Evidence-Based Review of Topical Treatments for Psoriasis. Maryann Mikhail and Noah Scheinfeld, MD

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1 DERMATOLOGY Evidence-Based Review of Topical Treatments for Psoriasis Maryann Mikhail and Noah Scheinfeld, MD ABSTRACT PURPOSE: To understand the appearance, clinical variation, epidemiology, and pathophysiology of psoriasis and the indications and options for its topical treatment. EPIDEMIOLOGY: Psoriasis occurs in 1% to 3% of the US population. In 20% to 25% of these individuals, the disease will be more than limited. Plaque psoriasis is more common in individuals with haplotypes HLA-B13, -B17, and -Cw6. It worsens with HIV infection, stress, other infection, and exposure to ultraviolet light. REVIEW SUMMARY: Limited plaque psoriasis can be treated effectively with topical therapies. The mainstay of treatment is topical corticosteroids, which come in a variety of strengths. Adjustments regarding their sites of application and their durations of use allow prescribers to maximize the therapeutic effects of topical corticosteroids and minimize their side effects for patients. The new sequential administration of calcipotriene and topical corticosteroids is an effective treatment; however, older agents such as anthralin, emollients, and keratolytics are useful, as well. Tazarotene, a vitamin A derivative, also is an effective topical agent. TYPE OF AVAILABLE EVIDENCE: Double-blinded randomized trials. GRADE OF AVAILABLE EVIDENCE: Good. CONCLUSION: Mild psoriasis can be treated effectively with topical medication. When the disease is present on more than 20% of the body surface area or has not responded to topical therapy, systemic treatment should be discussed with patient. Research should be directed toward developing more potent medications with fewer side effects that also possess the ability to induce a remission of the disease. (Adv Stud Med. 2004;4(8): ) Psoriasis is an eruption that can be systemic, chronic, and inflammatory, and that can involve the skin, nail, mucous membranes, gastrointestinal tract, and joints. It also may manifest with arthritis. Of the various cutaneous manifestations, plaque psoriasis is the most common. In these genetically predisposed individuals, environmental factors contribute to the development of sharply demarcated, erythematous, scaling plaques that may be pruritic, painful, and disfiguring. 1-3 This evidenced-based review focuses on the fundamental features of psoriasis and its topical care. EPIDEMIOLOGY Psoriasis occurs in 1% to 3% of the US population. Although it occurs at all ages, the initial Ms Mikhail is a medical student at New York University School of Medicine, New York, NY. Dr Scheinfeld is Assistant Clinical Professor of Dermatology, Columbia University; Director, Consultation Dermatology Service, St Luke Roosevelt Hospital Center, and Director of Consultation Dermatology Service, Beth Israel Medical Center, New York, NY. Conflict of Interest: Ms Mikhail and Dr Scheinfeld report no financial or advisory relationship with corporate organizations related to this activity. Off-Label Product Discussion: The authors do not include discussion of off-label use of products. Correspondence to: Noah Scheinfeld, MD, St Luke Roosevelt Hospital, Department of Dermatology, 1090 Amsterdam Ave, Suite 11B, New York, NY Vol. 4, No. 8 September 2004

2 PSORIASIS onset of psoriasis peaks in young adults between the ages of 16 and 22 years and in older persons 57 to 60 years of age. 2,3 More than 50% of patients have positive family histories, and concordance rates among monozygotic twins range from 65% to 72%. Psoriasis affects male and female patients equally, although female and genetically predisposed individuals tend to have earlier ages of initial onset. 4 Psoriasis can affect all races; however, epidemiological studies have shown a higher prevalence in northern European and Scandinavian populations. It is less common in Japanese and African populations. It almost never occurs in North American and South American Indian populations. GENETICS Plaque psoriasis is more common in individuals with haplotypes HLA-B13, -B17, and -Cw6. Polygenetic mechanisms and etiologies are probably involved, as well. HIV infection, stress, alcoholism, smoking, and ultraviolet light exposure all can affect the course, duration, and clinical picture of plaque psoriasis. Many kindred exhibit autosomal dominant patterns of inheritance with decreased penetrance. Studies of twin siblings have shown concordant disease in 73% of monozygotic twins, compared with 20% in dizygotic twins. Whereas this relationship suggests a genetic etiology for psoriasis, the absence of 100% concordance among monozygotes seems to indicate that environmental factors are related to the pathophysiology of psoriasis. 2 Investigations have defined 4 key genes (named psor1-4) that are related to the etiology of psoriasis. Of particular interest are the genes located in regions on specific chromosomes that are linked to HLA and tumor necrosis factor, an immune component strongly associated with psoriasis. 5 the appearance of minute blood droplets (Auspitz sign). 