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Topical Tacrolimus and the 308-nm Excimer Laser
A Synergistic Combination for the Treatment of Vitiligo
Thierry Passeron, MD; Nima Ostovari, MD; Wassim Zakaria, MD; Eric Fontas, MD;Jean-Claude Larrouy, MD; Jean-Philippe Lacour, MD; Jean-Paul Ortonne, MD Objective: To compare the efficacy of combined tacro-
Results: Forty-three lesions were treated (23 in group
limus and 308-nm excimer laser therapy vs 308-nm ex- A and 20 in group B). All patients completed the study.
cimer laser monotherapy in treating vitiligo.
Repigmentation was observed in all group A lesions(100%) and in 17 (85%) of the 20 group B lesions. Re- Design: Comparative, prospective, randomized, intra-
pigmentation was not observed in the untreated lesions (control group). A repigmentation rate of 75% or morewas obtained in 16 (70%) of the 23 group A lesions and Patients: Fourteen patients, aged 12 to 63 years, with
in 4 (20%) of the 20 group B lesions. In UV-sensitive areas (the face, neck, trunk, and limbs, with the exception ofbony prominences and extremities), 10 (77%) of 13 group Intervention: For each patient, 4 to 10 target lesions
A lesions had a repigmentation rate of 75% or more vs 4 were chosen. The treatment applied to each target le- (57%) of 7 group B lesions. In classically UV-resistant sion was randomized by drawing lots. Each lesion was areas, 6 (60%) of 10 group A lesions had a repigmenta- treated twice a week by the 308-nm excimer laser, for a tion rate of 75% or more vs 0 of the 13 group B lesions.
total of 24 sessions. Initial fluences were 12 mcal/cm2 (50 The mean number of sessions necessary for an improve- mJ/cm2) less than the minimal erythemal dose in viti- ment of repigmentation was 10 in group A and 12 in group liginous skin. Then, fluences were increased by 12 mcal/ B. Adverse effects have been limited, and tolerance was cm2 every second session. Moreover, topical 0.1% tacro- limus ointment was applied twice daily on target lesionsreceiving the combined tacrolimus and excimer laser treat- Conclusions: The combination treatment of 0.1% ta-
ment (group A). Group B target lesions received only ex- crolimus ointment plus the 308-nm excimer laser is su- cimer laser monotherapy. For each treated lesion, the un- perior to 308-nm excimer laser monotherapy for the treat- treated lesion on the opposite side served as the control.
ment of UV-resistant vitiliginous lesions (PϽ.002). The Tolerance was evaluated by a visual analog scale, and sec- efficacy and the good tolerance of the 308-nm excimer ondary events were recorded at each session.
laser in monotherapy for treating localized vitiligo werealso confirmed, but this treatment regimen should be pro- Main Outcome Measure: Treatment efficacy, which
was blindly evaluated by 2 independent physicians by di-rect and polarized light photographs taken before and af-ter treatment.
From the Department ofDermatology, Hoˆpital del’Archet 2 (Drs Passeron,Ostovari, Zakaria, Larrouy, VITILIGOISANACQUIREDCU- lineofnonsurgicaltherapyincludestopi-
therapy (solar exposition, psoralen–UV-A clinical presentation is characterized by well- edge, no treatment provides truly satisfac- fected by vitiligo have a vast reduction of CME course available at
quality of life caused by the color contrast Humaine, Hoˆpital de l’Archet 1 archdermatol.com
between healthy pigmented skin and the de- pigmented vitiliginous patches that give the financial interest in this article. patients psychological problems.1,2 The first (REPRINTED) ARCH DERMATOL / VOL 140, SEP 2004 2004 American Medical Association. All rights reserved.
therapy is considered the best treatment for extensive viti- TREATMENT
ligo vulgaris. The mechanism of action of the UV-B therapyon the vitiligo is still uncertain. Stimulation of melano- The laser used was a 308-nm xenon-chloride excimer laser cytic migration and proliferation starting from the niches (TALOS; WaveLight Laser Technology AG, Erlangen, Germany).
