**3. Topical antipsoriatic medications**

#### **3.1 Corticosteroids**

Topical corticosteroids, particularly high-potency corticosteroids, have been a mainstay in the topical treatment of psoriasis for decades (Bagel 2009). Their efficacy may be attributed to multiple mechanisms of action, including their anti-inflammatory, immunosuppressive and antiproliferative effects. Topical corticosteroids are often classified into seven classes in United States and four in UK and Germany based on potency. A detailed classification system has been discussed else where (Horn et al., 2010). In the United States, topical corticosteroids are classified as following: class I (superpotent), class II (potent), class III (upper mid strength), class IV (mid strength), class V (lower mid strength), class VI (mild) and class VII (least potent). Typically corticosteroids of lower potency are mainly used on the face and groin, and in infants and children. Mid-potency corticosteroids are typically used as initial therapy on all other areas in adults. Potent and superpotent corticosteroids are often used for stubborn, cutaneous plaques or lesions on the scalp, extremities, including palms, and/or soles as well as for initial therapy to achieve quick resolution of lesions. In this section detailed discussion of a few representative steroids are provided, however there are several other corticosteroids which are effective against psoriasis topically. Some steroids which are widely used in topical psoriasis treatment but have not been discussed in this section include, methylprednisolone aceponate (Ruzicka 2006), which has shown good efficacy against chronic therapy-resistant psoriasis, including both progressive and stationary phases. Although topical corticosteroids are effective in maintenance of the disease, these therapies can cause many potential local adverse effects including cutaneous atrophy, formation of telangiectasia, development of striae, steroid rosacea, perioral dermatitis, and skin infections (Horn et al., 2010). Risks of systemic adverse effects increase with prolonged use, or use of higher potency steroids, particularly with greater percent of BSA to which the topical steroid drug is applied. These risks include metabolic disturbances such as hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing like syndrome, osteonecrosis of the hip and immunosuppression are other rare but possible serious adverse events. Tachyphylaxis or tolerance often occurs with prolonged use, leading to less durable potency or lower effectiveness of topical steroids. Therefore, several strategies have been proposed to improve safety for long-term use of topical corticosteroids (Horn et al., 2010) such as, 1) using rotational treatment regimens that minimize side effects, 2) combination with other topical medications, 3) following package inserts on the maximum usage per week, and 4) caution when using in vulnerable body areas (such as face) and in children.

#### **3.1.1 Clobetasol**

Clobetasol propionate is a super high-potency glucocorticosteroid, initially approved for treatment of steroid-responsive dermatosis. Clobetasol propionate is traditionally formulated in an ointment base for treatment of psoriasis. However, several novel formulation of clobetasol propionate are now available such as spray, foam, lotion, and shampoo formulations, which may provide for improved convenience and acceptance in many patients with similar efficacy, safety, and tolerability as the traditional ointment and cream formulations (Feldman and Yentzer, 2009). While there are very few direct clinical comparison studies between clobetasol propionate in different vehicles, the efficacy rates of obtaining clear or almost clear of psoriasis are high for the novel formulations with most

