Feature: Atopic Dermatitis: Two Treatments Are Better than One - By James Q. Del Rosso, D.O., F.A.O.C.D. Combining a topical corticosteroid and a topical calcineurin inhibitor yields effective results. T reating atopic dermatitis continues to be one of our recurring challenges in dermatology practice. For five decades, we’ve effectively used topical corticosteroids to manage this chronic-recurrent disorder, always balancing overuse of these drugs so as to avoid adverse reactions, such as those well known to us — atrophy, striae and telangiectasia. The advent of the recent availability of two topical inhibitors of calcineurin (TICs), tacrolimus (Protopic) and pimecrolimus (Elidel), have offered new avenues of treatment for managing atopic dermatitis. Now, anecdotal observation suggests that some patients with atopic dermatitis benefit from combined therapy with concomitant use of a topical corticosteroid and a TIC, especially during the first few weeks of treatment. The combination of both agents appears to augment the initial response to treatment, with rapid reduction in signs and symptoms of disease. Choosing an Effective Combination Recently, I conducted an open-phase, randomized, pilot evaluation for which I presented the results in a poster at this year’s American Academy of Dermatology meeting. My goals were the following: 1. Evaluate the therapeutic benefit of initial combination therapy using sequential application of a mid-potency topical corticosteroid and a topical calcineurin inhibitor. 2. Assess the local tolerability of BMV foam and pimecrolimus 1% cream used in combination therapy. 3. Utilize both agents in conjunction with selected skin care products used for daily skin care maintenance in patients who have atopic dermatitis. I chose a combination treatment for atopic dermatitis that consisted of a mid-potency corticosteroid (betamethasone valerate in a foam vehicle [Luxiq]) and the TIC pimecrolimus 1% cream (Elidel). I used BMV in a foam vehicle because this vehicle has been found in other studies to exhibit a high degree of patient preference and satisfaction due to ease of use, rapid disappearance into skin, spreadability and effectiveness. The “quick break” dissipation of the foam base, with rapid penetration into skin upon application, supports its use as an appropriate and convenient vehicle applied prior to the subsequent application of a cream or ointment. In addition, I chose pimecrolimus as the TIC due to an overall patient acceptance of a cream over an ointment. For this study, adult and pediatric patients were treated with both agents applied twice daily for atopic dermatitis. Patients underwent these treatments in an ambulatory dermatology center setting. Responses were correlated with disease severity; efficacy evaluations include physician assessment and patient assessment of signs and symptoms of disease. Evaluation of tolerability and adverse reactions are also included. Rationale for Evaluation - Individuals with atopic dermatitis exhibit a genetically inherent immune dysregulation, with cutaneous hyper-responsiveness to multiple irritants and allergens; they are chronically predisposed to xerosis, pruritus and exacerbations of eczematous dermatitis.1 Inherent to treatment of atopic dermatitis are avoidance of irritants and other flare factors, use of a gentle skin cleanser, and emollient use for maintenance of skin hydration.2 The efficacy of topical calcineurin inhibitors (pimecrolimus, tacrolimus) for treatment of atopic dermatitis has been established in several studies.3-5 The range in rapidity of onset, especially for reduction in pruritus, may warrant initial combination therapy with a topical corticosteroid agent, at least in patients presenting with moderate to severe disease. Rapid onset of reduction in pruritus and resolution of visible disease is significant due to the marked negative psychological and physical impact of the disease, including disruption in sleep.6 The use of BMV foam in this analysis was prompted by ease of widespread application of the foam formulation, the observed high level of patient preference in studies comparing foam with other vehicles, superior clinical performance of versus BMV 0.1 % lotion for scalp disease and preliminary data (n = 18) suggesting no evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression in adult patients with atopic dermatitis or psoriasis treated twice daily for 7 days.7-9 This report utilizes initial combination therapy with BMV foam and pimecrolimus 1% cream, worked into a regimen inclusive of a gentle cleanser and emollient, both used as components of recommended long-term basic skin care for atopic dermatitis patients. Some studies with pimecrolimus have suggested use at the immediate onset of signs or symptoms of a disease flare, as an approach to long term control of atopic dermatitis, with medium potency topical corticosteroids used