Although several case reports and small clinical trials have reported promising outcomes with Janus kinase (JAK) inhibitors for vitiligo, high-quality evidence and guidelines are lacking. We evaluated the efficacy and safety of JAK inhibitors for the treatment of vitiligo using a meta-analysis of randomized controlled trials (RCTs). We searched the PubMed, Embase, and Cochrane Library databases up to August 2023, with additional studies from ClinicalTrials.gov and company websites. We assessed outcomes, including percentage improvement in total vitiligo area score index (TVASI) and facial vitiligo area score index (FVASI); the proportion of patients achieving 50% improvement in TVASI (TVASI50) and 50% and 75% improvement in FVASI (FVASI50 and FVASI75); the risk of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), infections, and skin-related adverse events (AEs). Five studies with 1,550 participants were included. JAK inhibitors were associated with a higher proportion of TVASI50 (relative risk [RR] 2.67, 95% confidence interval [CI] 1.24–5.78) and FVASI75 (RR 3.97, 95%CI 2.62–6.02) responders than placebo. JAK inhibitors significantly increased the risk of skin-related AEs (RR 1.96, 95% CI 1.29–2.98) compared with placebo. However, the risk of TEAEs, SAEs, and infections was not significantly different between the JAK inhibitor and placebo groups. Subgroup analysis showed that JAK1 and JAK1/2 inhibitors were more effective than JAK3 inhibitors. However, there was insufficient evidence to suggest that the route of administration affects the efficacy and safety of JAK inhibitors in vitiligo. These findings indicate that JAK inhibitors are effective in repigmentation and well tolerated in patients with vitiligo.

Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC?

There is a dearth of high-quality evidence regarding Janus kinase (JAK) inhibitor monotherapy in patients with vitiligo. Further, little is known about the factors that influence the efficacy and safety outcomes of JAK inhibitors, including selectivity (type of JAK inhibitor) and route of administration.

WHAT QUESTION DOES THIS STUDY ADDRESS?

This study evaluated the efficacy and safety of JAK inhibitors in patients with vitiligo through a comprehensive meta-analysis of available randomized controlled trials (RCTs).

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This meta-analysis provides robust evidence supporting the effectiveness of JAK inhibitors in repigmentation and their safety in patients with vitiligo. In addition, JAK1 and JAK1/2 inhibitors are more effective than JAK3 inhibitors, but with lower safety. However, there is insufficient evidence suggesting differences in the efficacy and safety of topical and systemic JAK inhibitors for vitiligo.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These findings shed light on the efficacy and safety of JAK inhibitors and further elucidate their differences in terms of selectivity and route of administration, which may influence therapeutic decisions for patients with vitiligo in the future.

Vitiligo is a chronic immune-mediated skin disorder characterized by the progressive loss of melanocytes, leading to white patches on the skin. It is estimated to affect 0.5–2% of individuals globally.¹ This disfiguring condition could have destructive mental consequences, including anxiety, depression, stress, and low self-esteem.² Traditional treatments for vitiligo include oral or topical corticosteroids, calcineurin inhibitors, and phototherapy. However, these treatments have limitations of significant side effects and unsatisfactory repigmentation.³ With the increased understanding of the importance of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the pathogenesis of vitiligo, JAK inhibitors are expected to be a new class of drugs for treating this condition.^{4, 5}

JAK inhibitors are small molecules that selectively block one or more of the JAK family enzymes (JAK1, JAK2, JAK3, and TYK2), which may be targeted to inhibit the effects of a wide array of cytokines, such as interferon-gamma (IFN-γ).^{6, 7} CD8+T cell-mediated autoimmunity is one of the pathogenic mechanisms of vitiligo. CD8+T cells secrete high levels of IFN-γ, which activates the JAK1/2 dimer, inducing CXC chemokine ligand (CXCL) 9/10 production by keratinocytes to recruit additional T cells, thereby promoting the progression of vitiligo.^{8, 9} Thus, it is well established that through blocking the JAK–STAT signaling pathway to inhibit the IFN-γ signaling pathway, the treatment of vitiligo can be achieved.¹⁰

In July 2022, topical ruxolitinib (Opzelura) was approved by the Food and Drug Administration (FDA) for the treatment of vitiligo, providing evidence of its efficacy and safety. However, other JAK inhibitors for vitiligo are still undergoing clinical trials. Therefore, we aimed to comprehensively evaluate the evidence for the efficacy and safety of JAK inhibitor monotherapy for vitiligo and determine whether their selectivity and route of administration influence treatment outcomes.

