- Email: [email protected]
Results of a randomized, double-blind, vehicle-controlled efficacy trial of pimecrolimus cream 1% for the treatment of moderate to severe facial seborrheic dermatitis
Results of a randomized, double-blind, vehiclecontrolled efficacy trial of pimecrolimus cream 1% for the treatment of moderate to severe facial seborrheic dermatitis Erin M. Warshaw, MD, MS,a,b Ross Jon Wohlhuter,a,b An Liu, MS,a Sarah A. Zeller, MD, MPH,c Rachel A. Wenner, MD,a,b Sacharitha Bowers, MD,a,b,d Julie C. Schultz, MD,b H. Irving Katz, MD,b Calogera L. McCormick, BA,e and Anne Parneix-Spake, MDe Minneapolis, Minnesota; Oklahoma City, Oklahoma; Springfield, Illinois; and East Hanover, New Jersey Background: Seborrheic dermatitis is commonly treated with anti-inflammatory products, including topical corticosteroids. Pimecrolimus cream 1% also exerts anti-inflammatory activity by inhibiting T-cell cytokine production. Objective: We sought to compare the efficacy and safety of twice-daily pimecrolimus for treatment of moderate to severe facial seborrheic dermatitis. Methods: This double-blind, vehicle-controlled, 4-week trial randomized patients with seborrheic dermatitis to pimecrolimus or vehicle (1:1). Clinical assessments (erythema [0-3] and scaling [0-3] combined for a total area score [0-6]) were performed at weeks 0, 2, and 4. Inclusion criteria included total area score 4 or greater and erythema 2 or greater. The prespecified primary variable, change from baseline in total area score at week 4, was analyzed using a two-sample t test for intent-to-treat and per protocol populations. Results: In all, 96 adults of mean age 59.6 years, 88.5% male, were randomized (n = 47 pimecrolimus; 49 vehicle). At week 4, the mean change from baseline in total area score was 3.7 versus 3.3 for pimecrolimus and vehicle groups, respectively (intent-to-treat: P = .1913; 95% confidence interval (CI) for difference [e0.195, 0.961]). Per protocol analysis (n = 41 pimecrolimus; 46 vehicle) indicated a significant difference between groups (mean change 3.9 pimecrolimus vs 3.2 vehicle; P = .0156; CI [0.129, 1.197]). The superiority of pimecrolimus was observed as early as week 2 (intent-to-treat: P = .0062; CI [0.132, 0.777]; per protocol: P = .0012; CI [0.410, 1.593]). No drug-related serious adverse events occurred. The most frequent drugrelated adverse events were local, mild, and transient (pimecrolimus = 26%; vehicle = 12%). Limitations: Generalizability is limited by the elderly male study population. Conclusion: This study suggests that pimecrolimus cream 1% is an effective and well-tolerated treatment for moderate to severe facial seborrheic dermatitis. ( J Am Acad Dermatol 2007;57:257-64.)
From the Minneapolis Department of Veterans Affairs Medical Centera; University of Minnesotab; Department of Dermatology, University of Oklahomac; Southern Illinois Universityd; and Novartis Pharmaceuticals Corporation, East Hanover.e This investigator-initiated study was supported by Novartis Pharmaceuticals Corporation. During this study, Dr Warshaw was supported by a Department of Veterans Affairs Cooperative Studies Clinical Research Career Development Award. Disclosure: Anne Parneix-Spake, MD, and Calogera L. McCormick are employees of Novartis Pharmaceuticals Corporation. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.
Accepted for publication November 3, 2006. Reprints not available from the authors. Correspondence to: Erin M. Warshaw, MD, MS, University of Minnesota, Dermatology Section, Minneapolis Veterans Affairs Medical Center, Department 111K, 1 Veterans Dr, Minneapolis MN 55417. E-mail: [email protected]. Published online December 30, 2006. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.11.007
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Seborrheic dermatitis is a common, chronic disease that affects 2% to 10% of the adult population, mainly between age 20 and 50 years. The prevalence is higher for males than females and for individuals with central nervous system disorders (eg, Parkinson’s disease, major truncal paralyses) and immunodeficiencies as compared with those without such disorders. Affected areas most often include the scalp, eyebrows, ears, nasolabial creases, axillae, sternum, and groin. The origin of seborrheic dermatitis is unknown. On histopathology, seborrheic dermatitis shows a perivascular mixed cell infiltrate with epidermal acanthosis and neutrophils, which is often indistinguishable from atopic dermatitis. Changes in the function of immune system may represent a possible pathogenic factor.1 The sebum-rich areas of the body support growth of the lipophilic yeast, Malassezia furfur yeast (formerly called Pityrosporum ovale). The role of M furfur yeast in the development of seborrheic dermatitis is not completely understood, however, it is acknowledged widely as an exacerbating factor of the disorder, and not necessarily the foundation of the condition.2-4 It has been hypothesized that the immobility of patients with neurologic disorders may play a role in the aggravation of their seborrheic dermatitis as a result of increased pooling of sebum in which M furfur may grow more readily.5 Standard topical treatments for seborrheic dermatitis include corticosteroid and antimycotic medications. The chronic use of topical corticosteroids, especially on the face, may not be advisable as corticosteroid side effects may include telangiectasia, atrophy, striae, perioral dermatitis, or tachyphylaxis.6,7 Pimecrolimus is a topical calcineurin inhibitor that prevents T-cell activation by down-regulating T-cell production of T-helper cells type 1 (interleukin [IL]-2, interferon gamma) and T-helper cells type 2 (IL-4, IL-10) type cytokines, therefore, inhibiting the proliferation of T cells after antigen-specific or unspecific stimulation. Pimecrolimus also prevents the IgE/ antigen-mediated degranulation of mast cells.8,9 Pimecrolimus is approved by the Food and Drug Administration (FDA) as a second-line treatment of mild to moderate atopic dermatitis for patients age 2 years and older. In clinical studies, pimecrolimus has demonstrated efficacy for treatment of atopic dermatitis of infants, children, adolescents, and adults.10-13 In addition, topical pimecrolimus cream does not cause skin atrophy and has a well-established local safety profile.10-14 The FDA recently recommended black box warnings for topical calcineurin inhibitors based on animal studies using high doses of these drugs, which suggested a possible increased rate of malignancy.15 To date, use of pimecrolimus twice daily has been shown to be effective for treatment of seborrheic
Abbreviations used: CI: FDA: IGA: IL: ITT: PP:
confidence interval Food and Drug Administration Investigator’s Global Assessment interleukin intent to treat per protocol
dermatitis in 4 open-label or single-blind trials involving 11 patients,16 5 patients,17 19 patients,18 and 37 patients,19 respectively. In addition, several single case reports have described complete clearing of severe facial seborrheic dermatitis within 30 days of twice-daily use of pimecrolimus cream 1%.20-23 Another topical immunomodulator, tacrolimus 0.1% ointment, was evaluated in an open-label study of 18 patients in which 11 patients (61%) showed complete clearing at 28 days. The purpose of this investigator-initiated study was to evaluate the efficacy and safety of pimecrolimus for the treatment of patients with moderate to severe facial seborrheic dermatitis in a double-blind, vehicle-controlled study design.
