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Department of Dermatology
Carl Gustav Carus
Psoriasis is a chronic inflammatory disease affecting approximately 2–2.5% of the population in Western countries. The most common form is chronic plaque psoriasis. Key features of the lesions are increased epidermal thickness, hyperkeratinisation and significant inflammation of dermis and epidermis. There is mounting evidence that patients suffering from psoriasis have lower quality of life associated with physical discomfort and negative body and self-image. Moreover, recent data demonstrate that signs of metabolic syndrome are more often present in psoriasis patients (eg, obesity, hypertension, diabetes).(1)
Psoriasis is considered to be a T-cell-mediated autoimmune disease.(2–6) Strong evidence derives from the development of a model of psoriasis using severe combined immunodeficient (SCID) mice (mouse–human skin chimeras) and from the therapeutic efficacy of immunosuppressive agents such as ciclosporin A. Immunohistochemical studies have shown that the majority of T-cells in psoriatic lesions are CD45RO+ memory effector T-cells trafficking into skin.(6) In terms of cytokine profile, psoriasis is characterised by the predominance of Th1 cytokines such as tumour necrosis factor α (TNFα), interferon γ (INFγ), interleukin (IL)-2 and -12.(2,7) Thus, to a large extent, psoriasis exhibits immunological features similar to those seen in rheumatic arthritis, ankylosing spondylitis and inflammatory bowel diseases (eg, Crohn’s disease). Therefore, these conditions are called immune-mediated inflammatory diseases (IMIDs).
Because activated T-cells and inflammatory cytokines play a crucial role in the pathophysiology of psoriasis, new immunomodulatory therapeutic approaches primarily include four targeted strategies:(8)
Biological agents represent a new group of compounds that are produced using biotechnology methods. In dermatology, these protein-based biologicals mainly include three different types of compounds (see Table 1). At present, more than 20 biological agents are approved or under development for psoriasis therapy.
The first biological agent that has been especially developed for treating psoriasis is alefacept (Amevive). This genetically engineered fully human fusion protein (LFA-3/IgG1) binds with the LFA-3 portion to CD2 of memory-effector T-lymphocytes, thus inhibiting their activation. Additionally, a significant part of the antipsoriatic efficacy of alefacept is due to its ability to reduce selectively the number of CD45RO+ T-cells by inducing apoptosis.(10) Activated T-cells release cytokines that induce hyperproliferation. Both mechanisms lead to an improvement of the psoriatic condition. Results of clinical trials reveal that alefacept administered both intramuscularly (15mg weekly) or intravenously (IV; 7.5mg weekly) significantly improves clinical outcomes and severity of chronic plaque psoriasis. As treatment modality, the manufacturer recommends the use of alefacept in treatment courses of 12 weeks, each followed by a 12-week treatment-free interval. Repeated courses are possible if the number of CD4+ T-cells in peripheral blood does not remain under the limit of 250 cells/ml; this should be controlled at least biweekly. Combination therapy with UVB may increase the resumption of disease activity. Based on currently available data and clinical experience, alefacept is a safe drug with delayed onset of action but long remission effect after cessation of therapy.(8,10,12) Alefacept is approved in the USA, Canada, Israel and Switzerland for the treatment of moderate to severe chronic plaque psoriasis. In Europe, a phase III trial is currently ongoing. Approval by the EMEA for EU countries should occur next year.
A second agent, efalizumab (Raptiva), is a humanised monoclonal antibody that blocks the LFA-1/ICAM-1 interaction, resulting in the inhibition of T-cell migration into the skin and activation of T-cells.(4,9) This biological agent has also been developed specifically for the treatment of psoriasis. Clinical trials confirmed substantial improvement, with an initial response after 2–4 weeks in patients with moderate to severe chronic plaque psoriasis. Treatment regimen consists of an initial conditioning dose of 0.7mg/kg in week 1, followed by once-weekly doses of 1mg/kg subcutaneously.
The most common side-effects include headache, chills, fever and flu-like syndrome, occurring within the first 48 hours following injection and often decreasing after the first few weeks of therapy. Control of blood count is recommended. Efalizumab has a good safety profile, with no organ toxicity, even for long-term use. After cessation of efalizumab, patients have to consider that relapse occurs on average within 60–80 days. Efalizumab has been approved by the FDA, the EMEA and in Switzerland. Both alefacept and efalizumab represent a therapeutic strategy with the common goal of reducing pathogenetic T-cells.
