Immunomodulation and safety of topical calcineurin inhibitors for the treatment of atopic dermatitis

Atopic dermatitis (AD) is a chronic or chronically relapsing inflammatory skin condition that primarily affects children. Topical corticosteroids have been the mainstay of treatment since the late 1950s. While providing excellent short-term efficacy, topical corticosteroid usage is limited by potential adverse effects, including impairment of the function and viability of Langerhans cells/dendritic cells. The recently introduced topical calcineurin inhibitors pimecrolimus cream 1% (Elidel) and tacrolimus ointment 0.03 and 0.1% (Protopic) exhibit a more selective mechanism of action and do not affect Langerhans cells/dendritic cells. For the immune system of young children 'learning' to mount a balanced Th1/Th2 response, this selective effect has particular benefits. In clinical experience, topical calcineurin inhibitors have been shown to be a safe and effective alternative to topical corticosteroids in almost 7 million patients (>5 million on pimecrolimus; >1.7 million on tacrolimus). Topical pimecrolimus is primarily used in children with mild and moderate AD, whereas tacrolimus is used preferentially in more severe cases. None of the topical calcineurin inhibitors have been associated with systemic immunosuppression-related malignancies known to occur following long-term sustained systemic immunosuppression with oral immunosuppressants (e.g., tacrolimus, cyclosporine A, and corticosteroids) in transplant patients. Preclinical and clinical data suggest a greater skin selectivity and larger safety margin for topical pimecrolimus.     

Repigmentation of pretibial vitiligo with calcineurin inhibitors under occlusion

Treatment of vitiligo is a challenge, especially in children. Recently, topical calcineurin inhibitors have been introduced in the management of vitiligo, but significant repigmentation is not achieved except on the face. Large pretibial lesions of a 15‐year‐old female with progressive vitiligo were treated twice daily over six months with 0.1% tacrolimus ointment on the right and 1% pimecrolimus cream on the left side without effect. Additional overnight occlusion with polyurethane and hydrocolloid foils during the following 18 months led to substantial repigmentation on both sides (tacrolimus‐treated side, 88% repigmented area; pimecrolimus‐treated side, 73%). Tacrolimus serum levels measured at four different time points did not exceed 1.8 ng/ml. This case report on a direct comparison of topical tacrolimus and pimecrolimus in vitiligo shows that on the shins considerable improvement could be induced with both agents only by additional long‐term occlusion and that tacrolimus was somewhat more effective than pimecrolimus.     

Role of Topical Calcineurin Inhibitors in the Treatment of Seborrheic Dermatitis

Seborrheic dermatitis (SD) is characterized by erythematous pruritic patches and plaques with greasy scale that occur in sebaceous areas. It is common, affecting up to 3% of the population. Past treatments have relied on a wide variety of anti-inflammatory and antifungal agents, but corticosteroids have limited use because of long-term adverse effects. Topical calcineurin inhibitors provide a safe alternative for the treatment of SD, as these drugs block the inflammatory cascade involved in the disease process and pose no risk of skin atrophy. Studies of topical pimecrolimus and tacrolimus in the treatment of SD have found that improvement occurred within 2 weeks, and if SD recurred after stopping treatment, it was significantly less severe. There have been no studies of the comparative efficacy of pimecrolimus versus tacrolimus for the treatment of SD. Common adverse effects of mild burning and irritation have been associated with the use of both of these agents. Safety profile studies are limited to studies of atopic dermatitis, which show no increase in infection rate, photocarcinogenicity, or signs of immunosuppression in patients using topical calcineurin inhibitors for long-term treatment. This article reviews the clinical trials of pimecrolimus and tacrolimus in the treatment of SD, focusing on efficacy and safety.     

