Tacrolimus

SKINmed: Dermatology for the Clinician® (ISSN 1540-9740) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Le Jacq is an imprint of Blackwell Publishing, which was acquired by John Wiley & Sons in February 2007. Blackwell’s programme has been merged with Wiley’s global Scientific, Technical, and Medical business to form Wiley-Blackwell. Copyright ©2008 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at [email protected] or 781-388-8511.

Ta c r o l i m u s i n D e r m a t o l o g y : P a r t I I

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Tacrolimus: Approved and Unapproved Dermatologic Indications/Uses—Physician’s Sequential Literature Survey: Part II Virendra N. Sehgal, MD;1 Govind Srivastava, MD;2 Sunil Dogra, MD, DNB3

Tacrolimus has been a useful therapeutic tool in dermatology practice ever since its inception. Accordingly, many “off-label” applications have been reported. Thus, its local immunosuppressive and steroid-sparing action stands recognized. Hence, its indications/uses were extended beyond atopic dermatitis to cover several dermatoses including other types of eczema, papulosquamous disorder of cornification, rosacea, other inflammatory skin conditions, vesicobullous disease, connective tissue disease, graft versus host disease, and follicular disorders. Many such diseases found to respond to tacrolimus therapy have been briefly recounted. It is worthwhile to conceive, however, that this topical immunomodulator should be reserved for use only as an alternative, should the conventional treatment be unresponsive. Hence, guarded use is warranted. Skinmed. 2008;7:73–77. ©2008 Le Jacq

use in various dermatologic indications is presented in this part.

Atopic Dermatitis

Several reports1–9 have recorded a favorable response to tacrolimus in atopic dermatitis among children 2 years and older and adults. Twice-daily topical application of either 0.03% or 0.1% ointment significantly improved face and neck lesions at the earliest time points. A marked reduction in pruritus was seen within 3 days of therapy. Lichenified lesions, however, took longer to show an appreciable improvement.10 After several years of experience, Hanifin and colleagues4 concluded that tacrolimus ointment therapy is a rapidly effective and safe treatment for the management of atopic dermatitis in pediatric and adult patients who were followed up to 4 years. The disease vis a vis tacrolimus have been enormously invesacrolimus ointment is currently tigated.1,4,5,8 Topical tacrolimus is similar to approved by the US Food and Drug publishing . symposia . patient education . trials review series potent topical corticosteroids and may have a Administration (FDA) only for the place for long-term use in patients with resistreatment of atopic dermatitis in children 2 tant atopic dermatitis on sites where adverse years and older and shows antiinflammatory effects from topical corticosteroids might effects without the local atrophogenic sequelae quickly develop. of topical corticosteroid use. Nevertheless, during the past decade, its use has been extended Vitiligo to several inflammatory dermatologic disorders Grimes and colleagues11 initially described with a varying degree of success. The common the efficacy of tacrolimus in vitiligo. They denominator of caution while using these treated 6 patients with generalized vitiligo drugs remains, however, as these calcineurin who showed no ability for spontaneous piginhibitors may be associated with an increased mentation. Moderate to excellent pigmentarisk of carcinogenesis. General recount about tion was observed in 5 patients after 1 to 5 topical tacrolimus is presented in part I of this months of treatment with topical tacrolimus. 2-part review. A brief depiction of its topical

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From the Dermato-Venereology (Skin/VD) Centre, Sehgal Nursing Home, Panchwati, Azadpur, Delhi;1 the Skin Institute and School of Dermatology, Greater Kailash, New Delhi;2 and the Department of Dermatology, Venereology and Leprology, Institute of Medical Education and Research, Chandigarh, India3 Address for correspondence: Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond), DermatoVenereology (Skin/VD) Centre, Sehgal Nursing Home, A/6, Panchwati, Delhi-110 033, India E-mail: [email protected] www.lejacq.com ID: 6514

