Juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA; formerly called juvenile rheumatoid arthritis) is a broad term for childhood rheumatic diseases that begin before the age of 16 and are characterized by joint inflammation that lasts more than 6 weeks. It is classified into various types based on the pattern of joint involvement, the presence of extra-articular manifestations (e.g., uveitis, rash, nail changes, lymphadenopathy, hepatosplenomegaly), laboratory findings, and disease prognosis. Oligoarticular JIA, which is the most common type, presents with asymmetric involvement of up to four joints (with the knee joint most often affected). Nearly half of all cases of oligoarticular JIA are associated with anterior uveitis, which may be diagnosed by slit-lamp examination. Laboratory tests such as ESR, rheumatoid factor (RF), antinuclear antibodies (ANA), and the HLA-B27 antigen test are used to classify and determine the prognosis of JIA. Treatment of JIA is similar to that of adult rheumatoid arthritis and involves the use of NSAIDs, intra-articular steroid injections, and disease-modifying antirheumatic drugs (DMARDs) such as methotrexate. Systemic glucocorticoid therapy should be avoided because of the risk of growth impairment.

• Prevalence: 1:1000 children [1]
• Sex: ♀ > ♂
• Age of onset: : < 16 years of age

Epidemiological data refers to the US, unless otherwise specified.

• Idiopathic
• Immunological predisposition: different HLA associations [2][3]
  • Oligoarticular JIA: HLA-DR8, HLA-DR5
  • Polyarticular JIA: HLA-DR4
  • Enthesis associated and psoriatic JIA: HLA-B27
• Possibly triggered by a viral or bacterial infection
• Exposure to antibiotics during childhood may increase the risk of JIA.

Autoimmune and/or autoinflammatory disease → chronic synovial inflammation with infiltration of plasma cells, B lymphocytes, and T lymphocytes → joint capsule hyperplasia → growth of fibrovascular connective tissue (pannus) → invasion of the articular surface → loss of joint function [4]

For the exact pattern of joint involvement and specific extra-articular symptoms, see “Subtypes and variants” below.

• Arthritic symptoms
  • Swollen joints, rarely erythema
  • Early morning stiffness
  • Limited or painful joint movement
• Extra-articular manifestations [1]
  • Fever (for ≥ 2 weeks)
  • Uveitis
  • Rash
  • Nail changes
  • Lymphadenopathy
  • Hepatosplenomegaly
• Nonspecific features
  • Excessive crying
  • Lethargy
  • Decreased scholastic performance

The affected joints are often stiff in the morning or after longer periods of inactivity (e.g., sitting). Joint stiffness improves with movement and decreases later in the day.

A prerequisite for the diagnosis of all forms of JIA is that arthritic symptoms begin before the age of 16 and last ≥ 6 weeks.

The clinical diagnosis of JIA can be supported by a number of diagnostic tests.

Laboratory tests

Blood tests are used to classify JIA, assess the prognosis, and rule out other similar conditions (see “Subtypes and variants” above).

• Autoantibodies levels [10]
  • Rheumatoid factor (RF)
    • Absent in most cases of JIA (except seropositive polyarticular JIA)
    • Associated with poor prognosis
  • ↑ ANA
    • Most commonly associated with oligoarticular JIA (∼ 70%)
    • Incidence of anterior uveitis increases when antinuclear antibodies (ANA) are present.
  • Anti-CCP antibodies: indicate a poor prognosis [11]
• Acute phase reactants
  • ↑ ESR: usually seen with all forms of JIA
  • ↑ CRP, ferritin: usually associated with systemic JIA
• CBC
  • Anemia
  • Leukocytosis
  • Thrombocytosis: denotes a more severe inflammatory response in polyarticular and systemic JIA

Imaging tests

• Ultrasound [12]
  • Used to detect synovial hypertrophy and intraarticular fluid collections
  • Best imagistic tool for the detection of early bone erosions
• X-ray [13]
  • May be used for the identification of JIA complications
  • Should not be performed routinely

Other diagnostic tests

• Synovial biopsy
  • Can provide a definitive diagnosis of JIA [14]
  • Shows infiltration of plasma cells, B lymphocytes, and T lymphocytes
• Slit lamp examination: : should be performed for regular ophthalmological screening in patients with anterior uveitis [10]
• Slit lamp examination [10][15]
  • Patients with a high risk of developing anterior uveitis (ANA positive; , age of onset ≤ 7 years, and disease duration ≤ 4 years) should undergo ophthalmic screening every 3 months.
  • All other patients should undergo ophthalmic screening every 12 months.
  • Patients with anterior uveitis should be monitored every 1–3 months, depending on the choice of therapy and response to treatment.

