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Dept of Dermatology
St Luke’s–Roosevelt Hospital Center
New York, NY
Tacrolimus ointment and pimecrolimus cream (ascomycin macrolactam derivatives) are approved in the USA and the EU for the treatment of atopic dermatitis. Specifically, topical tacrolimus is approved to treat moderate-to-severe atopic dermatitis, and topical pimecrolimus is approved to treat mild-to-moderate atopic dermatitis (see Box). Tacrolimus and pimecrolimus are both calcineurin inhibitors, block the effects of IL-2, decrease the function of T-cells, depress the function system and block transcriptional activation of several cytokine genes.(1,2) Both interfere with the function of Langerhans’ cells, basophil cells and mast cells. This article will discuss their utility in treating psoriasis but will not discuss their possible role in carcinogenesis, as that has been discussed extensively elsewhere.(3)
Oral tacrolimus(4) and pimecrolimus(5) are effective in the treatment of moderate-to-severe plaque psoriasis. However, neither medication has yet been approved by the FDA for this indication. Some authors have stated that, given orally, pimecrolimus is as potent as or superior to tacrolimus in treating allergic contact dermatitis in mice and rats.(6) In the treatment of psoriasis, consideration of the topical use of tacrolimus and pimecrolimus therefore has a firm scientific basis.
Science must be tested in practice, and practice has shown that neither tacrolimus ointment(7) nor pimecrolimus cream(8) can penetrate psoriatic plaques and thus are ineffective for treating plaque-type psoriasis when simply applied as commercially available. In the case of tacrolimus this occurs even though percutaneous absorption of tacrolimus is higher in diseased skin than in healthy skin.(9) In a pilot study of 70 patients – 23 in the calcipotriol (0.05%) twice-daily group, 24 in the tacrolimus (0.3%) ointment once-daily group and 23 in the placebo group – tacrolimus was not effective in the treatment of psoriasis.(10) The combination of 0.1% tacrolimus ointment and 6% salicylic acid gel, however, has been reported to be an effective treatment for plaque psoriasis.(11) It is felt that this combination is effective because salicylic acid gel increases the penetration of tacrolimus.
The use of tacrolimus is limited by its ability to penetrate the plaques of psoriasis. Penetration of topical tacrolimus can be increased by occlusion. Under occlusion, tacrolimus ointment decreases the erythema and infiltration of psoriatic plaques that are not covered by scale. Tacrolimus ointment applied in a Finn chamber has been reported as effective in treating plaque psoriasis.(12) Deeper penetration can have side-effects, and a study has reported deep dermatophytosis during topical tacrolimus therapy for psoriasis.(13) In the USA, the FDA recently changed the package insert of topical tacrolimus to read: “The safety of Protopic ointment under occlusion, which may promote systemic exposure, has been evaluated. Protopic ointment 0.03% and 0.1% should not be used with occlusive dressings.”
Occlusion is also associated with effectiveness of pimecrolimus in treating psoriasis.(14,15) Pimecrolimus (0.3% and 1.0%) under occlusion was used to treat 10 patients with chronic plaque-type psoriasis.(16) For control treatment, the corresponding ointment base (placebo) and open-labelled clobetasol-17-propionate ointment (0.05%) were used. The trial was a randomised, double-blind, within-subject comparison for two weeks using the microplaque assay. Evaluation was performed by daily determination of clinical scores for erythema and induration. The results of the study showed that, after two weeks of treatment, total scores decreased by 92% for clobetasol, by 82% for pimecrolimus (0.1%), by 63% for pimecrolimus (0.03%) and by 18% for the ointment base (placebo).
