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Juvenile Idiopathic Arthritis (JIA)

By

Jay Mehta

, MD, Perelman School of Medicine at The University of Pennsylvania

Last full review/revision Jun 2020| Content last modified Jun 2020
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Juvenile idiopathic arthritis is a group of rheumatic diseases that begins by age 16. Arthritis, fever, rash, adenopathy, splenomegaly, and iridocyclitis are typical of some forms. Diagnosis is clinical. Treatment involves intra-articular corticosteroids and disease-modifying antirheumatic drugs.

Juvenile idiopathic arthritis (JIA) is uncommon. The cause of JIA is unknown, but there seems to be a genetic predisposition as well as autoimmune and autoinflammatory pathophysiology. The vast majority of children with JIA have a disease that is distinct from adult rheumatoid arthritis (RA), but in 3 to 5% of children with JIA, the disease is analogous to adult RA.

Classification

Juvenile idiopathic arthritis is not a single disease; the term applies to a number of chronic, noninfectious arthritides that occur in children and share certain features. The current classification system, from the International League of Associations for Rheumatology, defines categories of disease based on clinical and laboratory findings. Some of the categories are subdivided into different forms. Categories include the following:

  • Oligoarticular JIA (persistent or extended)

  • Polyarticular JIA (rheumatoid factor [RF] negative or positive)

  • Enthesitis-related arthritis

  • Psoriatic JIA

  • Undifferentiated JIA

  • Systemic JIA

Many of these categories likely include more than one disease but are useful to help group children with a similar prognosis and response to treatment. Also, children sometimes move to different categories during the course of their illness.

Oligoarticular JIA is the most common form and typically affects young girls. It is characterized by involvement of 4 joints during the first 6 months of disease. Oligoarticular JIA is further divided into 2 types: persistent (always 4 joints involved) and extended (≥ 5 joints involved after the first 6 months of disease).

Polyarticular JIA is the second most common form. It affects 5 joints at onset and is divided into 2 types: RF negative and RF positive. Typically, young girls are RF negative and have a better prognosis. The RF-positive type typically occurs in adolescent girls and is analogous to adult rheumatoid arthritis. In both types, arthritis can be symmetric and frequently involves the small joints.

Enthesitis-related arthritis involves arthritis and enthesitis (painful inflammation at the insertion of tendons and ligaments). It is more common among older boys, and these patients may subsequently develop arthritis of their axial skeleton (sacroiliac and lumbar spine). Enthesitis-related arthritis tends to be in the lower extremities and asymmetric. The human leukocyte antigen–B27 (HLA-B27) allele is more common in this form of JIA.

Psoriatic JIA has a bimodal age distribution. One peak occurs in young girls, and the other peak occurs in older males and females (who are equally affected). It is associated with psoriasis, dactylitis (swollen digits), nail pits, or a family history of psoriasis in a 1st-degree relative. Arthritis is frequently oligoarticular.

Undifferentiated JIA is diagnosed when patients do not meet criteria for any one category or meet criteria for more than one.

Systemic JIA (Still disease) involves fever and systemic manifestations.

Symptoms and Signs

Manifestations involve the joints and sometimes the eyes and/or skin; systemic juvenile idiopathic arthritis may affect multiple organs.

Children typically have joint stiffness, swelling, effusion, pain, and tenderness, but some children have no pain. Joint manifestations may be symmetric or asymmetric, and involve large and/or small joints. Enthesitis typically causes tenderness of the iliac crest and spine, greater trochanter of the femur, patella, tibial tuberosity, Achilles insertion, or plantar fascia insertions.

Sometimes, JIA interferes with growth and development. Micrognathia (receded chin) due to early closure of mandibular epiphyses or limb length inequality (usually the affected limb is longer) may occur.

The most common comorbidity is iridocyclitis (inflammation of the anterior chamber and anterior vitreous) that is typically asymptomatic but sometimes causes blurring of vision and miosis. Rarely, in enthesitis-related arthritis, there are also the more common uveitis manifestations of conjunctival injection, pain, and photophobia. Iridocyclitis can result in scarring (synechia), cataracts, glaucoma, or band keratopathy. Iridocyclitis is most common in oligoarticular JIA, developing in nearly 20% of patients, especially if patients are positive for antinuclear antibodies (ANA). It may occur in the other forms but is exceedingly rare in polyarticular RF-positive JIA and systemic JIA.

