Jann Lübbe

Safety, Efficacy, and Dosage of 1% Pimecrolimus Cream for the Treatment of Atopic Dermatitis in Daily Practice

AbstractIntroduction: Although several controlled clinical trials have demonstrated the efficacy and good tolerability of 1% pimecrolimus cream for the treatment of atopic dermatitis, the results of these trials may not apply to real-life usage. The objective of this study was to evaluate the safety and efficacy of a pimecrolimus-based regimen in daily practice.n Methods: This was a 6-month, open-label, multicenter study in 947 patients aged ≥3 months with atopic dermatitis of all severities. The investigators incorporated 1% pimecrolimus cream into patients’ standard treatment protocols on the basis of their clinical diagnosis. Use of topical corticosteroids was allowed at the discretion of the physician. Safety and tolerability were evaluated by monitoring adverse events. Efficacy was evaluated by recording changes in the Investigators’ Global Assessment scores and pruritus scores at each visit.n Results: No clinically unexpected adverse events were reported. The discontinuation rate for adverse events was 2.3%. The disease improvement rate was 53.7% at week 1 and 66.9% at week 24. The pimecrolimus-based regimen was particularly effective for the treatment of lesions involving the face (improvement rate: 61.9% at week 1 and 76.7% at week 24). The greatest therapeutic response was experienced by pediatric patients with mild or moderate disease. Nonetheless, 64% and 65% of infants and children, respectively, with severe/very severe facial disease at baseline were clear/almost clear of signs of atopic dermatitis on their face at week 24. In patients aged <18 years, most of the improvement occurred within the first week of treatment, while in adults a progressive improvement was observed over the entire study period. Worsening of disease by the end of the study occurred in 9.5% of patients and was most frequent in adults (12.6%). The discontinuation rate for unsatisfactory therapeutic effect was 4.8%. The mean number of treatment days was 135.6 (SD 53.2). The mean drug consumption (non-US centers only) was 4.2g per treatment day. Drug consumption decreased over time as disease improved. In total, 47% of patients who completed the study never used topical corticosteroids over 6 months.n Conclusion: In daily practice, incorporation of 1% pimecrolimus cream into patients’ standard treatment regimen is well tolerated and improves atopic dermatitis in approximately two-thirds of patients. Disease improvement is particularly evident on the face. The greatest therapeutic response is experienced by pediatric patients with mild or moderate disease. In these patients, most of the improvement is observed within 1 week from the start of treatment.

Difficult to control atopic dermatitis

Difficult to control atopic dermatitis (AD) presents a therapeutic challenge and often requires combinations of topical and systemic treatment. Anti-inflammatory treatment of severe AD most commonly includes topical glucocorticosteroids and topical calcineurin antagonists used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, the topical calcineurin inhibitors tacrolimus and pimecrolimus are preferred in certain locations. Systemic anti-inflammatory treatment is an option for severe refractory cases. Microbial colonization and superinfection contribute to disease exacerbation and thus justify additional antimicrobial / antiseptic treatment. Systemic antihistamines (H1) may relieve pruritus but do not have sufficient effect on eczema. Adjuvant therapy includes UV irradiation preferably of UVA1 wavelength. “Eczema school” educational programs have been proven to be helpful.

Benefits from the Use of a Pimecrolimus-Based Treatment in the Management of Atopic Dermatitis in Clinical Practice

Background: Controlled studies established the efficacy and good tolerability of pimecrolimus cream 1% for the treatment of atopic dermatitis but they may not reflect real-life use. Objective: To evaluate the efficacy, tolerability and cosmetic acceptance of a pimecrolimus-based regimen in daily practice in Switzerland. Methods: This was a 6-month, open-label, multicentre study in 109 patients (55% ≧18 years) with atopic dermatitis. Pimecrolimus cream 1% was incorporated into patients’ standard treatment protocols. Results: The pimecrolimus-based treatment was well tolerated and produced disease improvement in 65.7% of patients. It was particularly effective on the face (improvement rate: 75.0%). Mean pimecrolimus consumption decreased from 6.4 g/day (months 1–3) to 4.0 g/day (months 3–6) as disease improved. Most patients (74.1%) rated their disease control as ‘complete’ or ‘good’ and 90% were highly satisfied with the cream formulation. Conclusion: The use of a pimecrolimus-based regimen in everyday practice was effective, well tolerated and well accepted by patients.

