Reactive 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

bDMARDs – Biologic disease-modifying antirheumatic drugs (ATC code L01XC – monoclonal antibodies)

GCs – Glucocorticoids (ATC code: H02AB)

GGT – Gamma-glutamyl transferase

DNA – Deoxyribonucleic acid

GI – Gastrointestinal tract

CT – Computed tomography

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)

ARI – Acute respiratory infection

ReA – Reactive arthritis

RF – Rheumatoid factor

ESR – Erythrocyte sedimentation rate

CRP – C-reactive protein

Ultrasound – Ultrasound examination

CMV – Cytomegalovirus

ALP – Alkaline phosphatase

EGD – Esophagogastroduodenoscopy

ECG – Electrocardiography

EchoCG – Echocardiography

Ig G, M, A – Immunoglobulin G, M, A

ILAR – International League of Associations for Rheumatology (International League of Associations for Rheumatology)

Per os – By mouth, orally

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

…^# – "information on the method of administration, dosage, and duration of drug use, accompanied by references to clinical trials on the efficacy and safety of the dosing regimen for this disease, or references to relevant literature sources if the thesis-recommendation pertains to a medication used off-label (outside the indications, contraindications, methods of administration, and dosages approved in the package insert)";

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)

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) is a chronic inflammatory disease belonging to the group of spondyloarthrites, characterized by mandatory involvement of the sacroiliac joints and/or spine with potential progression to ankylosis, with frequent involvement of entheses and peripheral joints in the pathological process

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

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Reactive arthritis is a spondyloarthropathy developing in response to an extra-articular intestinal or urogenital infection, characterized by conjunctivitis, urethritis, and arthritis, and is frequently associated with HLA-B27.

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

Etiological factors of ReA are presented in Table 1.

Table 1. Pathogens of arthritogenic infections.

Pathogenesis

Reactive arthritis predominantly develops in HLA-B27 carriers. HLA-B28 is associated with the frequency and severity of joint pain in ReA associated with intestinal infections (Yersinia, Salmonella, Shigella). The role of HLA-B27 in the pathogenesis of ReA is not fully understood. Similarities have been shown between the amino acid sequences of bacteria and HLA-B27. According to the arthritogenic peptide hypothesis, the HLA-B27 molecule binds a bacterial or self-antigenic peptide, which is then presented to cytotoxic (CD8+) T lymphocytes. The interaction of (CD8+) T lymphocytes with bacterial epitopes leads to inflammation and tissue damage. According to the hypothesis of impaired secondary and tertiary protein structure formation, HLA-B27 heavy chains accumulate in the endoplasmic reticulum. This leads to the activation of nuclear factor kB and the synthesis of pro-inflammatory cytokines. The same processes are responsible for the deposition of β2-microglobulin in the synovial membrane and, possibly, in other tissues, leading to inflammation. ReA associated with HLA-B27 is characterized by prolonged intracellular persistence of bacteria. The detection rate of HLA-B27 in ReA varies. In Chlamydia-associated ReA, as well as in mild forms of diseases caused by Yersinia and Campylobacter, the frequency of HLA-B27 carriage corresponds to the population value, whereas in other variants of ReA it is 60%. Arthritogenic infection (Yersinia, Salmonella, Shigella) damages the intestinal mucosa and replicates in polymorphonuclear leukocytes and macrophages. In children with ReA, components of arthritogenic bacteria (lipopolysaccharides, DNA, and RNA) are detected in synovial fluid cells and synovial membrane biopsies.

1.3 Epidemiology of the Disease or Condition

Reactive arthritis (ReA) develops in 5-10% of children who have had yersiniosis, and in 20% of those who have had diarrhea caused by Salmonella typhimurium. It is more common in boys aged 8-12 years. Reactive arthritis associated with intestinal infections can develop at any age; that associated with chlamydial infection develops in adolescents and sexually active teenagers. During the COVID-19 pandemic, several cases of acute arthritis following a viral infection were reported and classified as ReA.

1.4 Features of Coding the Disease or Condition

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

M02.8 Other reactive arthropathies

M02.9 Reactive arthropathy, unspecified

Examples of diagnoses:

Example No. 1. Post-dysenteric reactive arthritis of the right knee joint.

Example No. 2. Chlamydial reactive arthritis of the left ankle joint, dactylitis of one toe of the left foot, bilateral conjunctivitis.

1.5 Classification of the disease or condition

• urogenital

• post-enterocolitic

• viral

1.6 Clinical presentation of the disease or condition

Arthritis typically develops 1-4 weeks after the infection.

In intestinal infection caused by Shigella, the acute period (fever with or without watery diarrhea, crampy abdominal pain) lasts 48-72 hours. Arthritis develops after 7-21 days. It is characterized by an acute onset, manifesting as non-migratory oligoarthritis involving the knee and ankle joints, lasting from several weeks to 3-4 months. To diagnose ReA, data confirming a prior infection are required: detection of agglutinins to Shigella flexneri serotypes 2 or 2a and/or the pathogen in feces.

Following an intestinal infection caused by S. typhimurium or Salmonella enteritidis, oligoarthritis involving the knee and ankle joints develops after 1-3 weeks, accompanied by a low-grade fever. Bacteriological stool examination detects the pathogen even in the late stages of the disease; seroconversion is observed in 50% of patients.

Intestinal infection caused by Yersinia enterocolitica in young children usually presents as gastroenteritis; in children over 5 years of age, it presents in a pseudoappendicular form (right iliac fossa syndrome). In 1/3 of patients, arthritis can last from 3 to 22 months (an average of 6.5 months). HLA-B27 is detected in 85% of affected individuals.

Urogenital infection caused by Chlamydia trachomatis is generally asymptomatic, but may be accompanied by dysuria, frequent urination, urethral and/or vaginal discharge. In rare cases, ReA develops following a respiratory infection caused by C. pneumoniae.

Joint involvement

Onset variants:

• acute arthritis with severe pain, in some cases with skin hyperemia over the affected joints;

• arthritis with mild to moderately severe pain and joint swelling lasting for several weeks;

• isolated enthesitis or in combination with arthritis or tenosynovitis;

• arthralgia followed by the development of arthritis.

The knee and ankle joints are typically affected, less commonly the metatarsophalangeal, proximal and distal interphalangeal joints of the feet. Two or three joints of one or more digits are involved, and tenosynovitis and bursitis develop. Patients with a history of yersiniosis or salmonellosis may develop involvement of the small joints of the hands. Exudative manifestations are prominent in peripheral joints; proliferative synovitis is rare. Inflammatory phenomena in the joints of the axial skeleton may develop and be accompanied by back pain, pain in the sacroiliac joints, stiffness, and impaired mobility in the cervical and lumbar spine.

Extra-articular manifestations. HLA-B27 carriers develop iridocyclitis and the classic triad of symptoms: arthritis, conjunctivitis, urethritis. In the acute period of ReA, fever, weight loss, fatigue, and muscle weakness are observed, which may be combined with polyarthralgia, myalgia, and morning stiffness in the affected joints.

Mucosal and skin lesions are combined with arthritis and develop in the acute phase of the disease. Mucosal involvement manifests as painless, asymptomatic, shallow ulcers on the oral mucosa; in some cases, aphthous stomatitis. Urethritis and cervicitis develop rarely, primarily in sexually active adolescents with Chlamydia-induced ReA. Urogenital tract involvement is mild; in girls, it is asymptomatic and detected by the presence of sterile pyuria. Diarrhea occurs as a result of the infection but can be a manifestation of generalized mucositis.

Skin lesions manifest as erythema nodosum (more common in Yersinia ReA), balanopostitis, keratoderma with or without conjunctivitis, or urethritis. Keratoderma in ReA is clinically and histologically similar to psoriasis.

