**5. Combination topical therapies**

The commonly used topical medications described in this chapter provide efficacy through varying and divergent pathways. As these agents act through different mechanisms, there is a scientific rationale for their use in combination therapy. The rationale assumes that agents are selected on the basis of their individual mechanisms of action, which may offer the possibility of additive or synergistic efficacy, reduction in the dose of either or both products, and reduction in the occurrence of side effects (Norris 2005). Several studies have proven the advantages of using a combination of topical medications for treatment of psoriasis. Recently, a fixed dose combination ointment containing 50 μg/g calcipotriol and 0.5 mg/g betamethasone dipropionate (approved in US as Taclonex®) was found to be effective against psoriasis vulgaris (Claréus et al., 2009). This ointment formulation combines the keratinocyte differentiation and antiproliferative action of the vitamin D3 analogues (calcipotriol) with the anti-inflammatory effect of steroids (betamethasone dipropionate), thus enhancing effectiveness while reducing the side-effect profile of the individual agents (Saraceno et al., 2009). It was found that the combination product had a more rapid onset of action (Papp et al., 2003) than calcipotriol or betamethasone alone and was more effective (Douglas et al., 2002) than calcipotriol or betamethasone alone. In a clinical trial with 1605 randomized patients aged 18 years or older showed that the combination product (Taclonex®) was significantly more effective than betamethasone,

Topical Therapies for Psoriasis 323

Psoralen photochemotherapy uses a combination of topical application (or ingestion) of 8 methoxypsoralen followed by exposure of the affected skin area to long-wavelength UV (320 – 400 nm) (Nguyen et al., 2009). Other psoralen derivatives such as 5-methoxypsoralen and 4,5,8-trimethylpsoralen are also used in topical PUVA therapy. Bath psoralen UVA combination involves immersion of either localised areas (such as the hands or feet) or the whole body in water containing dissolved 8-methoxypsoralen prior to UVA exposure

Photodynamic therapy is another non-invasive technique used in the treatment of skin diseases. 5-aminolevulinic acid is a prodrug that is metabolized intracellularly to form the photosensitizing molecule protoporphyrin IX. When protoporphyrin IX is activated by light, cytotoxic reactive oxygen species and free radicals are generated. This phototoxic effect may be used for treatment of malignant and non-malignant hyperproliferative tissue (Gupta & Ryder 2003). Photodynamic therapies using 5-aminolaevulinic acid in plaque psoriasis has also been reported (Gupta & Ryder 2003), however these are not approved regimens. Side effects of the aforementioned regimens include short and long term adverse effects of visible and UV light, such as acute phototoxicity, and longer term effects such as photoaging and photocarcinogenesis. Protective clothing, sunblock and sunglasses should be used to protect

Sequential therapy is a strategy to treat psoriasis using a specific combination of therapeutic agents in a particular sequence with the aim of achieving initial efficacy followed by a safe maintenance regimen (Koo 1999). This treatment strategy maximizes efficacy of each medication while minimizing long term side effects. The strategy involves three main steps – 1) clearing phase, 2) transitional phase and 3) maintenance phase (Koo 1999). A combination of topical, systemic and phototherapy agents can be used to achieve the desired

The clearing phase involves the use of a rapid acting agent such as a potent or super-potent topical steroid at the maximum dermatologic dose with the main aim of promptly controlling an acute outbreak of psoriasis. This is followed by the transitional phase, in which a well tolerated maintenance agent such as acitrein or vitamin D analogue is introduced and administered along with the clearing agent. The clearing agent is slowly tapered off in this phase of treatment. The transitional phase can be challenging as it requires prevention of breakthrough of the disease, while tapering off the clearing agent and adjusting dose of the maintenance agent to ensure long term control with minimal side effects. Finally, in the third phase of the treatment, the patient is retained on the maintenance therapy, with additional therapy such as phototherapy, as needed (Koo 1999). Several combinations of therapeutic agents and regimen for sequential therapy have been proposed in literature (Lebwohl et. al., 2004; Bhutani et. al., 2011). However the choice of treatment agents needs careful consideration based on the severity and type of the disease, and the need to balance safety and efficacy. Recently, a sequential treatment regimen of clobetasol and calcitriol has been shown to be efficacious and safe for the management of moderate-to-severe plaque psoriasis (Brodell et. at., 2011). In a multicentre, open-label study in subjects aged 18-80 years with moderate-to-severe plaque psoriasis, the patients applied

outcome, depending on the severity of the disease (Lebwohl et. al., 2004).