METHODS This clinical study was performed in accordance with Good Clinical Practices and the Declaration of Helsinki (2000). The protocol was approved by the Minneapolis Veterans Affairs Medical Center Subcommittee on Human Studies, and written informed consent was obtained from each patient in the study before conducting study procedures. Study design and intervention This randomized, double-blind, vehiclecontrolled, single-center, 4-week clinical study of patients with moderate to severe facial seborrheic dermatitis was conducted at our dermatology clinical research division from September 2003 to November 2004. At the baseline visit, patients were randomized in a 1:1 ratio to pimecrolimus cream 1% or vehicle. The computer-generated randomization assignment (blocks of 4) was only accessible to the research pharmacist during the study. The two creams were packaged in identical tubes that were weighed before dispensing and at study end. Patients applied a thin layer of study medication twice daily (approximately every 12 hours) on the affected areas of seborrheic dermatitis for each day of the 4-week study period. Patients were permitted to gently wash the areas for treatment before the application of study medication and were instructed that skin was to be dry before an application of topical study drug. Treated areas were not to be
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washed for at least 3 hours after application of study medication. Patients were advised to minimize or avoid natural or artificial sunlight exposure while participating in the study. Patients were allowed to use nonmedicated shampoo and facial cleansers during the study. Study criteria Eligible patients for the study were at least 18 years of age with a diagnosis of moderate or severe facial seborrheic dermatitis24,25 and no active bacterial, viral, or fungal infection on the head or neck. At baseline, the minimum activity level of disease as assessed by the investigator was required to be a facial target area erythema score of at least 2 on a 0to-3 scale (0 = no erythema to 3 = bright red) and a facial total target area score (composite of erythema and scaling assessments, each measured on a scale of 0 = none to 3 = severe) of at least 4 on a 0-to-6 composite scale. Before enrollment, the study required a 2-week washout period of either topical or systemic antimycotic, antibacterial, or immunosuppressant medications. Women of childbearing potential consented to practice effective birth control during the study period. Patients who had any of the following conditions were excluded: known allergy to components of pimecrolimus cream 1%; those with active perioral dermatitis, acne vulgaris, or rosacea; those with poorly controlled chronic conditions; those with cancer, neurologic conditions, or HIV infection (or other immunosuppression); and pregnant and nursing women. Outcome assessments Clinic visits were performed at baseline (study entry), and weeks 2 and 4 after enrollment. At the baseline visit, a target area was identified on the face for each patient. Efficacy assessments for involvement of seborrheic dermatitis of the face and chest were performed by the principal investigator (E. M. W.) at baseline, week 2, and week 4. Erythema of the target area on the face was graded using a 4-point scale of: 0 (none), 1 (mild, faint red), 2 (moderate, dull red), or 3 (severe, bright red). Scale of the target area on the face was scored using a 4-point scale of: 0 (none), 1 (mild, # 10% of lesion), 2 (moderate, [10% to # 50% of lesion), or 3 (severe, [50% of lesion). The total target area score was the sum of the erythema and scale target area scores (0-6 scale). The Investigator’s Global Assessment (IGA) of disease severity was scored independently for the face and the chest, using a 5-point scale of: 0 (clear, no clinical evidence of seborrheic dermatitis overall), 1 (almost clear, minimal evidence), 2 (mild, mild evidence),
3 (moderate, moderate evidence), or 4 (severe, severe evidence). The primary efficacy variable was the change from baseline of total target area score at week 4. Secondary efficacy variables included the change from baseline of the erythema and scale target area scores at week 4. Additional secondary variables included the percentage of patients who were clear or almost clear at week 4 for facial IGA and chest IGA. All spontaneously reported adverse events were recorded. Approximately halfway through this study (after 56 patients had completed the predefined study period), a satisfaction instrument was added. After approval from our subcommittee on human studies, all patients from that time on were asked to complete a satisfaction survey of the study medication at week 4. Overall satisfaction with the cosmetic appearance of the product was rated as either ‘‘yes’’ or ‘‘no.’’ Patients recorded assessments of spreadability, ease of rub-in, nonsticky feel, and suitability of the product for use on the face using a 5-point scale ranging from ‘‘very good’’ to ‘‘very poor.’’ Patients also indicated whether or not they preferred to continue to use the study product and whether they would be likely to recommend the study product to others on a 6-point scale ranging from ‘‘definitely would’’ to ‘‘definitely would not.’’ Statistical analysis The improvement differences in target area score assessments between vehicle and pimecrolimus for each criterion and for the composite total score were analyzed using a two-sample t test for both intent-totreat (ITT) and per protocol (PP) populations. The IGA was analyzed using the Fisher’s exact test to compare the proportion of patients in each treatment group with IGA less than or equal to 1 (a composite result of clear/almost clear) at week 4. The distribution of the facial IGA scores for each level of severity was compared for the pimecrolimus and vehicle groups at weeks 2 and 4. Baseline data for the two groups were compared using a two-sample t test for continuous variables and a Fisher’s exact test for categorical variables. The rates of adverse events for the two treatment groups were compiled and then compared using descriptive statistics. A post hoc analysis was conducted to assess the efficacy of pimecrolimus cream 1% for patients based on severity of disease at baseline. For the post hoc analysis, patients were categorized into 3 groups based on facial IGA at baseline. The mild group included patients with a facial IGA less than or equal to 2, the moderate group included patients with a facial IGA greater than 2 and less than or equal to 3,
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Fig 1. Patient flow diagram. yTotal comprises intent-to-treat (ITT) population, n = 94. zOne patient used study medication on target area only and was excluded from per protocol analyses for global facial assessments. §One patient was unable to return for final assessment (week 4). This patient’s verbal report of diseases was used for ITT analysis.
and the severe group included patients with a facial IGA greater than 3.
