JAK Inhibitors for the Management of Atopic Dermatitis

JAK Inhibitors for the Management of Atopic Dermatitis Posted By:
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Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease estimated to affect up to 20% of children and 7% of adults. It is classically characterized a relapsing and remitting disease pattern characterized by pruritus (which can often be severe), redness, excoriation, lichenification, xerosis, oozing, crusting, and secondary skin infections. Chronic eczema can lead to physical and psychological impairment in many patients, and thus prompt treatment is important to improve quality of life. Topical corticosteroids are first-line management for AD; however, there are many patients for whom topical therapies are not adequate to control symptoms. In those patients, biologic or systemic agents are considered.

Janus kinase (JAK) inhibitors are among the newest agents for management of AD. JAK proteins have a role in the JAK-signal transducer and activator of transcription (STAT) signaling pathway involved in AD. This pathway is responsible for the progression of inflammation and itch in AD. JAK inhibition results in reduced symptoms by inhibiting the proteins' involvement in the signaling pathway; some JAK inhibitors are selective and only block 1 protein, while others block multiple.

Oral JAK inhibitors are approved for management in AD in patients whose disease is not controlled by other systemic or biologic therapies, or when biologics are not advisable. Many patients who are considering oral JAK inhibitors for AD have had inadequate response to biologics such as dupilumab or tralokinumab.

Two oral JAK inhibitors, upadacitinib and abrocitinib, are currently FDA-approved for management of AD. Upadacitinib is a selective JAK1 inhibitor that is approved as a once-daily option for management of AD; it is available in 2 doses, 15 mg and 30 mg. Upadacitinib has been shown to be very effective. In a 16-week phase III study, 70% and 80% of patients receiving the 15-mg and 30-mg doses, respectively, achieved 75% improvement in EASI score (EASI-75), compared with only 16% in the placebo group. When looking at 90% improvement in EASI score (EASI-90), 53% and 66% of patients receiving 15-mg and 30-mg once daily, respectively, had achieved this level of improvement; only 8% in placebo group achieved EASI-90. Itch scores were also significantly improved, with patients receiving upadacitinib achieving significant itch reduction as early as week 1. By week 16, 52% to 60% of patients receiving upadacitinib had significant reduction in their itch (controlled or almost controlled).

Abrocitinib is also a selective JAK1 inhibitor approved for once-daily dosing in 2 different strengths (100 mg, 200 mg). In a 12-week study of abrocitinib, 40% and 63% of patients receiving 100-mg and 200-mg abrocitinib, respectively, achieved EASI-75, compared with 12% in placebo group. Both doses of abrocitinib also improved itch reduction as compared with placebo. With concurrent topical corticosteroids, the improvement in EASI-75 and itch reduction was more robust.

Ruxolitinib (RUX) is a topical JAK1/2 inhibitor that is FDA-approved for short-term/noncontinuous AD management. Topical therapy with RUX 1.5% cream twice daily has shown significant improvement in AD and rapid itch reduction. In an 8-week study, topical RUX 1.5% was shown to improve Eczema Area and Severity Index (EASI) score in 72% of patients versus 16% with placebo. Improvement in EASI score was also greater for RUX than topical triamcinolone 0.1% cream. There were also significant improvements in itch scores with RUX—some as soon as 36 hours after starting treatment. Overall, RUX has been shown to be well-tolerated by patients with minimal side effects.

There is a black box warning on JAK inhibitors, with concerns for serious infections, development of malignancies, major cardiovascular events, and thrombosis, among others. These events are rare, but patients must be monitored. More common adverse events include nasopharyngitis, nausea, headache, herpes viral skin infections, elevated creatine phosphokinase, fatigue, and acne. Due to side effect profile and effectiveness of other therapies, it is likely that the oral JAK inhibitors will be less frequently utilized. However, it is excellent to have many different treatment options for our patients, especially those with comorbid autoimmune or rheumatologic conditions which would also benefit from use of a JAK inhibitor.

References
  • Chovatiya R, Paller AS. JAK inhibitors in the treatment of atopic dermatitis. J Allergy Clin Immunol. 2021;148:927.

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Filed under: Dermatology , Allergy/Immunology

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