Innovations in Inflammatory Bowel Disease
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Inflammatory Bowel Disease (IBD) can be a complex disease to treat. As part of Massachusetts General Hospital's multidisciplinary approach for IBD management, patients receive treatment from an integrated team of gastroenterologists, radiologists, surgeons, nutritionists, psychologists, and other specialists with extensive experience in both Crohn’s disease and ulcerative colitis.
Many of the physicians at the Crohn's and Colitis Center within the Mass General Digestive Healthcare Center are also on the front line of research and have developed innovations in IBD diagnosis and treatment, including the development of new biologic therapies, imaging protocols, and minimally invasive surgical techniques all designed to maximize patient comfort, preserve healthy bowel, and minimize flare-ups and treatment complications. In addition, the goal of treatment is to personalize therapy to the individual patient so that patients receive the most effective and appropriate evaluation and therapy for their particular disease severity and its effect on their quality of life.
Biologic Therapy Alters Natural History of IBD
Biologic therapy, in the form of antitumor necrosis factor (TNF) medications like infliximab (Remicade), adalimumab (Humira), and certolizumab pegol (Cimzia), and the anti-integrin drug natalizumab (Tysabri), has transformed the management of many cases of Crohn’s disease and ulcerative colitis (UC). These drugs have proven efficacy in inducing and maintaining disease remission in many patients, particularly with moderate-to-severe Crohn’s disease. Thus, a substantial portion of patients with Crohn’s disease or UC who fail to respond to oral agents are able to achieve disease remission through biologic therapy.
One of the primary goals of IBD management is to minimize progressive bowel damage from ongoing inflammation resulting in strictures, fistulas, and frank perforation. Biologic therapy, when given earlier in the course of the disease, particularly for patients with Crohn's disease, can be helpful in delaying or preventing these complications, for which repeated surgeries are often needed.
For many people with IBD, biologic therapies are more effective than traditional drugs. A meta-analysis of 27 randomized controlled trials funded by the American College of Gastroenterology found a treatment benefit with biologic therapies for patients with active Crohn’s disease or UC who have failed first- and second-line therapy or who are dependent on corticosteroids. In addition, a recent randomized controlled trial, the SONIC trial, demonstrated that infliximab either when used alone or in combination with azathioprine had significantly superior efficacy in achieving disease remission in patients with newly diagnosed Crohn's disease.
The philosophy followed by the IBD care team at Mass General is to maximize symptom control and enhance mucosal healing within the bowel. Mucosal healing prevents complications and improves patients' quality of life.
New Biologic Therapies
Because of the success of biologic therapies in improving symptom responses and mucosal healing, the IBD care team within the Digestive Healthcare Center's Crohn's and Colitis Center is moving toward earlier use of biologic treatment as a means to modify the natural history of Crohn’s disease and possibly UC. However, the key in the management of patients with IBD is to adopt a personalized approach to therapy, tailoring the risks and benefits of each treatment to each patient's likelihood of disease progression and treatment-related side effects. In addition, for a given disease severity, the disease may have varying impact on an individual's quality of life, and social and economic functioning. Recognizing this heterogeneity, the team at the Massachusetts General Hospital Crohn’s and Colitis Center adopts this tailored approach using the latest in serologic and genetic testing to guide the choice of medications or surgery in every patient.
Mass General also offers IBD patients clinical trials for a number of new biologic therapies, including several described below with a variety of different mechanisms. This work is part of the hospital's Center for the Study of IBD, an NIH-funded program designed to expedite research and treatment options for patients with Crohn's and UC. By offering new treatments with a wider spectrum of action, Mass General aims to treat a larger spectrum of IBD patients with targeted biologic alternatives.
Under the direction of Vijay Yajnik, MD, PhD, attending physician at the Mass General Crohn’s and Colitis Center, Mass General is participating in the multicenter UNITI-2 phase 3 study with ustekinumab, an injectable antibody that inhibits the inflammatory proteins IL-12 and IL-23. Because ustekinumab targets another pro-inflammatory component aside from TNF, it may likely prove effective in IBD patients who have failed anti-TNF treatment, a finding that has been supported in earlier phase 2 studies.
The UNITI-2 study includes patients who were previously treated and failed steroids or immunomodulators randomized into three treatment arms: placebo, or two doses of ustekinumab.
