**3.1.1 Administration**

338 Psoriasis

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).

being evaluated for their use in psoriasis and psoriatic arthritis.

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

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

**3. T-cell inhibitors** 

**3.1 Alefacept** 

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 (Biogen Inc., 2003).
