**2.3 Adalimumab**

334 Psoriasis

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

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

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,

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

and ulcerative colitis (Centocor Ortho Biotech, Inc., 2011).

combination therapy.

**2.2.1 Administration** 

**2.2.2 Clinical efficacy** 

2007).

**2.2 Infliximab** 

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 Laboratories, 2011).

### **2.3.1 Administration**

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 al, 2010).

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 337

The phase III GO-REVEAL clinical trial evaluated the efficacy of golimumab in 405 patients suffering from active psoriatic arthritis (Kavanaugh et al, 2009a). Patients received 50 mg, 100 mg or placebo once every 4 weeks. Achievement of ACR 20 criteria at week 14 was the primary end-point and was observed in 51% of patients treated with 50 mg, in 45% of patients receiving 100 mg of golimumab and in 9% of patients in the placebo group. At 24 weeks, Kavanaugh et al. reported further improvement, with 52% and 61% of patients treated with 50 mg and 100 mg achieving ACR 20 criteria, respectively, compared with only 12% of patients in the placebo group. At week 14, a PASI 75 was achieved in 40% and in 58% of patients receiving 50 mg and 100 mg golimumab, respectively, compared to 3% of patients receiving placebo (Kavanaugh et al, 2009a). Long-term efficacy of golimumab was evaluated in a 2-year trial (Kavanaugh et al, 2009b). At week 52, the percentage of patients treated with 50 mg of golimumab achieving ACR 20 and PASI 75 responses was 78% and 62%, respectively. At week 104, the proportion of patients with the aforementioned clinical responses increased to 91% and 69%, respectively. With regard to the group of patients who received 100 mg of golimumab, Kavanaugh et al. observed an ACR 20 response in 81% and in 73% of patients at week 52 and 104, respectively. At the same time points, the percentage of patients achieving a PASI 75 was 70% and 76%, respectively (Kavanaugh et al, 2009b). The authors also reported an improvement in physical function and quality of life

Certolizumab Pegol is another TNF antagonist approved for the treatment of rheumatoid arthritis and Crohn's disease (UCB, Inc., 2010). It is a pegylated Fab fragment of a humanized anti-TNF antibody. The presence of polyethylene glycol prolongs serum halflife of the drug. Certolizumab pegol is unable to induce antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity because of the lack of the Fc region (Bourne et al, 2008). Preliminary data from two phase II clinical trials showed that certolizumab pegol is effective in patients with moderate to severe plaque psoriasis (Ortonne et al, 2007, 2008a, 2008b). In these studies the efficacy and safety at two different dose regimens were evaluated. Patients were treated with 200 mg, 400 mg of certolizumab pegol or placebo every two weeks subcutaneously. At week 12, a PASI 75 response was observed in 74.6% of patients receiving 200 mg and in 82.8% of 400 mg treated-patients compared with 6.8% of patients in the placebo group (Ortonne et al, 2007). The same authors showed that at week 12 a higher number of patients achieved PASI 90 and had a greater improvement in health-related quality of life (Ortonne et al, 2008a, 2008b). A phase III trial

The aforementioned clinical trials show that TNF antagonists are well tolerated and safe. The commonest side effect associated with etanercept, adalimumab and golimumab treatment is a reaction at the site of injection, including redness, itching, bruising, pain, swelling and/or irritation as well as allergic reactions such as latex allergy (Kerbleski & Gottlieb, 2011). Treatment with infliximab is associated with infusion reactions, occurring in around 20% of patients, including pruritus, headache, rash, urticaria, fever or anaphylactic

of certolizumab pegol for psoriatic arthritis is ongoing (UCB, Inc., 2010).

**2.4.2 Clinical efficacy** 

(Kavanaugh et al, 2009a).

