REVIEW
Efficacy of Topical Calcineurin Inhibitors in Psoriasis Cong Wang and Andrew Lin Background: Topical calcineurin inhibitors (tacrolimus and pimecrolimus) are indicated for the treatment of atopic dermatitis but ive also been studied in the treatment of psoriasis. Objective: To define the efficacy of topical calcineurin inhibitors in the treatment of psoriasis. Methods: We searched for English-language articles published since 1990 in PubMed. Ovid/Cochrane, and Embase using "tacrolimus," "pimecrolimus," or "topical calcineurin inhibitors" and "psoriasis." Results: Nine double-blind and 13 open studies demonstrated the efficacy of topical tacrolimus in psoriasis, especially for facial, genital, and intertrigious psoriasis, and four double-blind and one open study demonstrated the efficacy of topical pimecrolimus. Conclusions: The evidence (double-blind and open studies) is strong that topical tacrolimus and, to a lesser extent, pimecrolimus have efficacy in the treatment of psoriasis. Since these agents do not cause cutaneous atrophy, they likely have a special role in facial, genital, and intertriginous psoriasis. Further studies would help define their roles in psoriasis. Contexte: Les inhibiteurs de la calcineurine topiques (tacrolimus et pimecrolimus) sont indiqués dans le traitement de la dermatite atopique, mais ils ont aussi fait l'objet de recherches dans le traitement du psoriasis. Objectif: L'étude visait à déterminer l'efficacité des inhibiteurs de la calcineurine topiques dans le traitement du psoriasis. Méthode: Une recherche d'articles publiés en anglais, depuis 1990 a été effectuée dans les bases de données PubMed, Cochrane (OVID) et Embase, à l'aide des mots «tacrolimus», «pimecrolimus» ou «inhibiteurs de la calcineurine topiques» et «psoriasis». Résultats: Neuf essais à double insu et 13 essais non à l'insu ont démontré l'efficacité du tacrolimus topique dans le psoriasis, notamment le psoriasis facial, génital et intertrigineux, et quatre essais à double insu et un essai non à l'insu ont démontré l'efficacité du pimecrolimus topique. Conclusions: D'après les données recueillies (essais à double insu et essais non à l'insu), tout porte à croire que le tacrolimus et, dans une moindre mesure, le pimecrolimus topiques sont efficaces dans le traitement du psoriasis. Comme ces substances ne causent pas d'atrophie cutanée, elles pourraient sans doute jouer un rôle particulier dans le psoriasis facial, génital et intertrigineux. Il faudrait mener d'autres études afin de préciser leur rôle dans le psoriasis.
T
OPICAL CALCINEURIN INHIBITORS (TCIs)
(tacrolimus and pimecrolimus) are indicated for tbe treatment of atopic dermatitis, but investigators bave studied tbeir efficacy in many off-label indications,^ These include double-blind studies, open studies, small case series, and case reports. Several disorders, including psoriasis, bave been evaluated in double-blind and open studies, and TCI tberapy appears to have a defined role in their treatment. In this article, we review studies of topical
From the Faculty of Mediane and Dentistry, University of Alberta, and Division of Dermatology and Cutaneous Sciences, Department of Mediane, Faculty of Medicine and Dentistry, University of Alberta, Fdmonton, AB. Presented as a poster at the 88th Annual Meeting of the Canadian Dermatology Association, Quebec City, QC, June 2013. Address reprint requests to: Andrew Lin, MD, FRCPC, 2-125 Clinical Sciences Building, Edmonton, AB T6G 2G3; e-mail: [email protected].
DOI 10.2310/7750.2013.13059 i.r 2014 Canadian Dermatology Association
tacrolimus and pimecrolimus in the treatment of psoriasis to define their roles in this condition.
Methods We used the terms "psoriasis" and "tacrolimus," "pimecrolimus," or "calcineurin inhibitor" when searching for case reports, small case series, open-label studies, and randomized controlled trials in the Medline, Cochrane Library, and Embase databases published since 1990. However, for the Embase system, we had to modify the search terms to "psoriasis" and "topical tacrolimus," "topical pimecrolimus," or "topical calcineurin inhibitor" to narrow the number of articles.
Results Tacrolimus Investigators have demonstrated the efficacy of topical tacrolimus in double-blind and open studies (Table 1),
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Table 1. Double-Blind and Open Studies of Topical Tacrolimus in Plaque and Facial/Inverse/Genital Psoriasis Study
Study Method
Double-blind studies Zonneveld et al (1998)^ et al (1999)'
Buder et al (2010)"
Maloney et al (2007)^ Nelson et al (2007)*^
Lebwohl et al (2004)'' Liao et al (2007)**
Kleyn et al (2005)"
Rajzer et al (2005)''
He (2008)'°
Open studies Carroll et al
Ortonne et al (2006)'^
Vissers et al (2008)'
Tirado-Sanchez et al (2012)'^
Compared tacrolimus 0.3% ointment to placebo {N = 70) Compared tacrolimus 0.3% ointment to placebo and other therapies (N = 16) Compared tacrolimus 0.1% ointment to methylprednisolone aceponate ointment and placebo (N = 14)
Compared tacrolimus 0.1% and 0.5% cream to placebo {N = 128) Compared tacrolimus combined with oral acitretin to placebo combined with oral acitretin Compared tacrolimus 0.1% ointment to placebo (N = 167) Compared tacrolimus 0.03% ointment to topical calcitriol (N = 50) Compared tacrolimus 0.1% ointment to clohetasone butyrate 0.005% ointment (N = 28) Compared tacrolimus 0.1% ointment to mometasone furoate 0.1% cream (N = 36) Compared tacrohmus 0.1% ointment to 5% pine tar ointment {N = 40) Left-right study compared 6% salicylic acid gel plus vehicle to 6% salicylic gel plus tacrolimus 0.15 ointment (N = 30) Compared tacrolimus 0.3% gel, 0.5% cream, and calcipotriol 0.005% ointment {N = 124) Compared tacrohmus 0.3% gel, 0.5% cream, and calcipotriol 0.005% ointment {N= 18) Compared calcipotriene (calcipotriol) ointment 0.005% plus tacrohmus ointment 0.1%, calcipotriene, and tacrolimus {N = 27)
Type of Psoriasis Plaque psoriasis Plaque psoriasis
Plaque psoriasis
Plaque psoriasis Psoriasis of body
Facial/intertriginous psoriasis Facial/genitofemoral psoriasis
Outcome No difference betv^een tacrolimus and placebo (p = .77) Tacrolimus superior to placebo {p < .001) (see text) Combination therapy with tacrolimus and methylprednisolone aceponate was similar to methylprednisolone aceponate monotherapy (see text) Both tacrolimus formulations were superior to placebo Tacrolimus and acitretin was superior to placebo and acitretin Tacrolimus was superior to placebo {p = .004) Tacrolimus was superior to calcitriol {p < .05)
Facial/flexural/genital psoriasis
Tacrolimus was similar to clobetasone butyrate
Facial/flexural psoriasis
Tacrolimus was superior to mometasone furoate
Plaque psoriasis of scalp and face
Tacrolimus was superior to pine tar
Plaque psoriasis
Tacrohmus plus salicylic acid was superior to vehicle plus salicylic acid (see text)
Plaque psoriasis
No statistically significant difference among all 3 modalities (see text)
Plaque psoriasis
Tacrolimus gel and calcipotriol ointment were superior to tacrolimus cream (see text)
Plaque psoriasis
Calcipotriene plus tacrolimus was superior to tacrolimus alone (p = 0.043) but not superior to calcipotriene alone (p = 0.056)
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Table 1. Continued Study Method
Study
Type of Psoriasis
Outcome
Rallis et al (2005)'
Tacrolimus 0.1% ointment (N= 10)
Genital and facial psoriasis
Freeman et al (2003)'^
Tacrolimus 0.1% ointment ( N = 21) Tacrolimus 0.1% ointment ( N = 11) Tacrolimus 0.1% ointment ( N = 21)
Face and intertriginous psoriasis Face psoriasis
Tacrolimus 0.1% ointment (N=4) Tacrolimus 0.1% ointment (N= 15) Tacrolimus 0.1% (N = 11) Tacrolimus 0.1% ointment (W= 12) Compared tacrolimus 0.1% ointment vs tacrolimus 0.1% ointment plus medium-dose UVAl [N = 6) Compared tacrolimus 0.1% ointment vs no treatment ( N = 21)
Extensive facial psoriasis
Marked improvement in all patients at end of first week of treatment 81% of patients had complete clearance at day 57 All except 1 patient showed improvement after 4 wk Complete or good response in 47.6% and 42.9% of patients, respectively All showed improvement
Face, intertriginous, or body plaque psoriasis Facial or inverse psoriasis Cenital psoriasis
All showed improvement compared to baseline (p < .001) AH showed improvement All showed improvement
Palmoplantar psoriasis
No dramatic changes in either treatment (see text)
Nail psoriasis
Improved Nail Psoriasis Severity Index in treated hands (p < .001)
Yamamoto Nishioka Yamamoto Nishioka
and (2000)'^ and (2003)''
Clayton et al (2003)^° Martin et al (2006)^' Brune et al Bissonnette et al (2008)^-^ Rivard et al (2006)^"*
De Simone et al
Face psoriasis
UVAt = ultraviolet Al.