Eye involvement. Conjunctivitis develops in 2/3 of patients at disease onset. In Yersinia ReA, it can be purulent, with a severe course. Acute iridocyclitis and anterior uveitis also develop. Acute iridocyclitis is characterized by an acute course, the presence of cells in the anterior chamber, small corneal precipitates, cells in the vitreous body, fibrinous exudate, posterior synechiae, and macular edema. Acute iridocyclitis can be unilateral or bilateral. Acute anterior uveitis is more frequently observed in S. typhimurium-associated ReA.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of "Reactive arthritis"

To date, universally accepted criteria for diagnosing ReA have not been established. Table 1 presents generalized criteria for ReA diagnosis based on ACR recommendations and the Berlin criteria (1999) [1,2].

Table 1. Diagnostic criteria for reactive arthritis

Evaluation of patients with suspected reactive arthritis

2.1 Complaints and Anamnesis

Comments: patients may complain of: patients with ReA may present with weight loss, weakness, fatigue, pain and/or swelling, and/or restricted range of motion in the joints, gait disturbance.

In ocular involvement, children may present with eye irritation and pain, decreased and/or blurred vision, floaters in front of the eyes, eye redness, photophobia, and lacrimation. However, most often in eye involvement (uveitis), there are either no complaints, or parents notice that the child's pupil has become deformed and they bump into objects due to decreased visual acuity.

As a rule, uveitis is asymptomatic. By anatomical location, uveitis can be anterior (iritis, anterior cyclitis, iridocyclitis) – inflammation of the iris and/or ciliary body; intermediate (posterior cyclitis) involving the ciliary body and the peripheral parts of the choroid proper; posterior (choroiditis, chorioretinitis) – inflammation of the choroid proper. Panuveitis may also develop. Depending on the course, uveitis can be acute, subacute, and chronic (indolent or recurrent). Depending on the number of affected eyes, it can be unilateral or bilateral.

Comments: determining the presence of urogenital and other infections (chlamydial, mycoplasmal, cytomegalovirus, herpetic, Epstein-Barr virus, etc.) that may be triggers of ReA in the child, before and during pregnancy. Data on the course of previous pregnancies. Data on the course of the current pregnancy (hazards the mother was exposed to during pregnancy, first and second half gestosis, threat of miscarriage in early and late stages, anemia of pregnancy, diseases suffered during pregnancy). Data on labor and delivery (timeliness of delivery, duration of the water-free interval, duration of the first and second stages of labor, nature of the amniotic fluid, timeliness of placental separation and its quality).

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

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

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

2.2 Physical Examination

Comments: in ReA, body temperature is usually low-grade (subfebrile), rarely febrile.

Comments: the general condition is usually moderate, rarely severe. Patients often report morning stiffness and pain in joints and muscles.

Comments: rashes are not characteristic of ReA.

Comments: in ReA, enlargement of almost all groups of lymph nodes up to 1.5–2 cm in diameter is detected in the majority of cases. Lymph nodes are usually mobile, painless, not fused to each other or to the underlying tissues, and have a soft-elastic or firm-elastic consistency.

Comments: cardiovascular involvement is not characteristic of patients with ReA.

Comments: in some cases, the child may complain of a cough, difficulty breathing, or shortness of breath. Lung involvement in children with ReA is rare. Visual inspection of the patient may not reveal signs of pulmonary involvement; in some cases, respiratory failure develops, manifested by shortness of breath, retraction of compliant areas of the chest, the epigastric region, and areas of diaphragmatic attachment to the costal margin, as well as cyanosis. Percussion note may be normal with a boxy tone, dull in the posterior-inferior lung regions; auscultation may reveal moist rales of various calibers, crackles, pleural friction rub, and decreased breath sounds in the posterior-inferior lung regions.

Comments: patients with ReA often complain of epigastric pain and dyspeptic symptoms. Periumbilical pain may be associated with enlargement of mesenteric lymph nodes.

Examination may reveal underweight, coated tongue, abdominal distension; abdominal percussion may show hepatomegaly and splenomegaly. Palpation may reveal tenderness in the epigastrium at the projection points of the gallbladder, duodenum, pancreas, as well as hepatomegaly and splenomegaly; in intestinal involvement, tenderness in the ileocecal region and along the course of the colon may be detected.

The majority of children with ReA develop inflammation of the upper gastrointestinal tract (GI) associated with the use of 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.

Comments: typically, the knee and ankle joints are affected, less commonly the metatarsophalangeal, proximal, and distal interphalangeal joints of the feet. The process involves 2 or 3 joints of one or more digits, with the development of tenosynovitis and bursitis. Patients with a history of yersiniosis or salmonellosis may present with involvement of the small joints of the hands. Exudative manifestations are prominent in the peripheral joints; proliferative synovitis is rare. Inflammatory changes in the joints of the axial skeleton may develop and are accompanied by back pain, sacroiliac joint pain, stiffness, and impaired function in the cervical and lumbar spine.

Comments: if there is no pain in the joints at a normal range of motion, it is necessary to assess the appearance of pain (protective muscle tension, resistance) at the maximum range of motion.

The range of motion is evaluated as follows:

— Cervical spine. Request the patient to: throw the head backward (normal extension is 50-60°), touch the chest with the chin (normal flexion is 45°), turn the head to the right and left (normal rotation is 60-80°), and touch the right and left shoulder with the head (lateral flexion is 40°).

— Temporomandibular joints. Request the patient to: open the mouth, protrude and re-trude the lower jaw, and perform side-to-side lateral movements of the lower jaw.

— Shoulder joints. Request the patient to: raise the arms laterally upwards, touch the right and left ear over the back of the head, reach the right and left scapula with the opposite hand from behind, independently put on a shirt or undershirt, and comb their hair.

— Elbow joints. Request 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. Request the patient to: make a tight fist, independently put on socks and tights, and button and unbutton clothes.

— Normally, the fingers easily touch the palm.

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

— Test for internal rotation 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 diseases of the hip joints, internal rotation is the first to be impaired.

— Knee joints. Request the patient to: flex the legs at the knees (should be able to touch the buttocks with the heel), sit on the knees and lower the buttocks onto the heels, extend the knees (180° angle), and squat.

— 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.

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),

— «antalgic» or waddling gait (bilateral hip joint involvement).

Observation of gait during walking and running: a patient's limp is an important diagnostic clue for identifying pain or stiffness.

Comments: reactive arthritis is typically characterized by weakness of the muscles surrounding the affected joints, muscle and tendon atrophy, and shortening, leading to flexion contractures in the joints. In the presence of active arthritis, muscle atrophy develops proximal to the affected joint.

Comments: conditions to be ruled out in the event of monoarthritis: enthesitis-related arthritis, psoriatic arthritis, septic arthritis, oncological diseases, leukemia, neuroblastoma, hemophilia, trauma, villonodular synovitis, sarcoidosis, tuberculosis, Lyme disease (systemic tick-borne borreliosis), hypertrophic osteoarthropathy (Pierre-Marie-Bamberger syndrome).

2.3 Laboratory Diagnostics

Comments: in the early inflammatory phase, there is a slight decrease in hemoglobin and hematocrit levels, moderate leukocytosis and neutrophilia, thrombocytosis, and an elevated ESR. In patients with severe reactive arthritis (with polyarthritis, polyenthesitis, fever, weight loss, fatigue, mucositis, or dermatitis), marked hypochromic anemia (80–100 g/L), thrombocytosis (>400×10⁹/L), and a significant increase in ESR are observed.

Comments: elevated levels of ferritin, triglycerides, ALT, AST, and LDH may be observed in secondary/primary macrophage activation syndrome (MAS), as well as due to drug toxicity, malignancy, hemoblastosis, lymphoproliferative disorders, other rheumatic diseases, or sepsis, which provides grounds for further differential diagnosis.

Comments: serum C-reactive protein levels are elevated in the majority of patients with reactive arthritis.

Comments: an elevated serum anti-streptolysin-O level indicates acute or chronic streptococcal infection and does not rule out the presence of reactive arthritis.

