Matthew C. Choy

An Overview of the Innate and Adaptive Immune System in Inflammatory Bowel Disease

Abstract: Inflammatory bowel diseases (IBDs) are thought to develop as a result of complex interactions between host genetics, the immune system and the environment including the gut microbiome. Although an improved knowledge of the immunopathogenesis of IBDs has led to great advances in therapy such as the highly effective anti-tumor necrosis factor class of medications, a significant proportion of patients with Crohns disease and ulcerative colitis do not respond to anti-tumor necrosis factor antibodies. Further understanding of the different immune pathways involved in the genesis of chronic intestinal inflammation is required to help find effective treatments for IBDs. In this review, the role of the mucosal innate and adaptive immune system in IBD is summarized, highlighting new areas of discovery which may hold the key to identifying novel predictive or prognostic biomarkers and new avenues of therapeutic discovery.

Letter: dose optimising infliximab in acute severe ulcerative colitis

SIRS, We read with great interest the article by Hindryckx et al. discussing the role of dose intensified infliximab rescue therapy in acute severe ulcerative colitis (ASUC), pertinent predictors of response and a proposal for a randomised controlled trial (RCT). Although the authors reported on three observational studies to highlight the potential benefits of dose intensification, it is important to note that Govani and colleagues in fact found a higher rate of colectomy amongst those who received accelerated dosing. Expert opinion suggests that dose acceleration is now the preferred schedule of administration for infliximab salvage therapy; however, there is limited evidence to support such practice. The proposed RCT protocol by Hindryckx and colleagues represents an elegant strategy to address dose adequacy in ASUC. Patient stratification based on clinical risk factors are proposed to determine the timing and intensity of the salvage regimen, rather than the traditional approach of relying on clinical gestalt alone. Nonetheless, several unknowns exist. The authors make reference to a population PK model as a key determinant of initial infliximab dosing; however, it is unclear as to whether the proposed PK model was derived from an ASUC specific cohort. Dose adjustment based on weekly serum infliximab is also of uncertain value, as thresholds earlier than week 2 have yet to be defined. Early faecal infliximab loss may be a better and superior predictor to serum infliximab levels in this context. Furthermore, such dose adjustment does not account for the substantial proportion of patients that often require additional infliximab infusions within 7 days of commencing salvage therapy. We acknowledge that infliximab is not a panacea, even in the face of dose intensification. Nonetheless, no new therapeutic targets applicable to ASUC have been identified for almost 20 years, highlighting the importance of ensuring optimal use of existing drug therapies. Despite improvements reported with induction therapy, long-term colectomy rates remain disappointing irrespective of the initial strategy, 8, 9 suggesting that other untreated and unidentified disease mechanisms persist. This points to a key failure in the maintenance therapy strategy following induction therapy of ASUC that has been largely ignored in the literature, but remains crucial to long-term outcomes. Although great strides have been made in understanding pharmacokinetic failure, 10 primary non-response with ostensibly adequate drug levels still remains a significant problem. It is therefore imperative that further studies examine not only the optimal induction and maintenance strategy, but also in this cohort of very severe disease, interrogate for early pharmacodynamic and immunological mechanisms responsible for treatment failure. Such studies may then reveal deeper insights into this life-threatening condition, and open doors to help identify both predictors of response and new targets to optimally manage ASUC in this novel era of personalised medicine.

Examining maintenance care following infliximab salvage therapy for acute severe ulcerative colitis

Data supporting the optimal maintenance drug therapy and strategy to monitor ongoing response following successful infliximab (IFX) induction, for acute severe ulcerative colitis (ASUC), are limited. We aimed to evaluate maintenance and monitoring strategies employed in patients post‐IFX induction therapy.

Predicting response after infliximab salvage in acute severe ulcerative colitis: Predicting response in severe colitis

Acute severe ulcerative colitis (ASUC) is a medical emergency requiring prompt therapeutic intervention. Although infliximab has been used as salvage therapy for over 15 years, clinical predictors of treatment success are lacking. We performed a retrospective analysis to identify factors that predict colectomy and may guide dose intensification.

Salvage therapy for acute severe ulcerative colitis during pregnancy

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with an age of onset that affects young people during the peak of their reproductive years. Management of flares of disease during pregnancy can be complex and there are few case reports of pregnant women with acute severe ulcerative colitis (ASUC). We present the case of a 31-year-old pregnant woman who at 16 weeks gestation developed ASUC in the context of primary non-response to infliximab therapy. She subsequently underwent an emergency laparoscopic colectomy after failing to respond to hydrocortisone and cyclosporine salvage therapy. Her pregnancy was further complicated by HELLP (Haemolysis, Elevated liver enzymes and Low Platelets) syndrome resulting in premature delivery at 27 weeks gestation. This case highlights the management issues involved in ASUC during pregnancy and the assessment of disease activity, use of salvage therapies, and provides a framework to approach this complex medical emergency.