METHODS

The study protocol was registered with PROSPERO (registration number: CRD42023459550) and executed according to the PRISMA guidelines (PRISMA checklist).¹¹

Search strategy

A summary of the JAK inhibitors currently used for the treatment of vitiligo is provided in Table 1. We searched the PubMed, Embase, and Cochrane Library databases from their inception dates to August 1, 2023, using MeSH or Emtree terms, such as vitiligo, JAK inhibitors, tofacitinib, ruxolitinib, baricitinib, ritlecitinib, povorcitinib, and upadacitinib, along with related keywords. Table S1 provides the details of the search strategies for each database. Clinical trials registered at ClinicalTrials.gov (http://clinicaltrials.gov) were searched for detailed information. In addition, we manually searched the official websites of relevant companies and obtained unpublished data.

Table 1. Summary of current Janus kinase inhibitors used for vitiligo treatment

Target	JAK inhibitor	Route of administration	Research stage for vitiligo
JAK1	Upadacitinib	Oral	Phase 3 study¹²
	Povorcitinib	Oral	Phase 3 study^{13, 14}
	Ivarmacitinib	Topical	Phase 2a study¹⁵
JAK1/2	Ruxolitinib	Topical	FDA-approved for vitiligo treatment¹⁶
JAK1/2	Baricitinib	Oral	Case series¹⁷
JAK1/3	Tofacitinib	Oral, topical	Open-label pilot study, case series^18-22
JAK1/3	Ifidancitinib	Topical	Open-label pilot study²³
JAK3, TEC	Ritlecitinib	Oral	Phase 3 study^24-26
JAK1/2/3, SYK	Cerdulatinib	Topical	Phase 2 study²⁷
JAK1/2/3, TYK2	Delgocitinib	Topical	Case reports²⁸

Abbreviations: JAK, Janus kinase; TEC, tyrosine kinase expressed in hepatocellular carcinoma; SYK, spleen tyrosine kinase; TYK2, tyrosine kinase 2.

Inclusion and exclusion criteria

Studies were selected based on the following inclusion criteria: (i) studies enrolling patients with non-segmental vitiligo (NSV) or segmental vitiligo (SV); (ii) studies in which patients were treated with JAK inhibitor monotherapy; (iii) studies providing efficacy outcomes including vitiligo area scoring index (VASI) or safety outcomes including any adverse events (AEs); and (iv) phase II or III RCTs.

The exclusion criteria were as follows: (i) non-RCTs, observational studies, case reports, case series, reviews, and abstracts; (ii) studies that did not report relevant outcomes or had missing data; (iii) studies of repeated publications or repeated reports of the same study group; and (iv) studies in which patients received therapies in addition to JAK inhibitors.

Study selection and data collection

Three investigators independently screened the included articles and extracted the study information, including study characteristics, baseline characteristics of the participants, intervention details, efficacy, and safety outcomes.

The following parameters were used to assess the efficacy outcomes: (i) percentage improvement in the total vitiligo area score index (TVASI) and facial vitiligo area score index (FVASI); (ii) proportion of patients achieving 50% improvement in TVASI (TVASI50); and (iii) proportion of patients achieving 50% and 75% improvement in FVASI (FVASI50 and FVASI75). Safety outcomes included the proportion of patients with (i) treatment-emergent adverse events (TEAEs), (ii) serious adverse events (SAEs), (iii) infections, and (iv) skin-related AEs.

Quality assessment

Two investigators independently assessed the risk of bias of each included trial using the Cochrane Risk of Bias Tool.²⁹ We evaluated the risk of bias, including selection, performance, detection, attrition, reporting, and other biases. Funnel plots were constructed to evaluate publication bias if 10 or more trials were available for an outcome. Any discrepancies were resolved by discussion, with the intervention of a third reviewer if necessary.

