LINDA HARDER | TRACEY BROWN
Crohn’s Disease, Celiac Disease and Pregnancy with IBD
Maryland gastroenterologists explain how to better manage the inflammation in Crohn’s and celiac disease, and how to help women with inflammatory bowel disease through pregnancy and childbirth.
The Challenge of Crohn’s Disease
Crohn’s disease, which affects an estimated 500,000 to 700,000 Americans, is a chronic inflammatory bowel disease (IBD) that can involve any part of the intestinal tract, from the mouth to the anus. However, the ileum and cecum are most commonly involved. Crohn’s may also affect the eyes, skin and joints, and cause inflammation in other organs.
Its primary symptoms are pain, weight loss, loss of appetite and abdominal fullness or mass. Some patients exhibit symptoms of colitis, with diarrhea or constipation. They may also have fevers, fatigue and a feeling of malaise. In contrast to the other type of IBD, ulcerative colitis, which only affects the inner lining of the colon or ileum, Crohn’s is transmural, potentially affecting the entire thickness of the bowel wall.
Another common feature unique to Crohn’s is ‘skip’ lesions – unaffected areas sandwiched between affected areas. More severe cases may result in fistulas that occur between two loops of the bowel, between the bowel and rectum or anus, or enterocutaneous fistulas between the bowel and skin. Patients also may demonstrate ‘crops’ of aphthous ulcers on the mucous membranes lining the mouth.
Michael Epstein, M.D., FACG, AGAF, founder of Annapolis-based Digestive Disorders Associates, says, “The manifestations of Crohn’s are protean, and symptoms overlap with those of other illnesses. They may be mild or severe, and they may relapse or remit in irregular intervals or be chronic.”
While Ashkenazi Jews, caucasians, teens and young adults are at higher risk; Dr. Epstein notes that the incidence in blacks and in older people is on the rise, perhaps due to better detection and diagnosis.
Crohn’s is believed to be caused by a dysregulated proinflammatory response to commensal gut bacteria. Due to mutations, some mucosal defense mechanisms are disrupted, including the presence of mucus-coated epithelium with tight junctions, IgA secretion, and defensins (naturally-occurring antibiotics that are produced by Paneth cells to maintain sterility of the crypt).
Mutations in the NOD2/CARD15 gene and the autophagy gene, ATG16L1, are associated with Crohn’s disease. The NOD2 gene is involved with recognition of bacterial peptidoglycans, and mutations in the gene cause a decrease in defensin production and secretion. Mutations in the ATG16L1 gene lead to a decrease in the exocytosis of secretory granules in Paneth cells, thereby decreasing concentrations in the crypt of defensins, lysozyme and phospholipase A2.
When defense mechanisms are depressed, uncontrolled microbial proliferation can occur, and certain genes are stimulated to produce proinflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, and the chemokine IL-8. Cytokine and chemokines attract T-cell infiltration (primarily Th-1 cells in Crohn’s disease) that in turn amplifies the inflammatory response.
“Certain triggers, such as bacterial infection of the gut, C. difficile, E. coli infection or other stressors may set off the disease,” Dr. Epstein explains. “Some medications, such as Advil or Motrin, also can cause a flare-up. We avoid aspirin, Aleve and the like because they may exacerbate the illness.”
While Crohn’s symptoms can mimic those of other gastrointestinal diseases, Dr. Epstein states, “We have very good imaging procedures like CT or MR enterography, balloon-assisted enteroscopy, colonoscopy and ileoscopy, as well as blood tests to aid in making an accurate diagnosis.”
Biologics such as anti-TNF-a therapy have emerged as second-line therapies for those who have failed conventional therapies. It has been supported by several large, randomized, controlled trials.
“Medications have evolved from a primary reliance on steroids and mesalamine to control inflammation, to a greater use of immunologics, such as Imuran® and Purinethol®,and biologic therapies such as Humira or Remicade,” notes Dr. Epstein. “Biologics, developed over the past decade, are the biggest boon to care since prednisone. Nonetheless, some 40 to 45% of patients don’t respond to them.”
Disease-related factors and co-infection should be ruled out, however, before determining that nonresponse is drug-related.
The SONIC (Study of Biological and Immunomodulator Naive Patients In Crohn’s Disease) study, published in the New England Journal of Medicine in 2010, found that for patients with early disease, combining infliximab and azathioprine was superior to using either drug alone for patients whose disease was refractory to mesalamine, budesonide or prednisone.
