The efficacy and safety of Janus kinase inhibitors in patients with atopic dermatitis: A systematic review and meta-analysis

To the Editor: Current treatments may not satisfactorily relieve symptoms of atopic dermatitis (AD), especially severe AD.1Leung D.Y. Guttman-Yassky E. Assessing the current treatment of atopic dermatitis: unmet needs.J Allergy Clin Immunol. 2017; 139: S47-S48Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Janus kinase inhibitors (JAKis) are increasingly being used in the treatment of AD, with both topical (ruxolitinib cream) and oral (upadacitinib and abrocitinib) versions recently receiving US Food and Drug Administration approval for this indication.2Kim B.S. Sun K. Papp K. Venturanza M. Nasir A. Kuligowski M.E. Effects of ruxolitinib cream on pruritus and quality of life in atopic dermatitis: results from a phase 2, randomized, dose-ranging, vehicle- and active-controlled study.J Am Acad Dermatol. 2020; 82: 1305-1313Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar We systematically review the efficacy and safety of JAKis among existing randomized, double-blinded, and placebo-controlled clinical trials of JAKis for the treatment of AD. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered in PROSPERO (CRD42020188514). We searched electronic databases (Embase, PubMed, and Cochrane Central Register of Controlled Trials) from their inception to September 16, 2021. We also searched unpublished clinical trials at ClinicTrials.gov. The search strategies and methods are provided in Supplementary Materials (available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2). We initially identified 1209 records from all 4 databases, as summarized in Supplementary Fig 1 (available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2). Of these, a total of 25 studies were finally included in the meta-analysis, including 8 studies on topical JAKis and 17 on oral JAKis. There were 9931 participants, consisting of 2383 involved in studies on topical JAKis and 7548 in studies on oral JAKis. Four kinds of topical JAKis (tofacitinib ointment, delgocitinib ointment, delgocitinib cream, and ruxolitinib cream) were applied, and 5 kinds of oral JAKis (baricitinib, abrocitinib, ASN002, SHR0302, and upadacitinib) were given at varying dosages. The detailed characteristics of the included studies are summarized in Supplementary Table I (available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2). We also assessed the risk of bias, as summarized in Supplementary Fig 2 (available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2) and Supplementary Table II (available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2). Overall, compared with placebos, the use of JAKis showed a significant improvement in the lesion score and pruritus: Eczema Area and Severity Index score (standard mean difference [95% CI], −0.79 [−0.97 to −0.61]; P < .00001); investigators’ global assessment score (odds ratio [OR] [95% CI], 5.08 [3.78-6.82]; P < .00001); and pruritus numerical rating scale (standard mean difference [95% CI], −0.49 [−0.67 to −0.32]; P < .00001) (Supplementary Table III [available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2] and Supplementary Figs 3 to 5 [available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2]). Although no significant adverse effects (AEs) were found for the topical JAKis, the oral JAKis showed an increased risk of at least 1 AE (OR [95% CI], 1.23 [1.11-1.36]; P < .0001) and the following most frequently reported AEs: gastrointestinal disorders (OR [95% CI], 2.49 [1.84-3.37]; P < .00001), nasopharyngitis (OR [95% CI], 1.23 [1.04-1.46]; P = .02), and headache (OR [95% CI], 1.57 [1.23-2.00]; P = .0003) (Supplementary Table IV, available via Mendeley at https://data.mendeley.com/datasets/89x8s56p5z/2). No malignancy or death was reported. Previous systematic reviews have reported that herpes zoster and serious infections are common in JAKi treatment.3Olivera P.A. Lasa J.S. Bonovas S. Danese S. Peyrin-Biroulet L. Safety of Janus kinase inhibitors in patients with inflammatory bowel diseases or other immune-mediated diseases: a systematic review and meta-analysis.Gastroenterology. 2020; 158: 1554-1573Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 4Bechman K. Subesinghe S. Norton S. et al.A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis.Rheumatology (Oxford). 2019; 58: 1755-1766Crossref PubMed Scopus (140) Google Scholar, 5Khoo J.K. Barnes H. Key S. Glaspole I.N. Östör A.J. Pulmonary adverse events of small molecule JAK inhibitors in autoimmune disease: systematic review and meta-analysis.Rheumatology (Oxford). 2020; 59: 2217-2225Crossref PubMed Scopus (17) Google Scholar However, these were infrequent in our systematic review. Creatine phosphokinase level elevations were mentioned in baricitinib and upadacitinib treatments: even though patients with creatine phosphokinase level elevation were asymptomatic, the incidence and relationship with JAKi therapy remain to be further investigated. Undoubtedly, long-term follow-up trials are needed for better assessing the safety profile. In conclusion, this systematic review and meta-analysis showed that JAKis are a promising treatment option for AD. Because of the higher risk of gastrointestinal disorders, nasopharyngitis, and headache during oral JAKi treatments, more attention should be paid to the AEs of patients treated with oral JAKis. Further studies with long follow-up in different conditions will be needed to fully elucidate the safety profile of the different JAKis. None disclosed.