located in the hair follicles are certainly leading factors. This The fixed technical variables were as follows: pulse frequency,200 Hz; pulse width, 60 nanoseconds; and distal pulse energy, stimulation probably involves the direct action of UV 1.1 mcal/cm2 (4.6 mJ/cm2). Beam transmission was achieved therapy on the melanocytes, and the action of the cyto- by an arm with moveable joints and changeable distal heads of kines secreted by the keratinocytes. Recent studies on the 15-, 20-, and 25-mm diameters for the spot sizes. For each pa- autoimmune origin of vitiligo also emphasize the prob- tient, 4 to 10 target lesions were chosen (2-5 vitiliginous mac- able implication of the immunosuppressive action of UV ules treated by either the combination therapy or laser mono- therapy in the repigmentation of vitiliginous plaques. This therapy and 2-5 untreated vitiliginous macules on the opposite immunomodulating photobiological action of the UV side). The treatment applied to each target lesion was ran- therapy involves the withdrawal of Langerhans cells and domly selected by drawing lots. Lesions were treated twice the decrease of their antigen presentation function, the ke- weekly, for a maximum of 24 sessions. Initial fluences were 12 ratinocytic cytokines, and moreover the apoptosis of the mcal/cm2 (50 mJ/cm2) less than the minimal erythemal dose activated T lymphocytes.6 Recently, the 308-nm excimer in vitiliginous skin, and fluences were increased by 12 mcal/cm2 every 2 sessions. In the presence of a vesicle, a bulla, or an laser, a new technique allowing for targeted photo- erythema lasting more than 8 hours over the treated lesions, therapy, was used to treat localized plaques of vitiligo.7-10 treatment was withheld and then resumed, after resolution, at On the other hand, tacrolimus, a new topical immunosup- the last dose without any adverse effect. Topical 0.1% tacroli- pressive drug developed for the treatment of atopic der- mus ointment was applied twice daily on the target lesion re- matitis, has shown some interesting results in treating viti- ceiving 308-nm excimer laser therapy plus tacrolimus treat- ligo in 2 prospective studies.11,12 However, although the ment (group A). Group B target lesions received only 308-nm repigmentation rate was high, the percentage of patients excimer laser monotherapy. Each treated lesion had an un- achieving at least 75% repigmentation was low. Interest- treated control target lesion on the opposite side.
ingly, patients with the best likely treatment response ben-efited from concomitant natural sunlight exposure.
ASSESSMENT
We hypothesized that the combined action of the Tolerance was evaluated by a visual analog scale, and second- 308-nm excimer laser and topical tacrolimus could be syn- ary events were recorded at each session. Efficacy was blindly ergistic, thus providing better results in the treatment of evaluated by 2 independent physicians (N.O. and W.Z.) using vitiligo. Therefore, we performed a prospective, random- direct and polarized light photographs (Fuji FinePix S1 pro; ized, left/right comparison pilot study to evaluate the ef- Fuji Photo Film USA, Inc) taken before and at the end of treat- ficacy of the association of 0.1% tacrolimus ointment plus ment. Repigmentation was graded on a 6-point scale (0 indi- the 308-nm excimer laser compared with 308-nm ex- cates no repigmentation; 1, repigmentation of 1%-24%; 2, re- cimer laser monotherapy in the treatment of vitiligo.
pigmentation of 25%-49%; 3, repigmentation of 50%-74%;4, repigmentation of 75%-99%; and 5, total repigmentation).