Skin abnormalities are present mainly in psoriatic JIA, in which psoriatic skin lesions, dactylitis, and/or nail pits may be present, and in systemic JIA, in which a typical transient rash often appears with fever. Rash in systemic JIA may be diffuse and migratory, with urticarial or macular lesions with central clearing.

Systemic abnormalities in systemic JIA include high fever, rash, splenomegaly, generalized adenopathy (especially of the axillary nodes), serositis with pericarditis or pleuritis, and interstitial lung disease. These symptoms may precede the development of arthritis. Fever occurs daily (quotidian) and is often highest in the afternoon or evening and may recur for weeks. In 7 to 10% of patients, systemic JIA may be complicated by macrophage activation syndrome, a life-threatening cytokine storm syndrome.

Diagnosis

  • Clinical evaluation

  • Rheumatoid factor (RF), antinuclear antibodies (ANA), anticyclic citrullinated peptide (anti-CCP) antibodies, and HLA-B27 tests

Juvenile idiopathic arthritis should be suspected in children with symptoms of arthritis, signs of iridocyclitis, generalized adenopathy, splenomegaly, or unexplained rash or prolonged fever, especially if quotidian. Diagnosis of JIA is primarily clinical. It is made when a chronic noninfectious arthritis lasting > 6 weeks has no other known cause.

Patients with JIA should be tested for RF, anti-CCP antibodies, ANA, and HLA-B27 because these tests may be helpful in distinguishing between forms. The test for ANA should be done by immunofluorescence because other methods may result in false-negative results.

In systemic JIA, RF and ANA are usually absent. In oligoarticular JIA, ANA are present in up to 75% of patients and RF is usually absent. In polyarticular JIA, RF usually is negative, but in some patients, mostly adolescent girls, it can be positive. HLA-B27 is present more commonly in enthesitis-related arthritis. In systemic JIA, laboratory abnormalities suggestive of systemic inflammation, such as elevated erythrocyte sedimentation rate (ESR), ferritin, and C-reactive protein, along with leukocytosis, anemia, and thrombocytosis are almost always present at diagnosis.

To diagnose iridocyclitis, a slit-lamp examination should be done even in the absence of ocular symptoms. A recently diagnosed patient with oligoarticular or polyarticular JIA should have an eye examination every 3 months if ANA test results are positive and every 6 months if ANA test results are negative.

Prognosis

Remissions occur in 50 to 70% of treated patients. Patients with RF-positive polyarticular JIA have a less favorable prognosis.

Treatment

  • Drugs that slow disease progression (particularly methotrexate, tumor necrosis factor [TNF] inhibitors, and interleukin [IL]-1 inhibitors)

  • Intra-articular corticosteroid injections

  • Sometimes nonsteroidal anti-inflammatory drugs (NSAIDs) for symptom relief

Similar to the therapy of patients with adult rheumatoid arthritis, disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate and the biologic agents (eg, etanercept, anakinra, canakinumab, tocilizumab, abatacept), have dramatically changed the therapeutic approach (1, 2, 3).

Methotrexate is useful for oligoarticular, psoriatic, and polyarticular forms of JIA. Adverse effects are monitored as in adults. Bone marrow depression and hepatic toxicity are monitored with complete blood count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin. Occasionally, sulfasalazine is used, especially in cases of suspected spondyloarthritis.

TNF inhibitors are used if methotrexate is not effective. Etanercept is used most commonly at doses of 0.8 mg/kg subcutaneously (up to 50 mg) once a week. Adalimumab and infliximab are other TNF inhibitors that have been shown to be effective. The IL-1 inhibitors anakinra or canakinumab are particularly effective for systemic JIA. Tocilizumab, an IL-6 receptor antagonist, is also indicated for the treatment of systemic JIA.

Except for severe systemic disease, systemic corticosteroids can usually be avoided. When necessary, the lowest possible dose is used (eg, range for oral prednisone, 0.0125 to 0.5 mg/kg 4 times a day, or the same daily dose given once or twice a day). Growth retardation, osteoporosis, and osteonecrosis are the major hazards of prolonged corticosteroid use in children. Intra-articular corticosteroid injections can be given. The dosage for children is adjusted based on weight. Some children may need to be sedated for intra-articular injection, especially if multiple joints require injection.

