Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis

William Damsky (), Alice Wang, Daniel J. Kim, Bryan D. Young, Katelyn Singh, Michael J. Murphy, Joseph Daccache, Abigale Clark, Ruveyda Ayasun, Changwan Ryu, Meaghan K. McGeary, Ian D. Odell, Ramesh Fazzone-Chettiar, Darko Pucar, Robert Homer, Mridu Gulati, Edward J. Miller, Marcus Bosenberg, Richard A. Flavell and Brett King ()
Additional contact information
William Damsky: Yale School of Medicine
Alice Wang: Yale School of Medicine
Daniel J. Kim: Yale School of Medicine
Bryan D. Young: Yale School of Medicine
Katelyn Singh: Yale School of Medicine
Michael J. Murphy: Yale School of Medicine
Joseph Daccache: Yale School of Medicine
Abigale Clark: Kansas City University of Medicine and Biosciences
Ruveyda Ayasun: New York University Langone Medical Center
Changwan Ryu: Yale School of Medicine
Meaghan K. McGeary: Yale School of Medicine
Ian D. Odell: Yale School of Medicine
Ramesh Fazzone-Chettiar: Yale School of Medicine
Darko Pucar: Yale School of Medicine
Robert Homer: Yale School of Medicine
Mridu Gulati: Yale School of Medicine
Edward J. Miller: Yale School of Medicine
Marcus Bosenberg: Yale School of Medicine
Richard A. Flavell: Yale School of Medicine
Brett King: Yale School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4+ T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity.

Date: 2022
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DOI: 10.1038/s41467-022-30615-x

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