Juvenile Idiopathic Arthritis
To more accurately assess the incidence of childhood arthritis and to better understand its etiology, it is necessary to both more rigorously and more inclusively define the diseases which cause arthritis in children. As a result, the older term juvenile rheumatoid arthritis (JRA) is being replaced by the term juvenile idiopathic arthritis (JIA). JIA will incorporate all of what has been called JRA in the past, but also will incorporate all other forms of "idiopathic" arthritis in childhood. JIA has classically been divided into three subsets based upon associated symptoms and the number of joints involved:
- Systemic-onset JIA (formerly called Still's disease) referred to patients with rash and intermittent fever, in addition to arthritis of any number of joints. It is responsible for about 10 to 15 percent of JIA cases.
- Pauciarticular-onset JIA includes those patients with involvement of fewer than five joints after six months of illness. It accounts for approximately 50 percent of cases of JIA. However, it is now recognized that this disease consists of several distinct subgroups with varying prognosis.
- Polyarticular-onset JIA is defined by the involvement of more than four joints after six months of illness. It is responsible for 30 to 40 percent of cases of JIA. As with pauciarticular-onset JIA, it is now recognized to contain many distinct subgroups with varying prognosis.
Although this classification serves to categorize patients into subsets with differing disease course and prognosis, it has long been recognized that subgroups existed within these distinctions and that many children were not adequately categorized.
Systemic arthritis defines the subset of patients that were previously called systemic-onset JRA or Still's disease. These patients will be further classified on the basis of the following descriptors: age at onset, duration and pattern of arthritis and the presence or absence of antinuclear antibodies (ANA) and rheumatoid factor, Children with clearly identifiable syndromes associated with fever and arthritis, such as polyarteritis nodosa, are considered separately. Although psoriatic arthritis is usually seronegative for rheumatoid factor, a family history of psoriasis is a specific exclusion in patients with rheumatoid positive disease for the diagnosis of polyarthritis. This distinction may be confusing for the clinician, but the distinction is important for entry into investigational trials, as it is crucial to have well-defined groups of patients entered into studies. There are several areas of confusion like this. It is important for clinicians to remember that all of these children can be diagnosed accurately as having JIA. Another example of a large group of children who clearly have arthritis but cannot be adequately categorized, incorporates children with spondyloarthropathies. At present, children with ANA, rheumatoid factor, or inflammatory bowel disease are specifically excluded from some clinical studies. However, it is well recognized that children with enthesitis associated arthritis may be ANA positive. All children with idiopathic arthritis of childhood have JIA.
Treatment
- Nonsteroidal antiinflammatory drugs (NSAID): none has shown any unique advantages for children with systemic onset JRA. If NSAIDs are used, careful monitoring is required. Celecoxib and Meloxicam are proven effective for children with systemic onset disease and having good gastric and intestinal tolerance. Sulfasalazine may be beneficial in selected cases. The usual dosage range is 30 to 50 mg/kg per day (up to 2 grams/day) given twice a day. Corticosteroids have to be used judiciously in systemic onset JRA to minimize toxicity. They may be necessary during the acute phase of the illness to preserve the ability to carry out activities of daily living, particularly in children who have not responded to a 6 to 12 week trial of NSAIDs. Every effort must be made to minimize the dosage and duration of therapy. The dosage of corticosteroids should be kept below 0.5 mg/kg per day of prednisone (or its equivalent) and the duration of therapy should be less than six months. Optimally, initiation of a disease modifying agent more appropriate for long-term management (like methotrexate or a biologic agent) should be initiated soon after the child is stabilized in order to facilitate the timely withdrawal of corticosteroids.
- Hydroxychloroquine (Plaquenil), has been used in children with systemic onset JRA. Many children improve while receiving hydroxychloroquine. Whenever hydroxychloroquine is used, it is important to keep the dose under the recommended 6.5 mg/kg per day in order to minimize the risk of potentially retinal toxicity, particularly in patients who weigh less than (or whose ideal body weight is less than) 31 kg. For these smaller patients, caregivers must carefully divide as accurately as possible the 200 mg tablets in which hydroxychloroquine is available to administer the appropriate dosage. Pharmacists can provide hydroxychloroquine in a liquid form for small children who are unwilling or unable to swallow tablets, or if it is too difficult to split the tablets to reliably administer the correct dosage. Methotrexate is effective for the control of disease manifestations in many children with systemic onset JRA. Hepatic toxicity may occur, but does not seem to be any more frequent than expected with the use of methotrexate in other subtypes of JRA. Appropriate clinical and laboratory monitoring is essential for patients treated with methotrexate. Most pediatric rheumatologists are comfortable administering methotrexate at an oral dose of 10 to 15 mg per week. Above this dose, oral absorption is unreliable and injectable administration is preferred. Folic acid should be given to minimize the gastrointestinal side effects associated with methotrexate therapy.
- Biologic anti-cytokine therapy: In general, TNF inhibitors are more beneficial for children with polyarticular disease than in those with systemic JRA. This difference may be due to different cytokines underlying the inflammatory response for each respective disorder. IL-6 and IL-1 rather than TNF-alpha may be the predominate proinflammatory cytokines in systemic JRA. Thus, biological agents that target IL-1 and IL-6 activity, such as anakinra and thalidomide, appear to be successful in treating patients with systemic JRA . Alternatively, the fixed doses of etanercept that have been used may be inadequate to inhibit TNF sufficiently to produce a robust response in systemic JRA. Other TNF inhibitors, such as infliximab or adalimumab, offer a wider range of dosing choices, and indeed high doses of this medication may be more effective for treating systemic JRA. Over a 10-year period (1998 to 2008), 30 cases of malignancies (half of which have been lymphomas) in children treated with a TNF inhibitor have been reported to the Food and Drug Administration (FDA) Adverse Event Reporting System. Based upon these reports and the uncertainty of a possible association between these agents and cancer, the FDA has initiated an Ongoing Safety Review. Pending the results of this investigation, the FDA has stated that clinicians, patients and parents should be aware of the possible association of these agents and malignancies but the "potential benefits of these agents may outweigh the potential risks in certain children and young adults having one of the diseases for which the TNF blockers are approved to treat". At the current time, we suggest that TNF inhibitor be used in patients with severe disease that is refractory to conventional therapy. In addition, there may be an increased risk of fungal infections with the use of these agents. In September 2008, a FDA alert highlighted this potential risk especially in endemic areas of histoplasmosis, such as the Ohio and Mississippi River valleys.