• It is recommended to measure blood immunoglobulin levels in all patients with frequent episodes of infectious diseases to assess their immune status [2,10]. (LoE 4, GoR C)

• It is recommended to test for antinuclear antibodies (ANA) and anti-DNA antibodies; rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP) antibodies in the blood of all patients to exclude other rheumatic diseases [2,4–6,9]. (LoE 5, GoR C)

• It is recommended to determine ABO blood groups, minor blood groups and subgroups A-1, A-2, D, Cc, E, Kell, Duffy, and Rhesus D antigen (Rh factor) in all patients prior to invasive procedures (esophagogastroduodenoscopy, colonoscopy with biopsy, bone biopsy) [2,11,11–13]. (LoE 5, GoR C)

• It is recommended to measure blood procalcitonin levels in patients with suspected septic arthritis and fever to detect or rule out sepsis [1,14–16]. (LoE 1, GoR B)

• It is recommended to test for HLA-B27 antigen by flow cytometry in all patients to exclude HLA-B27-associated diseases [1,2,8,10,17]. (LoE 4, GoR C)

Comments: the presence of HLA-B27 is associated with the development of spondyloarthropathies, including reactive arthritis.

Comments: micro- or macrohematuria may result from the toxic effect of NSAIDs. Usually, there are no changes in the urinalysis in reactive arthritis (ReA).

• It is recommended that all patients undergo a focal tuberculin skin test (Mantoux test, or test with recombinant tuberculosis allergen in standard dilution**) or a blood test for interferon-gamma against Mycobacterium tuberculosis complex antigens to detect/exclude Mycobacterium tuberculosis infection [1,2,8,18]. ( poziom wiarygodności danych: 5, poziom rekomendacji: C )

• It is recommended to determine antibodies of classes A, M, G (IgA, IgM, IgG) to *Chlamydia psittaci* in the blood; to determine antibodies to *Chlamydophila pneumoniae* in the blood; to determine antibodies to *Chlamydia trachomatis* in the blood; to determine antibodies of classes M, G (IgM, IgG) to Mycoplasma pneumoniae in the blood in all patients in order to detect/rule out an infectious process that may be the cause of reactive arthritis [1,4,8,17–20]. (LoE 4, GoR C)

• It is recommended to determine antibodies to *Salmonella enterica* in the blood, antibodies to *Salmonella typhi* in the blood, antibodies of classes M, G (IgM, IgG) to *Yersinia pseudotuberculosis* in the blood, and antibodies to serovars of *Yersinia enterocolitica* in the blood in all patients to detect/rule out an infectious process that may be the cause of reactive arthritis [1,4,17–20]. (LoE 4, GoR C)

• It is recommended to determine antibodies of classes M, G (IgM, IgG) to *Shigella boydii* in the blood, antibodies of classes M, G (IgM, IgG) to *Shigella dysenteriae* in the blood, antibodies of classes M, G (IgM, IgG) to *Shigella sonnei* in the blood, and antibodies of classes M, G (IgM, IgG) to *Shigella flexneri* in the blood in all patients in order to detect/rule out an infectious process that may be the cause of reactive arthritis [1,4,17–19]. (LoE 5, GoR C)

• It is recommended to determine Epstein-Barr virus DNA by PCR in peripheral and cord blood (quantitative assay), Epstein-Barr virus DNA in oropharyngeal swabs by PCR (qualitative assay), and Epstein-Barr virus DNA in urine by PCR (qualitative assay) in all patients to detect/exclude diseases caused by herpesviruses [1,4,19,21,22]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

• It is recommended to determine cytomegalovirus DNA by PCR in peripheral and cord blood (quantitative assay), cytomegalovirus DNA in oropharyngeal swabs by PCR (qualitative assay), and cytomegalovirus DNA in urine by PCR (qualitative assay) in all patients to detect/exclude diseases caused by herpesviruses [1,4,19,21,22]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

• It is recommended to determine Herpes simplex virus types 1 and 2 DNA by PCR in the blood (quantitative assay), Herpes simplex virus types 1 and 2 DNA in oropharyngeal swabs by PCR (qualitative assay), and Herpes simplex virus types 1 and 2 DNA in the urine by PCR (qualitative assay) in all patients to detect/exclude diseases caused by herpesviruses [1,4,19,21,22]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

• It is recommended to determine classes M, G (IgM, IgG) antibodies to Cytomegalovirus in the blood in all patients to detect/exclude active cytomegalovirus infection [1,4,19,21,22]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

• It is recommended to determine classes M, G (IgM, IgG) antibodies to Epstein-Barr virus in the blood in all patients to detect/exclude diseases caused by Epstein-Barr virus [1,4,19,21,22]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

• It is recommended to determine antibodies to the capsid antigen (VCA) of Epstein-Barr virus in the blood in all patients to detect/exclude diseases caused by Epstein-Barr virus [1,4,19,21,22]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

• It is recommended to determine class G (IgG) antibodies to early antigens (EA) of Epstein-Barr virus in the blood in all patients to detect/exclude diseases caused by Epstein-Barr virus [1,4,19,21,22]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

• It is recommended to determine antibodies to herpes simplex virus in the blood in all patients to detect/exclude diseases caused by herpes simplex virus [1,4,19,21,22]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

• It is recommended to determine antibodies of classes M (IgM) and G (IgG) to tick-borne borreliosis pathogens of the *Borrelia burgdorferi* sensu lato group in the blood for patients with a history of visiting a forest, living in tick-endemic areas, or a tick bite [1,4,18]. (LoE 5, GoR C)

• It is recommended to perform a microbiological (culture) examination of mucus from the tonsils and posterior pharyngeal wall for aerobic and facultatively anaerobic microorganisms in all patients to detect/exclude nasopharyngeal contamination with pathogenic and opportunistic flora [1,2,18]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

2.4 Instrumental Diagnostics

• It is recommended to perform a comprehensive ultrasound examination of the abdominal organs and ultrasound of the kidneys in all patients to detect enlargement and changes in the parenchyma of the kidneys, liver, spleen, and lymphadenopathy [2,9,23]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

• It is recommended to perform echocardiography in all patients to assess cardiac status [2,9,24]. ( poziom wiarygodności данных: 4, poziom rekomendacji: C )

• It is recommended to perform an electrocardiogram in all patients to assess cardiac function [2,9,24]. ( poziom wiarygodności данных: 4, poziom rekomendacji: C )

• It is recommended to perform joint ultrasound in all patients to assess the severity of joint effusion and the condition of the synovial membrane and cartilage [1,2,25,26]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

Comments: in ReA, thickening of the synovial membrane and ligaments, and accumulation of synovial fluid in the joint cavity and bursa are detected. Ultrasound allows for dynamic monitoring and assessment of the degree of joint involvement.

Comments: early stages reveal non-specific soft tissue swelling, periarticular osteopenia, and less commonly, slight periosteal irregularity at the sites of ligament attachment to bones. In severe synovitis, subchondral cysts and erosions are observed in the hips, proximal and distal interphalangeal joints of the hands and feet, and less commonly in the wrist joints

• It is recommended to perform magnetic resonance imaging of a single joint with or without contrast and with or without anesthesia/sedation (including early postoperative management) in patients with persistent joint syndrome and/or a clinical presentation atypical for ReA, to exclude traumatic injury to the tendon-ligament apparatus, menisci, or tumors, and to detect pannus growth and pathological changes in the synovial membrane and cartilage [1,2,25,26]. ( poziom wiarygodności данных: 5, poziom rekomendacji: C )

• It is recommended to perform esophagogastroduodenoscopy with or without anesthesia/sedation (including early postoperative management) in patients with gastrointestinal symptoms to rule out inflammatory, erosive, and ulcerative processes [20,20,27–29]. ( poziom wiarygodności данных: 4, poziom rekomendacji: C )

• It is recommended to perform microbiological (culture) examination of gastric mucosa biopsy specimens for Helicobacter pylori in patients with inflammatory and/or erosive, and/or ulcerative changes according to esophagogastroduodenoscopy in order to exclude GI pathology associated with Helicobacter pylori [20,29,30]. (Credence Level 4, Recommendation Grade C)

