Dermatologic Therapy, Vol. Vol.••, 28,2015, 2015,••–•• 131–134 Printed in the the United United States States · All All rights rightsreserved reserved
C 2015 Wiley Periodicals, Inc. V © 2015 Wiley Periodicals, Inc.
DERMATOLOGIC DERMATOLOGIC THERAPY THERAPY ISSN ISSN1396-0296 1396-0296
THERAPEUTIC HOTLINE Triple combination treatment with fractional CO2 laser plus topical betamethasone solution and narrowband ultraviolet B for refractory vitiligo: a prospective, randomized half-body, comparative study Lu Li, Yan Wu, Li Li, Yan Sun, Li Qiu, Xing-Hua Gao & Hong-Duo Chen Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
ABSTRACT: Vitiligo on extremities and/or bony prominences is very resistant to treatment. Twentyfive patients with symmetrical and stable vitiligo on extremities and/or bony prominences were enrolled. The treatment side received fractional carbon dioxide laser followed by topical compound betamethasone solution and narrowband ultraviolet B phototherapy. The control side received laser treatment plus phototherapy. The result of treatment side showed that 44% patients achieved over 50% re-pigmentation and patient satisfaction score was 5.12 ± 3.23, higher than those of control (p < 0.05). Adverse events were slight and tolerable. The triple combination treatment could be used as an alternative modality for refractory vitiligo. KEYWORDS: laser, therapy-topical, vitiligo
Introduction Vitiligo is an acquired disorder of skin de-pigmentation caused by the loss of functioning Address correspondence and reprint requests to: Yan Wu, MD, PhD, Associate Professor, Department of Dermatology, No. 1 Hospital of China Medical University, 155 North Nanjing Street, Shenyang 110001, China, email: [email protected]; or Xing-Hua Gao, MD, PhD, Professor, email: [email protected].
melanocytes from the epidermis (1). Conventional therapies include drugs, photo(chemo)therapy, surgery, etc. (2). Re-pigmentation occurs from either the melanocyte reservoir of hair follicles or the margins of the vitiliginous areas (3). Re-pigmentation of extremities or bony prominences is particularly poor due to the reduced numbers of follicle-based melanocytes in these areas. Narrowband ultraviolet B (NB-UVB) therapy or topical corticosteroid has long been used in
131 1
al. Li et al.
vitiligo. However, the re-pigmentation is always transient and time-consuming (4). Dermabrasion may increase the rate of re-pigmentation (5,6), using surgical therapies or erbium-doped yttrium aluminum garnet (Er:YAG) laser to stimulate melanocyte stem cells and enhance drug absorption and autoinoculation of melanocytes from the margin, but create wounds that take a longer time to heal (1,7–9). The newly developed fractional carbon dioxide (CO2) laser does not ablate the entire epidermis, leaving intact skin between coagulated necrotic columns. It decreases risk of potential side effects and minimizes duration of sick leave. Microscopic treatment zones made by fractional CO2 laser promote the penetration of externally applied agent, enabling improvement of efficacy. The present study introduced a triple combination treatment with fractional CO2 laser followed by topical betamethasone and NB-UVB therapy for refractory vitiligo on extremities and/or bony prominences.
