Digestive Health Center

Researchers find two distinct genetic subtypes in Crohn’s disease patients

Crohn’s disease, a common inflammatory disorder of the intestinal tract, can have devastating consequences for a patient’s quality of life and is notoriously hard to treat successfully, in part because its course and severity vary so much from one case to the next. Now, UNC School of Medicine scientists have made a discovery that could explain why Crohn’s is so variable: the disease appears to have at least two distinct subtypes, each with its own pattern of gene expression and mix of clinical features.

The discovery, published in the journal Gut, could lead to more effective strategies for treating Crohn’s, which affects close to one million people in the United States. Although people with the disease typically are treated with powerful immune-suppressing drugs, roughly 70 percent eventually require surgery to remove portions of the intestinal tract that have developed blockages or other problems caused by severe inflammation. Even after surgery, the disease often recurs and is therefore not curative.

A deeper understanding of the biology of Crohn’s disease should enable doctors to target it more effectively.

UNC researchers help create key diagnostic measures for gastrointestinal disorders

With no laboratory test available to diagnose functional gastrointestinal disorders, proper diagnostic criteria are critical for clinicians to make an accurate determination of what ails their patients.

Several University of North Carolina School of Medicine researchers played a key role in crafting diagnostic criteria and patient questionnaires for the Rome Foundation, an international nonprofit aimed at improving the lives of the millions of people suffering from functional GI disorders (FGIDs), while developing and legitimizing the field of FGIDs through science and research.

William E. Whitehead, PhD, professor of medicine in the division of gastroenterology and hepatology and director of the UNC Center for Functional GI and Motility Disorders has served on the Rome Foundation Board since its inception.

Functional GI disorders don’t have a clear, organic cause, and cannot be caught on any lab test, Whitehead said.

Study shows rates of IBD in Rhod Island among the highest in the country

A study led by the Hasbro Children’s Hospital Division of Pediatric Gastroenterology, Nutrition and Liver Diseases found that the incidence of inflammatory bowel disease (IBD) in Rhode Island is one of the highest ever reported in the United States and that IBD rates nationally are much higher than previously reported. The increased prevalence of IBD cases points to a need for more research into the causes of IBD and development of more targeted treatments.

IBD, which includes Crohn’s disease and ulcerative colitis, is a chronic, debilitating condition characterized by inflammation of the gastrointestinal tract. Studies have shown the incidence of IBD is increasing worldwide.

The study, recently published in the journal Inflammatory Bowel Diseases by Jason M. Shapiro, M.D., a pediatric gastroenterologist at Hasbro Children’s Hospital, examined the statewide incidence of IBD through his work with The Ocean State Crohn’s and Colitis Area Registry, a Centers for Disease Control and Prevention-funded registry of patients with IBD in Rhode Island. The study team reviewed medical records from all practicing adult and pediatric gastroenterologists in Rhode Island, as well as practices in Connecticut and Massachusetts that may care for RI residents, to determine the true incidence of IBD in Rhode Island between the years 2008-2010.

H. pylori infection may reduce risk of allergic esophageal condition

New research suggests that Helicobacter pylori (H. pylori) infection of the stomach, which occurs in about half of the world’s population and can cause peptic ulcers and stomach cancer in minority of cases, may help protect against an allergic disorder of the esophagus condition called eosinophilic esophagitis (EoE).

In a study of 58 adults with EoE and 116 aged- and sex-matched controls, H. pylori infection was inversely associated with EoE. The prevalence of H. pylori in the control group was 37.9%, whereas 3 EoE patients (5.2%) were currently infected with H. pylori and 5 EoE patients (8.6%) reported prior eradication of H. pylori. H. pylori infection was linked with a 76% reduced likelihood of having EoE.

“This adds to the evidence that allergic disorders in general may be less common in people with H. pylori infection,” said lead author Dr. Ulrike von Aarnim, of the University of Magdeburg, in Germany. The results are published in Alimentary Pharmacology & Therapeutics.

Controlling levels of specific gut bacteria could help prevent severe diarrhea

Everyone has suffered from it. It’s ranged from mild to severe. It’s a condition that’s most-often described in a whisper.

Diarrhea.

Severe cases of diarrhea, however, are no joking matter. Research led by Michigan State University and published in a recent issue of the journal Microbiome may offer patients suffering from acute cases new treatments that focus on intestinal microbial communities to prevent the disease.

In the U.S. alone, most diarrhea is caused by 31 different foodborne pathogens that are responsible for more than 9.4 million infections, nearly 56,000 hospitalizations and 1,351 deaths annually.

Tumor necrosis factor in colitis - bad actor or hero?

Investigators at Children’s Hospital Los Angeles have found that a common therapeutic target for the treatment of inflammatory bowel disease (IBD) may actually protect against intestinal inflammation by inhibiting pathogenic T-cells. This discovery, reported in the October 2015 issue of Gastroenterology, could lead to new treatment options for the 65 percent of individuals with IBD who do not respond or become resistant to anti-TNF medications.

According to lead author Shivesh Punit of The Saban Research Institute, discovering that tumor necrosis factor receptor 2 (TNFR2) mitigates inflammation in mice was surprising, given that therapies that target tumor necrosis factor (TNF) are the primary treatments for individuals with IBD.

“Understanding this mechanism allows us to target new therapeutic approaches for patients who don’t respond to current therapies,” said principal investigator Brent Polk, MD, who was senior author on this study. Polk is a pediatric gastroenterologist and director of The Saban Research Institute of Children’s Hospital Los Angeles, and is also professor and chairman of pediatrics at the Keck School of Medicine of the University of Southern California.

Thiopurine Immunosuppressives

Azathioprine is a pro-drug that is converted into 6-mercaptopurine (6-MP) and is subsequently metabolized by one of three different enzymes to form either active or inactive metabolites .

