May 22, 2012
Possible Prevention And Treatment For Bowel Diseases
New research being presented at Digestive Disease Week® (DDW) offers key insights into the prevention and treatment of bowel diseases, which affect millions of people worldwide. Several studies show that factors, including common dietary additives, hormone replacement therapy, oral contraceptives and even high-altitude travel may cause or exacerbate these diseases. Other research examines the effect of cutting-edge therapies on ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease (IBD). Although incompletely understood, this is a complex disease in which many factors, including heredity, diet and exposure to environmental factors, determine who develops IBD, the age of presentation, and the specific manifestations of disease.
"Research into the causes of and innovative treatments for bowel diseases is leading to better clinical results, as well as advances in prevention," said Jerrold R. Turner, MD, PhD, AGAF, Sarah and Harold Lincoln Thompson Professor and associate chair of pathology, University of Chicago, IL. "Findings like these are critically important since the prevalence of bowel diseases continues to increase." DDW is the largest international gathering of physicians and resarchers in the field of gastroenterology, hepatology, endoscopy, gastrointestinal pathology and gastrointestinal surgery.
Flying or traveling to high-altitude locations puts individuals with inflammatory bowel disease (IBD) at increased risk for flares, according to new research from Trieml Hospital, Zurich, Switzerland. This complication affects individuals with both Crohn's disease and ulcerative colitis (UC), although the risk appears to be greater with Crohn's disease.
First-hand reports from skiers and mountaineers with IBD who complained of flares within a day to a week of being at pronounced elevations triggered the researchers' study. They looked at 103 patients who were seen at several IBD clinics in Switzerland over a one-year period. A total of 52 patients with flares were matched with 51 patients who were in remission, and both groups were asked about their activities during the previous four weeks. Overall, individuals who had experienced flares had significantly more frequent flights or trips to areas 2,000 meters (6,562 feet) or more above sea level.
Oxygen depletion in any tissue (hypoxia) induces inflammation, yet little data has been available about how it might exacerbate IBD, according to Stephan Vavricka, PD, chief, division of gastroenterology and hepatology, Trieml Hospital. "We need to look more closely at how hypoxia may induce inflammation on a molecular level in the intestines," he said.
The two patient groups were controlled for factors such as age, smoking, sports activities, recent antibiotic treatment and chronic obstructive pulmonary disease. However, the study sample was too small to draw conclusions about symptoms or severity based on whether a person had been flying (and in an oxygen-controlled plane cabin) compared to skiing, hiking, climbing or even just visiting elevations with much thinner air.
Dr. Vavricka plans to study the hypoxia link in a prospective way with more patients. "It's too early to tell patients not to get on a plane or to restrict where they go," he said.
Dr. Vavricka will present these data on Sunday, May 20 at 8:30 a.m. PT in Room 33abc of the San Diego Convention Center.
Hormonal Replacement Therapy and Risk of Ulcerative Colitis and Crohn's Disease Among Postmenopausal Women: Results from a Large Prospective Cohort of U.S. Women (Abstract #401)
Hormone replacement therapy may play a role in the development of ulcerative colitis, according to a new study from Massachusetts General Hospital, Boston. Investigators sought to identify potential risk factors for development of ulcerative colitis and Crohn's disease, together, inflammatory bowel disease. Previous studies have shown an increased risk of Crohn's disease with regular use of oral contraceptives in younger, premenopausal women; researchers asked if hormone replacement therapy in older, postmenopausal women also increased risk.
Using the well-established Nurses' Health Study, investigators evaluated the risk of ulcerative colitis and Crohn's disease according to hormone use in more than 100,000 participants with more than 17 years of follow-up. Investigators found that hormone use was associated with a 70 percent increase in the risk of ulcerative colitis, however there was no association between hormone use and risk of Crohn's disease. The risk of ulcerative colitis increased with longer duration of hormone use and diminished with longer duration of discontinuation. There was no difference in the risk according to the type of hormone therapy used.
Hamed Khalili, MD, gastroenterology fellow, Massachusetts General Hospital, said that because ulcerative colitis and Crohn's disease are not very common, it is difficult to speculate on whether allowing women to use hormones will greatly impact the rates of these diseases in the general population. However, "the major implication of our study is we now know that estrogen-related pathways play a role in the development of ulcerative colitis, which may have significant consequences for treatment," said Dr. Khalili.
He added that there are several reasons why hormones seemed to play a role in ulcerative colitis, but not Crohn's disease. Estrogen receptors are mainly found in the colon and not the small intestine. This is significant because ulcerative colitis only involves the colon as opposed to Crohn's disease, which often affects the small bowel and colon. Also, oral estrogen use has been associated with alteration in colonic permeability, a process that has been implicated in the pathogenesis of ulcerative colitis.
