Systemic juvenile idiopathic 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

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: L01XC – monoclonal antibodies, L04AC – interleukin inhibitors)

GC – Glucocorticoids (ATC code: H02AB)

GGT – Gamma-glutamyl transferase

HPS – Hemophagocytic syndrome

DNA – Deoxyribonucleic acid

GI – Gastrointestinal tract

IL – Interleukin

CT – Computed tomography

CK – Creatine kinase

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)

LER – Level of evidence of recommendations

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, CCP antibodies) – 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 (ATC Code M01A) – a group of medicinal products possessing analgesic, antipyretic, and anti-inflammatory effects. They are subdivided into selective (s-NSAIDs) and nonselective (ns-NSAIDs) cyclooxygenase enzyme inhibitors.

Biologic disease-modifying antirheumatic drugs (ATC Code L01XC – monoclonal antibodies, L04AC – interleukin inhibitors, L04AB – tumor necrosis factor alpha (TNF-alpha) inhibitors) – a group of medicinal products of biological origin, including monoclonal antibodies (chimeric, humanized, fully human) and recombinant proteins (usually including human IgG Fc fragments) obtained using genetic engineering methods, characterized by a selective effect on specific mechanisms of chronic inflammation development, specifically suppressing the immuno-inflammatory 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

Systemic-onset juvenile arthritis (syn.: systemic juvenile idiopathic arthritis, sJIA; systemic juvenile arthritis, sJA) is arthritis of one or more joints accompanied by (or preceded by) confirmed intermittent fever lasting at least 3 days for a minimum of 2 weeks in combination with one or more of the following signs:

- short-lived (evanescent) erythematous rash;

- generalized lymphadenopathy;

- hepatomegaly and (or) splenomegaly;

- serositis (pericarditis, and (or) pleuritis, and (or) peritonitis) [1–3].

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

Systemic juvenile idiopathic arthritis is a multifactorial disease with unknown etiology and immunoaggressive pathogenesis [1,4,5].

At an early stage, the central link in the pathogenesis of sJIA is the activation of the innate immune system. The primary antigen is unknown; it may be viral, bacterial, or a stress signal. Recognition and interaction of PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns), such as ATP, nucleic acids, etc., as well as S100 proteins with membrane Toll-like receptor 4 (TLR4) of myeloid cells leads to the activation of the transcription factor NF-kB, its translocation into the cell nucleus followed by the activation of a large number of genes encoding the production of antimicrobial peptides, pro-inflammatory cytokines, stress proteins, and co-stimulatory molecules (tumor necrosis factor alpha, IL-1, IL-6, IL-8, IL-12, IL-18, CD80, CD86, CD40, etc.), as well as anti-apoptotic proteins [1,4,5].

Pro-inflammatory cytokines, primarily IL-1 and IL-18, also activate the transcription factor NF-kB via a feedback mechanism, which in turn leads to a persistent inflammatory response and the development of clinical and laboratory manifestations of sJIA (fever, coagulopathy, increased vascular permeability, synovitis, acute-phase protein synthesis, leukocytosis, thrombocytosis) [1,4,5].

The hyperproduction of pro-inflammatory cytokines is associated with the development of clinical manifestations of the disease (fever, polymorphic rash, serositis, enlargement of the liver, spleen, and lymph nodes, destructive arthritis; secondary macrophage activation syndrome (sMAS), osteoporosis) and pathological changes in laboratory parameters (leukocytosis, thrombocytosis, hyperproduction of amyloid A, haptoglobin, C-reactive protein (CRP), fibrinogen) [1,4,5].

IL-1 is one of the central pro-inflammatory cytokines whose hyperproduction "triggers" sJIA. There are two forms of the cytokine: IL-1α and IL-1β. The dominant form in humans is IL-1β. The biological properties of IL-1α and IL-1β are similar. IL-1β regulates inflammatory and immune processes, stimulates the proliferation of T and B lymphocytes, the synthesis of other cytokines and acute-phase proteins by hepatocytes, and is a potent pyrogen, causing a hyperinflammatory reaction in sJIA. The development of sMAS is also associated with the hyperproduction of IL-1β [1,4,5].

IL-6 is a cytokine synthesized by lymphocytes, monocytes, fibroblasts, and other cells in response to Toll-like receptor activation mediated by pathogen- and damage-associated molecular patterns. The systemic effects of IL-6 include activation of the hypothalamic-pituitary system, increased thermogenesis, and fever; formation of the acute-phase response characterized by hyperproduction of CRP, amyloid A, hepcidin, fibrinogen, and ferritin, leading to a hyperinflammatory reaction. IL-6 stimulates the secretion of hepcidin by hepatocytes, which decreases iron absorption in the intestine and inhibits its release from macrophages, causing iron deficiency for erythropoiesis and the development of anemia. At elevated concentrations, IL-6 blocks the production of adrenocorticotropic hormone, cortisol, and growth hormone, leading to fatigue, drowsiness, depression, cognitive impairment, and growth retardation in children with sJIA [1,4,5].

When exposed to a trigger factor (viral and/or bacterial infection), patients with sJIA develop pyroptosis, which is a pro-inflammatory cell death. Pyroptosis is triggered when viral PAMPs or DAMPs formed during virus-induced cell damage bind to a Nod-like membrane receptor, which is a component of the NLRP3 inflammasome consisting of a sensor (NLRP3 receptor), an adapter (apoptosis-associated speck-like protein containing a CARD, ASC), and an effector (procaspase-1). The NLRP3 inflammasome activates the classical caspase-1 inflammatory signaling cascade, which stimulates the hyperproduction of pro-inflammatory cytokines IL-1β and IL-18 from precursor molecules and cleaves gasdermin D. In this process, the N-terminal domain of gasdermin D forms pores in the plasma membrane through which intracellular contents (DAMPs) are released into the extracellular space, followed by the development and amplification of the inflammatory response and the destruction of infected cells. Under the action of PAMPs and DAMPs, a non-classical signaling pathway via caspases-4, -5, and -11 can also be activated, which likewise cleave gasdermin D, leading to pyroptosis. As a result of programmed cell death, cytokines IL-1, IL-18, and IFN-γ are released, which in turn serve as a triggering mechanism for the development of sMAS, resulting from the uncontrolled expansion of T lymphocytes and macrophages against the background of reduced cytolytic activity of NK cells and CD8⁺ T lymphocytes [1,4,5].

In the so-called arthritic stage of sJIA, accompanied by the development of persistent polyarthritis, along with the activation of innate immunity, the adaptive immune response is activated, which is accompanied by the proliferation of Th17 lymphocytes, hyperproduction of IL-17, IL-1, TNF-alpha, and other pro-inflammatory cytokines produced during the activation of the adaptive immune system [1,4,5].

1.3 Epidemiology of the Disease or Condition

The true global prevalence of sJIA is unknown. In Europe, it ranges from 0.3 to 0.8 per 100,000 children under 16 years of age. The proportion of sJIA in the structure of juvenile arthritis ranges from 5% to 15% in North America and Europe, and 50% in Japan [1,4,5].

According to the Federal Register of Persons with Hemophilia, Cystic Fibrosis, Pituitary Dwarfism, Gaucher Disease, Malignant Neoplasms of Lymphoid, Hematopoietic and Related Tissue, Multiple Sclerosis, Hemolytic-Uremic Syndrome, Systemic Juvenile Idiopathic Arthritis, Mucopolysaccharidosis Types I, II, and VI, Unspecified Aplastic Anemia, Hereditary Deficiency of Factors II (Fibrinogen), VII (Labile), X (Stuart-Prower), and Persons after Organ and/or Tissue Transplantation of the Russian Ministry of Health, 2,081 individuals with sJIA are registered, among them 1,310 children with sJIA, accounting for 3.5% of the structure of juvenile arthritis.

Systemic JIA develops in children aged 0 to 18 years. The peak incidence occurs at the age of 1–5 years. Boys and females are affected with equal frequency. No seasonality is observed [1,3–5].

1.4 Features of Coding the Disease or Condition

In the ICD, systemic juvenile idiopathic arthritis is coded in the section "Diseases of the musculoskeletal system and connective tissue (M00-M99)" – M08.2.

In accordance with ICD-10, the diagnosis is established as «Systemic juvenile idiopathic arthritis (M08.2) with active/inactive systemic manifestations, with active/inactive arthritis (oligo-/polyarthritis)». When formulating the diagnosis, the following data must be indicated:

— degree of disease activity (0–3): high (3), moderate (2), low (1), remission/absence of activity (0) on therapy / 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. Systemic juvenile idiopathic arthritis (M08.2) with absent or minor joint function impairment; radiographic stage I, no disease progression; with absent or present flares (no more than 1 time per year), degree 0 or I of inflammatory activity on therapy; FC I; no complications of the disease or ongoing pharmacotherapy (NSAIDs).