Efficacy and Economics of Topical Calcineurin Inhibitors for the Treatment of Atopic Dermatitis

Atopic dermatitis is a chronic, relapsing inflammatory skin disease that frequently affects infants and children. The worldwide prevalence of atopic dermatitis is estimated to be 5-20% of the pediatric population. Studies have shown that atopic dermatitis is associated with considerable economic costs and decreased quality of life. There is no proven curative therapy at present for atopic dermatitis; first-line therapy has generally consisted of dry skin care, avoidance of triggers, application of topical corticosteroids, and administration of histamine H1 receptor antagonists (antihistamines) and oral antibacterials as appropriate. Topical corticosteroids, while effective in many patients, carry the concern of local and systemic adverse effects. As a result, physicians and patients are reluctant to utilize stronger topical corticosteroids in certain areas of the body and for prolonged periods of time. The purpose of this article is to review the efficacy and economics of topical calcineurin inhibitors in the treatment of atopic dermatitis. This new class of agents (specifically tacrolimus ointment and pimecrolimus cream) represents an exciting advance in the treatment of atopic dermatitis. Clinical data show that topical calcineurin inhibitors are effective and do not cause the adverse effects associated with topical corticosteroids. Several studies have provided evidence that topical calcineurin inhibitors positively affect the quality of life of patients and their caregivers. Compared with branded topical corticosteroids and previous standards of care, topical calcineurin inhibitors appear to be a cost-effective treatment option. Drawing comparisons between tacrolimus and pimecrolimus is difficult because definitive head-to-head comparative studies involving these drugs have not been conducted.     

Topical noncorticosteroid immunomodulation in the treatment of atopic dermatitis

At present, the first-line drugs for treating atopic dermatitis are topical corticosteroids. They are effective when used short-term; however, long-term use of the corticosteroids is associated with suppressive effects on the connective tissue, seen as skin atrophy or resistance to therapy. Currently, two topical noncorticosteroid immunomodulators tacrolimus (FK506) and pimecrolimus (SDZ ASM 981) are under development, or already on the market in some countries for atopic dermatitis. These two compounds show structural similarity. In T lymphocytes they bind to the same cellular receptor, the FK-binding protein (FKBP) or macrophilin-12. Tacrolimus shows a 3-fold greater affinity to FKBP compared with pimecrolimus. The tacrolimus/ pimecrolimus-FKBP complex further binds to calcineurin, an enzyme vital for the early activation of T cells. The consequence of calcineurin binding is a lack of activation of both T helper cell types 1 and 2. Further effects of these compounds have been suggested on other inflammatory cells, such as Langerhans cells and mast cells/basophils. In contrast to corticosteroids, no suppressive effects on connective tissue cells have been observed. Taken together, treatment of inflammation results in healing of the barrier function of the skin. This again results in reduced bioavailability of the drug, as compared with systemic use. Placebo-controlled studies have shown the efficacy of both tacrolimus (at 0.03 and 0.1%) and pimecrolimus (at 0.6 and 1%). The main adverse event in these studies has been a burning sensation and increased pruritus at the site of application. Typically, these adverse events are observed only during the first days of treatment. Long-term safety studies, of up to one year, have not revealed any new adverse events. So far, long-term use of topical noncorticosteroid compounds has not been associated with signs of immune deficiency. Although there is currently no evidence for clinically relevant, prolonged adverse effects, some of these, such as an increased risk of photocarcinogenesis, need to be monitored. There is evidence from tacrolimus studies that monotherapy results in better long-term results when compared with combination therapy with corticosteroids. Tacrolimus and pimecrolimus could replace topical corticosteroids as the first-line treatment of atopic dermatitis.     

Topical calcineurin inhibitors in the treatment of atopic dermatitis - an update on safety issues

Atopic dermatitis is a common chronic skin disorder whose management is complex. Topical corticosteroids have been the mainstay of atopic dermatitis treatment for more than 50 years but have multiple side effects. Topical calcineurin inhibitors including tacrolimus and pimecrolimus are safe and efficacious in atopic dermatitis. In 2005 the FDA issued "black box" warnings for pimecrolimus cream and tacrolimus ointment because of potential safety risks, including skin cancers and lymphomas. However, these concerns are not supported by current data. Topical calcineurin inhibitors are particularly indicated for treating patients with atopic dermatitis in whom topical corticosteroid therapy cannot be employed or may cause irreversible side effects. They can be used advantageously in problem zones. A novel regimen of proactive treatment has been shown to prevent, delay and reduce exacerbations of atopic dermatitis. Therapy with topical calcineurin inhibitors should be managed by an experienced specialist and each patient should receive proper education on how to use them and what possible unwanted effects may be expected.     