• It is recommended to perform colonoscopy with anesthetic support (including early postoperative management) with endoscopic colonic biopsy and pathomorphological examination of the colonic biopsy (surgical) material in patients with febrile syndrome and/or clinical manifestations of bowel damage, and/or elevated fecal calprotectin levels in order to detect/exclude IBD [9,28,29]. (Credence Level 5, Recommendation Grade C)

• It is recommended to perform computed tomography of the chest organs with or without anesthetic support (including early postoperative management) in all patients in order to detect/exclude lung damage and detect/exclude other rheumatic diseases, oncological/oncohematological/lymphoproliferative diseases, tuberculosis [1,2,9,31]. (Credence Level 5, Recommendation Grade C)

• It is recommended to perform bone biopsy with anesthetic support (including early postoperative management) with pathomorphological examination of the bone biopsy (surgical) material in patients with bone destruction lesions and a clinical picture atypical for reactive arthritis, in order to detect/exclude malignant, benign tumors and metastatic bone lesions [32–34]. (Credence Level 5, Recommendation Grade C)

Comments: bone tissue destruction is not characteristic of reactive arthritis. Lytic lesions are characteristic of multifocal osteomyelitis, malignant neoplasms, hemoblastosis, which can be accompanied by episodes of febrile fever with pain in the abdomen, chest, joints, and bones.

2.5 Other Procedures

• It is recommended to perform an initial consultation (examination) by a rheumatologist in all patients in order to establish a diagnosis and determine treatment tactics [1,2] (Credence Level 5, Recommendation Grade C)

• It is recommended to perform an initial consultation (examination) by an otorhinolaryngologist in all patients with high ASO levels in order to identify foci of chronic ENT infection [1,3,6]. (Credence Level 5, Recommendation Grade C)

• It is recommended to perform an initial consultation (examination) by an ophthalmologist in all patients in order to detect/exclude uveitis [1,10,25,35]. (Credence Level 5, Recommendation Grade C)

• It is recommended to perform an initial consultation (examination) by a phthisiatrician in patients with positive tuberculin skin test spots and/or elevated blood interferon-gamma levels against Mycobacterium tuberculosis complex antigens and/or infiltrative lung lesions in order to exclude tuberculosis [2,31,36]. (Credence Level 5, Recommendation Grade C)

• It is recommended to perform an initial consultation (examination) by an orthopedic traumatologist in patients with destructive changes as well as bone deformities atypical for reactive arthritis [2,34,37,38]. (Credence Level 5, Recommendation Grade C)

• It is recommended to perform an initial consultation (examination) by an anesthesiologist-resuscitator in all patients scheduled for procedures under anesthesia in order to assess their condition [11,39,40]. (Credence Level 5, Recommendation Grade C)

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

3.1 Conservative Treatment

• It is recommended to prescribe NSAIDs (M01A) in patients with a confirmed diagnosis of reactive arthritis in order to achieve an anti-inflammatory effect and relieve joint syndrome [1,2,22]. (Credence Level 4, Recommendation Grade C)

• It is recommended to prescribe NSAIDs to achieve an anti-inflammatory, analgesic, and antipyretic effect [1,2,4,76]. (Credence Level 5, Recommendation Grade C)

Comments:

the following NSAID administration regimens are used:

— diclofenac** (M01AB) in accordance with the drug's instructions for use, or

— nimesulide (M01AX) in accordance with the drug's instructions for use, or

— meloxicam (M01AC) in accordance with the drug's instructions for use, or

— ibuprofen** (M01AE01) in accordance with the drug's instructions for use in order to achieve an anti-inflammatory, analgesic, and antipyretic effect.

Diclofenac** (M01AB) is used in children from 6 years of age in tablets and suppositories; intramuscular injections are approved from 18 years of age.

Nimesulide (M01AX) is used in children from 2 years of age as a suspension, and over 12 years of age as tablets.

Meloxicam (M01AC) is used in children from 2 years of age as a suspension, over 15 years of age as tablets; intramuscular injection is approved from 18 years of age.

Ibuprofen** (M01AE01) is used in children over 3 months of age as a suspension and over 6 years of age as tablets; the interval between doses is 6–8 hours.

Comments: systemic antibacterial drugs (J01) used off-label regarding age are prescribed by decision of the medical committee, after obtaining informed consent from parents and children over 15 years of age. In reactive arthritis caused by C. trachomatis, treatment is recommended not only for the patient, but also for their partners.

Comments: the use of glucocorticoids or immunosuppressants (#methotrexate** or #sulfasalazine**) in oncological and oncohematological diseases masked as reactive arthritis will significantly hinder subsequent verification of the diagnosis, as they have a pronounced immunosuppressive effect and mask the clinical and morphological picture of malignant neoplasms.

Comments: in case of arthritis flares occurring more often than once every 4 months, intra-articular administration of glucocorticoids is not performed. Indications for intra-articular glucocorticoids include pronounced exudative changes and pain syndrome in the affected joints.

#Betamethasone** (H02AB) or #triamcinolone used off-label regarding age are prescribed by decision of the medical committee after obtaining informed consent from the parents.

Comments: the duration of #sulfasalazine** (A07EC01) therapy in reactive arthritis is 3-6 months.

• It is recommended to prescribe local therapy to all patients with reactive arthritis-associated uveitis after an initial consultation (examination) by an ophthalmologist in order to induce uveitis remission [1,2,25,46–48]. (Credence Level 5, Recommendation Grade C)

• It is recommended to use intensive dexamethasone** (H02AB02) therapy in accordance with the drug's instructions for use in combination with NSAID-containing eye drops (diclofenac**) in all patients with acute uveitis in order to induce remission [1,2,46–48]. (Credence Level 5, Recommendation Grade C)

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

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

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

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

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

3.2 Main principles of reactive arthritis treatment

1. The main goal of treatment for patients with reactive arthritis (ReA) is the absence of symptoms of inflammatory activity.

2. The definition of the goal and the choice of therapy must be based on the individual characteristics of the child and agreed upon with the parent/patient.

3. The frequency of monitoring depends on the disease activity.

4. Therapy should be adjusted until the goal is achieved.

5. Monitoring must be continuous to ensure that remission (the goal) is maintained.

6. If articular syndrome persists and/or uveitis remission is not achieved during therapy, the diagnosis must be changed to juvenile arthritis, and treatment should be carried out in accordance with the clinical guidelines for juvenile arthritis.

3.3 Non-pharmacological treatment

Comments: during periods of disease exacerbation, the child's physical activity should be restricted. Running, jumping, and active games are undesirable during exacerbations. Complete immobilization is not indicated. Physical exercises help maintain the functional activity of the joints. After recovery, cycling, swimming, and walking are beneficial. Expose to psychoemotional stress and sun exposure should be avoided. Complete joint immobilization with splints is contraindicated as it contributes to muscle atrophy and osteoporosis development.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• It is recommended to provide medical rehabilitation services (Medical rehabilitation services for a patient with systemic connective tissue disorders, inflammatory arthropathies, spondyloarthropathies) to patients with ReA with impaired functional activity due to articular syndrome in order to restore functional activity [2,49]. (LoE 5, GoR C)

• It is recommended to prescribe physical therapy to all patients with joint involvement, muscle atrophy, and steroid myopathy once the stage of inactive disease/remission is reached [2,49]. (LoE 5, GoR C)

Comments: a plan is developed, and the goal and objectives of physical therapy are formulated for a patient with ReA when implementing an individual rehabilitation program; physical therapy methods, mechanotherapy, and spa treatment methods (climate therapy, mud baths, medicinal mineral baths) are chosen depending on the various periods of the disease course.

5. Prevention and Dispensary Observation

5.1 Prevention

Primary prevention is not performed.

