**1. Introduction**

330 Psoriasis

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of the clinical significance of new guidelines and systematic reviews on psoriasis

therapy of psoriasis: vehicle-controlled study of safety, efficacy, and duration of

Sefton J, Gibson JR, Walker PS; (2003). Tazarotene cream in the treatment of psoriasis: Two multicenter, double-blind, randomized, vehicle-controlled studies of the safety and efficacy of tazarotene creams 0.05% and 0.1% applied once daily for

CE, Mathew CG, Barker JN, Capon F, Trembath FC. (2008). Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease. Psoriasis is a chronic inflammatory skin disorder affecting 1–3% of the general population worldwide. Up to one-third of psoriatic patients have concomitant psoriatic arthritis (Gerdes et al, 2009). Multiple studies and clinical trials support an important role for dysregulation of the immune system in the development of psoriasis. In recent years, the improved understanding of the molecular basis underlying psoriasis has led to the introduction of biological drugs, providing a new effective treatment option for this disease. Biologics target key steps in the pathogenesis of psoriasis, and can be classified into three main categories: TNF inhibitors, T cell inhibitors and IL-12/IL-23 inhibitors (Weger, 2010). In this chapter we discuss the state of the art of biological therapies for psoriasis and psoriatic arthritis and give a brief overview of the new biological approaches that are currently undergoing evaluation for the treatment of both diseases.

### **2. TNF Inhibitors**

TNF is a proinflammatory cytokine that plays key roles in both innate and adaptive immunity. At high concentrations, it can trigger an excessive inflammatory response ending in organ damage. The development of anti-TNF biologics originated from a study by Brennan et al., which showed that the expression of pro-inflammatory cytokines by synoviocytes in rheumatoid arthritis patients was inhibited by TNF-neutralizing antibodies (Brennan et al, 1989). To date, the role of TNF in psoriasis and psoriatic arthritis has been fully investigated (Schottelius et al, 2004). Increased levels of TNF and a differential expression of TNF receptors I and II have been found in lesional psoriatic skin compared with normal-appearing skin; in addition, in psoriatic patients, the plasma concentration of TNF is higher and the mRNA expression of this cytokine is increased in peripheral blood

<sup>\*</sup> Valeria Iansante1, Mariafausta Fischietti1, Daniela Verzella1, Maria Concetta Fargnoli2, Ketty Peris2, Roberto Giacomelli3, Francesca Zazzeroni1 and Edoardo Alesse1

*<sup>1</sup>Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy* 

<sup>2</sup>*Department of Sciences and Biomedical Technology, University of L'Aquila, L'Aquila, Italy* 

<sup>3</sup>*Department of Internal Medicine and Public Health, University of L'Aquila, L'Aquila, Italy*

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 333

dose-related, reporting a PASI 75 response in 34% and 49% of patients treated with 25 mg and 50 mg twice weekly after 12 weeks of treatment, respectively. The improvement continued through week 24, with 44% and 59% of patients achieving a PASI 75, respectively (Leonardi et al, 2003). The same high-dose etanercept regimen was used in a recent study by Griffiths et al., who reported a PASI 75 response in 57% of patients after 12 weeks of treatment (Griffiths et al, 2010). In a further multicentre 24-week study, the efficacy of etanercept during the initial treatment phase and after dose reduction were evaluated (Papp et al, 2005). Patients were treated with a dose of 50 mg etanercept, 25 mg etanercept or placebo twice weekly for the first 12 weeks. During the second 12 weeks of treatment, the dosage was reduced to 25 mg twice weekly. Papp et al. reported a PASI 75 in 49% of patients treated with 50 mg twice weekly and in 34% of patients receiving 25 mg twice weekly of etanercept compared with 3% in the placebo group at week 12, and demonstrated that the effect obtained with the higher dose could be preserved in most patients after dose reduction (Papp et al, 2005). A further increase of the dose of etanercept to 100 mg did not demonstrate an improvement in efficacy (Cassano et al, 2006). Recent data by van de Kerkhof et al. demonstrated that etanercept 50 mg once weekly for 24 weeks was effective, with a PASI 75 response of 38% after 12 weeks, which increased to 71% after 24 weeks (van de Kerkhof et al, 2008). Similar results were reported by Sterry et al. (Sterry et al, 2010). Regarding long-term efficacy, etanercept response has been demonstrated to last up to 96 weeks, resulting in a statistically significant improvement (Tyring et al, 2007; Esposito et al, 2010). Etanercept is the only biological drug that has shown efficacy and safety in pediatric patients with moderate to severe plaque psoriasis (Paller et al, 2008). Paller et al. reported a PASI 75 response in 57% of children and adolescents treated with etanercept (0.8 mg/kg body weight) compared with 11% in placebo patients after 12 weeks. The efficacy of the treatment was maintained through 96 weeks (Paller et al, 2010). Treatment with etanercept also provides an improvement in the quality of life of patients, as measured by the Dermatology Life Quality Index (DLQI) (Leonardi et al, 2003; van de

