Novel biological treatments for psoriasis

teaser

Susana Cortijo-Cascajares
PharmD

Mª del Pilar García-Rodríguez
PharmD

Mercedes Campo-Angora
PharmD PhD

Olga Serrano-Garrote
PharmD

Alberto Herreros de Tejada
PharmD PhD
Head of Pharmacy
Department
Pharmacy Department
12 de Octubre University Hospital
Madrid, Spain
E:[email protected]

Psoriasis is a chronic, inflammatory illness characterised by epidermic proliferation and by the appearance of T-cell inflammatory infiltrates in the dermis and the epidermis.(1) It is estimated that it affects 2% of the population worldwide.(2) Psoriasis is a genetically predisposed autoimmune disease characterised by the presence of frequent recurrence–remission episodes. Symptoms may vary from mild to severe, and exfoliative cutaneous lesions of variable size to inflammatory arthropathies can be observed.(3)

The most common form of psoriasis, affecting 90% of patients, is plaque psoriasis or psoriasis vulgaris. In some patients (5–10%), it is accompanied by inflammation of the joints (psoriatic arthritis).

In general, treatment of patients with moderate to severe psoriasis is based on topical agents, phototherapy (UVB or psoralen plus UVA) and systemic agents such as ciclosporin, methotrexate or retinoids. New biological therapies were developed due to the occurrence of adverse events and the insufficient effectiveness achieved with conventional treatments.

Discussion
A better knowledge of the underlying immunology of psoriasis has opened the door to a rational design of new therapeutic agents. Mostly, these new agents are specific proteins designed to bind extracellular targets (see Table 1). Their main advantage is a greater selectivity, which contributes to minimise the incidence of adverse events.(4)

[[HPE20_table1_80]]

Alefacept
In January 2003, alefacept was the first biological agent approved by the FDA for the treatment of moderate to severe plaque psoriasis.

Alefacept is a protein formed by the fusion of LFA-3 and the Fc domain of a human IgG1. LFA-3 is a CD2 ligand receptor that is present in antigen-presenting cells (APCs). Binding of alefacept to CD2 receptors inhibits T-cell activation and proliferation. Furthermore, T-cell apoptosis is induced when the Fc portion of alefacept binds receptors present in macrophages and natural killer cells. This produces a reduction in the number of circulating memory T-cells involved in the pathogenesis of psoriasis, which correlates with an improvement of symptoms.(5-7) The B-cell and naive T-cell counts remain constant.(8,9)

Alefacept has been studied in multiple clinical trials with more than 2,300 patients, where it has been demonstrated as an effective therapy inducing prolonged remissions (seven to eight months).(1,10–12) Alefacept should be administered once weekly at a dose of 15mg intramuscularly (IM) for 12 weeks. Although the FDA has also approved intravenous (IV) alefacept, this formulation will not be available in the future due to low demand.

Administration of a 12-week additional cycle of therapy may be considered. Following this second cycle of therapy, the number of patients who responded to treatment was increased and longer remission periods were observed.(13,14) Circulating CD4+ T-cells should be monitored during treatment with alefacept; below 250 cells/ml, treatment should be interrupted.(13)

Overall, alefacept is well tolerated, and no reference has been made to severe adverse events. The most frequent adverse events are chills, shivers, pharyngitis, vertigo, nausea, itching, myalgia and pain,  and inflammation at the injection site.(15) The lowering of the memory T-cells population has not been associated with an increase in the risk of infections or malignancies.(16)

Efalizumab
Efalizumab is a humanised monoclonal antibody (MAb) that specifically binds the alfa subunit of LFA-1 (CD11a). It is the second biological agent approved by the FDA (in October 2003) for the treatment of moderate to severe psoriasis.

LFA-1 is a beta2 integrin, formed by two subunits (CD11a and CD18), which is present on the surface of T-cells. LFA-1 interacts with the intercellular adhesion molecule 1 (ICAM-1) present in APCs. This interaction is an important costimulatory signal in the activation of T-cells. LFA-1 also binds ICAM-1 expressed in endothelial cells as a necessary step for T-cell migration into the skin. The binding of efalizumab to CD11a blocks the interaction between LFA-1 and ICAM-1, preventing T-cell trafficking and T-cell activation.(17)

Efalizumab is administered subcutaneously at a dose of 1mg/kg once weekly. Following simple training, it can be self-administered by the patient. Some patients experienced headache, nausea, fever, shivers and myalgia following the initial doses. These adverse events were generally mild and usually disappeared after the third dose. There was no significant increase in opportunistic infections and malignancies. Efalizumab can cause thrombocytopenia. Platelet count should be monitored during treatment. Patients tend to relapse in the course of two months following therapy discontinuation, suggesting the possibility of continuous efalizumab treatment to maintain control of psoriasis.(18)

Etanercept
Etanercept is formed by the fusion of the two p75 extracellular domains of the tumour necrosis factor a (TNFalpha) receptor. Etanercept competitively inhibits the binding of TNFa to its cell surface receptor, which makes TNFalpha biologically inactive.(19) TNFalpha is a proinflammatory cytokine, and it has been observed that TNFalpha concentrations are higher in the skin and joints of psoriatic patients, playing an important role in T-cell activation and migration.(20,21)

Etanercept is approved for the treatment of arthritis and psoriatic arthritis and has been approved by the FDA in May 2003 for the treatment of moderate to severe chronic plaque psoriasis.

Etanercept is administered subcutaneously twice weekly. The most frequent adverse events are local reactions at the site of injection. In some patients, an increase in the risk of infections has been observed, and there have even been cases of tuberculosis reactivation. Rarely, etanercept treatment has been associated with demyelinating disorders such as multiple sclerosis, aplastic anaemia and allergic reactions.(22,23)

Infliximab
Infliximab is a chimeric MAb capable of specifically inhibiting TNFalpha. It is obtained by fusion of the variable regions of the human TNFa-specific murine antibody with the constant regions of human immunoglobulin IgG1kappa. The binding of infliximab to the TNFalpha receptor interrupts the TNFalpha-mediated activation sequence of inflammatory pathways. It is administered IV as a two-hour infusion.(24)

Infliximab has been approved for the treatment of rheumatoid arthritis and Crohn’s syndrome, but has not yet been approved by the FDA for the treatment of psoriasis. Infliximab has been well tolerated in all clinical trials, with low incidences of fever, nausea, dizziness, chills, hypotension, dyspnoea and thoracic pain reported.(25)

An increase of infections has been reported in patients treated with infliximab, and even some cases of latent tuberculosis reactivation have been described.(26) No increase of lymphoproliferative processes or malignancies has been notified.

Conclusion
Advances in the knowledge of the immunopathology of psoriasis have led to the development of new therapies specifically designed to act on the immunological targets involved in the pathogenesis of psoriasis.

Initial results suggest that these new agents have a better safety profile than traditional therapies and increase the response to treatment duration, affording prolonged periods free of illness; no long-term safety data are yet available for these new agents.

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