Comments: a protective regimen is ensured (psychoemotional and physical exertion are limited; during exacerbations, children are homeschooled and attend school during the inactive disease/remission stage; contacts are limited to reduce the risk of infectious diseases); insolation, trips to regions with high insolation levels, and UV therapy are excluded; sunscreens must be used, wearing clothing that covers the skin as much as possible and wide-brimmed hats is recommended; hypothermia is prevented; an individual vaccination approach is developed; the use of immunomodulators is excluded.

5.2 Follow-up monitoring of patients with reactive arthritis in a day hospital or outpatient setting

Examinations are performed every 3–6 months: at 3 and 6 months after the initiation of therapy; then every 6 months to monitor the efficacy and safety of therapy, and to detect disease complications and comorbid conditions [50].

Complaints and anamnesis: see section 2.1.1.

Physical examination: see section 2.1.2.

Comments: the main goal of treatment is clinical remission and the absence of symptoms of inflammatory activity.

• It is recommended that all patients with ReA undergo an initial consultation (examination) with a rheumatologist, including an evaluation of the efficacy and safety of therapy [1,2,50]. (LoE 5, GoR C)

• It is recommended to have follow-up consultations (examinations) with a rheumatologist (evaluating the efficacy and safety of therapy at least once a month after the initiation/adjustment of therapy, at 3 months after the initiation of therapy, at 6 months after the initiation of therapy, and every 6 months thereafter) to decide on continuing/adjusting therapy [1,2,50]. (LoE 5, GoR C)

• It is recommended to have a consultation (examination) with a pediatrician for all patients to ensure the continuity of therapy [1,2,50]. (LoE 5, GoR C)

• It is recommended to have a follow-up consultation (examination) with a pediatrician or a district pediatrician for patients with ReA in the absence of a rheumatologist at their place of residence at least once a month after the initiation/adjustment of therapy, at 3 months after the initiation of therapy, at 6 months after the initiation of therapy, and every 6 months thereafter to decide on continuing/adjusting therapy, to organize follow-up monitoring, and to evaluate the efficacy and safety of therapy [1,2,50]. (LoE 5, GoR C)

Comments: in accordance with the Procedure for Follow-up Monitoring of Children with Rheumatic Diseases, in the absence of a rheumatologist at the patient's place of residence, follow-up monitoring is carried out by the district pediatrician, pediatrician, or general practitioner (family physician) of the medical organization.

Comments: complete blood count parameters should be within normal ranges. Single-, dual-, or tri-lineage cytopenia may be an adverse manifestation of immunosuppressive treatment.

Leukopenia most frequently develops during treatment with #sulfasalazine**, and less frequently with #methotrexate**.

Thrombocytopenia may develop during treatment with any immunosuppressant.

If there is data on recurrent episodes of thrombocytopenia, therapy is adjusted.

• It is recommended to discontinue injections/administration of immunosuppressants (for 7 days) in all patients if the platelet count drops to ≤150>100×10⁹/L or the neutrophil count drops to <1.5≥1.0×10⁹/L in the complete blood count in order to manage adverse events associated with therapy [1,2]. (LoE 5, GoR C)

• It is recommended to withdraw the immunosuppressant in all patients if the absolute neutrophil count drops to <1.0×10⁹/L and/or the platelet count drops to <100×10⁹/L in the complete blood count to prevent the progression of cytopenia [1,2]. (LoE 5, GoR C)

Comments: repeat the complete blood count in one week.

• It is recommended to prescribe the colony-stimulating factor #filgrastim** (LO3AA) at a dose of 5–10 mcg/kg/day subcutaneously for leukopenia with an absolute neutrophil count of ≤1.0×10⁹/L for 3–5 days (or longer if necessary) until complete normalization of leukocyte and neutrophil counts [1,2,52,53]. (LoE 5, GoR C)

• It is recommended to prescribe the colony-stimulating factor #filgrastim** (LO3AA) at 5–10 mcg/kg/day subcutaneously combined with systemic antibacterial drugs (JO1) intravenously for febrile neutropenia (neutropenia accompanied by fever) with an absolute neutrophil count of ≤1.0×10⁹/L [1,2,52,53]. (LoE 5, GoR C)

Comments: treatment with #filgrastim** (LO3AA) is carried out for 3–5 days (or longer if necessary) until complete normalization of leukocyte and neutrophil counts.

• It is recommended to resume immunosuppressive therapy at the same dose in all patients after neutrophil count recovery to ≥1.5×10⁹/L based on the complete blood count, with the aim of maintaining reactive arthritis (ReA) remission [1,2]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to adjust immunosuppressive therapy in all patients if there is evidence of recurrent episodes of decreased blood cell counts on the complete blood count, with the aim of managing adverse events associated with therapy [1,2]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform blood total protein testing, blood albumin testing, blood total bilirubin testing, blood free and conjugated bilirubin testing, blood creatinine testing, blood urea testing, blood uric acid testing, blood glucose testing, blood aspartate aminotransferase activity assay, blood alanine aminotransferase activity assay, blood gamma-glutamyl transferase activity assay, and blood alkaline phosphatase activity assay in all patients to monitor disease activity, hepatic, renal, and pancreatic function during immunosuppressive therapy [1,2]. (Level of Evidence 5, Grade of Recommendation C)

Comments: elevation of creatinine and/or urea, and/or uric acid, and/or total bilirubin; increased LDH and/or ALT, and/or AST, and/or GGT, and/or ALP activity may be an adverse manifestation of NSAID and/or immunosuppressive therapy.

Comments: repeat general clinical blood chemistry panel in one week.

• It is recommended to resume immunosuppressive therapy in all patients at the same dose after normalization of general clinical blood chemistry parameters, with the aim of maintaining ReA remission [1,2]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to adjust immunosuppressive therapy in all patients if there is evidence of recurrent episodes of elevated biochemical parameter(s), with the aim of managing adverse events associated with therapy [1,2]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to test serum C-reactive protein levels in all patients to determine the severity of the inflammatory process [1,2]. (Level of Evidence 5, Grade of Recommendation C)

Comments: elevated serum C-reactive protein levels indicate secondary infection or ReA flare.

• It is recommended to perform quantitative PCR detection of Epstein-Barr virus DNA in peripheral and cord blood, qualitative PCR detection of Epstein-Barr virus DNA in oropharyngeal swabs, and qualitative PCR detection of Epstein-Barr virus DNA in urine in all patients receiving immunosuppressants, patients with clinical manifestations of herpetic infection, and patients with interstitial pneumonia, with the aim of detecting active herpetic infection as an infectious complication developing against the background of immunosuppressive therapy [1,4,19,21,22]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform quantitative PCR detection of Cytomegalovirus DNA in peripheral and cord blood, qualitative PCR detection of Cytomegalovirus DNA in oropharyngeal swabs, and qualitative PCR detection of Cytomegalovirus DNA in urine in all patients receiving immunosuppressants, patients with clinical manifestations of herpetic infection, and patients with interstitial pneumonia, with the aim of detecting active herpetic infection as an infectious complication developing against the background of immunosuppressive therapy [1,4,19,21,22]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to perform quantitative PCR detection of Herpes simplex virus types 1 and 2 DNA in blood, qualitative PCR detection of Herpes simplex virus types 1 and 2 DNA in oropharyngeal swabs, and qualitative PCR detection of Herpes simplex virus types 1 and 2 DNA in urine in all patients receiving immunosuppressants, patients with clinical manifestations of herpetic infection, and patients with interstitial pneumonia, with the aim of detecting active herpetic infection as an infectious complication developing against the background of immunosuppressive therapy [1,4,19,21,22]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to determine blood IgM and IgG antibodies to Cytomegalovirus in all patients with interstitial, focal, and/or infiltrative lung changes on chest computed tomography; in patients receiving immunosuppressants, patients with clinical manifestations of herpetic infection, and patients with interstitial pneumonia, with the aim of detecting active herpetic infection as an infectious complication developing against the background of immunosuppressive therapy [1,4,19,21,22]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to determine blood IgM and IgG antibodies to Epstein-Barr virus in all patients receiving immunosuppressants, patients with clinical manifestations of herpetic infection, and patients with interstitial pneumonia, with the aim of detecting active herpetic infection as an infectious complication developing against the background of immunosuppressive therapy [1,4,19,21,22]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to determine blood antibodies to Epstein-Barr virus capsid antigen (VCA) in all patients receiving immunosuppressants, patients with clinical manifestations of herpetic infection, and patients with interstitial pneumonia, with the aim of detecting active herpetic infection as an infectious complication developing against the background of immunosuppressive therapy [1,4,19,21,22]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to determine blood IgG antibodies to Epstein-Barr virus early antigens (EA) in all patients receiving immunosuppressants, patients with clinical manifestations of herpetic infection, and patients with interstitial pneumonia, with the aim of detecting active herpetic infection as an infectious complication developing against the background of immunosuppressive therapy [1,4,19,21,22] (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to determine blood antibodies to Herpes simplex virus in all patients receiving immunosuppressants, patients with clinical manifestations of herpetic infection, and patients with interstitial pneumonia, with the aim of detecting active herpetic infection as an infectious complication developing against the background of immunosuppressive therapy [1,4,19,21,22]. (Level of Evidence 5, Grade of Recommendation C)

