Juvenile rheumatoid arthritis (JRA) is a common connective tissue disorder in children, characterized primarily by chronic arthritis and often involving multiple systems, including joints, skin, muscles, liver, spleen, and lymph nodes. Younger patients typically present with persistent irregular fever, where systemic symptoms are more prominent than joint symptoms. Older children or adult patients, however, often exhibit primarily joint-related manifestations. The clinical presentation of this disease varies widely, leading to its classification into different types and numerous names, such as Still's disease (1897), juvenile Bi disease with recurrent high fever (Wissler-Fanconi syndrome), juvenile chronic arthritis (JCA), juvenile Bi disease (juvenile rheumatoid disease), and juvenile arthritis (JA).

bubble_chart Etiology

The exact mechanism remains incompletely understood. In general, it is believed to be related to immunity, infection, and genetics, resembling a type III hypersensitivity reaction that causes connective tissue {|###|}injury{|###|}. It may result from persistent microbial (bacteria, mycoplasma, viruses, etc.) infections stimulating the body to produce immunoglobulins, leading to elevated serum IgA, IgM, and IgG levels. Some patients exhibit increased antinuclear antibody titers. The serum of patients contains a {|###|}wind-dampness{|###|} factor, which is a macroglobulin—specifically, IgM with a sedimentation coefficient of 19S—capable of reacting with denatured IgG to form immune complexes. These complexes deposit in the joint synovial {|###|}membrane{|###|} or vascular walls, activating the complement system and triggering the release of lysosomal enzymes from granulocytes and monocytes, thereby inducing inflammatory tissue {|###|}injury{|###|}. Decreased complement levels and elevated IgM, IgG, and immune complexes in the serum and synovial {|###|}membrane{|###|} fluid of patients suggest that this disease is an immune complex-mediated disorder. Additionally, there is an imbalance in cellular immunity, with increased B lymphocytes among peripheral blood mononuclear cells, elevated interleukin IL-1, and reduced IL-2, which also contribute to the {|###|}mechanism of disease{|###|}.

bubble_chart Pathological Changes

The main manifestation is joint lesions, presenting as chronic non-suppurative synovitis. In the early stage, the synovial membrane becomes congested and edematous, accompanied by lymphocyte and plasma cell infiltration, with increased synovial fluid and synovial hyperplasia forming villous projections into the joint cavity. As synovitis progresses to the advanced stage, the villous hyperplasia of the synovium extends to the articular cartilage, forming vascular pannus. The cartilage may be absorbed, and the subchondral bone may be eroded, leading to joint ankylosis, deformity, or subluxation. Joint destruction rarely occurs in juvenile rheumatoid arthritis.

Non-specific fibrinous serositis may occur in the pleura, pericardium, and peritoneum. The histological changes of rheumatoid rash are characterized by subepithelial small vasculitis.

bubble_chart Clinical Manifestations

The clinical manifestations of this disease vary significantly among different types. In infants and young children, systemic symptoms mainly include remittent fever and rash, while older children may present with polyarthritis or only a few affected joints. Based on the clinical manifestations during the first six months of onset, the disease can be classified into three types (Table 17-5), which have guiding significance for treatment and prognosis.

Table 17-5 Clinical Characteristics of Different Types of Juvenile Wind-Dampness Arthritis

