lournal of Clinical Pharmacy and Therapeutics(1992)17,217-222
REVIEW ARTICLE
Progress in self treatment for psoriasis vulgaris J. Berth-Jones and P. E. Hutchinson Department of Dermatology, Leicester Royal Infirmary, Leicester LEI SWW, U.K.
SUMMARY
Chronic plaque psoriasis is by far the most frequent form of the disease and is usually amenable to home treatment. The therapeutic armamentarium for selftreatment of psoriasis has, until recently, been limited to emollients, tar, dithranol and topical corticosteroids. Although limited progress has been made in improving formulations and treatment regimes for these compounds, they still have significant drawbacks in terms of either unwanted effects or cosmetic acceptability. Topical vitamin D analogues offer a new, effective, convenient and safe option for self-treatment of psoriasis. Most research has been performed on calcipotriol. This has compared well to betamethasone valerate and short-contact dithranol in controlled studies. Skin irritation is frequently noticed by patients, but rarely requires treatment to be discontinued. The mechanism of action appears most likely to be a direct regulation of keratinocyte proliferation and differentiation. Calcipotriol has relatively little effect on calcium metabolism and appears to be safe when used according to established guidelines but hypercalcaemia may develop if excessive quantities are used.
INTRODUCTION
Psoriasis presents in numerous different forms but by far the most common is chronic plaque psoriasis (psoriasis vulgaris), in which scaly, erythematous, indurated plaques develop on the limbs and trunk, and may persist for many weeks or months. In the majority of individuals the disease is of mild to moderate severity, affecting less than 20% of the skin. Most patients affected in this way treat themselves, or are treated by relatives. This Correspondence:Dr J. Berth-Jones.
’home treatment’ is the subject of this review. Other variants, such as severe widespread chronic plaque, involvement of the nails, scalp, palms and soles, and generalized forms require different management and are not addressed here. In April 1991 the first topical vitamin D analogue (calcipotriol,calcipotriene, 50 pg/g in an ointment base, Dovonex@,DaivonexB), was licensed in the U.K.for the treatment of psoriasis vulgaris. This is the first new treatment for mild to moderate chronic plaque psoriasis since the development of topical corticosteroids. To place this development in perspective, we first discuss existing agents suitable for self treatment. We then review the research performed on calcipotriol to establish its efficacy, mode of action and safety, and conclude with our views on the role it is likely to play.
CURRENT TREATMENT OF PSORIASIS
The options for self treatment of psoriasis at home have been limited to the use of emollients, tar, dithranol and topical steroids. Emollients
Emollients (moisturising agents) may effect a considerable degree of improvement in psoriasis, particularly in scaling. They comprise soap substitutes, bath oils, ointments and creams free from pharmacologically active compounds. The most frequently used soap substitutes are aqueous cream BP and emulsifying ointment BP, these are rubbed over the skin and rinsed off in the bath or shower in place of soap. Bath oils (e.g. Alpha KeriB, Balneume or Oilaturn@)are often helpful. About 10-20 ml should be added to each bath. Moisturising creams and ointments should be applied immediately after bathing and as frequently as required for comfort. Useful compounds include white soft paraffin BP, aqueous cream BP, Unguentum MerckB, E45 Cream@
218
]. Berth-]ones and P. E. Hutchinson
and Diprobase Cream@. Greasy preparations such as white soft paraffin are most therapeutic but are less cosmetically acceptable than creams which rub in more pleasantly. Patients with extensive disease may require large quantities of moisturisers (perhaps 500 g/week) to keep their skin comfortable. Efficacy is in no way related to cost. Adverse effects are unusual, although emollients may cause folliculitis, and contact sensitization occasionally occurs to the bases or preservatives.
(6), in which patients receive daily ultraviolet light and applications of crude coal tar. Tar is less irritant than dithranol but longer contact times (several hours) are required. Like dithranol, tar is very messy. Creams containing tar extracts (AlphosyP, Carbo Dome@, Clinitar@,PragmatarB) have therefore been developed for home use and these are considerably more pleasant and convenient to use. Although they do represent an advance, such extracts are not as effective as crude coal tar.
Dithranol
Dithranol (anthralin) has been used to treat chronic plaque psoriasis since it replaced the naturally occurring analogue, chrysarobin, in 1916. In a wide variety of formulations and treatment regimes, it has proved to be safe and effective, and is widely regarded as the first-line treatment of psoriasis vulgaris. The principal disadvantages are irritancy and staining. Best results are therefore obtained during in-patient treatment with regimes such as that described in 1953 by Ingram, comprising daily tar baths, followed by ultraviolet irradiation and 24-h treatment with increasing concentrations of dithranol in Lassar’s paste (I). Fortunately, more convenient formulations and treatment schedules have been developed. Cream formulations are effective (2,3),and easier to remove than pastes. Shorter application times have been shown to be almost as effective as all-day treatment (4, 5). Shortcontact, self-treatment has therefore become very popular. Dithranol is applied once daily, initially using a low concentration (0.1%)for just 5 min. The duration of treatment is gradually increased to 30 min and this is then repeated with higher concentrations, until irritation becomes unacceptable. A range of proprietary preparations are available as ointments (e.g. Alphodithe, AnthranoP) or creams (e.g.Dithrocreama, PsoradrateB), which can be removed with soap and water. Cream formulations are removed more easily than ointments. Tar
The use of tar is slightly unsatisfactory to the scientifically minded because there is no standardized formulation, and neither the active constituent(s)nor the mechanism of action are known. However, the efficacy of crude coal tar is not doubted, and it has been used in psoriasis for over 100 years. The best results are obtained with regimes such as that used by Goeckerman
