Treatment Outcomes of Topical Calcineurin Inhibitor Therapy for Patients With Vitiligo

Key Points

Question

What outcomes are associated with topical calcineurin inhibitor (tacrolimus and pimecrolimus) therapy in patients with vitiligo?

Findings

In this meta-analysis of 46 studies including 1499 patients, topical calcineurin inhibitor monotherapy produced an at least mild response in 55.0% of the patients, at least moderate response in 38.5%, and a marked response in 18.1% after a median treatment duration of 3 months. At least moderate responses were achieved in 47.3% of children, 57.5% of lesions on the face and neck, and in 72.9% of participants when topical calcineurin inhibitors were used in combination with phototherapy.

Meaning

Topical calcineurin inhibitors appear to have significant therapeutic effects on vitiligo and it seems that their use should be encouraged in patients with vitiligo.

Abstract

Importance

Topical calcineurin inhibitors (TCIs), including tacrolimus and pimecrolimus, have been widely used for the treatment of vitiligo; however, the efficacy of TCI monotherapy is often underestimated.

Objectives

To estimate the treatment responses to both TCI monotherapy and TCI accompanied by phototherapy for vitiligo, based on relevant prospective studies, and to systematically review the mechanism of action of TCIs for vitiligo treatment.

Data Sources

A comprehensive search of the MEDLINE, Embase, Web of Science and Cochrane Library databases from the date of database inception to August 6, 2018, was conducted. The main key words used were vitiligo, topical calcineurin inhibitor, tacrolimus, pimecrolimus, and FK506.

Study Selection

Of 250 studies initially identified, the full texts of 102 articles were assessed for eligibility. A total of 56 studies were identified: 11 studies on the TCI mechanism, 36 studies on TCI monotherapy, 12 studies on TCI plus phototherapy, and 1 study on TCI maintenance therapy.

Data Extraction and Synthesis

Two reviewers independently extracted data on study design, patients, intervention characteristics, and outcomes. Random-effects meta-analyses using the generic inverse variance weighting were performed for the TCI monotherapy and TCI plus phototherapy groups.

Main Outcomes and Measures

The primary outcomes were the rates of at least mild (≥25%), at least moderate (≥50%), and marked (≥75%) repigmentation responses to treatment. These rates were calculated by dividing the number of participants in an individual study who showed the corresponding repigmentation by the total number of participants who completed that study.

Results

In the 56 studies included in the analysis, 46 (1499 patients) were selected to evaluate treatment response. For TCI monotherapy, an at least mild response was achieved in 55.0% (95% CI, 42.2%-67.8%) of 560 patients in 21 studies, an at least moderate response in 38.5% (95% CI, 28.2%-48.8%) of 619 patients in 23 studies, and a marked response in 18.1% (95% CI, 13.2%-23.1%) of 520 patients in 19 studies after median treatment duration of 3 months (range, 2-7 months). In the subgroup analyses, face and neck lesions showed an at least mild response in 73.1% (95% CI, 32.6-83.5%) of patients, and a marked response in 35.4% (95% CI, 24.9-46.0%) of patients. For TCI plus phototherapy, an at least mild response to TCI plus phototherapy was achieved in 89.5% (95% CI, 81.1-97.9%) of patients, and a marked response was achieved in 47.5% (95% CI, 30.6-64.4%) of patients.

Conclusions and Relevance

The use of TCIs, both as a monotherapy and in combination with phototherapy, should be encouraged in patients with vitiligo.

This systematic review and meta-analysis evaluates studies on the use of topical calcineurin inhibitors for treatment of vitiligo in adults and children.

Introduction

Vitiligo is a common depigmenting skin disorder affecting 0.5% to 1% of the population and is associated with low self-esteem and social stigma.^1,2 Among various treatment options, topical calcineurin inhibitors (TCIs) are recommended as first-line treatments for limited forms of vitiligo.^3,4 Moreover, combining TCIs with phototherapy has been shown to enhance the treatment response compared with phototherapy alone.^5,6 Despite ample evidence for the use of TCIs for the treatment of vitiligo,^5,7,8 the therapeutic efficacy of TCI monotherapy is often underestimated, and, to our knowledge, the mechanism of action of TCIs has yet to be established. In the present study, we performed a systematic review and meta-analysis of all relevant prospective studies to evaluate treatment responses to TCI monotherapy and TCI plus phototherapy for vitiligo.

Methods

A systematic review and meta-analyses were performed in the following 4 areas: (1) mechanism of action, (2) treatment responses (TCI monotherapy and TCI plus phototherapy), (3) the use of TCIs for maintenance therapy, and (4) safety. The study was conducted according to the PRISMA guideline.⁹

Databases

We performed a comprehensive search using predefined search terms (eTable 1 in the Supplement) in MEDLINE, Embase, Web of Science, and Cochrane Library databases from inception to August 6, 2018. The main search terms were vitiligo, topical calcineurin inhibitor, tacrolimus, pimecrolimus, and FK506. All prospective and experimental studies were included with no language restriction.

