Topical Management of Psoriasis and the Role of Vitamin D3 Analogues

Kathleen Katipunan, MD and Melinda Gooderham MD, MSc, FRCPC¹

¹Skin Centre for Dermatology and Skin Laser Clinic, Peterborough, ON, Canada

Introduction

Psoriasis is a chronic, recurrent, immune-mediated, papulosquamous skin condition characterized by rapid proliferation of keratinocytes. Worldwide prevalence is reported to be 2%¹ and incidence rates in the US and Canada have been reported to be as high as 4.6% and 4.7%, respectively.² Psoriasis is commonly manifested as well-defined erythematous plaques with silvery white scale on the elbows, knees, intergluteal cleft, and trunk. Between 50-80% of all psoriasis patients also develop scalp involvement at some stage.^3,4 Approximately 80% of patients affected with psoriasis have mild to moderate disease that can be managed with topical agents.¹ Various available topical therapies will be briefly discussed. The focus of this review will be on vitamin D3 analogues, including evidence from clinical trials investigating these agents.

Rationale for Treatment of Psoriasis

Although, in a vast majority of cases, psoriasis is not life threatening, it is associated with significant physical, psychological, social and economic burdens. Effective interventions are available that can dramatically improve disease symptoms and quality of life.

Patient-centered Care

The chronicity of psoriasis requires a long-term, patientspecific approach to management. From a pharmacologic perspective, factors that can influence treatment decisions include safety and efficacy, onset of action, product characteristics, and cost. As well, important considerations unique to each patient include medical history, disease severity, lifestyle, preferences, tolerability, and adherence.

The dominating factor for improving adherence to prescribed therapy is time invested by the physician, where clinical knowledge and experience are translated into patient care and treatment satisfaction. Strategies to build this interface include:

• Establishing good doctor-patient communications
• Modifying or adapting regimens based on response to therapy and patient feedback
• Selecting simple and effective therapeutic regimens
• Encouraging patient self-management (e.g. nonpharmacologic and lifestyle interventions)

Topical Treatments for Psoriasis

Corticosteroids

• Corticosteroids have anti-inflammatory, anti-pruritic, vasoconstrictive, and immunosuppressive properties.¹
• They are available in an array of formulations and strengths, which make them suitable for treating different areas.¹ In general, ointments have the highest potency (due to occlusion and moisturization), and lotions, foams or gels are preferred for hair-bearing areas (due to ease of spreadability and minimal residue).¹
• The most efficacious topicals for treating psoriasis are highest potency steroids, followed by vitamin D3 analogues.¹
• Use is limited by potential side-effects (e.g., skin atrophy, striae, telangiectasia, tachyphylaxis).¹ Overuse or misuse are associated with hypothalamic-pituitary-adrenal (HPA) axis suppression.⁵
• Generally, treatment should continue until the skin is clear, then tapered. Therapy may be limited to 2-4 weeks in certain areas.¹
• Adverse effects may be minimized by once daily use; longterm remission may be maintained by application on alternate days.²

Other Agents

• Calcineurin inhibitors (tacrolimus and pimecrolimus) are immunomodulating compounds that act through T-cell modulation. They are particularly effective for treating psoriasis of the face and intertriginous areas.¹
• Retinoids (e.g., tazarotene) modulate cell differentiation and proliferation.¹ Tazarotene is available in cream or gel formulations, applied once daily. It is particularly useful for palmoplantar psoriasis as it does not leave a greasy residue.
• Anthralin and coal tar have a long history of use for psoriasis, but they have largely been replaced by newer agents with superior efficacy and better patient acceptability.¹
• Combination therapy is generally more efficacious than monotherapy¹ and can have a lower incidence of adverse effects. Common combinations include two topical agents or a topical agent with phototherapy.

Vitamin D3 Analogues

Background

• In the 1990’s, the introduction of vitamin D3 analogues revolutionized the topical treatment for psoriasis. Due to their therapeutic efficacy and limited toxicity, vitamin D3 analogues have become a first-line option for psoriasis.¹
• Vitamin D3 analogues exert their effect by binding to nuclear vitamin D receptors, inhibiting keratinocyte proliferation and promoting differentiation. A recent study also showed calcipotriol induced apoptosis in psoriatic keratinocytes.⁶
• They can induce a steroid-sparing effect, thereby reducing side-effects such as skin atrophy, tachyphylaxis, and other adverse reactions related to corticosteroid use.
• Available vitamin D3 analogues in Canada include:
  • Calcipotriol ointment, cream, and scalp solution;
  • Calcitriol ointment; and
  • Calcipotriol + betamethasone dipropionate ointment and scalp gel.