RESULTS Demographics Of the 699 patients screened for the study, 96 met study entry criteria and were randomized (n = 47 to the pimecrolimus group and n = 49 to the vehicle group) (Fig 1). The majority of patients in the study were men (96% Caucasian), the most common target area was the glabella, and 31 patients (32%) had chest involvement. The ITT population included 47 patients in each treatment group and the PP population included 46 and 41 patients in the vehicle and pimecrolimus groups, respectively. At baseline, both groups had similar demographics (Table I), with the exception that a higher percentage of patients in the pimecrolimus group (38%) had previously used medication to treat their seborrheic dermatitis, compared with patients in the vehicle group (29%). In addition, patients in the vehicle group had milder disease at baseline compared with those in the pimecrolimus group with regard to mean scale target area score (2.12 vs 2.32,
respectively; P = .0369) and with regard to mean facial IGA (2.6 vs 2.9, respectively; P = .0471). Patients in both groups used comparable amounts of medication during the study, 30.5 g (SD: 21.4) in the vehicle group and 28.0 g (SD: 22.1) in the pimecrolimus group. Prespecified end points A summary of efficacy is presented in Table II. A statistically significant improvement was observed for the mean change from baseline in total, erythema, and scale target area scores at the week-2 assessment for patients in the pimecrolimus group compared with the vehicle group (P \.010, ITT and PP analyses). A statistically significant improvement was also seen at the week-4 assessment (P \.050, PP analyses) for the primary efficacy variable. Change from baseline in both ITT and PP populations at both weeks 2 and 4 were statistically significantly higher for the pimecrolimus group as compared with vehicle. Although the distribution of the facial IGA scores for the pimecrolimus and vehicle groups were not statistically significantly different at either week 2 or 4, by week 2, the distribution of facial IGA scores
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Table I. Baseline data Vehicle N = 49
Variable
Baseline demographics Male Mean age, y (SD) Age minimum-maximum, y Mean duration of seborrheic dermatitis, mo (SD) Use of prior medication for seborrheic dermatitis Patients with chest involvement Target location Glabella Nasolabial fold Chin Other Baseline disease activity Efficacy variable Mean total target area score, 0-6 scale (SD) Mean erythema target area score, 0-3 scale (SD) Mean scale target area score, 0-3 scale (SD) IGA of facial seborrheic dermatitis, 0-4 scale (SD) IGA of chest seborrheic dermatitis, 0-4 scale (SD)
45 59.6 20-88 134.9 14 13 19 6 7 17
4.4 2.3 2.1 2.6 2.0
Pimecrolimus cream 1% N = 47
92% (16.2) (156.5) 29% 27%
40 59.5 27-84 137.9 18 18
(150.9) 38% 38%
39% 12% 14% 35%
17 11 5 14
36% 23% 11% 30%
(0.6) (0.5) (0.4) (0.9) (1.0)
4.6 2.3 2.3* 2.9y 1.8
85% (13.9)
(0.6) (0.5) (0.5) (0.8) (1.0)
IGA, Investigator’s Global Assessment. *P = .0369 pimecrolimus cream 1% vs vehicle. y P = .0471 pimecrolimus cream 1% vs vehicle.
was more favorable in the pimecrolimus group compared with vehicle (clear: 36% vs 21%, almost clear: 41% vs 34%, mild: 18% vs 32%, moderate: 5% vs 9%, moderate/severe: 0% vs 2%, severe: 0% vs 2%). The percentage of patients with facial IGA less than or equal to 1 (clear or almost clear) in the ITT population at week 4 was numerically higher for the pimecrolimus group (78.7%) compared with the vehicle group (70.2%) as well. At week 4, the PP analysis showed better IGA results for pimecrolimus as compared with vehicle (clear: 46% vs 31%, clear/almost clear: 2% vs 0%, almost clear: 37% vs 38%, mild: 12% vs 20%, moderate: 2% vs 9%, moderate/severe: 0% vs 2%). Seborrheic dermatitis of the chest The sample size for evaluation of chest seborrheic dermatitis was too small to allow any meaningful comparison, although more patients were clear or almost clear in the pimecrolimus group both at weeks 2 and 4 (88% vs 73% at week 2 and 94% vs 83% at week 4, respectively, ITT). Post hoc analyses The post hoc analysis of efficacy based on baseline disease severity included 42, 34, and 20 patients with mild, moderate, and severe overall disease, respectively. The vehicle group had 53% mild, 31% moderate, and 16% severe cases and the
pimecrolimus group had 34% mild, 40% moderate, and 26% severe cases. Patients with mild or severe disease in both treatment groups had similar baseline demographics. Patients with moderate disease in the pimecrolimus group had a higher baseline mean scale target area score (2.4) compared with those in the vehicle group (2.0). Post hoc analyses for the ITT and PP populations showed similar results to the overall group (data not shown). Regardless of the severity of seborrheic dermatitis at baseline, numerically greater efficacy for the facial IGA was observed for the pimecrolimus group compared with the vehicle group at weeks 2 and 4. The greatest improvement at week 4 was recorded for patients with moderate disease at baseline in both treatment groups. Adverse events The percentage of patients with at least one adverse event reported was 32.7% and 46.8% in the vehicle and pimecrolimus groups, respectively. The most frequent drug-related adverse events were local, mild, and transient skin reactions. None of the adverse events with a suspected relationship to study drug were serious with the most frequent assessed by the investigator as cutaneous, mild, and transient (vehicle 12%, pimecrolimus 26%). No patients were discontinued because of an adverse event.
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Table II. Summary of efficacy Intent-to-treat approach Mean change from baseline
(SD)
Efficacy at 4 wk Secondary efficacy variables Efficacy at 2 wk Target area, erythema (0-3 scale) Target area, scaling (0-3 scale) Facial global assessment (0-4 scale) Efficacy at 4 wk Target area, erythema (0-3 scale) Target area, scaling (0-3 scale) Facial global assessment (0-4 scale)
N = 44 2.6 N = 47 3.3
(SD)
Pimecrolimus cream 1%
Vehicle
Primary efficacy variable Total target area score (0-6 scale) Efficacy at 2 wk
Mean change from baseline
Per protocol approach
(1.4)
N = 44 3.6* N = 47 3.7
1.1 1.5 1.1
(0.9) (0.8) (1.0)
1.6 1.7 1.5
(0.9) (0.8) (1.2)
(1.5)
Mean change from baseline
(SD)
(1.5)
N = 43 2.6 N = 45 3.2
1.7* 1.9* 1.9*
(0.8) (0.8) (1.0)
1.8 1.9 2.1*
(0.9) (0.9) (1.0)
(SD)
Pimecrolimus cream 1%
Vehicle
(1.2)
Mean change from baseline
(1.4)
N = 38 3.6* N = 41 3.9y
(1.1)
1.1 1.5 1.1
(0.9) (0.8) (1.1)
1.7* 1.9* 1.9*
(0.8) (0.7) (1.0)
1.5 1.7 1.5
(0.9) (0.7) (1.2)
1.9y 2.0y 2.2*
(0.7) (0.7) (0.9)
(1.5)
(1.2)
*P = .010 pimecrolimus cream 1% vs vehicle. y P = .050 pimecrolimus cream 1% vs vehicle.
Satisfaction with cosmetic aspects of the study cream All patients (n = 40) given the opportunity to complete the satisfaction survey at week 4 did so (n = 20 pimecrolimus; n = 20 vehicle). A total of 90% of patients (18 of 20) in the vehicle group and 95% (19 of 20) in the pimecrolimus group reported that they were satisfied with the cosmetic appearance of the study cream on their face. In all, 80% (16 of 20) and 90% (18 of 20) of patients in the vehicle and pimecrolimus groups, respectively, stated that they ‘‘definitely would’’ or were ‘‘very likely’’ to continue using the cream for treatment of their seborrheic dermatitis. Similarly, 75% (15 of 20) and 80% (16 of 20) of patients in the vehicle and pimecrolimus groups, respectively, stated that they ‘‘definitely would’’ or were ‘‘very likely’’ to recommend the cream to someone else for treatment of seborrheic dermatitis. Specific attributes of the cream were rated highly. In the vehicle group, the following parameters were rated ‘‘very good’’ or ‘‘good’’ on a 5-point rating scale: spreadability 100% (20/20); ease of rubin 85% (17/20); nonsticky feel 85% (17/20); and suitability for use on the face 100% (20/20). In the pimecrolimus group, the following parameters were rated ‘‘very good’’ or ‘‘good’’ on a 5-point rating scale: spreadability 100% (20/20); ease of rub-in 95% (19/20); nonsticky feel 95% (19/20); and suitability for use on the face 80% (16/20). Six of these 40
patients (15%) wrote in comments that the cream burned when applied too close to the eyes or when sweating.
