ORIGINAL

ARTICLE

Combination therapy with 308-nm excimer laser, topical tacrolimus, and short-term systemic corticosteroids for segmental vitiligo: A retrospective study of 159 patients Jung Min Bae, MD,a Hyun Ju Yoo, MD,a Hyub Kim, MD,b Ji Hae Lee, MD,a and Gyong Moon Kim, MD, PhDa Suwon and Seoul, Korea Background: Segmental vitiligo (SV) is characterized by a unilateral and localized distribution, early onset, and stable disease after rapid progression. And SV is often associated with poor response to various treatment modalities. Objective: We sought to evaluate the effectiveness of combination therapy with 308-nm excimer laser, topical tacrolimus, and short-term systemic corticosteroids for SV, and to search for factors associated with the treatment response. Methods: A retrospective interventional case-series study was performed on 159 patients with SV who were treated with the combination therapy for more than 3 months. Results: The rate of 75% or more repigmentation was 50.3% after a median treatment duration of 12.1 months; 36.5% and 13.8% of the patients showed nearly complete (75%-99%) and complete (100%) repigmentation, respectively. Multivariable analysis showed the following to be independent factors with poor response: disease duration longer than 12 months (odds ratio 0.372, 95% confidence interval 0.157-0.882, P = .025), poliosis (odds ratio 0.494, 95% confidence interval 0.247-0.988, P = .046), and plurisegmental subtype (odds ratio 0.175, 95% confidence interval 0.065-0.474, P = .001). Limitations: This was a retrospective study. Conclusion: The combination therapy is effective for SV. Prolonged disease duration, poliosis, and plurisegmental subtype were shown to be independent prognostic factors of poor response in patients with SV. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.04.008.) Key words: excimer laser; laser; segmental vitiligo; vitiligo.

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itiligo is a common acquired pigmentary disorder of the skin and mucous membranes, which affects 0.5% to 1% of the population. Vitiligo can be psychologically devastating, especially in ethnic populations, in whom it is more easily noticeable.1 Segmental vitiligo (SV) is a

From the Department of Dermatology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwona; and Sosom Dermatologic Clinic, Seoul.b Drs Bae and Yoo contributed equally to this work. Supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2014R1A1A1036218). Conflicts of interest: None declared.

Abbreviations used: NBUVB: OR: SV: UV:

narrowband ultraviolet B odds ratio segmental vitiligo ultraviolet

Accepted for publication April 6, 2015. Reprint requests: Gyong Moon Kim, MD, PhD, Department of Dermatology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, 93 Ji-dong, Paldal-gu, Suwon 440-060, Korea. E-mail: [email protected]. Published online May 6, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.04.008

