Diagnosis and management of juvenile idiopathic arthritis

History

After queries about joint pain and swelling (including previous episodes), ask patients and parents about morning stiffness that lasts for more than 15 minutes but improves during the day.7 9 Parents, other family members, or teachers may have noticed problems with, for example, walking, running, climbing stairs, standing up, writing, or sleeping. The child might need help with daily activities that were previously performed independently. Also ask about autoimmune disease in relatives, and in suspected psoriatic arthritis and enthesitis related arthritis (table 1) ask about specific family history.3 ^w7 Lastly, ask about any systemic features such as rash or intermittent pyrexia (see table 1).

Physical examination

Examine all joints for pain or tenderness, swelling, limited movement, decreased strength or muscle atrophy, and bony deformity.7 9 Observe the child while walking, standing up, sitting down, or climbing on to the examination table. In a general examination look for features such as lymphadenopathy, organ enlargement, systemic rashes, nail abnormalities, psoriatic rash, or enthesitis. Always measure growth parameters. Eyes should be checked by an ophthalmologist for uveitis.

Clinical features

Clinical features strongly depend on the subtype and differ in age at onset of disease, number and location of joints involved, disease course, presence of antinuclear antibodies or rheumatoid factor, presence of chronic or acute uveitis, presence of systemic features, and HLA allelic associations (table 1).^w8 Patients with oligoarthritis (one to four joints affected in first six months of disease) usually present with arthritis in the knees, ankles, or elbows rather than the hips. Chronic anterior uveitis develops in a fifth of these patients and most will be antinuclear antibody positive.10 ^w8 Most patients with polyarthritis (five or more joints affected in first six months) present with symmetrical arthritis in large and small joints and less commonly with uveitis. ^w8 Onset may be acute or insidious. Systemic disease is characterised by fever with one or more daily spikes for at least three days. As well as arthritis, which affects a variable number of joints, there are systemic features (table 1).3 Arthritis may start weeks or even years after the onset of systemic features and can present as a single episode or become persistent. Patients with enthesitis related arthritis can present with oligoarthritis or polyarthritis of the large or small joints as well as enthesitis (table 1).3 ^w8 Patients who also have psoriasis, a history of psoriasis in a first degree relative, nail pitting, or dactylitis will probably have psoriatic arthritis unless rheumatoid factor is positive.3 ^w8

Further investigations

Other investigations for all subtypes include laboratory tests—a full blood examination, inflammatory markers (erythrocyte sedimentation rate, C reactive protein), and autoimmune markers (rheumatoid factor, HLA B27, and antinuclear antibodies)—and imaging studies.7 9 Radiography can detect narrowing of the joint spaces or erosions and might show maturation differences or growth abnormalities in bones from an early stage.^w9 Magnetic resonance imaging studies can also show inflamed synovium and increased joint fluid.^w9

Referral

Refer all children with suspected or confirmed juvenile idiopathic arthritis to a paediatric rheumatologist as soon as possible to prevent delay in treatment. A cohort study of 128 patients with juvenile idiopathic arthritis and a placebo controlled trial showed that time to treatment is an important factor in response to treatment.11 12

Old versus new approach to treatment

In the past, juvenile idiopathic arthritis was treated with non-steroidal anti-inflammatory drugs (NSAIDs), with delayed addition of synthetic disease modifying antirheumatic drugs (DMARDs) or systemic corticosteroids (or both), and lastly biological DMARDs. However, accumulating evidence from cohort studies and trials has shown that a more aggressive approach to disease control, with earlier introduction of DMARDs, prevents or minimises long term sequelae of the disease.11 12 16 Existing guidelines on care have not been revised to include such advice but do advocate “tight” clinical control.2 ^w16

Drug treatment

Up to date international guidelines are currently lacking. The British Paediatric Rheumatology Group provided guidelines for the management of childhood arthritis in 2001,21 but because treatment is changing rapidly, this guideline needs revision. A recent guideline from the Royal Australian College of General Practitioners focuses on NSAID treatment only.9 New recommendations for the treatment of juvenile idiopathic arthritis were presented at the American College of Rheumatology 2010 November meeting but have not been published yet. They are based on studies also mentioned in this review and on expert opinions when evidence is lacking. The treatment modalities we describe are based on randomised controlled trials, case series, and cohort studies. The figure⇓ outlines a simplified approach to treatment.