DISCUSSION To our knowledge, this is the first double-blind, controlled trial of a topical calcineurin inhibitor for treatment of seborrheic dermatitis. Overall, we found that pimecrolimus cream 1% was significantly more effective than vehicle, with a maximum improvement noted at 2 weeks of treatment. The results of this study are consistent with those from 4 small, open-label trials of pimecrolimus for treatment of facial seborrheic dermatitis. Rigopoulos et al16 compared 11 patients treated with pimecrolimus cream 1% and 9 patients treated with betamethasone 17valerate 0.1% cream and found that there were no statistically significant differences in the reduction of erythema, scaling, and pruritus scores between the two groups. Similarly, Firooz et al19 compared 18 patients treated with pimecrolimus cream 1% and 19 patients treated with hydrocortisone acetate 1% cream and found that responses were similar. High and Pandya17 evaluated 5 African American patients with facial seborrheic dermatitis associated with hypopigmentation and found that all patients had marked reduction of a composite score of 4 facial sites and mexameter ratings for hypopigmentation when pimecrolimus cream 1% was used twice daily
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for 16 weeks. Rallis et al18 studied pimecrolimus use for 7 to 14 days or until clearance and observed significant improvement for all 19 patients by week 1 and full resolution by study end. In these 4 studies, significant improvement was noted between 9 to 14 days of treatment start. We also found rapid improvement of scaling and erythema in our study, with statistically significant differences noted at the week-2 visit for both outcome measures. A prior study of pimecrolimus for inverse psoriasis, a skin condition close to seborrheic dermatitis on the spectrum of skin diseases, also demonstrated a rapid onset of action with significant improvement of symptoms within 48 hours of treatment.26 It is possible that a week-1 evaluation in our study may have revealed a larger difference between treatments because the vehicle effect seems to continually increase over time. The clinical improvement for many patients in the vehicle group in our study (and their overall satisfaction with the cosmetic attributes of the vehicle cream) may likely be due to the emollient effects of the vehicle. We found that pimecrolimus cream 1% was well tolerated. Side effects were minimal and primarily consisted of a transient, initial, burning/stinging sensation. No patients reported rosaceiform dermatitis27 or alcohol-induced flushing.28 This study has several limitations. First, the study population consisted primarily of elderly men. Therefore, the results may not be generalizable to all patient populations. Second, strict study criteria excluded many patients. Because patients were able to self-refer from informational fliers, many patients had rosacea or actinic keratoses, not seborrheic dermatitis (n = 167). A significant number also had seborrheic dermatitis that was too mild (n = 130) or had an excluding neurologic condition (n = 41). Third, this study only followed patients for 4 weeks. Therefore, efficacy of intermittent or twice daily application of pimecrolimus over longer periods of time cannot be determined. Fourth, although the entry criteria specified that a target area was moderate to severe, the global assessment could have been mild, overall. The subgroup analyses for patients with mild and severe global assessments only found one statistically significant difference between the two treatment arms. Although this is likely because of small sample size, definite conclusions about these subgroups cannot be determined. In summary, these results suggest that pimecrolimus cream 1% is a well-tolerated and effective treatment for moderate to severe facial seborrheic dermatitis. More studies are needed to evaluate daily or other dosing regimens of pimecrolimus cream
1% for long-term maintenance therapy of seborrheic dermatitis. The administrative support of Xiaoli Zhang and Deborah A. Kedrowski, RN, is appreciated. REFERENCES 1. Hay RJ, Graham-Brown RA. Dandruff and seborrheic dermatitis: causes and management. Clin Exp Dermatol 1997;22:3-6. 2. Gupta AK, Nicol K, Batra R. Role of antifungal agents in the treatment of seborrheic dermatitis. Am J Clin Dermatol 2004; 5:417-22. 3. Mirza SH, Khan MA, Ahsan-ul-Haq M. Role of Malassezia yeast (pityrosporum) in seborrheic dermatitis (sd). J Coll Physicians Surg Pak 2005;15:771-3. 4. Parry ME, Sharpe GR. Seborrheic dermatitis is not caused by an altered immune response to Malassezia yeast. Br J Dermatol 1998;139:254-63. 5. Cowley NC, Farr PM, Shuster S. The permissive effect of sebum in seborrheic dermatitis: an explanation of the rash in neurological disorders. Br J Dermatol 1990;122:71-6. 6. Furue M, Terao H, Rikihisa W, Urabe K, Kinukawa N, Nose Y, et al. Clinical dose and adverse effects of topical steroids in daily management of atopic dermatitis. Br J Dermatol 2003; 148:128-33. 7. Hugues J, Rustin M. Corticosteroids. Clin Dermatol 1997;15: 715-21. 8. Hultsch T, Muller KD, Meingassner JG, Grassberger M, Schopf RE, Knop J. Ascomycin macrolactam derivative SDZ ASM 981 inhibits the release of granule-associated mediators and of newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin-dependent manner. Arch Dermatol Res 1998; 290:501-7. 9. Zuberbier T, Chong SU, Grunow K, Guhl S, Welker P, Grassberger M, et al. The ascomycin macrolactam pimecrolimus (pimecrolimus, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils. J Allergy Clin Immunol 2001;108:275-80. 10. Eichenfield LF, Lucky AW, Boguniewicz M, Langley RG, Cherill R, Marshall K, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002;46:495-504. 11. Ho VC, Gupta A, Kaufmann R, Todd G, Vanaclocha F, Takaoka R, et al. Safety and efficacy of nonsteroid pimecrolimus cream 1% in the treatment of atopic dermatitis in infants. J Pediatr 2003;142:155-62. 12. Meurer M, Fartasch M, Albrecht G, Vogt T, Worm M, Ruzicka T, et al. Long-term efficacy and safety of pimecrolimus cream 1% in adults with moderate atopic dermatitis. Dermatology 2004;208:365-72. 13. Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, et al. Efficacy and safety of pimecrolimus cream in the longterm management of atopic dermatitis in children. Pediatrics 2002;110:1-8. 14. Queille-Roussel C, Paul C, Duteil L, Lefebvre MC, Rapatz G, Zagula M, 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 2001;144:507-13. 15. Pediatric Advisory Committee. Available at: URL:http://www. fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed October 12, 2006. 16. Rigopoulos D, Ioannides D, Kalogeromitros D, Gregoriou S, Katsambas A. Pimecrolimus cream 1% vs betamethasone
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19.