1 The eruption of psoriasis is frequently bilateral and often symmetrical, usually sparing exposed areas and favoring the elbows, knees, sacrum, and scalp. Involvement may be universal, affecting the entire skin, or it may be localized to one area or region. 1 Nail findings, which may be a clue to the presence of psoriatic arthritis, include pitting, onycholysis, subungual hyperkeratosis, or the oil-drop sign. 2 Other variations Table 1. Defining Characteristics of the Various Types of Psoriasis Type Plaque psoriasis Guttate psoriasis Erythrodermic psoriasis Pustular psoriasis Nail psoriasis WBC = white blood cell. Characteristics Dry, scaling patches Drop-like, discrete papules and small plaques after streptococcal infection Exfoliation of fine scales, widespread, often accompanied by severe itching and pain Pus-like blisters, noninfectious, fluid contains WBCs Pitting, subungual hyperkeratosis, onycholysis, yellow/brown spots under nail plate Figure 1. Plaque Psoriasis on the Sacrum PATHOPHYSIOLOGY OF PSORIASIS Psoriasis is fundamentally a disease of human T cells. The abnormal T cells in psoriasis lead to abnormal epidermal differentiation and hyperproliferation. Whereas in normal skin the turnover of the epidermis takes 21 to 28 days, in psoriatic plaques it takes 3 to 4 days. CLINICAL PRESENTATION AND NATURAL HISTORY Psoriasis has a wide range of expressions and may involve the nails, scalp, and joints in addition to the skin (Table 1). The most frequent type is psoriasis vulgaris, which is characterized clinically by variably pruritic, erythematous, sharply demarcated, salmon-pink papules and rounded plaques covered by silvery, micaceous scales (Figure 1). Scales are lamellar, mica-like, and readily removed when scratched, which results in Advanced Studies in Medicine 421

3 DERMATOLOGY Figure 2. Guttate Psoriasis on the Back Figure 3. Nail Psoriasis Figure 4. The Koebner Phenomenon and Plaque Psoriasis of psoriasis that exist include guttate psoriasis, in which lesions are tear-shaped (Figure 2), and nail psoriasis (Figure 3). New psoriatic lesions can occur at sites of injury or trauma to the skin, the so-called Koebner phenomenon (Figure 4). STANDARD OF CARE Psoriasis is, at present, a chronic disease without a definitive cure. The aim of treatment is substantial improvement in and continued suppression of the disease to a level at which it no longer interferes with the patient s personal, social, or occupational wellbeing. 2,3 The 3 basic treatment modalities for the management of psoriasis are topical agents, phototherapy, and systemic agents. All of these may be used alone, in combination, or in rotation with one another. 6 Because psoriasis is a chronic skin condition that affects each patient differently, treatment regimens should be individualized based on the disease s impact on quality of life, body surfaces involved, lifestyle, comorbid health problems, and patient expectations. 7 Treatment of mild to moderate chronic plaque psoriasis often starts with emollients and keratolytics, topical corticosteroids, vitamin D analogs, coal tar, topical retinoids, and, less frequently, anthralin. A trial of topical therapy is indicated in patients with less than 5% body surface area involvement, unless they have previously failed topical therapy or are debilitated because of their symptoms or sites of involvement. 7 For more severe disease, options include therapy with ultraviolet B light, psoralen plus ultraviolet A light, oral retinoids, methotrexate (particularly for arthritis), cyclosporine, and biologics. 2,7 EMOLLIENTS AND KERATOLYTICS Emollients are an inexpensive, safe, active, but weak treatment for psoriasis that work by hydrating and softening the scaly hyperkeratotic surfaces of the plaques. Application of emollients is effective in reducing itching, soreness, redness, scaling, and lesional extension in about 35% of patients. 3 The only adverse effects seen are contact dermatitis and folliculitis. 8 Oilbased preparations such as petrolatum or aquaphor cream are more effective but less well tolerated because they are sticky and make the skin appear shiny. 3 While some patients find emollients alone to be sufficient, most require additional treatment. 9 Emollients that contain keratolytic agents such as salicylic acid can be useful for converting scaly, rough, or fissured plaques into smoother, pink plaques. 8 Ointments containing 2% to 10% salicylic acid often are used in conjunction with topical corticosteroids or agents such as anthralin or coal tar, which improve penetration Vol. 4, No. 8 September 2004

4 PSORIASIS A controlled, randomized, double-blind, parallelgroup, multicenter comparison in 408 psoriasis patients demonstrated that twice-daily use of a combination ointment that consisted of mometasone furoate 0.1% plus salicylic acid 5% was more effective than mometasone furoate 0.1% alone after 21 days of treatment. 11 Such combinations are most appropriate for use on thick, scaly, or recalcitrant plaques; however, caution should be exercised in the treatment of widespread psoriasis (>20% involvement) as overapplication may cause systemic side effects related both to the corticosteroid and the salicylate. 12 Signs of salicylate toxicity include tinnitus, dizziness, gastrointestinal distress, and psychic disturbances. 