Aquaretic treatment in polycystic kidney disease.

n engl j med 367;25 nejm.org december 20, 2012 2440 create an imbalance in the cytokine network, thereby driving or unmasking previously uncommon complications. The occurrence of pulmonary hypertension in one patient who received canakinumab and in two who received tocilizumab is notable, in light of a recent report of a significantly increased frequency of pulmonary hypertension in children with systemic JIA treated with a number of different therapies, including anti–interleukin-1 and anti– interleukin-6.7 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. It is interesting that the participants in these trials had marked similarities in the magnitude and timing of their responses, suggesting that interleukin-1 and interleukin-6 may be in the same pathway in systemic JIA. In contrast, there is anecdotal evidence that some patients have a response to anti–interleukin-1 but not to anti– interleukin-6, and vice versa, which is consistent with the complexity of proinflammatory cytokine networks.8 The partial or absent responses in a significant minority of patients in the trials of both canakinumab and tocilizumab suggest that genetic or environmental factors may result in different subsets of systemic JIA. Alternatively, there may be an early therapeutic window of opportunity during which higher response rates can be achieved,9 or inflammatory “escape” pathways may be activated because of the presence of these inhibitors. The search for the most proximal step that can be targeted in the inflammatory cascade will undoubtedly continue. 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.