tacrolimus and Skin-Diseases

The purpose of this study was to review currently available literature data concerning pathomechanisms of action, indications, treatment efficacy, as well as side effects of nonsteroidal immunomodulators used in dermatology, primarily for the treatment of allergic dermatoses. MEDLINE search was undertaken using the key words "Topical Immunomodulators, Dermatology and Allergy". Full articles, and nothing but full articles, were used.

Topics: Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Humans; Hypersensitivity; Immunologic Factors; Skin Diseases; Tacrolimus

Topics: Adalimumab; Adult; Anti-Inflammatory Agents; Breast; Cellulitis; Crohn Disease; Diagnosis, Differential; Female; Groin; Humans; Immunosuppressive Agents; Recurrence; Skin Diseases; Tacrolimus; Treatment Outcome

There have been many new developments in therapeutic modalities for the treatment of pediatric dermatological diseases in the past year. Advances in the treatment of atopic dermatitis, psoriasis, infantile hemangiomas and dystrophic epidermolysis bullosa will be discussed. The following review will update the reader on these exciting new possibilities for patient care and future directions for research to improve the lives of children suffering from skin diseases.. This review will discuss recent articles describing the use of topical tacrolimus for maintenance of remission in atopic dermatitis, utility of nurse educators in atopic dermatitis, safety and efficacy of etanercept for the treatment of psoriasis in children, narrow band ultraviolet B phototherapy for atopic dermatitis and psoriasis, use of topical timolol for infantile hemangiomas and bone marrow transplantation for dystrophic epidermolysis bullosa.. There are many new interesting, potentially useful therapeutic modalities emerging in pediatric dermatology. New treatments for atopic dermatitis, psoriasis, infantile hemangiomas and dystrophic epidermolysis bullosa are reviewed.

Topics: Adrenergic beta-Antagonists; Child; Dermatitis, Atopic; Epidermolysis Bullosa Dystrophica; Etanercept; Hemangioma; Humans; Immunoglobulin G; Immunosuppressive Agents; Pediatrics; Psoriasis; Receptors, Tumor Necrosis Factor; Skin Diseases; Skin Neoplasms; Tacrolimus; Timolol; Ultraviolet Therapy; Vitamin D; Vitamins

Topical tacrolimus and pimecrolimus are indicated for treatment of atopic dermatitis, but they have been studied in many off-label uses. Double-blind and open studies have shown favorable results with topical tacrolimus and pimecrolimus in oral lichen planus. In 1 study of oral lichen planus, blood tacrolimus was detected in 54% of patients, but there were no signs of systemic toxicity. Double-blind and open studies of vitiligo have shown favorable results with tacrolimus in combination with excimer laser, especially for lesions over bony prominences and on extremities. Similarly, double-blind studies of vitiligo have shown favorable results when pimecrolimus is combined with narrow-band UVB, especially for facial lesions. Double-blind and open studies of psoriasis have shown favorable results for tacrolimus and pimecrolimus, especially for inverse psoriasis. Topical calcineurin inhibitors have been effective in many other cutaneous disorders, and further studies would help clarify their roles.

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Child; Child, Preschool; Crohn Disease; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Lichen Planus, Oral; Lupus Erythematosus, Cutaneous; Male; Off-Label Use; Psoriasis; Rosacea; Skin Diseases; Tacrolimus; Therapies, Investigational; Vitiligo

Tacrolimus ointment has shown efficacy as monotherapy in both short- and long-term studies in atopic dermatitis. Absorption of tacrolimus after topical application is dependent on the barrier function of the skin. Absorption through the intact epidermis is very low and eczematic skin a little higher. In comparison to systemic tacrolimus used for prevention and treatment of rejection after organ transplantation, the bioavailability of topical tacrolimus in patients with atopic dermatitis is between 3 and 4%. Long-term safety studies of up to 4 years have not shown adverse events associated with systemic use of immunosuppressive agents, that is, increased risk of infections, lymphomas or skin cancers. Despite these findings, many physicians remain concerned about possible long-term malignancies associated with long-term treatment with a topical calcineurin inhibitor.. To identify in the published literature possible long-term safety issues associated with topical tacrolimus treatment.. PubMed was used to identify studies of atopic dermatitis therapy in which tacrolimus ointment was used for at least 6 months. We evaluated the safety data available from these studies. In addition, some safety data were evaluated from clinical follow-up of our own patients who have used tacrolimus ointment intermittently for up to 14 years.. During a follow-up period of 4 years in clinical studies, no increased risk of infections or cancer was associated with long-term use of tacrolimus ointment. Only short-term adverse events were detected. They included increased burning and stinging of the skin, and a temporary increase in skin infections. No signs of immunosuppression were observed after 1 - 4 years of intermittent treatment with tacrolimus ointment.

Topics: Administration, Topical; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Skin Diseases; Skin Neoplasms; Tacrolimus

The disseminated cutaneous granulomatosis (DCG) are heterogeneous cutaneous diseases histologically characterized by a granulomatous infiltrate. The most frequent cutaneous granulomatosis is sarcoidosis, but many other causes can be found, because DCG are probably a skin granulomatous reaction to different stimuli: infectious, inflammatory, neoplastic, metabolic or chemical. The histopathological examination is useful for the diagnosis of DCG, but gives rarely an etiological diagnosis. In this article, we will propose a strategy for the etiological diagnosis of DCG, and propose therapeutic recommendations based on recent data from the literature.

Topics: Administration, Cutaneous; Biopsy; Dermatologic Agents; Drug Therapy, Combination; Granuloma Annulare; Granulomatous Disease, Chronic; Humans; Immunosuppressive Agents; Phototherapy; Practice Guidelines as Topic; Retinoids; Sarcoidosis; Skin Diseases; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

Repeated courses of potent topical corticosteroids and maintenance therapy with moderately potent topical corticosteroids are frequently needed to treat various forms of vulvar dermatoses, which are often characterized by an abnormal proliferation or activation of T lymphocytes. Because such therapeutic regimen is associated with an increased risk of potential side effects, particularly skin atrophy, an anti-inflammatory alternative to topical corticosteroids is desirable. The two non-steroid topical calcineurin inhibitors pimecrolimus and tacrolimus are immunomodulators that block the release of inflammatory cytokines from T lymphocytes in the skin while promoting cutaneous innate host defences. They are currently approved in Europe and in the United States of America as second-line anti-inflammatory agents for the treatment of atopic dermatitis. We provide a comprehensive summary of existing case reports, series of cases, and open-label prospective studies concerning the use of topical pimecrolimus and tacrolimus for the treatment of anogenital lichen sclerosus, genital lichen planus, vulvar lichen simplex chronicus and related pruritic vulvar dermatoses (chronic vulvar pruritus and allergic contact dermatitis of the vulva). The available data suggest that both topical calcineurin inhibitors may be effective and well tolerated in these vulvar dermatoses, although topical pimecrolimus may exhibit a better long-term tolerability profile. Being devoid of steroid-related side effects, they may represent a useful second-line therapeutic option for patients who are intolerant of, or resistant to topical corticosteroids. Controlled clinical trials and comparative studies are warranted to substantiate the promising findings summarized in this review.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Female; Humans; Middle Aged; Skin Diseases; Tacrolimus; Vulvar Diseases

Topical tacrolimus is an immunosuppressant that acts through the inhibition of calcineurin and thus of the T cells. This causes a decrease in the production of interleukins, the granulocyte colony stimulating factor, alpha interferon and tumor necrosis factor. Although the use of topical tacrolimus is only indicated for the treatment of moderate or severe atopic dermatitis, its immunosuppressant effect and fewer side effects regarding topical corticosteroids have lead to the increase of its use in other types of inflammatory skin diseases. The purpose of this article is to review the use of tacrolimus in this group of diseases other than atopic dermatitis, this use not being authorized within the data sheet of the drug.

Topics: Adult; Autoimmune Diseases; Child; Clinical Trials as Topic; Dermatitis; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lichenoid Eruptions; Multicenter Studies as Topic; Off-Label Use; Pruritus; Psoriasis; Pyoderma Gangrenosum; Skin Diseases; Tacrolimus; Uremia; Vitiligo

The topical calcineurin inhibitors (TCIs) pimecrolimus and tacrolimus are approved for atopic dermatitis but have additional potential in other inflammatory skin diseases. This article reviews their clinical use in non-atopic dermatitis diseases. In seborrheic dermatitis, asteatotic eczema, and contact dermatitis, TCIs are of great benefit and can compete with topical corticosteroids. In psoriasis, TCIs have shown clinical efficacy and safety in facial and intertriginous lesions. Further investigations into possible combinations of TCIs with other established treatments such as UVB irradiation in this disorder are necessary. Initial studies in cutaneous lupus erythematosus have been promising, whereas the response in rosacea and rosacea-like eruptions has been mixed. TCIs have been associated with good clinical responses in oral lichen planus and anogenital lichen sclerosus et atrophicus. In vitiligo, TCIs are associated with some degree of repigmentation, with better results being seen in children and in facial and neck areas. TCIs have a synergistic effect with UVB irradiation in vitiligo. There is a long list of small series and case reports documenting use of TCIs in various other skin conditions that warrant further validation. Although the established mode of action of TCIs is T-cell control, other effects also need to be considered. Specifically, TCIs reduce pruritus and erythema, which cannot be explained by T-cell interactions, and further investigations are needed in these fields.

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus

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.

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Clinical Trials as Topic; Humans; Immunosuppressive Agents; Male; Skin Diseases; Tacrolimus

Pimecrolimus is an immune downregulator that belongs to the class of calcineurin inhibitors. Its efficacy is recognized for the topical treatment of the mild to moderate types of atopic dermatitis. In addition, the drug shows activity in a series of other dermatitides. We report a review of the international literature about this topic.

Topics: Dermatologic Agents; Humans; Skin Diseases; Tacrolimus

Using a newly developed model of allergic contact dermatitis in pigs, calcineurin inhibitors of the tacrolimus and ascomycin type were shown to have a highly anti-inflammatory action after topical application. These findings provided the first pharmacological evidence of the efficacy of this novel class of topical agents in the treatment of inflammatory skin diseases, and, thus, their potential to become the first alternative to corticosteroids in more than 40 years. As a result of a large research program into ascomycins, pimecrolimus (Elidel(R), SDZ ASM 981) was selected for development due to its favorable pharmacology and safety profile, alongside tacrolimus (Protopic(R), FK 506). In vitro, pimecrolimus inhibits the transcription and release of pro-inflammatory cytokines in T cells. Similar to the corticosteroids, betamethasone-17-valerate and dexamethasone, pimecrolimus is effective at nanomolar concentrations. Targeting mainly T cells, pimecrolimus has, however, a more specific mode of action. Moreover, in contrast to corticosteroids, pimecrolimus has no effect on Langerhans' cells, the professional antigen- presenting dendritic cells of the skin that are crucial for local immunosurveillance. When applied topically, pimecrolimus exerts a high and selective anti-inflammatory activity in the skin, shows minimal percutaneous absorption, and has a low potential to affect systemic immunoreactions. Pimecrolimus cream 1% has proven to be well tolerated, safe, and highly effective in clinical studies in patients with atopic dermatitis.