A 2008 phase 2 study of 104 patients with moderate-to-severe Crohn's disease showed a clinical response rate of 49 percent after eight weeks of ustekinumab. In a subgroup of 49 patients who were previously given infliximab, the clinical responses with ustekinumab were significantly greater (59 percent) than the placebo-treated group (26 percent) after eight weeks of treatment. Ustekinumab is already FDA-approved for psoriasis.
Similar to natalizumab, vedolizumab is an anti-alpha4 integrin blocker that interferes with leukocyte trafficking. While it acts the same way as natalizumab, it does not promote luekocyte migration in the brain, and the hope is that this will lessen the risk of progressive multifocal leukoencephalopathy associated with the drug.
Data from a 374-person trial involving patients with moderate-to-severe UC were reported at the Digestive Disease Week Conference in San Diego, Calif., in May 2012. All patients in the study had failed conventional therapy. At six weeks, 47 percent of those on vedolizumab achieved a clinical response, compared with 25.5 percent of placebo-controlled patients. Nearly 17 percent were in clinical remission compared with 5.4 percent in the placebo treatment arm. Almost 41 percent exhibited mucosal healing compared with about 25 percent on placebo. At one year, between 42 and 45 percent of those on vedolizumab remained in remission as compared with about 16 percent of the placebo-controlled participants. General results from a similar study in patients with moderate-to-severe Crohn’s disease (GEMINI-II) confirm efficacy in promoting remission in that population, but specific results have not yet been released.
Mass General participated in a vedolizumab study for UC patients under the leadership of Deanna Nguyen, MD. This trial has met its enrollment and is currently closed.
An oral, first-in-class drug known as CCX282B shows promise in maintaining remission in Crohn’s disease. The drug acts against the CCR9 chemokine receptor. In the phase 1/2 PROTECT-1 multinational 600-patient study, 64 percent of those in remission after receiving CCX282B maintained their status compared with 47 percent of placebo-controlled subjects.
Mass General provides this drug through enrollment in two phase 2/3 studies under the leadership of Ashwin N. Ananthakrishnan, MBBS, MPH.
Another anti-TNF drug, golimumab, is an injectable therapy that holds promise in inducing remission in patients with moderate to severe UC. The drug is already approved for use in rheumatoid arthritis. The Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT) SC study in 774 anti-TNF-naive patients showed that between 52 and 55 percent of patients who received two subcutaneous injections of golimumab had responded to treatment compared with 29.7 percent of placebo-controlled recipients. Approximately 18 percent of the golimumab-treated patients achieved clinical remission at six weeks.
Recognizing the advances provided by biologic therapy in IBD, Mass General physicians routinely offer enrollment in clinical trials of the latest new therapies for patients with Crohn's disease and UC in the hope of offering tomorrow's effective therapies several years ahead of widespread availability.
Imaging: Enhanced Visuals, Lower Radiation
Advances in small bowel imaging are helping guide medical and surgical treatment in IBD by providing physicians with a clearer picture of normal, diseased, and healing tissue. Enhanced imaging can help assess mucosal healing after medical intervention and spare surgical removal of otherwise non-diseased bowel. Under the leadership of Dushyant V. Sahani, MD, director of computed tomography (CT) at Mass General, and other researchers, new techniques in CT imaging of the small bowel have enabled physicians to capture needed visual information while lowering radiation exposure.
CT enterography (CTE) involves the use of a new oral contrast agent, volumin, to illuminate the small intestine in CT scan mode. The procedure improves the ability to detect luminal and extraluminal disease. As a result, the amount of radiation required for CT bowel imaging at Mass General has dropped significantly, to less than one-third the amount used in standard CT imaging elsewhere.
With CTE, physicians are evaluating IBD patients earlier in the disease history to detect and evaluate lesions. It also is used by surgeons to fine-tune the site of necessary surgical intervention when needed, eliminating excessive small bowel removal.
Research presented by Keith Quencer, MD, diagnostic radiologist at Mass General, in May 2012 at the American Roentgen Ray Society Annual Meeting shows that magnetic resonance enterography (MRE) is the diagnostic choice for evaluating pediatric patients with Crohn’s disease. In a small trial, Dr. Quencer found that MRE was 77.6 and 82 percent accurate for detecting bowel fistulas and inflammation, respectively, in a pediatric population. Because multiple imaging is a reality for many patients with IBD, improvements in MRE, which lacks radiation exposure, are especially welcome.
