To the Editor: Vitiligo is an autoimmune disease characterized by depigmented patches of skin and is challenging to manage with limited treatment options. Interferon (IFN)-γ-chemokine axis appears as a key driver of vitiligo. Melanocyte-specified CD8+ T cells produce IFN-γ when confront the melanocyte antigen, then activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in local keratinocytes, subsequently the keratinocytes produce the downstream chemokine C-X-C motif chemokine ligand 9 and 10 leading to additional recruitment of T cells to attack the melanocytes.

JAK belongs to a family of cytoplasmic tyrosine kinases and contains four domains JAK1, JAK2, JAK3, and TYK2. Many cytokines use the JAK/STAT pathway to achieve their effect. In vitiligo, JAK1 and JAK2 are recruited by IFN-γ-bound receptor complex, resulting in phosphorylation and nuclear translocation of STAT, leading to transcriptional activation of IFN-γ-inducible genes. Until now, there have been increasing case reports and clinical trials proving good results of JAK inhibitors for vitiligo treatment.[1]

Our study was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Web searches were carried on PubMed, Web of Science, Ovid Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effectiveness from January 2000 to October 2022. We combined the terms: “vitiligo” AND “Janus Kinase” OR “JAK inhibitor” OR “Janus Kinase inhibitors” OR “ruxolitinib OR tofacitinib OR baracitinib OR delgocitinib” as either key words or MeSH terms. The reference lists of these articles were also reviewed to identify potentially relevant studies. Vitiligo patient from cohort studies, clinical trials, case series and case reports treated with JAK inhibitors were all included in this study. Reviews, abstracts, expert opinions, or conference presentations were excluded.

In our study, major treatment outcomes including: any response (defined as 5%–100% repigmentation), good response (defined as 51%–100% repigmentation or a “good” or “excellent” outcome or vitiligo area scoring index (VASI50) response as described by authors) and partial response (defined as 5%–50% repigmentation). Other data including vitiligo subtype, duration of vitiligo, prior treatments, kind of JAK inhibitor, route of administration, time of initial repigmentation, duration of therapy, relapse rates, side effects were also collected.

Review Manager V.5.4 software (Cochrane Collaboration) and SPSS software V.24.0 (IBM Corp, Armonk, USA) were used for statistical analyses. Individual patient level data were analyzed using descriptive statistics. Univariable analysis was performed in terms of factors such as no phototherapy vs. phototherapy. P values <0.05 was considered as statistically different.

A total of 149 studies were picked out through six electronic data pool and other sources including reference lists. After excluding the irrelevant or duplicate articles, and studies with overlapping subjects, 32 potentially relevant studies were identified. Finally, 18 studies were included in the present study after a detailed evaluation, including two clinical trials (involving 831 subjects). Oral therapy was used in 2.8% (25/883) subjects and topical therapy was used in 97.2% (858/883) subjects. Combination of phototherapy was applied in 40% (10/25) of oral treatment cases and 1.9% (16/858) of topical treatment cases.

Summarized characteristics of included studies and cases are showed in Supplementary Table 1, https://links.lww.com/CM9/B525. The age of the patients ranged from 12 to 65 years, with 411 males, 463 females, and nine of unknown gender. The duration of vitiligo ranged from 1 to 480 months. Treatment duration ranged from 3 to 52 months. A total of 35 cases (16.7%) had autoimmune comorbidities including thyroid diseases, rheumatoid arthritis, alopecia areata, psoriasis and juvenile diabetes.

A total of 263 patients were excluded because of receiving vehicle cream. In total of 620 patients, the rate of patients reported any response was 73.4% (455/620). The rate of patients with good response was 51.8% (455/620) and the rate of partial responses was 21.6% (134/620). The average time of initial repigmentation was 3.6±2.6 months. The relapse of vitiligo only discussed in some case reports, two patients in oral group and one in topical group. The relapse occurred after an average of 9 months of drug withdrawal.