Topics: Administration, Topical; Animals; Calcineurin Inhibitors; Dermatologic Agents; Disease Models, Animal; Humans; Skin Diseases; Swine; Tacrolimus

Pimecrolimus is an ascomycin macrolactam. It is a specific calcineurin inhibitor that allows topical application. The highly lipophilic nature of this compound reduces the risk of systemic absorption through normal and inflammed skin. Pimecrolimus shows activity not only against T-cell activation, but also against mast cells and pruritus. Pimecrolimus 1% cream is approved for atopic dermatitis, and also has a great potential in other inflammatory skin diseases. Clinical trials have been performed in contact- and seborrhoeic dermatitis, genital lichen sclerosus, intertriginous psoriasis and cutaneous lupus erythematosus. In other diseases, the available data are limited to small case series, or individual cases of graft-versus-host disease or Netherton's disease. Although the use of calcineurin inhibitors in the treatment of vitiligo is promising, detailed studies with pimecrolimus and ultraviolet-irradiation are necessary and there is a need for prospective randomised, double-blind controlled trials.

Topics: Administration, Topical; Adolescent; Adult; Aged; Animals; Child; Dermatologic Agents; Evidence-Based Medicine; Female; Humans; Male; Randomized Controlled Trials as Topic; Skin Diseases; Tacrolimus; Treatment Outcome

Topics: Administration, Cutaneous; Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus

THE EFFICACY OF THE 308 NM EXCIMER LASER in the treatment of common psoriasis has been demonstrated. THE DOSES USED have progressively decreased, hence, limiting the adverse events that appear redhibitory with high doses. THE ADAPTATION OF THE DOSES not to the patients themselves but to each of the plaques treated should reduce the number of sessions and the cumulated close necessary to obtain clinical remission. THE 308 NM EXCIMER LASER is effective and tolerance is good in the treatment of vitiligo. It should be proposed for limited vitiligo and essentially of the "UV sensitive" areas, which have shown aesthetically correct percentage of repigmentation. THE PLACE AND INTEREST of its association with other treatments, notably with topical tacrolimus, remains to be defined. Although the results obtained in the treatment of vitiligo are promising, they have to be confirmed in larger cohorts and ensure the absence of median and long term side effects. This therefore limits its use in combined treatments in the context of controlled clinical traits. THE 30 NM EXCIMER LASER IS AN EFFECTIVE AND WELL TOLERATED TREATMENT in localised and non-nodular forms of mycosis fungoid (MF). Although the number of patients treated is limited, the clinical and histological cure observed demonstrates the interest of this new technique in the treatment of MF. These results must be confirmed in a greater number of patients. THE 308 NM EXCIMER LASER is an interesting therapeutic alternative in the treatment of plaques of alopecia areata, erosive oral lichen planus, post-surgical hypopigmentation, vergetures and localised forms of atopic dermatitis. Because of the sparcity of data and in the absence of long term follow-up, it must not be proposed in first intention.

Topics: Administration, Topical; Humans; Immunosuppressive Agents; Laser Therapy; Mycosis Fungoides; Phototherapy; Pilot Projects; Radiotherapy Dosage; Skin Diseases; Tacrolimus; Time Factors; Ultraviolet Therapy; Vitiligo

Tacrolimus ointment (Protopic) is a topically applied macrolide lactone immunomodulator effective in the treatment of atopic dermatitis. Its mechanism of action primarily involves calcineurin inhibition, which interrupts cytokine gene expression and leads to the downregulation of T-cell activity. Tacrolimus ointment (0.03% and 0.1% for adults and 0.03% for children) is an effective treatment for atopic dermatitis of the trunk and limbs, as well as sensitive skin areas such as the face. Its efficacy is similar to or greater than that of hydrocortisone acetate 1%, hydrocortisone butyrate 0.1% and betamethsone valerate 0.12% ointments and pimecrolimus 1% cream. Systemic absorption of tacrolimus from the ointment is minimal, and adverse events, which are mostly associated with the application site and include skin burning and pruritus, tend to resolve early in treatment. Unlike topical corticosteroids, tacrolimus ointment is not associated with skin atrophy, and it is a well tolerated treatment for adults or children with atopic dermatitis, particularly when long-term treatment is indicated or the face or skin-fold regions are involved.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Skin Diseases; Tacrolimus

Common pediatric skin conditions such as infantile atopic dermatitis, vitiligo, hemangiomas of infancy, warts, and molluscum contagiosum do not always respond to standard therapy. In some settings pediatricians will use "off-label" medications if the benefit-to-risk ratio is favorable. This article reviews important literature from the past year related to "off-label" immune-based treatment of skin disease, using the topical immunomodulators tacrolimus, pimecrolimus, and imiquimod, as well as intravenous Ig.. The topical immunomodulators tacrolimus and pimecrolimus have been embraced by pediatricians as long awaited alternatives for treating atopic dermatitis in children 2 years of age and older. Their unique appeal as nonsteroidal topical agents with good safety profiles has led to their frequent use for unapproved indications. A number of recent publications detail their use in infantile atopic dermatitis in children as young as 3 months of age, as well as use in other conditions such as vitiligo. Imiquimod, another topical immunomodulator, approved for genital wart treatment in adults, has also been examined for "off-label" pediatric use in nongenital warts, molluscum contagiosum, hemangiomas of infancy, and basal cell carcinoma. Finally, "off-label" use of intravenous Ig has been evaluated for the life-threatening dermatoses Stevens-Johnson syndrome and toxic epidermal necrolysis.. In the absence of larger controlled trials, pediatricians must consider the cumulative weight of smaller studies with their personal experience when assessing any role for "off label" therapy. The recent literature reviewed herein will facilitate such assessments of the non-steroid topical immune modifiers tacrolimus, pimecrolimus, and imiquimod as well as intravenous immunoglobulin.

Topics: Adjuvants, Immunologic; Aminoquinolines; Child; Clinical Trials as Topic; Dermatitis, Atopic; Hemangioma; Humans; Imiquimod; Immunoglobulins; Immunologic Factors; Immunosuppressive Agents; Infant; Molluscum Contagiosum; Skin; Skin Diseases; Stevens-Johnson Syndrome; Tacrolimus; Vitiligo; Warts

Topical tacrolimus (FK506, Protopic) has been developed and marketed for the treatment of atopic dermatitis (AD). Tacrolimus works as an inhibitor of calcineurin, which creates a downregulation of the inflammatory cascade. Numerous trials have shown the efficacy and safety of tacrolimus in treating AD in both adults and children. Additionally, comparison data with other medications commonly used for AD, such as topical steroids and pimecrolimus, show improved efficacy of tacrolimus. A comprehensive review of the off-label uses of tacrolimus in other dermatoses, including psoriasis, lichen planus and seborrhoeic dermatitis, is provided. The efficacy of tacrolimus in treating these diseases is based on Phase IV clinical trials and on case reports or series in the literature. Overall, tacrolimus has proven to be a safe and useful topical therapy for many inflammatory dermatological conditions, with AD being the principal indication.

Topics: Adult; Calcineurin Inhibitors; Child; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Skin Diseases; Tacrolimus

Pimecrolimus is the most recent member of calcineurin inhibitors available for the therapy for inflammatory skin diseases. It targets T-cells and mast cells and inhibits the production and release of cytokines and other inflammatory mediators, as well as the expression of signals essential for the activation of inflammatory T-lymphocytes. Pimecrolimus has a cell-selective mode of action. In contrast to corticosteroids, it does not affect, e.g., Langerhans'cells/dendritic cells (LC/DC), as demonstrated in vitro with human monocyte-derived DC and in vivo with epidermal LC in mice, nor human primary fibroblasts. As shown in vitro with human skin and by comparison of clinical pharmacokinetic data from patients with atopic dermatitis, pimecrolimus permeates less through skin than tacrolimus and much less than corticosteroids. It, thus, has a lower potential for transcutaneous resorption after topical administration, resulting in a lower risk of systemic effects. Pimecrolimus has high anti-inflammatory activity in animal models of skin inflammation, including a model reflecting neurogenic inflammation, but a more favourable balance of anti-inflammatory vs. immunosuppressive activity than tacrolimus. Pimecrolimus does not affect sensitization in a murine model of allergic contact dermatitis and has a lower potency in various models of immunosuppression after systemic administration, compared to tacrolimus. In conclusion, the results of preclinical studies show that pimecrolimus has a selective pharmacological profile, suited for effective and safe treatment for inflammatory skin diseases.

Topics: Animals; Anti-Inflammatory Agents; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Inflammation; Risk; Skin; Skin Diseases; T-Lymphocytes; Tacrolimus; Time Factors

Within the last decade, healthcare providers have had a larger selection of effective novel topical immunomodulatory agents to treat many dermatologic conditions. Novel mechanisms of action of newer topical agents have facilitated differentiation from well-established topical agents such as corticosteroids and 5-fluorouracil. Further, because of a growing understanding of the immune mechanisms within the skin, the opportunity has arisen to use the body's immune system to effectively treat many dermatologic conditions, such as condyloma acuminata, actinic keratosis, basal cell carcinoma, and atopic dermatitis, while maintaining a favorable safety profile. Imiquimod 5% cream, an immune response modifier, is safe and effective in the treatment of condyloma acuminata, actinic keratosis, and primary superficial basal cell carcinoma (sBCC). Pimecrolimus cream 1% and tacrolimus ointment (0.1% and 0.03%) are safe and effective in the treatment of atopic dermatitis. This review highlights newer data on approved and investigational indications for these topical immunomodulatory agents.

Topics: Adjuvants, Immunologic; Administration, Topical; Aminoquinolines; Condylomata Acuminata; Dermatitis, Atopic; Dermatitis, Seborrheic; Humans; Hutchinson's Melanotic Freckle; Imiquimod; Keratosis; Melanoma; Membrane Glycoproteins; Receptors, Cell Surface; Skin Diseases; Skin Diseases, Viral; Skin Neoplasms; Tacrolimus; Toll-Like Receptors

Immune response modifiers (IRMs) are agents that target the body's immune system (i.e., cytokines, receptors, and inflammatory cells) to combat disease. Topical IRM therapies, which encompass both proinflammatory and immunosuppressive therapeutics, have been used to successfully treat a number of dermatologic conditions. Proinflammatory treatments include Toll-like receptor agonists (e.g., imiquimod 5% cream) and interferon (e.g., interferon-alpha) therapies, which have been used in the treatment of external genital warts, basal cell carcinoma, and other dermatologic diseases. Immunosuppressive therapies include topical and intralesional corticosteroids, anti-tumor necrosis factor agents (e.g., infliximab and etanercept), and anti-CD4+ T-cell agents, including calcineurin inhibitors and mycophenolate. These agents have been used to treat a number of conditions, including atopic and seborrheic dermatitis and psoriasis. This article reviews the mechanism of action of IRMs and the application of IRMs in several dermatologic diseases.

