Chronic inflammatory bowel disease (IBD) remains difficult to control in the long term. Forty to 50 percent of IBD patients have frequent recurrences, reported Dr. Sharon Veenbergen from Rotterdam at the ECCO (European Crohn’s and Colitis Organization) 2018 Annual Meeting in Vienna. New findings from microbiome research could make it possible in the future to provide more targeted therapy than before. Promising new targets, directed e.g. against interleukins and endothelial proteins, are also being explored.
The composition of the microbiome is known to correlate with the development of many chronic diseases and has the potential for new diagnostic and therapeutic opportunities. Progress is particularly evident in chronic bowel diseases such as IBD; this is illustrated by data from two ongoing cohort studies in Switzerland [1]. Based on the microbiome, the correct diagnosis can be made in more than 80 percent of patients with Crohn’s disease or ulcerative colitis (CU), reported private lecturer Dr. Pascal Juillerat, gastroenterologist at the Inselspital Bern.
Approximately 2000 stool samples from nearly 800 individuals were examined, including nearly 350 patients from the Swiss CED Cohort Study (www.ibdcohort.ch) as well as an additional 156 CED patients and 240 control subjects from the Bern region. Intestinal microbial colonization differed markedly between IBD patients and controls, as well as between Crohn’s and CU patients, Juillerat said. A loss of beneficial microorganisms such as Faecalibacterium prausnitzii is particularly noticeable in Crohn’s patients. In contrast, the Gram-positive strains Actinobacillus and Firmicutes were detected significantly more frequently in CU patients than in control subjects. However, the ongoing projects focus less on the new diagnostic possibilities offered by the microbiome. Rather, observations of temporal changes in the microbiome will provide new insights into the course of IBD and drug response. The composition of the microbiome correlates with phases of inflammation and remission, and also with response to TNF-alpha blockers, for example, Juillerat reported.
The efficacy of fecal microbiota transplantation (FMT), which is being tested in trials in IBD patients, can also apparently be assessed early on by characteristic changes in the recipient’s microbiome. Dr. Sudarshan Paramsothy, a gastroenterologist at the University of New South Wales in Sydney, presented the results of the placebo-controlled FOCUS trial in patients with ulcerative colitis [2]. Stool samples from different donors were used for FMT. As gut flora diversity increased after FMT, the chance of remission increased, Paramsothy reported. Overall, clinical remission or endoscopic response was achieved in 27% of CU patients with FMT in this study (vs. 8% placebo).
There was also evidence for an association between specific bacterial strains in the intestinal flora and response or treatment failure. Remissions correlated mainly with Firmucites such as Clostridium XVIII and Eubacterium hallii. These bacteria have also been associated with beneficial metabolic pathways such as short-chain fatty acid biosynthesis and starch degradation.
The association between some bacterial strains and failure of an FMT was even clearer. Paramsothy primarily named Fusobacteria, but also Sutterella, Veillonella, Escherichia, Prevotella, and Haemophilus. Also associated with lack of remission were several metabolic pathways: Biosynthesis of heme and lipopolysaccharides (inflammatory markers) and oxidative phosphorylation.
Characteristic taxonomic profiles associated with treatment failure or response were also identified in donor stool samples. These findings could be used in the future to better select donors and CED patients for FMT, Paramsothy summarized.
Potential new target in pediatric patients: IL-1 metabolic pathway
The search for new drug targets in IBD is intense. Researchers have placed a focus on interleukin (IL) metabolic pathways in pediatric IBD disorders. In 10-15% of childhood-onset IBD, gene defects in the IL-10 pathway may contribute to disease onset, reported Veenbergen, Erasmus University Medical Center Rotterdam. It is still a hypothesis, she said, but a subset of IBD patients probably have suboptimal IL-10 function. These patients usually do not respond to conventional therapy or to TNF-alpha blockers. Impaired IL-10 function was also associated with changes in IL-1β expression, which could potentially be used in diagnostics, he said. Anti-IL-1 antibodies are also likely to be the most promising as a novel therapeutic approach, he said.
Somewhat closer to application for patients with moderate to severe Crohn’s disease are new monoclonal antibodies targeting endothelial proteins – for example, the antibody SHP647 against the protein MAdCAM-1 is being tested in phase 2 in refractory Crohn’s patients – and the oral Janus kinase-1 inhibitor upadacitinib (phase 2).
For patients with severe refractory Crohn’s disease, autologous hematopoietic stem cell transplantation (aHSCT) also offers a chance to regain control of the disease. According to the European Society for Bone and Marrow Transplantation (EBMT) registry, 99 patients from 27 centers were treated with aHSCT primarily for Crohn’s disease between 1997 and 2015. Detailed data are available on 82 treated individuals, reported Professor Dr. John Snowden from Sheffield, UK [3]. One year after HSCT, 43% of patients were still in remission. However, three-quarters of patients had to resume drug treatment, after a median of ten months. Many patients responded again to medications that had previously experienced loss of efficacy. Surgery had become necessary in 37% of patients. The toxicity of aHSCT showed the familiar profile in Crohn’s patients, Snowden said. 27% of patients developed infection during therapy, 11% developed secondary autoimmune disease, mostly of the thyroid gland, and five patients (of 82) developed new cancer. Many questions about aHSCT in Crohn’s patients remain unanswered, however, the British hematologist said, especially those about proper patient selection.
“It should not be forgotten, with new therapeutic options on the horizon, that available therapies are often underutilized. Many patients don’t even want to be treated with intensive drug therapy,” suggested Corey Siegel, MD, of the Dartmouth-Hitchcock IBD Center in Lebanon, USA, “whether because of fear of side effects or ignorance of the risk of complications.” Siegel and her colleagues conducted a study to evaluate the benefits of counseling Crohn’s patients more extensively about the benefits of early intensive combination therapy with a biologic plus an immunomodulator, “the greatest chance for steroid-free remission,” according to Siegel. The 133 participants in the intervention group were informed about their disease and the benefits and risks of combination therapy through a 25-minute video on the Internet. In addition, patients were provided with a tool to assess their personal risk of complications. Result: One quarter of the patients opted for the combination therapy, compared to only 5% in the control group. No therapy was wanted by only 1% of the intervention group vs. 18% in the control group. Simple means, great effect.
Source: ECCO 2018, Vienna, February 14-17, 2018. Scientific Session 7: ECCO Fellowships and Grants (Feb. 16, 2018, 15:30-16:10); presentations by Veenbergen, Paramsothy and Juillerat. Scientific Session 8: IBD horizons (Feb. 16, 16.10-17.10), lecture Snowden. Digital oral Presentation 8: treatment strategies (Feb. 16, 5:20-6:20 p.m.),
Lecture seal.
Literature:
- Swiss IBD Cohort Study: www.ibdcohort.ch
- Paramsothy S, et al: Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 2017; 389(10075): 1218-1228.
- Snowden J, et al: Autologous haematopoietic stem cell transplantation (AHSCT) in severe Crohn’s disease: a review on behalf of ECCO and EBMT. J Crohns Colitis 2018, epub Jan 8. doi: 10.1093/ecco-jcc/jjx184)
HAUSARZT PRAXIS 2018; 13(4): 43-44
