Relevance of the Cutaneous Vitamin D Endocrine System for Skin Physiology
3.4 Clinical Studies of Vitamin D and Its Analogues in Psoriasis and Other Skin Diseases
Because there is no cure for psoriasis at present, therapeutic strategies are intended to achieve and maintain remission—i.e., reduction of the extent (percentage of the body area involved) and severity (degree of erythema, scaling, plaque elevation)—
of the disease by minimizing adverse events. The importance of 1,25(OH)2D3 and its analogues for the treatment of psoriasis resulted from two independent lines of investigation. Because psoriasis is a hyperproliferative skin disorder, it seemed
32 L. Trémezaygues and J. Reichrath
rational that the antiproliferative effects of calcitriol could be used for the treatment of this disease. Before launching clinical trials in 1985, MacLaughlin and associates reported that psoriatic fibroblasts were partially resistant to the antiproliferative effects of 1,25(OH)2D3 (MacLaughlin et al. 1985). This observation led these researchers to speculate that calcitriol may be effective in the treatment of hyperpro- liferative skin diseases such as psoriasis. The second line of investigation resulted from a clinical observation. In 1985, Morimoto and Kumahara reported that a patient who was treated orally with 1a-hydroxyvitamin D3 for osteoporosis had a drastic remission of psoriatic skin lesions (Morimoto and Kumahara 1985). In a follow-up study, they demonstrated that almost 80% of 17 patients with psoriasis who were treated orally with 1a-hydroxyvitamin D3 at a dose of 1.0 mg/day for up to 6 month showed clinically significant improvement (Morimoto et al. 1986).
Up to now, various studies reported that numerous vitamin D analogues, including calcitriol, calcipotriol, tacalcitol, maxacalcitol, and beocalcidiol, are effective and safe for topical treatment of psoriasis (Holick et al. 1996; Perez et al. 1996a;
Kragballe et al. 1988; van de Kerkhof et al. 1989; Helfrich et al. 2007). It was dem- onstrated that topical calcitriol is highly effective and safe for long-term treatment of psoriasis vulgaris (Perez et al. 1996a). In clinical trials, calcipotriol ointment and cream reduced the mean Psoriasis Area and Severity Index (PASI) scores by 55–72%
and 49–50%, respectively, after treatment for 6–8 weeks (Van de Kerkhof and Vissers 2003). Applied topically twice a day in amounts of up to 100 g ointment (50 mg calcipotriol/g ointment) per week, calcipotriol, the synthetic analogue of calcitriol, was shown to be more effective for topical treatment of psoriasis than betamethasone 17-valerate ointment (Kragballe et al. 1991). Topical calcipotriol has been compared with other topical treatments for psoriasis. Calcipotriol cream has been reported to be as effective and cosmetically more favorable than coal tar in a small, observer-blinded trial in patients with psoriasis (Tzaneva et al. 2003).
Recently, twice-daily calcipotriol ointment was compared with once-daily short- contact dithranol cream therapy in a randomized controlled trial (RCT) of supervised treatment of psoriasis in a daycare setting (De Korte et al. 2008). This multicenter RCT, which was performed in six centers in The Netherlands, included 106 patients with chronic plaque psoriasis. Among them, 54 received calcipotriol ointment twice daily, and 52 were given dithranol cream once daily during a 12-week intensive treatment program. Patients were treated at the daycare center using the care instruction principle of daily visits during the first week and twice-weekly visits subsequently for up to 12 weeks. Quality of life (QOL) was assessed with the Skindex-29 and the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). No statistically significant differences were found between the calcipotriol and the dithranol group in any of the QOL domains or scales of the Skindex-29 and the SF-36 at the end of treatment.
Calcipotriol is available in three formulations: cream, ointment, and solution.
In a large, randomized, double-blind, controlled trial, twice-daily application of calcipotriol cream was significantly more effective than once-daily application of calcipotriol cream in terms of the mean percentage reduction in PASI from baseline (48.3% vs. 40.6%, P = 0.006) (Kragballe et al. 1998). In this study, the reduction in PASI with twice-daily application of calcipotriol cream did not differ from that
3 Relevance of the Cutaneous Vitamin D Endocrine System… 33
with application of calcipotriol cream in the morning plus clobetasone butyrate cream in the evening (53.7%) and was significantly lower than that with application of calcipotriol cream in the morning plus betamethasone valerate cream in the evening (57.5%).