Topical corticosteroids
The role of topical corticosteroids in the treatment of psoriasis is controversial. Potent compounds often produce prompt resolution of plaques. They have the advantage of being clean, convenient and cosmetically acceptable when compared to tar or dithranol. However, the duration of remission induced by steroids is brief (7), and psoriasis is a chronic condition so that the risk of accruing steroid atrophy of the skin is high. Many also believe that psoriasis may rebound, or even develop into the more severe pustular form on withdrawal of topical steroids (8-10). Systemic absorption may also be significant, particularly with very potent agents ( 9 , l l ) .The use of topical steroids is therefore best reserved for situations in which there is no alternative, and should be limited to short courses of the least potent agent which is effective. Tar and dithranol are not generally suitable for the face, genitalia, flexures, or hands; it is often necessary to use topical steroids in these situations. In chronic plaque psoriasis this treatment is rarely appropriate. VITAMIN D ANALOGUES
EfFcwY
Vitamin D became commercially available in 1930, and was prescribed for a very wide variety of diseases (12-14), including psoriasis (15, 16), though the doses required were toxic. In 1985, interest was reawakened by a report of a striking improvement in psoriasis in a patient treated for osteoporosis with oral 1 alpha hydroxyvitamin D (alphacalcidol) (17). This was followed by several reports from the same investigators (18-20) and others (21-26), that not only systemic, but also topical, vitamin D analogues could be used to treat psoriasis. Most of this research was performed using 1,25 dihydroxy-
Self beatmenffor psoriasis vulgaris
vitamin D3 (calcitriol). Systemic treatment still carried a considerable risk of toxicity but topical treatment allowed higher concentrations to be obtained in the skin, with relatively little absorption. Additional vitamin D analogues were investigated in an attempt to separate the therapeutic action from effects on calcium metabolism. 1.24 dihydroxycholecalciferol appeared to be effective when used topically (27), but this compound is almost as active as calcitriol in mineral metabolism. Calcipotriol is an analogue with less than 1% of the activity of calcitriol on calcium metabolism (28). In placebo-controlled studies, this compound proved highly effective when used topically in the treatment of psoriasis both as a cream (29, 30) and ointment formulation (31).The response was found to be optimal at 50 pg/g when different concentrations were compared (31).
In large, multicentre, double-blind studies of right/ left (32), and parallel group design (33), calcipotriol ointment (50pg/g) has been compared to betamethasone valerate ointment (0.1%). Each treatment was applied twice daily for 6 weeks. The response to the vitamin D analogue was of similar order to the corticosteroid. Calcipotriol has also been compared to self-treatment with short-contact dithranol therapy in a multicentre, open, parallel-group study. Two well-matched groups of 239 subjects with chronic plaque psoriasis used each regime for 8 weeks. Disease activity fell more on calcipotriol than on dithranol, and this difference was already highly statistically significant after just 2 weeks. Subjects also rated calcipotriol significantlymore acceptable than dithranol(34). The long-term use of calcipotriol is now undergoing intensive investigation (35, 36). The largest such study so far reported was of 12 months duration, and a total of 167 subjects participated (36).The response was maintained, in most subjects, for the entire year, although 15 were withdrawn due to deterioration. Fifty subjects noticed irritation but only nine withdrew as a result. No subject developed hypercalcaemia. Mechanism of action
Vitamin D analogues combine with highly specific nuclear receptors (37),found in most cell types studied, including keratinocytes, dermal fibroblasts, monocytes and activated lymphocytes (37-40). They regulate gene transcription by binding, in the presence of a nuclear
219
accessory factor (NAF), to a specific sequence of DNA, known as the vitamin D response element (VDRE)(41). In addition, more immediate 'non-genomic' effects are believed to operate through different mechanisms. These include elevation of intracellular calcium (42), and cyclic GMP levels (43). These effects promote keratinocyte differentiation and inhibit proliferation (44, 45).
In vitro studies have demonstrated a potent ability of calcitriol to inhibit cell proliferation and promote differentiation in both mouse (44) and human (45) keratinocyte cultures. Other vitamin D analogues (4648) including calcipotriol (28, 4 9 , also demonstrate these actions. Psoriasis is also known to respond extremely well to the immunosuppressant drug cyclosporin, a potent inhibitor of interleukin-2 transcription and lymphocyte activation. Calcitriol and its analogues share these properties with cyclosporin ( 5 0 , sI), which suggests the possibility of an immunologically mediated mechanism in which the lymphocyte or antigen-presenting cell may be the primary target. Histological studies during treatment have demonstrated improvement in keratinocyte differentiation, reduced proliferation and reduction of the inflammatory infiltrate (52,53). Side-effects
Irritant reactions have been reported in up to 19.5% of patients using calcipotriol in short-term studies (33). These are not usually severe but occasionally require treatment to be discontinued. The face is a particularly frequent site of these reactions (31). Contact allergic dermatitis has also been reported but is much more unusual (54). safpty An overdose of vitamin D leads to increased calcium absorption from the gut and resorption of bone, resulting in hypercalcaemia. Chronic hypervitaminosis may result in urinary stones or renal failure. The results from trials using topical vitamin D analogues are generally reassuring, although high concentrations of topical calcitriol may produce hypercalcaemia and increase urine calcium excretion (25). Calcipotriol has less than 1% of the activity on calcium metabolism of calcitriol (28, 55). This selectivity of action is due to the rapid elimination of calcipotriol(56).