In the case of disagreement between the 2 physicians, a sec- ond evaluation was done together. If the disagreement per-sisted, the lowest evaluation score was chosen. At the final visit, PATIENTS
the patients’ opinions about treatment efficiency and the de-gree of satisfaction were recorded (excellent, good, moderate, Fourteen patients were included in this comparative, prospec- tive, randomized study. The criteria for selection were as fol-lows: older than 12 years, the development of vitiligo before the STATISTICAL ANALYSIS
past 3 months, the presence of at least 2 pairs of symmetricalpatches of vitiligo (with surfaces of at least 4 cm2), and an un- The efficacy of combination treatment (excimer laser therapy derstanding of all information given by signing a written con- plus 0.1% tacrolimus ointment) and excimer laser therapy sent form. Exclusion criteria were as follows: pregnant or breast- alone was first compared with the symmetrical control feeding women; personal history of a hypertrophic scar, melanoma, plaques. Efficacy was measured in 2 different ways: (1) no re- or other skin cancer; immunosuppression or taking immuno- pigmentation vs repigmentation and (2) repigmentation of suppressive or photosensitizing drugs; and undergoing photo- less than 75% vs repigmentation of 75% or more. The latter therapy or other vitiligo treatment during the past 3 months. For was used to consider the aesthetic result. The McNemar ␹2 each patient, age, sex, skin type, date of onset of lesions, prior test was used to compare dichotomous variables on matching treatments for vitiligo with their results, and the localization of series. Then, the comparability between the 2 treatment the patches of vitiligo were noted. The characteristics of the 14 groups and the relationships between repigmentation of less patients (2 males [14%] and 12 females [86%]) are summarized than 75% vs 75% or more and the treatments were studied in as follows. Their mean age was 36.6 (range, 12-63) years, their single-variable analyses using ␹2 and Fisher exact tests for cat- mean disease duration was 18.1 (range, 3-33) years, and the mean egorical variables and the Kruskal-Wallis test for continuous number of sites treated per patient was 3 (range, 2-5). The Fitz- variables. Analysis with the potential confounding factors was patrick skin type of the patients was as follows: type II, 5 pa- performed with the same statistical tests. Finally, the relation- tients (36%); type III, 8 patients (57%); and type IV, 1 patient (7%).
ship between treatments and repigmentation was also studied All patients but 1 had already tried 1 or more other therapies for after adjustment to localization using the Mantel-Haenszel vitiligo (psoralen–UV-A therapy in 8, NB–UV-B therapy in 3, and test. All the tests were considered significant at a 5% type I er- antioxidant therapies in 9). None of these treatments had pro- ror rate (PϽ.05). Statistical analyses were performed using a duced a repigmentation rate of at least 75%, except for NB– commercially available software program (SPSS for Windows, version 11.0; SPSS Inc, Chicago, Ill).
(REPRINTED) ARCH DERMATOL / VOL 140, SEP 2004 2004 American Medical Association. All rights reserved.
Figure 1. Vitiliginous plaque of the knee by direct light photographs before treatment (A), after 24 sessions (B), and 1 month after the end of treatment (C).
Figure 2. Global repigmentation. Group A indicates those persons who were
Figure 3. Repigmentation in UV-sensitive areas. Groups A and B are
treated with the combination of the 308-nm excimer laser and 0.1% described in the legend to Figure 2. In group A, 0 patients achieved 0% to tacrolimus; group B, those persons who were treated with 308-nm excimer 24% repigmentation, 2 (15%) achieved 25% to 49% repigmentation, 1 (8%) laser monotherapy. In group A, 0 patients achieved 0% to 24% achieved 50% to 74% repigmentation, and 10 (77%) achieved 75% or more repigmentation, 2 (9%) achieved 25% to 49% repigmentation, 5 (22%) repigmentation. In group B, 0 patients achieved 0% repigmentation, 1 (14%) achieved 50% to 74% repigmentation, and 16 (70%) achieved 75% or more achieved 1% to 24% repigmentation, 1 (14%) achieved 25% to 49% repigmentation. In group B, 3 patients (15%) achieved 0% repigmentation, 8 repigmentation, 1 (14%) achieved 50% to 74% repigmentation, and 4 (57%) (40%) achieved 1% to 24% repigmentation, 3 (15%) achieved 25% to 49% achieved 75% or more repigmentation. (Percentages may not total 100 repigmentation, 2 (10%) achieved 50% to 74% repigmentation, and 4 (20%) achieved 75% or more repigmentation. (Percentages may not total 100because of rounding.) and limbs, except the bony prominences and extremi-ties), 10 (77%) of 13 group A lesions had a repigmenta- tion rate of 75% or more vs 4 (57%) of 7 group B lesions
(Figure 3). In classically UV-resistant areas, 6 (60%)
Forty-three lesions were treated (23 in group A and 20 of 10 group A lesions had a repigmentation rate of 75% in group B). All the patients completed the study. The or more vs 0 of 13 group B lesions (Figure 4).
degree of concordance between the 2 observers was ex- The study of the comparability between the 2 treat- cellent, as disagreement was noted for only 2 plaques.
