The Conundrum of Lung Disease and Drug Hypersensitivity‐like Reactions in Systemic Juvenile Idiopathic Arthritis

Abstract

An unusual form of lung disease has begun to affect some children with systemic juvenile idiopathic arthritis (JIA), coincident with increasing utilization of interleukin‐1 (IL‐1) and IL‐6 antagonists. Many children with systemic JIA–associated lung disease (SJIA‐LD) have a history of clinical and laboratory features resembling drug reaction with eosinophilia and systemic symptoms (DRESS), a presentation now convincingly associated with HLA–DRB1*15. Treatment of DRESS typically requires drug discontinuation, a daunting prospect for clinicians and families who rely upon these agents. Here we review SJIA‐LD and its associated DRESS‐like phenotype. We suggest an alternative explanation, the cytokine plasticity hypothesis, proposing that IL‐1 and IL‐6 blockers modulate the milieu in which T cells develop, leading to a pathologic immune response triggered through exposure to common microbes, or to other exogenous or endogenous antigens, rather than to the drugs themselves. This hypothesis differs from DRESS in mechanism but also in clinical implications, predicting that control of pathogenic T cells could permit continued use of IL‐1 and IL‐6 antagonists in some individuals. The spectrum posed by these two hypotheses provides a conceptual framework that will guide investigation into the pathogenesis of SJIA‐LD and may open up new therapeutic avenues for patients with systemic JIA.

Lung Involvement in Systemic Juvenile Idiopathic Arthritis: A Narrative Review

“…Other risk factors include trisomy 21 and a history of adverse reactions to biological drugs, especially tocilizumab. At least 40% of these patients showed adverse reactions to this drug, ranging from malaise to anaphylaxis [ 9 , 16 , 17 , 18 ].…”

“…They observed that a DRESS-type reaction in the first group of patients was closely correlated with the expression of Human Leukocyte Antigen (HLA) DRB1*15 [ 14 ]. Based on these findings, Binstadt et al [ 16 ] proposed two pathogenetic hypotheses. “The DRESS hypothesis” was based on the fact that approximately 50% of patients with sJIA-LD experienced adverse reactions to biological drugs (in particular tocilizumab) fitting the DRESS criteria [ 22 ].…”

“…The authors proposed that anakinra (interleukin-1 receptor antagonist), canakinumab (IL1β-specific monoclonal antibody) and tocilizumab (or their excipients) led to a pathogenic T cell-response. The drugs could activate T-lymphocytes: (1) by covalently binding to endogenous proteins and being recognized as non-self; (2) by non-covalently binding to the major histocompatibility complex (MHC) and/or T-cell receptor (TCR) outside the antigen-binding pocket, similar to bacterial superantigens [ 16 , 23 ]; (3) by binding within the MHC groove and altering it so that some self-peptides appear as non-self [ 16 ]. Thus, IL-1 and IL-6 blockers may achieve one of these interactions with DRB1*15:XX, although anakinra does not share any sequence peptides with canakinumab and tocilizumab.…”

“…Thus, IL-1 and IL-6 blockers may achieve one of these interactions with DRB1*15:XX, although anakinra does not share any sequence peptides with canakinumab and tocilizumab. However, these drugs share an excipient, such as polysorbate 80, even if it is a poor candidate trigger for DRESS, being a heterogeneous and almost ubiquitous chemical [ 16 ]. Moreover, anakinra should have a very low antigenic potential, being very similar to its endogenous homologue.…”

“…Moreover, anakinra should have a very low antigenic potential, being very similar to its endogenous homologue. The reactivation of herpesvirus infections with subsequent activation of CD8+ lymphocytes was observed in many DRESS reactions [ 16 ]. However, the underlying mechanism by which DRESS contributes to MAS and/or sJIA-LD is still unknown.…”