1. Systemic Type The systemic type, also known as Still's disease (previously referred to as subsepsis allergica), is characterized by systemic manifestations and an acute onset. Fever is of the remittent type, fluctuating daily between 36～41℃. Initially, high fever may be accompanied by chills, and the child appears lethargic, but returns to normal activity once the fever subsides after a few hours. The remittent fever may persist for weeks or months and resolve spontaneously, only to recur weeks or months later. Rash is another classic symptom of this type, often appearing during high fever and fading with temperature fluctuations. The rash typically consists of round, erythematous papules, about 0.2～1.0 cm in size, which may coalesce and are distributed over the chest and proximal limbs. Most children exhibit hepatosplenomegaly and generalized lymphadenopathy, possibly accompanied by grade I liver dysfunction. About half of the patients develop pleuritis and pericarditis. X-ray findings may show pleural thickening and small pleural effusions, occasionally with interstitial pneumonitis. Pericardial effusion is usually minimal, and a pericardial friction rub may be heard. Pericarditis generally resolves gradually, with rare cases progressing to constrictive pericarditis. Myocardial involvement may occur, but endocarditis is rare. Most children with this type develop polyarthritis at onset or within months, affecting both large and small joints. Due to the prominence of systemic symptoms at onset, arthritis is often overlooked. Some patients only experience arthralgia, myalgia, or transient arthritis. A few may develop arthritis months or years later. Grade I anemia may be present, along with marked leukocytosis, toxic granules in neutrophils, and even a leukemia-like reaction. About one-quarter of these children eventually develop severe arthritis. Studies have shown that those with hepatosplenomegaly, serositis, hypoalbuminemia, and persistent systemic symptoms with platelets ≥600×10⁹

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2. Polyarticular Type This type is characterized by chronic, symmetric polyarthritis involving ≥5 joints, with particular prominence in the small joints of the fingers and toes. It is more common in girls than boys. Onset may be insidious or acute, manifesting as joint stiffness, swelling, pain, and local fever, with minimal redness. It typically starts in large joints (e.g., knees, ankles, elbows) and gradually involves small joints, leading to fusiform fingers. About half of the children develop cervical spine involvement, limiting neck movement. Temporomandibular joint involvement may cause difficulty chewing. Rarely, cricoarytenoid (laryngeal cartilage) arthritis can lead to hoarseness and stridor. In advanced stages, hip involvement and femoral head destruction may occur, impairing mobility. Recurrent and persistent joint symptoms over years can result in joint ankylosis and deformity, with muscle atrophy near the joints. Systemic symptoms in this type are mild, including low-grade fever, anorexia, fatigue, and anemia. Grade I hepatosplenomegaly and lymphadenopathy may occur, but pericarditis or iridocyclitis is rare. About one-quarter of these children test positive for rheumatoid factor, with late childhood onset. Arthritis severity varies, but over half eventually develop severe arthritis.

3. Oligoarticular type: Involves no more than four joints, predominantly large joints. This type can be divided into two subtypes: ① Type I: More common in girls than boys, with onset usually before the age of 3. The knee, ankle, and elbow joints are frequently affected, and some cases may involve only a single knee joint. Occasionally, the temporomandibular joint or individual finger or toe joints may be involved. If no more than four joints are affected within the first 6 months of onset, the condition generally does not progress to polyarticular arthritis. Arthritis may recur, but severe functional impairment is rare. In addition to joint symptoms, the primary manifestation in these children is chronic iridocyclitis, affecting about half of the patients. Early stages are often asymptomatic and can only be detected by slit-lamp examination. It typically occurs after the onset of joint symptoms, sometimes even when arthritis is inactive. Chronic iridocyclitis can lead to blindness, so patients with oligoarticular type should undergo regular slit-lamp examinations every 3–4 months for early detection and timely treatment. During the arthritis attack stage, patients may experience no arthralgia but may present with low-grade fever, lack of strength, grade I hepatosplenomegaly and lymphadenopathy, and grade I anemia. ② Type II: More common in boys, with onset usually after the age of 8. There is often a family history, including relatives with oligoarticular-type Bi disease, ankylosing spondylitis, Reiter's syndrome (including arthritis, urethritis, and conjunctivitis), or psoriasis. The condition primarily affects the large joints of the lower limbs, with early involvement of the hip joints and sacroiliac joints. Heel pain and Achilles tendinitis are common. Transient arthritis of the ankles, wrists, or elbows may occasionally occur. Over many years, patients often develop ankylosing spondylitis of the lumbar spine. Approximately 75% of patients are positive for the histocompatibility antigen HLA-B27. Some patients may develop acute iridocyclitis, but it generally does not cause visual impairment.