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Lan and associates12 recorded that tacrolimus promotes melanocyte and melanoblast growth and creates a favorable milieu for cell migration via keratinocytes. Ostovari and colleagues,13 however, observed that there is a lack of efficacy of tacrolimus in the absence of UV-B exposure. In a double-blind half-side trial comparing topical tacrolimus with clobetasol in 20 children with vitiligo, Lepe and colleagues14 reported the agents to be equally effective. The mean percentage of repigmentation noted in their patients at the end of 2 months of treatment was 49.3% for clobetasol and 41.3% for tacrolimus. Side effects such as atrophy and telangiectasia were noted in 5 children treated with clobetasol and none in children treated with tacrolimus. Kanwar and colleagues15 reported more than 75% repigmentation in 57.9% and 50% to 75% repigmentation in 26.3% of children with topical tacrolimus (0.3%) in vitiligo. Long-term stability of repigmentation and effect of combinations of tacrolimus with other topical agents in vitiligo, however, remains to be seen.

Psoriasis

children who use tacrolimus ointment to treat psoriasis is warranted.18

Alopecia Areata Topical tacrolimus has been found to produce hair growth in severe combined immunodeficiency mice that lack T- and B-cell immunity, suggesting that the effect is not mediated through immunosuppression.19,20 Its benefit in humans, however, has not been reported. Thiers21 studied topical tacrolimus 0.3% in a boy with alopecia areata who subsequently progressed to alopecia totalis. Tricot and associates22 recently reported tacrolimus-induced alopecia in a female kidney and pancreas transplant recipient. Treatment failure may reflect insufficient depth of penetration of the ointment formulation and less than optimal patient selection.23

Contact Hypersensitivity Therapeutically, chronic actinic dermatitis (CAD) is a problematic condition. There are a few case reports of successful treatments, including resistant lesions of CAD. This beneficial effect may be attributed to the fact that CAD is characterized by a lymphohistiocytic infiltrate producing a chronic eczema and that tacrolimus blocks the activation of lymphocytes and other immune system cells, also inhibiting the release of mediators from cutaneous mast cells and basophils.24

Systemic tacrolimus therapy of 7 psoriatic patients undergoing organ transplant resulted in dramatic improvement of psoriasis, so Lichen Planus much so that the condition showed complete Treatment of symptomatic oral lichen planus remission by the 4th week. Jegasothy and remains a challenge. Severe recalcitrant erocolleagues,16 however, also found serious sive lichen planus has been found to respond side effects, including renal toxicity. At a favorably to tacrolimus. Donovan and collater date, the European FK506 Multicentre leagues25 recorded successful treatment of Psoriatic study group found similarly encourrefractory erosive oral lichen planus associaging results. Subsequently, several reports13 ated with hepatitis C. Vente and associates26 have reiterated the efficacy of tacrolimus as a publishing . symposia . patient education . trialstreated review series 6 such patients with 0.1% hydrophilic topical application in facial and genital psotacrolimus ointment and all reported rapid riasis. Zonneveld and colleagues,17 however, relief of pain and burning. Subsequently, 3 found that topical tacrolimus is ineffective in patients showed complete resolution withchronic plaque psoriasis. Topical tacrolimus in 4 weeks. In a comparative study of 20 has proved largely unsuccessful for plaquepatients each, topical tacrolimus 0.1% ointtype psoriasis, likely because of poor absorpment induced a better initial therapeutic tion through thick, psoriatic plaques. In response than triamcinolone acetonide 0.1% facial and inverse psoriasis, however, recent ointment. Relapses occurred frequently, howcase reports and studies have shown topical ever, within 3 to 9 weeks of the cessation of tacrolimus to be efficacious. Considering postreatment.27 Tacrolimus can be offered as sible long-term risk of malignancy in patients a safe and secure alternative therapy to be treated with calcineurin inhibitors, vigorous considered when lesions are resistant to consun protection, long-term monitoring, and ventional treatment. perhaps testing for potential absorption in

