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Montelukast treatment of moderate to severe atopic dermatitis in adults: A randomized, double-blind, placebo-controlled trial
BRIEF
REPORTS
Montelukast treatment of moderate to severe atopic dermatitis in adults: A randomized, double-blind, placebo-controlled trial Niels K. Veien, MD, PhD,a Michael Busch-Sørensen, MD,b and Birgitte Stausbøl-Grøn, MDc ˚ rhus, Denmark Aalborg, Glostrup, and A In a randomized, double-blind, placebo-controlled 4-week trial, 59 patients with moderate to severe atopic dermatitis were treated orally with 10 mg of the leukotriene antagonist montelukast. Forty-seven patients completed the study. No difference in efficacy was seen among patients who received montelukast and the group given a placebo. ( J Am Acad Dermatol 2005;53:147-9.)
A
topic dermatitis (AD) is a genetically determined, chronic, eczematous skin disease. The pathogenesis is complex, and although in most cases, the dermatitis fades during childhood, the course is unpredictable. Furthermore, there is no uniformly successful treatment. Most treatment options include time-consuming topical applications of the medicament. Leukotrienes are likely to play a role in the inflammation seen in AD. It is therefore of interest to attempt to reduce the activity of AD by the use of leukotriene antagonists. Oral treatment is an attractive alternative to topical treatment. Montelukast and zafirlukast have shown promising results in the treatment of both children and adults with AD, and the safety profile of these medicaments is excellent.1-5 We wished to carry out a randomized, prospective, placebo-controlled study to determine whether oral treatment with the cysteinyl leukotriene antagonist montelukast would reduce the activity of moderate to severe AD in adults.
MATERIAL AND METHODS Patients between the ages of 16 and 70 who had a diagnosis of AD based on Hanifin and Rajka’s From the Dermatology Clinic,a Merck Research Laboratories,b and the Department of Dermatology, A˚rhus University Hospital.c Supported by Merck, Sharp & Dohme. Disclosure: The authors Niels K. Veien and Birgitte Stausbøl-Grøn have no financial interest in Merck, Sharp & Dohme and are not paid consultants for the company. Reprints not available from the authors. Correspondence to: Niels K. Veien, The Dermatology Clinic, Vesterbro 99, DK-9000 Aalborg, Denmark. E-mail: veien@ dadlnet.dk. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.12.011
criteria6 and who had moderate to severe disease activity were included in the study. In addition, inclusion required the involvement of 5% to 35% of the body surface and a minimum score of 4.5 based on Rajka and Langeland’s grading system.7 Patients with infected AD, patients with a history of eczema herpeticum, pregnant and breastfeeding women, and patients who were HIV positive were excluded from the study. A study population of 46 patients with 23 in each group was predicted based on an anticipated reduction in score of 60% in the actively treated group and 20% in the placebo group, a type I error of 0.05 (two-tailed) and a type II error of 0.2. The study was carried out as a two-center, prospective, randomized, double-blind, parallel group study, comparing the effect of 10 mg montelukast given orally once daily with a placebo. Following a wash-out period of 2 weeks in which all patients were given one placebo tablet per day, the patients were randomized to receive either a 10 mg montelukast tablet or a placebo tablet once a day for 4 weeks. No other active topical or systemic treatment was permitted during the trial. The patients were given an ample supply of emollient to be used freely. The activity of the dermatitis was assessed at baseline, after the wash-out period of 2 weeks, and after 1, 2, and 4 weeks of receiving either active treatment or the placebo. Possible adverse experiences were recorded at each visit. Clinical assessment was based on an eczema area and severity index (EASI) score8 as well as a score for pruritus. The latter score was determined by the patient at each visit on a 10 cm visual analog scale with scores of 0 to 3 at intervals of 2.5 cm. The primary efficacy endpoint was the sum of the EASI and the pruritus scores (modified EASI score). The 147
148 Brief reports
J AM ACAD DERMATOL JULY 2005
Table I. Demographic data and treatment results Montelukast N = 29
Placebo n = 30
Male Female Mean age Modified EASI score at baseline
7 22 28 years 8.9
9 21 30 years 9.5
After treatment Modified EASI score e last recorded value (intention-to-treat) (P = .46)
n = 25 6.8
n = 28 7.6
Before treatment
EASI, Eczema area and severity index.
