COMMENTARY
CALCIPOTRIOL AND PSORIASIS COLIN A. RAMSAY, M.D., E.R.C.P., E.R.C.l'.C.
metabolism are retained, and the unwanted effects on calcium metabolism are markedly diminished, leading to the development of calcipotriol as a topical therapy for psoriasis.
Calcipotriol, which is an analogue of vitamin D3, has recently been shown to he an effective topical agent for psoriasis. The development of calcipotriol occurred as a consequence of the new knowledge concerning some of the cellular effects of vitamin D3.
CLINICAL USE BACKGROUND
The active natural form of vitamin D3 is 1,25-dihydroxy vitamin D3 also called calcitriol. It has heen known for many years that vitamin D3 has a profound effect on calcium metabolism, but it is only relatively recently that some other effects of vitamin D3 have been established. These other effects are mediated through vitamin D3 receptors present in a number of different cells,' including keratinocytes,^ and in normal and psoriatic skin.' In keratinocytes, vitamin D3 has been shown to stimulate terminal differentiation and to inhibit proliferation,^ and thus it might be expected to be of value in psoriasis. That this is indeed the case was observed by Morimoto et al.'' in Japan. A patient was being treated for osteoporosis with an oral analogue of vitamin D3, and the psoriasis that was also present in this patient cleared. This led to other studies that confirmed the beneficial effect of vitamin D3 or its analogues, either orally or topically, in psoriasis.'-'' There has been an understandable and justifiable concern about the use of these compounds because of their effect on calcium metabolism in the doses that are required to influence psoriasis. It is unlikely that vitamin D3 or the earlier analogues would ever have found a routine place in the management of psoriasis because of their hypercalcemic effects. Calcipotriol is a new analogue of vitamin D3, which has a similar affinity for the same receptors and has a similar effect on cellular proliferation and differentiation as the natural vitamin; however, from the point of view of the treatment of psoriasis, the most important property of calcipotriol is its effect on calcium metabolism. This effect is 100 to 200 times less than that of vitamin D3 itself.'' Thus, the desired effects on cellular From the Department of Medicine, University of Toronto Faculty of Medicine Toronto, Ontario, Canada. Address for correspondence: Colin A. Ramsay, M.D., 123 Edward Street, Suite 725, Toronto, Ontario, Canada M5C 1E2.
The first clinical trial of calcipotriol used it as a cream and compared it in a double-blind controlled manner with its base.** The results showed that calcipotriol improved psoriasis in a dose-related manner and that the histologic changes in the skin improved along with the clinical changes. A later trial used calcipotriol as an ointment and compared its effect at different concentrations in psoriasis and also compared it with its base.' It was found that the active compound was markedly more effective than the base and that 50 |a.g/g appeared to be the optimum concentration. The 50 |ig/g ointment was slightly better than the 25 |J.g/g preparation and equal to the 100 |ig/g preparation. Subsequent trials have used the ointment at 50 |Jg/g. The latest studies have compared calcipotriol ointment with betamethasone valerate ointment (0.1%). These have shown calcipotriol to be as effective as or superior to betamethasone in patients with chronic plaque psoriasis.'"'" Calcipotriol is now marketed in some countries (e.g., Denmark, Ireland, New Zealand, and the United Kingdom). Clinical trials have been completed in Canada ' and are underway in the United States. There are some adverse effects of the drug, but these reactions are usually mild and transient; they led to the withdrawal of only a few patients from the trials. The most common adverse effect was irritation of the skin on and around some psoriatic plaques. Burning or itching of the skin was associated with scaling and erythema. Some patients developed a mild dermatitis on the face, although this area was not treated. This effect probably occurred from unsuspected contamination of the face from ointment on the hands. Personal observation of this effect in a few patients has shown that the facial eruption settles quickly with a low potency topical steroid whilst the calcipotriol ointment is continued on the psoriatic plaques. The recommended maximutn weekly dose of calcipotriol ointment (50 |a.g/g) is 100 g, and at this dose there have been no reports of hypercalcemia, a reassuring observation. 549
International Jotirnal of Derniatolo(;y Vol. 31, No. 8, August 1992
CONCLUSIONS
Calcipotriol is the first new analogue of vitamin D3, which, when used topically, has been shown to be effective in the treatment of psoriasis with minimal side effects. The results of further studies of calcipotriol in combination with established methods of treatment of psoriasis are awaited with interest. Is it too much to hope that another analogue of vitamin D3 will be found that can safely be given orally and that will have a beneficial effect on psoriasis with no effect on calcium metabolism.'