phototherapy. The emission wavelength ranged from 300 to 320 nm (peak value of 311 nm). The phototherapies were performed twice to thrice a week, beginning at a dose of 100–150 mJ/cm2 and elevating by approximately 10–15% each time (up to a maximum of 1500 mJ/cm2). The total period of treatment was 6 months for both sides. Measurement Standard photos were taken with a digital camera (D40S, Nikon Corporation, Tokyo, Japan) at baseline, 3 months after the treatments (M3), and 6 months after the treatments (M6). Objective assessment of re-pigmentation was made by two blinded dermatologists using a 5 grading scale: no; 1–25% 26–50%; 51–75%; >75%. Patients were asked to rate their overall satisfaction (0 – not satisfactory to 10 – very satisfactory) and pain (0 – no feeling to 10 – bee sting agony) using a visual analog scale. Other adverse events were recorded. Statistic analysis
Materials and methods Patients This study was approved by the Institutional Review Board. All patients had symmetrical vitiligo lesions on extremities and/or bony prominences without improvement despite more than a year of conventional treatments. Patients with new, spreading lesions within the preceding 1 year were excluded. The informed consent documents were signed. Each side of the body was randomly assigned to fractional CO2 laser followed by topical compound betamethasone solution plus NB-UVB therapy (treatment side) or fractional CO2 laser plus NB-UVB therapy (control side). Equipment and treatment protocol A 10,600-nm laser device (KL, Jilin Province Kinglaser Co., Ltd, Changchun City, China) was performed at a half month interval. The treatment parameters settings were as follows: a pulse energy of 70–100 J/cm2, 5.4% coverage density, and 1stack static mode. Immediately after the laser treatment, compound betamethasone solution (Schering Pharmaceutical Company Limited, Shanghai, China) was topically applied to the wounds under occlusion with a plastic film. A NB-UVB instrument (SS03, Shanghai Sigma Hightech Co., Ltd, Shanghai, China) was used for
132 2
Data were analyzed using SPSS for Windows (version 19.0, SPSS Inc., Chicago, IL, USA). Comparisons were performed by nonparametric analysis and Student’s t-test. A p-value 75% 51–75% 26–50% 1–25% 0 M3 (N = 25) Treatment side Control side M6 (N = 25) Treatment side Control side
2 0
8 2
4 5
5 11
6 7
2 0
9 2
5 6
4 14
5 3
Note: M3, 3 months after the treatments; M6, 6 months after the treatments.
FIG. 2. Photograph of patches on lumbosacral portion of a female patient. Note: (A and B) pretreatment; (C and D) 6 months posttreatment; (C) treatment side; (D) control side.
FIG. 1. Representative photograph of a female patient at the age of 43. Note: (A and B) pretreatment; (C and D), 6 months posttreatment; (C) treatment side; (D) control side.
0.8) during the laser treatment, as well as slight burning sensation, and erythema, edema after laser treatment. The symptoms were tolerable and relieved within a day, and posttreatment crusting disappeared within a week.
Discussion Owing to minimal invasion and transdermal delivery of drugs, laser-assisted dermabrasion was
introduced for refractory vitiligo. In 2012, Bayoumi et al. combined Er:YAG laser with hydrocortisone 17-butyrate cream and NB-UVB therapy to treat vitiligo (6), and almost 50% lesions achieved at least 50% re-pigmentation. Despite the high rate of re-pigmentation, the patients’ final satisfaction was not very high. In our study, the mean pain score of fractional CO2 laser was 4.1 and the global satisfaction score was approximately 5.0. In the study of Bayoumi et al., the relatively severe pain during Er:YAG laser treatment (scored 6.2) and long healing process frustrated the global satisfaction (scored 4.0) (6). Er:YAG resurfacing also raises difficulties in regulation of resurfacing depth and wound care, and involves a possibility of scars due to excessive skin injury. Theoretically, fractional CO2 laser has the same mechanisms of re-pigmentation as ablative lasers, but can minimize the side effects. In 2012, Shin et al. used the laser followed by NB-UVB therapy to treat vitiligo, and 51–75% improvement was seen in 10% patients and 26–50% in 20% patients after two sessions of laser (5). In our study, the same protocol as Shin et al. was set as control and 8% and 28% patients achieved over 50% and 25% repigmentation after treatments, respectively. Our results were similar to those of Shin et al.; however, more sessions of laser were conducted. Combination with topical corticosteroid significantly increased the efficacy as more than 50% and 25% re-pigmentation were respectively seen on 40% and 56% patients. The present topical corticosteroid was a compound betamethasone ester, which contains betamethasone disodium phosphate and betamethasone dipropionate. The former ingredient is easily soluble and could be
133 3
al. Li et al.
quickly absorbed and metabolized within 1 week, whereas the latter ingredient is slightly soluble and could be gradually absorbed and metabolized within 4 weeks. Aided by the fractional CO2 laser, the compound formulation is expected to induce both rapid and lasting re-pigmentation responses. The present study suggests that combination treatment with fractional CO2 laser plus topical betamethasone and NB-UVB therapy could be effectively and safely used in refractory vitiligo. More studies are required to optimize the protocol.
2.
3.
4.
5.
Funding sources This study was funded by the VR Foundation (VRF09012013/01) and the Public Welfare Programme, Ministry of Health, China (201202013).
