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Genetically proxied IL-6 receptor inhibition and risk of polymyalgia rheumatica
  1. Sizheng Steven Zhao1,
  2. Dipender Gill2,3,4
  1. 1Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal and Dermatological Science, School of Biological Sciences, Faculty of Biological Medicine and Health, The University of Manchester, Manchester, UK
  2. 2Centre of Excellence in Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK
  3. 3Department of Epidemiology and Biostatistics, Imperial College London, London, UK
  4. 4Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK
  1. Correspondence to Dr Sizheng Steven Zhao, Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal and Dermatological Science, School of Biological Sciences, Faculty of Biological Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Oxford Road, Manchester, M13 9LJ, UK; sizheng.zhao{at}manchester.ac.uk

https://doi.org/10.1136/annrheumdis-2022-222578

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    Polymyalgia rheumatica (PMR) is among the commonest inflammatory rheumatic diseases for which the cornerstone of treatment is long-term glucocorticoids.1 Adverse effects of glucocorticoids in elderly and often comorbid individuals can lead to significant additional morbidity. Steroid-sparing treatment options are limited and remain a major unmet need. Interleukin 6 (IL-6) signalling is thought to play a key role in PMR pathophysiology, and open-label studies of IL-6 receptor inhibition (IL-6Ri) have shown promising efficacy.2 Open-label studies are susceptible to bias, while effective blinding may be challenging since IL-6Ri reduces C-reactive protein (CRP), which can unblind participants. Natural variation in the gene that encodes a protein drug target can offer insight into the clinical effects of perturbing that target pharmacologically.3 We leveraged large population-level data to examine the effect of genetically proxied IL-6Ri on risk of PMR.

    To proxy IL-6Ri, we used seven previously identified variants (online supplemental table S1) within or near the IL6R gene (±300 kilobases), which encode the receptor of IL-6; these variants were uncorrelated (r2 <0.1) and associated with circulating CRP levels at genome-wide significance (p<5×10−8) from a genome-wide association study of 204 402 European individuals.4 These instruments were validated through associations …

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    Footnotes

    • Handling editor Josef S Smolen

    • Twitter @stezhao, @dpsg108

    • Contributors Both authors contributed to all stages of this research.

    • Funding SSZ is supported by a National Institute for Health Research Clinical Lectureship and works in centres supported by Versus Arthritis (grant numbers 21755, 21173, 21754 and 21755). DG is supported by the British Heart Foundation Research Centre of Excellence (RE/18/4/34215) at Imperial College London. This research was funded by UK Research and Innovation Medical Research Council (MC_UU_00002/7).

    • Competing interests DG is employed part-time by Novo Nordisk. All authors declare no conflicts of interest that could bias this work.

    • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability UK Biobank data are available to all bona fide researchers for use in health-related research that is in the public interest. The application procedure is described at www.ukbiobank.ac.uk.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.