Severe delayed hypersensitivity reactions (DHR) are observed to various drugs that are otherwise highly efficacious. Particular human leukocyte antigen (HLA) class I and/or class II alleles are associated with DHR risk for particular drugs, allowing screening of patients to inform clinical decision making.
Recently, we observed drug-related eosinophilic systemic syndrome (DReSS), a form of DHR, in children with systemic juvenile idiopathic arthritis (sJIA), complicated by a novel, parenchymal, diffuse lung disease (DLD). 1 The lung pathology was a variant of pulmonary alveolar proteinosis ( Figure S1a, b) , and DHR features included drug eruptions (Figure S1c-h) and eosinophilia. The implicated drugs were IL-1 and IL-6 inhibitors. To determine whether risk of this DHR was HLA-associated, we accessed genotypes from a large, multi-ethnic sJIA case/control cohort 2 and from 34 sJIA subjects with DLD/DHR, 11 with DHR without DLD, and 18 carefully screened, drug-tolerant sJIA controls. Methods, ancestry/HLA data (Table S1 ) and additional information on clinical features (Table S2 , S3) are in Supplementary Appendix.
We first compared White subjects in the sJIA/DHR/DLD subgroup to 550 ancestry-matched ( Fig. S2 ) sJIA subjects without known DLD and to 3279 ancestry-matched healthy controls. 2 We found conspicuous enrichments for HLA-DRB1*15:01, HLA-DQA1*01:02 and HLA-DQB1*06:02 (Tables 1A, S4) , alleles in near-complete linkage in White individuals. Using White sJIA/all-DHR cases increased this haplotype-associated risk, linking it to DHR, as opposed to DLD. As expected, HLA-DRB1*11/HLA-DQB1*03:01, the sJIA-associated haplotype 2 , was present in sJIA cases with and without DHR (Table S4 ).
Using HLA-DRB1*15:01 as a haplotype proxy, we found a high frequency (75%) of this allele in White sJIA subjects with DHR with or without DLD vs 0% in drug-tolerant controls (Table 1B) .
To determine whether HLA-linked DHR required sJIA-specific immune dysfunction, we studied a small cohort (n=19) of children with Kawasaki disease (KD) in a Phase I/IIa trial of anakinra. Including White KD subjects with/without suspected anakinra reaction (sAR) yielded the same striking results (Table 1B ).
The addition of Non-White cases provided 49 subjects with DHR, of which a remarkable 37 carried HLA-DRB1*15:01 or the closely related *15:03 and *15:06; this allelic group was completely absent among drug-tolerant controls (Table 1B) . Notably, HLA-DRB1*15:02, which differs from HLA-DRB1*15:01 by one amino acid that influences peptide-binding (Fig S3) , was not associated with DHR. Analysis of the sJIA-DHR/KD-sAR group across ancestries, where patterns of linkage disequilibrium differ, suggested the operative locus is HLA-DRB1, as we find reduced effect for alleles at other loci on this haplotype (Table 1B ).
An unusual aspect of this DHR/HLA association is that the risk spans several inhibitors with different chemical structures ( Figure S4 ). These findings raise the possibility that an excipient common to these drugs and/or a molecule increased by inhibition of the IL-1/IL-6 network ( Figure S5 ) creates a stimulatory HLA class II molecule, which activates CD4+ T cells. The immune dysregulation in sJIA and KD likely underlies the failure to restrain this T cell response. 3 Our findings highlight the need for surveillance for DReSS to IL-1/IL-6 inhibitors, which is often missed, especially when it occurs during active systemic inflammatory disease. Importantly, DHR in sJIA may initiate or substantially contribute to DLD (Table S2) . Carriers of the risk alleles are common [27% (White), 15% (Hispanic), 27% (Black) and 16% (Asians) in US populations]. 4 Our results argue for consideration of prospective HLA screening in sJIA and its adult-onset counterpart. For other emergent inflammatory conditions for which these drugs are used, including COVID-19 and MIS-C, eosinophil and atypical lymphocyte counts should be monitored. 5 