220
]. Berth-]ones and
P. E. Hutchinson
Hypercalcaemiahas developed during calcipotriol treatment, though only when very large quantities were applied to a large surface area (33, 57). Serum calcium was monitored during all the studies performed on this compound and none has shown a rise in the mean level or hypercalcaemia in any subject using up to 1OOg of ointment (50pg/g) weekly. There has been less attention paid to the measurement of urinary calcium excretion during treatment with calcipotriol but three recent studies on a total of 69 subjects have shown no increase in calcium extraction (58,59) even with the long-term use of up to 100g of ointment weekly (60). THE FUTURE
Clinical research on calcipotriol has so far been conducted on adults but trials on the treatment of children are in progress. This compound may also find a place in the management of more severe forms of the disease, either alone or to provide a dose-sparing action with more toxic drugs. Additional vitamin D analogues are under development and may prove even more potent. CONCLUSIONS
Calcipotriol is now a first-line treatment for chronic plaque psoriasis and provides a welcome addition to a limited therapeutic armamentarium. For home treatment, it is at least as effective as betamethasone valerate, and conventional regimes for the use of tar or dithranol. It appears to be free from the significant side-effects of topical corticosteroids, and is much more convenient to use than tar or dithranol. The irritancy of calcipotriol unfortunately precludes its use on the face and flexures in many patients. Although it is far superior to dithranol in this respect, there remains a need for topical corticosteroids to treat these areas. Long-term continuous treatment appears to be safe, and even in patients with moderately severe disease, who may never totally clear their psoriasis, lesions can be kept smaller, flatter and less scaly. At present the cost of calcipotriol is probably the main factor limiting its use but it is possible this will fall, in relative terms, with time. REFERENCES 1. Ingram JT. (1953) The approach to psoriasis. British Medical Journal, 2,591-594. 2. Bochner H, Cohen E, David M et al. (1990) Ambulatory
treatment of psoriasis with short-contact dithrocream
therapy: a multicentre study. Israel Journal of Medical Sciences, 26,406-408. 3. Young E. (1986) Treatment of psoriasis with dithranol cream compared with dithranol paste. Dermatologica, 173,285-287. 4. Ryatt KS, Statham BN, Rowel1 NR. (1984) Short-contact modification of the Ingram regime. British Journal of Dermatology, 111,455-459. 5. Schaefer H, Farber EM, Goldberg L, Schalla W. (1980)
Limited application period for dithranol in psoriasis. BritishJournalof Dermatology, 102,571-573. 6. Goeckerman WH. (1933)Tar and ultra-violet radiation in treatment of psoriasis. BrifishIournal of Physical Medicine, 7,215-217. 7. Stevenson CJ, Whittington GE. (1963) Psoriasis treated
with topical fluocinolone acetonide and occlusive dressing. British Medical]ournal, i, 1450-1451. 8. Boxley ID, Dawber RPR, Summerly R. (1975)Generalized pustular psoriasis on withdrawal of clobetasol propionate ointment. British Medical]ottrnal, ii, 255-256. 9. Carruthers JA, August PJ, Staughton RCD. (1975) Observations on the systemic effect of topical clobetasol propionate (Dermovate). British Medical lournal, 4, 203-204.
10. Baker H. (1976) Corticosteroids and pustular psoriasis. British ]ournal of Dermatology, 94 (Suppl. 12), 83-88. 11. Hehir M, Du Vivier A, Eilon L, et al. (1983) Investigation of the phannacokinetics of clobetasol propionate and
clobetasone butyrate after a single application of ointment. Clinical and Experimental Dermatology, 8, 143. 12. King H, Hamilton CM. (1939) Pemphigus controlled by vitamin D. Archives of Dermafology and Syphilology, 39, 515-517. 13. Norman CF. (1946) Vitamin D therapy in the treatment
of scleroderma and allied conditions three cases. Geriatrics, 2.24-33. 14. Dowling GB, Thomas EWP. (1946) Treatment of lupus vulgaris with calciferol. Lancet, i, 919-922. 15. Krafka J. (1936) A simple treatment for psoriasis. Journal of Laboratory and Clinical Medicine, 21,1147-1148. 16. Thaker EA. (1940) The treatment of psoriasis with various vitamin D preparations. Illinois Medical Journal, 78,352-360. 17. Morimoto S, Kumahara Y. (1985)A patient with psoriasis cured by 1 alpha-hydroxyvitamin D3. Medical Journal of Osaka Universib, 35,51. 18. Takamoto S, Onishi T, Morimoto S, et al. (1986) Effect of
1 alpha-hydroxycholecalciferol on psoriasis vulgaris: a pilot study. Cak$ed Tissue International, 39,360-364. 19. Morimoto S, Onishi T, Imanaka S, et al. (1986) Topical administration of ~&dihydroxyvitamin D3 for psoriasis: report of five cases. Calc$ed Tissue International, 38, 119-122.
Self treatment for psoriasis vulgaris 20. Morimoto S, Yoshikawa K, Kozuka T, et al. (1986)An open study of vitamin D3 treatment in psoriasis vulgaris. British]ournal of Dermatology, 115,421-429. 21. Smith EL, Pincus SH, Donovan L, Holick MF. (1988) A novel approach for the evaluation and treatment of psoriasis. Journal of the American Academy of Dermatology, 19,516-28. 22. Holick MF, Pochi P, Bhawan J. (1989)Topically applied and orally administered 1-,25-dihydroxyvitamin D3 is a novel, safe, and effective therapy for the treatment of psoriasis: a three year experience and histologic analysis. ]ournal of Investigative Dermatology, 92,446. 23. Holland DB, Wood EJ, Roberts SG, et al. (1989) Epidermal cytokeratin levels during oral 1-alpha-hydroxyvitamin D3 treatment for psoriasis., Skin Pharmacology, 2,68-76. 24. Okano M. (1991) 1 alpha,25-(OH),D3 use on psoriasis and ichthyosis. International ]ournu1 of Dermatology, 30,
34. Berth-JonesJ, Chu AC, Dodd WAH, et al. (1992) A multi-
35.
36.
37.
38.
62-64.