6 Though the release of combination products in the United States has been hampered by regulatory issues, corticosteroid salicylic combinations such as 0.05% betamethasone dipropionate ointment plus 3% salicylic acid (Diprosalic ointment) are available in other countries. 13 CORTICOSTEROIDS Topical corticosteroids are the most widely used treatment for psoriasis in the United States because they are fast acting, cosmetically acceptable to patients, and relatively low in cost. In a survey of US dermatologists, 85% of responders indicated topical steroids as their first choice for the treatment of mild to moderate psoriasis. 14 The mechanism of action of corticosteroids is complex. They have anti-inflammatory, antiproliferative, immunosuppressive, and vasoconstrictive properties. 15 Clinical efficacy is directly related to potency, can be measured by vasoconstrictive ability, and varies depending on vehicle of delivery 16 (Table 2) and concomitant use of occlusive agents. 15 As monotherapy, topical corticosteroids are most appropriate for the treatment of limited disease. 10,17 Low-potency preparations (Table 3) are generally used in maintenance therapy as well as for treatment of thin plaques and plaques on thin skin surfaces, such as those of the face, groin, and genital region. 10 Stronger corticosteroid preparations are more suitable for acute flares, thick plaques, and resistant lesions as well as plaques on thickened skin surfaces, such as those of the palms and soles. 10 Treatment with both of the potent corticosteroids, betamethasone dipropionate optimized vehicle (OV) ointment and clobetasol 17-propionate, has been shown to improve moderate to severe psoriasis vulgaris by at least 75% in 75% of patients. SIDE EFFECTS OF CORTICOSTEROID THERAPY An uncommon but clinically important side effect of the use of high-potency corticosteroids is adrenal suppression. One out of 5 (20%) of those treated had temporary reversible suppression of the hypothalamic pituitary-adrenal axis, as evidenced by subnormal laboratory corticoid levels during the first weeks of management (Table 4). 18 In patients with sufficient adrenal reserve, such transient laboratory corticosteroid aberrations lack clinical significance. On the other hand, protracted use of potent agents in patients with poor adrenal reserve capacity or with impaired barrier function can lead to clinically significant, iatrogenic, topical corticosteroid induced adrenal insufficiency. 15 Other potential side effects include thinning of the skin, striae, masking of local infections, and hypopigmentation. 15 Repeated, long-term application of potent topical agents also can eventuate in loss of efficacy (tachyphlaxis), and the use of systemic or potent topical agents over large areas can result in rebound exacerbations immediately following withdrawal. 15,19 In order to prevent such side effects, superpotent corticosteroid use should be limited to less than 50 g per week for no longer than 2 to 4 weeks. Furthermore, all but the weakest of corticosteroids should not be used on the face or intertriginous areas and should be minimized in children whenever possible. 7 One maintenance regimen that is intended to lessen the side effects of potent corticosteroids is known as weekend therapy or intermittent pulse dosing. In this regimen clearing is achieved by treating patients with a potent corticosteroid twice daily for 2 to 3 weeks; remission is maintained with continued application of the steroid in 3 consecutive doses at 12-hour intervals once a week. In one clinical trial, administration of betamethasone OV in this fashion successfully kept 74% of patients in remission for 12 weeks. 20 A subsequent study that used augmented betamethasone dipropionate showed that this regimen could effectively extend remission to 6 months in 60% of patients. 21 No serious local or systemic treatment-related adverse events were reported in either trial (Table 4). 20,21 Table 2. Recommended Sites for Various Vehicles of Corticosteroid Delivery Vehicle Cream Gel Impregnated tape Lotion Ointment Preferred Site Glabrous, intertriginous, hair bearing Hair bearing Glabrous Intertriginous, hair bearing Glabrous, hair bearing Advanced Studies in Medicine 423

5 DERMATOLOGY RECENT NEW CORTICOSTEROID PREPARATIONS There have been several advances in topical corticosteroid therapy. Citing the association of psychosocial factors and anxiety with the onset and exacerbation of psoriasis, a group of investigators demonstrated significant differences in disease improvement and measures of psychologic status with the use of diflucortolone valerate ointment with moclobemide, an antidepressant, as opposed to the use of placebo. 22 Recently, the Food and Drug Administration (FDA) approved foam formulations designed by the pharmaceutical company Connetics (Palo Alto, Calif) for the delivery of betamethasone valerate (Luxíq, 0.12%) and clobetasol propionate (Olux, 0.05%). 