20. 21. 22.
17-valerate 0.1% cream in the treatment of seborrheic dermatitis: a randomized open-label clinical trial. Br J Dermatol 2004;151:1071-5. High WA, Pandya AG. Pilot trial of 1% pimecrolimus cream in the treatment of seborrheic dermatitis in African American adults with associated hypopigmentation. J Am Acad Dermatol 2006;54:1083-8. Rallis E, Nasiopoulou A, Kouskoukis C, Koumantaki E. Pimecrolimus cream 1% can be an effective treatment for seborrheic dermatitis of the face and trunk. Drugs Exp Clin Res 2004; 30:191-5. Firooz A, Solhpour AM, Gorouhi F, Daneshpazhooh M, Balighi K, Farsinejad K, et al. Pimecrolimus cream 1% vs hydrocortone acetate cream 1% in the treatment of facial seborrheic dermatitis: a randomized investigator-blind, clincial trial. Arch Dermatol 2006;142:1066-7. Crutchfield CE. Pimecrolimus: a new treatment for seborrheic dermatitis. Cutis 2002;70:207-8. Brownell I, Quan LT, Hsu S. Topical pimecrolimus in the treatment of seborrheic dermatitis. Dermatol Online J 2003;9:13. Kapteine L, Karls R, Zigure S. Pimecrolimus cream 1% in the treatment of seborrheic dermatitis. Eur Acad Dermatol Venereol. Poster presentation. Available at: http://www.
23.
24.
25.
26.
27.
28.
eadv2005.com/abstract/posters/P01.doc. Accessed November 28, 2006. Cunha PR. Pimecrolimus cream 1% is effective in seborrheic dermatitis refractory to treatment with topical corticosteroids. Acta Derm Venereol 2006;86:69-70. Chung JH, Yano K, Lee MK, Youn CS, Seo JY, Kim KH, et al. Differential effects of photoaging vs intrinsic aging on the vascularization of human skin. Arch Dermatol 2002;138:1437-42. Dupuy P, Maurette C, Amoric JC, Chosidow O. Randomized, placebo-controlled, double-blind study on the clinical efficacy of ciclopiroxolamine 1% cream in facial seborrheic dermatitis. Br J Dermatol 2001;144:1033-7. Gribetz C, Ling M, Lebwohl M, Pariser D, Draelos Z, Gottlieb AB, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: a double-blind, randomized study. J Am Acad Dermatol 2004;51:731-8. Gorman CR, White SW. Rosaceiform dermatitis as a complication of treatment of facial seborrheic dermatitis with 1% pimecrolimus cream. Arch Dermatol 2005;141:1168. Ehst B, Warshaw EM. Alcohol-induced, application siteerythema after topical immunomodulator use and its inhibition by aspirin: report of a double-blind, controlled pilot trial. Arch Dermatol 2004;140:1014-5.
From the Minneapolis Department of Veterans Affairs Medical Centera; University of Minnesotab; Department of Dermatology, University of Oklahomac; Southern Illinois Universityd; and Novartis Pharmaceuticals Corporation, East Hanover.e This investigator-initiated study was supported by Novartis Pharmaceuticals Corporation. During this study, Dr Warshaw was supported by a Department of Veterans Affairs Cooperative Studies Clinical Research Career Development Award. Disclosure: Anne Parneix-Spake, MD, and Calogera L. McCormick are employees of Novartis Pharmaceuticals Corporation. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.
Accepted for publication November 3, 2006. Reprints not available from the authors. Correspondence to: Erin M. Warshaw, MD, MS, University of Minnesota, Dermatology Section, Minneapolis Veterans Affairs Medical Center, Department 111K, 1 Veterans Dr, Minneapolis MN 55417. E-mail: [email protected]. Published online December 30, 2006. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.11.007
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Seborrheic dermatitis is a common, chronic disease that affects 2% to 10% of the adult population, mainly between age 20 and 50 years. The prevalence is higher for males than females and for individuals with central nervous system disorders (eg, Parkinson’s disease, major truncal paralyses) and immunodeficiencies as compared with those without such disorders. Affected areas most often include the scalp, eyebrows, ears, nasolabial creases, axillae, sternum, and groin. The origin of seborrheic dermatitis is unknown. On histopathology, seborrheic dermatitis shows a perivascular mixed cell infiltrate with epidermal acanthosis and neutrophils, which is often indistinguishable from atopic dermatitis. Changes in the function of immune system may represent a possible pathogenic factor.1 The sebum-rich areas of the body support growth of the lipophilic yeast, Malassezia furfur yeast (formerly called Pityrosporum ovale). The role of M furfur yeast in the development of seborrheic dermatitis is not completely understood, however, it is acknowledged widely as an exacerbating factor of the disorder, and not necessarily the foundation of the condition.2-4 It has been hypothesized that the immobility of patients with neurologic disorders may play a role in the aggravation of their seborrheic dermatitis as a result of increased pooling of sebum in which M furfur may grow more readily.5 Standard topical treatments for seborrheic dermatitis include corticosteroid and antimycotic medications. The chronic use of topical corticosteroids, especially on the face, may not be advisable as corticosteroid side effects may include telangiectasia, atrophy, striae, perioral dermatitis, or tachyphylaxis.6,7 Pimecrolimus is a topical calcineurin inhibitor that prevents T-cell activation by down-regulating T-cell production of T-helper cells type 1 (interleukin [IL]-2, interferon gamma) and T-helper cells type 2 (IL-4, IL-10) type cytokines, therefore, inhibiting the proliferation of T cells after antigen-specific or unspecific stimulation. Pimecrolimus also prevents the IgE/ antigen-mediated degranulation of mast cells.8,9 Pimecrolimus is approved by the Food and Drug Administration (FDA) as a second-line treatment of mild to moderate atopic dermatitis for patients age 2 years and older. In clinical studies, pimecrolimus has demonstrated efficacy for treatment of atopic dermatitis of infants, children, adolescents, and adults.10-13 In addition, topical pimecrolimus cream does not cause skin atrophy and has a well-established local safety profile.10-14 The FDA recently recommended black box warnings for topical calcineurin inhibitors based on animal studies using high doses of these drugs, which suggested a possible increased rate of malignancy.15 To date, use of pimecrolimus twice daily has been shown to be effective for treatment of seborrheic
Abbreviations used: CI: FDA: IGA: IL: ITT: PP:
confidence interval Food and Drug Administration Investigator’s Global Assessment interleukin intent to treat per protocol
dermatitis in 4 open-label or single-blind trials involving 11 patients,16 5 patients,17 19 patients,18 and 37 patients,19 respectively. In addition, several single case reports have described complete clearing of severe facial seborrheic dermatitis within 30 days of twice-daily use of pimecrolimus cream 1%.20-23 Another topical immunomodulator, tacrolimus 0.1% ointment, was evaluated in an open-label study of 18 patients in which 11 patients (61%) showed complete clearing at 28 days. The purpose of this investigator-initiated study was to evaluate the efficacy and safety of pimecrolimus for the treatment of patients with moderate to severe facial seborrheic dermatitis in a double-blind, vehicle-controlled study design.
