Topical Vitamin D Analogues in Psoriasis Treatment

Adam Natsheh, BScPharm, MD, FRCPC (Dermatology)^1,2,3
Cindy Truong Natsheh, BScPhm, ACPR, PharmD<sup>4,5

1</sup>Division of Dermatology, University of Toronto, Toronto, ON
²Womens College Hospital, Toronto, ON
³The Dermatology Group, North York, ON
⁴Department of Pharmacy,University Health Network, Toronto, ON
⁵Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON

Introduction

Psoriasis is a common, chronic, recurrent, and inflammatory skin disease that can be associated with significant psychosocial impact. While at present there is no known cure, there are many good treatment options to control psoriasis. This article will outline the role of a newer class of topical medications known as vitamin D analogues in the management of psoriasis.

What is Psoriasis?

• Psoriasis affects approximately 2% of the North American population.¹
• The exact cause is not known, but is multifactorial in originwith a combination of genetic and environmental factors (e.g., streptococcal infections, stress, or medications).
• Medications that can exacerbate psoriasis include gold salts, beta blockers, interferon, antimalarials (e.g., hydroxychloroquine), lithium, and oral steroids.
• There is a positive family history in approximately onethird of individuals.²
• Anxiety, smoking, and skin trauma may exacerbate psoriasis.
• It can occur at any age, but there is a bimodal peak distribution for age of onset - in the 20s and 60s.
• Psoriasis is characterized by a chronic course consisting of recurrent flares and periods of remission.
• Typical lesions appear as itchy pink plaques with silvery/ shiny scales that can be quite thick, and are most commonly seen on:
• extensor surfaces of limbs (e.g., knees, elbows, buttocks)
• hands and feet (usually palms and soles); patients complain of very dry skin with cracking and sometimes pain
• nails (yellowing), pitting (indents), onycholysis (lifting of nail plate from nail bed)
• scalp and ears (posterior and sides of scalp most common)
• It is somewhat itchy, but usually less so than atopic and other types of dermatitis (eczema)
• Being chronic, its impact on physical and mental function has been demonstrated to be similar to that of cancer, arthritis, hypertension, heart disease, diabetes, and depression.³
• There is a growing body of evidence suggesting that severe psoriasis may be an independent risk factor for cardiovascular disease.^4-6

Treatment Rationale

• Psoriasis is dominated by four skin abnormalities: redness or erythema, inflammation, hyperproliferation of the keratinocytic layer, and altered epidermal differentiation.⁷
• Treatment of psoriasis is often multimodal, using a combination of non-drug and pharmacological modalities.
• Like other chronic diseases (e.g., hypertension, diabetes, asthma) treatment requires long-term patient adherence, making choice of therapy that is acceptable to the patient even more important. Clinicians should not only choose therapies that work, but those that the patient will work with.⁸
• Topical treatments vary depending on body location, characteristics of the psoriasis being treated, including lesion thickness, degree of redness, and amount of scaling, as well as patient preference.
• The goal of therapy is to gain rapid control of flares, induce and prolong remission, and maintain normal skin, while preventing long-term complications from therapy.

Treatment Options

Topical Corticosteroids

• High-potency corticosteroids play a central role in the topical treatment of psoriasis. Their multiple mechanisms of action include anti-inflammatory, immunosuppressive, and antiproliferative effects.¹
• Corticosteroids are the most widely used agents for the topical treatment of psoriasis and have been the mainstay of therapy. They are well tolerated and come in a variety of vehicles, including ointments, creams, gels, foams, lotions, sprays, and solutions.
• Different potencies of corticosteroid treatment are available (Table 1), ranging from Class 1 (highest potency) to Class 7 (lowest potency).
• Typically, higher potency topical steroids are commonly prescribed for rapid clearing in acute flares. Following initial control of psoriasis, it is recommended that a gradual reduction in dosing be instituted.
• Very potent steroids (Class 1 or 2) are suitable for pulse therapy, chronic recalcitrant plaques, control of flares, or thickened lesions (i.e., palms and soles). They should not be used on thinner skin, such as the face, neck, or intertriginous areas (axillae or groin).
• The risk of adverse effects (e.g., atrophy or striae) increases if they are used continuously for longer periods of time.
• Fear of side-effects is a key reason patients use steroids less often than prescribed, leading to treatment failure. Similar to oral antibiotics, topical steroids should be used as directed.
• A more detailed discussion on topical steroids in psoriasis may be found at: http://www.skintherapyletter.ca/fp/2010/6.3/1.html