secondary efficacy endpoint was the pruritus score during the trial as a percent of the baseline value. The Fisher exact test was used to test for differences between the groups with regard to the primary endpoint. Analyses were based on the intention-totreat analysis. The code was not broken until completion of the trial and after all the statistical calculations had been carried out. The study was approved by the regional medical ethics committees of counties of A˚rhus, North Jutland, and Viborg. The manuscript was prepared in accordance with the CONSORT statement.
RESULTS Fifty-nine patients were included in the study. Fifty-three of them were seen at 1 or more of the 3 visits while receiving active treatment. Data for these 53 patients were used to determine the results of treatment with montelukast, applying the intentionto-treat analysis (Table I). Drop-out before the start of active treatment (6 patients) and during treatment (6 patients; 4 in the montelukast group and 2 in the placebo group) was caused by aggravation of the dermatitis or failure to return for scheduled follow-up visits. Forty-seven patients completed all visits. With regard to a modified EASI score, a test for proper randomization at baseline showed no significant difference between the two groups (Wilcoxon signed rank sum non-parametric test, P = .85). An analysis of individual differences between end point and baseline in the two groups showed no statistically significant difference between active treatment and the placebo (Wilcoxon signed rank sum nonparametric test, P = .46), nor was there any difference in drop-out rate between the two groups (chi-square test for contingency tables, P = .62).
No side effects were seen in either of the two groups that were felt to be related to study medication.
DISCUSSION In the current investigation, no difference was seen between montelukast and a placebo in the treatment of adults with moderate to severe atopic dermatitis. This is in contrast to the results of several other studies. Eustachio et al1 treated 20 men with severe AD for 6 weeks in a similar placebo-controlled study and found a significant difference in SCORAD reduction between the group that received montelukast and the group given a placebo. Yamose et al2 treated 8 adult patients with AD of moderate severity with 10 mg montelukast in a randomized, double-blind, placebo-controlled, cross-over study for a period of 8 weeks. After 4 weeks, statistically significant improvement was seen following treatment with montelukast. The shorter duration of the current study could explain the difference in treatment results. Capello et al3 carried out a single-blind study involving 32 adults in which he compared treatment with 10 mg montelukast per day and traditional treatment. Both groups had similar, reductions of SCORAD. Pei et al4 used 5 mg montelukast per day for 4 weeks to treat moderate to severe AD in 15 children ranging in age from 6 to 15 in a randomized, double-blind, placebo-controlled, cross-over study. Montelukast proved statistically significantly more effective than a placebo. In all of these studies the effect of montelukast was moderate. The inconsistent findings between this study and the previous ones may be related to nuances in study design, the severity of disease, the limited number of patients, and the simultaneous use of steroids in some of the trials. Most importantly, as this study was designed to detect a fairly large difference in efficacy, the results do not rule out the possibility of a modest treatment effect. In the current study, a type II error was fixed at 0.80, assuming a difference of effect 60% (reduction of score) for active treatment versus a 20% reduction in the placebo group. Montelukast remains a useful treatment of mild to moderate bronchial asthma. Its limited utility in AD highlights the fact that although these diseases are related, underlying pathology clearly differs and will require further research to elucidate. REFERENCES 1. Eustachio N, Alessandro P, Margherita F, Antonio F, Tursi A. Efficacy and tolerability of montelukast as a therapeutic agent
J AM ACAD DERMATOL
Brief reports 149
VOLUME 53, NUMBER 1
for severe atopic dermatitis in adults. Acta Derm Venereol 2002;82:297-320. 2. Yanase FJ, David-Bajar K. The leukotriene antagonist montelukast as a therapeutic agent for atopic dermatitis. J Am Acad Dermatol 2001;44:89-93. 3. Capella GL, Grigerio E, Altomare G. A randomized trial of leukotriene receptor antagonist montekulast in moderate-tosevere atopic dermatitis of adults. Eur J Dermatol 2001;11:209-13. 4. Pei AYS, Chan HHL, Leung TF. Montelukast in the treatment of children with moderate-to-severe atopic dermatitis: A pilot study. Pediatr Allergy Immunol 2001;12:154-8.