Conflict of interest
6.
7.
None declared. 8.
References 9. 1. Farajzadeh S, Daraei Z, Esfandiarpour I, Hosseini SH. The efficacy of pimecrolimus 1% cream combined with
134 4
microdermabrasion in the treatment of nonsegmental childhood vitiligo: a randomized placebo-controlled study. Pediatr Dermatol 2009: 26: 286–291. Colucci R, Lotti T, Moretti S. Vitiligo: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother 2012: 13: 1885–1899. Bakis-Petsoglou S, Le Guay JL, Wittal R. A randomized, double-blinded, placebo-controlled trial of pseudocatalase cream and narrowband ultraviolet B in the treatment of vitiligo. Br J Dermatol 2009: 161: 910–917. Kwon HB, Choi Y, Kim HJ, Lee AY. The therapeutic effects of a topical tretinoin and corticosteroid combination for vitiligo: a placebo-controlled, paired-comparison, left-right study. J Drugs Dermatol 2013: 12: e63–e67. Shin J, Lee JS, Hann SK, Oh SH. Combination treatment by 10 600 nm ablative fractional carbon dioxide laser and narrowband ultraviolet B in refractory nonsegmental vitiligo: a prospective, randomized half-body comparative study. Br J Dermatol 2012: 166: 658–661. Bayoumi W, Fontas E, Sillard L, et al. Effect of a preceding laser dermabrasion on the outcome of combined therapy with narrowband ultraviolet B and potent topical steroids for treating nonsegmental vitiligo in resistant localizations. Br J Dermatol 2012: 166: 208–211. Anbar T, Westerhof W, Abdel-Rahman A, El-Khayyat M, El-Metwally Y. Treatment of periungual vitiligo with erbiumYAG-laser plus 5-flurouracil: a left to right comparative study. J Cosmet Dermatol 2006: 5: 135–139. Wassef C, Lombardi A, Khokher S, Rao BK. Vitiligo surgical, laser, and alternative therapies: a review and case series. J Drugs Dermatol 2013: 12: 685–691. Mulekar SV, Isedeh P. Surgical interventions for vitiligo: an evidence-based review. Br J Dermatol 2013: 169 (Suppl. 3): 57–66.
C 2015 Wiley Periodicals, Inc. V © 2015 Wiley Periodicals, Inc.
DERMATOLOGIC DERMATOLOGIC THERAPY THERAPY ISSN ISSN1396-0296 1396-0296
THERAPEUTIC HOTLINE Triple combination treatment with fractional CO2 laser plus topical betamethasone solution and narrowband ultraviolet B for refractory vitiligo: a prospective, randomized half-body, comparative study Lu Li, Yan Wu, Li Li, Yan Sun, Li Qiu, Xing-Hua Gao & Hong-Duo Chen Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
ABSTRACT: Vitiligo on extremities and/or bony prominences is very resistant to treatment. Twentyfive patients with symmetrical and stable vitiligo on extremities and/or bony prominences were enrolled. The treatment side received fractional carbon dioxide laser followed by topical compound betamethasone solution and narrowband ultraviolet B phototherapy. The control side received laser treatment plus phototherapy. The result of treatment side showed that 44% patients achieved over 50% re-pigmentation and patient satisfaction score was 5.12 ± 3.23, higher than those of control (p < 0.05). Adverse events were slight and tolerable. The triple combination treatment could be used as an alternative modality for refractory vitiligo. KEYWORDS: laser, therapy-topical, vitiligo
Introduction Vitiligo is an acquired disorder of skin de-pigmentation caused by the loss of functioning Address correspondence and reprint requests to: Yan Wu, MD, PhD, Associate Professor, Department of Dermatology, No. 1 Hospital of China Medical University, 155 North Nanjing Street, Shenyang 110001, China, email: [email protected]; or Xing-Hua Gao, MD, PhD, Professor, email: [email protected].
melanocytes from the epidermis (1). Conventional therapies include drugs, photo(chemo)therapy, surgery, etc. (2). Re-pigmentation occurs from either the melanocyte reservoir of hair follicles or the margins of the vitiliginous areas (3). Re-pigmentation of extremities or bony prominences is particularly poor due to the reduced numbers of follicle-based melanocytes in these areas. Narrowband ultraviolet B (NB-UVB) therapy or topical corticosteroid has long been used in
131 1
al. Li et al.