For psoriasis on thin skin – the face, the groin or in intertriginous areas (inverse psoriasis) – pimecrolimus and tacrolimus are effective treatments. This adds an important therapeutic tool to the treatment of psoriasis because corticosteroids, even low-potency ones, can cause atrophy and striae in such areas of thin skin. In a study of 1% pimecrolimus cream used twice a day on inverse psoriasis at week 8, 20 (71%) of 28 and 6 (21%) of 29 patients treated with 1% pimecrolimus and vehicle, respectively, achieved an investigator global assessment of 0 or 1 (difference in response rate, 0.51; number needed to treat [NNT], 2). At week 8, 23 (82%) of 28 and 12 (41%) of 29 patients treated with 1% pimecrolimus cream and vehicle, respectively, achieved a patient self-assessment score of 0 or 1 (difference in response rate, 0.41; NNT, 3). The authors of this study concluded that topical pimecrolimus is an effective treatment of inverse psoriasis.(17) Similarly, psoriasis of the glans penis in a child has been successfully treated with pimecrolimus cream.(18)
Similarly, tacrolimus ointment seems most effective in treating psoriasis where the skin is thin (ie, on the face and intertriginous areas). Several case reports indicate that topical tacrolimus is effective in the treatment of facial psoriasis.(19,20) In one study, 21 patients (15 males and six females, mean age 51.1 years old) with facial psoriasis lesions applied tacrolimus (0.1%) ointment twice a day for four weeks without occlusion. A complete or good response was obtained in 10 (47.6%) and 9 (42.9%) patients, respectively. The mean score for erythema decreased from 1.76 to 0.62, the infiltration score decreased from 1.33 to 0.43, and the desquamation score decreased from 0.95 to 0.24.(21) The safety and efficacy of tacrolimus (0.1%) ointment for the treatment of psoriasis on the face, intertriginous areas or both were evaluated in an open-label, clinical trial of 21 patients with psoriasis. A total of 81% of patients (17 of 21) experienced complete clearance at day 57 (end of treatment). Only two patients reported adverse events, which were limited to itching and the feeling of warmth at the application site.(22) Twelve of 13 children had complete clearance of inverse psoriasis within two weeks of application of topical tacrolimus 0.1%.(23) Others have shown that topical tacrolimus 0.1% will effectively treat facial and genital psoriasis but does not result in any type of lasting remission as relapses are frequent when the medication in not used.(24)
Tacrolimus can be a useful treatment for other uncommon psoriasis variants. Acrodermatitis continua of Hallopeau (ACH) is a rare type of pustular psoriasis affecting the digits. In a case involving a 43-year-old female patient who had been suffering from ACH for more than 20 years and in which the disease was localised on one finger during the whole period, several topical and systemic treatments resulted in only temporary or partial improvement of the lesion. Although monotherapy treatment with calcipotriol and tacrolimus ointments gave no satisfying results in the long-term management of the disease, the combination of both agents led to a continuous improvement of the patient’s skin condition.(25) Generalised pustular psoriasis has been successfully treated with topical tacrolimus.(26)
Topical tacrolimus and pimecrolimus are very useful agents for treating inverse psoriasis. While interesting, this will not transform the topical treatment of psoriasis because inverse psoriasis is not common, and one study notes that only 3% of psoriasis patients have inverse psoriasis.(27) No head-to-head comparison of these agents exists for the treatment of inverse psoriasis, but the results of studies seem to suggest that both medications are very effective. This is important because other topical therapies are not useful for the treatment of inverse psoriasis. Topical corticosteroids cause atrophy and striae, and topical calcipotrine (Dovonex) is irritating. Nevertheless, topical tacrolimus and pimecrolimus should be considered as first-line therapy for inverse psoriasis. They are effective against facial psoriasis but are not first-line agents because cheaper topical low-to-middle-potency cortico‑steroids are usually effective. However, around the eyes (a rare location for psoriasis) they are first-line agents because corticosteroid use around the eyes is undesirable (due to cutaneous atrophy and possible induction of the development of cataracts). They seem useful for pustular types of psoriasis (probably because they can penetrate the skin), but other treatments are cheaper and probably as effective. As they are currently formulated, topical tacrolimus and pimecrolimus are not useful for stable plaque psoriasis and should not be used. It is possible that combinations with salicylic acid or occlusion might increase their utility for the treatment of plaque psoriasis.