Paul S. Yamauchi, MD, PhD

Paul Yamauchi is clinical assistant professor of Dermatology, David Geffen School of Medicine, UCLA, and adjunct associate professor, John Wayne Cancer Institute, Dermatology Institute &, Skin Care Center, Inc., Clinical Science Institute. Contact him at 

 Psoriasis is a common, chronic, immune-mediated disease that primarily affects the skin. Plaque psoriasis, the most prevalent type of psoriasis, can produce disfiguring, erythematous, scaly lesions. Dermatologists choose from an array of treatment approaches for their patients with psoriasis, often managing mild to moderate plaque psoriasis with topical therapy. Vitamin D analogs, corticosteroids, and sometimes topical retinoids are the mainstay of topical therapy. Each of these agents affects different aspects of the pathophysiologic process involved in psoriasis, including inflammation and abnormal differentiation and hyperproliferation of keratinocytes. In combination, these agents may provide additive and sometimes synergistic effects. Clinical studies have demonstrated that enhanced efficacy and tolerability can be achieved using fixed-combination therapy with topical vitamin D analogs and corticosteroids as opposed to using each agent alone. Pharmacists must understand the biologic rationale for the various treatment regimens prescribed for psoriasis, as well as the efficacy and safety profiles of each treatment, so that they can appropriately advise patients about their course of therapy. Factors that affect patient adherence also enter into the treatment decision, as these may affect treatment outcomes.

	Psoriasis is a chronic immune-mediated disease that manifests primarily in the skin. More than 7 million persons in the United States, or approximately 2% of the population,

are affected by this disease, which relapses and remits throughout a patient’s lifetime.

Plaque psoriasis, the most prevalent type, is characterized by three elements: erythema (redness), scaling (formation of white flakes due to excessive shedding of keratinocytes), and induration (thickness of the plaques).

Most patients with this condition have mild to moderate psoriasis, which the National Psoriasis Foundation defines as lesions covering less than 10% of the body surface area.

	Histologically, psoriasis is characterized by epidermal hyperproliferation with incomplete keratinocyte differentiation, inflammatory infiltration, and increased vascularity in the dermis.

The pathophysiologic process leading to psoriasis appears to be multifaceted, with cytokines produced by inflammatory T cells playing a crucial role. These immunoregulatory proteins stimulate the differentiation and proliferation of keratinocytes and increase the migration of inflammatory cells into the skin.

The result is clinically evident inflammation and epidermal hyperplasia at the lesion site.

Therapies that target both the immune-related and keratinocyte-related cellular functions are thus potentially more effective than those that target either function alone.

	Because the clinical features and triggers of psoriasis are highly variable,

the decision-making process for treatment can be complex. Adding to this complexity is the myriad of therapeutic options available,

including over-the-counter (OTC) topical agents (eg, salicylic acid, coal tar) and prescription topical agents (eg, vitamin D analogs, corticosteroids, topical retinoids) (Figure 1).

	It is important to note that although current therapies do not cure the disease, they reduce its severity and prolong the length of remissions.

Symptoms that often occur at the lesion site, including itching, burning, and soreness, may be minimized with topical therapy.

The American Academy of Dermatology and the National Psoriasis Foundation recommend the use of topical vitamin D analogs, corticosteroids, and retinoids as first-line therapy for patients with mild to moderate localized plaque psoriasis.

	Many patients approach pharmacists for advice on psoriasis therapy. Pharmacists make at least one dermatologic recommendation each day,

despite having received minimal formal training in dermatology and despite having little opportunity to interact with dermatologists in everyday practice to better understand their treatment strategies.

To enhance pharmacists’ understanding of psoriasis treatment, this article reviews the rationale for the widespread use of topical vitamin D analog and corticosteroid combination therapy. The article begins with a discussion of patient adherence, as this is critical to successful outcomes. By keeping in mind the factors that affect tolerability and patient adherence, pharmacists can give informed guidance to patients on their course of therapy.