The treatment of atopic dermatitis in adults with topical calcineurin inhibitors

In about 60% of cases, atopic eczema can persist in adulthood with distinctive clinical features and disease course. The introduction of the topical calcineurin inhibitors pimecrolimus 1% cream and tacrolimus 0.03 and 0.1% ointment clearly improves the long-term management of atopic eczema in adult patients; this has been shown in several large clinical studies and is confirmed by the growing practical experience with these substances. Topical calcineurin inhibitors are, even when applied for weeks and months, safe, well tolerated and efficient; they have a rapid and positive effect on pruritus and the potential--as shown in clinical studies with pimecrolimus 1% cream--to reduce the number of eczema flares, to significantly prolong the time to a first flare and to reduce or even eliminate the need for topical corticosteroids.     

Calcineurin Inhibitors in Pediatric Atopic Dermatitis

Atopic dermatitis (AD) is a common, chronic inflammatory dermatosis with a prevalence of 7-21% in school-aged children. Childhood AD has a profound impact on the social, personal, emotional, and financial perspectives of families. For the last half-century, topical corticosteroids of different potencies have been the mainstay of topical therapy. In recent years, two topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, have become available for the treatment of AD. Both tacrolimus and pimecrolimus have been extensively evaluated in the management of pediatric AD. Trials comparing them with placebo, topical corticosteroids, and each other have shown them to be effective and safe for continuous short-term use, and for noncontinuous use for up to 4 years. Long-term safety of TCIs is not known as they have been in clinical use for less than a decade.     

外用钙调磷酸酶抑制剂治疗面部脂溢性皮炎

脂溢性皮炎是一种常见的炎症性皮肤病,以红斑、鳞屑、不同程度瘙痒为特征,好发于皮脂腺分泌旺盛部位,给患者的生活、工作带来影响.由于其具有慢性、复发性的特点,更需要一种安全有效的、可以长期使用的治疗手段.过去,脂溢性皮炎的治疗主要为抗真菌药、角质剥脱剂和糖皮质激素.近年,外用免疫调节剂成为慢性炎症性皮肤病的新型治疗方法.多项脂溢性皮炎的临床研究表明,钙调磷酸酶抑制剂,如他克莫司、吡美莫司治疗面部脂溢性皮炎安全有效.     

Topical pimecrolimus in the treatment of genital lichen planus: a prospective case series

BACKGROUND: A potent topical steroid is the conventional therapy for genital lichen planus (GLP). Side-effects or steroid resistance can be encountered and second-line therapy such as topical tacrolimus may be required. In our experience tacrolimus may be poorly tolerated in genital skin because of a burning sensation. In addition, there is impairment of Langerhans cell function, raising concerns about its long-term use. These adverse effects may not be as marked with pimecrolimus. To our knowledge, pimecrolimus has not been used in the treatment of GLP. OBJECTIVES: To assess the efficacy and tolerability of topical pimecrolimus in the treatment of GLP. METHODS: Eleven women with GLP were recruited: 10 had erosive vulval disease and one had classical lichen planus of perianal skin. Ten patients had poor disease control, and despite using topical steroids appropriately, two of these also had steroid-related side-effects in adjacent unaffected skin. The eleventh patient had adequate disease control but marked steroid atrophy. Topical pimecrolimus 1% cream (Elidel cream; Novartis, Camberley, U.K.) was applied twice daily to affected areas. Patients were followed up between 4 and 6 weeks later. They remain under regular review and at the time of writing mean follow-up is 5.2 months (range 2-10). RESULTS: Nine patients (82%) tolerated pimecrolimus, including three patients previously intolerant of tacrolimus. These nine patients showed a clinical response at 4-6 weeks: two showed a complete response with no residual disease activity visible and seven had a partial response. With longer follow-up, six (55%) of the women had a complete response and three (27%) were considered to have a partial response. Eight patients noted symptomatic improvement and one felt that her symptoms were the same as with steroid use. Two patients (18%) with erosive lichen planus were unable to tolerate pimecrolimus due to local irritation. CONCLUSIONS: We have found that topical pimecrolimus 1% cream is an effective treatment for GLP. Local irritation can limit its use, but it may be better tolerated than topical tacrolimus: three of our complete responders had previously been intolerant of tacrolimus. Topical pimecrolimus may be a valuable second-line treatment for patients with steroid-related side-effects or steroid-resistant GLP.     