**2.5 Certolizumab pegol** 

**2.6 Safety of TNF inhibitors** 

#### **2.3.2 Clinical efficacy**

The clinical efficacy of adalimumab was analyzed by three main clinical trials (Gordon et al, 2006b; Menter et al, 2008; Saurat et al, 2008). In an earlier phase II study enrolling 147 psoriatic patients, two dose regimens of adalimumab were evaluated. Gordon et al. reported a PASI 75 improvement in 80% of patients treated with 40 mg weekly and in 53% of patients receiving 40 mg eow compared with 4% of patients in the placebo group at week 12. At week 60, PASI 75 response was observed in 64% and 56% of patients treated with 40 mg weekly or 40 mg eow, respectively (Gordon et al, 2006b). The phase III placebo-controlled randomized trial by Menter et al. of 1212 patients with plaque psoriasis evaluated the efficacy of adalimumab 40 mg eow. The authors reported a PASI 75 response rate in 71% of the patients after 16 weeks and in 70% after 24 weeks of 40 mg eow adalimumab therapy; the efficacy decreased during weeks 33 to 52 (Menter et al, 2008). The first head-to-head trial CHAMPION compared adalimumab vs methotrexate and reported a PASI 75 response in 80% of patients in the adalimumab 40 mg eow group, in 36% of patients in the methotrexate group and in 19% of those in the placebo group (Saurat et al, 2008). An improvement in DLQI after treatment with adalimumab has been reported by several studies (Menter et al, 2010; Revicki et al, 2008; Saurat et al, 2008; Shikiar et al, 2007).

The clinical efficacy of adalimumab in psoriatic arthritis has also been described (Genovese et al, 2007; Gladman et al, 2007; Mease et al, 2005, 2009). The ADEPT trial involving 315 psoriatic arthritis patients tested the long-term clinical efficacy of adalimumab through 2 years. Mease et al. reported that 58% of patients treated with adalimumab achieved the ACR 20 after 12 weeks compared with 14% of the patients in the placebo group and that similar percentages were maintained up to week 104 (Mease et al, 2005, 2009). These data were confirmed by Genovese et al. who reported an ACR 20 response in 65% of adalimumabtreated patients after week 24 (Genovese et al, 2007).

Recently, the use of adalimumab in combination with traditional therapies was evaluated in psoriasis. Adalimumab with methotrexate results in a lower discontinuation rate of the TNF antagonist (Heiberg et al, 2008); the concomitant administration of adalimumab with phototherapy seems to be clinically effective, but further investigations in controlled clinical trials are needed (Bagel, 2011). The use of topical agents in combination with adalimumab results in a higher short-term efficacy that decreases after 4 weeks (Thaçi et al, 2010).

#### **2.4 Golimumab**

Golimumab is a new TNF antagonist and, like adalimumab, is a fully human anti-TNF IgG monoclonal antibody, which binds to both soluble and transmembrane forms of TNF. Golimumab has been recently FDA- and EMA-approved for the treatment of psoriatic arthritis as monotherapy or in combination with methotrexate. Golimumab is also approved for controlling symptoms of rheumatoid arthritis and ankylosing spondylitis (Centocor Ortho Biotech, Inc., 2010).

#### **2.4.1 Administration**

Golimumab is the first patient-administered once-monthly anti-TNF drug. The recommended dosage is 50 mg subcutaneously every 4 weeks (Centocor Ortho Biotech, Inc., 2010).

### **2.4.2 Clinical efficacy**

336 Psoriasis

The clinical efficacy of adalimumab was analyzed by three main clinical trials (Gordon et al, 2006b; Menter et al, 2008; Saurat et al, 2008). In an earlier phase II study enrolling 147 psoriatic patients, two dose regimens of adalimumab were evaluated. Gordon et al. reported a PASI 75 improvement in 80% of patients treated with 40 mg weekly and in 53% of patients receiving 40 mg eow compared with 4% of patients in the placebo group at week 12. At week 60, PASI 75 response was observed in 64% and 56% of patients treated with 40 mg weekly or 40 mg eow, respectively (Gordon et al, 2006b). The phase III placebo-controlled randomized trial by Menter et al. of 1212 patients with plaque psoriasis evaluated the efficacy of adalimumab 40 mg eow. The authors reported a PASI 75 response rate in 71% of the patients after 16 weeks and in 70% after 24 weeks of 40 mg eow adalimumab therapy; the efficacy decreased during weeks 33 to 52 (Menter et al, 2008). The first head-to-head trial CHAMPION compared adalimumab vs methotrexate and reported a PASI 75 response in 80% of patients in the adalimumab 40 mg eow group, in 36% of patients in the methotrexate group and in 19% of those in the placebo group (Saurat et al, 2008). An improvement in DLQI after treatment with adalimumab has been reported by several studies (Menter et al,

