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          NIAMS Scientific Advances
          Severe Delayed Hypersensitivity Reactions to IL1 and IL6 Inhibitors Linked to a Common Genetic Profile








NIAMS Advances


Severe Delayed Hypersensitivity Reactions to IL1 and IL6 Inhibitors Linked to a Common Genetic Profile November 17, 2021
                                BASIC
        Michael J. Ombrello, M.D.
                                          |
              Translational Genetics and Genomics Section
                                          |
              NIAMS IRP
        DescriptionOver the past decade, a potentially lethal form of lung disease (LD) has emerged among a subset of children with systemic juvenile idiopathic arthritis (sJIA) receiving treatment with interleukin-1 (IL-1) and interleukin-6 (IL-6) inhibitors. Delayed hypersensitivity reactions (DHR) to medications can occur in some patients and cause severe or even fatal outcomes. In this study, the researchers used a validated DHR scoring system to evaluate whether sJIA and adult onset Still’s disease (AOSD) patients with LD were experiencing DHR to treatment with cytokine inhibitors. Researchers also compared genetic markers between sJIA-LD and sJIA without LD. The study found 1) all subjects with sJIA and LD had DHR; 2) some subjects with sJIA but not LD also had DHR, and 3) a genetic marker on the human leucocyte antigen—the proteins on cell surfaces that distinguish “self” from “nonself” tissues—(HLA-DRB1*15 alleles) was strongly linked to the development of DHR, both with and without LD. Therefore, pre-treatment screening for this gene can prevent DHR and improve treatment safety.What is exciting about this article?This study showed that some patients with inflammatory diseases develop DHR after IL-1 or IL-6 inhibitor treatment. It clarified that the severe, emergent LD recently described in sJIA develops in the context of DHR to cytokine inhibitors. This study showed that patients carrying a common genetic marker (HLA-DRB1*15 alleles) were remarkably more likely to develop this potentially life-threatening drug reaction than patients without it. Therefore, detection of this genetic marker before initiating therapy can improve treatment safety.How does this fit with the larger NIAMS portfolio?IL-1 and IL-6 inhibitor treatment for inflammatory diseases such as sJIA and AOSD induces severe DHR in some patients. Discovery of the DHR associated genetic marker provides a unique and significant preventative pre-treatment screening target.Grant support1ZIAAR041198
        Research Areas:
            Autoimmunity
      Genetics and Genomics
                                        Reference:
            Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles.

    Saper VE, Ombrello MJ, Tremoulet AH, Montero-Martin G, Prahalad S, Canna S, Shimizu C, Deutsch G, Tan SY, Remmers EF, Monos D, Hahn T, Phadke OK, Cassidy E, Ferguson I, Mallajosyula V, Xu J, Rosa Duque JS, Chua GT, Ghosh D, Szymanski AM, Rubin D, Burns JC, Tian L, Fernandez-Vina MA, Mellins ED, Hollenbach JA, Drug Hypersensitivity Consortium, INCHARGE Consortium
        

                    Ann Rheum Dis.
        
                    2022 Mar;
        
                    81(3).
        
                    doi: 10.1136/annrheumdis-2021-220578
                            PMID: 34789453
        Research reported in this publication was supported by the Intramural Research Program of the NIHʼs National Institute of Arthritis and Musculoskeletal and Skin Diseases.
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