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distinct subset, characterized by a unilateral distrimonths or who achieved complete repigmentation bution, early onset, and stable disease after rapid within 3 months were included. Exclusion criteria progression.2 SV is often associated with poor were as follows: patients with mixed, focal, or response to conventional treatments for vitiligo undifferentiated vitiligo, and patients who had including topical and systemic corticosteroids,3 undergone other treatment modalities for vitiligo at another hospital within the last 6 months. topical calcineurin inhibitors, and narrowband All patients were treated with the 308-nm ultraviolet (UV) B (NBUVB) phototherapy4,5 and xenon chloride excimer therefore frequently requires laser (XTRAC, PhotoMedex, surgical treatment.6 CAPSULE SUMMARY The 308-nm xenon chloHorsham, PA) on 2 nonconride excimer laser has been secutive days a week. The Segmental vitiligo is often associated introduced to treat vitiligo in initial dose was 100 to 300 with a poor response to various a targeted way that allows mJ/cm2, depending on the treatment modalities. the delivery of higher fluenbody site. If erythema lasted In this retrospective study, 50.3% of 159 ces to the depigmented more than 48 hours, the dose patients with segmental vitiligo lesions, sparing uninvolved was kept constant; otherachieved at least 75% repigmentation skin. Clinical studies showed wise, the dose was increased using combination therapy consisting that excimer laser treatment by 10 to 100 mJ/cm2 in each of 308-nm excimer laser, topical was associated with a faster subsequent session, dependtacrolimus, and short-term systemic onset of repigmentation and ing on the previous dose. If corticosteroids. fewer treatment sessions painful erythema or blisfor a successful response Disease duration longer than 12 months, tering developed, the treatcompared with conventional presence of poliosis, and plurisegmental ment was interrupted until phototherapy, and it subtype were shown to be independent resolution of the symptoms currently represents the prognostic factors of poor response in and resumed at the dose treatment of choice for localpatients with segmental vitiligo. used in the previous session. ized vitiligo.7 However, Topical tacrolimus 0.1% ointrecent studies on excimer ment was applied concurlaser treatment for SV produced unsatisfactory rently to all vitiliginous lesions throughout the results ($75% repigmentation: 23.8%),8 and a lower treatment period. The patients aged 19 years or older repigmentation rate than that of treatment for non-SV received 20 mg of prednisolone daily for the first 3 (odds ratio [OR] 0.42, P = .029).9 weeks, and the patients younger than 19 years This study was performed to evaluate the received 0.3 mg/kg prednisolone (maximum daily effectiveness of combination therapy with 308-nm dose: 20 mg). excimer laser, topical tacrolimus, and short-term systemic corticosteroids for SV and to determine Covariables independent prognostic factors associated with Age, sex, age of onset, Fitzpatrick skin type, body treatment success. site, disease duration, size, presence of poliosis, body side involved (right and left), and subtypes (unisegmental, bisegmental, and plurisegmental) METHODS were used as explanatory variables for this study. Study design and population The maximal and cumulative UV dosages, duration This is a retrospective interventional case-series of treatment, and number of treatment sessions were study in a private dermatology clinic. Medical collected from the medical records. All patients with records and photographs of 159 patients with SV vitiligo who had an onset of disease before 12 years (female 58.5%; median age 24 years, range 1-62; of age were categorized as having childhood-onset Fitzpatrick skin types III or IV) who were treated vitiligo. with 308-nm excimer laser, topical tacrolimus, and short-term systemic corticosteroids from July 2008 to Assessment of clinical outcomes December 2012 were retrieved and analyzed. SV was Clinical outcomes were evaluated based on defined as a unilateral depigmented lesions arranged clinical photographs obtained at baseline and on a in a linear or quasidermatomal distribution that weekly basis. Two blinded dermatologists (J. M. B. usually stopped abruptly at the midline of the and H. J. Y.) compared the initial pretreatment affected segment. All patients with SV who were photographs with the final follow-up photographs given a diagnosis for the first time and treated with and assessed the percentage of skin repigmentation 308-nm excimer laser therapy for more than 3 d

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using a quartile grading scale (grade 0, no repigmentation; grade 1, 1%-24%; grade 2, 25%-49%; grade 3, 50%-74%; grade 4, 75%-99%; grade 5, complete resolution). Treatment success was defined as 75% or more repigmentation of whole lesions in each patient (grade 4 or 5).10 Statistical analysis Univariable and multivariable logistic regression analysis were performed in sequence to determine the independent prognostic factors associated with the treatment success. All analyses were performed using R 3.0.1 (R Foundation for Statistical Computing, Vienna, Austria). Ethics statement The study protocol was designed in accordance with the Declaration of Helsinki and was approved by the ethics committee of the Catholic Medical Center Office of Human Research Protection Program (VC14RISE0024).