Topics: Adjuvants, Immunologic; Alefacept; Aminoquinolines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcineurin Inhibitors; CD11 Antigens; Dermatitis, Atopic; Glucocorticoids; Humans; Imiquimod; Interferons; Membrane Glycoproteins; Mycophenolic Acid; Psoriasis; Receptors, Cell Surface; Recombinant Fusion Proteins; Skin Diseases; Tacrolimus; Toll-Like Receptors

Topical corticosteroids (TCC) have significantly shaped dermatological therapy for five decades. A few months ago the TCC were joined by competition, the topical inhibitors of calcineurin (TIC), wrongly termed topical immunomodulators. The present paper reviews the pharmacological effects and clinical efficacy of TIC, compares the risks, benefits and costs of those two groups of topical drugs and develops a position on the use of TIC. While TIC have ushered in a new era of topical anti-inflammatory therapy, the age of TCC is far from over.

Topics: Acute Disease; Administration, Topical; Anti-Inflammatory Agents; Calcineurin Inhibitors; Cyclosporins; Dermatitis, Atopic; Eczema; Facial Dermatoses; Glucocorticoids; Humans; Immunosuppressive Agents; Neurodermatitis; Psoriasis; Pyoderma Gangrenosum; Risk Factors; Skin Diseases; Tacrolimus

This article aims to review the literature on the use of tacrolimus in dermatology. We tried to focus on the local application of tacrolimus. The local application of tacrolimus is known to be effective for several skin diseases, especially atopic dermatitis. Since the major action site of tacrolimus is activated T-lymphocytes, the drug showed efficiency mostly in inflammatory dermatological diseases including psoriasis, lichen planus, alopecia areata and pyoderma gangrenosum. Tacrolimus lacks most of side effects of local steroids and seems to have better results for short and long term application. We presume that tacrolimus will be widely used on skin diseases, especially when it becomes less expensive.

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Lymphocyte Activation; Skin Diseases; T-Lymphocytes; Tacrolimus

Controlled trials and clinical experience indicate that systemic cyclosporin A and tacrolimus are effective treatments for psoriasis, and that cyclosporin A also improves atopic eczema. A variety of other inflammatory and non-inflammatory skin diseases are probably also responsive to these drugs. However, the widespread and longer-term use of cyclosporin A and tacrolimus are limited by side effects. The molecular mechanisms of action of cyclosporin A, tacrolimus and a related drug, sirolimus, have been well defined in T cells and involve inhibition of critical signalling pathways that regulate T cell activation. For example cyclosporin and tacrolimus inhibit calcineurin phosphatase activity and thereby inhibit activation of the transcription factor NFAT. The therapeutic efficacy of topical calcineurin inhibitors in atopic eczema have restimulated interest in the mechanism of action of these drugs in skin disease. Recently the expression pattern of calcineurin and NFAT has been defined in non-immune tissues including the akin. The relevance of this to the mechanism of action of systemic and topical calcineurin inhibitors and sirolimus in skin disorders is discussed.

Topics: Administration, Topical; Calcineurin Inhibitors; Cyclosporins; Humans; Immunosuppressive Agents; Lymphocyte Activation; Sirolimus; Skin Diseases; Tacrolimus

Topics: Administration, Cutaneous; Adult; Animals; Child; Dermatologic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; In Vitro Techniques; Skin; Skin Diseases; Tacrolimus; Time Factors; Treatment Outcome

The newly developed immunomodulator tacrolimus (FK506) is the first of a new class of agents that have enormous potential to change the way that dermatoses are treated and managed. Tacrolimus has been found to be active in a topical formulation with the latter exerting its effects by acting on the signal transduction pathways inside T cells and inhibiting gene transcription. The result is decreased responsiveness of T cells to antigens. Percutaneous absorption of tacrolimus is higher in diseased skin as opposed to healthy skin and, therefore, the drug will be taken in at progressively lower quantities as lesions heal. There is limited systemic absorption of tacrolimus over the course of therapy. The most extensive experience with tacrolimus has been in treating atopic dermatitis. In numerous trials, tacrolimus ointment 0.03-0.3% has shown to be effective in reducing the symptoms and severity of atopic dermatitis in adults and the paediatric population. Furthermore, there have been no significant toxic effects associated with topical therapy with tacrolimus. The most common complaint is that of local irritation after applying the ointment. This is generally transient and the patient is able to continue with therapy. The other dermatoses where tacrolimus has been used include contact dermatitis, psoriasis and pyoderma gangrenosum.

Topics: Administration, Oral; Administration, Topical; Clinical Trials as Topic; Dermatitis, Atopic; Dermatitis, Contact; Female; Humans; Immunosuppressive Agents; Male; Prognosis; Psoriasis; Skin Absorption; Skin Diseases; Tacrolimus; Treatment Outcome

Tacrolimus (FK-506; Fujisawa Pharmaceutical Co Ltd) and pimecrolimus (SDZ-ASM-981; Novartis AG) are topical immunomodulators, which provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Both substances form a complex with cytosolic immunophilins. The complex blocks calcineurin and inhibits the transcription of NF-AT-dependent pro-inflammatory cytokine genes. Multicenter, randomized, double-blind clinical trials have shown the efficacy of both substances in atopic dermatitis. We review the physicochemical characteristics, mode of action, pharmacokinetic data, side effects, results of the clincal trials and further indications for tacrolimus and pimecrolimus.

Topics: Adjuvants, Immunologic; Administration, Topical; Dermatitis, Atopic; Humans; Randomized Controlled Trials as Topic; Skin Diseases; Tacrolimus

Immune modulators are being used with increasing frequency in dermatology. This article reviews two such agents, cyclosporine and tacrolimus. Discussion emphasizes the pharmacology, side effects, and uses of these two drugs in dermatologic disorders.

Topics: Cyclosporine; Dermatologic Agents; Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus

To review the data surrounding the use of tacrolimus for skin disorders.. Articles were obtained through a MEDLINE search of English-language literature (1990-May 2000); references of the retrieved publications were further reviewed for relevant literature.. Orginal studies in humans regarding the use of tacrolimus for skin disorders were included.. The major outcomes extracted from the literature involved patient response to therapy and adverse effects.. Tacrolimus offers an additional therapeutic approach to the treatment of immunologically based skin disorders. led trials and case reports indicates topical tacrolimus is a safe and effective alternative treatment in patients with atopic dermatitis. Case reports document efficacy in recalcitrant pyoderma gangrenosum, mucosal lichen planus, and ichthyosis linearis trolled trials and case reports indicate oral tacrolimus is effective in recalcitrant plaque psoriasis. Case reports document efficacy in recalcitrant pyoderma gangrenosum and leukocytclastic vascultis. The clinical utility of oral tacrolimus in skin disorders is limited due to potentially severe adverse effects such as infections, hypertension, hyperglcemia hyperkalemia, nephrotoxicity neurotoxicity, and increased risk of neoplasia.. Most of the available data indicate short-term (3 wk to 3 mo) topical tacrolimus is a safe and effective treatment alternative for inflammatory skin disorders. Further study is needed to evaluate long-term safety and efficacy and to determine the best dosage regimen. Although oral tacrolimus has demonstrated efficacy in inflammatory skin disorders, the potenial for serious adverse effects limits its utility to third-line therapy for patients who are resistant to, or intolerant of, conventional therapies.

Topics: Administration, Oral; Administration, Topical; Adolescent; Adult; Child; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Randomized Controlled Trials as Topic; Skin Diseases; Tacrolimus

The immunomodulatory macrolactams provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Tacrolimus (FK506), as well as the newer ascomycin derivative ASM 981 (pimecrolimus), penetrate the inflamed epidermis and are suitable for topical therapy. Both substances inhibit the transcription of proinflammatory cytokine genes such as interleukin 2, which are dependent on the nuclear factor NF-AT. They block the catalytic function of calcineurin, which leads to the inhibition of the transport of the cytoplasmic component of NF-AT to the cell nucleus. Multicenter, randomized, double-blind clinical trials with topical formulations have shown the efficacy of both substances in moderate to severe atopic dermatitis. A review is presented of the biochemical and cell biologic properties, mode of action, pharmacokinetic data, side effects, results of the clinical trials, and further indications for tacrolimus and ASM 981, along with an overview of the related substances cyclosporine and sirolimus (rapamycin).

Topics: Administration, Topical; Clinical Trials as Topic; Cyclosporine; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Inflammation; Sirolimus; Skin Diseases; Tacrolimus

The first topical immunomodulator approved for human use, tacrolimus ointment (Protopic, Fujisawa, Healthcare, Inc, Deerfield, IL), has been shown to be effective and safe in the treatment of children (aged 2 years and older) and adults with atopic dermatitis (AD). Clinical trials conducted worldwide have involved 12,000 patients, with safety and efficacy data available for up to 3 years of treatment. In addition to its beneficial effects in the management of AD, topical tacrolimus has also been reported to be of benefit in other immunologically mediated skin diseases including: hand dermatitis, contact dermatitis, eyelid dermatitis, erosive lichen planus, steroid-induced rosacea, pyoderma gangrenosum, and graft-versus-host disease. This article reviews the clinical experience of topical tacrolimus in the treatment of AD and other skin conditions.

Topics: Administration, Cutaneous; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Skin Diseases; Tacrolimus; Treatment Outcome

With the wide acceptance of cyclosporine in the treatment of skin disease, there has been an effort to find new immunomodulating agents with superior safety profiles for use in dermatology. Among the most promising of the classes are the new macrolide immunomodulators, including tacrolimus and pimecrolimus. Of these, only tocrolimus has had widespread use for nondermatologic indications, primarily solid organ transplantation. Both of these agents have been studied for inflammatory diseases of the skin. In this article, we review the systemic and topical toxicities of these macrolide immunomodulators.

Topics: Humans; Macrolides; Skin Diseases; Tacrolimus; Treatment Outcome

During the last decades, systemic and topical glucocorticosteroids assumed a dominant role in immunosuppressive therapy in dermatology. However, their administration is limited because of numerous adverse effects. Consequently, there is a large need for alternative non-steroidal anti-inflammatory therapeutics with a superior risk/benefit ratio. In recent years, a new class of anti-inflammatories, the macrolide lactones, has attracted special interest. During the last decade, a member of this class, tacrolimus, proved to be a powerful suppressor of the immune system. Introduced into clinical practice to prevent allograft rejection, it is now routinely used in organ transplantation. Recently, several placebo-controlled multicenter studies showed the therapeutic efficiency of systemic and topical tacrolimus in common inflammatory skin diseases such as psoriasis and atopic eczema.Short-term tacrolimus ointment therapy disclosed significant efficacy vs. placebo and a safety profile with only few local side effects in patients with atopic eczema. Further clinical trials including greater extent of exposure (experienced by children), and comparison between tacrolimus ointment and glucocorticosteroids are being conducted and the results will show whether this drug opens a new era in the treatment of inflammatory skin disorders. The aim of this review is to summarize the current knowledge regarding the pharmacokinetic properties, adverse effects and therapeutic indications of tacrolimus in dermatology.