Dr. Khalili cautioned against concluding that women should not use hormones given the findings in this study – "While the risk is real, the impact on one's absolute risk of developing ulcerative colitis is small."
The Nurses' Health Study was established in 1976 when more than 120,000 nurses completed mail questionnaires, providing information about medication use (such as oral contraceptives and hormone use), medical history, weight and height. Since then, these women have completed biennial questionnaires with a follow-up greater than 90 percent. The follow-up in this study was through 2008, with 138 incident cases of Crohn's disease and 138 incident cases of ulcerative colitis confirmed.
This research received no pharmaceutical funding.
Dr. Khalili will present these data on Sunday, May 20 at 10:30 a.m. PT in Room 30cde of the San Diego Convention Center.
Reproductive Factors and Risk of Ulcerative Colitis and Crohn's Disease: Results from Two Large Prospective Cohorts of U.S. Women (Abstract #402)
Oral contraceptive use is associated with risk of Crohn's disease, but not ulcerative colitis, according to new research from Massachusetts General Hospital, Boston. While previous studies have suggested that oral contraceptives increase the risk of Crohn's disease and possibly ulcerative colitis, these studies did not account for other reproductive factors associated with oral contraceptives that may also affect the risk, such as pregnancy, age at first child, total number of ovulatory years, and age at menarche (initiation menstruation). Because these factors all play a role in reproduction, it is possible that previous associations were explained by other reproductive factors and not necessarily oral contraceptives.
In this study, investigators led by Hamed Khalili, MD, gastroenterology fellow, Massachusetts General Hospital, used two large prospective cohorts from the Nurses' Health Study I, which enrolled more than 120,000 nurses in 1976 with follow-up through 2008, and the Nurses' Health Study II, which enrolled more than 114,000 nurses in 1989 with follow-up through 2007, with no prior history of ulcerative colitis or Crohn's disease.
Researchers investigated the link between reproductive factors and risk of ulcerative colitis and Crohn's disease, and found an almost three-fold increase in risk of Crohn's disease with oral contraceptive use. In the initial analyses, there was no association between oral contraceptive use and the risk of ulcerative colitis. However, when investigators conducted a subgroup analysis of women who were ever smokers, oral contraceptive use was associated with increased risk of ulcerative colitis. There was no association between other reproductive factors and risk of either ulcerative colitis or Crohn's disease. "We were interested to see what would happen if we adjusted and accounted for all these other reproductive factors, and what we found was none of these reproductive factors altered the association between oral contraceptive use and risk of Crohn's disease or ulcerative colitis," said Dr. Khalili.
He added that the study reinforces the importance of estrogen and estrogen-related pathways in the pathogenesis of ulcerative colitis Crohn's disease. One implication of the study is, considering the significant increase in risk of Crohn's disease with oral contraceptive use, physicians may consider providing alternative forms of contraception to individuals who have a strong family history of Crohn's disease to decrease their likelihood of developing the disease.
This research received no pharmaceutical funding.
Dr. Khalili will present these data on Sunday, May 20 at 10:30 a.m. PT in Room 30cde of the San Diego Convention Center.
PIANO: A 1000 Patient Prospective Registry of Pregnancy Outcomes in Women with IBD Exposed to Immunomodulators and Biologic Therapy (Abstract #865)
Among infants born to women with inflammatory bowel disease (IBD), the use of biologics and immunosuppressants was not associated with an increase in congenital anomalies, abnormal newborn growth and development, or other complications compared to infants of mothers not exposed to these medications, according to new research from the University of California at San Francisco (UCSF) Medical Center.
Investigators led by Uma Mahadevan, MD, associate professor of medicine and co-medical director, UCSF Center for Colitis and Crohn's Disease, developed a prospective study of 1,100 pregnant women at 30 IBD centers around the country to determine whether complication rates are higher among women with IBD and their offspring who are exposed to azathioprine (AZA), 6-MP or anti-TNF agents during pregnancy, compared to women with IBD who do not take these medications.
Patients were divided into four groups according to exposure between conception and delivery: unexposed (no thiopurines or anti-TNF agents); group A (6MP/AZA); group B (infliximab, adalimumab, certolizumab); and group AB (both thiopurines and anti-TNF). Pregnant women with IBD were prospectively enrolled and contacted every trimester; at the birth of their baby; and at four, nine and 12 months of age. Newborn complications for the first year of life and the mothers' medications, disease activity and complications of pregnancy were recorded.
Investigators found 33 (4.1 percent) spontaneous abortions and 37 infants with congenital anomalies (4.6 percent). The use of thiopurines and anti-TNF agents were not associated with an increase in "any complication," spontaneous abortions, congenital abnormalities, preterm birth, intrauterine growth retardation, caesarean section or neonatal intensive care unit stays, even when adjusted for disease type or disease activity. The study also found that the majority of newborns (72 percent) were breastfed and that breastfeeding was not associated with an increase or decrease in infection risk among drug exposures and within each drug category.
