Topical Tacrolimus and Pimecrolimus in Dermatology: An Overview

Introduction Tacrolimus (FK506) is a macrolide obtained from Streptomycestsukubaensis (a soil bacterium). It has a molecular weight of 804 Da, enabling better penetration of inflamed skin in patients with atopic dermatitis (AD). Apart from its topical use in dermatologic disorders, it has been used intravenously/orally to prevent organ rejection following renal/liver transplantation. Mechanism of Action The primary mechanism of action of tacrolimus is elucidated in Figure 1.1-4 Other mechanisms by which tacrolimus acts include: Blockade of Staphylococcus aureus induced T cell proliferation in peripheral blood mononuclear cells, obtained from patients with AD as well as normal controls,5 and Reduction of S. aureus colonization in lesional skin of AD by an unknown mechanism.6 Figure 1: Mechanism of action of tacrolimusIndications, contraindications, and pregnancy prescribing status of tacrolimus are represented in Figure 2.Figure 2: Indications, contraindications and pregnancy prescribing status of tacrolimusClinical Uses Atopic dermatitis Currently, tacrolimus ointment is indicated as first-line therapy for short term and noncontinuous treatment of moderate to severe AD in nonimmunocompromised adults and children, or as a second-line drug in those who have failed to respond adequately to other topical prescription treatments, including topical corticosteroids (TCSs).7 Besides, topical tacrolimus is safe and effective in AD, even if used for periods as long as 6–12 months.8 Topical tacrolimus rapidly ameliorates pruritus in AD; owing to its ability to desensitize cutaneous sensory nerves, and reduce neuropeptide levels in inflamed atopic skin. Moreover, as the cytokine subset inhibited by tacrolimus differs from those inhibited by TCS, it is suggested that combination treatment may be more effective than either agent alone; highlighting the importance of individualizing the choice of topical therapeutic agents in AD patients.9,10 These days, intensive topical treatment with tacrolimus is instituted for AD, till clearance of visible lesions; following which intermittent application is practiced, to prevent disease flares. This approach is based on evidence outlining persistence of subclinical inflammation and impaired barrier function, despite the observation of clear skin, and not only does this reduce and delay the occurrence of disease exacerbation, but attenuates progression of AD to allergic rhinitis or bronchial asthma; the so called atopic march.11 For children (2–15 years of age), 0.03% strength of the drug is indicated; and for individuals above this age, both 0.03% and 0.1% strengths of tacrolimus can be utilized. Safety and efficacy of tacrolimus has been repeatedly demonstrated in various studies. In one study, there was no significant difference between the efficacy of 0.1% and 0.03% tacrolimus for treating AD.12 However, in other reports, 0.1% strength was more effective.13,14 Tacrolimus ointment is applied once daily or twice daily in AD, with twice daily applications demonstrating significantly better results.15 Both strengths of tacrolimus ointment are superior than mild TCS like 1% hydrocortisone acetate, and comparable to medium potency TCS.16 Further, tacrolimus is advantageous over TCS in treating resistant AD over the face and intertriginous areas, where potent TCS can result in cutaneous atrophy and telangiectasia.17 Lichen planus Topical tacrolimus (0.1%) is a safe and effective treatment for oral lichen planus (LP), and its efficacy corresponds to clobetasol propionate (0.05%) ointment.18 A twice daily application schedule is the preferred regimen here. However, some clinicians have demonstrated good results even with once daily drug application programs.19 In an open-label trial using tacrolimus (0.1%) ointment in six patients with erosive oral LP for 3 months; substantial improvement was seen in all patients where tacrolimus was instituted as a second-line therapy following failed TCS treatment.20 Another study utilizing tacrolimus (0.1%) powder in Orabase on seven patients with oral LP (thrice daily application), demonstrated efficacy in bringing about disease control, as well as pain reduction, by the end of 2nd week of treatment. Besides, none of the patients developed yeast infections after application of tacrolimus. Tacrolimus is therefore a good alternative in those patients who are at risk of developing oral candidiasis following use of TCS.21 Resende etal.22 reiterated the beneficial properties of topical tacrolimus (0.1%) in oral LP. In this study, the ointment was applied twice daily for 8 weeks. Within 4 weeks of therapy, pain had completely subsided and lesions were almost imperceptible in few subjects, and completely gone in some. By the end of 8 weeks, further resolution of lesions was documented. In vulvar LP, outcomes with tacrolimus have been favorable, details of which are represented in Table 1.23-25Table 1: Reports on the