**3.1.4 Halobetasol**

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 & Hsu 2005).

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 events during the treatment period.

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

Topical Therapies for Psoriasis 317

A calcitriol ointment (Vectical) for mild-to-moderate plaque psoriasis was approved by the US Food and Drug Administration (FDA) in 2009 (Kowalzick 2009). Multicenter and randomized clinical trials have shown calcitriol ointment to be efficacious, safe and cosmetically acceptable as compared to placebo and other topical psoriasis therapies (Kircik 2009). Pharmacokinetic studies in patients with psoriasis and healthy control subjects have demonstrated that topical calcitriol ointment produced minimal systemic absorption of calcitriol and does not alter systemic calcium homeostasis significantly even when applied to approximately one third of the body surface area (Kircik 2009). However, the Vectical prescribing information limits the use to 200 gm per week due to concern of disturbance in calcium metabolism. The efficacy and safety of topical calcitriol ointment were examined in two placebo-controlled, randomized, multicenter, parallel-group double blind clinical trials of identical design in a total of 839 patients aged 18 years or older with mild-to-moderate plaque psoriasis (Lebwohl et al., 2007). Both studies showed that at the end of the treatment period, the patients in the calcitriol group showed significantly better clearing of psoriatic plaques than those in the vehicle group. The incidence of treatment related adverse events such as mild skin discomfort, pruritus, and erythema was similar for the calcitriol and the

Retinoids provide a distinct class of treatment option within antipsoriatic therapies, which are largely dominated by immunomodulatory effects. The mechanism of action of retinoids in psoriasis may include direct suppression of inflammation as well as inhibition of proliferation and normalization of differentiation in the epidermal layer (van de Kerkhof 2006). In the US topical retinoid for psoriasis is approved as tazarotene gel and cream (Tazorac) available in 0.05% and 0.1% formulations. It is recommended that treatment commences with the 0.05% formulation, and the concentration increased if necessary and tolerated. Tazarotene is applied once daily in the evening. All formulations and strengths can be used for plaque psoriasis. In general, gels and the more-concentrated strengths tend to have higher incidences of irritation, pruritus, erythema, stinging and desquamation (Yamauchi et al., 2004). The cream formulations are being marketed as less irritating (Linden & Weinstein 1999). A recent improvement in tazarotene therapy was a reduction of skin irritation by short contact applications or concurrent steroid use (Veraldi & Schianchi 2003). These side effects are most apparent on initial application, but are generally alleviated with continued usage. Tazarotene is contraindicated in pregnant women and in women who are not taking adequate birth control in view of its teratogenic potential, category X pregnancy status. In addition, tazarotene use should be avoided in nursing women, and patients who have substantial sun exposure, who do not use adequate sun protection and who use

The efficacy of once-daily topical tazarotene has been studied in four randomized, double or single blinded clinical trials; two trials on the tazarotene gel formulation (Lebwohl et al., 1998; Weinstein et al., 1997) and two trials on tazarotene cream formulation (Weinstein et al., 2003) in patients at least 18 years old and having plaque psoriasis in at least 2% of the total body surface area. The duration of active treatment was 12 weeks and an additional 12 weeks follow-up period without active treatment was incorporated in these studies. These studies showed that as early as at week 1, tazarotene 0.1% formulation showed a statistically

vehicle groups in both studies (Lebwohl et al., 2007).

photosensitisers or have photodermatitis (Veraldi & Schianchi 2003).

**3.3 Retinoids** 

13% of patients, the daily application of halobetasol propionate should be limited to a maximum of 14 days with a maximum dose of 50 g per 2 weeks (Rivera & Hsu 2005).

### **3.2 Vitamin D3 analogues**

The active form of vitamin D3 is known to play an important role in the regulation of intestinal calcium absorption, bone mineralization and the prevention of rickets. In addition to these actions, vitamin D3 has several additional biological effects including the stimulation of cellular differentiation, inhibition of proliferation and immunomodulation (Muller & Bendtzen, 1996). This makes vitamin D3 a potential candidate for treatment of psoriasis. However, parent vitamin D3 might not be suitable for treating psoriasis due to potential for hypercalcemia. Hence, several vitamin D3 analogues have been developed for treatment of psoriasis (Tanghetti 2009). Vitamin D analogues bind to the vitamin D receptor, thus causing biological actions on both corneocytes and on immune-competent cells in the skin. Analogues such as calcipotriol, calcitriol, tacalcitol and maxacalcitol inhibit corneocyte proliferation and stimulate corneocyte differentiation *in vitro*. In addition, these analogues have only minimal effects on calcium levels and calcium excretion (Barker et al., 1999). However, due to concerns with elevating the serum calcium levels with extensive application to large body surface area, these analogues usually have a limit on total amount used per week.

