By hunting for unique early biomarkers in multiple cohorts of patients, the PROMISE Consortium aims to stop Crohn’s disease before it starts.
In a pivotal 1932 study, a team of doctors from the Mount Sinai Medical Center described 14 patients whose symptoms and intestinal abnormalities did not fit any previously identified condition. The mystery illness, found mainly in young adults, led to fever, diarrhea, emaciation, and bowel inflammation. They defined a new disease, called regional ileitis, that closely resembles ulcerative colitis but affects different areas of the gastrointestinal tract.
Today, regional ileitis is better known as Crohn’s disease, named after the lead author of the original case series, Mount Sinai gastroenterologist Burrill B. Crohn, MD. More than half a million people in the United States have Crohn’s, a type of inflammatory bowel disease (IBD) with no known cure. IBD, which encompasses both Crohn’s and ulcerative colitis, has been on the rise worldwide since early 2000, and now affects up to 1 in 200 individuals in Western countries.
Recent research at Mount Sinai and other institutions has provided evidence of a preclinical phase of IBD, a crucial period of time before the onset of the disease. Changes in the intestinal environment associated with disease development have been observed in patients as far back as 10 years before diagnosis.
An innovative research initiative co-led by the Department of Genetics and Genomic Sciences aims to redefine the approach to Crohn’s disease by shifting the focus from treatment to early detection and prevention. The PROMISE Consortium (PRediction and PRevention through Omics, Microbiome, Immune System, and Environment) will integrate cutting-edge omics technologies, microbiome analysis, immune system study, and environmental factors to achieve a comprehensive understanding of Crohn’s disease in its earliest stages.
“There has been a paradigm shift in the field to focus on disease interception and prevention rather than a cure,” says Inga Peter, PhD, Vice Chair of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. “We’ve established this consortium to try and identify early life biomarkers of Crohn’s disease so that, in the future, they can be used for risk stratification and early intervention.”
The ambitious project is made possible by a generous grant of more than $4 million from The Leona M. and Harry B. Helmsley Charitable Trust. The PROMISE Consortium will bring together the Department of Genetics and Genomic Sciences and the Dr. Henry D. Janowitz Division of Gastroenterology at Mount Sinai, along with Mount Sinai Hospital in Toronto and Massachusetts General Hospital in Boston.
Medical treatment for Crohn’s disease has the ultimate goal of achieving and maintaining remission. In the last two decades, biologics such as anti-tumor necrosis factor (anti-TNF) agents have played an increasing role in the treatment of Crohn’s. For some patients, they work very well to control symptoms and even prevent disease progression. However, one-third of patients fail to respond to anti-TNF therapy altogether, while another subset initially respond but later lose response or become intolerant to the medication.
“Motivated by the current limitations in Crohn’s treatments, effective for only about half of patients, our research seeks to redefine our understanding of the disease’s origins,” says Dr. Peter, Co-Principal Investigator of the PROMISE Consortium. “Rather than solely concentrating on symptom management, our work aims to predict and prevent Crohn’s development.”
The study, “Defining the Pre-Disease Phase of Crohn’s Disease: Predict and Prevent,” will initially focus on analyzing blood-based biomarkers in healthy individuals before they develop Crohn’s disease, comparing them to those who remain disease-free. It will include data from a total of five patient cohorts, with three main discovery cohorts that originate from the Genetic, Environmental, and Microbial (GEM) Project, the PREDICTS study, and the Nurses’ Health Study.
The GEM Project, based at Mount Sinai Hospital in Toronto, has followed 5,000 healthy first-degree relatives of people with Crohn’s disease since its founding in 2008. More than 100 participants have developed Crohn’s themselves over the past 15 years, allowing for a comparison of the initial samples taken when those participants were healthy with initial samples taken from participants who did not develop the disease.
The PREDICTS study cohort draws from the US Defense Medical Surveillance System, which contains millions of blood samples taken from soldiers when they enlisted, and every two years of service thereafter, from 1998 through 2013. Some of these soldiers went on to develop Crohn’s, and the PROMISE researchers will be able to link these samples to their medical records and track the development of biomarkers for several years preceding their diagnosis.
Beginning in 1976, the Nurses’ Health Study has gathered data on over 230,000 nurses regarding their diet, lifestyle, medication use, and diagnoses of chronic diseases, including Crohn’s and ulcerative colitis. Blood and urine specimens from the study participants will provide PROMISE researchers with the opportunity to search for genetic and biochemical markers of preclinical IBD.
Dr. Peter is also the Principal Investigator of the MECONIUM (Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome) Study, which will provide one of two early life cohorts for the PROMISE Consortium. The MECONIUM Study aims to compare the bacterial profiles of pregnant women with and without IBD and their newborn babies, in order to understand the effects of maternal IBD on the initial bacterial colonization and development of the immune system.
“Having a mother with IBD increases risk by about sixfold. None of the babies in the study have developed IBD yet, but we have samples that may already demonstrate some kind of inflammatory processes early in life, simply because their mothers had IBD,”
she said. Lastly, the Road to Prevention (RTP) cohort encompasses subjects from large families with at least two first-degree relatives diagnosed with IBD. Led by IBD researchers at Icahn Mount Sinai, the study looked to identify high- and low-risk phenotypes based on blood and microbiome samples of participants prior to the onset of IBD.
Dr. Peter, in collaboration with Co-Principal Investigators Jean-Frédéric Colombel, MD, Ken Croitoru, MDCM, and Hamed Khalili, MD, MPH, will apply multiple analysis platforms – such as genomics, serology, proteomics, and metabolomics – to these cohort blood samples to achieve a better degree of disease prediction. The grant will also fund an international conference, set for next year, to bring together investigators working with other pre-disease cohorts from around the world to devise and advance Crohn’s disease interception and treatment strategies.
“A handful of individual biomarkers have been reported in the past, but this effort puts it all together with multiple cohorts that may capture the heterogeneity of the disease,” Dr. Peter says. “People have very different manifestations of the disease, so hopefully this approach will allow us to capture different subtypes or triggers that lead to the same diagnosis.”