Study Selection

Selection for the mechanism of action included both in vivo and in vitro experimental studies that have investigated the therapeutic mechanism of TCIs related to vitiligo or melanocytes. Selection for TCI treatment response studies was based on the following inclusion criteria (eTable 2 in the Supplement): (1) prospective study, including randomized and nonrandomized clinical trials and open-label trials; (2) participants of all age groups with a diagnosis of vitiligo; (3) at least 1 TCI monotherapy group or TCI plus phototherapy group; (4) at least 10 participants or 10 patches in each treatment arm, regardless of the dropout rate; (5) outcomes measured based on all vitiligo lesions on the participant’s whole body or each of the patches; and (6) outcomes measured according to the degree of repigmentation on a quartile scale (≥25%, ≥50%, and ≥75%). The types of phototherapy were restricted to narrowband UV-B (NBUVB) and excimer light or laser (EL). Studies that used TCI treatment in combination with any other intervention, such as systemic corticosteroids and antioxidant supplements, were excluded. The selection for maintenance therapy included all prospective studies in which TCIs were used to maintain therapeutic efficacy in patients who had completed treatment.

Two reviewers (J.H.L. and H.S.K.) independently identified relevant articles by searching titles and abstracts. If the abstract did not provide enough information to determine eligibility, the full text was reviewed.

Data Extraction, Synthesis, and Subgroup Analyses

Mechanism of Action

Studies related to the TCI mechanism of action were summarized as study design, participants, brief summary, and conclusion. The mechanism of action was categorized as follows: (1) immune suppression, (2) melanocyte migration and proliferation, (3) melanogenesis, and (4) other.

Treatment Response

The treatment response was evaluated as the degree of repigmentation based on a quartile scale: an at least mild response (≥25% repigmentation), at least moderate response (≥50% repigmentation), and marked response (≥75% repigmentation). The treatment response rates were calculated as the number of participants who achieved the corresponding degree of repigmentation divided by the total number of participants who completed the individual study. The degree of repigmentation was evaluated based on all lesions in each participant or individual patches.

Meta-analyses were carried out separately according to treatment protocol: TCI monotherapy or TCI plus phototherapy. Subgroup analyses were performed to investigate the treatment response to TCIs in children and according to body site, categorized as face and neck, trunk and extremities, and hands and feet. Outcomes for subgroups according to body site included studies containing at least 10 participants; studies with fewer than 10 participants per body part were excluded.

Maintenance Therapy

Studies of TCI maintenance therapy were reviewed and the following information was extracted: study design, number and characteristics of the participants, type of TCI used, previous treatment modalities, treatment frequency and duration, and numbers of participants with depigmentation.

Safety

We investigated all adverse events reported in the included studies of TCI monotherapy. We collected a list of common adverse events, pooled the frequencies, and identified serious adverse events.

Statistical Analysis

The rates of the corresponding treatment responses of the included studies were pooled by the generic inverse variance weighting and were combined using a random-effects model.¹⁰ Heterogeneity was assessed using the I² value,¹¹ and publication bias was evaluated using a funnel plot of sample size against log odds.¹² Meta-analyses were conducted in metagen package of R, version 3.5.1 (R Foundation for Statistical Computing) software.

Results

Search Results

A total of 250 records were identified through computerized database searches, of which 148 articles were removed after 2 independent reviewers (J.H.L. and H.S.K.) screened the titles and abstracts (Figure 1). A total of 102 full-text articles were assessed for eligibility, 46 of which were excluded for the following reasons: (1) the use of other interventions, such as combination therapy with topical corticosteroids (n = 1), (2) retrospective or observational study (n = 8), (3) fewer than 10 participants included (n = 11), (4) vitiligo refractory to previous conventional treatment (n = 2), (5) difference in outcome measures (n = 14), (6) duplicate reports (n = 9), and (7) not available after contacting authors (n = 1). Fifty-six studies fulfilled the inclusion criteria and were included in this review.

Figure 1. Flow Diagram Showing How Eligible Studies Were Identified .

Mechanism of Action

We identified 11 studies on the mechanism of action of TCIs (Table 1).^{8,13,14,15,16,17,18,19,20,21,22} First, TCIs downregulate proinflammatory cytokines, such as tumor necrosis factor,⁸ and induce anti-inflammatory cytokines, such as interleukin (IL)-10, in the vitiligo lesions.¹³ Second, calcineurin inhibitors promote the migration and proliferation of melanocytes and melanoblasts^15,18,19 through increasing matrix metalloproteinase (MMP-2 and MMP-9) levels¹⁷ and inducing endothelin B receptor expression in melanoblasts.¹⁶ In an in vitro study, proliferation of melanocytes was significantly enhanced by tacrolimus-treated keratinocyte supernatant.¹⁴ Third, calcineurin inhibitors induce melanogenesis^14,15,19,20 through increasing tyrosinase expression^15,19,20 and dopa oxidase activity.¹⁵ Finally, topical tacrolimus reduced oxidative stress and improved antioxidant capacity in 20 patients with vitiligo who applied topical tacrolimus twice daily for 7 months in a clinical study.²²

Table 1. Summary of Possible Mechanisms of TCI in Vitiligo.