REEERENCES 1.
Bhalla AK, Amento EP, Clemens TL, et al. Specific highaffinity receptors for 1,25-dihydroxy-vitamin Dj in human peripheral blood mononuclear cells: presence in nionocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab 1983; 57:1308-1312.
2.
Smith EL, Walworth NC, Holick MF. Effect of 1.25dihydroxy-vitamin Dj on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions. J Invest Dermatol 1986; 86:709-714.
3.
Milde P, Hauser U, Simon T, et al. Expression of 1, 25dihydroxy vitamin D3 receptors in normal and psoriatic skin. J Invest Dermatol 1991; 97:230-239.
4.
Morimoto S, Yoshikawa K, Kozuka T, et al. An open study of vitamin D treatment in psoriasis vulgaris. Br J Dermatol 1986; 115:421-429.
5.
Kato T, Rokugo M, Terui T, Tagami H. Successful treatment of psoriasis with topical application of active vitamin Dj analogue, l a , 24-dihydroxy-cholecalciferol. BrJ Dermatol 1986; 115:431-433.
6.
Smith EL, Pincus SH, Donovan L, Holick MF. A novel approach for the evaluation and treatment of psoriasis. J Am Acad Dermatol 1988; 193:516-528.
7.
Binderup L, Bramm E. Effects of a novel vitamin D analogue MC 903 on cell prohferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 1988; 37:889-895.
8.
Kragballe K, Beck H-1, Sogaard H. Improvement of psoriasis by a topical vitamin D analogue (MC 903) in a double-blind study. BrJ Dermatol 1988; 119:223-230.
9.
Kragballe K. Treatment of psoriasis by the topical application of the novel vitamin D3 analogue calcipotriol. Arch Dermatol 1989; 125:1647-1652.
10.
Kragballe K, Cjertsen BT, de Hoop D, et al. Doubleblind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 1991; 337:193-196.
11.
Cunliffe WJ, Claudy A, Fairiss C, et al. A multicentre comparative study of calcipotriol (MC 903) ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. BrJ Dermatol 1991; 125 (suppl. 38):27.
The Need for Controlled Studies Recently I was severely scolded in front of all participants at a conference because I didn't know that a certain product was the best method to heal pressure ulcers. The scolder was annoyed by my ignorance, proceeded to explain the physiological reasons why the product worked, and concluded by saying the product had been used for years and the ulcers always healed. An enterostomal therapy nurse on the panel with me eloquently and politely provided counter evidence and cited recent literature to document why that product was no longer appropriate. The enterostomal therapy nurse concluded by saying her patient care experiences demonstrated that the product retarded healing. Here were two opposite experiences with the same product. The evidence for the efficacy or lack of efficacy of the product was personal experience. Why is this possible? How can personal experience (case studies) in the use of products produce opposite outcomes.' The obvious answer is that there are other factors that contribute to the healing or the lack of heahng. What are these factors.' The most obvious is the patient's own healing mechanisms, own homeodynamic state that continuously adjusts for the effects of internal or external stressors. Two other factors are nutrition and pressure. If the body is placed in a homeodynamic state, it will heal itself. In other words, provide optimal nutrition and the arterial blood supply carried to the cells will enable the cells to heal pressure ulcers. Relieve pressure and the additional nutrients will be carried to the cells while the venous blood will carry away the waste products of metabolism from within the cells. Frorn Editorial. What causes pressure ulcers to heal. Decubitus 1992; S(l):6. • • , 550
CALCIPOTRIOL AND PSORIASIS COLIN A. RAMSAY, M.D., E.R.C.P., E.R.C.l'.C.
metabolism are retained, and the unwanted effects on calcium metabolism are markedly diminished, leading to the development of calcipotriol as a topical therapy for psoriasis.
