Exabis Library

MDT case discussions

IBD Multidisciplinary Team (nurses, dietitians, pharmacists, psychologists, etc.)

Tofacitinib treats ulcerative colitis, but how? Dr Kristina Lechner describe an elegant series of experiments elucidating the effects of tofacitinib on T cell function in colitis with some surprising findings on cellular trafficking.

Heike Schmitt describes her work dissecting the immunomodulatory effects of cobitolimod using material from murine studies and a human clinical trial.

1. To understand the chronicity of IBD and the need for continuous remission of symptoms
2. To review the drugs available to treat IBD, their indications, their limitations, their optimal use and their potential adverse reactions
3. To emphasise the concept of two goals of therapy which are the achievement of remission (induction therapy) and the prevention of disease flares (maintenance therapy)
4. To have an overview on the new drugs under development

1. To understand the chronicity of IBD and the need for continuous remission of symptoms
2. To review the drugs available to treat IBD, their indications, their limitations, their optimal use and their potential adverse reactions
3. To emphasise the concept of two goals of therapy which are the achievement of remission (induction therapy) and the prevention of disease flares (maintenance therapy)
4. To have an overview on the new drugs under development

Inflammatory Bowel Diseases are chronic diseases often with complex treatment. The treatment is lifelong and complex and may include several different pharmaceutical groups and sometimes surgery. Not rarely is treatment resistance developed and the treatment may come with different degrees of side effects. Earlier research has shown insufficient to medication adherence and a lower degree of health-related quality of life in patients with inflammatory bowel disease.

The aim is to describe the relationship between medication adherence and health-related quality of life in a Swedish population diagnosed with inflammatory bowel disease. Additional research questions are if any risk factors of low medication adherence can be identified from the collected variables.

This cross-sectional study included N=206 patients from three different regions in Sweden. The questionnaires MMAS-8 and Short Health Scale were used combined with a questionnaire regarding patient characteristics. The data and patient characteristics were described and analyzed using descriptive statistics.

Ethical approval has been received from the Regional Ethical Review Board, Linköping, Sweden (no.: 2015/369-31).

The majority of patients had Ulcerative Colitis (62.6%) There were no significant differences between the different groups of Inflammatory Bowel Disease regarding patient characteristics apart from having gone through surgical procedures, which were more common in patients with Crohn’s disease. A small correlation was shown between medication adherence and the health-related quality of life dimension social function (rho = -0.146; p <0.05). Medication adherence showed no significant correlations to the remaining health-related quality of life dimensions: disease related worry, symptom burden and sense of general well-being. Possible risk factors identified for low medication adherence were age between 30 and 50, working at high occupational level, and higher educational level.

The complexity of measuring medication adherence has been established, making it difficult to make any certain conclusions regarding the hypothesis in this report. This study showed no clear association between medication adherence and health-related quality of life in patients with inflammatory bowel disease. However, it visualized the need of optimizing the instruments used to measure medication adherence in individuals with a non-conventional treatment plan

Numerous small molecules and biologics are being tested in phase 1-3 trials. Regarding JAK inihibitors, we still do not know whether JAK selectivity is associated with an improved risk-benefit profile, especially regading zoster risk. TYK2, gut selective or not, look promising and also showed very encouraging results in psoriasis.  Other small molecules targeting integrins or PDE4 may be approbed in a near future. Regarding biologics and beyond biosimilars, many compounds are being developed such as Abivax. One question remains after 2 decades of biologics development : who will beat infliximab? Combination of biologics and bispecific antibodies might tackle this issue. Pending these molecules, many head to head trials are ongoing.

Numerous small molecules and biologics are being tested in phase 1-3 trials. Regarding JAK inihibitors, we still do not know whether JAK selectivity is associated with an improved risk-benefit profile, especially regading zoster risk. TYK2, gut selective or not, look promising and also showed very encouraging results in psoriasis.  Other small molecules targeting integrins or PDE4 may be approbed in a near future. Regarding biologics and beyond biosimilars, many compounds are being developed such as Abivax. One question remains after 2 decades of biologics development : who will beat infliximab? Combination of biologics and bispecific antibodies might tackle this issue. Pending these molecules, many head to head trials are ongoing.

Chronic endoplasmic reticulum stress (ER) in the intestinal epithelium is a pathophysiological hallmark of IBD. cGAS/STING is an innate immune pathway involved in the detection of double stranded DNA fragments leading to the subsequent induction of type I IFN responses. We here tested the hypothesis that chronic ER stress impairs cGAS/STING signalling in the intestinal epithelium. 

Mice with a conditional intestinal epithelial deletion of Xbp1 (Xbp1^ΔIEC, Xbp1^fl/fl) were used to assess intestinal epithelial STING expression in-vivo. Small intestinal organoids (Xbp1^ΔIEC, Xbp1^fl/fl) and cell lines (Mode K, iCtrl and iXbp1) were used to assess cGAS/STING signalling in-vitro using STING agonist (dsDNA, DMXAA). Murine cytomegalovirus (mCMV) infection assays were performed in iCtrl and iXbp1cells and Xbp1^ΔIEC, Xbp1^fl/fl mice to functionally link impaired cGAS/STING to pathogen response. LC-MS profiling was performed in iCtrl and iXbp1cells to identify underlying metabolic programs affecting cGAS/STING responses in ER-stressed cells. IBD biopsy samples (cross-sectional, longitudinal therapy response cohort) were used to validate key molecular phenotypes in human IBD. 

Compared to Xbp1^fl/fl mice, Xbp1^ΔIEC show completely abrogated STING expression in the basal crypt compartment of the small intestinal epithelium. In line with that iXbp1 ModeK cells displayed impaired pathway activation (TBK1) and interferon inducible gene expression (Cxcl10) in response to cGAS/STING stimulation and towards mCMV infection, leading to increased viral replication compared to iCtrl cells. In-vivo mCMV infection led to augmented small intestinal histopathological disease activity in Xbp1^ΔIEC, but not Xbp1^fl/fl mice. Using LC-MS, we show that ER-stress induces a metabolic adaptation towards increased serin/glycin metabolism, which is used to counterbalance reactive oxygen species (ROS) via glutathione (GSH) synthesis. Pharmacological interception of key pathways of GSH synthesis of deprivation of serin/glycin phenocopies ER-stress in abrogating STING signalling in IECs. Lastly, we show that key aspects of metabolic adaptation to ER-stress are present in intestinal biopsies of IBD patients. 

Our data describe a novel mechanism of metabolic adaptation to compensate ER-stress and maintain intestinal epithelial cGAS/STING signalling. We therefore put forward a model of ER-stress driven immunodeficiency via cGAS/STING signalling which renders the intestinal mucosa susceptible towards CMV infection in the context of IBD.

Educational objectives:
1. To understand the mechanism of action of Methotrexate
2. To review its efficacy and appropriate use (mono-, combitherapy)
3. To learn the appropriate management of Methotrexate and its potential adverse events in daily practice
4. To have an overview on other alternative indications