Lately, an investigator-masked, randomized, multicenter comparison of the efficacy and safety of twice-daily applications of calcitriol 3 mg/g ointment versus calcipotriol 50 mg/g ointment in patients with mild to moderate chronic plaque-type psoriasis has been reported (Zhu et al. 2007). In this study, a total of 250 patients of both sexes with mild to moderate chronic plaque-type psoriasis received either calcitriol or calcipotriol ointment twice a day for 12 weeks. Efficacy evaluations comprehend global improvement (on a four-point scale: 0 indicating no change or worse to 3 indicating clear or almost clear) assessed by the investigator and by the subject. Efficacy further included the “dermatological sum score” at each study visit. Safety evaluations included adverse event reporting, cutaneous safety assessed by the investigator, and cutaneous discomfort assessment by the patient (both were on a five-point scale from 0 indicating no discomfort to 4 indicating severe discomfort). At week 12, the LSMean score of global improvement measured by the investigator was 2.27 for calcitriol and 2.22 for calcipotriol. This difference was not statistically significant, demonstrating that calcitriol was not inferior to calci- potriol in terms of global improvement. This same parameter was also scored by the patient, with a mean of 2.12 for calcitriol and 2.09 for calcipotriol. The percentage of patients with at least marked improvement tended to be in favor of calcitriol (95.7% vs. 85.0% for calcipotriol), but the differences were not statistically significant.
The mean worst score for the cutaneous safety assessment was higher in the calcipotriol group (0.3 vs. 0.1 and 0.4 vs. 0.2, by the investigator and the patient, respectively). These differences were statistically significant in favor of a superior safety profile for calcitriol (P = 0.0035). A total of 14 dermatological and treatment- related adverse events were reported with calcipotriol whereas only five were reported with calcitriol for a total of 22 adverse events reported throughout the study.
The authors concluded that calcitriol applied twice daily over a 12-week treatment period demonstrated efficacy similar to that of calcipotriol, while showing a signifi- cantly better safety profile. It has been noted that a mild dermatitis is seen in about 10% of patients treated with calcipotriol (50 mg/g), particularly on the face (Serup 1994). This side effect was not reported after topical treatment with calcitriol.
More recently, a randomized, placebo-controlled, double-blind, multicentric study analyzing the efficacy and safety of topical becocalcidiol for the treatment of psoriasis vulgaris has been reported (Helfrich et al. 2007). Becocalcidiol is a vitamin D analogue that did not cause hypercalcemia or significant irritation in preclinical trials. In that study, the efficacy and safety of two dosing regimens of becocalcidiol ointment (low dose 75 mg/g once a day for 8 weeks; high dose 75 mg/g twice a day for 8 weeks) in the treatment of plaque-type psoriasis were evaluated. In all, 185 patients with chronic plaque-type psoriasis affecting 2–10% of their body surface area took part in a multicentric, double-blind, parallel-group, vehicle- controlled RCT comparing topical application of placebo, becocalcidiol 75 mg/g once daily (low dose) or becocalcidiol twice daily (high dose) for 8 weeks. Main outcomes included the Physician’s Static Global Assessment of Overall Lesion
34 L. Trémezaygues and J. Reichrath
Severity (PGA) score, the Psoriasis Symptom Severity (PSS) score, adverse events, and laboratory assessment. In this study, in the intention-to-treat population at week 8, high-dose becocalcidiol was statistically superior to the vehicle [P = 0.002; 95%
confidence interval (CI) 6.7–32.2], with 16 of 61 (26%) patients achieving a PGA score of clear or almost clear. Greater improvement in the PSS score was seen with high-dose becocalcidiol than with the vehicle, but this result did not quite achieve statistical significance (P = 0.052; 95% CI −16.2–0.1). In all groups, therapy was well tolerated and safe, with fewer patients experiencing irritation than is reported in studies using calcipotriol. The authors concluded that treatment with high-dose topical becocalcidiol for 8 weeks led to almost or complete clearing of moderate plaque-type psoriasis in more than one-fourth of the patients and that the therapy was safe and well tolerated (Helfrich et al. 2007).
In 1996, a long-term follow-up study reported the efficacy and safety of oral calcitriol for treating psoriasis (Perez et al. 1996b). Among the 85 patients included in the study who received oral calcitriol, 88.0% had some alleviation of their disease after 36 months; 26.5%, 26.3%, and 25.3% had complete, moderate, and slight improvement, respectively. Serum calcium concentrations and 24-h urinary calcium excretion increased by 3.9% and 148.2%, respectively, but were not outside the normal range. Bone mineral density of these patients remained constant.
An important point when considering the use of orally administered calcitriol is the dosing technique. To avoid its effects on enhancing dietary calcium absorption, it is extremely important to provide calcitriol at night time. Perez et al. (1996b) showed that as a result of this dosing technique doses of 2–4 mg/night are well tolerated by psoriatic patients. Lately, the combination of acitretin and oral calcitriol for successful treatment of plaque-type psoriasis has been reported (Ezquerra et al. 2007).
Patients with psoriasis may need intermittent treatment for their entire lives.
Vitamin D analogues have been demonstrated not to cause tachyphylaxis during treatment of psoriatic lesions and can therefore be used indefinitely. They are effective and safe for the treatment of skin areas that are usually difficult to treat in psoriatic patients and that respond slowly. Furthermore, vitamin D analogues are effective in the treatment of psoriatic skin lesions in children and in human immunodeficiency virus (HIV)-infected patients.