The clinical efficacy of adalimumab in psoriatic arthritis has also been described (Genovese et al, 2007; Gladman et al, 2007; Mease et al, 2005, 2009). The ADEPT trial involving 315 psoriatic arthritis patients tested the long-term clinical efficacy of adalimumab through 2 years. Mease et al. reported that 58% of patients treated with adalimumab achieved the ACR 20 after 12 weeks compared with 14% of the patients in the placebo group and that similar percentages were maintained up to week 104 (Mease et al, 2005, 2009). These data were confirmed by Genovese et al. who reported an ACR 20 response in 65% of adalimumab-

Recently, the use of adalimumab in combination with traditional therapies was evaluated in psoriasis. Adalimumab with methotrexate results in a lower discontinuation rate of the TNF antagonist (Heiberg et al, 2008); the concomitant administration of adalimumab with phototherapy seems to be clinically effective, but further investigations in controlled clinical trials are needed (Bagel, 2011). The use of topical agents in combination with adalimumab

Golimumab is a new TNF antagonist and, like adalimumab, is a fully human anti-TNF IgG monoclonal antibody, which binds to both soluble and transmembrane forms of TNF. Golimumab has been recently FDA- and EMA-approved for the treatment of psoriatic arthritis as monotherapy or in combination with methotrexate. Golimumab is also approved for controlling symptoms of rheumatoid arthritis and ankylosing spondylitis (Centocor

Golimumab is the first patient-administered once-monthly anti-TNF drug. The recommended dosage is 50 mg subcutaneously every 4 weeks (Centocor Ortho Biotech,

results in a higher short-term efficacy that decreases after 4 weeks (Thaçi et al, 2010).

2010; Revicki et al, 2008; Saurat et al, 2008; Shikiar et al, 2007).

treated patients after week 24 (Genovese et al, 2007).

**2.3.2 Clinical efficacy** 

**2.4 Golimumab** 

Ortho Biotech, Inc., 2010).

**2.4.1 Administration** 

Inc., 2010).

The phase III GO-REVEAL clinical trial evaluated the efficacy of golimumab in 405 patients suffering from active psoriatic arthritis (Kavanaugh et al, 2009a). Patients received 50 mg, 100 mg or placebo once every 4 weeks. Achievement of ACR 20 criteria at week 14 was the primary end-point and was observed in 51% of patients treated with 50 mg, in 45% of patients receiving 100 mg of golimumab and in 9% of patients in the placebo group. At 24 weeks, Kavanaugh et al. reported further improvement, with 52% and 61% of patients treated with 50 mg and 100 mg achieving ACR 20 criteria, respectively, compared with only 12% of patients in the placebo group. At week 14, a PASI 75 was achieved in 40% and in 58% of patients receiving 50 mg and 100 mg golimumab, respectively, compared to 3% of patients receiving placebo (Kavanaugh et al, 2009a). Long-term efficacy of golimumab was evaluated in a 2-year trial (Kavanaugh et al, 2009b). At week 52, the percentage of patients treated with 50 mg of golimumab achieving ACR 20 and PASI 75 responses was 78% and 62%, respectively. At week 104, the proportion of patients with the aforementioned clinical responses increased to 91% and 69%, respectively. With regard to the group of patients who received 100 mg of golimumab, Kavanaugh et al. observed an ACR 20 response in 81% and in 73% of patients at week 52 and 104, respectively. At the same time points, the percentage of patients achieving a PASI 75 was 70% and 76%, respectively (Kavanaugh et al, 2009b). The authors also reported an improvement in physical function and quality of life (Kavanaugh et al, 2009a).

### **2.5 Certolizumab pegol**

Certolizumab Pegol is another TNF antagonist approved for the treatment of rheumatoid arthritis and Crohn's disease (UCB, Inc., 2010). It is a pegylated Fab fragment of a humanized anti-TNF antibody. The presence of polyethylene glycol prolongs serum halflife of the drug. Certolizumab pegol is unable to induce antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity because of the lack of the Fc region (Bourne et al, 2008). Preliminary data from two phase II clinical trials showed that certolizumab pegol is effective in patients with moderate to severe plaque psoriasis (Ortonne et al, 2007, 2008a, 2008b). In these studies the efficacy and safety at two different dose regimens were evaluated. Patients were treated with 200 mg, 400 mg of certolizumab pegol or placebo every two weeks subcutaneously. At week 12, a PASI 75 response was observed in 74.6% of patients receiving 200 mg and in 82.8% of 400 mg treated-patients compared with 6.8% of patients in the placebo group (Ortonne et al, 2007). The same authors showed that at week 12 a higher number of patients achieved PASI 90 and had a greater improvement in health-related quality of life (Ortonne et al, 2008a, 2008b). A phase III trial of certolizumab pegol for psoriatic arthritis is ongoing (UCB, Inc., 2010).