13 Originally, these foam Table 3. Steroid Potency Chart Brand Name Generic Name Brand Name Generic Name CLASS 1 - Superpotent CLASS 2 - Potent Clobex Lotion, 0.05% Clobetasol propionate Cyclocort Ointment, 0.1% Amcinonide Cormax Cream/Solution, 0.05% Clobetasol propionate Diprolene Cream AF, 0.05% Betamethasone dipropionate Diprolene Gel/Ointment, 0.05% Betamethasone dipropinate Diprosone Ointment, 0.05% Betamethasone dipropionate Olux Foam, 0.05% Clobetasol propionate Elocon Ointment, 0.1% Mometasone furoate Psorcon Ointment, 0.05% Diflorasone diacetate Florone Ointment, 0.05% Diflorasone diacetate Temovate Cream/Ointment/ Halog Ointment/Cream, 0.1% Halcinonide Solution, 0.05% Clobetasol propionate Lidex Cream/Gel/Ointment, 0.05% Fluocinonide Ultravate Cream/Ointment, 0.05% Halobetasol propionate Maxiflor Ointment, 0.05% Diflorasone diacetate Maxivate Ointment, 0.05% Betamethasone dipropionate Psorcon Cream 0.05% Diflorasone diacetate Topicort Cream/Ointment, 0.25% Desoximetasone Topicort Gel, 0.05% Desoximetasone CLASS 3 - Upper Mid-Strength CLASS 4 - Mid-Strength Aristocort A Ointment, 0.1% Triamcinolone acetonide Aristocort Cream, 0.1% Triamcinolone acetonide Cutivate Ointment, 0.005% Fluticasone propionate Cordran Ointment, 0.05% Flurandrenolide Cyclocort Cream/Lotion, 0.1% Amcinonide Elocon Cream, 0.1% Mometasone furoate Diprosone Cream, 0.05% Betamethasone dipropinate Kenalog Cream/Ointment/ Florone Cream, 0.05% Diflorasone diacetate Spray, 0.1% Triamcinolone acetonide Lidex-E Cream, 0.05% Fluocinonide Synalar Ointment, 0.025% Fluocinolone acetonide Luxiq Foam, 0.12% Betamethasone valerate Uticort Gel, 0.025% Betamethasone benzoate Maxiflor Cream, 0.05% Diflorasone diacetate Westcort Ointment, 0.2% Hydrocortisone valerate Maxivate Cream/Lotion, 0.05% Betamethasone dipropionate Topicort Cream, 0.05% Desoximetasone Valisone Ointment, 0.1% Betamethasone valerate CLASS 5 - Lower Mid-Strength CLASS 6 - Mild Cordran Cream/Lotion/ Tape, 0.05% Flurandrenolide Aclovate Cream/Ointment, 0.05% Alclometasone dipropionate Cutivate Cream, 0.05% Fluticasone propionate Derma-Smoothe/FS Oil, 0.01% Fluocinolone acetonide DermAtop Cream, 0.1% Prednicarbate DesOwen Cream, 0.05% Desonide DesOwen Ointment, 0.05% Desonide Synalar Cream/Solution, 0.01% Fluocinolone acetonide Diprosone Lotion, 0.05% Betamethasone dipropionate Tridesilon Cream, 0.05% Desonide Kenalog Lotion, 0.1% Triamcinolone acetonide Valisone Lotion, 0.1% Betamethasone valerate Locoid Cream, 0.1% Hydrocortisone Pandel Cream 0.1% Hydrocortisone Synalar Cream, 0.025% Fluocinolone acetonide Uticort Cream/Lotion, 0.025% Betamethasone benzoate Valisone Cream/Ointment, 0.1% Betamethasone valerate Westcort Cream, 0.2% Hydrocortisone valerate CLASS 7 - Least Potent Topicals with hydrocortisone, dexamethasone, methylprednisolone and prednisolone Reprinted with permission from Steroids [booklet]. Portland, OR: National Psoriasis Foundation; 2004: Vol. 4, No. 8 September 2004

6 PSORIASIS preparations were indicated for the treatment of scalp psoriasis; however, Connetics received approval to expand label claims for Olux to include the short-term topical treatment of mild to moderate plaque-type psoriasis of nonscalp regions, excluding the face and intertriginous areas. 23 The hope is that continued development will lead to increases in the benefit/risk ratio and provide safer treatment options for patients who require continuous therapy as well as for those with involvement of steroid-sensitive areas. 13 COAL TAR (DHS TAR, DOCTAR, THERAPLEX T ) Coal tar is inexpensive, relatively free of side effects, and safe for use on large body surfaces. It is an antipruritic and antibacterial that inhibits deregulated epidermal proliferation and dermal infiltration without causing injury to normal skin when applied widely. Coal tar (5% liquor carbonis detergens solution) has been shown to be more effective than vehicle emollient following 4 weeks of treatment by its generation of a 48% improvement in disease severity compared with a 35% improvement with emollient alone. 24 A comparative study against calcipotriol, however, suggests that coal tar (15% solution in aqueous cream) is less effective than calcipotriol after 6 weeks of treatment (Table 5). 25 Exorex (1% prepared coal tar) is a relatively new coal tar based, FDA-approved psoriasis medication deemed safe for use on sensitive skin. It contains 1% coal tar and a synthetic esterified essential fatty acid that resembles a component of banana skin, which purportedly has therapeutic benefit in the treatment of inflammatory skin diseases. 28 Although 2 singleblinded studies a small pilot study and a subsequent trial in a slightly larger cohort found Exorex to be similar in efficacy to calcipotriene, 28,29 a doubleblind analysis revealed that it was no more effective than traditional coal tar, which suggests that the added component is functionally inert (Table 5). 30 In the United States, coal tar has fallen out of favor because it is messy, has an unpleasant odor, and stains clothing and other fabrics. 10 Also, it can cause skin irritation that may lead to acneiform eruptions and folliculitis and has been, in rare cases, implicated in the development of skin cancer. 31 In current therapeutic regimens, tar preparations are most often used in shampoos for treatment of scalp psoriasis or as a sensitizing agent prior to phototherapy in the Goeckerman treatment. 