Source	Study Design	TCI Used	Brief Description	Conclusion
Immune Suppression
Grimes et al,8 2004	In vivo, human	Tacrolimus	After 24-wk treatment with topical tacrolimus in 19 patients, elevated lesional TNF expression was decreased; while IFN-γ and IL-10 were not changed	Decrease of TNF; no change of IFN-γ and IL-10
Taher et al,13 2009	In vivo, human	Tacrolimus	After 3-mo treatment with topical tacrolimus in 20 patients, lesional IL-10 expression was significantly increased	Increase of IL-10
Melanocyte Migration and Proliferation
Lan et al,14 2005	In vitro, cultured MCs and MBs (NCCmelb4, NCCmelan5)	Tacrolimus	Proliferation of MCs and MBs was significantly enhanced; SCF and MMP-9 activity were increased with KC supernatant; tacrolimus did not alter cell migration without KC supernatant	Proliferation of MCs and MBs with KC supernatant; increase of SCF and MMP-9 with KC supernatant
Kang and Choi,15 2006	In vitro, cultured MCs	Tacrolimus	Tacrolimus enhanced MC migration in cell migration assay and Boyden chamber assay	Increased MC migration
Lan et al,16 2011	In vitro, cultured MBs (NCCmelb4)	Tacrolimus	Tacrolimus stimulated expression of PKA, PKC, and p38 MAPK of MBs, but cell motility was not enhanced; and dose dependently upregulated expression of ETBR; tacrolimus and ET-3 combination stimulated MB mobility	Induction of ETBR in MBs; increase of MB migration with ET-3
Lee et al,17 2013	In vitro, cultured MCs	Tacrolimus	Tacrolimus induced migration of MCs with Boyden chamber transwell migration assay and stimulated activities of MMP-2 and MMP-9	Increase of MC migration; increase of MMP-2 and MMP-9
Jung and Oh,18 2016	In vitro, cultured MCs and melanoma cells (B16F10)	Tacrolimus	Tacrolimus enhanced cell spreading on laminin-332 and increased migration in both MCs and melanoma cells. Tacrolimus also increased the expression of syndecan-2	Increase of MC migration and increase of syndecan-2
Xu et al,19 2017	In vitro, cultured MCs	Pimecrolimus	Pimecrolimus stimulates MC migration in wound scratch assay and transwell assays	Increased MC migration
Melanogenesis
Lan et al,14 2005	In vitro, cultured MCs and MBs (NCCmelb4, NCCmelan5)	Tacrolimus	Tacrolimus enhanced melanin formation in MCs but did not significantly alter the melanogenic capacity of MBs	Increased melanin contents
Kang and Choi,15 2006	In vitro, cultured MCs	Tacrolimus	Tacrolimus increased melanin contents, level of dopa oxidase activity, and expression of tyrosinase	Increased melanin contents, dopa oxidase, and tyrosinase
Park et al,20 2016	In vitro, cultured MCs	Tacrolimus	Tacrolimus plus excimer laser increased melanin contents and tyrosinase expression than either treatment alone; however, expression of TRP-2 protein was not changed; TRP-1 level was elevated in cells treated with tacrolimus or the combination treatment	Increase of melanin contents and tyrosinase with combination of excimer laser; no change in TRP-2; increase of TRP-1
Jung et al,21 2016	In vitro, cultured MCs and melanoma cells (B16F10, MNT-1)	Tacrolimus	Tacrolimus increased the melanin content and promoted melanosome maturation by increasing melanosomal pH and enhanced UV-B–mediated melanosome secretion and the uptake of melanosomes by KCs	Increase of melanin contents and promoted melanosome maturation; increased transfer of melanosome to KCs
Xu et al,19 2017	In vitro, cultured MCs	Pimecrolimus	Pimecrolimus significantly increased intracellular tyrosinase activity, MITF expression, and content of melanin	Increased melanin contents, tyrosinase, and MITF
Antioxidative Effect
Lubaki et al,22 2010	In vivo, human	Tacrolimus, pimecrolimus	After treatment with topical tacrolimus in 20 patients, significant reduction of oxidative stress and increased antioxidant capacity in serum observed with BAP test and D-Roms test; those treated with pimecrolimus did not show any significant changes	Decrease of serum oxidative stress with topical tacrolimus; no change of serum oxidative stress with topical pimecrolimus

Abbreviations: BAP, biological antioxidant potential; ET, endothelin; ETBR, endothelin B receptor; IFN, interferon; KC, keratinocyte; MAPK, mitogen-activated protein kinase; MB, melanoblast, MC, melanocyte; MITF, microphthalmia-associated transcription factor; MMP, matrix metalloproteinase; PKA, protein kinase A; PKC, protein kinase C; SCF, stem-cell factor; TCI, topical calcineurin inhibitor; TNF, tumor necrosis factor.

