Tacrolimus ointment: a new therapy for atopic dermatitis--review of the literature

Atopic dermatitis is a chronic inflammatory skin disease characterized by severe pruritus, typical morphology and distribution of skin lesions, and personal and family history of atopy. The management of atopic dermatitis is directed at preventing the inflammation, itch, and secondary lesions. Therapy relies on general management measures, anti-inflammatory agents, antiprurites, antibiotics, and immunosuppressants. Treatment options for patients with severe or longstanding disease, extensive body surface area involvement of facial lesions are limited. Tacrolimus ointment is the first in the class of topical immunomodulators that has been formulated for the treatment of atopic dermatitis in children (2 to 15 years of age) and adult patients. The mechanism of action of tacrolimus in atopic dermatitis seems to involve T-cells, Langerhans cells, mast cells and basophiles. Experimental evidence suggests that tacrolimus inhibits T-lymphocytes activation by binding to an intracellular protein, FKBP-12. This binding phenomenon inhibits the ability of calcineurin to activate the promotor region of the gene for IL-2, IL-3, IL-4, IL-5, interferon gamma, tumor necrosis factor alpha, and granulocyte macrophage colony-stimulating factor, all of which participate in the early immune response and play a role in the pathogenesis of atopic dermatitis. Tacrolimus ointment is not atrophogenic, and is associated with minimal systemic absorption. There were no consistent changes in any laboratory variable during topical tacrolimus therapy. The most common adverse events associated with its use were transient skin burning and pruritus at the site of application. Tacrolimus ointment is safe and efficacious therapy for the treatment of pediatric and adult patients with atopic dermatitis on all skin regions including the face, neck and intertriginous areas. An overview is given of tacrolimus in atopic dermatitis.     

Tacrolimus and pimecrolimus: from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis.

Tacrolimus ointment, a topical inhibitor of the phosphatase calcineurin, has recently been approved in the United States for use in the treatment of atopic dermatitis. It is the first topical immune suppressant that is not one of the hydrocortisone derivatives, important allies in dermatology for nearly 50 years. Although tacrolimus is less able to penetrate thick skin than glucocorticoids, it does not cause dermal atrophy, an important advantage over the hydrocortisone class. Pimecrolimus (ASM 981), a newer calcineurin inhibitor closely related to tacrolimus, is also being developed for atopic dermatitis therapy. Pimecrolimus has an altered skin penetration profile but the same mechanism of action as tacrolimus. In this review we chronicle the discovery of the calcineurin inhibitors, their presumed evolutionary role as a bacterial "smart bomb" against fungi, molecular and cellular mechanisms of action in the immune system, systemic and topical side effects, efficacy in atopic dermatitis, and future applications within the specialty of dermatology. Particular attention is given to the issues of systemic absorption of tacrolimus, the conditions in which absorption can become a concern, efficacy relative to glucocorticoids, and the choice of 0.03% or 0.1% tacrolimus ointment for use in adults and children.     

Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome

BACKGROUND: Tacrolimus is a macrolide immunosuppressant approved in oral and intravenous formulations for primary immunosuppression in liver and kidney transplantation. Topical 0.1% tacrolimus ointment has recently been shown to be effective in atopic dermatitis for children as young as 2 years of age, with minimal systemic absorption. We describe 3 patients treated with topical 0.1% tacrolimus who developed significant systemic absorption. OBSERVATION: Three patients previously diagnosed as having Netherton syndrome were treated at different centers with 0.1% tacrolimus ointment twice daily. Two patients showed dramatic improvement. All patients were found to have tacrolimus blood levels within or above the established therapeutic trough range for oral tacrolimus in organ transplant recipients. None of these patients developed signs or symptoms of toxic effects of tacrolimus. CONCLUSIONS: Patients with Netherton syndrome have a skin barrier dysfunction that puts them at risk for increased percutaneous absorption. The Food and Drug Administration recently approved 0.1% tacrolimus ointment for the treatment of atopic dermatitis. Children with Netherton syndrome may be misdiagnosed as having atopic dermatitis. These children are at risk for marked systemic absorption and associated toxic effects. If topical tacrolimus is used in this setting, monitoring of serum tacrolimus levels is essential.     