Statistical analysis

The efficacy and safety of JAK inhibitors were assessed using meta-analyses, including subgroup analyses stratified by JAK inhibitor selectivity (JAK1, JAK1/2, and JAK3) and administration route (topical and systemic). For dichotomous outcomes, the relative risk (RR) with a 95% confidence interval (CI) was reported; for continuous outcomes, the mean difference (MD) with a 95% CI was reported, and P < 0.05 was considered statistically significant. We used I² statistics to evaluate the heterogeneity between individual studies. Significant heterogeneity was indicated when an I² was greater than 50%, in which case a random-effects model was used; otherwise, a fixed-effects model was used. Sensitivity analyses were performed using the leave-one-out method. The meta-package (version 6.5-0) in R (version 4.3.1) was used to perform all analyses.

Evidence credibility

The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was applied to evaluate the certainty of evidence for each outcome.³⁰ The evidence was classified as high, moderate, low, or very low,³¹ which was based on study limitations,³² inconsistency of results,³³ indirectness of evidence,³⁴ imprecision,³⁵ and reporting bias.³⁶

RESULTS

Study selection

A total of 549 relevant records were identified from electronic databases and other resources. After excluding duplicates, 428 unique records remained, of which 320 were removed after screening the titles and abstracts. Another 103 articles were excluded for various reasons (e.g., case reports, case series, not RCTs, not reporting relevant outcomes, or data duplication). Overall, five studies^37-41 (six RCTs) that met the inclusion criteria were selected (Figure 1). The inclusion and exclusion criteria of the included studies are listed in Table S2.

Details are in the caption following the image — **Figure 1**
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Flow diagram of study selection.

Characteristics of included studies

The research characteristics of the six trials are presented in Table 2. Two studies^{37, 38} including three trials compared topical ruxolitinib with a placebo, and one study³⁷ analyzed two trials in one study. One trial³⁹ compared oral ritlecitinib with a placebo. Two articles^{40, 41} were retrieved from the official websites of Incyte and AbbVie, of which one trial⁴⁰ compared oral povorcitinib with a placebo and the other⁴¹ compared oral upadacitinib with a placebo. The pooled analysis included 1,550 patients with NSV, of whom 1,139 were randomized to the JAK inhibitor group and 411 to the placebo group.

Table 2. Characteristics of the included studies

Study	Year	Phase	Treatment regimen	No. of participants	Female, %	Age, mean (SD), y	TVASI, mean (SD)	FVASI, mean (SD)	Vitiligo subtype	Treatment duration, w	Outcomes
Rosmarin (TRuE-V1)	2022	3	T: topical ruxolitinib cream 1.5% BID C: topical vehicle cream BID	221 109	61.5 45.9	40.2 (15.9)	6.47 (1.99)	0.95 (0.59)	NSV	24	TVASI%, FVASI%, TVASI50, FVASI50, FVASI75, TEAEs, SAEs, infections, skin-related AEs
Rosmarin (TRuE-V2)	2022	3	T: topical ruxolitinib cream 1.5% BID C: topical vehicle cream BID	228 115	49.1 52.2	38.9 (14.3)	6.90 (2.10)	0.88 (0.52)	NSV	24	TVASI%, FVASI%, TVASI50, FVASI50, FVASI75, TEAEs, SAEs, infections, skin-related AEs
Rosmarin	2020	2	T1: topical ruxolitinib cream 0.15% QD T2: topical ruxolitinib cream 0.5% QD T3: topical ruxolitinib cream 1.5% QD T4: topical ruxolitinib cream 1.5% BID C: topical vehicle cream BID	31 31 30 33 32	56.1 38.7 63.3 45.5 62.5	48.3 (12.9)	17.96 (15.45)	1.26 (0.82)	NSV	24	TVASI%, FVASI%, TVASI50, FVASI50, FVASI75, TEAEs, SAEs, infections, skin-related AEs
Ezzedine	2023	2	T1: ritlecitinib 200 mg QD PO for 4 weeks, then 50 mg QD PO for 20 weeks T2: ritlecitinib 100 mg QD PO for 4 weeks, then 50 mg QD PO for 20 weeks T3: ritlecitinib 50 mg QD PO for 24 weeks T4: ritlecitinib 30 mg QD PO for 24 weeks T5: ritlecitinib 10 mg QD PO for 24 weeks C: placebo	65 67 67 50 49 66	46.2 46.3 58.2 56.0 51.0 60.6	45.0 (11.5)	17.2 (11.1)	0.8 (0.8)	NSV	24	TVASI%, FVASI%, TVASI50, FVASI50, FVASI75, TEAEs, SAEs, infections, skin-related AEs
Incyte	2023	2	T1: povorcitinib 15 mg QD PO T2: povorcitinib 45 mg QD PO T3: povorcitinib 75 mg QD PO C: placebo QD	43 43 42 43	67.4 48.8 45.2 55.8	48.8 (11.9)	25.45 (19.09)	NR	NSV	24	TVASI%, TVASI50, FVASI50, FVASI75, TEAEs, SAEs, infections, skin-related AEs
AbbVie	2023	2	T1: upadacitinib 6 mg QD PO T2: upadacitinib 11 mg QD PO T3: upadacitinib 22 mg QD PO C: placebo QD	49 47 43 46	NR	18–66	22	1.1	NSV	24	TVASI50, FVASI75

