Differential efficacy of TNF-α antagonists in granulomatous diseases: potential explanations

TNF-α antagonists show differential efficacy in granulomatous disorders. Both infliximab and adalimumab have been shown to be effective in Crohn's disease while etanercept lacks efficacy in this disease. Somewhat similar results have been reported with regard to Wegener's granulomatosis and pulmonary sarcoidosis. It is interesting to note that cases of mycobacterium tuberculosis (TB) occur earlier and more frequently in patients with infliximab relative to etanercept. These observations would suggest that infliximab (and possibly adalimumab) is superior to etanercept in blocking granulomatous inflammation. However, no conclusive data are available at present. Three attributes of the TNF antagonists are crucial to understanding the observed differences: mode of administration, the IgG antibody backbone and the nature of TNF-α binding. Infliximab (and presumably, adalimumab) is able to bind transmembrane TNF with greater avidity than etanercept. Besides, the two TNF receptors (p55 and p75) exhibit complex interactions involving the binding of TNF. Also, TNF receptor signalling pathways are mutually influenced by effects of other TNF receptors (e.g. TRAIL, FAS, CD40). It has been shown that p55 TNF receptor conveys both survival and death (apoptotic) signals, while the p75 receptor is thought to mostly convey survival signals, yet plays a clear role in Fas-FasL mediated apoptosis or activation induced cell death. On the basis of results of available studies one can conclude that a) acute administration of infliximab reduces inflammation and cellularity through apoptotic and non-apoptotic pathways, which vary as a function of organ and or disease process, b) chronic administration of infliximab and etanercept can induce macrophage apoptosis and this correlates with clinical response, arguing against a specific role for transmembrane TNF binding in inducing apoptosis, c) either methodologic or organ system differences must account for the differential findings in vitro, and d) although it is likely pharmacokinetics and pharmacodynamics play some role, only studies specifically designed to address these questions will resolve these issues.