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

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

长期外用他克莫司软膏对特应性皮炎患者免疫力的影响

目的:探讨特应性皮炎患者长期外用他克莫司软膏治疗后血药浓度的变化以及对外周血淋巴细胞亚群的影响。方法:使用他克莫司软膏(0.1%)治疗12例特应性皮炎患者,疗程12个月,于治疗前和治疗结束后使用流式细胞术检测外周血中淋巴细胞亚群,治疗一周时和治疗结束后使用ELISA检测患者他克莫司血药浓度,比较治疗前后的变化。结果:淋巴细胞亚群的变化在治疗前后比较,差异均无统计学意义(P值均>0.05);治疗1周时,他克莫司血药浓度为(1.73±0.48)ng/mL,治疗12个月后浓度为(1.07±0.42)ng/mL,两者差异具有统计学意义(t=16.85,P<0.05);他克莫司软膏使用总量与Th/Ts比值变化量无相关性(r=-0.40,P>0.05)。结论:特应性皮炎长期外用他克莫司软膏存在低水平的系统吸收,他克莫司低水平系统暴露对特应性皮炎患者的外周血淋巴细胞亚群无影响。     

Tacrolimus in Dermatology

Background: Tacrolimus (FK 506), a metabolite of the fungus Streptomyces tsukubaensis, is an anti-T-cell drug. It acts by inhibiting the production of IL-2, IL-3, IL-4, TNFa, and GM-CSF. More potent and with slightly less secondary effects than cyclosporine, it has been the object of considerable interest, especially in conditions that could benefit from the latter. Objective: In psoriasis, a placebo-controlled double-blind study has shown oral tacrolimus at 0.1 mg/kg/day to be effective in controlling recalcitrant lesions. In human, small studies have reported tacrolimus ointment to be effective in controlling acute contact dermatitis. Short-term trials of topical tacrolimus in the treatment of atopic dermatitis have recently shown excellent results in both adults and children. In animal studies of hair growth disorders, topical tacrolimus induces anagen and protects from chemotherapy-induced alopecia. Animal studies with the ointment for the prevention of skin graft rejection, lupus dermatoses, and skin papilloma formation have also shown to be promising. Conclusions: There are case reports of pyoderma gangrenosum, Sezary's syndrome, and Behcet's disease successfully treated with oral tacrolimus but, because of their small number, they remain anecdotal at this point.     

Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis

Background  Systemic exposure to tacrolimus following topical application of tacrolimus ointment is minimal. There are, however, no data on the distribution of tacrolimus in the skin.
Objectives  To assess the distribution of tacrolimus in the skin and the systemic pharmacokinetics of tacrolimus in adults with moderate to severe atopic dermatitis after first and repeated application of tacrolimus ointment.
Methods  We investigated skin distribution of topically applied tacrolimus and systemic pharmacokinetics of percutaneously absorbed tacrolimus in adults with atopic dermatitis after topical application of tacrolimus 0·1% ointment twice daily for 2 weeks. Tacrolimus concentrations were assessed in full-thickness skin biopsies and blood samples.
Results  Of 14 patients, 11 completed treatment and were analysed. Mean ± SD tacrolimus concentrations in the skin at 24 h after first and last ointment applications were 94 ± 20 and 595 ± 98 ng cm⁻³, respectively. At 168 h after stopping treatment, values were 97% lower than at 24 h after last application. Tacrolimus concentration decreased with increasing skin depth. Systemic tacrolimus exposure after ointment application was low and highly variable, with 31% of samples below the limit of quantification (0·025 ng mL⁻¹) and 94% below 1 ng mL⁻¹. Blood concentrations at 24 h after the first and last ointment applications were 750 and 1800 times lower, respectively, than those in skin. Physicians' assessments showed that tacrolimus ointment was effective and well tolerated.
Conclusions  Tacrolimus was primarily partitioned in the skin, with minimal systemic absorption after topical application, in patients with atopic dermatitis.     