ment groups for clinical variables (age, sex, skin type, Repigmentation was observed in all group A lesions duration of disease, and localization) showed no statis- (100%) and in 17 (85%) of the 20 group B lesions tical differences. Thus, the comparison of the 2 treat- (Figure 1). Repigmentation was not observed in any un-
ment regimens using the criterion repigmentation of at treated control lesions. When considering the criterion least 75% suggests a statistically significant superiority presence of repigmentation, both treatment regimens— of the combination treatment over laser monotherapy combined laser and tacrolimus therapy and laser therapy (PϽ.001). In single random variable analyses, we found alone—showed an efficacy statistically superior to un- no associations between response to treatment and the treated control lesions (PϽ.001 each). A repigmenta- following variables: age, sex, skin type, and minimal ery- tion rate of 75% or more was obtained in 16 (70%) of themal dose (P = .73, P = .39, P = .17, and P = .72, the 23 group A lesions and in 4 (20%) of the 20 group B respectively). However, response to treatment was asso- lesions (Figure 2). When considering the criterion pres-
ciated with the lesion’s localization. Special UV- ence of repigmentation of at least 75%, only the laser and sensitive lesions (in the face, neck, trunk, and limbs, ex- tacrolimus combination was statistically superior to un- cept for the bony prominences and extremities) responded treated control lesions (PϽ.001 for group A and P=.15 better than UV-resistant lesions (in the bony promi- for group B). In UV-sensitive areas (the face, neck, trunk, nences and extremities) (P = .004). The relationship be- (REPRINTED) ARCH DERMATOL / VOL 140, SEP 2004 2004 American Medical Association. All rights reserved.
monotherapy showed a nonnegligible rate of response of at least 75%, but the rather small size of the sample probably explains the absence of statistical significance.
Interestingly, localization seems to be clearly associatedwith the response to treatment, whereas factors such as age, sex, skin type, and minimal erythemal dose are not.
When adjustment is made for localization, combinationtreatment is clearly superior to laser monotherapy when treating UV-resistant areas, confirming our initial hy- pothesis. On the other hand, no statistical difference can be found between the 2 treatments when treating UV-sensitive areas. For technical reasons, it was impossible to also evaluate the efficiency of tacrolimus ointment alone in this study. The results of previous studies11,12 suggestthat tacrolimus ointment alone can induce repigmenta- Figure 4. Repigmentation in UV-resistant areas. Groups A and B are
tion. This repigmentation is clearly more observed in UV- described in the legend to Figure 2. In group A, 0 patients achieved 0% to49% repigmentation, 4 (40%) achieved 50% to 74% repigmentation, and 6 exposed areas and is less important compared with that (60%) achieved 75% or more repigmentation. In group B, 3 patients (23%) obtained with combination treatment. However, a com- achieved 0% repigmentation, 7 (54%) achieved 1% to 24% repigmentation, parative study between combination treatment and ta- 2 (15%) achieved 25% to 49% repigmentation, 1 (8%) achieved 50% to74% repigmentation, and 0 achieved 75% or more repigmentation.
crolimus ointment alone is necessary to confirm theseresults.
To date, NB–UV-B therapy is one of the most effec- tween response to treatment and treatment groups has tive treatments for extensive vitiligo vulgaris. However, been further studied, adjusting it to the lesion’s localiza- the 308-nm excimer laser presents many advantages com- tion. In UV-resistant areas, combination treatment was pared with NB–UV-B therapy for treating localized viti- statistically superior to laser monotherapy (PϽ.002), but ligo. Photobiological effects seem more effective be- no statistical difference has been shown in UV-sensitive cause the induction of lymphocyte apoptosis is superior.13 Moreover, the articulate arm can reach any kind of lo- Cumulative doses ranged from 0.45 to 4.16 (mean, calization and selectively target vitiliginous lesions while 2.01) cal/cm2 (1.9-17.4 J/cm2) in group A and from 0.79 sparing the healthy skin. The results obtained in group to 4.83 (mean, 2.56) cal/cm2 (3.3-20.2 J/cm2) in group B (308-nm excimer laser monotherapy) confirm the ef- B. Treatment was stopped at the 15th and 16th sessions ficacy of this technique. Repigmentation has been ob- for 2 lesions in group A and at the 16th session for 1 le- served in most of the lesions by the end of the sessions.
