Interleukin (IL)-1/IL-6-Inhibitor–Associated Drug Reaction With Eosinophilia and Systemic Symptoms (DReSS) in Systemic Inflammatory Illnesses

Background: After introducing IL-1/IL-6 inhibitors, some patients with Still and Still-like disease developed unusual, often fatal, pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease. Objective: To facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not stopping IL-1/IL-6 inhibitors after DReSS reaction began. Methods: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6 inhibitors with 37 cases not stopping these drugs. Results: Before the reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease-onset age for reaction cases with preexisting cardiothoracic comorbidities. After the reaction began, increased rates of pulmonary complications and macrophage activation syndrome differentiated drug-reaction cases from drug-tolerant controls (P = 4.7 × 10⁻³⁵ and P = 1.1 × 10⁻²⁴, respectively). The initial DReSS feature was typically reported 2 to 8 weeks after initiating IL-1/IL-6 inhibition. In drug-reaction cases stopping versus not stopping IL-1/IL-6–inhibitor treatment, reaction-related features were indistinguishable, including pulmonary complication rates (75% [39 of 52] vs 76% [28 of 37]). Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of macrophage activation syndrome, and improved survival (P = .005, multivariate regression). Resolution of pulmonary complications occurred in 67% (26 of 39) of drug-reaction cases who stopped and in none who continued inhibitors. Conclusions: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor–associated reactions followed by avoidance of IL-1/IL-6 inhibitors significantly improved outcomes.