Topics: Administration, Topical; Autoimmune Diseases; Female; Humans; Immunosuppressive Agents; Male; Signal Transduction; Skin Diseases; Tacrolimus

The use of immunosuppressive agents in dermatology has increased widely. The role of these medications has become increasingly important for the treatment of dermatologic disorders in an inpatient setting, where there is frequently a requirement for highly potent, fast-acting, effective agents. This article presents an overview of the general application, mechanisms of action, metabolism, and adverse effects commonly associated with systemic immunosuppressive agents used in dermatology.

Topics: Azathioprine; Chlorambucil; Cyclosporine; Humans; Immunosuppressive Agents; Methotrexate; Mycophenolic Acid; Skin Diseases; Tacrolimus; Thioguanine

Ascomycin derivatives represent a novel class of anti-inflammatory macrolactams currently under development for the treatment of skin diseases. The main biological effect of ascomycins is an inhibition of the synthesis of both Th1 and Th2-type cytokines in target cells. Several compounds are being developed with SDZ ASM 981 being at the most advanced stage. It has high anti-inflammatory activity in animal models of skin inflammation and does not induce skin atrophy. Topical application of SDZ ASM 981 was shown to be effective in atopic dermatitis (AD), allergic contact dermatitis and also in psoriasis under semi-occlusive conditions. In patients with AD, SDZ ASM 981 cream led to consistently low systemic exposure even when applied on large areas of skin. SDZ ASM 981 overcomes the drawbacks of current topical therapies of inflammatory skin diseases as its safety profile is better than that of topical corticosteroids. Studies continue to investigate its efficacy and safety in the treatment of inflammatory skin diseases.

Topics: Adult; Animals; Anti-Inflammatory Agents; Child; Clinical Trials as Topic; Dermatitis, Atopic; Dermatitis, Contact; Dermatologic Agents; Drug Evaluation, Preclinical; Humans; Models, Animal; Rats; Skin Diseases; Tacrolimus

Topics: Adjuvants, Immunologic; Humans; Mycophenolic Acid; Skin Diseases; Tacrolimus; Thalidomide

Topics: Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus

Tacrolimus has been shown to be a powerful suppressor of the immune system. It was introduced into clinical use to prevent allograft rejection and is now routinely used in kidney, liver, and heart transplantation. Recently, 2 double-blind multicenter studies demonstrated the therapeutic efficacy of topical and systemic tacrolimus in the inflammatory skin diseases atopic dermatitis and psoriasis.. MEDLINE was searched for relevant publications and combined with our own clinical, in vitro, and in vivo studies.. All studies dealing with tacrolimus and dermatology were reviewed.. Publications with clinically relevant data were included in this review.. Topical tacrolimus is a safe and effective therapeutic agent that may open a new era in the treatment of inflammatory skin diseases, particularly for patients with atopic dermatitis. Before its full potential in dermatology can be assessed, more clinical experience in treating children and comparison with the criterion standard of anti-inflammatory therapy, glucocorticosteroids, are needed.

Topics: Dermatitis, Atopic; Humans; Immunosuppressive Agents; Psoriasis; Skin Diseases; Tacrolimus

Ascomycin derivatives represent a novel class of anti-inflammatory macrolactams that are under development for the treatment of skin diseases. The main biological effect of ascomycins is a blockage of the synthesis of both Th1- and Th2-type cytokines in target cells. SDZ ASM 981 is the most advanced ascomycin derivative under development. It has high antiinflammatory activity in animal models of allergic contact dermatitis and does not induce skin atrophy. Topical application of SDZ ASM 981 has been shown to be effective in atopic dermatitis (AD) and allergic contact dermatitis. Clinical studies using semi-occlusive conditions have also shown effectiveness in psoriasis. SDZ ASM 981 holds promise in overcoming the drawbacks of topical corticosteroids and studies are ongoing to further investigate its efficacy and safety in the treatment of inflammatory skin diseases.

Topics: Animals; Anti-Inflammatory Agents; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus

Drug therapy for the major inflammatory skin diseases, which include atopic dermatitis, psoriasis and allergic contact dermatitis, is often inadequate due to poor efficacy, toxicity, or both. Much research has focused on the macrolactam T cell inhibitors as a promising new class of agents for immunotherapy, and medicinal chemistry efforts to design novel ascomycin analogs have produced clinically promising agents. A synthetic program to modify the ascomycin nucleus to alter its physicochemical properties and promote systemic clearance is described. A biologic screening strategy to identify analogs with reduced systemic activity and rapid pharmacokinetic elimination led to identification of the clinical candidate, ABT-281. A swine contact hypersensitivity model was used as a stringent indicator of skin penetration as human doses of topical corticosteroids produced inhibition only in the 50% range and ED50 values were 100-fold less potent than in rat. Also, cyclosporine was confirmed to be topically inactive in swine, as seen in human. ABT-281 had topical potency equal to tacrolimus (FK506) despite a severalfold lower potency for inhibiting swine T cells in vitro, consistent with superior skin penetration. ABT-281 was found to have a shorter duration of action after i.v. dosing in monkeys using an ex vivo whole blood IL-2 production assay. Systemic potency was reduced by 30-fold or more in rat popliteal lymph node hyperplasia and contact hypersensitivity assays. Following i.v. or i.p. administration in the swine contact hypersensitivity model, ABT-281 was 19- and 61-fold less potent, respectively, than FK506. Pharmacokinetic studies showed that ABT-281 had a shorter half life and higher rate of clearance than FK506 in all three species. The potent topical activity and reduced systemic exposure of ABT-281 may thus provide both efficacy and a greater margin of safety for topical therapy of skin diseases.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Cyclosporine; Dermatitis; Drug Design; Humans; Immunosuppressive Agents; Inflammation; Interleukin-2; Skin Diseases; T-Lymphocytes; Tacrolimus

Cyclosporine and tacrolimus are potent immunosuppressant agents that have been used extensively in humans, primarily for prevention of transplant rejection but also for the treatment of autoimmune disorders. Both agents have similar mechanisms of action and pharmacokinetic profiles. However, the expected toxicity of the agents is dissimilar. Although cyclosporine usage in veterinary medicine is limited, it has been used enough for therapeutic guidelines to be established. Tacrolimus, however, has undergone limited use in veterinary medicine. The drug is too toxic in dogs for its use to be recommended in most clinical situations. This article reviews the mechanism of action, pharmacokinetics, expected drug interactions and toxicities, and clinical usage of cyclosporine and tacrolimus in veterinary medicine.

Topics: Animals; Autoimmune Diseases; Cat Diseases; Cats; Cyclosporine; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Drug Interactions; Eye Diseases; Glomerulonephritis; Graft Rejection; Immunosuppressive Agents; Skin Diseases; Tacrolimus; Transplantation

Sclerotic skin manifestations of chronic graft-versus-host disease (ScGVHD) lead to significant morbidity, including functional disability from joint range of motion (ROM) restriction. No superior second-line therapy has been established for steroid-refractory disease. Imatinib mesylate is a multikinase inhibitor of several signaling pathways implicated in skin fibrosis with in vitro antifibrotic activity. We performed an open-label pilot phase II trial of imatinib in children and adults with corticosteroid-refractory ScGVHD. Twenty patients were enrolled in a 6-month trial. Eight received a standard dose (adult, 400 mg daily; children, 260 mg/m(2) daily). Because of poor tolerability, 12 additional patients underwent a dose escalation regimen (adult, 100 mg daily initial dose up to 200 mg daily maximum; children, initial dose 65 mg/m(2) daily up to 130 mg/m(2) daily). Fourteen patients were assessable for primary response, improvement in joint ROM deficit, at 6 months. Primary outcome criteria for partial response was met in 5 of 14 (36%), stable disease in 7 of 14 (50%), and progressive disease in 2 of 14 (14%) patients. Eleven patients (79%), including 5 with partial response and 6 with stable disease, demonstrated a positive gain in ROM (range of 3% to 94% improvement in deficit). Of 13 patients with measurable changes at 6 months, the average improvement in ROM deficit was 24.2% (interquartile range, 15.5% to 30.5%; P = .011). This trial is registered at http://clinicaltrials.gov as NCT007020689.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Drug Administration Schedule; Fasciitis; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Imatinib Mesylate; Joints; Leukemia; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prednisone; Range of Motion, Articular; Recurrence; Skin Diseases; Tacrolimus; Transplantation, Homologous

Cutaneous Crohn's Disease is a notoriously difficult condition to treat and causes significant morbidity, impacting heavily on quality of life. This is the first study in adults examining the effect of topical tacrolimus on the different cutaneous manifestations of Crohn's Disease.. This open label observational study of 20 patients with heterogeneous forms of cutaneous Crohn's disease used topical tacrolimus 0.1% ointment once daily to affected areas for 12 weeks with a maximal total dose of 90g. Therapy was stopped at 12 weeks to assess whether the condition relapsed. Thereafter relapsing patients optionally continued an open label extension of topical tacrolimus therapy and were observed for a total of 12 months.. Of seventeen patients completing the twelve-week study, fifteen improved using a specifically designed physicians' global severity scale. One patient cleared, four showed a pronounced improvement (51-75%) and ten demonstrated a mild (1-25%) or moderate improvement (25-50%) in twelve weeks. Over twelve months eleven patients remained in the study, nine of which improved, one cleared and one showed no change. Perineal disease responded better with two out of twelve clearing, four showing pronounced benefit and four mild to moderate improvement. Long-term application of 0.1% tacrolimus applied to broken skin and mucosa was safe and serum levels of tacrolimus were undetectable in all subjects throughout the study.. 0.1% tacrolimus ointment was safe and effective in treating cutaneous manifestations of Crohn's disease, particularly perineal disease and pyoderma gangrenosum, yet it seldom cleared the condition.. ClinicalTrials.gov Protocol Registration System ID: 33000332.

Topics: Administration, Topical; Adolescent; Adult; Aged; Child; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Skin Diseases; Tacrolimus; Young Adult

Graft-versus-host disease (GVHD) may be resistant to accepted treatments. Therefore, the aim of the present preliminary study was to evaluate the efficacy of topical treatment with tacrolimus, an immunosuppressive agent, for cutaneous GVHD. Ten patients with chronic steroid-dependent cutaneous GVHD were treated with 0.03-0.1% tacrolimus ointment, twice to three times a day. The dermal manifestations of GVHD were monitored, and a score was given to the cutaneous response by both the physician and patient. Seven patients demonstrated a response to the tacrolimus ointment. Three out of the ten patients were scored as showing a "good" or "complete" response in the objective examiner's view or subjective patient's view. Another four patients showed "moderate" or "mild" response; only three patients showed "no response". Topical tacrolimus is suggested as an alternative treatment for cutaneous chronic steroid-dependent GVHD. This conclusion concurs with a previous study on this medication.

