according to Nechyporenko in all patients in order to rule out renal involvement [1, 3, 4, 65, 159]. (LEL 5, GOR C)

Comments: micro- and macrohematuria may result from the nephrotoxic effects of NSAIDs and methotrexate**; proteinuria may be a manifestation of renal amyloidosis. Microhematuria, macrohematuria, and proteinuria may manifest as acute kidney injury in hemophagocytic lymphohistiocytosis. In juvenile arthritis, urinalysis is typically normal.

2.4 Instrumental Diagnostics

Comments: hepatosplenomegaly, changes in liver, spleen, and pancreatic parenchyma, cholestasis, altered renal parenchyma, decreased blood flow in acute kidney injury, and enlargement of mesenteric lymph nodes may be detected.

Comments: in juvenile arthritis without systemic manifestations, cardiac abnormalities are generally not detected; in ankylosing spondyloarthritis associated with juvenile arthritis, typical features of aortic regurgitation or left ventricular systolic dysfunction may rarely be identified. Transesophageal echocardiography reveals aortic valve involvement in 82% of adult patients with ankylosing spondylitis. Nodular thickening of the aortic valve cusps may also be detected.

Performed for differential diagnosis with other rheumatic diseases. Myocarditis is characterized by left ventricular dilatation, decreased left ventricular ejection fraction, hypokinesia of the posterior left ventricular wall and/or interventricular septum, aortitis, signs of relative mitral, aortic and/or tricuspid regurgitation, and increased pulmonary artery pressure. Pericarditis is characterized by separation of the pericardial layers and the presence of free fluid in the pericardial cavity. The endocardium and valve apparatus are generally unaffected in juvenile arthritis. In case of endocardial involvement, acute rheumatic fever and infective endocarditis must be ruled out.

Comments: in juvenile arthritis without systemic manifestations, there are typically no abnormalities. It is performed for differential diagnosis with other rheumatic diseases.

Comments: Ultrasound allows for dynamic monitoring and assessment of the degree of joint involvement. Ultrasound makes it possible to evaluate synovial thickening, joint effusion, tenosynovitis, enthesitis, and bone erosions. Synovial involvement is manifested by the presence of abnormally hypoechoic tissue associated with joint lines or surrounding tendons.

Comments: juvenile arthritis reveals: osteoporosis, destructive changes in bone structures, joint space narrowing, integrity of the articular surfaces of the bones forming the joint, presence of erosions, usurations of articular surfaces, cysts, areas of bone necrosis, subluxations, fractures, osteophytes, calcifications, etc. Simultaneous examination of symmetrical joints is necessary. Cartilage and bone tissue changes are detected in the majority of patients. It reveals osteoporosis, destructive changes in bone structures, joint space narrowing, integrity of the articular surfaces of the bones forming the joint, presence of erosions, usurations of articular surfaces, cysts, areas of bone necrosis, subluxations, fractures, osteophytes, calcifications, etc. Simultaneous examination of symmetrical joints is necessary. Cartilage and bone tissue changes are detected in the majority of patients.

In RF-negative polyarthritis, 2 years after disease onset, 30% of patients show joint space narrowing, 35% have erosions, and 10% have bone growth abnormalities. Early radiological changes develop in the wrist, hip, and shoulder joints. After 6.5 years, 39% of patients exhibit joint space narrowing, 64% have erosions, and 25% have bone growth abnormalities. Atlantoaxial subluxation also develops.

In RF-positive polyarthritis, joint space narrowing and articular surface erosions develop 1–2 years after disease onset, most frequently in the wrist joints, small joints of the hands, and shoulder joints. In the wrists, cartilage loss develops in the proximal carpal and intercarpal joints, leading to carpal ankylosis and hand shortening.

In oligoarthritis, joint space narrowing and articular surface erosions in the early stages of the disease develop in 5% and 10% of patients, respectively; in 15% and 25% after 6 years. Accelerated bone growth, predominantly of the knee joint, is observed in 20% of patients in the early stages of the disease.

In aggressive juvenile arthritis, ankylosis develops in the wrists and apophyseal joints of the cervical spine, along with avascular necrosis of the hip joints.

Early changes in peripheral joints in enthesitis-related arthritis correspond to those in other variants of juvenile idiopathic arthritis. Radiological signs of enthesitis are more frequently detected in the region of the calcaneal tuberosity and less frequently in the knee joint. They are characterized by blurred contours and bone erosions at the Achilles tendon insertion site into the calcaneal tuberosity, and spur formation. Ankylosing tarsitis develops. As the disease progresses, significant joint space narrowing and ankylosis in peripheral joints may occur.

• It is recommended to perform computed tomography of the joint with or without anesthesia (including early postoperative management) in patients with mono-oligoarthritis and MRI changes atypical for juvenile arthritis, in order to rule out bone tuberculosis, osteomyelitis, benign and malignant tumors, and bone metastases [1,3,32,88,91,92,163,167–169]. (UBD 5, GOR C)

• 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 arthritis to rule out traumatic injuries to the tendon-ligament apparatus, menisci, and tumors, and to detect pannus growth, pathological changes in the synovial membrane, and cartilage in the early stages of juvenile arthritis [1,3,32,170]. (UBD 1, GOR A)

• It is recommended to perform magnetic resonance imaging of the spine (single segment), computed tomography of the spine (single segment), or computed tomography of the pelvic bones with or without anesthesia (including early postoperative management) in patients with complaints of back pain, presence of enthesopathies (according to physical examination), patients with positive HLA-B27, and suspected juvenile ankylosing spondylitis, to detect/exclude involvement of the spine and sacroiliac joints [1,3,24,32,45,171–178]. (UBD 5, GOR C)

Comments: in juvenile ankylosing spondylitis, radiological signs of sacroiliitis appear several years after the onset of peripheral arthritis and are the first signs of spinal involvement. The stages of sacroiliitis are presented in Table 1. Anatomical changes in the spine generally appear in adulthood, but with early disease onset and an aggressive course, spinal involvement may also develop in children.

Table 1. Radiological stages of sacroiliitis (J. Kallgren modified by K. Dale, 1979).

• It is recommended to perform ultrasound examination of the salivary glands in patients with positive RF and/or anti-CCP, and in patients suspected of developing Sjogren's syndrome, to rule out/confirm their involvement [1,179–182]. (UBD 5, GOR C)

• It is recommended to perform contrast-enhanced magnetic resonance imaging of the soft tissues of the head with or without anesthesia (including early postoperative management) in patients with positive RF and/or anti-CCP, and in patients suspected of developing Sjogren's syndrome, to detect/rule out salivary gland involvement in Sjogren's syndrome [1,179–182]. (UBD 5, GOR C)

Comments: Sjögren's syndrome most commonly develops in patients with rheumatoid factor-positive juvenile arthritis.

• It is recommended to perform esophagogastroduodenoscopy with or without anesthesia (including early postoperative management) in all patients to rule out inflammatory, erosive, and ulcerative processes [3,32,160,161,183–185,185–191]. (Reliability Level of Evidence 4, Recommendation Grade C)

• It is recommended to perform a microbiological (culture) examination of gastric mucosal biopsies for *Helicobacter pylori* in patients with inflammatory and/or erosive and/or ulcerative changes according to esophagogastroduodenoscopy, in order to rule out GI pathology associated with *Helicobacter pylori* [3,32,160,161,184–188,190–193]. (Reliability Level of Evidence 4, Recommendation Grade C)

• It is recommended to perform endoscopic biopsy of the esophagus, endoscopic biopsy of the stomach, endoscopic biopsy of the duodenum, and endoscopic biopsy of the jejunum with or without anesthesia (including early postoperative management), followed by pathomorphological examination of the biopsy (surgical) material of the esophagus, stomach, duodenum, and jejunum in patients with inflammatory, erosive, and/or ulcerative changes of the mucous membrane, in order to rule out inflammatory bowel diseases [3,32,160,161,186,194–197]. (Reliability Level of Evidence 4, Recommendation Grade C)

• It is recommended to perform colonoscopy with or without anesthesia (including early postoperative management) in all patients to rule out inflammatory bowel diseases [3,32,160,161,186,194–197]. (Reliability Level of Evidence 4, Recommendation Grade C)

• It is recommended to perform an endoscopic biopsy of the large intestine with pathomorphological examination of the biopsy (surgical) material of the large intestine in patients who show inflammatory, erosive, and/or ulcerative changes in the large intestine according to colonoscopy, in order to rule out inflammatory bowel diseases [3,32,160,161,186,194–197]. (Reliability Level of Evidence 4, Recommendation Grade C)

• It is recommended to perform video capsule endoscopy of the small intestine in patients with clinical signs of inflammatory bowel disease and/or elevated fecal calprotectin levels when esophagogastroduodenoscopy and colonoscopy show no abnormalities, in order to rule out Crohn's disease with isolated small bowel involvement [3,32,160,161,184–188,198]. (Reliability Level of Evidence 4, Recommendation Grade C)

• It is recommended to perform computed tomography of the chest organs with or without anesthesia (including early postoperative management) in all patients to rule out/detect pulmonary involvement, other rheumatic diseases, oncological/oncohematological/lymphoproliferative diseases, and tuberculosis [1,3,32,41,91,92,168,199–201]. (Reliability Level of Evidence 4, Recommendation Grade C)

• It is recommended to perform contrast-enhanced brain MRI, intravenous contrast-enhanced abdominal MRI, intravenous contrast-enhanced retroperitoneal MRI, and intravenous contrast-enhanced pelvic MRI with or without anesthesia (including early postoperative management) in patients with a severe general condition, fever, and inconsistency between the general condition and joint involvement, in order to detect/rule out oncological/oncohematological/lymphoproliferative diseases, tuberculosis, and abscesses [3,32,41,91,168,199,202,203]. (Reliability Level of Evidence 5, Recommendation Grade C)

• It is recommended to perform intravenous bolus contrast-enhanced computed tomography of the abdominal organs and intravenous bolus contrast-enhanced computed tomography of the retroperitoneal space with or without anesthesia (including early postoperative management) in patients with contraindications to MRI, in order to rule out internal organ involvement in systemic juvenile arthritis, and to detect/rule out oncological/oncohematological/lymphoproliferative diseases, tuberculosis, and abscesses [1,3,32,168,204,205]. (Reliability Level of Evidence 5, Recommendation Grade C)

• It is recommended to obtain a bone marrow cytologic specimen via puncture and a bone marrow histologic specimen using anesthesia (including early postoperative management), with bone marrow smear cytologic examination (myelogram) and pathomorphological examination of the bone marrow biopsy (surgical) material using immunohistochemical methods, in patients with a severe general condition, fever, and inconsistency between the general condition and joint involvement, at the diagnostic stage prior to prescribing glucocorticoids and/or immunosuppressants and/or biologic agents, in order to detect/rule out oncological/oncohematological/lymphoproliferative diseases / metastatic bone marrow involvement, and macrophage activation syndrome [3,32,41,81,155,168,169,204–208]. (Reliability Level of Evidence 5, Recommendation Grade C)

Comments: if glucocorticoids or immunosuppressants are used, the test is performed no earlier than 2 weeks after their discontinuation.

Comments: the study is performed at the stage of diagnosis establishment prior to prescribing glucocorticoids and/or immunosuppressants, and/or targeted biologic DMARDs. If glucocorticoids or immunosuppressants have been used, the study is performed no earlier than 2 weeks after their discontinuation.

• 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 with severe arthralgia, myalgia, ossalgia, destructive bone changes, subcutaneous fat infiltrates, and lesions in parenchymal organs, the brain, or spinal cord, in order to detect/rule out oncological/oncohematological/lymphoproliferative diseases [3,32,41,168,204–206,209,210]. (Reliability Level of Evidence 5, Recommendation Grade C)

• It is recommended to perform multi-position bone scintigraphy with or without anesthesia (including early postoperative management) in patients with bone destruction foci atypical for juvenile arthritis, in order to detect/rule out malignant and benign bone tumors and bone metastases [168,169]. (Reliability Level of Evidence 5, Recommendation Grade C)

• It is recommended to perform CT-guided pelvic bone trephine biopsy with anesthesia (including early postoperative management), including pathomorphological examination of the bone marrow biopsy (surgical) material using immunohistochemical methods; cytologic examination of bone marrow trephine biopsy imprints; immunocytochemical examination of bone marrow trephine biopsy imprints; and immunophenotyping of hematopoietic progenitor cells in the bone marrow, in patients with a severe general condition, fever, and inconsistency between the general condition and joint involvement, for differential diagnosis during the workup prior to prescribing glucocorticoids and/or immunosuppressants and/or biologic agents, in order to rule out oncological/oncohematological/lymphoproliferative diseases / metastatic bone marrow involvement [3,32,169,204–207,210,211]. (Reliability Level of Evidence 5, Recommendation Grade C)

Comments: in cases where GCs or immunosuppressants have been used, the procedure should be performed no earlier than 2 weeks after their discontinuation.

Comments: destruction foci are characteristic of multifocal osteomyelitis, malignant neoplasms, and hemoblastoses, which can present with episodes of febrile fever accompanied by pain in the abdomen, chest, joints, and bones. Bone biopsy is required for differential diagnosis [169].

2.5 Other Procedures

2.1.5 Other diagnostic procedures

Comments: performed based on the results of examinations (computed tomography of the chest cavity organs; magnetic resonance imaging of the brain, magnetic resonance imaging of the abdominal cavity, magnetic resonance imaging of the retroperitoneal space and pelvis 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 with tumorotropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)); bone scintigraphy; pathomorphological examination of bone marrow biopsy (surgical) material (trephine biopsy) using immunohistochemical methods, bone biopsy with pathomorphological examination of biopsy (surgical) material).

• It is recommended to perform an initial consultation (examination) by a phthisiatrician for patients with a positive focal tuberculin test and/or intradermal test with a tuberculosis allergen, and/or an elevated blood level of interferon-gamma in response to Mycobacterium tuberculosis complex antigens, and/or infiltrative pulmonary lesions, in order to rule out tuberculosis [3,32,88,90–92,212,213]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination) by an orthopedic traumatologist for patients with space-occupying and destructive bone lesions, as well as bone deformities atypical for juvenile arthritis, in order to rule out septic arthritis, osteomyelitis, and other surgical pathologies [1,3,32,214]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination) by an otorhinolaryngologist for all patients in order to detect foci of chronic infection in ENT organs [1,3,32,95]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination) by an ophthalmologist with mandatory ocular biomicroscopy for all patients in order to detect visual system involvement [1,3,15,32]. (Level of Evidence 5, Grade of Recommendation C)

Comments: ocular biomicroscopy is mandatory.

• It is recommended to perform an initial consultation (examination) by a pediatric dentist for all patients in order to assess the condition of the oral cavity [1,3,4,32,215]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination) by a neurologist for patients with neurological symptoms, severe pain syndrome, psychomotor developmental delay, or psychotic reactions, in order to rule out central and peripheral nervous system pathology, including malignant and benign neoplasms [1,3,4,32,216,217]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination) by an audiologist-otorhinolaryngologist and an audiogram for patients with suspected autoinflammatory syndromes in order to rule out/confirm hearing loss [1,3,32,77,82]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial examination (consultation) by an anesthesiologist-resuscitologist for patients scheduled for procedures under general anesthesia, in order to assess their condition [60,61,218–220]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial examination (consultation) by an anesthesiologist-resuscitologist for critically ill patients in order to address the issue of transfer to the intensive care unit [60,61,218–220]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to provide 24-hour monitoring by an anesthesiologist-resuscitologist for all critically ill patients (multiple organ dysfunction syndrome, macrophage activation syndrome) in order to provide care in the intensive care unit setting [60,61,218–220]. (Level of Evidence 5, Grade of Recommendation 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) in order to harmonize the development of the child's personality in the context of a severe chronic disease and optimize parent-child relationships; to increase treatment adherence and cooperation with the physician and medical staff to achieve disease remission; to achieve psychological adaptation in society; and to develop an individual psychological rehabilitation program for the patient and their parents [32,221–227]. (Level of Evidence 1, Grade of Recommendation A)

2.1.6 Criteria for establishing the diagnosis of juvenile arthritis

The diagnosis of "juvenile arthritis" is established in the presence of arthritis in one or more joints lasting for more than 6 weeks [1].

Depending on the number of affected joints and the presence or absence of RF, the following forms of the disease are distinguished:

Oligoarticular subtype (oligoarthritis) – arthritis involving 1 to 4 joints during the first 6 months of the disease.

Polyarticular RF-negative subtype (polyarticular RF-) – arthritis involving 5 or more joints during the first 6 months of the disease, with a negative RF test.

Polyarticular RF-positive subtype (polyarticular RF+) – arthritis involving 5 or more joints during the first 6 months of the disease, associated with a positive RF test on two occasions at least 3 months apart or a positive test for antibodies to cyclic citrullinated peptide (cyclic citrullinated peptide [CCP]).

Juvenile ankylosing spondylitis (syn.: enthesitis-related arthritis) – arthritis and enthesitis, or arthritis or enthesitis combined with at least 2 of the following features:

• presence of tenderness of the sacroiliac joints and/or inflammatory back pain;

• presence of HLA-B27;

• onset of arthritis in a boy older than 6 years of age;

• presence of ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis associated with inflammatory bowel disease, reactive arthritis, or acute anterior uveitis in a first-degree relative (parents, siblings);

• acute anterior uveitis.

The diagnosis of oligoarticular or polyarticular juvenile arthritis cannot be established in the presence of [18]:

- psoriasis (including a history thereof) in the patient or first-degree relatives (parents, siblings);

- arthritis associated with the class I major histocompatibility complex antigen B27 (HLA-B27) in boys older than 6 years of age;

- ankylosing spondylitis;

- enthesitis-related arthritis;

- sacroiliitis associated with inflammatory bowel disease;

- Reiter's syndrome;

- acute anterior uveitis;

- any of these diseases in a first-degree relative;

- presence of systemic arthritis.

The diagnosis of enthesitis-related arthritis cannot be established in the presence of [18]:

• psoriasis (including a history thereof) in the patient or in a first-degree relative;

• positive IgM RF in at least 2 tests taken at an interval of

  - not less than 3 months;

• systemic JIA in the patient.

Additional information for the diagnosis of juvenile ankylosing spondylitis and enthesitis-related arthritis:

Table 2. Rome diagnostic criteria for AS [228].

Table 3. New York diagnostic criteria for AS [229].

Table 4. Criteria for AS by the European Spondyloarthropathy Study Group [230].

Table 5. Amor AS criteria [231].

Table 6. Garmisch-Partenkirchen JAS criteria.

Table 7. Criteria for AS in children [232,233].

In 2019, the Paediatric Rheumatology International Trials Organisation (PRINTO) proposed a new provisional classification of juvenile idiopathic arthritis, which outlines new diagnostic criteria for enthesitis-related/spondylitis-related arthritis (Table 8).

Table 8. Criteria for enthesitis-related/spondylitis-related arthritis according to the PRINTO classification [234].

2.2. Evaluation of patients with juvenile arthritis and suspected hemophagocytic syndrome

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a JIA complication, a dangerous hyperinflammatory syndrome representing the terminal stage of a severe uncontrolled reaction characterized by hypercytokinemia with a significant yet ineffective immune response. It is a consequence of the innate or acquired inability of the immune system to cope with the triggering factor—most commonly an infectious agent [235,236].

Secondary HLH is triggered by viruses (cytomegalovirus, Epstein-Barr virus, herpesviruses, etc.), medications (NSAIDs, gold preparations, sulfasalazine**, etc.). Secondary HLH results from the 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. Overall, the MPS functions as a unique biological filter of blood and lymph, removing tumor and virus-infected cells, microorganisms, toxins, various metabolites, and circulating immune complexes. Histiocytes (syn.: macrophages) also perform antigen-presenting functions [235,236].

In JIA without systemic manifestations, sHLH develops significantly less frequently than in systemic JIA, but it can be triggered by a viral or bacterial infection.

sHLH is a consequence of the 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. Overall, the MPS functions as a unique biological filter of blood and lymph, removing tumor and virus-infected cells, microorganisms, toxins, various metabolites, and circulating immune complexes. Histiocytes (syn.: macrophages) also perform antigen-presenting functions.

It is not always possible to establish a diagnosis of sHLH because its clinical and laboratory manifestations may resemble an infectious process [235,236].

2.2.1 Physical examination

• It is recommended that diagnostic evaluations, including differential diagnosis, be performed in a rheumatology inpatient setting for all patients with suspected secondary hemophagocytic lymphohistiocytosis to confirm or rule it out [1,3,32]. ( poziom wiarygodności danych — 5, poziom siły zaleceń — C)

• It is recommended to evaluate the severity and pattern of fever in all patients to identify characteristics typical of HLH [1,3,32,235–238]. ( poziom wiarygodności danych — 5, poziom siły zaleceń — 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.

Comments: the course of secondary hemophagocytic lymphohistiocytosis (sHLH) varies from mild, with minimal symptoms, to severe. In severe uncontrolled sHLH, impaired consciousness and coma may develop, and a fatal outcome is possible.

Comments: pallor and jaundice of the skin indicate the development of anemia, progression of hepatitis, and coagulopathy; edema syndrome indicates the development of capillary leak syndrome and renal failure.

The frequency of skin manifestations in sHLH ranges from 6 to 65%. Skin lesions may present as a generalized maculopapular rash, erythroderma, edema, panniculitis, morbilliform rash, and purpura. Some manifestations are similar to those seen in Kawasaki disease.

Pathological and anatomical examination of skin biopsy (surgical) material reveals lymphohistiocytic infiltration of the dermis with phenomena of hemophagocytosis.

Comments: with the development of sHLH, lymph node size significantly increases, and generalized lymphadenopathy develops.

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

Signs of cardiovascular complications in sHPS include pain in the heart region, behind the sternum, in the chest, epigastric pain radiating to the back, left shoulder, or neck, cough, shortness of breath worsening in a supine position, and progressive cyanosis.

Physical examination may reveal increased precordial pulsation, enlargement of the relative cardiac dullness boundaries, arrhythmias, and pathological murmurs over heart valve projection areas.

As sHLH progresses, heart failure generally develops.

Comments: acute respiratory distress syndrome may develop in sHLH due to microangiopathy with pulmonary vascular thrombosis. Pulmonary involvement can 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 over sHLH 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.

Comments: upon examination, abdominal enlargement may be determined due to hepatomegaly and/or splenomegaly, and/or the presence of fluid in the abdominal cavity. Percussion and palpation reveal enlargement of the liver and/or spleen, and tenderness upon palpation across the entire abdominal surface.

Liver involvement occurs in the vast majority of patients with sHLH, ranging from an asymptomatic course with blood test abnormalities to the development of hepatic encephalopathy, severe hypocoagulation, and edema-ascites syndrome. Spontaneous onset ofveno-occlusive disease has been described.

The degree of splenic enlargement varies from marked to moderate, with splenomegaly detected only during instrumental examinations.

2.2.2 Laboratory diagnostic tests

Comments: thrombocytopenia, leukopenia, erythropenia, and a decreased ESR develop in sHLH.

Comments: in sHLH, the levels of D-dimer and fibrin degradation products increase (an early preclinical sign), while the fibrinogen level decreases.

• It is recommended to test the heparin level in the blood of all patients to assess the severity of hemostatic disorders and the risk of thrombosis/bleeding [1,3,32,46,50,56,56,244,245]. (Credibility Level 5, Recommendation Grade C)

• It is recommended to perform thromboelastography in all patients to assess the severity of hemostatic disorders and the risk of thrombosis/bleeding/disseminated intravascular coagulation [50,56–59,246–248]. (Credibility Level 4, Recommendation Grade C)

• It is recommended to test total blood protein, blood albumin, total bilirubin, free and conjugated bilirubin, creatinine, urea, uric acid, blood glucose, ferritin, triglycerides, cholesterol, sodium, potassium, total calcium, lactate dehydrogenase (LDH) activity, aspartate aminotransferase (AST) activity, alanine aminotransferase (ALT) activity, gamma-glutamyl transferase (GGT) activity, alkaline phosphatase activity, serum iron, creatine kinase activity, pancreatic amylase activity, and lipase activity in all patients to detect pathological changes characteristic of sHLH [3,32,235–238,240,249–251]. (Credibility Level 4, Recommendation Grade C)

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

With the progression of multiple organ dysfunction syndrome, hyperbilirubinemia, elevated creatinine, uric acid, and urea levels may be observed. Elevated creatinine, uric acid, and urea levels indicate the development of acute kidney injury associated with secondary hemophagocytic lymphohistiocytosis (sHLH-AKI).

Comments: serum CRP levels are significantly elevated in sHLH.

