The real‐life efficacy of methotrexate in vitiligo: A retrospective study and literature review

Despite the challenging treatment of vitiligo, there is little information on the role of systemic immunosuppressants. The JAK/STAT pathway has gained increased attention for the treatment of vitiligo due to several successful trials with JAK inhibitors. Interestingly, methotrexate has also been reported as a folate-independent suppressor of JAK/STAT activation at normal therapeutic dosages.1 We performed a retrospective study with a low dosage methotrexate of 7.5 mg/week in vitiligo (dosage based on personal experience) and carried out a review of the literature. This study was approved by the ethical committee of UZ Gent. Fifty patients with vitiligo (non-segmental) started methotrexate 7.5 mg/week (+1 mg folic acid on non-methotrexate days) between January 2018 and July 2021. Patients also used topical therapy (steroids [TCS] or calcineurin inhibitors [TCI]: tacrolimus, and/or pimecrolimus) (Table 1). The average follow-up time was 11.7 months with assessment intervals ranging from 3 to 6 months. At each appointment, the disease activity (Vitiligo Disease Activity 15 [VDAS15] and VDAS60) and the disease extent (Vitiligo Extent Score plus [VESplus]) were measured.2-4 Additionally, we performed a review on the efficacy of systemic methotrexate in vitiligo based on a systematic search in Embase, PubMed and Google Scholar on 12 January 2023 using the keywords ‘vitiligo’ and ‘methotrexate’. Only 10/38 (26.3%) and 8/38 (21.1%) of the patients with active vitiligo at baseline (n = 23) had some remaining disease activity at the first and second follow-ups (p < 0.001 and p < 0.001 respectively). The VDAS60 fell significantly after 2–6 months as compared to baseline (median: 6.2; interquartile range [IQR]: 3.3–8.0 vs. median: 0; IQR: 0–1.0; p < 0.001; Figure 1). This was also true in patients that already applied TCS/TCI before the start of methotrexate (median: 6.0 [IQR: 4.0–8.0] vs. median: 0 [IQR: 0–1.0]; p = 0.002), illustrating the added value of systemic treatment in lowering disease activity. Similarly, a substantial drop in VDAS15 was found (p < 0.001). Methotrexate monotherapy decreased the overall disease extent based on VESplus by 19.8% (IQR: 3.7%–32.5%) while methotrexate combined with NB-UVB reduced the disease extent by 38.1% (IQR: 11.2%–70.6%). The results were slightly better in patients already applying topicals at baseline (20.9% [IQR: 1.7–38.6] and 43.8% [IQR: 14.1–79.2] respectively) and were worse in patients previously treated with phototherapy (5.1% [IQR: 3.3%–23.3%] and 31.7% [IQR: 14.3–52.4] respectively). Facial vitiligo decreased by 88.9% (IQR: 50.1%–99.8%) in patients receiving methotrexate with NB-UVB and 47.5% (IQR: 8.2%–72.9%) without phototherapy. Facial repigmentation (>50%) was seen in 48% of patients with monotherapy methotrexate and 81% of methotrexate-plus-NB-UVB patients. The repigmentation percentage did not correlate with disease duration when adjusted for the follow-up time, but correlated positively with a higher age of vitiligo onset in patients receiving NB-UVB (p = 0.033). Limitations of this study are that most patients had moderate to severe vitiligo for a long time (median: 114 months) and the lack of a control group. Higher methotrexate doses (15–20 mg/week), as used in other chronic skin conditions, may improve response rates. The systematic search identified 10 studies including 184 vitiligo patients. None of the studies were randomized clinical trials, three randomized open label studies, one prospective controlled trial, one prospective single-arm trial, one pilot prospective study, one retrospective study and three case series/reports. Disease activity was stopped in 68/84 (81.0%) of patients with active vitiligo after treatment with methotrexate. The results of methotrexate concerning stop of disease progression were comparable to oral mini-pulse steroids (OMP).5 Nine out of ten studies reported repigmentation with methotrexate and 2/3 mentioned similar repigmentation compared to OMP.5-10 Overall, these data support the use of methotrexate to decrease disease activity in vitiligo on top of topical treatments. Methotrexate may be useful as a long-term treatment given the well-known side effect profile of this drug. Especially on the face, promising rates of repigmentation can be observed with or without NB-UVB. The research activities of R. Speeckaert and N. van Geel are supported by the Scientific Research Foundation-Flanders (FWO Senior Clinical Investigator: 18B2721N and 1831512N respectively). The research activities of R. Speeckaert are supporteed by the Special Research Fund (Bijzonder Onderzoeksfonds, BOF) of Ghent University and Ghent University Hospital. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.