Off-Label Use of Janus Kinase Inhibitors in Inflammatory Cutaneous Diseases

December 2023 | Volume 22 | Issue 12 | 1183 | Copyright © December 2023


Published online November 29, 2023

Aneesh Agarwal BS, Aisleen Diaz MD, Roudha Al-Dehneem MD MSc, Raphaela Martina Pineda MD, Saakshi Khattri MD

Department of Dermatology, Icahn School of Medicine at Mount Sinai, NY

Abstract
Dysregulation of Janus kinase (JAK) pathways from uncontrolled cytokine signaling comprises the pathological basis for many complex inflammatory cutaneous disorders. Oral JAK inhibitors, upadacitinib, tofacitinib, and baricitinib targeting JAK 1 and JAK 1/3, respectively, are currently US Food and Drug Administration (FDA)-approved for several rheumatic conditions. However, studies have shown that JAK-mediated signaling pathways are involved in many immune-related dermatologic conditions. As a result, for recalcitrant diseases, JAK inhibitors are potential alternative therapies due to their broad targeted inhibitory mechanisms.

In this case series, we present the successful off-label treatment of 6 cases across dermatomyositis, hidradenitis suppurativa, cutaneous lupus, and cutaneous Crohn’s disease, which failed conventional therapies with upadacitinib or tofacitinib. In the 3 dermatomyositis cases, use of upadacitinib or tofacitinib demonstrated positive clinical outcomes, with no recurrent symptoms in cases where upadacitinib was used. In treatment-resistant hidradenitis suppurativa, upadacitinib demonstrated reduced systemic flares and moderate cutaneous symptom improvement. In the case of cutaneous Crohn’s disease, upadacitinib resulted in reduced cutaneous symptoms without new flares. Tofacitinib resulted in completed resolution of cutaneous symptoms in our patient’s case of cutaneous lupus erythematosus. JAK inhibitors upadacitinib and tofacitinib may be potential drug candidates in patients with treatment-resistant disease, especially in cases of inflammatory cutaneous conditions such as dermatomyositis, hidradenitis suppurativa, cutaneous lupus, and cutaneous Crohn’s disease. Further studies with larger sample sizes among these conditions are warranted to assess potential broader applicability of the positive results demonstrated in our patient cases.

J Drugs Dermatol. 2023;22(12):1183-1190. doi:10.36849/JDD.7500

INTRODUCTION

Dysregulation of Janus kinase (JAK) pathways from uncontrolled cytokine signaling comprises the pathological basis for many complex inflammatory disorders.1 Since JAK-family receptors are activated by numerous ligands, including several interleukins (IL), interferons (IFN), and hematopoietic growth factors, JAK inhibition can interfere with many different cellular pathways, potentially resulting in both desired efficacy as well as side effects.2

While most JAK inhibitors are US Food and Drug Administration (FDA)-approved for treating rheumatic conditions and are often used in patients not responding to disease-modifying antirheumatic drugs and biologics, there are several other inflammatory indications for which JAK inhibitors have demonstrated clinical promise.3,4 For example, JAK-mediated signaling pathways are involved in many immune-related dermatologic conditions, including atopic dermatitis (IL-4/5/13), psoriasis (IL-23/17), dermatomyositis (IFN-α/β, IL-6/15), and vitiligo (IFN-γ), among others.1,4 Additionally, in cases of cytokines that do not involve JAK pathways, JAK inhibitors have demonstrated utility by indirectly suppressing related molecules including upstream precursors that are later involved with JAK mechanisms, suggesting broader benefits of this drug class.4 

Upadacitinib is an oral JAK inhibitor associated with reductions in IL-6 and IFN-γ that selectively targets JAK1, and is an example of an agent approved for use in rheumatoid arthritis, atopic dermatitis, and psoriatic arthritis, in addition to non-cutaneous autoimmune conditions.3,5,6 Tofacitinib is an oral JAK 1/3 inhibitor disrupting IL-2/4/15/21 signaling, and is approved for broader use in rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis.3,7 

In this report, we present different inflammatory systemic disorders that failed conventional treatment but were treated successfully with upadacitinib or tofacitinib, including dermatomyositis (DM), hidradenitis suppurativa (HS), cutaneous lupus, and cutaneous Crohn’s disease. 
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