Potential future dermatological indications for tacrolimus ointment

ARTICLE

Auteur(s) : Thomas Ruzicka*, Till Assmann*, Mark Lebwohl^†

*Department of Dermatology, University of Dsseldorf, Moorenstr 5, D-40225 Dsseldorf, Germany
^† Department of Dermatology, The Mount Sinai Hospital, New York, USA

Article accepted on 09/04/2003

Article accepted on 09/04/2003

Conventional treatment for many inflammatory skin disorders relies primarily on the use of topical corticosteroids. Although these agents are usually effective, their clinical utility is limited by the potential for local and systemic side effects [1, 2]. For decades, there were no effective alternatives to corticosteroids. Cyclosporin, an immunosuppressant, was one of the first non-steroidal drugs used successfully in dermatology and has had a major impact on the treatment of severe inflammatory skin disorders [3]. However, it is not effective when applied topically [4-6], and oral administration is limited by serious adverse events such as nephrotoxicity and hypertension [7]. More recently, immunomodulatory compounds with topical activity, such as tacrolimus (previously known as FK506), have been evaluated in large-scale clinical trials and have shown great promise in the treatment of inflammatory diseases [8].

In the late 1980s, tacrolimus was isolated from the fermentation broth of Streptomyces tsukubaensis, a fungus-like bacterium first identified in Japan [9]. Preclinical studies revealed that tacrolimus blocked T-cell activation and had the potential to modulate the immunological mechanisms underlying many inflammatory skin disorders. In the early 1990s, an ointment formulation of tacrolimus was developed for the treatment of atopic dFermatitis.

Despite differences in chemical structure, the mechanism of action of tacrolimus and cyclosporin is similar, as both are calcineurin inhibitors and block early stages of T-cell activation and subsequent cytokine production [10, 11]. While the skin penetration of tacrolimus is superior to that of cyclosporin, due in part to differences in molecular weight [12, 13], systemic absorption of topically applied tacrolimus is minimal and decreases with continued treatment [14, 15]. In addition to inhibiting calcineurin activity and suppressing cytokine production from T cells, tacrolimus targets other processes implicated in the pathogenesis of inflammatory skin disorders. Its actions include: reducing cell-surface expression of receptors and costimulatory molecules on epidermal antigen-presenting cells [16, 17]; blocking the release of inflammatory mediators from mast cells and basophils [18, 19]; reducing levels of Staphylococcus aureus colonisation in atopic dermatitis lesions [20, 21]; decreasing intercellular adhesion molecule (ICAM)-1 and E-selectin expression on blood vessels [22]; as well as reducing levels of both interleukin (IL)-8 and IL-8 receptors [23, 24].
Clinical studies with tacrolimus ointment have been conducted in Europe, Japan and North America in what has become the most extensive and comprehensive clinical development programme conducted in dermatology [25]. More than 16,000 adult and paediatric atopic dermatitis patients have participated in over 30 clinical studies [26]. The efficacy and safety of tacrolimus ointment, for both short- and long-term treatment of moderate to severe atopic dermatitis, has been demonstrated in large, multicentre studies [15, 27-31]. Tacrolimus ointment is well tolerated. Application-site skin burning and pruritus are the most common side effects, but are typically transient, lasting 15-20 minutes, and primarily occurring during the first few days of treatment [15]. As tacrolimus provides the efficacy of commonly prescribed topical corticosteroids without adverse effects on skin thickness or other steroidal side effects, its development as a topical agent represents a significant advance in therapy for atopic dermatitis [30-32]. Tacrolimus ointment is currently approved for the treatment of atopic dermatitis in adults and children at least two years of age in numerous European countries, the US and Canada, and for adults only in Japan.
Data from pilot studies and case reports indicate that topical tacrolimus may provide effective and well-tolerated therapy for a variety of other inflammatory skin disorders. This review will focus on the use of tacrolimus in psoriasis, lichen planus, pyoderma gangrenosum, lichen sclerosus, contact dermatitis, leg ulcers in rheumatoid arthritis, steroid-induced rosacea and alopecia areata. An overview of the current clinical experience with topical tacrolimus in these and other diseases can be found in the summary table (Table I).

