Topical vitamin D3 gained U.S. Food and Drug

Transcription

1 Topical Vitamin D 3 Analogues: Unapproved Uses, Dosages, or Indications JENNIFER L. PARISH, MD Topical vitamin D3 gained U.S. Food and Drug Administration (FDA) approval in 1994 as an effective therapy for plaque-type psoriasis. Advances in the understanding of its effect on the inhibition of cellular proliferation, cellular differentiation, and immune modulation have led to its usage in other skin diseases. Studies have demonstrated the effectiveness of topical vitamin D 3 analogues in the treatment of several disorders, such as congenital ichthyoses, 1 pityriasis rubra pilaris, 2 other forms of psoriasis, 3 5 morphea, 6 and other diseases. The potential clinical applications of topical vitamin D 3 analogues continue to broaden with further knowledge of the mechanism by which vitamin D 3 functions. History Vitamin D 3 is a hormone, rather than a vitamin, that is crucial in calcium homeostasis. Its misclassification as a vitamin originates in the discovery of the cure for rickets. In 1919, the British physician Sir Edward Mellanby demonstrated through experiments with dogs that diet played a key role in the treatment of rickets. By feeding cod-liver oil to the dogs in which he had induced rickets, Mellanby cured the animals of the debilitating disease. 7,8 In 1922, Elmer V. McCollum expanded on the work of Mellanby. McCollum isolated the effective component of cod-liver oil. In the publication of his work, McCollum followed the alphabetical ordering of vitamins and designated the nutrient as vitamin D. 9 Further studies in the 20th century elucidated the molecular structure and the biologic actions of vitamin D proving it to be a hormone and not a vitamin. Mechanism of Action From the Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, Philiadelphia, Pennsylvania, USA Address correspondence to Jennifer L. Parish, MD, 1819 J.F. Kennedy Blvd., Suite 465, Philadelphia, PA address: jenderm@yahoo.com The biologically active form of vitamin D 3, 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], is generated in the skin or absorbed from the intestine. In the epidermis, 7-dehydrocholesterol is converted to vitamin D 3 after exposure to UV radiation. 10 Further conversion of vitamin D 3 occurs first in the liver and then in the kidney. It is in the kidney that the active metabolite 1,25(OH) 2 D 3, calcitriol, is synthesized (Fig 1). 11 1,25(OH) 2 D 3 modulates cellular differentiation, cellular proliferation, and immune function via its interaction with the vitamin D receptor (VDR). The VDR belongs to the thyroid hormone, retinoic acid, and steroid nuclear receptor gene family. The binding of the VDR by 1,25(OH) 2 D 3 results in activation of this nuclear receptor. The activated VDR complex binds to the vitamin D response elements located in the nucleus. 12 Subsequently, there is either an induction or repression of the genes that contain vitamin D response elements. 10 Studies investigating the affects of 1,25(OH) 2 D 3 on epidermal keratinocyte have demonstrated that 1,25(OH) 2 D 3 modulates cellular differentiation and growth. In cultured keratinocytes, active vitamin D 3 decreases epidermal proliferation and increases differentiation. Specifically, 1,25(OH) 2 D 3 enhances the formation of the cornified envelope and the transcription of involucrin, as well as raises the level of transglutaminase activity. 10,13 The influence of 1,25(OH) 2 D 3 on keratinocytes aids in understanding the proven beneficial effect of vitamin D 3 in psoriasis and indicates a possible use in disorders of keratinization. In vitro studies have also revealed that active vitamin D 3 has an effect on the mediators of inflammation. 1,25(OH) 2 D 3 blocks both the production of interleukin (IL)-2 and IL-6 by T cells and the proliferation of T cells, inhibits the transcription of granulocyte-macrophage colony stimulating factor (GM-CSF) and of gammainterferon (IFN- ), as well as inhibits the activity of cytotoxic and natural killer cells. In addition, 1,25(OH) 2 D 3 enhances the cytotoxicity of macrophages and blocks the release of arachidonic acid by neutrophils These findings suggest a role for vitamin D 3 in inflammatory diseases. Vitamin D 3 Analogues The hypercalcemia and hypercalciuria produced by calcitriol, 1,25(OH) 2 D 3, has led to the development of several vitamin D 3 analogues that have a lower risk in 2002 by Elsevier Science Inc. All rights reserved X/02/$ see front matter 655 Avenue of the Americas, New York, NY PII S X(02)