RESULTS The clinical characteristics of 159 patients with SV are summarized in Table I. The median age of onset and median disease duration were 24 years (range 1-62) and 12 months (range 1-260), respectively. The majority of patients had Fitzpatrick skin type IV (68.6%), followed by type III (31.4%). The most common site was the face (67.9%), and other involved locations were upper extremities (10.7%), trunk (10.1%), neck (9.4%), and lower extremities (1.9%). The median number of treatment sessions was 71 (range 16-387), and the median duration of treatment was 12.1 months (range 1.1-52.5). The median cumulative and maximal dosages were 35,960 mJ/cm2 and 700 mJ/cm,2 respectively. The overall treatment success, the rate of 75% or more repigmentation, was 50.3%; 36.5% and 13.8% of the patients showed nearly complete (grade 4, 75%-99%) and complete (grade 5, 100%) repigmentation, respectively (Fig 1). In the univariable analysis, older age ([12 years, P = .002), later-onset disease ([12 years, P = .017), disease duration longer than 12 months (compared with \3 months, P = .004), presence of poliosis (P = .033), and plurisegmental subtype (P \ .001) were statistically significant covariates negatively associated with treatment success (Table II). In multivariable analysis, disease duration longer than 12 months (compared with \3 months; OR 0.372, 95% confidence interval 0.157-0.882, P = .025), presence of poliosis (OR 0.494, 95% confidence interval 0.247-0.988, P = .046), and plurisegmental subtype (OR 0.175, 95% confidence interval

Table I. Clinical parameters of 159 patients with segmental vitiligo in this study Characteristic

Male:female Median age of onset (range), y Median duration of onset (range), mo Skin type, n (%) III IV Site of vitiligo, n (%) Face Neck Trunk Upper extremities Lower extremities Median of no. of treatment sessions (range) Median duration of treatment (range), mo Median cumulative UV dosage (range), mJ/cm2 Median maximal UV dosage (range), mJ/cm2

Value

66:93 24 (1-62) 12 (1-260)

50 (31.4) 109 (68.6) 108 15 16 17 3 71

(67.9) (9.4) (10.1) (10.7) (1.9) (16-387)

12.1 (1.1-52.5) 35,960 (1125-233,050) 700 (210-2050)

UV, Ultraviolet.

0.065-0.474, P = .001) were identified to be independent factors associated with poor response to the combination therapy (Fig 2).

DISCUSSION Since its first report in 2001,11 308-nm excimer laser treatment for vitiligo has been reported to show a faster onset of repigmentation and better repigmentation rates compared with NBUVB phototherapy.7 The excimer laser emits monochromatic, coherent 308-nm wavelength UVB light in short impulses using a combination of noble gas (xenon) and reactive gas (chlorine).12 Because the 308-nm excimer laser is superior to NBUVB phototherapy in its induction of T-cell apoptosis13 and delivery of high-intensive fluence exclusively to depigmented areas,14,15 it has become the treatment of choice for localized vitiligo. Recently, Lan et al16 demonstrated that irradiance (mW/cm2), rather than fluence (mJ/cm2), played a crucial role in UVB-induced immature pigment cell development, and elucidated the superior efficacy of excimer compared with NBUVB lights on primitive melanoblasts. SV is often associated with a poor response to medical treatments including conventional phototherapy and excimer laser therapy compared with non-SV.4,5 One study that evaluated the response of vitiligo to psoralen plus UVA revealed that all patients with SV showed no or poor repigmentation.5 In

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Fig 1. Clinical photographs of patients with segmental vitiligo (SV). A and B, A 9-year-old patient with SV and disease duration of 3 months showed complete repigmentation after 5.1 months of combination therapy with 308-nm excimer laser, topical tacrolimus, and short-term systemic corticosteroids. C and D, A 55-year-old patient with SV showed complete repigmentation after 28 months of the combination therapy. E and F, Lesion containing white hair remained depigmented, whereas other lesions without white hair were repigmented.