Another fundamental strategy for treating psoriasis has recently emerged: the inhibition of pro-inflammatory cytokines.(2,7) As the role of Th1 cytokines (especially TNFα) in psoriasis has become increasingly clear, the use of TNFα-blocking biologicals has been extended from rheumatoid arthritis and Crohn’s disease to psoriasis and psoriatic arthritis.(12–14) Considerable evidence supports the role of TNFα as a key inflammatory cytokine involved in the pathophysiology of both entities. Increased levels are found, for example, in psoriatic skin and synovial fluid.(15,16) In recent years, efforts have been made to standardise the nomenclature of the members of the TNFα superfamily and their receptors.(15) To date, three TNFα antagonists are available: etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira).
The fusion protein etanercept was the first TNFα antagonist approved for the treatment of psoriasis and psoriatic arthritis in the USA and EU. The drug consists of a soluble, fully human TNFα receptor and IgG1.(9) It binds to biologically active TNFα, which results in a reduction of inflammatory activity.
Efficacy has been confirmed by recent clinical trials in patients suffering from psoriasis and psoriatic arthritis. These studies highlighted the efficacy in terms of skin symptoms and joint involvement. The usual dose of etanercept is 25mg subcutaneously twice weekly. Higher dosage of 50mg biweekly as monotherapy or concomitantly with other immunomodulatory drugs such as methotrexate or leflunomide may be used.(17) Unwanted effects associated with the use of etanercept should be strictly monitored (eg, injection reactions, risk of activating latent infections or formation of autoantibodies). Serious adverse effects, including some fatalities, have been reported. Nevertheless, etanercept is generally well tolerated and possesses a good safety profile. Recommendations from the manufacturer should be noted.
Infliximab is a chimeric (mouse/human) IgG1 monoclonal antibody with high affinity for human TNFα.(16,18–20) This biological agent has been approved by FDA and the EMEA for the treatment of rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis and psoriatic arthritis. Because of its high efficacy in psoriasis, approval in chronic plaque psoriasis should occur in 2005. Data from placebo-controlled clinical trials in patients with psoriasis and psoriatic arthritis indicate a rapid onset of action and a sustained, high level of relief, even in cases of severe recalcitrant psoriasis. (9,11–13,16) Infliximab therapy shows a benefit on the symptoms of arthritis and on skin lesions. Infliximab has a long elimination half-life and is administered by IV infusion (3–5mg/kg) in week 0, 2, 6 (induction phase) and thereafter in time intervals of 8–12 weeks (maintenance phase). In most cases, infliximab is used in combination with methotrexate. As with other TNFα antagonists, some adverse events have to be monitored (eg, infusion reactions, reactivation of infections such as tuberculosis, risks of induction of lymphoproliferative disorders and antibody/autoantibody production).(16,19,21–24) Some serious adverse events, including fatalities, have been reported in patients receiving infliximab. However, assuming that patients are strictly controlled by experienced physicians, infliximab is generally well tolerated and has a good safety profile. To date, over 650,000 patients worldwide have been treated with infliximab.(25)
Adalimumab, a fully human anti-TNFα monoclonal antibody, has been approved by the FDA and the EMEA for the treatment of rheumatoid arthritis.(11,20) The recommended dose of 40mg is administered every other week subcutaneously. Although efficacy and safety of adalimumab in the management of chronic stable psoriasis have not yet been established, the drug has been used successfully in patients suffering from psoriasis arthritis and approval by the FDA for this condition should occur in 2005. Further studies are needed to evaluate the use of adalimumab in the treatment of chronic plaque psoriasis.
The development of novel biological agents and their therapeutic use has changed and extended our armamentarium for the treatment of psoriasis. The five agents presented in this article are only the first biologicals available, and others are in development (eg, anti-CD4- antibody, antiinflammatory cytokines such as IL-4, IL-10 and IL-11 or newly developed TNFα antagonists such as onercept).(2,7,11) The understanding of psoriasis as a T-cell-mediated disease creates opportunities for targeted therapeutic interventions with no organ toxicity. Nevertheless, the development of new drug modalities for psoriasis is not restricted to the group of biologicals, but also includes conventional pharmacological compounds such as leflunomide, which was approved in 2004 for the treatment of psoriatic arthritis.(26)