Treatment Response to TCI Monotherapy

We analyzed 46 studies involving 1499 patients to evaluate treatment response to TCI therapy (Table 2); 36 studies with 941 patients were included in the TCI monotherapy group^{7,8,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,64} and 12 studies with 558 patients were in the TCI plus phototherapy group.^{30,36,55,56,57,58,59,60,61,62,63,65} The median duration of treatment was 3 months (range, 2-7 months). An at least mild response (≥25% repigmentation) to TCI monotherapy was achieved in 55.0% (95% CI, 42.2%-67.8%) of 560 patients in 21 studies (Figure 2) (Table 3) (eFigure in the Supplement),^{7,8,22,23,24,25,27,29,30,31,32,33,34,35,37,38,39,41,42,43,64} an at least moderate response (≥50% repigmentation) was achieved in 38.5% (95% CI, 28.2%-48.8%) of 619 patients in 23 studies,^{7,8,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43} and a marked response (≥75% repigmentation) was achieved in 18.1% (95% CI, 13.2%-23.1%) of 520 patients in 19 studies.^{7,24,25,26,27,28,29,30,31,32,33,34,35,37,38,39,41,42,43} In children, an at least mild response to TCI monotherapy was achieved in 66.4% (95% CI, 43.2%-89.7%) of 162 patients in 5 studies,^{7,25,32,35,41} and a marked response to TCI monotherapy was achieved in 31.7% of patients (31.7%; 95% CI, 6.7%-56.8%) in 5 studies.^{7,25,32,35,41}

Table 2. Characteristics of Prospective Studies on TCIs for Vitiligo Treatment.

