teaser
Efstathios Rallis
PhD
Vasileios Anyfantakis
MD
Department of Dermatology
General Military Hospital
Athens
Greece
Department of Dermatology
St Louis Hospital
Paris
France
E:[email protected]
Psoriasis is a common skin disease with approximately 2−3% prevalence in the Caucasian population.(1) It is a chronic inflammatory disorder that has traditionally been considered as a disease of excessive keratinocyte proliferation and abnormal differentiation. Additionally, an inflammatory infiltration of the affected skin is observed with polymorphonuclear leukocytes, macrophages and activated T-cells.
Pathogenesis
The exact pathogenesis of psoriasis is not fully understood. However, current evidence suggests that it is a T-cell-mediated inflammatory disease(1) involving the expression of several cytokines such as interferon γ (INFγ), tumour necrosis factor α (TNFα), interleukins (ILs) 1, 2, 3, 6 and 8, granulocyte-macrophage colony-stimulating factor (GM-CSF), epidermal growth factor (EGF), fibroblast growth factor (FGF) and transforming growth factor α (TGFα) produced by almost all cells present in the skin lesions. Epidermal hyperplasia is believed to be a reaction to the activation of the immune system in focal regions, triggered by a nonidentified antigen and mediated by CD8 and CD4 lymphocytes accumulated in the affected skin.(2)
Conventional systemic therapies
In terms of systemic medication the main agents used to treat psoriasis include agents such as methotrexate, ciclosporin, photochemotherapy with psoralens and ultraviolet A (PUVA), phototherapy with ultraviolet B and retinoids. Recently, selective immunomodulatory agents that block cellular inflammatory pathways with less toxic side-effect profiles were put on the market. This constitutes an improvement as, in general, one-quarter of all patients presenting with chronic plaque psoriasis require systemic therapy.(3)
Biological therapies
Increased understanding of molecular interactions in the immune response has led to the development of new agents that target specific steps in the pathogenesis of psoriasis without global immunosuppression. The main goal of biological therapies is to prevent pathological effector’s immune responses in skin tissue.(4) Biological therapies for psoriasis can be divided in two functional groups:
- Agents targeting the cytokine TNFα.
- Agents targeting T-cells or antigen-presenting cells (APC).
Depending on their structure these agents comprise four distinct groups:
- Chimeric antibodies (Ac), which are fused segments of mouse and human antibodies – designated by the suffix -ximab.
- Humanised Ac, which are individual amino acids in a human backbone replaced with specific binding sequences derived from a murine monoclonal antibody – designated by the suffix -zumab.
- Human sequenced Ac, which are generated in genetically engineered mice – designated by the suffix -mumab.
- Fusion proteins, a more diverse category, usually consist of the receptor domain of a human protein fused to the constant region sequences of human IgG. Therefore, the fusion protein has binding specificity for a particular ligand or coreceptor and is soluble in human plasma – suffix -cept.(2)
- Biological therapies currently used in the treatment of psoriasis will now be described.
Infliximab (Remicade)
This is a murine/human chimeric anti-TNFα monoclonal antibody. It binds with high affinity to the soluble and transmembrane forms of TNFα, thus neutralising its activity. Infliximab, also indicated for Crohn’s disease and rheumatoid arthritis (RA), is given by intravenous infusion at 3−5mg/kg at weeks 0, 2 and 6, and it may be followed by repeat single infusions at 8−12 week intervals.(5,6)
Alefacept (Amevive)
This is a recombinant LFA-3IgG1 fusion protein that contains only the external domain of the leukocyte function-associated antigen-3 (LFA-3). It blocks the interaction between LFA-3 expressed on APC and CD2 expressed on T-lymphocytes through competitive inhibition, thereby inhibiting T-cell activation and proliferation. It also results in apoptosis of T-cells expressing high levels of CD2 (memory T-cells). It is administered intramuscularly (IM), at 15mg weekly for 12 weeks followed by a 12 weeks pause and re-evaluation.(7)
Efalizumab (Raptiva)
It is a humanised murine antibody directed against CD11α, one of the subunits of LFA-1. LFA-1 is a T-cell surface integrin, a heterodimeric molecule composed of an α-chain (CD11α) and a β-chain (CD18), which binds to the intercellular adhesion molecule type 1 (ICAM-1) present in APC cells. The blockade of LFA-1/ICAM-1 binding inhibits T-cell activation, cutaneous trafficking and adhesion to keratinocytes. Efalizumab is administered as a subcutaneous (SC) injection at 0.7mg/kg the first week and then 1mg/kg weekly for at least 12 weeks.(8,9)
Adalimumab (Humira)
It is a recombinant anti-TNFα human IgG1 monoclonal antibody that blocks its interaction with the p55 and p75 cell surface receptors. Adalimumab, also used in moderate-to-severe RA, is administered as a SC injection at 40mg every two weeks for a period of 12 weeks.(10,11)
Etanercept (Enbrel)
This is a fusion protein of the constant Fc portion of human IgG1 and the extracellular ligand-binding domain of TNF receptor-2. It binds to soluble and membrane-bound TNFα with specificity and affinity, thus blocking its interaction with cell surface receptors. Etanercept, which is also indicated for children with refractory juvenile RA, adults with severe RA, psoriatic arthritis and ankylosing spondylitis, is administered as a SC injection at 25mg or 50mg twice weekly for 12 weeks followed by 50mg SC once a week.(12,13) Randomised, double-blind, placebo-controlled studies have been carried out for all these biological agents. Efficacy has been demonstrated by a statistically significant reduction of the Psoriasis Area and Severity Index (PASI) score; in addition, tolerability and safety tests showed no major adverse effects. Alefacept, efalizumab and etanercept have been approved by the US FDA for moderate-to-severe plaque psoriasis.
New therapies for psoriasis
In addition to biological agents, other molecules are being tested for the treatment of psoriasis.
Pimecrolimus (Elidel)
Pimecrolimus is an ascomycin derivative that inhibits T-cell activation and proliferation. It has already been evaluated as 1% cream in the treatment of atopic dermatitis with excellent results. Recently it has been tested both in an oral form as well as as a topical agent (Elidel cream 1%) for psoriasis.(14,15)
Tacrolimus (Prograf, Protopic)
Systemic tacrolimus (Prograf) seemed promising in the treatment of chronic plaque psoriasis.(16) Topical tacrolimus (Protopic ointment 0.05% and 0.1%) was reported as an ineffective agent in the treatment of plaque-type psoriasis.(17) However, recent studies emphasise the safety and effectiveness of topical tacrolimus in the treatment of some specific types of psoriasis, such as genital and facial psoriasis.(15,18)
Oral tazarotene
Oral tazarotene, an acetylenic retinoid, is in clinical development for the treatment of psoriasis.(19) Phase III clinical trials have demonstrated a beneficial effect in moderate-to-severe plaque psoriasis.(20) In addition, oral tazarotene is not associated with any other adverse events than those typically observed with oral retinoids, such as hypertriglyceridaemia and hypercholesterolaemia, with the exception of teratogenicity, which may limit use in female patients.(20)
Rosiglitazone maleate (Avandia)
Rosiglitazone maleate is an oral thiazolidenedione administered in the treatment of diabetes mellitus that seems to have a beneficial action in psoriasis through inhibition of the production of multiple cytokines.(21,22)
Conclusion
The use of biological agents in the treatment of psoriasis has led to promising results, as well as improved safety, tolerability and convenience. However, the causative antigen has not been identified, risks of systemic immunosuppression have not yet been evaluated and long-term follow-ups are still missing. Currently, only partial remissions can be achieved.
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