Leading Surgical Interventions
With advances in medical management, many patients with IBD have positive clinical responses and enjoy extended periods of remission with medical therapy only, but when surgeries are needed, several new minimally invasive laparoscopic procedures and bowel-sparing techniques are helping patients recover more quickly and retain as much noninvolved bowel tissue as possible. These include the following:
Laparoscopic surgery. Laparoscopic surgery in IBD patients is becoming increasingly more feasible in the hands of IBD surgery experts. Minimally invasive strategies are technically complex and lengthier, yet they provide patients with the benefit of faster recovery and less scarring. Mass General surgeons report that fear of surgical intervention has been reduced given the ability to offer less-invasive techniques.
Restorative proctocolectomy. For severe UC not amenable to further medical therapy, Mass General surgeons are able to offer a surgery in which the entire colon and rectum is removed and a reconstruction of the intestinal continuity is then accomplished by creating a neorectum from a part of the small bowel. This neorectum is called an ileal J pouch. However, this reconstruction can only be offered at first surgery when and if the patient has intestines that can hold sutures well. Patients who are extremely sick with their colitis sometimes need to undergo so-called salvage surgery, in which the reconstruction is deferred for a second operation.
At Mass General, the decision to perform surgery is done in close collaboration between surgeons and gastroenterologists, and this close collaboration has drastically reduced the need for salvage surgery. Liliana G. Bordeianou, MD, MPH, a surgeon at the Digestive Healthcare Center, describes the rate of salvage surgery at Mass General to be approximately 18 percent. This compares with a 30 to 50 percent rate at other nationally ranked medical centers.
She also points out that despite a higher rate of reconstruction, which increases surgical complexity, Mass General’s rates of surgical complications remain far below those reported by others in this group of very sick patients. (Bordeianou L, et al. (2010). Preoperative infliximab treatment in patients with ulcerative and indeterminate colitis does not increase rate of conversion to emergent and multi-step abdominal surgery. Int J Colorectal Disease, 25(3): 401-4.)
Bowel-sparing techniques. For some Crohn's patients, repeated surgeries may be necessary given the chronic nature of the disease. Since surgery is not curative for Crohn's disease, the goal of surgical intervention is to remove problematic intestinal tissue while preserving as much bowel as possible. Excessive bowel removal can put Crohn's patients at risk for short bowel syndrome—a condition leading to malnourishment and the possible need for parenteral nutrition.
In a bowel-sparing technique called strictureplasty, surgeons rearrange and surgically alter narrow strictures of the intestine as opposed to excising them. In short strictures, surgeons cut longitudinally along the bowel stricture and close it transversely to widen the narrowing. Other more complex techniques are utilized for longer strictures. Research has proven that the rates of recurrence and return of Crohn’s disease symptoms are equal between strictureplasty and bowel stricture removal. Since strictures are one of the most common causes of surgery in Crohn's disease, bowel rearranging approaches can spare patients unnecessary loss of intestine.
Due to the advances in medical therapy and surgical techniques, patients with IBD have many treatment options. As a high-volume IBD care center with a strong clinical research competency, Mass General is applying the latest strategies in biologic therapy and surgical care. Since new drugs and bowel-sparing surgeries have significantly improved the quality of life for many IBD patients, the team of IBD specialists at Mass General represents a core of research and clinical treatment expertise committed to building on these successes to ease the suffering of those negotiating this chronic disease.
Ananthakrishnan A, Korzenik JR, Hur C. (2012). Can mucosal healing be a cost-effective endpoint for biologic therapy in Crohn’s disease? A decision analysis. Inflamm Bowel Dis, doi: 10.1002/ibd.22951. Epub 2012 Mar 13.
Bordeianou L, Hodin R. (2009). Total proctocolectomy with ileoanal J-pouch reconstruction utilizing the handassisted laparoscopic approach. J Gastrointest Surg, 13(12): 2314-20.
Bordeianou L, et al. (2010). Preoperative infliximab treatment in patients with ulcerative and indeterminate colitis does not increase rate of conversion to emergent and multi-step abdominal surgery. Int J Colorectal Disease, 25(3): 401-4.
de Silva PS, et al. (2012). Long-term outcome of a third anti-TNF monoclonal antibody after the failure of two prior anti-TNFs in inflammatory bowel disease. Aliment Pharmacol Ther, 36(5): 459-66. Epub 2012 July 11.