vitiligo. However, the re-pigmentation is always transient and time-consuming (4). Dermabrasion may increase the rate of re-pigmentation (5,6), using surgical therapies or erbium-doped yttrium aluminum garnet (Er:YAG) laser to stimulate melanocyte stem cells and enhance drug absorption and autoinoculation of melanocytes from the margin, but create wounds that take a longer time to heal (1,7–9). The newly developed fractional carbon dioxide (CO2) laser does not ablate the entire epidermis, leaving intact skin between coagulated necrotic columns. It decreases risk of potential side effects and minimizes duration of sick leave. Microscopic treatment zones made by fractional CO2 laser promote the penetration of externally applied agent, enabling improvement of efficacy. The present study introduced a triple combination treatment with fractional CO2 laser followed by topical betamethasone and NB-UVB therapy for refractory vitiligo on extremities and/or bony prominences.
phototherapy. The emission wavelength ranged from 300 to 320 nm (peak value of 311 nm). The phototherapies were performed twice to thrice a week, beginning at a dose of 100–150 mJ/cm2 and elevating by approximately 10–15% each time (up to a maximum of 1500 mJ/cm2). The total period of treatment was 6 months for both sides. Measurement Standard photos were taken with a digital camera (D40S, Nikon Corporation, Tokyo, Japan) at baseline, 3 months after the treatments (M3), and 6 months after the treatments (M6). Objective assessment of re-pigmentation was made by two blinded dermatologists using a 5 grading scale: no; 1–25% 26–50%; 51–75%; >75%. Patients were asked to rate their overall satisfaction (0 – not satisfactory to 10 – very satisfactory) and pain (0 – no feeling to 10 – bee sting agony) using a visual analog scale. Other adverse events were recorded. Statistic analysis
Materials and methods Patients This study was approved by the Institutional Review Board. All patients had symmetrical vitiligo lesions on extremities and/or bony prominences without improvement despite more than a year of conventional treatments. Patients with new, spreading lesions within the preceding 1 year were excluded. The informed consent documents were signed. Each side of the body was randomly assigned to fractional CO2 laser followed by topical compound betamethasone solution plus NB-UVB therapy (treatment side) or fractional CO2 laser plus NB-UVB therapy (control side). Equipment and treatment protocol A 10,600-nm laser device (KL, Jilin Province Kinglaser Co., Ltd, Changchun City, China) was performed at a half month interval. The treatment parameters settings were as follows: a pulse energy of 70–100 J/cm2, 5.4% coverage density, and 1stack static mode. Immediately after the laser treatment, compound betamethasone solution (Schering Pharmaceutical Company Limited, Shanghai, China) was topically applied to the wounds under occlusion with a plastic film. A NB-UVB instrument (SS03, Shanghai Sigma Hightech Co., Ltd, Shanghai, China) was used for
132 2
Data were analyzed using SPSS for Windows (version 19.0, SPSS Inc., Chicago, IL, USA). Comparisons were performed by nonparametric analysis and Student’s t-test. A p-value 75% 51–75% 26–50% 1–25% 0 M3 (N = 25) Treatment side Control side M6 (N = 25) Treatment side Control side
2 0
8 2
4 5
5 11
6 7
2 0
9 2
5 6
4 14
5 3
Note: M3, 3 months after the treatments; M6, 6 months after the treatments.
FIG. 2. Photograph of patches on lumbosacral portion of a female patient. Note: (A and B) pretreatment; (C and D) 6 months posttreatment; (C) treatment side; (D) control side.
FIG. 1. Representative photograph of a female patient at the age of 43. Note: (A and B) pretreatment; (C and D), 6 months posttreatment; (C) treatment side; (D) control side.
0.8) during the laser treatment, as well as slight burning sensation, and erythema, edema after laser treatment. The symptoms were tolerable and relieved within a day, and posttreatment crusting disappeared within a week.
