D.RIGOPOULOS, D.IOANNIDES,* D.KALOGEROMITROS, S.GREGORIOU AND A.KATSAMBAS

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1 British Journal of Dermatology 24; 151: DOI: /j x Therapeutics Pimecrolimus cream 1% vs. betamethasone 17-valerate Æ1% cream in the treatment of seborrhoeic dermatitis. A randomized open-label clinical trial D.RIGOPOULOS, D.IOANNIDES,* D.KALOGEROMITROS, S.GREGORIOU AND A.KATSAMBAS National University of Athens Medical School, A. Syrgos Hospital, Athens, Greece *Aristotle University of Thessaloniki Medical School, Thessaloniki, Greece Accepted for publication 11 April 24 Summary Background Seborrhoeic dermatitis is a chronic inflammatory disease with remissions and exacerbations, characterized by erythema, scaling and pruritus primarily on the face, scalp and chest. Corticosteroids and antifungals are the mainstay of therapy. However, chronic use of corticosteroids is associated with side-effects such as skin atrophy and telangiectasia. Pimecrolimus, an inhibitor of calcineurin, has been used successfully in one patient with seborrhoeic dermatitis. Objectives The objective of this randomized open-label clinical trial was to compare the efficacy and tolerability of pimecrolimus in comparison with a potent corticosteroid (betamethasone 17-valerate) in the treatment of seborrhoeic dermatitis. Methods Twenty patients with seborrhoeic dermatitis were included in this study, 11 patients in the pimecrolimus 1% cream group and nine patients in the betamethasone 17-valerate Æ1% cream group. Patients were instructed to use a thin layer of the study products twice daily at the lesional area and to discontinue treatment as soon as symptoms were absent. Clinical measures assessed were erythema, scaling and pruritus which were evaluated using a four-point scale ( 3). Results Both pimecrolimus and betamethasone were highly effective in the treatment of seborrhoeic dermatitis. reduced all three parameters, erythema, scaling and pruritus, faster than pimecrolimus, but the differences in reduction were not statistically significant. Relapses were observed more frequently and were more severe with betamethasone than with pimecrolimus. Moreover, pruritus was not observed after discontinuation of treatment from day 15 and beyond in the pimecrolimus group, whereas it was reported in most patients of the betamethasone group. This difference was statistically significant. Conclusions It appears that pimecrolimus, a nonsteroidal topical treatment, may be an excellent alternative therapeutic modality for treating seborrhoeic dermatitis. Key words: betamethasone 17-valerate, pimecrolimus, seborrhoeic dermatitis Correspondence: D.Rigopoulos. drigop@hol.gr Conflicts of interest statement: none of the authors is a shareholder of Novartis or has any financial ties with the company or financial interest in Elidel Ò (pimecrolimus) cream. No funds supported this study beyond the resources of ÔA. SygrosÕ Hospital. Seborrhoeic dermatitis is a chronic inflammatory disease with remissions and exacerbations, characterized by its typical location (face, scalp and chest) and its clinical appearance (erythema, scaling and pruritus). Endogenous and genetic factors are implicated in its aetiology, and the increase of Pityrosporum ovale is also a constant finding. Sebum excretion rate is normal, although the disease is located in areas with increased numbers of sebaceous glands. Treatment of seborrhoeic dermatitis includes topical Ó 24 British Association of Dermatologists 171