Topics: Administration, Topical; Adult; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Pilot Projects; Retreatment; Skin Diseases; Steroids; Tacrolimus; Treatment Failure; Treatment Outcome

Tacrolimus (formerly FK 506) is an immunosuppressive drug that works by inhibiting calcineurin, a calcium-dependent protein phosphatase required for immune function. Tacrolimus has been shown to be effective topically in atopic dermatitis and systemically in psoriasis and graft-vs-host disease (GVHD). However, its efficacy in treating cutaneous GVHD when applied topically has not been reported.. To assess the therapeutic efficacy of 0.1% tacrolimus ointment on chronic cutaneous GVHD in patients with symptoms refractory to systemic corticosteroid therapy.. Tacrolimus ointment effectively treated pruritus and/or erythema in 13 (72%) of 18 patients with chronic GVHD. Responding patients had a rapid effect within several hours to days. Effectiveness was measured by means of patient report, results of physical examination, side-by-side comparisons of tacrolimus vs a vehicle control, and temporal flares of the cutaneous symptoms of the disease in the context of stopping tacrolimus ointment therapy. Because of the progression of GVHD and in 2 cases, loss of drug efficacy, all patients eventually went on to receive more aggressive treatment, including increases in steroid dosage, psoralen-UV-A therapy, and extracorporeal photopheresis.. This case series suggests that tacrolimus ointment has efficacy in treating the erythema and pruritus of steroid-refractory, chronic cutaneous GVHD in most patients. The rapid response of tacrolimus ointment may provide a useful therapeutic bridge to systemic therapies that have slower onset, such as psoralen-UV-A therapy or extracorporeal photopheresis.

Topics: Adult; Bone Marrow Transplantation; Chronic Disease; Erythema; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Pruritus; Skin Diseases; Tacrolimus; Treatment Outcome

Topics: Dapsone; Humans; Skin Diseases; Tacrolimus

The stratum corneum (SC) is the skin's outermost layer, organized by clusters of corneocytes among a lipid matrix, acting as a barrier. This "brick and mortar" organization is modified in many skin diseases. We proposed a lesioned-skin model for assessing the permeability of topical formulations and the impact of skin integrity on the permeability of molecules. We anticipate that removal of the SC compromises the skin barrier function, making it more permeable, affecting the biopharmaceutics of topical formulations. By stripping with 25 strips (Corneofix®), the thickness of the SC was considerably reduced, exposing the viable epidermis. Transversal and upper views of the skin by electronic microscopy and histology confirm the removal of the SC. After, we evaluated the permeability of tacrolimus (Protopic®, 0.1 % and 0.03 %) by HPLC-UV. The non-lesioned skin presented 20-25 % of tacrolimus in the SC and no drug permeated through the skin's inner layers. Contrary, the lesioned-skin model allowed the permeation of tacrolimus to the epidermis, dermis, and also in the receptor medium. These results highlight the importance of using diseased skin tissue as opposed to normal skin when assessing the permeability of pharmaceutical formulations for local topical delivery, closely mimicking the occurred events in clinical scenario.

Topics: Epidermis; Humans; Permeability; Pharmaceutical Preparations; Skin; Skin Diseases; Tacrolimus

Dear Editor, cutaneous chronic graft versus host disease (cGVHD) is a pathological process consisting of donor-derived T-cells aimed at the antigens of the recipient. It exhibits a large range of clinical presentations resembling morphea and deep sclerosis/fasciitis, all characterized by both inflammation and progressive dermal and hypodermic fibrosis (1). Although classic scleroderma-like lesions in cGVHD are nummular or irregular plaques and linear bundles associated with hypo- or hyperpigmentation (2), we report an atypical case with ulcerative presentation. No other case-reports of morphea-like or scleroderma-like cGVHD with an ulcerated appearance after liver transplantation (LT) and magnetic resonance imaging (MRI) correlation have been found in the literature. CASE REPORT Ten months after LT due to an end-stage cirrhosis associated with multifocal hepatocarcinoma (HCC), a 61-year-old man on immunosuppressive therapy with Tacrolimus (1 mg) and Everolimus (10 mg) presented to our clinic for a skin lesion in the right scapular region. We observed a flat ulcerated plaque with areas of sclerosis, minimal necrosis, and well-defined slightly erythematous margins (Figure 1, a). On palpation, the plaque had a hard consistency and was slightly painful. The skin lesion had been preceded by subjective discomfort with stinging sensation for seven months before its onset. Gradually lesion developed starting from a small, flat, oval purplish plaque associated with a progressive increase in pain. Patient denied dysphagia, retrosternal heartburn, Raynaud's phenomenon, arthralgia, and dyspnea. A previous MRI (Figure 2, a,b) showed subcutaneous and muscle edema. Blood tests showed abnormal liver function indexes due to extrahepatic cholestasis, while C-reactive protein, erythrocyte sedimentation rate, and leukocytes were within normal ranges. Self-reactive antibodies were negative. Histological examination (Figure 1, b) identified rare dyskeratotic keratinocytes and basal lymphocyte infiltrate, a dermal dense fibrosis with the disappearance of the skin appendages, and large fibrous septa in the adipose panniculus. It led to the diagnosis of scleroderma/morphea, based on the patient's clinical history. The diagnosis of graft versus host disease scleroderma-like post liver transplant was established. The lesion was treated by topical application of 0.05% clobetasol once a day. We did not use systemic immunosuppressive therapy in order to prevent HCC recurrence. The pat

Topics: C-Reactive Protein; Clobetasol; Everolimus; Fibrosis; Graft vs Host Disease; Humans; Inflammation; Liver Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Scleroderma, Localized; Sclerosis; Skin Diseases; Tacrolimus; Ulcer

Ocular graft-versus-host disease (GVHD) is one of the most severe complications of hematopoietic stem cell transplantation. It manifests as an impairment of the ocular surface, such as severe dry eye disease, and deteriorates the recipient's visual function and quality of life. We encountered an "overlap syndrome" of ocular GVHD, which is characterized by the presence of both acute and chronic GVHD symptoms. In this report, we present the treatment progress of the overlap syndrome in a case with ocular GVHD.. A 57-year-old man with acute myeloblastic leukemia underwent hematopoietic stem cell transplantation. Six weeks after the treatment, the recipient complained of eye pain and discharge. He was diagnosed with the overlap syndrome due to low tear volume, severe corneal epithelitis, hyperemia, and a pseudomembrane on the conjunctiva. Immune cells infiltration, fibrinoid degeneration, fibroblastic and spindle-shaped cells, and fibrosis were observed in the pathology of the pseudomembrane. The recipient was treated with topical immunosuppression and pseudomembrane removal. One week after the initial treatment, ocular GVHD improved. Twelve weeks after the treatment, the topical steroid was discontinued due to the elevation of intraocular pressure.. The assessment of conjunctival pseudomembrane in ocular GVHD is important to determine the stage of the case and to assess systemic GVHD. Furthermore, prompt removal of the pseudomembrane after diagnosis is an appropriate management to reduce the symptoms of ocular GVHD. The combination of topical steroids and immunosuppressive agents is suggested to be an effective treatment in management of overlap syndrome.

Topics: Acute Disease; Betamethasone; Chronic Disease; Conjunctival Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Intestinal Diseases; Leukemia, Myeloid, Acute; Male; Middle Aged; Ophthalmologic Surgical Procedures; Skin Diseases; Tacrolimus

Indeterminate cell histiocytosis (ICH) is an extremely rare clonal proliferative disorder of dendritic cells which presents with skin lesions in the majority of cases. Although extra-cutaneous manifestations are very rare, ICH may involve the mucosa, cornea, and conjunctiva as well as the visceral organs. Since the clinical appearance of cutaneous lesions of ICH is not distinctive, it is diagnosed with histopathological and immunohistochemical findings after clinical suspicion. Herein, we report a 27-year-old man with a two-year history of asymptomatic reddish papules and papulonecrotic lesions on his face, arms and buttocks. He was previously diagnosed with systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS), and he had been treated with hydroxychloroquine and low-dose aspirin. Diffuse dermal infiltration of a mixture of histiocytes and lymphocytes accompanied with multinuclear giant cells, the positive CD68 and Factor XIIIa and negative Langerin immunoreactions, along with the positive staining with CD1a and S100, led us to the diagnosis of ICH. To the best of our knowledge, this is the first case of ICH associated with SLE and APS.

Topics: Administration, Topical; Adult; Antiphospholipid Syndrome; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Skin Diseases; Tacrolimus

Topics: Administration, Cutaneous; Anti-Infective Agents, Local; Child; Drug Therapy, Combination; Ethacridine; Humans; Immunosuppressive Agents; Male; Penile Diseases; Skin Diseases; Tacrolimus

Emberger syndrome with underlying guanine-adenine-thymine-adenine 2 (GATA2) mutation is a rare disorder and very few successful nonmyeloablative allogeneic hematopoietic stem cell transplants (HSCTs) have been reported. We report a case of Emberger syndrome with GATA2 mutation in a 9-year-old girl who presented with congenital sensorineural deafness, warts, lymphedema, and Myelodysplastic syndrome. Her sister had died of a similar illness. She underwent a nonmyeloablative matched related donor peripheral blood HSCT with rabbit antithymoglobulin (5 mg/kg), fludarabine (160 mg/m), cyclophophamide (29 mg/kg), and total body irradiation (2 Gray). Graft versus host disease prophylaxis consisted of tacrolimus and mycophenolate moefetil. She had neutrophil engraftment on day+15 and fully donor chimerism by day+30. She developed limited chronic skin graft versus host disease on tapering off immunosuppression. She is disease free on day+475. The review of literature showed a total of 28 patients with GATA2 mutation have undergone HSCT mostly nonmyeloablative and overall survival is 75%. Nonmyeloablatove HSCT is feasible and safe for the patients with GATA2 mutation.

