62 Topical Immunomodulators in the Treatment of Atopic Eczema

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1 Chapter Topical Immunomodulators in the Treatment of Atopic Eczema S. Reitamo, A. Remitz 62.1 Introduction The new topical noncorticosteroid immunomodulators, tacrolimus (FK506, Protopic) and the ascomycin derivative pimecrolimus (ASM 981, Elidel) have shown efficacy in clinical studies as topical monotherapy of atopic dermatitis [1 5]. Here the mode of action, efficacy, and safety of the two available topical immunomodulators are reviewed and compared to standard treatment of atopic dermatitis (eczema) with topical corticosteroids Activation of Inflammatory Cells in Atopic Eczema In atopic eczema (AE), the inflamed skin shows impaired barrier properties and therefore large exogenous polypeptides can penetrate eczematous skin and cause an eczematous reaction of the skin [6]. Various celltypescontributetothepathogenesisofae[7].the lesional skin in atopic dermatitis contains a large number of T cells, which show characteristic cytokine profiles. In a fresh lesion, the infiltrate is dominated by cells of the T helper 2 type cytokine profile, whereas in the chronic lesion, the T helper 1 type dominates in the skin. Most patients with atopic dermatitis have increased levels of IgE in their blood as well as in the skin. The IgE observed is polyclonal, i.e., it shows multiple specificities to environmental antigens, such as bacteria and pollen, house dust mite, animal proteins, and also sometimes to intrinsic antigens. This IgE of multiple specificity traps environmental antigens penetrated through the eczematous skin and binds these antigens to the Fc-receptors of antigen-presenting cells of the skin, such as Langerhans cells and inflammatory dendritic epidermal cells (IDEC), which both contain increased densities of the high-affinity receptor to IgE (Fc 5 RI) on their cell surface [8, 9]. This results in activation of specific T cells. T cells also are activated through nonspecific polyclonal T cell activation by superantigens such as staphylococcal enterotoxins shown to be common in eczema skin [10, 11]. Other cells contributing to the inflammation in atopic dermatitis include eosinophils, basophils, and mast cells TheModeofActionofTopicalImmunomodulatory Agents Tacrolimus is a natural product of the fungus Streptomyces tsukubaensis [12] and pimecrolimus is a semisynthetic product of the natural product ascomycin [13]. Their molecular weight is approximately twice that of glucocorticoids, above 800 D. Therefore, these compounds do not penetrate normal skin. The activation of both antigen-presenting cells and T cells can be suppressed by the topical immunomodulators. Tacrolimus and pimecrolimus block the early activation of T cells by binding to the FK506 binding protein (FKBP- 12), a 12-kD macrophilin [13, 14]. The FKBP-12-tacrolimus or FKBP-12-pimecrolimus complex inhibits calcineurin and thereby the dephosphorylation of NF- ATp and expression of inflammatory T cell cytokines. This inhibition of early T cell activation is caused after both antigen-specific and superantigen-mediated T cell activation [15]. In addition, cytokines in other inflammatorycellssuchaseosinophilsandmastcells are inhibited.