5. Carucci JA, Washenik K, Weinstein A, Shupack J, Cohen DE. The leukotriene antagonist zafirlukast as a therapeutic agent for atopic dermatitis. Arch Dermatol 1998;134:785-6. 6. Hanifin RG. Diagnostic features of atopic dermatitis Y2. Acta Derm Venereol Suppl (Stockh) 1980;92:44-7. 7. Rajka, Langeland T. Grading of the severity of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1989;144:13-4. 8. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermato 2001;10:11-8.
Treatment of uremic pruritus with narrowband ultraviolet B phototherapy: An open pilot study ¨ zdemir, MDc Simin Ada, MD,a Deniz Sec¸kin, MD,a I_ rem Budakoglu, MD,b and Fatma Nurhan O Ankara, Turkey
We report the results of a pilot study of narrowband ultraviolet B phototherapy for the treatment of 20 patients with uremic pruritus. Ten patients completed the 6-week study period. A total of 8 patients were found to be responders. Of the remaining 10 patients who left the study before 6 weeks, 6 were satisfied with the response. In the follow-up period, 7 responders could be examined, and 3 were in remission 6 months after completing treatment. However, pruritus recurred in the remaining 4 responders. Narrowband ultraviolet B phototherapy may be an effective treatment for patients with uremic pruritus. Recurrence of pruritus, however, is a frequent problem. ( J Am Acad Dermatol 2005;53:149-51.)
P
ruritus is a frequent and troublesome symptom in patients with chronic renal failure receiving hemodialysis.1 However, it also may occur in patients on conservative uremia treatment or undergoing continuous ambulatory peritoneal dialysis.1 For patients who are not candidates for kidney transplantation, broadband (BB) UVB phototherapy is considered by some authors as a treatment of choice.2 However, little is known about the efficacy of narrowband (NB) UVB phototherapy in this condition. In this study, we aimed to evaluate the efficacy of NB UVB in alleviating uremic pruritus.
From the Departments of Dermatology,a Public Health,b and Nephrology,c Baskent University Faculty of Medicine. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Simin Ada, MD, Baskent University Faculty of Medicine, Department of Dermatology, 5. sok No: 48 Bahc¸elievler, Ankara, Turkey 06490. E-mail: siminada@ baskent-ank.edu.tr. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.12.052
The study included 20 patients (12 men and 8 women) with uremic pruritus. The patients gave informed consent to the study, which was approved by the institutional ethical committee. All except one was undergoing maintenance hemodialysis. Uremic pruritus had to have appeared after the diagnosis of chronic renal failure, without any other systemic, dermatologic, or psychologic causes that could explain it. All patients had been unresponsive to oral antihistamines and topical emollients. The intensity of pruritus was evaluated at baseline using a visual analog scale (VAS) score (0 [no pruritus]-10 [most severe pruritus]) and a detailed cumulative score (DCS) assessing various characteristics of pruritus.3 The same investigator determined the pruritus intensity at every phototherapy session just before the irradiation procedure by VAS score and weekly thereafter by DCS. Phototherapy was administered to the whole body surface 3 times a week for 6 weeks in a UV irradiation cubicle (Waldmann 7001K, Waldmann Mediziniche Technik, VillingenSchwenningen, Germany) equipped with 20 100-W fluorescent lamps (TL01, Philips Co, Eindhoven, The Netherlands). The cubicle had its own cooling fan for
REPORTS
Montelukast treatment of moderate to severe atopic dermatitis in adults: A randomized, double-blind, placebo-controlled trial Niels K. Veien, MD, PhD,a Michael Busch-Sørensen, MD,b and Birgitte Stausbøl-Grøn, MDc ˚ rhus, Denmark Aalborg, Glostrup, and A In a randomized, double-blind, placebo-controlled 4-week trial, 59 patients with moderate to severe atopic dermatitis were treated orally with 10 mg of the leukotriene antagonist montelukast. Forty-seven patients completed the study. No difference in efficacy was seen among patients who received montelukast and the group given a placebo. ( J Am Acad Dermatol 2005;53:147-9.)
