Precise cell types that correlate with a patient’s resistance to the standard therapy for Crohn’s disease—anti-inflammatory drugs called TNF inhibitors—have been identified for the first time by researchers at the Icahn School of Medicine at Mount Sinai and published in the September 5, 2019, issue of Cell. TNF inhibitors are used in Crohn’s disease to stop inflammation, but as many as 30 percent of patients do not respond to this treatment and require surgical intervention within 10 years after diagnosis. The new discovery could open the door to identifying biomarkers and tailoring better therapeutic options for these patients.
At the same time, two studies in the September 26, 2019, issue of The New England Journal of Medicine validate effective therapies for patients with treatment-resistant ulcerative colitis (UC), a chronic inflammatory disease of the large intestine. Both of these studies were led by Bruce E. Sands, MD, the Dr. Burrill B. Crohn Professor of Medicine and Chief of the Dr. Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine at Mount Sinai.
The results of Dr. Sands’ first clinical trial validated ustekinumab as a UC therapy. In the phase lll clinical trial, Dr. Sands and his team tested more than 900 patients with moderate-to-severe UC who were unable to tolerate or had an inadequate response to TNF inhibitors. The results from this trial led the U.S. Food and Drug Administration in October to approve ustekinumab for adult patients with moderately to severely active ulcerative colitis. Ustekinumab had previously been approved for treating patients with Crohn’s disease.
The second study was the first ever head-to-head comparison of two biologic therapies for inflammatory bowel disease: vedolizumab and adalimumab. In total, 769 participants with moderate to severe UC were recruited for this randomized phase 3b study, with 383 patients receiving 300 mg of vedolizumab intravenously at weeks 0, 2, and 6, then every 8 weeks, and with subcutaneous placebo injections, and 386 receiving placebo intravenously and adalimumab subcutaneously (160 mg week 1, 80 mg week 2, and then 40 mg every 2 weeks).
Researchers found that patients who received vedolizumab achieved significantly higher week 52 clinical remission rates than patients who received adalimumab (31.3% versus 22.5%) and endoscopic improvement (39.7% versus 27.7%). The remission rates for both therapies were similar among the 20% of participants who had previous exposure to TNF inhibitors.
In the study in Cell, Mount Sinai researchers used single-cell RNA sequencing and CyTOF technology to examine inflamed and noninflamed small intestine tissue samples as soon as they were removed from Crohn’s disease patients. Looking at the lesions in real time on a single-cell level, the investigators identified the immune cells and the circulating blood cells and their interactions, and mapped a landscape of thousands of cells in the lesion.
“Single-cell profiling provides unprecedented information on the make-up of the disease,” says co-corresponding author Miriam Merad, MD, PhD, Director of the Precision Immunology Institute and the Human Immune Monitoring Center at the Icahn School of Medicine at Mount Sinai. “This type of analysis will help us understand why patients respond to or resist specific treatment and what else we could
be targeting.”
Co-corresponding author Judy H. Cho, MD, Director of The Charles Bronfman Institute for Personalized Medicine, and Ward-Coleman Professor of Translational Genetics and Medicine at the Icahn School of Medicine at Mount Sinai, says, “We designed this study in a way that defines inflammation with unprecedented precision using immunology and computational biology to get a better understanding of this disease.”
Computational biologist Ephraim Kenigsberg, PhD, Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, and co-corresponding author of the Cell study, says, “Single-cell analysis revealed different cellular signatures, and when we integrated this with larger data sets, including clinical trials, we were able to make our findings clinically relevant.”