TNF superfamily ligands (top) are active primarily as non-covalently associated homotrimers and can be soluble or membrane-expressed. TNF superfamily receptors (bottom) contain variable numbers of cysteine-rich domains in their ligand-binding extracellular regions. TNFRSF are mainly membrane-expressed, but can form soluble receptors via enzymatic cleavage of the ectodomains. Also depicted are the primary cell targets that respond to TNFSF through TNFRSF signalling, although this list is not comprehensive in terms of the expression characteristics of each molecule. TNFRSF molecules whose main function is to promote apoptotic cell death (TNFR1, Fas, TRAIL1 and TRAIL2) can recruit a death-inducing signalling complex to their cytoplasmic domains via a death domain.

a | TNFR1 signalling is activated by both soluble and transmembrane TNF. TNFR1 bears a death domain that recruits the adaptor protein TRADD. Ligation of TNFR1 by soluble TNF or transmembrane TNF leads initially to the assembly of complex I, which activates NFκB and MAPKs. TNFR1–complex I signalling induces inflammation, tissue degeneration, cell survival and proliferation, and orchestrates the immune defence against pathogens. Alternative signalling modalities, associated with programmed cell death, can also be activated downstream of TNFR1. The formation of the complexes IIa and IIb (also known as ripoptosome) results in apoptosis, whereas complex IIc (necrosome) induces necroptosis and inflammation. b | TNFR2 is proposed to be fully activated primarily by transmembrane TNF, in the context of cell-to-cell interactions. TNFR2 recruits TRAF2 via its TRAF domain, triggering the formation of complex I and the downstream activation of NFκB, MAPKs and AKT. TNFR2 mediates primarily homeostatic bioactivities including tissue regeneration, cell proliferation and cell survival. This pathway can also initiate inflammatory effects and host defence against pathogens.

• Infliximab is a chimeric (mouse-human) monoclonal antibody in which the variable domains of mouse antibody to human TNF are fused to the constant domains of a human antibody. A biosimilar of infliximab is now available in Europe.
• Adalimumab and golimumab are fully humanized monoclonal antibodies.
• Certolizumab pegol is a humanized antigen-binding (Fab) fragment covalently bound to polyethylene glycol. Thus, it does not have a fragment crystallizable (Fc) domain of an immunoglobulin.
• Etanercept contains an Fc immunoglobulin backbone and a dimer of the extracellular portion of the human TNF receptor.

Over and above introducing a choice in regimen, differences in the structure of TNF inhibitors infer differences in their modes of action [1], which has implications for their efficacy (poor response to one TNF inhibitor does not denote poor response to others) and safety. For example, etanercept has been associated with a lower risk of tuberculosis reactivation and certolizumab may be less likely to cross the placenta than other TNF inhibitors (perhaps due to its lack of the fixed fragment of immunoglobulin) [2,3].

1. Mease, P. Atlas of Psoriatic Arthritis. London, UK: Current Medicine Group; 2005.
2. Wolf D, Mahadevan U. Certolizumab Pegol use in pregnancy: low levels detected in cord blood (abstract). Arthritis Rheum. 2010;62(suppl10):299.
3. Porter C, Kopotsha T, Smith B, Nesbitt A, Urbaniak S, Armstrong-Fisher S. No significant transfer of certolizumab pegol compared with IgG in the perfused human placenta in vitro (abstract). Ann Rheum Dis. 2010;69 (suppl 3):210.

TNF-α acts through binding to two receptors (p55 and p75) that form dimers at the cell surface. In vitro assays suggest that whilst all TNF inhibitors bind soluble and membranebound TNF-α, preventing binding and activation of the p55 and p75 receptors, the potency of binding varies amongst the agents: certolizumab pegol and the monoclonal antibodies inhibit the effects of membrane-bound TNF-α in a concentration-dependant manner, whilst etanercept was found to be two-fold less potent [1].

1. Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): In vitro comparison with other anti-tumor necrosis factor α agents. Inflamm Bowel Dis. 2007;13:1323-1332.