Symptoms of juvenile idiopathic arthritis may be reduced with NSAIDs but they do not alter long-term joint disease or prevent complications. NSAIDs are most useful for enthesitis. Naproxen 5 to 10 mg/kg orally 2 times a day, ibuprofen 5 to 10 mg/kg orally 4 times a day, and indomethacin 0.5 to 1.0 mg/kg orally 3 times a day are among the most useful.

Iridocyclitis is treated with ophthalmic corticosteroid drops and mydriatics and may require systemic methotrexate and anti-TNF therapy.

Physical therapy, exercises, splints, and other supportive measures may help prevent flexion contractures. Adaptive devices can improve function and minimize unnecessary stresses on inflamed joints.

Treatment references

  • 1. Ringold S, Angeles-Han ST, Beukelman T, et al: 2019 American College of Rheumatology/Arthritis Foundation guideline for the treatment of juvenile idiopathic arthritis: Therapeutic approaches for non-systemic polyarthritis, sacroiliitis, and enthesitis. Arthritis Rheumatol 71(6):846–863, 2019. doi: 10.1002/art.40884.

  • 2. Ringold S, Weiss PF, Beukelman T, DeWitt EM, et al: 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: Recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum 65(10):2499–2512, 2013. doi: 10.1002/art.38092.2013.

  • 3. Mehta J, Beukelman T: Biologic agents in the treatment of childhood-onset rheumatic disease. J Pediatr 189:31–39, 2017. doi: 10.1016/j.jpeds.2017.06.041.

Key Points

  • Juvenile idiopathic arthritis (JIA) encompasses a number of different chronic, noninfectious arthritides in children that differ in clinical and laboratory manifestations.

  • Suspect JIA in children with symptoms of arthritis, signs of iridocyclitis, generalized adenopathy, splenomegaly, or unexplained rash or prolonged fever.

  • Diagnose JIA clinically; use laboratory testing (of RF, anti-CCP antibodies, ANA, and HLA-B27) mainly to distinguish between forms.

  • Slow disease progression with methotrexate and/or biologic drugs (eg, etanercept, anakinra, canakinumab, tocilizumab) and treat symptoms with intra-articular corticosteroid injections and/or NSAIDs.

  • Treat iridocyclitis with ophthalmic corticosteroid drops and mydriatics, or systemic therapy if refractory.

Macrophage Activation Syndrome

Macrophage activation syndrome is hemophagocytic lymphohistiocytosis associated with juvenile idiopathic arthritis (JIA; particularly systemic JIA) and with several other rheumatic diseases (particularly adult-onset Still disease).

Macrophage activation syndrome is a severe, overwhelming, and life-threatening cytokine storm syndrome caused by an uncontrolled macrophage and T lymphocyte expansion. It occurs in 10% of children with systemic JIA.

Symptoms and Signs

Features macrophage activation syndrome include high, nonremitting fever, hepatosplenomegaly, generalized lymphadenopathy, rash, hemorrhagic manifestations, central nervous system dysfunction (including seizures and coma), and shock.

Diagnosis

Features that help distinguish macrophage activation syndrome from systemic JIA include the constant fever (unlike the intermittent daily fevers of JIA), constant rash (unlike the transient rash of systemic JIA), hemorrhagic manifestations, seizures, coma, and shock. Despite marked systemic inflammation, the erythrocyte sedimentation rate (ESR) is paradoxically depressed because of low fibrinogen levels.

Often, however, macrophage activation syndrome cannot be differentiated from active systemic JIA; discriminatory criteria have been developed and include ferritin > 684 ng/mL ( > 684 mcg/L) plus any 2 of the following:

  • Platelets ≤ 181,000/mcL (≤ 181 × 109/L)

  • Aspartate aminotransferase > 48 units/L (> 0.80 microkat/L)

  • Triglycerides > 156 mg/dL (> 1.76 mmol/L)

  • Fibrinogen ≤ 360 mg/dL (≤ 10.58 g/L)

Prognosis

Macrophage activation syndrome has a mortality rate of 8%, due to multiorgan failure.

Treatment

No consensus exists regarding specific treatment.

Macrophage activation syndrome may respond well to successful treatment of the underlying rheumatic disease. Specific treatment of this syndrome in systemic JIA usually includes high-dose corticosteroids and may include other drugs (eg, cyclosporine, interleukin [IL]-1 inhibitors, cyclophosphamide) and stem cell transplantation.

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