• It is recommended to prescribe #acyclovir** (J05AB) at a dose of 200 mg daily orally in 5 divided doses (maximum 1000 mg/day) in children over 2 years of age, or at a dose of 5–10 mg/kg/administration intravenously every 8 hours for localized herpetic infection; prescribing #acyclovir** at a dose of 10 mg/kg/administration intravenously every 8 hours in children aged <1 year; and at 500 mg/m² intravenously every 8 hours in children aged ≥1 year for Herpes zoster, in accordance with clinical guidelines for the management of herpesvirus infections in children, including immunocompromised patients [54,54–59]. (Level of Evidence 5, Grade of Recommendation C)

Comments: #Acyclovir** (J05AB) in children aged <3 years is prescribed by decision of a medical commission after obtaining informed parental consent.

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

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

Comments: administration of the immunosuppressant is discontinued for the duration of antiviral therapy.

• It is recommended to resume immunosuppressant therapy in all patients no earlier than 1 week after the complete resolution of clinical and laboratory signs of infection and the completion of antiviral therapy [1,2]. (LE 5, GR C)

• It is recommended to screen for the presence/absence of tuberculosis (tuberculin skin test, recombinant tuberculosis allergen test in standard dilution**, blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens, chest computed tomography) in all patients receiving immunosuppressants at least once a year [2,63–68]. (LE 4, GR C)

• It is recommended to discontinue the immunosuppressant in all patients with a positive intradermal tuberculin skin test (papule >5 mm) and/or elevated interferon-gamma levels, and/or lung lesions, and/or intrathoracic lymphadenopathy [2]. (LE 5, GR C)

• It is recommended that all patients with a positive intradermal tuberculin skin test (papule >5 mm) and/or elevated interferon-gamma levels and/or lung lesions and/or intrathoracic lymphadenopathy undergo an initial consultation/examination by a phthisiatrician to address the issue of further evaluation and specific therapy [2]. (LE 5, GR C)

Comments: if tuberculosis infection without a primary focus is detected, specific anti-tuberculosis chemotherapy is administered for 3–6 months (as determined by the phthisiatrician). Immunosuppressant treatment is continued under the supervision of a rheumatologist, general (clinical) blood count, and standard general biochemistry blood tests.

• It is recommended to resume immunosuppressant therapy in all patients after the completion of specific anti-tuberculosis therapy and consultation with a phthisiatrician [2]. (LE 5, GR C)

• It is recommended to determine antibodies to Salmonella enterica in the blood, antibodies to Salmonella typhi in the blood, IgM and IgG antibodies to Yersinia pseudotuberculosis in the blood, and antibodies to Yersinia enterocolitica serovars in the blood in patients with suspected salmonellosis to detect intestinal bacterial infection developed during immunosuppressant therapy [1,4,17–19,28,69]. (LE 5, GR C)

• It is recommended to determine IgM and IgG antibodies to Shigella boydii in the blood, antibodies to Shigella dysenteriae in the blood, IgM and IgG antibodies to Shigella sonnei in the blood, and IgM and IgG antibodies to Shigella flexneri in the blood in patients with suspected shigellosis and/or yersiniosis to detect intestinal bacterial infection developed during immunosuppressant therapy [1,4,17–19]. (LE 5, GR C)

• It is recommended to administer etiotropic therapy upon detection of diagnostic titers of IgA and IgM, as well as high titers of IgG antibodies to Yersinia pseudotuberculosis, Yersinia enterocolitica serovars, Salmonella enterica, and Salmonella typhi in the blood in accordance with clinical guidelines for the diagnosis and treatment of intestinal infections in children [17,18,20,70]. (LE 4, GR C)

Comments: injections/administration of the immunosuppressant are stopped for the entire period of systemic antibacterial therapy.

Immunosuppressant treatment is resumed no earlier than 1 week after the decrease in laboratory markers of infection and the completion of antibacterial therapy.

• It is recommended to determine IgA, IgM, and IgG antibodies to Chlamydia psittaci in the blood; antibodies to Chlamydia trachomatis in the blood; antibodies to Chlamydia pneumoniae in the blood; and IgM and IgG antibodies to Mycoplasma pneumoniae in the blood in patients with suspected chlamydial infection to detect mycoplasma and chlamydial infection developed during immunosuppressant treatment [1,4,8,17–20]. (LE 4, GR C)

• It is recommended to administer etiotropic therapy upon detection of diagnostic titers of IgA and IgM, as well as high titers of IgG antibodies to Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae in the blood in all patients in accordance with clinical guidelines for the diagnosis and treatment of mycoplasma and chlamydial infections in children [8,17,18,20,70]. (LE 5, GR C)

Comments: injections/administration of the immunosuppressant are stopped for the entire period of systemic antibacterial therapy. Immunosuppressant treatment is resumed no earlier than 1 week after the decrease in laboratory markers of infection and the completion of antibacterial therapy.

Comments: if nasopharyngeal contamination by pathogenic and/or opportunistic microorganisms is detected, an otorhinolaryngologist consultation is performed to address the need for sanitation.

In the absence of clinical manifestations, immunosuppressant therapy is not discontinued.

In the presence of inflammatory changes in the nasopharynx, antibacterial therapy is administered. Administration of the immunosuppressant is discontinued for the duration of antiviral therapy. Immunosuppressant treatment is resumed no earlier than 1 week after the complete resolution of clinical and laboratory signs of infection and the completion of antiviral therapy.

• It is recommended to perform a general (clinical) urinalysis in all patients to monitor renal function [2,3]. (LE 5, GR C)

• It is recommended to perform an electrocardiogram in all patients to monitor cardiac function [2,24]. (LE 4, GR C)

• It is recommended to perform a comprehensive ultrasound examination of internal organs in all patients to detect/exclude pathological changes [2]. (LE 5, GR C)

Comments: performed in all patients. Includes comprehensive ultrasound examination of the abdominal organs and kidneys. Findings may include: 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 from NSAIDs and/or immunosuppressants.

• It is recommended to perform echocardiography in all patients to monitor cardiac function and detect myocardial, pericardial, or endocardial involvement [2,24]. (LE 4, GR C)

• It is recommended to perform a joint ultrasound examination in all patients to monitor treatment efficacy [1,2,25]. (LE 5, GR C)

• It is recommended to perform a chest computed tomography scan with or without anesthesia support (including early postoperative management) in patients receiving immunosuppressants to rule out pneumonia, pneumonitis, and tuberculosis [1,2,9,9,31,71,72]. (LE 5, GR C)

Comments: pneumonia (interstitial, focal, lobar, polysegmental) may develop during immunosuppressant treatment.

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

Comments: immunosuppressive therapy is discontinued for the duration of antibacterial treatment.