外用钙调磷酸酶抑制剂治疗面部脂溢性皮炎

脂溢性皮炎是一种常见的炎症性皮肤病,以红斑、鳞屑、不同程度瘙痒为特征,好发于皮脂腺分泌旺盛部位,给患者的生活、工作带来影响.由于其具有慢性、复发性的特点,更需要一种安全有效的、可以长期使用的治疗手段.过去,脂溢性皮炎的治疗主要为抗真菌药、角质剥脱剂和糖皮质激素.近年,外用免疫调节剂成为慢性炎症性皮肤病的新型治疗方法.多项脂溢性皮炎的临床研究表明,钙调磷酸酶抑制剂,如他克莫司、吡美莫司治疗面部脂溢性皮炎安全有效.     

外用钙调磷酸酶抑制剂治疗面部脂溢性皮炎

脂溢性皮炎是一种常见的炎症性皮肤病,以红斑、鳞屑、不同程度瘙痒为特征,好发于皮脂腺分泌旺盛部位,给患者的生活、工作带来影响.由于其具有慢性、复发性的特点,更需要一种安全有效的、可以长期使用的治疗手段.过去,脂溢性皮炎的治疗主要为抗真菌药、角质剥脱剂和糖皮质激素.近年,外用免疫调节剂成为慢性炎症性皮肤病的新型治疗方法.多项脂溢性皮炎的临床研究表明,钙调磷酸酶抑制剂,如他克莫司、吡美莫司治疗面部脂溢性皮炎安全有效.     

Potential new indications of topical calcineurin inhibitors

The topical calcineurin inhibitors pimecrolimus (Elidel) and tacrolimus (Protopic) were initially developed for the treatment of atopic eczema (atopic dermatitis), a chronic or chronically relapsing skin condition most prevalent in infants and children. Their main advantages compared with conventional topical corticosteroid therapy are that they are more selective in their mode of action, do not induce skin atrophy and are not associated with significant systemic absorption. In addition, topical calcineurin inhibitors may represent a useful alternative to topical corticosteroids for the treatment of a number of other inflammatory skin diseases. Preferred sites for the use of topical calcineurin inhibitors are areas such as the face, neck, flexures, and genital areas, which are more susceptible to topical corticosteroid side effects. The efficacy of topical calcineurin inhibitors has been demonstrated for flexural psoriasis, seborrhoeic, contact and hand eczema. Preliminary data also support the efficacy of topical calcineurin inhibitors in lichen planus, facial lupus erythematosus, autoimmune bullous dermatosis, and vitiligo. In these latter indications, controlled studies are needed to better understand the efficacy and safety of topical calcineurin inhibitors and their role in disease management.     

Impact of Topical Calcineurin Inhibitors on Quality of Life in Patients with Atopic Dermatitis

This review considers randomized trials of topical calcineurin inhibitors in atopic dermatitis that have included quality-of-life (QOL) data. Relatively few trials were identified and several different QOL measures have been used, partly because trial subjects included adults, children, and the parents of affected infants. Tacrolimus 0.1% and 0.03% ointment and pimecrolimus 1% cream were found to be superior to vehicle treatment in terms of QOL for active AD. In adults, tacrolimus 0.1% ointment provided a greater improvement in QOL than the 0.03% strength. Pimecrolimus 1% cream was superior to vehicle treatment for flare prevention in the studies that contained QOL outcomes but no data are available for tacrolimus ointment in this regard. QOL data comparing topical calcineurin inhibitors with other active treatments such as topical corticosteroids are sparse and it would be useful for future randomized trials to include QOL measures as a primary outcome.     

Four Cases of Facial Discoid Lupus Erythematosus Successfully Treated with Topical Pimecrolimus or Tacrolimus

Discoid lupus erythematosus (DLE), which is a cutaneous form of lupus erythematosus (LE), is generally refractory to a wide range of topical or systemic therapies. Although the main treatment option for DLE is topical steroids, it is often ineffective or likely to produce long-term side effects. New drugs, including tacrolimus and pimecrolimus, have been developed to overcome the adverse effects of steroids and treat the lesions of DLE for a prolonged period. We herein report 4 cases of facial DLE successfully treated with therapeutic adjuvants, topical tacrolimus or pimecrolimus.     

