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Arthritis, Juvenile Idiopathic (Rheumatoid)

Description

Chronic synovial inflammation of unknown etiology in at least 1 joint, for at least 6 weeks. Age of onset must be <16 years old. In 1997, a new classification system was introduced to classify JIA into 7 subtypes:

  • Oligoarticular arthritis affects <5 joints during the 1st 6 months of the disease. Tends to involve large joints, especially the knee. Peak age of onset is 1–6 years; 80% are antinuclear antibody (ANA) positive.
    • Persistent oligoarticular JIA remains in <5 joints.
    • Extended oligoarticular JIA spreads to involve 5 or more joints. Has worse prognosis than persistent oligoarthritis.
  • Polyarticular juvenile idiopathic arthritis affects ≥5 joints. Can occur at any age: peak ages of onset are 1–4 and 7–10 years.
    • Rheumatoid factor positive (RF+) polyarticular juvenile idiopathic arthritis is like adult-onset idiopathic arthritis that occurs in a child. It is often quite aggressive.
    • Rheumatoid factor negative (RF-) polyarticular juvenile idiopathic arthritis is usually less aggressive and easier to control.
  • Systemic-onset idiopathic juvenile arthritis:
    • Characterized by high, spiking quotidian or diquotidian fevers and an evanescent pink/salmon-colored macular rash
    • Affected children may also have lymphadenopathy, hepatosplenomegaly, pericarditis, or pleuritis.
    • Arthritis may not appear until weeks to months after the onset of the systemic symptoms.
    • Can occur at any age
  • Enthesitis-related arthritis (ERA) generally affects boys, many of whom are human leukocyte antigen (HLA)-B27 positive, in late childhood or adolescence
  • Psoriatic arthritis is associated with psoriasis. It often begins in a few joints and then becomes polyarticular. Often involves small joints of hands and feet, as well as knees. Dactylitis seen in nearly 50% patients.

Epidemiology

Incidence

  • Incidence ranges from 1–22/100,000 per year
  • Affects ~70,000–100,000 children in the US

Prevalence
  • Prevalence ranges from 8–150/100,0000
  • Girls are affected twice as often as boys, but usually affects boys more frequently (Male: Female = 10:1).
  • ~50% of children with juvenile idiopathic arthritis have the pauciarticular type.
  • 30% have the polyarticular type.
  • 10% have systemic-onset juvenile idiopathic arthritis.

Risk Factors

Genetics

  • Rare in siblings, but many studies have demonstrated increased frequencies of various human leukocyte antigen markers in juvenile idiopathic arthritis.
  • Each marker may be associated with a different subtype of juvenile idiopathic arthritis.
    • Human leukocyte antigen-DR4: Rheumatoid factor-positive (RF+) polyarticular juvenile idiopathic arthritis
    • Human leukocyte antigen-DR1: Oligioarticular disease without uveitis
    • Human leukocyte antigen-DR5: Oligioarticular juvenile idiopathic arthritis with uveitis
    • Human leukocyte antigen-B27: ERA
    • Human leukocyte antigen-A2: Early-onset pauciarticular juvenile idiopathic arthritis

Pathophysiology

Chronic synovial inflammation

Etiology

The etiology of juvenile idiopathic arthritis is unknown, but genetic predisposition, autoimmunity, and/or infection may play a role.

Signs and Symptoms

History

  • Morning stiffness that improves after a warm shower/bath or with stretching and mild exercise is common in juvenile idiopathic arthritis. Many young children do not complain of pain, but walk with a limp or refuse to walk down stairs in the morning.
  • Joints often become sore/painful again in the late afternoon or evening.
  • Patients with juvenile idiopathic arthritis generally do not complain of severe pain, but rather they avoid using joints that are particularly affected. If a child has severe pain in a joint, especially pain that seems out of proportion to the physical findings, diagnoses other than juvenile idiopathic arthritis should be entertained.
  • The fever curve is important to document. Between fever spikes the child is often completely afebrile. The rash is evanescent and patients often have a history of fatigue, malaise, and weight loss.