Double-Blind Studies Two studies showed that topical tacrolimus is superior to placebo for plaque psoriasis.^'^ In one of these, 16 patients were randomized to receive one of six treatments: tacrolimus 0.3% ointment with 1% diisopropyl adipate as a penetration enhaneer, tacrolimus 0.3% ointment without diisopropyl adipate, tacrolimus ointment base, 0.1% betamethasone 17 alpha-valerate ointment, betamethasone ointment base, and 0.005% calcipotriol ointment.^ Compared to vehicle controls, sites treated with tacrolimus ointment (with or without a penetration enhancer) showed a significant reduction in erythema and infiltration (p < .001), a signifieant reduetion in superficial blood fiow (p < .01), and a significant decrease in epidermal thickness (p ^ .001). However, betamethasone performed better than tacrolimus and calcipotriol, and tacrolimus performed better than calcipotriol. It should be noted that tacrolimus is currently available as 0.03% and 0.1% ointment but not 0.3% ointment, which was the test medication in this study. However, additional studies showed less favorable results. One study showed significant improvement. 10
compared to baseline, for tacrolimus 0.1% ointment and methylprednisolone aceponate ointment, but combination therapy with both agents only showed results similar to those for methylprednisolone aceponate monotherapy. An early pilot study showed no statistically significant difference between tacrolimus and placebo. Another study showed that topical tacrolimus combined with oral aeitretin was superior to placebo combined with aeitretin.^ Additional studies focusing on facial, intertriginous, or genital psoriasis have shown that tacrolimus is superior not only to placebo^ but also to topical calcitriol,^ mometasone furoate,' and pine tar.'° Its efficacy was similar to that of clobetasone butyrate.'^
Open Studies Several open studies have shown favorable results with tacrolimus ointment, espeeially for facial and intertriginous involvement. Thirty adults with symmetrical plaque-type psoriasis were randomized to treatment with 6% salicylic acid gel
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plus vehicle or 6% salicylic acid gel plus 0.1% tacrolimus ointment in a 12-week left-right comparison study.'^ At weeks 1, 2, and 8, there was greater improvement in the SUM (sum of erythema, thickness and scale) score in plaques treated with tacrolimus plus salicylic acid than in plaques treated with vehicle plus salicylic acid (p < .05). However, at the end of 12 weeks, no significant difference was found in the SUM score between treatment groups. In one study of 124 adult patients with mild to moderate plaque psoriasis, patients were randomized to receive tacrolimus 0.3% gel, tacrolimus 0.5% cream, or calcipotriol 0.005% ointment, applied twice daily for a maximum of 12 weeks.'' By week 12, the median percent changes in the local psoriasis severity index of the target lesions for the tacrolimus gel, tacrolimus cream, and calcipotriol groups were 55.6%, 50.0%, and 58.6%, respectively (no statistically significant difference). In another study, 18 patients with plaque psoriasis were randomized to receive calcipotriol ointment 0.005% twice daily, tacrolimus gel 0.3% twice daily, or tacrolimus cream 0.5% twice daily.'" The mean reductions in the SUM score between day 0 and week 12 for calcipotriol ointment, tacrolimus gel, and tacrolimus cream were significant. Calcipotriol and tacrolimus gel both reduced several lesional T-cell subsets significantly, whereas the effect induced by tacrolimus cream was modest. Another open study showed that calcipotriene (calcipotriol) ointment 0.005% plus tacrolimus ointment 0.1% was superior to tacrolimus alone (p = .043).'^ Other studies have demonstrated the efficacy of tacrolimus ointment in facial,'^^' genital,'*'^""" and intertriginous psoriasis.'^'^°~^~ In one open-label, double-arm study of five patients with palmoplantar psoriasis, patients received twice-daily tacrolimus 0.1% ointment versus tacrolimus 0.1% ointment plus medium-dose ultraviolet Al (UVAl).^* No dramatic changes in plaque thickness or scaling were seen with either tacrolimus alone or with the combination of tacrolimus and UVAL In an open study of 21 patients with nail psoriasis, the nails of one of the patient's hands were randomized for treatment with tacrolimus 0.1% ointment, whereas the nails of the other hand did not receive any treatment. At week 12, statistically significant (p < .001) improvement occurred in the treated hands, using the Nail Psoriasis Severity Index.^^ Case Reports Favorable results with tacrolimus ointment have also been documented in several case reports,^''"^^ sometimes in
combination with other therapies.'"*'^" Two women with palmoplantar pustular psoriasis improved after treatment with tacrolimus 1%.^' A patient with generalized pustular psoriasis who refused treatment with oral immunosuppressive agents was treated vwth approximately 10 g/day of tacrolimus 0.01% ointment (a formulation that is not available in Canada or America) applied to the entire body for 1 week. On day 7, the plasma levels of tacrolimus before and 1 hour after application were 1.1 and 1.7 ng/mL, respectively; 5 to 10 ng/mL is considered the safe range in organ transplant recipients."'' Another patient with generalized pustular psoriasis was given approximately 7 g/day of tacrolimus 0.1% ointment for 5 days, and on day 5, plasma tacrolimus levels before and 1 hour after application were undetectable.^^ One case report mentioned that treatment with topical tacrolimus and pimecrolimus was unsuccessful in a 68year-old woman with plaque psoriasis.^' Other Studies One retrospective review reported that 12 of 13 children with inverse psoriasis showed complete clearance within 2 weeks after initiating treatment with tacrolimus 0.1% (12 patients) or tacrolimus 0.03% ointment (1 patient).^"* Oral tacrolimus was given to seven patients with refractory psoriasis (four organ transplant patients and three nontransplant patients). All seven patients showed dramatic resolution of psoriasis, which remained in remission as long as they received flill-dose therapy.-'^ Other double-blind studies showed that oral tacrolimus was superior to placebo in plaque psoriasis.^'^'^'' Oral administration of a novel, investigative cakineurin inhibitor (ISA247) was superior to placebo in plaque psoriasis double-blind phase 11^** and phase III studies.""^ Pimecrolimus Four double-blind studies and one open study have shown efficacy of topical pimecrolimus in psoriasis (Table 2). Double-Blind Studies Two studies showed that topical pimecrolimus is superior to placebo. In an early study, 10 patients with chronic plaquetype psoriasis were treated with pimecrolimus (then known as SDZ ASM 981) 0.3% and 1.0% ointment, ointment base (placebo), or open-label clobetasol-17-propionate ointment 0.05% in a randomized, double-blind, within-subject
