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Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare - 11/02/20

Doi : 10.1016/j.jaad.2019.05.098 
William Damsky, MD, PhD a, , Durga Thakral, PhD a, Meaghan K. McGeary, BA b, Jonathan Leventhal, MD a, Anjela Galan, MD a, Brett King, MD, PhD a,
a Department of Dermatology, Yale School of Medicine, New Haven, Connecticut 
b Department of Pathology, Yale School of Medicine, New Haven, Connecticut 

Correspondence to: William Damsky, MD, PhD OR Brett King MD, PhD, Yale Department of Dermatology, 333 Cedar St, LCI 501, PO Box 208059, New Haven, CT 06520.Yale Department of Dermatology333 Cedar St, LCI 501, PO Box 208059New HavenCT 06520

Abstract

Background

Sarcoidosis and granuloma annulare (GA) are cutaneous granulomatous disorders that can be difficult to treat. There is evidence of underlying Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway activation in sarcoidosis, suggesting that JAK inhibition might be effective.

Objective

To evaluate treatment with tofacitinib, a JAK inhibitor, in patients with recalcitrant sarcoidosis and GA.

Methods

A prospective evaluation of tofacitinib in 4 consecutive patients with recalcitrant cutaneous sarcoidosis (n = 3) and generalized GA (n = 1) was conducted. Immunohistochemical analysis of skin biopsy specimens from other patients with sarcoidosis (n = 21) and GA (n = 17) was performed to characterize patterns of JAK-STAT pathway activation.

Results

Tofacitinib resulted in a mean improvement in the baseline Cutaneous Sarcoidosis Activity and Morphology Instrument and Granuloma Annulare Scoring Index scores of 96% (standard deviation, 2%). Histologic resolution of disease was documented in all patients (3 out of 3) who had skin biopsies while receiving therapy. Constitutive STAT1 and STAT3 activation was observed in both sarcoidosis and GA, albeit in different patterns. Signal regulatory protein α may explain the differences in JAK-STAT signaling between sarcoidosis and GA.

Limitations

The study is limited by the small number of participants.

Conclusions

Tofacitinib resulted in dramatic improvement in 4 patients with cutaneous sarcoidosis and GA. Larger studies are underway to better understand this effect.

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Graphical abstract




Le texte complet de cet article est disponible en PDF.

Key words : sarcoidosis, granuloma annulare, tofacitinib, JAK-STAT, JAK inhibitor

Abbreviations used : CSAMI, GA, GASI, IFN, IHC, IL, JAK, mTORC1, PBMC, p, RNAseq, SIRP, STAT, TNF


Plan


 Funding sources: Supported by a grant to Dr King from the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research. Dr Damsky is supported by a Career Development Award from the Dermatology Foundation. Dr Thakral is supported by a Medical Science Training program grant (T32GM007205).
 Disclosures: Dr Damsky has served as a consultant for Eli Lilly in unrelated work and is the recipient of investigator-initiated trial support from Pfizer; the latter award did not support the current study. Dr Leventhal served on an advisory board for Amgen in unrelated work. Dr King is an investigator for Concert Pharmaceuticals Inc, Eli Lilly and Company, and Pfizer Inc; is a consultant to and/or has served on advisory boards for Aclaris Therapeutics, Arena Pharmaceuticals, Concert Pharmaceuticals Inc, Dermavant Sciences, Eli Lilly and Company, and Pfizer Inc; and is on the speakers bureau for Pfizer Inc, Regeneron, and Sanofi Genzyme, all in unrelated work. Drs Thakral, Galan, and McGeary have no conflicts of interest to declare.
 Reprints not available from the authors.


© 2019  American Academy of Dermatology, Inc.. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 82 - N° 3

P. 612-621 - mars 2020 Retour au numéro
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