#### **3.2.1 Calcipotriol (Calcipotriene)**

Calcipotriol is a synthetic vitamin D3 analogue formulated as a cream and scalp solution (Dovonex) at a drug loading of 0.005%. The calcipotriol cream is effective in treatment of plaque psoriasis and statistically significantly better than the placebo alone (Staberg et al., 1989). In addition, a solution has been developed for scalp psoriasis (Klaberg et al., 1994), and calcipotriol ointment has also been investigated for nail psoriasis (Tosti et al., 1998).

A comparison of calcipotriol ointment with a combination of betamethasone dipropionate and salicylic acid ointment (Diprosalic) showed that calcipotriol was as effective as the combination product for treating nail psoriasis (Tosti et al., 1998). Comparisons of 0.005% calcipotriol ointment and 5% coal tar ointment in conjunction with sun exposure in 10 adult patients with stable plaque psoriasis showed that both calcipotriol and coal tar ointment had comparable efficacies in treating stable plaque psoriasis when used simultaneously with sun exposure, although the initial response to calcipotriol was faster (Kaur et al., 2001).

The calcipotriol cream formulation is less greasy than the ointment formulation and hence has better patient acceptability. It was the impression that the effect of calcipotriol is more pronounced on lesional infiltration and scaling, whereas the effect is less pronounced on the vascular component of psoriasis, as determined by redness. Finally, the therapeutic response to calcipotriol ointment can be increased by occlusion with a polyethylene film (Boyrke et al., 1993).

#### **3.2.2 Calcitriol**

Calcitriol is a synthetic form of the active metabolite of vitamin D3. It has anti-proliferative, prodifferentiating and immunomodulating effects on human keratinocytes (Lehmann 2009).

13% of patients, the daily application of halobetasol propionate should be limited to a

The active form of vitamin D3 is known to play an important role in the regulation of intestinal calcium absorption, bone mineralization and the prevention of rickets. In addition to these actions, vitamin D3 has several additional biological effects including the stimulation of cellular differentiation, inhibition of proliferation and immunomodulation (Muller & Bendtzen, 1996). This makes vitamin D3 a potential candidate for treatment of psoriasis. However, parent vitamin D3 might not be suitable for treating psoriasis due to potential for hypercalcemia. Hence, several vitamin D3 analogues have been developed for treatment of psoriasis (Tanghetti 2009). Vitamin D analogues bind to the vitamin D receptor, thus causing biological actions on both corneocytes and on immune-competent cells in the skin. Analogues such as calcipotriol, calcitriol, tacalcitol and maxacalcitol inhibit corneocyte proliferation and stimulate corneocyte differentiation *in vitro*. In addition, these analogues have only minimal effects on calcium levels and calcium excretion (Barker et al., 1999). However, due to concerns with elevating the serum calcium levels with extensive application to large body surface area, these analogues usually have a limit on total amount

Calcipotriol is a synthetic vitamin D3 analogue formulated as a cream and scalp solution (Dovonex) at a drug loading of 0.005%. The calcipotriol cream is effective in treatment of plaque psoriasis and statistically significantly better than the placebo alone (Staberg et al., 1989). In addition, a solution has been developed for scalp psoriasis (Klaberg et al., 1994), and calcipotriol ointment has also been investigated for nail psoriasis (Tosti et al., 1998).