(Nguyen et al., 2009).

unaffected areas of the body.

**7. Sequential therapy** 

calcipotriol and placebo. The local adverse reactions were also low compared to the other drugs. It was concluded that two different treatment regimens (i.e. application once or twice daily) employing the two-compound product provided rapid and marked clinical efficacy as compared to calcipotriol or betamethasone alone and also were safe therapies for psoriasis vulgaris (Saraceno et al., 2009). Combination of calcipotriol and betamethasone has also been shown to have significant advantages in treatment of scalp and nail psoriasis (Saraceno et al., 2009). More recently, a combination of 0.005% calcipotriol and 0.064% betamethasone dipropionate (Taclonex Scalp in US and Xamiol in Europe) has been approved for the treatment of moderate to severe scalp psoriasis vulgaris in adults. This once-daily therapy has a quick onset of action and greater efficacy than monotherapy with either ingredient. At 8 weeks, the combination product had a safety profile comparable with betamethasone dipropionate and was associated with significantly fewer adverse events than calcipotriol (Guenther 2009).

A combination of betamethasone dipropionate and salicylic acid (Diprosalic) is available as ointment and lotion formulations. Faster improvement in scaling, itching, and redness has been observed with Diprosalic as compared to betamethasone dipropionate alone (Guenther 2004). It has also been shown that the combination ointment has similar efficacy to clobetasol and calcipotriene (calcipotriol) ointments.

A multicentre, randomised, double-blind, vehicle-controlled, parallel-group study was carried out to study the effect of the addition of calcipotriol ointment to methotrexate in patients aged 18 years or older with psoriasis vulgaris (De Jong 2003). From this study, it was concluded that the combined use of calcipotriol with methotrexate resulted in a methotrexate-sparing effect, while still maintaining the efficacy. Calcipotriol treatment increased the time to relapse of psoriasis following discontinuation of methotrexate. The combination of calcipotriol and methotrexate was safe and well tolerated. The combination resulted in lower cumulative doses of methotrexate as compared to monotherapy, thus significantly reducing the risk of methotrexate side effects (De Jong 2003).

The combination of calcipotriol ointment (twice daily) and tazarotene gel (once daily) was compared with clobetasol ointment (twice daily) in the treatment of psoriasis (Bowman et al., 2002). The vitamin D3 analogue plus retinoid treatment had comparable efficacy to that of the potent topical steroid. Similarly a comparison of twice-daily calcipotriol ointment against the combination of tazarotene gel and 0.1% mometasone furoate cream was superior during the first 2 weeks of treatment. However, by 8 weeks of treatment, both groups exhibited similar responses (van de Kerkhof 2006).

#### **6. Combination of topical therapy with phototherapy**

Phototherapy for psoriasis includes narrowband and broadband UVB phototherapy; psoralens combined with UVA, targeted excimer laser phototherapy, and combination treatments (Nguyen et al., 2009). The combination of phototherapy with topical products has long been used for treatment of plaque psoriasis. In the 1920s, William Goeckerman combined the use of UVB phototherapy with topical application of tars (Su & Fang 2008; Witman 2001). This in-patient psoriasis regimen, known as the Goeckerman regimen, is still occasionally used in major dermatologic centers.