2. Systemic juvenile idiopathic arthritis (M08.2) with moderate joint function impairment (FC II); radiographic stage II; progressive disease course: flares 2–4 times per year, persistent degree I or II inflammatory activity on immunosuppressive therapy; need for therapy adjustment, possibility of achieving remission only with immunosuppressive therapy using drugs from several (2 or more) pharmacotherapeutic groups (excluding NSAIDs), including bDMARDs; presence of complications of the disease and ongoing pharmacotherapy.

3. Systemic juvenile arthritis (M08.2) 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 per year), functional class (FC) II or III; persistent inflammation activity of grade 2 or 3 despite immunosuppressive therapy; remission achievable only with immunosuppressive therapy using drugs from multiple (2 or more) pharmacotherapeutic groups (excluding NSAIDs), including biologic DMARDs; presence of complications from the disease and ongoing pharmacotherapy.

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

1.5 Classification of the disease or condition

According to the ILAR classification, the disease is classified as systemic juvenile idiopathic arthritis (sJIA).

The American College of Rheumatology (ACR, 2021) distinguishes the following variants of the disease [6]:

— systemic JIA (systemic-onset juvenile arthritis) without macrophage activation syndrome (MAS);

— systemic JIA (systemic-onset juvenile arthritis) with macrophage activation syndrome (MAS).

1.6 Clinical presentation of the disease or condition

The main clinical manifestations are: febris, macules, maculopapular rash, arthralgia, myalgia and/or oligo-, polyarthritis, enlargement of peripheral lymph nodes, and/or liver and/or spleen, and/or polyserositis.

Fever. Body temperature rises to ≥39°C once or twice a day at any time, but most often closer to the evening; typically accompanied by the appearance or worsening of a rash, drenching sweats, rarely chills; rapidly normalizes or drops below normal values, especially in the early morning hours; at disease onset, it may not have the typical sJIA pattern, and the clinical picture is often indistinguishable from sepsis. At the peak of the fever, the child's general condition is compromised, and it normalizes when the body temperature drops [1,3–5,7].

Rash. Typically, the rash in sJIA is macules and/or maculopapular, and/or linear, rarely urticarial or hemorrhagic (in macrophage activation syndrome). The size of the macules reaches 2–5 mm. The macules are usually surrounded by a pale halo, and a clearing area forms in the center of larger elements. The rash is non-pruritic, transient, appears and disappears without leaving a trace within a short time, intensifies at the peak of the fever, and is localized predominantly in the joint areas, on the face, lateral surfaces of the trunk, buttocks, and limbs [1,3–5,7].

Vasculitis. Typically, palmar and/or plantar capillaritis develops, causing a cyanotic discoloration of the palms and soles and mottling of the skin. Local angioedema is possible, most frequently localized in the hand area [1,3–5,7].

Lymphadenopathy. In most cases, enlargement of lymph nodes of almost all groups up to 4–6 cm in diameter is detected. The lymph nodes are typically mobile, painless, not matted together or to underlying tissues, and have a soft-elastic or dense-elastic consistency [1,3–5,7].

Cardiac involvement. Pericarditis develops in 40% of patients, mostly in older children regardless of sex, age at disease onset, and severity of joint syndrome; it may precede the manifestation of arthritis, usually develops at the peak of systemic exacerbations at any stage of the disease; often runs asymptomatically, but may be accompanied by dyspnoea, precordial pain aggravated in the supine position and radiating to the back, shoulders, and neck. The duration of the episode is 1–8 weeks. Physical examination reveals muffled heart sounds, tachycardia, enlargement of relative cardiac dullness borders, and a pericardial friction rub. In most cases, pericarditis is not accompanied by low QRS voltage, ST-segment elevation, or T-wave inversion on the electrocardiogram and is diagnosed only by echocardiography. Cardiac tamponade is a rare but serious complication of pericarditis. Chronic constrictive pericarditis occurs rarely.

Myocarditis develops much less frequently than pericarditis and may be accompanied by cardiomegaly and heart failure.

Endocarditis is not typical for sJIA [1,3–5,7].

Pulmonary involvement. Pulmonary parenchymal involvement is observed rarely. Pleuritis usually develops in combination with pericarditis, is often asymptomatic, and is diagnosed during instrumental examinations [1,3–5,7].

Liver and spleen involvement. Splenomegaly is most pronounced in the first years of the disease. Enlargement of the spleen can be significant, yet not accompanied by neutropenia.

Moderate or pronounced hepatomegaly in sJIA is quite common. Progressive hepatomegaly is characteristic of secondary amyloidosis. In some cases, fatty liver degeneration develops, associated with the use of glucocorticoids. An increase in liver transaminase levels is observed in approximately 25% of patients at disease onset. A rapid increase in AST, LDH, ALT, GGT, and ALP activity is characteristic of the development of MAS.

Cytolysis is a manifestation of the toxic effect on the liver of NSAIDs, immunosuppressants, and biologic DMARDs [1,3–5,7].

Nervous system involvement. Central nervous system (CNS) involvement in patients with sJIA is rare, but significantly increases the risk of a fatal outcome. The development of encephalopathy, seizures, and intracranial hemorrhage is observed in secondary macrophage activation syndrome. Fatal cases have been observed in patients with aseptic meningitis, neutrophilic cerebrospinal fluid pleocytosis, and brain edema associated with the rapid development of hyponatremia, likely linked to the syndrome of inappropriate antidiuretic hormone secretion. The risk of developing hyponatremia is noted in patients with a sharp rise in body temperature and vomiting. One of the manifestations of CNS involvement in children with sJIA is a slight increase in intracranial pressure [1,3–5,7].

Joint involvement. Arthritis may be absent at disease onset and manifest as the disease progresses, in the vast majority of children within the first 3 months.

Joint syndrome is characterized by the development of polyarthritis; mono- and oligoarthritis are rare. Most commonly, the wrists, knees, and ankles are involved. In more than 50% of patients, the cervical spine, small joints of the hands, and temporomandibular joints are also affected. In some cases, for several months and sometimes years, joint syndrome is mild and manifests as arthralgias. In certain cases, severe polyarthritis develops with pronounced functional joint impairment, resistant to antirheumatic therapy. Patients with polyarthritis frequently develop tenosynovitis and synovial cysts [1,3–5,7].

2. Diagnostics, medical indications and contraindications for diagnostic methods

2.1. Evaluation of patients with suspected systemic-onset juvenile arthritis

2.1 Complaints and Anamnesis

Complaints of elevated body temperature above 38°C from one to several times a day, skin rashes worsening at the peak of fever, fatigue, malaise at the peak of fever, muscle pain, pain and/or swelling in the joints, and/or morning stiffness.

(LoE 5, GoR C)

Comments: elucidating the presence of urogenital and other infections (chlamydial, mycoplasmal, cytomegalovirus, herpetic, Epstein-Barr virus, etc.), which may be triggers of sJIA in the child, before and during pregnancy. Data on the course of previous pregnancies. It is necessary to find out whether intrauterine fetal death, chronic pregnancy loss, premature birth, primary or secondary infertility occurred. All these pathologies can be a consequence of intrauterine infection of the fetus, in particular viral and bacterial infection. Data on the course of the current pregnancy (hazards the mother was exposed to during pregnancy, first- and second-half gestoses, threat of miscarriage in early and late stages, anemia of pregnancy, diseases suffered during pregnancy). Data on the course of labor (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).

(LoE 5, GoR C)

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.

(LoE 5, GoR C)

Comments: it is necessary to determine whether the patient has first- or second-degree relatives suffering from the following conditions: 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.

(LoE 5, GoR C)

Comments: evaluate the nature of the onset (acute or subacute, with or without joint involvement); potential trigger factors for the disease. Systemic juvenile idiopathic arthritis (sJIA) is typically characterized by an acute onset. Trigger factors most commonly include respiratory or intestinal infections, physical or psychological stress, hypothermia, sun exposure (insolation), and trauma. It is necessary to determine whether the patient received antibacterial drugs and/or glucocorticosteroids: which ones, what their dose was, and the duration of administration.

2.2 Physical Examination

(LoE 5, GoR C)

(Level of Evidence 4, Grade of Recommendation C).

Comments: in sJIA, body temperature rises to ≥ 38°C once or twice a day at any time, but most frequently closer to the evening. It is sometimes accompanied by drenching sweats, rarely by chills, and rapidly normalizes or drops below normal values, especially in the early morning hours. At disease onset, the fever may not exhibit the typical pattern of sJIA. When macrophage activation syndrome (MAS) develops, the fever becomes hectic.

(LoE 4, GoR C)

Comments: at the peak of the fever, the general condition of children is moderate to severe. Not infrequently, the child cries from joint and muscle pain, cannot turn over in bed, and exhibits stiffness and weakness. As the body temperature drops, well-being normalizes, and the child becomes active. With the development of MAS, the condition deteriorates sharply. Altered consciousness and coma may develop. In severe uncontrolled cases, a fatal outcome is possible.