#### **2.6 Safety of TNF inhibitors**

The aforementioned clinical trials show that TNF antagonists are well tolerated and safe. The commonest side effect associated with etanercept, adalimumab and golimumab treatment is a reaction at the site of injection, including redness, itching, bruising, pain, swelling and/or irritation as well as allergic reactions such as latex allergy (Kerbleski & Gottlieb, 2011). Treatment with infliximab is associated with infusion reactions, occurring in around 20% of patients, including pruritus, headache, rash, urticaria, fever or anaphylactic

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 339

(Krueger, 2002). Alefacept also causes the depletion of CD45RO+ memory T cells via cytotoxic cell-mediated apoptosis; this occurs between CD2 on target T lymphocytes and Fc receptors, primarily FcRIII+, on natural killer cells and macrophages (Cooper et al, 2002). Alefacept was the first FDA-approved biologic agent in 2003 for the treatment of moderate to severe chronic plaque psoriasis in patients who are candidates for systemic treatment or phototherapy (Biogen Inc., 2003) but it is not currently approved for the treatment of psoriasis by EMA. It is also being investigated for the treatment of other conditions caused by T-cell dysregulation, such as psoriatic arthritis (Kraan et al, 2002; Mease & Reich, 2009).

The recommended administration of alefacept is a once-weekly 15 mg intramuscular injection (IM) for 12 weeks (Biogen Inc., 2003), although intravenous bolus injection (IV) has also been evaluated in several studies. A comparison of the pharmacokinetic and biologic activity of IM and IV administration showed that an adequate dose of IM alefacept leads to similar bioavailability and efficacy compared to IV administration and it is associated with minimal adverse effects (Vaishnaw & TenHoor, 2002). Retreatment with an additional 12 week course may be initiated if CD4+ T-lymphocyte counts are within the normal range, and a minimum of a 12-week interval has passed since the previous course of treatment

A series of clinical trials showed significant improvement in the PASI score in patients treated with alefacept. The first multicenter, randomized, controlled phase II trial was conducted in 229 patients who received alefacept 0.025, 0.075 and 0.150 mg/kg IV or placebo weekly for 12 weeks, with a 12-week follow-up (Ellis & Krueger, 2001). Patients achieved a reduction in PASI by 38%, 53% and 53%, respectively, compared with 21% reduction by placebo. A significant improvement in quality of life was also reported, and long-term follow-up showed a sustained response for a median of 10 months (Ellis &

Two phase III clinical trials showed similar results (Krueger et al, 2002; Lebwohl et al, 2003). In these trials, patients with chronic plaque psoriasis received a once-weekly administration of alefacept IV or IM for 12 weeks, with a 12-week follow-up. In the first study (Krueger et al, 2002), a total of 553 patients was randomized to receive 7.5 mg of IV alefacept or placebo, while in the second trial (Lebwohl et al, 2003) 507 patients were treated with 10 or 15 mg of IM alefacept or placebo. Both trials showed a significant clinical improvement in psoriatic patients: a PASI 75 was achieved by 28% in IV-treated patients compared to 8% in placebotreated patients, and by 28% and 33% in 10 or 15 mg IM-treated patients, respectively, compared to 13% in the placebo group. Most responder patients maintained a 50% or greater reduction in PASI in the follow-up period. Other studies have been performed to investigate alefacept efficacy and safety in the long-term treatment of plaque psoriasis. Treatment of up to 5 courses provided incremental efficacy in responders, while maintaining the safety profile (Menter et al, 2006; Roberts et al, 2010). Although these studies are limited by the decreasing number of patients over multiple treatment courses or the lack of appropriate controls, but do they suggest that multiple courses of alefacept are

well tolerated and maintain clinical improvement in responder patients.

**3.1.1 Administration** 

(Biogen Inc., 2003).

Krueger, 2001).