2 172 D.RIGOPOULOS et al. imidazole derivatives with or without steroids, or steroids alone. Pimecrolimus, a derivative of the macrolactam ascomycin, binds to the cytosolic receptor macrophilin-12 and the resulting drug protein complex inhibits the phosphatase calcineurin, resulting in the blockage of signal transduction in target cells. As a consequence, it selectively inhibits the release of both T-helper (Th) 1 [interleukin (IL)-2 and interferon-c] and Th2 (IL-4 and IL-1) cytokines and of T-helper clones. 1 Pimecrolimus 1% cream was as effective as betamethasone 17-valerate Æ1%, clobetasol 17-propionate Æ5%, diflucortolone 21-valerate Æ1%, mometasone 17-furoate Æ1% and fluticasone propionate Æ5% creams at reducing gross lesions in pigs sensitized and topically challenged with 2,4-dinitrofluorobenzene. 2 Pimecrolimus has been used successfully in one patient with seborrhoeic dermatitis. 3 In contrast to topical corticosteroids, pimecrolimus does not appear to induce skin atrophy. 4 In this open-label study, the efficacy of pimecrolimus 1% cream was compared with that of betamethasone 17-valerate Æ1% cream in the treatment of seborrhoeic dermatitis and in the control and prevention of posttreatment flares of the disease. Patients and methods Twenty patients with seborrhoeic dermatitis were included in this open-label study. Exclusion criteria were as follows: other dermatoses of the face; topical treatments during the 14 days before inclusion in the protocol; systemic retinoids during the 6 months prior to entry in the study; and pregnancy or lactation. Patch tests with the standard European series were performed in all patients to exclude contact dermatitis. Demographic data of the treated patients are shown in Table 1. Patients were randomly assigned to treatment with pimecrolimus 1% or betamethasone Æ1% cream using a program that allocated every consecutive group of two patients to one patient in each group. The random Table 1. Demographic data of treated patients Pimecrolimus Men 9 7 Women 2 2 Age range (years) Mean age (years) 36Æ4 37Æ2 Median disease duration (years) 2Æ1 2Æ2 numbers were generated by a computer and were assigned to the patients by the investigator s assistant. The same assistant enrolled and assigned the treatment of the patients, while the assessment of efficacy was performed by the investigators, in an attempt to make the assessments investigator masked. Eleven patients were included in the pimecrolimus 1% cream group and nine patients in the betamethasone 17-valerate Æ1% cream group. There was no statistically significant difference in sex, age range or disease duration between the groups (Table 1). The mean baseline score for erythema, pruritus and scaling did not differ significantly between the two treatment groups. The mean scores for erythema were 2Æ18 and 2Æ33, for pruritus 1Æ63 and 1Æ66, and for scaling 1Æ72 and 1Æ98 in the pimecrolimus and betamethasone groups, respectively. Patients were instructed to use a thin layer of the study products twice daily on the lesional area and to discontinue treatment as soon as symptoms were absent. On day 21 all patients with a disease flare started treatment with pimecrolimus 1% cream, and were re-examined after 3 days. Efficacy and cutaneous tolerance were assessed seven times over the trial period, at baseline and at days 3, 7, 9, 15, 21 and 24. Erythema, scaling and pruritus were evaluated at each visit, using a four-point scale (, absent; 1, mild; 2, moderate; 3, severe). Statistical analysis was performed using the Friedman two-way analysis of variance by ranks to test whether the values for one treatment at the seven time points were different. In the case of multiple comparisons, as in our study, the a-level was adjusted according to the Bonferroni adjustment. To compare between the treatments at each of the seven time points the Wilcoxon Mann Whitney test was used. Results Treatment period There was a gradual reduction in the erythema, scaling and pruritus scores in both treatment groups (Figs 1 4). One patient in the pimecrolimus group and four patients in the betamethasone group discontinued treatment by day 7, due to the resolution of their disease. By day 9 all patients had discontinued treatment, because all symptoms were absent. The reduction in scores within each group between baseline and day 9 was statistically significant according to the Friedman two-way analysis of variance by ranks. Ó 24 British Association of Dermatologists, British Journal of Dermatology, 151,

3 PIMECROLIMUS VS. BETAMETHASONE IN SEBORRHOEIC DERMATITIS a 2 Total score 15 1 Cessation of treatment Days ERYTHEMA Pimecrolimus Figure 1. Improvement of erythema (score reduction). b Total score Cessation of treatment Days SCALING Pimecrolimus c Figure 2. Improvement of scaling (score reduction) Total score Cessation of treatment Days PRURITUS Pimecrolimus d Figure 3. Improvement of pruritus (score reduction). Both drugs reduced erythema from day 3 of treatment until complete resolution of the symptom at day 9, with betamethasone acting slightly more quickly than pimecrolimus. Both drugs also reduced scaling from day 3 of treatment, with betamethasone again acting more quickly. Similarly, both drugs improved Figure 4. Clinical appearance of two patients with seborrhoeic dermatitis (a,b) before and (c,d) 3 days after treatment with pimecrolimus. Ó 24 British Association of Dermatologists, British Journal of Dermatology, 151,