Topics: Allografts; Antilymphocyte Serum; Child; Cyclophosphamide; Female; GATA2 Deficiency; GATA2 Transcription Factor; Graft vs Host Disease; Humans; Mutation; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Skin Diseases; Tacrolimus; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation

Decreased interferon (IFN)-γ levels and increased levels of macrophage-derived chemokine (MDC) and intercellular adhesion molecule (ICAM)-1 are known to be involved in allergic skin diseases, such as eczema and atopic dermatitis. Activation of the IFN-γ and its downstream interleukin-12 (IL-12) pathway can correct these diseases. Suppressor of cytokine signaling 1 (SOCS1) is a cytokine signaling inhibitor that blocks downstream pathways of IFN-γ by blocking the mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) signaling pathways. Oxymatrine (OMT), a quinolizidine alkaloid extracted from the herbal medicine Radix Sophorae flavescentis, is used to treat allergic skin diseases in China. The non-cytotoxic concentrations of OMT in HaCaT cells were determined through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Tumor necrosis factor (TNF)-α and IFN-γ were used to stimulate HaCaT cells, and OMT was added to this system with tacrolimus (FK506) as a positive control. The mRNAs of cytokines, MDC, ICAM-1, IL-12p35, IL-12p40, and IFN-γ receptor (IFN-γR)α were detected by RT-PCR. Western blot analyses were performed to assess activation of the MAPK (p38, Jun N-terminal kinase, and extracellular signal-regulated kinase) and Akt signaling pathways. OMT increased the mRNA levels of the IL-12 and IFN-γRα, reduced the mRNA levels of ICAM-1, MDC, and SOCS1. But FK506 increased the mRNA levels of IL12 and inhibited the expression of ICAM-1 mRNAs and had no effects on the IFN-γRα, MDC, and SOCS1 mRNA in HaCaT cells stimulated with TNF-α and IFN-γ. Thus, the mechanisms through which OMT and FK506 ameliorate allergic skin diseases differ.

Topics: Alkaloids; Cell Line; Chemokine CCL22; Down-Regulation; Humans; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Interferon-gamma; Keratinocytes; MAP Kinase Signaling System; Quinolizines; RNA, Messenger; Skin Diseases; Suppressor of Cytokine Signaling 1 Protein; Tacrolimus

Granuloma gluteale infantum is a rare nodular complication of irritant diaper dermatitis. The association of this condition with the widespread use of nondisposable cloth diapers has been increasingly recognized. We present the case of an 18-month-old girl with granuloma gluteale infantum. Our aims are to emphasize the importance of clinical recognition of this re-emerging complication of diaper dermatitis and to point out the potential role of topical calcineurin inhibitors as a treatment option.

Topics: Administration, Cutaneous; Buttocks; Calcineurin Inhibitors; Dermatologic Agents; Diaper Rash; Diapers, Infant; Female; Granuloma; Humans; Infant; Ointments; Skin Diseases; Tacrolimus

A collection of plasma cells in the skin can represent a broad spectrum of disease entities. Secondary syphilis, primary cutaneous plasmacytoma, primary cutaneous plasmacytosis, cutaneous lymphoid hyperplasia and nodular amyloidosis are considered possible differential diagnoses. The primary cutaneous plasma cell disorders can range from malignant to benign plasma cell neoplasms. The malignant conditions are neoplastic diseases having monoclonal proliferations, rapid progression and fatal outcome while the benign plasma cell disorders usually show polyclonality, chronicity and benign process, including plasmacytosis. We present a case of cutaneous plasmacytosis. The patient was a 34-year-old man, presented with disseminated reddish-brown plaques and nodules on the right side of the hips, inguinal groove, and the thigh. Histopathologically, mature plasma cells perivascular infiltrates were observed mainly in the dermis. Polyclonality of infiltrating plasma cells with coexistence of both kappa and gamma chain-positive cells demonstrated with immunohistochemistry, as well as CD20+++, CD38++++, CD79a++++, CD138++, Ki67<30%. The diagnosis, cutaneous plasmacytosis, was established by the pertinent laboratory findings. Primary cutaneous plasmacytosis was an uncommon reactive lymphoplasmacytic disorder of uncertain etiology. Cutaneous plasmacytosis is a rare disease characterized by peculiar multiple eruptions and hyper gamma globulinemia. It has been mainly described in patients of Japanese descent, with only few reports in Caucasians and Chinese, although information concerning the disorder was limited to individual case reports. Cutaneous plasmacytosis is a rare disorder, which is characterized by multiple red to dark-brown nodules and plaques on the trunk and usually associated with polyclonal hyper gamma globulinaemia. Primary cutaneous plasmacytosis or cutaneous plasmacytosis was thought to be a reactive process with unknown etiology. Histologically, lesions contain dense perivascular infiltration of mature polyclonal plasma cells without any atypia, in the dermis and subcutaneous fat. The clinical course is chronic and benign without spontaneous remission. Available treatments for cutaneous plasmacytosis include psoralen ultraviolet A radiotherapy, systemic chemotherapy and intralesional steroid injection. The patient with cutaneous plasmacytosis in this report was treated with tacrolimus ointment and psoralen ultraviolet A.

Topics: Adult; Humans; Hyperplasia; Immunosuppressive Agents; Male; Plasma Cells; Plasmacytoma; Skin; Skin Diseases; Tacrolimus

Due to the low cutaneous bioavailability of tacrolimus (TAC), penetration enhancers are used to improve its penetration into the skin. However, poor loading capacity, non-biodegradability, toxicity, and in some cases inefficient skin penetration are challenging issues that hamper their applications for the dermal TAC delivery. Here we present poly(lactide-co-glycerol) (PLG) as a water soluble, biodegradable, and biocompatible TAC-carrier with high loading capacity (14.5% w/w for TAC) and high drug delivery efficiencies into the skin. PLG was synthesized by cationic ring-opening copolymerization of a mixture of glycidol and lactide and showed 35 nm and 300 nm average sizes in aqueous solutions before and after loading of TAC, respectively. Delivery experiments on human skin, quantified by fluorescence microscopy and LC-MS/MS, showed a high ability for PLG to deposit Nile red and TAC into the stratum corneum and viable epidermis of skin in comparison with Protopic® (0.03% w/w, TAC ointment). The cutaneous distribution profile of delivered TAC proved that 80%, 16%, and 4% of the cutaneous drug level was deposited in the stratum corneum, viable epidermis, and upper dermis, respectively. TAC delivered by PLG was able to efficiently decrease the IL-2 and TSLP expressions in human skin models. Taking advantage of the excellent physicochemical and biological properties of PLG, it can be used for efficient dermal TAC delivery and potential treatment of inflammatory skin diseases.

Topics: Administration, Cutaneous; Cells, Cultured; Drug Delivery Systems; Fibroblasts; Humans; In Vitro Techniques; Inflammation; Keratinocytes; Polylactic Acid-Polyglycolic Acid Copolymer; Skin Absorption; Skin Diseases; Tacrolimus

Topics: Adult; Atrioventricular Block; Bone Marrow Transplantation; Bradycardia; Electrocardiography; Female; Graft vs Host Disease; Heart Block; Hemorrhage; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Liver Diseases; Lung Diseases; Methicillin-Resistant Staphylococcus aureus; Methylprednisolone; Mycophenolic Acid; Pneumonia, Staphylococcal; Skin Diseases; Tacrolimus; Transplantation, Homologous

Wells syndrome (WS) or eosinophilic cellulitis is a rare, idiopathic, inflammatory dermatosis. The typical clinical presentation is urticarial plaque without preferential location that usually heals without scarring. We present a 62-year-old man with history of lung cancer that had undergone a right superior lobectomy 12 months previously. The patient had a relapsing dermatosis beginning about 6 months before the diagnosis of the lung cancer, characterised by pruritic, erythematous plaques located on the trunk and arms. These lesions spontaneously resolved within a few weeks without scarring. A skin biopsy revealed findings compatible with WS. Several diseases have been associated with WS. These include haematological diseases, fungal, parasitic and viral infections, drug reactions and rarely non-haematological malignancies. We present a case of this rare syndrome in a patient with history of lung cancer that we believe acted as a triggering event. To our knowledge, this is the second case reporting this association.

Topics: Administration, Topical; Biopsy; Cellulitis; Clobetasol; Dermatologic Agents; Eosinophilia; Humans; Loratadine; Lung Neoplasms; Male; Middle Aged; Recurrence; Skin Diseases; Tacrolimus; Treatment Outcome

Topics: Administration, Cutaneous; Female; Histiocytosis; Humans; Immunosuppressive Agents; Lymphatic Vessels; Middle Aged; Skin Diseases; Tacrolimus

Topics: Dermatology; Humans; Randomized Controlled Trials as Topic; Skin Diseases; Tacrolimus; Vitiligo

Metatarsal fistulation is an uncommon cutaneous condition reported almost exclusively in German shepherd dogs and their cross-breeds. To the best of the authors' knowledge this is the first reported case of focal metatarsal fistulae syndrome affecting a greyhound. Remission was obtained within 6 weeks of commencing treatment using compounded 0.1% tacrolimus ointment twice daily and the dog remained stable for another 6 months with twice weekly application before treatment was discontinued. The dog remained in remission at the time of writing, which is 1 year after treatment withdrawal.

Topics: Administration, Topical; Animals; Dog Diseases; Dogs; Female; Metatarsus; Skin Diseases; Tacrolimus

Tacrolimus, a macrolide immunosuppressant, is used topically for the treatment of cutaneous manifestations of graft-versus-host disease (GVHD) for rapid, symptomatic relief of pruritus and erythema. Despite the manufacturer's product information reporting minimal systemic effects of topical tacrolimus, this has not been evaluated in patients with cutaneous GVHD and with occlusive dressings. We describe two patients with cutaneous GVHD who developed toxic tacrolimus levels after receiving several applications of tacrolimus ointment along with occlusive dressings to enhance skin effectiveness. The first patient was a 62-year-old woman with a history of acute myelogenous leukemia (AML) who underwent allogeneic bone marrow transplantation and developed chronic GVHD involving 70% of her body surface area. Her GVHD treatment plan consisted of oral corticosteroids, oral tacrolimus, topical corticosteroids, topical tacrolimus 0.1% ointment twice/day, emollient creams, intravenous rituximab, and photopheresis. The patient's tacrolimus trough levels rose rapidly over the course of 6 days from less than 2 ng/ml to 23 ng/ml, despite oral tacrolimus dosage adjustments. The second patient was a 25-year-old man who developed severe, chronic skin GVHD after undergoing allogeneic sibling bone marrow transplantation for AML. In addition to intravenous corticosteroids, corticosteroid creams, and oral tacrolimus, the patient also received topical tacrolimus twice/day with occlusive dressings. Over the course of 2 days, his tacrolimus trough levels increased from 7.10 ng/ml to 22.10 ng/ml. Although improvement was noted in both patients' skin GVHD with application of the occlusive dressings, the practice was discontinued due to increased and erratic systemic tacrolimus absorption. These case reports suggest that substantial use of topical tacrolimus with occlusive dressings in patients with cutaneous GVHD may contribute to increased systemic absorption resulting in toxic tacrolimus levels. Based on the findings from our two patients as well as published case reports, systemic absorption appears to increase with greater skin permeability, skin barrier dysfunction, amount of body surface area applied, and use of occlusive dressings. When one or more of these factors are present, it may be prudent to monitor tacrolimus levels.

