1,25-Dihydroxyvitamin D 3 and the Skin: A Unique Application for the Treatment of Psoriasis

Abstract

Conclusion

Psoriasis is a most perplexing disease that continues to afflict approximately 50 million people worldwide. Although many theories have been proposed for the cause of psoriasis, the primary cause of this hyperpro-liferative cutaneous disorder is unknown. Most treatments for psoriasis are associated with toxic side effects and there continues to be a need for a safe and effective method for treating this disfiguring disorder (27).

In the 1930s and 1940s vitamin D was touted to be an effective agent for the treatment of a variety of skin diseases. Extremely high doses of up to 2.5 mg/day were perscribed for the treatment of a variety of skin disorders including scleroderma, acne, eczema, and psoriasis (39). In addition, vitamin D was added to soaps, skin creams, and shaving creams with the intent of providing some benefit to skin. Although some favorable responses of high-dose vitamin D for psoriasis have been reported, the amounts were so high as to cause significant toxicity and as a result this therapeutic approach lost favor.

There is an association between disturbances in calcium metabolism and psoriasis. Patients with psoriasis with surgically induced hypoparathyroidism or primary hypoparathyroidism and attendant hypocalcemia often have a reactivation or exacerbation of their skin disease. Patients with pustular psoriasis of von Zumbusch, impetigo herpetiformis, and psoriasis vulgaris have been found to experience reactivation of their disease during episodes of hypocalcemia (40–42). Remission was often achieved when serum calcium concentrations were restored to normal. In addition, it has been shown that chloroquine can exacerbate psoriasis. Recently, chloroquine was shown to decrease circulating concentrations of 1,25-(OH)₂D₃ in sarcoid patients whose extrarenal production 1,25-(OH)₂D₃ is responsible for their calcium disorder (43).

The initial observation that demonstrated a variety of tissues possess receptors for 1,25-(OH)₂D₃ was thought to be an interesting curiosity but of no practical value. However, the fact that 1,25-(OH)₂D₃ inhibited the proliferative activity and caused differentiation of a variety of tumor cells and prompted speculation that this hormone may be valuable in the treatment of a variety of cancers including breast cancer and some leukemias (34, 44, 45). Although 1,25-(OH)₂D₃ may have some marginal beneficial effect for lymphoma, preleukemia, and leukemia, the effect does not appear to be long-lasting and there are significant toxic consequences (34). For example, in one study to evaluate the therapeutic efficacy of 1,25-(OH)₂D₃ for the treatment of preleukemia, it was found that 50% of the patients developed hypercalcemia and that 7 of 18 patients progressed to acute myelogenous leukemia (34). This observation is not entirely unexpected because it is known that the effect of 1,25-(OH)₂D₃ on cultured leukemic cells is reversible (46).

We reason that the known effect of 1,25-(OH)₂D₃ on inhibiting proliferation and inducing terminal differentiation in cultured human epidermal cells may be useful in the treatment of a nontumor hyperproliferative disorder such as psoriasis. Because epidermal keratinocytes undergo a nonreversible terminal differentiation process, if the epidermal cells responded to 1,25-(OH)₂D₃ by decreasing their proliferative activity, then once the cells committed to differentiate they would do so in a terminal manner.

Based on several reports and our own experience, it appears that both topical and oral 1,25-(OH)₂D₃ can be used as a safe and effective treatment for psoriasis. We have treated over 100 patients with 1,25-(OH)₂D₃. Our experience to date suggests that 60% who topically apply 1,25-(OH)₂D₃ have complete clearing of their localized lesions as evidenced by visual observation and histologic analysis of skin biopsies of the lesions that were treated with 1,25-(OH)₂D₃. An additional 30% of patients who used topical 1,25-(OH)₂D₃ showed significant decrease in scale, plaque thickness, and erythema.

Of 45 patients treated with oral 1,25-(OH)₂D₃ at night, approximately 60% of the patients on 1,25-(OH)₂D₃ showed significant decrease in scale, plaque thickness, erythema, and central clearing of their lesions. Approximately 25% of the patients had complete resolution of their disease.

The major limitation for treatment of psoriasis with 1,25-(OH)₂D₃ is the potential of developing hypercalciuria and hypercalcemia. We have found, however, that by giving the drug at night and increasing it in a stepwise fashion that patients can tolerate up to 2–3 μg of 1,25-(OH)₂D₃/day. By giving 1,25-(OH)₂D₃ at night in a stepwise fashion, it is likely that (i) there is less calcium in the intestine and therefore for the next 6–8 hr 1,25-(OH)₂D₃ has a minimum effect on the enhancement of intestinal calcium absorption; (ii) exogenous 1,25-(OH)₂D₃ decreases the endogenous metabolism of 25-OH-D to 1,25-(OH)₂D₃; and (iii) exogenous 1,25-(OH)₂D₃ may increase the catabolism of 1,25-(OH)₂D₃ in target tissues. For the past 2 years, we have not seen any significant sustained hypercalcemia in any of the patients on this medication. Transient hypercalciuria was often seen but this quickly resolved when the dose of the drug was decreased.

Results from our laboratory as well as others suggest that 1,25-(OH)₂D₃ or one of its analogs may be useful for the treatment of psoriasis. Topical 1,25-(OH)₂D₃ appears to be extremely effective and there does not appear to be any other side effect on the skin, including thinning of skin that is caused by steroids. Although oral 1,25-(OH)₂D₃ has been shown to provide some significant benefit to patients, it is likely that there would have been more benefit if the dosage of the drug could have been increased. However, this was limited by the potential of developing hypercalciuria and hypercalcemia. There continues to be a need to develop analogs of 1,25-(OH)₂D₃ that are potent antiproliferative agents that have a minimal effect on intestinal calcium transport. A series of analogs have been synthesized and evaluated for such activity. As seen in Table II, there are several analogs of 1,25-(OH)₂D₃ that have minimal effect on intestinal calcium transport while maintaining a very high antiproliferative activity (47). One such analog, MC903, has recently been reported to be effective as a topical agent for the treatment of psoriasis (48). The authors state that this analog which contains a cyclopropane moiety between carbons 25, 26, 27 and hydroxyl groups on carbons 1 and 24 chain has minimum activity on calcium metabolism.