Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB115 alleles

• Published in: Annals of the rheumatic diseases Vol. 81; no. 3; pp. 406 - 415
• Main Authors: Saper, Vivian E, Ombrello, Michael J, Tremoulet, Adriana H, Montero-Martin, Gonzalo, Prahalad, Sampath, Canna, Scott, Shimizu, Chisato, Deutsch, Gail, Tan, Serena Y, Remmers, Elaine F, Monos, Dimitri, Hahn, Timothy, Phadke, Omkar K, Cassidy, Elaine, Ferguson, Ian, Mallajosyula, Vamsee, Xu, Jianpeng, Rosa Duque, Jaime S, Chua, Gilbert T, Ghosh, Debopam, Szymanski, Ann Marie, Rubin, Danielle, Burns, Jane C, Tian, Lu, Fernandez-Vina, Marcelo A, Mellins, Elizabeth D, Hollenbach, Jill A, Aziz, Rabheh Abdul, Berard, Roberta, Bingham, Catherine A, Bonaparth, Alexis D, Casey, Alicia, Collins, Kathleen P, Cidon, Michal, Goodman, Steven I, Grom, Alexei A, Hazen, Melissa, Hoftman, Alice, Ibarra, Maria, Jerath, Rita, Kingsbury, Daniel J, Klein-Gitelman, Marisa S, Lai, Khanh, Lapidus, Sivia, Mendoza-Londono, Roberto, Onel, Karen, Perez, Maria, Radhakrishna, Suhas M, Reinhardt, Adam, Riskalla, Mona, Roth, Johannes, Rosenwasser, Natalie, Saad, Nadine, Schulert, Grant S, Shenoi, Susan, Smith, Judith A, Soep, Jennifer, Stingl, Cory, Stoll, Matthew L, Tesher, Melissa, Whitehead, Benjamin, Zemel, Lawrence, Anton, Jordi, Bohnsack, John F, Cobb, Joanna, Demirkaya, Erkan, Foell, Dirk, Gattorno, Marco, Grom, Alexei, Hilario, Maria Odete, Ilowite, Norman T, Haas, Johannes-Peter, Hinks, Anne, Kastner, Daniel L, Langfeld, Carl D, Martini, Alberto, Minden, Kirsten, Oliveira, Sheila, Özen, Seza, Rosen-Wolff, Angela, Rosenberg, Alan, Russo, Ricardo, Signa, Sara, Tachmazidou, Ioanna, Tenbrock, Klaus, Thompson, Susan, Thomson, Wendy, Wedderburn, Lucy R, Woo, Patricia, Yeung, Rae S M, Zeft, Andrew S, Len, Claudio
• Format: Journal Article
• Language: English
• Published: United States BMJ Publishing Group Ltd and European League Against Rheumatism 01.03.2022; Elsevier Limited
• Subjects: Adult; adult-onset; Alleles; Antigens; Antirheumatic Agents - adverse effects; Arthritis; biological therapy; Case-Control Studies; Cell activation; Children; Classification; Cytokines; Drb1 protein; Drug Hypersensitivity Syndrome - genetics; Drug Hypersensitivity Syndrome - immunology; Drug Tolerance - genetics; Eosinophilia; Female; Gene frequency; Haplotypes; Histocompatibility antigen HLA; HLA-DRB1 Chains - genetics; HLA-DRB1 Chains - immunology; Humans; Hypersensitivity (delayed); Hypersensitivity, Delayed - genetics; Hypersensitivity, Delayed - immunology; Interleukin 1; Interleukin 1 receptor antagonist; Interleukin 6; Interleukin-1 - antagonists & inhibitors; Interleukin-6 - antagonists & inhibitors; juvenile; Kawasaki disease; Laboratories; Lung diseases; Lymphocytes; Macrophages; Male; Mucocutaneous lymph node syndrome; Mucocutaneous Lymph Node Syndrome - drug therapy; Mucocutaneous Lymph Node Syndrome - genetics; Patients; Peptides; pharmacogenetics; Retrospective Studies; Steroids; Still's disease; Still's Disease, Adult-Onset - drug therapy; Still's Disease, Adult-Onset - genetics; Still's Disease, Adult-Onset - immunology; Tissue typing; Treatment; Vigilance; Still's disease; adult-onset; juvenile; arthritis; biological therapy; pharmacogenetics
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/annrheumdis-2021-220578

ObjectivesDrug 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.MethodsIn 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.ResultsStill’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.ConclusionsDRESS-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.