A
topic dermatitis (AD) is a genetically determined, chronic, eczematous skin disease. The pathogenesis is complex, and although in most cases, the dermatitis fades during childhood, the course is unpredictable. Furthermore, there is no uniformly successful treatment. Most treatment options include time-consuming topical applications of the medicament. Leukotrienes are likely to play a role in the inflammation seen in AD. It is therefore of interest to attempt to reduce the activity of AD by the use of leukotriene antagonists. Oral treatment is an attractive alternative to topical treatment. Montelukast and zafirlukast have shown promising results in the treatment of both children and adults with AD, and the safety profile of these medicaments is excellent.1-5 We wished to carry out a randomized, prospective, placebo-controlled study to determine whether oral treatment with the cysteinyl leukotriene antagonist montelukast would reduce the activity of moderate to severe AD in adults.
MATERIAL AND METHODS Patients between the ages of 16 and 70 who had a diagnosis of AD based on Hanifin and Rajka’s From the Dermatology Clinic,a Merck Research Laboratories,b and the Department of Dermatology, A˚rhus University Hospital.c Supported by Merck, Sharp & Dohme. Disclosure: The authors Niels K. Veien and Birgitte Stausbøl-Grøn have no financial interest in Merck, Sharp & Dohme and are not paid consultants for the company. Reprints not available from the authors. Correspondence to: Niels K. Veien, The Dermatology Clinic, Vesterbro 99, DK-9000 Aalborg, Denmark. E-mail: veien@ dadlnet.dk. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.12.011
criteria6 and who had moderate to severe disease activity were included in the study. In addition, inclusion required the involvement of 5% to 35% of the body surface and a minimum score of 4.5 based on Rajka and Langeland’s grading system.7 Patients with infected AD, patients with a history of eczema herpeticum, pregnant and breastfeeding women, and patients who were HIV positive were excluded from the study. A study population of 46 patients with 23 in each group was predicted based on an anticipated reduction in score of 60% in the actively treated group and 20% in the placebo group, a type I error of 0.05 (two-tailed) and a type II error of 0.2. The study was carried out as a two-center, prospective, randomized, double-blind, parallel group study, comparing the effect of 10 mg montelukast given orally once daily with a placebo. Following a wash-out period of 2 weeks in which all patients were given one placebo tablet per day, the patients were randomized to receive either a 10 mg montelukast tablet or a placebo tablet once a day for 4 weeks. No other active topical or systemic treatment was permitted during the trial. The patients were given an ample supply of emollient to be used freely. The activity of the dermatitis was assessed at baseline, after the wash-out period of 2 weeks, and after 1, 2, and 4 weeks of receiving either active treatment or the placebo. Possible adverse experiences were recorded at each visit. Clinical assessment was based on an eczema area and severity index (EASI) score8 as well as a score for pruritus. The latter score was determined by the patient at each visit on a 10 cm visual analog scale with scores of 0 to 3 at intervals of 2.5 cm. The primary efficacy endpoint was the sum of the EASI and the pruritus scores (modified EASI score). The 147
148 Brief reports
J AM ACAD DERMATOL JULY 2005
Table I. Demographic data and treatment results Montelukast N = 29
Placebo n = 30
Male Female Mean age Modified EASI score at baseline
7 22 28 years 8.9
9 21 30 years 9.5
After treatment Modified EASI score e last recorded value (intention-to-treat) (P = .46)
n = 25 6.8
n = 28 7.6
Before treatment
EASI, Eczema area and severity index.