Table I. Off-label use of topical tacrolimus in dermatological disorders.*

Admin. = administration; AEs = adverse events; aza. = azathioprine; b.i.d. = twice daily; BV = betamethasone valerate; bud. = budesonide; cal. = calcipotriol; CHX = chlorhexidine; CP = clobetasol propionate; CyA = cyclosporin; d. = day; dex. = dexamethasone; DNCB = dinitrochlorobenzene; LoQ = limit of quantification; mins. = minutes; mths. = months; MTX = methotrexate; NS = not stated; o.d. = once daily; oint. = ointment; para. = paraffin; p.c. = propylene carbonate; p.g. = propylene glycol; q.i.d. = four times daily; rap. = rapamycin; SCID = severe combined immunodeficient; soln. = solution; s.a. = stearyl alcohol; tacro. = tacrolimus; t.i.d. = three times daily; t.w. = twice weekly; veh. = vehicle; w.p. = white petrolatum; wk. = week.
*Topical treatment unless otherwise stated; ^†dose not stated; ^‡topical corticosteroids (n = 2), antifungals (n = 4), tretinoin (n = 1); ^§with and without penetration enhancer.

Psoriasis

Psoriasis is a common, chronic, relapsing inflammatory skin disorder that occurs in approximately 2% of the population in Europe and North America [33]. Characteristic clinical signs include erythematous plaques covered in white scales, increased epidermal thickness and infiltration of T cells into the skin. First-line therapy consists of topical drugs (such as dithranol, tar-based creams, corticosteroids, vitamin D derivatives and retinoids), while ultraviolet (UV) light therapy (psoralens plus UVA [PUVA] photochemotherapy and broad- or narrow-band UVB) and systemic drugs (including immunosuppressants, such as methotrexate and cyclosporin, fumaric acid esters and retinoids) are used in severe disease refractory to topical treatment. The potential adverse effects of many of these treatments, particularly when systemically administered, are well documented [1, 2, 7].
T cells appear to play an important role in psoriasis, initiating immunological responses that result in epidermal hyperproliferation (reviewed in reference [34]). Activation of T-helper (TH)-1 cells present in the upper dermis results in production of cytokines, including IL-2, IL-8, interferon (IFN)-γ, and tumour necrosis factor (TNF)-α. These cytokines produce inflammation and stimulate T-cell infiltration and proliferation. In vitro studies and clinical experience with systemically administered tacrolimus have shown that tacrolimus targets abnormal immune responses associated with psoriasis, reducing T-cell activation, expression of molecules involved in cell migration, such as ICAM-1 and E-selectin, as well as levels of IL-2 receptors, IL-8 and IL-8 receptors [22-24]. As oral tacrolimus provides effective treatment for psoriasis but is limited by the potential for systemic side effects [35], the use of topical tacrolimus was assessed in several small studies (Table I).
In a 6-week, randomised, pilot study with 70 psoriasis patients, once-daily treatment with tacrolimus 0.3% ointment or vehicle, or twice-daily treatment with calcipotriol 0.005% ointment was evaluated under non-occlusive conditions [36]. Clinical improvement with tacrolimus was not significantly different from vehicle, and tacrolimus was less effective than calcipotriol. These results may be due to poor tacrolimus penetration through thick, scaly lesional skin, as results of a subsequent study suggest that the use of occlusion is associated with greater efficacy. In this randomised, double-blind trial involving 16 patients, tacrolimus 0.3% ointment (applied with or without a penetration enhancer) was compared with betamethasone valerate 0.1% ointment, calcipotriol 0.005% ointment and the ointment bases for tacrolimus and betamethasone [37]. Study ointments were applied on descaled lesions under occlusive conditions every 2-3 days for 2 weeks using a microplaque assay. Both tacrolimus treatments produced significant improvements in erythema and infiltration (both p < 0.001), superficial blood flow (p < 0.01) and epidermal thickness (p = 0.001) compared with vehicle. The two tacrolimus treatments were more effective than calcipotriol on day 7, but results were similar by day 14. Betamethasone was more effective than the other three active treatments. All of the study medications were well tolerated, and no application-site or systemic adverse events were observed.
Psoriatic lesions on facial and intertriginous areas are usually thinner than lesions on the trunk and extremities and are not suitable for treatment with potent topical corticosteroids. As tacrolimus ointment is well tolerated for the treatment of atopic dermatitis affecting these areas, its clinical utility was evaluated in psoriatic lesions on the face and intertriginous regions. In an open-label study, 11 patients with facial psoriasis applied tacrolimus 0.1% ointment twice daily for 4 weeks [38]. Marked improvement was observed in five patients after 2 weeks and in 10 patients at the end of the study. Of these 10 patients, there were five complete remissions and five partial remissions at the end of the trial. No adverse events affecting liver or renal function were observed. A similar open-label, non-comparative study evaluated twice-daily treatment with tacrolimus 0.1% ointment in 21 patients with psoriasis on the face and/or intertriginous areas [39]. Significant improvement was observed in erythema, infiltration and desquamation from baseline to the end of the 8-week trial (p value not stated). All patients experienced clearance or marked (≥ 75%) improvement within 1-4 weeks based on the physician’s global evaluation of change in disease status. After 8 weeks of treatment, clearance occurred in 17 patients and marked improvement was observed in the remaining four patients. Tacrolimus was well tolerated. Adverse events were reported by two patients, who experienced mild application-site burning or pruritus during the first few days of treatment. These results are in accordance with our own clinical experience, which indicates that tacrolimus ointment may provide effective treatment for psoriasis affecting seborrhœic skin regions (unpublished observations).
Taken together, the available evidence suggests a promising role for tacrolimus ointment in the management of psoriasis, particularly for the treatment of facial and intertriginous areas where potent corticosteroids cannot be used due to safety concerns. However, further studies are required to fully evaluate the safety and efficacy of topical tacrolimus in this indication.