2 Clinics in Dermatology Y 2002;20: TOPICAL VITAMIN D 3 ANALOGUES 559 Figure 1. Calcitriol. causing the aforementioned side effects. The most thoroughly investigated of the analogues is calcipotriol (calcipotriene). Calcipotriol is similar to 1,25(OH) 2 D 3 in its binding affinity for the VDR, its modulation of epidermal proliferation and differentiation, and its effect on inflammation. The advantage of calcipotriol is that it is 100 to 200 times less active than 1,25(OH) 2 D 3 in causing hypercalcemia. 11,15 17 Tacalcitol, 1,24(OH) 2 D 3, is another topical synthetic analogue of vitamin D 3. Unlike calcipotriol, tacalcitol is unavailable in the United States. The mechanism of action of tacalcitol is comparable to 1,25(OH) 2 D 3 and calcipotriol; however, calcipotriol is more selective than tacalcitol in its influence on calcium metabolism. 15 Unapproved Uses of Vitamin D 3 Analogues Other Forms of Psoriasis Although the FDA has approved topical calcipotriol for plaque-type psoriasis, studies have shown calcipotriol to be effective in other forms of psoriasis. In an uncontrolled and open trial, 12 patients with intertriginous psoriasis applied calcipotriol twice daily to affected areas. Within 3 weeks, 5 of the 12 patients had a rapid response, and within 6 weeks, another 5 of the 12 patients had a slow response. Two of the 12 patients did not sufficiently improve. The results of the trial suggest that calcipotriol may be efficacious in the treatment of intertriginous psoriasis. 3 A double-blind, randomized study also has shown calcipotriol ointment to be beneficial in the treatment of nail psoriasis. The study compared calcipotriol ointment to the combination of betamethasone dipropionate and salicylic acid ointment applied twice daily for 3 to 5 months. Both therapies were similarly advantageous in reducing subungual hyperkeratoses. 4 Calcipotriol may be an effective therapeutic option for pustular psoriasis. Several case reports have indicated that calcipotriol may be beneficial in the treatment of pustular psoriasis and its variants. In one study, three patients with generalized pustular psoriasis improved with the application of twice-daily calcipotriol ointment. In all three cases, pustulation resolved within 24 to 48 hours. In addition, the patients did not develop hypercalcemia from the calcipotriol. 5 Case studies with calcipotriol for the treatment of acrodermatitis continua of Hallopeau, which many consider to be a variant of pustular psoriasis, are promising. 18,19 In one report, a 71-year-old patient who had failed to respond to topical tar, dithranol, and steroids and was unable to tolerate etretinate was treated with calcipotriol twice daily. After 6 weeks, there was marked improvement. 19 In contrast, there was a case report in which a patient with plaque-type psoriasis developed generalized pustular psoriasis after using calcipotriol for 2 weeks. 20 Therefore, double-blind, randomized studies evaluating the safety and efficacy of calcipotriol in the treatment of pustular psoriasis and its variants are needed. Pityriasis Rubra Pilaris Case reports have indicated the potential use of calcipotriol in the treatment of pityriasis rubra pilaris. Because of the clinical and histologic similarities between psoriasis and pityriasis rubra pilaris, it would be logical to conclude that calcipotriol would be advantageous in pityriasis rubra pilaris. In two patients with classic juvenile pityriasis rubra pilaris and one patient with atypical adult-onset pityriasis rubra pilaris, the