Anterior uveitis that occurs with JIA may be asymptomatic (especially in the case of chronic anterior uveitis). However, untreated anterior uveitis is associated with a high risk of developing glaucoma, cataracts, and optic nerve damage. Therefore, early detection via slit lamp examination and swift initiation of treatment are of paramount importance.

The differential diagnosis of JIA includes other causes of nonsuppurative arthritis in children: [16]

• Acute lymphocytic leukemia
• Reactive arthritis
• Acute rheumatic fever
• Juvenile ankylosing spondylitis
• Connective tissue disease (e.g., SLE, Sjögren syndrome)
• Trauma
• Hemophilia
• Growing pains

The differential diagnoses listed here are not exhaustive.

Definitive therapy

First-line therapy [17]

• NSAIDs
  • Indomethacin
    • Commonly used; highly effective in the treatment of JIA
    • Has severe side effects: headaches, renal failure, and bone marrow depression
  • Other commonly used NSAIDs: naproxen, ibuprofen, meloxicam, celecoxib, and tolmetin
• Local intra-articular steroids (e.g., triamcinolone): indicated in the case of active arthritis

Second-line therapy

• Disease-modifying antirheumatic drugs (DMARDs) [18]
  • Therapy with DMARDs should be started as early as possible in the case of high disease activity.
  • The DMARD of choice is determined on an individual basis with methotrexate being used in most cases.
• Biologic agents
  • Indicated if the response to DMARDs is poor.
  • Examples: etanercept, adalimumab, tocilizumab, anakinra
• Systemic glucocorticoid therapy (oral, IV) [19]
  • Rarely used in children because of the risk of catabolic side effects (e.g., osteoporosis, growth impairment)
  • A short course of systemic glucocorticoid therapy may be prescribed in the following situations:
    • Severe systemic involvement (e.g., severe serositis; see “Still disease”)
    • As bridge therapy when DMARDs are initiated
    • Acute anterior uveitis
    • Macrophage activation syndrome

Supportive therapy

• Physiotherapy: to prevent joint deformities
• Surgery, splints, and/or orthotics: to correct limb length discrepancy and/or joint deformities

Most drugs that are used to treat adult rheumatoid arthritis may be used to treat JIA as well (see “Therapy” in “Rheumatoid arthritis”). However, certain forms of therapy (e.g., systemic glucocorticoid therapy) should, as a rule, be avoided in children.

• Articular complications
  • Joint destruction → joint subluxation and/or deformities (e.g., swan-neck deformity, boutonniere deformity)
  • Limb length discrepancy
  • Growth retardation
• Extra-articular complications
  • Chronic anterior uveitis → blindness
  • Pericarditis, pleuritis
  • Macrophage activation syndrome (MAS) [4]
    • A rare complication of JIA (most commonly systemic JIA) characterized by thrombocytopenia, elevated transaminases, low fibrinogen, and markedly increased ferritin levels
    • In a patient with systemic JIA, the presence of a normal or decreased WBC count, falling ESR, and/or increased triglyceride levels should raise the suspicion of MAS.

We list the most important complications. The selection is not exhaustive.

The clinical course and prognosis are highly variable (see “Subtypes and variants” above) . Most cases (∼ 95%) resolve by puberty.

• Factors associated with a poor prognosis [17]
  • Early onset
  • Prolonged active systemic disease
  • Hip and/or wrist involvement
  • Polyarticular involvement
  • Symmetrical disease
  • Presence of RF
  • Presence of anti-CCP antibodies

Early disease onset is associated with a greater degree of growth impairment and deformity.