2,32 CALCIPOTRIENE (DOVONEX ) Calcipotriene, known as calcipotriol or Dovonex, is a synthetic vitamin D analog that is an effective first- or second-line treatment for mild to moderate chronic plaque psoriasis. Like calcitriol, the biologically active form of vitamin D, calcipotriene is a potent regulator of cell differentiation and an inhibitor of proliferation in keratinocytes. The advantage of calcipotriene over calcitriol is that the adverse effects on calcium metabolism of the former are 100 to 200 times lesser than those of the latter. 33 Several double-blind studies have demonstrated the superiority of vitamin D analogs over placebo in the treatment of plaque psoriasis (Table 6). The vitamin s efficacy is comparable or slightly better than mid- to high-potency corticosteroids. 3,13 In one trial s evaluations, patient s treated with calcipotriol 50 µg/g had a 68% reduction in disease, while those treated Table 4. Corticosteroids in the Treatment of Psoriasis: Review of Clinical Studies Study Published Source Popul. (N) Study Description Kanof and Blau. 60 Double-blind comparison showed that halci- Cutis nonide 0.1% was effective in 80% of patients vs active corticosteroid control, which was effective in 65%. 26 Lynfield and Watsky. 59 Double-blind comparison showed that halci- Cutis nonide cream was significantly more effective than fluocinonide cream after 1 and 2 weeks of treatment with twice-daily application. 27 Katz et al. J Am 40 Randomized, double-blind comparison Acad Dermatol showed that both betamethasone dipropionate OV and clobetasol 17-propionate resulted in at least 75% improvement in 75% of patients. 18 Katz et al. Arch 38 Single-center pilot study: after 12 weeks, 74% Dermatol of patients who received intermittent pulse dosing with betamethasone OV (3 consecutive doses at 12-hour intervals once weekly) maintained remission compared to 21% of patients who received placebo. 20 Katz et al. 90 Multicenter, double-blind, placebo-controlled Dermatologica trial: after 6 months, remission was maintained in 60% of patients who received intermittent pulse dosing with augmented betamethasone dipropionate 0.05% vs 20% of patients who received placebo. 21 Alpsoy et al. J Am E=60 Randomized, placebo-controlled, double-blind Acad Dermatol A=42 study: after 6 weeks, patients who received moclobemide 450 mg/day + diflucortolone valerate had a 79% improvement in psoriasis vs 64% improvement in those who received placebo + diflucortolone valerate (P<0.025). 22 E = enrolled; A = assessed. Advanced Studies in Medicine 425

7 DERMATOLOGY with 0.1% betamethasone valerate (applied sufficiently to cover the lesions) had a 61% reduction. 3,36 Another study showed calcipotriene (ointment 0.005% twice a day) was significantly better than fluocinonide (ointment 0.05% twice a day). 37 In general, class I corticosteroids appear to be more efficacious in the short term than calcipotriene alone and one double-blind study has shown that a combination regimen of both calcipotriene ointment in the morning and halobetasol ointment in the evening was Table 5. Coal Tar in the Treatment of Psoriasis: Review of Clinical Studies Study Published Source Popul. (N) Study Description Kanzler and 18 Randomized, bilaterally controlled, double- Gorsulowsky. Br J blind trial: after 4 weeks, plaques treated with Dermatol % liquor carbonis detergens in an emollient base had a mean improvement of 48.7% versus 35.3% with the emollient base alone, a difference that was statistically significant. 24 Tham et al. Br E=30 Prospective, right/left randomized, investiga- J Dermatol A=27 tor-blinded controlled study: calcipotriol ointment 50 µg/g bid was applied to one half of the body and, to the other half, white soft paraffin was applied in the morning, and coal tar solution BP (benzo[a]pyrene) 15% solution in aqueous cream in the evening. After 6 weeks, the clinical improvement of psoriasis was statistically significant in favor of calcipotriol. 25 Veronikis et al. E=20 Single-blind, intrapatient comparison pilot Arch Dermatol A=15 study: 2 similar psoriatic lesions in each patient were treated with either 0.1 g of calcipotriene or 0.1 g Exorex bid for 2 months. No difference was observed in improvement of scaling, erythema, or plaque elevation. 28 Smith et al. Clin E=20 Double-blind, randomized, controlled trial: 4 Exp Dermatol A=19 similar target plaques were treated with Exorex or coal tar control (identical in composition to Exorex but without the esterified essential fatty acid) bid for 8 weeks. No difference was observed in cumulative score (based on erythema, induration, and desquamation), Psoriasis Area Severity Index score, and cosmetic acceptability of treatment. 30 Tzaneva et al. Br J E=40 Randomized, observer-blind, intrapatient com- Dermatol A=38 parison trial: in each patient 2 comparable target plaques were treated twice daily with 1% coal tar preparation or calcipotriol cream. There was no difference in mean reduction or psoriasis (P=0.77), time to resolution (P=0.76), or duration of remission (P=0.32); however, cosmetic acceptability was in favor of calcipotriol. 29 E = enrolled; A = assessed. significantly superior to twice-daily use of either agent exclusively. 38 A subsequent study showed that longterm maintenance with halobetasol ointment twice daily on weekends and calcipotriene twice daily on weekdays was superior to weekend therapy with halobetasol and placebo during the week (Table 6). 39 Calcipotriene ointment is colorless and, unlike coal tar, does not stain clothing. 