Vitamin D Analogues (Table 2)

• Vitamin D analogues induce differentiation and suppress proliferation of keratinocytes, thus reversing the abnormal keratinocyte changes in psoriasis.⁹
• Unlike their oral counterpart, topical vitamin D analogues have minimal effects on systemic calcium metabolism. However, serum calcium levels should be monitored if risk factors for hypercalcemia are present, such as renal disease or impaired calcium metabolism.
• There are two available vitamin D analogues available in Canada - calcitriol and calcipotriol. Combination products with betamethasone dipropionate are also available.
• Calcitriol and calcipotriol were found to be comparably effective in one study with 250 subjects treated twice-daily with mild to moderate psoriasis over a 12 week period.¹⁰
• In addition to topical corticosteroids, the Canadian Psoriasis Consensus Guidelines recommends vitamin D analogues, i.e., either calcipotriol or combination calcipotriol/ betamethasone diproprionate, as first-line options for mild psoriasis.⁸
• Vitamin D compounds can induce a steroid-sparing effect, resulting in reduced adverse reactions such as skin atrophy, tachyphylaxis, and other side-effects associated with corticosteroid use.

Calcitriol (Silkis™)

• It is the naturally occurring and biologically active metabolite of vitamin D3 [1 alpha-25-dihydroxyvitamin D3, abbreviated as 1,25 (OH)2 D3], which is primarily produced in the skin by exposure to ultraviolet light.
• It is indicated to treat mild to moderate plaque-type psoriasis in adults ≥18 years of age with up to 35% body surface area (BSA) involvement and is suitable for long-term therapy.⁹
• Calcitriol has been found to be very well tolerated in intertriginous areas with minimal irritation on application.⁷ It is not suitable for use on the face.
• In a 52-week uncontrolled, open label study of 324 patients, efficacy did not appear to diminish over time.¹¹
• It is available as an ointment and recommended dosing is twice-daily. The maximum weekly dose should not exceed 200 g.
• Calcitriol ointment produces little systemic absorption of calcitriol and does not result in systemic hypercalcemia even when applied to approximately one-third of BSA.¹¹

Calcipotriol (Dovonex®)

• It is a derivative of the naturally occurring vitamin D3 and is as potent as 1,25 (OH)2 D3 in regulating cell proliferation and cell differentiation.
• Calcipotriol has been compared with Class 2 (potent) corticosteroid ointments and found to be comparable or slightly more effective than these agents.¹²
• In comparison with other topical therapies, vitamin D3 analogues were associated with a relatively low rate of adverse events. The most common adverse effect associated with calcipotriol is a mild irritant contact dermatitis.¹³ Avoid application on the face.
• Hypercalcemia has also been reported, but is rare with the doses used in clinical settings, which should be limited to 100 g of calcipotriol cream or ointment per week.¹⁴
• It is available as a cream, ointment, and scalp solution.
• Calcipotriol is clinically effective in children with very little risk of local or systemic side-effects.⁸

Combination Treatment

Calcipotriol and Betamethasone Dipropionate (Dovobet®, Xamiol®)

• In general, combination therapy is more efficacious and can result in reduced incidence of adverse effects when compared with monotherapy, as more than one pathogenic factor is targeted.
• Studies have shown that the two agents in combination have a more rapid onset of action and greater efficacy than monotherapy with either agent.^15-17
• As a fixed combination, the different modes of action of the two molecules become synergistic, resulting in enhanced efficacy and reduced side-effects.¹⁷
• In a 52-week study comparing once-daily use of (a) combination product, (b) combination alternating with calcipotriol, and (c) calcipotriol alone, the combination product was consistently more effective than the other treatment groups. Furthermore, patients treated throughout with combination product had the fewest side-effects.¹⁸
• In the same study above, the combination product was also found to be safe and well tolerated by patients, whether used on its own or alternating with calcipotriol.¹⁹
• Betamethasone dipropionate is a Class 2 corticosteroid, and therefore, to minimize local cutaneous side-effects, the combination product should not be used on the face and intertriginous sites.
• It is available as an ointment or scalp gel. The scalp gel is alcohol free, which makes it less irritating for patients.
• A study investigating the combination scalp gel formulation showed that 92% of patients achieved marked improvement to clearance of their scalp psoriasis following once-daily use for up to 8 weeks with very few side-effects.²⁰
• It is an appropriate first-line therapy that is effective and well tolerated across all grades of psoriasis severity.⁸
• Although treatment is indicated for once-daily application for 4 weeks, long-term studies of both the ointment¹⁹ and scalp gel¹³ formulations have demonstrated good tolerability and safety with as-needed use over 52 weeks.