25. Langner A, Vejans H, Stapor V, et al. (1991)Treatment of chronic plaque psoriasis by 1 alpha,25-dihydroxyvitamin D3 ointment. In: Proceedings of the Eighth Workshop on vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). 26. Long CC, Marks R. (1991)Calcipotriol and betamethasone valerate for psoriasis. Lancet, 337,922-923. 27. Kato T, Rokugo M, Terui T, Tagami H. (1986)Successful treatment of psoriasis with topical application of active vitamin D3 analogue, 1 alpha, 24-dihydroxycholecalciferol. British ]ournu1 of Dermatology, 115,431-433. 28. Binderup L, Bramm E. (1988)Effects of a novel vitamin D analogue MC903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochemical Pharmacology, 37,889-895. 29. Kragballe K, Breck HI, Sogaard H. (1988)Improvement of psoriasis by a topical vitamin D, analogue (Mc903)in a double-blind study. British lournal of Dermatology, 119, 223-230. 30. Staberg B, Roed-Petersen J,Menne T. (1989)Efficacy of topical treatment in psoriasis with MC903, a new vitamin D analogue. Acta Dermatologica et Venereologica, 69, 147-150. 31. Kragballe K. (1989)Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotrio1 (MC903).Archives of Dermatology, 125,1647-1652. 32. Kragballe K, Gjertesen BT, de Hoop D, et al. (1991) Double-blind, rightlleft comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet, 337, 193-196. 33. Cunliffe WJ, Berth-Jones J, Claudy A, et al. (1992) A multicentre comparative study of calcipotriol (MC903) ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. Journal of the American Academy of Dermatology,(in press).
221
39.
40.
41.
42.
43.
44.
45.
46.
centre parallel group comparison of calcipotriol ointment and shortcontact dithranol in chronic plaque psoriasis. British Journal of Dermatology, 127,266-271. Kragballe K, Fogh K, Sogaard H. (1991) Long-term efficacy and tolerability of topical calcipotriolin psoriasis. Acta Dermatologica et Venereologica,71,475-478. Klaber MR, Hutchinson PE, Holden C, et al. (1992) Long term treatment of psoriasis with calcipotriol. British Journal of Dermatology, 1 2 7 (Suppl. 4, (in press). Stumpf WE, Sar M, Reid FA, et al. (1979) Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary and parathyroid. Science, 206, 1188-1 190. Colston K, Hirst, M, Feldman, D. (1980)Organ distribution of the cytoplasmic ~,25-dihydroxycholecalciferol receptor in various mouse tissues. Endocrinology, 107, 1916-1922. Smith EL, Pincus SH, Donovan L, Holick MF. (1988) A novel approach for the evaluation and treatment of psoriasis. ]ournu1 of the American Academy of Dermatology, 19,516-528. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. (1983) 1,25-Dihydroxyvitamin D3 receptors in human leukocytes. Science, 221,1181-1183. Ozono K, Kemer S, Scott R, Pike JW. (1991)Interaction of the vitamin D receptor with natural and palindromic vitamin D response elements. In: Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). Bittiner B, Bleehen SS, MacNeil S. (1991) I alpha, 25(OH), vitamin D, increases intracellular calcium in human keratinocytes. British]ournal of Dermatology, 124, 230-235. Barsony J, McCoy Maw SJ. (1991) Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). Hosomi J, Hosoi J, Abe E, et al. (1983) Regulation of terminal differentiation of mouse cultured epidermal cells by la,25-dihydroxyvitamin D3. Endocrinology, 113, 1950-195 7. Smith EL, Walworth NC, Holick MF. (1986) Effect of la,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions. Journal of Investigative Dermatology, 86, 709-714. Calverley MJ, Binderup E, Binderup L. (1991)The 20-epi modification in the vitamin D series: selective enhancement of non-classical receptor-mediated effects. In: Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press).
222 J. Berfh-Jones and P. E. Hutchinson
47. Hansen K, Calverley MJ, Binderup L. (1991) Synthesis and biological activity of 22-oxa vitamin D analogues. In: Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). 48. Binderup E, Calverley MI, Binderup L. (1991) Synthesis and biological activity of 1 alpha-hydroxylated vitamin D analogues with poly-unsaturated side chains. In: Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). 49. Kragballe K, Wildfang IL. (1990)Calcipotriol (MC903),a novel vitamin D3 analogue stimulates terminal differentiation and inhibits proliferation of cultured human keratinocytes. Archives of Dermatological Research, 282, 164-167. 50. Rigby WFC, Stacy T, Fanger MW.(1984) Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). Journal of Clinical Investigation, 74, 1451-1455. 51. Tsoukas CD, Provvedini DM, Manolagas SC. (1984) 1,25-dihydroxyvitamin D3, a novel immunoregulatory hormone. Science, 24, 1438-1440. 52. Berth-Jones J, Fletcher A, Hutchinson PE. (1992) Epidermal cytokeratin and immunocyte responses during treatment of psoriasis with calcipotriol and betamethasone valerate. British Journal of Dermatology, 126, 356-361.
53. De Jong EMGJ, Van de Kerkhof PCM. (1991) Simultaneous assessment of inflammation and epidermal proliferation in psoriatic plaques during long-term
treatment with the vitamin D3 analogue MC903: modulations and interrelations. British Journal of Dermatology, 124,221-229.
54. Yip 1, Goodfield M. (1991) Contact dermatitis from MC903, a topical vitamin D3 analogue. Contact Dermatitis, 25,139-140. 55. Thieroff-Ekerdt R, Rach P, Brautigam M. (1991) 1-alpha, 25(OH),cholecalciferol and MC903 enhance epidermal dfierentiation but do not inhibit hyperproliferation, in animal skin in vivo. Presented t o The Eighth Workshop on Vitamin D, Paris, 1991. 56. Kissmeyer AM, Binderup L. (1991) Pharmacokinetics of calcipotrioland 1,25(OH)2D3in rats. In: Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). 57. Dwyer C, Chapman RS. (1991) Calcipotriol and hypercdcaemia. Lancet, 338,764-765. 58. Saurat J-H, Sunek DG, Rizzoli R. (1991)Topical calcipotriol and hypercalcaemia. Lancet, 337, 1287. 59. Mortensen L, Kragballe K, Schifter S, Charles P. (1991) Effect of calcipotriol on psoriasis: A double-blind, placebo-controlled study of calcipotriol (MC903) and calcium metabolism. In: Proceedings of the Ez$fh Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). 60. Berth-JonesJ, Bourke JF,Elouzi H, et al. (1992) Immediate and long term effects of topical calcipotriol on calcium homeostasis during treatment of psoriasis. British Journal of Dermatology, 127 (Suppl. 40) 17.