Topical pimecrolimus and tacrolimus do not accelerate photocarcinogenesis in hairless mice after UVA or simulated solar radiation

Abstract:  Pimecrolimus and tacrolimus are topical calcineurin inhibitors developed specifically for the treatment of atopic eczema. Experience with long-term use of topical calcineurin inhibitors is limited and the risk of rare but serious adverse events remains a concern. We have previously demonstrated the absence of carcinogenic effect of tacrolimus alone and in combination with simulated solar radiation (SSR) on hairless mice. The aim of this study is to determine whether pimecrolimus accelerates photocarcinogenesis in combination with SSR or pimecrolimus and tacrolimus accelerate photocarcinogenesis in combination with UVA. We used 11 groups of 25 hairless female C3.Cg/TifBomTac immunocompetent mice ( n  = 275). Pimecrolimus cream or tacrolimus ointment was applied on their dorsal skin three times weekly followed by SSR (2, 4, or 6 standard erythema doses, SED) or UVA (25 J/cm²) 3–4 h later. This was done up to 365 days in the SSR-treated groups and up to 500 days in the UVA-treated groups. Pimecrolimus did not accelerate the time for development of the first, second or third tumor in any of the groups. Median time to the first tumor was 240 days for the control-2SED group compared with pimecrolimus-2SED group (233 days), control-4SED group (156 days) compared with pimecrolimus-4SED group (163 days) and control-6SED group (162 days) compared with pimecrolimus-6SED group (170 days). Only one mouse in each of the three UVA groups developed a tumor. We conclude that pimecrolimus in combination with SSR and both pimecrolimus and tacrolimus in combination with UVA do not accelerate photocarcinogenesis in hairless mice.     

Calcineurin Inhibitors

Cyclosporine A (CsA), tacrolimus and pimecrolimus are calcineurin inhibitors that affect T cell function and growth. CsA and tacrolimus have been used for the treatment of autoimmune blistering diseases, but are limited by a number of side effects including renal toxicity and hypertension. Several small studies indicate that oral CsA, used in lower doses, can be effective in controlling blister formation in patients with autoimmune bullous diseases while minimizing systemic toxicity. In addition, topical intraoral CsA solution has been effective for controlling mouth blisters and erosions in these patients. To date little information exists on the use of tacrolimus, but it is believed that this agent also could be effective for treating autoimmune bullous disorders. This article outlines the effects and side effects of CsA, tacrolimus and pimecrolimus and reviews their utility in the treatment of autoimmune blistering diseases.     

Topical pimecrolimus and tacrolimus transiently induce neuropeptide release and mast cell degranulation in murine skin

BACKGROUND: The topical calcineurin inhibitors pimecrolimus and tacrolimus have been demonstrated to be an effective new anti-inflammatory therapy. The only clinically relevant side-effect reported is transient application site burning and stinging itch at the beginning of topical therapy. OBJECTIVES: In order to understand the underlying mechanism of this effect, we examined whether or not the compounds are able to stimulate neuropeptide release in normal murine skin as well as in a mouse model of experimentally induced irritant contact dermatitis. METHODS: Balb/c mice were treated with 1% pimecrolimus cream or 0.1% tacrolimus ointment. Untreated and corresponding vehicle-treated mice served as controls. Skin specimens were investigated by light, immunofluorescence and electron microscopy as well as enzyme-linked immunosorbent assay and polymerase chain reaction. RESULTS: Topical application of pimecrolimus and tacrolimus was followed by an initial release of substance P and calcitonin gene-related peptide from primary afferent nerve fibres in murine skin during the early inflammatory response. The release of the neuropeptides and their binding to mast cells (MCs) led to MC degranulation. Mediators of MCs such as histamine and tryptase may induce pruritus and burning by binding to the corresponding receptors (histamine receptor 1, proteinase-activated receptor 2) on sensory nerve fibres, which explains the initial side-effects during therapy with calcineurin inhibitors. CONCLUSIONS: It may be speculated that calcineurin inhibitors directly stimulate intracellular signalling pathways or bind to ion channels such as transient receptor potential vanilloid 1 or receptors involved in nociception.