Two pivotal studies have demonstrated the efficacy of etanercept in the treatment of psoriatic arthritis. In these studies, the American College of Rheumatology (ACR) criteria is the most frequently parameter used to assess the severity of psoriatic arthritis. A doubleblind, placebo-controlled study enrolling 60 patients suffering from psoriatic arthritis showed achievement of ACR 20, ACR 50 and ACR 70 response in 73%, 50% and 13% of patients after 12 weeks of treatment with etanercept, compared with 13%, 3% and 0% in the placebo group (Mease et al, 2000). Furthermore, the same authors reported an additional double-blind, placebo-controlled clinical trial in 250 patients with psoriatic arthritis. At 12 weeks, an ACR 20 response was observed in 59% of etanercept-treated patients compared with 15% of the placebo group. This study also reported an improvement in quality of life measured by the Health Assessment Questionaire (HAQ) (Mease et al, 2004). The improvements observed were maintained for up to 2 years (Mease et al, 2010). A recent study by Saougou et al. reported a PASI 90 response in 68% of etanercept-treated patients

Although highly effective as monotherapy, few studies have been published on the combination of etanercept with cyclosporine, narrowband UVB, acitretin and methotrexate (reviewed in Foley et al, 2010). Preliminary data from short-term analysis support the use of etanercept in combination therapy which does not seem to be associated with additional

affected by psoriatic arthritis after 5 years (Saougou et al, 2011).

Kerkhof et al, 2008).

mononuclear cells. Currently, four TNF antagonists are approved for the treatment of psoriasis and/or psoriatic arthritis, namely etanercept, infliximab, adalimumab and golimumab; a new TNF inhibitor (certolizumab pegol) is currently undergoing a phase III trial for the treatment of psoriatic arthritis.

#### **2.1 Etanercept**

Etanercept is a recombinant human fusion protein consisting of a dimer of the extracellular portion of TNF receptor II linked to the Fc portion of IgG1 (Amgen, Inc, 2011). Etanercept binds to both the trimeric form of soluble TNF and to the transmembrane form, antagonizing their biological actions (Bachmann et al, 2010). Several studies reported a reduction of different inflammatory cell types in psoriatic lesions during etanercept treatment, such as T cells, natural killer cells, neutrophils, macrophages and plasmocytoid dendritic cells (de Groot et al, 2010). Etanercept also blocks downstream T-cell mediated events inducing apoptosis of CD11c+ myeloid dendritic cells (Malaviya et al, 2006). In addition, etanercept has been shown to down-regulate Th17 cell markers, as well as Th17 cell products and effector molecules (Antiga et al, 2010; Zaba et al, 2007). Etanercept is FDAand EMA-approved for the treatment of psoriasis and psoriatic arthritis. It is also approved for the treatment of other autoimmune conditions such as rheumatoid arthritis, juvenile idiopathic arthritis and ankilosing spondilytis (Amgen, Inc., 2011).