METHODS This clinical study was performed in accordance with Good Clinical Practices and the Declaration of Helsinki (2000). The protocol was approved by the Minneapolis Veterans Affairs Medical Center Subcommittee on Human Studies, and written informed consent was obtained from each patient in the study before conducting study procedures. Study design and intervention This randomized, double-blind, vehiclecontrolled, single-center, 4-week clinical study of patients with moderate to severe facial seborrheic dermatitis was conducted at our dermatology clinical research division from September 2003 to November 2004. At the baseline visit, patients were randomized in a 1:1 ratio to pimecrolimus cream 1% or vehicle. The computer-generated randomization assignment (blocks of 4) was only accessible to the research pharmacist during the study. The two creams were packaged in identical tubes that were weighed before dispensing and at study end. Patients applied a thin layer of study medication twice daily (approximately every 12 hours) on the affected areas of seborrheic dermatitis for each day of the 4-week study period. Patients were permitted to gently wash the areas for treatment before the application of study medication and were instructed that skin was to be dry before an application of topical study drug. Treated areas were not to be
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washed for at least 3 hours after application of study medication. Patients were advised to minimize or avoid natural or artificial sunlight exposure while participating in the study. Patients were allowed to use nonmedicated shampoo and facial cleansers during the study. Study criteria Eligible patients for the study were at least 18 years of age with a diagnosis of moderate or severe facial seborrheic dermatitis24,25 and no active bacterial, viral, or fungal infection on the head or neck. At baseline, the minimum activity level of disease as assessed by the investigator was required to be a facial target area erythema score of at least 2 on a 0to-3 scale (0 = no erythema to 3 = bright red) and a facial total target area score (composite of erythema and scaling assessments, each measured on a scale of 0 = none to 3 = severe) of at least 4 on a 0-to-6 composite scale. Before enrollment, the study required a 2-week washout period of either topical or systemic antimycotic, antibacterial, or immunosuppressant medications. Women of childbearing potential consented to practice effective birth control during the study period. Patients who had any of the following conditions were excluded: known allergy to components of pimecrolimus cream 1%; those with active perioral dermatitis, acne vulgaris, or rosacea; those with poorly controlled chronic conditions; those with cancer, neurologic conditions, or HIV infection (or other immunosuppression); and pregnant and nursing women. Outcome assessments Clinic visits were performed at baseline (study entry), and weeks 2 and 4 after enrollment. At the baseline visit, a target area was identified on the face for each patient. Efficacy assessments for involvement of seborrheic dermatitis of the face and chest were performed by the principal investigator (E. M. W.) at baseline, week 2, and week 4. Erythema of the target area on the face was graded using a 4-point scale of: 0 (none), 1 (mild, faint red), 2 (moderate, dull red), or 3 (severe, bright red). Scale of the target area on the face was scored using a 4-point scale of: 0 (none), 1 (mild, # 10% of lesion), 2 (moderate, [10% to # 50% of lesion), or 3 (severe, [50% of lesion). The total target area score was the sum of the erythema and scale target area scores (0-6 scale). The Investigator’s Global Assessment (IGA) of disease severity was scored independently for the face and the chest, using a 5-point scale of: 0 (clear, no clinical evidence of seborrheic dermatitis overall), 1 (almost clear, minimal evidence), 2 (mild, mild evidence),
3 (moderate, moderate evidence), or 4 (severe, severe evidence). The primary efficacy variable was the change from baseline of total target area score at week 4. Secondary efficacy variables included the change from baseline of the erythema and scale target area scores at week 4. Additional secondary variables included the percentage of patients who were clear or almost clear at week 4 for facial IGA and chest IGA. All spontaneously reported adverse events were recorded. Approximately halfway through this study (after 56 patients had completed the predefined study period), a satisfaction instrument was added. After approval from our subcommittee on human studies, all patients from that time on were asked to complete a satisfaction survey of the study medication at week 4. Overall satisfaction with the cosmetic appearance of the product was rated as either ‘‘yes’’ or ‘‘no.’’ Patients recorded assessments of spreadability, ease of rub-in, nonsticky feel, and suitability of the product for use on the face using a 5-point scale ranging from ‘‘very good’’ to ‘‘very poor.’’ Patients also indicated whether or not they preferred to continue to use the study product and whether they would be likely to recommend the study product to others on a 6-point scale ranging from ‘‘definitely would’’ to ‘‘definitely would not.’’ Statistical analysis The improvement differences in target area score assessments between vehicle and pimecrolimus for each criterion and for the composite total score were analyzed using a two-sample t test for both intent-totreat (ITT) and per protocol (PP) populations. The IGA was analyzed using the Fisher’s exact test to compare the proportion of patients in each treatment group with IGA less than or equal to 1 (a composite result of clear/almost clear) at week 4. The distribution of the facial IGA scores for each level of severity was compared for the pimecrolimus and vehicle groups at weeks 2 and 4. Baseline data for the two groups were compared using a two-sample t test for continuous variables and a Fisher’s exact test for categorical variables. The rates of adverse events for the two treatment groups were compiled and then compared using descriptive statistics. A post hoc analysis was conducted to assess the efficacy of pimecrolimus cream 1% for patients based on severity of disease at baseline. For the post hoc analysis, patients were categorized into 3 groups based on facial IGA at baseline. The mild group included patients with a facial IGA less than or equal to 2, the moderate group included patients with a facial IGA greater than 2 and less than or equal to 3,
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Fig 1. Patient flow diagram. yTotal comprises intent-to-treat (ITT) population, n = 94. zOne patient used study medication on target area only and was excluded from per protocol analyses for global facial assessments. §One patient was unable to return for final assessment (week 4). This patient’s verbal report of diseases was used for ITT analysis.
and the severe group included patients with a facial IGA greater than 3.