Source	Country	Study Design	Population	Subtype	Assessment	Treatment Duration, mo	Intervention (Patients Enrolled/Completed, No.)
Soriano et al,23 2002	United States	SA, OL	All	ND	Total patches	6	Tacrolimus, 0.1%, twice daily (23/19)
Lepe et al,7 2003	Mexico	WP, DB, RCT	Children	NSV	Total patches	2	Tacrolimus, 0.1%, twice daily; clobetasol, 0.05%, twice daily (20/20)
Tanghetti,24 2003	United States	SA, OL	All	ND	Total patches	9	Tacrolimus, 0.1%, twice daily (15/15)
Grimes et al,8 2004	United States	SA, OL	All	NSV	Individual patch, total patches	6	Tacrolimus, 0.1%, twice daily (23/19)
Kanwar et al,25 2004	India	SA, OL	Children	NSV, SV	Total patches	3	Tacrolimus, 0.03%, twice daily (25/22)
Passeron et al,55 2004	France	WP, RCT	All	NSV, SV	Total patches	3	Tacrolimus, 0.1%, twice daily + EL twice weekly; EL twice weekly (14/14)
Rodríguez and Cervantes,45 2004	Mexico	SA, OL	All	ND	Individual patch	4.5	Pimecrolimus, 1%, twice daily (50/33)
Almeida et al,26 2005	Spain	SA, OL	All	ND	Individual patch, total patches	6	Tacrolimus, 0.1%, twice daily (12/12)
Dawid et al,64 2006	Austria	WP, DB, RCT	Adult	NSV	Total patches	6	Pimecrolimus, 1%, twice daily; placebo (20/14)
Şendur et al,27 2006	Turkey	SA, OL	All	NSV, SV	Total patches	6	Pimecrolimus, 1%, once daily (23/19)
Fai et al,56 2007	Italy	SA, OL	Adult	NSV	Individual patch, total patches	4	Tacrolimus, 0.03%, once daily (facial lesions) and tacrolimus, 0.1%, once daily (other areas) + NBUVB twice weekly (124/110)
Kanwar,28 2007	India	SA, OL	ND	ND	Total patches	4	Pimecrolimus, 1%, twice daily (22/20)
Seirafi et al,29 2007	Iran	SA, OL	All	NSV	Individual patch, total patches	3	Pimecrolimus, 1%, twice daily (30/30)
Hartmann et al,46 2008	Germany	WP, OL	Adult	NSV	Total patches	12	Tacrolimus, 0.1%, twice daily, partial occlusion; emollient (31/21)
Lotti et al,30 2008	Italy	PD, OL	Adult	NSV, SV	Total patches	6	Tacrolimus, 0.1%, twice daily (22/19); pimecrolimus, 1%, twice daily (19/18); betamethasone dipropionate, 0.05%, twice daily (23/20); calcipotriol, 50 μg/g, twice daily (18/17); L-phenylalanine, 10%, twice daily (18/17); tacrolimus, 0.1%, twice daily + NBUVB biweekly (59/58); pimecrolimus, 1%, twice daily + NBUVB biweekly (63/63); Betamethasone dipropionate, 0.05%, twice daily + NBUVB biweekly (28/26); Calcipotriol, 50 μg/g, twice daily + NBUVB biweekly (60/60); L-phenylalanin 10% twice daily + NBUVB biweekly (60/60); NBUVB biweekly (100/100)
Eryilmaz et al,31 2009	Turkey	WP, DB, RCT	All	ND	Total patches	2	Pimecrolimus, 1%, twice daily; clobetasol propionate, 0.05%, twice daily (16/14)
Esfandiarpour et al,63 2009	Iran	PD, DB, RCT	All	NSV	Individual patch, total patches	3	Pimecrolimus, 1%, twice daily + NBUVB thrice weekly; NBUVB thrice weekly (34/25)
Farajzadeh et al,32 2009	Iran	WP, RCT	Children	ND	Total patches	3	Pimecrolimus, 1%, once daily with occlusion for 10 d (assessed after 3 mo); pimecrolimus, 1%, once daily with occlusion for 10 d + microdermabrasion (assessed after 3 mo); placebo (65/60)
Hui-Lan et al,57 2009	China	WP, RCT	Children	NSV	Total patches	4	Pimecrolimus, 1%, twice daily + EL twice weekly; EL twice weekly (49/48)
Klahan and Asawanonda,58 2009	Thailand	WP, RCT	Adult	ND	Total patches	3	Tacrolimus, 0.1%, twice daily + NBUVB twice weekly; NBUVB twice weekly (15/15)
Radakovic et al,33 2009	Austria	WP, RCT	All	NSV	Total patches	6	Tacrolimus, 0.1%, once daily; tacrolimus, 0.1%, twice daily; untreated (17/15)
Stinco et al,47 2009	Italy	PD, RCT	Adult	ND	Individual patch	7	Pimecrolimus, 1%, twice daily (16/13); tacrolimus, 0.1%, twice daily (15/12); NBUVB thrice weekly (13/13)
Xu et al,34 2009	China	SA, OL	All	NSV, SV	Individual patch, total patches	4	Tacrolimus, 0.1%, twice daily (30/30)
Köse et al,35 2010	Turkey	PD, OL	Children	NSV, SV	Total patches	3	Pimecrolimus, 1%, twice daily (25/20); mometasone, 0.1%, once daily (25/20)
Lo et al,48 2010	Taiwan	SA, OL	All	NSV	Total patches	3	Tacrolimus, 0.1%, twice daily (61/37)
Lubaki et al,22 2010	Belgium	WP, DB, RCT	All	NSV	Total patches	7	Tacrolimus, 0.1%, twice daily; vehicle (20/20)
Lubaki et al,22 2010	Belgium	SA, OL	All	NSV	Total patches	7	Pimecrolimus, 1%, twice daily (20/20)
Majid,59 2010	India	WP, OL	All	NSV	Total patches	12	Tacrolimus 0.1%, twice daily + NBUVB thrice weekly; NBUVB thrice weekly (80/74)
Paracha et al,49 2010	Pakistan	PD, OL	All	ND	Total patches	3	Tacrolimus, 0.03%, twice daily (30/28); superoxide dismutase and catalase twice daily (30/30)
Suo et al,36 2010	China	PD, RCT	All	ND	Individual patch, total patches	4	Tacrolimus, 0.1%, twice daily + NBUVB twice weekly (28/28); tacrolimus, 0.1%, twice daily (27/27); NBUVB twice weekly (27/27)
Ho et al,44 2011	Canada	PD, DB, RCT	Children	NSV, SV	Individual patch	6	Tacrolimus, 0.1% (33/31); clobetasol propionate, 0.05% (33/30); placebo (34/29)
Juan et al,37 2011	China	WP, OL	All	NSV, SV	Total patches	3	Tacrolimus, 0.1%, or 0.03% (age <12 y), twice daily; mometasone furoate once daily (36/31)
Tamler et al,50 2011	Brazil	SA, OL	ND	ND	Individual patch	4	Tacrolimus, 0.1%, twice daily (12/10)
Udompataikul et al,38 2011	Thailand	SA, OL	All	NSV, SV	Individual patch, total patches	6	Tacrolimus, 0.1%, twice daily (42/38)
Kathuria et al,39 2012	India	PD, RCT	All	SV	Total patches	6	Tacrolimus, 0.1%, twice daily (29/26); fluticasone, 0.05%, once daily (31/26)
Du et al,40 2013	China	SA, OL	ND	ND	Total patches	3	Tacrolimus, 0.1%, twice daily (46/34)
Farajzadeh et al,41 2013	Iran	WP, OL	Children	ND	Total patches	3	Pimecrolimus, 1%, twice daily; mometasone furoate, 0.1%, once daily; pimecrolimus, 1%, twice daily + mometasone furoate, 0.1%, once daily (40/40)
Satyanarayan et al,60 2013	India	WP, RCT	All	NSV	Individual patch, total patches	6	Tacrolimus, 0.1%, once daily + NBUVB thrice weekly; NBUVB thrice weekly (25/25)
Wu et al,51 2013	China	WP, RCT	ND	ND	Total patches	3	Tacrolimus, 0.03%, twice daily; EL, 10 times a month (30/27)
Baldo et al,52 2014	Italy	WP, RCT	All	ND	Individual patch	9	Tacrolimus, 0.1%, twice daily; NBUVB twice weekly (12/12)
Bilal et al,61 2014	Pakistan	PD, DB, RCT	All	NSV, SV	Total patches	3	Tacrolimus, 0.1%, twice daily + NBUVB thrice weekly (30/30); placebo + NBUVB thrice weekly (30/30)
Dayal et al,62 2016	India	WP, OL	Adult	ND	Total patches	6	Tacrolimus, 0.03%, twice daily + NBUVB thrice weekly; NBUVB thrice weekly (20/20)
Rafiq et al,42 2016	Pakistan	PD, OL	All	ND	Total patches	6	Tacrolimus, 0.03%, twice daily (30/30); clobetasol, 0.05%, 3 wk in 1 mo (30/30)
Roy et al,43 2016	Bangladesh	PD, OL	All	NSV, SV	Total patches	4	Tacrolimus, 0.1% (44/44); clobetasol, 0.05% (34/34); tacrolimus, 0.1%, + clobetasol, 0.05% (34/34)
Silpa-Archa et al,53 2016	Thailand	WP, OL	Adult	ND	Individual patch	6	Tacrolimus, 0.1%, twice daily; mometasone furoate, 0.1%, twice daily (20/18)
Rokni et al,54 2017	Iran	SA, OL	All	ND	Individual patch	6	Tacrolimus, 0.1%, twice daily (30/30)
Ullah et al,65 2017	Pakistan	PD, RCT	All	ND	Total patches	6	Tacrolimus, 0.1%, twice daily + NBUVB thrice weekly (47/47); NBUVB thrice weekly (47/47)
Maintenance Therapy
Cavalié et al,66 2015	France	PD, DB, RCT	Adult	NSV	Total patches	6	Tacrolimus, 0.1%, twice weekly for maintenance (19/15); placebo twice weekly (16/15)