Topics: Administration, Cutaneous; Adult; Bone Marrow Transplantation; Dose-Response Relationship, Drug; Female; Glucocorticoids; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Middle Aged; Occlusive Dressings; Skin Absorption; Skin Diseases; Tacrolimus; Transplant Recipients

Topics: Administration, Cutaneous; Crohn Disease; Granuloma; Humans; Immunosuppressive Agents; Male; Penile Diseases; Recurrence; Skin Diseases; Tacrolimus; Young Adult

The topical calcineurin antagonist tacrolimus plays an important role in the treatment of different forms of eczema because of its favorable risk profile. In addition, different off-label indications have been clinically tested where tacrolimus ointment has achieved clinical improvement. This article discusses off-label treatment of vitiligo, seborrheic dermatitis, steroid rosacea, perioral dermatitis, rosacea and lichen sclerosus.

Topics: Administration, Topical; Chronic Disease; Dermatologic Agents; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Off-Label Use; Skin Diseases; Tacrolimus; Treatment Outcome

A 50-year-old female patient, who had had a long-term history of myelodysplastic syndrome and type II diabetes mellitus, had developed acute myelogenous leukemia and received allogeneic bone marrow transplantation (BMT). She was being treated with tacrolimus, methotrexate and prednisolone for prophylaxis and treatment of graft-versus-host disease, and with intensive insulin therapy for better glycemic control. The patient suddenly developed marked leg edema at 27 days after starting intensive insulin therapy (on day 40 after BMT) without coexistence or exacerbation of apparent causes such as renal failure, cardiac dysfunction or leg thrombosis around the onset of leg edema. Interestingly, the leg edema regressed soon after daytime hyperglycemia and intensive insulin therapy were performed. Histopathological examination revealed slight dermal edema and small bullae with little inflammatory infiltration but no signs of autoimmune blistering diseases or vasculitis. These findings indicate that the present case may be considered a form of so-called insulin edema occurring during intensive insulin therapy after BMT.

Topics: Bone Marrow Transplantation; Diabetes Mellitus, Type 2; Edema; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Insulin; Leg; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Prednisolone; Skin Diseases; Tacrolimus; Treatment Outcome

A 45-year-old woman with personal history of hypertension presented with an erythematous lesion in the neckline for a year and with a progressive growth. A physical examination revealed an annular lesion with erythematous papules in the edge. Histological exam showed phagocytosis of elastic fibers by multinucleated cells compatible with annular elastolytic giant-cell granuloma. The patient did not present any other associated systemic manifestation. Treatment with tacrolimus 0.1 percent ointment was prescribed with a very good response after two months.

Topics: Erythema; Female; Granuloma, Giant Cell; Humans; Immunosuppressive Agents; Middle Aged; Skin Diseases; Tacrolimus

FK506 binding protein 12 (FK506BP) is an immunophilin that acts as a receptor for the immunosuppressant drug FK506. Although the precise action of FK506BP remains unclear, it has emerged as a potential drug target for several inflammatory diseases. This study investigated the protective effects of FK506BP on inflammation in vitro and in vivo using protein transduction. A cell-permeable expression vector PEP-1-FK506BP was constructed. Lipopolysaccharide (LPS)- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated Raw 264.7 cells and ICR mice were treated with PEP-1-FK506BP. The expression of inflammatory response enzymes and cytokines was analyzed by Western blot, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and electrophoretic mobility shift assay. PEP-1-FK506BP efficiently transduced into Raw 264.7 cells and markedly inhibited the expression levels of cyclooxygenase-2 as well as pro-inflammatory cytokines. Furthermore, transduced PEP-1-FK506BP significantly reduced activation of nuclear factor-kappa B (NF-κB) and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in the cells, whereas PEP-1-FK506BP reduced phosphorylation of p38 and extracellular signal-regulated kinase (ERK) in the animal models. These results indicate that PEP-1-FK506BP inhibits inflammatory response cytokines and enzymes by blocking NF-κB and MAPK including the phosphorylation of p38 and/or ERK MAPK in vitro and in vivo, suggesting that PEP-1-FK506BP may be a therapeutic agent against inflammatory skin diseases.

Topics: Animals; Cell Line; Cyclooxygenase 2; Extracellular Signal-Regulated MAP Kinases; Humans; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Macrophages; Mice; Mice, Inbred ICR; Models, Animal; NF-kappa B; Signal Transduction; Skin Diseases; Tacrolimus; Tacrolimus Binding Proteins; Transduction, Genetic

Papular elastolytic giant cell granuloma is an unusual variant of annular elastolytic giant cell granuloma. Its rarity makes the assessment of the real efficacy of any treatment difficult, as spontaneous remission is possible. We report a case whose interest, besides the rarity of the occurrence, rests in the pure papular expression of the clinical features, the association with a monoclonal gammopathy and the apparent efficacy of topical tacrolimus.

Topics: Adult; Female; Granuloma, Giant Cell; Humans; Immunosuppressive Agents; Paraproteinemias; Skin Diseases; Tacrolimus; Treatment Outcome

Although clinical trials for new drugs are often limited in children because of safety concerns or restrictions, new therapies or novel strategies with old drugs have recently expanded dermatologic armamentarium for pediatric patients. Oral propranolol is currently the first choice in the treatment of alarming infantile hemangiomas. In atopic dermatitis, proactive strategy with topical calcineurin inhibitors can safely prevent disease exacerbation. Tacrolimus, in particular, is also useful for the treatment of vitiligo occurring in sensitive areas such as the eyelids. Among biologic drugs, use of etanercept is safe and efficient in children and adolescents with moderate-to-severe plaque psoriasis. Engineered tissues with special antimicrobial properties (silver-coated fabrics or engineered silk) are now used to treat eczema and fungal diseases in children. In athlete's foot, the use of 5-finger socks can also be helpful.

Topics: Adolescent; Adrenal Cortex Hormones; Alopecia Areata; Autoimmune Diseases; Child; Child, Preschool; Dermatitis, Atopic; Eczema; Female; Hemangioma; Humans; Immunosuppressive Agents; Male; Propranolol; Psoriasis; Randomized Controlled Trials as Topic; Skin Diseases; Tacrolimus; Therapies, Investigational; Vitiligo

Topics: Adult; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Skin Diseases; Tacrolimus

Because morbidity early after hematopoietic cell transplantation (HCT) results in large part from the development of acute graft-versus-host disease (GVHD), we previously proposed that a longitudinal assessment of morbidity involving the skin, liver, and gastrointestinal (GI) tract might provide a more complete, objective approach for comparing 2 arms of open-label randomized clinical trials for acute GVHD prevention. In this study, we determined both morbidity across time and GVHD across time in a retrospective analysis of a database from an open-label randomized clinical trial comparing tacrolimus/methotrexate and cyclosporine/methotrexate after myeloablative conditioning and marrow transplantation from HLA-matched unrelated donors. The results confirm differences in overall morbidity across time in patients with peak grade II-IV GVHD compared with those with grade 0-I GVHD, but no significant differences in morbidity associated with grade II GVHD compared with grade 0-I GVHD. We observed less skin morbidity and a trend toward less liver morbidity across time in the tacrolimus group (P = .04 and .09, respectively), but not for GI morbidity or overall morbidity, despite significantly decreased skin and liver stages and overall grades of GVHD across time in this group. Thus, our objective assessment of differences in morbidity (regardless of cause) as a measure of acute GVHD in a randomized clinical trial of acute GVHD prevention has only limited utility. The difficulty of demonstrating clinical benefits from objective parameters, such as survival and morbidity, and the subjectivity of grading acute GVHD emphasize the need for blinded assessments in clinical trials of GVHD prevention.

Topics: Acute Disease; Clinical Trials, Phase III as Topic; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Gastrointestinal Diseases; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Liver Diseases; Methotrexate; Organ Specificity; Postoperative Complications; Randomized Controlled Trials as Topic; Retrospective Studies; Skin Diseases; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

Cutaneous and systemic plasmacytosis (CSP) is an exceedingly rare condition arising primarily in patients of Japanese descent. Herein, we describe a patient of mainland Chinese origin suffering CSP. A 49-year-old Chinese male had asymptomatic brownish-red plaques and papules of the face and trunk for 6 years. Physical examination revealed innumerable symmetric red-brownish macules on face and trunk with fewer red-brownish papules scattered among the macules. Chemical analysis revealed hypergammaglobulinemia. Computerized tomography scan discovered some lymphadenopathy in the axillary, paratracheal and pulmonary regions. Histological examination showed focal perivascular and periadnexal infiltrate of mainly plasma cells in the superficial and deep dermis. Immunohistochemical study showed that a great number of the infiltrating cells were CD20-positive. The infiltrated polyclonal plasma cells expressed both kappa and lambda light chains. Topical therapy with tacrolimus 0.1% ointment for 2 months reduced the thickness and pigmentation of the facial skin lesions. The lesions resumed the original appearance 3 weeks after discontinuing the therapy. To the best of our knowledge, this is the first case of CSP from mainland China.

Topics: Administration, Topical; Antigens, CD20; Asian People; Humans; Hypergammaglobulinemia; Immunoglobulin Light Chains; Lymphatic Diseases; Male; Middle Aged; Ointment Bases; Plasma Cells; Skin; Skin Diseases; Tacrolimus

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Colectomy; Colonic Neoplasms; Dermatologic Agents; Female; Humans; Skin Diseases; Tacrolimus

Topics: Asian People; Bone Marrow Transplantation; Graft vs Host Disease; Humans; Immunosuppressive Agents; Japan; Leukemia, Monocytic, Acute; Male; Middle Aged; Ointments; Skin Diseases; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

Topics: Administration, Topical; Chemotherapy, Adjuvant; Child, Preschool; Dapsone; Drug Resistance; Female; Humans; Immunosuppressive Agents; Ointments; Skin Diseases; Tacrolimus

Erosive pustular dermatosis (EPD) is a rarely reported condition that primarily involves the actinically damaged scalp of elderly women. Although the condition is well recognized in the United Kingdom and Europe, no US cases have heretofore been reported.. We sought to document the presence, and determine the clinical characteristics, of EPD in the US population.. Patients were recruited from the dermatology clinic at a university in California and from the private practices of dermatologists in the Northern California region.. Eleven patients with EPD were identified. Eight were women and 3 were men. The scalp was involved in 9 patients and the extremities in two patients. The involved skin was actinically damaged in 9 patients. The patients were elderly (66-90 years) but one patient was a 15-year-old boy. All lesions resolved or greatly improved with the application of high-potency steroids or tacrolimus.. Not all patients were examined personally by the authors of this article. The length of follow-up was relatively short.. EPD is a fairly common disease and is the most likely diagnosis in instances where chronic, nonhealing, shallow erosions occur on actinically damaged, or otherwise atrophic, skin. In spite of the name, intact pustules are rarely present. The histology is that of moderate to marked, nonspecific chronic inflammation. EPD responds well to high-potency topical steroids.