Patient adherence considerations in psoriasis

	An important consideration in the treatment choice for an individual patient with psoriasis is the effect of the formulation on treatment adherence.

Adherence with topical agents is known to be suboptimal.

The vehicle, in particular, can affect patient adherence and disease modification.

Patients with psoriasis prefer medications that are easy to apply, lack greasiness and smell, and will not stain clothes.

Patients may prefer topical agents in petrolatum-based vehicles, as these vehicles do not sting when applied to skin areas with fissures.

Because topical agents are available in a variety of vehicle formulations (ointments, creams, emollients, suspensions/gels, lotions, solutions, and foams),

there are many opportunities to satisfy patient preference while still achieving clinical efficacy. The occlusive nature of ointments makes them useful for treating dry or thick hyperkeratotic lesions

; however, they tend to be greasy, which often leads to poor patient satisfaction and adherence.

Patients find creams and suspensions/gels to be more cosmetically appealing because they are readily absorbed by the skin.

Solutions, foams, sprays, and shampoos are easily applied and readily spreadable, particularly in hairy areas.

	Adherence is also affected by the dosing frequency.

Vitamin D analogs and corticosteroids can be used sequentially, with each agent applied once per day separately from the other (for a twice-daily regimen), or can be applied simultaneously (for a once-daily regimen).

A fixed-combination topical product containing a vitamin D analog and a corticosteroid has been developed, thereby simplifying the treatment regimen. In one survey of patients with psoriasis, approximately 40% said that having to apply medication less frequently would improve adherence.

A study among patients treated in a dermatology outpatient clinic reported a mean rate of medication adherence of 82% with a once-daily psoriasis regimen, as compared with 44% for a twice-daily regimen.

	Topical corticosteroids are the cornerstone of psoriasis treatment.

Corticosteroids reduce local areas of inflammation and the rate of skin cell growth and suppress local immune responses.

They also modulate local production of cytokines and vasodilatory substances in the skin via interference with the proinflammatory cytokines and chemokines that interact with dendritic cells and macrophages to cause inflammation.

Although the exact mechanism of action of corticosteroids in psoriasis is not completely understood, corticosteroids are described to patients as anti-inflammatory agents that reduce the redness and swelling associated with psoriatic lesions.

	Corticosteroids are categorized into seven strengths based on the degree of cutaneous vasoconstriction produced.

Categorizations range from very strong or "superpotent" class 1 agents (eg, clobetasol propionate) to very weak or "least potent" class 7 agents (eg, OTC hydrocortisone).

Low-potency corticosteroids are the safest agents for long-term use and for use on areas of the body with thinner, sensitive skin, such as the face, groin, and breasts.

High-potency agents are beneficial for areas of the body with thicker skin, such as the knees and elbows.

	The potency of a corticosteroid-containing medication can be influenced by the vehicle in which the corticosteroid is formulated. 

Some vehicles are lubricating and allow for more effective drug penetration.

	Topical corticosteroids are effective for most patients with mild to moderate plaque psoriasis on the body and scalp.

Studies using the Psoriasis Area and Severity Index (PASI) score as the primary efficacy outcome measure showed a mean improvement of approximately 45% to 60% with topical corticosteroids after 4 to 8 weeks of treatment (Table 1).

	Most topical corticosteroids are applied once or twice daily.

The recommended duration of use for topical high-potency corticosteroids is a maximum of 2 to 4 weeks; this maximum duration minimizes the potential for adverse effects.

 Additionally, high-potency corticosteroids should be gradually tapered rather than abruptly discontinued to avoid the occurrence of rebound symptoms.

Cutaneous or local adverse effects associated with higher-potency corticosteroids include skin atrophy, easily contused skin, purpura, striae, and telangiectasis.

 Chronic application of topical corticosteroids has been associated with tachyphylaxis, or the loss of medication effectiveness; however, this reaction could be the result of poor patient adherence rather than a feature of medication response.

