Sonographic Assessment in Severe Ulcerative Colitis Patients Admitted for Intravenous Corticosteroids and Eligible for Infliximab Rescue Therapy; a Prospective Clinician-blinded Observational Study Protocol.

Introduction

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), typically diagnosed between the age of 15 and 40 and characterized by colonic mucosal inflammation and ulcerations. These mucosal changes lead to bloody diarrhea and in severe cases, fever, anemia, weight loss and death if not treated appropriately. The condition requires prompt immunosuppressive treatment and monitoring. To characterize disease severity and guide treatment decisions, clinicians typically use a combination of clinical scores based on patients symptoms, endoscopic scoring systems based on mucosal appearance endoscopic assessments of disease extent and blood and stool markers of inflammation.

Most patients experience a mild to moderate disease course with varying periods of activity and remission. However, 15-25 % will experience a flare of acute severe UC (ASUC), a condition characterized by extensive and deep ulcerations on endoscopy combined with a high clinical score of severity. Due to the risk of bowel wall perforation, these patients are usually admitted to the hospital ward for intensive monitoring and medical therapy. The medical therapy ultimately aims at avoiding acute colectomy, a procedure that still carries a 30-day mortality rate of 5 %, which is higher compared to elective surgery (OR 1.82; CI 95 % 1.19 - 2.62). Initial therapy is well established and consists of intravenous corticosteroids, which in early clinical trials dramatically improved the disease outcome by reducing the mortality rate from 24 to 7 %. Unfortunately, even today 30 - 50 % of patients with ASUC fails to respond to initial corticosteroid treatment and are therefore eligible for medical rescue treatment if surgery is not imminent.

Accordingly, primary non-responders to high dose intravenous corticosteroids are usually switched to infliximab (or at certain centers ciclosporine) after 5-7 days, if an acute colectomy is not needed. Infliximab is an anti-tumor necrosis factor (TNF) alpha antibody, which blocks TNFα, a key inflammatory mediator in UC,and has been proven effective in corticosteroid resistant UC reducing the risk of acute colectomy from 58 % to 29 %.

Despite advances in medical treatment ASUC still carries a 10 % risk of acute colectomy. Further improvement in medical therapy and strategy is therefore highly warranted. A decrease in serum albumin is associated with an increased clearance of infliximab, and it has been suggested that postponement of infliximab treatment in ASUC could reduce the bioavailability of the drug as a result of severe hypoalbuminemia. In addition, infliximab is lost in feces in the setting of ASUC, suggesting that an accelerated infliximab induction regimen or an increased starting dose compared to standard procedures could be beneficial. However, a recent review of retrospective studies showed no difference in colectomy rates when comparing an accelerated infliximab induction regimen with standard induction regimen (both induced after 3-5 days of corticosteroid treatment), although confounding by disease severity cannot be excluded. Hence it is currently unresolved if optimized timing and dosing of infliximab rescue treatment could be of major importance to reduce the need of acute colectomies and thereby the morbidity and mortality among ASUC patients. Therefore, data to support clinician's recognition of corticosteroid non-responders early in the process are warranted.