Topical corticosteroids, particularly high-potency corticosteroids, have been a mainstay in the topical treatment of psoriasis for decades (Bagel 2009). Their efficacy may be attributed to multiple mechanisms of action, including their anti-inflammatory, immunosuppressive and antiproliferative effects. Topical corticosteroids are often classified into seven classes in United States and four in UK and Germany based on potency. A detailed classification system has been discussed else where (Horn et al., 2010). In the United States, topical corticosteroids are classified as following: class I (superpotent), class II (potent), class III (upper mid strength), class IV (mid strength), class V (lower mid strength), class VI (mild) and class VII (least potent). Typically corticosteroids of lower potency are mainly used on the face and groin, and in infants and children. Mid-potency corticosteroids are typically used as initial therapy on all other areas in adults. Potent and superpotent corticosteroids are often used for stubborn, cutaneous plaques or lesions on the scalp, extremities, including palms, and/or soles as well as for initial therapy to achieve quick resolution of lesions. In this section detailed discussion of a few representative steroids are provided, however there are several other corticosteroids which are effective against psoriasis topically. Some steroids which are widely used in topical psoriasis treatment but have not been discussed in this section include, methylprednisolone aceponate (Ruzicka 2006), which has shown good efficacy against chronic therapy-resistant psoriasis, including both progressive and stationary phases. Although topical corticosteroids are effective in maintenance of the disease, these therapies can cause many potential local adverse effects including cutaneous atrophy, formation of telangiectasia, development of striae, steroid rosacea, perioral dermatitis, and skin infections (Horn et al., 2010). Risks of systemic adverse effects increase with prolonged use, or use of higher potency steroids, particularly with greater percent of BSA to which the topical steroid drug is applied. These risks include metabolic disturbances such as hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing like syndrome, osteonecrosis of the hip and immunosuppression are other rare but possible serious adverse events. Tachyphylaxis or tolerance often occurs with prolonged use, leading to less durable potency or lower effectiveness of topical steroids. Therefore, several strategies have been proposed to improve safety for long-term use of topical corticosteroids (Horn et al., 2010) such as, 1) using rotational treatment regimens that minimize side effects, 2) combination with other topical medications, 3) following package inserts on the maximum usage per week, and 4) caution when using in vulnerable body areas (such as face) and in children.

Clobetasol propionate is a super high-potency glucocorticosteroid, initially approved for treatment of steroid-responsive dermatosis. Clobetasol propionate is traditionally formulated in an ointment base for treatment of psoriasis. However, several novel formulation of clobetasol propionate are now available such as spray, foam, lotion, and shampoo formulations, which may provide for improved convenience and acceptance in many patients with similar efficacy, safety, and tolerability as the traditional ointment and cream formulations (Feldman and Yentzer, 2009). While there are very few direct clinical comparison studies between clobetasol propionate in different vehicles, the efficacy rates of obtaining clear or almost clear of psoriasis are high for the novel formulations with most

**3. Topical antipsoriatic medications** 

**3.1 Corticosteroids** 

**3.1.1 Clobetasol** 

patients achieving success after 2-4 weeks of treatment in well controlled clinical trials, but the response rates are similar for all presentations. Small differences in vasoconstrictor potency or cutaneous absorption have been noted among the formulations, but the clinical significance of these observations is difficult to discern.

The development of a foam formulation of clobetasol propionate 0.05% (e.g. Olux®) provides an effective and cosmetically appealing treatment option for patients with plaquetype psoriasis because it spreads easily and is cosmetically elegant. Olux is based on VersaFoam® platform, a thermolabile and low-residue foam. A randomised, placebocontrolled, double-blinded study of 279 patients aged 18 years or older with mild-tomoderate plaque-type psoriasis demonstrated the efficacy and tolerability of clobetasol propionate foam (Gottlied et al., 2003). After 2 weeks of twice-daily applications of clobetasol propionate foam versus vehicle foam, 68% of patients in the active treatment arm were clear of lesions versus 21% of patients receiving placebo. The treatment was well tolerated with 5% of patients receiving clobetasol propionate foam and 7% of those receiving placebo reported burning at the site of application. Although the efficacy of the clobetasol propionate foam can partially be attributed to patient adherence, the foam also delivers the active drug more efficiently than other formulations that have been compared. This may be due to the easier spread of foam onto the skin. In *in vitro* skin penetration studies, application of foam to donor skin resulted in higher drug accumulation and increased rate of permeation into skin layers (Huang et al., 2005).

A study comparing two novel formulations containing 0.05% clobetasol propionate, Clobex® spray and Olux® foam clearly highlighted the difference in efficacy from two products containing the same active ingredient (Mraz et al., 2008). In a study of 77 randomized patients aged 18 years or older with moderate to severe plaque psoriasis the products were applied as per the product labeling. At the end of the treatment period (2 weeks for foam and 4 weeks for spray), patients treated with clobetasol propionate spray showed a significantly greater median reduction in affected body surface area compared to the clobetasol propionate foam. Improvements in quality of life were statistically significantly greater at all time points for patients treated with clobetasol propionate spray compared to patients treated with the foam formulation. The majority of adverse events for both products were mild in severity (Mraz et al., 2008).

