Effect of sequential applications of topical tacrolimus and topical corticosteroids in the treatment of pediatric atopic dermatitis: An open-label pilot

study
Yasuo Kubota, MD,a Kozo Yoneda, MD,a Kozo Nakai, MD,a Junko Katsuura, MD,a Tetsuya Moriue, MD,a Yoshie Matsuoka, MD,a Izumi Miyamoto, MD,a and Yukihiro Ohya, MDb Kagawa and Tokyo, Japan
Background: The efcacy of combination therapy with topical corticosteroids and tacrolimus in the treatment of atopic dermatitis remains to be established. Objective: Our aim was to determine whether a regimen of sequential application of topical corticosteroids and topical tacrolimus is effective in the treatment of pediatric atopic dermatitis. A second goal was to assess the impact of this treatment regimen on quality of life (QOL) and the response shift on QOL changes. Methods: The study regimen consisted of 3 phases. In the induction phase, patients were treated for a 2week period with application of 0.03% tacrolimus ointment in the morning and application of a strong- or weak-potency corticosteroid ointment in the evening. In the transitional phase, they were treated for an additional 2 weeks with 0.03% tacrolimus ointment twice daily on weekdays and concurrent application of tacrolimus and a topical corticosteroid ointment on weekend days. In the maintenance phase, the corticosteroid ointment was discontinued and 0.03% tacrolimus ointment was applied twice daily for an additional 2 weeks. Daily application of tacrolimus ointment was then discontinued and replaced by an emollient with application of 0.03% tacrolimus ointment only when necessary for an additional 6 weeks. The Eczema Area and Severity Index score, Investigators Global Assessment, severity of pruritus and sleep disturbance scores, and QOL evaluation were measured. After 12 weeks, the patients completed a retrospective version of the pretreatment QOL evaluation for analysis of response shift bias. Results: Eczema Area and Severity Index scores decreased by the sixth week, and continued improvement was observed during an additional 6-week period. Both the pruritus and sleep disturbance scores decreased throughout the study. Of patients, 90% showed marked clinical improvement at week 6 and 96% at week 12. On the Childrens Dermatology Life Quality Index and the Infants Dermatology QOL Index survey, mean QOL scores improved after completion of therapy at week 12. The mean difference between the pretest and the retrospective pretest scores indicated the presence of a response shift bias. Limitations: This was an uncontrolled, open-label study. Conclusions are limited by the small sample size. Conclusions: A xed sequential regimen of application of tacrolimus ointment with tapering of topical corticosteroids may limit the long-term use and adverse effects of topical corticosteroids, while maintaining clinical control of pediatric atopic dermatitis and improving the QOL. The nding of a response shift bias suggests that parents/guardians underestimate the seriousness of skin disease and its impact on QOL. ( J Am Acad Dermatol 2009;60:212-7.)

From the Department of Dermatology, Faculty of Medicine, Kagawa University,a and Division of Allergy, Department of Medical Specialties, National Center for Child Health and Development, Tokyo.b Funding sources: None. Conflicts of interest: None declared. Accepted for publication September 23, 2008. Reprint requests: Yasuo Kubota, MD, Department of Dermatology, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe,

Miki-cho, Kita-gun, Kagawa, Japan 761-0793. E-mail: kubotay@ kms.ac.jp. Published online November 25, 2008. 0190-9622/$36.00 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2008.09.034

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Atopic dermatitis (AD) has a negative impact on the quality of life (QOL) of children and their parents1,2 and poses a therapeutic challenge to dermatologists.3,4 Topical corticosteroids have been the mainstay of treatment of AD for 40 years. Topical immunomodulators present a more recent therapeutic option.5 Evaluation of these treatments in combination therapy for AD is of interest because they have different6 and possibly complementary mechanisms of action.7 In one study8 of adolescent and adult patients with AD, concomitant treatment with clocortolone pivalate cream and tacrolimus ointment for 3 weeks proved superior to monotherapy with either agent in improving overall dermatologic skin scores and in reducing pruritus. We examined the efcacy and safety of topical sequential therapy in the treatment of skin lesions for 12 weeks in pediatric patients with AD. Patients with chronic diseases are faced with the necessity to adapt to their illness. An important mediator of this adaptation process is the response shift.9 We examined the impact of therapy on the QOL and response-shift bias by using a Japanese version of the Childrens Dermatology Life Quality Index (CDLQI) and the Infants Dermatology QOL Index (IDQOL) questionnaire.10

Abbreviations used: AD: Atopic dermatitis CDLQI: Childrens Dermatology Life Quality Index EASI: Eczema Area and Severity Index IDQOL: Infants Dermatology Quality of Life Index QOL: quality of life