REVIEW ARTICLE
Progress in self treatment for psoriasis vulgaris J. Berth-Jones and P. E. Hutchinson Department of Dermatology, Leicester Royal Infirmary, Leicester LEI SWW, U.K.
SUMMARY
Chronic plaque psoriasis is by far the most frequent form of the disease and is usually amenable to home treatment. The therapeutic armamentarium for selftreatment of psoriasis has, until recently, been limited to emollients, tar, dithranol and topical corticosteroids. Although limited progress has been made in improving formulations and treatment regimes for these compounds, they still have significant drawbacks in terms of either unwanted effects or cosmetic acceptability. Topical vitamin D analogues offer a new, effective, convenient and safe option for self-treatment of psoriasis. Most research has been performed on calcipotriol. This has compared well to betamethasone valerate and short-contact dithranol in controlled studies. Skin irritation is frequently noticed by patients, but rarely requires treatment to be discontinued. The mechanism of action appears most likely to be a direct regulation of keratinocyte proliferation and differentiation. Calcipotriol has relatively little effect on calcium metabolism and appears to be safe when used according to established guidelines but hypercalcaemia may develop if excessive quantities are used.
INTRODUCTION
Psoriasis presents in numerous different forms but by far the most common is chronic plaque psoriasis (psoriasis vulgaris), in which scaly, erythematous, indurated plaques develop on the limbs and trunk, and may persist for many weeks or months. In the majority of individuals the disease is of mild to moderate severity, affecting less than 20% of the skin. Most patients affected in this way treat themselves, or are treated by relatives. This Correspondence:Dr J. Berth-Jones.
’home treatment’ is the subject of this review. Other variants, such as severe widespread chronic plaque, involvement of the nails, scalp, palms and soles, and generalized forms require different management and are not addressed here. In April 1991 the first topical vitamin D analogue (calcipotriol,calcipotriene, 50 pg/g in an ointment base, Dovonex@,DaivonexB), was licensed in the U.K.for the treatment of psoriasis vulgaris. This is the first new treatment for mild to moderate chronic plaque psoriasis since the development of topical corticosteroids. To place this development in perspective, we first discuss existing agents suitable for self treatment. We then review the research performed on calcipotriol to establish its efficacy, mode of action and safety, and conclude with our views on the role it is likely to play.
CURRENT TREATMENT OF PSORIASIS
The options for self treatment of psoriasis at home have been limited to the use of emollients, tar, dithranol and topical steroids. Emollients
Emollients (moisturising agents) may effect a considerable degree of improvement in psoriasis, particularly in scaling. They comprise soap substitutes, bath oils, ointments and creams free from pharmacologically active compounds. The most frequently used soap substitutes are aqueous cream BP and emulsifying ointment BP, these are rubbed over the skin and rinsed off in the bath or shower in place of soap. Bath oils (e.g. Alpha KeriB, Balneume or Oilaturn@)are often helpful. About 10-20 ml should be added to each bath. Moisturising creams and ointments should be applied immediately after bathing and as frequently as required for comfort. Useful compounds include white soft paraffin BP, aqueous cream BP, Unguentum MerckB, E45 Cream@
218
]. Berth-]ones and P. E. Hutchinson
and Diprobase Cream@. Greasy preparations such as white soft paraffin are most therapeutic but are less cosmetically acceptable than creams which rub in more pleasantly. Patients with extensive disease may require large quantities of moisturisers (perhaps 500 g/week) to keep their skin comfortable. Efficacy is in no way related to cost. Adverse effects are unusual, although emollients may cause folliculitis, and contact sensitization occasionally occurs to the bases or preservatives.
(6), in which patients receive daily ultraviolet light and applications of crude coal tar. Tar is less irritant than dithranol but longer contact times (several hours) are required. Like dithranol, tar is very messy. Creams containing tar extracts (AlphosyP, Carbo Dome@, Clinitar@,PragmatarB) have therefore been developed for home use and these are considerably more pleasant and convenient to use. Although they do represent an advance, such extracts are not as effective as crude coal tar.
Dithranol
Dithranol (anthralin) has been used to treat chronic plaque psoriasis since it replaced the naturally occurring analogue, chrysarobin, in 1916. In a wide variety of formulations and treatment regimes, it has proved to be safe and effective, and is widely regarded as the first-line treatment of psoriasis vulgaris. The principal disadvantages are irritancy and staining. Best results are therefore obtained during in-patient treatment with regimes such as that described in 1953 by Ingram, comprising daily tar baths, followed by ultraviolet irradiation and 24-h treatment with increasing concentrations of dithranol in Lassar’s paste (I). Fortunately, more convenient formulations and treatment schedules have been developed. Cream formulations are effective (2,3),and easier to remove than pastes. Shorter application times have been shown to be almost as effective as all-day treatment (4, 5). Shortcontact, self-treatment has therefore become very popular. Dithranol is applied once daily, initially using a low concentration (0.1%)for just 5 min. The duration of treatment is gradually increased to 30 min and this is then repeated with higher concentrations, until irritation becomes unacceptable. A range of proprietary preparations are available as ointments (e.g. Alphodithe, AnthranoP) or creams (e.g.Dithrocreama, PsoradrateB), which can be removed with soap and water. Cream formulations are removed more easily than ointments. Tar
The use of tar is slightly unsatisfactory to the scientifically minded because there is no standardized formulation, and neither the active constituent(s)nor the mechanism of action are known. However, the efficacy of crude coal tar is not doubted, and it has been used in psoriasis for over 100 years. The best results are obtained with regimes such as that used by Goeckerman
Topical corticosteroids
The role of topical corticosteroids in the treatment of psoriasis is controversial. Potent compounds often produce prompt resolution of plaques. They have the advantage of being clean, convenient and cosmetically acceptable when compared to tar or dithranol. However, the duration of remission induced by steroids is brief (7), and psoriasis is a chronic condition so that the risk of accruing steroid atrophy of the skin is high. Many also believe that psoriasis may rebound, or even develop into the more severe pustular form on withdrawal of topical steroids (8-10). Systemic absorption may also be significant, particularly with very potent agents ( 9 , l l ) .The use of topical steroids is therefore best reserved for situations in which there is no alternative, and should be limited to short courses of the least potent agent which is effective. Tar and dithranol are not generally suitable for the face, genitalia, flexures, or hands; it is often necessary to use topical steroids in these situations. In chronic plaque psoriasis this treatment is rarely appropriate. VITAMIN D ANALOGUES
EfFcwY
Vitamin D became commercially available in 1930, and was prescribed for a very wide variety of diseases (12-14), including psoriasis (15, 16), though the doses required were toxic. In 1985, interest was reawakened by a report of a striking improvement in psoriasis in a patient treated for osteoporosis with oral 1 alpha hydroxyvitamin D (alphacalcidol) (17). This was followed by several reports from the same investigators (18-20) and others (21-26), that not only systemic, but also topical, vitamin D analogues could be used to treat psoriasis. Most of this research was performed using 1,25 dihydroxy-
Self beatmenffor psoriasis vulgaris
vitamin D3 (calcitriol). Systemic treatment still carried a considerable risk of toxicity but topical treatment allowed higher concentrations to be obtained in the skin, with relatively little absorption. Additional vitamin D analogues were investigated in an attempt to separate the therapeutic action from effects on calcium metabolism. 1.24 dihydroxycholecalciferol appeared to be effective when used topically (27), but this compound is almost as active as calcitriol in mineral metabolism. Calcipotriol is an analogue with less than 1% of the activity of calcitriol on calcium metabolism (28). In placebo-controlled studies, this compound proved highly effective when used topically in the treatment of psoriasis both as a cream (29, 30) and ointment formulation (31).The response was found to be optimal at 50 pg/g when different concentrations were compared (31).