Lichen planus

Lichen planus is a chronic, recurring, inflammatory, papular skin disorder of unknown aetiology that is relatively common, affecting up to 2% of Europeans and Caucasian Americans [40-42]. Oral mucosal lichen planus is the most common variant, but flexor surfaces, genitalia and other mucosal membranes may also be involved. Although oral lichen planus is often asymptomatic, severe exacerbations may cause erosive and ulcerative lesions that are painful and interfere with eating, speech and swallowing [43]. Severe erosive mucosal lichen planus is often resistant to topical drugs [44], and treatment with systemic drugs, such as retinoids or corticosteroids, carries the risk of systemic side effects [45]. Antibiotics, antifungal agents and antimalarial drugs may also be prescribed, but evidence of efficacy from controlled trials is currently not available.
As cytokines produced by T cells and keratinocytes are thought to play a role in the pathogenesis of lichen planus [46, 47], the potential efficacy of topical tacrolimus was investigated. In a series of case reports, severe recalcitrant erosive mucosal lichen planus resolved completely within 4 weeks in three out of six patients treated with extemporaneous tacrolimus 0.1% ointment twice a day [48]. In the three remaining patients, substantial improvement was observed after 4 weeks, and further once-daily treatment resulted in additional improvement or complete resolution. Treatment led to rapid relief from lesional pain as well as burning and was well tolerated. Two patients reported slight, transient burning immediately after application which diminished as erosions cleared. Tacrolimus blood levels were measured weekly during therapy and were undetectable in samples from five of the six patients. Elevated tacrolimus levels, ranging from 9 to 15 ng/mL, occurred in three samples from a single patient with extensive erosions and were not associated with systemic side effects. Within 3-8 weeks of treatment discontinuation, the lesions relapsed in five patients, suggesting that long-term tacrolimus treatment may be required in this indication.
Subsequent reports have yielded promising indications that tacrolimus treatment may be effective in lichen planus (Table I) [44, 45, 49-52]. One study included 19 patients with erosive or ulcerative oral disease refractory to or dependent on systemic corticosteroids or other immunosuppressive therapies [45]. All 17 patients who completed the 8-week trial experienced significant improvement in symptoms of pain and discomfort after 1 week of therapy with extemporaneous tacrolimus 0.1% ointment (p < 0.001 vs baseline). At the end of an 8-week treatment period, lesional surface area was reduced by an average of 73% (p < 0.001 vs baseline). Ten patients reported transient, minor adverse events, the most common of which were burning or tingling sensations in the mouth that resolved within 72 hours of cessation of therapy.
A retrospective review of several case studies included 13 patients with oral lichen planus treated with extemporaneous tacrolimus 0.03%, 0.1% or 0.3% ointment two, three or four times a day [44]. Seven patients received concomitant therapy with antifungal agents, mouthwash, topical corticosteroids or retinoids. Clinical improvement, defined as reduction in pain, irritation or altered sensation, was observed in 11 of the 13 patients, with six patients responding to therapy by week 1 and a further five patients responding within 1 month. Lesions were completely cleared in three patients, while eight experienced a partial response. All tacrolimus concentrations were associated with clinical responses, although only the tacrolimus 0.1% and 0.3% led to complete responses. The only adverse events reported were burning sensations in two patients and a sore throat in one patient.
In an open-label trial, six patients with erosive oral lichen planus were treated with either commercially available or extemporaneous tacrolimus 0.1% ointment two or three times daily [51]. Each patient had failed to respond to potent topical corticosteroids and had been affected with the disease for 2-9 years. After three months of tacrolimus treatment, all patients experienced substantial clinical improvement, and no local or systemic adverse events were reported. In five patients, tacrolimus blood levels were very low or undetectable. In one patient, improvement may have been due to a systemic effect as an elevated tacrolimus level of 9.6 ng/mL (and a repeat level of 9.9 ng/mL) was measured.