calcipotriol and placebo. The local adverse reactions were also low compared to the other drugs. It was concluded that two different treatment regimens (i.e. application once or twice daily) employing the two-compound product provided rapid and marked clinical efficacy as compared to calcipotriol or betamethasone alone and also were safe therapies for psoriasis vulgaris (Saraceno et al., 2009). Combination of calcipotriol and betamethasone has also been shown to have significant advantages in treatment of scalp and nail psoriasis (Saraceno et al., 2009). More recently, a combination of 0.005% calcipotriol and 0.064% betamethasone dipropionate (Taclonex Scalp in US and Xamiol in Europe) has been approved for the treatment of moderate to severe scalp psoriasis vulgaris in adults. This once-daily therapy has a quick onset of action and greater efficacy than monotherapy with either ingredient. At 8 weeks, the combination product had a safety profile comparable with betamethasone dipropionate and was associated with significantly fewer adverse events than calcipotriol

A combination of betamethasone dipropionate and salicylic acid (Diprosalic) is available as ointment and lotion formulations. Faster improvement in scaling, itching, and redness has been observed with Diprosalic as compared to betamethasone dipropionate alone (Guenther 2004). It has also been shown that the combination ointment has similar efficacy

A multicentre, randomised, double-blind, vehicle-controlled, parallel-group study was carried out to study the effect of the addition of calcipotriol ointment to methotrexate in patients aged 18 years or older with psoriasis vulgaris (De Jong 2003). From this study, it was concluded that the combined use of calcipotriol with methotrexate resulted in a methotrexate-sparing effect, while still maintaining the efficacy. Calcipotriol treatment increased the time to relapse of psoriasis following discontinuation of methotrexate. The combination of calcipotriol and methotrexate was safe and well tolerated. The combination resulted in lower cumulative doses of methotrexate as compared to monotherapy, thus

The combination of calcipotriol ointment (twice daily) and tazarotene gel (once daily) was compared with clobetasol ointment (twice daily) in the treatment of psoriasis (Bowman et al., 2002). The vitamin D3 analogue plus retinoid treatment had comparable efficacy to that of the potent topical steroid. Similarly a comparison of twice-daily calcipotriol ointment against the combination of tazarotene gel and 0.1% mometasone furoate cream was superior during the first 2 weeks of treatment. However, by 8 weeks of treatment, both groups

Phototherapy for psoriasis includes narrowband and broadband UVB phototherapy; psoralens combined with UVA, targeted excimer laser phototherapy, and combination treatments (Nguyen et al., 2009). The combination of phototherapy with topical products has long been used for treatment of plaque psoriasis. In the 1920s, William Goeckerman combined the use of UVB phototherapy with topical application of tars (Su & Fang 2008; Witman 2001). This in-patient psoriasis regimen, known as the Goeckerman regimen, is still

significantly reducing the risk of methotrexate side effects (De Jong 2003).

to clobetasol and calcipotriene (calcipotriol) ointments.

exhibited similar responses (van de Kerkhof 2006).

occasionally used in major dermatologic centers.

**6. Combination of topical therapy with phototherapy** 

(Guenther 2009).

Psoralen photochemotherapy uses a combination of topical application (or ingestion) of 8 methoxypsoralen followed by exposure of the affected skin area to long-wavelength UV (320 – 400 nm) (Nguyen et al., 2009). Other psoralen derivatives such as 5-methoxypsoralen and 4,5,8-trimethylpsoralen are also used in topical PUVA therapy. Bath psoralen UVA combination involves immersion of either localised areas (such as the hands or feet) or the whole body in water containing dissolved 8-methoxypsoralen prior to UVA exposure (Nguyen et al., 2009).

Photodynamic therapy is another non-invasive technique used in the treatment of skin diseases. 5-aminolevulinic acid is a prodrug that is metabolized intracellularly to form the photosensitizing molecule protoporphyrin IX. When protoporphyrin IX is activated by light, cytotoxic reactive oxygen species and free radicals are generated. This phototoxic effect may be used for treatment of malignant and non-malignant hyperproliferative tissue (Gupta & Ryder 2003). Photodynamic therapies using 5-aminolaevulinic acid in plaque psoriasis has also been reported (Gupta & Ryder 2003), however these are not approved regimens. Side effects of the aforementioned regimens include short and long term adverse effects of visible and UV light, such as acute phototoxicity, and longer term effects such as photoaging and photocarcinogenesis. Protective clothing, sunblock and sunglasses should be used to protect unaffected areas of the body.