another study, 92.3% of patients with SV showed no or mild response (\25% repigmentation) to NBUVB treatment.4 Recently, Do et al8 reported that 23.8% of patients with SV showed 75% or more repigmentation with 308-nm excimer laser treatment, although none of them achieved complete repigmentation. In our study, 50.3% of 159 patients with SV showed 75% or more repigmentation with combination therapy after a median duration of treatment of 12.1 months (range: 1.1-52.5 months). The concurrent treatment of topical tacrolimus and short-term systemic corticosteroids seemed to have contributed to our high repigmentation rate. Passeron and Ortonne17 demonstrated that combined tacrolimus and excimer laser therapy is more effective than excimer laser monotherapy for the treatment of vitiligo, especially in UV-resistant sites. Tacrolimus has been reported to have an effect on melanocyte migration and pigmentation by Kang and Choi.18 Systemic corticosteroid has been observed to have an

effect on reduction in complement mediated cytotoxicity by autoantibodies to melanocytes.19 Recently, in 1 pilot study, 4 of 5 patients with SV (80%) showed 75% or more repigmentation with combination therapy of systemic corticosteroids, topical tacrolimus, and excimer laser.20 The high efficacy of this combination therapy was also demonstrated in our study with large population. In addition, all treatments in our study were conducted in 1 primary clinic, so the extent of the lesions and disease duration might be smaller and shorter, respectively, than those of patients who visited tertiary hospitals. This may be one of the reasons for a higher response rate in our study compared with previous studies that were performed at tertiary hospitals, and it could reflect the genuine effectiveness of the 308-nm excimer laser treatment for SV. Long-term treatment also contributed to the good treatment response in our study, as previously described by Park et al12 in their comprehensive review.

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Table II. Prognostic factors influencing the response of patients with segmental vitiligo (n = 159) Category

Gender

Male Female Age, y #12 [12 Fitzpatrick skin type III IV Site Head and neck Trunk Extremities Onset age, y #12 [12 Duration, mo \3 3-6 6-12 [12 Side Right Left Size, cm2 \5 5-10 10-20 [20 Poliosis ( ) (1) Subtype Unisegment and bisegment Plurisegment

n (%)

Success rate

Odds ratio (95% CI)

(41.5) (58.5) (27.7) (72.3) (31.4) (68.6) (77.4) (10.1) (12.6) (37.1) (62.9) (25.2) (15.1) (16.4) (43.4) (48.4) (51.6) (40.3) (29.6) (23.3) (6.9) (55.3) (44.7) (79.9)

53.0% 48.4% 70.5% 42.6% 52.0% 49.5% 49.6% 43.8% 60.0% 62.7% 43.0% 65.0% 58.3% 57.7% 36.2% 48.1% 52.4% 51.6% 57.4% 43.2% 36.4% 58.0% 40.8% 58.3%

Reference 0.830 (0.441-1.562) Reference 0.311 (0.148-0.656) Reference 0.906 (0.464-1771) Reference 0.791 (0.277-2.257) 1.525 (0.583-3.989) Reference 0.449 (0.232-0.868) Reference 0.754 (0.267-2.132) 0.734 (0.266-2.023) 0.306 (0.136-0.691) Reference 1.192 (0.640-2.222) Reference 1.268 (0.594-2.707) 0.716 (0.317-1.616) 0.537 (0.143-2.015) Reference 0.501 (0.265-0.945) Reference

32 (20.1)

18.8%

66 93 44 115 50 109 123 16 20 59 100 40 24 26 69 77 82 64 47 37 11 88 71 127

Odds ratio (95% CI)

P

Reference 0.874 (0.289-2.643) 0.587 (0.202-1.701) 0.372 (0.157-0.882)

.110 .811 .326 .025

.033

Reference 0.494 (0.247-0.988) Reference

.046

0.165 (0.064-0.430) \.001

0.175 (0.065-0.474)

.001

P

.564 .002 .773 .594 .661 .390 .017 .020 .594 .550 .004 .580 .465 .539 .421 .357

CI, Confidence interval.

Fig 2. Response rates after combination therapy with 308-nm excimer laser, topical tacrolimus, and short-term systemic corticosteroids according to the independent poor prognostic factors.