• It is recommended to perform microbiological (culture) blood test for sterility, microbiological (culture) test 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 identify an active bacterial and/or fungal infection as a triggering factor for sHLH [1,237,238,249,252–255]. (Credibility Level 5, Recommendation Grade C)

• It is recommended to determine antibodies of classes A, M, G (IgA, IgM, IgG) to Chlamydia psittaci; antibodies to Chlamydia trachomatis; antibodies to Chlamydophila pneumoniae in the blood; and IgM and IgG antibodies to Mycoplasma pneumoniae in the blood of all patients to detect/exclude active mycoplasma and/or chlamydial infection as a triggering factor for sHLH [1,3,32,81,237,238,253,253–255]. (Credibility Level 5, Recommendation Grade C)

• It is recommended to detect Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR when interstitial and/or focal and/or infiltrative changes in the lungs are detected on chest computed tomography, in order to identify/exclude active mycoplasma infection as a triggering factor for sHLH [1,124,249,252,253,256–259]. (Credibility Level 4, Recommendation Grade C)

• It is recommended to perform quantitative Epstein-Barr virus DNA detection by PCR in peripheral and cord blood, qualitative Epstein-Barr virus DNA detection by PCR in oropharyngeal swabs, and qualitative Epstein-Barr virus DNA detection by PCR in urine in all patients to identify/exclude active herpesvirus infection as a triggering factor for sHLH [1,113–118,124,249,252,253,260,261]. (Credibility Level 4, Recommendation Grade C)

• It is recommended to perform quantitative Cytomegalovirus DNA detection by PCR in peripheral and cord blood, qualitative Cytomegalovirus DNA detection by PCR in oropharyngeal swabs, and qualitative Cytomegalovirus DNA detection by PCR in urine in all patients to identify/exclude active herpesvirus infection as a triggering factor for sHLH [1,115,116,119,121,122,124,125,237,238,249,252,253]. (Credibility Level 5, Recommendation Grade C)

• It is recommended to perform quantitative Herpes simplex virus types 1 and 2 DNA detection by PCR in blood, qualitative Herpes simplex virus types 1 and 2 DNA detection by PCR in oropharyngeal swabs, and qualitative Herpes simplex virus types 1 and 2 DNA detection by PCR in urine in all patients to identify/exclude active herpesvirus infection as a triggering factor for sHLH [1,3,32,115–117,123,124,249,252,253,262,263]. (Credibility Level 4, Recommendation Grade C)

• It is recommended to determine class M and G antibodies (IgM, IgG) to Cytomegalovirus in the blood of all patients to detect/rule out active cytomegalovirus infection as a triggering factor for sHLH [1,32,124,125,237,238]. (LeveL of Evidence (LE) 5, Grade of Recommendation (GR) C)

• It is recommended to determine class M and G antibodies (IgM, IgG) to Epstein-Barr virus in the blood of all patients to detect/rule out active Epstein-Barr virus infection as a triggering factor for sHLH [112,113,121,237,238,252,253,264]. (LE 4, GR C)

• It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus in the blood of all patients to detect/rule out active Epstein-Barr virus infection as a triggering factor for sHLH [112,113,121,237,238,252,253,264]. (LE 4, GR C)

• It is recommended to determine class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus in the blood of all patients to detect/rule out active Epstein-Barr virus infection as a triggering factor for sHLH [112,113,121,237,238,252,253,264]. (LE 4, GR C)

• It is recommended to determine antibodies to Herpes simplex virus in the blood of all patients to detect/rule out active herpetic infection as a triggering factor for sHLH [32,123,130,237,238,251,252,265]. (LE 4, GR C)

• It is recommended to perform a microbiological (culture) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms using automated seeding with determination of microorganism susceptibility to antimicrobial chemotherapeutic agents when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography to identify the etiological factor of lung lesion [237,238,266,267]. (LE 4, GR C)

• It is recommended to determine Epstein-Barr virus DNA in sputum and bronchoalveolar lavage fluid by PCR when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography to detect/rule out active Epstein-Barr virus infection as a triggering factor for sHLH [237,238,266–269]. (LE 4, GR C)

• It is recommended to determine Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography to detect/rule out active cytomegalovirus infection as a triggering factor for sHLH [237,238,266–269]. (LE 4, GR C)

• It is recommended to perform quantitative determination of Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, and bronchoalveolar lavage fluid by PCR when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography to detect/rule out active pneumocystis infection as a triggering factor for sHLH [119,238,252,270–276]. (LE 4, GR C)

• It is recommended to determine class M and G antibodies to Pneumocystis jirovecii in the blood when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography to detect/rule out active pneumocystis infection as a triggering factor for sHLH [238,249,252,272,277,278]. (LE 5, GR C)

• It is recommended to perform a microbiological (culture) examination of bronchoalveolar lavage fluid for Pneumocystis carinii cysts when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography to detect/rule out active pneumocystis infection as a triggering factor for sHLH [112,237,238,252,270–273,275,276,279,280]. (LE 4, GR C)

• It is recommended to perform a microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeasts and molds) when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography to detect/rule out mycosis as a triggering factor for sHLH [237,252,266,267,270,281,282]. (LE 4, GR C)

• It is recommended to determine mannan antigen of Candida albicans and galactomannan antigen of Aspergillus spp. in blood serum by enzyme-linked immunosorbent assay (ELISA) when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography to detect/rule out aspergillosis as a triggering factor for sHLH [252,266,267,270,281,282]. (LE 4, GR C)

• It is recommended to determine mannan antigen of Candida albicans and galactomannan antigen of Aspergillus spp. in bronchoalveolar lavage fluid by enzyme-linked immunosorbent assay (ELISA) when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography to detect/rule out aspergillosis as a triggering factor for sHLH [252,266,267,270,281,282]. (LE 4, GR C)

• It is recommended to measure blood procalcitonin levels in all patients to rule out sepsis [150,150,153,156,237,238]. (LE 3, GR C)

Comments: an elevated procalcitonin level should raise suspicion of a superimposed infection and the development of sepsis.

Comments: tubular necrosis – the predominant form of renal injury in acute kidney injury associated with sHLH (sHLH-AKI). However, histopathological changes may also include interstitial inflammation, glomerular abnormalities, 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 casts.

2.2.3 Instrumental diagnostic tests

• It is recommended to perform a comprehensive ultrasound examination (ultrasound) of internal organs (including a comprehensive abdominal ultrasound and renal ultrasound) in all patients to detect kidney damage, hepatosplenomegaly, and intra-abdominal lymphadenopathy [1,3,32,237,238,284,285]. (LE 4, GR C)

• It is recommended to perform echocardiography in all patients to assess cardiac status [1,3,32,235–238,240]. (LE 4, GR C)

• It is recommended to perform electrocardiography in all patients to evaluate cardiac function [1,3,32,235–238,286]. (LE 5, GR C)

• It is recommended to perform computed tomography of the chest with or without anesthesia support (including early postoperative management) in all patients to detect/rule out lung involvement [1,3,32,235–238,284]. (LE 4, GR C)

Comments: MAS may be complicated by hemorrhagic alveolitis, alveolar and interstitial pulmonary edema of the acute respiratory distress syndrome (ARDS) type; pneumonia (focal, lobar, interstitial, polysegmental) may also be detected.

Comments: sHLH may manifest with ischemic/hemorrhagic strokes, well-defined demyelinating lesions, and posterior reversible encephalopathy syndrome (PRES).

• It is recommended to perform magnetic resonance imaging of the abdominal cavity, retroperitoneal space, and pelvic organs with or without anesthesia support (including early postoperative management) in the event of multiple organ dysfunction in all patients to detect organomegaly, abdominal lesions, intra-abdominal lymphadenopathy, renal involvement, and free fluid in the abdominal and pelvic cavities [1,3,32,235–238,288]. (LE 5, GR C)

• It is recommended to obtain a bone marrow cytologic specimen via puncture with anesthesia support (including early postoperative management) and a bone marrow histologic specimen, accompanied by cytologic examination of the bone marrow smear (myelogram) and pathomorphological examination of the bone marrow biopsy (surgical) specimen in all patients to identify differentiated macrophages phagocytosing hematopoietic cells [1,3,32,235–238,289,290]. (LE 4, GR C)

Comments: in severe sHMA, bone marrow aplasia may develop.

2.2.4 Other diagnostic procedures

Comments: 30–35% of patients develop symptoms of central nervous system involvement; seizures, meningism, depressed level of consciousness, cranial nerve palsy, psychomotor agitation, ataxia, hypotonia, irritability.

In half of the patients with neuropsychiatric symptoms, cerebrospinal fluid analysis reveals pleocytosis, hyperproteinorachia (elevated CSF protein), and hemophagocytic cells.

Peripheral neuropathy and marked generalized weakness, disproportionate to the degree of anemia, are also encountered.

Comments: prior to all procedures requiring anesthesia/sedation, an examination (consultation) by an anesthesiologist-reanimatologist is required.

• It is recommended to perform an initial examination (consultation) by an anesthesiologist-resuscitologist for patients in serious/critical condition in order to decide on transfer to the intensive care unit [60,61,218–220]. (Credibility Level 5, Recommendation Grade C)

• It is recommended to perform 24-hour monitoring by an anesthesiologist-resuscitologist for patients with pancytopenia, single-organ or multiple-organ failure, or CNS involvement in order to provide care in an intensive care unit setting [60,61,218–220]. (Credibility Level 5, Recommendation Grade C)

• It is recommended to perform an initial appointment (examination, consultation) by an ophthalmologist for patients with hemorrhagic syndrome in order to assess the state of the media and membranes of the eye, optic nerve, retina, and fundus [1,3,32,235–238,291–293]. (Credibility Level 4, Recommendation Grade C)

Comments: patients with MAS may exhibit retinal hemorrhages, optic neuritis, and uveal infiltration.

2.2.5 Criteria for diagnosing "Secondary hemophagocytic lymphohistiocytosis".

A. Ravelli et al. criteria[236]:

Serum ferritin concentration >684 ng/ml combined with a febrile fever and 2 of the following:

- blood platelet count ≤180×10⁹/L;

- serum AST concentration >48 IU/L;

- serum triglyceride concentration >1.75 mmol/L;

- blood fibrinogen concentration ≤3.60 g/L.

2.2.6. Personalized diagnostic algorithm for secondary hemophagocytic lymphohistiocytosis in patients with juvenile arthritis

All patients with a confirmed diagnosis of juvenile arthritis in the presence of febrile fever require [294]:

Assessment of clinical parameters:

- fever, rash, hepatosplenomegaly, lymphadenopathy, myalgia, hemorrhagic syndrome, central nervous system involvement (seizures, paresthesia, confusion, cranial or peripheral neuropathy), renal, pulmonary, and cardiac involvement.

Assessment of laboratory test results:

- 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, PCT, total protein and serum albumin, blood electrolyte composition (sodium, potassium, chlorides, iron), glomerular filtration rate (with increasing azotemia), blood clotting capability (Quick's prothrombin, thrombin time, prothrombin time, INR, aPTT, D-dimer, fibrinogen, fibrin monomer, von Willebrand factor, protein S, protein C);

Assessment of imaging and diagnostic test results:

- Instrumental:

- ECG, echocardiography, ultrasound of the abdominal organs, kidneys (comprehensive), chest CT, abdominal MRI, brain MRI; microbiological: blood for sterility, urine, swabs from the tonsils and the posterior pharyngeal wall, feces for aerobic and facultatively anaerobic opportunistic microorganisms with determination of microorganism susceptibility to antimicrobial chemotherapeutic agents;

- molecular biological: screening for viruses of the Herpesviridae family (cytomegalovirus, Epstein-Barr virus, herpes simplex virus types 1 and 2) (list of included tests – see corresponding section)

After analyzing the above-described clinical data and test results, it is necessary to verify the diagnosis of sHLH 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 juvenile arthritis with hemophagocytic lymphohistiocytosis (see section 3.1.2).

Monitoring of early markers of sHLH development [294]:

All patients with juvenile arthritis need monitoring of early markers of sHLH development:

Early clinical markers of secondary HPS:

- Lymphadenopathy

Early instrumental markers of secondary HPS:

- Decreased blood red blood cell count <4.34 million/µl

- Decrease in blood platelet count <208 thousand/µL

- Decreased blood chloride concentration <101.9 mmol/l

- Increase in serum LDH activity >412 IU/L

If early markers of MAS development are identified, immunosuppressive therapy must be initiated in accordance with the treatment algorithm for systemic-onset juvenile idiopathic arthritis with hemophagocytic syndrome (see section 3.1.2).

2.3. Examination of patients with a confirmed diagnosis of juvenile arthritis in the active disease stage for the purpose of prescribing/adjusting therapy

Complaints and anamnesis (see section 2.1)

Physical examination (see section 2.2)

2.3.1 Laboratory diagnostic tests

Comments: in the majority of patients with oligoarthritis, complete blood count parameters are generally within reference ranges; in some cases, an increase in ESR is noted. In patients with polyarthritis or juvenile ankylosing spondylitis, moderate leukocytosis and elevated ESR may be observed; in dry polyarthritis, complete blood count parameters are within reference ranges.

In sHLH, leukopenia and/or thrombocytopenia, and/or erythropenia, and a possible decrease in ESR may occur. Normal leukocyte and platelet counts in patients with fever may indicate ongoing sHLH. Single-, double-, or triple-line cytopenia may also be an undesirable manifestation of treatment with NSAIDs and/or methotrexate**, and/or biologic DMARDs.

Comments: changes in the hemostatic system resembling hypercoagulation can be observed in patients with seropositive polyarthritis and vasculitis, or juvenile ankylosing spondylitis, and resembling hyper-/hypocoagulation during the development of sHLH.

• It is recommended to test for blood heparin level in patients with signs of vasculitis before prescribing/adjusting anticoagulant therapy in order to evaluate its effectiveness [3,32,46–48,50,51,56,244,245]. (Credibility Level 5, Recommendation Grade C)

• It is recommended to perform thromboelastography in patients with signs of vasculitis before prescribing/adjusting therapy in order to develop an anticoagulant therapy strategy [46,47,50,51,56–59,246,247]. (Credibility Level 4, Recommendation Grade C)

• It is recommended to test for 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, lactate dehydrogenase activity in the blood, aspartate aminotransferase activity in the blood, alanine aminotransferase activity in the blood, gamma-glutamyltransferase activity in the blood, alkaline phosphatase activity in the blood, serum iron, creatine kinase activity in the blood, pancreatic amylase activity in the blood, and lipase activity in the blood in all patients before prescribing/adjusting antirheumatic therapy in order to assess electrolyte composition, liver, kidney, and pancreatic function, and to detect markers of HLH [1,3,4,32,42,44,64–67]. (Credibility Level 5, Recommendation Grade C)

Comments: elevated triglycerides, ferritin, LDH, AST, and ALT indicate the development of sHLH; elevated creatinine and/or urea, and/or ALT, AST, and/or amylase, and/or GGT, and/or ALP, and/or K, and/or total bilirubin, and/or glucose, and/or cholesterol, and triglycerides can be an undesirable manifestation of treatment with NSAIDs and/or immunosuppressants, and/or biologic DMARDs, and/or glucocorticoids.

Some patients show a decrease in serum iron levels, reflecting the presence of anemia of chronic disease.

• It is recommended to determine the main AB0 blood groups, sub-groups and other minor blood groups (A-1, A-2, D, Cc, E, Kell, Duffy), and to determine the Rh blood group D antigen (Rhesus factor) in all patients prior to invasive procedures (esophagogastroduodenoscopy, colonoscopy with biopsy, kidney biopsy) or blood transfusions [1,3,60–63]. (Reliability Level of Evidence: 5, Recommendation Strength: C)

• It is recommended to measure the blood procalcitonin level in patients with fever prior to prescribing or adjusting antirheumatic therapy in order to rule out a septic process [32,150–153]. (Reliability Level of Evidence: 3, Recommendation Strength: C)

Comments: procalcitonin levels rise during bacterial infection and acute inflammatory response.

• It is recommended to measure the serum C-reactive protein level in all patients prior to prescribing or adjusting antirheumatic therapy in order to assess disease activity [1,3,4,43,44,65,68,69]. (Reliability Level of Evidence: 3, Recommendation Strength: C)

• It is recommended to determine anti-streptolysin-O in the blood serum of all patients prior to prescribing or adjusting antirheumatic therapy in order to detect/rule out group A $\beta$-hemolytic streptococcus infection [1,3,4,44,65,72,73]. (Reliability Level of Evidence: 3, Recommendation Strength: C)

Comments: if the serum anti-streptolysin-O level is elevated, an otorhinolaryngologist consultation is required to determine the need for further examination to rule out chronic foci of ENT infection.

Comments: an elevated level of antinuclear antibodies (ANA) is typically observed in patients at risk for developing uveitis or already presenting with uveitis, as well as in patients with seropositive polyarthritis; elevated levels of antinuclear antibodies (ANA) and anti-double-stranded DNA antibodies are observed in patients receiving TNF-alpha inhibitors as a manifestation of a lupus-like reaction.

• It is recommended to perform lymphocyte subset analysis in all patients receiving #rituximab** (L01XC), as well as in patients with a high frequency of viral and purulent bacterial infections, including opportunistic infections, prior to prescribing or adjusting antirheumatic therapy in order to rule out an immunodeficiency state developed during immunosuppressive therapy and to address the management strategy [3,32,83–85,295–297]. (Reliability Level of Evidence: 4, Recommendation Strength: C)

• It is recommended to perform a focal tuberculin skin test (Mantoux test, recombinant tuberculosis allergen test in standard dilution**) and to test blood interferon-gamma in response to Mycobacterium tuberculosis complex antigens in all patients prior to prescribing or adjusting antirheumatic therapy in order to rule out Mycobacterium tuberculosis infection [3,32,86–94,212,298]. (Reliability Level of Evidence: 4, Recommendation Strength: C)

• It is recommended to determine blood antibodies to Salmonella enterica, antibodies to Salmonella typhi, IgM and IgG antibodies to Yersinia pseudotuberculosis, and antibodies to Yersinia enterocolitica serovars in all patients prior to prescribing or adjusting antirheumatic therapy in order to rule out enteric bacterial infection and to decide on etiotropic therapy [1,3,32,95,96]. (Reliability Level of Evidence: 5, Recommendation Strength: C)

• It is recommended to determine blood IgM and IgG antibodies to Shigella boydii, IgM and IgG antibodies to Shigella dysenteriae, IgM and IgG antibodies to Shigella sonnei, and IgM and IgG antibodies to Shigella flexneri in all patients prior to prescribing or adjusting antirheumatic therapy in order to rule out enteric bacterial infection and to decide on etiotropic therapy [1,3,32,95,96]. (Reliability Level of Evidence: 5, Recommendation Strength: C)

• It is recommended to determine blood 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 all patients prior to prescribing or adjusting antirheumatic therapy in order to confirm or rule out active chlamydial and/or mycoplasmal infection and to decide on etiotropic therapy [1,3,32,81,95–97]. (Reliability Level of Evidence: 5, Recommendation Strength: C)

• It is recommended to perform quantitative Epstein-Barr virus DNA detection by PCR in peripheral and cord blood, qualitative Epstein-Barr virus DNA detection by PCR in oropharyngeal swabs, and qualitative Epstein-Barr virus DNA detection by PCR in urine in patients with clinical manifestations of Epstein-Barr virus infection and/or with fever, and/or receiving #rituximab**, prior to prescribing or adjusting antirheumatic therapy, in order to laboratory confirm or rule out active Epstein-Barr virus infection and to decide on etiotropic therapy [1,3,32,81,113–118,299]. (Reliability Level of Evidence: 5, Recommendation Strength: C)

• It is recommended to perform quantitative Cytomegalovirus DNA detection by PCR in peripheral and cord blood, qualitative Cytomegalovirus DNA detection by PCR in oropharyngeal swabs, and qualitative Cytomegalovirus DNA detection by PCR in urine in patients with clinical manifestations of cytomegalovirus infection and/or with fever, and/or receiving #rituximab**, prior to prescribing or adjusting antirheumatic therapy, in order to laboratory confirm or rule out active cytomegalovirus infection and to decide on etiotropic therapy [1,3,32,115,116,119–122]. (Reliability Level of Evidence: 4, Recommendation Strength: C)

• It is recommended to perform quantitative Herpes simplex virus types 1 and 2 DNA detection by PCR in blood, qualitative Herpes simplex virus types 1 and 2 DNA detection by PCR in oropharyngeal swabs, and qualitative Herpes simplex virus types 1 and 2 DNA detection by PCR in urine in patients with clinical manifestations of herpetic infection and/or with fever, and/or receiving #rituximab**, prior to prescribing or adjusting antirheumatic therapy, in order to laboratory confirm or rule out active herpetic infection and to decide on etiotropic therapy [1,3,32,115,116,119]. (Reliability Level of Evidence: 4, Recommendation Strength: C)

• It is recommended to determine blood antibodies to Herpes simplex virus in patients with clinical signs of herpetic infection, and/or with fever, and/or receiving #rituximab**, in order to confirm or rule out active herpetic infection and to decide on etiotropic therapy [3,32,113,115,119,126–130]. (Reliability Level of Evidence: 4, Recommendation Strength: C)

• It is recommended to determine blood IgM and IgG antibodies to Cytomegalovirus in patients with clinical manifestations of cytomegalovirus infection and/or with fever, and/or receiving #rituximab**, prior to prescribing or adjusting antirheumatic therapy in order to confirm or rule out active cytomegalovirus infection and to decide on etiotropic therapy [1,112,115,121,122,124,125]. (Reliability Level of Evidence: 4, Recommendation Strength: C)

• It is recommended to determine blood IgM and IgG antibodies to Epstein-Barr virus in patients with clinical manifestations of Epstein-Barr virus infection and/or with fever, and/or receiving #rituximab**, prior to prescribing or adjusting antirheumatic therapy in order to rule out active Epstein-Barr virus infection and to decide on etiotropic therapy [3,32,112,113,115,124,126]. (Reliability Level of Evidence: 4, Recommendation Strength: C)

• It is recommended to determine blood antibodies to the Epstein-Barr virus capsid antigen (VCA) in patients with clinical manifestations of Epstein-Barr virus infection and/or with fever, and/or receiving #rituximab**, prior to prescribing or adjusting antirheumatic therapy in order to rule out active Epstein-Barr virus infection and to decide on etiotropic therapy [3,32,112,113,115,124,126]. (Reliability Level of Evidence: 5, Recommendation Strength: C)

• It is recommended to determine class G antibodies (IgG) to early antigens (EA) of Epstein-Barr virus in the blood of patients with clinical manifestations of Epstein-Barr virus infection and/or with fever, and/or receiving #rituximab**, before prescribing/adjusting antirheumatic therapy in order to exclude active Epstein-Barr virus infection and address the issue of etiotropic therapy [3,32,112,113,115,124,126]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform a microbiological (culture) examination of bronchoalveolar lavage fluid for Pneumocystis cysts (Pneumocystis carinii) in all patients with interstitial, focal, and/or infiltrative changes in the lungs according to computed tomography of the chest organs in order to confirm/exclude Pneumocystis pneumonia and address the issue of etiotropic therapy [276,277,279,280,300–303]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to perform quantitative PCR detection of Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, and bronchoalveolar lavage fluid in all patients with interstitial, focal, and/or infiltrative changes in the lungs according to computed tomography of the chest organs in order to confirm/exclude Pneumocystis pneumonia and address the issue of etiotropic therapy [276–278,300–304]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to determine class M and G antibodies to Pneumocystis jirovecii in the blood when interstitial, focal, and/or infiltrative changes in the lungs are detected by computed tomography of the chest organs in order to confirm/exclude Pneumocystis pneumonia and address the issue of etiotropic therapy [276,277,279,280,300–303]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to detect Mycobacterium tuberculosis complex DNA (M. tuberculosis, M. bovis, M. bovis BCG) with species differentiation in sputum, bronchoalveolar lavage fluid, or bronchial washings using PCR in all patients with interstitial, focal, and/or infiltrative lung changes according to computed tomography of the chest organs in order to identify the etiology of pneumonia and address the issue of etiotropic therapy [124,267,270,305–310]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to detect Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid using PCR in all patients with interstitial, focal, and/or infiltrative lung changes according to computed tomography of the chest organs in order to identify the etiology of pneumonia and address the issue of etiotropic therapy [256–259]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to detect Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid using PCR in all patients with interstitial, focal, and/or infiltrative lung changes according to computed tomography of the chest organs in order to identify the etiology of pneumonia and address the issue of etiotropic therapy [125,311,312]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform a microbiological (culture) examination of sputum for fungi (yeast and mold) in all patients with interstitial, focal, and/or infiltrative lung changes according to computed tomography of the chest organs in order to identify the etiology of pneumonia and address the issue of etiotropic therapy [124,270,271,273,300,313,314]. (Level of Evidence 3, Grade of Recommendation B)

• It is recommended to perform a microbiological (culture) examination of bronchoalveolar lavage fluid for fungi (yeast and mold) in all patients with interstitial, focal, and/or infiltrative lung changes according to computed tomography of the chest organs in order to identify the etiology of pneumonia and address the issue of etiotropic therapy [124,270,271,273,300,313,314]. (Level of Evidence 3, Grade of Recommendation B)

• It is recommended to perform a microbiological (culture) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms in all patients with interstitial, focal, and/or infiltrative lung changes according to computed tomography of the chest organs in order to identify the etiology of pneumonia and address the issue of etiotropic therapy [124,270,271,273,300,313,314]. (Level of Evidence 3, Grade of Recommendation B)

• It is recommended to determine antibodies to Aspergillus spp. in the blood of all patients with interstitial, focal, and/or infiltrative lung changes according to computed tomography of the chest organs in order to identify the etiology of pneumonia and address the issue of etiotropic therapy. (Level of Evidence 3, Grade of Recommendation B)

• It is recommended to determine mannan and galactomannan in lavage fluid and blood in all patients with interstitial, focal, and/or infiltrative lung changes according to computed tomography of the chest organs in order to identify the etiology of pneumonia and address the issue of etiotropic therapy [124,270,271,273,300,313,314]. (Level of Evidence 3, Grade of Recommendation B)

• 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 by computed tomography of the chest organs in order to identify the etiology of pneumonia and address the issue of etiotropic therapy [124,270,271,273,300,313,314]. (Level of Evidence 4, Grade of Recommendation 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 by computed tomography of the chest organs in order to identify the etiology of pneumonia and address the issue of etiotropic therapy [124,270,271,273,300,313,314]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to perform a general (clinical) urinalysis and urine test according to Nechiporenko in all patients before prescribing/adjusting antirheumatic therapy in order to assess the functional state of the urinary system [1,3,4,32,65,159]. (Level of Evidence 5, Grade of Recommendation C)

Comments: micro- and macrohematuria may result from the toxic effect of NSAIDs and methotrexate** on the kidneys; proteinuria may be a manifestation of renal amyloidosis.