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Table. Tacrolimus: Approved and Unapproved Dermatologic Indications/Uses: Physician Sequential Survey Authors Schuppe et al28 Lyon et al37 Lally et al31 Pabby et al39 Bamford et al40 Hall et al41 and Lebeau et al42 Hall et al41 Rallis et al,43 Lebwohl et al,44 Steele et al,45 Kroft et al,46 and Carroll et al47 Jain et al48 Couriel et al49 Numakura et al50 Maruyama et al51 Mackelfresh et al7a Moreno-Arias et al8a and Hernandez-Machin et al52 Brill et al6a Ginarte et al5a Baldo et al4a Toutous-Trellu et al3a Mitsui et al9a Lampropoulos and D’Cruz53 Seez et al54 Chapman et al55 Yokota et al56 Heffernan et al57 Rubegni et al11a aReferences cited in part I.

Year 1998 2001 2005 2003 2004 2003 2003 2005

Diagnosis

No.

Pyoderma gangrenosum

Rosacea Ocular mucous membrane pemphigoid Ocular pemphigus vulgaris Psoriasis

2005 2005 2005 2006 2005 2005

Nephrotoxicity Chronic graft versus host disease Diabetes mellitus Lupus nephritis Venous ulcer Plasma cell balanitis of Zoon

2005

Acrodermatitis continua of Hallopeau

2005 2005 2005 2005

Vulvar lichen sclerosus Chronic actinic dermatitis Eosinophilic folliculitis Refractory dermatomyositis

2005 2005 2005

Erosive pustular dermatosis of the scalp Intertrigo Annular erythema associated with Sjögren syndrome Discoid lupus erythematosus Darier disease

2005 2006

Pyoderma Gangrenosum

of

Cases

Outcome

1 1 1 1 1 2 1 5

—

2 1 5 1 1 1 1 1

— — — — Partly successful Successful

1 1 1 1 1 1 1 1

Successful — — Successful Successful Successful Successful Successful

1 1

Partly successful Successful

— — — —

Successful if combined sequential with calcipotriol

Ichthyosis Linearis Circumflexa

Schuppe and colleagues28 reported a synergistic Suga and associates33 successfully treated icheffect of oral prednisolone and topical 0.5% tacthyosis linearis circumflexa in a 20-year-old rolimus under hydrocolloid dressing for prompt man by using topical tacrolimus. Subsequent healing of ulcers of pyoderma gangrenosum follow-up for over a year revealed him to be (PG). Reich and associates29 used only 0.1% nearly disease free. He showed only intermittent mild scaling when the drug was applied tacrolimus ointment twice daily on such lesions, without renal symptoms or hypertension. which caused clearing within 3 weeks. Jolles . . . and colleagues30 combined oral andpublishing topicalsymposia patient education trials review series tacrolimus therapy in the treatment of resistant Skin Grafting/Transplant PG. Recently, Lally and colleagues31 successfully Although not tested in human beings, several treated penile PG with topical tacrolimus. In research workers34–36 have reported a prolonged skin addition, in a recent open-label study of topiallograft survival after the use of topical or intravecal tacrolimus ointment 0.1% under occlusion nous tacrolimus. A study of tacrolimus ointment in for the treatment of PG, 2 of the 5 patients had rats revealed that the drug is useful and effective in resolution of lesions by 16 weeks, and 3 were the suppression of allograft skin rejection.37. 32 withdrawn due to local side effects.

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Miscellaneous Indications/Uses

Available evidence suggests that tacrolimus ointment 0.1% may be helpful in the treatment of mild cases of PG and especially useful in peristomal PG.


Woo and James38 have recently reviewed the uses of tacrolimus in dermatology. Due to its potent immunosuppressant and steroid-sparing actions, tacrolimus has been tested in a variety of skin

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disorders including other types of eczema, papulosquamous disorder of cornification, rosacea, other inflammatory skin conditions, vesicobullous disease, connective tissue disease, graft versus host disease, and follicular disorders. Many such diseases found to respond to tacrolimus have been presented. The salient briefs of which, as well as other unapproved indications, are displayed sequentially in the Table.