(LEL 4, GRC C)

Comments: sJIA is characterized by a rash that is macular and/or maculopapular, linear, and rarely urticarial or hemorrhagic (in macrophage activation syndrome [MAS]). The size of the spots reaches 2–5 mm. The spots are usually surrounded by a pale halo, with a central area of clearing forming within larger elements. The rash is non-pruritory, transient, appears and disappears without leaving a trace within a short period, worsens at the height of fever, and is localized predominantly around the joints, on the face, lateral surfaces of the torso, buttocks, and extremities. When MAS develops, a pruritic, linear, atypical, and hemorrhagic rash appears.

sJIA typically features palmar and/or plantar capillaritis, causing a cyanotic coloration of the palms and soles and a "mottled" skin appearance. Local angioedema is possible, most frequently localized in the hand region.

(LEL 4, GRC C)

Comments: in the majority of patients with sJIA, enlargement of practically all groups of lymph nodes is detected. The lymph nodes are usually mobile, painless, not fused to each other or to underlying tissues, and have a soft-elastic or firm-elastic consistency.

(LEL 4, GRC C)

Comments: pericarditis develops more frequently in older children and is usually asymptomatic, but may be accompanied by shortness of breath, chest pain that intensifies in the recumbent position and radiates to the back, shoulders, and neck; in some cases, it precedes the manifestation of arthritis, develops at the peak of systemic manifestation exacerbations at any stage of the disease, and is accompanied by a systemic inflammatory response. The duration of the episode is 1–8 weeks. Pericarditis in sJIA is in most cases not accompanied by low voltage, ST-segment elevation, or T-wave inversion according to electrocardiography (ECG). It is frequently diagnosed via echocardiography (EchoCG).

Myocarditis develops significantly less frequently than pericarditis and may be accompanied by cardiomegaly and heart failure.

Percussion may reveal widening of the relative cardiac dullness borders; auscultation may reveal muffled heart sounds, a systolic murmur at the mitral valve projection point, tachycardia, less commonly bradycardia; rarely, a pericardial friction rub.

Endocarditis is not characteristic of sJIA.

(LEL 4, GRC C)

Comments: in some cases, the child may complain of a cough, difficulty breathing, or shortness of breath. In sJIA, pulmonary parenchyma involvement is rarely observed. Pleuritis usually develops in combination with pericarditis, is frequently asymptomatic, and is diagnosed via radiological examination of the lungs. Visually, upon patient examination, signs of pulmonary involvement may not be detected; in some cases, signs of respiratory failure may be present: tachypnea, retractions of compliant chest areas, the epigastric region, and areas of diaphragmatic attachment to the costal margin; cyanosis. The percussion sound may be normal with a tympanic note, or dullness of the percussion sound may be detected in the posterior-inferior lung regions; auscultation may reveal moist rales of various calibers, crepitant rales, pleural friction rubs, and decreased breath sounds in the posterior-inferior lung regions.

(LoE 5, GoR C)

Comments: patients with sJIA often complain of epigastric pain and dyspeptic symptoms. Periumbilical pain may be associated with enlargement of mesenteric lymph nodes. Physical examination may reveal underweight, coated tongue, abdominal distension; percussion reveals enlargement of the liver and spleen (splenomegaly is most pronounced in the first years of the disease; spleen enlargement can be significant). Hepatomegaly develops less frequently than splenomegaly. Progressive enlargement of the liver is characteristic of secondary amyloidosis. Palpation may reveal tenderness in the epigastrium at the projection points of the gallbladder, duodenum, and pancreas, as well as hepatosplenomegaly; in case of intestinal involvement, tenderness in the ileocecal region and along the colon may be detected.

The majority of children with sJIA develop inflammation of the upper gastrointestinal tract (GI), associated with the use of large amounts of antipyretics and NSAIDs.

If there are complaints of frequent loose stools with mucus and/or blood and/or greenish discoloration, pain in the ileocecal region, and abdominal distension, inflammatory bowel disease (IBD) should be suspected and differential diagnosis continued.

(LEL 4, GRC C)

Comments: sJIA is characterized by pronounced arthralgia, especially at the peak of fever; morning stiffness of varying duration; and inflammatory joint pain that develops after periods of rest and diminishes with physical activity. The articular syndrome in sJIA has a diverse clinical course: disease onset may present solely with arthralgia and myalgia; evanescent arthritis affecting large joints; persistent symmetric oligo- or polyarthritis primarily affecting large joints; or generalized polyarthritis involving small joints and the cervical spine. In some patients, the disease may follow a prolonged course (months, years) without persistent joint syndrome.

The majority of patients with sJIA develop polyarthritis, which is characterized by resistance to antirheumatic therapy and pronounced functional joint impairment. Patients with polyarthritis frequently develop tenosynovitis and synovial cysts. Most commonly involved are the wrist, knee, and ankle joints. In more than 50% of patients, the cervical spine joints, small joints of the hands, and temporomandibular joints are also affected. At disease onset, the articular syndrome may be minimal, but its extent increases over several months. In some cases, for several years, the joint syndrome is mild and manifests only as arthralgia. Joints must be examined for the presence of swelling. The skin temperature over the joints should be assessed, followed by the temperature difference between symmetrical skin areas.

(LoE 5, GoR C)

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.

Assessment of the range of motion:

— Cervical spine. Ask the patient to: tilt the head backward (normal extension is 50–60°), touch the sternum with the chin (normal flexion is 45°), turn the head to the right and left (normal rotation is 60–80°), touch the right and left shoulder with the head (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 laterally and upward, touch the right and left ear over the back of the head, touch the right and left scapula with the contralateral hand from behind, independently remove 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: make a tight fist, independently remove socks and tights, and button and unbutton clothes.

— Normally, the fingers easily touch the palm.

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

— 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 knees (the heel should touch the buttock), kneel down and lower the buttocks onto the heels, extend the knees (180° angle), and squat down.

— Check for the patellar tap (ballotment) sign.

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

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

(LoE 5, GoR C)

Comments: gait variants:

— with rapid weight transfer from the affected leg to the healthy one (involvement of the knee, hip joints, or feet). The patient steps on the entire foot or forefoot (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 detecting pain or stiffness. Limping and gait abnormalities are most pronounced in children with sJIA in the morning hours due to morning stiffness. When examining the patient in the afternoon, there may be no limp, and gait abnormalities may be minimal or absent.

(LoE 5, GoR C)

Comments: myalgia is characteristic of sJIA and often occurs at the peak of systemic manifestations activity. In terms of pain severity, myalgia may exceed arthralgia. Some patients experience myositis with muscle edema, pain, and elevated blood levels of muscle breakdown enzymes. In the presence of active arthritis, muscle atrophy develops proximal to the affected joint.

(LoE 5, GoR C)

Comments: diseases that should be excluded during diagnosis:

— malignancies (neuroblastoma, solid tumors, hemoblastoses, lymphoproliferative diseases);

— autoinflammatory syndromes;

— IBD;

— other rheumatic diseases (systemic lupus erythematosus, dermatomyositis, polyarteritis nodosa, Kawasaki disease, sarcoidosis, Castleman disease);

— immunodeficiency states;

— infectious diseases (acute inflammatory response, tuberculosis, bacterial endocarditis, acute rheumatic fever, yersiniosis, salmonellosis, cat-scratch disease, toxoplasmosis, Lyme disease, borreliosis, leishmaniasis, Mycoplasma infection, infections caused by cytomegalovirus, Epstein-Barr virus, etc.);

— toxic-allergic reactions to medications.

2.3 Laboratory Diagnostics

(LoE 5, GoR C)

Comments: findings in sJIA include: leukocytosis with a neutrophil left shift, elevated erythrocyte sedimentation rate (ESR), hypochromic anemia, and thrombocytosis. The complete blood count findings are not specific for sJIA; therefore, the differential diagnostic workup must continue. First and foremost, hemoblastoses, lymphoproliferative disorders, and oncological diseases must be excluded.

(LoE 5, GoR C)

Comments: sJIA is characterized by hypocoagulation or hypercoagulation changes in the hemostatic system, whereas MAS is characterized by hypocoagulation.

(LEL 4, GRC C)

(LoE 5, GoR C)

(Level of Evidence 3, Grade of Recommendation C)

Comments: serum C-reactive protein levels are significantly elevated in sJIA.

(LoE 5, GoR C)

Comments: an elevated serum ferritin, triglycerides, ALT, AST, and LDH may be observed in secondary/primary macrophage activation syndrome (MAS), as well as drug toxicity, malignancy, hemoblastosis, lymphoproliferative disease, other rheumatic diseases, or sepsis, which provides grounds for continuing the differential diagnosis.

(Level of Evidence 3, Grade of Recommendation C)

Comments: in systemic juvenile idiopathic arthritis (sJIA), complement fractions C3 and C4 are within normal limits or elevated. Autoantibodies are not detected.

Comments: blood immunoglobulin levels in sJIA are within normal limits.

Comments: the presence of HLA-B27 is an exclusion criterion for the diagnosis of sJIA.

(LoE 5, GoR C)

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.

