Published in UAB Insight, Winter 2008
ABSTRACT: Research into the pathogenesis of inflammatory bowel disease is identifying therapeutic targets in the dysregulated immune mechanisms.
CME OBJECTIVE: The reader will understand the need for thorough evaluation and the medical and surgical options for treatment.
Inflammatory bowel disease (IBD) is a chronic inflammatory condition that can affect any part of the gastrointestinal (GI) tract and is characterized by flares and remission. IBD affects an estimated 1.4 million Americans. “Although IBD was once considered predominately a disease of whites, 40% of UAB’s IBD patients are African Americans. IBD also is associated with poor nutritional status, however more than 50% of our IBD patients are obese,” says UAB gastroenterologist Alexandra Gutierrez, MD.
Disruption of the GI tract’s immunoregulatory mechanism causes the diffuse pathological manifestations seen in both Crohn disease and ulcerative colitis (UC). Patients presenting with symptoms including GI bleeding, weight loss, abdominal pain, diarrhea, appendicitis, and infectious colitis all meet the differential diagnosis for Crohn disease and UC. Overlapping symptoms makes a thorough and accurate medical evaluation critical to define the underlying process, Gutierrez says.
Evaluating Diverse Symptomology
Extraintestinal autoimmune disease presentations such as iritis, uveitis, pyoderma gangrenosum, and primary sclerosing cholangitis are all possible extraintestinal manifestations of IBD and reflect immune system dysregulation.
“New onset symptoms such as weight loss, rectal bleeding, anemia, or abdominal pain should trigger a thorough GI evaluation,” Gutierrez says. “Diagnosis of IBD requires a whole body, multidisciplinary approach. This is a disabling disease, and clinicians should have a high index of suspicion to prompt an evaluation.”
Medical evaluation for IBD includes a complete family history, travel history, history of stool frequency and consistency, fecal urgency, rectal bleeding, abdominal pain, and a complete physical exam including a perianal examination (Gut. 2004;53[S5]:VI-V16).
Crohn Disease and UC
Keys for Successful
Treatment of IBD
- Early diagnosis
- Whole-body approach
- Well-defined therapeutic goals
- Steroid-sparing therapy
- Recognition of extraintestinal symptoms
- Multidisciplinary/multispecialty approach
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Crohn disease is a patchy, transmural inflammatory process that may affect any part of the GI tract from the mouth to the anus. Diffuse patterns of disease activity, location, expression, and complications make severity difficult to define and manage. It is often associated with significant morbidity and complications, including abscesses, fistulas, strictures, and bowel stenosis.
Unlike Crohn disease, UC is confined to the large bowel mucosa and submucosa. In most cases, the disease begins distally and extends proximally; the diseased segment of bowel is continuous. Clinically, UC is characterized by the frequency and toxicity of stools. Colonoscopy reveals the extent and severity of disease.
Two self-limiting subclasses of colitis have been delineated based on the affected mucosal lining or the involved cell population. Both present with watery diarrhea and normal findings at colonoscopy. Colon biopsy specimens, however, show microscopic inflammation. Collagenous colitis features subepithelial collagen band thickening on biopsy. Lymphocytic colitis is defined histologically by increased intraepithelial lymphocytes in the lamina propria. “Once optimally treated, patients with these subtypes of microscopic colitis may remain in remission and may not require prolonged therapy,” she says.
Clinical Intervention
“Crohn disease and ulcerative colitis both require long-term care. Despite advances, there is no cure for Crohn disease, and goals of medical therapy are inducing and maintaining remission,” Gutierrez says.
“Surgical intervention in Crohn disease is reserved for treatment of complications, including bleeding, strictures, perforations, fistulas, failure to thrive, abscesses, cancer and precancerous lesions, and for refractory disease,” says UAB GI surgeon Ernesto R. Drelichman, MD.
Surgical goals in Crohn disease focus on preservation of absorptive intestinal surface. “Strictureplasty, designed to spare absorptive surface area, is a bowel-sparing procedure.” he says.
Ileal pouch-anal anastomosis (IPAA) is a sphincter-saving operation that avoids a permanent ileostomy and maintains fecal continence. “We remove the colon and the rectum and rebuild a reservoir from the small bowel in a two-stage process,” Drelichman says. “The operation cures ulcerative colitis and eliminates the risk of colon cancer. The disadvantage is that IPAA requires two operations and alters bowel function, with most patients having 6 to 8 bowel movements a day. Despite this, most patients report greatly improved health status — often equal to that of the general population — after the operation.”
Improved Quality of Life
“Twenty years ago, corticosteroids were the standard of care for moderate to severe IBD, but in the last 10 years, new treatments have evolved,” Gutierrez says. Tumor necrosis factor (TNF) antagonists to augment or replace conventional therapy can offer long-term remission, healing of bowel mucosa, tapering or discontinuing steroids, and reduced need for IBD-related surgery and hospitalizations.
Two TNF antagonists — infliximab and adalimumab — are Food and Drug Administration (FDA)-approved for treatment of Crohn disease. Infliximab is FDA-approved for moderate to severe refractory UC, and phase 3 trials are underway at UAB for a monthly subcutaneous injectable anti-TNF agent in patients with UC and Crohns disease.
“Up to 40% of patients respond to anti-TNF therapy within 6 weeks of starting therapy, decreasing risks of hospitalization and improving quality of life,” she says.
At UAB, clinical trials are evaluating different delivery systems for approved therapies as well as therapies that target alternate defects in the immune regulatory pathway. Investigators are examining multiple formulations of anti-TNF antibodies that use various delivery modes or fusion proteins. Improved delivery systems promote compliance, improve patient outlook, and enhance quality of life, Gutierrez says.
UAB scientists are investigating pegylated certolizumab, a suspended extended-release fragment of a humanized anti-TNF, as a monthly injection for Crohn disease. This alternate delivery method reduces patients’ visits to once a month versus twice-a-month home injections or intravenous infusions every 8 weeks. “This potentially effective drug may minimize interruptions in patients’ lives,” Gutierrez says.
UAB also is participating in clinical trials of drugs aimed at new molecular targets. These include antibodies targeting overactive interleukins, with others investigating mechanisms that activate immune response.
Patients’ lifestyles, as well as drug side effects, efficacy, and risks, have always been priorities in IBD treatment, Gutierrez says. “Initial disease usually presents between ages 15 and 30, a time when young adults are most likely to be troubled by the condition’s embarrassing aspects. Treatment options that consider reproductive needs and minimize long-term adverse side effects associated with steroid use provide patients with optimal choices and improved outcomes,” she says.
Azathioprine, for example, is currently used to treat both Crohn disease and UC. “Steroid-sparing azathioprine is a safer drug now than in the past because we can evaluate its enzyme metabolism profile before starting therapy and further minimize complications by checking for tuberculosis and hepatitis B exposure,” Gutierrez says. “Clinically we now know its side effects and that it is suitable for pregnant women. These therapeutic choices, made in the interest of promoting patient quality of life, improve disease outcomes.”
For more information:
Dr. Alexandra Gutierrez
Dr. Ernesto Drelichman
1.800.UAB.MIST
mist@uabmc.edu