Comments: prescription/adjustment of therapy is performed after the resolution of clinical, radiological, and laboratory signs of interstitial pneumonia.

• It is recommended that all patients undergo an initial/follow-up examination (evaluation, consultation) by an otorhinolaryngologist to identify foci of chronic ENT infection and decide on their sanitation for the prevention of infectious complications during immunosuppressive treatment, or to assess the efficacy of ENT sanitation in patients who have already undergone it [1,3,6]. (Reliability of Evidence Level: 5, Actionability of Evidence Level: C)

• It is recommended that all patients undergo an initial ophthalmological examination (evaluation, consultation) with mandatory ocular biomicroscopy to rule out uveitis [1,10,25,35,74,75]. (Reliability of Evidence Level: 5, Actionability of Evidence Level: C)

• It is recommended that all patients with functional joint insufficiency, subluxations, or back pain undergo an initial orthopedic trauma consultation to address the potential need for reconstructive surgery [2,34,37,38]. (Reliability of Evidence Level: 5, Actionability of Evidence Level: C)

• It is recommended to adjust anti-rheumatic therapy in a inpatient rheumatology department / day hospital / outpatient clinic that initiated immunosuppressive treatment if inactive disease status is not achieved after 3 months, remission is not achieved after 6 months, and subsequently every 6 months, as well as at any stage of treatment if adverse events occur during immunosuppressive therapy [2,73]. (Reliability of Evidence Level: 5, Actionability of Evidence Level: C)

6. Organization of Medical Care

6.1 Indications for hospitalization and discharge of patients

Suspected Reactive Arthritis (ReA)

Diagnosis, including differential diagnosis and prescription of anti-rheumatic therapy for all patients, is performed in an inpatient rheumatology department, day hospital, or outpatient setting.

Indications for discharge

• Completion of evaluation; establishment of a diagnosis of ReA.

• Prescription of NSAID therapy or immunosuppressive therapy.

• Absence of side effects or intolerance.

• Stabilization of the condition during pharmacotherapy.

Established diagnosis of active ReA

Evaluation and adjustment of therapy in case of its inefficacy is performed for all patients in an inpatient rheumatology department, day hospital, or outpatient setting.

Indications for discharge

• Completion of examination.

• Adjustment of therapy.

• Absence of side effects or drug intolerance.

Established diagnosis of ReA in remission

Monitoring the efficacy and safety of anti-rheumatic therapy is performed in an inpatient rheumatology department, day hospital, or outpatient setting at 3 months after therapy initiation, at 6 months after therapy initiation, and every 6 months thereafter.

Indications for discharge

• Completion of examination.

• Absence of side effects or drug intolerance.

6.2 Regulatory and legal documents governing the provision of medical care to children with reactive arthritis

1. 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 October 12, 2016), registered with the Ministry of Justice of the Russian Federation on December 25, 2012, Registration No. 26370.

2. 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).

3. 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).

4. 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.

5. 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).

6. 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).

7. 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).

8. 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."

9. 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."

10. 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".

7. Additional Information

7.1 Outcomes and prognosis

The majority of children with Yersinia- and Campylobacter-associated ReA experience a single episode of monoarthritis or oligoarthritis.

ReA caused by other microorganisms is characterized by a relapsing course of oligoarthritis or the development of polyarthritis and enthesitis. These patients may achieve recovery or progress to enthesitis-related arthritis or spondyloarthritis with sacroiliac joint involvement. If joint symptoms persist for more than 6 months, chronic arthritis is diagnosed. Prognostically unfavorable factors indicating a potentially more severe and prolonged disease course include male sex, age of onset under 16 years, presence of HLA-B27 antigen, dactylitis, oligoarthritis, and sacroiliitis. The prognosis for children with Chlamydia- and Yersinia-induced ReA is better than that for Shigella- and Salmonella-induced ReA [1,2].

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 reactive arthritis

Table 2. Quality assessment criteria for reactive arthritis treatment

Table 3. Quality assessment criteria for dispensary follow-up of patients with reactive arthritis, including therapy safety monitoring, in a day care unit or out-patient setting

References

Appendix A1. Working Group Composition

These clinical guidelines were prepared by the professional association of pediatric rheumatologists and approved by the working group of the Association of Pediatric Rheumatologists.

1. Alekseeva E.I., MD, Professor, Corresponding Member of the Russian Academy of Sciences

2. Dvoryakovskaya T.M., MD

3. Shilgrot I.Yu., PhD

4. Kostik M.M., MD

5. Nikishina I.P., PhD

6. Ushakova S.A., MD, Professor

7. Ulyanova E.A., PhD

8. Glazyrina G.A., PhD

9. Zholobova E.S., MD, Professor

10. Sudareva O.O., PhD

11. Igisheva L.N., MD, Associate Professor

12. Ligostaeva E.A., PhD

13. Malievsky V.A., MD, Professor

14. Kriulin I.A., PhD in Medicine

15. Kriulina T.Yu., Junior Research Fellow

Conflict of interest: the working group members declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience:

1. Pediatricians

2. Trauma and orthopedic surgeons

3. Infectious disease specialists

4. Pediatric rheumatologists of pediatric rheumatology departments

5. Pediatric rheumatologists of pediatric rheumatology offices in outpatient clinics

Methods used for collecting/selecting evidence: electronic database search.

Description of methods used for assessing the quality and strength of evidence: the evidence base for the recommendations includes publications from the Cochrane Library, EMBASE, MEDLINE, and PubMed databases. The search depth is 5 years.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with the rating scheme.

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Description of methods used for analyzing evidence

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations.

To minimize potential bias, each study was evaluated independently. Any discrepancies in evaluations were discussed by the full panel of authors. If a consensus could not be reached, an independent expert was involved.

Evidence tables: compiled by the authors of the clinical guidelines.

Methods used for formulating recommendations: expert consensus.

Economic analysis

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation

• External expert review.

• Internal expert review.

Description of the recommendation validation method

These draft recommendations were reviewed by independent experts who were asked primarily to comment on the clarity of the interpretation of the evidence underlying the recommendations. Comments were received from primary care pediatric rheumatologists regarding the clarity of presenting the importance of the proposed recommendations as a tool for daily practice.

All comments received from experts were carefully systematized and discussed by the authors of the recommendations. Each point was discussed individually.

Consultation and peer review

The draft recommendations were reviewed by independent experts who evaluated the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

Authors

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Main Recommendations

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Appendix B. Physician Action Algorithms

Appendix B. Physician Action Algorithms

Diagram 1

Diagram 3

Diagram 4

Appendix C. Patient Information

1. What is idiopathic arthritis?

What is it?

Reactive arthritis (ReA) is an acute condition characterized by joint inflammation following a prior infection (most commonly intestinal or urogenital). Typical signs of joint inflammation include pain, swelling, and restricted range of motion.

What are the causes of the disease?

Our immune system protects us against infections caused by various microorganisms, such as viruses or bacteria. It is capable of distinguishing between what is potentially foreign and harmful and subject to destruction, versus what is part of our own body. ReA is an abnormal reaction of our immune system, which, after encountering an infection, partially loses the ability to distinguish between "foreign" cells and "self", attacking its own body parts and leading to inflammation, particularly of the joints and possibly the eyes.

Is this a hereditary disease?

Reactive arthritis (ReA) is not a hereditary disease; it cannot be transmitted directly from parents to their children. However, there is an association with the genetic marker HLA-B27. Patients carrying this genetic marker are more predisposed to developing ReA than those without it.

On what basis is this disease diagnosed?

The diagnosis of ReA is based on the presence of arthritis and its association with a prior infection, while thoroughly ruling out any other conditions through a review of the medical history, physical examination, and laboratory and instrumental tests.

What happens to the joints?