#### **2.1.1 Administration**

Etanercept is administered subcutaneously at a dose of 50 mg twice a week in patients with plaque psoriasis or at 25 mg twice a week in patients with psoriatic arthritis during the first 12 weeks of treatment. After the initiation phase, the dosage for plaque psoriasis is reduced to 25 mg twice a week or 50 mg weekly during the maintenance phase (Amgen, Inc., 2011). Etanercept can be administered either continuously or intermittently. Gordon et al reported no loss of efficacy with intermittent therapy, with a similar response between retreatment and initial therapy in psoriatic patients (Gordon et al, 2006a). However, a multicenter European open-label study showed that both regimens provide a significant improvement in quality of life, with a greater improvement in the continuous treatment group (Dauden et al, 2009). Non-neutralizing anti-etanercept antibodies have been observed by several authors, but the relevance of them is still debated (Bachmann et al, 2010).

#### **2.1.2 Clinical efficacy**

Several high-quality clinical trials (Cassano et al, 2010; Gottlieb et al, 2003; Leonardi et al, 2003, 2010; Papp et al, 2005; Tyring et al, 2007; van de Kerkhof et al, 2008) have evaluated both the short-term and long-term efficacy of etanercept in the treatment of psoriasis. In clinical trials, the severity of psoriasis is assessed by the Psoriasis Area and Severity Index (PASI). PASI 75 is defined as a 75% reduction in PASI score compared with baseline. An initial randomized, double-blind, placebo-controlled, multicenter trial of 112 patients demonstrated a PASI 75 response in 30% of patients receiving 25 mg etanercept twice a week compared with 2% of placebo-treated patients after 12 weeks. After 24 weeks, PASI 75 response increased to 56% in the etanercept-treated arm compared with 5% in the placebo group (Gottlieb et al, 2003). Leonardi et al. demonstrated that the efficacy of etanercept is

mononuclear cells. Currently, four TNF antagonists are approved for the treatment of psoriasis and/or psoriatic arthritis, namely etanercept, infliximab, adalimumab and golimumab; a new TNF inhibitor (certolizumab pegol) is currently undergoing a phase III

Etanercept is a recombinant human fusion protein consisting of a dimer of the extracellular portion of TNF receptor II linked to the Fc portion of IgG1 (Amgen, Inc, 2011). Etanercept binds to both the trimeric form of soluble TNF and to the transmembrane form, antagonizing their biological actions (Bachmann et al, 2010). Several studies reported a reduction of different inflammatory cell types in psoriatic lesions during etanercept treatment, such as T cells, natural killer cells, neutrophils, macrophages and plasmocytoid dendritic cells (de Groot et al, 2010). Etanercept also blocks downstream T-cell mediated events inducing apoptosis of CD11c+ myeloid dendritic cells (Malaviya et al, 2006). In addition, etanercept has been shown to down-regulate Th17 cell markers, as well as Th17 cell products and effector molecules (Antiga et al, 2010; Zaba et al, 2007). Etanercept is FDAand EMA-approved for the treatment of psoriasis and psoriatic arthritis. It is also approved for the treatment of other autoimmune conditions such as rheumatoid arthritis, juvenile

Etanercept is administered subcutaneously at a dose of 50 mg twice a week in patients with plaque psoriasis or at 25 mg twice a week in patients with psoriatic arthritis during the first 12 weeks of treatment. After the initiation phase, the dosage for plaque psoriasis is reduced to 25 mg twice a week or 50 mg weekly during the maintenance phase (Amgen, Inc., 2011). Etanercept can be administered either continuously or intermittently. Gordon et al reported no loss of efficacy with intermittent therapy, with a similar response between retreatment and initial therapy in psoriatic patients (Gordon et al, 2006a). However, a multicenter European open-label study showed that both regimens provide a significant improvement in quality of life, with a greater improvement in the continuous treatment group (Dauden et al, 2009). Non-neutralizing anti-etanercept antibodies have been observed by several