Potential future dermatological indications for tacrolimus ointment

Tacrolimus ointment is a steroid-free topical immunomodulator developed for the treatment of atopic dermatitis, a common, chronic inflammatory skin disease. By inhibiting T-cell activation and cytokine production, topically applied tacrolimus modulates inflammatory responses in the skin. Numerous clinical trials have shown that it is effective and well tolerated for the treatment of atopic dermatitis, its licensed indication. In addition, numerous publications suggest that tacrolimus ointment may provide effective treatment for a variety of other inflammatory skin disorders, many of which are very difficult to manage with standard therapy. This paper reviews currently available evidence regarding the use of tacrolimus ointment in a range of dermatological disorders, including psoriasis, lichen planus, pyoderma gangrenosum, lichen sclerosus, contact dermatitis, leg ulcers in rheumatoid arthritis, steroid-induced rosacea and alopecia areata. It also provides recommendations for future clinical studies with tacrolimus ointment.     

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

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

Eczema molluscatum in tacrolimus treated atopic dermatitis

Eczema molluscatum describes the occurrence of molluscum contagiosum virus infection in a patient with underlying atopic dermatitis. Novel, safe and effective treatment options in atopic dermatitis are the topical immunomodulators tacrolimus and pimecrolimus. One major advantage over corticosteroids is that they do not induce skin atrophy. Some physicians fear that topical immunomodulators may predispose patients to skin infections. We observed a patient with atopic dermatitis who developed eczema molluscatum during treatment with tacrolimus 0.1% ointment. After withdrawal of tacrolimus, the lesions resolved spontaneously over 3 weeks.     

Tacrolimus clinical studies for atopic dermatitis and other conditions

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.     

An open study of a lotion formulation to improve tolerance of tacrolimus in facial atopic dermatitis

BACKGROUND: We identified 19 patients with facial atopic eczema who failed to respond to tacrolimus (FK506) ointment, although tacrolimus ointment has shown excellent benefit for the treatment of recalcitrant facial erythema in most patients with atopic dermatitis. OBJECTIVES: We attempted to determine the efficacy of an original lotion formulation of tacrolimus for facial atopic dermatitis resistant to tacrolimus ointment. PATIENTS/METHODS: Recalcitrant facial erythema of these 19 patients was treated with an original tacrolimus lotion preparation for 6 months. Patch testing with white petrolatum was performed in both the 19 patients and in 30 other atopic dermatitis patients who had experienced excellent results with tacrolimus ointment. RESULTS: Of the 19 resistant patients, those whose symptoms were greatly or moderately improved by the lotion were 95%, 89% and 89% after 2 weeks, 3 months and 6 months of treatment, respectively. Further, patch testing to petrolatum showed positive reactions in several (six of 19) patients, compared with none of 30 controls with atopic eczema that had responded to topical tacrolimus ointment. CONCLUSIONS: The tacrolimus lotion had a significant effect on the recalcitrant facial erythema in adult patients with atopic dermatitis who were resistant to tacrolimus ointment. We suggest that one reason for the unresponsiveness to tacrolimus ointment may be because of contact sensitivity to white petrolatum.     

Efficacy and safety of topical JTE‐052, a Janus kinase inhibitor,in Japanese adult patients with moderate‐to‐severe atopic dermatitis: a phase II,multicentre randomized,vehicle‐controlled clinical study

Atopic dermatitis (eczema) is a chronic, and sometimes debilitating, inflammatory skin disease which causes itching and damaged skin barrier function. Current treatments include topical (applied to the skin) corticosteroids and calcineurin inhibitors such as tacrolimus; unfortunately long‐term use of topical corticosteroids may cause thinning of the skin and tacrolimus can be irritant. Kinases are enzymes that are important to many roles of cells within the body, and the Janus Kinase (JAK) pathway plays a role in inflammation. In recent years, medicines that inhibit this pathway have been developed, with potential benefit in inflammatory skin diseases such as eczema or psoriasis. The authors, based in Tokyo and Hokkaido, Japan, studied the effect of different concentrations (0.5‐3%) of a topical JAK inhibitor, JTE‐052, in adults with moderate to severe atopic dermatitis, compared with the vehicle on its own (the ointment to which the medicine is added), and with 0.1% tacrolimus ointment. They used a modified Eczema Area and Severity Score before and after 4 weeks of treatment to allow them to see how well each of the treatments was working. In the patients using the 3% concentration there was 73% improvement in the score, compared with 12% using the placebo (vehicle) ointment. There was a 62% improvement in the patients using tacrolimus. Even the 3% concentration of JTE‐052 was very well tolerated, without the irritancy and burning seen with tacrolimus, and the patients using JTE‐052 noticed a reduction in itching within a day of starting treatment. The authors conclude that topical use of this JAK inhibitor is effective in the treatment of atopic dermatitis.     

