They have approved analysis of the mucosal biopsies. When targeting IL-6, the differential responsiveness of target cells has to be taken into account, as IL-6 on the one side promotes acute and chronic mucosal inflammation soluble IL-6R signaling but on the other side also strongly contributes to epithelial cell survival membrane bound IL-6R signaling. soluble IL-6R signaling, but also strongly contributes to epithelial cell survival mIL-6R signaling. INTRODUCTION Ulcerative colitis (UC) is usually defined as a chronic relapsing inflammatory bowel disease (IBD) that is pathologically characterized by intestinal inflammation and epithelial injury. Insights into the immunopathogenesis of UC have implicated that pro-inflammatory cytokines are GDC-0575 (ARRY-575, RG7741) critically involved in the induction and perpetuation of the inflammatory process. Targeted GDC-0575 (ARRY-575, RG7741) anti-cytokine therapies are therefore considered as a stylish treatment option, which is best reflected by the introduction of anti-TNF antibodies as an efficacious treatment option. Nevertheless, in the pivotal GDC-0575 (ARRY-575, RG7741) clinical trials for anti-TNF brokers in UC, the initial response rate was approximately 60%, with a considerable proportion of these patients losing response within one 12 months. Therefore alternate cytokine targeted methods are being sought after. Interleukin-6 (IL-6) has been implicated to play an important role in the immunopathogenesis of IBD. In agreement with this concept, mucosal IL-6 expression has been found to be elevated in active IBD. Furthermore, serum-levels of IL-6 correlated with clinical disease activity in UC patients. As these observations provide strong evidence for any potential functional role of IL-6 in chronic intestinal inflammation, we decided to treat an UC patient refractory to standard therapies with a humanized anti-IL-6 receptor (IL-6R) antibody. CASE Statement The patient, a 53-year-old woman, was diagnosed with ulcerative pancolitis at the age of 28 years by histopathological criteria. She initially responded to combined therapy with oral (3 g) and local (2 g) aminosalicylates and later systemic corticosteroids, but showed recurrent inflammatory episodes in the following years. The patient designed a steroid-dependent disease course with GDC-0575 (ARRY-575, RG7741) a requirement for steroid therapy 10 mg/d. Azathioprine 100 mg (2 mg/kg) therapy was initiated in 2005, upon which clinical response was achieved for 6 mo. No endoscopic examinations were performed at that time to assess endoscopic response to azathioprine therapy. Upon subsequent relapses that required repeated prednisolone treatment, azathioprine treatment was halted and methotrexate therapy was initiated in 2008 outside our medical center, but had to be discontinued due to severe skin reactions. Azathioprine therapy was again started thereafter, as the patient reported more aggravated disease without azathioprine therapy. Therapy with the anti-TNF antibody infliximab was initiated in 2010 2010 in addition to azathioprine therapy due to chronic active disease. After an initial response for over one year, even an intensified therapy with infliximab (10 mg/kg every four weeks) failed to ameliorate UC activity and the treatment was halted thereafter. Anti-TNF antibody therapy with adalimumab (in the beginning 160 mg and 80 mg, then 40 mg every two weeks) in addition to ongoing azathioprine therapy similarly failed to ameliorate colitis activity and was halted after 3 mo. Therapy with the calcineurin-inhibitor tacrolimus was initiated thereafter, but had to be discontinued due to impairment of renal function in 2013. At this point the patient experienced up to 10 loose bowel movements per day with obvious blood. Blood count showed moderate hypochromic anaemia (Hb 11.6 g/dL). C-reactive protein (CRP) levels were elevated (28.3 mg/L). The Truelove Col4a2 and Witts severity index indicated moderate disease. There was no tachycardia or pyrexia. Endoscopy revealed continuous colonic inflammation with enhanced granularity and isolated ulcerations (Physique ?(Figure1A).1A). The total Mayo score was 10, indicating severe disease. Endomicroscopic evaluation exhibited dilated microvessels, leakage and disturbed crypt architecture as indicators of mucosal inflammation (Physique ?(Physique1C).1C). Histopathological analysis of sigmoid biopsies by a pathologist resulted in a Riley histologic score of 15 and a Geboes score of 0.3/1.3/2A.3/2B.3/3.2/4.3/5.4; both indicative of severe UC. An infection with cytomegalovirus (CMV) was repeatedly excluded and stool samples were usually unfavorable for infectious pathogens, including blockade of the membrane bound IL-6R (mIL-6R) on intestinal epithelial cells. This adverse effect might be reflected by the reported heightened risk of gastrointestinal perforations upon tocilizumab treatment in rheumatoid arthritis patients. Furthermore, one statement showed the formation of multiple mucosal ulcers in the small and large intestine during tocilizumab treatment in rheumatoid arthritis. Consistent with these reported clinical observations, tocilizumab treatment led to augmented mucosal ulcers in our UC patient, probably due to further impairment of epithelial barrier integrity with subsequent activation of mucosal immune cells resulting in pro-inflammatory.