METHODS
This pilot study was an open-label 12-week trial that involved 28 pediatric patients with a diagnosis of AD based on the Hanin and Rajka criteria11 and with an evaluation of severity based on Rajka and Langeland criteria.12 Patients or the parents/guardians gave informed consent. The institutional review board approved this protocol. The study consisted of 3 phases (Fig 1). In the induction phase, patients were initially treated for a 2-week period with application of a thin coating of 0.03% tacrolimus ointment in the morning and a strong- or weak-potency corticosteroid ointment in the evening (after bathing or showering). In some cases, a weak-class corticosteroid ointment was applied to the face in the evening as needed. In the transitional phase, for an additional 2 weeks patients were treated with 0.03% tacrolimus ointment alone twice daily on weekdays and concomitant application of topical corticosteroid, as in the induction phase, only on weekends. Finally, in the maintenance phase, use of the corticosteroid ointment was discontinued and 0.03% tacrolimus ointment twice daily was continued; this was tapered from twice daily to once a day for an additional 2 weeks. When the dermatitis cleared almost completely, 0.03% tacrolimus ointment was replaced by an emollient with use of 0.03% tacrolimus ointment

only for disease ares for an additional 6 weeks. Patients were evaluated at baseline and at weeks 2, 4, 6, and 12 of treatment by the same dermatologist. Patients were not permitted to start taking an oral antihistamine during the study. However, they continued to take an oral antihistamine if it was prescribed before inclusion in the study. All other systemic therapies for AD were discontinued for at least 4 weeks before the study. Eczema Area and Severity Index (EASI) score, Investigators Global Assessment, severity of pruritus and sleep disturbance, and CDLQI or IDQOL were measured. Changes from baseline to the end of treatment (mean 6 SD) for EASI scores were analyzed by Wilcoxon signed rank test for nonparametric analysis. All statistical tests were two-sided with a signicance level of P less than .05, unless otherwise specified. To determine global efcacy, Investigators Global Assessment was evaluated on the basis of the physicians assessment of clinical signs of AD. This evaluation was based on changes in the lesions of AD that were dened as: worse (\0%); no appreciable (0%-29%) improvement; slight (30%49%) improvement; moderate (50%-74%) improvement; marked (75%-89%) improvement; excellent (90%-99%) improvement; and cleared (100%). Patient assessments of pruritus and sleep disturbance were performed using a 4-point scale: 0 = no evidence; 1 = mild; 2 = moderate; and 3 = severe. The CDLQI and the IDQOL questionnaires were translated into Japanese and developed by Ohya et al.13 The translation validation of the Japanese version was confirmed by the authors of the original version. The CDLQI questionnaire contains 10 items that comprise 6 categories, including symptoms/ feelings, leisure, school/work, personal relationships, sleep disturbance, and inconvenience of therapy. The responses to each survey item range from 0 (not at all affected) to 3 (very much affected). Both a total QOL score based on all survey items and an individual category score were calculated. Patients younger than 4 years were given the IDQOL questionnaire. Changes from baseline to the end of sequential applications for both the total

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Fig 1. Schematic presentation of topical sequential therapy and data-sampling periods using Eczema Area and Severity Index, pruritus and sleep disturbance scores, and quality-of-life (QOL) survey.

Fig 2. Change from baseline to end of treatment (for up to 12 weeks) in Eczema Area and Severity Index (EASI ) scores in pediatric patients with atopic dermatitis. Significant improvement was observed throughout the course of sequential therapy (P \ .001).

Table I. Demographic data at baseline (n = 31)

Male/female Age, y Age $ /\ 4 y Height, cm Weight, kg Disease duration, y Mild/moderate/severe 12-/6-wk Observation period 18/13 7.1 6 4.2 (2-15) 21/10 115.1 6 23.8 (83-162) 23.5 6 13.2 (11-55) 3.8 6 3.3 (0.1-13) 2/25/4 28/3

Data expressed as number of patients or mean 6 SD (range).

score and individual category scores were analyzed by Wilcoxon signed rank test. We dened response shift as the change in the meaning of ones evaluation of a target construct as a result of a change in the respondents internal standards of measurement, and a change in the respondents values or a redenition of the target construct (reconceptualization of QOL).14 After 12 weeks of sequential applications, patients or their parents completed a retrospective version of the pretreatment QOL evaluation for the analysis of response shift bias.

Fig 3. Change from baseline to end of treatment (12 weeks) in patients assessment of pruritus (A) and sleep disturbance (B) in pediatric patients with atopic dermatitis. Significant improvement was observed throughout the course of sequential therapy (P \ .001).