Digestive Disorders Associates is participating in several global clinical trials to assess the efficacy of treatment regimens that involve drugs in the interleukin class, plus multiple antibiotics. “DNA from tuberculosis- (TB) like organisms is present in those with Crohn’s. The theory is that bacteria similar to TB cause some of the cases of Crohn’s.”
About 15% of patients with Crohn’s will be affected by strictures in the small intestine. Less invasive alternatives to bowel resection include strictureplasty, in which the narrowed section of bowel is opened without removing bowel tissue, and endoscopic balloon dilation, in which physicians dilate the stenosed section with a balloon introduced during endoscopy.
Perianal fistulas, the most common fistulas to present in Crohn’s, can be treated surgically if antibiotics plus anti-TNF-a drugs fail. “In the past, about half of patients ended up with surgery at some point,” says Dr. Epstein. “However, with today’s medications and alternative therapies, that percentage is decreasing.”
While fecal microbial transplants are being eyed for Crohn’s, only one small study has indicated they may have value, and gastroenterologists generally are skeptical of their potential. According to Dr. Epstein, “The microbiome is the next big area, but we have lots of theory and very limited data. Some 90% of bacteria in the gut are unknown. We don’t yet know the optimal dose, amount or number to give people. Well-done studies found that the ovum of pork tapeworm was not effective in treating Crohn’s, and it remains to be seen if microbiologic therapy can alter the course of the disease.”
Dr. Epstein advocates, “The most important thing with Crohn’s is to educate patients so they can be in control of their health. The Crohn’s and Colitis Foundation website is an excellent online resource. No two patients are alike, so no two have the same needs. It takes lots of compassion and patience to deal with patients with this disorder – it can be exhausting, but also very rewarding.”
Celiac Disease: Underdiagnosed GI Disorder
Celiac disease is a disorder in which those with a genetic predisposition cannot tolerate gluten, a protein found in wheat and some other grains. Gluten triggers an autoimmune response that engenders an inflammatory cascade inside and outside the gastrointestinal (GI) tract. Gliadin, the toxic component of gluten, binds to the intestinal receptor CXCR3, which releases the protein zonulin. Zonulin makes the intestine more permeable to large molecules. This triggers an autoimmune response in which a celiac patient’s immune system identifies gluten as an intruder, and responds by attacking the intestine instead of the intruder.
Despite growing awareness of the potential impact of gluten on many digestive systems, celiac disease remains a vastly under-diagnosed disorder, especially in the U.S. “It’s estimated that more than 1% of Americans, or about three million people, have celiac disease, yet only about 60,000 have been diagnosed,” says David Doman, M.D., FACP, FACG, clinical professor of Medicine, George Washington University School of Medicine, and founding partner, Montgomery Gastroenterology in Silver Spring.
That is likely due in part to the wide spectrum of clinical manifestations, age of onset and severity of symptoms in celiac disease. Children are more likely to exhibit malnourishment, weight loss and diarrhea, while adults commonly have symptoms that manifest outside the GI tract. An adult’s only symptoms may be migraines, depression, ADHD, recurring miscarriages or infertility, or skin disorders such as unexplained, hives, uticaria or dermatitis herpetiformis.
Many people have genetic susceptibility to celiac but never get the disease. According to Dr. Doman, “It’s still unclear what the trigger is and why some patients get celiac as children while others are affected as adults. It’s likely that some mutations are more aggressive than others.”
Malabsorption of Vitamin D, folic acid and other nutrients can cause osteoporosis at a young age. “If a 30-year-old patient has osteoporosis, physicians should consider undiagnosed celiac disease as a possible culprit,” he advises.
Diagnostic tests can include serologic testing, malabsorption screening, genetic testing, radiographic evaluation, wireless capsule endoscopy and small bowel biopsy. Dr. Doman cautions, “No single laboratory test can completely establish a diagnosis of celiac disease. Antibody testing is only 90 to 95% reliable, and false negatives are an issue when the patient has adhered to a gluten-free diet or is taking immunosuppressants.”
He also warns physicians against interpreting positive genetic test results as indicative of celiac. “A positive test only means that the individual is at higher risk for celiac. It’s only helpful in ruling out celiac when the test finds the patient to be free of celiac-related mutations.”
Dr. Doman adds, “The gold standard in diagnosing celiac disease continues to be the small bowel biopsy. The endoscopic procedure takes about half a dozen random biopsies, and histologic changes can range from mild with lymphocytic infiltration, to complete villus atrophy. The patient can have a complete absence of villi in the most extreme cases.”