Conclusions Tacrolimus is an intriguing immunomodulator. Its explicit immunosuppressor and steroid-sparing impact seem to have gathered recent momentum for use in atopic dermatitis and several other dermatoses. It should be used only as an alternative topical agent, however, in instances of failure of conventional therapy.

References

hood vitiligo. Arch Dermatol. 2003;139:581–585. 1 Reitamo S, Ortonne JP, Sand C, et al. A mul 15 Kanwar AJ, Dogra S, Parsad D. Topical tacrolimus ticentre, randomized, double-blind, controlled for treatment of childhood vitiligo in Asians. Clin study of long-term treatment with 0.1% tacExp Dermatol. 2004;29:589–592. rolimus ointment in adults with moder 16 Jegasothy BV, Ackerman CD, Todo S, et al. ate to severe atopic dermatitis. Br J Dermatol. Tacrolimus (FK-506)—a new therapeutic agent 2005;152(6):1282–1289. for severe recalcitrant psoriasis. Arch Dermatol. 2 Rubins A, Gutmane R, Valdmane N, et al. 1992;128:781–785. Pharmacokinetics of 0.1% tacrolimus ointment 17 Zonneveld IM, Rubins A, Jablonska S, et al. after first and repeated application in adults with Topical tacrolimus is not effective in chronic moderate to severe atopic dermatitis. J Invest plaque psoriasis. A pilot study. Arch Dermatol. Dermatol. 2005;125:68–71. 1998;134:1101–1102. 3 Chapman MS, Schachner LA, Breneman D, et al. 18 Brune A, Miller DW, Lin P, et al. Tacrolimus ointTacrolimus ointment 0.03% shows efficacy and ment is effective for psoriasis on the face and safety in pediatric and adult patients with mild to intertriginous areas in pediatric patients. Pediatr moderate atopic dermatitis. J Am Acad Dermatol. Dermatol. 2007;24:76–80. 2005;53:S177–S185. 19 McElwee KJ, Rushton DH, Trachy R, et al. Topical 4 Hanifin JM, Paller AS, Eichenfield L, et al. Efficacy FK506: a patient immunotherapy for alopecia and safety of tacrolimus ointment treatment for areata? Studies using the Dundee experimental up to 4 years in patients with atopic dermatitis. J bald rat model. Br J Dermatol. 1997;137:491–497. Am Acad Dermatol. 2005;53:S186–S194. 20 Yamamoto S, Kato R. Hair growth stimulating 5 Koo JY, Fleischer AB Jr, Abramovits W, effects of cyclosporine and FK506, potent immuet al. Tacrolimus ointment is safe and effecnosuppressants. J Dermatol Sci. 1994;7:S47–S54. tive in the treatment of atopic dermatitis: 21 Thiers BH. Topical tacrolimus: treatment failure results in 8000 patients. J Am Acad Dermatol. in a patient with alopecia areata. Arch Dermatol. 2005;53:S195–S205. 2000;136:124. 6 Garside R, Stein K, Castelnuovo E, et al. The effec 22 Tricot L, Lebbe C, Pillebout E, et al. Tacrolimustiveness and cost-effectiveness of pimecrolimus induced alopecia in female kidney -panand tacrolimus for atopic eczema: a systematic creas transplant recipients. Transplantation. review and economic evaluation. Health Technol 2005;80:1546–1549. Assess. 2005;9:1–230. 23 Price VH, Willey A, Chen BK. Topical tacroli 7 Tan J, Langley R. Safety and efficacy of tacrolimus mus in alopecia areata. J Am Acad Dermatol. ointment 0.1% (Protopic) in atopic dermatitis: a 2005;52:138–139. Canadian open-label multicenter study. J Cutan 24 Grone D, Kunz M, Zimmermann R, et al. Med Surg. 2004;8:213–219. Successful treatment of nodular actinic retic 8 Naylor M, Elmets C, Jaracz E, et al. Non-melanoma uloid with tacrolimus ointment. Dermatology. skin cancer in patients with atopic dermatitis 2006;212:377–380. treated with topical tacrolimus. J Dermatolog 25 Donovan JC, Hayes RC, Burgess K, et al. Refractory Treat. 2005;16:149–153. erosive oral lichen planus associated with hepati 9 Schachner LA, Lamerson C, Sheehan MP, et al. tis C: response to topical tacrolimus ointment. J Tacrolimus ointment 0.03% is safe and effective Cutan Med Surg. 2005;9:43–46. for the treatment of mild to moderate atopic 26 Vente C, Reich K, Rupprecht R, et al. Erosive dermatitis in pediatric patients: results from mucosal lichen planus: response to topia randomized, publishing double-blind, vehicle-controlled . symposia . patient education . trials review cal series treatment with tacrolimus. Br J Dermatol. study. Pediatrics. 2005;116:e334–e342. 1999;140:338–342. 10 Nakagawa H, Etoh T, Ishibashi Y, et al. 27 Laeijendecker R, Tank B, Dekker SK, et al. A comTacrolimus ointment for atopic dermatitis. parison of treatment of oral lichen planus with Lancet. 1994;344:883. topical tacrolimus and triamcinolone acetonide 11 Grimes PE, Soriano T, Dytoc MT. Topical tacroliointment. Acta Derm Venereol. 2006;86:227–229. mus for repigmentation of vitiligo. J Am Acad 28 Schuppe HC, Homey B, Assmann T, et al. Topical Dermatol. 2002;47:789–791. tacrolimus for pyoderma gangrenosum. Lancet. 12 Lan CC, Chen GS, Chiou MH, et al. FK506 1998;351:832. promotes melanocyte and melanoblast growth 29 Reich K, Vente C, Neumann C. Topical tacroliand creates a favourable milieu for cell migramus for pyoderma gangrenosum. Br J Dermatol. tion via keratinocytes: possible mechanisms of 1998;139(4):755–757. how tacrolimus ointment induces repigmenta 30 Jolles S, Niclasse S, Benson E. Combination tion in patients with vitiligo. Br J Dermatol. oral and topical tacrolimus in therapy-resis2005;153:498–505. tant pyoderma gangrenosum. Br J Dermatol. 13 Ostovari N, Passeron T, Lacour JP, et al. Lack of 1999;140:564–565. efficacy of tacrolimus in the treatment of vitiligo 31 Lally A, Hollowood K, Bunker CB, et al. Penile in the absence of UV-B exposure. Arch Dermatol. pyoderma gangrenosum treated with topical tac2006;142:252–253. rolimus. Arch Dermatol. 2005;141:1175–1176. 14 Lepe V, Moncada B, Castanedo-Cazares JP, et al. A 32 Kontos AP, Kerr HA, Fivenson DP, et al. An double-blind randomized trial of 0.1% tacrolimus open-label study of topical tacrolimus ointment vs 0.05% clobetasol for the treatment of child-

