Safety of upadacitinib in patients with moderate-to-severe atopic dermatitis

Published: October 1, 2022

Atopic dermatitis (AD) is a common inflammatory skin disorder associated with intense itch and discomfort that can be relentless and interfere with daily activities, interrupt sleep, weaken self-esteem, and negatively impact school or work performance. Although the underlying causes of AD are not fully understood, this chronic, systemic disease is linked to an overactive immune system. An overactive immune system may cause excess inflammation, leading to the rash and intense itch that patients with AD endure. Janus kinase (JAK) inhibitors, a relatively new class of drugs, block some of the signals that drive an overactive immune system. Upadacitinib, a JAK inhibitor, is taken orally once daily and approved in multiple countries to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and AD.

In a recent issue of The Journal of Allergy and Clinical Immunology (JACI), Guttman-Yassky and colleagues assessed the safety of upadacitinib through 1 year of treatment using combined data gathered from a phase 2b and 3 ongoing phase 3 randomized, placebo controlled clinical trials. Across the phase 3 trials, adults and adolescents with moderate-to-severe AD were randomized to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or a placebo administered orally once daily alone (in the Measure Up 1 [NCT03569293] and Measure Up 2 [NCT03607422] trials) or in combination with topical corticosteroids (in the AD Up [NCT03568318] trial). After 16 weeks, patients receiving placebo in the phase 3 trials were randomized to receive either 15 mg or 30 mg of upadacitinib; patients originally assigned to upadacitinib treatment continued with their assigned dose with no switching permitted. Safety was analyzed using the 16-week data comparing upadacitinib versus placebo from the phase 3 trials and the phase 2b (NCT02925117) trial, which only included adult patients. Long-term safety of upadacitinib was evaluated using phase 3 trial data from 1239 patients receiving 15 mg of upadacitinib and 1246 patients receiving 30 mg of upadacitinib. Treatment-emergent adverse events (AEs), AEs of special interest, and abnormalities observed in laboratory tests were assessed.

In the 16-week analysis, rates of any AEs were slightly higher in patients receiving upadacitinib compared with patients receiving placebo. However, the rates of serious AEs and AEs resulting to treatment termination were lower with upadacitinib treatment than placebo. The rates of AEs and AEs of special interest with upadacitinib through approximately 1 year of treatment were generally consistent with rates reported through 16 weeks of treatment, and generally occurred at lower rates with 15 mg of upadacitinib than with 30 mg of upadacitinib. The most frequently reported AE was acne, which was more commonly reported in adolescents and adults aged younger than 40 years than in older adults. Serious infection rates were low (< 3 events per 100 patient-years) and were consistent with serious infection rates observed with other JAK inhibitors in the treatment of AD. Herpes zoster (shingles) was reported more often in patients receiving upadacitinib than those receiving placebo; the rate was highest with upadacitinib 30 mg. Most herpes zoster events were nonserious and had localized skin involvement. Major adverse cardiovascular events and venous thromboembolic events were observed less common (≤ 0.1 events per 100 patient-years) than those among patients with rheumatoid arthritis who were treated with upadacitinib (0.4-1.0 events per 100 patient-years) and similar to those reported for other JAK inhibitors (0.1-0.3 events per 100 patient-years) used in patients with AD. Cancer rates were low (≤ 0.5 events per 100 patient years); the number of cancers reported was within the expected range as those in the general population. Abnormalities seen in laboratory tests, including decreases in hemoglobin, neutrophil, and lymphocyte counts and increases in creatine phosphokinase and liver transaminase levels, were generally mild or moderate in severity, and mostly transient; few of these AEs led to treatment discontinuation. The safety profile in adolescents was similar to that observed in the overall population (adults + adolescents).

In summary, upadacitinib was generally safe and well tolerated through approximately 1 year of treatment among over 2500 adults and teenagers with moderate-to-severe AD. Results from this pooled analysis of long-term safety are consistent with results previously published in short-term safety reports. No new safety risks with upadacitinib treatment were observed.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI and is the most-cited journal in the field of allergy and clinical immunology.

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