Calcipotriol

• Calcipotriol 50 mcg/g ointment or cream (Dovonex®) is available for use on the body and 50 mcg/mL scalp solution is used on the scalp and other hair-bearing areas. It is used twice daily on affected areas and application can be reduced to once daily maintenance therapy when appropriate, and then discontinued after satisfactory improvement.
• In mild to moderate chronic plaque psoriasis, a systematic review showed calcipotriol was as effective as moderately potent topical steroids (e.g., betamethasone valerate ointment). It was also more effective when compared to calcitriol, coal tar, and short-contact dithranol.⁷
• Calcipotriol cream is also a highly efficacious maintenance treatment used alone or in an alternating regimen with calcipotriol/betamethasone dipropionate ointment.⁸
• Irritation can occur on sensitive areas (e.g., flexures, face and hairline). Up to 35% of patients can experience redness, burning, scaling, and pruritus in lesional / perilesional skin.¹
• Hypercalcemia is a rare concern; doses should be limited to 100 g/week of calcipotriol cream or ointment.¹
• Calcipotriol is clinically effective in children with very little risk of local or systemic side-effects.⁹ Maximum doses are calculated based on body surface area (BSA) and age.

Calcitriol

• Calcitriol ointment 3 mcg/g (Silkis™) is indicated for topical treatment of mild to moderate plaque-type psoriasis with up to 35% BSA involvement. Applied twice daily, no more than 30 g of ointment should be used daily, or 200 g per week.
• In two identically designed, randomized, double-blind, placebo-controlled trials of twice daily calcitriol ointment on mild to moderate psoriasis over 8 weeks, efficacy was seen as early as 2 weeks. At the end of 8 weeks, efficacy was sustained and significantly higher than placebo.¹⁰
• In two long-term studies over 52 weeks, no major safety concerns were reported. Adverse events (e.g., erythema, pruritus and skin discomfort) were mild.¹⁰ Calcitriol is less irritating than other vitamin D analogues, making it more suitable for use on the face and flexural areas.¹¹
• Treatment is approved for patients ≥18 years of age. Safety and efficacy in children have not yet been studied.

Calcipotriol and Betamethasone Dipropionate

• Calcipotriol/betamethasone dipropionate in ointment (Dovobet®) or scalp gel (Xamiol®) has a more rapid onset of action, greater efficacy, and comparable safety vs. either agent alone.^12-14
• It promotes normal keratinization, inhibits inflammation, and modulates epidermal proliferation and differentiation.
• When combined, the different modes of action of the two molecules become synergistic, enhancing efficacy and reducing side-effects.¹⁵
• It is an appropriate first-line therapy that is effective and well tolerated across all grades of disease severity.⁹
• Treatment is indicated for once daily application for 4 weeks, but long-term studies of both the ointment¹⁶ and scalp gel¹⁷ formulations have shown good tolerability and safety with as-needed use over 52 weeks.¹⁴
• Avoid use on the face, intertriginous or sensitive areas (e.g., flexural and genital regions).
• Up to 30% of BSA may be treated.
• Calcipotriol/betamethasone dipropionate therapy showed improvements in health-related quality of life measures and cost effectiveness through pharmacoeconomic analyses.¹⁴
• Treatment was well tolerated, the most common side-effects were mild to moderate lesional or perilesional irritation.¹⁴
• A 4-week, double-blind study in 24 patients with extensive psoriasis did not show HPA axis suppression. Furthermore, a follow-up study involving a subset of 19 patients over 52 weeks, some of who alternated with calcipotriol every 4 weeks, also did not demonstrate HPA axis suppression.¹⁴
• Calcipotriol/betamethasone dipropionate ointment cannot be compounded from its two individual ingredients, as this will result in a mixture that is both unstable and ineffective. However, the commercially available combination product is a stable preparation.

Role of Family Physicians in Psoriasis Management

Even though the majority of psoriasis patients may be managed with topical medication, nonadherence rates for topical treatment is estimated at 40%,¹⁸ including up to 50% for unfilled prescriptions.¹⁹

As the primary contact for people seeking healthcare, family physicians play a crucial role in promoting treatment adherence among psoriasis patients. This may be achieved by adopting a more patient-specific approach to management, through engaging in ongoing discussions with patients about treatment expectations, choice of therapy, including offering simplified dosing regimens, as well as regularly assessing tolerability and side-effects from medications.

Conclusion

Vitamin D3 analogues offer a form of topical treatment for plaque-type psoriasis that is effective, safe, and in the long run, cost-effective. Single product, fixed-dose, combination therapy is an important, once daily, topical option for the symptomatic treatment of psoriasis that yields comparable safety, increased efficacy, and improved cosmetic acceptance, resulting in higher patient adherence and optimized outcomes.

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