Our experience with tacrolimus ointment in this indication has been similarly positive (Fig. 1; unpublished observations). Collectively, these data indicate that tacrolimus ointment may provide effective and well-tolerated treatment for lichen planus. However, further clinical experience is required to confirm these promising results.

Pyoderma gangrenosum

Pyoderma gangrenosum is an uncommon, chronic skin condition characterised by painful, rapidly enlarging necrotic ulcers with undermined purplish margins and surrounding erythema. It typically presents on the trunk or lower extremities and may be precipitated or aggravated by a minor injury. Up to 50% of pyoderma gangrenosum cases are associated with systemic inflammatory diseases, such as ulcerative colitis, Crohn’s disease, rheumatoid arthritis and monoclonal gammopathy [53]. The precise cause of pyoderma gangrenosum is unknown. While various immunological abnormalities, such as altered delayed-type hypersensitivity responses, have been reported in individual patients, a common abnormality has not yet been identified (reviewed in reference [54]). The cellular infiltrate present in lesions is primarily composed of neutrophils, and elevated levels of IL-8, a chemotactic factor for neutrophils, have also been reported in lesional skin [55, 56]. Topical treatment for pyoderma gangrenosum consists of wound care and corticosteroids. However, systemic treatment is often necessary, particularly in patients with severe and rapid development of the disease. Currently, there is no standard treatment and various systemic agents are used including corticosteroids, dapsone, sulphasalazine, cyclosporin and thalidomide [53, 57].
Tacrolimus has a similar mode of action to cyclosporin but displays superior topical activity in inflammatory diseases, suggesting that it may provide effective topical treatment for pyoderma gangrenosum. Additionally, in other inflammatory skin diseases, tacrolimus has been shown to suppress production of IL-8, which appears to be an important pathogenic factor in pyoderma gangrenosum [23, 24, 56]. It was therefore of interest to evaluate the clinical utility of topical tacrolimus in the treatment of this disease.
Several case studies provide preliminary evidence of the efficacy of topical tacrolimus in this disease (Table I). In one case, a 32-year-old woman, who had previously undergone unsuccessful therapy with systemic corticosteroids, experienced complete resolution after 12 weeks of therapy with 0.5% tacrolimus solution and hydrocolloidal dressings [58]. In addition, treatment with extemporaneous tacrolimus 0.1% ointment or a topical solution (ranging from 0.5-5 mg/mL) was associated with healing or marked improvement in three case reports with a total of four patients [59-61]. These case reports include a 63-year-old patient with painful, rapidly growing ulcers of the lower legs. After systemic therapy failed and pyoderma gangrenosum-associated diseases were excluded, the patient was successfully treated with tacrolimus 0.5% solution and hydrocolloidal dressing, which resulted in complete healing within 12 weeks (Fig. 2) [59]. Topical tacrolimus was similarly effective in a comparative study involving 24 patients with peristomal pyoderma gangrenosum, who received once-daily topical treatment with either tacrolimus 0.3% paste or clobetasol propionate 0.05% (as a lotion or ointment under occlusion) [62]. Of the 11 patients who received tacrolimus, seven experienced complete healing. In comparison, complete healing occurred with five of the 13 patients in the clobetasol propionate group. Tacrolimus was significantly more effective than clobetasol propionate in healing large ulcers greater than 2 cm in diameter (p < 0.05). In this study, tacrolimus-mediated healing was associated with prominent granulation at the base of ulcers, which was treated effectively with flurandrenolone-impregnated tape. Topical tacrolimus was also used successfully in combination with oral tacrolimus or corticosteroids in two patients [63, 64].
In all of the case studies reported to date, topical tacrolimus was well tolerated. In addition to the over-granulation described above, transient application-site burning was reported in more than one patient. These preliminary data indicate that topical tacrolimus is a promising treatment option for patients who are resistant to or intolerant of conventional therapy for pyoderma gangrenosum.