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Table 2. Double-Blind and Open Studies of Topical Pimecrolimus in Plaque and Intertriginous/Facial Psoriasis Study Method
Study Double-blind studies Mroweitz et al (1998)'*''
Mroweitz et al (2003)*
Gribetz et al (2004)*^ Kreuter et al (2006)*
Open study Jacobi et al (2008)*'*
Outcome
Compared pimecrolimus (SDZ ASM 981) 0.3% and 1.0% ointment and placebo; also open-label comparison to clobetasol-17propionate 0.05% placebo (N = 10) Compared pimecrolimus 1% ointment to vehicle, calcipotriol, and clobetasol ointment {N = 23)
Plaque psoriasis
Pimecrolimus 1% ointment was similar to clobetasol (see text)
Plaque psoriasis
Compared pimecrolimus 1% cream with vehicle (N = 57) Compared pimecrolimus 1% cream, 0.005% calcipotriol, and 0.1% betamethasone valerate (N = 80)
Inverse psoriasis
Pimecrolimus 1% ointment was significantly more effective than vehicle but less effective than calcipotriol and clobetasol ointment (see text) Pimecrolimus was superior to vehicle
Jntertriginous psoriasis
Betamethasone was significantly more effective than pimecrolimus (see text)
Pimecrolimus 1% cream (N = 20)
Facial psoriasis
All clinical parameters showed improvement after 8 and 16 wk
comparison for 2 weeks, using the microplaque assay. The authors concluded that the efficacy of pimecrolimus 1% ointment was similar to that of clobetasol-17-propionate 0.05% in plaque-type psoriasis when applied under occlusion.'*" In a more recent randomized, double-blind, vehicleand positive-controlled, within-patient study of 23 adult psoriasis patients, the investigators showed that pimecrolimus 1% in the experimental ointment formulation was significantly more effective than its corresponding vehicle but less effective than calcipotriol or clobetasol ointment.*' Two other studies showed that pimecrolimus is effective for inverse psoriasis. In a randomized, double-blind study of pimecrolimus 1% cream versus vehicle in 57 patients with inverse psoriasis, the investigators observed a significant between-group difference early on, with 54% of the pimecrolimus group versus 21% of the vehicle group having an investigator's global assessment score of 0 or 1 (complete clearance or almost clear) at week 2 (p < .0169). By week 8, 82% of patients using pimecrolimus scored their disease as well or completely controlled versus 41% of the vehicle group {p = .0007). The authors concluded that pimecrolimus cream 1% is an effective treatment for inverse psoriasis with a rapid onset of action and is safe and well tolerated. A 4-week double-blind, randomized, vehicle-controlled study assessed 1% pimecrolimus cream, 0.005% calcipotriol, and 0.1% betamethasone '12
Typ,e of Psoriasis
valerate in the treatment of 80 adults with intertriginous psoriasis.*^ The results showed that 0.1% betamethasone was significantly more effective than 1% pimecrolimus {p < .05). No significant difference was found between 0.005% calcipotriol and 0.1% betamethasone or between 0.005% calcipotriol and 1% pimecrolimus. Open Study In one study, 20 adults with facial psoriasis applied pimecrolimus 1% cream twice daily over an 8-week period. All clinical parameters showed a significant improvement after 8 and 16 weeks compared to baseUne."*"* Case Reports
Favorable results were also reported in several case reports.«-*» Other Studies Three double-blind studies showed that oral pimecrolimus was superior to placebo.*^"^' However, oral pimecrolimus is currently not approved for clinical use.
Discussion Topical tacrolimus and pimecrolimus appear to have a defined role in the treatment of psoriasis.
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Concerning tacrolimus, two double-blind studies showed superiority to placebo,-*'^ whereas another showed superiority to topical calcitriol.^ More specifically, open studies have shown efficacy in facial,"'"^' genital,""'-"^^^ and intertriginous psoriasis.'^'^""^^ These observations are important because potent topical corticosteroids are not suitable for facial, genital, or intertriginous psoriasis, which affect areas prone to corticosteroid-induced atrophy. There are two case reports of patients with psoriasis who applied topical tacrolimus to widespread areas of the body. In one patient, plasma levels were below the safe range in organ transplant recipients^*; in the other, they were undetectable.^^ It is known that topical tacrolimus can result in detectable blood levels in patients with a damaged dermal-epidermal barrier, such as Netherton syndrome,' and additional studies wül further define the safety of widespread application of topical tacroHmus to the body. The efficacy of pimecrolimus has been evaluated in fewer studies, but the results are favorable. Two doubleblind studies showed that topical pimecrolimus is superior to vehicle''" but less effective than calcipotriol or clobetasol ointment.*' Two other double-blind studies showed that pimecrolimus is effective for inverse Conclusion Topical tacrolimus and pimecrolimus are promising agents in treating psoriasis based on double-blind and open studies, especially for facial, genital, and intertriginous psoriasis. Euture studies would be helpful in further defining their roles in psoriasis. Eor example, additional double-blind studies comparing TCIs to placebo and to an accepted treatment, such as topical calcipotriol, topical calcitriol, or topical corticosteroids of various potency, would be informative. In addition, it would be useful to know if TCIs can enhance phototherapy. Also, doubleblind studies comparing topical tacrolimus and pimecrolimus, especially for facial and intertriginous psoriasis, would be informative. Acknowledgment Einancial disclosure of authors: Dr. Lin has served as a paid speaker for Astellas Pharma Canada. Financial disclosure of reviewers: None reported. References 1. Lin AN. Topical calcineurin inhibitors. In: Wolverton SE, editor. Comprehensive dermatologie drug therapy. 3rd ed. Edinburgh: Elsevier/Saunders; 2013. p. 535-12.
