June 2003
Vol.10 No. 3

Editors: Dr. Sam SP Lau
Drs. Dr. Karen L Kwong, KY Wong

An Update in Juvenile Idiopathic Arthritis

Dr. TL Lee and Prof. YL Lau
Department of Paediatrics and Adolescent Medicine,
The University of Hong Kong, Queen Mary Hospital


Editor's Notes

JIA is a serious but fortunately uncommon condition (affecting only 75,000 children in the U.S.A.). The presentation in this article is clear, concise and readable. The message for practicing paediatricians is obvious; we need to recognize this disease early and to initiate appropriate procedures to assure comprehensive and continuous management in view of the serious long-term outcome of these unfortunate children.

Summary:

I. Definition and Classification of JIA

Juvenile Idiopathic Arthritis (JIA) is defined as presence of arthritis (swelling or effusion, or presence of two or more of the following signs: limitation of range of motion, tenderness or pain on motion, and increased heat) in one or more joints. The age at onset is less than 16 years old. The duration of arthritis lasts for 6 weeks or longer and other causes of arthritis (e.g. septic arthritis, malignancy) are excluded.

Chronic arthritis in children represents a heterogeneous group of diseases with unknown aetiology. Previously, there are two classification systems for chronic arthritis in childhood by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR). To classify these patients in more well-defined diagnostic categories, a task force of the International League Against Rheumatism (ILAR) proposed a new classification with precise criteria. The ILAR classification and its revision were proposed by an international group of paediatric rheumatologists (including experts from the United States, the United Kingdom, Canada, China, France, Australia, South Africa, Argentina and Mexico) with the aim of achieving as much homogeneity within categories as possible in order to facilitate communication and clinical research and patient care. The ILAR classification is shown in Table 1.

Table 1. ILAR classification criteria for the idiopathic arthritis of childhood


Disease (Onset type) Disease (Course subtype)
Systemic arthritis
Polyarthritis RF-
Polyarthritis RF+
Oligoarthritis Persistent Oligoarthritis
Extended Oligoarthritis
(>= joints after the first 6 months of disease)
Enthesitis-related arthritis
Psoriatic arthritis
Others

II. Prognosis and Outcome of JIA

From most outcome studies of JIA, active disease often persists into adult life in all subtypes of JIA. Several long term studies conducted from 1960s to 1990s showed that 31% to 55% patients with JIA have active disease when followed for at least 10 years. Persistently active disease is associated with poor outcome and long term disability. Active disease occurred most often in patients with extended oligoarthritis, polyarthritis and systemic arthritis. There are some studies identifying predictors of poor outcome early in the disease course. In oligoarthritis JIA, involvement of more than one joint, involvement of an upper limb joint, and elevated ESR at disease onset may predict an extended oligoarthritis, which carries a worse prognosis than persistent oligoarthritis. In polyarthritis JIA, rheumatoid factor positivity is associated with early erosive changes and is predictive of ongoing destructive arthritis. In systemic arthritis, disease that begins at 5 to 7 years of age and polyarthritis within the first 6 months of disease onset are associated with poor outcome. Persistent systemic symptoms, the need for corticosteroids to control systemic symptoms, and thrombocytosis (platelet >600 x109/dl) 6 months after disease onset predict severe destructive arthritis and poor functional outcome.

Chronic uveitis occurs in approximately 20% of patients with oligoarthritis JIA and in 5-10% of those with polyarthritis JIA. Potential complications include synechiae, band keratopathy, cataracts, glaucoma, and rarely phthisis bulbi (shrinkage of eyeball after uveitis). Recent studies report significant visual impairment in up to 30% of those with uveitis. The importance of ophthalmologic slit lamp examination at the time of diagnosis as well as the need for ongoing ocular surveillance cannot be overemphasized.

Two-thirds of death occurs in systemic arthritis and the most important causes are macrophage activation syndrome (MAS), infections (secondary to immuno-suppressive therapy), and cardiac complications. Macrophage activation syndrome belongs to one of the secondary haemophagocytic lymphohistocytosis syndromes in which patients develop sudden onset of sustained fever, generalized lymphadenopathy, hepatosplenomegaly, and bruising and mucosal bleeding, as a result of disseminated intravascular coagulopathy. The followings were shown to be the most sensitive and specific criteria for the diagnosis of MAS in a study of 88 children: serum ferritin (>= 10,000 mg/ml), triglycerides (>= 160 mg/dl), SGOT (>= 40 IU/ml), fibrinogen (>= 250 mg/dl), SGPT (>= 40 IU/ml) and gGT (>= 40 IU/ml).

III. State-of-art Management of JIA

A. Multi-disciplinary Approach
A coordinated multi-disciplinary team care consisting of paediatric rheumatologist, nurse specialist, social worker, physical therapist, occupational therapist, orthopaedic surgeon and clinical psychologist is the key to success of management of JIA. The aims of treatment are to preserve cartilage, control pain and preserve range of motion, muscle strength, and function; to manage systemic complications; to facilitate normal nutrition, growth, and physical and psychological development.