sion in group B because of achievement of 100% repig- However, because aesthetic results are expected, we have mentation. On average, the onset of repigmentation was focused on the percentage of targeted plaques achieving observed at session number 10 in group A (range, 4-15) at least 75% repigmentation. Therefore, when regarding vs session number 12 in group B (range, 5-24). Cumu- aesthetic results, the overall efficacy is clearly less im- lative doses before the onset of repigmentation were 0.69 portant, yet remains interesting. Differences between clas- (range, 0.17-1.27) cal/cm2 (2.9 J/cm2; range, 0.7-5.3 J/cm2) sic UV-sensitive and UV-resistant areas are marked, and in group A and 1.00 (range, 0.19-2.68) cal/cm2 (4.2 J/cm2; are comparable to those observed using other photo- range, 0.8-11.2 J/cm2) in group B. Adverse events were therapy techniques. Even if it was not statistically proved, quite similar in both groups: moderate to severe ery- a marked difference depending on localization has also thema (observed at least 1 time in all the patients) and been noted in the latest study10 evaluating excimer laser localized bullous eruptions in 4 lesions (2 in group A and efficiency in treating vitiligo. Thus, according to our re- 2 in group B). However, stinging was reported by 5 pa- sults, the treatment of bony prominences and extremi- tients in group A vs 0 in group B. Tolerance was evalu- ties by the 308-nm excimer laser induces only few aes- ated by the patients at 8.9 of 10 in group A vs 9.2 of 10 thetic good results. In UV-sensitive areas, our results are in group B, on average. Finally, the degree of patient sat- comparable to those obtained in the 3 previous re- isfaction was excellent for 10 patients in group A and 0 ports,8-10 confirming the medical interest of this tech- in group B, good for 3 patients in group A and 7 in group nique in the treatment of localized vitiligo. Interest- B, moderate for 1 patient in group A and 5 in group B, ingly, a pilot study14 performed with localized high- and poor for 0 patients in group A and 2 in group B.
intensity UV-B phototherapy (B Clear) and tacrolimusointment reports similar conclusions as ours and sug- gests that tacrolimus ointment and UV therapy could besynergistic in the treatment of vitiligo.
Our results demonstrate that the combination treat- The tolerance of both treatments was good and ad- ment of 0.1% tacrolimus ointment plus 308-nm ex- verse effects were not significant. Erythema was con- cimer laser and 308-nm excimer laser monotherapy are stant, but bullous lesions were rare. Adjunction of twice- effective for the treatment of vitiligo. However, in this daily application of 0.1% tacrolimus only induces a study, only the combination treatment showed statisti- moderate stinging (noted in 5 [36%] of the 14 patients).
cally significant efficacy compared with controls for This study was not designed to determine if the use of achieving a repigmentation rate of at least 75%. Laser an immunosuppressive drug plus UV exposure can in- (REPRINTED) ARCH DERMATOL / VOL 140, SEP 2004 2004 American Medical Association. All rights reserved.
duce long-term adverse effects. Minimizing or avoiding elbows, and the dorsal surfaces of the hands and feet seem natural or artificial sunlight exposure during tacroli- to respond better than the tips of the fingers and toes, mus ointment treatment is recommended. The restric- the ankles, and the wrists. All these data make any com- tion of UV exposure during local treatment with tacro- parison of treatments difficult, and stress the impor- limus results from the increased risk of cutaneous cancers tance of comparing laser therapy with those treatments observed in patients who have undergone organ trans- of reference noted within the same study, especially now plantation and have been treated with systemic tacroli- that the effectiveness of the 308-nm excimer laser has been mus. However, the barrier function of vitiliginous skin is normal. This results in poor penetration of tacroli- In conclusion, the efficacy of the 308-nm excimer mus ointment within the interfollicular epidermis. Fur- laser for the treatment of localized vitiligo is confirmed, thermore, recent studies15 in mouse skin have shown but should be proposed only for UV-sensitive areas. The that tacrolimus applications protect UV-induced dam- combination of 0.1% tacrolimus ointment applied twice age on DNA. Moreover, the UV exposures and tacroli- daily and 308-nm excimer laser therapy performed twice mus applications are limited in duration and surface area, a week gives excellent results on UV-sensitive and UV- which limits the risk of inducing carcinogenic muta- resistant areas. The treatment was well tolerated, and the tions. However, this combination treatment should be patients were satisfied. A monitored study (with con- used with caution and limited to controlled studies or trols) on a larger population would be in order to con- firm these encouraging preliminary results.
