Arthritis, Juvenile Idiopathic – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • Most common chronic rheumatic illness in children and a significant cause of short- and long-term disability
  • General characteristics:
    • Age of onset <16 years
    • Signs of arthritis: Joint swelling, limitation of motion, pain, heat, or tenderness
    • >6 weeks of symptoms
  • 7 subtypes exist, according to the International League of Associations for Rheumatology, determined by clinical characteristics seen in 1st 6 months of illness:
    • Systemic: Occurs in 10–20% of affected children; usually characterized by febrile onset and evanescent rash with multiple physical and laboratory abnormalities
    • Polyarticular RF (+): Occurs in 5–10% of affected children; multiple (≥5) joint involvement; large and small joints affected. RF positive 2x on tests at least 3 months apart
    • Polyarticular RhF (-): Occurs in 30% of affected children; ≥5 joint involvement, large and small joints affected; RF negative
    • Oligoarticular: Occurs in 40–50% of affected children; involvement of ≤4 joints, usually larger joints, especially of lower extremities; risk for chronic uveitis in young girls and axial skeletal involvement in older boys
    • Psoriatic arthritis: Occurs in 2–15% of affected children. Arthritis with psoriasis or arthritis with at least 2 of following: dactylitis, nail pitting or onycholysis, psoriasis in 1st-degree relative.
    • Enthesitis arthritis: Occurs in 1–7% of affected children. Includes ankylosing spondylitis and inflammatory bowel disease–related arthritis. Peripheral and axial involvement.
    • Undifferentiated arthritis: Arthritis that does not fulfill above categories or fills 2 or more categories
  • System(s) affected: Hematologic/Lymphatic/Immunologic; Musculoskeletal
  • Synonym(s): Juvenile chronic arthritis; Juvenile arthritis; Juvenile rheumatoid arthritis (JRA); Still disease

Epidemiology

  • Predominant age: 1–4 years and 9–14 years old
  • Predominant sex:
    • Poly/oligoarticular: Female > Male
    • Systemic: Female = Male
    • Enthesitis: Male > Female

Incidence

1–22 per 100,000 children <16 years per year

Prevalence

8–150 per 100,000 children <16 years

Pediatric Considerations

Behavioral and compliance problems frequent in toddlers and teenagers

Pregnancy Considerations

Unpredictable effect on disease activity

Risk Factors

  • Rheumatoid factor (RF) positivity increases risk for severe arthritis in polyarticular juvenile idiopathic arthritis (JIA).
  • Antinuclear antibody (ANA) positivity increases risk for uveitis in oligo-JIA and poly-JIA.

Genetics

  • Certain HLA class I and II alleles
  • HLA-A2 in early-onset oligoarthritis in girls
  • HLA-DRB1*11 confers increased risk of systemic and oligo-JIA.
  • HLA-B27 risk of enthesitis-related arthritis
  • HLA-DR4 associated with RF (+) polyarticular disease

General Prevention

No known preventive measures

Etiology

Multifactorial, including:

  • Immunodysregulation
  • Genetic predisposition
  • Environmental triggers, possibly infectious:
    • Rubella or parvovirus B19 (1)
    • Heat shock proteins (1)
  • Immunoglobulin or complement deficiency

Commonly Associated Conditions

  • Other autoimmune disorders
  • Chronic anterior uveitis (iridocyclitis)
  • Nutritional impairment
  • Growth disturbances (1)

Arthritis, Juvenile idiopathic arthritis, Inflammatory bowel disease, Rheumatoid factor, Synovial fluid, Rheumatology, juvenile chronic arthritis,

Diagnosis

Clinical diagnostic criteria: Age of onset <16 years and >6 weeks duration of objective arthritis in ≥1 joints, defined as swelling or limitation of motion of a joint accompanied by heat, pain, or tenderness

History

  • Arthralgias, fever, fatigue, malaise, myalgias, weight loss, morning stiffness, rash, limp in patients with lower extremity involvement
  • Arthritis for at least 6 weeks

Physical Exam

  • Arthritis: Swelling, effusion, limitation of motion, tenderness, pain on motion, warmth
  • Rash, rheumatoid nodules, lymphadenopathy, hepato- or splenomegaly, enthesitis, dactylitis

Diagnostic Tests & Interpretation

Lab

Initial lab tests

  • Complete blood count (CBC):
    • Leukocyte count normal or markedly elevated (systemic), lymphopenia
    • Reactive thrombocytosis
    • Anemia
  • Joint-fluid aspiration and analysis helpful in excluding infection
  • Inflammatory markers: Erythrocyte sedimentation rate and C-reactive protein may be elevated
  • ANA positive (>1:80): 40% (polyarticular or oligoarticular): Increased risk of uveitis
  • RF positive: 2–10% (usually polyarticular): Poor prognosis
  • HLA-B27 positive: Enthesitis-related arthritis

Follow-Up & Special Considerations

  • In polyarticular RF-positive variant, positivity should be confirmed at least twice, 3 months apart (2).
  • RF and ANA may be present in mixed connective tissue disease.