Abbreviations: TRuE-V1/ TRuE-V2, A Study of Ruxolitinib Cream for Vitiligo; NR, not reported.

Quality assessment

Details of the bias assessment are presented in Table S3. Two studies^{40, 41} were considered as having a high risk of bias because of incomplete outcome data and selective reporting. We did not construct funnel plots to evaluate publication bias because fewer than 10 RCTs were included in our study.

Efficacy of JAK inhibitors

Change from baseline TVASI

The percentage improvement in TVASI was evaluated in five RCTs with 1,156 patients. Significant heterogeneity was observed among the studies (I² = 71%) and a random-effects model was adopted. The pooled results suggested that JAK inhibitors for patients with vitiligo resulted in a significant reduction in the TVASI compared with placebo (MD −15.80, 95% CI −22.40 to −9.19, P < 0.01, GRADE assessment: moderate certainty) (Figure 2a; Table 3).

Table 3. Summary of findings for Janus kinase inhibitors treatment for vitiligo

Outcome	Pooled results	Heterogeneity	Certainty of evidence	Selectivity				Route of administration
Outcome	Pooled results	I² (%)	Certainty of evidence	JAK1	JAK1/2	JAK3	P value	Topical	Systemic	P value
Efficacy outcomes
Change from baseline TVASI	−15.80 (−22.40, −9.19)	71	Moderatea	-15.28 (−26.09, −4.46)	−19.24 (−23.44, −15.04)	-4.24 (−11.51, 3.03)	< 0.01	-19.24 (−23.44, −15.04)	−9.00 (−19.71, 1.71)	0.08
Change from baseline FVASI	−28.20 (−36.01, −20.38)	57	Moderatea	Not estimable	−31.22 (−37.11, −25.33)	−18.50 (−27.41, −9.59)	0.02	−31.22 (−37.11, −25.33)	−18.50 (−27.41, −9.59)	0.02
TVASI50	2.67 (1.24, 5.78)	56	Moderatea	3.97 (0.96, 16.48)	3.86 (2.24, 6.64)	0.69 (0.28, 1.66)	< 0.01	3.86 (2.24, 6.64)	1.69 (0.45, 6.38)	0.26
FVASI50	3.20 (2.42, 4.23)	13	High	3.25 (1.23, 8.56)	2.99 (2.24, 4.01)	10.12 (1.43, 71.89)	0.48	2.99 (2.24, 4.01)	4.72 (1.96, 11.41)	0.34
FVASI75	3.97 (2.62, 6.02)	0	High	6.31 (1.55, 25.62)	3.58 (2.31, 5.55)	8.53 (0.52, 139.43)	0.64	3.58 (2.31, 5.55)	6.79 (1.94, 23.85)	0.34
Safety outcomes
TEAEs	1.14 (0.97, 1.34)	51	Lowa,b, a,b	1.07 (0.73, 1.56)	1.27 (1.08, 1.50)	0.96 (0.83, 1.10)	0.04	1.27 (1.08, 1.50)	0.97 (0.85, 1.11)	0.01
SAEs	1.62 (0.56, 4.66)	0	Lowc	0.67 (0.06; 7.17)	2.69 (0.61, 11.84)	0.66 (0.07, 6.29)	0.46	2.69 (0.61, 11.84)	0.67 (0.13, 3.41)	0.21
Infections	1.19 (0.74, 1.93)	52	Very lowa,c, a,c	1.00 (0.39, 2.59)	1.71 (0.73, 3.99)	0.82 (0.58, 1.17)	0.29	1.71 (0.73, 3.99)	0.84 (0.61, 1.17)	0.13
Skin-related AEs	1.96 (1.29, 2.98)	11	High	7.73 (0.47, 128.35)	2.15 (1.33, 3.47)	0.89 (0.35, 2.27)	0.16	2.15 (1.33, 3.47)	1.46 (0.62, 3.47)	0.45