Patients requiring continuous treatment with corticosteroids should be maintained on the least-potent corticosteroid for the shortest duration of time necessary to maintain clinical effectiveness while minimizing the risk of adverse events.

	Symptomatic suppression of the hypothalamic-pituitary-adrenal (HPA) axis is not commonly seen with low-potency topical corticosteroids. HPA axis suppression was seen in 20% of adult patients with psoriasis vulgaris treated with high-potency clobetasol ointment.

	As with corticosteroids, the exact mechanism of action of vitamin D in psoriasis is unknown.

The skin is an important target tissue for vitamin D’s genomic and nongenomic effects. Nongenomic effects of vitamin D are regulated by intracellular calcium.

Studies in human cultured keratinocytes have shown that free cytosolic calcium levels increase with vitamin D exposure.

Genomic effects of vitamin D in the skin are mediated by vitamin D receptor binding.

In keratinocytes, vitamin D is thought to induce terminal differentiation and suppress hyperproliferation

; it is also thought to suppress the production and release of proinflammatory cytokines.

Treatment of psoriatic plaques with the vitamin D analog calcipotriene suppresses the expression of alarmins, antimicrobial peptides that amplify inflammation.

	Vitamin D analogs are synthetic forms of vitamin D

. Analogs available for the topical treatment of plaque psoriasis in the United States include calcitriol and calcipotriene (calcipotriol). These vitamin D analogs are available in ointment, cream, solution, and foam formulations,

and they are also available in fixed-combination products consisting of calcipotriene and betamethasone dipropionate.

	A systematic literature review of 11 studies evaluating vitamin D analog monotherapy reported a treatment success rate (ie, marked improvement or clearance, or PASI 

75) of 4% to 40% among patients with mild to moderate psoriasis treated for 6 to 12 weeks.

The wide range in improvement rates may be attributed, in part, to the heterogeneity among the studies in terms of treatment duration, population size, and definition of success.

Dermatologists often prescribe topical vitamin D analogs as adjuncts to topical corticosteroids for added efficacy.

	The most common adverse effect seen with vitamin D analog therapy is mild irritant contact dermatitis.

Localized irritation in lesional and perilesional skin, which occurs in up to 35% of patients, may involve itching, burning, and erythema.

Systemic side effects rarely occur with topical administration of vitamin D analogs; however, transient effects may be seen in patients applying more than the recommended 100 g per week of calcipotriene or 200 g per week of calcitriol.

Combination therapy with vitamin D analogs and corticosteroids

	Vitamin D analogs and corticosteroids appear to act through different mechanisms to control the underlying inflammation and keratinocyte differentiation and proliferation associated with psoriasis. There is a paucity of preclinical study data, however, to provide a mechanistic explanation for the efficacy of the two agents used in combination. One preclinical study in human T cells showed that the addition of the vitamin D analog calcipotriene to the corticosteroid betamethasone dipropionate in a fixed-combination formulation produced an enhanced immunoregulatory response that was different from the immunosuppressive effect seen with betamethasone dipropionate alone.

Combination formulations and characteristics

	When a vitamin D analog and a corticosteroid are used in combination, each agent is applied at different times of day for a twice-daily application course.

This is recommended because some topical corticosteroids will inactivate the vitamin D analog.

Use of a fixed-combination formulation counteracts this situation.

The fixed-combination product of calcipotriene plus betamethasone dipropionate has been uniquely formulated to overcome the inherent instability of the vitamin D analog in the presence of the acidic betamethasone dipropionate and to optimize the delivery of both agents in a once-daily formulation.

	Multiple studies support the enhanced efficacy observed with the combination of topical vitamin D analogs and corticosteroids (Table 2).

	First-line use of a vitamin D analog plus a corticosteroid improves psoriasis within 2 weeks of initiation and produces maximal improvement after 4 weeks of treatment in most patients.

Randomized, controlled studies assessing efficacy using the PASI score have reported a mean improvement of approximately 50% to 75% with once-daily application of topical calcipotriene and betamethasone dipropionate in a fixed-combination formulation after 4 to 8 weeks.