Tips for the Pharmacist

Counsel Patients on How Much to Apply

• A "Finger Tip Unit" is the amount of cream applied from end of finger to first knuckle (about 500 mg of cream) and should be enough to cover one of the patient's "hand-sized" amount of skin, or approximately 1% BSA.
• Apply a sufficient amount of medication on plaques in a circular motion until the medication is distributed evenly (i.e., a visible thin film covering the psoriatic lesion).
• Counselling patients on proper usage (e.g., sufficient dosage, application, and duration) and therapeutic objectives can optimize adherence and outcomes.
• Avoid using the term "apply sparingly", particularly in association with topicals, which may convey to patients the prescribed medication is harmful, inadvertently contributing to poor treatment follow-through.

Avoid Triggers

• Encourage patients to quit smoking, if possible, and review cardiac risk factors.
• Avoid known triggers or medications that may exacerbate psoriasis.

Compounding

• Calcipotriol can be unstable under certain circumstances, particularly when compounded with a more acidic product (e.g., salicylic acid).²¹ Therefore, other products should be applied at another time, e.g., Dovobet® ointment applied at bedtime and a salicylic acid-containing product applied in the morning.
• Calcipotriol should not be repackaged in a smaller plastic container (e.g., 30 g) because the product loses stability. Dovobet® should be dispensed in its original container and once opened it is stable for 1 year.²²
• The individual components should not be mixed together (i.e., calcipotriol compounded with betamethasone dipropionate or another high potency corticosteroid), as the resultant preparation is unstable and not equivalent to the combination product due to the degradation of calcipotriol.
• Similarly, there have not been any studies showing the efficacy of calcipotriol used at the same time with another high potency steroid cream, and therefore should not be applied directly at the same time.

Conclusion

Vitamin D analogues are a newer class of topical medications that have been shown to be safe and effective in the treatment for psoriasis. Single product, fixed-dose, once-daily topical combination therapy is a significant advance in treating psoriasis. The synergistic effects from dual agent therapies, such as calcipotriol/betametasone diproprionate, able to target multiple pathogenic factors (e.g., erythema, inflammation, hyperproliferation, and epidermal differentiation) provide simplified dosing and enhanced efficacy and safety, which can lead to improved patient adherence and treatment outcomes.

References

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6. Mehta NN, et al. Eur Heart J 31(8):1000-6 (2010 Apr).
7. Bhalerao J, et al. Hum Mol Genet 7(10):1537-45 (1998).
8. Canadian Psoriasis Guidelines Committee. Canadian Guidelines for the Management of Plaque Psoriasis, 1st edition. June 2009. Accessed September 14, 2011 at: http://www.dermatology.ca/guidelines/cdnpsoriasisguidelines.pdf
9. Compendium of Pharmaceuticals and Specialties (CPS). Ottawa: Canadian Pharmacists Association (2011).
10. Zhu X, et al. J Eur Acad Dermatol Venereol 21(4):466-72 (2007 Apr).
11. Lebwohl M, et al. Cutis 83(4):205-12 (2009 Apr).
12. Kragballe K, et al. Lancet 337(8735):193-6 (1991 Jan 26).
13. Lebwohl M, et al. J Am Acad Dermatol 45(4):487-98 (2001 Oct).
14. Mortensen L, et al. Acta Derm Venereol 73(4):300-4 (1993 Aug).
15. Luger TA, et al. Dermatology 217(4):321-8 (2008).
16. Jemec GB, et al. J Am Acad Dermatol 59(3):455-63 (2008 Sep).
17. Vissers WH, et al. Exp Dermatol 13(2):106-12 (2004 Feb).
18. Kragballe K, et al. Dermatology 213(4):319-26 (2006).
19. Kragballe K, et al. Br J Dermatol 154(6):1155-60. (2006 Jun)
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21. Patel B, et al. J Am Acad Dermatol 38(6 Pt 1):1010-1 (1998 Jun).
22. Dovobet® (calcipotriol and betamethasone) product monograph, version 2.0. LEO Pharma Inc., Thornhill, ON (2008 Nov 5).

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