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Genetically proxied TYK2 inhibition is associated with reduced sarcoidosis susceptibility
  1. Sizheng Steven Zhao1,
  2. Anne Barton2,3,
  3. John Bowes2
  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 for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  3. 3NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, 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 M13 9PL, Manchester, UK; sizheng.zhao{at}manchester.ac.uk

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Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology that can affect any organ, including the lung, joints and skin. Clinical presentation can be highly heterogeneous and lead to significant morbidity and mortality.1 Glucocorticoids remain the cornerstone of pharmacological therapy but are limited by toxicities with long-term use. Although steroid-sparing agents are available, there are no licensed therapeutics for sarcoidosis. Many cytokines implicated in sarcoidosis (eg, gamma interferon and other type 1 cytokines) signal via the JAK-STAT pathway, and inhibition of this pathway has proved successful in several immune-mediated inflammatory diseases (IMIDs). Interestingly, tofacitinib, a JAK-STAT inhibitor, was associated with skin improvement and suppression of type 1 cytokines in an open-label trial of 10 patients with cutaneous sarcoidosis.2 However, these preliminary findings await confirmation by phase III trials and are caveated by tofacitinib’s potential adverse cardiovascular profile.

Inhibition of TYK2, one member of the JAK family, has shown promise for IMIDs (eg, deucravcitinib for psoriasis and psoriatic arthritis (PsA)).3 Germline mutations causing loss-of-function of genes encoding drug targets have been used to correctly predict the effect of their pharmacological inhibition4; therefore, we used a naturally occurring loss-of-function mutation to evaluate the therapeutic potential …

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Footnotes

  • Handling editor Josef S Smolen

  • Twitter @stezhao

  • Contributors SSZ had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: SSZ. Acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: SSZ. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: SSZ. Administrative, technical or material support: all authors.

  • Funding SSZ is supported by a National Institute for Health Research (NIHR) Academic Clinical Lectureship. This work was supported by vs Arthritis (grant number 21173, 21 754 and 21755) and by the NIHR Manchester Biomedical Research Centre.

  • Disclaimer The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health.

  • Competing interests None declared.

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

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

  • 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.