2 62.6 Efficacy of Topical Immunomodulators Used as Monotherapy in Atopic Eczema Staphylococcal Colonization Contributes to Severity of Atopic Eczema The skin in atopic dermatitis shows signs of immune suppression as well as colonization with bacteria, viruses, and yeasts. This could be mainly due to the relative lack of T helper type 1 cells, which are needed to destroy foreign microbes. This is supported by functional studies that show decreased T helper 1 type functions, such as impaired reactions to recall antigens. Colonization of atopic dermatitis skin with superantigen-producing Staphylococcus aureus contributes to the severity of atopic skin disease [16, 17]. Superantigen-mediated activation of T cells is resistant to corticosteroids, which may increase the clinical severity of atopic dermatitis. We studied the colonization with S. aureus during a 1-year study and found that staphylococcal colonization of AE lesions significantly decreased as early as 1 week of treatment compared with baseline [18], followed by clinical improvement. The decrease in staphylococcal colonization probably reflects improvement of skin barrier function [19]. No similar studies with pimecrolimus have been published Treatment with Topical Immunomodulators Does Not Suppress Connective Tissue Compared to healthy dermis, the dermis in AE shows decreased synthesis of collagens type I and III. These two collagens are used identically to form collagen bundles. Corticosteroids inhibit collagen synthesis, which can lead to visual atrophy. One-week treatment with tacrolimus under occlusion did not have any effect on collagen synthesis of treated skin in healthy controls and atopic dermatitis patients [20]. Betamethasone, in contrast, reduced type I collagen synthesis to 20% and that of type III collagen to 30% of baseline value. Betamethasone, but not tacrolimus, also reduced skin thickness both in controls and in AE patients by approximately 9% over 1 week. Pimecrolimus was studied under nonoccluded conditions in healthy subjects for 28 days [21]. No effect on skin thickness was seen. However, the true clinical situation is long-term treatment. We noticed an increase in collagen synthesis after 1 year of tacrolimus therapyinpatientspreviouslytreatedwithcorticosteroids, suggesting that repair is possible after prolonged steroid treatment [22]. Interestingly, this positive effect also occurred in patients undergoing therapy with inhaled corticosteroids, which are potent inhibitors of collagen synthesis in the skin [22] Efficacy of Topical Immunomodulators Used as Monotherapy in Atopic Eczema Short-Term Studies Several placebo-controlled studies with tacrolimus [1, 2, 23] and pimecrolimus [4, 5, 24 26] have shown significant efficacy of these compounds as compared to vehicle treatment. Tacrolimus showed efficacy at 0.03%, the lowest concentration studied, whereas pimecrolimus showed modest efficacy at 0.2%, but not at lower concentrations. Tacrolimus has an ointment vehicle, whereas pimecrolimus has a cream vehicle. Pimecrolimus has also been tried in studies in which corticosteroids served as rescue medication. In these, 1% pimecrolimus was clearly superior to vehicle treatment. Short-term monotherapy studies lasting 3 weeks compared tacrolimus to hydrocortisone acetate in children and hydrocortisone butyrate in adults [27, 28], and pimecrolimus to betamethasone valerate [5]. In 3- week studies, 0.1% tacrolimus showed similar efficacy as 0.1% hydrocortisone butyrate ointment, both 0.1% and 0.03% tacrolimus showed superior efficacy to 1% hydrocortisone acetate [27, 28]. In children, tacrolimus once or twice daily, even at the lower concentration of 0.03%, was superior to hydrocortisone acetate twice daily [29]. A 1% pimecrolimus cream showed approximately 50% of the efficacy of betamethasone valerate cream, from which it could be calculated that 1% pimecrolimus would have a similar efficacy as 1% hydrocortisone acetate cream Long-Term Studies In long-term monotherapy studies of patients with moderate to severe atopic eczema, tacrolimus was compared to hydrocortisone acetate for face and neck andhydrocortisonebutyrateointmentforotherparts

3 Topical Immunomodulators in the Treatment of Atopic Eczema a b Fig. 62.1a, b. Intermittent monotherapy of severe atopic eczema with 0.1% tacrolimus ointment. a Baseline. b After 18 months of tacrolimus treatment without corticosteroids of the body [30]. Pimecrolimus was compared to triamcinolone acetate cream [31]. In these studies, tacrolimus showed superior efficacy to the steroid, whereas pimecrolimus was inferior to the respective corticosteroid treatment. Moderate to severe atopic dermatitis usually needs long-term continuous or intermittent treatment of all eczema until the skin is totally cleared and the itch gone. When such patients are treated with tacrolimus ointment, an improvement of at least 90 % canbeexpectedinhalfofthem[32].insuchpatients, the total use of tacrolimus ointment decreased with time, and some also had treatment-free periods of several weeks (Fig. 62.1). Pimecrolimus cream has shown efficacy in moderate but not severe atopic dermatitis Efficacy of Topical Immunomodulators Used Together with Topical Corticosteroids Sugiura et al. showed that by treating the face only with tacrolimus, and the rest of the body with corticosteroids, there were, after an initial response, poor longterm results on the face treated with tacrolimus. These results were dependent on the severity of dermatitis, with treatment results inversely related to severity