Imaging

Diagnostic radiography, magnetic resonance (MR) imaging, ultrasonography, and computed tomography all play an important role in diagnosing or monitoring juvenile idiopathic arthritis (JIA); no one modality has evidence for superior diagnostic value (3)[A].

Initial approach

  • Radiograph of affected joint(s)
  • Early radiographic changes: Soft tissue swelling, periosteal reaction, juxta-articular demineralization
  • Later changes include joint-space loss, articular surface erosions, subchondral cyst formation, sclerosis, joint fusion
  • Electrocardiogram (pericarditis)
  • Radionuclide scans (infection, malignancy)
  • MRI can assess synovial hypertrophy, cartilage degeneration, and clinical responsiveness to treatment in peripheral joints in JIA (4)[B].

Follow-Up & Special Considerations

In interpreting results of dual energy x-ray photon absorptiometry scans, it is important to use pediatric, not adult, controls as normative data.

Diagnostic Procedures/Surgery

  • Synovial biopsy occasionally indicated
  • Arthrocentesis

Pathological Findings

Synovium shows hyperplasia of synovial cells, hyperemia, and infiltration of small lymphocytes and mononuclear cells.

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Differential Diagnosis

  • Other rheumatic diseases:
    • Systemic lupus erythematosus, dermatomyositis, mixed connective tissue disease, sarcoidosis
  • Musculoskeletal:
    • Legg-Calve-Perthes, toxic synovitis, growing pains
  • Infectious:
    • Septic arthritis, osteomyelitis, Lyme disease
  • Reactive arthritis:
    • Postinfectious, rheumatic fever, Reiter’s syndrome
  • Inflammatory bowel disease:
    • Crohn’s disease and ulcerative colitis
  • Hemoglobinopathies
  • Malignancy:
    • Leukemia, bone tumors, neuroblastoma
  • Vasculitis
  • Kawasaki disease

Treatment

Medication

First Line

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) are adequate in ∼50% of patients, symptoms often improve within days, full efficacy 2–3 months
  • Drugs for children include:
    • Ibuprofen (Motrin, Advil, Nuprin): 30–40 mg/kg/d, divided q.i.d., max 800 mg t.i.d.
    • Naproxen (Naprosyn, Aleve): 10–20 mg/kg/d divided b.i.d., max dose of 500 mg b.i.d.
    • Tolmetin sodium: 15–30 mg/kg/d; t.i.d. or q.i.d., max dose 600 mg t.i.d.
    • Diclofenac 2–3 mg/kg, divided t.i.d., max of 50 mg t.i.d.
    • Indomethacin 3 mg/kg/d, max of 200 mg/d
  • Contraindications to NSAIDs: Known allergies
  • Precautions: May worsen bleeding diatheses; use caution with all NSAIDs in renal insufficiency and hypovolemic states
  • Significant possible interactions: NSAIDs may lower serum levels of digitalis and anticonvulsants and blunt the effect of loop diuretics. NSAIDs may increase serum methotrexate levels.
  • Intra-articular long-acting corticosteroids especially for oligo-JIA. Immediately effective, local treatment. Improve synovitis, joint damage, contractures, and prevent leg length discrepancy (2)[B]:
    • Triamcinolone hexacetonide
  • Glucocorticoids: Only in patients with extreme pain and functional limitation, while waiting for a 2nd-line agent to show some effect

Second Line

  • 30–40% of patients will require addition of disease-modifying antirheumatic drugs (DMARDs), including methotrexate, sulfasalazine, leflunomide, and tumor necrosis factor antagonists (etanercept, infliximab, adalimumab). Newer biologic therapies including IL-1 and IL-6 receptor antagonists currently under investigation.
  • Methotrexate: Standard dose 8–12.5 mg/m2/wk p.o. or SC. 10 mg/m2/wk is most frequently used (2)[B]:
    • Plateau of efficacy reached with 15 mg/m2/wk; further increase in dosage is not associated with therapeutic benefit (5)
  • Sulfasalazine: Oligoarticular and HLA B27 spondyloarthritis
  • Leflunomide: Not Food and Drug Administration approved for JIA
  • Etanercept (Enbrel) 0.4 mg/kg, max of 25 mg, given SC twice weekly (2)[B]
  • Infliximab 3–6 mg/kg q6–8 weeks
  • Adalimumab 40 mg SC every 2 weeks (6)[B]
  • Tocilizumab IL-6 antibody demonstrating efficacy in phase III open label trials, ongoing studies to evaluate efficacy and appropriate dosing regimen (2)
  • Anakinra IL-1 receptor antibody under investigation with phase II and III clinical trials for systemic JIA (2)
  • Alternative drugs:
    • Other NSAIDs and salicylates: Avoid salicylate therapy during serious viral illness, especially influenza or varicella, secondary to risk of Reye syndrome
  • Analgesics for pain control, including narcotics