X-ray examination: In the early stage, soft tissue swelling near the joints and bone sparsity in the epiphyseal region can be observed. In advanced stages, severe joint patients exhibit bone surface destruction, narrowing of the joint space, cystic changes in the bone, bone membrane reaction, and joint semi-dislocation.

bubble_chart Auxiliary Examination

This disease lacks specific laboratory tests. During the active phase, anemia, leukocytosis (commonly between 20,000 and 40,000), and a markedly increased erythrocyte sedimentation rate are often observed. The white blood cell count can reach as high as 60,000, with a left shift. Platelet counts are elevated, and in severe systemic cases, they may reach as high as 1 million. Plasma albumin levels are decreased, while α₂ and γ globulins are increased. C-reactive protein is mostly positive. In the polyarticular type, 25% of those negative for wind-dampness factor have positive antinuclear antibodies, while 75% of those positive for wind-dampness factor are positive. In oligoarticular type I, 60% have positive antinuclear antibodies. Occasionally, lupus erythematosus cells may be found. The wind-dampness factor is an antibody specific to IgG, a 19S IgM molecule that can agglutinate sensitized sheep red blood cells, with a positive agglutination titer of 1:32 or higher. In juvenile wind-dampness arthritis, positivity is more common in older girls (around 8 years or older) and those with severe joint symptoms. Serum IgG, IgM, and IgA levels are elevated, while complement levels are normal or increased. Synovial fluid analysis reveals turbid appearance, elevated white blood cell counts (up to 5,000–80,000/mm³), predominantly polymorphonuclear leukocytes, increased protein, normal or decreased glucose, elevated IgG and IgM, decreased complement, and negative bacterial cultures.

bubble_chart Diagnosis

The diagnosis of this disease primarily relies on clinical manifestations. If systemic symptoms or joint inflammation symptoms persist for more than 6 weeks and other diseases can be ruled out, this disease should be considered. Early cases should be differentiated from acute suppurative infections, osteomyelitis, sepsis, suppurative arthritis, subcutaneous nodule disease, leukemia and malignant tumors, traumatic arthritis, and viral arthritis. Additionally, it should also be distinguished from collagen diseases such as wind-dampness fever and systemic lupus erythematosus. Compared to wind-dampness fever, the joint lesions of this disease are mostly bilateral and symmetrical, relatively fixed, less migratory than wind-dampness arthritis, with a lower incidence of subcutaneous nodules, and rarely involve heart valve membrane lesions. Immunodeficiency diseases, especially selective IgA deficiency and congenital X-linked recessive hypogammaglobulinemia, may present similarly to rheumatoid arthritis and should be differentiated. It should also be distinguished from coxa plana, but rheumatoid arthritis rarely starts from the hip joint and is not limited to this area.

bubble_chart Treatment Measures

The purpose of treatment is to alleviate symptoms, maintain joint function, and prevent joint deformities. Due to the prolonged course of the disease, it is essential to show sympathy to the patient and their parents, explain the condition patiently, and secure their long-term cooperation for follow-up.

General Treatment: Comprehensive therapy should be adopted early, with attention to rest and proper nutrition. Physical therapies such as thermotherapy, hot compresses, wax therapy, infrared irradiation, and exercise therapy—including Grade I joint mobility training, muscle flexion and extension exercises, and riding a small bicycle—should be employed to preserve joint function, enhance muscle strength, and prevent joint stiffness and muscle atrophy. For severe cases, psychological support should be provided to encourage adherence to treatment. Additionally, upper respiratory infections should be avoided. If conditions such as tonsillitis, stuffy nose, or dental caries are present, they should be treated promptly.

Drug Treatment:

1. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Aspirin is the first choice. If ineffective or intolerable, switch to other NSAIDs. The treatment course is long, and maintenance therapy should continue for at least six months after symptoms are controlled.

(1) Aspirin: Dosage and administration are as described in the wind-dampness heat treatment section, but the course is longer, with maintenance doses required for over six months or even several years. Effects are usually seen within 1–4 weeks. If no improvement occurs after 10 days, measure serum salicylate levels. If the effective concentration (20–25 mg/dL) is not reached, increase the dose, but be cautious of toxic reactions.

