|Vol.10 No. 3|
Editors: Dr. Sam SP Lau
Dr. TL Lee and Prof. YL Lau
Department of Paediatrics and Adolescent Medicine,
The University of Hong Kong, Queen Mary Hospital
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.
New classification of JIA is implemented to enhance more homogeneous subgroup of patients for treatment and research outcome comparison.
Multi-disciplinary approach and patient education is the key to success in management of JIA.
Diagnosis of JIA is based mainly on clinical ground and there is a list of differential diagnoses.
Regular uveitis screening is mandatory in order to prevent sequel of visual impairment in the long term.
It is important to diagnose early, treat early and be aggressive early if necessary.
Methotrexate is the first choice of second line disease modifying anti-rheumatic medication when NSAID fails.
Intra-articular steroid injection is an effective and safe modality of treatment.
Systemic corticosteroid should be avoided in most cases of JIA except systemic arthritis.
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)|
(>= joints after the first 6 months of disease)
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).
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.
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
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.
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