of dermatitis [33]. This suggests that monotherapy should be the primary way of using topical immunomodulators. Most of the patients undergoing successful pimecrolimus treatment in clinical trials had either mild or moderate disease, although a few had severe eczema. From the studies available, it can be concluded that approximately half of such patients can use pimecrolimus monotherapy (for review see [34]). The others should use corticosteroids for disease flare-ups Comparison of Tacrolimus Ointment and Pimecrolimus Cream Both in vitro and in vivo preclinical studies suggest that tacrolimus is a more potent calcineurin inhibitor than pimecrolimus. Blinded clinical comparison of the marketed compounds is difficult because of the differences in the vehicle used in these two compounds. Tacrolimus ointment does not contain any water in the vehicle, whereas pimecrolimus is a cream formulation. However, the differences in the formulation do not explain the differences in clinical efficacy, as it has so far not been possible to increase the clinical efficacy of pimecrolimus in an ointment base. On the other hand, tacrolimus in a cream base is less effective compared to that in the ointment base. Comparative studies of tacrolimus and pimecrolimus suggest that the clinical efficacy of 0.1% tacrolimus ointment is clearly superior to 1% pimecrolimus cream (for

4 62.11 Does Topical Immunomodulation Increase the Risk of Skin Cancer? 573 review see [34]). Studies also suggest that 0.03% tacrolimus ointment has better efficacy than 1% pimecrolimus cream. This difference in efficacy was not significant when patients with mainly mild disease were studied. Despite the significant difference in clinical efficacy in favor of tacrolimus ointment, there have been no significant differences in adverse events during the comparative studies. The initial burning and prolonged itch depend on the baseline severity of the disease and not on the treatment Safety Burning and Increased Pruritus Burning sensation and increased pruritus of the skin have been the only adverse events that showed a higher incidence with tacrolimus ointment or pimecrolimus cream compared with the control vehicle in short-term studies. In long-term studies, skin burning, erythema, and pruritus were common but tended to occur only during the first few days of treatment [2 5, 27, 28, 31]. Burninganderythemaofthefacewereaggravatedby alcohol intake in some patients [32]. The cause of burning is not known. However, it can be pretreated with acetosalicylic acid if needed Long-Term Safety of Topical Immunomodulators Uncontrolled safety studies have not shown any concerns (for review see [34, 35]). Herpes simplex infections during long-term treatment have not increased compared to historical controls. It seems that the present immunomodulatory compounds have a good safety profile and can therefore be used for a long time. Laboratory profiles during several long-term studies have been unremarkable. Drug levels decreased within a few days after starting therapy for both tacrolimus and pimecrolimus. During long-termtreatment,about75%ofpatientsdidnotshow detectable blood levels of tacrolimus [32, 34 37]. There are no data available on drug levels during long-term treatment with pimecrolimus. The only safety concern seems to refer to children with Netherton s syndrome, an autosomal recessive disease characterized by congenital erythroderma, who despite a good treatment result showed high tacrolimus blood levels [38]. There was no evidence of an increased risk of any type of infection compared with historical data from the literature Adverse Events Are Related to Disease Severity A total of over 1,000 patients were followed in 6-week comparative studies of tacrolimus ointment and pimecrolimus cream. Despite a significant difference in clinical efficacy in favor of tacrolimus ointment, there were no significant differences in adverse events in these comparative studies (for review see [34]). The main adverse events were initial burning an increased itch. These seem to be dependent on the baseline severity of the disease and not on the type of immunomodulatory agent used for treatment of atopic eczema Does Topical Immunomodulation Increase the Risk of Skin Cancer? Previous studies have shown that systemic immune suppression in patients with previous organ transplantation results in a linear increase in the incidence of nonmelanoma skin cancer over the years. The steepness of the linearity is correlated to the amount of UV radiation. Therefore countries with high UV radiation have higher numbers of patients with nonmelanoma skin cancer than countries with low UV radiation. Nonmelanoma skin cancer on immune-suppressed patients is preceded by viral infections of the skin. The bioavailability of immunosuppressive drugs is much higher in systemic immunosuppression compared to topical immunomodulation. Hence, there has been no longterm increase in skin infections after topical immunomodulatory treatment. Long-term treatment with tacrolimus ointment did not increase the incidence of skin cancer in United States males compared to matched healthy controls (reviewed in [34]). We have shown a recovery of Th1-type function in the recall antigen test during long-term treatment of atopic dermatitis with tacrolimus ointment (unpublished). As the risk of skin canceriscorrelatedwithlowth1typereactions,itcan be concluded that at present there are no human data to suggest that topical immunomodulation would cause an increase in skin cancer (see also [38a]).

