JAK Inhibitor Safety Compared to Traditional Systemic Immunosuppressive Therapies

December 2022 | Volume 21 | Issue 12 | 1298 | Copyright © December 2022


Published online November 18, 2022

doi:10.36849/JDD.7187

Stefano G. Daniele PhDa, Christopher G. Bunick MD PhDb,c

aMedical Scientist Training Program (MD/PhD), Yale School of Medicine, New Haven, CT
bDepartment of Dermatology, Yale School of Medicine, New Haven, CT
cProgram in Translational Biomedicine, Yale School of Medicine, New Haven, CT

Abstract
Dermatologists treating atopic dermatitis are interested in the safety profile of the recently available JAK inhibitors, upadacitinib and abrocitinib, especially after they received boxed safety warnings. Long-term clinical trial data using these JAK inhibitors for the treatment of atopic dermatitis suggest that they are associated with very low incidence rates of malignancy, major adverse cardiac events, and thromboembolic events. However, a knowledge gap exists regarding the incidence of adverse events for JAK inhibitors compared to traditional systemic therapies used to treat poorly controlled atopic dermatitis as well as baseline rates in both atopic dermatitis and reference control populations. To address this gap, we analyzed data regarding adverse events of special interest for methotrexate, cyclosporine, and systemic corticosteroids and calculated the incidence of adverse events per 100 patient-years for these drugs. We also examined data regarding baseline incidence of adverse events in atopic dermatitis and control patients. We found that compared to upadacitinib and abrocitinib, traditional systemic therapies for atopic dermatitis demonstrated equal or higher incidence rates for malignancy (excluding non-melanoma skin cancer), non-melanoma skin cancer, major adverse cardiac events, and venous thromboembolism. Moreover, the use of upadacitinib and abrocitinib also exhibited either comparable or lower incidence of malignancy (excluding non-melanoma skin cancer), major adverse cardiac events, and venous thromboembolism, but higher rates of non-melanoma skin cancer, in comparison to baseline rates in atopic dermatitis or control patients. These findings indicate that JAK inhibitors should be positioned, at least based on safety, ahead of traditional systemic therapies for atopic dermatitis treatment.

J Drugs Dermatol. 2022;21(12):1298-1303. doi:10.36849/JDD.7187

INTRODUCTION

Inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway have arrived in dermatology with a big bang: three oral JAK inhibitors were approved by the Food and Drug Administration (FDA) in 2022. These include two oral medicines (upadacitinib and abrocitinib) for moderate-to-severe atopic dermatitis (AD) and one for severe alopecia areata (baricitinib). One other topical JAK inhibitor, ruxolitinib, is FDA-approved for the treatment of mild-to-moderate AD and non-segmental vitiligo. Furthermore, there is ongoing investigation into the clinical efficacy of JAK inhibitors in other dermatologic diseases, including hidradenitis suppurativa, granulomatous (granuloma annulare, sarcoidosis) disorders, and inflammatory (psoriasis, psoriatic arthritis, cutaneous lupus) skin disorders.

Yet what unifies all the FDA-approved JAK inhibitors, and has consequentially occupied much of their discussion, is the boxed safety warning required by the FDA on all medicines in this class. Dermatologists now entertain questions such as "Are these medicines safe?" and "To which patients can I prescribe these medicines?" It is opportune to review how we arrived at this clinical crossroad.

On February 4th, 2021, the FDA issued a Drug Safety Communication (DSC) alerting the public about preliminary results from a post-marketing safety trial comparing the use of tofacitinib to tumor necrosis factor-alpha (TNF-α) inhibitors in rheumatoid arthritis (RA) patients who were ≥50 years of age, simultaneously on methotrexate, and had at least one pre-existing cardiovascular risk factor.1 The study revealed a higher risk of major adverse cardiovascular events (MACE) and cancer in patients exposed to tofacitinib when compared to TNF-α inhibitors. On September 1st, 2021, review of the final results of the safety trial data prompted the FDA to conclude that there is an increased risk of MACE, blood clots, cancer (ie, lymphomas, lung cancer), and death with tofacitinib compared to TNF-α inhibitors. This held true for tofacitinib dosed at 5 mg twice daily or 10 mg twice daily. These results led the FDA to mandate the inclusion of a boxed warning for tofacitinib, which also extended to other JAK inhibitors because they share similar mechanisms of action, regardless of their respective molecular selectivity (ie, preferentially targeting JAK1, JAK2, and/or JAK3). This class-based boxed warning is not unusual or specific to JAK inhibitors, but is in accordance with routine FDA procedures to maintain medication safety.2 An examination of the safety of