In 2014, the standard of care is a lifelong gluten-free diet. While many patients find this diet provides compliance challenges, gluten-free food is far more readily available at most supermarkets or online today than in the past.
Phase 2 and Phase 3 clinical trials are currently underway on a number of fronts to develop new treatment approaches, including the following:
- New types of genetically engineered wheat that will not cause the inflammatory cascade
- Therapeutic probiotics that can metabolize gliadin
- A therapeutic vaccine that can induce gluten oral tolerance
- Transglutaminase inhibitors for targeted immune suppression
- Antizonulin therapy to restore small bowel cellular junction integrity
Today, a strict gluten-free diet is mandatory for successful treatment, but these new clinical trials present hope for other options in the future,” Dr. Doman concludes.
Pregnancy and IBD
Given the thousands of gastroenterologists in the country, perhaps it’s surprising that only a handful specialize in pregnancy and IBD. Mary Harris, M.D., medical director, The Center for Inflammatory Bowel and Colorectal Diseases at Mercy Medical Center, is one of the few.
“I became an expert by default because other colleagues didn’t want to deal with this issue,” she says. “Crohn’s and colitis are almost invariably diagnosed in people of childbearing years, and it takes careful planning for these patients to have a successful pregnancy and birth.” Fortunately, with good care and planning, it’s entirely possible for most women with IBD to conceive.
“However, patient education and planning is a requisite,” Dr. Harris emphasizes. “Patients must be in remission for at least three months before getting pregnant, and folic acid prior to conception is even more important for this group than for the general population.”
“These patients have high anxiety levels,” Dr. Harris explains. “And they can tell a physician’s level of discomfort. They come to me with a list of questions that often includes, ‘Am I healthy enough to enjoy sex?’ and ‘Will I have impaired fertility?’”
Active disease can affect fertility because it can cause inflammation in the ovaries (particularly the right ovary) and the fallopian tubes. Transmural inflammation can potentiate a tubal pregnancy, and scar tissue from a prior surgery can also impact fertility. She notes, “Those who have had a colectomy have their fertility cut in half. That makes it critical for physicians to discuss the potential issues before performing an elective colectomy on a young woman.”
Good nutrition is critical for patients with IBD during pregnancy, and low maternal weight gain has been associated with a lag in fetal growth. Active disease also is associated with prematurity and low fetal weight.
Dr. Harris comments, “Pregnancy and the postpartum period can worsen IBD, so patients generally should be seen once each trimester, as well as four-to-six weeks post-partum. If they have a flare-up, they should see their specialist immediately. Active disease in the first trimester can lead to spontaneous abortion or congenital malformation. It’s critical that physicians and patients understand that the risk from active disease is greater than the risk of taking medications to treat the disease.”
She notes, “Biologic therapy, including Remicade®, Humira and others, has greatly improved the medical management of IBD during pregnancy. Remicade and Humira can be taken up to 32 weeks of pregnancy, while Cimzia® can be continued throughout pregnancy.”
Cimzia blocks the action of TNF, a substance produced by cells of the immune system to induce inflammation. It’s the first and only PEGylated biologic treatment for Crohn’s disease, which refers to the process by which the drug’s proteins are covalently joined with polyethylene glycol (PEG), an FDA-approved polymer, providing enhanced therapeutic capability. Because of that, it’s too large to pass through the placenta.
Delivery and Breastfeeding
Dr. Harris notes, “If the disease is refractory even with medications, in-vitro or other fertilization techniques present a viable alternative for many women with IBD.”
Perhaps surprisingly, most women with IBD can safely deliver vaginally. The two exceptions are patients with an ileal pouch, which can be torn during delivery, and patients with Crohn’s disease who have perirectal fistulas or abscesses. The C-section rate, which approaches 30 to 35% in this population, is lower than might be expected.
“I personally believe no patient should breastfeed while taking biologics,” Dr. Harris exclaims. “However, some medications, such as mesalamine, in low doses, may be safe to take while breastfeeding.”
“These patients should be seen by an expert,” she concludes. “I see the relief on patients’ faces when they know that I’m not intimidated. But I assure them that, with careful management, they usually can have a successful pregnancy and delivery.”
Mary Harris, M.D, medical director, The Center for Inflammatory Bowel and Colorectal Diseases at Mercy Medical Center
David Doman, FACP, FACG, clinical professor of Medicine, George Washington University School of Medicine and founding partner, Montgomery Gastroenterology
Michael Epstein, M.D., FACG, AGAF, founder of Digestive Disorders Associates, Annapolis