2. Maloney JM, Flores J, Sheehan M, et al. Efficacy and safety of 0.1 % and 0.5% tacrolimus cream versus vehicle for treatment of mild to moderate plaque psoriasis in adults. J Am Acad Dermatol 2007;56: ABIO. 3. Remitz A, Reitamo S, Erkko P, et al. Tacrolimus ointment improves psoriasis in a microplaque assay. Br J Dermatol 1999;141: 103-7, doi: 10.1046/). 1365-2133.1999.02927.x. 4. Buder K, Knuschke P, Wozel G. Evaluation of methylprednisolone aceponate, tacrolimus and combination thereof in the psoriasis plaque test using sum score, 20-MHz-ultrasonography and optical coherence tomography, hit J Clin Pharmacol Ther 2010;48:814-20. 5. Zonneveld IM, Rubins A, Jablonska S, et al. Topical tacrolimus is not effective in chronic plaque psoriasis. A pilot study. Arch Dermatol 1998;134:1101-2, doi:10.1001/archderm.l34.9.1101. 6. Nelson A, Krejci-Manwaring J, Eleischer A, et al. A randomized, double-blind, vehicle-controlled, right/left comparative study of the efficacy of acitretin with and without the co-administration of 0.1% tacrolimus topical ointment in the treatment of moderate to severe psoriasis. J Am Acad Dermatol 2007;56: AB181. 7. Lebwohl M, Freeman AK, Chapman MS, et al. Tacrolimus ointment is effective for facial and intertriginous psoriasis. J Am Acad Dermatol 2004;51:723-30, doi:10.1016/j.jaad.2004.07.011. 8. Liao YH, Chiu HC, Tseng YS, et al. Comparison of cutaneous tolerance and efficacy of calcitriol 3 microg g(-l) ointment and tacrolimus 0.3 mg g(-l) ointment in chronic plaque psoriasis involving facial or genitofemoral areas: a double-blind, randomized controlled trial. Br J Dermatol 2007;157:1005-12, doi:10. 111 l/j. 1365-2133.2007.08201.x. 9. Rajzer L, Wojas-Pelc A, Obtulowicz A. The efficacy and safety of an ointment containing 0.1% tacrolimus in facial and flexural psoriasis. J Eur Acad Dermatol 2005; 19:178. 10. He Y. Clinical efficacy of 0.1% tacrolimus ointment on plaque psoriasis of scalp and face. J Clin Dermatol 2008;37:254-5. 11. Kleyn CE, Woodcock D, Sharpe GR. The efficacy of 0.1% tacrolimus ointment compared with clobetasone butyrate 0.05% ointment in patients with facial, flexural or genital psoriasis. Br J Dermatol 2005;153:33. 12. Carroll CL, Clarke J, Camacho F, et al. Topical tacrolimus ointment combined with 6% salicylic acid gel for plaque psoriasis treatment. Arch Dermatol 2005;141:43-6, doi:10.1001/archderm. 141.1.43. 13. Ortonne JP, Van de Kerkhof PC, Prinz JC, et al. 0.3% tacrolimus gel and 0.5% tacrolimus cream show efficacy in mñd to moderate plaque psoriasis: results of a randomized, open-label, observerblinded study. Acta Derm Venereol 2006;86:29-33. 14. Vissers WH, Van Vlijmen I, Van Erp PE, et al. Topical treatment of mild to moderate plaque psoriasis with 0.3% tacrolimus gel and 0.5% tacrolimus cream: the effect on SUM score, epidermal proliferation, keratinization, T-cell subsets and HLA-DR expression. Br J Dermatol 2008; 158:705-12, doi:10.1111/j.l365-2133.2008.08442.x. 15. Tirado-Sanchez A, Ponce-OIivera RM. Preliminary study of the efficacy and tolerability of combination therapy with calcipotriene ointment 0.005% and tacrolimus ointment 0.1% in the treatment of stable plaque psoriasis. Cutis 2012;90:140-4. 16. Rallis E, Nasiopoulou A, Kouskoukis C, et al. Successful treatment of genital and facial psoriasis with tacrolimus ointment 0.1%. Drugs Exp Clin Res 2005;31:141-5,
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17. Freeman AK, Linowski GJ, Brady C, et al. Tacrolimus ointment for the treatment of psoriasis on the face and intertriginous areas. J Am Acad Dermatol 2003;48:564-8, doi: 10.1067/mjd.2003.169. 18. Yamamoto T, Nishioka K. Topical tacrolimus is effective for facial lesions of psoriasis. Acta Derm Venereol 2000;80:451. 19. Yamamoto T, Nishioka K. Topical tacrolimus: an effective therapy for facial psoriasis. Eur J Dermatol 2003;13:471-3. 20. Clayton TH, Harrison PV, NichoUs R, et al. Topical tacrolimus for facial psoriasis. Br J Dermatol 2003;149:419-20, doi:10.1046/ J.1365-2133.2003.05426.X. 21. Martin EG, Sanchez RM, Herrera AE, et al. Topical tacrolimus for the treatment of psoriasis on the face, genitalia, intertriginous areas and corporal plaques. J Drugs Dermatol 2006;5:334-6. 22. Brune A, Miller DW, Lin P, et al. Tacrolimus ointment is effective for psoriasis on the face and intertriginous areas in pédiatrie patients. Pediatr Dermatol 2007;24:76-80, doi:10.1111/i.l525-1470. 2007.00341.x. 23. Bissonnette R, Nigen S, Bolduc C. Efficacy and tolerahüity of topical tacrolimus ointment for the treatment of male genital psoriasis. J Cutan Med Surg 2008;12:230-4. 24. Rivard J, Janiga J, Lim HW. Tacrolimus ointment 0.1% alone and in combination with medium-dose UVAl in the treatment of palmar or plantar psoriasis. J Drugs Dermatol 2006;5:505-10. 25. De Simone C, Maiorino A, Tassone F, et al. Tacrolimus 0.1% ointment in nail psoriasis: a randomized controlled open-label study. J Eur Acad Dermatol Venereol 2013;8:1003-6. 26. Nagao K, Ishiko A, Yokoyama T, et al. A case of generalized pustular psoriasis treated with topical tacrolimus. Arch Dermatol 2003;139:1219. 27. Kroft EB, Erceg A, Maimets K, et al. Tacrolimus ointment for the treatment of severe facial plaque psoriasis. J Eur Acad Dermatol Venereol 2005; 19:249-51, doi:10.1111/j.l468-3083.2005.01122.x. 28. Carrascosa JM, Soria X, Domingo H, et al. Treatment of inverse psoriasis with excimer therapy and tacrolimus ointment. Dermatol Surg 2007;33:361-3, doi:10.1111/).1524-4725.2007.33074.x. 29. Sehgal VN, Sehgal S, Verma P, et al. Exclusive plaque psoriasis of the lips: efficacy of combination therapy of topical tacrolimus, calcipotriol, and betamethasone dipropionate. Skinmed 2012;10:183-4. 30. Yamamoto T, Nishioka K. Successful treatment with topical tacrolimus for oral psoriasis. J Eur Acad Dermatol Venereol 2006; 20:1137-8, doi: 10.1111 /¡. 1468-3083.2006.01630.x. 31. Laino L, DiCarlo A. Palmoplantar pustular psoriasis: clinical and video thermographie evaluation before and after topical tacrolimus treatment. Arch Dermatol 2011; 147:760, doi: 10.1001/archdermatol.2011.120. 32. Rodriguez GE, Fagundo GE, Cabrera-Paz R, et al. Generalized pustular psoriasis successfully treated vnth topical tacrolimus. Br J Dermatol 2005;152:587-8, doi:10.1111/¡.1365-2133.2005.06468.x. 33. RaUis E, Verros CD. Ustekinumab treats psoriasis refractory to seven conventional and biologic therapies. Dermatol Online J 2011;17:14. 34. Steele JA, Choi C, Kwong PC. Topical tacrolimus in the treatment of inverse psoriasis in children. J Am Acad Dermatol 2005;53:7136, doi:10.1016/i.iaad.2005.05.036. 35. Jegasothy BV, Ackerman CD, Todo S, et al. Tacrolimus (EK 506)—a new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol 1992;128:781-5, doi:10.1001/archderm.l992.01680160065005. 36. The European FK 506 Multicentre Psoriasis Study Group. Systemic tacrolimus (FK 506) is effective for the treatment of psoriasis in a
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49.