• It is recommended to perform a microbiological (culture) examination of mucus from the tonsils and posterior pharyngeal wall for aerobic and facultatively anaerobic microorganisms in all patients before prescribing/adjusting antirheumatic therapy in order to rule out nasopharyngeal contamination by aerobic and facultatively anaerobic microorganisms [1,3,32,81,95,157,158]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform a microbiological (culture) examination of blood for sterility, and a microbiological (culture) examination of urine for aerobic and facultatively anaerobic opportunistic microorganisms in patients with febrile and hectic fever before prescribing/adjusting antirheumatic therapy in order to rule out sepsis [1,3,32,81,150,151,154–156]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to determine the fecal calprotectin level in patients with clinical manifestations of inflammatory bowel diseases before prescribing/adjusting antirheumatic therapy to determine further management and diagnostic tactics [3,32,160–162]. (Level of Evidence 4, Grade of Recommendation C)

2.3.2 Instrumental diagnostic tests

Comments: in active juvenile arthritis, enlargement and parenchymal changes of the liver and spleen, as well as lymphadenopathy, may be detected. Pathological changes in the kidneys are generally not detected in juvenile arthritis. With the development of secondary amyloidosis, pathological changes in the abdominal cavity and kidneys typical of this complication may be observed.

Comments: myocarditis is characterized by left ventricular dilatation, decreased left ventricular ejection fraction, hypokinesia of the posterior left ventricular wall and/or interventricular septum, signs of relative mitral, aortic, and/or tricuspid valve regurgitation, and increased pulmonary artery pressure. The pericardium, endocardium, and valve apparatus are typically unaffected in juvenile arthritis.

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 Holter ECG monitoring in patients with arrhythmias or pathological electrocardiographic changes prior to prescribing or adjusting antirheumatic therapy in order to develop an individualized cardiotropic therapy program [1,3,32,34,315–317]. (LEL 5, GR C)

• It is recommended to perform 24-hour ambulatory blood pressure monitoring in patients with arterial hypertension prior to prescribing or adjusting antirheumatic therapy in order to detect blood pressure abnormalities and develop an individualized antihypertensive therapy program [1,3,32,34,315–317]. (LEL 5, GR C)

• It is recommended to perform joint ultrasound in all patients with active arthritis to assess the condition of the synovial membrane and cartilage, and to detect joint effusion [1,3,32,42,163–166]. (LEL 5, GR C)

Comments: active arthritis is characterized by an increase in synovial fluid volume, thickening (hypertrophy) of the synovial membrane, cartilage fibrillation, and cartilage erosions.

Comments: findings may include: osteoporosis, destructive changes in bone structures, joint space narrowing, the integrity of the articular surfaces of the bones forming the joint, the presence of erosions, joint surface saucerization, cysts, areas of bone tissue necrosis, subluxations, fractures, osteophytes, calcifications, etc. Progression of destructive changes in joint cartilage and bone tissue during treatment with targeted synthetic and/or biologic DMARDs combined with (or without) an immunosuppressant is an indication for therapy adjustment.

• It is recommended to perform contrast-enhanced magnetic resonance imaging of the joints (single joint) with or without anesthetic support (including early postoperative management) in all patients with active arthritis prior to prescribing or adjusting antirheumatic therapy to determine the degree of synovial membrane proliferation (pannus), cartilage damage, bone marrow edema, early manifestations of avascular necrosis, and Baker's cysts [1,3,32,166,170,318,319]. (LEL 1, GR A)

• It is recommended to perform magnetic resonance imaging of the spine (single segment), computed tomography of the spine (single segment), or computed tomography of the pelvic bones with or without anesthetic support (including early postoperative management) in patients with complaints of back pain and enthesopathy (based on physical examination) when juvenile ankylosing spondylitis is suspected, prior to prescribing or adjusting antirheumatic therapy in order to detect or rule out involvement of the spine and sacroiliac joints [1,3,24,32,45,171–178] (LEL 5, GR C)

• It is recommended to perform contrast-enhanced magnetic resonance imaging of the brain with or without anesthetic support (including early postoperative management) in patients with neurological symptoms in order to detect brain involvement [1,3,32,307,320–324]. (LEL 4, GR C)

• It is recommended to perform intravenous contrast-enhanced magnetic resonance imaging of the abdominal cavity, retroperitoneal space, and pelvic organs with or without anesthetic support (including early postoperative management) in patients with a severe general condition, fever, and a discrepancy between the general condition and the severity of joint involvement, prior to prescribing or adjusting antirheumatic therapy in order to detect polyserositis, as well as involvement of the abdominal organs, retroperitoneal space, and pelvis [1,3,32,41,91,168,199,202,203,210]. (LEL 5, GR C)

• It is recommended to perform intravenous bolus contrast-enhanced computed tomography of the abdominal cavity and retroperitoneal space with or without anesthetic support (including early postoperative management) in the presence of contraindications to MRI in patients with a severe general condition, fever, and a discrepancy between the general condition and joint involvement, prior to prescribing or adjusting antirheumatic therapy in order to detect involvement of the abdominal organs and retroperitoneal space [1,3,32,168,204,205,325]. (LEL 5, GR C)

• It is recommended to perform esophagogastroduodenoscopy with or without anesthetic support (including early postoperative management) in all patients prior to prescribing or adjusting antirheumatic therapy in order to rule out inflammatory diseases of the upper gastrointestinal tract associated with the underlying disease and/or Helicobacter pylori and/or the use of NSAIDs and/or glucocorticoids [3,32,160,161,184–191]. (LEL 4, GR C)

• It is recommended to perform endoscopic gastric/duodenal biopsy with pathomorphological examination of the gastric biopsy (surgical) material and microbiological (culture) examination of gastric mucosal biopsy specimens for Helicobacter pylori in patients with inflammatory, erosive, and/or ulcerative mucosal changes prior to prescribing or adjusting antirheumatic therapy in order to rule out upper gastrointestinal inflammatory diseases associated with Helicobacter pylori and/or the use of NSAIDs and/or glucocorticoids [3,32,160,161,184–188,190–193,326]. (LEL 4, GR C)

• It is recommended to perform chest computed tomography with or without anesthetic support (including early postoperative management) in all patients prior to prescribing or adjusting antirheumatic therapy, as well as in patients receiving immunosuppressants and/or biologic DMARDs combined with (or without) glucocorticoids, to rule out focal, lobar, or interstitial pneumonia and pulmonary tuberculosis [1,3,32,41,86,90–92,168,168,199–201,212]. (LEL 4, GR C)

Comments: interstitial pneumonia most commonly develops during treatment with ^#rituximab**, less frequently with tocilizumab**, and extremely rarely with TNF-alpha inhibitors. Focal and lobar pneumonia develop during therapy with tocilizumab** and TNF-alpha inhibitors.

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.

Focal or lobar pneumonia developing during tocilizumab** therapy is typically characterized by an asymptomatic course.

• It is recommended to perform bronchoscopy with anesthetic support (including early postoperative management) in patients with pulmonary involvement prior to prescribing or adjusting antirheumatic therapy in order to assess the condition of the bronchial mucosal membrane and obtain bronchoalveolar lavage fluid for further examination [124,270,271,273,300,313,314]. (LEL 3, GR B)

• It is recommended to perform X-ray densitometry in patients currently or previously treated with glucocorticoids, prior to prescribing or adjusting antirheumatic therapy in order to detect osteopenia or osteoporosis and develop a therapeutic management plan [3,32,327,328]. (LEL 5, GR C)

• It is recommended to perform respiratory flowmetry in all patients with lung damage before prescribing or adjusting antirheumatic therapy to assess the functional state of the bronchopulmonary system. (LoE 5, GoR C)

2.3.3 Other diagnostic procedures

Specialist consultations aimed at diagnosing and treating manifestations of the underlying disease, comorbidities, and/or complications.

• It is recommended to perform an initial consultation (examination, assessment) by an otorhinolaryngologist in all patients before prescribing or adjusting therapy to identify foci of chronic infection in ENT organs and resolve the issue of sanitation [1,3,32,95,329]. (LoE 5, GoR C)

• It is recommended to perform an initial consultation (examination, assessment) by a pediatric dentist in all patients before prescribing or adjusting antirheumatic therapy to determine the condition of the oral cavity and the need for its sanitation [1,3,4,32,215,330,331]. (LoE 5, GoR C)

• It is recommended to perform an initial consultation (examination, assessment) by an ophthalmologist with mandatory ocular biomicroscopy in all patients before prescribing or adjusting antirheumatic therapy to rule out uveitis, as well as in patients receiving GCs to rule out complicated cataracts [1,3,15,32,332,333]. (LoE 5, GoR C)

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

• It is recommended to perform an initial consultation (examination, assessment) by a pediatric cardiologist in patients with cardiac disorders and/or arterial hypertension to address the issue of cardiotropic and/or antihypertensive therapy before prescribing or adjusting antirheumatic therapy [1,3,32,34,334]. (LoE 5, GoR C)

• It is recommended to perform an initial consultation (examination, assessment) by a phthisiatrician before prescribing or adjusting antirheumatic therapy in patients with a positive focal tuberculin test and/or intradermal test with tuberculosis allergen, and/or elevated blood interferon-gamma levels to Mycobacterium tuberculosis complex antigens, and/or focal or infiltrative lung changes to address the issue of chemoprophylaxis or anti-tuberculosis chemotherapy [3,32,86,88,90–92,212,213]. (LoE 5, GoR C)

• It is recommended to perform an initial consultation (examination, assessment) by a pediatric endocrinologist in patients with comorbid endocrinological pathology, including steroid diabetes, to address the issue of therapy management [1,3,32,327,328,335,336]. (LoE 5, GoR C)

• It is recommended to perform an initial consultation (testing, assessment) by a medical psychologist for patients aged 1 year and older and their parents to harmonize the development of the child's personality in the context of a severe chronic disease and optimize parent-child relationships; to increase treatment adherence and cooperation with the physician and medical staff to achieve disease remission; to achieve psychological social adaptation; and to develop an individual psychological rehabilitation program for the patient and their parents [32,221–227,337–339]. (LoE 2, GoR A)

• It is recommended to perform an initial consultation (examination, assessment) by a neurologist in patients with neurological symptoms, psychomotor developmental delay, or psychotic reactions to address the issue of therapy management [1,3,4,32,216]. (LoE 5, GoR C)

• It is recommended to perform an initial consultation (examination, assessment) by a dietitian in patients with weight loss, amyotrophy, osteopenia/osteoporosis, constitutional obesity, Cushing's syndrome, and steroid diabetes to develop an individual dietary nutrition program [1,3,32,340,341]. (LoE 5, GoR C)

• It is recommended to perform an initial consultation (examination, assessment) by an orthopedic traumatologist in patients with joint functional insufficiency, impaired bone longitudinal growth, subluxations, back pain, as well as to address the issue of reconstructive surgery and joint replacement [1,3,32,214]. (LoE 5, GoR C)

• It is recommended to perform an initial consultation (examination) by an anesthesiologist-resuscitologist in all patients scheduled for examinations under anesthesia to assess their condition [60,61,218–220]. (LoE 5, GoR C)

• It is recommended to perform an initial consultation (examination) by an anesthesiologist-resuscitologist in all patients in critical condition to address the issue of transfer to the intensive care unit [60,61,218–220]. (LoE 5, GoR C)

• It is recommended to provide 24-hour monitoring by an anesthesiologist-resuscitologist for all patients in critical condition (single/multiple organ failure, MAS) to provide care in the intensive care unit setting [60,61,218–220]. (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 JIA diagnosis in a rheumatology inpatient setting to monitor the safety and efficacy of treatment [1,3,32]. (LoE 5, GoR C)

• It is recommended to switch to another selective immunosuppressant (JAK inhibitor) and/or generic drug exclusively for medical indications; automatic switching is not recommended in order to maintain disease remission and prevent adverse events [342–344]. (LoE 5, GoR C)

• It is recommended to switch to another biological disease-modifying antirheumatic drug (bDMARD) and/or biosimilar exclusively for medical indications; automatic switching is not recommended in order to maintain disease remission, prevent the formation of neutralizing antibodies, and avoid adverse events [342–344]. (LoE 5, GoR C)

Comments: currently, biosimilars of tumor necrosis factor alpha (TNF-alpha) inhibitors (anti-TNF) as well as generics of JAK inhibitors are registered, which are structurally equivalent. Some of these drugs have demonstrated efficacy similar to original drugs in clinical trials in adult patients [345]. However, clinical trials of biosimilars and generics of immunosuppressants and selective immunosuppressants have not been conducted in the pediatric population with juvenile arthritis.

The original immunosuppressant and/or selective immunosuppressant, and/or biologic DMARD cannot be automatically replaced with a generic or biosimilar. Drug substitution may only be carried out based on a consensus of the attending physician who initiated therapy with the immunosuppressant and/or selective immunosuppressant, and/or biologic DMARD, after obtaining informed consent from parents and children over 15 years of age.

3.1 Conservative Treatment

3.1.1 Treatment of juvenile polyarthritis (seronegative and seropositive polyarticular juvenile idiopathic arthritis)

• It is recommended to evaluate the efficacy of any medicinal product used for pathogenetic therapy at 3 and 6 months, and then every 6 months of therapy (a drug is considered effective upon achieving a 50% improvement according to ACRpedi criteria at 3 months, or inactive disease status at 6 months, or remission at 12 months according to C. Wallace criteria) (see Appendix 3) [1,3,32,346,347]. (LoE 5, GoR C)

• It is recommended to adjust therapy (switch drugs) until efficacy or minimal/low disease activity is achieved in patients with long-standing disease, regardless of the drug used [1,3,32,346,347]. (LoE 5, GoR C)

• It is recommended to prescribe NSAID monotherapy (M01A) for a duration of no more than 1 month at the diagnostic stage in patients with an unconfirmed JIA diagnosis to achieve an anti-inflammatory effect [1,3,42,348–357]. (LoE 5, GoR C)

• It is recommended to prescribe NSAIDs (M01A) to relieve fever and pain syndrome in patients with an established JIA diagnosis [1,3,42,348–357]. (LoE 5, GoR C)

Comments: the following NSAID administration regimens are used:

— 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 to achieve anti-inflammatory, analgesic, and antipyretic effects [3,32,355,357–364].

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.

#Diclofenac** (M01AB), #nimesulide (M01AX), #meloxicam (M01AC) off-label are prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

• It is not recommended to perform NSAID monotherapy (M01A) lasting more than 1 month in order to minimize side effects of long-term NSAID use [1,3,32]. (LoE 5, GoR C)

• It is not recommended to prescribe glucocorticoids (H02AB) orally and/or intravenously, and/or intra-articularly, and/or immunosuppressants (methotrexate** (L01BA) or #leflunomide** (L04FFAA)), and/or bDMARDs (tocilizumab** (L04AC), or adalimumab** (L04AB), or etanercept** (L04AB), or golimumab** (L04AB), or abatacept** (L04AA24), or #rituximab** (L04AC10)), and/or tofacitinib** (L04AA), or #upadacitinib** (L04AA), or baricitinib** (L04AA) until the complete laboratory and instrumental evaluation is completed, oncological, hemato-oncological, and infectious diseases are ruled out, and the JIA diagnosis is established (see sections 2, 3) [1,3,42,348]. (LoE 5, GoR C)

Comments: the use of glucocorticoids (H02AB), immunosuppressants (methotrexate** (L01BA) or #leflunomide** (L04FFAA)), and/or bDMARDs (tocilizumab** (L04AC), or adalimumab** (L04AB), or etanercept** (L04AB), or golimumab** (L04AB), or abatacept** (LO4AA24), or #rituximab** (L04AC10)) and/or tofacitinib** (L04AA), or ^#upadacitinib** (L04AA), or baricitinib** (L04AA) in oncological and hemato-oncological diseases presenting under the mask of juvenile arthritis will significantly hinder subsequent diagnosis verification, as they have a pronounced immunosuppressive effect and obscure the clinical and morphological presentation of malignant neoplasms.

Comments: if arthritis flares frequently (more often than once every 4 months), intra-articular GC administration is not performed. Indications for intra-articular GC administration are pronounced exudative changes and pain syndrome in the affected joints.

#Betamethasone** (H02AB) and #triamcinolone off-label are prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: pulse therapy with #methylprednisolone** (H02AB) is prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: The subcutaneous route of administration of methotrexate** (L01BA) is preferred due to higher bioavailability.

Methotrexate** (L01BA) is preferably administered using graduated syringes (here and below).

Off-label, #methotrexate** (L01BA) is prescribed by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of treatment efficacy – see Appendices G1-G4

Comments: off-label, #methotrexate** (L01BA) is prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: off-label, #methotrexate** (L01BA) is prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: increasing the dose of methotrexate** (L01BA) is not associated with additional therapeutic benefits.

Comments: the subcutaneous route of administration of methotrexate** (L01BA) is preferred as it provides stable bioavailability.

In case of intolerance to subcutaneous methotrexate** (L01BA), oral methotrexate** (L01BA) tablets are prescribed.

Off-label, methotrexate** (L01BA) is prescribed by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of treatment efficacy – see Appendices G1-G4

Comments: off-label, #folic acid** (B03BB) is prescribed for vital indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comment: #leflunomide** (L04FFAA) is preferably prescribed to adolescent patients with seropositive juvenile arthritis.

• It is recommended to prescribe #leflunomide** (L04FFAA) orally: for children with a body weight < 20 kg – 10 mg daily every other day; for children with a body weight of 20–40 kg – 10 mg daily; for children with a body weight > 40 kg – 20 mg daily in order to maintain/induce disease remission [3,32,42,348,358,385,386]. (LoE 4, GoR C)

• It is recommended to switch to a bDMARD or targeted synthetic immunosuppressant in case of intolerance to methotrexate** (L01BA) or #leflunomide** (L04FFAA) in order to induce/maintain remission [1,42,348,387–393]. (LoE 5, GoR C)

• It is recommended to switch to one of the following drugs:

  - TNF alpha inhibitors (L04AB) [332,387–390,394] (LoE 2, GoR B)

  - tocilizumab** (L04AC) [387,391] (for intravenous tocilizumab – (LoE 2, GoR B), for subcutaneous tocilizumab – (LoE 4, GoR C)

  - tofacitinib** (L04AA) [392] (LoE 2, GoR B)

  - #upadacitinib** (L04AA) [395–402] (LoE 4 GoR C)

  - baricitinib** (L04AA) [614,615] (LoE 2, GoR B)

  - abatacept** (LO4AA24) [387] (LoE 2, GoR B)

  in case of intolerance to methotrexate** (L01BA) or #leflunomide** (L04FFAA) in order to induce/maintain remission.

• It is recommended to prescribe a bDMARD or targeted synthetic immunosuppressant in combination with methotrexate in case of its inefficacy, or #leflunomide in case of its inefficacy, or as monotherapy, or at any stage of treatment in case of persistent/increasing disease activity in order to induce remission [1,42,348,387–393]. (LoE 5, GoR C)

• It is recommended to prescribe one of the following drugs:

  - TNF alpha inhibitors (L04AB) [332,387–390,394] (for regimens using TNF alpha inhibitors in combination with methotrexate** – (LoE 2, GoR B); in combination with #leflunomide** – (LoE 5, GoR C)

  - tocilizumab** (L04AC) [387,391] (for regimens using intravenous tocilizumab** in combination with methotrexate** – (LoE 2, GoR B); in combination with #leflunomide** – (LoE 5, GoR C); for regimens using subcutaneous tocilizumab** in combination with methotrexate** – (LoE 4, GoR C); in combination with #leflunomide** – (LoE 5, GoR C)

  - tofacitinib** (L04AA) [392] (for regimens using #tofacitinib** in combination with methotrexate** – (LoE 2, GoR B); in combination with #leflunomide** – (LoE 5, GoR C)

  - upadacitinib** (L04AA) [395–402] (LoE 5, GoR C)

  - baricitinib** (L04AA) [614,615] (LoE 2, GoR B)

  - abatacept** (LO4AA24) [387] (for regimens using #abatacept** in combination with methotrexate** – (LoE 2, GoR B); in combination with #leflunomide** – (LoE 5, GoR C)

  in combination with methotrexate** (L01BA) in case of its inefficacy, or #leflunomide** (L04FFAA) in case of its inefficacy in order to induce remission.

Comments: criteria for inefficacy are failure to achieve a 50% improvement according to ACRpedi criteria at 3 months, or the inactive disease state at 6 months, or remission at 12 months according to C. Wallace criteria, or at any stage of treatment in case of persistent/increasing disease activity.

Similarly, switching to one of the above-mentioned drugs in combination with methotrexate** (L01BA) or #leflunomide** (L04FFAA), or as monotherapy, is performed if the current drug combination is ineffective.

Monitoring of therapy efficacy – see Appendices G1-G4.

For dosing regimens, see below.

Comments: in case of ineffectiveness of methotrexate** (L01BA) or ineffectiveness of #leflunomide** (L04FFAA), TNF-alpha inhibitors are preferred as first-line bDMARDs.

Monoclonal antibodies to TNF-alpha (adalimumab**, golimumab**) (L04AB) are preferably prescribed in combination with methotrexate** or #leflunomide** to reduce the risk of neutralizing antibodies forming.

For doses and administration schedule of methotrexate** (L01BA) and #leflunomide** (L04FFAA), see above.

Off-label, #adalimumab** (L04AB), #etanercept** (L04AB), and #golimumab** (L04AB) are prescribed for vital indications, by decision of the medical panel, after obtaining informed consent from the parents [348].

The indication for use in children and adolescents with juvenile arthritis aged 2 to 17 years and weighing less than 62.5 kg applies only to the etanercept** medicinal product "lyophilisate for solution for subcutaneous injection". The etanercept** medicinal product "solution for subcutaneous injection" has a contraindication for use in children under 12 years of age and weighing less than 62.5 kg. [408–411]

According to the FAS clarification letter No. TN/109573/21 dated December 22, 2021, and the medical instructions for the medical use of Etanercept** [412]:

the use of the dosage form "solution for subcutaneous injection" instead of "lyophilisate for solution for subcutaneous injection" in children under 12 years of age and body mass less than 62.5 kg is not recognized as acceptable due to differences in the final concentration of solutions and the lack of studies allowing to evaluate the tolerability, efficacy, and pharmacokinetics of the 50 mg/ml solution in children. Thus, the substitution of the dosage form "lyophilisate for solution for subcutaneous injection" in this patient is impossible.

For the treatment of patients with JA, it is advisable to use the adalimumab** medicinal product citrate-free formulation 40 mg/0.4 ml to avoid causing unjustified pain to children, which occurs with the use of the adalimumab** medicinal product citrate formulation 40 mg/0.8 ml [404–407,413].

Considering the pronounced pain syndrome when using the adalimumab** medicinal product citrate formulation 40 mg/0.8 ml, the use of this formulation in pediatric patients is impossible [404–407,413].

Comments: for doses and administration schedule of methotrexate** (L01BA) and #leflunomide** (L04FFAA), see above.

#Tocilizumab** (L04AC) is prescribed for vital indications in children under 2 years of age intravenously or in children under 1 year of age subcutaneously by decision of the medical panel, after obtaining informed consent from the parents [348].

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: for doses and administration schedule of methotrexate** (L01BA) and #leflunomide** (L04FFAA), see above.

#Tofacitinib** (L04AA) is prescribed for vital indications in children aged ≤ 2 years, by decision of the medical panel, after obtaining informed consent from the parents [415].

#Baricitinib** (L04AA) is prescribed for vital indications in children aged ≤ 2 years, by decision of the medical panel, after obtaining informed consent from the parents [614,615].

#Upadacitinib** (L04AA) is prescribed for vital indications, by decision of the medical panel, after obtaining informed consent from the parents and children over 15 years of age [392,395,397–402].

Comments: abatacept** (LO4AA24) is preferably used as a first-line bDMARD for the treatment of seropositive polyarthritis.

For doses and administration schedule of methotrexate** (L01BA) and #leflunomide** (L04FFAA), see above.

#Abatacept** (LO4AA24) in children under 6 years of age is prescribed for vital indications by decision of the medical panel, after obtaining informed consent from the parents [348].

Comments: criteria of ineffectiveness: failure to achieve 50% improvement according to ACRpedi criteria in 3 months, inactive disease stage according to criteria in 6 months, remission in 12 months according to C. Wallace criteria, or at any stage of treatment with persistent/increasing disease activity.

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: #rituximab** (L01XC) is prescribed for vital indications, by decision of the medical panel, after obtaining informed consent from the parents and children over 15 years of age.

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: in seropositive polyarthritis #rituximab** (L01XC) can be a first-line bDMARD in case of ineffectiveness of methotrexate** (L01BA) or #leflunomide** (L04FFAA), as well as a second-line bDMARD in case of ineffectiveness/intolerance of #abatacept** (LO4AA24).

For doses and administration schedule of methotrexate** (L01BA) and #leflunomide** (L04FFAA), see above.

Courses of treatment with #rituximab** (L01XC) (4 infusions over 4 consecutive weeks) are administered once every 22–24 weeks if disease activity persists, taking into account infectious and non-infectious complications. If clinical inactivity / remission is not achieved after the 3rd course of treatment with #rituximab** (L01XC), rituximab treatment should be discontinued.

#Rituximab** (L01XC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Monitoring of therapy efficacy – see Appendices G1-G4.