In large, multicentre, double-blind studies of right/ left (32), and parallel group design (33), calcipotriol ointment (50pg/g) has been compared to betamethasone valerate ointment (0.1%). Each treatment was applied twice daily for 6 weeks. The response to the vitamin D analogue was of similar order to the corticosteroid. Calcipotriol has also been compared to self-treatment with short-contact dithranol therapy in a multicentre, open, parallel-group study. Two well-matched groups of 239 subjects with chronic plaque psoriasis used each regime for 8 weeks. Disease activity fell more on calcipotriol than on dithranol, and this difference was already highly statistically significant after just 2 weeks. Subjects also rated calcipotriol significantlymore acceptable than dithranol(34). The long-term use of calcipotriol is now undergoing intensive investigation (35, 36). The largest such study so far reported was of 12 months duration, and a total of 167 subjects participated (36).The response was maintained, in most subjects, for the entire year, although 15 were withdrawn due to deterioration. Fifty subjects noticed irritation but only nine withdrew as a result. No subject developed hypercalcaemia. Mechanism of action
Vitamin D analogues combine with highly specific nuclear receptors (37),found in most cell types studied, including keratinocytes, dermal fibroblasts, monocytes and activated lymphocytes (37-40). They regulate gene transcription by binding, in the presence of a nuclear
219
accessory factor (NAF), to a specific sequence of DNA, known as the vitamin D response element (VDRE)(41). In addition, more immediate 'non-genomic' effects are believed to operate through different mechanisms. These include elevation of intracellular calcium (42), and cyclic GMP levels (43). These effects promote keratinocyte differentiation and inhibit proliferation (44, 45).
In vitro studies have demonstrated a potent ability of calcitriol to inhibit cell proliferation and promote differentiation in both mouse (44) and human (45) keratinocyte cultures. Other vitamin D analogues (4648) including calcipotriol (28, 4 9 , also demonstrate these actions. Psoriasis is also known to respond extremely well to the immunosuppressant drug cyclosporin, a potent inhibitor of interleukin-2 transcription and lymphocyte activation. Calcitriol and its analogues share these properties with cyclosporin ( 5 0 , sI), which suggests the possibility of an immunologically mediated mechanism in which the lymphocyte or antigen-presenting cell may be the primary target. Histological studies during treatment have demonstrated improvement in keratinocyte differentiation, reduced proliferation and reduction of the inflammatory infiltrate (52,53). Side-effects
Irritant reactions have been reported in up to 19.5% of patients using calcipotriol in short-term studies (33). These are not usually severe but occasionally require treatment to be discontinued. The face is a particularly frequent site of these reactions (31). Contact allergic dermatitis has also been reported but is much more unusual (54). safpty An overdose of vitamin D leads to increased calcium absorption from the gut and resorption of bone, resulting in hypercalcaemia. Chronic hypervitaminosis may result in urinary stones or renal failure. The results from trials using topical vitamin D analogues are generally reassuring, although high concentrations of topical calcitriol may produce hypercalcaemia and increase urine calcium excretion (25). Calcipotriol has less than 1% of the activity on calcium metabolism of calcitriol (28, 55). This selectivity of action is due to the rapid elimination of calcipotriol(56).
