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
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