• It is recommended to prescribe #rituximab** (L01XC) in combination with #co-trimoxazole** (J01EE) at a dose of 5 mg/kg based on trimethoprim orally 3 times a week or daily for the prevention of Pneumocystis pneumonia in accordance with international guidelines [303,3,32,276]. (LeD 5, LoR C)

• It is recommended to withdraw biologic DMARDs (bDMARDs), tofacitinib** (L04AA), #upadacitinib** (L04AA), or baricitinib** (L04AA) in case of their intolerance, and to prescribe oral glucocorticoids (H02AB) at a dose of 0.25–0.5 mg/kg/day in combination with methotrexate** (L01BA) or #leflunomide** (L04FFAA) at any stage of treatment to induce disease remission [1,3,42,348,356,401,421]. (LeD 5, LoR C)

Comments: for doses and administration schedule of methotrexate** (L01BA) and #leflunomide** (L04FFAA), see above.

Comments: criteria for inefficacy: failure to achieve a 50% improvement according to the ACRpedi criteria at 3 months, inactive disease stage at 6 months, or remission at 12 months according to C. Wallace criteria, or at any stage of treatment upon persistence/increase of disease activity.

For doses and administration schedule of methotrexate** (L01BA) and #leflunomide** (L04FFAA), see above.

Comments: the main goal of treatment for juvenile arthritis (JA) is to achieve inactive disease/remission; therapy is adjusted until a 50% reduction in disease activity is achieved at least by 3 months, and the goal (inactive disease/remission) by 6 months of treatment, regardless of the drug used.

3.1.2 Treatment of pauciarticular juvenile arthritis (oligoarticular juvenile idiopathic arthritis, persistent)

• It is recommended to prescribe NSAID monotherapy (M01A) for a duration of no more than 1 month at the diagnostic stage in patients with an unconfirmed JIA diagnosis to achieve an anti-inflammatory effect [1,3,42,348–357]. (LoE 5, GoR C)

• It is recommended to monitor the efficacy of any medicinal product used for pathogenetic therapy at 3 and 6 months, and then every 6 months of therapy (the drug is effective if a 50% improvement according to ACRpedi criteria is achieved at 3 months, or inactive disease stage at 6 months, or remission at 12 months according to C. Wallace criteria) [1,3,32,346,347]. (LeD 5, LoR C)

• It is recommended to adjust therapy (drug switching) until efficacy or minimal/low disease activity is achieved in patients with a long-standing disease, regardless of the drug used [1,3,32,346,347]. (LeD 5, LoR C)

• It is recommended to prescribe NSAIDs (M01A) to relieve fever and pain syndrome in patients with an established JIA diagnosis [1,3,42,348–357]. (LoE 5, GoR C)

Comments: the following NSAID administration regimens are used:

— 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 to achieve anti-inflammatory, analgesic, and antipyretic effects [3,32,355,357–364].

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.

#Diclofenac** (M01AB), #nimesulide (M01AX), #meloxicam (M01AC) off-label are prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

• It is not recommended to perform NSAID (M01A) monotherapy lasting more than 2 months in order to minimize side effects of long-term NSAID use [1,3,32,424–426]. (LeD 5, LoR C)

• It is not recommended to prescribe oral and/or intravenous and/or intra-articular glucocorticoids (H02AB), and/or methotrexate** (L01BA), and/or bDMARDs (#adalimumab** (L04AB) or #etanercept** (L04AB), or #golimumab** (L04AB), or tocilizumab** (L04AC), or abatacept** (LO4AA24), or #rituximab** (L01XC)), and/or tofacitinib** (L04AA), or #upadacitinib** (L04AA), or baricitinib** (L04AA) prior to completing a full laboratory and instrumental workup, ruling out oncological, hemato-oncological, and infectious diseases, and establishing a diagnosis of JA (see sections 2, 3) [1,3,42,348]. (LeD 5, LoR C)

Comments: the use of GCs (H02AB), methotrexate** (L01BA), bDMARDs (#adalimumab** (L04AB) or #etanercept** (L04AB), or #golimumab** (L04AB), or tocilizumab** (L04AC), or abatacept** (LO4AA24), or #rituximab** (L01XC)), and/or #tofacitinib** (L04AA), or #upadacitinib** (L04AA), or baricitinib** (L04AA) in oncological and hemato-oncological diseases presenting under the guise of JA significantly complicates subsequent diagnosis verification, as they possess a pronounced immunosuppressive effect and mask the clinical and morphological picture of malignant neoplasms.

• It is recommended to perform intra-articular administration of:

  — betamethasone** (H02AB) in children over 3 years of age in accordance with the instructions for use or

  — #triamcinolone (H02AB) in children over 12 years of age at a dose of 1-2 mg/kg (maximum dose 80 mg) when administered into the knee joints, 0.5-1 mg/kg (maximum dose 40 mg) into the ankle and elbow joints, and 0.3-0.5 mg/kg (maximum dose 40 mg) into the wrist joints and small joints of the hands and feet [365–368]

• in patients with active mono- or oligoarthritis no more than once every 4 months to rapidly relieve the inflammatory process in the joints [1,3,32,86,348,365–370]. (LeD 5, LoR C)

Comments: if arthritis flares frequently (more often than once every 4 months), intra-articular GC administration is not performed. Indications for intra-articular GC administration are pronounced exudative changes and pain syndrome in the affected joints.

#Betamethasone** (H02AB) and #triamcinolone off-label are prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

• It is recommended to prescribe methotrexate** (L01BA) at a dose of 10–15 mg/m²/week once a week orally or subcutaneously to patients with active oligoarthritis immediately after diagnosis verification in case of high disease activity, regardless of the presence of poor prognostic factors, to induce disease remission [1,3,42,348,376–381,427]. (LeD 5, LoR C)

• It is recommended to prescribe methotrexate** (L01BA) at a dose of 10–15 mg/m²/week once a week orally or subcutaneously to patients with active oligoarthritis immediately after diagnosis verification in case of moderate disease activity and the presence of poor prognostic factors, to induce disease remission [1,3,42,348,376–381,427]. (LeD 5, LoR C)

• It is recommended to prescribe methotrexate** (L01BA) at a dose of 10–15 mg/m²/week once a week orally or subcutaneously to patients with active oligoarthritis in case of NSAID treatment failure for 1–2 months and intra-articular GC injections (need for injections more frequently than once every 4 months), with low disease activity and the presence of poor prognostic factors, or moderate disease activity and the absence of poor prognostic factors, to induce disease remission [1,3,42,348,376–381,427]. (LeD 5, LoR C)

• It is not recommended to increase the dose of methotrexate** (L01BA) > 15 mg/m²/week (not exceeding 25 mg/week) in patients with active arthritis to prevent the development of toxic reactions [1,3,42,348,376–381,427,428]. (LeD 2, LoR B)

Comments: increasing the dose of methotrexate** (L01BA) is not associated with additional therapeutic benefits.

Comments: the subcutaneous route of administration of methotrexate** (L01BA) is preferred as it ensures stable bioavailability.

In case of intolerance to subcutaneous methotrexate, oral methotrexate tablets are prescribed.

Monitoring of treatment efficacy – see Appendices G1-G4

Comments: #folic acid** (B03BB) off-label use is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

• It is recommended to switch to a bDMARD or a targeted synthetic DMARD in case of methotrexate** (L01BA) intolerance to induce/maintain remission [1,42,348,390,392,393,403,415,430–433]. (LeD 5, LoR C)

• It is recommended to switch to one of the following drugs:

  — TNF alpha inhibitors (L04AB) [45,348,390,403] (LeD 5, LoR C)

  — #tocilizumab** (L04AC) [372,431,432] (LeD 5, LoR C)

  — #tofacitinib** (L04AA) [392,415,430] (LeD 5, LoR C)

  — #upadacitinib** (L04AA) [395–402] (LeD 5, LoR C)

  — baricitinib** (L04AA) [614,615] (LeD 2, LoR B)

  — #abatacept** (LO4AA24) [42,45,372,433] (LeD 5, LoR C)

  in case of intolerance to methotrexate** (L01BA) to induce/maintain disease remission.

Comment: switching from one of the specified drugs to another is performed similarly at any stage of treatment in case of their intolerance. For dosing regimens, see below.

Monitoring treatment efficacy – see Appendix G1-G4

• It is recommended to prescribe a bDMARD or a targeted synthetic DMARD in combination with methotrexate** in case of its inefficacy, or as monotherapy, or at any stage of treatment upon persistence/increase of disease activity to induce remission [1,42,348,390,392,393,403,415,430–433]. (LeD 5, LoR C)

• It is recommended to prescribe one of the following drugs:

  — TNF alpha inhibitors (L04AB) [45,348,390,403] (LeD 5, LoR C)

  — #tocilizumab** (L04AC) [372,431,432] ( száll. 5, bizonyítékcsoport C / Level of Evidence 5, Grade of Recommendation C )

  — #tofacitinib** (L04AA) [372,392,415,430] (Level of Evidence 5, Grade of Recommendation C)

  — #upadacitinib** (L04AA) [395–402] (Level of Evidence 5, Grade of Recommendation C)

  — baricitinib** (L04AA) [614,615] (LeD 2, LoR B)

  — #abatacept** (LO4AA24) [42,45,372,433] (LeD 5, LoR C)

  in combination with methotrexate** (L01BA) in case of its ineffectiveness, with the aim of inducing remission.

Comments: criteria for inefficacy are failure to achieve a 50% improvement according to ACRpedi criteria at 3 months, or the inactive disease state at 6 months, or remission at 12 months according to C. Wallace criteria, or at any stage of treatment in case of persistent/increasing disease activity.

Similarly, patients are switched to one of the aforementioned drugs in combination with methotrexate** or as monotherapy if the current drug combination proves ineffective.

For monitoring the efficacy of therapy, see Appendices G1-G4.

Comments: if methotrexate** (L01BA) is ineffective, TNF-alpha inhibitors are preferred as first-line bDMARDs.

Monoclonal antibodies against TNF-alpha (#adalimumab**, #golimumab**) (L04AB) are preferably prescribed in combination with methotrexate** (L01BA) to reduce the risk of neutralizing antibodies.

For doses and administration regimen of methotrexate** (L01BA), see above.

#Adalimumab** (L04AB) is prescribed off-label for vital indications, by decision of the medical commission, and after obtaining informed consent from the parents [348]. For the treatment of patients with juvenile arthritis (JA), it is advisable to use the citrate-free formulation of adalimumab 40 mg/0.4 mL to avoid causing unjustified pain in children, which occurs with the citrate-containing formulation of adalimumab 40 mg/0.8 mL [404–407,413].

Given the pronounced pain syndrome associated with the use of the citrate-containing formulation of #adalimumab** 40 mg/0.8 mL, the use of this formulation in pediatric patients is impossible [404–407,413].

#Etanercept** (L04AB) is prescribed for vital indications, by decision of the medical commission, and after obtaining informed consent from parents and children over 15 years of age [348].

The indication for use in children and adolescents with juvenile arthritis aged 2 to 17 years and with a body weight of less than 62.5 kg applies only to the medicinal product #etanercept** "lyophilisate for solution for subcutaneous administration". The medicinal product #etanercept** "solution for subcutaneous administration" has a contraindication for use in children under 12 years of age and with a body weight of less than 62.5 kg_. [408–411]

According to the FAS clarification letter No. TN/109573/21 dated 22.12.2021 and medical instructions for the use of the medicinal product #Etanercept** [412]:

the use of the dosage form "solution for subcutaneous injection" instead of "lyophilisate for solution for subcutaneous injection" in children under 12 years of age and body mass less than 62.5 kg is not recognized as acceptable due to differences in the final concentration of solutions and the lack of studies allowing to evaluate the tolerability, efficacy, and pharmacokinetics of the 50 mg/ml solution in children. Thus, the substitution of the dosage form "lyophilisate for solution for subcutaneous injection" in this patient is impossible.

#Golimumab** (L04AB) is prescribed for vital indications, by decision of the medical commission, and after obtaining informed consent from parents and children over 15 years of age [348].

Comments: for doses and administration regimen of methotrexate** (L01BA), see above

#Tocilizumab** (L04AC) is prescribed for vital indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age [348].

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: for doses and administration regimen of methotrexate** (L01BA), see above.

#Tofacitinib** (L04AA) and #upadacitinib** (L04AA) are prescribed for vital indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age [395–402,415].

#Baricitinib** (L04AA) is prescribed for vital indications in children aged ≤ 2 years, by decision of the medical panel, after obtaining informed consent from the parents [614,615].

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: for doses and administration regimen of methotrexate** (L01BA), see above.

#Abatacept** (LO4AA24) is prescribed for vital indications, by decision of the medical commission, and after obtaining informed consent from parents and children over 15 years of age [348].

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: #rituximab** (L01XC) is prescribed for vital indications, by decision of the medical panel, after obtaining informed consent from the parents and children over 15 years of age.

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: for doses and administration regimen of methotrexate** (L01BA), see above.

Courses of treatment with #rituximab** (L01XC) (4 infusions over 4 consecutive weeks) are administered every 22–24 weeks if disease activity persists, taking into account infectious and non-infectious complications. If after the 3rd course of treatment with #rituximab** (L01XC) the state of inactive disease/remission is not achieved, treatment with #rituximab is recommended to be discontinued.

#Rituximab** (L01XC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

For monitoring therapy efficacy – see Appendices G1–G4.

• It is recommended to prescribe #rituximab** (L01XC) in combination with #co-trimoxazole** (J01EE) at a dose of 5 mg/kg based on trimethoprim orally 3 times a week or daily for the prevention of Pneumocystis pneumonia in accordance with international guidelines [303,3,32,276]. (LeD 5, LoR C)

• It is recommended to discontinue bDMARDs, #tofacitinib** (L04AA), or #upadacitinib** (L04AA), or baricitinib** (L04AA) in case of their intolerance, and to prescribe glucocorticoids (H02AB) orally at a dose of 0.25–0.5 mg/kg/day in combination with methotrexate** (L01BA) at any stage of treatment with the aim of inducing disease remission [1,3,42,348,356,401,421]. (Level of Evidence 5, Grade of Recommendation C)

Comments: for doses and administration regimen of methotrexate**, see above.

Comments: criteria of ineffectiveness: failure to achieve 50% improvement according to ACRpedi criteria at 3 months, inactive disease state according to criteria at 6 months, remission at 12 months according to C. Wallace criteria, or at any stage of treatment with persistence/increase in disease activity.

Comments: the main goal of JA treatment is to achieve a state of inactive disease/remission; therapy is adjusted until a 50% decrease in disease activity is achieved in at least 3 months, and the target (inactive disease/remission) in 6 months of treatment, regardless of the drug used.

3.1.3 Treatment of juvenile ankylosing spondylitis

• It is recommended to monitor the efficacy of any medicinal product used for pathogenetic therapy at 3 and 6 months, and then every 6 months of therapy (the drug is effective if a 50% improvement according to ACRpedi criteria is achieved at 3 months, or inactive disease stage at 6 months, or remission at 12 months according to C. Wallace criteria) [1,3,32,346,347]. (LeD 5, LoR C)

• It is recommended to adjust therapy (drug switching) until efficacy or minimal/low disease activity is achieved in patients with a long-standing disease, regardless of the drug used [1,3,32,346,347]. (LeD 5, LoR C)

• It is recommended to prescribe NSAID monotherapy (M01A) for a duration of no more than 1 month at the diagnostic stage for patients with an unestablished diagnosis of juvenile arthritis with the aim of achieving an anti-inflammatory effect [1,3,42,348–357]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to prescribe NSAIDs (M01A) to relieve fever and pain in patients with a confirmed diagnosis of juvenile arthritis [1, 3, 42, 348–357]. (Level of Evidence (LoE) 5, Grade of Recommendation (GoR) C)

Comments: the following NSAID administration regimens are used:

— 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 to achieve anti-inflammatory, analgesic, and antipyretic effects [3,32,355,357–364].

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.

#Diclofenac** (M01AB), #nimesulide (M01AX), #meloxicam (M01AC) off-label are prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

• It is not recommended to perform NSAID monotherapy (M01A) lasting more than 1 month in order to minimize side effects of long-term NSAID use [1,3,32]. (LoE 5, GoR C)

• It is not recommended to prescribe glucocorticoids (H02AB) orally and/or intravenously and/or intra-articularly, and/or immunosuppressants (methotrexate** (L01BA) or #sulfasalazine** (A07EC01)), and/or bDMARDs (TNF-alpha inhibitors (L04AB), or #tocilizumab** (L04AC), or secukinumab** (L04AC10)), and/or #tofacitinib** (L04AA), or #upadacitinib** (L04AA), or baricitinib** (L04AA) before completing a full laboratory and instrumental workup, ruling out oncological, onco-hematological, and infectious diseases, and establishing a diagnosis of juvenile arthritis (see sections 2, 3) [1, 3, 42, 348]. (LoE 5, GoR C)

Comments: the use of GCs, immunosuppressants (#methotrexate** (L01BA) or #sulfasalazine** (A07EC01)), bDMARDs (#adalimumab** (L04AB) or #etanercept** (L04AB), or #golimumab** (L04AB), or secukinumab** (L04AC10), or #tocilizumab** (L04AC), and/or #tofacitinib** (L04AA), #upadacitinib** (L04AA), baricitinib** (L04AA) in oncological and onco-hematological diseases mimicking juvenile arthritis will significantly complicate subsequent diagnosis verification, as they have a pronounced immunosuppressive effect and mask the clinical and morphological features of malignant neoplasms.

• It is recommended to perform intra-articular administration of:

  — betamethasone** (H02AB) in children over 3 years of age in accordance with the instructions for use or

  — #triamcinolone (H02AB) in children over 12 years of age at a dose of 1-2 mg/kg (maximum dose 80 mg) when administered into the knee joints, 0.5-1 mg/kg (maximum dose 40 mg) into the ankle and elbow joints, and 0.3-0.5 mg/kg (maximum dose 40 mg) into the wrist joints and small joints of the hands and feet [365–368]

• in patients with active mono- or oligoarthritis no more than once every 4 months to rapidly relieve the inflammatory process in the joints [1,3,32,86,348,365–370]. (LeD 5, LoR C)

Comments: if arthritis flares frequently (more often than once every 4 months), intra-articular GC administration is not performed. Indications for intra-articular GC administration are pronounced exudative changes and pain syndrome in the affected joints.

#Betamethasone** (H02AB) and #triamcinolone off-label are prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: recommended for use in case of NSAID failure, after the first intra-articular GC injection, or in moderate to high disease activity regardless of the presence of poor prognostic factors.

Off-label, #methotrexate** (L01BA) is prescribed by decision of the medical commission, after obtaining informed consent from the parents.

Off-label use of #sulfasalazine** (A07EC01) is prescribed by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: increasing the dose of methotrexate** (L01BA) is not associated with additional therapeutic benefits.

Comments: the subcutaneous route of methotrexate** (L01BA) administration is preferred due to its higher bioavailability.

In case of intolerance to subcutaneous methotrexate** (L01BA), oral methotrexate** (L01BA) tablets are prescribed.

Off-label, #methotrexate** (L01BA) is prescribed by decision of the medical commission, after obtaining informed consent from the parents.

Comments: off-label, #folic acid** (B03BB) is prescribed for vital indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Monitoring of therapy efficacy – see Appendices G1-G4.

• It is recommended to prescribe a bDMARD or targeted synthetic DMARD in combination with sulfasalazine** (A07EC01) in case of its inefficacy, or with methotrexate** (L01BA) in case of its inefficacy, or as monotherapy, or at any stage of treatment in case of persistent/increasing disease activity for the purpose of inducing remission [1, 3, 42, 348, 376–381, 427, 428, 437, 441]. (LoE 5, GoR C)

• It is recommended to prescribe one of the following drugs:

  - TNF-alpha inhibitors (L04AB) [25, 442–451] (LoE 2, GoR B)

  - secukinumab** (L04AC10) [452–454] (LoE 2, GoR B)

  - #tofacitinib** (L04AA) [392, 455] (LoE 5, GoR C)

  - #upadacitinib** (L04AA) [402, 456] (LoE 5, GoR C)

  - baricitinib** (L04AA) [614, 615] (LoE 2, GoR B)

  in combination with sulfasalazine** (A07EC01) or #methotrexate** (L01BA), or as monotherapy, or at any stage of treatment in case of persistent/increasing disease activity for the purpose of inducing remission.

Comments: criteria for inefficacy are failure to achieve a 50% improvement according to ACR JIA 50 criteria at 3 months, inactive disease status at 6 months, or remission at 12 months according to C. Wallace criteria, or at any stage of treatment with persistent/increasing disease activity.

Similarly, patients are switched to one of the aforementioned drugs in combination with sulfasalazine** (A07EC01) or methotrexate** (L01BA), or as monotherapy in case of inefficacy of the drug combination used.

For monitoring the effectiveness of therapy, see Appendices G1–G4. Dosage regimens are provided below.

Comments: if sulfasalazine** (A07EC01) or #methotrexate** (L01BA) is ineffective, TNF-alpha inhibitors are preferred as first-line bDMARDs.

Monoclonal antibodies to TNF-alpha (#adalimumab**, #golimumab**) (L04AB) are preferably prescribed in combination with sulfasalazine** (A07EC01) or methotrexate** (L01BA) to reduce the risk of neutralizing antibody formation.

For doses and administration schedule of sulfasalazine** (A07EC01) or #methotrexate**, see above.

For the treatment of patients with juvenile arthritis, it is advisable to use the citrate-free formulation of #adalimumab** 40 mg/0.4 mL to avoid causing children unnecessary pain that occurs with the citrate-containing formulation of #adalimumab** 40 mg/0.8 mL [404–407, 413].

Given the pronounced pain syndrome associated with the use of the citrate-containing formulation of #adalimumab** 40 mg/0.8 mL, the use of this formulation in pediatric patients is impossible [404–407,413].

#Etanercept** (L04AB) is prescribed for vital indications, by decision of the medical commission, and after obtaining informed consent from parents and children over 15 years of age [348].

The indication for use in children and adolescents with juvenile arthritis aged 2 to 17 years and with a body weight of less than 62.5 kg applies only to the medicinal product #etanercept** "lyophilisate for solution for subcutaneous administration". The medicinal product #etanercept** "solution for subcutaneous administration" has a contraindication for use in children under 12 years of age and with a body weight of less than 62.5 kg_. [408–411]

According to the FAS clarification letter No. TN/109573/21 dated 22.12.2021 and medical instructions for the use of the medicinal product #Etanercept** [412]:

the use of the dosage form "solution for subcutaneous injection" instead of "lyophilisate for solution for subcutaneous injection" in children under 12 years of age and body mass less than 62.5 kg is not recognized as acceptable due to differences in the final concentration of solutions and the lack of studies allowing to evaluate the tolerability, efficacy, and pharmacokinetics of the 50 mg/ml solution in children. Thus, the substitution of the dosage form "lyophilisate for solution for subcutaneous injection" in this patient is impossible.

#Golimumab** (L04AB) is prescribed for vital indications, by decision of the medical commission, and after obtaining informed consent from parents and children over 15 years of age [348].

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: for doses and administration schedule of sulfasalazine** (A07EC01) or methotrexate** (L01BA), see above.

Secukinumab** (L04AC10) is prescribed for vital indications in children under 6 years of age subcutaneously by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: for doses and administration schedule of #methotrexate** and sulfasalazine (L01BA), see above.

#Tofacitinib** (L04AA) and #upadacitinib** (L04AA) are prescribed for vital indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

#Baricitinib** (L04AA) is prescribed for vital indications in children aged ≤ 2 years by decision of the medical commission, after obtaining informed consent from parents [614, 615].

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: for doses and administration regimen of methotrexate** (L01BA), see above.

#Tocilizumab** (L04AC) is prescribed on vital indications for children under 2 years of age intravenously or for children under 1 year of age subcutaneously by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1-G4.

Comments: for doses and administration schedule of #methotrexate** (L01BA) and GCs (H02AB), see below.

Comments: criteria for inefficacy: failure to achieve a 50% improvement according to the ACRpedi criteria at 3 months, inactive disease stage at 6 months, or remission at 12 months according to C. Wallace criteria, or at any stage of treatment upon persistence/increase of disease activity.

Comments: the main goal of JA treatment is to achieve a state of inactive disease/remission; therapy is adjusted until a 50% decrease in disease activity is achieved in at least 3 months, and the target (inactive disease/remission) in 6 months of treatment, regardless of the drug used.

3.1.4 Treatment of juvenile arthritis-associated uveitis.

Comment: all patients with juvenile arthritis must be examined by an ophthalmologist to prescribe uveitis therapy if it is detected.

Comments: currently, biosimilars of anti-tumor necrosis factor alpha (anti-TNF-alpha) inhibitors, as well as generics of Janus kinase inhibitors, which are structurally equivalent to them, have been approved. Some of these drugs have demonstrated efficacy similar to original drugs in clinical trials in adult patients [345]. However, clinical trials of biosimilars and generics of immunosuppressants and selective immunosuppressants have not been conducted in the pediatric population with juvenile arthritis-associated uveitis.

The original immunosuppressant and/or selective immunosuppressant, and/or biologic DMARD cannot be automatically replaced with a generic or biosimilar. Drug substitution may only be carried out based on a consensus of the attending physician who initiated therapy with the immunosuppressant and/or selective immunosuppressant, and/or biologic DMARD, after obtaining informed consent from parents and children over 15 years of age.

Comment: the regimen of administration, dose reduction, and discontinuation of #dexamethasone** (H02AB02) and NSAID-containing drops is determined by the ophthalmologist.

Comment: the regimen of administration, dose reduction, and discontinuation of #dexamethasone** (H02AB02) and NSAID-containing drops is determined by the ophthalmologist.