(LoE 3, GoR C)

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

(LoE 3, GoR C)

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

(LEL 4, GRC C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(Level of Evidence 3, Grade of Recommendation B)

(LoE 3, GoR B)

(LoE 5, GoR C)

Comments: in patients with sJIA, hepatitis may develop due to the uncontrolled use of NSAIDs and may also be a sign of secondary hemophagocytic lymphohistiocytosis

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

2.4 Instrumental Diagnostics

(LoE 5, GoR C)

(LEL 4, GRC C)

Comments: myocarditis manifests as left ventricular dilation, decreased left ventricular ejection fraction, hypokinesia of the left ventricular posterior wall and/or interventricular septum, aortitis, signs of relative mitral, aortic, and/or tricuspid valve regurgitation, and elevated pulmonary artery pressure. Pericarditis manifests as separation of pericardial leaflets and free fluid in the pericardial cavity. The endocardium and valve apparatus are typically unaffected in sJIA. If endocardial involvement is present, acute rheumatic fever and infective endocarditis must be ruled out.

(LEL 4, GRC C)

Comments: if myocarditis is present, signs of left and/or right heart overload are detected. In most cases, pericarditis is not accompanied by decreased QRS voltage, ST-segment elevation, or T-wave inversion on the ECG.

(LoE 5, GoR C)

Comments: sJIA is characterized by increased synovial fluid volume, thickening (hypertrophy) of the synovial membrane, cartilage fibrillation, and cartilage erosion.

(LoE 5, GoR C)

Comments: sJIA findings include osteoporosis, destructive changes in bone structures, joint space narrowing, status of articular surfaces of bones forming the joint, erosions, surface usuration, cysts, foci of bone necrosis, subluxations, fractures, osteophytes, calcifications, etc. Simultaneous examination of symmetrical joints is required. Cartilage and bone tissue changes are detected in the majority of patients. X-ray examination 2 years after disease onset reveals joint space narrowing in 30% of patients, erosions in 35%, and bone growth disturbances in 10%. Early radiographic changes develop in the wrist, hip, and shoulder joints. After 6.5 years, joint space narrowing is detected in 39% of patients, erosions in 64%, and bone growth disturbances in 25%. Aggressive sJIA leads to ankylosis of the wrist and cervical spine apophyseal joints, as well as avascular necrosis of the hip joints.

(LEL 1, GOR A)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

Comments: if GCs or immunosuppressants are used, the test should be performed no earlier than 2 weeks after their withdrawal. In all patients with pronounced enlargement of peripheral and/or intrathoracic, and/or intra-abdominal lymph nodes at the diagnostic stage prior to prescribing GCs and/or immunosuppressants, and/or bDMARDs, it is recommended to perform a lymph node biopsy (peripheral, or intra-abdominal/intrathoracic as indicated) with cytological examination of the lymph node tissue preparation and pathomorphological examination of the lymph node biopsy (surgical) material to rule out hemoblastoses, lymphoproliferative diseases, and metastatic lymph node involvement.

(LoE 5, GoR C)

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.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

Comments: in case of GC or immunosuppressant administration, the test is performed no earlier than 2 weeks after their discontinuation.

(LEL 4, GRC C)

Comments: destruction lesions 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 necessary for differential diagnosis [154].

2.5 Other Procedures

2.1.5. Other diagnostic procedures

(LEL 4, GRC C)

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).

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: ocular biomicroscopy is mandatory.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 2, GOR A)

2.1.6. Criteria for diagnosing systemic-onset juvenile arthritis

Currently, 3 sets of classification criteria have been developed that can be used in the diagnosis of sJIA.

Core metrics

International League of Associations for Rheumatology (ILAR) classification criteria [2].

The diagnosis of systemic juvenile idiopathic arthritis is established in the presence of arthritis in one or more joints accompanied by (or preceded by) documented intermittent fever lasting for at least 3 days for a minimum of 2 weeks, combined with one or more of the following features:

- short-lived (evanescent) erythematous rash;

- generalized lymphadenopathy;

- hepatomegaly and (or) splenomegaly;

- serositis (pericarditis, and/or pleuritis, and/or peritonitis) with other diseases excluded.

A diagnosis of systemic juvenile idiopathic arthritis cannot be established in the presence of:

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

- arthritis associated with the class I major histocompatibility complex antigen 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 first-degree relatives;

- positive rheumatoid factor of immunoglobulin M (IgM) class in at least 2 samples taken at least 3 months apart.

Additional criteria are not validated in the pediatric population or are under development.

Yamaguchi classification criteria for adult-onset Still's disease [175].

Patients with sJIA may lack arthritis for a significant period of time (especially at disease onset).

Yamaguchi criteria may be useful in this subgroup of patients during the pre-arthritis phase of the disease.

• Major criteria

  - fever of 39°C or higher for at least 1 week

  - arthralgia for 2 weeks or more

  - maculopapular rash

  - leukocytosis >10.0*10⁹/L with neutrophils >80%

• Minor criteria

  - sore throat

  - lymphadenopathy and/or splenomegaly

  - elevated AST, ALT levels

  - negative ANA and RF

• Exclusion criteria

  - infections

  - oncological and hematological diseases

  - other rheumatic diseases

The diagnosis can be established in the presence of 5 criteria, including at least 2 major criteria.

Preliminary classification criteria for juvenile idiopathic arthritis developed by the Paediatric Rheumatology International Trials Organisation (PRINTO) [176].

The diagnosis of systemic juvenile idiopathic arthritis is established in patients with disease onset under the age of 18 in the presence of fever for at least 3 days over a minimum of 2 weeks, combined with two major criteria or one major and two minor criteria:

• Major criteria

  - short-lived, evanescent erythematous rash

  - arthritis (of any duration)

• Minor criteria

  - generalized lymphadenopathy, hepato- and/or splenomegaly

  - serositis

  - arthralgia lasting ≥2 weeks

  - leukocytosis >15.0*10⁹/L with neutrophilia

2.2. Evaluation of patients with suspected hemophagocytic syndrome

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a complication of systemic JIA, a dangerous hyperinflammatory syndrome representing the culmination of a severe uncontrolled reaction characterized by hypercytokinemia with a massive yet ineffective immune response. It is a consequence of the innate or acquired inability of the immune system to cope with the trigger—most commonly an infectious agent [36,177–183].

Secondary hemophagocytic lymphohistiocytosis (sHLH) is triggered by viruses (cytomegalovirus, Epstein-Barr virus, herpesviruses, etc.), medications (NSAIDs, gold preparations, sulfasalazine, etc.). Secondary sHLH is a consequence of excessive activation and expansion of mononuclear phagocyte system (MPS) cells and T lymphocytes, manifested by cytopenia, systemic inflammatory response, and damage to the liver and spleen. The cells comprising the MPS form a single differentiation lineage, which includes bone marrow progenitor cells as well as a pool of monocytes and macrophages. Overall, the MPS acts as a specific biological filter for blood and lymph, removing tumor cells, virus-infected cells, microorganisms, toxins, various metabolites, and circulating immune complexes. Histiocytes (syn.: macrophages) also perform antigen-presenting functions [36,177–183].

It is not always possible to diagnose sHLH because its clinical and laboratory manifestations may resemble a flare of systemic JIA, as well as an infectious process [36,177–183].

2.2.1. Physical examination

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: fever (persistent or non-remitting) is one of the main clinical symptoms of sHLH. It is invariably refractory 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 the diagnosis of HLH.

(LoE 5, GoR C)

Comments: the course of sHLH ranges from mild, with minimal symptom severity, to severe. In severe uncontrolled sHLH, impaired consciousness or coma may develop, and a fatal outcome is possible.

(LoE 5, GoR C)

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 examination of skin biopsy (surgical) material reveals lymphohistiocytic infiltration of the dermis with evidence of hemophagocytosis.

(LoE 5, GoR C)

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

(LoE 5, GoR C)

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

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

Physical examination may reveal enhanced cardiac pulsation, expansion of the boundaries of relative cardiac dullness, arrhythmias, and pathological murmurs over the projection areas of heart valves. As sHPS progresses, heart failure typically develops.

(LoE 5, GoR C)

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.

(LoE 5, GoR C)

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

(LEL 4, GRC C)

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

(LoE 5, GoR C)

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

(LEL 4, GRC C)

Comments: in sHLH, thromboelastography reveals signs of hypercoagulation, and hypocoagulation upon the development of consumption coagulopathy. Thromboelastography data are necessary to determine anticoagulant therapy tactics and monitor its efficacy.

(LoE 5, GoR C)

(LEL 4, GRC C)

Comments: sHLH is characterized by elevated serum ferritin, triglycerides, ALT, AST, LDH, hyperbilirubinemia, hyponatremia, hypochloremia, and hypoalbuminemia.