Additional Treatment

General Measures

  • Treatment goal: Control active disease and extra-articular manifestations to maintain musculoskeletal function as normal as possible.
  • Outpatient care except for initial diagnostic workup of systemic JIA disease and complications for all subtypes
  • All patients require regular (every 3–4 months for oligo-JIA and in ANA-positive patients) ophthalmic exams to uncover asymptomatic eye disease, at least for 1st 3 years.
  • Moist heat, sleeping bag, or electric blanket to relieve morning stiffness
  • Splints for contractures

Issues for Referral

  • In general, a pediatric rheumatologist is best suited to manage juvenile idiopathic arthritis.
  • Orthopedic surgeon: Need for surgery (joint replacement)
  • Ophthalmologist: Uveitis
  • Physical therapist for joint protection, to maintain range of motion, improve muscle strength, prevent deformities
  • Occupational therapist to maintain and improve the normal life function
  • Psychologists for coping

Additional Therapies

Physical therapy including daily home exercise program and orthotics for support

Surgery/Other Procedures

  • Total hip and/or knee replacement may be needed for severe disease.
  • Soft tissue release, if splinting, traction unsuccessful
  • Limb length or angular deformity corrections
  • Synovectomy is rarely performed.

In-Patient Considerations

Admission Criteria

  • Patient loses ambulatory ability
  • Signs/symptoms of pericarditis
  • Persistent fever

Discharge Criteria

Resolution of fever and swelling or serositis

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

Determined by medication:

  • NSAIDs: Periodic complete blood count (CBC), urinalysis, liver function tests (LFTs), renal function tests
  • Aspirin and/or other salicylates: Transaminase and salicylate levels, weekly for 1st month, then every 3–4 months
  • Methotrexate: Monthly LFTs, CBC, blood urea nitrogen, creatinine

Diet

Regular diet with special attention to adequate calcium, iron, protein, and caloric intake

Patient Education

  • Ongoing education of patients and families with attention to:
    • Psychosocial needs
    • School issues, educational needs
    • Behavioral strategies for dealing with pain and noncompliance
    • Use of health care resources
  • Printed and audiovisual information available from local arthritis foundation

Prognosis

  • 50–60% ultimately remit, but functional ability depends on adequacy of long-term therapy (disease control, maintaining muscle and joint function).
  • Poorest prognosis in patients with RF + poly-JIA or patients with systemic JIA

Complications

  • Blindness, band keratopathy, glaucoma
  • Short stature
  • Micrognathia if temporomandibular joint involvement
  • Debilitating joint disease
  • Disseminated intravascular coagulation; hemolytic anemia
  • Patient on NSAIDs: Peptic ulcer, GI hemorrhage, central nervous system reactions, renal disease, leukopenia
  • Patient on DMARD: Bone marrow suppression, hepatitis, renal disease, dermatitis, mouth ulcers, retinal toxicity (antimalarials, rare)
  • Patients on tumor necrosis factor antagonists: Higher risk of infection
  • Osteoporosis
  • Macrophage activation syndrome:
    • Decreased blood cell precursors secondary to histiocyte degradation of marrow

References

1. Weiss JE, Ilowite NT. Juvenile Idiopathic Arthritis. Rheum Dis Clin N Am. 2007;33:441–70.

2. Kahn P, et al. Juvenile idiopathic arthritis–current and future therapies. Bulletin of the NYU hospital for joint diseases. 2009;67:291–302.

3. McKay GM, Cox LA, Long BW, et al. Imaging juvenile idiopathic arthritis: assessing the modalities. Radiol Technol. 2010;81:318–27.

4. Miller E, Uleryk E, Doria AS. Evidence-based outcomes of studies addressing diagnostic accuracy of MRI of juvenile idiopathic arthritis. AJR Am J Roentgenol. 2009;192:1209–18.

5. Takken T, van der Net J, Helders P. Methotrexate for treating juvenile idiopathic arthritis. The Cochrane Database of Systematic Reveiws. 2009, Issue 1.

6. Lovell DJ, et al. Adalimumbab with or without Methotrexate in Juvenile Rheumatoid Arthritis. New Engl J Med. 2008;359(8):810–20.

Codes

ICD9

  • 714.30 Chronic or unspecified polyarticular juvenile rheumatoid arthritis
  • 714.31 Acute polyarticular juvenile rheumatoid arthritis
  • 714.32 Pauciarticular juvenile rheumatoid arthritis
  • 714.33 Monoarticular juvenile rheumatoid arthritis

Snomed

410502007 Juvenile idiopathic arthritis (disorder)

Clinical Pearls

  • Consult pediatric rheumatologist
  • High-titer RF correlates with severity
  • ANA confers risk of uveitis
  • No specific biomarker or test
  • Diagnosis is one of exclusion

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