#Dexamethasone** (L04AC) is prescribed on vital indications for children under 6 years of age by decision of the medical commission, after obtaining informed consent from the parents.

Comment: parabulbar injections of #betamethasone** (H02AB) are prescribed and performed by an ophthalmologist. The dose, administration schedule, dose reduction, and discontinuation of #betamethasone** (H02AB) are determined by the ophthalmologist.

#Betamethasone** (H02AB) outside of age indications is prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: the administration regimen of #tropicamide** (S01FA06) is determined by the ophthalmologist.

#Tropicamide** (S01FA06) outside of age indications is prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: the administration regimen of #taurine** (S01XA) and #dexpanthenol** (D03AX03) is determined by the ophthalmologist.

#Taurine** (S01XA) and #dexpanthenol** (D03AX03) outside of age indications are prescribed by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: the subcutaneous route of administration of #methotrexate** (L01BA) is preferred as it provides stable bioavailability.

In case of intolerance to subcutaneous #methotrexate**, oral #methotrexate** is prescribed.

Monitoring of therapy efficacy – see Appendices G3, G4

Comments: increasing the dose of #methotrexate** (L01BA) is not associated with additional therapeutic benefits.

Comments: #folic acid** (B03BB) is prescribed off-label for vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: switching from one of the specified drugs to another at any stage of treatment in case of their intolerance is performed similarly. For dosing regimens, see below.

Comments: the criterion for treatment failure is failure to achieve uveitis remission after 3 months of therapy (assessed by an ophthalmologist).

#Cyclosporine** (L04DA01) is prescribed for life-saving indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: the criterion for treatment failure is failure to achieve uveitis remission after 3 months of therapy (assessed by an ophthalmologist).

#Mycophenolate mofetil** (L04AA06) is prescribed for life-saving indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: the criterion for treatment failure is failure to achieve uveitis remission after 3 months of therapy (assessed by an ophthalmologist). Dosing regimens are given below.

• It is recommended to promptly prescribe a TNF-alpha inhibitor (L04AB) in combination with #methotrexate** (L01BA) and/or #cyclosporine** (L04DA01), or #mycophenolate mofetil** (L04AA06) combined with local therapy at any stage of treatment in severe uveitis, panuveitis, or risk of blindness, to induce uveitis remission [372,462–465]. (Quality of Evidence 5, Strength of Recommendation C)

• It is recommended to prescribe:

  - #adalimumab** (L04AB) citrate-free formulation (40 mg/0.4 mL) in patients aged ≥ 2 years with a body weight of 10–30 kg at a dose of 20 mg subcutaneously once every 2 weeks; > 30 kg at a dose of 40 mg subcutaneously once every 2 weeks [372,404–407,462–465] (Quality of Evidence 4, Strength of Recommendation C) or

  - #golimumab** (L04AB) at a dose of 30 mg/m² (maximum dose 50 mg) subcutaneously once every 4 weeks to induce uveitis remission [372,404–407,462–465]. (Quality of Evidence 4, Strength of Recommendation C)

  in combination with #methotrexate** (L01BA) and/or #cyclosporine** (L04DA01), or #mycophenolate mofetil** (L04AA06) combined with local therapy to induce uveitis remission.

Comments: the criterion for efficacy is achievement of uveitis remission after 3 months of therapy (assessed by an ophthalmologist).

For doses and administration procedures of #methotrexate** (L01BA), #cyclosporine** (L04DA01), and #mycophenolate mofetil** (L04AA06), see above.

#Adalimumab** (L04AB) is prescribed for life-saving indications, by decision of the medical commission, after obtaining informed consent from parents in children under 2 years of age.

For the treatment of patients with JIA-associated uveitis, it is advisable to use the citrate-free formulation of #adalimumab** 40 mg/0.4 mL to avoid causing unjustified pain in children, which occurs with the citrate-containing formulation of adalimumab 40 mg/0.8 mL [404–407].

Given the pronounced pain syndrome when using the 40 mg/0.8 mL dosage form, the use of this formulation in pediatric patients is impossible [404–407].

#Golimumab** (L04AB) is prescribed for life-saving indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: the criterion for treatment failure is failure to achieve uveitis remission after 3 months of therapy (assessed by an ophthalmologist).

Similarly, switching from one of these drugs to another is performed in case of their failure and at any stage of treatment in case of their intolerance.

#Tocilizumab** (L04AC), #tofacitinib** (L04AA), #abatacept** (L04AA24), and #upadacitinib** (L04AA) are prescribed for life-saving indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age. Dosing regimens are given below.

Comments: the criterion for efficacy is achievement of uveitis remission after 3 months of therapy (assessed by an ophthalmologist).

#Tocilizumab** (L04AC) is prescribed for life-saving indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: the criterion for efficacy is achievement of uveitis remission after 3 months of therapy (assessed by an ophthalmologist).

#Tofacitinib** (L04AA), #upadacitinib** (L04AA), and #baricitinib** (L04AA) are prescribed for life-saving indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age [401,415,475,614-617].

Monitoring of therapy efficacy – see Appendices G3, G4

Comments: the criterion for efficacy is achievement of uveitis remission after 3 months of therapy (assessed by an ophthalmologist).

#Abatacept** (L04AA24) is prescribed for life-saving indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

For monitoring the efficacy of therapy, see Appendices G3, G4.

Comments: efficacy criterion: achievement of uveitis remission after 3 months of therapy (assessed by an ophthalmologist).

#Rituximab** (L01XC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: the criterion for efficacy is achievement of uveitis remission after 3 months of therapy (assessed by an ophthalmologist).

#Rituximab** (L01XC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: courses of #rituximab** (L01XC) therapy (4 infusions over 4 consecutive weeks) are administered once every 22–24 weeks if disease activity persists, taking into account infectious and non-infectious complications.

#Rituximab** (L01XC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

• It is recommended to prescribe #rituximab** (L01XC) in combination with #co-trimoxazole** (J01EE) at a dose of 5 mg/kg based on trimethoprim orally 3 times a week or daily to prevent Pneumocystis pneumonia in accordance with international guidelines for the treatment of immunocompromised patients [303,3,32,276]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to discontinue bDMARDs or #tofacitinib** (L04AA), or #upadacitinib** (L04AA), or #baricitinib** (L04AA) in case of their intolerance, and to prescribe oral glucocorticoids (H02AB) at a dose of 0.25 mg/kg/day in combination with #methotrexate** (L01BA) and/or #cyclosporine** (L04AA01), or #mycophenolate mofetil** (L04AA06) at any stage of treatment to induce uveitis remission [17,30,32,332,333,356]. (Level of Evidence 5, Grade of Recommendation C)

Comments: for doses and administration schedules of #methotrexate** (L01BA), #cyclosporine** (L04AA01), and #mycophenolate mofetil** (L04AA06), see above.

For GCs doses and administration schedule, see below.

Comments: resistance to therapy with all bDMARDs, #tofacitinib** (L04AA), #upadacitinib** (L04AA), #baricitinib** (L04AA) in combination with #methotrexate** (L01BA) and/or #cyclosporine** (L04AA01), or #mycophenolate mofetil** (L04AA06) is an indication for prescribing GCs.

Efficacy criterion: achievement of uveitis remission by 3 months of treatment (evaluated by an ophthalmologist).

3.1.5 Treatment of juvenile arthritis with hemophagocytic syndrome

• It is recommended to prescribe and administer therapy in a rheumatology inpatient unit after performing diagnostics, including differential diagnosis, and establishing/confirming the diagnosis of JIA with secondary macrophage activation syndrome in all patients to ensure the prevention and timely management of severe complications [1,3,32]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to prescribe targeted etiotropic therapy with systemic antibacterial agents (J01) and/or systemic antifungal agents (J02A), and/or systemic antiviral agents (J05) in patients with a known infectious etiological factor to stop the activation of the innate immune system [1,237,238,252]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to prescribe GCs (H02AB) in combination with #cyclosporine** (L04AD) and #normal human immunoglobulin** (J06BA) in all patients to relieve MAS [237,238,250,477–481]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform pulse therapy with #methylprednisolone** (H02AB) at a dose of 20–30 mg/kg/administration intravenously or to prescribe #dexamethasone** (H02AB) at a dose of 10–20 mg/m²/day intravenously in all patients to relieve MAS [237,250,477,478,480–484]. (Level of Evidence 5, Grade of Recommendation C)

Comments: #dexamethasone** (H02AB) and #cyclosporine** (L04AD) are prescribed on vital indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

• It is recommended to gradually taper the dose of intravenous GCs after clinical and laboratory signs of MAS are resolved according to the following regimens:

  — #dexamethasone** (H02AB) starting 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/m³/day for 7–8 weeks;

  — #methylprednisolone** starting from an initial dose of 20–30 mg/kg/administration for 3–5 days, tapering the dose by 25% once every 2–3 days to prevent withdrawal syndrome [1,3,237,478,481,485–488]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to prescribe #cyclosporine** at a dose of 3–5 mg/kg/day intravenously or orally to all patients to relieve MAS [237,238,250,477,478,480,481,485,489]. (Level of Evidence 4, Grade of Recommendation 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 to achieve an immunosuppressive effect and relieve MAS [250,481,485,490–492]. (Level of Evidence 5, Grade of Recommendation C)

Comments: administration of the entire course dose of #normal human immunoglobulin** is carried out by continuous prolonged infusion administered at once to ensure the blocking of IgG Fc receptors on phagocytic cells; suppression of T-lymphocyte proliferation and immunoglobulin production; interaction with the complement system; blocking the activation and action of cytokines; blocking the expression of adhesion molecules on endothelial cells.

#Normal human immunoglobulin** (J06BA) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: upon achieving a response, therapy should be continued until the inactive disease stage is reached.

Comments: #anakinra** (L04AC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: #ruxolitinib** and #tofacitinib** are prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

Comments: #rituximab** (L01XC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

• It is recommended to prescribe #co-trimoxazole** (J01EE) at a dose of 5 mg/kg based on trimethoprim orally 3 times a week or daily in combination with #rituximab** (L01XC) to prevent Pneumocystis pneumonia [303,3,32,276,502]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to prescribe #prednisolone** at a dose of 1–2 mg/kg/orally or #methylprednisolone** (H02AB) at a dose equivalent to prednisolone, in case of inefficacy of combination MAS therapy or MAS reactivation during tapering/withdrawal of intravenous GCs to relieve MAS [236–238,250]. (Level of Evidence 4, Grade of Recommendation 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 HLH [3,32,213,503–506]. (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 infection caused by Herpes simplex virus to suppress the triggering factor of HLH [3,32,504,507]. (LoE 5, GoR C)

Comments: #acyclovir** (J05AB) for children < 3 years of age is prescribed by decision of the medical commission after obtaining informed consent from the parents.

Treatment is carried out until complete relief of herpetic infection.

Comments: #ganciclovir** (J05AB) for children < 12 years of age is prescribed by decision of the medical commission after obtaining informed consent from the parents and permission from the local ethics committee of the medical organization.

Comments: #ganciclovir** (J05AB) for children < 12 years of age is prescribed by decision of the medical commission after obtaining informed consent from the parents and permission from the local ethics committee of the medical organization.

Comments:

Regimens:

— #rituximab** (L01XC) – at a dose of 375 mg/m²/week intravenously for 1–4 consecutive weeks [513];

— #cyclosporine** (L04AD) – 3–5 mg/kg/day [250,513];

— #normal human immunoglobulin** (J06BA) – 1–2 g/kg/course over 2 days [250,513];

— #sulfamethoxazole and trimethoprim** (J01EE) – for the prescription procedure and doses of #sulfamethoxazole and trimethoprim** (J01EE), see above [303,502].

#Rituximab** (L01XC) is prescribed for life-saving indications, by decision of the medical commission, after obtaining informed consent from parents/patients over 15 years of age.

Comments: antithrombotic agents (B01A) outside of age indications are prescribed by decision of the medical panel, after obtaining informed consent from parents and children older than 15 years.

Comments: in case of consumption coagulopathy, blood transfusion and blood products (B05A) are administered: red blood cell mass, fresh frozen plasma, blood coagulation factor VII, platelet concentrate, cryoprecipitate, 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 blood neutrophil count and prevent infectious complications [1,3,32,517,518]. (LoE 5, GoR C)

• It is recommended to prescribe systemic antibacterial drugs (J01) in combination with systemic antifungal drugs (J02A) until resolution of agranulocytosis when the absolute neutrophil count decreases to ≤ 1.0×10⁹/L as a planned measure to prevent infectious complications [3,32,150,151,519,520]. (LoE 5, GoR C)

• It is recommended to prescribe empirical systemic antibacterial therapy (J01) covering gram-positive, gram-negative, and anaerobic flora, and/or systemic antifungals (J02A), and/or systemic antivirals (J05) upon the development of sepsis/infectious complications prior to the identification of the etiological factor, with the aim of arresting/preventing the progression of the infectious process [81,150,151,154–156,237,238,516,519–523]. (LoE 5, GoR C)

Comments: systemic anti-infectives (J01), systemic antifungals (J02A), and antivirals (J05) outside of age indications are prescribed by decision of the medical panel, after obtaining informed consent from parents and children older than 15 years.

• It is recommended to prescribe targeted therapy based on microbial susceptibility once the etiological factor of sepsis/infectious complication is confirmed, depending on the clinical situation, using systemic antibacterial drugs (J01) (combinations of penicillins, including beta-lactamase inhibitor combinations (J01CR), and/or 4th-generation cephalosporins (J01DE), and/or carbapenems (J01DH), and/or other antibacterials (J01XX), and/or glycopeptide antibiotics (J01XA), and/or other aminoglycosides (J01GB)), with or without systemic antifungals (J02A) and/or systemic antivirals (J05), with the aim of resolving sepsis/infectious complications [81,150,151,154–156,238,516,519–522]. (LoE 5, GoR C)

• It is recommended to continue treatment of macrophage activation syndrome (sHLH) until criteria for the inactive phase 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)) with the aim of preventing multiple organ failure and death [524]. (LoE 5, GoR C)

Comments: after resolving sHLH, therapy should be continued in accordance with the established JIA subtype (see above).

3.1.6 General principles of treatment of juvenile idiopathic arthritis

1. The primary goal of treatment in patients with JIA is clinical remission—the absence of symptoms of inflammatory activity, including systemic manifestations (2bC)* (see Appendices G1–G4).

2. Minimal (or low) disease activity may be an alternative goal exclusively in patients with long-standing disease (2cB)* (see Appendices G1–G4).

3. Goal setting and therapy selection must be based on the individual characteristics of the child and agreed upon with the parent/patient (5D)*.

4. Disease activity must be regularly assessed and documented using validated comprehensive instruments (2cC)* (see Appendices G1–G4).

5. The frequency of monitoring depends on the type of JIA, disease activity, and the presence of systemic manifestations (5C)*.

6. A 50% reduction in disease activity should be achieved in all patients in at least 3 months, and the target (inactive disease/remission) in 6 months of treatment. In patients with sJIA with active systemic manifestations, fever should resolve within 1 week (2bB)*.

7. Therapy should be adjusted until the target is achieved (2bC)*.

8. Monitoring must be continuous to ensure the maintenance of remission (treatment goal) (2bC)*.

A. The therapeutic strategy for JIA management is based on the cooperation of the parents/patient and the pediatric rheumatology team providing treatment and rehabilitation.

B. Juvenile idiopathic arthritis is a heterogeneous group of diseases, which implies various therapeutic approaches.

C. The main goals of JIA treatment are: control of clinical and laboratory manifestations of the disease, prevention of the progression of osteocartilaginous destruction and eye damage; avoidance of comorbid conditions and adverse drug reactions; ensuring functional activity, normal growth, development, high quality of life, and social adaptation of the child.

D. Cessation of the inflammatory process is a necessary condition for achieving the set goals.

E. Long-term use of systemic GCs is unacceptable for achieving the goal.

F. To achieve the goal, monitoring of disease activity and adjustment of therapy are necessary.

* PRES criteria [347].

3.2. Surgical treatment

3.3. Non-pharmacological treatment

Comments: complete joint immobilization with splints is contraindicated as it contributes to the development of contractures, muscle atrophy, worsening of osteoporosis, and rapid development of ankylosis. Physical exercises help maintain joint functional activity. Cycling, swimming, and walking are beneficial. Running, jumping, and active games are undesirable. It is recommended to maintain an upright posture when walking and sitting, and to sleep on a firm mattress and a thin pillow.

Exclude psycho-emotional stress and sun exposure.

• It is recommended that all patients with juvenile arthritis consume a diet high in calcium and vitamin D to prevent osteoporosis [1,3,32,327,328,371,527,528]. (LoE 5, GoR C)

• It is recommended to use splints, casts, and insoles in patients with joint deformities and lower limb growth abnormalities in order to correct orthopedic disorders [1,3,32,214]. (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

Comments: performed in all patients; an individual rehabilitation program is developed; goals and objectives of rehabilitation measures are formulated based on the rehabilitation diagnosis and rehabilitation potential for a day, a week, and the entire rehabilitation period; the motor regimen and individual intensity limits of interventions applied to a patient with impaired functions 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 technology, psychological correction, ergotherapy; forms of medical rehabilitation are selected at various stages of its application and in various periods of the disease course (individual, group classes, telemedicine-based classes); legal representatives of children in need of medical rehabilitation are consulted and trained in home-safe rehabilitation techniques and care skills for severely ill children.

Comments: a plan is developed, and the goal and objectives of physiotherapy in a patient with sJIA are formulated during the implementation of the individual rehabilitation program; methods of physiotherapy (electro-, magneto-, photo-, mechano-, hydro-, thermotherapy) and sanatorium-resort treatment (climatotherapy, balneotherapy, pelotherapy) are selected depending on the various periods of the disease course.

Comments: medical rehabilitation is necessarily combined with the psychological rehabilitation of children and their parents; an individual psychological rehabilitation program and psychotherapeutic program are 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, and psychotherapeutic targets; psychological intervention methods (psychological therapy, psychological counseling, psychological correction, and psychological rehabilitation) are chosen; types of psychotherapy include dynamic, cognitive-behavioral, existential-humanistic, and non-mainstream modalities (art therapy, body-oriented psychotherapy, psychodrama, suggestive psychotherapy, etc.); forms of psychotherapy include individual, family/couple, group, natural environment, and milieu therapy.

Comments: the objective of the "School for Children with Rheumatic Diseases and Their Parents" is to inform parents and children about the features, mechanisms of development, clinical presentation of the disease, treatment, mechanisms of action of medications, their efficacy, potential side effects; methods of medical and psychological rehabilitation, disease outcomes; vaccination, prevention of exacerbations, complications of the disease and adverse effects of antirheumatic drugs. Training on methods to monitor the efficacy and safety of medications using generally accepted rheumatological scales and questionnaires.

5. Prevention and Dispensary Observation

5.1. Prevention

Primary prevention has not been established, as the etiology of juvenile arthritis remains definitively undetermined.

Comments: to prevent exacerbations and complications of juvenile arthritis under the constant monitoring of clinical and laboratory parameters of disease activity, long-term maintenance therapy is carried out, developed taking into account the individual characteristics of the patient and the disease variant, with its correction if necessary; a protective regimen is ensured (psycho-emotional and physical loads are limited, during the exacerbation period children are homeschooled and attend school during the inactive disease/remission stage, contacts are limited to reduce the risk of infectious diseases); insolation, trips to regions with high levels of insolation, and UV therapy are excluded, sunscreens must be used, wearing clothing that covers the skin as much as possible and wide-brimmed hats is recommended; hypothermia is prevented; an individual vaccination approach is developed; the use of live vaccines and immunomodulators is excluded.

To reduce the risk of side effects from antirheumatic drugs, regular monitoring of clinical and laboratory safety parameters is performed; the use of medications that increase the toxicity of GCs, immunosuppressants, and bDMARDs is avoided.

Comments: the safety of such a combination has not been established. An exacerbation of juvenile arthritis 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 carry out 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 the prescription or at any stage of therapy with immunosuppressants and/or bDMARDs combined with or without glucocorticoids, by passive immunization with antiviral monoclonal antibody preparations (J06BD) [554]. (LoE 4, GoR C)

• It is recommended to administer vaccination with a 13-valent pneumococcal conjugate polysaccharide adsorbed vaccine** containing capsular polysaccharides of 13 pneumococcal serotypes to all patients with juvenile arthritis, prior to the prescription or at any stage of therapy with immunosuppressants and/or bDMARDs combined with or without glucocorticoids (excluding #rituximab**) in order to prevent pneumococcal infection, increase treatment adherence, and prevent exacerbations in accordance with international guidelines [552,555–558]. (LoE 3, GoR B)

Comments: vaccination with the 13-valent pneumococcal polysaccharide conjugate vaccine in patients receiving tocilizumab** is carried out 2 weeks before the planned infusion or 2 weeks after; in patients receiving #etanercept** — 1 week before the planned injection or 1 week after; in patients receiving #adalimumab** and #golimumab** — 2 and 4 weeks before the planned injection or 2 and 4 weeks after, respectively; in patients for whom #rituximab** is planned to be prescribed — before the first infusion to prevent infectious complications, increase treatment adherence, and prevent juvenile arthritis exacerbations.

5.2. Follow-up examination of patients with juvenile arthritis in an inpatient/day-care hospital setting who have initiated bDMARD/immunosuppressant therapy.

The examination is performed every 3–6 months: at 3 and 6 months after starting therapy; thereafter every 6 months to monitor the efficacy and safety of therapy, and to detect disease complications and comorbid conditions.

For complaints and anamnesis, see section 2.1.

For physical examination, see section 2.2.

Comments: the main treatment goal is to achieve 50% improvement according to the American College of Rheumatology criteria at 3 months and the inactive disease stage according to C. Wallace's inactive disease/remission criteria at 6 months.

Monitoring of treatment efficacy — see Appendices G1–G4.

Comments: parameters of the complete blood count with differential should be within normal limits. Single-, bi-, or pancytopenia may be, among other things, an adverse manifestation of bDMARD and/or immunosuppressant treatment.

Leukopenia most frequently develops during the use of tocilizumab** and #rituximab**, and less frequently during treatment with abatacept**, TNF-alpha inhibitors, methotrexate**, leflunomide**, mycophenolate mofetil** (L04AA06).

Thrombocytopenia may develop during treatment with any bDMARD and immunosuppressant. If there is evidence of recurrent episodes of thrombocytopenia, the bDMARD and/or immunosuppressant therapy is modified.

Comments: Previously prescribed oral glucocorticoids should be continued. Repeat the complete blood count in 1 week.

Comments: Previously prescribed oral glucocorticoids should be continued. Repeat the complete blood count in 1 week.

Comments: in children aged < 1 year, #filgrastim** (LO3AA) is prescribed by decision of a medical commission, after obtaining informed consent from the parents

Comments: Previously prescribed oral GCs should be continued.

In children < 1 year of age, #filgrastim** (LO3AA) is prescribed by decision of a medical commission, after obtaining informed consent from the parents.

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 anti-infective agents (JO1) in all patients with febrile neutropenia (neutropenia accompanied by fever) in order to resolve febrile fever and normalize the leukocyte formula according to complete blood count data [1,3,32,430,517–519]. (LoE 5, GoR C)

• It is recommended to resume treatment with the immunosuppressant and/or bDMARD at the same dose in all patients after recovery of the neutrophil count to ≥ 1.5×10⁹/L according to complete blood count data in order to maintain systemic juvenile idiopathic arthritis remission [1,3,32,430]. (LoE 5, GoR C)

• It is recommended to adjust the therapy with an immunosuppressant and/or biological DMARD in all patients in case of recurrent episodes of decreased blood cell counts in the complete blood count, in order to control adverse events associated with therapy [1,3,32,430]. (LoE 5, GoR C)

• It is recommended to prescribe fluconazole** intravenously at 3-12 mg/kg/day depending on the severity and duration of induced neutropenia in patients with neutropenia to prevent fungal infections resulting from treatment with immunosuppressants and/or #rituximab** [1,3,32,430,562]. (LoE 4, GoR C)

• It is recommended to perform a blood test for total protein, blood test for albumin, blood test for total bilirubin, blood test for free and conjugated bilirubin, blood test for creatinine, blood test for urea, blood test for uric acid, blood test for glucose, blood test for ferritin, blood test for triglycerides, blood test for cholesterol, blood test for sodium, blood test for potassium, blood test for total calcium, determination of lactate dehydrogenase activity in blood, determination of aspartate aminotransferase activity in blood, determination of alanine aminotransferase activity in blood, determination of gamma-glutamyltransferase activity in blood, determination of alkaline phosphatase activity in blood, blood serum iron test, low-density lipoprotein cholesterol test, high-density lipoprotein cholesterol test in blood, determination of creatine kinase activity in blood, determination of pancreatic amylase activity in blood, and determination of lipase activity in blood in all patients to monitor disease activity, liver, kidney, and pancreatic function, and electrolyte balance during immunosuppressive and/or biological therapy [1,3,32,42,64,65,430,561]. (LoE 5, GoR C)

Comments: an increase in creatinine and/or urea, and/or uric acid, and/or total bilirubin, and/or K, and/or cholesterol, and/or triglycerides; an increase in LDH and/or ALT, and/or AST, and/or GGT, and/or ALP, and/or amylase activity may be an adverse manifestation of treatment with NSAIDs and/or immunosuppressants, and/or biologic agents, and/or GCs.

Serum iron during disease remission corresponds to reference values.

Comments: previously prescribed oral GCs should be continued. Repeat the general biochemical blood test in 1 week.