application of calcipotriol ointment resulted in clinical improvement. One patient with classic juvenile pityriasis rubra pilaris did discontinue treatment because of irritation caused by the drug. 2 To determine the therapeutic role of calcipotriol, controlled studies are necessary. Inflammatory Linear Verrucous Epidermal Nevus Several investigators have reported the efficacy of calcipotriol in the treatment of inflammatory linear verrucous epidermal nevus In one report, a 5-year-old boy with inflammatory linear verrucous epidermal nevus on the right side of his trunk and lower extremity applied the medication twice daily. During a 12-week period, there was flattening of the lesions and a reduction in pruritus. Laboratory results did not reveal hypercalcemia. 21 The advantageous results raise the question of whether inflammatory linear verrucous epidermal nevus is a linear variant of psoriasis. Ichthyoses and Other Disorders of Keratinization Controlled studies have demonstrated the therapeutic benefit of calcipotriol in congenital ichthyoses and several other disorders of keratinization. The recognition of the modulatory effect of vitamin D 3 on epidermal differentiation and proliferation has created interest in its potential use in diseases with defects in cornification. In a randomized, double-blind, vehicle-controlled, right/ left comparative study, the efficacy of calcipotriol in

3 560 PARISH Clinics in Dermatology Y 2002;20: certain disorders of keratinization was determined. The multicenter investigation included patients with ichthyosis vulgaris, congenital ichthyoses (epidermolytic hyperkeratosis, lamellar ichthyosis, Sjögren-Larsson syndrome, ichthyosis linearis circumflexa, and congenital ichthyosiform erythroderma), 1,24 X-linked ichthyosis, hereditary palmoplantar keratoderma, keratosis pilaris, and Darier s disease. The patients applied calcipotriol twice daily to one side of the body and a placebo ointment to the other side for 12 weeks. There was a statistically significant improvement in those patients with congenital ichthyoses and those with X-linked ichthyosis. Although ichthyosis vulgaris was responsive, it was not statistically significant. Keratosis pilaris and palmoplantar keratoderma appeared to be unresponsive. Seven of the 12 patients with Darier s disease withdrew from the study due to either irritation induced by calcipotriol or exacerbation of the disease. None of the patients developed hypercalcemia. 25 Therefore, it appears that vitamin D 3 may be advantageous in certain disorders of keratinization. An earlier study from Japan comparing the effect of 1,25(OH) 2 D 3 on psoriasis vulgaris, ichthyosis vulgaris, and X-linked vulgaris had results that conflicted with those of the multicenter investigation. The patients applied 1,25(OH) 2 D 3 three times daily to the lesion. Neither the patients with ichthyosis vulgaris nor the patients with X-linked ichthyosis responded. Because of the effectiveness of 1,25(OH) 2 D 3 in patients with psoriasis only, the authors of this study concluded that the main mechanism of action is its effect on epidermal cell proliferation Therefore, the authors hypothesized that vitamin D 3 is ineffective in diseases that are not hyperproliferative, such as ichthyosis vulgaris and X-linked vulgaris. 26 However, the investigators of the multicenter trial theorized that the discrepancy between the two studies was a result of the lower drug concentration used in the Japanese study. 25 Thus, there is a need for further research into the efficacy of vitamin D 3 analogues in the treatment of the normoproliferative ichthyoses. Grover s Disease Treatment with calcipotriol proved effective in one patient with Grover s disease. The patient had not responded to topical steroids with oxytetracycline, dapsone, or etretinate. After 1 month of calcipotriol ointment alternating with a topical steroid ointment, there was clearance of the lesions. Any cessation of topical therapy resulted in recurrence. 