UnDRESSing Systemic Juvenile Idiopathic Arthritis Lung Disease

One of the current pressing issues facing pediatric rheumatologists is obtaining a better understanding of the cause and treatment of systemic juvenile idiopathic arthritis lung disease (JIA-LD). Systemic JIA-LD can be a progressive, fatal complication with features of endogenous lipoid pneumonia, pulmonary alveolar proteinosis, and interstitial lung disease. Because our perception that this complication of systemic JIA was previously unheard of prior to its first reports in 2013 (1), a very natural hypothesis that some new environmental exposure must be generating a new complication of an old disease has been forwarded. An obvious candidate, the use of interleukin 1 (IL-1) blocking and other biologic agents for the treatment of systemic JIA, which began in the mid-2000s (2), has been proposed. Some of the initial literature focusing on systemic JIA-LD has suggested that the complication is associated with eosinophilia, reports of drug intolerance symptoms, and HLA–DRB1*15:01 carriage (3–5). Taken together, these findings have been suggested to represent a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome that leads to lung inflammation and progression of systemic JIA-LD. Yet, many features of systemic JIA-LD are not reminiscent of DRESS syndrome, and many of the features used by the Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria for DRESS syndrome overlap with the exact features present in active systemic JIA. This raises the specter that DRESS syndrome may not be the best explanation for systemic JIA-LD, and thus alternatively the cytokine plasticity hypothesis has been offered. This hypothesis posits that cytokine blockade in systemic JIA redirects cytokine mediated CD4 T cell fate choices in a manner that leads to systemic JIA-LD (6). Importantly, direct evidence for either DRESS syndrome or cytokine plasticity as a causal factor is lacking. The implications are not trivial, as it may change choice of therapy, or even starting a therapy based on HLA risk stratification. If the hypothesis that a drug-linked causal factor is not correct, an inappropriate choice might be made, denying children an otherwise effective therapy. Importantly, some implications of these hypotheses might be testable through observational data. In the case of the DRESS syndrome hypothesis, one would predict that eosinophilia should temporally follow drug exposure. Likewise, if DRB1*15:01 is the risk allele for such a reaction, carriage rates in the systemic JIA-LD drug-exposed populations should be higher than in the non-systemic JIA-LD population. Articles by Lerman et al (7) and Womba et al (8), included in this issue of Arthritis Care & Research, test these hypotheses using retrospective data and conclude that neither of these predicted observations are true. Lerman and colleagues show that eosinophilia precedes drug therapy in 43% of patients with systemic JIA (7). This suggests eosinophilia is a feature of the disease rather than drug reaction. The authors point out that many of the RegiSCAR criteria for DRESS syndrome overlap with features that are part of systemic JIA itself. It appears eosinophilia is yet an another one of these features. In agreement with this observation, Wobma et al find that eosinophilia is common and equally prevalent in systemic and nonsystemic JIA patients using IL-1 or IL-6 inhibitors and that eosinophilia may be a marker of more severe disease (8). These data are in keeping with the idea that systemic inflammation may be responsible for, or at least associated with, eosinophilia rather than acting as a marker of drug reaction. Since patients with more severe systemic disease are more likely to be treated with biologic therapy, these factors will be highly confounded with each other. The DRB1*15:01 major histocompatibility complex (MHC) allele has also been implicated as a potential causal mechanism for systemic JIA-LD. This possibility was also explored in the aforementioned studies. Wobma et al find that the MHC haplotype does not statistically associate with eosinophilia (8). Furthermore, Lerman et al show that DRB1*15:01 is enriched in systemic JIA more broadly, perhaps as a risk factor for severe disease, but not