Research in context
Evidence before this study
Upadacitinib is an oral selective Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2, which is approved in the USA, Europe, and other countries to treat moderately or severely active rheumatoid arthritis and is under investigation for atopic dermatitis and other immune-mediated inflammatory conditions. Results from a phase 2b study (NCT02925117) showed that monotherapy with upadacitinib is well tolerated and effective in treating patients with moderate-to-severe atopic dermatitis. For many patients with moderate-to-severe atopic dermatitis, systemic therapy in addition to topical corticosteroids is recommended to control symptoms. This combination treatment framework is largely based on the poor efficacy of systemic therapies as monotherapy observed to date. Use of systemic immunosuppressive treatments are limited by the risk of adverse events and the potential for cumulative toxicity. We searched ClinicalTrials.gov for clinical trials done on or before Nov 5, 2020, using the search terms “TCS” and “combination” with “interventional phase 3 studies in atopic dermatitis”. Our search yielded ten studies: one study was not yet recruiting, two studies did not have published results, one study was done in children, three studies were in adults who were not adequately controlled with or had contraindications for ciclosporin A, and three studies were in a population similar to that of AD Up (adolescents or adults with moderate-to-severe atopic dermatitis). In the LIBERTY AD CHRONOS study, the addition of topical corticosteroids to dupilumab, an anti-interleukin (IL)-4 receptor α monoclonal antibody, increased the response rate compared with that for dupilumab monotherapy by approximately 10–20% in patients with moderate-to-severe atopic dermatitis. Similarly in the ECZTRA 3 and BREEZE-AD7 studies, the addition of topical corticosteroids to tralokinumab, an anti-IL-13 monoclonal antibody, or baricitinib, a selective JAK1 and JAK2 inhibitor, increased response rates by approximately 20–30% when compared with either drug as monotherapy.
Added value of this study
This study provides evidence for the safety and efficacy of upadacitinib in combination with topical corticosteroids, which is the current treatment framework for moderate-to-severe atopic dermatitis. Upadacitinib 15 mg and 30 mg plus topical corticosteroids were superior to placebo plus topical corticosteroids for the coprimary endpoints and all key secondary endpoints, with upadacitinib 30 mg plus topical corticosteroids showing numerically better results than upadacitinib 15 mg plus topical corticosteroids for all. A substantial proportion of patients achieved the stringent endpoint of at least a 90% improvement in Eczema Area and Severity Index score from baseline at week 16 in both upadacitinib groups (15 mg or 30 mg plus topical corticosteroids); 63% of patients in the upadacitinib 30 mg plus topical corticosteroids group achieved this endpoint, demonstrating a depth of response that has not previously been reported in studies of other atopic dermatitis therapies. Both doses of upadacitinib were well tolerated in combination with topical corticosteroids and no new important safety signals were observed beyond the known safety profile of upadacitinib in patients with rheumatoid arthritis; however, more patients given upadacitinib reported acne than did patients given placebo in this study. No patients had active tuberculosis, lymphoma, adjudicated gastrointestinal perforations, or adjudicated venous thromboembolisms.
Implications of all the available evidence
The results of this study support the potential of upadacitinib as a treatment option for adults and adolescents with moderate-to-severe atopic dermatitis. The magnitude of the clinical responses observed were generally similar to those observed for upadacitinib monotherapy, which might indicate that the incremental benefit of adding topical corticosteroids to upadacitinib is minimal compared with upadacitinib as monotherapy. A substantial proportion of patients were able to discontinue topical corticosteroids while maintaining a strong treatment response at week 16, suggesting that upadacitinib therapy could align with steroid-sparing treatment goals. These results challenge the current standard of care that asserts combination therapy with topical corticosteroids is essential to optimise outcomes.