Clobex® shampoo containing 0.05% clobetasol propionate is a once-daily, short-contact, shampoo treatment for moderate-to-severe scalp psoriasis (Feldman & Yentzer, 2009). The efficacy and safety of clobetasol propionate 0.05% shampoo was evaluated in a randomized, double-blind, vehicle-controlled clinical trial of 142 patients aged 12 years and older with moderate-to-severe scalp psoriasis (Jarratt et al., 2004). Patients applied clobetasol propionate shampoo or vehicle shampoo once daily for 15 minutes for four weeks. Treatment success (defined as a global psoriasis rating of "clear" or "minimal") was obtained for 42% of patients who used clobetasol propionate shampoo versus 2% of patients who used vehicle shampoo. Recurrence of the scalp psoriasis, assessed during a two week follow-up period, showed that the clobetasol propionate shampoo was more effective than the vehicle shampoo in preventing recurrence after treatment was discontinued. Similar safety profile was established between the clobetasol propionate shampoo and vehicle shampoo. No skin atrophy, telangiectasia, acne or severe adverse events were noted for either treatment group (Jarratt et al., 2004).

Topical Therapies for Psoriasis 315

et al., 2009). Betamethasone dipropionate is commonly formulated as a gel. Several attempts have been made to increased betamethasone dipropionate skin permeation by encapsulating in liposomes. The liposomal formulations achieved improved corticosteroid dermal delivery (Fresta & Puglisi 1997). However, in a double blind randomized trial comparing a liposomal formulation containing 0.039% betamethasone dipropionate against the gel containing 0.064% betamethasone dipropionate, showed that the gel was more effective in reducing psoriatic plaques than the liposome after application for 14 days (Korting et al., 1990). Hence, liposome encapsulation of betamethasone dipropionate may increase the anti-

Betamethasone valerate (BMV) is also available as a foam formulation (Luxiq®) containing 0.12% betamethasone valerate for use as a treatment for psoriasis affecting the scalp (Feldman et al., 2001) and non-scalp (Stein et al., 2001) regions of the body. Betamethasone valerate foam formulated in a thermolabile hydroethanolic foam vehicle is absorbed more rapidly, and demonstrated 2-fold greater skin penetration in a human cadaver skin model, than the betamethasone valerate lotion (Franz et al., 1999). Safety and efficacy of the betamethasone valerate foam was evaluated in a randomized, multicenter, double-blind, active- and placebo-controlled trial in adult patients with moderate to severe scalp psoriasis (Franz et al., 1999). At the end of 28-days of treatment, patients on betamethasone valerate foam showed significantly better clearing of plaques than those on betamethasone valerate lotion and placebo. Further, there was no evidence of increased toxicity for betamethasone

Halobetasol propionate (HP) is a high potency corticosteroid available as 0.05% ointment and cream (Rivera & Hsu 2005). Halobetasol is a synthetic trihalogenated corticosteroid structurally similar to clobetasol propionate but with an additional fluorine atom (Rivera &

The efficacy and safety of 0.05% halobetasol ointment (Ultravate) in the treatment of patients aged 18 years or older with moderate plaque psoriasis was demonstrated in two multicenter, randomized, double-blind, and placebo controlled studies in 204 patients (Bernhard et al., 1991). In both studies the medication and placebo were applied twice daily for 2 weeks. At the end of the treatment period, 0.05% halobetasol ointment was found to be more effective over placebo. No systemic adverse events or findings of skin atrophy were reported in these studies. Reports of "stings" or "burns" were equally divided between halobetasol formulation and its vehicle. These two studies demonstrated that 0.05% halobetasol ointment was clinically beneficial and without evidence of significant adverse

Three clinical studies separately compared the 0.05% halobetasol propionate ointment to 0.05% clobetasol propionate ointment (Goldberg et al., 1991), 0.05% betamethasone dipropionate (BDP) ointment (Mensing et al., 1991) and 0.1% betamethasone valerate (BMV) ointment (Blum & Yawalkar 1991) in plaque psoriasis. The efficacy of the halobetasol propionate ointment was significantly superior to those of the other products in these studies. Neither skin atrophy nor systemic adverse effects were observed for halobetasol propionate during 4 weeks. However, because of the risks associated with prolonged use reported in upto

inflammatory action but not the antiproliferative effect.

valerate foam (Franz et al., 1999).

events during the treatment period.