Tacrolimus ointment (Protopic) for atopic dermatitis

Tacrolimus ointment (Protopic, Fujisawa) is an effective agent in a class of topical immunomodulators. Its mechanism of action is based on calcineurin inhibition, which results in decreased T-cell activation and inflammatory cytokine release. Tacrolimus ointment is safe and effective for short- and long-term treatment of atopic dermatitis (AD) in pediatric and adult patients. The most common adverse events associated with its use are a transient burning sensation and pruritus at the site of application. Unlike topical corticosteroid agents, tacrolimus ointment does not cause a reduction in collagen synthesis or skin thickness. Because tacrolimus ointment does not cause skin atrophy, it may be safely used for months or years on all skin areas, including the face and intertriginous areas.     

A single‐center open‐label long‐term comparison of tacrolimus ointment and topical corticosteroids for treatment of atopic dermatitis

Background: Atopic dermatitis is a chronic or recurrent inflammatory skin disease that often requires treatment over years. According to its severity, atopic dermatitis is often managed with use of emollients, topical corticosteroids, topical calcineurin inhibitors or systemic agents. This long‐term study compares the efficacy of tacrolimus 0.1% ointment with topical corticosteroids as standard therapy in patients with moderate atopic dermatitis. Patients and methods: 50 patients were enrolled. They were allocated to treatment groups by the investigator (tacrolimus group or standard group), and followed over a period of six to twenty months. Efficacy was evaluated by the Eczema Area Severity Index (EASI), the percentage of affected body surface area, and the score of Rajka and Langeland. In addition, ointment usage was documented and analyzed. Results: The improvement of the skin condition was statistically significant in both groups. The comparison of the two groups, however, did not show a statistically significant advantage of one or the other treatment. Ointment usage was slightly higher in the standard group. Conclusions: The efficacy of tacrolimus 0.1% ointment was confirmed. In terms of emollient usage, no regular pattern could be demonstrated.     

Non-steroidal topical immunomodulators provide skin-selective, self-limiting treatment in atopic dermatitis

Topical corticosteroids are the mainstay of treatment for atopic dermatitis; however, their clinical utility is limited by potential side effects. Recently, the steroid-free topical immunomodulators tacrolimus ointment and pimecrolimus cream have become available. These agents provide effective treatment without causing skin atrophy or other steroidal side effects, and their physiochemical properties, such as relatively large molecular size and high lipophilicity, limit diffusion through skin and into the bloodstream, providing skin-selective treatment. Clinical trials with more than 1,700 paediatric and adult patients have demonstrated that treatment with either agent is associated with minimal systemic absorption of tacrolimus or pimecrolimus. Additionally, studies have shown that percutaneous absorption of tacrolimus decreases as treatment continues and clinical improvement occurs. This self-limiting facet of the treatment, together with the skin-selectivity of topical immunomodulators, is reflected in the good safety and tolerability profiles of these agents, which promise to significantly improve the long-term management of atopic dermatitis.     

Topical noncorticosteroid immunomodulation in the treatment of atopic dermatitis

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

特应性皮炎皮损HSP70的表达及他克莫司对其表达的影响

目的:探讨热休克蛋白(HSP)70在特应性皮炎(AD)中的表达及外用他克莫司对HSP70表达的影响。方法:采用免疫组化二步法检测8例中至重度AD患者急性发作期炎性皮损HSP70表达及外用0.1%或0.03%他克莫司软膏治疗AD3周后HSP70表达的变化。结果:免疫组化检测显示HSP70在AD急性发作期炎性皮损角质形成细胞(KC)的胞核,胞浆及胞膜外过度表达,其中在3例大面积泛发或红皮病型急性AD皮损KC中,HSP70以弥漫性细胞核表达伴胞浆表达为特征,主要定位于基底层至颗粒层;外用他克莫司软膏治疗3周后特应性皮炎皮损KCHSP70的核表达消失,胞浆及膜(表面)表达信号减弱。结论:急性期AD皮肤KC的HSP70过度表达;他克莫司可通过直接或间接作用抑制KC的HSP70诱导性或过度表达,从而可抑制或下调与内源性HSP70危险信号有关的AD皮肤天然自身免疫炎症反应。