Physical Exam
  • Arthritis must be present in at least 1 joint in pauciarticular or polyarticular juvenile idiopathic arthritis.
    • May be restricted range of motion in the affected joints and soft tissue contractures as well
  • Enthesitis and sacroiliac tenderness are often seen in ERA.
  • In systemic juvenile idiopathic arthritis the rash, if present, is almost pathognomonic for this disease.
  • Lymphadenopathy and hepatosplenomegaly may be seen in systemic juvenile idiopathic arthritis.
  • A careful cardiac and pulmonary examination must be done to look for pericarditis and pleuritis.

ALERT
Arthritis must be present for at least 6 weeks before a patient can be diagnosed with juvenile idiopathic arthritis. Many viral illnesses can produce joint pain and swelling that mimics juvenile idiopathic arthritis, but resolves within 4–6 weeks.

Tests

Lab

  • No laboratory finding is diagnostic for juvenile idiopathic arthritis.
  • Many patients with juvenile idiopathic arthritis, especially the polyarticular and systemic types, have elevated sedimentation rates and anemia.
  • Patients with systemic juvenile idiopathic arthritis often have a leukocytosis (predominantly neutrophils), a thrombocytosis, and an elevated ferritin level.
  • Antinuclear antibody is a useful test in classifying patients with juvenile idiopathic arthritis and determining the risk of uveitis. Positive in:
    • 80% of oligioarticular
    • 40–60% of polyarticular
    • 15% of normal population
  • Rheumatoid factor will be positive in 15–20% of patients with polyarticular arthritis and usually indicates a more aggressive form of arthritis.

Imaging
  • Radiography is often normal early in juvenile idiopathic arthritis.
  • Later, if arthritis persists, bone demineralization, loss of articular cartilage, erosions, and joint fusion may be seen.

Differential Diagnosis

  • Monoarticular juvenile idiopathic arthritis:
    • Septic joint
    • Toxic synovitis
    • Trauma
    • Hemarthrosis
    • Villonodular synovitis
  • Monoarticular or oligioarticular juvenile idiopathic arthritis:
    • Lyme disease
    • Acute rheumatic fever or poststreptococcal arthritis
    • Malignancies
    • Sarcoidosis
    • Inflammatory bowel disease
  • Polyarticular juvenile idiopathic arthritis:
    • Viral or postviral illness (especially parvovirus)
    • Lyme disease
    • Lupus
  • Systemic-onset juvenile idiopathic arthritis:
    • Infection
    • Oncologic process (leukemia, lymphoma)
    • Inflammatory bowel disease
    • Lupus

General Measures

  • Responses to treatments for juvenile idiopathic arthritis vary tremendously.
    • Some patients may respond to nonsteroidal anti-inflammatory drugs within 1–2 weeks.
    • Others take 4–6 weeks to improve, and some may not respond at all.
    • Steroids usually start to relieve symptoms within a few days.
    • Methotrexate usually takes 4–8 weeks until a benefit is seen.
    • Anti–tumor necrosis factor therapy can start decreasing symptoms in as little as 1–2 weeks, or it may take up to 3 months.
    • Other second-line agents can take up to 16 weeks until the maximum benefit is seen.
  • The waxing and waning nature of juvenile idiopathic arthritis itself adds to the variability of patient responses to treatments.

Diet
  • Maintain adequate calcium and vitamin D intake to minimize osteoporosis.
  • Patients on methotrexate should take folate supplements daily, except on the days that the methotrexate is given.

Special Therapy

Physical Therapy

  • Physical and occupational therapy are important in the management of juvenile idiopathic arthritis.
  • The goal is to maintain range of motion, muscle strength, and function.

Medication

First Line
NSAIDs:

  • First-line therapy for juvenile idiopathic arthritis
  • If there is no response to the initial NSAID after 4–6 weeks of an adequate dose, a different one should be tried. Patients will often respond differently to the various nonsteroidal drugs.
  • If patients experience GI upset or excessive bruising, COX-2 inhibitors may be used.

Second Line
If NSAIDs are ineffective in controlling the disease, a second-line agent should be added, such as methotrexate or sulfasalazine.
  • Methotrexate: If the arthritis does not respond to NSAIDs, methotrexate is often started. Laboratory values must be monitored closely in these patients, looking for bone marrow suppression or elevation of transaminase levels.
  • Sulfasalazine is most often used in ERA.