A comparison of calcipotriol ointment with a combination of betamethasone dipropionate and salicylic acid ointment (Diprosalic) showed that calcipotriol was as effective as the combination product for treating nail psoriasis (Tosti et al., 1998). Comparisons of 0.005% calcipotriol ointment and 5% coal tar ointment in conjunction with sun exposure in 10 adult patients with stable plaque psoriasis showed that both calcipotriol and coal tar ointment had comparable efficacies in treating stable plaque psoriasis when used simultaneously with sun

The calcipotriol cream formulation is less greasy than the ointment formulation and hence has better patient acceptability. It was the impression that the effect of calcipotriol is more pronounced on lesional infiltration and scaling, whereas the effect is less pronounced on the vascular component of psoriasis, as determined by redness. Finally, the therapeutic response to calcipotriol ointment can be increased by occlusion with a polyethylene film

Calcitriol is a synthetic form of the active metabolite of vitamin D3. It has anti-proliferative, prodifferentiating and immunomodulating effects on human keratinocytes (Lehmann 2009).

exposure, although the initial response to calcipotriol was faster (Kaur et al., 2001).

maximum of 14 days with a maximum dose of 50 g per 2 weeks (Rivera & Hsu 2005).

**3.2 Vitamin D3 analogues** 

used per week.

(Boyrke et al., 1993).

**3.2.2 Calcitriol** 

**3.2.1 Calcipotriol (Calcipotriene)** 

A calcitriol ointment (Vectical) for mild-to-moderate plaque psoriasis was approved by the US Food and Drug Administration (FDA) in 2009 (Kowalzick 2009). Multicenter and randomized clinical trials have shown calcitriol ointment to be efficacious, safe and cosmetically acceptable as compared to placebo and other topical psoriasis therapies (Kircik 2009). Pharmacokinetic studies in patients with psoriasis and healthy control subjects have demonstrated that topical calcitriol ointment produced minimal systemic absorption of calcitriol and does not alter systemic calcium homeostasis significantly even when applied to approximately one third of the body surface area (Kircik 2009). However, the Vectical prescribing information limits the use to 200 gm per week due to concern of disturbance in calcium metabolism. The efficacy and safety of topical calcitriol ointment were examined in two placebo-controlled, randomized, multicenter, parallel-group double blind clinical trials of identical design in a total of 839 patients aged 18 years or older with mild-to-moderate plaque psoriasis (Lebwohl et al., 2007). Both studies showed that at the end of the treatment period, the patients in the calcitriol group showed significantly better clearing of psoriatic plaques than those in the vehicle group. The incidence of treatment related adverse events such as mild skin discomfort, pruritus, and erythema was similar for the calcitriol and the vehicle groups in both studies (Lebwohl et al., 2007).

#### **3.3 Retinoids**

Retinoids provide a distinct class of treatment option within antipsoriatic therapies, which are largely dominated by immunomodulatory effects. The mechanism of action of retinoids in psoriasis may include direct suppression of inflammation as well as inhibition of proliferation and normalization of differentiation in the epidermal layer (van de Kerkhof 2006). In the US topical retinoid for psoriasis is approved as tazarotene gel and cream (Tazorac) available in 0.05% and 0.1% formulations. It is recommended that treatment commences with the 0.05% formulation, and the concentration increased if necessary and tolerated. Tazarotene is applied once daily in the evening. All formulations and strengths can be used for plaque psoriasis. In general, gels and the more-concentrated strengths tend to have higher incidences of irritation, pruritus, erythema, stinging and desquamation (Yamauchi et al., 2004). The cream formulations are being marketed as less irritating (Linden & Weinstein 1999). A recent improvement in tazarotene therapy was a reduction of skin irritation by short contact applications or concurrent steroid use (Veraldi & Schianchi 2003). These side effects are most apparent on initial application, but are generally alleviated with continued usage. Tazarotene is contraindicated in pregnant women and in women who are not taking adequate birth control in view of its teratogenic potential, category X pregnancy status. In addition, tazarotene use should be avoided in nursing women, and patients who have substantial sun exposure, who do not use adequate sun protection and who use photosensitisers or have photodermatitis (Veraldi & Schianchi 2003).