Simplified approach to treatment of patients with juvenile idiopathic arthritis. Steps often rapidly succeed one another or are combined. DMARDs, disease modifying antirheumatic drugs; IAS, intra-articular steroids; IL, interleukin; NSAIDs, non-steroidal anti-inflammatory drugs; TNF, tumour necrosis factor

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Non-steroidal anti-inflammatory drugs

During diagnosis, while other causes of arthritis are being excluded, most patients are given NSAIDs. These drugs relieve pain usually within a few days and do not, as more aggressive treatments can, interfere with the disease course in case of misdiagnosis. Several NSAIDs are used, and none has proved to be superior to another.22 Recent randomised trials found that the newer cyclo-oxygenase-2 inhibitors (rofecoxib, celecoxib, and meloxicam) were no more effective or safer than the most commonly prescribed NSAID, naproxen.^w17-w19 More than half of patients achieved an ACR pediatric 30 response (box 2) after three months of NSAID monotherapy, an NSAID added to a stable dose of a synthetic DMARD, or biological DMARD treatment, although these responses were not compared with placebo.^w17-w19

Corticosteroids (intra-articular and systemic)

Children with oligoarticular disease are often given NSAID monotherapy, intra-articular corticosteroids alone, or a combination of both. Intra-articular corticosteroids are increasingly being used, and earlier in the disease course. In a retrospective study of 121 injected joints, all joints responded within one week, and after one year 52% were still in remission.w20 A randomised double blind trial confirmed this rapid and long lasting effect and showed that triamcinolone hexacetonide is superior to triamcinolone acetonide (85% of joints still in remission after one year) and should be the drug of first choice.23 Skin atrophy at the injection site occurred in 2.3% of the treated joints.23 The systemic absorption of triamcinolone, which peaks at eight hours after injection, is usually not clinically relevant, although cases of Cushing’s syndrome and transient increases in blood glucose in patients with diabetes have been reported after intra-articular injection.^{w21 w22}

The long term use of systemic corticosteroids has declined because of side effects, particularly reduced growth and bone health.w12 These drugs are mainly used while waiting for DMARDs to take effect and in patients with severe systemic or polyarticular juvenile idiopathic arthritis unresponsive to treatment with synthetic and biological DMARDs.22 w7

Synthetic disease modifying antirheumatic drugs

Patients with a definite diagnosis of polyarticular disease or oligoarticular disease refractory to intra-articular steroids are candidates for second line agents (DMARDs). Table 2⇓ lists the typical doses, side effects, and contraindications of such drugs used in juvenile idiopathic arthritis.

Methotrexate is the most widely used and first choice synthetic DMARD. A randomised placebo controlled trial (127 patients), a randomised placebo controlled crossover trial (43 patients with extended oligoarticular arthritis), and a dose finding trial (80 patients, mostly unresponsive to low dose methotrexate) found it to be effective—with significant reductions in active and limited joint counts, and high overall improvement—in patients with polyarticular and oligoarticular extended disease.24 w23 w24 However, it produced no overall improvement in systemic disease—the most difficult subtype to treat.24 It is unclear how long after remission methotrexate should be withdrawn; a recent randomised clinical withdrawal trial found no differences in relapse rates in patients who continued the drug for six or 12 months (57% v 56%) after induction of remission.w25

A randomised placebo controlled trial (69 patients) also found sulfasalazine to be effective in the management of juvenile idiopathic arthritis, with a higher response rate than placebo (69% v 45%) after 24 weeks of treatment.25 However, the drug was not well tolerated, and nearly a third of patients discontinued treatment.25 With the development of newer biological DMARDs, the use of sulfasalazine has decreased. In a relatively small randomised controlled trial, leflunomide was found to be less effective than methotrexate but with similar adverse event rates.26 There are no controlled studies of ciclosporin A in juvenile idiopathic arthritis, although small case series show a beneficial effect in severe systemic disease.w26 w27 A large observational study of 329 patients treated with ciclosporin A found a 9% complete response rate; most patients discontinued the drug because of inefficacy.w28 Case series have shown that ciclosporin A might be effective in macrophage activation syndrome.w29 w30 The use of leflunomide and ciclosporin A in juvenile idiopathic arthritis is limited. Other synthetic DMARDs (auranofin, penicillamine, and hydroxychloroquine) have not been shown to have a significant therapeutic advantage over placebo, in contrast to findings in adult patients with rheumatoid arthritis.w31 w32

Biological disease modifying antirheumatic drugs

With the introduction of biological DMARDs (also know as biologicals or biologics) the goal has shifted from reducing inflammation to “switching off” the autoimmune system by targeting inflammatory cytokines. Table 3⇓ lists the biological DMARDs currently available or under investigation for juvenile idiopathic arthritis.

