Efficacy and safety of topical ruxolitinib cream for the treatment of vitiligo: A systematic review and meta-analysis of randomized controlled trials

Vitiligo is an autoimmune condition with an estimated prevalence of 0.5%–2% worldwide.1 Besides the visible cosmetic concerns associated with vitiligo, it is marked by psychological concerns such as anxiety and distress leading to reduced quality of life.1 The disease is known to be mediated by interferon-gamma (IFN-γ) which acts through the Janus kinase-signal transducer and activator of transcription (JAK–STAT) pathway to recruit CD8+ T cells, which in turn drive the cytotoxicity directed against melanocytes via detachment and apoptosis, leading to the characteristic white skin patches.1 Ruxolitinib acts as a JAK1 and JAK2 inhibitor to suppress the IFN-γ-mediated pathway and prevent melanocyte damage, allowing them to heal and re-pigment.2 Phase 3 trials of ruxolitinib have recently been published and demonstrate encouraging outcomes in vitiligo patients. This meta-analysis aims to systematically collate outcomes from the relatively limited data available and evaluate the efficacy and safety of ruxolitinib in vitiligo patients. This meta-analysis was registered on PROSPERO (CRD42022375736) and was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.3 MEDLINE (via PubMed), Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception till December 2022. We also retrieved relevant articles by screening the bibliographies of the pertinent articles and reviews. Our eligibility criteria are as follows: (1) population: patients diagnosed with vitiligo; (2) intervention: 1.5% topical ruxolitinib cream twice daily; (3) comparator: placebo or standard care; (4) outcome: reporting any outcome of interest; and (5) study design: randomized controlled trials (RCTs). No age or language restrictions were applied. We excluded observational studies, studies that lacked a comparator group, and data on ruxolitinib doses other than 1.5%. The study selection and data extraction were carried out by two authors independently, and any subsequent conflicts were settled by discussion. The primary outcomes were the proportion of patients who attained a ≥50% and ≥75% improvement in the Facial-Vitiligo Area Scoring Index (F-VASI50 and F-VASI75, respectively). The secondary outcomes were the proportion of patients achieving F-VASI90 and ≥50% improvement in the Total-Vitiligo Area Scoring Index (T-VASI50), mean change in body surface area (BSA), treatment-related adverse events (TAEs), and serious adverse events (SAEs). The revised Cochrane Risk-of-Bias tool for RCTs (Rob 2.0) was used for quality assessment.4 We used Review Manager 5.4 to perform the meta-analysis under a random-effects model, using risk ratio (RR) and mean difference (MD) as our effect measures. The I2 statistic was used to evaluate heterogeneity. We were unable to assess publication bias as the number of included studies was less than 10. After the screening of the articles according to our eligibility criteria, two studies reporting the results for 3 RCTs were included.2, 5 The selection process is illustrated through a PRISMA flowchart (Figure S1). The study characteristics are detailed in Table 1. All three RCTs had a low risk of bias (Figure S2). The ruxolitinib group was associated with a higher proportion of participants achieving the F-VASI50 response (RR 2.96; 95% CI: 1.96 to 4.57; p < 0.00001; I2 = 34%) and the F-VASI75 response (RR 3.38; 95% CI: 2.0 to 5.72; p < 0.00001; I2 = 14%) as compared to the vehicle control group (Figure 1). The ruxolitinib group was also associated with a higher proportion of patients showing the F-VASI90 response (RR 8.90; 95% CI: 3.10 to 25.56; p < 0.00001; I2 = 0%; Figure S3) and the T-VASI50 response (RR 3.83; 95% CI: 2.19 to 6.72; p < 0.00001; I2 = 0%; Figure S4). The ruxolitinib group was associated with a greater decrease in mean BSA affected by vitiligo (MD −19.94; 95% CI: −24.61 to −15.27; p < 0.00001; I2 = 0%; Figure S5). We found no significant difference in the incidence of TAEs (RR 1.49; 95% CI: 0.79 to 2.82; p = 0.22; I2 = 57%; Figure S6) and SAEs (RR 2.84; 95% CI: 0.62 to 12.92; p = 0.18; I2 = 0%; Figure S7) between the ruxolitinib and vehicle control groups. After performing leave-one-out sensitivity analyses on the two primary outcomes, F-VASI50 and F-VASI75, we found that the effect of ruxolitinib on F-VASI50 and F-VASI75 became non-significant on removing the TRuE-V1 study (Table S1). We found ruxolitinib to possess significantly greater efficacy for vitiligo than vehicle control on all the efficacy outcomes studied, with a comparable incidence of adverse events between the two groups. Although it remains to be seen if ruxolitinib is more efficacious than the currently approved first-line topical options such as corticosteroids and calcineurin inhibitors, it will likely have a better safety profile even if its efficacy profile is comparable. Unlike corticosteroids and calcineurin inhibitors that are limited by adverse events such as skin atrophy and local skin reactions (for instance, burning), respectively,6 ruxolitinib has demonstrated very few noticeable adverse events such as itching. However, the phase 3 trials in this meta-analysis did not demonstrate significant improvement in patient-reported quality of life index (Dermatology Life Quality Index; DLQI).5 To the best of our knowledge, this is the first meta-analysis assessing the efficacy and safety of ruxolitinib for vitiligo. Our results, however, were limited by a small sample size owing to the novelty of the topic. Moreover, in the trials included in this meta-analysis, ruxolitinib was tested only for patients with nonsegmental depigmentation and <10% body surface area involved. Further trials are needed to expand the population to include more widespread and/or segmental disease, and to compare ruxolitinib with currently approved topical therapies for vitiligo. In conclusion, topical ruxolitinib causes significant re-pigmentation of vitiligo lesions over 24–52 weeks of use with a mild and tolerable adverse event profile. Limited data suggest that it may be an effective alternative and/or additive to the currently approved management options such as steroids and calcineurin inhibitors. However, larger-scale trials and direct comparisons with other established interventions are crucial to establish the role of ruxolitinib in the treatment of vitiligo. Muhammad Ehsan: Conceptualization, Methodology, Formal analysis, Resources, Writing—Review & Editing, Project Administration. Aqeeb Ur Rehman: Methodology, Formal analysis, Resources, Writing—Original draft preparation. Muhammad Ayyan: Formal analysis, Data curation, Writing—Original draft preparation. Huzaifa Ahmad Cheema: Formal analysis, Investigation, Writing—Original draft preparation. Talha Zartash Ahmad: Formal analysis, Investigation, Writing—Original draft preparation. Biah Mustafa: Writing—Review & Editing, Supervision, Validation, Project administration. Abia Shahid: Conceptualization, Investigation, Writing—Review & Editing. Tarek Khedro: Writing—Review & Editing, Supervision, Validation, Project administration. Heba Ismail: Conceptualization, Investigation, Writing—Review & Editing. Abdulqadir J. Nashwan: Methodology, Writing—Reviewing and Editing, Visualization. Final approval of the version to be published: All authors. All authors agree to be accountable for all aspects of the work. The authors report no relationships that could be construed as a conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.