secondary efficacy endpoint was the pruritus score during the trial as a percent of the baseline value. The Fisher exact test was used to test for differences between the groups with regard to the primary endpoint. Analyses were based on the intention-totreat analysis. The code was not broken until completion of the trial and after all the statistical calculations had been carried out. The study was approved by the regional medical ethics committees of counties of A˚rhus, North Jutland, and Viborg. The manuscript was prepared in accordance with the CONSORT statement.
RESULTS Fifty-nine patients were included in the study. Fifty-three of them were seen at 1 or more of the 3 visits while receiving active treatment. Data for these 53 patients were used to determine the results of treatment with montelukast, applying the intentionto-treat analysis (Table I). Drop-out before the start of active treatment (6 patients) and during treatment (6 patients; 4 in the montelukast group and 2 in the placebo group) was caused by aggravation of the dermatitis or failure to return for scheduled follow-up visits. Forty-seven patients completed all visits. With regard to a modified EASI score, a test for proper randomization at baseline showed no significant difference between the two groups (Wilcoxon signed rank sum non-parametric test, P = .85). An analysis of individual differences between end point and baseline in the two groups showed no statistically significant difference between active treatment and the placebo (Wilcoxon signed rank sum nonparametric test, P = .46), nor was there any difference in drop-out rate between the two groups (chi-square test for contingency tables, P = .62).
No side effects were seen in either of the two groups that were felt to be related to study medication.
DISCUSSION In the current investigation, no difference was seen between montelukast and a placebo in the treatment of adults with moderate to severe atopic dermatitis. This is in contrast to the results of several other studies. Eustachio et al1 treated 20 men with severe AD for 6 weeks in a similar placebo-controlled study and found a significant difference in SCORAD reduction between the group that received montelukast and the group given a placebo. Yamose et al2 treated 8 adult patients with AD of moderate severity with 10 mg montelukast in a randomized, double-blind, placebo-controlled, cross-over study for a period of 8 weeks. After 4 weeks, statistically significant improvement was seen following treatment with montelukast. The shorter duration of the current study could explain the difference in treatment results. Capello et al3 carried out a single-blind study involving 32 adults in which he compared treatment with 10 mg montelukast per day and traditional treatment. Both groups had similar, reductions of SCORAD. Pei et al4 used 5 mg montelukast per day for 4 weeks to treat moderate to severe AD in 15 children ranging in age from 6 to 15 in a randomized, double-blind, placebo-controlled, cross-over study. Montelukast proved statistically significantly more effective than a placebo. In all of these studies the effect of montelukast was moderate. The inconsistent findings between this study and the previous ones may be related to nuances in study design, the severity of disease, the limited number of patients, and the simultaneous use of steroids in some of the trials. Most importantly, as this study was designed to detect a fairly large difference in efficacy, the results do not rule out the possibility of a modest treatment effect. In the current study, a type II error was fixed at 0.80, assuming a difference of effect 60% (reduction of score) for active treatment versus a 20% reduction in the placebo group. Montelukast remains a useful treatment of mild to moderate bronchial asthma. Its limited utility in AD highlights the fact that although these diseases are related, underlying pathology clearly differs and will require further research to elucidate. REFERENCES 1. Eustachio N, Alessandro P, Margherita F, Antonio F, Tursi A. Efficacy and tolerability of montelukast as a therapeutic agent
J AM ACAD DERMATOL
Brief reports 149
VOLUME 53, NUMBER 1
for severe atopic dermatitis in adults. Acta Derm Venereol 2002;82:297-320. 2. Yanase FJ, David-Bajar K. The leukotriene antagonist montelukast as a therapeutic agent for atopic dermatitis. J Am Acad Dermatol 2001;44:89-93. 3. Capella GL, Grigerio E, Altomare G. A randomized trial of leukotriene receptor antagonist montekulast in moderate-tosevere atopic dermatitis of adults. Eur J Dermatol 2001;11:209-13. 4. Pei AYS, Chan HHL, Leung TF. Montelukast in the treatment of children with moderate-to-severe atopic dermatitis: A pilot study. Pediatr Allergy Immunol 2001;12:154-8.