RESULTS
In all, 37 pediatric patients participated in this study. A total of 31 patients (mean age 6 SD = 7.1 6 4.2 years) completed the study; 18 were male and 13 female (Table I). In all, 25 patients had moderate AD, 4 had severe AD, and two had mild AD. A total of 28 patients completed the 12-week study. After the sequential therapy, mean EASI scores significantly decreased from 12.87 at baseline to 1.43 at 6 weeks, and continuous improvement was observed throughout the following 6-week period (1.39 at 12 weeks) (Fig 2). The patient assessment of pruritus score decreased during the initial 2 weeks, from 2.35 at baseline to 1.03, and this improvement was maintained throughout the study (1.00 at 12 weeks) (Fig 3, A). Sleep disturbance score also decreased (from 1.00 at baseline to 0.03 at 6 weeks, and to 0.04 at 12 weeks) (Fig 3, B). Investigators Global Assessment at 6 weeks showed 3% clear, 48% excellent, 39% marked, and 10% moderate improvement, and 7%, 46%, 42%, and 4% at 12 weeks, respectively (data not shown). Fig 4 depicts clinical improvement of a patient before and after sequential therapy. In the CDLQI survey, the mean QOL score significantly improved after completion of sequential therapy up to 12 weeks, indicated from 5.14 at

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Fig 5. A, Childrens Dermatology Life Quality Index (CDLQI ). B, Infants Dermatology Quality of Life (QOL) Index (IDQOL). QOL change scores from baseline to end of treatment (at maintenance phase). Significant improvement of QOL was observed throughout the course of sequential therapy (P \ .05).

DISCUSSION
Fig 4. Clinical improvement of patient before (A) and after (B) 10 weeks of sequential therapy with tacrolimus ointment 0.03% and corticosteroid ointment (betamethasone valerate 0.12%).

baseline to 2.33 at 6 weeks and to 2.63 at 12 weeks (Fig 5, A). On the IDQOL survey, the mean QOL score also significantly improved, from 6.40 at baseline to 2.20 at 6 weeks and 2.75 at 12 weeks (Fig 5, B). Topical sequential therapy improved the areas in which AD has the greatest impact, including symptoms/feelings and sleep disturbance (Fig 6). The mean difference between the pretest (QOL score before the study) and the retrospective pretest scores was significant (P \ .05), indicating that a response shift bias was present (Fig 7). A greater change after completion of sequential therapy is observed if the retrospective pretest scores and posttest are compared, instead of the pretest and the posttest scores. Serious side effects and laboratory abnormalities were absent; there was one case of folliculitis.

AD is a difcult skin disease to treat and keep under control for long periods. Dermatologists should seek to minimize the impact of this chronic disease on the lives of patients and their guardians.15 In this sequential trial with tacrolimus ointment and topical corticosteroids, we began with an aggressive approach to achieve a quick response in terms of reduction of inammatory skin lesions. The EASI score was reduced by about 80% during rst 2 weeks. Next, to prevent the long-term use of topical corticosteroids and to reduce the risk of recurrence or rebound after abruptly stopping the use of corticosteroids, we tapered off the initial therapy. After completing this sequential therapy at 6 weeks, the EASI score and the patients assessment of pruritus and sleep disturbance signicantly decreased (P \ .001). Continuous improvement was observed throughout the succeeding period (up to 12 weeks). We believe that many patients would be enabled to individualize their treatment with the type of approach presented here. Recalcitrant lesions are prone to receive longer initial treatment. However, patients with lesions that respond faster can move

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Fig 7. Median difference between pretest (quality-of-life score before study) and retrospective pretest scores was signicant at group level (P \ .05), indicating that response shift bias was present. CDLQI, Childrens Dermatology Life Quality Index.

Fig 6. A, Childrens Dermatology Life Quality Index (CDLQI ). B, Infants Dermatology Quality of Life Index (IDQOL). Topical sequential therapy significantly improved areas in which atopic dermatitis has greatest impact, including symptoms/feelings (CDLQI, IDQOL) and sleep disturbance (CDLQI).

