Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles

Abstract

Objectives: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still's disease with atypical lung disease. We sought to characterise features of patients with Still's disease with DRESS compared with drug-tolerant Still's controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.

Methods: In a case/control study, we collected a multicentre series of patients with Still's disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still's controls (n=65). We retrospectively analysed clinical data from all Still's subjects and typed 94/131 for HLA. European Still's-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still's cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still's-DRESS cases (n=64) compared with drug-tolerant Still's controls (n=30). KD subjects (n=19) were similarly studied.

Results: Still's-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still's-DRESS (64%) versus drug-tolerant Still's (3%; p=1.2×10^-14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still's-DRESS cases versus INCHARGE Still's controls (p=7.5×10^-13) and versus self-identified, ancestry-matched Still's controls (p=6.3×10^-10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.

Conclusions: DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.

Keywords: Still's disease; adult-onset; arthritis; biological therapy; juvenile; pharmacogenetics.

Figure 1:. Study design

Clinical information was collected on Still’s disease subjects with and without clinical suspicion of drug reaction to inhibitors of IL-1 or IL-6 (A). Classification of Still’s patients was verified by RegiSCAR scoring for DRESS. Similar numbers of Still’s-DRESS (n=65 + 1 suspected delayed anakinra reaction Still’s; see methods) and Still’s controls (n=65) subjects were enrolled for case/control comparison and do not reflect the incidence of inhibitor-triggered DRESS in Still’s disease. HLA genotyping was performed on the subset of patients with available sample or sequence data. All 19 Kawasaki disease subjects were enrolled in a Phase I/IIa clinical trial of anakinra in KD patients with coronary artery abnormalities (B) and were clinically scored as suspected anakinra reaction or drug-tolerant; all were HLA typed. Details of scoring and HLA genotyping are provided in methods and supplementary information. Still’s Disease: sJIA, systemic onset juvenile idiopathic arthritis (Still’s onset <16yrs) and AOSD, adult-onset Still’s Disease (Still’s onset ≥16yrs)^,; RegiSCAR, registry of experts assembled to clinically classify drug induced severe cutaneous reactions; DRESS, drug reaction with eosinophilia and systemic symptoms

Figure 2:. RegiSCAR for DRESS scores in Still’s-DRESS cases

Numbers of Still’s-DRESS cases with RegiSCAR for DRESS scores of definite or probable are shown (n=65). The Still’s case with suspected delayed anakinra reaction is not included. RegiSCAR classifies a case as definite (6–9), probable (4–5), possible (2–3) or no case (0 to negative 4). For DRESS cases reacting to more than one IL-1/IL-6 inhibitor, the highest RegiSCAR value is shown. By definition, no drug-tolerant subject scored ≥4. RegiSCAR scoring elements are shown in supplementary information.

Figure 3:. Unusual clinical features in inhibitor-treated Still’s patients

Images of non-evanescent rash, typically pruritic, are shown. Upper left: On anakinra, erythema and prominent edema affecting knee; upper right: on tocilizumab, excoriated and areas of hyperpigmentation on abdomen; lower left: On canakinumab, erythematous, edematous rash on hand [similar rash on face and ear is not shown]; lower right: On anakinra, erythema, edema and non-herpetic vesiculation on face. Skin biopsy of drug-associated rash shows vacuolar interface dermatitis and eosinophils. Higher power images (sections a, b) show lymphocytes, vacuolation at the dermal-epidermal junction, focal dyskeratotic keratinocytes (asterisk) and perivascular eosinophils (arrows). Acute digital clubbing, often erythematous, was frequently the first indication of lung involvement in patients with DRESS and diffuse lung disease. Images of acute clubbing on tocilizumab (top), anakinra (middle), on canakinumab (bottom). Lung biopsy showing variant pulmonary alveolar proteinosis/endogenous lipoid pneumonia and arterial wall thickening (c). Higher power image (below) shows cholesterol clefts (arrowhead) and scattered eosinophils (arrows). 8/16 reviewed cases showed eosinophils in many fields (see supplementary methods). Increased lung eosinophils are consistent with DRESS and also seen in various inflammatory diseases. Table: In DRESS cases, median (interquartile range) of peak absolute eosinophil count was 1500/ul (980,3080) and peak eosinophil % of WBC was 18% (12,33). AST-ALT elevation was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) measuring >2x the upper limit of normal more than once, without alternative (e.g., non-drug) explanation. The frequency of DRESS reactions did not differ significantly when combined anti-IL-1 inhibitors were compared to the IL-6 inhibitor (tocilizumab) or when each inhibitor was analyzed separately (table S1c). Analyses of specific clinical findings yielded similar results when AOSD patients were omitted (table S5). See supplementary information for detailed methods and additional clinical data (tables S1c, S2, S3a–b). DRESS, drug reaction with eosinophilia and systemic symptoms; MAS, macrophage activation syndrome, a form of secondary hemophagocytic lymphohistiocytosis^,; P value, by Fisher’s exact; OR (95% CI), odds ratio (95% confidence interval) ¹Eosinophil information was unavailable in 2 cases (n=64); AST-ALT values were unavailable in 1 case, (n=65).

Figure 4:. HLA-DRB1*15:XX appears enriched in delayed drug reactions across ancestries

Table shows carrier frequencies of HLA-DRB1*15:01 and HLA-DRB1*15:XX in Still’s-DRESS cases and Still’s controls. To compare groups with balanced ancestry, 9 Still’s-DRESS cases were excluded from this analysis (leaving n=55), as they could not be matched with Still’s controls (n=30). (A, B) Pie charts of cases (A) and controls (B) indicate the proportions of subjects with each self-identified ancestry; absolute numbers in each group are shown. (C) Percentages are shown of delayed hypersensitivity reaction cases and drug-tolerant controls with HLA-DRB1*15:XX, in Still’s + KD subjects of all ancestries and in self-identified White subjects. (D) The number of cases in Still’s disease + KD subjects (Still’s-DRESS and KD-sAR) with and without HLA-DRB1*15:XX in all ancestries and in each indicated ancestry group are shown. All subjects with HLA-DRB*3/4/5 information (n=34) carry both HLA-DRB1*15 and HLA-DRB5*01:01. Additional information is on tables S1a–b and S7a. HLA-DRB1*15:XX, any HLA-DRB1*15; self-identified, self-reported ancestry; KD, Kawasaki disease, Mixed White, White + non-White ancestry ¹Includes one Still’s drug-reactive case with suspected delayed anakinra reaction.