Several high-quality clinical trials (Cassano et al, 2010; Gottlieb et al, 2003; Leonardi et al, 2003, 2010; Papp et al, 2005; Tyring et al, 2007; van de Kerkhof et al, 2008) have evaluated both the short-term and long-term efficacy of etanercept in the treatment of psoriasis. In clinical trials, the severity of psoriasis is assessed by the Psoriasis Area and Severity Index (PASI). PASI 75 is defined as a 75% reduction in PASI score compared with baseline. An initial randomized, double-blind, placebo-controlled, multicenter trial of 112 patients demonstrated a PASI 75 response in 30% of patients receiving 25 mg etanercept twice a week compared with 2% of placebo-treated patients after 12 weeks. After 24 weeks, PASI 75 response increased to 56% in the etanercept-treated arm compared with 5% in the placebo group (Gottlieb et al, 2003). Leonardi et al. demonstrated that the efficacy of etanercept is

idiopathic arthritis and ankilosing spondilytis (Amgen, Inc., 2011).

authors, but the relevance of them is still debated (Bachmann et al, 2010).

trial for the treatment of psoriatic arthritis.

**2.1 Etanercept** 

**2.1.1 Administration** 

**2.1.2 Clinical efficacy** 

dose-related, reporting a PASI 75 response in 34% and 49% of patients treated with 25 mg and 50 mg twice weekly after 12 weeks of treatment, respectively. The improvement continued through week 24, with 44% and 59% of patients achieving a PASI 75, respectively (Leonardi et al, 2003). The same high-dose etanercept regimen was used in a recent study by Griffiths et al., who reported a PASI 75 response in 57% of patients after 12 weeks of treatment (Griffiths et al, 2010). In a further multicentre 24-week study, the efficacy of etanercept during the initial treatment phase and after dose reduction were evaluated (Papp et al, 2005). Patients were treated with a dose of 50 mg etanercept, 25 mg etanercept or placebo twice weekly for the first 12 weeks. During the second 12 weeks of treatment, the dosage was reduced to 25 mg twice weekly. Papp et al. reported a PASI 75 in 49% of patients treated with 50 mg twice weekly and in 34% of patients receiving 25 mg twice weekly of etanercept compared with 3% in the placebo group at week 12, and demonstrated that the effect obtained with the higher dose could be preserved in most patients after dose reduction (Papp et al, 2005). A further increase of the dose of etanercept to 100 mg did not demonstrate an improvement in efficacy (Cassano et al, 2006). Recent data by van de Kerkhof et al. demonstrated that etanercept 50 mg once weekly for 24 weeks was effective, with a PASI 75 response of 38% after 12 weeks, which increased to 71% after 24 weeks (van de Kerkhof et al, 2008). Similar results were reported by Sterry et al. (Sterry et al, 2010). Regarding long-term efficacy, etanercept response has been demonstrated to last up to 96 weeks, resulting in a statistically significant improvement (Tyring et al, 2007; Esposito et al, 2010). Etanercept is the only biological drug that has shown efficacy and safety in pediatric patients with moderate to severe plaque psoriasis (Paller et al, 2008). Paller et al. reported a PASI 75 response in 57% of children and adolescents treated with etanercept (0.8 mg/kg body weight) compared with 11% in placebo patients after 12 weeks. The efficacy of the treatment was maintained through 96 weeks (Paller et al, 2010). Treatment with etanercept also provides an improvement in the quality of life of patients, as measured by the Dermatology Life Quality Index (DLQI) (Leonardi et al, 2003; van de Kerkhof et al, 2008).

Two pivotal studies have demonstrated the efficacy of etanercept in the treatment of psoriatic arthritis. In these studies, the American College of Rheumatology (ACR) criteria is the most frequently parameter used to assess the severity of psoriatic arthritis. A doubleblind, placebo-controlled study enrolling 60 patients suffering from psoriatic arthritis showed achievement of ACR 20, ACR 50 and ACR 70 response in 73%, 50% and 13% of patients after 12 weeks of treatment with etanercept, compared with 13%, 3% and 0% in the placebo group (Mease et al, 2000). Furthermore, the same authors reported an additional double-blind, placebo-controlled clinical trial in 250 patients with psoriatic arthritis. At 12 weeks, an ACR 20 response was observed in 59% of etanercept-treated patients compared with 15% of the placebo group. This study also reported an improvement in quality of life measured by the Health Assessment Questionaire (HAQ) (Mease et al, 2004). The improvements observed were maintained for up to 2 years (Mease et al, 2010). A recent study by Saougou et al. reported a PASI 90 response in 68% of etanercept-treated patients affected by psoriatic arthritis after 5 years (Saougou et al, 2011).

