Systemic juvenile idiopathic arthritis (JIA) is a chronic disease that takes a real toll on its young patients. In addition to painful, arthritic swelling and stiffening of some of their joints, these children experience whole-body (systemic) symptoms such as fevers, rashes, enlarged lymph nodes and anemia. Patients' blood shows elevated levels of inflammatory markers, signaling that inflammation plays an important, though poorly understood, role in the disease.
The most severe form of the disease, systemic JIA can be extremely difficult to treat. That's why the medical community is closely watching reports of two new potential drugs for the disease, whose Phase 3 trials were published this week in the New England Journal of Medicine. The drugs, called canakinumab and tocilizumab, inhibit interleukin-1 beta and interleukin-6, respectively. The interleukin molecules are part of the body's inflammatory response.
In an accompanying editorial (subscription required), two Stanford rheumatologists describe the promise and challenges of these drugs. The doctors, Christy Sandborg, MD, and Elizabeth Mellins, MD, note that the drugs produced remarkable reductions in the frequency of patients' fevers and the severity of other JIA symptoms, with more than 70 percent of patients hitting the benchmark that the study scientists had set for evaluating the medications' success. Many patients were also able to reduce their use of the steroid hormones (glucocorticoids) they take to manage the disease, a desirable outcome because of glucocorticoids' many side effects.
However, as the editorial also explains, it will be quite challenging to figure out the safety profile of the new drugs. Based on their assumed mechanisms, these drugs could increase patients' risk of infection, neutropenia and liver dysfunction. These drugs' safety will be more complicated than most to evaluate, for several reasons: systemic JIA is rare, so it's challenging to assemble enough patients to study; the patients' disease is complicated, making it difficult to tease apart drug side effects from the effects of the disease itself; and the patients are usually taking several medications.
Sandborg and Mellins conclude:
To address the challenge of evaluating long-term and infrequent adverse events that occur with these therapies, new approaches are needed, such as consolidated disease registries designed to evaluate safety signals in the context of the underlying disease and exposure to multiple agents.
Despite important remaining questions about regulation of inflammation, the pathogenesis of systemic JIA, and appropriate interventions, there is no doubt that the agents tested in these trials signal a new era in the treatment of systemic JIA and will shed light on the mechanisms driving this enigmatic disorder. Continued investigation of systemic JIA is likely to inform our understanding of other multigenic autoinflammatory diseases — a growing category that now includes type 2 diabetes and inflammatory bowel disease — as well as our understanding of the regulation of inflammation.