Topics: Administration, Topical; Adolescent; Aged; Aged, 80 and over; Atrophy; Calcineurin Inhibitors; Clobetasol; Extremities; Female; Follow-Up Studies; Glucocorticoids; Humans; Male; Photosensitivity Disorders; Scalp Dermatoses; Skin Diseases; Skin Diseases, Vesiculobullous; Steroids; Tacrolimus; Treatment Outcome

Topics: Administration, Cutaneous; Administration, Oral; Cord Blood Stem Cell Transplantation; Drug-Related Side Effects and Adverse Reactions; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Male; Severe Combined Immunodeficiency; Skin Diseases; Tacrolimus; Time Factors; Transplantation, Homologous

(1) In clinical trials of topical tacrolimus (an immunosuppressant), transient skin irritation, usually at the site of application, occurred in about 0.5% to 1.3% of adult patients who had also ingested ethyl alcohol. This adverse effect has also been observed with topical pimecrolimus, a related drug. (2) Three paediatric cases have also been published. The alcohol they ingested was one of the excipients of an oral drug. (3) If skin irritation occurs at the application site for topical tacrolimus, the role of ethyl alcohol, which may have been used as an excipient for a co-administered oral drug, should be borne in mind.

Topics: Adult; Child; Dermatitis, Atopic; Ethanol; Exanthema; Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus

We report a case of lichenoid sarcoidosis in a young girl treated by oral tacrolimus and methylprednisolone. The patient had had a skin eruption from 1 year of age and had developed uveitis at 2 years of age. Her sight had become affected by the uveitis at 8 years of age. When she was 14, she was admitted to the ophthalmology department of our hospital to start treatment with tacrolimus (FK506). She was referred to the department of dermatology for her skin lesions, which were flat, pinkish or normal skin-colored papules scattered on her extremities and the backs of her hands. Upon histology, epithelioid granulomas were seen in the upper dermis and around the erector pili muscles. She received tacrolimus (FK506) 6 mg/day for 3 months for her uveitis. The eye lesions subsided somewhat, and the skin lesions were almost healed after the 3-month course of tacrolimus. However, 4 months after stopping the tacrolimus, her skin and eye lesions relapsed. At that point, she was started on methylprednisolone 16 mg/day for her uveitis. With the methylprednisolone treatment, the inflammation of the eye lesion immediately healed, as did the skin lesions.

Topics: Administration, Oral; Adolescent; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Leg; Methylprednisolone; Sarcoidosis; Skin Diseases; Tacrolimus; Uveitis

Dendritic cells are the coordinators of the adaptive immune response. Chronic activation of skin dendritic cells by keratinocyte expression of CD40 ligand (CD40L; CD154) leads to autoimmunity. In this issue, systemic administration of tacrolimus is shown by Loser et al. to effectively treat autoimmunity in a murine model involving transgenic keratinocyte expression of CD40L.

Topics: Animals; Autoimmune Diseases; Calcineurin Inhibitors; Dendritic Cells; Disease Models, Animal; Immunosuppressive Agents; Mice; Skin; Skin Diseases; Tacrolimus

Topics: Algorithms; Anti-Bacterial Agents; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Dermatologic Agents; Dermatology; Doxycycline; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Eye Diseases; Female; Humans; Interprofessional Relations; Lung Neoplasms; Medical Oncology; Middle Aged; Ophthalmology; Quinazolines; Referral and Consultation; Skin Diseases; Tacrolimus

Topics: Administration, Cutaneous; Arm; Dermatologic Agents; Diagnosis, Differential; Drug Therapy, Combination; Female; Granuloma, Giant Cell; Humans; Hydroxychloroquine; Middle Aged; Skin Diseases; Tacrolimus

Sarcoidosis encompasses a heterogeneous spectrum of clinical presentations, including sarcoidosis in association with tattoos. We report the development of cutaneous and pulmonary sarcoidosis in a patient with long-standing eyebrow tattoos whose cutaneous sarcoidosis almost completely resolved when treated with tacrolimus 0.1% ointment. A 70-year-old woman with a 3-year history of an erythematous eruption circumscribing her eyebrow tattoos presented with a chronic, nonproductive cough of 8 months' duration. Skin biopsy results demonstrated naked tubercles consistent with sarcoidosis. Results of radiographs and a computed tomography scan of the chest revealed multiple pulmonary nodules with mediastinal and hilar adenopathy. The results of transbronchial biopsy were consistent with the diagnosis of pulmonary sarcoidosis. Initial treatment with oral prednisone only improved the pulmonary sarcoidosis. The cutaneous sarcoidosis almost completely resolved after the addition of tacrolimus 0.1% ointment.

Topics: Aged; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Prednisone; Sarcoidosis; Skin Diseases; Tacrolimus; Tattooing

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, as one of the new classes of immunomodulating macrolactams, is specifically effective in the treatment of inflammatory skin diseases. The interest in pimecrolimus is highly important for its significant anti-inflammatory activity, cell-selective inhibition of inflammatory cytokines, immunomodulatory capabilities, and low systemic immunosuppressive potential. The mechanism of action of pimecrolimus is the blockage of T cell activation, blocking signal transduction pathways in T cells, and inhibition of the synthesis of inflammatory cytokines, specifically Th1- and Th2-type cytokines. Several studies have evaluated the effectiveness of pimecrolimus as the treatment of choice for inflammatory skin diseases.

Topics: Chronic Disease; Dermatitis, Atopic; Eczema; Immunologic Factors; Immunosuppressive Agents; Inflammation; Psoriasis; Skin Diseases; Tacrolimus

Topics: Administration, Cutaneous; Aged; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pseudolymphoma; Skin Diseases; Tacrolimus

Topics: Administration, Topical; Dermatologic Agents; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Skin Diseases; Tacrolimus; Treatment Outcome

Topics: Absorption; Administration, Topical; Autoimmune Diseases; Bone Marrow Transplantation; Child, Preschool; Graft vs Host Disease; Humans; Male; Skin Diseases; Tacrolimus

We report a case of generalized cutaneous chronic graft-versus-host disease in a 17-month-old infant. Topical treatment with the novel ascomycin substance pimecrolimus once daily for 4 weeks led to a near complete clearance of skin lesions. Importantly, this excellent clinical response was obtained without additional use of systemic immunosuppressive treatment.

Topics: Administration, Topical; Graft vs Host Disease; Humans; Infant; Leukemia, Myelomonocytic, Acute; Male; Peripheral Blood Stem Cell Transplantation; Skin Diseases; Tacrolimus; Treatment Outcome

Immunomodulators include both immunostimulatory and immunosuppressive agents. Obligate contact sensitizers such as diphencyprone or dinitrochlorobenzene have been used against viral and autoimmune diseases. Newer agents such as the toll-like receptor agonists imiquimod and resiquimod have been clinically used to treat viral infections and skin cancers in immunocompetent and immunosuppressed patients. On the other hand, the topical immunosuppressive agents tacrolimus and pimecrolimus have been used with great success in the treatment of chronic inflammatory diseases in children and adults. The introduction of this new class of drugs (i.e. Calcineurin inhibitors) marked the beginning of the post-cortisone era in clinical dermatology. Toll-like receptor agonists and calcineurin antagonists will supplement corticosteroids to improve specific dermatological therapy. Topical immunotherapy with both immunostimulatory and immunosuppressive agents show potential for effective and patient-friendly treatment of inflammatory, infectious and neoplastic skin diseases. Long-term evaluation will define the tolerability and the safety profile.

Topics: Adjuvants, Immunologic; Administration, Topical; Adult; Aged; Aged, 80 and over; Aminoquinolines; Asthma; Autoimmune Diseases; Bowen's Disease; Child; Cyclopropanes; Dermatitis, Atopic; Dinitrochlorobenzene; Female; Follow-Up Studies; Herpes Simplex; Humans; Imidazoles; Imiquimod; Immunity, Cellular; Immunocompromised Host; Immunoglobulin A; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Male; Molluscum Contagiosum; Papillomavirus Infections; Precancerous Conditions; Skin Diseases; Skin Diseases, Viral; Skin Neoplasms; Tacrolimus; Time Factors; Warts

Topics: Anti-Inflammatory Agents; Bronchoscopy; Cyclophosphamide; Diagnosis, Differential; Drug Therapy, Combination; Follow-Up Studies; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Middle Aged; Prednisone; Radiography, Thoracic; Skin; Skin Diseases; Tacrolimus; Time Factors; Tomography, X-Ray Computed

A 56-year old female patient with cutaneous sarcoidosis in the face was treated with fumaric acid esters and doxycycline without any effect. Topical tacrolimus led clinically and histologically to a nearly complete remission within three months, which continued after 4 months of follow-up.

Topics: Biopsy; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Middle Aged; Ointments; Sarcoidosis; Skin; Skin Diseases; Tacrolimus; Time Factors

Topics: Beverages; Calcium Channel Blockers; Citrus; Cyclosporine; Digestive System; Drug Interactions; Felodipine; Humans; Immunosuppressive Agents; Liver; Skin Diseases; Tacrolimus; Xenobiotics

Topics: Administration, Topical; Adult; Adverse Drug Reaction Reporting Systems; Animals; Autoimmune Diseases; Child; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus; Treatment Outcome

SDZ ASM 981, a novel ascomycin macrolactam derivative, has high anti-inflammatory activity in animal models of allergic contact dermatitis and shows clinical efficacy in atopic dermatitis, allergic contact dermatitis and psoriasis, after topical application. Here we report on the in vitro activities of this promising new drug. SDZ ASM 981 inhibits the proliferation of human T cells after antigen-specific or non-specific stimulation. It downregulates the production of Th1 [interleukin (IL)-2, interferon-gamma] and Th2 (IL-4, IL-10) type cytokines after antigen-specific stimulation of a human T-helper cell clone isolated from the skin of an atopic dermatitis patient. SDZ ASM 981 inhibits the phorbol myristate acetate/phytohaemagglutinin-stimulated transcription of a reporter gene coupled to the human IL-2 promoter in the human T-cell line Jurkat and the IgE/antigen-mediated transcription of a reporter gene coupled to the human tumour necrosis factor (TNF)-alpha promoter in the murine mast-cell line CPII. It does not, however, affect the human TNF-alpha promoter controlled transcription of a reporter gene in a murine dendritic cell line (DC18 RGA) after stimulation via the FcgammaRIII receptor. SDZ ASM 981 also prevents the release of preformed pro-inflammatory mediators from mast cells, as shown in the murine cell line CPII after stimulation with IgE/antigen. In summary, these results demonstrate that SDZ ASM 981 is a specific inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro.

Topics: Animals; Calcineurin; Cell Division; Cells, Cultured; Cytokines; Dermatologic Agents; Humans; Immunophilins; Lymphocyte Culture Test, Mixed; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Skin Diseases; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; Tacrolimus; Tacrolimus Binding Proteins

Topics: Cyclosporine; Female; Gingival Diseases; Humans; Immunosuppressive Agents; Male; Mouth Diseases; Skin Diseases; Tacrolimus