Elevated levels of creatinine, uric acid, and urea indicate the development of acute kidney injury associated with secondary hemophagocytic lymphohistiocytosis (sHLH-AKI)

(LEL 4, GRC C)

Comments: serum C-reactive protein levels are significantly elevated in sHLH.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(Level of Evidence 3, Grade of Recommendation C)

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

(LoE 5, GoR C)

Comments: tubular necrosis is the predominant form of renal injury in macrophage activation syndrome-associated acute kidney injury (MAS-AKI). However, histopathological changes may also include interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Patients with MAS-AKI typically present with oliguria, azotemia, and nephrotic syndrome. Urinalysis reveals proteinuria of varying severity, macroscopic and microscopic hematuria, and cylindruria.

2.2.3. Instrumental diagnostic procedures

(LEL 4, GRC C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LEL 4, GRC 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.

(LEL 4, GRC C)

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

(LoE 5, GoR C)

(LEL 4, GRC C)

Comments: bone marrow aplasia may develop in severe HFS.

2.2.4. Other diagnostic procedures

(LoE 5, GoR C)

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 levels), and hemophagocytic cells.

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

(LoE 5, GoR C)

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

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

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

2.2.5. Criteria for diagnosing secondary hemophagocytic syndrome.

A. Ravelli et al. criteria [235]:

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 syndrome in patients with systemic-onset juvenile idiopathic arthritis

All patients with a confirmed diagnosis of sJIA who present with a febrile fever require:

Evaluation of the following 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.

Evaluation of the results of the following tests:

- laboratory tests: hemoglobin level, absolute red blood cell count, white blood cell count, neutrophil, lymphocyte, and platelet counts, ESR, ALT, AST, GGT, LDH activity, serum creatinine, urea, CRP, ferritin, triglycerides, PCT, total protein and albumin concentrations, blood electrolyte profile (sodium, potassium, chlorides, iron), glomerular filtration rate (in case of worsening azotemia), blood clotting parameters (Quick's prothrombin, thrombin time, prothrombin time, INR, APTT, D-dimer, fibrinogen, fibrin monomer, von Willebrand factor, protein S, protein C);

- instrumental tests – ECG, echocardiography, ultrasound of the abdominal organs, kidneys, chest CT, abdominal MRI, brain MRI;

- microbiological tests of blood, urine, nasopharyngeal mucus, intestinal discharge;

- molecular biological tests using PCR to determine DNA of viruses from the Herpesviridae family (cytomegalovirus, Epstein-Barr virus, herpes simplex virus types 1 and 2). After analyzing the clinical data and test results described above, patients must have their diagnosis of MAS verified according to the 2016 criteria by A. Ravelli et al. (see section 2.3) and immunosuppressive therapy initiated in accordance with the treatment algorithm for systemic-onset juvenile idiopathic arthritis with hemophagocytic syndrome (see section 3.1.2).

Monitoring early markers of MAS development [236]:

All patients with sJIA require monitoring of early markers of MAS development:

Early clinical markers of secondary HPS:

- Lymphadenopathy

Early instrumental markers of secondary HPS:

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

- Decreased blood platelet count <208 thousand/µl

- Decreased blood chloride concentration <101.9 mmol/l

- Increased 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 Evaluation of patients with a confirmed diagnosis of systemic-onset juvenile idiopathic arthritis in the active disease stage for the purpose of prescribing/adjusting therapy

(LoE 5, GoR C)

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: biosimilars of anti-tumor necrosis factor alpha (TNF-alpha) inhibitors, as well as generic JAK inhibitors that are structurally equivalent, are currently approved. Some of these drugs have demonstrated efficacy similar to the original drugs in clinical trials in adult patients [281]. However, clinical trials of biosimilars and selective immunosuppressants have not been conducted in the pediatric population with juvenile idiopathic arthritis.

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

3.1 Conservative Treatment

3.1.1 Systemic juvenile idiopathic arthritis with active systemic manifestations and varying degrees of arthritis activity

(LoE 5, GoR C)

(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 instructions for medical use [1,3,7,282–289]. (CLE 5, LER C)

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 in tablets; intramuscular injections are 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, with dosing intervals of 6–8 hours.

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

(LoE 5, GoR C)

Comments: the use of GCs, immunosuppressants (methotrexate** or ^#leflunomide**), bDMARDs (tocilizumab** or canakinumab**, or anakinra**, or ^#adalimumab**, or ^#etanercept**, or golimumab**, or ^#rituximab**, or ^#abatacept**), selective immunosuppressants (^#tofacitinib** or ^#upadacitinib**) in oncological and oncohematological diseases mimicking sJIA will significantly hinder subsequent diagnosis verification, as they have a pronounced immunosuppressive effect and mask the clinical and morphological presentation of malignant neoplasms.

(LoE 5, GoR C)

(LoE 5, GoR C)

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

(LoE 5, GoR C)

Comments: the duration of the maximum dose is 4–8 weeks, after which the dose is gradually and slowly tapered to maintenance. If a disease flare develops, the dose of ^#prednisolone** or ^#methylprednisolone** may be increased to the maximum.

To minimize GC side effects, administration of ^#prednisolone** or ^#methylprednisolone** is not recommended to be continued for longer than 6 months [293].

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

— ^#triamcinolone (H02AB) for 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, small joints of the hands and feet [298–300]

for patients with active mono- or oligoarthritis no more than once every 4 months for the purpose of rapidly relieving the inflammatory process in the joints [1,3,7,291,298–302]. (UBD 5, GRS 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 outside of age-related indications are prescribed by decision of a medical commission, after obtaining informed consent from parents and children over 15 years of age.

(LoE 2, GoR B)

Comments: methotrexate** (L01BA) is prescribed for active oligo-polyarthritis. The subcutaneous route of administration for methotrexate** (L01BA) is preferred due to higher bioavailability.

Methotrexate** (L01BA) is preferably used in graduated syringes (here and hereinafter).

Outside of age-related indications, ^#methotrexate** (L01BA) is prescribed by decision of a medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1–G5

(LoE 5, GoR C)

(LEL 4, GRC C)

Comments: ^#Leflunomide** (L04FFAA) is prescribed for life-saving indications, by decision of a medical commission, after obtaining informed consent from parents and children over 15 years of age.

Monitoring of therapy efficacy – see Appendices G1–G5

— in children with body weight <30 kg – at a dose of 12 mg/kg/administration, in children with body weight ≥30 kg – at a dose of 8 mg/kg/administration intravenously once every 2 weeks. (UBD 1, GRS B)

or

— in children with body weight <30 kg at a dose of 162 mg subcutaneously once every 2 weeks, in children with body weight ≥30 kg – at a dose of 162 mg subcutaneously once a week. (UBD 3, GRS B)

for the purpose of inducing remission of sJIA [296,314–320].

Comments: in children younger than 2 years of age, ^#tocilizumab** (L04AC) in the intravenous formulation, or in children younger than 1 year of age, ^#tocilizumab** (L04AC) in the subcutaneous formulation is prescribed for life-saving indications, by decision of a medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1–G5

— in children with body weight <30 kg – at a dose of 12 mg/kg/administration, in children with body weight ≥30 kg – at a dose of 8 mg/kg/administration intravenously, intravenously once every 2 weeks.

or

— in children with body weight <30 kg at a dose of 162 mg subcutaneously once every 2 weeks, in children with body weight ≥30 kg – at a dose of 162 mg subcutaneously once a week.

to induce remission of sJIA [6,291,292,296,314–320] (for intravenous tocilizumab** combined with methotrexate** – LoE 1, GoR B; for subcutaneous tocilizumab** combined with methotrexate** – LoE 3, GoR B; for intravenous and subcutaneous tocilizumab** combined with ^#leflunomide** – LoE 5, GoR C).

Comments: in children younger than 2 years of age, ^#tocilizumab** (L04AC) in the intravenous formulation, or in children younger than 1 year of age, ^#tocilizumab** (L04AC) in the subcutaneous formulation is prescribed for life-saving indications, by decision of a medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1–G5.

(Level of Evidence 1, Grade of Recommendation B)

Comments: in children under 2 years of age, ^#canakinumab** (L04AC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1–G5.

Comments: in children under 2 years of age, ^#canakinumab** (L04AC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1–G5.

(LoE 5, GoR C)

Comments: in children under 8 months of age and with a body weight less than 10 kg, ^#anakinra** (L04AC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1–G5.

(LoE 5, GoR C)

Comments: in children under 8 months of age and with a body weight less than 10 kg, ^#anakinra** (L04AC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1–G5.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: in children under 2 years of age, ^#canakinumab** (L04AC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from the parents.

In children under 8 months of age and with a body weight less than 10 kg, ^#anakinra** (L04AC) is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1–G5.

Comments: in children under 2 years of age, ^#tocilizumab** (L04AC) intravenous formulation, or in children under 1 year of age, ^#tocilizumab** (L04AC) subcutaneous formulation is prescribed on vital indications, by decision of the medical commission, after obtaining informed consent from the parents.

Monitoring of therapy efficacy – see Appendices G1–G5.