Calcipotriol, which is an analogue of vitamin D3, has recently been shown to he an effective topical agent for psoriasis. The development of calcipotriol occurred as a consequence of the new knowledge concerning some of the cellular effects of vitamin D3.
CLINICAL USE BACKGROUND
The active natural form of vitamin D3 is 1,25-dihydroxy vitamin D3 also called calcitriol. It has heen known for many years that vitamin D3 has a profound effect on calcium metabolism, but it is only relatively recently that some other effects of vitamin D3 have been established. These other effects are mediated through vitamin D3 receptors present in a number of different cells,' including keratinocytes,^ and in normal and psoriatic skin.' In keratinocytes, vitamin D3 has been shown to stimulate terminal differentiation and to inhibit proliferation,^ and thus it might be expected to be of value in psoriasis. That this is indeed the case was observed by Morimoto et al.'' in Japan. A patient was being treated for osteoporosis with an oral analogue of vitamin D3, and the psoriasis that was also present in this patient cleared. This led to other studies that confirmed the beneficial effect of vitamin D3 or its analogues, either orally or topically, in psoriasis.'-'' There has been an understandable and justifiable concern about the use of these compounds because of their effect on calcium metabolism in the doses that are required to influence psoriasis. It is unlikely that vitamin D3 or the earlier analogues would ever have found a routine place in the management of psoriasis because of their hypercalcemic effects. Calcipotriol is a new analogue of vitamin D3, which has a similar affinity for the same receptors and has a similar effect on cellular proliferation and differentiation as the natural vitamin; however, from the point of view of the treatment of psoriasis, the most important property of calcipotriol is its effect on calcium metabolism. This effect is 100 to 200 times less than that of vitamin D3 itself.'' Thus, the desired effects on cellular From the Department of Medicine, University of Toronto Faculty of Medicine Toronto, Ontario, Canada. Address for correspondence: Colin A. Ramsay, M.D., 123 Edward Street, Suite 725, Toronto, Ontario, Canada M5C 1E2.
The first clinical trial of calcipotriol used it as a cream and compared it in a double-blind controlled manner with its base.** The results showed that calcipotriol improved psoriasis in a dose-related manner and that the histologic changes in the skin improved along with the clinical changes. A later trial used calcipotriol as an ointment and compared its effect at different concentrations in psoriasis and also compared it with its base.' It was found that the active compound was markedly more effective than the base and that 50 |a.g/g appeared to be the optimum concentration. The 50 |ig/g ointment was slightly better than the 25 |J.g/g preparation and equal to the 100 |ig/g preparation. Subsequent trials have used the ointment at 50 |Jg/g. The latest studies have compared calcipotriol ointment with betamethasone valerate ointment (0.1%). These have shown calcipotriol to be as effective as or superior to betamethasone in patients with chronic plaque psoriasis.'"'" Calcipotriol is now marketed in some countries (e.g., Denmark, Ireland, New Zealand, and the United Kingdom). Clinical trials have been completed in Canada ' and are underway in the United States. There are some adverse effects of the drug, but these reactions are usually mild and transient; they led to the withdrawal of only a few patients from the trials. The most common adverse effect was irritation of the skin on and around some psoriatic plaques. Burning or itching of the skin was associated with scaling and erythema. Some patients developed a mild dermatitis on the face, although this area was not treated. This effect probably occurred from unsuspected contamination of the face from ointment on the hands. Personal observation of this effect in a few patients has shown that the facial eruption settles quickly with a low potency topical steroid whilst the calcipotriol ointment is continued on the psoriatic plaques. The recommended maximutn weekly dose of calcipotriol ointment (50 |a.g/g) is 100 g, and at this dose there have been no reports of hypercalcemia, a reassuring observation. 549
International Jotirnal of Derniatolo(;y Vol. 31, No. 8, August 1992
CONCLUSIONS
Calcipotriol is the first new analogue of vitamin D3, which, when used topically, has been shown to be effective in the treatment of psoriasis with minimal side effects. The results of further studies of calcipotriol in combination with established methods of treatment of psoriasis are awaited with interest. Is it too much to hope that another analogue of vitamin D3 will be found that can safely be given orally and that will have a beneficial effect on psoriasis with no effect on calcium metabolism.'