(2) Tolmetin (Tolectin): Strong anti-inflammatory, analgesic, and antipyretic effects with fewer side effects than aspirin, suitable for long-term use. Particularly effective for oligoarticular type. Initial dose: 15 mg/kg/day, gradually increased to 30 mg/kg/day, divided into 3–4 doses. Maximum daily dose: 1.8 g.

(3) Naproxen (Naproxyn): Belongs to the ibuprofen class, with efficacy similar to aspirin but fewer adverse effects. Completely absorbed orally, peak plasma concentration reached in 2–4 hours, half-life of 12–14 hours, 95% excreted renally. Dose: 10–15 mg/kg/day, divided into 2 doses. Maximum daily dose: 1.0 g.

(4) Ibuprofen (Brufen): Suspension form (100 mg/5 mL), daily dose 20–40 mg/kg. Initial dose: 20 mg/kg/day, increased to 30 mg/kg/day in the second week, divided into 3 doses. Use for 3–6 months. Efficacy is similar to aspirin but with fewer gastrointestinal side effects.

(5) Indomethacin (Indocin): Initial dose: 0.5 mg/kg/day, gradually increased to 2.5 mg/kg/day, divided into 3 doses. Maximum daily dose: 100 mg. Often effective for oligoarticular type. Side effects include gastrointestinal, central nervous system, and allergic reactions, as well as hematopoietic suppression (leukopenia, rarely aplastic anemia).

(6) Diclofenac Sodium (Voltaren): A potent new anti-inflammatory and analgesic drug. Features strong efficacy, few side effects, rapid oral absorption (peak concentration in 1–2 hours), and fast excretion without accumulation during long-term use. Dose: 0.5–3 mg/kg/day, divided into 3 oral doses.

2. Slow-Acting Anti-Wind-Dampness Drugs: These drugs act slowly, often taking months to half a year to take effect, and are more toxic. Thus, they are only suitable for polyarticular cases where long-term NSAID therapy fails to control the disease or remains active and progressive, with a risk of joint erosion. Options include: (1) Gold preparations: Sodium aurothiomalate, Auranofin (Ridaura); (2) D-penicillamine.

3. Corticosteroids are only applicable to patients with severe systemic type complicated by cardiopulmonary involvement or oligoarticular type complicated by iridocyclitis. Generally, prednisone 1–2 mg/kg/d is administered, and after symptoms alleviate, the dosage is gradually reduced to 0.5 mg/kg/d within 1–2 weeks, then further tapered to the minimum effective dose over 3–4 weeks, administered on alternate days, with aspirin added concurrently. When corticosteroids are used with aspirin, the renal clearance rate of the latter may increase, leading to decreased blood concentration. Therefore, blood drug levels should be monitored to adjust the aspirin dosage. Due to the side effects of corticosteroids, such as osteoporosis, cartilage destruction, aseptic necrosis of the femoral head, increased risk of infection, growth retardation, and adrenal insufficiency, long-term use should be avoided. Hormones should not be used in cases of simple arthritis. For chronic arthritis that persists, hydrocortisone acetate may be injected into the synovial cavity.

4. Immunosuppressants For patients with severe systemic symptoms and progressive arthritis who show no response to aspirin and other non-steroidal anti-inflammatory drugs, immunosuppressants such as azathioprine (1–2.5 mg/kg/day) may be tried. However, due to their significant side effects, caution is advised. In recent years, methotrexate has been used at a dose of 5–10 mg/m² per week. A recent report described 29 patients who did not respond to gold preparations, penicillamine, or corticosteroid therapy. These patients were treated with methotrexate at a dose of 7.5 mg/m2, taken either once or divided into two doses every 12 hours. After 8–39 months of treatment (average 18.5 months), 83% of systemic-onset children experienced fever reduction, and half showed improvement in joint symptoms, with no significant side effects. It is suggested that methotrexate may be an appropriate substitute for chronic anti-wind-dampness medications.