Comments: ^#rituximab** is prescribed in case of persistence of systemic manifestations and/or failure of the patient to achieve a 50% improvement according to the ACR pediatric criteria at 3 months, or the inactive disease state according to the C. Wallace criteria at 6 months during treatment with a second/third biologic DMARD (tocilizumab** (L04AC), canakinumab** (L04AC), or anakinra** (L04AC)) combined with (or without) methotrexate** or ^#leflunomide** (L04FFAA) [326].

Courses of ^#rituximab** (L01XC) therapy (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 the inactive disease state/remission is not achieved after the 3rd course of ^#rituximab** (L01XC) treatment, rituximab therapy 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–G5.

(LoE 5, GoR C)

Comments: monitoring of therapy efficacy – see Appendices G1–G5.

— ^#adalimumab** (L04AB) for children ≥2 years of age with a body weight of 15–30 kg at a dose of 20 mg; with a body weight >30 kg at a dose of 40 mg subcutaneously once every 2 weeks [343].

— or ^#etanercept** (L04AB) at a dose of 0.2–0.4 mg/kg/administration 2 times a week or 0.8 mg/kg/administration once a week [343,344],

— or ^#golimumab** (L04AB) for children ≥2 years at a dose of 30 mg/m² (maximum 50 mg) subcutaneously once every 4 weeks [333,345]

in combination with methotrexate** (L01BA) or ^#leflunomide** (L04AA13), or as monotherapy for the purpose of induction/maintenance of remission in sJIA [333–338,343–345]

(Level of Evidence 5, Grade of Recommendation C).

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

For doses and administration schedule of methotrexate** (L01BA) and ^#leflunomide** (L04AA13), see above.

Off-label, ^#adalimumab** (L04AB), ^#etanercept** (L04AB), and ^#golimumab** (L04AB) are prescribed for vital indications, by decision of the medical commission, after obtaining informed consent from the parents [313].

The indication for use in children and adolescents with juvenile arthritis aged 2 to 17 years and with a body mass 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: childhood under 12 years of age and body mass less than 62.5 kg [346–349].

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** [350]:

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 sJIA, it is advisable to use the medicinal product adalimumab** citrate-free formulation 40 mg/0.4 ml in order to avoid causing children unjustified pain that develops when using the medicinal product adalimumab** citrate-containing formulation 40 mg/0.8 ml [351–355].

Taking into account the pronounced pain syndrome when using the medicinal product adalimumab** citrate-containing formulation 40 mg/0.8 ml, the use of this formulation in pediatric patients is impossible [351–355].

Comments: ^#tofacitinib** (L04AA29) 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–G5

Comments: ^#upadacitinib** (L04AA44) 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–G5

Comments: ^#abatacept** (L04AA44) 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–G5

(LEL 4, GRC C)

(LEL 4, GRC C)

3.1.2. Systemic-onset juvenile arthritis with hemophagocytic syndrome

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: ^#dexamethasone** (H02AB) and ^#cyclosporine** (L04AD01) are prescribed for vital indications by decision of the medical commission, after obtaining informed consent from parents and children over 15 years of age.

— ^#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/m³/day for 5–6 weeks, 1.25–2.5 mg/m⁴/day for 7–8 weeks;

— ^#methylprednisolone** starting from an initial dose of 20–30 mg/kg/administration for 3–5 days with a dose reduction of 25% once every 2–3 days to prevent withdrawal syndrome [1,188,363,364,366,368–371].

(LoE 5, GoR C)

(LEL 4, GRC C)

(LoE 5, GoR C)

Comments: administration of the full course dose of ^#normal human immunoglobulin** is carried out via continuous prolonged infusion as a single dose to ensure blockade of IgG Fc receptors on phagocytic cells; suppression of T-lymphocyte proliferation and immunoglobulin production; interaction with the complement system; blockade of cytokine activation and action; and blockade of adhesion molecule expression on endothelial cells.

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

(LoE 5, GoR C)

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

(LEL 4, GRC C)

Comments: ^#anakinra** (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.

— ^#ruxolitinib** orally

• for children weighing up to 10 kg – 2.5 mg × 2 times/day;

• for children weighing from 10 to 25 kg – 5 mg × 2 times/day;

• for children weighing >25 kg – 10 mg × 2 times/day (Level of Evidence 4, Grade of Recommendation C)

— or ^#tofacitinib** (L04AA) orally at a dose of 10 mg × 2 times/day to relieve HFS [188,381,382]. (Level of Evidence 4, Grade of Recommendation C)

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

(LEL 4, GRC C)

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

(LoE 5, GoR C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: ^#acyclovir** (JO5AB) for children <3 years of age is prescribed by decision of the medical commission, after obtaining informed consent from parents.

Treatment is carried out until complete relief of herpetic infection.

(LoE 5, GoR C)

Comments: ^#Ganciclovir** (J05AB) in children <12 years of age is prescribed by decision of the medical panel, after obtaining informed consent from parents and approval from the local ethics committee of the medical organization.

(LoE 5, GoR C)

Comments: ^#Ganciclovir** (J05AB) in children <12 years of age is prescribed by decision of the medical panel, after obtaining informed consent from parents and approval from the local ethics committee of the medical organization.

(LoE 5, GoR C)

Comments:

Regimens:

— ^#rituximab** (L01XC) – at a dose of 375 mg/m²/week intravenously for 1–4 consecutive weeks [396];

— ^#cyclosporine** (L04AD) – 3–5 mg/kg/day [193,396];

— ^#normal human immunoglobulin** (J06BA) – 1–2 g/kg/course over 2 days [193,396];

— ^#sulfamethoxazole + trimethoprim** (J01EE) – for administration schedule and doses of ^#sulfamethoxazole + trimethoprim** (J01EE), see above [243,384].

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

(LoE 5, GoR C)

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.

(LoE 5, GoR C)

Comments: in case of consumption coagulopathy development, blood transfusion and blood products (B05A) are administered: red blood cells, fresh frozen plasma, blood coagulation factor VII, platelets, cryoprecipitate, etc., according to indications.

(LoE 5, GoR C)

(LoE 5, GoR C)

(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.

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: after MAS resolution, therapy is recommended to maintain remission of sJIA (see above).

3.1.3. Main principles of treatment for juvenile idiopathic arthritis (Paediatric Rheumatology European Society, PRES)

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

2. Minimal (or low) disease activity can be an alternative goal exclusively in patients with long-standing disease (2cB)* (see Appendices G1–G5).

3. Target setting and choice of therapy should 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 should be continuous to ensure the maintenance of remission (target) (2bC)* [317].

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 bone and cartilage destruction; avoidance of comorbid conditions and side effects of medications; ensuring functional activity, 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 target.

F. Achieving the target requires monitoring of disease activity and adjustment of therapy [317].

* PRES criteria

3.2. Surgical treatment

(LEL 4, GRC C)

3.3. Non-pharmacological treatment

(LoE 5, GoR C)

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.

(LoE 5, GoR C)

(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

(LoE 2, GoR B)

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.

(LoE 5, GoR C)

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.

(Level of Evidence 3, Grade of Recommendation C)

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.

(Level of Evidence 3, Grade of Recommendation C)

Comments: the objective of the "School" is to inform parents and children about the features, mechanisms of development, clinical picture of the disease, treatment, mechanisms of drug action, 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 in methods for monitoring drug efficacy and safety using generally accepted rheumatologic scales and questionnaires.

5. Prevention and Dispensary Observation

5.1. Prevention

Primary prevention has not been developed since the etiology of sJIA has not been definitively established.

(LoE 5, GoR C)

Comments: to prevent flares and complications of sJIA, long-term maintenance therapy is administered under the constant monitoring of clinical and laboratory indicators of disease activity, tailored to the patient's individual characteristics and disease variant, with adjustments made when necessary; a protective regimen is ensured (psycho-emotional and physical loads are limited; during flares, children are homeschooled and attend school only during inactive disease/remission; contacts are restricted to reduce the risk of infectious diseases); sun exposure, trips to regions with high solar radiation, and UV therapy are strictly avoided, 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.

(LoE 5, GoR C)

Comments: the safety of such a combination has not been established. An sJIA flare may develop. There are no data on the secondary transmission of infection from patients vaccinated with live vaccines to patients receiving bDMARDs.

(LEL 4, GRC C)

(LoE 3, GoR B)

Comments: vaccination with the 13-valent pneumococcal polysaccharide conjugate vaccine in patients receiving tocilizumab** and canakinumab** is performed 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** therapy is planned — prior to the first infusion to prevent infectious complications, improve treatment adherence, and prevent sJIA flares.

5.2. Follow-up examination of patients with systemic juvenile idiopathic arthritis in an inpatient/day hospital setting following the initiation of bDMARD/immunosuppressant therapy.

The examination is performed every 3–6 months: at 3 and 6 months after initiation of 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.

(LoE 5, GoR C)

Comments: the primary treatment goal is to achieve a 50% improvement according to the American College of Rheumatology criteria at 3 months and an inactive disease state according to the C. Wallace inactive disease/remission criteria at 6 months.

(LoE 5, GoR C)

Comments: CBC parameters should be within the normal range. Single-, bi-, or pancytopenia may indicate disease flare and/or an adverse effect of biologic disease-modifying antirheumatic drugs (bDMARDs) and/or immunosuppressants.