4 174 D.RIGOPOULOS et al. Patients (%) Days ERYTHEMA PRURITUS SCALING Pimecrolimus seven of nine (78%) in the betamethasone group (Fig. 6). All symptoms were milder than at baseline in both groups. The mean score of the three parameters was 4 for the pimecrolimus group and 5Æ67 for the betamethasone group, indicating that relapse in the betamethasone group was not only observed in more patients than in the pimecrolimus group, but was also more severe. On day 24, all symptoms disappeared. A burning sensation was observed in three patients in the pimecrolimus and in one patient in the betamethasone group at the beginning of treatment. It was mild and transient, and no discontinuation of treatment was reported because of this adverse event. Figure 5. Relapse of symptoms on days 15 and 21 after treatment. Patients (%) pruritus, with complete disappearance of the symptom from day 7. Based on the daily recording by patients in a diary, pimecrolimus gave a faster reduction of pruritus, with complete disappearance of the symptom on day 5, while with betamethasone pruritus disappeared on day 7. Follow-up period Pimecrolimus Figure 6. Number of patients relapsed on day 21 with at least one symptom. Following discontinuation of treatment, no symptoms reappeared earlier than day 21 in the group treated with pimecrolimus (with complete absence of pruritus in these patients), while in the betamethasone group all symptoms relapsed from day 15, with scores increasing at day 21 (Fig. 5). The difference in scores between the two treatments was significant for erythema at day 15 and for pruritus at day 21, using the Wilcoxon Mann Whitney test. On day 21 six of 11 (55%) patients treated with pimecrolimus had had a relapse in comparison with Discussion The results of this study indicate that both pimecrolimus and betamethasone are highly effective in the treatment of seborrhoeic dermatitis. Although low and moderate potency steroids are the mainstay of therapy in facial dermatoses, our choice of betamethasone 17-valerate as comparator was dictated by the need to assess the efficacy of topical pimecrolimus 1% cream in seborrhoeic dermatitis in comparison with a potent topical steroid. gave a more rapid reduction in all three parameters, erythema, scaling and pruritus, than did pimecrolimus, but the differences were not statistically significant. Relapses were observed more frequently and were more severe with betamethasone than with pimecrolimus. Moreover, pruritus was not observed after discontinuation of treatment at day 15 and thereafter in the pimecrolimus group, whereas it was reported in most patients of the betamethasone group. This difference was statistically significant. Pimecrolimus has previously been used with success in a male with seborrhoeic dermatitis. 3 In this report, complete clearance was obtained after approximately 8 days of twice-daily application. In our study, seborrhoeic dermatitis was completely resolved by day 9 in all patients who used pimecrolimus twice daily. In one patient all symptoms resolved on day 7, but his dermatitis was milder, with a total score of 4. In the case of betamethasone, four patients were completely clear by day 7, with a mean total score of 6Æ25. The difference was not statistically significant, indicating that pimecrolimus has a comparable onset of action with betamethasone in controlling seborrhoeic dermatitis. The fast action of the drug was confirmed when all patients who relapsed on day 21 were given Ó 24 British Association of Dermatologists, British Journal of Dermatology, 151,

5 PIMECROLIMUS VS. BETAMETHASONE IN SEBORRHOEIC DERMATITIS 175 pimecrolimus. Their symptoms resolved in only 3 days, suggesting that pimecrolimus could be used during the maintenance period, or in a preventive way. An interesting observation in our study was the excellent response of pruritus in the patients treated with pimecrolimus. Although pruritus is not a constant symptom of seborrhoeic dermatitis, when it appears it is rather frustrating. influenced pruritus to a lesser degree than pimecrolimus, and the difference was significant. Tacrolimus Æ1% ointment has also proven to be efficacious and safe in the short-term treatment of seborrhoeic dermatitis in 16 patients in a recent openlabel pilot study. 5 Corticosteroids are the mainstay of therapy in seborrhoeic dermatitis. However, their chronic use is associated with well-known side-effects especially on the face, such as skin atrophy and telangiectasia. In this study, pimecrolimus was compared with betamethasone and was found to be equally effective in controlling symptoms of seborrhoeic dermatitis, with fewer relapses and no rebounds, as frequently observed with corticosteroids. Therefore, this nonsteroidal topical treatment may be an excellent alternative therapeutic modality in the treatment of seborrhoeic dermatitis. References 1 Dupuy P, Maurette C, Amoric JC, Chosidow O and the Study Investigator Group. Randomized, placebo-controlled, double-blind study on clinical efficacy of ciclopiroxolamine 1% cream in facial seborrhoeic dermatitis. Br J Dermatol 21; 144: Meingassner JG, Grassberger M, Fahrgruber H et al. A novel antiinflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology. Br J Dermatol 1997; 137: Crutchfield CE. Pimecrolimus: a new treatment for seborrheic dermatitis. Cutis 22; 7: Queille-Roussel C, Paul C, Duteil L et al. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study. Br J Dermatol 21; 144: Braza TJ, DiCarlo JB, Soon SL, McCall CO. Tacrolimus.1% ointment for seborrhoeic dermatitis: an open-label pilot study. Br J Dermatol 23; 148: Ó 24 British Association of Dermatologists, British Journal of Dermatology, 151,

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