Data are presented as MD or RR (95% CI).
^a Downgraded one level for serious inconsistency due to statistical heterogeneity (I² ≥ 50%).
^b Downgraded one level for serious imprecision due to the 95% CI overlapping the line of no effect and the wide 95% CI (RR below 0.75 or above 1.25).
^c Downgraded two levels for very serious imprecision due to the 95% CI overlapping the line of no effect and the very wide 95% CI (RR below 0.50 or above 1.50).

Change from baseline FVASI

The percentage improvement in FVASI was evaluated in four RCTs with 1,055 patients. Significant heterogeneity was observed among the studies (I² = 57%) and a random-effects model was adopted. The pooled results suggested that JAK inhibitors significantly reduced the FVASI of patients with vitiligo compared with placebo (MD −28.20, 95% CI −36.01 to −20.38, P < 0.01, GRADE assessment: moderate certainty) (Figure 2b; Table 3).

TVASI50 response

Six RCTs with 1,469 patients reported TVASI50 response rates. The meta-analysis results of the random-effects model showed a higher proportion of TVASI50 responders in the JAK inhibitors group than the placebo group (RR 2.67, 95% CI 1.24 to 5.78, I² = 56%, P = 0.01, GRADE assessment: moderate certainty) (Figure 2c; Table 3).

FVASI50 response

Five RCTs with 1,302 patients reported FVASI50 response rates. The meta-analysis results of the fixed-effects model showed that the JAK inhibitors group was associated with a higher proportion of FVASI50 responders than the placebo group (RR 3.20, 95% CI 2.42 to 4.23, I² = 13%, P < 0.01, GRADE assessment: high certainty) (Figure 2d; Table 3).

FVASI75 response

Six RCTs with 1,477 patients reported FVASI75 response rates. The meta-analysis results of the fixed-effects model showed that the JAK inhibitors group was associated with a higher proportion of FVASI75 responders than the placebo group (RR 3.97, 95% CI, 2.62 to 6.02, I² = 0%, P < 0.01, GRADE assessment: high certainty) (Figure 2e; Table 3).

Safety of JAK inhibitors

JAK inhibitors did not significantly increase the proportion of patients with TEAEs (RR 1.14, 95% CI 0.97 to 1.34, I² = 51%, P = 0.12, GRADE assessment: low certainty) and SAEs (RR 1.62, 95% CI 0.56 to 4.66, I² = 0%, P = 0.37, GRADE assessment: low certainty), compared with the placebo group (Figure 3a,b; Table 3).

