Inflammatory Bowel Diseases
Human inflammatory bowel diseases (IBD) represent a group of immune-mediated disorders, in which currently unknown trigger factors cause chronic relapsing-remitting destructive inflammation in the gut. IBD comprise two main disease entities: ulcerative colitis (UC) and Crohn´s disease (CD). The diseases differ in anatomical distribution, with continuous, uniform inflammation restricted to the colon in UC, and multifocal inflammation extended throughout the entire gastrointestinal tract from mouth to anus in CD.
- Clinical symptoms of IBD
Clinical symptoms of IBD may include bloody stools, abdominal pain, fatigue, diarrhoea, fever and weight loss. Extra-intestinal symptoms occurring in up to 40% of patients, e.g. anaemia, skin lesions, arthritis and uveitis, and other complications directly related to the disease organ, such as fistula in CD are considered to reflect an overwhelming systemic inflammatory state. Disease onset typically manifests at age 15-35 years, men and women are almost equally affected. In addition, pediatric forms of IBD, that often represent complex, severe forms of the disease, are seen.
The incidence rates of IBD in Europe are about 6.3 (CD) and 11.8 (UC) per 100.000 persons. With growing incidence rates and overall reduced mortality the lifetime prevalence of IBD is expected to rise. The estimated lifetime prevalence of 0.3%-0.5% of the European population corresponds to estimates of 1.5-2 million patients with IBD (Burisch et al. Journal of Crohn`s and Colitis, 2013, Ng et al., Lancet 2018). Importantly, a steep rise of diagnoses is seen in emerging Asian countries, pointing to an important role of “westernized” lifestyle and making IBD a world-wide problem.
A large degree of heterogeneity is seen with regard to disease courses. One has to differentiate between disease activity (i.e. mild, moderate and severe) and disease complexity, which can range from easily controlled trajectory to a severe destructive course. The latter leads to permanent (non-inflammatory) impairment of intestinal function with a severe impact on the quality of life, making disease control an important new goal of new therapies.
- Current therapy strategies and achievements
A landmark advancement in the therapy of IBD has been the development of targeted therapies, specifically those inhibiting cytokines. In particular, anti-TNF therapy in the past 15 years has led to significant improvements of the quality of life for many patients. Despite this success, targeted treatments (e.g. anti TNF therapies) only achieve long-term clinical remission rates of 20-30% with high degrees of both primary and secondary non-responders. Another layer of complexity is added by novel therapeutic targets (anti-integrin therapies), new anti-cytokine therapies (anti IL6, anti-p40 (IL12/23) or anti-IL-23(p19)) and anti-Janus-kinase agents (tofacitinib (approved), filgotinib, upadacitinib) for which it remains unclear in which order these should be used or how to define the most responsive patient for a particular mechanism of action.
While comparative clinical studies would have to be very large and need the support of multiple manufacturers, there is considerable interest to benchmark these therapies against TNF blockade at a molecular modelling level using small cohorts of well-defined patients and a dense, comprehensive biomarker approach. Appropriate selection of therapies and their timing of introduction (decision support) in the course of IBD will be essential to reach a higher degree of disease control (across patients and within individual patients) than it is achieved today. In many instances, comparative data is missing and combinations or sequential therapies are not developed.
In summary, despite some treatment successes, major challenges remain: 1) There is a significant non-response rate to each treatment; 2) all the drugs have significant side effects in some patients; 3) treatments are currently prescribed on a trial-and-error basis rather than targeting drugs according to the underlying aberrant pathway driving the disease; 4) a group of patients remains refractory to all currently available therapies and, 5) the treatments are expensive. It is likely not only that targeted therapies will benefit subsets of patients rather than the entire population but also that disease mechanisms are shared across multiple diseases, which could be targeted following a pathway-driven approach.