New therapies for the treatment of psoriasis

teaser

Laura Mahiques Santos
MD

Teresa Martínez Menchón

Gerard Pitarch Bort

José Miguel Fortea Baixauli
Servicio de Dermatología
Hospital General Universitario
Valencia
Spain
E:[email protected]

Psoriasis is a chronic inflammatory disease of the skin that affects 2–3% of the population.(1,2) While the underlying aetiology has not been fully clarified, the existence of hereditary factors has been postulated, with a complex polygenic hereditary trait and the intervention of external triggering and immune factors.(1,3) At present, psoriasis is believed to result from keratinocyte hyperproliferation secondary to lymphocyte activation in the dermis. Different studies have shown that this lymphocyte infiltrate is of T-cell lineage, and that an increased presence of Th1-subtype cytokines is found at psoriasis plaque level.(1,4–7) These findings have led to the development of new treatments for the disease, specifically targeted to inhibit certain points within the inflammatory cascade. Since these therapeutic strategies are more selective, they produce fewer side-effects than the treatments used to date, and could be applied for longer periods of time.(8,9)

Current and emerging immunomodulatory therapies for psoriasis

Alefacept
Alefacept (Biogen) is a recombinant fusion protein composed of the terminal portion of LFA-3 and the Fc portion of human immunoglobulin IgG1. It blocks the costimulating inflammatory signal by binding its LFA-3 portion to its match on the T-cell, the CD2 receptor, and reduces the number of activated T-cells by inducing apoptosis via activation of the perforin/granzyme system on natural killer (NK) cells. This explains why the response to therapy correlates with the number of activated T-cells found in the circulation.(10–12) Several studies have shown the efficacy of alefacept in plaque-type psoriasis when administered either intravenously or intramuscularly.(13,14) Patients who can benefit from alefacept therapy include those who have moderate-to-severe psoriasis (affecting >10% of body surface area) or who are candidates for systemic agents or phototherapy. A pretreatment CD4 count must be obtained, and alefacept is administered intramuscularly at a weekly dose of 15mg for 12 weeks.(10,15)

Efalizumab
Efalizumab (Raptiva; Genentech/Xoma)(16) is a humanised IgG1 monoclonal antibody that binds to the CD11a subunit of the LFA-1 surface molecule found on T-cells. It blocks interaction of T-cells with ICAM, thereby blocking T-cell trafficking to the skin, T-cell activation and T-cell adhesion to keratinocytes and endothelial cells.(9) Efalizumab is administered once a week subcutaneously at a dose of 1mg/kg. The initial dose may be lower (0.7mg/kg) in order to minimise possible transient flu-like symptoms.(16) Several studies have shown the efficacy of efalizumab in plaque-type psoriasis,(17,18) and long-term treatment studies are currently underway.(17) Efalizumab is associated with an early onset of action,(17) and psoriasis relapse is usually seen within 60–70 days of discontinuation of therapy.(20) Rebound (defined as a flare >125% of the baseline psoriasis area severity index [PASI] score) could occur during or after efalizumab therapy in 1–5% of patients.(21)

Etanercept
Etanercept (Enbrel; Amgen) is a fully human dimeric fusion protein comprising the human tumour necrosis factor (TNF)-a p75 receptor and the Fc portion of human IgG1 molecule. It acts by binding to and inactivating soluble TNFa – thereby preventing interactions with its surface receptors. Unlike other anti-TNFs, etanercept does not induce complement-mediated cell lysis in vitro.(21–23) Several studies have shown the efficacy of etanercept in plaque-type psoriasis, and levels of TNF have been shown to correlate to disease severity.(24,25) Progressive clearance of psoriasis is seen with the treatment, and there is no rebound. Long-term studies of treatment efficacy and safety are currently underway. The approved etanercept dosage for plaque-type psoriasis is 50mg/week during 24 weeks or, alternatively, 100mg/week during 12 weeks followed by 50mg/week for another 12 weeks.(22) Retreatment with etanercept is possible without a concomitant decrease in efficacy. It can be used with methotrexate, and there are anecdotal reports of its use with phototherapy or immunosuppressants such as hydroxyurea, acitretin or ciclosporin. The most frequent side-effects of etanercept are mild transient injection site reactions, respiratory infections, headache and rhinitis. Rare cases of pancytopenia or demyelinisation have been reported.(26,27) A percentage of patients develop antinuclear antibodies, but there have been only rare cases of etanercept-induced systemic lupus erythematosus.(28) Etanercept should be avoided in patients with advanced heart failure.(21–23,29)

Infliximab
Infliximab (Remicade; Centocor) is a mouse/human chimeric anti-TNFa monoclonal antibody comprising a mouse variable region and a human IgG1 constant region. It binds to soluble and transmembrane TNFa molecules, blocking their action, and induces complement-mediated cell lysis of cells expressing transmembrane TNFa.(21,30) The drug is currently licensed for the treatment of rheumatoid arthritis and Crohn’s disease. Infliximab has shown efficacy in the treatment of plaque-type and even recalcitrant psoriasis, alone or combined with methotrexate.(31–33) It offers rapid onset of action (two weeks) after a 5 or 10mg/kg infusion dose, and there are several reports of sustained benefit after an induction dose or in maintenance therapy.(34,35)

However, in our personal experience, infliximab as long-term monotherapy shows a decrease in efficacy, reflected in a shortening of drug clearance between doses, or a lesser reduction in PASI score after infusions.(36) This loss of efficacy could be related to the formation of human antichimeric antibodies – a situation that could be prevented by concomitant use of methotrexate.(36,37)

The most frequent side-effects of infliximab are infusion-related reactions, infections, headache, vertigo, flushing, abnormal hepatic function and fatigue. Like other anti-TNFa drugs, it could produce antinuclear antibodies, demyelinating disorders, worsening of heart failure and an increased rate of infections. For this reason, a tuberculin test is required in all patients undergoing therapy with infliximab.(21,30)

[[HPE21_fig1_78]]

Adalimumab
Adalimumab (Humira; Abbott) is a fully human monoclonal antibody IgG1 that binds and blocks soluble and transmembrane TNFa. It is currently approved for rheumatoid arthritis, and some phase II and III studies show clinical efficacy by lowering the PASI scores.(25,38,39) Dosing in psoriasis varies from 40mg weekly to 40mg every other week, with a loading dose of 80mg. Its fully human structure makes adalimumab theoretically less immunogenic than its predecessors. The primary side-effect is pain at the injection site, while other commonly reported problems are mild headache, nausea, elevated triglycerides, cough, sinus congestion and fatigue. Like other anti-TNFa therapies, it could produce other infrequent side-effects(39) (see etanercept and infliximab).

[[HPE21_table1_79]]

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