3 The most common side effect is the development of an irritant contact dermatitis at the site of application. 33,37,39 The face and intertriginous areas are most susceptible to this effect, with up to 20% of patients developing local irritation after treatment of those sites. 13 Development of hypercalcemia has been reported after application of excessive amounts of calcipotriene 40 ; however, studies of numerous parameters of calcium metabolism have revealed that there are no clinically significant changes in patients who apply less than the maximum dose of 100 g per week. 41 Because vitamin D analogs are almost comparable to corticosteroids in efficacy without the associated side effects, they may be useful as adjuncts or alternatives in the design of long-term treatment regimens. 3,13 TAZORAC (TOPICAL TAZAROTENE) Tazarotene is a topical retinoid approved by the FDA in It effects normalization of abnormal keratinocyte differentiation, a reduction in keratinocyte proliferation, and a reduction in inflammation. Because it selectively binds retinoid receptor subtypes beta and gamma, it is associated with fewer side effects than are other retinoids. 8 It is available as a cream or a gel. In a randomized double-blind trial, tazarotene 0.1% and 0.05% gels were more effective than placebo when applied once daily for 12 weeks to the plaques of psoriasis. Furthermore, its therapeutic effects were sustained for an additional 12 weeks after the cessation of treatment. 42 In another trial, tazarotene gel applied once daily was as effective as the corticosteroid fluocinonide 0.05% cream applied twice daily. 43 The major side effect of tazarotene is local skin irritation, including pruritis, burning, and erythema, which occurs in a dose-related manner in up to 25% of patients. 44 Though the 0.1% formulation is more effective than the 0.05%, it is also associated with a greater incidence and severity of irritation. 8 For the purpose of preventing retinoid dermatitis, regimens that combine tazarotene with topical corticosteroids have been studied. 13 Concomitant use of mometasone furoate 0.1% cream (class IV) or fluocinonide 0.05% cream (class II) with tazarotene 0.1% gel applied once daily enhanced improvement and diminished local cutaneous irritation compared to topical tazarotene used alone Vol. 4, No. 8 September 2004

8 PSORIASIS In a study that focused on long-term therapy, a regimen of tazarotene gel 0.1% applied Mondays, Wednesdays, and Fridays and clobetasol ointment applied Tuesdays and Thursdays maintained remission in approximately 75% of patients for at least 5 months. 46 In addition, tazarotene has been shown to counteract the atrophogenic tendencies of corticosteroids. Compared with corticosteroid alone, concomitant application of tazarotene resulted in a statistically and clinically significant reduction in epidermal thinning. 47 Such adjunctive use of tazarotene not only facilitates the long-term control of psoriasis but helps to minimize cumulative corticosteroid exposure and associated adverse effects. 48 The nonsteroidal combination of calcipotriene and tazarotene, while chemically compatible, offers no statistically significant benefit over monotherapy with the corticosteroid clobetasol. 49 ANTHRALIN Anthralin, or dithranol, slows cellular proliferation, decreases inflammation, and increases cellular differentiation in psoriasis. 8 Since the introduction of vitamin D analogs, use of anthralin has declined, mainly because of its propensity to cause perilesional irritation and stain skin and clothing. 10 Historically, anthralin has been used according to the Ingram regimen, which consists of a daily coal tar bath, ultraviolet B phototherapy, and the 24-hour application of an anthralin paste that contains salicylic acid to prevent oxidation of anthralin to inactive compounds. 3,50 Current usage patterns of anthralin include short contact regimens and novel, more acceptable formulations. Short contact regimens, in which higher concentrations of anthralin are applied for a shorter period, are more efficacious, cause less staining, and are more convenient for patients than longer applications of lower concentrations. 53 In a modern version of this regimen, anthralin (1% or greater) is applied for 5 minutes on the first day and then increased by 5 minutes every other day until minimal irritation develops. Thereafter, the period of application is maintained until clearing. Staining of the skin can be minimized by application of triethanolamine before removal of the anthralin. 7,13 Micanol is a 1% anthralin formulation in a temperature-sensitive vehicle so that active medication is only released at skin surface temperature. While staining of skin can still occur, it is more acceptable to patients because staining of household fabrics and furniture is minimized. In a 6-week, randomized, open, parallel-group study of 49 patients with psoriasis, Micanol was shown to be effective in both long and short contact regimens, reducing Psoriasis Area Severity Index scores by 78% in the long contact group and by 73% in the short. 54 It has also been particularly useful for refractory scalp psoriasis. 