B. Medical Therapy
1. Non-steroidal Anti-inflammatory Medications (NSAIDs)
Traditional NSAIDs still constitute the first line therapy for most children with JIA. The COX-2 inhibitors (rofecoxib and celecoxib) do not inhibit production of gastroproductive prostaglandins and gastrointestinal side effects are less. Since COX-2 inhibitors reduce prostacyclin synthesis without platelet activation, it is postulated that in susceptible patients with a pre-existing prothrombotic state the COX-2 inhibitors may predispose to thrombosis. The potential adverse effects of nephrotoxicity and thrombosis are still not clarified.

2. Disease Modifying Anti-Rheumatic Medications (DMARDs)

a) Methotrexate (MTX)
Methotrexate remains remission-inducing agent of first choice for persistent and active arthritis. Most paediatric rheumatologists will initiate methotrexate therapy early in the disease course, sometime within 8 to 12 weeks of initiation of NSAID therapy in order to preserve the cartilage if the patient fails to respond to NSAIDs. The starting dose is recommended to be 15 mg/m2/week per oral route. Daily folic acid supplementation (1 mg/day) may alleviate the side effects of nausea, vomiting, gastrointestinal upset and mucosal stomatitis without compromising the therapeutic effect. If the response is inadequate, it could be stepped up with an increment of 2.5 mg/week. Subcutaneous route is advised if the dose reached 15-20 mg/week or more. The maximum dose is around 1 mg/kg/week (or total dose 30-40mg/week). Methotrexate may be discontinued after a sustained period of improvement and remission.

Most studies have demonstrated no severe liver damage in children taking methotrexate for extended periods. There is no clear evidence that methotrexate increases the risk of malignancy in children. Methotrexate is teratogenic and adolescent patients are advised about prevention of pregnancy and total abstinence from alcohol drinking.

The patients should be informed of the nature, toxicities, precautions, expected duration of therapy and subcutaneous injection technique. Combined care with a paediatric rheumatologist is desirable in terms of assessment of underlying arthritis, patient counselling, fine titration of methotrexate and anticipatory planning in case of methotrexate failure (around 15-20%) in order to avoid patient frustration and poor drug compliance as a consequence.

b) Corticosteroid

  1. Systemic Corticosteroid
    Moderate or high dose systemic corticosteroid therapy should be reserved for patients with systemic arthritis with severe systemic symptoms that cannot be controlled with NSAID, such as macrophage activation syndrome, symptomatic serositis and myocarditis. For all other subtypes of JIA, even low dose corticosteroid should be used selectively because the potential toxicity may outweigh any long-term benefits for articular disease.
  2. Intra-articular Corticosteroid Injection
    Intra-articular corticosteroid is safe and effective treatment in managing synovial inflammation in a child with monoarticular or oligoarticular arthritis. It is sometimes indicated in treatment of particular symptomatic joints in a child with polyarticular arthritis. It provides sustained anti-inflammatory effect on synovium lasting at least 6 months in most cases. It has been shown by magnetic resonance imaging studies that intra-articular steroid therapy resulted in significant suppression of inflammation and pannus formation while cartilage integrity is well preserved.

c) Sulphasalazine (SSZ)
There are studies showing efficacy of SSZ in some forms of JIA at doses 30-50 mg/kg/day (maximum dose 2000 mg/day). The adverse effects are gastrointestinal intolerance, rash, leukopenia and hypogamma-globulinemia. They are shown to be particularly effective in late-onset oligoarthritis group and patients with spondylitis. Since there are reports of association of SSZ with MAS in patients with systemic arthritis, they should not be prescribed to this patient sub-group.

d) Hydroxychloroquine (HCQ)
A number of studies have documented the symptomatic benefit of HCQ particularly for patients with early and milder disease. Rash, abdominal cramps, and diarrhoea are infrequent adverse effects. HCQ is generally well tolerated and requires no routine laboratory monitoring, although patients need periodic ophthalmologic examinations for early detection of reversible retinal toxicity. It is accepted that at doses of less than 6.5 mg/kg/day adverse effects in the retina are unlikely. The risk of retinal toxicity is increased when the dose exceeds 6 mg/kg or the medication has been given for more than 10 years. Vision changes, fundoscopic and visual fields examination every 12 months is advised. The length of time to benefit may vary from 1 month to as long as 6 months.

