Topical vitamin D analogues partnered with corticosteroid for psoriasis enhances efficacy

Kaanapali, Hawaii - Use of combination therapy as a means to improve efficacy and minimize toxicity is a well-accepted principle in medicine. As it applies to the management of psoriasis, the results of multiple studies support the value of combination topical therapy with a vitamin D analogue and corticosteroid, said two speakers at the 2012 Winter Clinical Dermatology Conference.

“Combination therapy for treatment of psoriasis and many other skin diseases is something we do routinely, but it is nice to know there is an evidence base that supports the benefits we see in clinical practice,” says David M. Pariser, M.D., professor of dermatology, Eastern Virginia Medical School, Norfolk, Va.

The safety of the therapy long-term may make it particularly attractive for clinicians treating patients with psoriasis.

“Psoriasis is a chronic disease, and we need therapies that can be used safely and effectively over the long term. Data from studies of vitamin D analogue monotherapy show it is effective treatment, but safety with long-term use is its main advantage,” says Mark Lebwohl, Sol and Clara Kest Professor and chairman, department of dermatology, Mount Sinai School of Medicine, New York.

“Topical vitamin D analogues are almost always used to treat psoriasis in combination with a topical corticosteroid. While I will never continue a superpotent corticosteroid daily for months, a topical vitamin D preparation can be used safely on an ongoing basis,” he notes, citing a one-year study he reviewed that included extensive laboratory testing to determine systemic safety (Lebwohl M, Ortonne JP, Andres P, et al. Cutis. 2009;83:205-212).

Superior efficacy
Results from a two-week study conducted more than 15 years ago by Dr. Lebwohl and colleagues were unequivocal in demonstrating a therapeutic advantage of combination corticosteroid-vitamin D analogue treatment (calcipotriene ointment in the morning with halobetasol ointment in the evening) versus monotherapy with either agent alone (Lebwohl M, Siskin SB, Epinette W, et al. J Am Acad Dermatol. 1996;35(2 Pt 1):268-269).

At study completion, rates of “clear” or “almost clear” in the investigator’s global assessment were 71 percent for the combination group versus 57 percent for patients using halobetasol twice daily and 30 percent with twice daily application of the vitamin D analogue.

A recently published meta-analysis of combination therapies for psoriasis (Bailey EE, Ference EH, Alikhan A, et al. Arch Dermatol. 2012;148(4):511-522) that included data from seven randomized controlled clinical trials also showed increased efficacy for using a combination regimen. According to the results, the addition of a corticosteroid to a vitamin D analogue increased the likelihood of clearing by 28 percent with use of a class 1 corticosteroid and by 14 percent with the addition of a class 2 corticosteroid. However, there was no benefit for adding a class 3 corticosteroid, Dr. Pariser says.

Countless combinations
When combining medications from the two classes, dermatologists can choose to use the fixed combination product containing calcipotriene and betamethasone dipropionate (Taclonex, Leo) or they can create their own combinations using individual products in an array of different dosing regimens. Dr. Pariser points out that the fixed combination product features an innovative formulation that overcomes the inherent instability of the vitamin D analogue in the presence of the acidic betamethasone dipropionate and optimizes delivery of both active ingredients.

In addition, it offers a convenience benefit that can promote patient compliance and has been shown safe and efficacious when used continuously for up to 52 weeks (Kragballe K, Austad J, Barnes L. Dermatology. 2006;213(4):319-326).

In the latter study, patients were treated with the combination product for four weeks and then received maintenance therapy with either 1.) the fixed combination, 2.) alternating four-week courses of the fixed combination and calcipotriene ointment, or 3.) calcipotriene only. However, Dr. Lebwohl says a low rate of cutaneous atrophy occurred in all treatment groups during the maintenance phase; 2 percent among patients using the fixed combination, 0.5 percent in the alternating treatment group, and 1 percent among patients who switched to calcipotriene only, and a single patient using the alternating regimen developed striae.

“These data should remind physicians that patients continuing to use a corticosteroid need to be seen periodically to check for cutaneous side effects,” Dr. Lebwohl says.

Use of extemporaneously devised regimens of combination corticosteroid-vitamin D analogue therapy offers flexibility to match the regimen and its components to the individual based on patient-specific factors and formulary considerations, and it may allow use of a lower potency corticosteroid or less frequent corticosteroid use, Dr. Pariser says.

There are a variety of approaches for combining a vitamin D analogue with a topical corticosteroid, including different iterations for sequential or pulse therapy, and their utility is support by the results of published studies. For example, two recently published papers reporting outcomes from four-week, open-label studies documented the efficacy and safety of combination regimens where patients used clobetasol propionate 0.05 percent spray in the morning and calcitriol 3 mcg/g ointment in the evening (Menter A, Sofen H, Smith S, et al. Cutis. 2011;88:46-51) or calcitriol ointment twice daily on weekdays and clobetasol spray twice daily on weekends (Hudson CP, Kempers S, Menter A, et al. Cutis. 2011;88:201-207).

Dr. Lebwohl says that when using a vitamin D analogue-corticosteroid combination, he often prescribes a superpotent corticosteroid twice daily for two to four weeks and then switches to a pulse regimen where the corticosteroid is applied on weekends only and the vitamin D analogue on weekdays. The efficacy and safety of this approach for maintenance are supported by the results of a clinical trial conducted by Dr. Lebwohl and colleagues (Lebwohl M, Yoles A, Lombardi K, et al. J Am Acad Dermatol. 1998;39(3):447-450) in which patients were treated initially with halobetasol ointment in the evening and calcipotriene ointment in the morning.

After two weeks, patients who achieved at least moderate improvement were randomized to continue using halobetasol twice daily on weekends and either calcipotriene or placebo twice daily on weekdays. After six months, the proportion of patients who maintained remission was nearly twofold higher in the combination treatment group compared with the patients using halobetasol with placebo, 76 versus 40 percent.

In a more recent paper, investigators reported outcomes for a sequential combination regimen where patients were treated with clobetasol propionate 0.05 percent spray twice daily for four weeks and then continued treatment for up to eight weeks with calcitriol ointment twice daily (Brodell RT, Bruce S, Hudson CP, et al. J Drugs Dermatol. 2011;10(2):158-64). The proportion of patients achieving a physican’s global assessment rating of clear or almost clear was 93 percent after four weeks and 74 percent at the end of the study.

Simultaneous use
Dr. Lebwohl notes there is some research that has been presented at scientific meetings but not published that indicates compatibility of calcitriol ointment applied simultaneously with clobetasol spray and shows that the efficacy of the combination is similar, regardless of the order of product application.

“I would have predicted a benefit from applying the corticosteroid spray first and then occluding it with the calcitriol ointment. However, results of a split-side study in 13 patients with bilaterally symmetrical psoriasis showed equal efficacy whether the clobetasol spray was applied first or the calcitriol ointment,” Dr. Lebwohl says.

Disclosures: Dr. Pariser is an investigator for Leo Pharma and Galderma. Dr. Lebwohl has been a consultant or investigator for most of the companies making psoriasis products.