13 CONCLUSION Despite the wide range of treatment options, there is currently no cure for psoriasis. Topical therapies possess the fewest side effects and are successful in treating most patients with limited disease. Nevertheless, for those who have widespread involvement, disabling disease, or who do not respond to the existing topical agents, more aggressive treatment is required. Table 6.Vitamin D Analogs in the Treatment of Psoriasis Study Published Source Popul. (N) Study Description Kragballe et al. 15 Open study: after 6 months of calcipotriol oint- Acta Derm Venereol. ment 50 µg/g qd, 80% of patients showed moderate improvement. 51 Kragballe et al. 345 Multicenter, prospective, randomized, double- Lancet blind, right/left trial: mean reduction in psoriasis was 68% with calcipotriol (50 µg/g) vs 61% with 0.1% betamethasone valerate ointment. 52 Dubertret et al. 566 Double-blind, right/left comparison: after 4 weeks, J Am Acad patients treated with calcipotriol (50 µg/g bid) Dermatol had 50% greater improvement of psoriasis. 33 Bruce et al. J Am 99 Randomized, multicenter, double-blind, parallel- Acad Dermatol group, active-controlled trial: calcipotriene (ointment 0.005% bid) was significantly better than fluocinonide (ointment 0.05% bid). 37 Highton and Quell. E=227 Double-blind, multicenter, placebo-controlled J Am Acad Dermatol. A=247 trial: after 8 weeks patients treated with cal cipotriene showed 75% improvement in plaque elevation, erythema, scaling, and overall disease severity compared with 19% of vehicletreated patients. 35 Perez et al. Br J 84 Double-blind, placebo-controlled, right/left com- Dermatol parison: after 2.4 months, 96.5% responded to topical calcitriol therapy (1.5 µg qd) compared with 15.5% with petroleum jelly alone. 34 Lebwohl et al. 44 Double-blind, multicenter trial: after 2 weeks, a J Am Acad regimen of calcipotriene ointment applied in the Dermatol morning and halobetasol ointment applied in the evening was superior to monotherapy with either halobetasol or calcipotriene bid. 38 Lebwohl et al. E=44 Double-blind, placebo-controlled, parallel group J Am Acad A=40 study: remission (at least 75% improvement) at Dermatol months was maintained in 76% of patients given calcipotriene 0.005% bid on weekdays and halobetasol 0.05% bid on weekends compared to 40% in the placebo-halobetasol group (P=0.045). 39 E = enrolled; A = assessed. Advanced Studies in Medicine 427

9 DERMATOLOGY REFERENCES 1. Fitzpatrick TB, Johnson R, Wolff K, et al. Color Atlas and Synopsis of Clinical Dermatology. 4th ed. Boston: McGraw- Hill; Lui H, Mamelak A. Psoriasis, plaque. Emedicine Web site. Psoriasis, plaque Available at: com/derm/ topic365.htm. Accessed July 25, Greaves MW, Weinstein GD. Treatment of psoriasis. N Engl J Med. 1995;332: Swerlick R, Lawley T. Eczema, psoriasis, cutaneous infections, acne, and other common skin disorders. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 15th ed. New York: McGraw-Hill. 2001: Bowcock AM, Barker JN. Genetics of psoriasis: the potential impact on new therapies. J Am Acad Dermatol. 2003;49(suppl 2):S51-S Shelley WB, Shelley ED. Psoriasis. In: Advanced Dermatologic Therapy II. 2nd ed. Toledo, OH: WB Saunders; 2001: Lebwohl M. Psoriasis. In: Lebwohl MG, Heymann W, Berth- Jones J, et al, eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. New York: Mosby International; 2002: Peters BP, Weissmann FG, Gill MA. Pathophysiology and treatment of psoriasis. Am J Health Syst Pharm. 2000; 57: Stern RS. Psoriasis. Lancet. 1997;350: Linden KG, Weinstein GD. Psoriasis: current perspectives with an emphasis on treatment. Am J Med. 1999;107: Koo J, Cuffie CA, Tanner DJ, et al. Mometasone furoate 0.1%-salicylic acid 5% ointment versus mometasone furoate 0.1% ointment in the treatment of moderate-to-severe psoriasis: a multicenter study. Clin Ther. 1999;20: Lebwohl M. The role of salicylic acid in the treatment of psoriasis. Int J Dermatol. 1999;38: Lebwohl M, Ali M. Treatment of psoriasis. Part 1. Topical therapy and phototherapy. J Am Acad Dermatol. 2001;45: Liem WH, McCullough JL, Weinstein GD. Effectiveness of topical therapy for psoriasis: results of a national survey. Cutis. 1995;55: Katz HI. Topical corticosteroids. Dermatol Clin. 1995; 13: Cornell RC, Stoughton RB. Correlation of the vasoconstriction assay and clinical activity in psoriasis. Arch Dermatol. 1985;121: Lebwohl M, Abel E, Zanolli M, et al. Topical therapy for psoriasis. Int J Dermatol. 1995;34: Katz HI, Hien NT, Prawer SE, et al. Superpotent topical steroid treatment of psoriasis vulgaris: clinical efficacy and adrenal function. J Am Acad Dermatol. 1987;16: du Vivier A, Stoughton RB. Tachyphylaxis to the action of topically applied corticosteroids. Arch Dermatol. 1975; 111: Katz HI, Hien NT, Prawer SE, et al. Betamethasone dipropionate in optimized vehicle. Intermittent pulse dosing for extended maintenance treatment of psoriasis. Arch Dermatol. 1987;123: Katz HI, Prawer SE, Medansky RS, et al. Intermittent corticosteroid treatment of psoriasis: a double-blind multicenter trial of augmented betamethasone dipropionate ointment in a pulse dose treatment regimen. Dermatologica. 1991;183: Alpsoy E, Ozcan E, Cetin L, et al. Is the efficacy of topical corticosteroid therapy for psoriasis vulgaris enhanced by concurrent moclobemide therapy? A double-blind, placebo-controlled study. J Am Acad Dermatol. 