Abbreviations: DB, double-blind; EL, excimer laser; ND, not determined; NBUVB, narrow-band UV-B phototherapy; NSV, nonsegmental vitiligo; OL, open label; PD, parallel design; RCT, randomized clinical trial; SA, single arm; SV, segmental vitiligo; TCI, topical calcineurin inhibitor; TNF, tumor necrosis factor; WP, within-patient.

Figure 2. Treatment Response to Topical Calcineurin Inhibitors (TCIs) in Patients With Vitiligo.

A, Treatment response to TCI monotherapy. B, Treatment response to TCI plus phototherapy.

Table 3. Treatment Response Rates to TCIs for Vitiligo.

Condition	Treatment Response Rate, % (95% CI)			Included Studies
	≥75% Repigmentation	≥50% Repigmentation	≥25% Repigmentation
TCI Monotherapy
Total	18.1 (13.2-23.1)	38.5 (28.2-48.8)	55.0 (42.2-67.8)	653 Patients in 25 studies (7, 8, 22-43, 64)
Children	31.7 (6.7-56.8)	47.3 (19.0-75.7)	66.4 (43.2-89.7)	177 Patients in 6 studies (7, 28, 32, 35, 41, 44)
Face and neck	35.4 (24.9-46.0)	57.5 (44.4-70.7)	73.1 (32.6-83.5)	392 Patients in 18 studies (8, 22, 26, 29, 34, 36, 38, 44-54)
Trunk and extremities	2.3 (0.3-4.3)	10.6 (5.3-15.8)	34.2 (13.9-54.6)	174 Patients in 9 studies (8, 26, 29, 38, 44, 47, 52-54)
Hands and feet	0.00 (NA)	1.71 (0.00-4.6)	15.1 (6.7-23.4)	52 Patients in 4 studies (26, 29, 47, 52)
TCI Plus Phototherapy
Total	47.5 (30.6-64.4)	72.9 (57.6-88.2)	89.5 (81.1-97.9)	533 Patients in 11 studies (30, 36, 55-62, 65)
Face and neck	55.2 (24.6-85.9)	81.5 (10.3-92.7)	93.7 (87.6-99.8)	129 Patients in 5 studies (36, 56, 60, 62, 63)
Trunk and extremities	16.1 (10.2-22.0)	44.9 (30.3-59.5)	85.3 (79.8-90.7)	161 Patients in 3 studies (56, 62, 63)

Abbreviations: NA, not available; TCI, topical calcineurin inhibitor.