REEERENCES 1.
Bhalla AK, Amento EP, Clemens TL, et al. Specific highaffinity receptors for 1,25-dihydroxy-vitamin Dj in human peripheral blood mononuclear cells: presence in nionocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab 1983; 57:1308-1312.
2.
Smith EL, Walworth NC, Holick MF. Effect of 1.25dihydroxy-vitamin Dj on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions. J Invest Dermatol 1986; 86:709-714.
3.
Milde P, Hauser U, Simon T, et al. Expression of 1, 25dihydroxy vitamin D3 receptors in normal and psoriatic skin. J Invest Dermatol 1991; 97:230-239.
4.
Morimoto S, Yoshikawa K, Kozuka T, et al. An open study of vitamin D treatment in psoriasis vulgaris. Br J Dermatol 1986; 115:421-429.
5.
Kato T, Rokugo M, Terui T, Tagami H. Successful treatment of psoriasis with topical application of active vitamin Dj analogue, l a , 24-dihydroxy-cholecalciferol. BrJ Dermatol 1986; 115:431-433.
6.
Smith EL, Pincus SH, Donovan L, Holick MF. A novel approach for the evaluation and treatment of psoriasis. J Am Acad Dermatol 1988; 193:516-528.
7.
Binderup L, Bramm E. Effects of a novel vitamin D analogue MC 903 on cell prohferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 1988; 37:889-895.
8.
Kragballe K, Beck H-1, Sogaard H. Improvement of psoriasis by a topical vitamin D analogue (MC 903) in a double-blind study. BrJ Dermatol 1988; 119:223-230.
9.
Kragballe K. Treatment of psoriasis by the topical application of the novel vitamin D3 analogue calcipotriol. Arch Dermatol 1989; 125:1647-1652.
10.
Kragballe K, Cjertsen BT, de Hoop D, et al. Doubleblind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 1991; 337:193-196.
11.
Cunliffe WJ, Claudy A, Fairiss C, et al. A multicentre comparative study of calcipotriol (MC 903) ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. BrJ Dermatol 1991; 125 (suppl. 38):27.
The Need for Controlled Studies Recently I was severely scolded in front of all participants at a conference because I didn't know that a certain product was the best method to heal pressure ulcers. The scolder was annoyed by my ignorance, proceeded to explain the physiological reasons why the product worked, and concluded by saying the product had been used for years and the ulcers always healed. An enterostomal therapy nurse on the panel with me eloquently and politely provided counter evidence and cited recent literature to document why that product was no longer appropriate. The enterostomal therapy nurse concluded by saying her patient care experiences demonstrated that the product retarded healing. Here were two opposite experiences with the same product. The evidence for the efficacy or lack of efficacy of the product was personal experience. Why is this possible? How can personal experience (case studies) in the use of products produce opposite outcomes.' The obvious answer is that there are other factors that contribute to the healing or the lack of heahng. What are these factors.' The most obvious is the patient's own healing mechanisms, own homeodynamic state that continuously adjusts for the effects of internal or external stressors. Two other factors are nutrition and pressure. If the body is placed in a homeodynamic state, it will heal itself. In other words, provide optimal nutrition and the arterial blood supply carried to the cells will enable the cells to heal pressure ulcers. Relieve pressure and the additional nutrients will be carried to the cells while the venous blood will carry away the waste products of metabolism from within the cells. Frorn Editorial. What causes pressure ulcers to heal. Decubitus 1992; S(l):6. • • , 550