Leukopenia most frequently develops during treatment with tocilizumab** and ^#rituximab**, and less commonly with other immunosuppressants and bDMARDs.

Thrombocytopenia may develop during treatment with any bDMARD and immunosuppressant.

If there is evidence of recurrent thrombocytopenia, the bDMARD and/or immunosuppressant therapy should be adjusted.

(LoE 5, GoR C)

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

(LoE 5, GoR C)

Comments: Previously prescribed oral GCs should be continued.

Repeat the complete blood count in 1 week.

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: Previously prescribed oral GCs should be continued.

Treatment with ^#filgrastim** (L03AA) is carried out for 3–5 days (or longer if necessary) until complete normalization of leukocyte and neutrophil counts.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(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.

(LoE 5, GoR C)

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

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(Level of Evidence 3, Grade of Recommendation C)

Comments: an elevated serum C-reactive protein level is a sign of secondary infection and/or macrophage activation syndrome (MAS) development.

(LoE 5, GoR C)

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

(LoE 5, GoR C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(Level of Evidence 3, Grade of Recommendation C)

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

(LEL 4, GRC C)

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

(LoE 5, GoR C)

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 sJIA activity, pulse therapy with ^#methylprednisolone** (see above) is performed and/or oral GCs are prescribed (dose increased) (see sJIA treatment).

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR 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.

(LoE 5, GoR C)

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.

(LEL 4, GRC C)

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

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LoE 5, GoR C)

Comments: ^#acyclovir** (J05AB) in children aged <3 years is prescribed by decision of a medical commission, after obtaining informed consent from the parents.

Treatment with ^#acyclovir** is carried out for 7–10 days until the herpetic rashes completely disappear.

(LoE 5, GoR C)

Comments: ^#ganciclovir** (J05AB) in children aged <12 years is prescribed by decision of a medical commission, after obtaining informed consent from the parents and approval from the local ethics committee of the medical organization.

(LoE 5, GoR C)

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

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

Comments: Previously prescribed oral GCs should be continued.

(LoE 5, GoR C)

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.

(LoE 5, GoR C)

Comments: the issue of resuming therapy and choosing a bDMARD and/or immunosuppressant is resolved after the completion of specific chemotherapy and consultation with a phthisiatrician.

(LoE 5, GoR C)

Comments: the issue of continuing biologic DMARD therapy is decided on an individual basis.

(LoE 5, GoR C)

(LoE 5, GoR C)

(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.

(LoE 5, GoR C)

(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.

(LoE 5, GoR C)

Comments: if nasopharyngeal contamination with pathogenic and/or opportunistic microorganisms is detected, an otorhinolaryngologist consultation is required to address the need for sanitization.

In the absence of clinical manifestations, 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.

(LEL 4, GRC C)

Comments: if proteinuria worsens, immunosuppressive therapy is adjusted (see treatment of sJIA).

(LoE 5, GoR C)

(LEL 4, GRC C)

Comments: performed in all patients. In patients with sJIA remission, no pathological changes are detected on the electrocardiogram.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: performed in all patients. Includes comprehensive abdominal ultrasound and renal ultrasound. Examinations 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 GC, and/or immunosuppressant therapy.

(LEL 4, GRC C)

Comments: performed in all patients. In patients with sJIA remission, no pathological changes are detected on echocardiography.

(LEL 4, GRC C)

(LEL 4, GRC C)

(LoE 5, GoR 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.

(LoE 5, GoR C)

Comments: eradication therapy outside of age indications is prescribed by decision of a medical commission, after obtaining informed consent from parents and children aged ≥15 years.

(LoE 5, GoR C)

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.

(Level of Evidence 1, Grade of Recommendation B)

(LEL 4, GRC C)

Comments: during treatment with biologic DMARDs, especially in combination with immunosuppressants and glucocorticoids, pneumonia (interstitial, focal, lobar, polysegmental) may develop.

Pneumonia developing during biologic DMARD therapy is characterized by low-grade fever or its complete absence, a scant clinical picture, and no elevation of acute-phase inflammation markers: ESR, blood leukocyte count, and serum C-reactive protein level.

Interstitial pneumonia most frequently develops during the use of ^#rituximab**, and less commonly other immunosuppressants.

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 pneumonia should be suspected if dry/wet cough or throat clearing appears.

(LoE 3, GoR B)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LoE 3, GoR B)

(LoE 3, GoR B)

(LoE 3, GoR B)

(LoE 3, GoR B)

(LoE 3, GoR B)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LoE 5, GoR C)

Comments: systemic antibacterial drugs (J01) outside of age indications are prescribed by decision of a medical commission, after obtaining informed consent from parents and children older than 15 years.

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.

(LoE 5, GoR C)

Comments: ^#cotrimoxazole** (J01EE) outside of age indications is prescribed by decision of a medical commission, after obtaining informed consent from parents and approval from the local ethics committee of the medical organization.

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.

(LoE 5, GoR C)

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.

(LEL 4, GRC C)

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.

(LoE 5, GoR C)

Comments: systemic antibacterial drugs (J01) used off-label for age are prescribed by decision of a medical commission after obtaining informed parental consent.

(LoE 5, GoR C)

Comments: treatment with biologic DMARDs and/or immunosuppressants is suspended for the duration of antibacterial therapy. Previously prescribed oral glucocorticoids should be continued.

(LoE 5, GoR C)

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

(LoE 5, GoR C)

Comments: performed no more than once every 12 months.

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: bisphosphonates (M05BA) are prescribed for life-health indications, by decision of the medical commission, after obtaining informed consent from parents and children aged ≥15 years.

— ^#pamidronic acid (maximum dose 60 mg/infusion) [272]:

• in patients <1 year of age 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) [272]:

• at a dose of 1–2 mg/kg/week orally,

• in patients with body weight <40 kg at a dose of 5 mg/day or 35 mg/week,

• in patients with body weight >40 kg at a dose of 10 mg/day or 70 mg/week.

— or ^#zoledronic acid** at a dose of 0.0125–0.05 mg/kg/infusion IV every 6–12 months (maximum dose 4 mg) [272];

— or ^#ibandronic acid:

• at a dose of 3 mg/infusion IV once every 3 months [468]

• or 150 mg orally once a month [467]

in patients with osteopenia/osteoporosis for the treatment of osteoporosis [272,466–468].

(LoE 5, GoR C)

Comments: bisphosphonates (M05BA) are prescribed for life-health indications, by decision of the medical commission, after obtaining informed consent from parents and children aged ≥15 years.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: patients with complicated cataract undergo evaluation of therapy efficacy and assessment of the need for surgical treatment.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 2, GOR A)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LE 1, GR C)

(LoE 2, GoR B)

(LE 1, GR C)

(LoE 5, GoR C)

Monitoring of treatment efficacy – see Appendices G1–G5

(LoE 5, GoR C)

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).

(LEL 4, GRC C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LEL 4, GRC C)

(LEL 4, GRC C)

(LEL 4, GRC C)

5.3. Follow-up evaluation as part of dispensary observation in outpatient and polyclinic settings

(LoE 5, GoR C)

Comments: the rheumatologist examines the patient at least once a month, assesses their general condition, presence of systemic manifestations, and joint syndrome activity; analyzes the efficacy and safety of antirheumatic therapy using standard questionnaires and scales (see Appendices G1–G5); analyzes the results of laboratory and instrumental examinations; conducts health education work with the patient and their parents (legal representatives), explaining the necessity of treatment adherence, psychological and medical rehabilitation; explains which adverse events may develop during treatment with bDMARDs, GCS, and immunosuppressants; how infections manifest under bDMARD therapy; and what actions parents should take in the event of infections and adverse reactions to antirheumatic drugs; interacts with medical specialists and with the rheumatologist of the inpatient rheumatology department, including via telemedicine.

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: the pediatric rheumatologist examines the patient, assesses their general condition, the presence of systemic manifestations, and lupus nephritis activity; analyzes the efficacy and safety of antirheumatic therapy using generally accepted questionnaires and scales (see Appendices G1-G5); analyzes the results of laboratory and instrumental examinations; conducts health education for the patient and their parents (legal representatives), explaining the necessity of treatment adherence, as well as psychological and medical rehabilitation; explains what adverse events may develop during treatment with biologic DMARDs, glucocorticoids, and immunosuppressants; explains how infections present under biologic DMARD treatment; what actions parents should take if infections and adverse events of antirheumatic drugs develop; interacts with medical specialists, as well as with the inpatient rheumatologist of the rheumatology department, including via telehealth.

(LEL 4, GRC C)

Comments: an allergic reaction can occur at any stage of treatment with a biologic DMARD and/or immunosuppressant.

(LEL 4, GRC C)

Comments: the choice of drug and its route of administration depend on the severity of the allergic reaction.

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: repeat the complete blood count with differential in one week.

(LoE 5, GoR C)

Comments: neutropenia most frequently develops during treatment with ^#rituximab**.