Current interest in AEs resulting from JAK inhibitors has focused on infections and skin-related conditions. The infections most commonly reported in the investigated studies were nasopharyngitis, upper respiratory tract infections (URTI), viral URTI, urinary tract infections (UTI), and sinusitis. The results showed that the risk of infections was not significantly different between the JAK inhibitors group and the placebo group (RR 1.19, 95% CI 0.74 to 1.93, I² = 52%, P = 0.4691, GRADE assessment: very low certainty) (Figure 3c; Table 3). Five trials, including 998 patients receiving JAK inhibitors and 364 patients receiving a placebo, reported skin-related AEs (acne, application site acne, pruritus, and application site pruritus). The pooled results suggested that JAK inhibitors increased the proportion of patients with skin-related AEs compared with placebo (RR 1.96, 95% CI 1.29 to 2.98, I² = 11%, P < 0.01, GRADE assessment: high certainty) (Figure 3d; Table 3).

Subgroup analysis

JAK inhibitors were analyzed based on their selectivity and classified as JAK1, JAK1/2, or JAK3. The percentage improvement of TVASI in the JAK1 (MD −15.28, 95% CI −26.09 to −4.46) and JAK1/2 (MD −19.24, 95% CI −23.44 to −15.04) inhibitor groups was higher than that in the JAK3 inhibitor group (MD −4.24, 95% CI −11.51 to 3.03, P < 0.01), and a significant difference was observed in FVASI between JAK1/2 (MD −31.22, 95% CI −37.11 to −25.33) and JAK3 (MD −18.50, 95% CI −27.41 to −9.59, P = 0.02) inhibitors. In addition, JAK1 (RR 3.97, 95% CI 0.96 to 16.48) and JAK1/2 (RR 3.86, 95% CI 2.24 to 6.64) inhibitors appeared to be associated with a higher proportion of TVASI50 responders than JAK3 inhibitors (RR 0.69, 95% CI 0.28 to 1.66, P < 0.01); however, no significant differences were observed in FVASI50 and FVASI75 (Figure S1; Table 3). Significant differences in the proportion of patients with TEAEs among JAK inhibitors of diverse selectivity (JAK1, JAK1/2, and JAK3) were observed (P = 0.04), but no significant differences were found in SAEs, infections, and skin-related AEs (Figure S2; Table 3).

An analysis was also performed to compare the outcomes of topical and systemic administration of JAK inhibitors, resulting in significant differences in the improvement of FVASI scores from baseline (P = 0.02); however, no significant differences were found in the other efficacy endpoints (Figure S3; Table 3). Topical JAK inhibitors (RR 1.27, 95% CI 1.08 to 1.50) had a higher incidence of TEAEs than systemic JAK inhibitors (RR 0.97, 95% CI 0.85 to 1.11, P = 0.01); however, no such differences were observed for SAEs, infections, and skin-related AEs (Figure S4; Table 3).

Sensitivity analysis

Leave-one-out sensitivity analysis of efficacy and safety outcomes showed that seven outcomes (change from baseline TVASI, change from baseline FVASI, FVASI50, FVASI75, SAEs, infections, and skin-related AEs) were stable and not notably influenced by any single study. The results of the TEAEs were inconsistent with the primary analysis after excluding the study by Ezzedine et al.,³⁹ and the results of the TVASI50 were influenced by omitting the study by Rosmarin et al.²⁰ (Figures S5 and S6).

DISCUSSION

Currently, increasing evidence suggests that JAK inhibitors may have potential therapeutic uses for vitiligo.^{42, 43} However, this evidence is mainly based on low-quality studies, including case reports and case series. In this systematic review and meta-analysis, we combined the available evidence from six RCTs with 1,550 patients to evaluate the efficacy and safety of JAK inhibitors in patients with vitiligo. Although most JAK inhibitors for vitiligo are still undergoing clinical trials, several important findings of this meta-analysis may influence future therapeutic decisions. First, JAK inhibitors were effective in reducing TVASI and FVASI scores and were associated with a higher proportion of TVASI50, FVASI50, and FVASI75 responders in patients with vitiligo than placebo. Second, although JAK inhibitor therapy might increase the incidence of skin-related AEs, no significant difference was observed in other AEs, including TEAEs, SAEs, and infections, compared with the placebo. Lastly, subgroup analysis found that JAK1 inhibitors (povorcitinib and upadacitinib) and the JAK1/2 inhibitor (ruxolitinib) were more efficient than the JAK3 inhibitor (ritlecitinib), although with lower safety performance.