220
]. Berth-]ones and
P. E. Hutchinson
Hypercalcaemiahas developed during calcipotriol treatment, though only when very large quantities were applied to a large surface area (33, 57). Serum calcium was monitored during all the studies performed on this compound and none has shown a rise in the mean level or hypercalcaemia in any subject using up to 1OOg of ointment (50pg/g) weekly. There has been less attention paid to the measurement of urinary calcium excretion during treatment with calcipotriol but three recent studies on a total of 69 subjects have shown no increase in calcium extraction (58,59) even with the long-term use of up to 100g of ointment weekly (60). THE FUTURE
Clinical research on calcipotriol has so far been conducted on adults but trials on the treatment of children are in progress. This compound may also find a place in the management of more severe forms of the disease, either alone or to provide a dose-sparing action with more toxic drugs. Additional vitamin D analogues are under development and may prove even more potent. CONCLUSIONS
Calcipotriol is now a first-line treatment for chronic plaque psoriasis and provides a welcome addition to a limited therapeutic armamentarium. For home treatment, it is at least as effective as betamethasone valerate, and conventional regimes for the use of tar or dithranol. It appears to be free from the significant side-effects of topical corticosteroids, and is much more convenient to use than tar or dithranol. The irritancy of calcipotriol unfortunately precludes its use on the face and flexures in many patients. Although it is far superior to dithranol in this respect, there remains a need for topical corticosteroids to treat these areas. Long-term continuous treatment appears to be safe, and even in patients with moderately severe disease, who may never totally clear their psoriasis, lesions can be kept smaller, flatter and less scaly. At present the cost of calcipotriol is probably the main factor limiting its use but it is possible this will fall, in relative terms, with time. REFERENCES 1. Ingram JT. (1953) The approach to psoriasis. British Medical Journal, 2,591-594. 2. Bochner H, Cohen E, David M et al. (1990) Ambulatory
treatment of psoriasis with short-contact dithrocream
therapy: a multicentre study. Israel Journal of Medical Sciences, 26,406-408. 3. Young E. (1986) Treatment of psoriasis with dithranol cream compared with dithranol paste. Dermatologica, 173,285-287. 4. Ryatt KS, Statham BN, Rowel1 NR. (1984) Short-contact modification of the Ingram regime. British Journal of Dermatology, 111,455-459. 5. Schaefer H, Farber EM, Goldberg L, Schalla W. (1980)
Limited application period for dithranol in psoriasis. BritishJournalof Dermatology, 102,571-573. 6. Goeckerman WH. (1933)Tar and ultra-violet radiation in treatment of psoriasis. BrifishIournal of Physical Medicine, 7,215-217. 7. Stevenson CJ, Whittington GE. (1963) Psoriasis treated
with topical fluocinolone acetonide and occlusive dressing. British Medical]ournal, i, 1450-1451. 8. Boxley ID, Dawber RPR, Summerly R. (1975)Generalized pustular psoriasis on withdrawal of clobetasol propionate ointment. British Medical]ottrnal, ii, 255-256. 9. Carruthers JA, August PJ, Staughton RCD. (1975) Observations on the systemic effect of topical clobetasol propionate (Dermovate). British Medical lournal, 4, 203-204.
10. Baker H. (1976) Corticosteroids and pustular psoriasis. British ]ournal of Dermatology, 94 (Suppl. 12), 83-88. 11. Hehir M, Du Vivier A, Eilon L, et al. (1983) Investigation of the phannacokinetics of clobetasol propionate and
clobetasone butyrate after a single application of ointment. Clinical and Experimental Dermatology, 8, 143. 12. King H, Hamilton CM. (1939) Pemphigus controlled by vitamin D. Archives of Dermafology and Syphilology, 39, 515-517. 13. Norman CF. (1946) Vitamin D therapy in the treatment
of scleroderma and allied conditions three cases. Geriatrics, 2.24-33. 14. Dowling GB, Thomas EWP. (1946) Treatment of lupus vulgaris with calciferol. Lancet, i, 919-922. 15. Krafka J. (1936) A simple treatment for psoriasis. Journal of Laboratory and Clinical Medicine, 21,1147-1148. 16. Thaker EA. (1940) The treatment of psoriasis with various vitamin D preparations. Illinois Medical Journal, 78,352-360. 17. Morimoto S, Kumahara Y. (1985)A patient with psoriasis cured by 1 alpha-hydroxyvitamin D3. Medical Journal of Osaka Universib, 35,51. 18. Takamoto S, Onishi T, Morimoto S, et al. (1986) Effect of
1 alpha-hydroxycholecalciferol on psoriasis vulgaris: a pilot study. Cak$ed Tissue International, 39,360-364. 19. Morimoto S, Onishi T, Imanaka S, et al. (1986) Topical administration of ~&dihydroxyvitamin D3 for psoriasis: report of five cases. Calc$ed Tissue International, 38, 119-122.
Self treatment for psoriasis vulgaris 20. Morimoto S, Yoshikawa K, Kozuka T, et al. (1986)An open study of vitamin D3 treatment in psoriasis vulgaris. British]ournal of Dermatology, 115,421-429. 21. Smith EL, Pincus SH, Donovan L, Holick MF. (1988) A novel approach for the evaluation and treatment of psoriasis. Journal of the American Academy of Dermatology, 19,516-28. 22. Holick MF, Pochi P, Bhawan J. (1989)Topically applied and orally administered 1-,25-dihydroxyvitamin D3 is a novel, safe, and effective therapy for the treatment of psoriasis: a three year experience and histologic analysis. ]ournal of Investigative Dermatology, 92,446. 23. Holland DB, Wood EJ, Roberts SG, et al. (1989) Epidermal cytokeratin levels during oral 1-alpha-hydroxyvitamin D3 treatment for psoriasis., Skin Pharmacology, 2,68-76. 24. Okano M. (1991) 1 alpha,25-(OH),D3 use on psoriasis and ichthyosis. International ]ournu1 of Dermatology, 30,
34. Berth-JonesJ, Chu AC, Dodd WAH, et al. (1992) A multi-
35.
36.
37.
38.
62-64.
25. Langner A, Vejans H, Stapor V, et al. (1991)Treatment of chronic plaque psoriasis by 1 alpha,25-dihydroxyvitamin D3 ointment. In: Proceedings of the Eighth Workshop on vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). 26. Long CC, Marks R. (1991)Calcipotriol and betamethasone valerate for psoriasis. Lancet, 337,922-923. 27. Kato T, Rokugo M, Terui T, Tagami H. (1986)Successful treatment of psoriasis with topical application of active vitamin D3 analogue, 1 alpha, 24-dihydroxycholecalciferol. British ]ournu1 of Dermatology, 115,431-433. 28. Binderup L, Bramm E. (1988)Effects of a novel vitamin D analogue MC903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochemical Pharmacology, 37,889-895. 29. Kragballe K, Breck HI, Sogaard H. (1988)Improvement of psoriasis by a topical vitamin D, analogue (Mc903)in a double-blind study. British lournal of Dermatology, 119, 223-230. 30. Staberg B, Roed-Petersen J,Menne T. (1989)Efficacy of topical treatment in psoriasis with MC903, a new vitamin D analogue. Acta Dermatologica et Venereologica, 69, 147-150. 31. Kragballe K. (1989)Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotrio1 (MC903).Archives of Dermatology, 125,1647-1652. 32. Kragballe K, Gjertesen BT, de Hoop D, et al. (1991) Double-blind, rightlleft comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet, 337, 193-196. 33. Cunliffe WJ, Berth-Jones J, Claudy A, et al. (1992) A multicentre comparative study of calcipotriol (MC903) ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. Journal of the American Academy of Dermatology,(in press).