The synovial membrane is a thin inner layer of the joint capsule. In arthritis, it becomes significantly thickened, infiltrated with inflammatory cells, and its tissue becomes inflamed. At the same time, the production of synovial fluid inside the joint increases. This causes swelling, pain, and restricted movement. A characteristic feature of joint inflammation is stiffness, which occurs after prolonged periods of rest, especially noticeable in the morning (morning stiffness).

Often, a child tries to minimize pain by holding the joint in a semi-flexed position. This is called an "antalgic" position, emphasizing that its purpose is to reduce pain. If not properly treated, joint inflammation can lead to joint damage. This occurs through two main mechanisms: severe thickening of the synovial membrane (with the formation of a so-called synovial pannus) and the release of various substances that cause the loss of joint cartilage and bone tissue. Prolonged maintenance of the antalgic position causes muscle atrophy, tension or shortening of muscles and soft tissues, leading to flexion contractures.

2. Diagnosis and Treatment

What laboratory tests are required?

At the time of diagnosis, laboratory and instrumental examinations are performed, along with specialist consultations.

Various additional tests are also conducted to rule out other pathologies (trauma, orthopedic disorders, infectious processes, parasitic and onco-hematological diseases). Depending on the treatment used, patients may need periodic testing (such as complete blood count, liver function tests, urinalysis) to detect adverse reactions and determine the degree of potential drug toxicity, which may be asymptomatic. Joint inflammation is assessed primarily through clinical examination, as well as imaging techniques such as ultrasound, CT, and MRI.

How can we treat this?

To treat infection-associated ReA, antibacterial drugs, nonsteroidal anti-inflammatory drugs, and intra-articular corticosteroid injections are used. The goals of treatment are to relieve pain, fatigue, and stiffness, and to prevent joint destruction. While there are general principles for treatment planning, therapy must be individualized for each child. Active parental involvement in treatment decision-making is essential.

Treatment is generally based on medications that suppress systemic and/or joint inflammation. It is comprehensive and requires the collaboration of multiple specialists (pediatric rheumatologist, ophthalmologist, physical therapist, orthopedic trauma surgeon).

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs remain the mainstay of treatment for ReA and other childhood rheumatic diseases. These are anti-inflammatory and antipyretic medications. Diclofenac, nimesulide, and meloxicam are most commonly used. NSAIDs are generally well tolerated by children; gastric discomfort, the most common side effect in adults, is less frequent in children. Sometimes one NSAID may be effective when another is not sufficiently so. Combining different NSAIDs is not recommended. The optimal effect on joint inflammation is observed a few weeks after starting treatment.

Intra-articular Corticosteroid (CS) Injections

Intra-articular injections are used when one or more joints have pronounced inflammation that significantly restricts normal joint movement and/or is accompanied by severe joint pain. Long-acting corticosteroids are injected into the joint. In the Russian Federation, preference is given to betamethasone, a long-acting drug (often effective for many months). Its systemic absorption is minimal. Intra-articular injections may be performed under local anesthesia or general anesthesia (usually in younger children), depending on the child's age, the type of joint, and the number of joints being injected. As a rule, it is recommended to perform no more than 3–4 injections per year into the same joint.

Second-Line Drugs

Second-line drugs are indicated for children whose ReA progresses despite adequate treatment with NSAIDs and CS injections. The full effect of most second-line agents becomes apparent only after several weeks or months of treatment.

Methotrexate

Among the second-line drugs used to treat children with ReA and various forms of juvenile arthritis, methotrexate is preferred worldwide. Numerous studies have proven its efficacy and evaluated its safety profile over several years of use. Medical literature currently defines the maximum effective dose as 15 mg/m² of body surface area. Methotrexate is usually administered via subcutaneous injections. It is generally well tolerated by children. The most common adverse effects are gastrointestinal intolerance (nausea, vomiting) and elevated blood liver enzymes. Because the drug has potential toxicity, laboratory parameters must be monitored periodically during treatment. Combination therapy with methotrexate and folic acid—a vitamin that reduces the risk of side effects, particularly concerning liver function—is also recommended.

Sulfasalazine is an alternative to methotrexate, especially for treating children who do not tolerate methotrexate. Sulfasalazine is administered in tablet form. This therapy has been studied in patients with ReA and juvenile arthritis, and its efficacy has also been proven.

Biologic Agents

Genetically engineered biologic agents are practically never used for the treatment of ReA. If ReA transforms into juvenile arthritis (persistent joint changes, prolonged disease course), patients are treated in accordance with relevant clinical guidelines using various immunosuppressive drugs, including biologics.

Other Complementary Treatments

Rehabilitation

Rehabilitation is an important component of treatment. It includes appropriate exercises. Rehabilitation should be initiated early and performed routinely to improve or preserve joint and muscle function.

What about alternative medicine / complementary therapies?

There are many complementary and alternative treatments, which can be confusing for patients and their families. It is important to weigh the risks and benefits of such therapies, as their efficacy is unproven and they can be costly in terms of time, burden on the child, and financial expense. If you wish to explore complementary and alternative treatment options, please discuss them with your rheumatologist.

3. Daily Life

Can diet affect the course of the disease?

There is no evidence that diet can influence the disease. In general, a child should follow a balanced, age-appropriate diet.

Can climate affect the course of the disease?

There is no evidence that climate affects the manifestations of the disease. However, a change of climate, intense sun exposure, and acute respiratory, intestinal, and other infections that children frequently contract in hot climates can trigger disease flares.

What can physical activity and exercise therapy achieve?

The goal of physical activity and therapeutic exercise is to ensure that the child can optimally participate in all daily activities and fulfill all necessary social roles. In addition, physical activity and therapeutic exercise can be used to motivate children toward an active, healthy lifestyle. A prerequisite for achieving these goals is healthy joints and muscles. Physical activity and therapeutic exercise can be used to improve joint mobility, stabilize joints, increase muscle flexibility, muscle strength, coordination, and endurance (vitality). These aspects of a healthy musculoskeletal system enable the child to successfully and safely participate in school and extracurricular activities, such as active recreation and sports. Treatment and a home exercise program can be useful for achieving the required level of strength and endurance.

Are sports allowed?

Team and recreational sports are an important aspect of a healthy child's daily life. One of the main goals of reactive arthritis (ReA) management is to enable the child to maintain a lifestyle and consider themselves no different from their peers. It is preferable to choose sports where mechanical stress on the joints is absent or minimal, such as swimming or cycling.

Can the child regularly attend school?

It is extremely important for the child to attend school consistently. Limited mobility can pose a challenge for school attendance; it may cause walking difficulties, rapid fatigue, pain, or stiffness. During the acute phase of the disease, home-schooling is preferable. Outside of disease activity, the child can attend school just like their healthy peers. Physical education and participation in sports activities are recommended taking into account any mobility limitations caused by disease activity. School for children is as important as work for adults—it is a place where the child learns to become an independent, productive, and self-reliant individual. Parents and teachers must do everything possible to encourage children to participate in school activities routinely, so that they succeed academically, are able to communicate with peers and adults, and are accepted and valued by their friends.

Are routine vaccinations allowed?

If the patient is receiving immunosuppressive therapy (methotrexate, sulfasalazine), vaccinations with live attenuated microorganisms (such as rubella, measles, mumps, and BCG vaccines) are not recommended due to the potential risk of infection spreading as a result of depressed immune defense. Vaccines that do not contain live microorganisms but contain only pathogenic proteins are administered according to an individual schedule, based on clinical indications, following a consultation with a rheumatologist.

Will the child have a normal adult life?

This is the primary goal of treatment, and in most cases, this is indeed the outcome. Currently, the use of modern treatment and rehabilitation makes it possible to prevent joint destruction in the majority of patients. Parents often form a strong emotional attachment to their child, and to preempt potential problems, they may become overprotective. A positive attitude from parents who support the child and encourage them to be as independent as possible, despite the disease, will be an invaluable help in overcoming disease-related challenges, enabling the child to cope on an equal footing with peers and develop into an independent, well-balanced individual.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Rating scales, questionnaires, and other assessment tools are not required.