For efficacy and safety outcomes, the level of evidence ranged from very low to high, and outcomes were downgraded owing to imprecision and inconsistency. The level of evidence for efficacy outcomes was higher than that for safety outcomes. We downgraded the level of evidence for safety outcomes because most of the 95% CIs were wide and overlapped with the line of no effect (RR = 1). However, despite the fact that wide 95% CIs were also found in efficacy outcomes, we did not downgrade the level because it did not cross the no-effect line.

Previous studies have reported that the VASI is a reliable and widely cited tool for evaluating the degree of depigmentation in vitiligo,^{44, 45} with TVASI50 and FVASI75 identified as clinically meaningful thresholds.⁴⁶ Our findings revealed that JAK inhibitor monotherapy for vitiligo reduced TVASI and FVASI scores and increased the proportion of FVASI75 and TVASI50 responders compared with placebo. For patients with vitiligo, the face is one of the most important sites for achieving satisfactory results.⁴⁷ Compared with the proportion of FVASI50 and TVASI50 responders, we found that the facial therapeutic response was better after the use of JAK inhibitors, which was consistent with other studies.^{22, 48} The reason for this might be the lower melanocyte density observed in acral lesions.⁴⁹ Thus, these study findings suggest that the use of JAK inhibitors in patients with vitiligo could achieve a desirable therapeutic benefit.

Based on previously reported studies,^{7, 37-39, 50} AEs from JAK inhibitor monotherapy are frequently mild to moderate, predictable, and easy to manage. Safety analyses showed that JAK inhibitors did not significantly increase the incidence of TEAEs or SAEs compared with placebo. Infectious diseases and skin-related AEs are the most recognized AEs of JAK inhibitors.^51-53 In our study, the pooled results indicated that JAK inhibitors were associated with skin-related AEs but not with infections, suggesting their relative safety for the treatment of vitiligo. However, our findings should be interpreted with caution for the following reasons: First, the six RCTs included in this analysis evaluated the safety outcomes at 24 weeks. Long-term data from extension studies were not included because there were no comparison groups. Second, four of the six RCTs reporting AEs were phase II clinical trials, and we did not distinguish among different dose groups owing to the limited number of included studies. Owing to this, for the high-dose groups, the pooled safety results of our study could have been exaggerated. Finally, safety results in the real world can be influenced by confounding factors, including age differences, smoking habits, and the presence of other comorbidities such as diabetes and hypertension.⁵⁴ For these reasons, further studies are needed to assess the safety of these treatment agents.

We used a subgroup analysis to explore the differences in the efficacy and safety of JAK inhibitors with different selectivities. JAK1 and JAK1/2 inhibitors showed a better response in terms of total-body repigmentation than JAK3 inhibitors; however, this difference was diminished for facial repigmentation. In terms of safety, JAK3 inhibitors were associated with a lower incidence of TEAEs. The differences in the efficacy and safety among JAK1, JAK1/2, and JAK3 inhibitors can be explained by two main reasons. First, the inhibition of JAK1/2 is necessary to block IFN-γ signaling, which is central to vitiligo⁵⁵; whereas the inhibition of JAK3 is irrelevant to the production of IFN-γ.⁵⁶ Second, JAK3 is exclusively associated with the gamma chain (γc) cytokines while JAK1 is associated with a broader spectrum of cytokines, implying that JAK1 inhibitors would have a wider array of effects and a higher risk of AEs than JAK3 inhibitors.⁵⁷ In addition, we found that differences in effects among JAK inhibitors depend on body site, but there is not enough evidence to support this. Thus, further subgroup or network analyses should be conducted if new RCTs are published.