In the current study, disease duration longer than 12 months, presence of poliosis, and plurisegmental subtype were independent prognostic factors associated with poor treatment response. Disease duration has been consistently stated to be an important factor associated with treatment outcome

of nonsurgical treatment. Park et al21 revealed that SV patients with short disease duration showed a better response to medical treatments such as systemic corticosteroids, topical tacrolimus, and phototherapy compared to SV patients with longer disease duration. Do et al8 also reported duration of SV as

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being an important factor that influenced treatment outcome of 308-nm excimer laser therapy. In our study, disease duration longer than 12 months was an independent poor prognostic factor associated with the combination therapy compared with that with a duration less than 3 months. The presence of poliosis is another well-known poor prognostic factor in vitiligo treatments, and complete repigmentation cannot be achieved when poliosis is present. Presence of poliosis has been reported in 48.6% to 100% of patients with SV,6,22 and 44.7% of 159 patients with SV in our study showed poliosis. Patients without poliosis showed 75% or more repigmentation of 58.3% and complete repigmentation was present in 17.3%; however, patients with poliosis showed 75% or more repigmentation of 40.8% and none achieved complete repigmentation. These findings confirmed that poliosis is one of the strong poor prognostic factors associated with treatment outcome of SV. Some patients with poliosis showed resistance to the combination therapy in the vitiliginous lesions around the poliosis, although other lesions without white hair became repigmented (Fig 1, E and F ). It has been suggested that the melanocytes of hair follicles may be responsible for the major sources for repigmentation in vitiligo treatment,23,24 and our observation supports this hypothesis. Plurisegmental subtype was another independent factor associated with poor response to the combination therapy compared with unisegmental and bisegmental subtypes. In other studies, affected body site was also an important factor affecting treatment response.4,25 Acral areas and bony prominences showed poor repigmentation after NBUVB4 or 308-nm excimer laser treatment.25 In our study, however, there was no correlation between anatomical involved site and treatment outcome, perhaps because there were too few cases of acral involvement to verify the significance of body site. The major limitation of this study was the inherent nature of a retrospective chart and photographic review. In addition, selection bias should be considered, because those lost to follow-up within 3 months might have poor outcomes. Nevertheless, our study evaluated the effectiveness of the combination therapy in relatively large number of patients with SV in a private clinic, and this may reflect practical treatments of SV. Our study also identified independent factors associated with treatment success rate of the combination therapy in patients with SV, which could suggest important implications for SV treatment. However, further controlled clinical trials are needed to confirm these observations.

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In conclusion, combination therapy of 308-nm excimer laser, topical tacrolimus, and short-term systemic corticosteroids could be an effective treatment modality for SV with a great safety profile. Disease duration longer than 12 months, presence of poliosis, and plurisegmental subtype were identified to be independent poor prognostic factors associated with the combination therapy for patients with SV. Therefore, we suggest that early treatment should be introduced to patients with SV, and evaluation of poliosis and subtype could be important to predict the treatment outcome. REFERENCES 1. Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview. Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol. 2011;65:473-491. 2. Ezzedine K, Lim HW, Suzuki T, et al. Revised classification/ nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference. Pigment Cell Melanoma Res. 2012;25:E1-E13. 3. Koga M. Vitiligo: a new classification and therapy. Br J Dermatol. 1977;97:255-261. 4. Anbar TS, Westerhof W, Abdel-Rahman AT, El-Khayyat MA. Evaluation of the effects of NB-UVB in both segmental and non-segmental vitiligo affecting different body sites. Photodermatol Photoimmunol Photomed. 2006;22:157-163. 5. Tallab T, Joharji H, Bahamdan K, Karkashan E, Mourad M, Ibrahim K. Response of vitiligo to PUVA therapy in Saudi patients. Int J Dermatol. 2005;44:556-558. 6. Lee DY, Kim CR, Park JH, Lee JH. The incidence of leukotrichia in segmental vitiligo: implication of poor response to medical treatment. Int J Dermatol. 2011;50:925-927. 7. Alhowaish AK, Dietrich N, Onder M, Fritz K. Effectiveness of a 308-nm excimer laser in treatment of vitiligo: a review. Lasers Med Sci. 2013;28:1035-1041. 8. Do JE, Shin JY, Kim DY, Hann SK, Oh SH. The effect of 308nm excimer laser on segmental vitiligo: a retrospective study of 80 patients with segmental vitiligo. Photodermatol Photoimmunol Photomed. 2011;27:147-151. 9. Cheng YP, Chiu HY, Jee SH, Tsai TF. Excimer light photototherapy of segmental and non-segmental vitiligo: experience in Taiwan. Photodermatol Photoimmunol Photomed. 2012;28:6-11. 10. Gonzalez U, Whitton M, Eleftheriadou V, Pinart M, Batchelor J, Leonardi-Bee J. Guidelines for designing and reporting clinical trials in vitiligo. Arch Dermatol. 2011;147:1428-1436. 11. Baltas E, Nagy P, Bonis B, et al. Repigmentation of localized vitiligo with the xenon chloride laser. Br J Dermatol. 2001;144: 1266-1267. 12. Park KK, Liao W, Murase JE. A review of monochromatic excimer light in vitiligo. Br J Dermatol. 2012;167:468-478. 13. Novak Z, Bonis B, Baltas E, et al. Xenon chloride ultraviolet B laser is more effective in treating psoriasis and in inducing T cell apoptosis than narrow-band ultraviolet B. J Photochem Photobiol B. 2002;67:32-38. 14. Baltas E, Csoma Z, Ignacz F, Dobozy A, Kemeny L. Treatment of vitiligo with the 308-nm xenon chloride excimer laser. Arch Dermatol. 2002;138:1619-1620. 15. Spencer JM, Nossa R, Ajmeri J. Treatment of vitiligo with the 308-nm excimer laser: a pilot study. J Am Acad Dermatol. 2002; 46:727-731.