Lesions on the face and neck showed an at least mild response in 73.1% (95% CI, 32.6%-83.5%) of 312 patients in 14 studies,^{8,29,34,38,45,46,47,48,49,50,52,53,54,64} and a marked response 35.4% (95% CI, 24.9%-7 46.0%) of 353 patients in 16 studies.^{8,22,26,29,34,38,45,46,47,48,49,50,51,52,53,54} Lesions on the trunk and extremities showed an at least mild response in 34.2% (95% CI, 13.9%-54.6% of 153 patients in 7 studies,^{8,29,38,47,52,53,54} and a marked response in 2.3% (95% 10 CI, 0.3%-4.3%) of 185 patients in 8 studies.^{8,29,38,47,52,53,54} Lesions on the hands and feet showed an at least mild response in 15.1% (95% CI, 6.7%-23.4%) in 48 patients in 3 studies,^29,47,52 and no marked response was observed among 52 patients in 4 studies.^26,29,47,52

Treatment Response to TCI Plus Phototherapy

Of the 12 studies in the TCI plus phototherapy group, 10 combined TCI treatment with NBVUB^{30,36,56,58,59,60,61,62,63,65} and 2 combined TCI treatment with EL.^55,57 An at least mild response to TCI plus phototherapy was achieved in in 89.5% (95% CI, 81.1%-97.9%) of 433 patients in 8 studies,^{30,55,56,57,59,60,61,62} an at least moderate response was achieved in 72.9% (95% CI, 57.6%-88.2%) of 486 patients in 10 studies,^{30,36,55,56,57,58,59,60,61,62} and a marked response was achieved in 47.5% (95% CI, 30.6%-64.4%) of 490 patients in 9 studies.^{30,55,56,57,59,60,61,62,65}

In TCI plus phototherapy treatment of face and neck lesions, an at least mild response was achieved 93.7% (95% CI, 87.6%-99.8%) of 103 patients in 4 studies,^56,60,62,63 and a marked response was achieved in 55.2% (95% CI, 24.6%-85.9%) of 103 patients in 4 studies.^56,60,62,63 In lesions on the trunk and extremities, 85.3% (95% CI, 79.8%-90.7%) of 161 patients in 3 studies achieved an at least mild response,^56,62,63 and 16.1% (95% CI, 10.2%-22.0%) of 161 patients in 3 studies achieved a marked response.^56,62,63 We did not perform subgroup analyses for hand and foot lesions because only 2 studies met the criteria and the response rate was minimal.

TCI Maintenance Therapy

We identified 1 study that investigated the use of TCIs for maintenance therapy (Table 2). Cavalié et al⁶⁶ performed a randomized, double-blind, placebo-controlled study to evaluate the efficacy of TCI maintenance therapy with patients achieving 75% or more repigmentation from any treatment modality. Patients were randomized to twice-weekly application of tacrolimus, 0.1%, ointment (n = 19) or placebo (n = 16). Some degree of depigmentation was observed in 9.7% of patients in the tacrolimus group and 40.0% of those in the placebo group after 24 weeks.

Safety of TCI

Of the 36 clinical studies of TCI monotherapy included in this analysis, 25 referred to adverse events and 12 reported the number of occurrences of each adverse event.^{7,8,22,25,26,27,29,34,35,39,46,48} We pooled the total occurrences of common adverse events seen in TCI monotherapy. In 296 patients, the most common were a burning sensation (29 [9.8%]), pruritus (22 [7.4%]), and erythema (7 [2.4%]).^{7,8,22,25,26,27,29,34,35,39,46,48} All of the events were transient and did not require additional treatment. Other adverse events, including verruca, dysesthesia, and contact dermatitis, were rarely reported, and no studies reported adverse effects leading to discontinuation of treatment.

Discussion

We systematically reviewed the mechanism of action (11 studies); treatment responses of monotherapy (36 studies), combination therapy with phototherapy (12 studies), and maintenance therapy (1 study); and the safety profiles (12 studies) of TCI for vitiligo in the literature. We also conducted meta-analyses where possible.