Although highly effective as monotherapy, few studies have been published on the combination of etanercept with cyclosporine, narrowband UVB, acitretin and methotrexate (reviewed in Foley et al, 2010). Preliminary data from short-term analysis support the use of etanercept in combination therapy which does not seem to be associated with additional

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 335

year resulted in a sustained improvement in PASI score (Reich et al, 2010). Moreover, infliximab provides a substantial improvement in quality of life, with a meaningful decrease in DLQI both in short-term and long-term treatment (Feldmann et al, 2005; Gottlieb et al,

The IMPACT trial evaluated the efficacy of infliximab in 104 patients with psoriatic arthritis (Antoni et al, 2005a). At week 16, 65% of patients achieved ACR 20 compared with 10% of the placebo group and 46% and 29% achieved ACR 50 and ACR 70, respectively. The efficacy of infliximab has been evaluated in a larger cohort of patients (n=200) in the IMPACT 2 trial. At week 14, 64% of infliximab-treated patients showed a PASI 75 response and 58% achieved ACR 20; in addition ACR 20 criteria were maintained up to 1 year (Antoni et al, 2005b; Kavanaugh et al, 2007). The long-term efficacy of infliximab was evaluated by a two-year extension of the IMPACT trial (Antoni et al, 2008). At week 98, maintenance of the ACR 20 criteria was observed in 68% of infliximab-treated patients and

Regarding combination therapy, the concomitant administration of methotrexate has been reported to prolong the long-term efficacy of infliximab by decreasing the development of

Adalimumab is the first fully humanized recombinant anti-TNF monoclonal antibody. Adalimumab is able to bind both soluble and membrane-bound TNF in a dose-dependent manner (Abbott Laboratories, 2011). It has been shown that adalimumab lyses TNF bearing cells in the presence of complement and induces apoptosis *in vitro*; in addition adalimumab affects the biological responses controlled by TNF, such as the expression of adhesion molecules, serum concentration of cytokines, reactive oxygen species and dendritic cells in psoriatic plaques (Papoutsaki et al, 2007). Moreover, adalimumab is able to modulate Toll-like receptors expression on basal keratinocytes (De Pità et al, 2011). Adalimumab is FDA- and EMA-approved for the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, juvenile idiopathic arthritis and ankylosing spondylitis (Abbott

Adalimumab is administered as a subcutaneous injection and the recommended dose for psoriasis is a loading dose of 80 mg at week one, followed by 40 mg at week two and continuous 40 mg injection every other week (eow) for maintenance. In psoriatic arthritis the ideal dosage regimen is 40 mg every second week (Abbott Laboratories, 2011). The continuous therapy with adalimumab seems to be more effective than intermitted therapy to provide a sustained response (Menter et al, 2008). Recently, encouraging results have been obtained in the retreatment of patients who relapsed after interruption of adalimumab therapy (Papp et al, 2011) and patients who lost efficacy during treatment with another TNF antagonist (Van et al, 2008). Development of anti-adalimumab antibodies may occur, as demonstrated in patients with rheumatoid arthritis (Bartelds et

human anti-infliximab neutralizing antibodies (Klotz et al, 2007).

2004; Menter et al, 2007; Reich et al, 2006, 2010).

64% of them achieved PASI 75.

**2.3 Adalimumab** 

Laboratories, 2011).

**2.3.1 Administration** 

al, 2010).

toxicities. This provides an attractive option for patients inadequately responding to monotherapy. However, further long-term studies are needed to confirm the safety of combination therapy.