27 The mode of action of vitamin D 3 in Grover s disease is unknown. Acanthosis Nigricans One patient with acanthosis nigricans is known to have had an improved clinical response to calcipotriol. A 60-year-old man with a history of transitional cell carcinoma of the bladder developed acanthosis nigricans of the hands, forearms, axillae, neck, and groin. After 3 months of twice-daily application of calcipotriol cream, there was a reduction in papillomatosis and hyperkeratosis. 28 Randomized, controlled trials are necessary to substantiate this application. Confluent and Reticulated Papillomatosis There are several reports of treatment of confluent and reticulated papillomatosis of Gougerot and Carteaud with calcipotriol In one case study, a 25-year-old woman with biopsy-proven confluent and reticulated papillomatosis had marked clinical improvement after 1 month of twice-daily application. 29 The etiology of this disease is unknown; however, the response to calcipotriol appears to support the theory that it is a disorder of keratinization. Prurigo Nodularis Vitamin D 3 analogues may be advantageous in the management of prurigo nodularis. Both tacalcitol and calcipotriol appear to be effective therapy for prurigo nodularis. 32,33 In a randomized, prospective, doubleblind, right/left comparative trial, calcipotriol ointment was superior to betamethasone ointment in reducing the number and size of nodules. Ten patients applied calcipotriol ointment twice daily to lesions on one leg and betamethasone ointment twice daily to the opposite leg for 8 weeks. Serum calcium levels remained within normal range. The authors were uncertain as to the mechanism of action of calcipotriol in the treatment of prurigo nodularis. 33 A larger-scale study is necessary to further assess the benefit of vitamin D 3 analogues in this recalcitrant disease. Keratosis Lichenoides Chronica Keratosis lichenoides chronica, which some consider to be a rare variant of lichen planus, may be responsive to topical calcipotriol. Case studies of the use of calcipotriol for this rare dermatosis are promising. 34,35 In one report of a 53-year-old patient, once-daily application of calcipotriol for 4 months proved to be efficacious. Systemic therapy, which included etretinate, griseofulvin, cryotherapy, and steroids, had failed previously to induce a significant improvement. 34 Lichen Amyloidosis A double-blind, right/left comparison pilot study investigated calcipotriol ointment vs betamethasone 17- valerate ointment in the treatment of lichen amyloidosis. The trial included 16 Asian patients who applied calcipotriol ointment twice daily to one leg and steroid ointment to the contralateral leg for 12 weeks. The investigators concluded that there was no statistically significant difference in treatment response between the two drugs; however, three patients complained of scal-

4 Clinics in Dermatology Y 2002;20: TOPICAL VITAMIN D 3 ANALOGUES 561 ing and redness with the calcipotriol. The authors suggested that the side effects induced by calcipotriol might exacerbate the underlying pruritus of lichen amyloidosis. Therefore, betamethasone 17-valerate ointment may be superior to calcipotriol for lichen amyloidosis. 36 Further large-scale studies are necessary to determine the role of calcipotriol in the treatment of lichen amyloidosis. Vitiligo Topical calcipotriol combined with psoralen-uva (PUVA) may decrease the length of therapy for vitiligo. A randomized, double-blind, right/left comparative study demonstrated the effectiveness of adding calcipotriol to thrice-weekly PUVA. The patients applied calcipotriol ointment twice daily to one side of the body and a placebo ointment to the opposite side. The addition of calcipotriol resulted in marked improvement and faster repigmentation compared with placebo. 37 Other trials have confirmed the benefit of the combination of calcipotriol and PUVA for vitiligo. 