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51.
double-blind, placebo-controlled study. The European FK 506 Multicentre Psoriasis Study Group. Arch Dermatol 1996;132:41923, doi:10.1001/archderm.l996.03890280081011. Rubins A. A double blind clinical trial of FK-506 (tacrolimus) in 16 patients with psoriasis. J Eur Acad Dermatol Venereol 1995;5 Suppl 1:S146, doi:10.1016/0926-9959(95)96361-B. Bissonnette R, Papp K, Poulin Y, et al. A randomized, multicenter, double-blind, placebo-controUed phase 2 trial of ISA247 in patients vnth chronic plaque psoriasis. J Am Acad Dermatol 2006;54:472-8, doi:10.1016/¡.iaad.2005.10.061. Papp K, Bissonnette R, Rosoph L, et al. Efficacy of ISA247 in plaque psoriasis: a randomised, multicentre, double-blind, placebo-controlled phase III study. Lancet 2008;371:1337-42, doi:10. 1016/S0140-6736(08)60593-0. Mrowietz U, Graeber M, Bräutigam M, et al. The novel ascomycin derivative SDZ ASM 981 is effective for psoriasis when used topically under occlusion. Br J Dermatol 1998; 139:992-6, doi:10.1046/i.l365-2133.1998.02554.x. Mrowietz U, Wustlich S, Hoexter G, et al. An experimental ointment formulation of pimecrolimus is effective in psoriasis without occlusion. Acta Derm Venereol 2003;83:351-3, doi:10. 1080/00015550310003791. Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: a double-blind, randomized study. J Am Acad Dermatol 2004;51:731-8, doi:10.1016/ i.iaad.2004.06.010. Kreuter A, Sommer A, Hyun J, et al. 1% pimecrolimus, 0.005% calcipotriol, and 0.1% betamethasone in the treatment of intertriginous psoriasis: a double-blind, randomized controlled study. Arch Dermatol 2006;142:1138-43, doi:10.1001/archderm.l42.9.1138. Jacobi A, Braeutigam M, Mahler V, et al. Pimecrolimus 1% cream in the treatment of facial psoriasis: a 16-week open-label study. Dermatology 2008;216:133-6, doi:10.1159/000111510. Mansouri P, Farshi S. PimecroUmus 1 percent cream in the treatment of psoriasis in a child. Dermatol Online J 2006;12:7. Ahn SJ, Oh SH, Chang SE, et al. A case of infantile psoriasis with pseudoainhum successfully treated with topical pimecrolimus and low-dose narrowband UVB phototherapy. J Eur Acad Dermatol Venereol 2006;20:1332-4, doi:10.1111/).1468-3083. 2006.01680.x. Canpolat F, Cemil BC, Tatlican S, et al. Pimecrolimus 1% cream is effective in the treatment of psoriasis in an infant. Eur J Dermatol 2009; 19:168-9. Amichai B. Psoriasis of the glans penis in a child successfully treated with elidel (pimecrolimus) cream. J Eur Acad Dermatol Venereol 2004;18:742-3, doi:10.1111/i.l468-3083.2004.01054.x. Rappersberger K, Komar M, Ebelin ME, et al Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated. J Invest Dermatol 2002;l 19:876-87, doi:10.1046/j.1523-1747.2002. 00694.x. Gottlieb AB, Griffiths CE, Ho VC, et al. Oral pimecrolimus in the treatment of moderate to severe chronic plaque-type psoriasis: a double-blind, multicentre, randomized, dose-finding trial. Br J Dermatol 2005;152:1219-27, doi:10.1111/i.l365-2133. 2005.06661.x. Griffiths C, Dubertret L, Gottlieb A. Treatment with oral pimecrolimus significantly improves psoriasis with a clear doseresponse effect [abstract]. J Invest Dermatol 2003;121:66.
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Efficacy of Topical Calcineurin Inhibitors in Psoriasis Cong Wang and Andrew Lin Background: Topical calcineurin inhibitors (tacrolimus and pimecrolimus) are indicated for the treatment of atopic dermatitis but ive also been studied in the treatment of psoriasis. Objective: To define the efficacy of topical calcineurin inhibitors in the treatment of psoriasis. Methods: We searched for English-language articles published since 1990 in PubMed. Ovid/Cochrane, and Embase using "tacrolimus," "pimecrolimus," or "topical calcineurin inhibitors" and "psoriasis." Results: Nine double-blind and 13 open studies demonstrated the efficacy of topical tacrolimus in psoriasis, especially for facial, genital, and intertrigious psoriasis, and four double-blind and one open study demonstrated the efficacy of topical pimecrolimus. Conclusions: The evidence (double-blind and open studies) is strong that topical tacrolimus and, to a lesser extent, pimecrolimus have efficacy in the treatment of psoriasis. Since these agents do not cause cutaneous atrophy, they likely have a special role in facial, genital, and intertriginous psoriasis. Further studies would help define their roles in psoriasis. Contexte: Les inhibiteurs de la calcineurine topiques (tacrolimus et pimecrolimus) sont indiqués dans le traitement de la dermatite atopique, mais ils ont aussi fait l'objet de recherches dans le traitement du psoriasis. Objectif: L'étude visait à déterminer l'efficacité des inhibiteurs de la calcineurine topiques dans le traitement du psoriasis. Méthode: Une recherche d'articles publiés en anglais, depuis 1990 a été effectuée dans les bases de données PubMed, Cochrane (OVID) et Embase, à l'aide des mots «tacrolimus», «pimecrolimus» ou «inhibiteurs de la calcineurine topiques» et «psoriasis». Résultats: Neuf essais à double insu et 13 essais non à l'insu ont démontré l'efficacité du tacrolimus topique dans le psoriasis, notamment le psoriasis facial, génital et intertrigineux, et quatre essais à double insu et un essai non à l'insu ont démontré l'efficacité du pimecrolimus topique. Conclusions: D'après les données recueillies (essais à double insu et essais non à l'insu), tout porte à croire que le tacrolimus et, dans une moindre mesure, le pimecrolimus topiques sont efficaces dans le traitement du psoriasis. Comme ces substances ne causent pas d'atrophie cutanée, elles pourraient sans doute jouer un rôle particulier dans le psoriasis facial, génital et intertrigineux. Il faudrait mener d'autres études afin de préciser leur rôle dans le psoriasis.
T
OPICAL CALCINEURIN INHIBITORS (TCIs)
(tacrolimus and pimecrolimus) are indicated for tbe treatment of atopic dermatitis, but investigators bave studied tbeir efficacy in many off-label indications,^ These include double-blind studies, open studies, small case series, and case reports. Several disorders, including psoriasis, bave been evaluated in double-blind and open studies, and TCI tberapy appears to have a defined role in their treatment. In this article, we review studies of topical
From the Faculty of Mediane and Dentistry, University of Alberta, and Division of Dermatology and Cutaneous Sciences, Department of Mediane, Faculty of Medicine and Dentistry, University of Alberta, Fdmonton, AB. Presented as a poster at the 88th Annual Meeting of the Canadian Dermatology Association, Quebec City, QC, June 2013. Address reprint requests to: Andrew Lin, MD, FRCPC, 2-125 Clinical Sciences Building, Edmonton, AB T6G 2G3; e-mail: [email protected].