Lichen sclerosus

An uncommon disorder that usually involves the genitals, lichen sclerosus is characterised by white atrophic plaques in females and phimosis in males. Postmenopausal women are most commonly affected, but the disease can occur in both sexes at any age, and extragenital regions such as the inner thighs, neck, breasts and shoulders may be involved. The aetiology of lichen sclerosus is unclear. There is preliminary evidence of a genetic, autoimmune component, as an association with several major histocompatibility complex (MHC) class II antigens has been reported [65]. The disease is chronic and usually permanent, although spontaneous resolution may occur at puberty in paediatric patients. Conventional treatment usually consists of topical corticosteroids, but potent formulations are often required and skin atrophy may occur with long-term use. Ointments containing progesterone, oestrogen or testosterone may also be prescribed, although their efficacy is questionable. Retinoids are often effective [66, 67], but topical use is limited by the potential for irritation, and oral treatment is associated with side effects that include dryness of the skin and mucous membranes, rheumatic symptoms and teratogenicity.
The efficacy of topical tacrolimus in other inflammatory skin disorders, together with its lack of atrophogenicity, suggest that tacrolimus ointment may be a useful therapeutic option for lichen sclerosus. Tacrolimus was therefore used in a case study with two female patients who suffered from recalcitrant vulvar lichen sclerosus for more than 10 years and were unresponsive to topical corticosteroids (Table I) [68]. Twice-daily treatment with tacrolimus 0.1% ointment for 6 weeks led to considerable improvement in itching, pain and clinical signs (Fig. 3). Therapy was well tolerated, and the only notable adverse event was slight application-site burning during the first week of therapy. Our experience in a larger series of patients with lichen sclerosus of the vulva and penis adds further support for the use of tacrolimus in this indication and highlights the need for controlled clinical studies (unpublished observations).