38,39 There are several factors that may contribute to the effectiveness of calcipotriol in vitiligo. Investigators have demonstrated the presence of VDRs on melanocytes and have suggested that vitamin D 3 may serve a function in the regulation of melanin synthesis. In addition, research has revealed defective calcium homeostasis in melanocytes and keratinocytes of depigmented skin. 37 Therefore, calcipotriol may be efficacious in vitiligo because of the expression of VDR by melanocytes and the modification of faulty calcium uptake. Morphea An open-label study has indicated the potential benefit of calcipotriol in morphea and linear scleroderma. Twelve patients applied calcipotriol ointment under occlusion twice daily. For a 3-month period, all patients had statistically significant improvement in their lesions. 6 In addition, earlier trials with oral calcitriol for the treatment of systemic scleroderma were promising. 40 The findings of in vitro studies further illustrated that vitamin D 3 may be advantageous in the management of localized scleroderma. The addition of calcipotriol to cultured morphea fibroblasts resulted in inhibition of cell proliferation. 41 The mechanism of action of calcipotriol in the treatment of morphea is unknown; however, immunomodulatory function of calcipotriol may play a role. Research has revealed that there are elevated levels of IL-2 receptor in patients with morphea, and therefore, the etiology of morphea may involve activation of T cells. The inhibition of IL-2 and other mediators of activated T cells by calcipotriol may contribute to its therapeutic benefit in morphea. 6 Further investigation into the effect of calcipotriol on immune function and into the pathogenesis of morphea is necessary. Conclusions Multiple studies have demonstrated the exciting potential uses of topical vitamin D 3 analogues in diseases other than plaque-type psoriasis. In several disorders such as X-linked ichthyoses, congenital ichthyoses, and vitiligo, controlled trials have indicated that calcipotriol may be an effective treatment. Case reports of Grover s disease and keratosis lichenoides chronica have suggested that calcipotriol may be efficacious, particularly in those patients who cannot tolerate systemic medications. Despite the concern of hypercalcemia, calcipotriol ointment is safe if the amount does not exceed 100 g per week. Skin irritation is also a potential side effect, but it occurs in 2% of patients. 16 Therefore, further research into the mode of action of vitamin D 3 should create new indications for the topical vitamin D 3 analogues. References 1. Lucker GP, van de Kerkhof PC, van Dijk MR, Steijlen PM. Effect of topical calcipotriol on congenital ichthyoses. Br J Dermatol 1994;131: Van de Kerkhof PC, Steijlen PM. Topical treatment of pityriasis rubra pilaris with calcipotriol. Br J Dermatol 1994;130: Kienbaum S, Lehmann P, Ruzicka T. Topical calcipotriol in the treatment of intertriginous psoriasis. Br J Dermatol 1996;135: Tosti A, Piraccini BM, Cameli N, et al. Calcipotriol ointment in nail psoriasis: a controlled double-blind comparison with betamethasone dipropionate and salicylic acid. Br J Dermatol 1998;139: Berth-Jones J, Bourke J, Bailey K, et al. Generalised pustular psoriasis: response to topical calcipotriol. BMJ 1992; 305: Cunningham BB, Landells ID, Langman C, et al. Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol 1998;39(2 Pt 1): Mellanby E, Cantag MD. Experimental investigations on rickets. Lancet 1919;196: Mellanby E. Experimental rickets. Medical Research (G.B.). Special Report Series 1921;SRS-61: McCollum EV, Simmonds N, Becker JE, Shipley PG. Studies on experimental rickets, XXI: an experimental demonstration of the existence of a vitamin which promotes calcium deposition. J Biol Chem 1922;53: Czarnetzki BM. Vitamin D 3 in dermatology: a critical appraisal. Dermatologica 1989;178: Sachs D, Baur S, Kang S. Topical vitamin D 3. In: Wolverton SE, editor. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders Co, 2001; Kragballe K. Vitamin D 3 and skin diseases. Arch Dermatol Res 1992;284(Suppl 1):S Van de Kerkhof PCM. In vivo effects of vitamin D 3 analogues. J Derm Treat 1998;9:S25 9.