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16. Lan CC, Yu HS, Lu JH, Wu CS, Lai HC. Irradiance, but not fluence, plays a crucial role in UVB-induced immature pigment cell development: new insights for efficient UVB phototherapy. Pigment Cell Melanoma Res. 2013;26: 367-376. 17. Passeron T, Ortonne JP. Use of the 308-nm excimer laser for psoriasis and vitiligo. Clin Dermatol. 2006;24:33-42. 18. Kang HY, Choi YM. FK506 increases pigmentation and migration of human melanocytes. Br J Dermatol. 2006;155: 1037-1040. 19. Hann SK, Kim HI, Im S, Park YK, Cui J, Bystryn JC. The change of melanocyte cytotoxicity after systemic steroid treatment in vitiligo patients. J Dermatol Sci. 1993;6:201-205. 20. Jang YH, Jung SE, Shin J, Kang HY. Triple combination of systemic corticosteroids, excimer laser, and topical tacrolimus

21.

22. 23. 24. 25.

in the treatment of recently developed localized vitiligo. Ann Dermatol. 2015;27:104-107. Park JH, Park SW, Lee DY, Lee JH, Yang JM. The effectiveness of early treatment in segmental vitiligo: retrospective study according to disease duration. Photodermatol Photoimmunol Photomed. 2013;29:103-105. Hann SK, Lee HJ. Segmental vitiligo: clinical findings in 208 patients. J Am Acad Dermatol. 1996;35:671-674. Cui J, Shen LY, Wang GC. Role of hair follicles in the repigmentation of vitiligo. J Invest Dermatol. 1991;97:410-416. Arrunategui A, Arroyo C, Garcia L, et al. Melanocyte reservoir in vitiligo. Int J Dermatol. 1994;33:484-487. Ostovari N, Passeron T, Zakaria W, et al. Treatment of vitiligo by 308-nm excimer laser: an evaluation of variables affecting treatment response. Lasers Surg Med. 2004;35:152-156.

Combination therapy with 308-nm excimer laser, topical tacrolimus, and short-term systemic corticosteroids for segmental vitiligo: A retrospective study of 159 patients.

Segmental vitiligo (SV) is characterized by a unilateral and localized distribution, early onset, and stable disease after rapid progression. And SV i...
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