5. Carucci JA, Washenik K, Weinstein A, Shupack J, Cohen DE. The leukotriene antagonist zafirlukast as a therapeutic agent for atopic dermatitis. Arch Dermatol 1998;134:785-6. 6. Hanifin RG. Diagnostic features of atopic dermatitis Y2. Acta Derm Venereol Suppl (Stockh) 1980;92:44-7. 7. Rajka, Langeland T. Grading of the severity of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1989;144:13-4. 8. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermato 2001;10:11-8.
Treatment of uremic pruritus with narrowband ultraviolet B phototherapy: An open pilot study ¨ zdemir, MDc Simin Ada, MD,a Deniz Sec¸kin, MD,a I_ rem Budakoglu, MD,b and Fatma Nurhan O Ankara, Turkey
We report the results of a pilot study of narrowband ultraviolet B phototherapy for the treatment of 20 patients with uremic pruritus. Ten patients completed the 6-week study period. A total of 8 patients were found to be responders. Of the remaining 10 patients who left the study before 6 weeks, 6 were satisfied with the response. In the follow-up period, 7 responders could be examined, and 3 were in remission 6 months after completing treatment. However, pruritus recurred in the remaining 4 responders. Narrowband ultraviolet B phototherapy may be an effective treatment for patients with uremic pruritus. Recurrence of pruritus, however, is a frequent problem. ( J Am Acad Dermatol 2005;53:149-51.)
P
ruritus is a frequent and troublesome symptom in patients with chronic renal failure receiving hemodialysis.1 However, it also may occur in patients on conservative uremia treatment or undergoing continuous ambulatory peritoneal dialysis.1 For patients who are not candidates for kidney transplantation, broadband (BB) UVB phototherapy is considered by some authors as a treatment of choice.2 However, little is known about the efficacy of narrowband (NB) UVB phototherapy in this condition. In this study, we aimed to evaluate the efficacy of NB UVB in alleviating uremic pruritus.
From the Departments of Dermatology,a Public Health,b and Nephrology,c Baskent University Faculty of Medicine. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Simin Ada, MD, Baskent University Faculty of Medicine, Department of Dermatology, 5. sok No: 48 Bahc¸elievler, Ankara, Turkey 06490. E-mail: siminada@ baskent-ank.edu.tr. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.12.052
The study included 20 patients (12 men and 8 women) with uremic pruritus. The patients gave informed consent to the study, which was approved by the institutional ethical committee. All except one was undergoing maintenance hemodialysis. Uremic pruritus had to have appeared after the diagnosis of chronic renal failure, without any other systemic, dermatologic, or psychologic causes that could explain it. All patients had been unresponsive to oral antihistamines and topical emollients. The intensity of pruritus was evaluated at baseline using a visual analog scale (VAS) score (0 [no pruritus]-10 [most severe pruritus]) and a detailed cumulative score (DCS) assessing various characteristics of pruritus.3 The same investigator determined the pruritus intensity at every phototherapy session just before the irradiation procedure by VAS score and weekly thereafter by DCS. Phototherapy was administered to the whole body surface 3 times a week for 6 weeks in a UV irradiation cubicle (Waldmann 7001K, Waldmann Mediziniche Technik, VillingenSchwenningen, Germany) equipped with 20 100-W fluorescent lamps (TL01, Philips Co, Eindhoven, The Netherlands). The cubicle had its own cooling fan for