Combination Regimens Linked to Accelerated VASI Reductions in Vitiligo

This article was originally published by Dermatology Times^®.

Vitiligo management continues to evolve with the introduction of targeted therapies and optimized phototherapy protocols. However, direct comparative data on monotherapy vs combination regimens remain limited, particularly in real-world longitudinal settings. In a novel multicenter retrospective cohort study, investigators evaluated the comparative effectiveness of monotherapy vs combination therapy in 500 patients over 12 months.¹

The trial included patients with vitiligo treated at 2 tertiary centers in Saudi Arabia, where the prevalence of vitiligo is notably higher than the global average.² The cohort included 500 patients with an age range of 1 to 75 years, contributing approximately 5000 visit-level Vitiligo Area Scoring Index (VASI) assessments. Approximately 52% were women. Patients were classified retrospectively according to treatment modality: 179 received monotherapy and 321 received combination therapy.

Monotherapies included topical corticosteroids (TCS), topical calcineurin inhibitors (TCIs), narrowband UVB (NB-UVB), excimer laser, or Janus kinase (JAK) inhibitors (topical ruxolitinib or oral tofacitinib). Combination regimens incorporated predefined pairings or multiagent protocols, including TCI plus TCS; TCI plus TCS and NB-UVB; excimer-based combinations; and JAK inhibitor–based regimens with or without phototherapy and topical agents.

Baseline demographic characteristics were similar across groups for age, sex, and nationality, although modest differences in vitiligo subtype distribution were observed. Acrofacial, vulgaris, and focal types were most common overall. Universal and segmental vitiligo were relatively rare but more frequently represented in the combination cohort.

All treatment modalities were associated with statistically significant longitudinal reductions in VASI scores (P < .001). Among monotherapies, NB-UVB and JAK inhibitors produced the most substantial 12-month improvements (70.7% and 48.2% VASI reduction, respectively), whereas TCS and TCI monotherapy yielded more modest improvements (22.5% and 32%). In contrast, several combination regimens demonstrated markedly greater reductions. For example, TCI plus TCS and NB-UVB achieved a 93.1% reduction in VASI at 12 months, whereas TCS plus excimer laser resulted in a 92.4% reduction. JAK inhibitor–based combinations also showed robust efficacy, particularly when paired with NB-UVB.

To account for repeated measures and interpatient variability, the investigators applied linear mixed-effects models with random intercepts and slopes. Model comparison using AIC, BIC, and likelihood ratio testing identified a final model incorporating both patient-level random effects and an interaction term between therapy modality and visit order as the best fit. In a multivariable analysis without the interaction term, combination therapy was associated with a 2.1-point lower VASI score than monotherapy (P < .001), after adjustment for age, sex, nationality, and vitiligo subtype. Age was independently associated with slightly worse outcomes (0.02-point VASI increase per year; P = .019). Gender and nationality were not significant predictors.

When the therapy-by-visit interaction was introduced, the direct main effect of therapy modality became nonsignificant, but the interaction term was strongly significant (−0.31 VASI points per visit for combination therapy; P < .001). This finding indicates that the therapeutic advantage of combination regimens accumulates over time, resulting in progressively steeper VASI declines compared with monotherapy. In other words, although baseline differences may partially reflect confounding by indication, the longitudinal trajectory clearly favored combination approaches.

Vitiligo phenotype significantly influenced outcomes. Compared with vulgaris vitiligo, genital (−9.4 VASI), focal (−6.9), and acrofacial (−4.6) subtypes demonstrated greater improvement (all P < .001). Universal vitiligo was strongly associated with worse outcomes (+48.5 VASI; P < .001), reflecting its known therapeutic resistance. Segmental vitiligo did not differ significantly from vulgaris in adjusted analyses.

The intraclass correlation coefficient (ICC) was 0.95, indicating that 95% of the variability in VASI scores was attributable to between-patient differences rather than within-patient change over time. The marginal R² of the final model was 0.42, and the conditional R² was 0.97, reflecting excellent overall model performance. However, the high ICC underscores substantial interpatient heterogeneity, likely reflecting genetic, immunologic, and clinical variability not fully captured in routine documentation.

This research has several strengths, including a relatively large sample size, standardized VASI assessments, and rigorous longitudinal modeling. Plus, the use of mixed-effects models allowed adjustment for repeated measures, partial control of confounding, and robust estimation of dynamic treatment effects. Some limitations include its retrospective design, lack of randomization, and potential confounding by indication, as patients with more severe or progressive disease were more likely to receive combination therapy. Although the models adjusted for baseline severity and phenotype, residual confounding cannot be excluded. Additionally, the analysis was limited to patients with complete 12-month follow-up, introducing potential survivorship bias. Generalizability may also be limited by the predominantly Saudi population and tertiary care setting.

The real-world analysis demonstrates that combination therapy—particularly regimens incorporating NB-UVB and/or JAK inhibitors—achieves faster and more sustained VASI reductions than monotherapy in vitiligo. Treatment response varies significantly by phenotype and age, reinforcing the need for individualized severity- and subtype-guided management strategies.

“Our results emphasize the need for prospective trials and network meta-analyses to optimize regimen design and explore the biological mechanisms underlying the substantial interpatient variability observed in treatment response,” the researchers concluded.

References

1. Molla A, Althobaiti S. Comparative effectiveness of monotherapy versus combination therapy in vitiligo: a mixed-effects model analysis of longitudinal VASI scores. Dermatol Ther. 2026;1:7443487. doi:10.1155/dth/7443487

2. Molla A, Alayoubi AM, Jannadi R. First cousin marriages and the risk of childhood-onset vitiligo: exploring the genetic background: a cross-sectional study. Clin Cosmet Investig Dermatol. 2024;17:1471-1479. doi:10.2147/CCID.S470937