5 Topical Immunomodulators in the Treatment of Atopic Eczema Practical Use of Topical Immunomodulators In clinical studies, tacrolimus has been used mainly as monotherapy for atopic dermatitis in an intermittent fashion, so that treatment is started when the early signs of inflammation such as itch and dry skin are present. Treatment is usually pursued until all signs of dermatitis are cleared. Studies on preventive use of tacrolimus ointment are in progress. In clinical practice, tacrolimus is often used together with topical corticosteroids, mainly for economical reasons. In those patients in whom tacrolimus ointment alone does not have sufficient efficacy, the eczema is usually located on the hands and/or feet. In these patients, we use intermittent potent corticosteroids for the treatment-resistant areas. Otherwise we think that intermittent monotherapy with tacrolimus ointment should be used for optimal long-term treatment results, as shown by Sugiura et al. [33]. When pimecrolimus was used in a long-term study as monotherapy for adult patients with moderate to severe atopic dermatitis, treatment results suggested that it was not effective as monotherapy of severe disease. In patients with moderate disease, the efficacy is better, although addition of corticosteroids for disease flare-ups are often needed. In contrast to studies with tacrolimus, addition of corticosteroids was allowed for disease flare-ups for several studies with pimecrolimus cream where it was used daily in a preventive way. Many patients could use monotherapy when pimecrolimus was applied in this way. Taken together, ideally for the best results both compounds should be used as monotherapy, and addition of topical corticosteroids should be restricted to areas resistant to treatment. Tacrolimus once daily is effective for most patients after the initial treatment period, whereas pimecrolimus cream should be used twice daily for optimal results. Although there are no human data available to suggest that topical immunomodulators could cause skin cancer, they should not be combined with UV therapy at present. Because of insufficient data on the use of topical immunomodulators in patients under 2 years of age, they should not be used routinely with this age group Conclusions The main advantage of topical noncorticosteroid immunomodulatory agents compared to steroids is lack of suppression of the connective tissue. Therefore these compounds are not atrophogenic on the skin. Tacrolimus treatment can be used to enhance collagen synthesis in patients with signs of skin atrophy. Compared to oral immunosuppressive agents, the main advantage is limited bioavailability, which is regulated by the improved skin barrier function. The clinical data collected so far indicate that there is no increased risk of skin cancer, infection, or other undesirable immunosuppressive effects. The immunomodulatory compounds are clearly contenders for topical corticosteroids as a first-line treatment of atopic eczema. References 1. Nakagawa H, Etoh T, Ishibashi Y et al (1994) Tacrolimus ointment for atopic dermatitis (letter). Lancet 344: Ruzicka T, Bieber T, Schöpf E et al (1997) A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 337: Boguniewicz M, Fiedler VC, Raimer S et al (1998) A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. J Allergy Clin Immunol 102: Van Leent EJ, Gräber M, Thurston M et al (1998) Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch Dermatol 134: Luger T, van Leent EJ, Graeber M et al (2001) SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 144: Reitamo S, Visa K, Kähönen K et al (1986) Eczematous reactions in atopic dermatitis caused by epicutaneous testing with inhalant allergens. Br J Dermatol 114: Novak N, Bieber T (2004) The pathogenesis of the atopic eczema/dermatitis syndrome. In: Ruzicka T, Reitamo S (eds) Tacrolimus ointment. A topical immunomodulator for atopic dermatitis. Springer, Berlin Heidelberg New York, pp Panhans-Groß A, Novak N, Kraft S et al (2001) Human epidermal Langerhans cells are targets for the immunosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 107: Wollenberg A, Sharma S, von Bubnoff D et al (2001) Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol 107: Hauk PJ, Hamid QA, Chrousos GP, Leung DYM (2000) Induction of corticosteroid insensitivity in human periph-

