Original article
Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare

https://doi.org/10.1016/j.jaad.2019.05.098Get rights and content

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.

Section snippets

Patients

Patients were referred to a tertiary dermatology practice at an academic medical center (Yale, New Haven, CT). Patients had biopsy-proven, moderate to severe cutaneous sarcoidosis or generalized GA that was uncontrolled with other systemic medication and were offered treatment with tofacitinib (off label) after discussion of possible adverse effects. Patients provided verbal informed consent.

Histologic case series

Skin biopsy specimens were identified by searching the Yale dermatopathology database by diagnosis.

Tofacitinib induces clinical disease remission in patients with sarcoidosis and GA

Four consecutive patients, 3 with sarcoidosis (1 recently reported elsewhere19 and 2 additional patients) and 1 with generalized GA, were treated with tofacitinib 5 mg twice daily. The average age of the patients was 54 years, and the average disease duration was 11.25 years; patient characteristics are listed in Table I. Common therapies, including hydroxychloroquine, methotrexate, and adalimumab, among others, had failed for these patients.

An average improvement in baseline disease activity

Discussion

Cutaneous sarcoidosis and GA are difficult to treat, and there are no reliably effective therapies for these disorders, except prednisone. Here, we show the efficacy of the JAK1/3 inhibitor tofacitinib in a series of 4 patients with treatment-recalcitrant disease and expand the findings of our prior report of a single patient.19 Complete or near-complete clinical remission was observed in all patients, and histologic resolution of granulomatous inflammation was also seen. Clinical improvement

References (27)

  • W.E. James et al.

    Treatment of sarcoidosis: grading the evidence

    Expert Rev Clin Pharmacol

    (2018)
  • W.H. Sauer et al.

    High-risk sarcoidosis. Current concepts and research imperatives

    Ann Am Thorac Soc

    (2017)
  • A. Chen et al.

    The role of biologics in the treatment of chronic granuloma annulare

    Int J Dermatol

    (2019)
  • Cited by (0)

    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.

    View full text