Topical calcineurin inhibitors possess a dual mechanism of action for the treatment of vitiligo: immunosuppression and melanocyte induction. First, TCIs inhibit cytotoxic CD8⁺ T cells, an effector arm of autoimmunity in vitiligo, by inhibiting calcineurin-mediated phosphorylation of the nuclear factor of activated T cells.⁶⁷ In in vivo studies, TCI treatment led to a decrease in tumor necrosis factor and an increase in IL-10 in vitiligo lesions.^8,13 Second, TCIs induce the repigmentation of vitiligo by stimulating melanocyte proliferation and migration^{14,15,17,18,19} and melanin synthesis.^14,15,19,20 This process involves increasing MMP-2 and MMP-9 activity,¹⁷ increasing endothelin B receptor expression in melanoblasts,¹⁶ and promoting the secretion of stem cell factor from keratinocytes following TCI treatment.¹⁴ In addition, reduced oxidative stress and increased antioxidant capacity have also been observed in the serum samples of patients treated with topical tacrolimus.²²

We identified a positive treatment response of TCI monotherapy for vitiligo. We found that TCI monotherapy achieved a favorable treatment response rate, with 55.0% of patients achieving an at least mild response (≥25% repigmentation) after a median treatment duration of 3 months. Topical calcineurin inhibitor monotherapy was particularly effective in pediatric patients: 66.4% of children achieved an at least mild response and 31.7% achieved a marked response (≥75% repigmentation). Among the body parts, face and neck showed the best response, and an at least mild response was achieved in 73.1% of patients, whereas such a response was not found for other body parts. Some hypotheses can help to explain these results. Since hair follicles, which serve as reservoirs of melanocytes, are built in the early fetal period and move apart according to the growth of the skin after birth,⁶⁸ children have a higher hair follicle density than adults and so do the face and neck.⁶⁹ In addition, daily exposure to sunlight for the head and neck is likely to be associated with better outcomes.

The treatment responses of TCIs combined with phototherapy (an at least mild response achieved in 89.5% of patients) were higher than those of TCI monotherapy. The results were also better than treatment responses to phototherapy alone (an at least mild response achieved in 62.1% of subjects after 3 months of NBUVB phototherapy) published in a previous systematic review,⁷⁰ which supports the synergistic effects of this combination therapy. The difference in treatment response of TCI monotherapy and TCI combined with phototherapy was particularly evident in sun-protected areas of the body (ie, the trunk and extremities). Our findings are consistent with recent reports on Janus kinase inhibitors showing the improved treatment response with the concomitant use of NBUVB,^71,72 and reaffirm the synergistic role of phototherapy and TCI treatment.⁷³ The treatment of vitiligo may require melanocyte induction via UV exposure as well as suppression of the autoimmune response.⁷¹ Tacrolimus-induced endothelin B receptor expression in melanoblasts and UV-B–induced endothelin secretion from keratinocytes can serve as a theoretical basis for this synergism.¹⁶

One possible issue in the concurrent use of TCI with phototherapy is that the potential photocarcinogenicity of UV light could be enhanced by the immunosuppressive effects of TCIs. However, in rodent studies, TCIs did not accelerate photocarcinogenesis in combination with phototherapy.⁷⁴ Rather, TCIs have been shown to prevent DNA photodamage by UV light⁷⁵ and even to inhibit skin tumor induction in a mouse model.⁷⁶ In addition, although there is a long history of the use of TCIs accompanied by phototherapy for the treatment of vitiligo, to our knowledge, no clinical evidence has been reported for increased carcinogenicity of this combination of therapies in humans. Guidelines thus advocate the use of TCIs in combination with phototherapy for patients with vitiligo to enhance the treatment response.^3,4 An additional benefit of combination therapy is that it could shorten the total duration of phototherapy with the enhanced treatment response. Further studies are needed to clarify this issue.

One study demonstrated that maintenance therapy using TCIs prevented the recurrence of vitiligo after successful repigmentation.⁶⁶ Proactive treatment with TCIs has been recommended for the management of atopic dermatitis for preventing new flare-ups.⁷⁷ Likewise, TCIs seem to be effective for preventing appearance of new depigmented patches in patients with vitiligo.

Limitations

Our systematic review has limitations. First, there was considerable heterogeneity in study designs, characteristics of the patients, and protocols. However, we assumed that prospective studies with identical protocols would have minimal biases regarding the efficacy of TCIs. Second, the quartile scale may be somewhat arbitrary. However, it has been the most commonly used measure and would have been one of the best estimates of the treatment response at this time.

Conclusions

Topical calcineurin inhibitors are believed to be beneficial in the treatment of vitiligo not only by inhibiting autoimmunity associated with the disease but also by promoting melanocyte induction. Topical calcineurin inhibitor monotherapy appears to produce a favorable therapeutic response, especially in children and in lesions on the face and neck. Therefore, TCI monotherapy is worth attempting for the treatment of face and neck lesions, particularly in children, when phototherapy is not available. Moreover, as phototherapy and TCI treatment have synergistic effects, TCI treatment should also be encouraged in patients with vitiligo who are undergoing phototherapy. In addition, the proactive use of TCIs to maintain remission of vitiligo could be promising, considering its high recurrence rate.

Supplement.

eTable 1. Predetermined Search Terms in Each Database

eTable 2. Inclusion and Exclusion Criteria Used in This Study

eFigure. Forest Plots of Treatment Response of Topical Calcineurin Inhibitors (TCIs) for Vitiligo