OtherThird Line
  • Biologic agents are often added when patients do not respond adequately to methotrexate or cannot tolerate its side effects.
  • Anti-tumor necrosis factor therapy is frequently used: Etanercept is a receptor for tumor necrosis factor that is given SC once or twice a week. Inflixamab is a chimeric antibody to tumor necrosis factor that is given IV every 4 to 8 weeks. Adalimumab is a fully humanized antibody to tumor necrosis factor given SC every other week.
  • Anakinra is a recombinant IL-1 receptor antagonist. It is given as a daily SC injection.
  • Abatacept is a co-stimulation blocker. It blocks the interaction of CD28 on T cells with CD80 and CD86 receptors on antigen presenting cells. It is given IV every 4 weeks. It is currently approved for use in adult RA but is still being studied in children.
  • Rituximab is an antibody to CD20, which is present on all B cells. It is approved for use in adult RA but not in JIA.
  • Anti- IL-6 therapy is currently being studied in children with systemic onset juvenile idiopathic arthritis.
  • Medications such as cyclophosphamide or thalidomide are sometimes necessary to control severe systemic-onset juvenile idiopathic arthritis.

OtherGlucocorticoids
  • In systemic juvenile idiopathic arthritis with high fevers, systemic glucocorticoids are often necessary, either as oral (daily or every other day) doses or as IV pulses, every 2 to 8 weeks. Systemic steroids are also used for patients with polyarticular juvenile idiopathic arthritis whose arthritis is unresponsive to other medications. Because of the many side effects, patients should be weaned off steroids as soon as possible.
  • Intra-articular steroids are often used in patients with only one or a few active joints.

Prognosis

  • Varies considerably
  • Children with oligioarticular juvenile idiopathic arthritis usually do well and often go into remission within a few years of starting treatment. They may have flares, however, even up to 10 years after being symptom free and off all medications.
  • Patients with polyarticular juvenile idiopathic arthritis who are idiopathic factor positive often develop a severe arthritis that may persist into adulthood.
  • Rheumatoid factor-negative polyarticular patients generally do better, and many outgrow their disease.
  • 50% of patients with systemic-onset juvenile idiopathic arthritis will develop severe chronic polyarticular arthritis.

Complications

  • Joint degeneration with loss of articular cartilage
  • Soft tissue contractures
  • Leg-length discrepancies
  • Micrognathia
  • Cervical spine dislocations
  • Rheumatoid nodules
  • Growth retardation
  • Uveitis: Pauciarticular juvenile idiopathic arthritis, especially with a positive antinuclear antibody, is associated with a chronic uveitis, which can lead to loss of vision if not detected early with routine slit-lamp eye examinations.
  • Pericarditis and pleuritis, as well as severe anemia, may develop in patients with systemic-onset juvenile idiopathic arthritis.
  • Macrophage activation syndrome, or hemophagocytic syndrome:
    • Rare, but potentially lethal complication of systemic-onset juvenile idiopathic arthritis, resulting from an overproduction of inflammatory cytokines
    • May present as an acute febrile illness with pancytopenia and hepatosplenomegaly
    • Diagnosis is made by bone marrow aspiration.
    • Treatment is often with high-dose steroids and cyclosporine.

ICD-9

714.30 Polyarticular juvenile idiopathic arthritis, chronic or unspecified

FAQ

  • Q: Will the patient outgrow juvenile idiopathic arthritis?
  • A: Prognosis depends on the type of juvenile idiopathic arthritis. In some studies, up to 50% of patients with juvenile idiopathic arthritis still had active disease 10 years after diagnosis. Only 15%, however, had any loss of function.
  • Q: Will siblings of patients with juvenile idiopathic arthritis develop the disease?
  • A: Rarely, but it can occur

AUTHOR

Elizabeth Candell Chalom, MD

BIBLIOGRAPHY

  1. Patel H , Goldstein D. Pediatric uveitis. Pediatr Clin North Am. 2003;50(1):125–136.
  2. Schneider R. Passo MH. Juvenile idiopathic arthritis. Rheum Dis Clin North Am. 2002;28(3):503–530.
  3. Tse SM. Laxer RM. Juvenile spondyloarthropathy. Curr Opin Rheumatol. 2003;15(4):374–379.
  4. Weiss J and Ilowite N. Juvenile idiopathic arthritis. Pediatr Clin North Am. 2005;52(2).

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