The differences in pharmacokinetic characteristics of topical and systemic JAK inhibitors could potentially influence their efficacy and safety. To ensure that topical and systemic JAK inhibitors were comparable and to further investigate their differences, we conducted a subgroup analysis based on the route of administration. The analysis revealed no significant difference in the efficacy of topical and systemic JAK inhibitors. Although a difference was observed in the improvement of the FVASI scores, we believe that this was more likely caused by the selectivity of the JAK inhibitors rather than by the route of administration. This hypothesis is supported by the fact that JAK inhibitors of diverse selectivity showed different effects in improving TVASI scores and the proportion of TVASI50 responders, whereas efficacy results were consistent for the different administration routes. In addition, it is difficult to compare the safety of topical and systemic JAK inhibitors in patients with vitiligo because of the lack of available extensive data. A meta-analysis assessing the efficacy and safety of JAK inhibitors for alopecia areata indicated that there were no significant differences between systemic and topical administration in terms of safety outcomes,⁵⁸ which is consistent with our findings. Herein, we observed that systemic JAK inhibitors resulted in a lower occurrence of TEAEs than topical JAK inhibitors, which could be attributed to the better safety profile of JAK3 inhibitors, which are systemic agents. Despite being administered differently, JAK1 and JAK1/2 inhibitors exhibited similar incidence of TEAEs. According to existing studies,^{59, 60} systemic JAK inhibitors, particularly JAK1 and JAK1/2 inhibitors, result in a higher frequency of laboratory abnormalities than topical JAK inhibitors. In summary, the current evidence is insufficient to suggest that the efficacy and safety of JAK inhibitors in the treatment of vitiligo can be influenced by the route of administration.

We acknowledge several limitations to our study. First, as previously discussed, we were unable to evaluate the long-term efficacy and safety of JAK inhibitors because of the lack of a comparison group. Second, we could not compare JAK inhibitors with other therapies because different measurement methods were used to assess vitiligo in other studies. Third, the pooled results of our study showed some deviations because we did not distinguish among the different dose groups. Fourth, we excluded studies, including case reports and case series, which could have demonstrated the feasibility and acceptability of JAK inhibitors in the real world. However, these excluded studies would have limited our ability to discern whether any outcomes resulted from the intervention because of a lack of comparators and sufficient sample sizes.

In conclusion, this meta-analysis supports the efficacy and safety of JAK inhibitors in patients with vitiligo and elucidates their differences in terms of selectivity and route of administration, which may influence therapeutic decisions for vitiligo in the future. Larger and longer duration trials are required to fully evaluate the efficacy and safety profile of JAK inhibitors for the treatment of vitiligo.

ACKNOWLEDGMENTS

None.

FUNDING

This work was supported by the Research Ward Demonstration Construction Project of Beijing Municipal Science and Technology Commission (grant No. 4102000007) and the Scientific and Technological Innovation Team Project of Hebei Innovation Capability Enhancement Plan (grant No. 235A2601D).

CONFLICT OF INTEREST

The authors declared no competing interests for this work.

ETHICAL APPROVAL

As this is a secondary literature-based study, ethical approval is not necessary.

AUTHOR CONTRIBUTIONS

F.H., D.H., and H.F. wrote the manuscript. F.H., D.H., H.F., X.L., Y.L. D.Y., R.D., S.N., L.C., X.N., and Y.F. designed the research. F.H., D.H., and H.F. performed the research. F.H., D.H., B.H., Y.L., and W.D. analyzed the data.

Supporting Information

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Efficacy and Safety of Janus Kinase Inhibitors in Patients with Vitiligo: A Systematic Review and Meta-Analysis

Abstract

Study Highlights

METHODS

Search strategy

Inclusion and exclusion criteria

Study selection and data collection

Quality assessment

Statistical analysis

Evidence credibility

RESULTS

Study selection

Characteristics of included studies

Quality assessment

Efficacy of JAK inhibitors

Change from baseline TVASI

Change from baseline FVASI

TVASI50 response

FVASI50 response

FVASI75 response

Safety of JAK inhibitors

Subgroup analysis

Sensitivity analysis

DISCUSSION

ACKNOWLEDGMENTS

FUNDING

CONFLICT OF INTEREST

ETHICAL APPROVAL

AUTHOR CONTRIBUTIONS

Supporting Information

References

Figures

References

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