1998;38(2, pt 1): Connetics Corporation. Products and Pipeline: Olux. Available at: Accessed June 1, Kanzler MH, Gorsulowsky DC. Efficacy of topical 5% liquor carbonis detergens vs. its emollient base in the treatment of psoriasis. Br J Dermatol. 1993;129: Tham SN, Lun KC, Cheong WK. A comparative study of calcipotriol ointment and tar in chronic plaque psoriasis. Br J Dermatol. 1994;131: Kanof NB, Blau S. Psoriasis: treatment with a new topical corticosteroid. Cutis. 1976;17: Lynfield Y, Watsky M. Psoriasis: topical corticosteroid therapy. Cutis. 1976;18:133, Veronikis IE, Malabanan AO, Holick MF. Comparison of calcipotriene (Dovonex) with a coal tar emulsion (Exorex) in treating psoriasis in adults: a pilot study. Arch Dermatol. 1999;135: Tzaneva S, Honigsmann H, Tanew A. Observer blind, randomized, intrapatient comparison of a novel 1% coal tar preparation (Exorex) and calcipotriol cream in the treatment of plaque type psoriasis. Br J Dermatol. 2003;149: Smith CH, Jackson K, Chinn S, et al. A double blind, randomized, controlled clinical trial to assess the efficacy of a new coal tar preparation (Exorex) in the treatment of chronic, plaque type psoriasis. Clin Exp Dermatol. 2000; 25: Pittelkow MR, Perry HO, Muller SA, et al. Skin cancer in patients with psoriasis treated with coal tar. A 25-year follow-up study. Arch Dermatol. 1981;117: Perry HO, Soderstrom CW, Schulze RW. The Goeckerman treatment of psoriasis. Arch Dermatol. 1968;98: Dubertret L, Wallach D, Souteyrand P, et al. Efficacy and safety of calcipotriol (MC 903) ointment in psoriasis vulgaris. A randomized, double-blind, right/left comparative, vehicle-controlled study. J Am Acad Dermatol. 1992;27(6, pt 1): Perez A, Chen TC, Turner A, et al. Efficacy and safety of topical calcitriol (1,25-dihydroxy vitamin D3) for the treatment of psoriasis. Br J Dermatol. 1996;134: Highton A, Quell J. Calcipotriene ointment 0.005% for psoriasis: a safety and efficacy study. Calcipotriene Study Group. J Am Acad Dermatol. 1995;32: Kragballe K, Fogh K, Soggard H. Long-term efficacy and tolerability of topical calcipotriol in psoriasis. Results of an open study. Acta Derm Venereol. 1991;71: Bruce S, Epinette WW, Funicella T, et al. Comparative study of calcipotriene (MC 903) ointment and fluocinonide ointment in the treatment of psoriasis. J Am Acad Dermatol. 1994;31(5, pt 1): Lebwohl M, Siskin SB, Epinette W, et al. A multicenter trial of calcipotriene ointment and halobetasol ointment compared with either agent alone for the treatment of psoriasis. J Am Acad Dermatol. 1996;35(2, pt 1): Lebwohl M, Yoles A, Lombardi K, et al. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol. 1998;39: Georgiou S, Tsambaos D. Hypercalcaemia and hypercalciuria after topical treatment of psoriasis with excessive amounts of calcipotriol. Acta Derm Venereol. 1999;79: Mortensen L, Kragballe K, Wegmann E, et al. Treatment of psoriasis vulgaris with topical calcipotriol has no short-term effect on calcium or bone metabolism: a randomized, double-blind, placebo-controlled study. Acta Derm Venereol. 1993;73: Weinstein GD, Krueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: vehicle-controlled study of safety, efficacy, and duration of therapeutic effect. J Am Acad Dermatol. 1997;37: Lebwohl M, Ast E, Callen JP, et al. Once-daily tazarotene gel versus twice-daily fluocinide cream in the treatment of 428 Vol. 4, No. 8 September 2004

10 PSORIASIS plaque psoriasis. J Am Acad Dermatol. 1998;38 (5, pt 1): Marks R. Clinical safety of tazarotene in the treatment of plaque psoriasis. J Am Acad Dermatol. 1997;37(2, pt 3):S25-S Lebwohl MG, Breneman DL, Goffe BS, et al. Tazarotene 0.1% gel plus corticosteroid cream in the treatment of plaque psoriasis. J Am Acad Dermatol. 1998;39(4, pt 1): Lebwohl M, Lombardi K, Tan MH. Duration of improvement in psoriasis after treatment with tazarotene 0.1% gel plus clobetasol propionate 0.05% ointment: comparison of maintenance treatments. Int J Dermatol. 2001;40: Kaidbey K, Kopper SC, Sefton J, et al. A pilot study to determine the effect of tazarotene gel 0.1% on steroid-induced epidermal atrophy. Int J Dermatol. 2001;40: Lebwohl M. Strategies to optimize efficacy, duration of remission, and safety in the treatment of plaque psoriasis by using tazarotene in combination with a corticosteroid. J Am Acad Dermatol. 2000;43(2, pt 3):S43-S Bowman PH, Maloney JE, Koo JY. Combination of calcipotriene (Dovonex) ointment and tazarotene (Tazorac) gel versus clobetasol ointment in the treatment of plaque psoriasis: a pilot study. J Am Acad Dermatol. 2002;46: Ingram JT. The approach to psoriasis. Br Med J. 1953; 4836: Kragballe K, Fogh K, Sogaard H. Long-term efficacy and tolerability of topical calcipotriol in psoriasis. Results of an open study. Acta Derm Venereol. 1991;71: Kragballe K, Gjertsen BT, De Hoop D, et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris [correction published in Lancet. 1991;337:988]. Lancet. 1991;337: Runne U, Kunze J. Short duration ('minutes') therapy with dithranol for psoriasis: a new out-patient regimen. Br J Dermatol. 1982;106: Thune P, Brolund L. Short- and long-contact therapy using a new dithranol formulation in individually adjusted dosages in the management of psoriasis. Acta Derm Venereol Suppl (Stockh). 1992;172: Advanced Studies in Medicine 429