to control “breakthrough” exacerbations.10-12 Other physicians may elect to use intermittent topical corticosteroid therapy, based on disease severity and frequency of use. How We Proceeded Adult and pediatric patients were diagnosed with atopic dermatitis based on clinical presentation, past medical history and family history of associated atopic diseases (asthma, seasonal rhinitis, recurrent childhood eczema). Patients were excluded if they had used topical corticosteroids, systemic corticosteroids, systemic antihistamines or topical calcineurin inhibitors within 4 weeks of presentation. The overall duration of atopic dermatitis and onset of the current exacerbation were noted. Investigator assessment of disease severity and clinical improvement and patient assessment of the extent and timing of disease improvement and reduction in pruritus were noted. Affected anatomic sites, history of previous treatments, locations of resistant disease, assessment of local tolerability and adverse reactions were noted. The protocol was designed to simulate the evaluation and treatment of atopic dermatitis from an ambulatory general dermatology practice perspective. Verbal education and written materials were provided regarding the diagnosis of atopic dermatitis. Instructions were given regarding the use of a specified well-recognized, non-irritating skin cleanser (Cetaphil Liquid Cleanser) and a specified, recognized, non-fragranced emollient cream (Cetaphil Moisturizer Cream) applied after medication application. Skin cleanser and emollient were supplied for the patient. Instructions were also given on the order of application of medications to affected areas. BMV foam was applied first, followed in 5 to 10 minutes by application of pimecrolimus 1% cream. Medication was applied in this fashion twice daily. The time separation between application of both medications was put in place to allow for reporting and differentiation of any quick-onset local tolerability reactions (ie. stinging, burning). At baseline, the severity of overall disease was rated by the investigator and patient/parent (mild, moderate, severe) and the severity of pruritus was rated by the patient/parent (none, mild, moderate, severe). Patients were evaluated at baseline and followed within 1 to 3 weeks. At follow-up, the patient/parent and the investigator rated the time course and extent of improvement (none, mild, moderate, marked, completely clear). The patient/parent also rated the time course and extent of reduction in severity (none, mild, moderate, marked, completely clear). Local tolerability associated with medication use was also assessed. Patient characteristics and responses are detailed in the table “Patient Characteristics and Treatment Responses” on pages 42-43. With the exception of patient six, all patients completed the treatment regimen without reported interruptions in therapy. Points to Consider From Chart - • Patients 2,3,4,8 and 10 previously treated with low- or mid- potency topical corticosteroids had no treatment for at least 4 weeks prior to inclusion in trial. • Patient 7 with similar response with two independent disease exacerbations — on both occasions patient stopped pimecrolimus 1% cream maintenance therapy at least 4 weeks prior to inclusion in trial. • Patient 12 experienced moderate post-inflammatory hypopigmentation at sites of resolved eczematous dermatitis which resolved spontaneously. Results at a Glance The results of this pilot evaluation suggest that a topical corticosteroid and a TIC may be used in combination as initial therapy to gain rapid control of pruritus and to clear the skin eruption of atopic dermatitis. Specifically, twice daily application of BMV foam followed by pimecrolimus 1% cream proved to be highly effective with marked improvement or complete resolution of pruritus and eczematous dermatitis within 7 days or less — with most patients reporting a response within 3 days. Rapid resolution of pruritus was a significant and consistent observation. Vehicle-controlled studies evaluating the efficacy of pimecrolimus 1% cream applied twice daily for 6 weeks in children with predominantly moderate-severity atopic dermatitis reported mild or no pruritus in 44.2% of patients within the first week of therapy and 61.4% after 4 weeks of treatment. The rapid reductions in signs and symptoms of atopic dermatitis with combination therapy using a topical corticosteroid and TIC supports the model of rapid disease control followed by maintenance of remission with a TIC. The BMV foam/pimecrolimus 1% cream combination regimen was used in conjunction with selected and well-established skin care products (cleanser, emollient) without any apparent interference with clinical response. When utilized, the emollient cream was applied after application of both medications. Overall, both BMV foam and pimecrolimus 1% cream were well tolerated. Transient