• It is recommended to resume therapy with the immunosuppressant and/or biological DMARD in all patients at the same dose after normalization of general clinical blood chemistry parameters in order to maintain JIA remission [1,3,32,213,356,430]. (LoE 5, GoR C)

• It is recommended to adjust the therapy with an immunosuppressant and/or biological DMARD in all patients in the presence of data on repeated episodes of elevated biochemical parameter(s) in order to control adverse events associated with therapy [1,3,32,430]. (LoE 5, GoR C)

• It is recommended to test the serum C-reactive protein level in all patients to monitor the degree of activity of the underlying disease and the development of infectious complications [1,3,32,42,44,68,356,430,561]. (LoE 3, GoR C)

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

If the serum C-reactive protein level increases, it is necessary to evaluate clinical and other markers of inflammatory activity of JIA; if they are absent, infectious complications and/or macrophage activation syndrome (MAS) should be ruled out.

Comments: an elevated blood procalcitonin level combined with leukocytosis/leukopenia and an elevated serum C-reactive protein level indicates the development of an acute inflammatory response (sepsis). In JIA without infectious complications, it remains within reference values.

Comments: performed in patients with febrile, hectic fever, leukocytosis/leukopenia, thrombocytopenia, elevated serum C-reactive protein and procalcitonin levels not associated with JIA activity.

Comments: off-label systemic antibacterial agents (J01) are prescribed by decision of the medical board, after obtaining informed consent from parents and children over 15 years of age.

Upon the development of sepsis, the administration of biologic agents and injections/intake of immunosuppressants are suspended for the entire duration of antibiotic treatment. Previously prescribed oral GCs should be continued.

With increasing JIA activity, pulse therapy with #methylprednisolone** (see above) is performed and/or oral glucocorticoids are prescribed (dose increased) (see JIA treatment).

• It is recommended to temporarily discontinue the immunosuppressant and/or biological DMARD and continue previously prescribed oral glucocorticoids for the entire period of etiotropic therapy upon the development of sepsis/infectious complication in order to prevent toxic reactions and the progression of the infectious process [1,3,32,565]. (LoE 5, GoR C)

• It is recommended to resume therapy with the immunosuppressant and/or biological DMARD no earlier than one week after the complete resolution of clinical and laboratory signs of sepsis and completion of antibacterial therapy in all patients to maintain JIA remission [1,3,32,213,430,565]. (LoE 5, GoR C)

• It is recommended to determine prothrombin index, test blood soluble fibrin monomer complexes, determine prothrombin (thromboplastin) time in blood or plasma, determine activated partial thromboplastin time, determine thrombin time in blood, test blood plasminogen level, test blood fibrinogen level, determine blood D-dimer concentration, test von Willebrand factor activity and properties in blood, and determine antithrombin III activity in blood in patients with signs of vasculitis and/or sepsis and/or MAS in order to assess the state of the hemostatic system [3,32,42,46–49,51,53–55,65,561]. (LoE 5, GoR C)

• It is recommended to perform thromboelastography in patients with signs of vasculitis and/or sepsis, and/or macrophage activation syndrome (MAS), signs of hyper- and/or hypocoagulation, and patients receiving antithrombotic agents (B01A) to assess the efficacy of anticoagulant therapy and determine further management strategy [47,50,51,56–59,246,247,563]. (Level of Evidence: 4, Strength of Recommendation: C)

• It is recommended to test blood heparin levels in patients with vasculitis to assess the hemostatic system status and the efficacy of anticoagulant therapy [47,50,51,56,57,244,563]. (Level of Evidence: 5, Strength of Recommendation: C)

• It is recommended to prescribe/adjust therapy with antithrombotic agents (B01A): heparin group drugs (B01B) or direct factor Xa inhibitors (B01AF); antiplatelet agents excluding heparin (B01AC); antifibrinolytic agents (B02A) in the event of hypercoagulation, coagulopathy, or disseminated intravascular coagulation according to coagulogram data (screening hemostasis test) and thromboelastogram to normalize hemocoagulation [46,47,50,51,57,245,356]. (Level of Evidence: 5, Strength of Recommendation: C)

Comments: off-label use of antithrombotic agents (B01A) is determined by a medical commission decision, after obtaining informed consent from parents and children aged over 15 years.

Comments: in the event of consumption coagulopathy, blood transfusion is performed in the form of transfusion of blood and blood products (B05A): packed red blood cells, fresh frozen plasma, coagulation factor VII, platelet concentrate, etc., according to indications.

Comments: an increase in the levels of anti-nuclear antibodies and/xor anti-double-stranded DNA antibodies is observed during TNF-alpha inhibitor treatment and indicates the development of a lupus-like syndrome.

If lupus-like syndrome develops, TNF-alpha inhibitors are discontinued and the patient is switched to a biologic DMARD with a different mechanism of action.

An increase in RF and anti-CCP levels indicates an increase in the immunological activity of the disease.

Comments: decreased immunoglobulin levels occur in secondary immunodeficiency states, predominantly during treatment with #rituximab** under conditions of B-cell depletion.

• It is recommended to prescribe #normal human immunoglobulin** (J06BA) at a dose of 400 mg/kg, or at a dose of 500 mg/kg at least once every 2–4 weeks if adequate blood immunoglobulin levels are not achieved, until blood immunoglobulin levels normalize in case of hypogammaglobulinemia, with the aim of correcting blood immunoglobulin levels and preventing infectious complications during immunodeficiency secondary to immunosuppressive and/or biological therapy [1,3,32,430,567–571]. (Level of Evidence: 5, Strength of Recommendation: C)

• It is recommended to skip a scheduled #rituximab** infusion, continue treatment with the immunosuppressant and previously prescribed oral glucocorticoids (GC) in case of decreased blood immunoglobulin levels to manage adverse events associated with the therapy [1,3,32,430,567–571]. (Level of Evidence: 4, Strength of Recommendation: C)

• It is recommended to resume #rituximab** infusions after the recovery of blood immunoglobulin levels to maintain juvenile arthritis remission [1,3,32,430,567–571]. (Level of Evidence: 4, Strength of Recommendation: C)

• It is recommended to perform lymphocyte subset testing in all patients receiving #rituximab** (L01XC), as well as in patients with frequent viral, purulent bacterial infections, including opportunistic infections, to evaluate the main lymphocyte subpopulations [1,3,32,83,84,112,295–297,417,418,572–574]. (Level of Evidence: 4, Strength of Recommendation: C)

Comments: a decrease in T- and/or B-lymphocyte subpopulations and/or natural killer cells indicates the development of secondary immunodeficiency during treatment with an immunosuppressant and/or biologic agent. Complete depletion of CD19+ B lymphocytes develops during treatment with CD20+ monoclonal antibodies, #rituximab**.

• 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 patients with clinical manifestations of Epstein-Barr virus infection and/or fever, and/or when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography, to identify active Epstein-Barr virus infection as an infectious complication developing against the background of treatment with immunosuppressants and/or biologic agents combined with (or without) glucocorticoids, and to address the issue of etiotropic therapy [1,3,32,81,113–118,299,575]. (Level of Evidence: 4, Strength of Recommendation: C)

• It is recommended to perform quantitative PCR testing for cytomegalovirus (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 patients with clinical manifestations of cytomegalovirus infection and/or fever, and/or when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography, to identify active cytomegalovirus infection as an infectious complication developing against the background of treatment with immunosuppressants and/or biologic agents combined with (or without) glucocorticoids, and to address the issue of etiotropic therapy [1,3,32,115,116,119–122]. (Level of Evidence: 4, Strength of Recommendation: C)

• It is recommended to perform quantitative PCR testing for herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in blood, qualitative PCR testing for herpes simplex virus types 1 and 2 DNA in oropharyngeal swabs, and qualitative PCR testing for herpes simplex virus types 1 and 2 DNA in urine in patients with clinical manifestations of herpetic infection and/or fever, and/or when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography, to identify active herpetic infection as an infectious complication developing against the background of treatment with immunosuppressants and/or biologic agents combined with (or without) glucocorticoids, and to address the issue of etiotropic therapy [1,3,32,115,116,119,123,576]. (Level of Evidence: 4, Strength of Recommendation: C)

• It is recommended to determine blood antibodies of classes M and G (IgM, IgG) to cytomegalovirus (Cytomegalovirus) in patients with clinical manifestations of cytomegalovirus infection and/or fever, and/or when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography, to identify active cytomegalovirus infection as an infectious complication developing against the background of treatment with immunosuppressants and/or biologic agents combined with (or without) glucocorticoids, and to address the issue of etiotropic therapy [1,115,119,121,122,124,125]. (Level of Evidence: 4, Strength of Recommendation: C)

• It is recommended to determine blood antibodies of classes M and G (IgM, IgG) to Epstein-Barr virus (Epstein-Barr virus) in patients with clinical manifestations of Epstein-Barr virus infection and/or fever, and/or when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography, to identify active Epstein-Barr virus infection as an infectious complication developing against the background of treatment with immunosuppressants and/or biologic agents combined with (or without) glucocorticoids, and to address the issue of etiotropic therapy [3,32,113,115,119,126]. (Level of Evidence: 4, Strength of Recommendation: C)

• It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus (Epstein-Barr virus) in the blood of patients with clinical manifestations of Epstein-Barr virus infection and/or fever, and/or when interstitial and/or focal and/or infiltrative lung changes are detected on chest computed tomography, to identify active Epstein-Barr virus infection as an infectious complication developing against the background of treatment with immunosuppressants and/or biologic agents combined with (or without) glucocorticoids, and to address the issue of etiotropic therapy [3,32,113,115,119,126]. (Level of Evidence: 5, Strength of Recommendation: C)

• It is recommended to determine class G antibodies (IgG) to early proteins (EA) of Epstein-Barr virus in the blood of patients with clinical manifestations of Epstein-Barr virus infection and/or with fever, and/or upon detection of interstitial and/or focal, and/or infiltrative changes in the lungs according to computed tomography of the chest organs in order to detect active Epstein-Barr virus infection as an infectious complication that developed during treatment with immunosuppressants and/or bDMARDs combined with (or without) GCs and to address the issue of etiotropic therapy [3,32,113,115,119,126]. (LoE 5, GoR C)

• It is recommended to determine antibodies to Herpes simplex virus in the blood of patients with clinical manifestations of herpetic infection and/or with fever, and/or upon detection of interstitial and/or focal, and/or infiltrative changes in the lungs according to computed tomography of the chest organs in order to detect active herpetic infection as an infectious complication that developed during treatment with immunosuppressants and/or bDMARDs combined with (or without) GCs and to address the issue of etiotropic therapy [1,3,32,81,115,119,127,128,130,577]. (LoE 4, GoR C)

• It is recommended to prescribe #acyclovir** (JO5AB) at a dose of 200 mg orally 5 times a day (not exceeding 1000 mg/day) for children older than 2 years or at a dose of 5–10 mg/kg/infusion intravenously every 8 hours in the event of local herpetic infection; prescribing #acyclovir** at a dose of 10 mg/kg/infusion intravenously every 8 hours in children aged < 1 year; at a dose of 500 mg/m² intravenously every 8 hours in children aged ≥ 1 year in the event of Herpes zoster in accordance with clinical guidelines for the treatment of herpesvirus infections in children, including those with immunocompromised status [3,32,213,503,504,507,508]. (LoE 5, GoR C)

Comments: #acyclovir** (JO5AB) in children aged < 3 years is prescribed by decision of a medical commission, after obtaining informed parental consent.

Treatment with #acyclovir** is carried out for 7–10 days until the complete resolution of herpetic eruptions.

Comments: #ganciclovir** (JO5AB) in children aged < 12 years is prescribed by decision of a medical commission, after obtaining informed parental consent and approval from the local ethics committee of the medical organization.

Comments: Administration of immunosuppressants and/or bDMARDs is discontinued for the duration of antiviral therapy. Previously prescribed oral GCs should be continued.

• It is recommended to resume therapy with the immunosuppressant and/or bDMARD in all patients no earlier than 1 week after the complete resolution of clinical and laboratory signs of infection and the completion of antiviral therapy [1,3,32,213,430,565,574,578,579]. (LoE 5, GoR C)

• It is recommended to screen for the presence/absence of tuberculosis (focal tuberculin skin test, test with recombinant tuberculosis allergen in standard dilution**, blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens, computed tomography of the chest organs) in all patients receiving bDMARDs and/or immunosuppressants combined with (or without) GCs at least twice a year [1,3,32,88,90,91,91,94,212,213,430,580]. (LoE 5, GoR C)

• It is recommended to withdraw the immunosuppressant and/or bDMARD in all patients with a detected positive intradermal tuberculin test (papule > 5 mm) and/or elevated interferon-gamma levels, and/or lung lesions, and/or intrathoracic lymphadenopathy [1,3,32,88,90,91,91,94,212,213,430,580]. (LoE 5, GoR C)

Comments: Previously prescribed oral GCs should be continued.

Comments: if a tuberculous infection without a focus is detected, specific anti-tuberculosis chemotherapy is administered for 3–6 months (as decided by the phthisiatrician). Treatment with the immunosuppressant is continued under the supervision of a rheumatologist, complete blood count (CBC), and general biochemical blood tests; the issue of continuing bDMARD therapy is decided on an individual basis.

Comments: the issue of resuming and selecting bDMARDs and/or an immunosuppressant is resolved after the completion of specific chemotherapy and a consultation with a phthisiatrician.

Comments: the issue of continuing bDMARD 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 Yersinia enterocolitica serovars in the blood in all patients in order to detect infection with enteric bacteria that developed during treatment with immunosuppressants and/or bDMARDs combined with (or without) GCs [1,3,32,124,582–589]. (LoE 5, GoR C)

• It is recommended to determine class M and G antibodies (IgM, IgG) to Shigella boydii in the blood, determine antibody classes to Shigella dysenteriae in the blood, determine class M and G antibodies (IgM, IgG) to Shigella sonnei in the blood, and determine class M and G antibodies (IgM, IgG) to Shigella flexneri in the blood in all patients in order to detect infection with enteric bacteria that developed during treatment with immunosuppressants and/or bDMARDs combined with (or without) GCs [1,3,32,124,582–589]. (LoE 5, GoR C)

• It is recommended to perform etiotropic therapy upon the detection of class A and M antibodies in diagnostic titer, as well as high-titer class G antibodies to Yersinia pseudotuberculosis, Yersinia enterocolitica serovars, Salmonella enterica, Salmonella typhi, Shigella boydii, Shigella dysenteriae, Shigella sonnei, and Shigella flexneri in the blood in accordance with clinical guidelines for the diagnosis and treatment of intestinal infections in children [1,3,32,124,582–589]. (LoE 5, GoR C)

Comments: Administration of bDMARDs and injections/intake of immunosuppressants are discontinued for the entire period of systemic antibacterial drug therapy. Previously prescribed oral GCs should be continued.

Treatment with bDMARDs and/or immunosuppressants is resumed no earlier than 1 week after the decrease in laboratory markers of infection and completion of antibacterial therapy.

• It is recommended to determine class A, M, and G antibodies (IgA, IgM, IgG) to Chlamydia psittaci in the blood; determine antibodies to Chlamydia trachomatis in the blood; determine antibodies to Chlamydophila pneumoniae in the blood, and determine class M and G antibodies (IgM, IgG) to Mycoplasma pneumoniae in the blood in all patients in order to detect mycoplasma and chlamydial infection that developed during treatment with immunosuppressants and/or bDMARDs combined with (or without) GCs [1,3,32,95,582,585–590]. (LoE 5, GoR C)

• It is recommended to perform etiotropic therapy upon the detection of class A and M antibodies in diagnostic titer, as well as high-titer class G antibodies to Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, and Chlamydophila pneumoniae in the blood in all patients in accordance with clinical guidelines for the diagnosis and treatment of mycoplasma and chlamydial infection in children [1,3,32,95,582,585–590]. (LoE 5, GoR C)

Comments: Administration of bDMARDs and injections/intake of immunosuppressants are discontinued for the entire period of systemic antibacterial drug therapy. Previously prescribed oral GCs should be continued.

Treatment with bDMARDs and/or immunosuppressants is resumed no earlier than 1 week after the decrease in laboratory markers of infection and completion of antibacterial therapy.

Comments: if nasopharyngeal contamination by pathogenic and/or opportunistic microorganisms is detected, an appointment (examination, consultation) with an otolaryngologist is performed to address the issue of sanitization.

In the absence of clinical manifestations, bDMARD and/or immunosuppressant therapy is not discontinued.

If inflammatory changes in the nasopharynx are present, antibacterial therapy is administered. bDMARD treatment and immunosuppressant injections/intake are suspended for the duration of antiviral therapy. Previously prescribed oral GCs should be continued. Treatment with bDMARDs and/or immunosuppressants is resumed no earlier than 1 week after the complete resolution of clinical and laboratory signs of infection and completion of antiviral therapy.

Comments: the presence of isolated microhematuria may be an adverse event of NSAID and/or methotrexate** therapy.

If persistent microhematuria develops, methotrexate** is discontinued. Administration of biologic DMARDs should be continued, and immunosuppressive therapy is adjusted.

The presence of proteinuria may indicate the development of secondary renal amyloidosis.

Comments: performed in all patients. In patients with juvenile arthritis in remission, no pathological changes are detected on ECG

• It is recommended to perform 24-hour Holter monitoring in patients with arrhythmia or pathological ECG findings to determine the type of arrhythmia [1,3,32,34,315,317,430]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform 24-hour ambulatory blood pressure monitoring in patients with arterial hypertension to detect blood pressure deviations from the norm and develop an antihypertensive treatment strategy [1,3,32,34,317,430,591]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform a comprehensive ultrasound examination of internal organs (including comprehensive abdominal ultrasound and renal ultrasound) in all patients to detect/rule out pathological changes [1,3,32,430]. (Level of Evidence 5, Grade of Recommendation C)

Comments: performed in all patients. Examination may reveal: mild hepatomegaly, biliary dyskinesia, reactive changes in the pancreas, gallbladder wall thickening, gastric and intestinal wall thickening. All changes may be associated with adverse events of NSAID and/or glucocorticoid, and/or immunosuppressive therapy.

Comments: performed in all patients. In patients with juvenile arthritis in remission, no pathological changes are detected on echocardiography.

• It is recommended to perform esophagogastroduodenoscopy with or without anesthesia (including early postoperative management) in patients receiving NSAIDs (M01A) and/or glucocorticoids (H02AB), and in patients with dyspeptic symptoms to rule out upper gastrointestinal inflammatory diseases associated with the underlying disease and/or Helicobacter pylori and/or the use of NSAIDs and/or glucocorticoids [3,32,160,161,183–191]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to perform a microbiological (culture) examination of gastric mucosal biopsies for *Helicobacter pylori* in patients with inflammatory and/or erosive and/or ulcerative changes according to esophagogastroduodenoscopy, in order to rule out GI pathology associated with *Helicobacter pylori* [3,32,160,161,184–188,190–193]. (Reliability Level of Evidence 4, Recommendation Grade C)

• It is recommended to prescribe drugs for the treatment of peptic ulcer disease and gastroesophageal reflux disease (A02B) when reflux disease and/or inflammatory gastropathy, erosive and/or ulcerative processes in the esophagus and/or stomach, and/or duodenum are detected by esophagogastroduodenoscopy, in accordance with clinical guidelines for the treatment of inflammatory gastropathy and gastroesophageal reflux disease in children and international guidelines [3,32,184]. (Level of Evidence 5, Grade of Recommendation C)

Comments: for the duration of anti-inflammatory therapy, administration of bDMARDs and/re-injections/intake of immunosuppressants are suspended; previously prescribed GCs should be continued.

Resumption of treatment with biologic DMARDs and/or immunosuppressants is carried out after the end of anti-inflammatory therapy.

Comments: eradication therapy outside of approved age indications is prescribed by decision of a medical commission, after obtaining informed consent from parents and children aged ≥ 15 years.

Comments: previously prescribed glucocorticoids should be continued. Resumption of treatment with immunosuppressants and/or biologic DMARDs is carried out after the end of eradication therapy.

• It is recommended to perform magnetic resonance imaging of a joint (single joint) with or without anesthesia (including early postoperative management) in all patients to monitor therapy efficacy [1,3,32,166,170,318,319]. (Level of Evidence 1, Grade of Recommendation B)

• It is recommended to perform computed tomography of the chest organs in all patients with anesthesia (including early postoperative management) to monitor the infection safety of antirheumatic therapy and rule out pneumonia and tuberculosis [32,88,90,200,201,212]. (Level of Evidence 4, Grade of Recommendation C)

Comments: during treatment with biologic DMARDs, especially in combination with immunosuppressants and glucocorticoids, pneumonia (interstitial, focal, lobar, polysegmental) may develop.

Interstitial pneumonia most commonly develops during treatment with #rituximab**, less commonly with tocilizumab**, and extremely rarely with TNF-alpha inhibitors and abatacept**.

Interstitial pneumonia should be suspected if low-grade/high-grade fever, dry cough/cough with a small amount of sputum, dyspnea, crackles/decreased breath sounds on auscultation appear.

Focal or lobar pneumonia develops more frequently during treatment with tocilizumab** and TNF-alpha inhibitors, and less frequently with #rituximab** and abatacept**.

Pneumonia developing during treatment with tocilizumab** or, less commonly, TNF-alpha inhibitors is characterized by low-grade fever or its complete absence, sparse clinical presentation, and no elevation of acute-phase inflammatory markers: ESR, blood leukocyte count, and serum C-reactive protein 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 all patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to obtain bronchoalveolar lavage fluid and analyze it [90,124,212,267,270,271,273,300,313,314]. (Level of Evidence 3, Grade of Recommendation B)

• It is recommended to perform microbiological (culture) testing of bronchoalveolar lavage fluid for Pneumocystis carinii cysts in all patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to confirm/rule out pneumocystis etiology of pneumonia and decide on etiotropic therapy [267,270–273,276,277,279,280,301–303]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to perform quantitative PCR detection of Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, or bronchoalveolar lavage fluid in all patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to confirm/rule out pneumocystis etiology of pneumonia and decide on etiotropic therapy [112,270–273,276–278,301–304]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to determine blood class M and G antibodies to Pneumocystis jirovecii in all patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to identify the etiology of pneumonia and decide on etiotropic therapy [112,270–273,276–278,301–304,592]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to perform microbiological (culture) testing of sputum for fungi (yeasts and molds) in all patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to identify the etiology of pneumonia and decide on etiotropic therapy [124,267,270–273,313,314]. (Level of Evidence 3, Grade of Recommendation B)

• It is recommended to perform microbiological (culture) testing of bronchoalveolar lavage fluid for fungi (yeasts and molds) in all patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to identify the etiology of pneumonia and decide on etiotropic therapy [124,267,270–273,313,314]. (Level of Evidence 3, Grade of Recommendation B)

• It is recommended to perform microbiological (culture) testing of lavage fluid for aerobic and facultatively anaerobic microorganisms in all patients with interstitial, focal, and/or infiltrative lung changes detected on chest computed tomography to identify the etiology of pneumonia and decide on etiotropic therapy [124,267,270–273,313,314]. (Level of Evidence 3, Grade of Recommendation B)

• It is recommended to determine antibodies to fungi of the genus Aspergillus (Aspergillus spp.) in the blood of all patients with interstitial and/or focal, and/or infiltrative changes in the lungs according to computed tomography of the chest cavity in order to identify the etiology of pneumonia and resolve the issue of etiotropic therapy [124,270–273,282,313,314,593,594]. (CLE 3, LEV C)

• It is recommended to determine mannan and galactomannan in lavage fluid and blood in all patients with interstitial and/or focal, and/or infiltrative changes in the lungs according to computed tomography of the chest cavity in order to identify the etiology of pneumonia and resolve the issue of etiotropic therapy [124,270–273,282,313,314,593,594]. (CLE 3, LEV B)

• It is recommended to determine Mycoplasma pneumoniae DNA in bronchoalveolar lavage fluid by PCR in all patients with interstitial and/or focal, and/or infiltrative changes in the lungs according to computed tomography of the chest cavity in order to identify the etiology of pneumonia and resolve the issue of etiotropic therapy [256–259,267,270,271,273]. (CLE 4, LEV C)

• 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 changes in the lungs according to computed tomography of the chest cavity in order to identify the etiology of pneumonia and resolve the issue of etiotropic therapy [116,124,267,270,271,311]. (CLE 5, LEV C)

• It is recommended to determine Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG) DNA with species differentiation in sputum, bronchoalveolar lavage fluid, or bronchial washings by PCR in all patients with interstitial and/or focal, and/or infiltrative changes in the lungs according to computed tomography of the chest cavity in order to identify the etiology of pneumonia and resolve the issue of etiotropic therapy [90,112,124,212,267,270,271,305–310,595]. (CLE 4, LEV C)

• It is recommended to prescribe empirical antibacterial therapy: #cotrimoxazole** (J01EE) in combination with systemic antibacterial drugs (J01) active against gram-positive, gram-negative, and anaerobic flora (penicillin combinations, including beta-lactamase inhibitor combinations (J01CR) and/or 4th generation cephalosporins (J01DE), and/or carbapenems (J01DH), and/or other antibacterial drugs (J01X)) combined with systemic antifungals (J02A) and systemic antivirals (J05) before identifying the etiological factor of interstitial pneumonia, depending on the clinical situation, in accordance with the guidelines for the treatment of pneumonia in immunocompromised children in order to prevent the progression of the infectious process [150,151,276,303,521,585–589,596–598]. (CLE 5, LEV C)

Comments: systemic antibacterial drugs (J01), systemic antifungals (J02A), and systemic antivirals (J05) used off-label regarding age are prescribed by decision of the medical commission after obtaining informed consent from parents and children over 15 years of age.