#### **2.2 Infliximab**

Infliximab is a chimeric IgG anti-TNF monoclonal antibody constiting of a human constant (75%) region and murine variable (25%) regions (Centocor Ortho Biotech, Inc., 2011). *In vivo*, infliximab binds to human TNF and forms stable complexes, resulting in the loss of biological activity of this pro-inflammatory cytokine (Scallon et al, 1995). Infliximab is able to neutralize both soluble and trans-membrane TNF and induces the elimination of TNF bearing cells, such as macrophages, dermal dendritic cells, and T cells (Gisondi et al, 2004; Zaba et al, 2007). Recently, it has been suggested that infliximab induces p53-related keratinocytes apoptosis, highlighting another effect of this drug in psoriasis (Raho et al, 2011). Infliximab is FDA- and EMA-approved for the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, adult and pediatric Crohn's disease and ulcerative colitis (Centocor Ortho Biotech, Inc., 2011).

#### **2.2.1 Administration**

Infliximab is administered as a 2-3 hour intravenous infusion at a dose of 5mg/kg. The infusions are given at weeks 0, 2 and 6 (induction period) and then every 8 weeks (maintenance period) (Centocor Ortho Biotech, Inc., 2011). The efficacy of continuous versus intermittent treatment was evaluated in the clinical trial EXPRESS II, reporting that continuous treatment achieved better results than intermittent therapy to maintain PASI response and to reduce the occurrence of anti-infliximab antibodies, the most common cause of decreased drug efficacy (Haraoui et al, 2006; Menter et al, 2007; Vena & Cassano, 2007).

#### **2.2.2 Clinical efficacy**

Several pivotal clinical trials demonstrated the clinical efficacy of infliximab in the treatment of plaque psoriasis (Chaudhari et al, 2001; Gottlieb et al, 2004; Reich et al, 2005, 2006). Two phase II studies evaluated the efficacy of infliximab at different doses, 5 and 10 mg/kg and 3 and 5 mg/kg, respectively (Chaudhari et al, 2001; Gottlieb et al, 2004). In the first study of 33 psoriatic patients, a PASI 75 response was observed in 82% and 73% of patients receiving 5 and 10 mg/kg of infliximab, respectively, and in 8% of the patients receiving placebo after 10 weeks. In the second study (SPIRIT) of 249 plaque psoriasis patients, 72% and 88% of patients receiving 3 and 5 mg/kg of infliximab, respectively, achieved PASI 75 at week 10 compared with 6% of the placebo-treated patients. These results demonstrated a high shortterm efficacy of infliximab and identified 5 mg/kg as the ideal dosage regimen in the treatment of psoriasis. The rapid response induced by infliximab decreased after 50 weeks (Reich et al, 2005). The phase III multi-center, double-blind, placebo-controlled trial EXPRESS enrolled 378 patients with plaque psoriasis and showed a PASI 75 response in 80% of the patients after 10 weeks compared with 3% in placebo group. The response was maintained through week 24 and decreased to 61% by week 50. Nevertheless, the retrospective analysis of the EXPRESS trial showed that infliximab continuous therapy for 1 year resulted in a sustained improvement in PASI score (Reich et al, 2010). Moreover, infliximab provides a substantial improvement in quality of life, with a meaningful decrease in DLQI both in short-term and long-term treatment (Feldmann et al, 2005; Gottlieb et al, 2004; Menter et al, 2007; Reich et al, 2006, 2010).

The IMPACT trial evaluated the efficacy of infliximab in 104 patients with psoriatic arthritis (Antoni et al, 2005a). At week 16, 65% of patients achieved ACR 20 compared with 10% of the placebo group and 46% and 29% achieved ACR 50 and ACR 70, respectively. The efficacy of infliximab has been evaluated in a larger cohort of patients (n=200) in the IMPACT 2 trial. At week 14, 64% of infliximab-treated patients showed a PASI 75 response and 58% achieved ACR 20; in addition ACR 20 criteria were maintained up to 1 year (Antoni et al, 2005b; Kavanaugh et al, 2007). The long-term efficacy of infliximab was evaluated by a two-year extension of the IMPACT trial (Antoni et al, 2008). At week 98, maintenance of the ACR 20 criteria was observed in 68% of infliximab-treated patients and 64% of them achieved PASI 75.

Regarding combination therapy, the concomitant administration of methotrexate has been reported to prolong the long-term efficacy of infliximab by decreasing the development of human anti-infliximab neutralizing antibodies (Klotz et al, 2007).