use of topical tacrolimus (0.1%) in vulvar lichen planusIn nail LP, successful treatment with tacrolimus (0.1%) ointment in a series of five patients was reported, with clinical superiority of tacrolimus over super potent TCS.26 Similarly, in childhood cutaneous LP, topical tacrolimus (0.03%) was effective following unsuccessful attempts with TCS.27 Interestingly, there are no clinical trials of topical tacrolimus for cutaneous LP and its variants. Apart from one prospective study for LP pigmentosus, all others are limited to case reports and are detailed in Table 2.28-36Table 2: Summary of studies of topical tacrolimus for cutaneous lichen planusLichen striatus Tacrolimus (0.03%) ointment (applied twice daily for 12 weeks) was successful in treating lichen striatus (LS) in a 6-year-old girl who had the disease for 1 month.37 In another report, a 22-year-old female with facial LS responded favorably to tacrolimus (0.03%) ointment, dramatically improving within a short period of time.38 Lichen nitidus Both 0.03% and 0.1% strengths of tacrolimus are effective in treating lichen nitidus (LN). In a 32-year-old Filipino male with penile LN, 1 month of treatment with tacrolimus (0.1%) ointment was effective.39 In another report, tacrolimus (0.03%) ointment was successful in the treatment of persistent generalized LN.40 Psoriasis Tacrolimus (0.1%) ointment has illustrated value in facial and intertriginous psoriasis, details of which are documented in Table 3.41-46Table 3: Salient features of studies utilizing tacrolimus for facial/intertriginous psoriasisEven in pediatric psoriasis, tacrolimus has proven to be effective. It is observed that one-third patients with psoriasis have a childhood onset, with facial and inverse psoriasis commonly encountered in this setting. The use of topical calcineurin inhibitors for facial/intertriginous psoriasis allows patients to have greater psoriasis control and simultaneously overcome adverse effects associated with long-term use of TCS. There have been studies evaluating the utility of topical tacrolimus in chronic plaque psoriasis,47 nail psoriasis,48 and pustular psoriasis.49 Owing to its high molecular weight, penetration of tacrolimus is poor for thick plaques, thereby considerably reducing its efficacy in the above psoriasis variants. However, when combined with penetration enhancers, significant improvement has been reported.50 Zoon's balanitis Both 0.03% and 0.1% strengths of tacrolimus have been used in Zoon's balanitis (ZB). It has been postulated that in ZB tacrolimus may affect the plasma cell response via its action on helper T cells or a possible underlying T cell dysfunction.51-54 Santos-Juanes etal.51 reported complete control of ZB within 4–5 months of treatment with topical tacrolimus (0.1% ointment, twice daily application) in three patients. In another report, tacrolimus (0.1% ointment, twice daily application) demonstrated improvement of ZB within 3–4 weeks of treatment.53 Further, in 2 individual case reports of ZB, tacrolimus (0.03%) ointment applied twice daily was found to be effective in bringing about complete remission in one patient, and marked clinical improvement in another, after 8 weeks of therapy.52,54 Vitiligo Tacrolimus (0.1%) ointment has been successfully used for the treatment of vitiligo, and is considered an alternative to TCS in younger patients, especially for sensitive areas like the eyelid skin. Facial vitiligo of the segmental type has shown remarkable response with topical tacrolimus.55 Mechanism of action for tacrolimus in vitiligo is linked with its ability to suppress tumor necrosis factor-α.56 In a study of 19 patients with generalized vitiligo, treatment with 0.1% tacrolimus ointment applied twice daily for 24 weeks resulted in 17 patients achieving varying levels of pigmentation. Of the 17 patients, 13 elucidated ≥75% pigmentary improvement over the lesions on the head and neck.56 Kanwar etal.57 reported topical tacrolimus (0.03%) applied twice daily for 12 weeks to be effective in bringing about pigmentation in 19 out of the 25 pediatric patients studied. In 11 children, marked to complete improvement was recorded, in five patients there was moderate improvement and in three patients improvement was mild. In a randomized, double-blind trial comparing 0.1% tacrolimus with 0.05% clobetasol in 20 children; the mean percentage of repigmentation was 49.3% for clobetasol and 41.3% for tacrolimus with 18 patients out of the 20 experiencing some repigmentation.58 Tacrolimus (0.1%) in combination with 308 nm excimer laser, as well as narrow band-UVB (NBUVB) therapy has shown synergistic activity in bringing about repigmentation in vitiligo.59,60 Pemphigus There have been anecdotal reports suggesting the utility of topical tacrolimus as an adjunct, in pemphigus vulgaris (PV). In a report by Gach and Ilchyshyn,61 a recalcitrant lesion of PV on the cheek cleared only after tacrolimus (0.1%) ointment was added to the existing therapy, consisting of cyclophosphamide