The administration of biologic DMARDs and injections/administration of immunosuppressants are suspended for the duration of antibacterial therapy. Previously prescribed oral glucocorticoids should be continued. If signs of respiratory failure appear, the patient is transferred to the intensive care unit;

Treatment with tbDMARDs and immunosuppressants should be resumed no earlier than 1 week after complete resolution of pneumonia according to laboratory tests, follow-up computed tomography of the chest with or without anesthesia support (including early postoperative management), and completion of antibacterial therapy; prescription/adjustment of tbDMARDs is carried out after resolution of clinical, radiological, and laboratory signs of interstitial pneumonia.

• It is recommended to prescribe targeted antibacterial therapy: #cotrimoxazole** (J01EE) in combination with systemic antibacterial drugs (J01) active against gram-positive, gram-negative, and anaerobic flora (penicillin combinations, including beta-lactamase inhibitor combinations (J01CR) and/or 4th generation cephalosporins (J01DE), and/or carbapenems (J01DH), and/or other antibacterial drugs (J01X)) combined with systemic antifungals (J02A) and systemic antivirals (J05) upon confirmation of the etiological factor of pneumonia, depending on the clinical situation, in accordance with the guidelines for the treatment of pneumonia in immunocompromised children in order to prevent the progression of the infectious process [150,151,276,303,521,585–589,596–598]. (CLE 5, LEV C)

• It is recommended to prescribe intravenous glucocorticoids and #cotrimoxazole** (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 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, in accordance with international guidelines for the treatment of immunocompromised children [3,32,276,303]. (CLE 5, LEV C)

Comments: #cotrimoxazole** (J01EE) used off-label regarding age is prescribed by decision of the medical commission after obtaining informed consent from the parents. If signs of respiratory failure appear, the patient is transferred to the intensive care unit. Administration of biologic DMARDs and injections/administration of immunosuppressants are discontinued during antibacterial therapy. Previously prescribed oral glucocorticoids should be continued. Treatment with biologic DMARDs and immunosuppressants is resumed no earlier than 1 week after complete resolution of pneumonia according to laboratory tests, follow-up computed tomography of the chest cavity with or without anesthetic support (including early postoperative management), and completion of antibacterial therapy; prescription/adjustment of biologic DMARDs is carried out after the resolution of clinical, radiological, and laboratory signs of interstitial pneumonia.

Comments: Administration of tbDMARDs and injections/intake of immunosuppressants are discontinued during antibacterial therapy. Previously prescribed oral GCs should be continued. If signs of respiratory failure appear, the patient is transferred to the intensive care unit. Treatment with tbDMARDs and immunosuppressants is resumed no earlier than 1 week after complete resolution of pneumonia according to laboratory tests, follow-up computed tomography of the chest with or without anesthesia support (including early postoperative management), and completion of antibacterial therapy; prescription/adjustment of tbDMARDs is carried out after resolution of clinical, radiological, and laboratory signs of interstitial pneumonia.

Comments: Administration of tbDMARDs and injections/intake of immunosuppressants are discontinued during antibacterial therapy. Previously prescribed oral GCs should be continued. If signs of respiratory failure appear, the patient is transferred to the intensive care unit. Treatment with tbDMARDs and immunosuppressants is resumed no earlier than 1 week after complete resolution of pneumonia according to laboratory tests, follow-up computed tomography of the chest with or without anesthesia support (including early postoperative management), and completion of antibacterial therapy; prescription/adjustment of tbDMARDs is carried out after resolution of clinical, radiological, and laboratory signs of interstitial pneumonia.

Comments: systemic antibacterial drugs (J01) used off-label regarding age are prescribed by decision of the medical commission after obtaining informed consent from the parents.

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

Comments: performed no more than once every 12 months, or earlier if indicated.

• It is recommended to perform X-ray densitometry in all patients receiving or having received glucocorticoids to detect osteopenia/osteoporosis [327,328]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to prescribe calcium preparations (A12A) and vitamin D and its analogues (A11CC) to patients with osteopenia/osteoporosis in accordance with clinical guidelines for the diagnosis and treatment of secondary osteoporosis in children to prevent the progression of osteoporosis and the development of its complications [327,328,528,601]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to prescribe #pamidronic acid or #alendronic acid**, or #zoledronic acid**, or #ibandronic acid to patients with osteopenia/osteoporosis for the treatment of osteoporosis [328,512,602–605]. (Level of Evidence 5, Grade of Recommendation C)

Comments: bisphosphonates (M05BA) are prescribed for life-saving indications, by decision of the medical commission, after obtaining informed consent from the parents and children aged ≥ 15 years.

• The following regimens for prescribing bisphosphonates (M05BA) are recommended:

  — #pamidronic acid (maximum dose 60 mg/infusion) [602]:

  • for patients < 1 year at a dose of 0.5 mg/kg IV every 2 months,

  • in patients aged 1–2 years at a dose of 0.25–0.5 mg/kg/day IV for 3 days every 3 months,

  • in patients aged 2–3 years at a dose of 0.375–0.75 mg/kg/day IV for 3 days every 3 months,

  • in patients older than 3 years at a dose of 0.5–1 mg/kg/day IV for 3 days every 4 months.

  — or #alendronic acid** (maximum dose 70 mg/week) [602]:

  • at a dose of 1–2 mg/kg/week orally,

  • for patients with body weight < 40 kg at a dose of 5 mg/day or 35 mg/week,

  • for patients with body weight > 40 kg at a dose of 10 mg/day or 70 mg/week.

  — or #zoledronic acid** at a dose of 0.0125–0.05 mg/kg/infusion IV every 6–12 months (maximum dose 4 mg) [602];

  — or #ibandronic acid:

  • at a dose of 3 mg/infusion IV once every 3 months [603]

  • or 150 mg orally once a month [604]

• to patients with osteopenia/osteoporosis for the treatment of osteoporosis [328,512,602–605]. (Level of Evidence 5, Grade of Recommendation C)

Comments: bisphosphonates (M05BA) are prescribed for life-saving indications, by decision of the medical commission, after obtaining informed consent from the parents and children aged ≥ 15 years.

• It is recommended to perform an initial consultation (examination, check-up) by an otorhinolaryngologist in all patients to identify foci of chronic infection of the ENT organs and address the issue of their sanitation for the prevention of infectious conditions under treatment with immunosuppressants and/or biologic DMARDs combined (or not) with glucocorticoids; to assess the efficacy of ENT organ sanitation in patients who have undergone it [1,3,32,45,95,329,430]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination, check-up) by a pediatric dentist in all patients receiving immunosuppressants and/or biologic DMARDs combined (or not) with glucocorticoids, to determine the state of the oral cavity, resolve the issue of its sanitation or assess its efficacy [1,3,32,45,330,430]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination, check-up) by an ophthalmologist with mandatory biomicroscopy of the eye in all patients to rule out uveitis, as well as in patients receiving glucocorticoids to rule out complicated cataract [1,3,4,15,32,45,332,333,430]. (Level of Evidence 5, Grade of Recommendation C)

Comments: children at high risk for developing uveitis (patients with RF-negative oligo- or polyarthritis, positive ANA, juvenile ankylosing spondylitis, disease onset before 7 years of age, and disease duration under 4 years) must be examined by an ophthalmologist at least once every 3 months.

Children at moderate and low risk of developing uveitis (RF-positive oligo- and polyarthritis with negative ANA, onset after 7 years of age, and disease duration of more than 4 years) must be examined by an ophthalmologist at least once every 6 months.

During uveitis therapy, including local agents – examination by an ophthalmologist at least once a month.

In patients with complicated cataract, treatment efficacy is monitored and the need for surgical treatment is determined.

• It is recommended to perform an initial consultation (examination, check-up) by a pediatric cardiologist in patients with cardiac dysfunction and/or arterial hypertension to address the issue of cardiotropic and/or antihypertensive therapy [3,4,34,45,334,430]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination, check-up) by a phthisiatrician in all patients with a positive focal tuberculin test and/or intradermal test with tuberculosis allergen, and/or elevated interferon-gamma levels in response to Mycobacterium tuberculosis complex antigens in the blood, and/or focal or infiltrative lung changes to address the issue of chemoprophylaxis or antituberculosis chemotherapy [1,3,4,45,45,86,88,91,92,213,580,581]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination, check-up) by a pediatric endocrinologist in patients with endocrinological pathology, including those receiving glucocorticoids, to monitor treatment efficacy [1,3,4,32,327,328,335,336]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination, check-up) by a dietitian in patients with underweight, amyotrophy, osteopenia/osteoporosis, constitutional obesity and Cushing's syndrome, steroid diabetes to develop an individual dietary program and recommendations for eating behavior in outpatient settings [1,3,32,45,340,341,430]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination, check-up) by a traumatologist-orthopedist in all patients with functional joint insufficiency, bone length growth disorders, subluxations, back pain, to address the issue of reconstructive surgery and joint replacement [1,3,32,45,214,430,525]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (examination, check-up) by a neurologist in all patients with neurological symptoms, psychomotor developmental delay, psychotic reactions to address the issue of therapy [1,3,4,32,45,216,430]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform a follow-up consultation (examination, check-up) by a neurologist in all patients with neurological symptoms, psychomotor developmental delay, psychotic reactions to assess the efficacy of the therapy administered [1,3,4,32,45,216,430]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform an initial consultation (testing, check-up) by a medical psychologist in all patients aged 1 year and older and their parents to harmonize the process of child personality formation under conditions of a severe chronic disease and optimize child-parent relationships; to increase treatment adherence and cooperation with the physician and medical personnel to achieve disease remission and psychological adaptation in society [1,3,32,221–227,338,430]. (Level of Evidence 2, Grade of Recommendation A)

• It is recommended to perform an initial examination (consultation) by a physical therapy physician in all patients with functional insufficiency to develop a physiotherapy program within the individual rehabilitation program [1,3,32,337,430,529–531,606]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform a follow-up examination (consultation) by a physical therapy physician in patients after completing the physiotherapy program to assess its efficacy [1,3,32,48,337,430,529,530,606]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform a consultation (examination, check-up) by an exercise therapy physician in all patients with functional insufficiency to develop an exercise therapy set within the individual rehabilitation program [1,3,32,337,430,529–531,607]. (Level of Evidence 1, Grade of Recommendation C)

• It is recommended to provide medical rehabilitation to all patients with functional insufficiency to restore functional capacity [1,3,32,337,430,529–541]. (Level of Evidence 2, Grade of Recommendation B)

• It is recommended to perform a follow-up consultation (examination, check-up) by an exercise therapy physician in all patients with functional insufficiency after completion of the rehabilitation program to assess its efficacy [1,3,32,337,430,529–531,607]. (Level of Evidence 1, Grade of Recommendation C)

• It is recommended to perform an initial examination (consultation) by an anesthesiologist-intensivist in patients scheduled for procedures under general anesthesia, to assess their condition [60,61,218–220]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to adjust anti-rheumatic therapy in the inpatient rheumatology department that initiated treatment with a biologic DMARD and/or immunosuppressant if the inactive disease stage is not achieved at 6 months, remission at 12 months, and further every 6 months [1,3,32,430]. (Level of Evidence 5, Grade of Recommendation C)

Monitoring of treatment efficacy – see Appendices G1-G4

5.2.1. Oncological alertness in patients with systemic juvenile idiopathic arthritis receiving bDMARDs/immunosuppressants

Considering that one of the adverse effects of bDMARD therapy is oncological/oncohematological/lymphoproliferative diseases, it is essential to maintain oncological alertness at any stage of treatment (both in inpatient settings and during follow-up dispensary observation).

• It is recommended to maintain oncological alertness due to the potential development of oncological/onco-hematological/lymphoproliferative diseases during targeted biologic therapy at any stage of treatment [3,32,81,168,169,204–208,608]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to immediately discontinue the immunosuppressant/targeted biologic and hospitalize the patient if an oncological/onco-hematological/lymphoproliferative disease is suspected, in order to perform appropriate investigations [3,32,81,168,169,204–208,608]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to obtain a bone marrow cytologic specimen using anesthetic support (including early postoperative management) via puncture, along with a bone marrow histologic specimen with cytologic examination of a bone marrow smear (myelogram) and pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods, in patients receiving an immunosuppressant and/or targeted biologic with an atypical disease course, in order to rule out oncological/onco-hematological/lymphoproliferative diseases/metastatic bone marrow involvement [3,32,81,168,169,204–208,608]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to perform a lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) using anesthetic support (including early postoperative management) with cytologic 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 an immunosuppressant and/or targeted biologic and present with an atypical disease course, in order to rule out oncological/onco-hematological/lymphoproliferative diseases/metastatic lymph node involvement [3,32,81,168,169,204–208,608]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform contrast-enhanced magnetic resonance imaging of the brain, contrast-enhanced magnetic resonance imaging of the abdominal organs, contrast-enhanced magnetic resonance imaging of the retroperitoneal space, and contrast-enhanced magnetic resonance imaging of the pelvic organs, with or without anesthetic support (including early postoperative management), in patients receiving an immunosuppressant and/or targeted biologic with an atypical disease course, in order to rule out oncological/onco-hematological/lymphoproliferative diseases [3,32,81,168,169,204–208,608]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to perform contrast-enhanced computed tomography of the chest organs with intravenous bolus injection, with or without anesthetic support (including early postoperative management), in patients receiving an immunosuppressant and/or targeted biologic with an atypical disease course, in order to rule out pulmonary metastases/mediastinal organ involvement in oncological/onco-hematological/lymphoproliferative diseases [3,32,81,168,169,204–208,608]. (Level of Evidence 4, Grade of Recommendation 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 anesthetic support (including early postoperative management), in patients receiving an immunosuppressant and/or targeted biologic with an atypical disease course, in order to rule out oncological/onco-hematological diseases [3,32,81,168,169,204–208,608]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to perform computed tomography of the bone and computed tomography of the joint, with or without anesthetic support (including early postoperative management), in patients receiving an immunosuppressant and/or targeted biologic who have bone destruction foci that are atypical for juvenile arthritis, in order to rule out oncological/onco-hematological diseases [3,32,81,168,169,204–208,608]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to perform positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)), with contrast enhancement, and if necessary, whole-body positron emission tomography with tumor-tropic radiopharmaceuticals (diagnostic radiopharmaceuticals (V09)), with or without anesthetic support (including early postoperative management), in patients receiving an immunosuppressant and/or targeted biologic who present with severe arthralgia, myalgia, ossalgia, bone destruction changes, subcutaneous fat infiltrates, or lesions in parenchymal organs, the brain, or spinal cord, in order to rule out oncological/onco-hematological/lymphoproliferative diseases [1,3,32,168,210]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform multi-position bone scintigraphy, with or without anesthetic support (including early postoperative management), in patients receiving an immunosuppressant and/or targeted biologic who have bone destruction foci atypical for juvenile arthritis, in order to rule out malignant neoplasms/metastatic bone involvement [1,3,32,168,169,210]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform CT-guided trephine bone biopsy of the pelvis with anesthetic support (including early postoperative management), including pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods; cytologic examination of bone marrow trephine biopsy imprints; immunocytochemical examination of bone marrow trephine biopsy imprints; and immunophenotyping of hematopoietic progenitor cells in the bone marrow, in patients receiving an immunosuppressant and/or targeted biologic with an atypical disease course, in order to rule out hemoblastoses/lymphoproliferative diseases/metastatic bone marrow involvement [3,32,81,168,169,204–208,608]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended to perform a bone biopsy with anesthetic support (including early postoperative management) and pathomorphological examination of bone tissue biopsy (surgical) material in patients receiving an immunosuppressant and/or targeted biologic who have bone destruction foci atypical for juvenile arthritis, in order to rule out malignant neoplasms/metastatic bone involvement [3,32,81,168,169,204–208,608]. (Level of Evidence 4, Grade of Recommendation C)

• It is recommended that patients in whom an oncological/onco-hematological/lymphoproliferative disease or metastatic involvement is suspected or detected based on examination results undergo an initial consultation (examination) by a pediatric oncologist to decide on transferring the child to a specialized facility for further evaluation and treatment [3,32,81,168,169,204–208,608]. (Level of Evidence 4, Grade of Recommendation C)

5.3. Follow-up evaluation as part of dispensary observation in outpatient and polyclinic settings

(LoE 5, GoR C)

• It is recommended that all patients undergo a follow-up consultation (examination) by a rheumatologist (with an evaluation of therapy efficacy and safety at least once a month after initiation/adjustment of therapy and at least once every 3 months after achieving disease remission; assessing the need for referral for unplanned hospitalization to the inpatient rheumatology department that initiated therapy with a targeted biologic and/or immunosuppressant at any stage of treatment if exacerbation/complications, comorbidities, complications/side effects, or persistent intolerance to therapy develop; providing referrals for planned hospitalization to the inpatient rheumatology department that initiated therapy with a targeted biologic and/or immunosuppressant at 3 and 6 months after prescription/adjustment of therapy and every 6 months thereafter; and conducting remote consultations with the inpatient rheumatologist who initiated therapy, for all patients who develop any signs of inefficacy and/or intolerance to therapy) [1,3,32,430]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended that all patients undergo a consultation (examination) by a pediatrician to ensure continuity of care and referral for medical and social expertise [1,3,32,430, 618]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to schedule a follow-up outpatient appointment (examination, consultation) with a pediatrician or a district pediatrician for patients with juvenile arthritis in the absence of a rheumatologist at the patient's place of residence at least once a month after initiation/adjustment of therapy, and at least once every 3 months after achieving disease remission, in order to organize follow-up care and evaluate the efficacy and safety of therapy [1,3,32,430, 618]. (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.

Comments: currently, biosimilars of anti-tumor necrosis factor alpha (anti-TNF-alpha) agents, as well as generics of Janus kinase inhibitors, which are structurally equivalent to them, have been approved. Some of these drugs have demonstrated efficacy in clinical trials in adult patients similar to that of the original drugs [345].

Clinical trials of biosimilars and generics of immunosuppressants and selective immunosuppressants have not been conducted in the pediatric population with juvenile arthritis.

The indication for use in children and adolescents with juvenile arthritis aged 2 to 17 years and with a body weight of less than 62.5 kg applies only to the medicinal product etanercept "lyophilisate for solution for subcutaneous injection". The medicinal product etanercept "solution for subcutaneous injection" has a contraindication for use in children under 12 years of age and with a body weight of less than 62.5 kg [408–411].

According to the FAS clarification letter No. ТН/109573/21 dated December 22, 2021, and the medical instructions for the use of the medicinal product Etanercept [412]:

the use of the dosage form "solution for subcutaneous injection" instead of "lyophilisate for solution for subcutaneous injection" in children under 12 years of age and body mass less than 62.5 kg is not recognized as acceptable due to differences in the final concentration of solutions and the lack of studies allowing to evaluate the tolerability, efficacy, and pharmacokinetics of the 50 mg/ml solution in children. Thus, the substitution of the dosage form "lyophilisate for solution for subcutaneous injection" in this patient is impossible.

The original immunosuppressant and/or selective immunosuppressant, and/or biologic DMARD cannot be automatically replaced with a generic or biosimilar. Drug substitution may only be carried out based on a consensus of the attending physician who initiated therapy with the immunosuppressant and/or selective immunosuppressant, and/or biologic DMARD, after obtaining informed consent from parents and children over 15 years of age.

Automatic replacement of the initially prescribed immunosuppressant and/or selective immunosuppressant, and/or biologic DMARD may lead to a loss of therapeutic effect and the development of adverse events [342–344].

Comments: an allergic reaction may occur at any stage of treatment with a biologic DMARD and/or immunosuppressant.

Comments: the choice of drug and its route of administration depend on the severity of the allergic reaction.

• It is recommended to have an appointment (examination, consultation, including remote) with a hospital rheumatologist who initiated the therapy, in the event of an allergic reaction to the administration and/or infusion of a biologic DMARD and/or immunosuppressant, in order to decide on the need for therapy adjustment and the conditions under which it should be carried out [1,3,32,430,609]. (LoE 4, GoR C)

• It is recommended to perform an emergency hospitalization in the event of an allergic reaction to the administration and/or infusion of a biologic DMARD and/or immunosuppressant in order to decide on the need for therapy adjustment [1,3,32,430,609]. (LoE 4, 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 white blood cell count [leukocyte formula], and total hemoglobin level) in all patients at least once every 2–4 weeks to monitor disease activity and bone marrow-related adverse effects of antirheumatic drugs [1,3,32]. (LoE 5, GoR C)

• It is recommended to discontinue the immunosuppressant and/or bDMARD, while continuing the previously prescribed oral GCs if the platelet count decreases to ≤ 150 > 100×10⁹/L and the neutrophil count decreases to < 1.5 ≥ 1.0×10⁹/L according to the complete blood count with differential, in order to prevent the development of infectious complications [1,3,32,574,579]. (Level of Evidence 5, Grade of Recommendation C)

Comments: repeat the complete blood count with differential in one week.

Comments: for children aged < 1 year, #filgrastim**(L03AA) is prescribed by decision of a medical commission, following receipt of informed consent from the parents and approval by the local ethics committee of the medical organization.

Neutropenia is more commonly observed with the use of #rituximab** and tocilizumab**, less frequently with abatacept**, TNF-alpha inhibitors, and immunosuppressants.

Comments: previously prescribed oral GCs should be continued.

• It is recommended to continue therapy with the immunosuppressant and/or biological DMARD at the previous dose after normalization of the complete blood count and an increase in the blood neutrophil count to ≥ 1.5×10⁹/L in order to prevent an increase in disease activity/maintain disease remission [1,3,32]. (LoE 5, GoR C)

• It is recommended to prescribe fluconazole at 3–12 mg/kg/day, depending on the severity and duration of induced neutropenia, orally to patients with neutropenia for the prevention of fungal infections resulting from treatment with immunosuppressants and/or bDMARDs [1,3,32,430,562]. (LoE 4, GoR C)

• It is recommended to have an appointment (examination, consultation, including remote ones) with the hospital rheumatologist who initiated the therapy for all patients with a recurrent episode of decreased neutrophil count, development of febrile neutropenia, and/or decreased blood platelet count according to the complete blood count (CBC), to decide on the need for therapy adjustment and the setting in which it should be administered [1,3,32]. (LoE 5, GoR C)

• It is recommended to test blood total protein, blood albumin, total bilirubin, free and conjugated bilirubin, blood creatinine, blood urea, blood uric acid, blood glucose, blood ferritin, blood triglycerides, blood cholesterol, blood sodium, blood potassium, blood total calcium, lactate dehydrogenase (LDH) activity, aspartate aminotransferase (AST) activity, alanine aminotransferase (ALT) activity, gamma-glutamyl transferase (GGT) activity, and alkaline phosphatase (ALP) activity in serum for all patients at least once every 2–4 weeks to monitor disease activity, liver, kidney, and pancreatic function, as well as electrolyte balance during immunosuppressive and biologic therapy [1,3,32,574,579]. (LoE 5, GoR C)

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

Comments: a general biochemical blood test should be repeated in a week.

• It is recommended to continue immunosuppressive therapy and/or biologic DMARDs at the same dose after normalization of the biochemical parameter(s) to prevent an increase in disease activity / maintain disease remission [1,3,32]. (LoE 5, GoR C)

• It is recommended to conduct an in-person appointment (examination, consultation, including remote ones) with the inpatient rheumatologist who initiated the therapy, if there are data on repeated episodes of an increase in biochemical parameter(s), to resolve the issue of the need for therapy adjustment and the conditions under which it should be carried out [1,3,32]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to determine the blood level of rheumatoid factor (RF) and antibodies to cyclic citrullinated peptide (anti-CCP) at least once every 3 months in patients with seropositive juvenile arthritis to assess the immunological activity of the disease [1,3,4,65,68,70,71]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to determine the blood levels of antinuclear antibodies (ANA) and anti-DNA antibodies in all patients receiving TNF-alpha inhibitors at least once every 3 months to assess the immunological activity of the disease and monitor side effects developing during treatment with immunosuppressants and targeted biologic DMARDs [1,3,574,610]. (Level of Evidence 5, Strength of Recommendation C)

Comments: the serum levels of antinuclear antibodies and anti-DNA antibodies increase in patients receiving TNF-alpha inhibitors (most commonly adalimumab**) when an adverse event occurs, namely a lupus-like reaction.

• It is recommended to discontinue TNF-alpha inhibitor therapy while continuing previously prescribed subcutaneous or oral immunosuppressants and/or oral GCs if serum levels of antinuclear antibodies and anti-DNA antibodies increase, in order to prevent the development of drug-induced lupus [1,3,32]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to conduct an appointment (examination, consultation, including remote ones) with the inpatient rheumatologist who initiated the therapy, if serum levels of antinuclear antibodies and anti-DNA antibodies increase, to resolve the issue of the need for therapy adjustment and the conditions under which it should be carried out [1,3,32].

Comments: if autoantibody titers increase, the decision on the need for therapy adjustment and the setting in which it should be carried out is made by the hospital rheumatologist who initiated the therapy, based on the results of an appointment (examination, consultation, including remote) with the hospital rheumatologist who initiated the therapy.

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

Serum C-reactive protein levels increase with the development of infectious complications and exacerbation of the underlying disease.

An appointment (examination, consultation, including remote ones) is conducted with the inpatient rheumatologist who initiated the therapy.

The decision on the need for therapy adjustment and the conditions under 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 ones).

Comments: a decrease in blood immunoglobulin levels develops in secondary immunodeficiency states, predominantly during #rituximab** therapy under conditions of B-lymphocyte depletion.