5. Other Drugs Intravenous immunoglobulin (IVIG) has been used in recent years to treat juvenile rheumatoid arthritis with some success. A study reported six children who did not respond to aspirin, corticosteroids, penicillamine, or immunosuppressants. They were treated with IVIG at 400 mg/kg, administered every other day for three doses, followed by monthly doses for 6–9 months. In the early stages of treatment, three cases showed significant improvement, and one case improved. However, the effects were unsatisfactory in the late stage (third stage), indicating the need for further research. Tripterygium wilfordii (Root, Leaf, or Flower of Common Threewingnut) preparations have been used to treat active cases, with reports suggesting that two months of treatment can alleviate arthritis and achieve optimal efficacy. However, side effects such as diarrhea, abdominal pain, dry mouth, and itching may occur, which resolve after dose reduction. Other drugs, including phenylbutazone, hydroxychloroquine, and sulfasalazine, have been tried, but their efficacy is uncertain, and some have significant side effects, limiting their use in pediatrics.

Surgical and Ophthalmologic Treatment For joint ankylosis and deformities, joint traction, arthroplasty, and other orthopedic treatments may be performed. Artificial joint replacement may be necessary in some cases.

Iridocyclitis should be promptly treated with the assistance of an ophthalmologist. General treatments include mydriatics and topical dexamethasone eye drops. Subconjunctival corticosteroid injections may be required during seasonal epidemics.

bubble_chart Prognosis

The course of this disease can last for several years, with alternating acute episodes and remissions. Most cases resolve spontaneously by adulthood, but a few may persist. If arthritis remains unhealed for many years, it can lead to severe joint deformities and movement impairments, commonly seen in polyarticular types, older girls at onset, and systemic cases with polyarthritis. In oligoarticular types, girls who develop the disease before age 4 often experience chronic iridocyclitis, which can cause blindness. Ankylosing spondylitis may occur in older boys at onset. Overall, with timely treatment, 75% of patients achieve remission with normal joint function, while only a few develop lifelong disabilities. Rare cases may die from concurrent infections or amyloidosis, the latter being more common in systemic cases.

bubble_chart Differentiation

1. Ankylosing Spondylitis This is a relatively rare spinal disease in childhood. The differences from Bi disease are as follows: ① This disease mainly affects the sacroiliac and lumbar spine joints, whereas the joint changes in Bi disease involve the whole body; ② Eye symptoms often appear; ③ It occurs more frequently in boys, and family members often have similar joint and eye symptoms.

2. Lyme Disease (Lyme disease) Refer to the chapter on spirochetal diseases. It is named Lyme disease because many cases occurred in the town of Lyme in the northeastern United States. Epidemiological observations of adult cases have been reported in the Hailin Liang forest area of Heilongjiang Province, China. Caused by the tick-borne spirochete (Borrelia burgdorferi), this disease manifests as a multisystem disorder, including transient acute arthritis, with symptoms resembling rheumatoid arthritis, wind-dampness heat, pestilential mononucleosis, aseptic meningitis, and viral hepatitis, requiring differential diagnosis. A history of tick bites is common. Typical small red papules often appear on the back, armpits, thighs, or buttocks, gradually expanding into annular rings with central pallor, which may develop blisters or necrosis. Systemic symptoms include malaise, fatigue, frequent shivering, fever, intermittent headache, as well as myalgia, back pain, neck stiffness, nausea, vomiting, and non-exudative pharyngitis. Occasionally, abdominal pain and facial nerve paralysis, among other central nervous system complications, may occur. The rash may persist for days to weeks, followed by arthritis and encephalopathy. The arthritis is oligoarticular, mostly involving the knees, and antinuclear antibodies are often negative. About half of the patients exhibit elevated erythrocyte sedimentation rate and serum IgM levels. Diagnosis primarily relies on the typical presentation of early-stage rash, detection of the pathogen from the patient's blood, skin, or cerebrospinal fluid, and serological antibody testing to confirm the disease. Early treatment with penicillin can alleviate joint symptoms. For those allergic to penicillin, erythromycin may be used. To prevent complications, the treatment course should last about 2 weeks or longer.