DOI 10.2310/7750.2013.13059 i.r 2014 Canadian Dermatology Association
tacrolimus and pimecrolimus in the treatment of psoriasis to define their roles in this condition.
Methods We used the terms "psoriasis" and "tacrolimus," "pimecrolimus," or "calcineurin inhibitor" when searching for case reports, small case series, open-label studies, and randomized controlled trials in the Medline, Cochrane Library, and Embase databases published since 1990. However, for the Embase system, we had to modify the search terms to "psoriasis" and "topical tacrolimus," "topical pimecrolimus," or "topical calcineurin inhibitor" to narrow the number of articles.
Results Tacrolimus Investigators have demonstrated the efficacy of topical tacrolimus in double-blind and open studies (Table 1),
DECKEI^ Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No I (January/February), 2014: pp 8-14
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Table 1. Double-Blind and Open Studies of Topical Tacrolimus in Plaque and Facial/Inverse/Genital Psoriasis Study
Study Method
Double-blind studies Zonneveld et al (1998)^ et al (1999)'
Buder et al (2010)"
Maloney et al (2007)^ Nelson et al (2007)*^
Lebwohl et al (2004)'' Liao et al (2007)**
Kleyn et al (2005)"
Rajzer et al (2005)''
He (2008)'°
Open studies Carroll et al
Ortonne et al (2006)'^
Vissers et al (2008)'
Tirado-Sanchez et al (2012)'^
Compared tacrolimus 0.3% ointment to placebo {N = 70) Compared tacrolimus 0.3% ointment to placebo and other therapies (N = 16) Compared tacrolimus 0.1% ointment to methylprednisolone aceponate ointment and placebo (N = 14)
Compared tacrolimus 0.1% and 0.5% cream to placebo {N = 128) Compared tacrolimus combined with oral acitretin to placebo combined with oral acitretin Compared tacrolimus 0.1% ointment to placebo (N = 167) Compared tacrolimus 0.03% ointment to topical calcitriol (N = 50) Compared tacrolimus 0.1% ointment to clohetasone butyrate 0.005% ointment (N = 28) Compared tacrolimus 0.1% ointment to mometasone furoate 0.1% cream (N = 36) Compared tacrohmus 0.1% ointment to 5% pine tar ointment {N = 40) Left-right study compared 6% salicylic acid gel plus vehicle to 6% salicylic gel plus tacrolimus 0.15 ointment (N = 30) Compared tacrolimus 0.3% gel, 0.5% cream, and calcipotriol 0.005% ointment {N = 124) Compared tacrohmus 0.3% gel, 0.5% cream, and calcipotriol 0.005% ointment {N= 18) Compared calcipotriene (calcipotriol) ointment 0.005% plus tacrohmus ointment 0.1%, calcipotriene, and tacrolimus {N = 27)
Type of Psoriasis Plaque psoriasis Plaque psoriasis
Plaque psoriasis
Plaque psoriasis Psoriasis of body
Facial/intertriginous psoriasis Facial/genitofemoral psoriasis
Outcome No difference betv^een tacrolimus and placebo (p = .77) Tacrolimus superior to placebo {p < .001) (see text) Combination therapy with tacrolimus and methylprednisolone aceponate was similar to methylprednisolone aceponate monotherapy (see text) Both tacrolimus formulations were superior to placebo Tacrolimus and acitretin was superior to placebo and acitretin Tacrolimus was superior to placebo {p = .004) Tacrolimus was superior to calcitriol {p < .05)
Facial/flexural/genital psoriasis
Tacrolimus was similar to clobetasone butyrate
Facial/flexural psoriasis
Tacrolimus was superior to mometasone furoate
Plaque psoriasis of scalp and face
Tacrolimus was superior to pine tar
Plaque psoriasis
Tacrohmus plus salicylic acid was superior to vehicle plus salicylic acid (see text)
Plaque psoriasis
No statistically significant difference among all 3 modalities (see text)
Plaque psoriasis
Tacrolimus gel and calcipotriol ointment were superior to tacrolimus cream (see text)
Plaque psoriasis
Calcipotriene plus tacrolimus was superior to tacrolimus alone (p = 0.043) but not superior to calcipotriene alone (p = 0.056)
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Table 1. Continued Study Method
Study
Type of Psoriasis
Outcome
Rallis et al (2005)'
Tacrolimus 0.1% ointment (N= 10)
Genital and facial psoriasis
Freeman et al (2003)'^
Tacrolimus 0.1% ointment ( N = 21) Tacrolimus 0.1% ointment ( N = 11) Tacrolimus 0.1% ointment ( N = 21)
Face and intertriginous psoriasis Face psoriasis
Tacrolimus 0.1% ointment (N=4) Tacrolimus 0.1% ointment (N= 15) Tacrolimus 0.1% (N = 11) Tacrolimus 0.1% ointment (W= 12) Compared tacrolimus 0.1% ointment vs tacrolimus 0.1% ointment plus medium-dose UVAl [N = 6) Compared tacrolimus 0.1% ointment vs no treatment ( N = 21)
Extensive facial psoriasis
Marked improvement in all patients at end of first week of treatment 81% of patients had complete clearance at day 57 All except 1 patient showed improvement after 4 wk Complete or good response in 47.6% and 42.9% of patients, respectively All showed improvement
Face, intertriginous, or body plaque psoriasis Facial or inverse psoriasis Cenital psoriasis
All showed improvement compared to baseline (p < .001) AH showed improvement All showed improvement
Palmoplantar psoriasis
No dramatic changes in either treatment (see text)
Nail psoriasis
Improved Nail Psoriasis Severity Index in treated hands (p < .001)
Yamamoto Nishioka Yamamoto Nishioka
and (2000)'^ and (2003)''
Clayton et al (2003)^° Martin et al (2006)^' Brune et al Bissonnette et al (2008)^-^ Rivard et al (2006)^"*
De Simone et al
Face psoriasis
UVAt = ultraviolet Al.