RESULTS Demographics Of the 699 patients screened for the study, 96 met study entry criteria and were randomized (n = 47 to the pimecrolimus group and n = 49 to the vehicle group) (Fig 1). The majority of patients in the study were men (96% Caucasian), the most common target area was the glabella, and 31 patients (32%) had chest involvement. The ITT population included 47 patients in each treatment group and the PP population included 46 and 41 patients in the vehicle and pimecrolimus groups, respectively. At baseline, both groups had similar demographics (Table I), with the exception that a higher percentage of patients in the pimecrolimus group (38%) had previously used medication to treat their seborrheic dermatitis, compared with patients in the vehicle group (29%). In addition, patients in the vehicle group had milder disease at baseline compared with those in the pimecrolimus group with regard to mean scale target area score (2.12 vs 2.32,
respectively; P = .0369) and with regard to mean facial IGA (2.6 vs 2.9, respectively; P = .0471). Patients in both groups used comparable amounts of medication during the study, 30.5 g (SD: 21.4) in the vehicle group and 28.0 g (SD: 22.1) in the pimecrolimus group. Prespecified end points A summary of efficacy is presented in Table II. A statistically significant improvement was observed for the mean change from baseline in total, erythema, and scale target area scores at the week-2 assessment for patients in the pimecrolimus group compared with the vehicle group (P \.010, ITT and PP analyses). A statistically significant improvement was also seen at the week-4 assessment (P \.050, PP analyses) for the primary efficacy variable. Change from baseline in both ITT and PP populations at both weeks 2 and 4 were statistically significantly higher for the pimecrolimus group as compared with vehicle. Although the distribution of the facial IGA scores for the pimecrolimus and vehicle groups were not statistically significantly different at either week 2 or 4, by week 2, the distribution of facial IGA scores
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Table I. Baseline data Vehicle N = 49
Variable
Baseline demographics Male Mean age, y (SD) Age minimum-maximum, y Mean duration of seborrheic dermatitis, mo (SD) Use of prior medication for seborrheic dermatitis Patients with chest involvement Target location Glabella Nasolabial fold Chin Other Baseline disease activity Efficacy variable Mean total target area score, 0-6 scale (SD) Mean erythema target area score, 0-3 scale (SD) Mean scale target area score, 0-3 scale (SD) IGA of facial seborrheic dermatitis, 0-4 scale (SD) IGA of chest seborrheic dermatitis, 0-4 scale (SD)
45 59.6 20-88 134.9 14 13 19 6 7 17
4.4 2.3 2.1 2.6 2.0
Pimecrolimus cream 1% N = 47
92% (16.2) (156.5) 29% 27%
40 59.5 27-84 137.9 18 18
(150.9) 38% 38%
39% 12% 14% 35%
17 11 5 14
36% 23% 11% 30%
(0.6) (0.5) (0.4) (0.9) (1.0)
4.6 2.3 2.3* 2.9y 1.8
85% (13.9)
(0.6) (0.5) (0.5) (0.8) (1.0)
IGA, Investigator’s Global Assessment. *P = .0369 pimecrolimus cream 1% vs vehicle. y P = .0471 pimecrolimus cream 1% vs vehicle.
was more favorable in the pimecrolimus group compared with vehicle (clear: 36% vs 21%, almost clear: 41% vs 34%, mild: 18% vs 32%, moderate: 5% vs 9%, moderate/severe: 0% vs 2%, severe: 0% vs 2%). The percentage of patients with facial IGA less than or equal to 1 (clear or almost clear) in the ITT population at week 4 was numerically higher for the pimecrolimus group (78.7%) compared with the vehicle group (70.2%) as well. At week 4, the PP analysis showed better IGA results for pimecrolimus as compared with vehicle (clear: 46% vs 31%, clear/almost clear: 2% vs 0%, almost clear: 37% vs 38%, mild: 12% vs 20%, moderate: 2% vs 9%, moderate/severe: 0% vs 2%). Seborrheic dermatitis of the chest The sample size for evaluation of chest seborrheic dermatitis was too small to allow any meaningful comparison, although more patients were clear or almost clear in the pimecrolimus group both at weeks 2 and 4 (88% vs 73% at week 2 and 94% vs 83% at week 4, respectively, ITT). Post hoc analyses The post hoc analysis of efficacy based on baseline disease severity included 42, 34, and 20 patients with mild, moderate, and severe overall disease, respectively. The vehicle group had 53% mild, 31% moderate, and 16% severe cases and the
pimecrolimus group had 34% mild, 40% moderate, and 26% severe cases. Patients with mild or severe disease in both treatment groups had similar baseline demographics. Patients with moderate disease in the pimecrolimus group had a higher baseline mean scale target area score (2.4) compared with those in the vehicle group (2.0). Post hoc analyses for the ITT and PP populations showed similar results to the overall group (data not shown). Regardless of the severity of seborrheic dermatitis at baseline, numerically greater efficacy for the facial IGA was observed for the pimecrolimus group compared with the vehicle group at weeks 2 and 4. The greatest improvement at week 4 was recorded for patients with moderate disease at baseline in both treatment groups. Adverse events The percentage of patients with at least one adverse event reported was 32.7% and 46.8% in the vehicle and pimecrolimus groups, respectively. The most frequent drug-related adverse events were local, mild, and transient skin reactions. None of the adverse events with a suspected relationship to study drug were serious with the most frequent assessed by the investigator as cutaneous, mild, and transient (vehicle 12%, pimecrolimus 26%). No patients were discontinued because of an adverse event.
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Table II. Summary of efficacy Intent-to-treat approach Mean change from baseline
(SD)
Efficacy at 4 wk Secondary efficacy variables Efficacy at 2 wk Target area, erythema (0-3 scale) Target area, scaling (0-3 scale) Facial global assessment (0-4 scale) Efficacy at 4 wk Target area, erythema (0-3 scale) Target area, scaling (0-3 scale) Facial global assessment (0-4 scale)
N = 44 2.6 N = 47 3.3
(SD)
Pimecrolimus cream 1%
Vehicle
Primary efficacy variable Total target area score (0-6 scale) Efficacy at 2 wk
Mean change from baseline
Per protocol approach
(1.4)
N = 44 3.6* N = 47 3.7
1.1 1.5 1.1
(0.9) (0.8) (1.0)
1.6 1.7 1.5
(0.9) (0.8) (1.2)
(1.5)
Mean change from baseline
(SD)
(1.5)
N = 43 2.6 N = 45 3.2
1.7* 1.9* 1.9*
(0.8) (0.8) (1.0)
1.8 1.9 2.1*
(0.9) (0.9) (1.0)
(SD)
Pimecrolimus cream 1%
Vehicle
(1.2)
Mean change from baseline
(1.4)
N = 38 3.6* N = 41 3.9y
(1.1)
1.1 1.5 1.1
(0.9) (0.8) (1.1)
1.7* 1.9* 1.9*
(0.8) (0.7) (1.0)
1.5 1.7 1.5
(0.9) (0.7) (1.2)
1.9y 2.0y 2.2*
(0.7) (0.7) (0.9)
(1.5)
(1.2)
*P = .010 pimecrolimus cream 1% vs vehicle. y P = .050 pimecrolimus cream 1% vs vehicle.
Satisfaction with cosmetic aspects of the study cream All patients (n = 40) given the opportunity to complete the satisfaction survey at week 4 did so (n = 20 pimecrolimus; n = 20 vehicle). A total of 90% of patients (18 of 20) in the vehicle group and 95% (19 of 20) in the pimecrolimus group reported that they were satisfied with the cosmetic appearance of the study cream on their face. In all, 80% (16 of 20) and 90% (18 of 20) of patients in the vehicle and pimecrolimus groups, respectively, stated that they ‘‘definitely would’’ or were ‘‘very likely’’ to continue using the cream for treatment of their seborrheic dermatitis. Similarly, 75% (15 of 20) and 80% (16 of 20) of patients in the vehicle and pimecrolimus groups, respectively, stated that they ‘‘definitely would’’ or were ‘‘very likely’’ to recommend the cream to someone else for treatment of seborrheic dermatitis. Specific attributes of the cream were rated highly. In the vehicle group, the following parameters were rated ‘‘very good’’ or ‘‘good’’ on a 5-point rating scale: spreadability 100% (20/20); ease of rubin 85% (17/20); nonsticky feel 85% (17/20); and suitability for use on the face 100% (20/20). In the pimecrolimus group, the following parameters were rated ‘‘very good’’ or ‘‘good’’ on a 5-point rating scale: spreadability 100% (20/20); ease of rub-in 95% (19/20); nonsticky feel 95% (19/20); and suitability for use on the face 80% (16/20). Six of these 40
patients (15%) wrote in comments that the cream burned when applied too close to the eyes or when sweating.