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0.1% under occlusion for the treatment of pyoderma gangrenosum. Int J Dermatol. 2006;45:1383–1385. 33 Suga Y, Tsuboi R, Hashimoto Y, et al. A case of ichthyosis linearis circumflexa successfully treated with topical tacrolimus. J Am Acad Dermatol. 2000;42:520–522. 34 Inamura N, Nakahara K, Kino T, et al. Prolongation of skin allograft survival in rats by a novel immunosuppressive agent, FK506. Transplantation. 1988;45:206–209. 35 Wada H, Monden M, Gotoh M, et al. An attempt to induce tolerance to skin grafts in cogentic mice with FK506. Transplant Proc. 1991;23:3280–3281. 36 Fujita T, Takahashi S, Yagihashi A, et al. Prolonged survival of rat skin allograft by treatment with FK506 ointment. Transplantation. 1997;64:922–925. 37 Lyon CC, Stapleton M, Smith AJ, et al. Topical tacrolimus in the management of peristomal pyoderma gangrenosum. J Dermatolog Treat. 2001;12:13–17. 38 Woo DK, James WD. Topical tacrolimus: a review of its uses in dermatology. Dermatitis. 2005;16:6–21. 39 Pabby A, An KP, Laws RA. Combination therapy of tetracycline and tacrolimus resulting in rapid resolution of steroid-induced periocular rosacea. Cutis. 2003;72:141–142. 40 Bamford JT, Elliott BA, Haller IV. Tacrolimus effect on rosacea. J Am Acad Dermatol. 2004;50:107–108. 41 Hall VC, Liesegang TJ, Kostick DA, et al. Ocular mucous membrane pemphigoid and ocular pemphigus vulgaris treated topically with tacrolimus ointment. Arch Dermatol. 2003;139:1083–1084. 42 Lebeau S, Mainetti C, Masouye I, et al. Localized childhood vulval pemphigoid treated with tacrolimus ointment. Dermatology. 2004;208:273–275. 43 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;31:141–145. 44 Lebwohl M, Freeman A, Chapman MS, et al. Proven efficacy of tacrolimus for facial and intertriginous psoriasis. Arch Dermatol. 2005;141:1154. 45 Steele JA, Choi C, Kwong PC. Topical tacrolimus in the treatment of inverse psoriasis in children.