The efficacy of once-daily topical tazarotene has been studied in four randomized, double or single blinded clinical trials; two trials on the tazarotene gel formulation (Lebwohl et al., 1998; Weinstein et al., 1997) and two trials on tazarotene cream formulation (Weinstein et al., 2003) in patients at least 18 years old and having plaque psoriasis in at least 2% of the total body surface area. The duration of active treatment was 12 weeks and an additional 12 weeks follow-up period without active treatment was incorporated in these studies. These studies showed that as early as at week 1, tazarotene 0.1% formulation showed a statistically

Topical Therapies for Psoriasis 319

the patient monitored closely for signs of salicylate toxicity. Contact with eyes and other

These agents inhibit the activity of calcineurin phosphatase, an enzyme important for the translocation of the pluripotent transcription factor, nuclear factor of activated T cell, from the cytoplasm to the nucleus where it activates a number of proinflammatory cytokines associated with T-cell activation. Hence, these agents have potential for treatment of skin diseases mediated by calcineurin phosphatase (Luger & Paul 2007). Currently these calcineurin inhibitors are approved for use in mild to moderate atopic dermatitis only, any use in psoriasis is off-label, and therefore not within approved US-FDA prescribing information. A black box warning has been added to the labels of these medications stating that the long-term safety of topical calcineurin inhibitors has not been established and that rare cases of cancer have been reported in patients who used the medications, although a causal relationship in human beings has not been established. Apart from topical tacrolimus and pimecrolimus, another new oral calcineurin inhibitor, voclosporin is also in clinical

Tacrolimus is an immunosuppressive drug whose main use is after allogenic organ transplant to reduce the activity of the patient's immune system and hence reduce the risk of organ rejection. It is also used in a topical ointment preparation (Protopic) for the treatment of severe atopic dermatitis, vitiligo and psoriasis. Tacrolimus ointment was approved in the United States in 2000, and Europe in 2001 for atopic dermatitis. However, new research has proven the potential use of tacrolimus in psoriasis (Luger & Paul 2007; Beck 2005). The introduction of tacrolimus ointment marked the advent of a new, nonsteroidal drug class,

Tacrolimus ointment seems most effective in treating psoriasis where the skin is thin, that is on the face, genitelia and intertriginous areas (Martín Ezquerra et al. 2006). In one study 21 patients with facial psoriasis lesions applied tacrolimus (0.1%) ointment twice a day for 4 weeks without occlusion. A complete or good response was obtained in majority of the

The efficacy and tolerability of tacrolimus ointment has also been investigated for the treatment of male genital psoriasis (Bissonnette et al., 2008). In an open-label study in 12 adult male patients with genital psoriasis, patients received topical tacrolimus 0.1% ointment twice daily for 8 weeks followed by a 4-week observational period. Psoriasis severity also improved significantly for the glans, shaft of the penis, and scrotum. The ointment was very well tolerated, with only mild pruritus or burning sensation of limited

The safety and efficacy of tacrolimus (0.1 %) ointment for the treatment of psoriasis on the face, intertriginous areas, or both were evaluated in an open-label, clinical trial of 21 patients with psoriasis (Freeman et al., 2003). A total of 81 percent of patients experienced complete

topical immunomodulators, for the management of inflammatory dermatoses.

mucous membranes should be avoided.

**4.1 Calcineurin Inhibitors** 

**4.1.1 Tacrolimus** 

patients (Yamamoto & Nishioka 2003).

duration reported (Bissonnette et al., 2008).

**4. Novel agents for topical treatment of psoriasis** 

development for treatment of plaque psoriasis (Papp & Carey 2010).

significant improvement as compared to the vehicle, with the 0.05% tazarotene formulations showing statistically significant improvement at week 4. Twelve weeks after the discontinuation of therapy (post-treatment phase), both 0.1% and 0.05% tazarotene cream were significantly better as compared to the vehicle (Weinstein et al., 2003). Comparative studies between calcipotriol and tazarotene monotherapy have been carried out, showing superior efficacy of calcipotriol during the first 8 weeks but equal efficacy after 12 weeks' treatment (Tzung et al., 2005). The penetration of tazarotene through human skin is limited. The systemic availability after topical tazarotene 0.05% or 0.1% gel is < 1% after single application, and 2.6% and 5.3%, respectively, after once-daily applications following 2 weeks of treatment. After 12 weeks of treatment, the systemic availability of tazarotene 0.05% was 1.8% and for the 0.1% tazarotene preparation it was 3.9% (Tang-Liu et al., 1999).

### **3.4 Other topical agents**

While tars, anthralins and salicylic acid containing products have been used for decades in the United States for the treatment of plaque psoriasis, recent innovative delivery technologies have provided new versions of these products, offering the prospect of enhanced tolerability, convenience and compliance. Some of these novel topical products are discussed in this section.