(LoE 5, GoR C)

Comments: Previously prescribed oral GCs should be continued.

(LoE 5, GoR C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR C)

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

(LoE 5, GoR C)

Comments: previously prescribed oral glucocorticoids should be continued.

Repeat the general clinical biochemistry blood test in one week.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: if autoantibody titers increase, an appointment (examination, consultation, including telehealth) with the inpatient rheumatologist who initiated the therapy is performed.

The decision regarding the need to adjust therapy and the setting in which it should be administered is made by the inpatient rheumatologist who initiated the therapy, based on the results of an appointment (examination, consultation, including remote) with the inpatient rheumatologist who initiated the therapy.

(Level of Evidence 3, Grade of Recommendation C)

Comments: if serum C-reactive protein levels increase, an appointment (examination, consultation, including telehealth) with the inpatient rheumatologist who initiated the therapy is performed.

The decision regarding the need to adjust therapy and the setting in which it should be administered is made by the inpatient rheumatologist who initiated the therapy, based on the results of an appointment (examination, consultation, including remote) with the inpatient rheumatologist who initiated the therapy.

(LoE 5, GoR C)

Comments: decreased blood immunoglobulin levels develop in secondary immunodeficiency states, predominantly during ^#rituximab** treatment under conditions of B-lymphocyte depletion.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: an elevated serum anti-streptolysin-O level indicates acute or chronic streptococcal infection.

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LE 5, GR C)

Comments: interstitial pneumonia most frequently develops during the use of ^#rituximab**, and less commonly other immunosuppressants and bDMARDs.

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).

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: in children aged <3 years, ^#acyclovir** (J05AB) is prescribed by decision of a 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 herpetic rashes completely disappear.

(LoE 5, GoR C)

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

(LoE 5, GoR C)

Comments: an appointment (examination, consultation, including remote ones) is conducted with the inpatient rheumatologist who initiated the therapy, to resolve the issue of further patient management.

(LoE 5, GoR C)

(LoE 5, GoR C)

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

The decision regarding the need for therapy adjustment and the setting in which it should be performed is made by the inpatient rheumatologist who initiated the therapy based on the consultation results (including remote).

Monitoring of therapy efficacy – see Appendices G1–G5

(LoE 5, GoR C)

(LEL 4, GRC C)

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.

(LoE 5, GoR C)

(LEL 4, GRC C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(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).

(LoE 5, GoR C)

(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).

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 2, GoR B)

(LoE 5, GoR C)

(LoE 5, GoR C)

(LoE 5, GoR C)

Comments: performed in all patients with systemic juvenile idiopathic arthritis

(LoE 5, GoR C)

Monitoring of therapy efficacy – see Appendices G1–G5

(LoE 5, GoR C)

6. Organization of Medical Care

6.1. Indications for hospital admission and discharge of patients.

Suspected sJIA

Diagnostic procedures, including differential diagnostics and prescription of antirheumatic therapy, are performed for all patients in an inpatient rheumatology department.

Indications for discharge

• Completion of examination; establishment of the diagnosis of systemic juvenile idiopathic 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 sJIA diagnosis, 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 systemic juvenile idiopathic arthritis with active macrophage activation 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 trend towards normalization / normalization of laboratory indicators of systemic juvenile idiopathic arthritis activity.

Established sJIA diagnosis, regardless of 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.

Established sJIA diagnosis, in remission

Monitoring the efficacy and safety of antirheumatic therapy is carried out in the hospital rheumatology department 3 months after initiating therapy, 6 months after initiating therapy, 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 further every 6 months.

• Absence of adverse events / drug intolerance

A patient with an established diagnosis of systemic juvenile idiopathic arthritis who develops an exacerbation/complications of the disease, comorbid conditions, complications/side effects/persistent intolerance to biologic DMARDs/immunosuppressants must be urgently hospitalized in the rheumatology department of the hospital that initiated the prescription of biologic DMARDs/immunosuppressants for examination and therapy adjustment at any stage of treatment.

Indications for antirheumatic therapy, including genetically engineered biologic drugs (intramuscular and subcutaneous administration), in patients with systemic juvenile idiopathic arthritis in a medical organization (pediatric rheumatology department in an inpatient and/or day hospital setting; procedural room of a primary care medical organization; procedural room of a paramedic-midwife station [if a pediatric rheumatology office is unavailable]):

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 targeted immunosuppressants with or without glucocorticoid pulse therapy, and/or immunosuppressants, and/or high-dose normal human immunoglobulin in patients with systemic juvenile idiopathic arthritis with high/moderate inflammatory activity and/or resistance to ongoing drug therapy.

6.2. Regulatory and legal documents governing the provision of medical care to children with systemic juvenile idiopathic 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 Profiled in '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 for 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, Timeliness, Quality, and Conditions of Medical Care Provision 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, Registration No. 63410).

7. Order of the Ministry of Health of the Russian Federation 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, Registration No. 54643).

8. Order of the Ministry of Health of the Russian Federation No. 789n dated December 13, 2022, "On Amendments to the Rules of Compulsory Medical Insurance Approved by Order of the Ministry of Health of the Russian Federation No. 108n dated February 28, 2019" (Registered with the Ministry of Justice of the Russian Federation on December 30, 2022, Registration No. 71905).

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 Fundamentals of Protecting Public Health in the Russian Federation" (with amendments and additions, effective June 29, 2022): "Standards of medical care for children and clinical guidelines may include a medicinal product registered in the territory of the Russian Federation used in accordance with indications (characteristics) of the medicinal product not specified in its instructions for use, provided that such medicinal product complies with the requirements established by the Government of the Russian Federation. The list of diseases or conditions (groups of diseases or conditions) for which the use of a medicinal product in accordance with indications (characteristics) not specified in its instructions for use is permitted shall be established by the Government of the Russian Federation."

10. Order of the Government of the Russian Federation No. 1180-r dated May 16, 2022 "List of diseases or conditions (groups of diseases or conditions) in which the use of a medicinal product is permitted in accordance with the indications (characteristics) of the medicinal product not specified in the instructions for its use."

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 Therapeutic 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 Recognition of a Person as Disabled" (as amended by Decrees of the Government of the Russian Federation No. 2121 dated November 23, 2022, No. 77 dated January 24, 2023, No. 1887 dated November 10, 2023, No. 2003 dated November 28, 2023, No. 289 dated April 12, 2024).

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 Medico-Social Expertise of Citizens by Federal State Institutions of Medico-Social Expertise"

3. Subclause 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 medico-social expertise by federal state institutions of medico-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 delayed provision of pathogenetic biologic therapy to a child with systemic JIA, there is a high probability of disease flare/increased activity, development of multiorgan failure, progression of joint damage, and functional impairment in the patient.

7.1 Outcomes and prognosis

In 40% of patients, the disease follows a monocyclic course with full recovery after a certain period. Individual patients experience a polycyclic course of systemic JIA, characterized by episodes of disease activity and drug-free remission periods. In 50% of children, the disease has a persistent course with progressive polyarthritis and functional impairment. Patients receiving long-term glucocorticoids also develop complications from hormonal therapy. Remission is achieved in 1/3 of patients. Mortality is 1% in Europe and <0.5% in North America. Macrophage activation syndrome remains a severe and potentially fatal complication. Death may occur due to neurological and cardiological complications [1,3,7].

Poor prognostic factors (ACR, 2021) [6,16,326]

— In systemic JIA without active articular syndrome: active systemic disease manifestations for 6 months (fever, elevated laboratory parameters), need for repeated systemic glucocorticoid therapy; recurrent macrophage activation syndrome.

— In systemic JIA with active articular syndrome without active systemic manifestations: involvement of the hip joints, cervical spine, wrist joints, and/or joint destruction according to radiological imaging (erosions of articular surfaces, narrowing of joint spaces).

Criteria for Evaluating the Quality of Medical Care

Organizational and technical conditions for the provision of medical care.

Table 1. Criteria for assessing the quality of initial diagnosis for establishing the diagnosis of systemic juvenile idiopathic arthritis

Table 2. Diagnostic quality criteria for hemophagocytic lymphohistiocytosis

Table 3. Criteria for assessing the quality of examination of patients with an established diagnosis of systemic juvenile idiopathic arthritis prior to the initiation/adjustment of antirheumatic therapy

Table 4. Quality assessment criteria for the treatment of systemic juvenile idiopathic arthritis with active systemic manifestations and varying degrees of arthritis activity

Table 5. Quality assessment criteria for the treatment of systemic-onset juvenile idiopathic arthritis complicated by macrophage activation syndrome

Table 6. Quality assessment criteria for dispensary follow-up of patients with systemic-onset juvenile idiopathic arthritis, including therapy safety monitoring, in an inpatient/day-hospital setting that initiated the prescription of a genetically engineered biologic drug/immunosuppressant

Table 7. Criteria for evaluating the quality of follow-up control for patients with systemic juvenile arthritis, including therapy safety monitoring, in outpatient settings

References