Discussion Owing to minimal invasion and transdermal delivery of drugs, laser-assisted dermabrasion was
introduced for refractory vitiligo. In 2012, Bayoumi et al. combined Er:YAG laser with hydrocortisone 17-butyrate cream and NB-UVB therapy to treat vitiligo (6), and almost 50% lesions achieved at least 50% re-pigmentation. Despite the high rate of re-pigmentation, the patients’ final satisfaction was not very high. In our study, the mean pain score of fractional CO2 laser was 4.1 and the global satisfaction score was approximately 5.0. In the study of Bayoumi et al., the relatively severe pain during Er:YAG laser treatment (scored 6.2) and long healing process frustrated the global satisfaction (scored 4.0) (6). Er:YAG resurfacing also raises difficulties in regulation of resurfacing depth and wound care, and involves a possibility of scars due to excessive skin injury. Theoretically, fractional CO2 laser has the same mechanisms of re-pigmentation as ablative lasers, but can minimize the side effects. In 2012, Shin et al. used the laser followed by NB-UVB therapy to treat vitiligo, and 51–75% improvement was seen in 10% patients and 26–50% in 20% patients after two sessions of laser (5). In our study, the same protocol as Shin et al. was set as control and 8% and 28% patients achieved over 50% and 25% repigmentation after treatments, respectively. Our results were similar to those of Shin et al.; however, more sessions of laser were conducted. Combination with topical corticosteroid significantly increased the efficacy as more than 50% and 25% re-pigmentation were respectively seen on 40% and 56% patients. The present topical corticosteroid was a compound betamethasone ester, which contains betamethasone disodium phosphate and betamethasone dipropionate. The former ingredient is easily soluble and could be
133 3
al. Li et al.
quickly absorbed and metabolized within 1 week, whereas the latter ingredient is slightly soluble and could be gradually absorbed and metabolized within 4 weeks. Aided by the fractional CO2 laser, the compound formulation is expected to induce both rapid and lasting re-pigmentation responses. The present study suggests that combination treatment with fractional CO2 laser plus topical betamethasone and NB-UVB therapy could be effectively and safely used in refractory vitiligo. More studies are required to optimize the protocol.
2.
3.
4.
5.
Funding sources This study was funded by the VR Foundation (VRF09012013/01) and the Public Welfare Programme, Ministry of Health, China (201202013).
Conflict of interest
6.
7.
None declared. 8.
References 9. 1. Farajzadeh S, Daraei Z, Esfandiarpour I, Hosseini SH. The efficacy of pimecrolimus 1% cream combined with
134 4
microdermabrasion in the treatment of nonsegmental childhood vitiligo: a randomized placebo-controlled study. Pediatr Dermatol 2009: 26: 286–291. Colucci R, Lotti T, Moretti S. Vitiligo: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother 2012: 13: 1885–1899. Bakis-Petsoglou S, Le Guay JL, Wittal R. A randomized, double-blinded, placebo-controlled trial of pseudocatalase cream and narrowband ultraviolet B in the treatment of vitiligo. Br J Dermatol 2009: 161: 910–917. Kwon HB, Choi Y, Kim HJ, Lee AY. The therapeutic effects of a topical tretinoin and corticosteroid combination for vitiligo: a placebo-controlled, paired-comparison, left-right study. J Drugs Dermatol 2013: 12: e63–e67. Shin J, Lee JS, Hann SK, Oh SH. Combination treatment by 10 600 nm ablative fractional carbon dioxide laser and narrowband ultraviolet B in refractory nonsegmental vitiligo: a prospective, randomized half-body comparative study. Br J Dermatol 2012: 166: 658–661. Bayoumi W, Fontas E, Sillard L, et al. Effect of a preceding laser dermabrasion on the outcome of combined therapy with narrowband ultraviolet B and potent topical steroids for treating nonsegmental vitiligo in resistant localizations. Br J Dermatol 2012: 166: 208–211. Anbar T, Westerhof W, Abdel-Rahman A, El-Khayyat M, El-Metwally Y. Treatment of periungual vitiligo with erbiumYAG-laser plus 5-flurouracil: a left to right comparative study. J Cosmet Dermatol 2006: 5: 135–139. Wassef C, Lombardi A, Khokher S, Rao BK. Vitiligo surgical, laser, and alternative therapies: a review and case series. J Drugs Dermatol 2013: 12: 685–691. Mulekar SV, Isedeh P. Surgical interventions for vitiligo: an evidence-based review. Br J Dermatol 2013: 169 (Suppl. 3): 57–66.
