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Role of biologics: anti-TNFs

The role of biologics in moderate-to-severe psoriasis: anti-TNFs

Tumour necrosis factor has a crucial role in psoriasis pathogenesis, and biologics that target it have changed the therapeutic paradigm for psoriasis and for other autoimmune diseases

Dra Anna López-Ferrer Dr Lluís Puig Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain

Over the past decade, new biologics that specifically target tumour necrosis factor (TNF) and the T helper (Th)1 and Th17 pathway-inducing cytokines interleukin (IL)-12 and IL-23 have changed the therapeutic paradigm for psoriasis and other autoimmune diseases. TNF is highly expressed in psoriatic skin. This cytokine has a crucial role in psoriasis pathogenesis, as demonstrated by the efficacy of TNF- targeted therapeutic agents. Binding of TNF to its receptor induces adaptor proteins to bind to the receptor’s cytoplasmic domain, inducing a signal transduction cascade that leads to activation of nuclear factor kappa-B1 (NF-κB1). NF-κB1 is a rapid- acting transcription factor that regulates genes controlling multiple functions, including cell proliferation, survival, and cytokine production, which become blocked through TNF neutralisation.1 The biologics that target TNF do not

have the exact same mechanism of action. Etanercept (ETN) is a genetically engineered protein, composed of a dimer of the human, TNFR2 fused to the Fc portion of human immunoglobulin (Ig)G1. It binds to only a single trimer of TNF, resulting in complexes of ETN and TNF in a 1:1 ratio. Structurally, infliximab (IFX) is a

mouse–human IgG1 chimeric anti-TNF monoclonal antibody, whereas adalimumab (ADA) is a fully human anti-TNF monoclonal antibody (IgG1). In contrast to ETN, IFX can bind to both the monomer and trimer forms of TNF. As bivalent antibodies, IFX and ADA can also bind to two different TNF trimers, allowing for the formation of large multimeric complexes of soluble TNF molecules linked together by anti-TNF monoclonal antibodies.1

The bound TNF lacks bioactivity but, when released from the

complex, it once again becomes functional. These complexes will bind and release TNF with different on and off rates, depending on the type of TNF antagonist administered. Ultimately, the half-life of these complexes and their rate of TNF release will impact the overall efficacy of each drug. In this regard, ETN–TNF complexes have been shown to release bioactive TNF more rapidly than IFX–TNF complexes. Monoclonal antibodies, because of their crosslinking ability, can induce reverse signalling, leading to suppression of cytokine secretion, decreased T-cell proliferation, and apoptosis; they can also be directly cytotoxic to transmembrane TNF-bearing cells by inducing antibody- dependent cellular cytotoxicity and complement-mediated cytotoxicity.1 Differences in Fc receptor and C1q binding may contribute to the differences in efficacy and indications of the TNF antagonists. Finally, the effects of TNF inhibition lead to early downregulation of other cytokines, most notably IL-17, and this may yet be another way in which these biologic agents differ from one another.

Differences in pharmacokinetics, route of administration, half-lives and immunogenicity also impact the biological effectiveness of anti-TNF agents. Patients with rheumatoid arthritis (RA) with an immunogenic response against a first TNF-blocking agent have a better clinical response to a subsequent TNF blocker compared to patients with RA without anti-drug antibodies. Hence,


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