**3.1.2 Clinical efficacy** 

reactions (Leman & Burden, 2008). For all TNF inhibitors, the primary concern is the increased risk for viral, bacterial and fungal infections, mainly of the upper respiratory tract (Kunz, 2009). Therapy with anti-TNF agents can lead to reactivation of latent tuberculosis, more frequently with infliximab (associated with the highest risk) and adalimumab than etanercept (Dixon et al, 2006). Another safety issue is the development of malignancies. The use of TNF inhibitors is associated with an increased risk of non-melanoma skin cancer (NMSC); the occurence of NMSC may be due to the previous use of phototeraphy and immunosuppressive agents, even if a potential risk to develop cancer after anti-TNFtherapy cannot be excluded (Kerbleski & Gottlieb, 2011). A paradoxical side effect of anti-TNF therapies is the new onset and worsening of psoriasis, which have been reported in some cases (Ko et al, 2009). Infliximab, adalimumab and golimumab have been shown to cause hepatotoxicity (Kavanaugh et al, 2009a; Reich et al, 2005). On the contrary, etanercept seems to be effective and safe in the treatment of psoriatic patients with chronic hepatitis C virus-infection (Piccolo et al, 2008; Zeinn et al, 2005). Moreover, TNF inhibitors can potentially worsen congestive heart failure (Chung et al, 2009). The TNF blockade can lead to development of antinuclear antibodies and anti-double-stranded DNA antibodies. A lupus-like syndrome may occur with TNF antagonists, but it is a rare event that reverts after discontinuation of therapy (Ramos-Casals et al, 2008). Other rare events associated with TNF antagonists are the development of serious hematological diseases, such as leukopenia, neutropenia, thrombocytopenia, pancytopenia or aplastic anemia and the development or worsening of peripheral and central demyelinating disorders (Montane et al, 2007; Roberts & McColl, 2004). Rare dermatological diseases such as erythema multiforme, Steven's Johnson syndrome and toxic epidermal necrolysis have been reported during etanercept, infliximab and adalimumab treatment (Kerbleski & Gottlieb, 2011).

### **3. T-cell inhibitors**

Psoriasis is defined as a T cell-mediated autoimmune disease based on the advanced understanding of its pathogenesis. Primarily, a deregulated Th1/Th17 response has been reported in psoriatic skin (Lowes et al, 2008). Due to the primary role that T cells play in this disease, a new class of biologics has been designed to interfere with T-cell activation and functions. Currently, alefacept is the only T cell inhibitor drug approved for the treatment of psoriasis. Efalizumab was withdrawn from the market because of the associated risk of progressive multifocal leukoencephalopathy. Two other T-cell modulators are currently being evaluated for their use in psoriasis and psoriatic arthritis.

#### **3.1 Alefacept**

Alefacept is a recombinant human fusion protein consisting of the soluble lymphocyte function-associated antigen-3 (LFA-3) and the IgG1 Fc fragment (Biogen Inc., 2003). The LFA-3 portion binds to CD2, highly expressed on CD4+ and CD8+ memory-effector T cells (CD45RO+), while the IgG1 portion binds to Fc receptors on cytotoxic cells (da Silva et al, 2002). Alefacept inhibits T-cell activation and proliferation, by interfering with the downstream activation of cytokines by interfering with the binding between CD2 on T lymphocytes and LFA-3 on antigen-presenting cells (da Silva et al, 2002). Since CD2 is highly expressed on CD45RO+ T cells, alefacept mainly inhibits memory-effector T cells, which represent the majority of T lymphocytes in psoriatic lesions, and preserves naïve cells (Krueger, 2002). Alefacept also causes the depletion of CD45RO+ memory T cells via cytotoxic cell-mediated apoptosis; this occurs between CD2 on target T lymphocytes and Fc receptors, primarily FcRIII+, on natural killer cells and macrophages (Cooper et al, 2002). Alefacept was the first FDA-approved biologic agent in 2003 for the treatment of moderate to severe chronic plaque psoriasis in patients who are candidates for systemic treatment or phototherapy (Biogen Inc., 2003) but it is not currently approved for the treatment of psoriasis by EMA. It is also being investigated for the treatment of other conditions caused by T-cell dysregulation, such as psoriatic arthritis (Kraan et al, 2002; Mease & Reich, 2009).