e) Combination DMARD Therapy
If conventional treatment with a single DMARD fails to adequately control clinical symptoms or to prevent disease progression. Rheumatologists are increasingly prescribing combination DMARD therapy. In such cases, rheumatologist referral is strongly recommended for patients being considered for initiation of combination therapy. Early open-label studies showed promising results, but often there was increased toxicity. Cyclosporine plus MTX was found to be more effective than MTX alone, but long-term follow-up revealed the development of hypertension and elevated creatinine levels. A randomized controlled clinical trial has demonstrated that the triple-DMARD combination of MTX, HCQ, and SSZ has substantially increased efficacy compared with MTX alone and with the combination of HCQ plus SSZ, without increased toxicity in adult studies. The efficacy of this 3-DMARD combination without the occurrence of additional toxicity was confirmed in another randomized trial. Recently, the triple-DMARD combination of MTX, SSZ, and HCQ has been shown to be superior to the double-DMARD combinations of MTX plus SSZ or MTX plus HCQ in both early and more advanced RA. Since there are no such controlled studies in JIA, paediatric rheumatologists borrowed their results and use triple combination DMARD therapy (MTX + SSZ + HCQ) in persistent arthritis despite MTX monotherapy.

f) Other Medications

  1. Cycloporine A (CsA)
    There are no controlled trials on the use of CsA in JIA treatment. A few open studies suggest that it may have a role in the treatment of systemic symptoms of systemic-onset JIA and steroid sparing effect but less convincing efficacy for arthritis control. The usual dose is 3-5 mg/kg/day. Adverse effects include hypertension, hand tremor, impaired renal function, gingival hyperplasia and hypertrichosis.
  2. Cyclophosphamide
    Cyclophosphamide is not used commonly for JIA. Benefit has been shown from 12-20 intravenous pulse cyclophosphamide with intravenous methy-prednisolone for refractory severe JIA.
  3. Leflunomide
    This medication has been shown in preliminary studies to be safe and statistically more effective than placebo in children. Headache, diarrhoea, abdominal pain, elevated liver enzymes, reversible hair loss and skin rash are the reported side effects. A controlled trial of leflunomide has been initiated.
  4. Biologic Agents
    1. TNF Inhibitors
      The tumour necrosis factor (TNF) inhibitors, etanercept and infliximab, have shown promising results in the treatment of refractory JIA. The safety profile of etanercept is satisfactory. Adverse effects include injection site reaction, increased upper respiratory tract infections and rashes. There are no controlled studies of the use of infliximab in children.
    2. Anakinra
      Anakinra is a recombinant form of agonist to interleukin-1 receptor (IL-1Ra) and its use in arthritis treatment is associated with reduction in mononuclear cell infiltration of the synovial membrane.
    3. Other Biologic Agents
      Other potential biologic agents that look promising in treatment for inflammatory joint disease include monoclonal antibodies to interleukin-10, interferons and agents that diminish the effect of interleukin-6.
    4. Remarks
      However, these biologic agents are prohibitively expensive and they are not available in Hong Kong yet. It is hoped that children with refractory JIA in Hong Kong can benefit from these new agents when they are available locally and the price goes down to reasonable level.
  5. Autologous Stem Cell Transplantation (ASCT)
    Despite the emergence of new therapeutic agents which appear to be more effective in treating JIA, there surely will still be some patients who remain resistant to medical therapies. Autologous stem-cell transplantation (ASCT) may be the final alternative therapy for this group of patients. Reports of good response of children with JIA to ASCT have been published. A comprehensive review of the international experience with ASCT to treat JIA reported 5 mortalities among 36 children treated. In another Dutch study, in which 18 patients with refractory JIA underwent transplantation, 8 were drug-free (follow up of 24 to 58 months) with normal ESR and C-reactive protein. Four children showed partial response. Four children relapsed and 2 initial cases died from MAS. After modification of induction therapy with less profound T-cell depletion prior to ASCT and a slower tapering of steroids following ASCT, there had been no further deaths. We have also performed autologous stem cell transplantation for a 10-year-old girl with refractory JIA in 2001. After transplantation, all medications were able to be stopped and she remained in full remission in terms of symptoms, joint inflammation and laboratory inflammatory markers during 18-month follow-up period. At present, this treatment should be considered experimental and should be only reserved for those patients who have most severe disease unresponsive to standard treatment.

IV. Conclusion

Progress in achieving international consensus concerning the classification of JIA has been made in order to facilitate more effective international collaboration in the study of these diseases. There are many promising developments in the understanding and improved treatment options in JIA. In order to prevent long term disability, earlier and more aggressive therapy is advised for those with persistent arthritis. A multidisciplinary team approach is very important in management of JIA. It is hoped that with increased awareness of the long term morbidity of JIA and the availability of new treatment options in JIA, the outcome of patients with JIA could be further improved.

References

  1. Petty RE, Southwood TR, Baum J, et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 1998;25:1991-4.
  2. Schneider R, Passo MH. Juvenile rheumatoid arthritis. Rheum Dis Clin North Am 2002;28:503-30.
  3. Hull RG. Guidelines for management of childhood arthritis. Rheumatology (Oxford) 2001;40:1309-12.
  4. Manners PJ. State of the art: Juvenile idiopathic arthritis. APLAR J Rheumatol 2002;5:29-34.

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