DISCUSSION To our knowledge, this is the first double-blind, controlled trial of a topical calcineurin inhibitor for treatment of seborrheic dermatitis. Overall, we found that pimecrolimus cream 1% was significantly more effective than vehicle, with a maximum improvement noted at 2 weeks of treatment. The results of this study are consistent with those from 4 small, open-label trials of pimecrolimus for treatment of facial seborrheic dermatitis. Rigopoulos et al16 compared 11 patients treated with pimecrolimus cream 1% and 9 patients treated with betamethasone 17valerate 0.1% cream and found that there were no statistically significant differences in the reduction of erythema, scaling, and pruritus scores between the two groups. Similarly, Firooz et al19 compared 18 patients treated with pimecrolimus cream 1% and 19 patients treated with hydrocortisone acetate 1% cream and found that responses were similar. High and Pandya17 evaluated 5 African American patients with facial seborrheic dermatitis associated with hypopigmentation and found that all patients had marked reduction of a composite score of 4 facial sites and mexameter ratings for hypopigmentation when pimecrolimus cream 1% was used twice daily
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for 16 weeks. Rallis et al18 studied pimecrolimus use for 7 to 14 days or until clearance and observed significant improvement for all 19 patients by week 1 and full resolution by study end. In these 4 studies, significant improvement was noted between 9 to 14 days of treatment start. We also found rapid improvement of scaling and erythema in our study, with statistically significant differences noted at the week-2 visit for both outcome measures. A prior study of pimecrolimus for inverse psoriasis, a skin condition close to seborrheic dermatitis on the spectrum of skin diseases, also demonstrated a rapid onset of action with significant improvement of symptoms within 48 hours of treatment.26 It is possible that a week-1 evaluation in our study may have revealed a larger difference between treatments because the vehicle effect seems to continually increase over time. The clinical improvement for many patients in the vehicle group in our study (and their overall satisfaction with the cosmetic attributes of the vehicle cream) may likely be due to the emollient effects of the vehicle. We found that pimecrolimus cream 1% was well tolerated. Side effects were minimal and primarily consisted of a transient, initial, burning/stinging sensation. No patients reported rosaceiform dermatitis27 or alcohol-induced flushing.28 This study has several limitations. First, the study population consisted primarily of elderly men. Therefore, the results may not be generalizable to all patient populations. Second, strict study criteria excluded many patients. Because patients were able to self-refer from informational fliers, many patients had rosacea or actinic keratoses, not seborrheic dermatitis (n = 167). A significant number also had seborrheic dermatitis that was too mild (n = 130) or had an excluding neurologic condition (n = 41). Third, this study only followed patients for 4 weeks. Therefore, efficacy of intermittent or twice daily application of pimecrolimus over longer periods of time cannot be determined. Fourth, although the entry criteria specified that a target area was moderate to severe, the global assessment could have been mild, overall. The subgroup analyses for patients with mild and severe global assessments only found one statistically significant difference between the two treatment arms. Although this is likely because of small sample size, definite conclusions about these subgroups cannot be determined. In summary, these results suggest that pimecrolimus cream 1% is a well-tolerated and effective treatment for moderate to severe facial seborrheic dermatitis. More studies are needed to evaluate daily or other dosing regimens of pimecrolimus cream
1% for long-term maintenance therapy of seborrheic dermatitis. The administrative support of Xiaoli Zhang and Deborah A. Kedrowski, RN, is appreciated. REFERENCES 1. Hay RJ, Graham-Brown RA. Dandruff and seborrheic dermatitis: causes and management. Clin Exp Dermatol 1997;22:3-6. 2. Gupta AK, Nicol K, Batra R. Role of antifungal agents in the treatment of seborrheic dermatitis. Am J Clin Dermatol 2004; 5:417-22. 3. Mirza SH, Khan MA, Ahsan-ul-Haq M. Role of Malassezia yeast (pityrosporum) in seborrheic dermatitis (sd). J Coll Physicians Surg Pak 2005;15:771-3. 4. Parry ME, Sharpe GR. Seborrheic dermatitis is not caused by an altered immune response to Malassezia yeast. Br J Dermatol 1998;139:254-63. 5. Cowley NC, Farr PM, Shuster S. The permissive effect of sebum in seborrheic dermatitis: an explanation of the rash in neurological disorders. Br J Dermatol 1990;122:71-6. 6. Furue M, Terao H, Rikihisa W, Urabe K, Kinukawa N, Nose Y, et al. Clinical dose and adverse effects of topical steroids in daily management of atopic dermatitis. Br J Dermatol 2003; 148:128-33. 7. Hugues J, Rustin M. Corticosteroids. Clin Dermatol 1997;15: 715-21. 8. Hultsch T, Muller KD, Meingassner JG, Grassberger M, Schopf RE, Knop J. Ascomycin macrolactam derivative SDZ ASM 981 inhibits the release of granule-associated mediators and of newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin-dependent manner. Arch Dermatol Res 1998; 290:501-7. 9. Zuberbier T, Chong SU, Grunow K, Guhl S, Welker P, Grassberger M, et al. The ascomycin macrolactam pimecrolimus (pimecrolimus, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils. J Allergy Clin Immunol 2001;108:275-80. 10. Eichenfield LF, Lucky AW, Boguniewicz M, Langley RG, Cherill R, Marshall K, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002;46:495-504. 11. Ho VC, Gupta A, Kaufmann R, Todd G, Vanaclocha F, Takaoka R, et al. Safety and efficacy of nonsteroid pimecrolimus cream 1% in the treatment of atopic dermatitis in infants. J Pediatr 2003;142:155-62. 12. Meurer M, Fartasch M, Albrecht G, Vogt T, Worm M, Ruzicka T, et al. Long-term efficacy and safety of pimecrolimus cream 1% in adults with moderate atopic dermatitis. Dermatology 2004;208:365-72. 13. Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, et al. Efficacy and safety of pimecrolimus cream in the longterm management of atopic dermatitis in children. Pediatrics 2002;110:1-8. 14. Queille-Roussel C, Paul C, Duteil L, Lefebvre MC, Rapatz G, Zagula M, 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 2001;144:507-13. 15. Pediatric Advisory Committee. Available at: URL:http://www. fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm. Accessed October 12, 2006. 16. Rigopoulos D, Ioannides D, Kalogeromitros D, Gregoriou S, Katsambas A. Pimecrolimus cream 1% vs betamethasone
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