Double-Blind Studies Two studies showed that topical tacrolimus is superior to placebo for plaque psoriasis.^'^ In one of these, 16 patients were randomized to receive one of six treatments: tacrolimus 0.3% ointment with 1% diisopropyl adipate as a penetration enhaneer, tacrolimus 0.3% ointment without diisopropyl adipate, tacrolimus ointment base, 0.1% betamethasone 17 alpha-valerate ointment, betamethasone ointment base, and 0.005% calcipotriol ointment.^ Compared to vehicle controls, sites treated with tacrolimus ointment (with or without a penetration enhancer) showed a significant reduction in erythema and infiltration (p < .001), a signifieant reduetion in superficial blood fiow (p < .01), and a significant decrease in epidermal thickness (p ^ .001). However, betamethasone performed better than tacrolimus and calcipotriol, and tacrolimus performed better than calcipotriol. It should be noted that tacrolimus is currently available as 0.03% and 0.1% ointment but not 0.3% ointment, which was the test medication in this study. However, additional studies showed less favorable results. One study showed significant improvement. 10
compared to baseline, for tacrolimus 0.1% ointment and methylprednisolone aceponate ointment, but combination therapy with both agents only showed results similar to those for methylprednisolone aceponate monotherapy. An early pilot study showed no statistically significant difference between tacrolimus and placebo. Another study showed that topical tacrolimus combined with oral aeitretin was superior to placebo combined with aeitretin.^ Additional studies focusing on facial, intertriginous, or genital psoriasis have shown that tacrolimus is superior not only to placebo^ but also to topical calcitriol,^ mometasone furoate,' and pine tar.'° Its efficacy was similar to that of clobetasone butyrate.'^
Open Studies Several open studies have shown favorable results with tacrolimus ointment, espeeially for facial and intertriginous involvement. Thirty adults with symmetrical plaque-type psoriasis were randomized to treatment with 6% salicylic acid gel
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plus vehicle or 6% salicylic acid gel plus 0.1% tacrolimus ointment in a 12-week left-right comparison study.'^ At weeks 1, 2, and 8, there was greater improvement in the SUM (sum of erythema, thickness and scale) score in plaques treated with tacrolimus plus salicylic acid than in plaques treated with vehicle plus salicylic acid (p < .05). However, at the end of 12 weeks, no significant difference was found in the SUM score between treatment groups. In one study of 124 adult patients with mild to moderate plaque psoriasis, patients were randomized to receive tacrolimus 0.3% gel, tacrolimus 0.5% cream, or calcipotriol 0.005% ointment, applied twice daily for a maximum of 12 weeks.'' By week 12, the median percent changes in the local psoriasis severity index of the target lesions for the tacrolimus gel, tacrolimus cream, and calcipotriol groups were 55.6%, 50.0%, and 58.6%, respectively (no statistically significant difference). In another study, 18 patients with plaque psoriasis were randomized to receive calcipotriol ointment 0.005% twice daily, tacrolimus gel 0.3% twice daily, or tacrolimus cream 0.5% twice daily.'" The mean reductions in the SUM score between day 0 and week 12 for calcipotriol ointment, tacrolimus gel, and tacrolimus cream were significant. Calcipotriol and tacrolimus gel both reduced several lesional T-cell subsets significantly, whereas the effect induced by tacrolimus cream was modest. Another open study showed that calcipotriene (calcipotriol) ointment 0.005% plus tacrolimus ointment 0.1% was superior to tacrolimus alone (p = .043).'^ Other studies have demonstrated the efficacy of tacrolimus ointment in facial,'^^' genital,'*'^""" and intertriginous psoriasis.'^'^°~^~ In one open-label, double-arm study of five patients with palmoplantar psoriasis, patients received twice-daily tacrolimus 0.1% ointment versus tacrolimus 0.1% ointment plus medium-dose ultraviolet Al (UVAl).^* No dramatic changes in plaque thickness or scaling were seen with either tacrolimus alone or with the combination of tacrolimus and UVAL In an open study of 21 patients with nail psoriasis, the nails of one of the patient's hands were randomized for treatment with tacrolimus 0.1% ointment, whereas the nails of the other hand did not receive any treatment. At week 12, statistically significant (p < .001) improvement occurred in the treated hands, using the Nail Psoriasis Severity Index.^^ Case Reports Favorable results with tacrolimus ointment have also been documented in several case reports,^''"^^ sometimes in
combination with other therapies.'"*'^" Two women with palmoplantar pustular psoriasis improved after treatment with tacrolimus 1%.^' A patient with generalized pustular psoriasis who refused treatment with oral immunosuppressive agents was treated vwth approximately 10 g/day of tacrolimus 0.01% ointment (a formulation that is not available in Canada or America) applied to the entire body for 1 week. On day 7, the plasma levels of tacrolimus before and 1 hour after application were 1.1 and 1.7 ng/mL, respectively; 5 to 10 ng/mL is considered the safe range in organ transplant recipients."'' Another patient with generalized pustular psoriasis was given approximately 7 g/day of tacrolimus 0.1% ointment for 5 days, and on day 5, plasma tacrolimus levels before and 1 hour after application were undetectable.^^ One case report mentioned that treatment with topical tacrolimus and pimecrolimus was unsuccessful in a 68year-old woman with plaque psoriasis.^' Other Studies One retrospective review reported that 12 of 13 children with inverse psoriasis showed complete clearance within 2 weeks after initiating treatment with tacrolimus 0.1% (12 patients) or tacrolimus 0.03% ointment (1 patient).^"* Oral tacrolimus was given to seven patients with refractory psoriasis (four organ transplant patients and three nontransplant patients). All seven patients showed dramatic resolution of psoriasis, which remained in remission as long as they received flill-dose therapy.-'^ Other double-blind studies showed that oral tacrolimus was superior to placebo in plaque psoriasis.^'^'^'' Oral administration of a novel, investigative cakineurin inhibitor (ISA247) was superior to placebo in plaque psoriasis double-blind phase 11^** and phase III studies.""^ Pimecrolimus Four double-blind studies and one open study have shown efficacy of topical pimecrolimus in psoriasis (Table 2). Double-Blind Studies Two studies showed that topical pimecrolimus is superior to placebo. In an early study, 10 patients with chronic plaquetype psoriasis were treated with pimecrolimus (then known as SDZ ASM 981) 0.3% and 1.0% ointment, ointment base (placebo), or open-label clobetasol-17-propionate ointment 0.05% in a randomized, double-blind, within-subject
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Wang and Lin
Table 2. Double-Blind and Open Studies of Topical Pimecrolimus in Plaque and Intertriginous/Facial Psoriasis Study Method
Study Double-blind studies Mroweitz et al (1998)'*''
Mroweitz et al (2003)*
Gribetz et al (2004)*^ Kreuter et al (2006)*
Open study Jacobi et al (2008)*'*
Outcome
Compared pimecrolimus (SDZ ASM 981) 0.3% and 1.0% ointment and placebo; also open-label comparison to clobetasol-17propionate 0.05% placebo (N = 10) Compared pimecrolimus 1% ointment to vehicle, calcipotriol, and clobetasol ointment {N = 23)
Plaque psoriasis
Pimecrolimus 1% ointment was similar to clobetasol (see text)
Plaque psoriasis
Compared pimecrolimus 1% cream with vehicle (N = 57) Compared pimecrolimus 1% cream, 0.005% calcipotriol, and 0.1% betamethasone valerate (N = 80)
Inverse psoriasis
Pimecrolimus 1% ointment was significantly more effective than vehicle but less effective than calcipotriol and clobetasol ointment (see text) Pimecrolimus was superior to vehicle
Jntertriginous psoriasis
Betamethasone was significantly more effective than pimecrolimus (see text)
Pimecrolimus 1% cream (N = 20)
Facial psoriasis
All clinical parameters showed improvement after 8 and 16 wk
comparison for 2 weeks, using the microplaque assay. The authors concluded that the efficacy of pimecrolimus 1% ointment was similar to that of clobetasol-17-propionate 0.05% in plaque-type psoriasis when applied under occlusion.'*" In a more recent randomized, double-blind, vehicleand positive-controlled, within-patient study of 23 adult psoriasis patients, the investigators showed that pimecrolimus 1% in the experimental ointment formulation was significantly more effective than its corresponding vehicle but less effective than calcipotriol or clobetasol ointment.*' Two other studies showed that pimecrolimus is effective for inverse psoriasis. In a randomized, double-blind study of pimecrolimus 1% cream versus vehicle in 57 patients with inverse psoriasis, the investigators observed a significant between-group difference early on, with 54% of the pimecrolimus group versus 21% of the vehicle group having an investigator's global assessment score of 0 or 1 (complete clearance or almost clear) at week 2 (p < .0169). By week 8, 82% of patients using pimecrolimus scored their disease as well or completely controlled versus 41% of the vehicle group {p = .0007). The authors concluded that pimecrolimus cream 1% is an effective treatment for inverse psoriasis with a rapid onset of action and is safe and well tolerated. A 4-week double-blind, randomized, vehicle-controlled study assessed 1% pimecrolimus cream, 0.005% calcipotriol, and 0.1% betamethasone '12
Typ,e of Psoriasis
valerate in the treatment of 80 adults with intertriginous psoriasis.*^ The results showed that 0.1% betamethasone was significantly more effective than 1% pimecrolimus {p < .05). No significant difference was found between 0.005% calcipotriol and 0.1% betamethasone or between 0.005% calcipotriol and 1% pimecrolimus. Open Study In one study, 20 adults with facial psoriasis applied pimecrolimus 1% cream twice daily over an 8-week period. All clinical parameters showed a significant improvement after 8 and 16 weeks compared to baseUne."*"* Case Reports
Favorable results were also reported in several case reports.«-*» Other Studies Three double-blind studies showed that oral pimecrolimus was superior to placebo.*^"^' However, oral pimecrolimus is currently not approved for clinical use.