**3.1.4 Halobetasol** 

Hsu 2005).

### **3.1.2 Mometasone**

Mometasone furoate (Elocon® cream) is a potent synthetic glucocorticoid, which is commonly used in dermatological conditions (Prakash & Benfield 1998). It is available as cream, ointment and lotion formulations for the treatment of patients with atopic dermatitis, seborrhoeic dermatitis, scalp psoriasis and psoriasis vulgaris. Although mometasone demonstrates greater anti-inflammatory activity and a longer duration of action than betamethasone, it has low potential to cause adverse systemic effects such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Moreover, its atrophogenic potential is low and no greater than that of other glucocorticoids in its class, such as betamethasone valerate. Transient, mild to moderate, local adverse effects such as burning, stinging, folliculitis, dryness, acneiform eruptions and signs of skin atrophy have been reported with mometasone. Mometasone has shown a low risk of primary sensitization and crossreactions in preliminary patch test studies.

In clinical studies with patients aged between 12 and 90 years, with moderate to severe scalp psoriasis (Swinehart et al., 1989; Vanderploeg et al., 1989) or psoriasis vulgaris (Bressinck et al., 1988; Svensson et al., 1992), who had not used topical glucocorticoids for 2 weeks or taken systemic glucocorticoids for 6 weeks prior to enrolment showed that in general, mometasone (0.1% lotion, ointment or cream applied once or twice daily) was significantly superior to topical glucocorticoid preparations of similar and weaker potency. The ointment formulation of mometasone was significantly superior to once-daily hydrocortisone 1.0% ointment (Bressinck et al., 1988; Katz et al., 1989), twice-daily betamethasone valerate 0.1% ointment (Svensson et al., 1992; Medansky et al., 1987), triamcinolone acetonide 0.1% ointment (Medansky et al., 1988), and 3 times daily fluocinolone acetonide 0.025% ointment (Medansky et al., 1988).

The effectiveness of alternate-day treatment with mometasone 0.1% ointment in maintenance therapy of psoriasis vulgaris was evaluated in a randomized, double-blind, 3 week study in 48 adult patients with moderate psoriasis vulgaris. After 1 week (n = 48) of once-daily application of mometasone 0.1% ointment, patients either continued with daily application (n = 25) or applied mometasone 0.1% ointment on alternate days (n =19) for 2 weeks. At the end of the study period both regimens were effective in treating disease signs and symptoms with no detectable difference between the treatment groups (Prakash & Benfield 1998).

In patients with scalp psoriasis, the effects of mometasone lotion were significantly superior to those of twice-daily application of betamethasone valerate 0.1% lotion or triamcinolone acetonide 0.1% lotion (Swinehart et al., 1989; Vanderploeg et al., 1989).

A study in 24 patients with moderate to severe psoriasis evaluated the response to mometasone 0.1% ointment applied once daily on the face and intertriginous areas and other affected body areas (Lebwohl et al., 1993) After 2 weeks, the face and intertriginous areas showed a quicker and significantly superior response to treatment as compared with other body areas (Lebwohl et al., 1993).

#### **3.1.3 Betamethasone**

Betamethasone dipropionate (BDP, Diprolene®) is a mid-potency synthetic fluorinated corticosteroid and is commonly used in combination with vitamin D3 analogues (Saraceno

Mometasone furoate (Elocon® cream) is a potent synthetic glucocorticoid, which is commonly used in dermatological conditions (Prakash & Benfield 1998). It is available as cream, ointment and lotion formulations for the treatment of patients with atopic dermatitis, seborrhoeic dermatitis, scalp psoriasis and psoriasis vulgaris. Although mometasone demonstrates greater anti-inflammatory activity and a longer duration of action than betamethasone, it has low potential to cause adverse systemic effects such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Moreover, its atrophogenic potential is low and no greater than that of other glucocorticoids in its class, such as betamethasone valerate. Transient, mild to moderate, local adverse effects such as burning, stinging, folliculitis, dryness, acneiform eruptions and signs of skin atrophy have been reported with mometasone. Mometasone has shown a low risk of primary sensitization and cross-