The study showed a significant increase in infant infections at 12 months of age in the combination therapy group relative to the unexposed group (group AB, RR 1.50 [1.08-2.09]). Infant height, weight and developmental milestones – adjusted for disease activity – were similar among infants in all groups at four, nine and 12 months of age. These results are preliminary, as not all 1,100 infants of the women with IBD have reached one year of age.
Implications for treatment are significant since biologics are prescribed not only for gastrointestinal diseases, but also for rheumatoid and dermatologic problems. Therefore, even though the study looked only at women with IBD, the fact that it suggests no increase in birth defects could help manage pregnant women with other conditions in addition to those with IBD.
"We can continue biologic medications in pregnant women, thereby keeping them in remission, which not only reduces complications from disease activity, but also allows them to take better care of their newborn," said Dr. Mahadevan.
Next, investigators will continue to follow the 1,100 enrolled women and infants until the one-year mark and then begin a three-year follow-up study to look at developmental milestones, which has never been done before.
Crohn's disease and ulcerative colitis often affect women of childbearing age, so investigators sought to determine the safety of medication during pregnancy. Women with IBD and their physicians often have concerns regarding the safety of biologic and immunosuppressant medication use during pregnancy, but stopping medication for these diseases can be dangerous. Furthermore, previous data regarding the safety of these medications are sparse due to limited sample size at any one center and lack of uniform data collection methods.
The study received no pharmaceutical funding, but was fully funded by two senior awards from the Crohn's and Colitis Foundation of America.
Dr. Mahadevan will present these data on Monday, May 21 at 5 p.m. PT in 20d, San Diego Convention Center.
Environmental Risk Factors for Crohn's Disease: Maltodextrin (MDX), a Ubiquitous Dietary Additive in Western Diets, Enhances Biofilm Formation and Adhesivness of E. coli (Abstract #Tu1844)
Western diets that include significant amounts of the additive maltodextrin, a filler compound added to the sweeteners Splenda and Equal, may contribute to an increased susceptibility to Crohn's disease, according to new research from the Cleveland Clinic Lerner Research Institute, OH. There is a clear link between bacteria and inflammatory bowel disease (IBD), with previous studies reporting differences in the types of bacteria and location of bacteria in the intestines of individuals with Crohn's disease.
Investigators led by Christine McDonald, PhD, assistant staff, pathobiology department, Lerner Research Institute, looked at how bacteria were altered by components of the Western diet to better understand how diet affects bacteria associated with IBD, an area of research not well understood. They reviewed how certain components of this diet alter E. coli bacteria to increase their ability to form biofilms and adhere to intestinal epithelial cells – features associated with the disease.
The investigators grew E. coli bacteria isolated from a Crohn's disease patient in the lab with different substances found in a Western diet and tested their ability to form biofilm structures similar to those found in the gut of Crohn's disease patients. Initially, they compared bacteria that were fed glucose (the simplest form of sugar) to bacteria that were fed artificial sweeteners. Surprisingly, Dr. McDonald's group found that the sweeteners alone didn't have an effect, but maltodextrin dramatically changed the bacteria.
When the researchers looked at how well the bacteria adhered to plastic or live intestinal cells, they found that bacteria grown in maltodextrin were stickier, resulting in thicker biofilms, and a greater number of bacteria piled up on the surface of intestinal cells. This finding is significant since maltodextrin is in a wide variety of products ranging from sweeteners and processed foods to medications and other products. Dr. McDonald cautioned that it is too early to conclude that maltodextrin promotes disease, though their results suggest that maltodextrin can cause E. coli to gain features associated with disease and therefore, potentially, increases an individual's overall risk of developing IBD. Studies are planned to test this more directly in experimental mouse models of IBD. "While dietary additives like maltodextrin are generally considered safe, these findings suggest that perhaps people who are prone to develop IBD should consider limiting their maltodextrin intake," Dr. McDonald said.
Previous research suggests that consumption of a Western diet – one that is high in fat, low in fiber and rich in processed foods – is associated with the development of Crohn's disease. Other studies have observed striking differences between the bacteria found in healthy intestines and those affected by Crohn's disease. In a healthy gut, the normal bacterial community is separated from direct contact with the intestinal cells, while in Crohn's disease patients, gut bacteria form a dense structure (a biofilm) in close contact with the cells. Additionally, some studies have shown an increase in the amounts of E. coli and demonstrated that Crohn's disease-associated E. coli has special features, making the strain more adhesive and invasive.
This study received no pharmaceutical funding. It was supported by the National Institutes of Health (R01DK082437) and the Howard Hughes Medical Institute "Med into Grad" Initiative.
Dr. McDonald will present these data on Tuesday, May 22 at noon PT in Halls C-G of the San Diego Convention Center.
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