The good response rate in patients who only received JAK inhibitors was lower than those received concurrent phototherapy, with statistically significant difference (45.7% vs. 96.2%, P < 0.001). When subgrouped according to route of administration, this difference was also remarkable both in topical treatment group (47.8% vs. 93.8%, P < 0.001) and oral treatment group (26.7% vs. 100%, P < 0.005).

For oral treatment patients, treatment-related adverse events included mild elevations of lipids (16.0%, 4/25), upper respiratory infection (8.0%, 2/25), weight gain (4.0%, 1/25) and arthralgias (4.0%, 1/25). No serious adverse event was reported. For patients with topical JAK inhibitors, severe side effects of myalgias and creatine phosphokinase (CPK) elevation was reported in two cases (0.3%, 2/595) which led to discontinuation of the treatment. Minor complications included acne (8.2%, 49/595), application site pruritus (6.4%, 38/595), pruritus (0.8%, 5/595) and erythema (0.7%, 4/595). No new malignancy or tuberculosis reactivation was reported. Complications are summed up in Supplementary Table 1, https://links.lww.com/CM9/B525.

In the past several years, there had been increasing literatures supporting the use of JAK inhibitors in vitiligo.[2,3] Our study revealed that for those patients using Jak inhibitors, the proportion with any response was 73.4%, and good response were found in 51.8% of the patients. It should be noted that 38.7% of the patients were reluctant to systemic therapy or phototherapy before using JAK inhibitors. Concurrent phototherapy might significantly improve the good response rate in patients using JAK inhibitors, the result was statistically different in both topical treatment group (P < 0.001) and oral treatment group (P < 0.005). It was speculated that photoactivation of melanocytes make them leave the stem cell niche and feed the epidermis to be pigmented, and in the meantime, the JAK inhibitors restrain the autoimmune CD8+ T cells and IFN-γ dependent responses which attack melanocytes and lead to depigmentation.[4]

In our analysis, an overall low complication rate was found. The most common side-effects of oral treatment were mild elevations of lipids, upper respiratory infection, weight gain and arthralgias. For topical treatment, the common side-effects included pruritus, acne and erythema. There was no case of newly reported malignancy or reactivation of tuberculosis, although the follow-up for the involving subjects was limited and still ongoing. Myalgias and CPK elevation should be noticed in cases using JAK inhibitors topically. There was an interpretation that the sudden increased myocyte proliferation might damage the muscle cell, resulting in myositis symptoms or myalgias, and also raise the serum CPK expression.[5]

Our study had several limitations. The number of randomized controlled trial was limited. And there might also be selection bias and publication bias, in consideration of that it was probably only positive outcomes are published. At the same time, there were differences in the type and severity of vitiligo in included study.

In conclusion, there have been promising results for JAK inhibitors in the treatment of vitiligo. Concurrent phototherapy might improve the efficacy of JAK inhibitors, both orally and topically. Further large scale RCTs are required to conform the efficacy and safety of JAK inhibitors in vitiligo treatment.

Conflicts of interest

None.

References 1. Rosmarin D, Pandya AG, Lebwohl M, Grimes P, Hamzavi I, Gottlieb AB, et al. Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial. Lancet 2020; 396:110–120. doi: 10.1016/S0140-6736(20)30609-7. 2. Rosmarin D, Passeron T, Pandya AG, Grimes P, Harris JE, Desai SR, et al. TRuE-V study group. Two phase 3, randomized, controlled trials of ruxolitinib cream for vitiligo. N Engl J Med 2022; 387:1445–1455. doi: 10.1056/NEJMoa2118828. 3. Qi F, Liu F, Gao L. Janus Kinase inhibitors in the treatment of vitiligo: a review. Front Immunol 2021; 12:790125doi: 10.3389/fimmu.2021.790125. 4. Liu LY, Strassner JP, Refat MA, Harris JE, King BA. Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure. J Am Acad Dermatol 2017; 77:675–682.e1. doi: 10.1016/j.jaad.2017.05.043. 5. Narla S, Oska S, Lyons AB, Lim HW, Hamzavi IH. Association of myalgias with compounded topical Janus kinase inhibitor use in vitiligo. JAAD Case Rep 2020; 6:637–639. doi: 10.1016/j.jdcr.2020.05.002.