Hypersensitivity reactions to IL-1 and IL-6 inhibitors are linked to common HLA-DRB1*15 alleles

Abstract

In Saper et al (2019), we described systemic JIA patients who developed a high-fatality diffuse lung disease (DLD) while on IL-1 or IL-6 inhibitors. We observed severe delayed drug hypersensitivity reactions (DHR) in a significant subset. Because alleles of the human leukocyte antigen (HLA) loci can mediate DHR, we investigated HLA genotype association with these DHR. We typed subjects treated with these inhibitors: 34 sJIA/DHR/DLD, 11 sJIA/DHR without DLD, 18 drug-tolerant sJIA, and 19 Kawasaki disease (KD) patients in an anti-IL-1(anakinra) trial. We also accessed genotypes from a large sJIA case/control cohort. We first compared White subjects with sJIA/DHR to 550 ancestry-matched sJIA subjects. We found striking enrichments of HLA-DRB1*15:01, HLA-DQA1*01:02, and DQB1*06:02, alleles in near-complete linkage (White individuals). HLA-DRB1*15:01 (as haplotype proxy) was increased in White sJIA subjects with DHR/DLD versus sJIA drug-tolerant controls and was observed upon inclusion of sJIA+DHR-only and KD+DHR White subjects. In our entire cohort regardless of ancestry, 75% carried HLA-DRB1*15:01 or the structurally related DRB1*15:03 and DRB1*15:06, which were absent among drug-tolerant subjects (p=5 x 10-13; Odds Ratio lower bound=20.11). Patients who harbor HLA-DRB1*15 alleles are at high risk of developing DHR to anti-IL-1/IL-6. Our data also suggest DHR maybe a trigger/enhancer of DLD in sJIA patients and support performing prospective HLA screening in sJIA, its adult-onset counterpart, and other inflammatory conditions where these drugs are used, such as KD.

Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers

“…Previously, we reported atypical rashes (56%) and eosinophilia (37%) during treatment with IL-1 or IL-6 inhibitors in sJIA-PAP 7 . These clinical findings, a minimally-fibrotic lung pathology, recent evidence for a remarkable HLA association 44 , and the above serum chemokine elevations (particularly CCL11 and CCL17), are together consistent with a delayed-type drug hypersensitivity reaction 45 . In the current study, we were unable to analyze the impact of IL-1/6 inhibition on the serum proteome profile, as all the sJIA-PAP patients with therapeutic information were under IL-1/6 inhibition at sample collection.…”

Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate

“…In AA, HLA-DRB1*15:03 is the most common HLA-DRB1*15 allele and has a similar peptide binding affinity as HLA-DRB1*15:01. 27 Interestingly, HLA-DRB1*15:03 has an established role in the susceptibility of autoimmune diseases 27 and drug-induced DRESS 34 . AA cases were also enriched in HLA-DRB1*15:02, a known risk factor for AC-DILI among people of Indian or Pakistani origin 35 .…”

CME Exam: Drug-Induced Hypersensitivity Syndrome (DIHS)/Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS): Clinical Features and Pathogenesis

“…sJIA) and adult-onset Still's a disease (AOSD) that is strongly associated with HLA-DRB1*15:01 and the related class II HLA alleles HLA-DRB1*15:03 and HLA-DRB1*15:06 38. …”