6 References 575 eral blood mononuclear cells by microbial superantigens. J Allergy Clin Immunol 105: Hauk PJ, Leung D (2001) Tacrolimus (FK506): new treatment approach in superantigen-associated diseases like atopic dermatitis? J Allergy Clin Immunol 107: Goto T, Kino T, Hatanaka H, et al (1987) Discovery of FK- 506, a novel immunosuppressant isolated from Streptomyces tsukubaensis. Transpl Proc 19 [Suppl] 6: Grassberger M, Baumruker T, Enz A et al (1999) A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol 141: Kino T, Hatanaka H, Hashimoto M et al (1987) FK 506, a novel immunosuppressant isolated from a streptomyces. I. Fermentation, isolation, and physio-chemical and biological characteristics. J Antibiot (Tokyo) 49: Reitamo S (2001) Tacrolimus: a new topical immunomodulatory therapy for atopic dermatitis. J Allergy Clin Immunol 107: Nomura I, Tanaka K, Tomita H et al. (1999) Evaluation of the staphylococcal exotoxins and their specific IgE in childhood atopic dermatitis. J Allergy Clin Immunol 104: Bunikowski R, Mielke MEA, Skarabis H et al. (2000) Evidence for a disease promoting effect of S. aureus-derived exotoxins in atopic dermatitis. J Allergy Clin Immunol 105: Remitz A, Kyllönen H, Granlund H, Reitamo S (2001) Tacrolimus ointment reduces staphylococcal colonization of atopic dermatitis lesions (letter). J Allergy Clin Immunol 107: Pournaras CC, Lübbe J, Saurat J-H (2001) Staphylococcal colonization in atopic dermatitis treatment with topical tacrolimus (FK506) (letter). J Invest Dermatol 116: Reitamo S, Rissanen J, Remitz A et al (1998) Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial. J Invest Dermatol 111: Queille-Roussel C, Paul C, Duteul L et al (2001) 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 144: Kyllönen H, Remitz A, Mandelin JM et al (2004) Effects of 1-year intermittent treatment with topical tacrolimus monotherapy on skin collagen synthesis in patients with atopic dermatitis. Br J Dermatol 150: Paller A, Eichenfield LF, Leung DY et al (2001) A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 44: S47 S Wahn U, Bos JD, Goodfield M et al (2002) Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 110:e2 25. Eichenfield LF, Lucky AW, Boguniewicz M et al (2002) Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of atopic dermatitis in children and adolescents J Am Acad Dermtol 46: MeurerM,FartaschM,AlbrechtGetal(2004)Long-term efficacy and safety of pimecrolimus cream 1% in adults with moderate atopic dermatitis. Dermatology 20: Reitamo S, Van Leent EJM, Ho V, Harper J, Ruzicka T, Kalimo K, Cambazard F, Rustin M, Taïeb A, Gratton D, Sauder D, Sharpe G, Smith C, Jünger M, de Prost Y (2002) Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol 109: Reitamo S, Rustin M, Ruzicka T, Cambazard F, Kalimo K, Friedmann PS, Schoepf E, Lahfa M, Diepgen TL, Judodihardjo H, Wollenberg A, Berth-Jones J, Bieber T (2002) Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J Allergy Clin Immunol 109: Reitamo S, Harper J, Bos J, Cambazard F, Bruijneel-Koomen C, van der Valk P, Smith C, Moss C, Dobozy A, Palatsi R (2004) 0.03% tacrolimus ointment applied once or twice daily is more efficacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis. Br J Dermatol 150: Reitamo S, Ortonne JP, Sand C et al (2005) A multicentre, randomized, double-blind, controlled study of long-term treatment with 0.1% tacrolimus ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol 152: Luger TA, Lahfa M, Folster-Hölst R et al (2004) Long-term safety and tolerability of pimecrolimus 1% and topical corticosteroid in adults with moderate to severe atopic dermatitis. J Dermatol Treat 15: Reitamo S, Wollenberg A, Schöpf E et al (2000) Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol 136: Sugiura H, Tsukinowacho S, Uehara M et al (2000) Longterm efficacy of tacrolimus ointment for recalcitrant facial erythema resistant to topical corticosteroids in adult patients with atopic dermatitis. Arch Dermatol 136: Alomar A, Berth-Jones J, Bos JD et al (2004) The role of topical calcineurin inhibitors in atopic dermatitis. Br J Dermatol 151 [Suppl 70]: Reitamo S, Remitz A, Kyllönen H, Saarikko J (2002) Topical immunomodulation in the treatment of atopic dermatitis. Am J Clin Dermatol 3: Soter NA, Fleischer AB, Webster GF et al (2001) Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part II, Safety. J Am Acad Dermatol 44:S39 S Kang S, Lucky AW, Pariser D et al (2001) Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 44: S58 S Allen A, Siegfried E, Silverman R (2001) Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol 137: a. Ring J, Barker J, Behrendt H et al. (2005) Review of the potential photococareinogenicity of topical calcineurin inhibitors. Position statement of the European Dermatology Forum (JEADV), in press