Based on data from post-marketing clinical trials, ulcerative colitis has been added as an adverse event to the product labelling of Enbrel® (etanercept) . This is not the case for the other anti-TNF agents (adalimumab and infliximab) [2,3]. On the contrary, infliximab has currently been approved for use in Crohn’s disease , and a recent publication indicates that infliximab may also be effective in treatment of ulcerative colitis . Due to lack of comparative studies, differences in effect and risk profile are difficult to assess . We report here a case of colitis associated with etanercept and believed to be the first published case.
A 72-year-old man who had been receiving SC etanercept 25 mg twice weekly for rheumatoid arthritis developed over the last months watery diarrhoea. The clinical investigation and positive hemo FEC® and FeCal-test were consistent with an inflammatory condition of the colon (colitis). Etanercept was withdrawn for two weeks and the patient’s condition improved rapidly. After rechallenge the symptoms reappeared promptly. Etanercept was once again withdrawn, and the patient has fully recovered. The patient was also using methotrexate and candesartan before, during and after treatment with etanercept.
Anti-TNF agents target the same molecule (TNF-alpha), but through different mechanisms. This may imply differences in clinical effects and risk profile. The structural differences may at least partly explain the differences in risk/benefit profile of these drugs. While adalimumab and infliximab are both monoclonal IgG antibodies, etanercept is a soluble TNF-alpha receptor. All three agents bind to and neutralise soluble TNF-alpha in the extracellular space. Etanercept also binds to membrane TNF-alpha, but the reaction is reversible and the binding is of lower affinity than that of infliximab. Infliximab and adalimumab have the ability to bind to and cross-link membrane TNF-alpha, which initiates a cascade reaction that results in apoptotic cell death. Cells in inflamed tissues express TNF-alpha, and it is speculated that the lysis of these cells may be important in suppressing the inflammatory responses underlying e.g. Crohn’s disease . The different anti-TNF agents are administered in different ways and with different intervals. Because infliximab is administered as bolus injection every 4 to 8 weeks, there is great variability in concentration over time (high peaks separated by periods of low levels). High peaks could contribute to greater tissue (gut wall) penetration, which could be more relevant in certain diseases than maintaining stable concentrations with little variations, as observed with etanercept, which is administered SC once or twice weekly . However, whether this influences activity, is not yet known.