80. J Am Acad Dermatol. 2005;53:713–716. 46 Kroft EB, Erceg A, Maimets K, et al. Tacrolimus ointment for the treatment of severe facial plaque psoriasis. J Eur Acad Dermatol Venereol. 2005;19:249–251. 47 Carroll CL, Clarke J, Camacho F, et al. Topical tacrolimus ointment combined with 6% salicylic acid gel for plaque psoriasis treatment. Arch Dermatol. 2005;141:43–46. 48 Jain A, Vekatramanan R, Eghtesad B, et al. Long-term outcome of adding mycophenolate mofetil to tacrolimus for nephrotoxicity following liver transplantation. Transplantation. 2005;80:859–864. 49 Couriel DR, Saliba R, Escalon MP, et al. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol. 2005;130:409–417. 50 Numakura K, Satoh S, Tsuchiya N, et al. Clinical and genetic risk factors for posttransplant diabetes mellitus in adult renal transplant recipients treated with tacrolimus. Transplantation. 2005;80:1419–1424. 51 Maruyama M, Yamasaki Y, Sada K, et al. Good response of membranous lupus nephritis to tacrolimus. Clin Nephrol. 2006;65:276–279. 52 Hernandez-Machin B, Hernando LB, Marrero OB, et al. Plasma cell balanitis of Zoon treated successfully with topical tacrolimus. Clin Exp Dermatol. 2005;30:588–589. 53 Lampropoulos CE, D’Cruz DP. Topical tacrolimus treatment in a patient with dermatomyositis. Ann Rheum Dis. 2005;64:1376–1377. 54 Seez M, Rodriguez-Martin M, Sidro M, et al. Successful treatment of erosive pustular dermatosis of the scalp with topical tacrolimus. Clin Exp Dermatol. 2005;30:599–600. 55 Chapman MS, Brown JM, Linowski GJ. 0.1% tacrolimus ointment for the treatment of intertrigo. Arch Dermatol. 2005;141:787. 56 Yokota K, Shichinohe R, Hayasaka T. Topical tacrolimus in the treatment of annular erythema associated with Sjögren’s syndrome. Clin Exp Dermatol. 2005;30:450–451. 57 Heffernan MP, Nelson MM, Smith DI, et al. 0.1% tacrolimus ointment in the treatment of discoid lupus erythematosus. Arch Dermatol. 2005;141:1170–1171.

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