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23-11-2021 | Adult-onset Still's disease | News

Severe hypersensitivity to IL-1, IL-6 inhibitors linked to HLA-DRB1*15

Laura Cowen

medwireNews: Human leucocyte antigen (HLA)-DRB1*15 haplotypes are strongly associated with delayed drug reaction with eosinophilia and systemic symptoms (DRESS) in people receiving interleukin (IL)-1 or IL-6 inhibitors for Still’s disease, research suggests.

Based on their findings, Vivian Saper (Stanford University, California, USA) and colleagues believe that “[c]onsideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.”

The study included data for 66 individuals with a DRESS-like delayed hypersensitivity reaction (DHR) to anakinra, canakinumab, rilonacept, and/or tocilizumab as well as 65 drug-tolerant Still’s controls from 37 centers in the USA, Canada, and Australia.

DRESS reactions occurred among individuals receiving anakinra, canakinumab, and tocilizumab monotherapy, “indicating that each is capable of triggering DRESS,” say the researchers who also note that that 26 participants reacted to multiple IL-1/6 inhibitors.

The majority (95%) of people with DRESS had a non-evanescent rash (involving the face in 88% of 48 cases with details), eosinophilia (89%), and elevated aspartate aminotransferase and/or alanine aminotransferase (75%). Furthermore, macrophage activation syndrome (MAS) was significantly more common in this group than in controls (64 vs 3%).

Saper and team note that “[t]he drug reactions were often unrecognised, as reflected by continuation of inhibitor therapy after DRESS criteria were met.” Indeed, just 26% of participants with Still’s and DRESS stopped IL-1 or IL-6 inhibition for 3 months or longer. Yet, in this group, DRESS symptoms resolved in all cases following treatment termination and inflammation subsequently became easier to manage but the investigators caution that restarting suspended IL-1 inhibitors was associated with fatal MAS in four of six cases.

In the subset of 94 Still’s participants with HLA data, the researchers found that DHR was significantly associated with the HLA class II haplotype DRB1*15.

Specifically, 83% of 36 self-identified White individuals with DRESS were positive for HLA-DRB1*15:01 compared with none of the 19 self-identified White Still’s controls.

The difference was also significant when compared with 550 individuals of European ancestry with unknown drug exposure from the INCHARGE childhood onset Still’s (systemic juvenile idiopathic arthritis) cohort, of whom 24% carried HLA-DRB1*15:01. In this comparison, individuals with DRESS were a significant 15.5 times more likely to carry HLA-DRB1*15:01 than the European controls.

Saper and team acknowledge that a lack of non-White participants limited their analysis, but say that “HLA-DRB1*15:XX appears enriched in delayed drug reactions across ancestries.”

They also observed similar findings in a small group of individuals with Kawasaki disease and a suspected delayed reaction to anakinra. Three of these four individuals carried HLA-DRB1*15:XX compared with two of 15 drug-tolerant individuals with Kawasaki disease.

Writing in the Annals of the Rheumatic Diseases, Saper and co-authors conclude that the effect size they observed “is substantially greater than those seen in HLA/disease associations and instead is comparable to those observed in other HLA associations with severe drug-related delayed hypersensitivity.”

They add: “The frequency of the risk alleles across populations, the strength of the HLA association, and reaction severity, argue for preprescription risk analysis” but caution that the “data are insufficient as a basis for specific recommendations on when or if it is safe to use these inhibitors in patients with Still’s disease with the reaction-associated HLA haplotypes.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

Ann Rheum Dis 2021; doi:10.1136/annrheumdis-2021-220578

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