Discussion Topical tacrolimus and pimecrolimus appear to have a defined role in the treatment of psoriasis.
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Concerning tacrolimus, two double-blind studies showed superiority to placebo,-*'^ whereas another showed superiority to topical calcitriol.^ More specifically, open studies have shown efficacy in facial,"'"^' genital,""'-"^^^ and intertriginous psoriasis.'^'^""^^ These observations are important because potent topical corticosteroids are not suitable for facial, genital, or intertriginous psoriasis, which affect areas prone to corticosteroid-induced atrophy. There are two case reports of patients with psoriasis who applied topical tacrolimus to widespread areas of the body. In one patient, plasma levels were below the safe range in organ transplant recipients^*; in the other, they were undetectable.^^ It is known that topical tacrolimus can result in detectable blood levels in patients with a damaged dermal-epidermal barrier, such as Netherton syndrome,' and additional studies wül further define the safety of widespread application of topical tacroHmus to the body. The efficacy of pimecrolimus has been evaluated in fewer studies, but the results are favorable. Two doubleblind studies showed that topical pimecrolimus is superior to vehicle''" but less effective than calcipotriol or clobetasol ointment.*' Two other double-blind studies showed that pimecrolimus is effective for inverse Conclusion Topical tacrolimus and pimecrolimus are promising agents in treating psoriasis based on double-blind and open studies, especially for facial, genital, and intertriginous psoriasis. Euture studies would be helpful in further defining their roles in psoriasis. Eor example, additional double-blind studies comparing TCIs to placebo and to an accepted treatment, such as topical calcipotriol, topical calcitriol, or topical corticosteroids of various potency, would be informative. In addition, it would be useful to know if TCIs can enhance phototherapy. Also, doubleblind studies comparing topical tacrolimus and pimecrolimus, especially for facial and intertriginous psoriasis, would be informative. Acknowledgment Einancial disclosure of authors: Dr. Lin has served as a paid speaker for Astellas Pharma Canada. Financial disclosure of reviewers: None reported. References 1. Lin AN. Topical calcineurin inhibitors. In: Wolverton SE, editor. Comprehensive dermatologie drug therapy. 3rd ed. Edinburgh: Elsevier/Saunders; 2013. p. 535-12.
2. Maloney JM, Flores J, Sheehan M, et al. Efficacy and safety of 0.1 % and 0.5% tacrolimus cream versus vehicle for treatment of mild to moderate plaque psoriasis in adults. J Am Acad Dermatol 2007;56: ABIO. 3. Remitz A, Reitamo S, Erkko P, et al. Tacrolimus ointment improves psoriasis in a microplaque assay. Br J Dermatol 1999;141: 103-7, doi: 10.1046/). 1365-2133.1999.02927.x. 4. Buder K, Knuschke P, Wozel G. Evaluation of methylprednisolone aceponate, tacrolimus and combination thereof in the psoriasis plaque test using sum score, 20-MHz-ultrasonography and optical coherence tomography, hit J Clin Pharmacol Ther 2010;48:814-20. 5. Zonneveld IM, Rubins A, Jablonska S, et al. Topical tacrolimus is not effective in chronic plaque psoriasis. A pilot study. Arch Dermatol 1998;134:1101-2, doi:10.1001/archderm.l34.9.1101. 6. Nelson A, Krejci-Manwaring J, Eleischer A, et al. A randomized, double-blind, vehicle-controlled, right/left comparative study of the efficacy of acitretin with and without the co-administration of 0.1% tacrolimus topical ointment in the treatment of moderate to severe psoriasis. J Am Acad Dermatol 2007;56: AB181. 7. Lebwohl M, Freeman AK, Chapman MS, et al. Tacrolimus ointment is effective for facial and intertriginous psoriasis. J Am Acad Dermatol 2004;51:723-30, doi:10.1016/j.jaad.2004.07.011. 8. Liao YH, Chiu HC, Tseng YS, et al. Comparison of cutaneous tolerance and efficacy of calcitriol 3 microg g(-l) ointment and tacrolimus 0.3 mg g(-l) ointment in chronic plaque psoriasis involving facial or genitofemoral areas: a double-blind, randomized controlled trial. Br J Dermatol 2007;157:1005-12, doi:10. 111 l/j. 1365-2133.2007.08201.x. 9. Rajzer L, Wojas-Pelc A, Obtulowicz A. The efficacy and safety of an ointment containing 0.1% tacrolimus in facial and flexural psoriasis. J Eur Acad Dermatol 2005; 19:178. 10. He Y. Clinical efficacy of 0.1% tacrolimus ointment on plaque psoriasis of scalp and face. J Clin Dermatol 2008;37:254-5. 11. Kleyn CE, Woodcock D, Sharpe GR. The efficacy of 0.1% tacrolimus ointment compared with clobetasone butyrate 0.05% ointment in patients with facial, flexural or genital psoriasis. Br J Dermatol 2005;153:33. 12. Carroll CL, Clarke J, Camacho F, et al. Topical tacrolimus ointment combined with 6% salicylic acid gel for plaque psoriasis treatment. Arch Dermatol 2005;141:43-6, doi:10.1001/archderm. 141.1.43. 13. Ortonne JP, Van de Kerkhof PC, Prinz JC, et al. 0.3% tacrolimus gel and 0.5% tacrolimus cream show efficacy in mñd to moderate plaque psoriasis: results of a randomized, open-label, observerblinded study. Acta Derm Venereol 2006;86:29-33. 14. Vissers WH, Van Vlijmen I, Van Erp PE, et al. Topical treatment of mild to moderate plaque psoriasis with 0.3% tacrolimus gel and 0.5% tacrolimus cream: the effect on SUM score, epidermal proliferation, keratinization, T-cell subsets and HLA-DR expression. Br J Dermatol 2008; 158:705-12, doi:10.1111/j.l365-2133.2008.08442.x. 15. Tirado-Sanchez A, Ponce-OIivera RM. Preliminary study of the efficacy and tolerability of combination therapy with calcipotriene ointment 0.005% and tacrolimus ointment 0.1% in the treatment of stable plaque psoriasis. Cutis 2012;90:140-4. 16. Rallis E, Nasiopoulou A, Kouskoukis C, et al. Successful treatment of genital and facial psoriasis with tacrolimus ointment 0.1%. Drugs Exp Clin Res 2005;31:141-5,
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