• It is recommended to temporarily discontinue immunosuppressant and/or targeted biologic DMARD therapy while continuing previously prescribed oral GCs when blood immunoglobulin levels decrease, in order to prevent infectious complications [1,3,32,574,579]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to conduct an appointment (examination, consultation, including remote ones) with the inpatient rheumatologist who initiated the therapy, in case of decreased blood immunoglobulins, to resolve the issue of the need for therapy adjustment and the conditions under which it should be carried out [1,3,32]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to hospitalize patients with decreased blood immunoglobulin levels to administer replacement therapy with normal human immunoglobulin** [1,3,32]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to determine antistreptolysin-O in blood serum to detect/exclude infection with group A beta-hemolytic Streptococcus at least once every 3 months [1,3,32,44]. (Level of Evidence 5, Strength of Recommendation C)

Comments: an elevated serum anti-streptolysin-O level indicates acute or chronic streptococcal infection.

• It is recommended to maintain vigilance regarding the possible development of infectious diseases in patients with juvenile arthritis receiving targeted biologic DMARDs and/or immunosuppressants with or without GCs [1,3,32,44,582]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to temporarily discontinue immunosuppressant and/or targeted biologic DMARD therapy and continue previously prescribed oral GCs in all patients when signs of an infectious complication appear [1,3,32,44,578]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to conduct an appointment (examination, consultation, including remote ones) with the inpatient rheumatologist who initiated the therapy for all patients when signs of an infectious complication appear, to resolve the issue of the need for therapy adjustment and the conditions under which it should be carried out [1,3,32,44,578]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to hospitalize urgently in case of suspected/developed pneumonia [1,3,32,44]. (Level of Evidence 5, Strength of Recommendation C)

Comments: interstitial pneumonia most commonly develops during the use of #rituximab**, and less commonly with other immunosuppressants and targeted biologic DMARDs.

Pneumonia should be suspected if low-grade/febrile fever, dry/productive cough or minor coughing and/or low-grade/febrile fever unrelated to an exacerbation of the underlying disease, and/or dyspnea/breathing difficulty, and/or crepitations/decreased breath sounds upon auscultation appear.

The child is urgently hospitalized in the inpatient rheumatology department for diagnosis and treatment (see above).

• It is recommended to temporarily discontinue immunosuppressant and/or targeted biologic DMARD therapy and continue previously prescribed oral GCs in all patients in case of suspected/developed pneumonia [1,3,32,44,578]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to conduct an appointment (examination, consultation, including remote ones) with the inpatient rheumatologist who initiated the therapy for all patients in case of suspected/developed pneumonia, to resolve the issue of the need for therapy adjustment and the conditions under which it should be carried out [1,3,32,44]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to prescribe #acyclovir** (J05AB) at a dose of 200 mg orally 5 times a day for children older than 2 years (no more than 1000 mg/day) in accordance with clinical guidelines for the treatment of herpesvirus infections in children, including immunocompromised ones, upon the development of a localized herpes infection [3,32,507,508]. (Level of Evidence 5, Strength of Recommendation C)

Comments: for children aged < 3 years #acyclovir** (J05AB) is prescribed by decision of the medical commission after obtaining informed consent from the parents.

Previously prescribed oral GCs should be continued.

Treatment with direct-acting and systemic antiviral drugs is carried out until the complete resolution of the viral infection and the completion of antiviral therapy.

Treatment with #acyclovir** is carried out for 7–10 days until the complete resolution of herpetic eruptions.

• It is recommended to temporarily discontinue immunosuppressant and/or targeted biologic DMARD therapy and continue previously prescribed oral GCs upon the development of a herpesvirus infection for the entire duration of antiviral therapy to prevent toxic reactions and the progression of the infectious process [1,3,32,574,579]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to hospitalize all patients with generalized herpes infection / suspected cytomegalovirus or Epstein-Barr virus infection to determine further management tactics [1,3,32]. (Level of Evidence 5, Strength of Recommendation C)

Comments: an appointment (examination, consultation, including remote ones) is conducted with the inpatient rheumatologist who initiated the therapy to determine further patient management.

• It is recommended to resume immunosuppressant and/or targeted biologic DMARD therapy at the same dose in all patients no earlier than 1 week after the complete resolution of clinical and laboratory signs of herpes infection and the completion of antiviral therapy, in order to prevent increased disease activity / maintain remission [1,3,32,574,579]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to perform a focal tuberculin test (Mantoux test, test with recombinant tuberculosis allergen in standard dilution**) in all patients at least once every 6 months (more frequently if clinically indicated) to exclude Mycobacterium tuberculosis infection during anti-rheumatic therapy [1,3,32,44,88,90–92,212,430,580,581,609]. (Level of Evidence 4, Strength of Recommendation C)

• It is recommended to perform a complete blood count and urinalysis (Nechiporenko test) at least once a month in all patients to monitor renal function [1,3,32,44]. (Level of Evidence 5, Strength of Recommendation C)

Comments: microhematuria, and rarely macrohematuria, develops as an adverse event of methotrexate** therapy.

• It is recommended to discontinue methotrexate** therapy while continuing targeted biologic DMARD therapy and previously prescribed oral GCs if hematuria appears, to prevent the progression of renal damage [1,3,32]. (Level of Evidence 5, Strength of Recommendation C)

• It is recommended to have an initial examination, consultation (including remote consultation) by a hospital rheumatologist who initiated the therapy, if hematuria occurs, to address the need for therapy adjustment and determine the appropriate setting for it [1,3,32]. (LoE 5, GoR C)

• It is recommended to perform an electrocardiogram for all patients at least once every 3 months as part of dispensary follow-up to monitor the cardiovascular system [1,3,32,34]. (LoE 5, GoR C)

• It is recommended to perform a comprehensive ultrasound of the abdominal organs, echocardiography, and renal ultrasound for all patients at least once every 6 months as part of dispensary follow-up to monitor disease activity and adverse events of antirheumatic therapy [1,3,4,32]. (LoE 5, GoR C)

• An initial examination and consultation by an otorhinolaryngologist was performed (for patients with ENT pathology, no later than 7 days after discharge from the hospital) to identify foci of chronic ENT infection and address the issue of their sanitation, as well as to diagnose acute ENT infection developed during antirheumatic therapy [1,3,32,95,329]. (LoE 5, GoR C)

• A dispensary examination and consultation by an otorhinolaryngologist was performed (at least once every 6 months) to monitor the condition of ENT organs, early detection of pathology, its treatment, and prevention of infectious complications during antirheumatic therapy [1,3,32,95,329]. (LoE 5, GoR C)

• It is recommended to have an initial examination and consultation by a pediatric cardiologist based on medical indications to develop an individualized therapy program based on the recommendations of the inpatient pediatric cardiologist [1,3,32,34,334]. (LoE 5, GoR C)

• It is recommended to have a dispensary examination and consultation by a pediatric cardiologist based on medical indications to monitor the efficacy of the individualized therapy program developed on the recommendations of the inpatient pediatric cardiologist [1,3,32,34,334]. (LoE 5, GoR C)

• It is recommended to have an initial examination and consultation by a pediatric dentist for patients who need sanitation of chronic infection foci and treatment of acute oral infection in order to detect inflammatory changes in the oral cavity [1,3,32,215,330,331]. (LoE 5, GoR C)

• It is recommended to have a dispensary examination and consultation by a pediatric dentist based on medical indications for the early detection of oral pathology, its treatment, and the prevention of infectious complications during antirheumatic therapy [1,3,32,215,330,331]. (LoE 5, GoR C)

• It is recommended to have an initial examination and consultation by an ophthalmologist (with biomicroscopy of the eye no later than 7 days after discharge from the hospital in the presence of ophthalmological pathology) to develop an individualized treatment program based on the recommendations of the inpatient ophthalmologist [1,3,15,332,333,430]. (LoE 5, GoR C)

• It is recommended to have a follow-up examination and consultation by an ophthalmologist with mandatory eye biomicroscopy for all patients with ophthalmological pathology based on individual indications to monitor treatment efficacy and adjust it if necessary [1,3,15,332,333,430]. (LoE 5, GoR C)

• It is recommended to have a dispensary examination and consultation by an ophthalmologist (with eye biomicroscopy at least once every 3 months) to monitor the state of the visual organ [1,3,15,332,333,430]. (LoE 5, GoR C)

• It is recommended to have an initial examination and consultation by a dietitian based on medical indications to develop an individualized dietary program [1,3,32,340,341,527]. (LoE 5, GoR C)

• It is recommended to have a follow-up examination and consultation by a dietitian based on individual indications to monitor/adjust the individualized dietary program [340,341,527]. (LoE 5, GoR C)

• It is recommended to have an initial examination and consultation by 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 anti-tuberculosis therapy [1,3,32,86,88,91,92,213,430,581]. (LoE 5, GoR C)

Comments: the decision on the need for therapy adjustment and the setting in which it should be carried out is made by the rheumatologist of the hospital that initiated the therapy, based on the results of the consultation (including remote consultation).

• It is recommended to have an examination, consultation (including remote consultation) by a hospital rheumatologist who initiated the therapy, for patients with a positive intradermal tuberculin test to resolve the issue of whether to continue treatment with genetically engineered biologic drugs and/or immunosuppressants [1,3,32,86,88,91,92,213,430,581]. (LoE 5, GoR C)

• It is recommended to have a follow-up examination and consultation by a phthisiatrician for patients with a positive focal tuberculin test and/or intradermal test with a tuberculosis allergen, and/or an elevated level of interferon-gamma to Mycobacterium tuberculosis complex antigens in the blood, and/or focal, infiltrative changes in the lungs to monitor/adjust chemoprophylaxis or anti-tuberculosis chemotherapy [1,3,32,86,88,91,92,213,430,581]. (LoE 5, GoR C)

Comments: the decision on the need for therapy adjustment and the conditions under which it should be carried out is made by the rheumatologist of the inpatient facility that initiated the prescription of therapy based on the results of the consultation (including remote ones).

• It is recommended to have an initial examination and consultation by a pediatric endocrinologist based on medical indications to prescribe an individualized program recommended by the inpatient pediatric endocrinologist [1,3,32,327,328,335,336,430]. (LoE 5, GoR C)

• It is recommended to have a dispensary examination and consultation by a pediatric endocrinologist based on medical indications to monitor/adjust the individualized program recommended by the inpatient pediatric endocrinologist [1,3,32,327,328,335,336,430]. (LoE 5, GoR C)

• It is recommended to have an initial examination and consultation by an orthopedic traumatologist based on medical indications to address the need for orthopedic correction [1,3,32,214,430]. (LoE 5, GoR C)

• It is recommended to have a follow-up examination and consultation by an orthopedic traumatologist based on medical indications to monitor the efficacy of orthopedic correction [1,3,32,214,430]. (LoE 5, GoR C)

• It is recommended to have a dispensary examination and consultation by an orthopedic traumatologist based on medical indications to identify functional impairments and monitor orthopedic correction [1,3,32,214,430]. (LoE 5, GoR C)

• It is recommended to have an initial examination (testing, consultation) by a medical psychologist based on medical indications to develop a psychological rehabilitation program for the patient and their parents [1,3,32,221,222,337–339]. (LoE 5, GoR C)

• It is recommended to have a follow-up examination (testing, consultation) by a medical psychologist based on medical indications after completion of the psychological rehabilitation program to assess its efficacy [1,3,32,221,222,337–339]. (LoE 5, GoR C)

• It is recommended to have a dispensary examination (testing, consultation) by a medical psychologist based on medical indications to test the psychological state of patients and their parents [1,3,32,221,222,337–339]. (LoE 5, GoR C)

• It is recommended to have an initial examination and consultation by a physical therapy doctor based on medical indications to develop a program of physiotherapeutic procedures based on the recommendations of the inpatient physical therapy doctor [1,3,32,337,529–531,606]. (LoE 5, GoR C)

• It is recommended to have an initial examination and consultation by a sports medicine and exercise therapy doctor based on medical indications to develop an individualized rehabilitation program based on the recommendations of the inpatient exercise therapy doctor [1,3,32,337,529–531]. (LoE 5, GoR C)

• It is recommended to provide medical rehabilitation to all patients with functional impairment as part of an individualized rehabilitation program [1,3,32,337,430,529–541]. (LoE 2, GoR B)

• It is recommended to have a follow-up examination and consultation by a physical therapy doctor for all patients who have completed the medical rehabilitation program to monitor its efficacy [1,3,32,337,529–531,606] (LoE 5, GoR C)

• It is recommended to have a follow-up examination and consultation by a sports medicine and exercise therapy doctor for all patients who have completed the medical rehabilitation program to monitor its efficacy [1,3,32,337,529–531]. (LoE 5, GoR C)

• It is recommended to conduct a follow-up dispensary appointment (examination, consultation) with a physical therapy doctor based on medical indications in order to monitor the effectiveness of/correct the rehabilitation program [1,3,32,337,529–531]. (LEL 5, GR C)

Comments: performed in all patients with juvenile arthritis

Comments: scheduled efficacy monitoring is performed at 3 and 6 months after therapy initiation and further every 6 months to monitor the efficacy and safety of antirheumatic therapy.

• It is recommended to carry out an unscheduled hospitalization as indicated to the rheumatology department of the inpatient facility that initiated the prescription of GEBDs/immunosuppressants for the purpose of examination and therapy adjustment at any stage of treatment upon the development of exacerbation/complications of systemic juvenile idiopathic arthritis, comorbid conditions, complications/side effects/persistent intolerance to GEBDs/immunosuppressants [1,3,4,32]. (LEL 5, GR C)

• It is recommended to monitor the efficacy of GEBDs and/or immunosuppressants in order to timely resolve the issue of "switching" to an immunosuppressant and/or GEBD with a different mechanism of action to achieve disease remission, prevent the development of disease complications and the progression of patient disability [347,423,611]. (LEL 5, GR C)

Comments: monitoring the efficacy of anti-inflammatory and antirheumatic drugs is carried out at least once a month, with special attention paid to the development of secondary inefficacy. Secondary inefficacy of GEBDs and/or immunosuppressants manifests as a "loss" of effect and an increase in disease activity at any stage of treatment. When secondary inefficacy develops, an urgent appointment (examination, consultation, including remote ones) with a rheumatologist of the inpatient facility that initiated the therapy is carried out.

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).

Monitoring of treatment efficacy – see Appendices G1-G4

Comments: intolerance to bDMARDs and/or immunosuppressants can develop at any stage of treatment. If intolerance develops, regardless of its severity, the bDMARD and/or immunosuppressant is discontinued. Previously prescribed oral GCs should be continued.

• It is recommended to conduct an appointment (examination, consultation, including remote ones) with a rheumatologist of the inpatient facility that initiated the therapy for all patients upon the development of any signs of intolerance to the immunosuppressant and/or GEBD to resolve the issue of the need for therapy adjustment and the conditions under which it should be carried out [1,3,32,574]. (LEL 5, GR C)

• It is recommended to conduct an appointment (examination, consultation, including remote ones) with a rheumatologist of the inpatient facility that initiated the therapy when clinical and/or laboratory indicators of disease activity increase and/or any signs of intolerance to the immunosuppressant and/or GEBD develop, to resolve the issue of the need for therapy adjustment and the conditions under which it should be carried out [1,3,32]. (LEL 5, GR C)

6. Organization of Medical Care

6.1. Indications for hospital admission and discharge of patients.

Suspicion of juvenile arthritis.

Diagnostic procedures, including differential diagnosis and prescribing antirheumatic therapy for all patients, are carried out in a hospital rheumatology department.

Indications for discharge

• Completion of examination; establishment of a diagnosis of juvenile arthritis.

• Prescription of antirheumatic therapy.

• Absence of side effects or intolerance.

• Stabilization of the condition during drug therapy: relief of fever and other systemic manifestations, reduction in the activity of joint syndrome.

• Pronounced trend toward normalization / normalization of laboratory markers of activity.

Established diagnosis of juvenile arthritis, active stage.

Examination and adjustment of therapy in case of its ineffectiveness are performed for all patients in an inpatient rheumatology department.

Indications for discharge

• Completion of examination.

• Adjustment of therapy.

• Absence of adverse effects or drug intolerance. Stabilization of the condition under pharmacological therapy: resolution of fever, other systemic manifestations, and decrease in joint syndrome activity.

• Pronounced trend toward normalization / normalization of laboratory markers of activity.

Established diagnosis of juvenile arthritis, with active hemophagocytic syndrome.

Diagnosis, including differential diagnosis, and prescription of therapy for all patients, intravenous administration of drugs, including biologic disease-modifying antirheumatic drugs, are carried out in the setting of the inpatient rheumatology department.

Indications for discharge

• Completion of examination.

• Prescription of therapy.

• Absence of side effects or drug intolerance.

• Stabilization of the condition during drug therapy: relief of fever and other systemic manifestations, reduction in the activity of joint syndrome.

• Relief of clinical and laboratory signs of hemophagocytic syndrome.

• Pronounced tendency toward normalization/normalization of laboratory indicators of juvenile arthritis activity.

Established diagnosis of juvenile arthritis in the remission stage.

Monitoring the efficacy and safety of antirheumatic therapy is carried out in the rheumatology department of the inpatient facility 3 months after therapy initiation; 6 months after therapy initiation; and every 6 months thereafter.

Indications for discharge

• 50% improvement according to ACR Pedi criteria / inactive disease stage according to C. Wallace criteria at 3 months.

• Inactive disease stage at 6 months; remission according to C. Wallace criteria at 12 months and every 6 months thereafter

• Absence of adverse events / drug intolerance

Established diagnosis of juvenile arthritis regardless of the stage.

Examination and adjustment of therapy upon the development of complications/intolerance to drug treatment are performed in an inpatient rheumatology department.

Indications for discharge

• Completion of examination.

• Relief of side effects.

• Adjustment of therapy.

• Absence of side effects or drug intolerance.

• Absence of signs of disease activity.

A patient with an established diagnosis of juvenile arthritis, upon the development of disease exacerbation/complications, comorbid conditions, complications/side effects/persistent intolerance to GEBDs/immunosuppressants, must be urgently hospitalized in the rheumatology department of the inpatient facility that initiated the prescription of GEBDs/immunosuppressants for examination and therapy adjustment at any stage of treatment.

Indications for administering antirheumatic therapy to patients with juvenile arthritis, including genetically engineered biologic drugs (intramuscular and subcutaneous drug administration) in a medical organization (pediatric rheumatology department in a 24-hour inpatient setting and/or day hospital; procedural room of a medical organization providing primary health care; procedural room of a feldsher-midwife station (if a pediatric rheumatology office is absent):

Inability of parents (legal representatives) and/or the patient aged over 15 years to independently administer genetically engineered biologic drugs (intramuscular and subcutaneous administration) at home due to low compliance and lack of drug administration skills.

Indications for consultation with a federal-subordinate medical organization, including via telemedicine technologies:

prescription and/or replacement of genetically engineered biologic drugs and/or selective immunosuppressants in combination with or without glucocorticoid pulse therapy, and/or immunosuppressants, and/or high-dose normal human immunoglobulin in patients with systemic-onset juvenile arthritis with high/moderate inflammatory activity and/or resistance to ongoing drug treatment.

6.2. Regulatory legal documents in accordance with which medical care is provided to children with juvenile arthritis:

1. 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).

2. 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).

3. 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).

4. 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).

5. 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).

6. 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).

7. 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).

8. Order of the Ministry of Health of the Russian Federation No. 789n dated December 13, 2022 "On Amending the Rules for 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, No. 71905).

9. Amendment 14.1 to Article 37. Organization of Medical Care of Federal Law No. 323-FZ dated November 21, 2011 (as amended on June 11, 2022, with amendments dated July 13, 2022) "On the Basics of Protecting the Health of Citizens in the Russian Federation" (with amendments and additions, entered into force on June 29, 2022) "It is permitted to include in the standards of medical care for children and clinical guidelines a medicinal product registered in the territory of the Russian Federation used in accordance with the indications (characteristics) of the medicinal product not specified in its instructions for use, if such medicinal product complies with the requirements established by the Government of the Russian Federation. The list of diseases or conditions (groups of diseases or conditions) for which the use of a medicinal product in accordance with the indications (characteristics) of the medicinal product not specified in its instructions for use is permitted is established by the Government of the Russian Federation.

10. 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".

11. 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".

12. 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).

7. Additional Information

Assignment of the status of "disabled child" to children with JIA is carried out in accordance with the following regulatory and legal documents:

1. 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).

2. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019 (as amended on November 6, 2021) "On Classifications and Criteria Used in Carrying out Medical and Social Expertise of Citizens by Federal State Institutions of Medical and Social Expertise"

3. 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, Art. 3528; 2013, No. 22, Art. 2809; No. 36, Art. 4578; No. 37, Art. 4703; No. 45, Art. 5822; No. 46, Art. 5952; 2014, No. 21, Art. 2710; No. 26, Art. 3577; No. 29, Art. 4160; No. 32, Art. 4499; No. 36, Art. 4868; 2015, No. 2, Art. 491; No. 6, Art. 963; No. 16, Art. 2384; 2016, No. 2, Art. 325; No. 4, Art. 534; No. 23, Art. 3322; No. 28, Art. 4741; No. 29, Art. 4812; No. 43, Art. 6038; No. 47, Art. 6659; 2017, No. 1, Art. 187; No. 7, Art. 1093; No. 17, Art. 2581; No. 22, Art. 3149; No. 28, Art. 4167; 2018, No. 10, Art. 1494; No. 24, Art. 3530; No. 36, Art. 5634; No. 46, Art. 7052; No. 49, Art. 7600; No. 53, Art. 8678; 2019, No. 1, Art. 31; No. 5, Art. 408; No. 21, Art. 2563)

4. 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. 585n dated August 27, 2019

Quantitative scoring system for the severity of persistent impairments of body functions in children under 18 years of age caused by diseases, consequences of injuries, or defects (in percentages, applied to the clinical and functional characteristics of persistent impairments of human body functions)

If the "disabled child" status is granted, the child and their parents will be entitled to a number of social services; preferential travel; benefits for medical devices, instruments, and medications; benefits for admission to secondary and higher educational institutions; free travel for the child and an accompanying adult to the place of treatment (sanatorium, resort) and back; an annual sanatorium-treatment voucher for the child and the accompanying adult.

In the event of untimely provision of a pathogenesis-based GEBD to a child with juvenile arthritis, there is a high probability of disease exacerbation/increased disease activity, multiple organ failure, progression of joint damage and functional impairment in the patient.

7.1. Outcomes and prognosis

Oligoarticular juvenile arthritis. Approximately 40% of patients achieve remission. More than 50% of patients maintain disease activity, 40% of whom have oligoarthritis transform into polyarthritis, but the number of affected joints is smaller than in polyarthritis at disease onset. With a long-term disease course, osteoarthritis may develop after clinical remission. Mortality is very low. Blindness develops in 10% of patients with uveitis [1,529,613].

Poor prognostic factors (ACR, 2011) in oligoarticular JIA: Involvement of the hip joints or cervical spine, involvement of the ankle or wrist joint, significant or prolonged elevation of laboratory markers, joint destruction according to radiological imaging (erosions of the articular surfaces or narrowing of the joint spaces) [347,348,423,550].

Polyarticular RF-negative juvenile idiopathic arthritis. The course of arthritis in most patients is relatively benign. Severe destructive changes develop in 10% of patients, mainly in the hip and temporomandibular joints. All children with early-onset RF-negative polyarticular JIA have a poor prognosis, a high risk of developing severe destructive arthritis, and musculoskeletal disability [347,348,423,550].

Poor prognostic factor (ACR, 2011): hip joint involvement.

All children with RF-positive polyarticular JIA have a poor prognosis, a high risk of developing severe destructive arthritis, and musculoskeletal disability. With timely initiated adequate therapy, the remission rate is up to 65%. Fatal outcomes are primarily associated with the development of amyloidosis.

Poor prognostic factors in RF-positive polyarticular JIA (ACR, 2011):

• Hip joint involvement, positive RF or presence of ACPA [347,348,423,550].

Poor prognostic factors for the course of JIA-associated uveitis [31].

• Early onset of uveitis

• Short interval between arthritis onset and uveitis (< 6 months2)

• Development of uveitis before arthritis onset

• High inflammatory activity (> 2+ anterior chamber cell count at disease onset)

• Complicated initial course at uveitis onset

• Continuous course of uveitis, short remission

Presence of complications:

• Development of synechiae

• High inflammatory activity (> 2+ cells in the anterior chamber)

• Dense vitreous infiltration

• Cataract

• Glaucoma

• Macular edema

Criteria for Evaluating the Quality of Medical Care

Organizational and technical conditions for the provision of medical care.

Table 1. Quality assessment criteria for initial diagnosis in establishing a diagnosis of juvenile arthritis.

Table 2. Diagnostic quality criteria for hemophagocytic lymphohistiocytosis

Table 3. Quality assessment criteria for the evaluation of patients with established juvenile arthritis prior to the initiation or adjustment of antirheumatic therapy

Table 4. Quality assessment criteria for the treatment of juvenile polyarthritis (seronegative polyarticular juvenile idiopathic arthritis, seropositive polyarticular juvenile idiopathic arthritis)

Table 5. Criteria for assessing the quality of treatment of pauciarticular juvenile arthritis (oligoarticular juvenile idiopathic arthritis, persistent)

Table 6. Criteria for assessing the quality of treatment of juvenile ankylosing spondylitis

Table 7. Criteria for assessing the quality of treatment of juvenile arthritis-associated uveitis

Table 8. Quality assessment criteria for the treatment of juvenile arthritis with hemophagocytic syndrome

Table 9. Quality assessment criteria for follow-up examination of patients with juvenile arthritis in an inpatient/day care setting who initiated bDMARD/immunosuppressant therapy