Journal Article

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

Murphy, Michael J., Daccache, Joseph, Ayasun, Ruveyda, Singh, Katelyn, Flavell, Richard A., McGeary, Meaghan K., Odell, Ian D., Wang, Alice, Clark, Abigale, Pucar, Darko, Ryu, Changwan, Fazzone-Chettiar, Ramesh, Homer, Robert, King, Brett, Damsky, William, Kim, Daniel J., Young, Bryan D., Miller, Edward J., Bosenberg, Marcus, Gulati, Mridu

2022

Overview

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. Sarcoidosis is a heterogenous disorder often treated with glucocorticoids. Here the authors show, in an open label, non-randomized, single arm clinical trial involving 10 patients, that treatment with tofacitinib, a Janus kinase inhibitor, is associated with improved clinical symptoms and reduced activity of Th1 cytokines such as IFN-γ and IL-12.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/39 / 631/250/127/1212 / 692/308/409 / 692/4023/1670 / 692/699/249/1313 / CD4 antigen / Cell activation / Cytokines / Cytokines - metabolism / Enzyme inhibitors / Glucocorticoids / Granulocyte-macrophage colony-stimulating factor / Humanities and Social Sciences / Humans / Immunity / Inflammatory diseases / Interleukin 12 / Interleukin 15 / Interleukin 6 / Janus kinase / Kinases / Lymphocytes / Lymphocytes T / Macrophages / multidisciplinary / Pathogenesis / Patients / Piperidines - pharmacology / Piperidines - therapeutic use / Pyrimidines - pharmacology / Pyrimidines - therapeutic use / Sarcoidosis / Sarcoidosis - drug therapy / Sarcoidosis - pathology / Science / Science (multidisciplinary) / γ-Interferon