and prednisolone. Similarly, Hodgson etal.62 reported topical tacrolimus (0.1% ointment) to be an effective adjunct to mycophenolate mofetil in a 37-year-old woman with a recalcitrant lip ulcer of PV. Resolution of the lesion was documented after 1 month of initiating therapy with tacrolimus. Bullous pemphigoid Topical tacrolimus is a useful adjuvant in bullous pemphigoid (BP). A report documented two patients with BP, who improved when topical tacrolimus (0.1%) was added to the treatment regimen of oral prednisolone, tetracycline and niacinamide.63 In another report, an 84-year-old man with lesions of BP on the palms and soles, improved after 2 weeks of treatment with topical tacrolimus (0.03%) and oral anti-histamines;64 suggesting a place for topical tacrolimus in localized BP. Cicatricial pemphigoid There are only few anecdotal reports of topical tacrolimus in cicatricial pemphigoid (CP). Tacrolimus (0.1%) ointment as an adjunct to systemic CS has been of value in treating genital lesions and eye lesions associated with CP.65,66 Pyoderma gangrenosum Tacrolimus is reported to be of particular value in peristomal pyoderma gangrenosum (PG), with quicker and better healing when compared to topical 0.05% clobetasol propionate.67 Besides, as an adjunct to systemic therapy, topical tacrolimus (0.1%) is found useful in the management of PG involving the legs and hips.68,69 Lichen sclerosus et atrophicus The efficacy of tacrolimus in the treatment of lichen sclerosus et atrophicus (LSetA) is reported in several case series, but no comparative randomized studies are available presently, and this is lucidly elaborated in Table 4.70-73 Yet, despite effective results with topical tacrolimus in LSetA, avoidance of its use in male genital LSetA is suggested, owing to a theoretical risk of developing squamous cell carcinoma.74Table 4: Salient features of studies using tacrolimus ointment for lichen sclerosus et atrophicusAlopecia areata Several small series and case reports show tacrolimus to be ineffective in alopecia areata.75,76 Ichthyosis linearis circumflexa An anecdotal report from Tokyo described the profitability of topical tacrolimus in ichthyosis linearis circumflexa.77 Adverse Effects General Local burning, pricking, itching and redness are commonly encountered with topical tacrolimus. Irritation though, is transient, and decreases within the first few days of treatment. Attenuation of irritation occurs because repeated application results in desensitization of sensory neurons, eventually nullifying the irritant response.15 However, in sensitive patients, application of TCS prior to initiating topical tacrolimus, helps alleviating stinging, and offers a smoother therapeutic transition.78 Infections These include herpes simplex, molluscum contagiosum and dermatophytosis.79-81 Non melanoma skin cancers In April 2005, the FDA issued a public health advisory saying in part, "The FDA is issuing a public health advisory to inform healthcare providers and patients about potential cancer risk from the use of pimecrolimus and tacrolimus, products that are applied to the skin." This concern is based on information obtained from animal studies, case reports in a small number of patients, and how these drugs work.82 In response, the American Academy of Dermatology (AAD) issued a statement, in part citing the quote, "The AAD is disappointed that the FDA has taken this action, despite the fact that there are no data that prove proper topical use of tacrolimus or pimecrolimus is dangerous to people." In addition, the AAD noted, "Because these medications are applied to the skin, virtually none of it gets inside the body. It is not the same as taking a pill."83 Pimecrolimus Introduction Pimecrolimus (SDZ ASM 981), an ascomycin derivative, is one of the new classes of immunomodulatory macrolactams that was specifically developed for treating inflammatory skin conditions, particularly AD. This agent provides an effective and safe alternative to TCS, especially for long-term control of AD, and other inflammatory skin conditions. Mechanism of action of pimecrolimus is portrayed in Figure 3.84,85Figure 3: Mechanism of action of pimecrolimusIndications, contraindications, and pregnancy prescribing status of pimecrolimus are described in Figure 4.Figure 4: Indications, contraindications and pregnancy prescribing status of pimecrolimusClinical Uses Atopic dermatitis Pimecrolimus is currently approved by the US FDA and the European Medicines Agency for short term and intermittent long-term treatment of mild to moderate AD in nonimmunocompromised patients, 2 years of age or older. There are several human studies that have evaluated the efficacy of pimecrolimus in AD. Some of them are elaborated in Table 5.86-89Table 5: Studies evaluating the efficacy of pimecrolimus in atopic dermatitisFurther, systemic absorption of pimecrolimus is very low, and no accumulation has been observed, making it a highly safe and effective topical agent for AD. Although