5 562 PARISH Clinics in Dermatology Y 2002;20: Van de Kerkhof PC, Wittenhorst M, Gerritsen MJP, et al. Possible indications for vitamin D 3 analogues in conditions other than psoriasis vulgaris. J Derm Treat 1996;7: Fogh K, Kragballe K. Vitamin D 3 analogues. Clin Dermatol 1997;15: Kragballe K. Vitamin D 3 analogues. Dermatol Clin 1995; 13: Nicolaidou E, Katsambas AD. Vitamins A, B, C, D, E, F, trace elements and heavy metals: unapproved uses or indications. Clin Dermatol 2000;18: Mozzanica N, Cattaneo A. The clinical effect of topical calcipotriol in acrodermatitis continua of Hallopeau. Br J Dermatol 1998;138: Emtestam L, Weden U. Successful treatment for acrodermatitis continua of Hallopeau using topical calcipotriol. Br J Dermatol 1996;135: Georgala S, Rigopoulos D, Aroni K, Stratigos JT. Generalized pustular psoriasis precipitated by topical calcipotriol cream. Int J Dermatol 1994;33: Micali G, Nasca MR, Musumeci ML. Effect of topical calcipotriol on inflammatory linear verrucous epidermal nevus. Pediatr Dermatol 1995;12: Gatti S, Carrozzo AM, Orlandi A, Nini G. Treatment of inflammatory linear verrucous epidermal naevus with calcipotriol. Br J Dermatol 1995;132: Bohm I, Bieber T, Bauer R. Successful therapy of an IL- VEN in a 7-year-old girl with calcipotriol. Hautarzt 1999; 50: Lucker GP, van de Kerkhof PC, Cruysberg JR, et al. Topical treatment of Sjogren-Larsson syndrome with calcipotriol. Dermatology 1995;190: Kragballe K, Steijlen PM, Ibsen HH, et al. Efficacy, tolerability, and safety of calcipotriol ointment in disorders of keratinization: results of a randomized, double-blind, vehicle-controlled, right/left comparative study. Arch Dermatol 1995;131: Okano M. 1-alpha,-25-(OH) 2 D 3 use on psoriasis and ichthyosis. Int J Dermatol 1991;30: Keohane SG, Cork MJ. Treatment of Grover s disease with calcipotriol (Dovonex). Br J Dermatol 1995;132: Bohm M, Luger TA, Metze D. Treatment of mixed-type acanthosis nigricans with topical calcipotriol. Br J Dermatol 1998;139: Kurkcuoglu N, Celebi CR. Confluent and reticulated papillomatosis: response to topical calcipotriol. Dermatology 1995;191: Gulec AT, Seckin D. Confluent and reticulated papillomatosis: treatment with topical calcipotriol. Br J Dermatol 1999;141: Carrozzo AM, Gatti S, Ferranti G, et al. Calcipotriol treatment of confluent and reticulated papillomatosis (Gougerot-Carteaud syndrome). J Eur Acad Dermatol Venereol 2000;14: Katayama I, Miyazaki Y, Nishioka K. Topical vitamin D 3 (tacalcitol) for steroid-resistant prurigo. Br J Dermatol 1996;135: Wong SS, Goh CL. Double-blind, right/left comparison of calcipotriol ointment and betamethasone ointment in the treatment of prurigo nodularis. Arch Dermatol 2000;136: Grunwald MH, Hallel-Halevy D, Amichai B. Keratosis lichenoides chronica: response to topical calcipotriol. J Am Acad Dermatol 1997;37(2 Pt 1): Chang SE, Jung EC, Hong SM, et al. Keratosis lichenoides chronica: marked response to calcipotriol ointment. J Dermatol 2000;27: Khoo BP, Tay YK, Goh CL. Calcipotriol ointment vs. betamethasone 17-valerate ointment in the treatment of lichen amyloidosis. Int J Dermatol 1999;38: Parsad D, Saini R, Verma N. Combination of PUVAsol and topical calcipotriol in vitiligo. Dermatology 1998;197: Yalcin B, Sahin S, Bukulmez G, et al. Experience with calcipotriol as adjunctive treatment for vitiligo in patients who do not respond to PUVA alone: a preliminary study. J Am Acad Dermatol 2001;44: Ermis O, Alpsoy E, Cetin L, Yilmaz E. Is the efficacy of psoralen plus ultraviolet A therapy for vitiligo enhanced by concurrent topical calcipotriol? A placebo-controlled double-blind study. Br J Dermatol 2001;145: Humbert P, Dupond JL, Agache P, et al. Treatment of scleroderma with oral 1,25-dihydroxyvitamin D 3 : results of an open prospective trial. Acta Derm Venereol 1993;73: Bottomley WW, Jutley J, Wood EJ, Goodfield MD. The effect of calcipotriol on lesional fibroblasts from patients with active morphoea. Acta Derm Venereol 1995;75:364 6.