Finally, it is difficult to compare the 308-nm ex- cimer laser with other vitiligo treatments. In a meta- Accepted for publication February 20, 2004. analysis16 of the literature assessing the effectiveness and Correspondence: Thierry Passeron, MD, Department the safety of nonsurgical vitiligo repigmentation thera- of Dermatology, Hoˆpital de l’Archet 2, BP 3079, 06202 Nice pies, class 3 topical corticosteroids and NB–UV-B therapy CEDEX 3, France (t.passeron@free.fr). seemed the best choices for localized and generalized viti-ligo, respectively. When regarding the percentage of le- sions achieving at least 75% repigmentation, class 3 cor-ticosteroids showed 56% (95% confidence interval, 50%- 1. Kent G, Al’Abadie M. Psychologic effects of vitiligo: a critical incident analysis.
62%) for localized vitiligo and NB–UV-B therapy showed J Am Acad Dermatol. 1996;35:895-898.
63% (95% confidence interval, 50%-76%) for general- 2. Parsad D, Pandhi R, Dogra S, Kanwar AJ, Kumar B. Dermatology Life Quality ized vitiligo. Compared with these data, the results ob- Index score in vitiligo and its impact on the treatment outcome. Br J Dermatol.
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tained with combined treatment (70%; 95% confidence 3. Mofty ME, Zaher H, Esmat S, et al. PUVA and PUVB in vitiligo—are they equally interval, 51%-88%) are good, but the results obtained with effective? Photodermatol Photoimmunol Photomed. 2001;17:159-163.
the 308-nm excimer laser alone are poor (20%; 95% con- 4. Scherschun L, Kim JJ, Lim HW. Narrow-band ultraviolet B is a useful and well- fidence interval, 6%-44%). However, 2 important facts tolerated treatment for vitiligo. J Am Acad Dermatol. 2001;44:999-1003.
have to be considered. First, the total duration of our treat- 5. Taneja A. Treatment of vitiligo. J Dermatolog Treat. 2002;13:19-25.
6. Horio T. Indications and action mechanisms of phototherapy. J Dermatol Sci. ments was shorter than that in previous studies (3 months vs 5-8 months, on average).16 It is highly probable, as is 7. Baltas E, Nagy P, Bonis B, et al. Repigmentation of localized vitiligo with the xe- the case with other therapies for vitiligo, that an in- non chloride laser. Br J Dermatol. 2001;144:1266-1267.
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tion of repigmentation has been observed up until 40 ses- 10. Taneja A, Trehan M, Taylor CR. 308-nm excimer laser for the treatment of lo- sions in the study by Taneja et al.10 Second, and prob- calized vitiligo. Int J Dermatol. 2003;42:658-662.
ably most important, only a few studies have addressed 11. Lepe V, Moncada B, Castanedo-Cazares JP, Torres-Alvarez MB, Ortiz CA, Torres- Rubalcava AB. A double-blind randomized trial of 0.1% tacrolimus vs 0.05% clo- criteria such as age, skin type, and localization of viti- betasol for the treatment of childhood vitiligo. Arch Dermatol. 2003;139:581-585.
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percentage of UV-resistant areas induces a decrease of 15. Tran C, Lubbe J, Sorg O, Carraux P, Didierjean L, Saurat J. Topical tacrolimus results in terms of efficacy. Moreover, within the UV- decreases UVB-induced DNA damage in mouse skin. J Invest Dermatol. 2003;121:P1072.
resistant areas, heterogeneity is also observable. Even if 16. Njoo MD, Spuls PI, Bos JD, Westerhof W, Bossuyt PM. Nonsurgical repigmen- the number of localizations treated is too small in our tation therapies in vitiligo: meta-analysis of the literature. Arch Dermatol. 1998; series to show statistically significant differences, knees, (REPRINTED) ARCH DERMATOL / VOL 140, SEP 2004 2004 American Medical Association. All rights reserved.

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