mild stinging after application of BMV foam was reported in four patients and didn’t result in alteration of the treatment regimen or discontinuation in therapy. In two patients, the stinging sensation no longer occurred after 1 to 2 days of use. One patient experienced marked stinging after application of BMV foam to eczematous dermatitis involving the legs and had to discontinue treatment. For more specific results pertaining to all of the patients studied, see the table “Patient Characteristics and Treatment Responses.” This patient had moderate atopic dermatitis on the trunk of the body. Therapy with a combination of a BMV foam and pimecrolimus cream was undertaken. The patient had marked clearance after undergoing treatment within 3 or 4 days with significant reduction in pruritus in 1 to 2 days. Here’s a look at the overall results in a nutshell: • Initial combination therapy with a mid-potency topical corticosteroid and a topical calcineurin inhibitor demonstrated rapid efficacy as determined by reduction in presence and/or severity of pruritus and clearance of eczematous dermatitis. • With regard to specific therapeutic agents used in this evaluation, twice daily application of BMV foam followed by pimecrolimus 1% cream produced rapid improvement or complete resolution of pruritus and eczematous dermatitis in adult and pediatric patients with atopic dermatitis. • The BMV foam-pimecrolimus 1% cream combination regimen was used successfully in conjunction with recommended basic skin care products (cleanser, emollient). This allowed for effective treatment of disease exacerbation without interruption of a prescribed skin care routine designed to maintain skin hydration and barrier function. • Overall, treatment was well tolerated with excellent tolerability reported by most patients. Transient stinging was reported in some younger pediatric patients using BMV foam and did not interfere with continued treatment. One patient did experience local intolerance requiring discontinuation of treatment. This patient was suffering from moderate atopic dermatitis of the antecubital area. Therapy was initiated with BMV foam and pimecrolimus cream twice daily. The patient experienced excellent clearing within 4 days and complete resolution of pruritus in 2 days. The Next Step Although this study yielded positive results, it was small and additional study is needed to evaluate the tolerability of BMV foam alone and in combination with other treatments in a larger collection of patients with atopic dermatitis, especially children. In addition, whether or not the combined use of a topical corticosteroid and a TIC produces an additive or a synergistic impact on efficacy can’t be determined from a study of this size or design. This observational study was investigator initiated and not funded. References 1. Boguniewicz M, Leung DYM. Pathophysiologic mechanisms in atopic dermatitis. Sem Cutan Med Surg 2001;20:217-225. 2. Boguniewicz M. Conventional topical treatment of atopic dermatitis. In: Bieber T, Leung DYM, Eds. Atopic Dermatitis, First Edition. Marcel Dekker Inc., New York, 2002, pp 453-477. 3. Cheer SM, Plosker GL. Tacrolimus ointment: a review of its therapeutic potential as a topical therapy in atopic dermatitis. Am J Clin Dermatol 2001;2:389-406. 4. Wellington KW, Jarvis B. Spotlight on topical pimecrolimus in atopic dermatitis. Am J Clin Dermatol 2002;3:435-438. 5. Reitamo S. Topical macrolide immunomodulators for therapy of atopic dermatitis. In: Bieber T, Leung DYM, Eds. Atopic Dermatitis, First Edition. Marcel Dekker Inc., New York, 2002, pp 541-565. 6. Koblenzer CS. The psychological aspects of atopic dermatitis. In: Bieber T, Leung DYM, Eds. Atopic Dermatitis, First Edition. Marcel Dekker Inc., New York, 2002, pp 519-539. 7. Feldman SR, Salam TN, Rapp SR, et al. Quantitative assessment of psoriasis patients’ preference for foam vehicle. Presented at American Academy of Dermatology; 2002; Washington, DC. 8. Gottlieb AB, Ford RO, Spellman MC. The safety and efficacy of clobetasol propionate foam, 0.05 %, in the treatment of mild to moderate plaque-type psoriasis of non-scalp regions. J Cutan Med Surg. Submitted. 9. Franz TJ, Parsell DA, Halualani RM, et al. Betamethasone valerate foam 0.12 %: a novel vehicle with enhanced delivery and efficacy. Int J Dermatol 1999;38:628-632. 10. Kapp A, Papp K, Bingham A, et al. Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol 2002;110:277-284. 11. Wahn U, Bas JD, Goodfield M, et al. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 2002;110:1-8. 12. Meurer M, Folster-Holst R, Wozel G, et al. Pimecrolimus cream in the long-term management of atopic dermatitis in adults: a six-month study. Dermatology 2002;205:271-277. 13. Eichenfield LF, Lucky AW, Boguniewicz M, 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. Skin & Aging - ISSN: 1096-0120 - Volume 11 - Issue 04 - April 2003 - Pages: 40 - 46