#### **3.4.1 Anthralins**

A timed-release cream of anthralin (Psoriatec®) has been developed with the potential to reduce skin irritations that are sometimes observed with generic anthralin. Psoriatec can be a relatively convenient formulation to reduce side effects, such as irritation and skin staining, by following instructions for short contact anthralin therapy (SCAT).

#### **3.4.2 Coal tar**

An emollient foam formulation of coal tar (Scytera™) has been developed for convenient usage to relief of the symptoms of psoriasis. This formulation is neither intended for use for prolonged periods nor in areas such as rectum, genital area, or eyes. As with other tar containing products, skin exposure to sunlight should be avoided after application and it has the potential to stain clothing, contact lenses, and hair. Some tar products are also available as co-packaged kits, one such example is Clobeta Plus. This product is copackaging of clobetasol cream and coal tar solution.

#### **3.4.3 Salicylic acid**

Salicylic acid as a topical agent aids in the removal of excessive keratin in hyperkeratotic skin disorders, including psoriasis (including body, scalp, palms and soles) (Beani 2002). Salicylic acid has been shown to produce desquamation of the horny layer of skin while not effecting qualitative or quantitative changes in the structure of the viable epidermis. It has been used as monotherapy or as combination therapy to reduce the size and scale of psoriatic plaques. Recent development of foam formulations of salicylic acid such as Salvax® and Salkera® may lead to broader use of this agent. In children under 12 years of age and those patients with renal or hepatic impairment, the area to be treated should be limited and

significant improvement as compared to the vehicle, with the 0.05% tazarotene formulations showing statistically significant improvement at week 4. Twelve weeks after the discontinuation of therapy (post-treatment phase), both 0.1% and 0.05% tazarotene cream were significantly better as compared to the vehicle (Weinstein et al., 2003). Comparative studies between calcipotriol and tazarotene monotherapy have been carried out, showing superior efficacy of calcipotriol during the first 8 weeks but equal efficacy after 12 weeks' treatment (Tzung et al., 2005). The penetration of tazarotene through human skin is limited. The systemic availability after topical tazarotene 0.05% or 0.1% gel is < 1% after single application, and 2.6% and 5.3%, respectively, after once-daily applications following 2 weeks of treatment. After 12 weeks of treatment, the systemic availability of tazarotene 0.05% was 1.8% and for the 0.1% tazarotene preparation it was 3.9% (Tang-Liu et al., 1999).

While tars, anthralins and salicylic acid containing products have been used for decades in the United States for the treatment of plaque psoriasis, recent innovative delivery technologies have provided new versions of these products, offering the prospect of enhanced tolerability, convenience and compliance. Some of these novel topical products

A timed-release cream of anthralin (Psoriatec®) has been developed with the potential to reduce skin irritations that are sometimes observed with generic anthralin. Psoriatec can be a relatively convenient formulation to reduce side effects, such as irritation and skin

An emollient foam formulation of coal tar (Scytera™) has been developed for convenient usage to relief of the symptoms of psoriasis. This formulation is neither intended for use for prolonged periods nor in areas such as rectum, genital area, or eyes. As with other tar containing products, skin exposure to sunlight should be avoided after application and it has the potential to stain clothing, contact lenses, and hair. Some tar products are also available as co-packaged kits, one such example is Clobeta Plus. This product is co-

Salicylic acid as a topical agent aids in the removal of excessive keratin in hyperkeratotic skin disorders, including psoriasis (including body, scalp, palms and soles) (Beani 2002). Salicylic acid has been shown to produce desquamation of the horny layer of skin while not effecting qualitative or quantitative changes in the structure of the viable epidermis. It has been used as monotherapy or as combination therapy to reduce the size and scale of psoriatic plaques. Recent development of foam formulations of salicylic acid such as Salvax® and Salkera® may lead to broader use of this agent. In children under 12 years of age and those patients with renal or hepatic impairment, the area to be treated should be limited and

staining, by following instructions for short contact anthralin therapy (SCAT).

packaging of clobetasol cream and coal tar solution.

**3.4 Other topical agents** 

are discussed in this section.

**3.4.1 Anthralins** 

**3.4.2 Coal tar** 

**3.4.3 Salicylic acid** 

the patient monitored closely for signs of salicylate toxicity. Contact with eyes and other mucous membranes should be avoided.