Tumour necrosis factor is a proinflammatory cytokine that plays a central role in the pathogenesis of juvenile idiopathic arthritis.^w33 In systemic disease, interleukin 1 (a proinflammatory cytokine synthesised by fibroblasts in the synovium and macrophages) and interleukin 6 (concentrations of which correlate with fever, disease activity, and platelet counts) are also thought to be important.w33-w35 If inhibition of these cytokines is not sufficient, other drugs aimed at T cell blockade and B cell depletion are available.w36 Only etanercept, adalimumab, and abatacept have been approved by the European Medicines Agency and the Food and Drug Administration for the treatment of juvenile idiopathic arthritis after testing in placebo controlled withdrawal trials.27 28 29 These trials are designed so that all patients start the drug in an initial open label part of the trial. Those with an ACR pediatric 30 response to treatment (box 2) enter a double blind study and are randomly assigned to receive placebo or the biological DMARD until the disease flares. The response rates (ACR pediatric scores) reported from these trials come from the open label phase and represent the initial responders.^w37 Results from the randomised blinded phase are presented as flare rates. This design is used in paediatric rheumatology trials to minimise the consequences of placebo treatment.

Other biological DMARDs are prescribed off label, although some (infliximab, anakinra, tocilizumab) have been tested in patients with juvenile idiopathic arthritis in placebo controlled withdrawal trials (table 3).^w38-w40 Choice of biological DMARD is based on effectiveness, safety, route of administration, and arthritis subtype.

Etanercept was the first and for a long time the only registered biological DMARD for the treatment of juvenile idiopathic arthritis; 74% of patients previously resistant to other drugs, including methotrexate, met the ACR pediatric 30 target after three months in the placebo controlled withdrawal trial.27 Many observational studies have provided data on safety and response; the drug seems to be well tolerated and effective.^w41-w46 It is the most commonly prescribed biological DMARD for patients with this disease, followed by adalimumab. A prospective registry study found that etanercept reduced disease activity and improved quality of life in all aspects affected by the disease.17 A health related quality of life study of abatacept showed similar results.w47 A placebo controlled withdrawal trial showed that abatacept was effective in patients for whom anti-tumour necrosis factor was not effective (ACR pediatric 30 response in 39%), thereby providing a valuable alternative treatment.29

The treatment of systemic disease is challenging.15 In a controlled clinical withdrawal trial and case series anakinra seemed to be better than etanercept in reducing systemic symptoms.15 ^{w38 w48-w50} Other biological DMARDs (table 3) have shown promising results in clinical trials or case series. No head to head trials on choice of biological DMARD exist for these patients. Today, most experts favour anakinra when systemic features are prominent, but the timing of this treatment is debatable.30 More studies on management of systemic arthritis are needed.

The most commonly encountered adverse events of biological DMARDs are local reactions at injection sites and opportunistic infections.31 w51 Most injection site reactions resolve as a result of tolerance. Consult a paediatric rheumatologist if the drug has to be discontinued because of a serious infection. Less commonly encountered but important adverse events are neurological or neuropsychological disorders, new onset autoimmune diseases, and cancer. The most common cancers reported related to anti-tumour necrosis factor treatment are hepatosplenic T cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and leukaemia, although there is no convincing evidence of an increased risk.31 w52 w53 Similarly, although safety studies with long term follow-up have shown new onset of the above complications in patients taking biological DMARDs, we have insufficient data to compare incidence rates in patients taking biological DMARDs with those in patients not taking biological DMARDs.^w41-w46 If one of these conditions is suspected in a patient taking a biological DMARD or other immunosuppressive drug, consult the treating paediatric rheumatologist immediately to discuss discontinuing the drug. Box 3 provides recommendations for safety and monitoring of DMARDs.

Other treatments

Depending on the subtype and severity of disease, the British Society for Paediatric and Adolescent Rheumatology standards of care recommends regular checks by a paediatric rheumatologist, ophthalmologist, dermatologist, orthopaedic surgeon, orthodontist, general practitioner, psychologist, and physiotherapist or occupational therapist. The idea is that a well chosen multidisciplinary team will enable the best possible care.2

A Cochrane review has shown that physiotherapy is important to maintain normal muscle and joint function.^w63 Rehabilitation—using heat or cold treatment, massage, therapeutic exercise, and splints—is crucial to returning to activities of daily living again once these have been limited by disease.9 The British Society for Paediatric and Adolescent Rheumatology standards of care guideline also recommends psychological therapy and education.2

Supplements may be needed to prevent certain side effects of treatment. During corticosteroid treatment patients are at increased risk of osteoporosis and osteopenia. Several studies, including a randomised clinical trial, found a small but significant beneficial effect of calcium and vitamin D supplements on bone mineral density.^{w64 w65} Children using methotrexate might benefit from folic acid supplements. Although evidence that weekly folic acid reduces methotrexate related adverse effects in children is weak, studies in adults with rheumatoid arthritis have shown significant effects.^{w66 w67}

Autologous stem cell transplantation was used in autoimmune diseases before biological agents were available, and several patients with juvenile idiopathic arthritis have been successfully transplanted. ^{w68 w69} However, because of the risks involved (9% transplant related mortality) and relatively high relapse rates (>30%), this treatment is reserved for patients who are resistant to combinations of synthetic DMARDs, corticosteroids, and biological DMARDs and who have severe, debilitating, and potentially fatal disease.