A meta-analysis of 11 randomized, controlled clinical trials compared combination therapy with a vitamin D analog plus a corticosteroid to vitamin D analog monotherapy. The probability of clinical success (eg, Investigator’s Global Assessment of “clear” or “almost clear,” or “absence of disease” or “very mild disease,” or PASI 

90) was two times greater with the combination treatment than with vitamin D alone.

Similarly, a recent Cochrane review of randomized, controlled trials determined that the combination of a vitamin D analog plus a corticosteroid performed better than either a vitamin D analog or a corticosteroid alone.

The inconsistencies in study designs and outcome criteria among large comparative and controlled studies make it difficult to compare the rates of treatment success with different combination regimens. Nonetheless, the recommendations for topical vitamin D and corticosteroid combination therapy are based on consistent and high-quality patient-oriented evidence.

	Combination therapy appears to be safe and well tolerated for both short- and long-term use.

In a meta-analysis, the tolerability of topical therapy with a vitamin D analog plus a corticosteroid was comparable to that of potent corticosteroids and significantly better than the tolerability of vitamin D alone.

In a pooled safety analysis of 9 randomized clinical trials of calcipotriene and betamethasone dipropionate in a fixed-combination suspension, the incidence of ≥1 adverse drug reaction was 6% and 8% in patients applying the combination to the body and scalp, respectively.

In a study of calcipotriene and betamethasone dipropionate treatment in 3 different regimens for up to 52 weeks’ duration, corticosteroid-related cutaneous adverse reactions occurred in only 2.8%, 2.9%, and 4.8% of patients.

	The low risk of cutaneous adverse events with simultaneously applied combination therapy may be a function of the complementary mechanisms of action of vitamin D analogs and corticosteroids. The anti-inflammatory actions of corticosteroids are thought to reduce the local irritation caused by vitamin D analogs, whereas vitamin D analogs have the potential to restore epidermal function and counteract corticosteroid-induced atrophy.

	Systemic adverse events of concern with the combination include vitamin D analog-induced alteration of calcium homeostasis and corticosteroid-induced suppression of the HPA axis. No significant effects of this nature have been observed in clinical studies.

Application of a maximum dose of 100 g per week of calcipotriene and betamethasone dipropionate for 4 to 8 weeks resulted in serum levels of both agents below the level of quantification.

Additionally, calcipotriene did not affect albumin-corrected serum calcium levels in any study.

Although calcipotriene and betamethasone dipropionate did not suppress the HPA axis at doses ≤100 g per week, a weak suppression has been detected with very high doses.

Application of calcipotriene and betamethasone dipropionate suspension to the scalp and of calcipotriene and betamethasone dipropionate ointment formulation to the body for 4 to 8 weeks in 32 patients with extensive psoriasis resulted in a borderline decrease in cortisol response at 30 minutes after challenge with corticotropin in 5 of 32 patients (15.6%) at 4 weeks and in 2 of 11 patients (18.2%) at 8 weeks. Serum cortisol levels were normal by 60 minutes after the challenge.

The clinical relevance of these findings has not yet been established.

	Dermatologists approach the treatment of mild to moderate psoriasis with individualized treatment plans that take into account disease severity, tolerability of therapy, and potential side effects, as well as factors affecting adherence to the treatment regimen. Topical treatment with vitamin D analogs and corticosteroids is the mainstay of first-line therapy for patients with localized psoriasis. Pharmacists involved in the care of patients with psoriasis can use their understanding of the pathophysiology of psoriasis and the efficacy and safety associated with various treatment options to provide patients with up-to-date recommendations.

	Editorial support was provided by Trina Ricci, PhD, of 

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Currents in Pharmacy Teaching and Learning

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Articles

Topical treatment with vitamin D analogs and corticosteroids is the mainstay of first-line therapy for patients with localized psoriasis.

Author | Paul S. Yamauchi, MD, PhD

Articles

Vitamin D analogues and corticosteroids in the treatment of plaque psoriasis