Contact dermatitis

Contact dermatitis is triggered by exogenous irritants or allergens in various objects and substances such as jewellery, chemicals or plants [69]. Treatment involves identification, avoidance of the irritant and use of emollients, moisturisers, antihistamines and topical corticosteroids. Systemic corticosteroids may be required if severe blistering is present.
The efficacy of topical tacrolimus in atopic dermatitis has stimulated interest in the use of tacrolimus ointment in contact dermatitis. Preclinical studies in pigs and guinea pigs suggest that topical tacrolimus may be effective in the prevention and treatment of acute allergic and irritant contact dermatitis (Table I) [12, 70]. It was therefore of interest to evaluate the efficacy of tacrolimus in clinical studies. In an open-label trial, healthy forearm skin of five volunteers with contact hypersensitivity to dinitrochlorobenzene (DNCB) was pretreated with tacrolimus 0.01%, 0.1% and 1% in ethanol and with vehicle (ethanol) for 48 hours [71]. Subsequent application of DNCB led to dermatitis 24 hours later only on the vehicle-treated area; histological changes were not present on any of the tacrolimus-treatment sites. In one volunteer, skin biopsies were obtained from areas pretreated with tacrolimus 1% and vehicle. No inflammatory changes were present at the tacrolimus-treatment site, while intense dermatitis was observed at the site pretreated with vehicle. No systemic adverse events occurred, and cutaneous side effects were not mentioned in the report. These positive findings indicate that further studies with topical tacrolimus are warranted in the treatment of acute contact dermatitis.

Leg ulcers in rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory, auto-immune disease that primarily affects cartilage and bone. The cause of this disease is not known, although activated T cells in the synovial fluid appear to play a major pathogenic role by secreting cytokines that trigger inflammatory responses. Dermatological manifestations of rheumatoid arthritis range from nodules to severe vasculitis with digital infarcts, palpable purpura and cutaneous ulcers. Leg ulcers occur in 0.6-8% of patients and are often associated with vasculitis, venous insufficiency, arterial disease, diabetes and corticosteroid-induced skin fragility [72-74]. Treatment of severe skin ulcers in rheumatoid arthritis is complicated because topical therapies are largely ineffective and systemic therapies, such as plasmapheresis and corticosteroids, cyclosporin as well as other immunosuppressants, are restricted by potentially severe side effects [75, 76]. In view of the involvement of T cells in the pathogenesis of rheumatoid arthritis and the need for effective topical treatments, interest has focused on the use of topical tacrolimus in this indication (Table I).
A 65-year-old woman with an 8-year history of severe rheumatoid arthritis received topical tacrolimus treatment for a painful and rapidly growing vasculitic ulcer [77]. Intensive, long-term topical treatment including corticosteroids and cyclosporin solution had previously failed to heal the ulcer, and systemic therapy could not be administered due to corticosteroid-induced osteoporosis and prior adverse reactions to non-steroidal therapies. Daily, topical application of tacrolimus 0.5% solution combined with wound care led to almost complete healing after 5 months. Burning pain during application was the only adverse event reported, and the drug was not detectable in blood samples. In another case study, a 62-year-old female patient receiving methotrexate and prednisone for rheumatoid arthritis developed a leg ulceration that failed to respond to conventional topical wound treatment [68]. Adjunctive therapy with tacrolimus 0.5% solution healed the ulcer within 7 weeks. These preliminary results and those of others (S Reitamo, personal communication) suggest that topical tacrolimus may greatly improve treatment options for leg ulcers associated with rheumatoid arthritis.

Steroid-induced rosacea

Prolonged use of corticosteroids, especially on the face, can cause a rosacea-like skin disorder in susceptible individuals [78, 79]. Steroid-induced rosacea is an inflammatory facial dermatosis characterised by erythema, papules, pustules and telangiectasia that usually worsens after discontinuation of corticosteroid treatment. As the vasoconstrictive properties of corticosteroids cause nitric oxide and other vasodilatory agents to accumulate in the skin, the withdrawal of corticosteroids can lead to vasodilation, which potentiates erythema, pruritus and burning [80]. The immunosuppressive properties of corticosteroids may also facilitate the growth of micro-organisms in the skin, such as Staphylococcus aureus, that contribute to disease pathogenesis by producing superantigens and triggering inflammation once corticosteroid therapy ceases. Treatment is often difficult and prolonged, and strict avoidance of corticosteroids is necessary. Topical and systemic antibiotics with anti-inflammatory properties, such as metronidazole and tetracycline, are commonly used in conjunction with antihistamines, emollients and moisturisers. The anti-inflammatory properties of tacrolimus and limited clinical experience suggest that it may provide effective treatment for steroid-induced rosacea (Table I).
In one case study, three patients with steroid-induced rosacea applied tacrolimus 0.075% ointment twice daily for 7-10 days while avoiding topical corticosteroids and rosacea-aggravating substances [81]. All three patients experienced disease improvement within 7 days. Treatment was well tolerated, with transient application-site burning the only side effect reported. When tacrolimus treatment was withdrawn, all three patients experienced mild flares of rosacea that resolved within a few days or several weeks of topical or oral antibiotic therapy.
These case reports and our own experience in a limited number of patients (Fig. 4; unpublished observations) suggest that tacrolimus ointment may be effective and well tolerated in this indication. Furthermore, the rapid response to tacrolimus ointment observed in several cases suggests it may act more quickly than conventional therapies; however, large, randomised, controlled studies are required to confirm these preliminary findings.