221
39.
40.
41.
42.
43.
44.
45.
46.
centre parallel group comparison of calcipotriol ointment and shortcontact dithranol in chronic plaque psoriasis. British Journal of Dermatology, 127,266-271. Kragballe K, Fogh K, Sogaard H. (1991) Long-term efficacy and tolerability of topical calcipotriolin psoriasis. Acta Dermatologica et Venereologica,71,475-478. Klaber MR, Hutchinson PE, Holden C, et al. (1992) Long term treatment of psoriasis with calcipotriol. British Journal of Dermatology, 1 2 7 (Suppl. 4, (in press). Stumpf WE, Sar M, Reid FA, et al. (1979) Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary and parathyroid. Science, 206, 1188-1 190. Colston K, Hirst, M, Feldman, D. (1980)Organ distribution of the cytoplasmic ~,25-dihydroxycholecalciferol receptor in various mouse tissues. Endocrinology, 107, 1916-1922. Smith EL, Pincus SH, Donovan L, Holick MF. (1988) A novel approach for the evaluation and treatment of psoriasis. ]ournu1 of the American Academy of Dermatology, 19,516-528. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. (1983) 1,25-Dihydroxyvitamin D3 receptors in human leukocytes. Science, 221,1181-1183. Ozono K, Kemer S, Scott R, Pike JW. (1991)Interaction of the vitamin D receptor with natural and palindromic vitamin D response elements. In: Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). Bittiner B, Bleehen SS, MacNeil S. (1991) I alpha, 25(OH), vitamin D, increases intracellular calcium in human keratinocytes. British]ournal of Dermatology, 124, 230-235. Barsony J, McCoy Maw SJ. (1991) Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). Hosomi J, Hosoi J, Abe E, et al. (1983) Regulation of terminal differentiation of mouse cultured epidermal cells by la,25-dihydroxyvitamin D3. Endocrinology, 113, 1950-195 7. Smith EL, Walworth NC, Holick MF. (1986) Effect of la,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions. Journal of Investigative Dermatology, 86, 709-714. Calverley MJ, Binderup E, Binderup L. (1991)The 20-epi modification in the vitamin D series: selective enhancement of non-classical receptor-mediated effects. In: Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press).
222 J. Berfh-Jones and P. E. Hutchinson
47. Hansen K, Calverley MJ, Binderup L. (1991) Synthesis and biological activity of 22-oxa vitamin D analogues. In: Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). 48. Binderup E, Calverley MI, Binderup L. (1991) Synthesis and biological activity of 1 alpha-hydroxylated vitamin D analogues with poly-unsaturated side chains. In: Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). 49. Kragballe K, Wildfang IL. (1990)Calcipotriol (MC903),a novel vitamin D3 analogue stimulates terminal differentiation and inhibits proliferation of cultured human keratinocytes. Archives of Dermatological Research, 282, 164-167. 50. Rigby WFC, Stacy T, Fanger MW.(1984) Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). Journal of Clinical Investigation, 74, 1451-1455. 51. Tsoukas CD, Provvedini DM, Manolagas SC. (1984) 1,25-dihydroxyvitamin D3, a novel immunoregulatory hormone. Science, 24, 1438-1440. 52. Berth-Jones J, Fletcher A, Hutchinson PE. (1992) Epidermal cytokeratin and immunocyte responses during treatment of psoriasis with calcipotriol and betamethasone valerate. British Journal of Dermatology, 126, 356-361.
53. De Jong EMGJ, Van de Kerkhof PCM. (1991) Simultaneous assessment of inflammation and epidermal proliferation in psoriatic plaques during long-term
treatment with the vitamin D3 analogue MC903: modulations and interrelations. British Journal of Dermatology, 124,221-229.
54. Yip 1, Goodfield M. (1991) Contact dermatitis from MC903, a topical vitamin D3 analogue. Contact Dermatitis, 25,139-140. 55. Thieroff-Ekerdt R, Rach P, Brautigam M. (1991) 1-alpha, 25(OH),cholecalciferol and MC903 enhance epidermal dfierentiation but do not inhibit hyperproliferation, in animal skin in vivo. Presented t o The Eighth Workshop on Vitamin D, Paris, 1991. 56. Kissmeyer AM, Binderup L. (1991) Pharmacokinetics of calcipotrioland 1,25(OH)2D3in rats. In: Proceedings of the Eighth Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). 57. Dwyer C, Chapman RS. (1991) Calcipotriol and hypercdcaemia. Lancet, 338,764-765. 58. Saurat J-H, Sunek DG, Rizzoli R. (1991)Topical calcipotriol and hypercalcaemia. Lancet, 337, 1287. 59. Mortensen L, Kragballe K, Schifter S, Charles P. (1991) Effect of calcipotriol on psoriasis: A double-blind, placebo-controlled study of calcipotriol (MC903) and calcium metabolism. In: Proceedings of the Ez$fh Workshop on Vitamin D, Paris, 1991. Norman AW, Bouillon R, Thomasset M, eds, Walter de Gruyter & Co., Berlin, (in press). 60. Berth-JonesJ, Bourke JF,Elouzi H, et al. (1992) Immediate and long term effects of topical calcipotriol on calcium homeostasis during treatment of psoriasis. British Journal of Dermatology, 127 (Suppl. 40) 17.