In clinical studies with patients aged between 12 and 90 years, with moderate to severe scalp psoriasis (Swinehart et al., 1989; Vanderploeg et al., 1989) or psoriasis vulgaris (Bressinck et al., 1988; Svensson et al., 1992), who had not used topical glucocorticoids for 2 weeks or taken systemic glucocorticoids for 6 weeks prior to enrolment showed that in general, mometasone (0.1% lotion, ointment or cream applied once or twice daily) was significantly superior to topical glucocorticoid preparations of similar and weaker potency. The ointment formulation of mometasone was significantly superior to once-daily hydrocortisone 1.0% ointment (Bressinck et al., 1988; Katz et al., 1989), twice-daily betamethasone valerate 0.1% ointment (Svensson et al., 1992; Medansky et al., 1987), triamcinolone acetonide 0.1% ointment (Medansky et al., 1988), and 3 times daily fluocinolone acetonide 0.025% ointment

The effectiveness of alternate-day treatment with mometasone 0.1% ointment in maintenance therapy of psoriasis vulgaris was evaluated in a randomized, double-blind, 3 week study in 48 adult patients with moderate psoriasis vulgaris. After 1 week (n = 48) of once-daily application of mometasone 0.1% ointment, patients either continued with daily application (n = 25) or applied mometasone 0.1% ointment on alternate days (n =19) for 2 weeks. At the end of the study period both regimens were effective in treating disease signs and symptoms with no detectable difference between the treatment groups (Prakash &

In patients with scalp psoriasis, the effects of mometasone lotion were significantly superior to those of twice-daily application of betamethasone valerate 0.1% lotion or triamcinolone

A study in 24 patients with moderate to severe psoriasis evaluated the response to mometasone 0.1% ointment applied once daily on the face and intertriginous areas and other affected body areas (Lebwohl et al., 1993) After 2 weeks, the face and intertriginous areas showed a quicker and significantly superior response to treatment as compared with

Betamethasone dipropionate (BDP, Diprolene®) is a mid-potency synthetic fluorinated corticosteroid and is commonly used in combination with vitamin D3 analogues (Saraceno

acetonide 0.1% lotion (Swinehart et al., 1989; Vanderploeg et al., 1989).

**3.1.2 Mometasone** 

(Medansky et al., 1988).

Benfield 1998).

other body areas (Lebwohl et al., 1993).

**3.1.3 Betamethasone** 

reactions in preliminary patch test studies.

et al., 2009). Betamethasone dipropionate is commonly formulated as a gel. Several attempts have been made to increased betamethasone dipropionate skin permeation by encapsulating in liposomes. The liposomal formulations achieved improved corticosteroid dermal delivery (Fresta & Puglisi 1997). However, in a double blind randomized trial comparing a liposomal formulation containing 0.039% betamethasone dipropionate against the gel containing 0.064% betamethasone dipropionate, showed that the gel was more effective in reducing psoriatic plaques than the liposome after application for 14 days (Korting et al., 1990). Hence, liposome encapsulation of betamethasone dipropionate may increase the antiinflammatory action but not the antiproliferative effect.

Betamethasone valerate (BMV) is also available as a foam formulation (Luxiq®) containing 0.12% betamethasone valerate for use as a treatment for psoriasis affecting the scalp (Feldman et al., 2001) and non-scalp (Stein et al., 2001) regions of the body. Betamethasone valerate foam formulated in a thermolabile hydroethanolic foam vehicle is absorbed more rapidly, and demonstrated 2-fold greater skin penetration in a human cadaver skin model, than the betamethasone valerate lotion (Franz et al., 1999). Safety and efficacy of the betamethasone valerate foam was evaluated in a randomized, multicenter, double-blind, active- and placebo-controlled trial in adult patients with moderate to severe scalp psoriasis (Franz et al., 1999). At the end of 28-days of treatment, patients on betamethasone valerate foam showed significantly better clearing of plaques than those on betamethasone valerate lotion and placebo. Further, there was no evidence of increased toxicity for betamethasone valerate foam (Franz et al., 1999).