more quickly along the sequence. If the AD worsens during the maintenance phase, patients can move backward to the initial treatment phase. This exibility could give patients with AD or their parents more positive control over their topical treatments. Measurement of the impact of AD on QOL is essential for clinical decision making. Child QOL measurements differ markedly from those of adults. Before language development, infants require a different QOL questionnaire from the one designed for older children. Several studies examining the impact of treatment with tacrolimus ointment monotherapy on the QOL of adult and pediatric patients with AD have been conducted.16 In the current study, the evaluation of QOL of pediatric patients with AD using CDLQI or IDQOL demonstrated significant improvement resulting from the topical sequential therapy. In general, patients with chronic diseases are faced with the necessity to accommodate to their illness. An important mediator of this adaptation process is the response shift.9 Response shift here refers to the change in the meaning of ones

self-evaluation of a target construct as a result of a change in the respondents internal standards of measurement and values, or a redefinition of the target construct (reconceptualization of QOL).14 Integrating response shift into QOL research would allow a better understanding of how QOL is affected by changes in health.17 To our knowledge, reported QOL studies in children with AD have not considered the effects of response-shift bias. Our results from the retrospective version of the pretreatment QOL evaluation suggest that the patients and their parents underestimated the seriousness of the skin disease and overestimated QOL before therapy, indicating a response shift. The beneficial treatment results could lead patients or parents to realize that the situation before topical sequential applications was worse than they had thought. A significant change took place in the respondents internal standard of QOL measurement during this study. The dynamic nature of a QOL measurement, manifested as a change in the patients or parents frame of reference, needs to be considered. This study of QOL evaluation after topical sequential application did not include comparisons of the effects of standard topical corticosteroids or tacrolimus monotherapy on QOL. Further detailed clinical trials are warranted to explore the efcacy of sequential or combination therapy. However, we believe that sequential or combination therapies could have a profound effect on the management of pediatric AD.
REFERENCES 1. Morgan M, McCreedy R, Simpson J, Hay RJ. Dermatology quality of life scales: a measure of the impact of skin diseases. Br J Dermatol 1997;136:202-6. 2. Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic eczema: its impact on the family and financial cost. Arch Dis Child 1997;76:159-62. 3. Hanifin JM, Cooper KD, Ho VC, Kang S, Krafchik BR, Margolis DJ, et al. Guideline of care for atopic dermatitis: developed in

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4. 5.

6.

7.

8.

9.

10.

accordance with the American Academy of Dermatology (AAD)/American Academy of Dermatology Association administrative regulations for evidence-based clinical practice guideline. J Am Acad Dermatol 2004;50:391-404. Sidbury R, Hanifin JM. Old, new, and emerging therapies for atopic dermatitis. Dermatol Clin 2000;38:1-11. Ruzicka T, Bieber T, Schopf E, Rubins A, Dobozy A, Bos JD, et al. A short-term trail of tacrolimus ointment for atopic dermatitis. N Engl J Med 1998;337:816-21. Caproni M, Torchia D, Antiga E, Terranova M, Volpi W, Del Bianco E, et al. The comparative effects of tacrolimus and hydrocortisone in adult atopic dermatitis: an immunohistochemical study. Br J Dermatol 2007;156:312-9. Norris DA. Mechanisms of action of topical therapies and the rationale for combination therapy. J Am Acad Dermatol 2005; 53(Suppl):S17-25. Torok HM, Maas-Irslinger R, Slayton RM. Clocortolone pivalate cream 0.1% used concomitantly with tacrolimus ointment 0.1% in atopic dermatitis. Cutis 2003;72:161-6. Sprangers MAG, Schwartz CE. Integrating response shift into health-related quality of life research: a theoretical model. Soc Sci Med 1999;48:1507-15. Finlay AY. Quality of life assessments in dermatology. Semin Cutan Med Surg 1998;17:291-6.

11. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1980;92:44-7. 12. Rajka G, Langeland T. Grading of the severity of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1989;144: 13-4. 13. Ohya Y, Sasaki R, Matsumoto M, Riazi A, Lewis-Jones SM, Finlay A. Development of the Japanese version of the Childrens Dermatology Life Quality Index (CDLQI) [abstract]. Arerugi 2002;51:265. 14. Schwartz CE, Sprangers MAG. Methodological approaches for assessing response shift in longitudinal quality of life research. Soc Sci Med 1999;48:1531-48. 15. Susan J, Tofte RN, Hanifin JM. Current management and therapy of atopic dermatitis. J Am Acad Dermatol 2001; 44(Suppl):S13-6. 16. Drake L, Prendergast M, Maher R, Breneman D, Korman N, Satoi Y, et al. The impact of tacrolimus ointment on healthrelated quality of life of adult and pediatric patients with atopic dermatitis. J Am Acad Dermatol 2001;44(Suppl): S65-72. 17. Timmerman AA, Anteunis LJC, Meesters CMG. Response-shift bias and parent-reported quality of life in children with otitis media. Arch Otolaryngol Head Neck Surg 2003;129: 987-91.