There is substantial inter-individual variation in azathioprine metabolism so an understanding of these mechanisms is essential to safe and effective administration of thiopurine therapy. Metabolism of 6-MP by xanthine oxidase produces 6-thiouric acid, which is inactive. Metabolism by hypoxanthine phosphoribosyltransferase produces the active 6-thioguanine (6-TG) nucleotides which are associated with improved efficacy in Crohn’s disease, but also an increased risk of leukopenia. Lastly, metabolism by thiopurine methyltransferase (TPMT) produces an inactive metabolite, 6- methylmercaptopurine (6-MMP), which can be hepatotoxic at higher concentrations. The active metabolite, 6-TG, is a purine analogue that incorporates into cellular DNA, inhibits proliferation of lymphocytes, and stimulates apoptosis of T cells in the lamina propria. There are genetic polymorphisms in TPMT enzyme activity that profoundly impact the metabolism of azathioprine. It is advised to check TPMT activity prior to initiating thiopurines in order to select optimal dosing and avoid toxicity. One in 300 patients has very low or absent TPMT activity, which can lead to severe leukopenia even with small doses of azathioprine and another 11 % have intermediate enzyme activity and may require dose reduction . For patients with a high 6-MMP to 6-TG ratio, a xanthine oxidase inhibitor, allopurinol, can be added in conjunction with thiopurine dose reduction in order to favorably alter the 6-TG and 6-MMP metabolite profile. The addition of allopurinol in these patients has been shown to improve disease activity scores, reduce daily prednisone dosage, and decrease aminotransferase levels .

However, this strategy carries a significant risk of leukopenia and requires close follow-up and careful monitoring.

Glucocorticoids

Glucocorticoids are highly effective for the short- term control of Crohn’s disease-related symptoms, but they are less effective for maintenance of remission, and have significant adverse effects that preclude safe long-term administration.

They work by interacting with glucocorticoid receptors in the cell nucleus to alter expression of inflammatory genes, inhibit the expression of adhesion molecules, and inhibit the migration of inflammatory cells into tissues.

In a 23-year population-based study of the natural history of Crohn’s disease, the short-term benefit of steroids was substantial with 84 % of patients demonstrating complete or partial response at 30 days. However, only 32 % of these patients were able to maintain remission at the end of a year without ongoing steroid use.

Anti-Integrin Therapies

Integrins are glycoproteins expressed on the surface of circulating leukocytes and mediate their adhesion to the vascular endothelium and their subsequent migration into adjacent tissue.

Anti- integrin therapies have been developed to selectively block this critical step in the recruitment of leukocytes to the gut in patients with inflammatory bowel disease. Natalizumab, the first anti- integrin therapy studied in Crohn’s disease is a humanized IgG4 monoclonal antibody that leads to inhibition of both α4β7 integrin (responsible for leukocyte trafficking to the GI tract) and α4β1 (responsible for leukocyte trafficking to the central nervous system). As a result, natalizumab induces a selective immunosuppression of both the GI tract and the brain and has demonstrated benefit in treating both Crohn’s disease and multiple sclerosis. Results of the pivotal ENCORE and ENACT studies showed that natalizumab was superior to placebo for induction 43and maintenance of response and remission in patients with moderately to severely active Crohn’s disease. The benefit of natalizumab was most pronounced for patients with an elevated CRP at baseline and in those previously treated with anti-TNF therapy.
Unfortunately, use of natalizumab has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare but devastating demyelinating disease of the CNS caused by reactivation of the JC polyomavirus. PML usually presents with sub-acute neurologic deficits, including cognitive deficits (48 %), motor deficits (37 %), language disturbances (31 %), and visual difficulties (26 %). Although JC virus infection is quite common (affecting up to 86 % of the general population) PML is only seen in immunosuppressed individuals, suggesting that depletion of CNS lymphocytes is responsible for the increased risk in natalizumab-treated patients. Among patients receiving natalizumab, concomitant immunosuppression, longer duration of natalizumab therapy, and a positive JC virus antibody test at baseline or during treatment are all associated with a higher risk of PML . In recognition of the risk of PML, patients receiving natalizumab must be enrolled in a safety monitoring program that involves periodic testing for JC virus antibody, avoidance of adjunctive immunosuppression, and consideration of drug holidays for patients on long-term therapy.

Antibiotics

Antibiotics have a role in treating infectious complications of Crohn’s disease, including perianal and intra-abdominal abscesses, and in the longer term management of perianal fistulizing disease, and prevention of recurrence after ileocecal resection. Antibiotics may also play a role to a lesser extent in reducing mucosal inflammation in luminal Crohn’s disease. It is hypothesized that the effect of antibiotics on intestinal inflammation may be mediated through alterations of the intestinal microbiota, resulting in a decreased antigenic stimulus in patients with a genetic predisposition to immune dysregulation.

Antibiotics that have historically been used for Crohn’s disease include metronidazole and ciprofioxacin, although more recent studies have evaluated a potential role for rifaximin. Studies of metronidazole in active Crohn’s disease have not consistently signaled a clear benefit over placebo, although there has been a suggestion of symptom reduction in patients with colonic disease. A small randomized controlled trial of combination ciprofioxacin and metronidazole versus methylprednisolone in active Crohn’s disease showed similar rates of clinical remission at 12 weeks. Unfortunately, long-term use of metronidazole is associated with many side effects, including peripheral neuropathy, dysgeusia, and nausea, causing a significant percentage of patients to discontinue the therapy.

In the treatment of perianal fistulizing disease, an open-label study of metronidazole showed complete or advanced healing in 15 of 18 patients treated with metronidazole .