an increased risk in the development of noncutaneous cancers, including lymphomas has been stated on a theoretical basis; there is no evidence to indicate that any such increased risk occurs with topical therapy in humans. However, significant systemic immunosuppression, in animals and humans, does increase cancer risk. Psoriasis Efficacy of pimecrolimus in treating inverse psoriasis has been documented in a randomized, double-blind, placebo-controlled trial involving 57 adult patients. A large proportion (71%) of patients had their lesions clear or almost clear after 8 weeks of therapy with pimecrolimus. Benefits with pimecrolimus were noticed as early as 3 days after initiation of therapy. Further, the drug was tolerated well by all patients, with only one patient complaining of application site paresthesia.90 In another study, the efficacy of an ointment formulation of pimecrolimus (1%) was compared with calcipotriol (0.005%) ointment and clobetasol propionate (0.05%) ointment in the treatment of plaque psoriasis. At day 21, it was observed that pimecrolimus ointment was significantly less effective than calcipotriol and clobetasol in reducing erythema, induration and scaling.91 Seborrheic dermatitis The efficacy of pimecrolimus in the treatment of seborrheic dermatitis has been compared with a potent TCS in an open-label clinical trial involving 22 adult patients. Efficacy of both treatments in reducing erythema, scaling and pruritus was almost similar. Both drugs reduced symptoms completely by day 9, with betamethasone acting faster than pimecrolimus. However, following discontinuation of treatment, relapses were more frequent and severe in the betamethasone group.92 Chronic hand dermatitis In a large, randomized, double-blind, vehicle-controlled study involving 294 adult patients with chronic hand dermatitis (CHD), pimecrolimus induced complete or almost complete clearance in 30% of patients after 22 days of continuous therapy, including overnight occlusion. The proportion of patients achieving treatment success was greater in the active group compared with placebo, but the difference was not statistically significant. Patients without palmar involvement responded better to treatment than those with palmar involvement, due to impaired drug absorption in the thick palmar skin.93 Moreover, it is observed that overnight occlusion in subjects with CHD does not lead to massive permeation through the skin, because pimecrolimus blood concentrations are consistently low, even below the limit of quantification (0.1 ng/ml).94 Vitiligo Pimecrolimus (1%) cream has shown to be highly effective, particularly in facial vitiligo. The drug is applied twice daily for a period of at least 5–6 months to obtain complete repigmentation.95 In a study by Coskun etal.,96 1% pimecrolimus cream was considered comparable to 0.05% clobetasol propionate in treating 10 vitiligo patients. Lichen planus Pimecrolimus (1%) cream is effective in treating oral and genital LP. An 81-year-old woman with oral LP responded after 4 months of pimecrolimus (1%) cream mixed with equal parts of hydrophilic adhesive gel base.97 Swift etal.,98 in a series of 20 patients with oral LP, demonstrated pimecrolimus (1%) cream to bring about significant improvement of lesions when compared to placebo. Improvement of genital LP was reported by Lonsdale-Eccles and Velangi,99 with pimecrolimus (1%) cream in 9 women who suffered from the disease. Besides, anecdotal reports have delineated topical pimecrolimus (1%) to be effective in actinic LP and palmar/plantar LP.100,101 Lichen sclerosus et atrophicus There have been reports suggesting pimecrolimus to be effective in anogenital and vulvar LSetA in the pediatric population.102,103 Contact dermatitis In a report by Queille-Roussel etal.,104 0.6% pimecrolimus cream was found to be more effective than the vehicle for treating nickel dermatitis in 66 volunteers. Topical pimecrolimus further emphasized utility in treating vulvar eczema, secondary to sensitization with bee's glue (propolis).105 Miscellaneous Other dermatological entities demonstrating improvement with topical pimecrolimus in isolated reports include granuloma annulare, granuloma faciale, chronic graft versus host disease, and cutaneous lupus erythematosus.106-109 Adverse Effects Pruritus Burning sensation of skin Infections: varicella zoster (1.3%), herpes simplex (2.3%), warts (1.3%), molluscum contagiosum (0.9%), and eczema herpeticum (0.9%) Rarely hyperesthesia Rarely occurrence of nonmelanoma skin cancers. Conclusion Both topical tacrolimus and pimecrolimus are effective in the treatment of AD. However, tacrolimus ointment (both strengths) is more effective than pimecrolimus cream for the same. In addition, tacrolimus outlines higher tolerance than pimecrolimus, with lower rates of treatment discontinuation occurring secondary to lack of drug efficacy. Besides, adverse events for both drugs are comparable.110-112 Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.