Supporting a role for tmTNF in extra-articular manifestations, recent studies in human Crohn’s disease indicated that tmTNF expression in the gut is a good predictor of response to TNF inhibition (Atreya et al., 2014) and that binding of anti-TNF antibodies to tmTNF activates a macrophage-mediated immunoregulatory response that is crucial for the therapeutic effects in inflammatory bowel disease (Levin et al., 2016a; Levin et al., 2016b). This evidence concerns the gene TNF and Crohn disease.