Alopecia areata

Alopecia areata is characterised by sudden, circumscribed hair loss and appears to be an autoimmune disease. It can occur in both sexes at any age and usually affects the scalp and beard, although all areas of hair growth are susceptible. The disease course is variable; hair loss may resolve spontaneously with time or progress to affect the entire scalp or body [82, 83]. Current treatment options include minoxidil, dithranol, intralesional and topical corticosteroids, diphencyprone, PUVA therapy and combination regimens. However, topical irritants and sensitisers can cause allergic reactions, and corticosteroid treatment may lead to adverse effects such as skin atrophy. Furthermore, extreme cases of alopecia areata do not respond well to current treatment options [84].
Preclinical studies have shown that topical tacrolimus stimulates hair growth in several animal models. In mice, rats and hamsters, hair growth was observed at sites treated with various concentrations of topical tacrolimus (Table I) [85-87]. As topical tacrolimus stimulated hair growth in severe combined immunodeficient (SCID) mice, which lack functional B and T cells, it seems unlikely that hair growth was caused by the immunomodulatory properties of tacrolimus [87]. These preclinical results led physicians to investigate the use of topical tacrolimus in patients who failed to respond to conventional therapy for alopecia areata. An 11-year-old girl with alopecia universalis experienced partial hair regrowth following twice-daily treatment with tacrolimus 2% solution [88]. The new hair was thinner than her previous hair and included dense and patchy areas as well as vellus hairs. A second case study involved a 9-year-old boy with alopecia areata who had been treated unsuccessfully with topical steroids and dithranol [89]. This patient had no hair growth after 6 months of therapy with tacrolimus 0.3% ointment and eventually progressed to alopecia totalis. These findings indicate that further studies are required to establish conclusively whether tacrolimus ointment is effective for the treatment of alopecia areata.

Other potential dermatological indications

In addition to the indications discussed above, clinical experience with tacrolimus ointment extends to several other dermatological disorders (Table I). These include: atopic blepharitis [90]; chronic actinic dermatitis [91, 92]; Crohn’s disease [93-95]; discoid lupus erythematosus [96]; eyelid dermatitis [97]; seborrhœic dermatitis [98]; uremic pruritus [99] and vitiligo [100-103].

Conclusions

Tacrolimus ointment is a steroid-free topical immunomodulator with proven efficacy in atopic dermatitis. Case reports and small pilot studies suggest that topical tacrolimus may be effective in numerous other inflammatory skin disorders, particularly T-cell mediated skin diseases and other disorders that respond to therapy with cyclosporin or corticosteroids [104]. On the basis of the preliminary findings reported in this review, there is a promising role for topical tacrolimus in a range of inflammatory dermatoses and large, systematic, controlled studies are warranted to confirm the efficacy and safety of topical tacrolimus in several indications, including psoriasis, lichen planus, pyoderma gangrenosum, lichen sclerosus, leg ulcers in rheumatoid arthritis and steroid-induced rosacea.

Acknowledgements. The authors would like to thank Catrin Lougher and Molly Heitz for their assistance in drafting the manuscript. Catrin Lougher and Molly Heitz are medical writers with ACUMED®.

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