Topical Tacrolimus for Atopic Dermatitis: Euphoria and Vigilance

Accessible online at: www.karger.com/journals/drm Today, there is ample scientific evidence for the clinical effectiveness, safety and patient comfort of tacrolimus ointment in the treatment of moderate to severe atopic dermatitis. Recent, well-documented reports on doubleblind, vehicle-controlled, randomized clinical studies encompass data from 419 adults [1] and 235 children [2] who were successfully treated with 0.1 and 0.03% tacrolimus ointment for up to 3 months. Concerning long-term treatment, two open studies have observed 316 adults [3] and 255 children [4] who were treated with 0.1% tacrolimus ointment for up to 1 year. Transient local burning and pruritus, occurring in every second patient, were the principal adverse effects, and there is apparently little risk of skin infections. This bright picture is endorsed by a significantly positive health-related quality of life assessment in 900 children and adults [5]. Tacrolimus ointment has not yet been released in most countries. For use in daily practice, a topical formulation is easily prepared from available FK-506 capsules on a prescription basis [6]. Most of the existing evidence on the treatment of atopic dermatitis with tacrolimus ointment stems from the particular clinical settings that are inherent in double-blind, randomized study protocols, not always representative of real-life conditions. One example is the steroid washout phase required by these studies prior to patient enrollment. Complete abstinence from any topical treatment throughout the resulting rebound phase is itself part of a rational treatment strategy for chronic atopic facial dermatitis. With the tacrolimus option at hand, management of this therapeutic cul-de-sac of the corticosteroid treatment era should be reversed [7], and therapeutic abstinence is likely to become obsolete in daily practice. However, this realistic perspective raises questions that have not been answered by the clinical trials. Kawakami and coworkers, reporting in this issue of Dermatology [8], show that topical tacrolimus treatment of steroidaggravated facial atopic dermatitis is effective without a washout, and not associated with a rebound phenomenon. Remarkably, the authors have excluded patients with severe dermatitis from their study, as the use of topical tacrolimus on erosive lesions is officially prohibited in Japan, where the ointment is already marketed (Protopic). Erosive dermatitis increases the systemic absorption of the FK-506 molecule and is more prone to secondary bacterial or viral infection. Clinically infected atopic dermatitis also excluded patients from participation in the clinical trials. Early herpes simplex infection is much more difficult to spot amidst erosive, excoriated lesions. Is the above-mentioned assessment of the risk of infectious complications associated with tacrolimus ointment really representative of field conditions? Have a second look! The two recent vehicle-controlled clinical studies report 22 (3.4%) cases of herpes simplex infection during treatment with tacrolimus ointment, of which 3 presented as eczema herpeticum [1, 2]. In the two open long-term studies, 31 (5.4%) cases of herpes simplex infection were observed, of which 7 presented as eczema herpeticum [3, 4]. Taken together, every fifth herpes simplex infection diagnosed in these trials during tacrolimus treatment presented as an eczema herpeticum; in the vehicle-controlled

Sirolimus-induced inflammatory papules with acquired reactive perforating collagenosis.

Sirolimus is an immunosuppressive macrolide with antineoplasic properties that is increasingly used in posttransplantation immunosuppression. The treatment is frequently associated with cutaneous side effects such as sirolimus-associated acneiform facial dermatitis, which has been observed in up to 50% of treated patients. We report a 51-year-old female with liver transplantation who developed inflammatory papules and nodules on the face and the upper chest 3 weeks after the initiation of sirolimus therapy. Sequential biopsies revealed lymphocytic infiltration of the dermis with a peculiar pattern of sebotropism, while older lesions showed acquired reactive perforating collagenosis. The lesions were responsive to hydroxychloroquine treatment despite continued sirolimus treatment.

Evidence-based corneotherapy.

Accessible online at: www.karger.com/journals/drm 1 The term ‘corneotherapy’ has been coined by Prof. A.M. Kligman [pers. commun.]. In this issue of Dermatology, Tagami and his group propose a practical method to evaluate the hydrating properties of various skin moisturizers used in adjuvant skin care. The authors’ objective was to develop a test based on a non-invasive biophysical approach that allows to compare the remanence of the hydrating effect of various skin moisturizers. They determined stratum corneum hydration by electrical conductance measurement, a method that assesses superficial skin hydration and has been well evaluated. The results are clear-cut and show what one would expect, i.e. that skin moisturizers really moisturize the skin, and that some, containing urea or heparinoids, provide a longer-lasting effect. The authors ascribe this remanent action of topical skin hydration to a pharmacological effect, and use the term of ‘corneotherapy’1, instead of simple ‘repeated application of moisturizers’. Now, what makes the difference between ‘corneotherapy’ and ‘repeated application of moisturizers’? Corneotherapy takes its rationale from a ‘corneal’ perspective of the pathogenesis of skin diseases. The stratum corneum is recognized as a dynamic and interactive tissue. Epidermal IL-1· was just an early candidate link between skin barrier disruption and subsequent dermal inflammatory reactions [1]. Increasing knowledge about the physiology of the permeability barrier and the sequential events between barrier insults and epidermodermal responses have led to a new outside-inside concept of skin disease triggering. For example, the sustained barrier abnormality in overlying epidermis [2] has been proposed as the trigger in keloid development (as opposed to the orthodox view of dermo-epidermal triggering), offering a rationale for occlusive treatment (for an exhaustive discussion, see Elias [3, 4]). Further progress in basic research on the mechanisms regulating skin barrier homoeostasis is needed to open up the perspectives for rational corneotherapy, and this rational base may indeed make a difference to simple repeated application of moisturizers. Is it pharmacological versus non-pharmacological action that discerns corneotherapy from repeated application of moisturizers? This would be a rather dogmatic position that might be difficult to maintain, because one would have to argue with eminent proponents of, say, ‘water dermatology’ [5]. It is scientifically more honest to accept that any product applied to the skin acts pharmacologically, be the effect measurable or not. The real question is the indication of the application of the product and the evaluation of the manufacturer’s product claims. It is in regard to this latter point that the study of Tagami and his group is pertinent, as it demonstrates the power of today’s biophysical methods to discern subtle differences between products with similar intention profiles. Finally, corneotherapy is, as a term, en vogue, and dermatologists are trendsetters in the application of noninvasive methods for clinical investigation. If the call for a base of evidence, for treatments that are so much part of clinical common sense as adjuvant skin moisturizing,

Generalized Xerotic Dermatitis with Neutrophilic Spongiosis Induced by Erlotinib (Tarceva

Erlotinib is a small molecule tyrosine kinase inhibitor that is used as an anticancer agent. Most patients develop a pustular facial dermatitis within the first week of treatment. Pyogenic granulomas of the nail folds are another typical adverse event occurring in about 10–15% of cases. We report on a patient who developed a generalized dermatitis characterized by neutrophilic spongiosis. Neutrophilic inflammation has been observed in several drugs that interfere with EGFR signaling, suggesting a class effect. The present case may be yet another manifestation of this particular reaction pattern.