Ulcerative Colitis Blog

Marylou wrote into the blog asking about medical treatment for ulcerative colitis that is no longer responding to imuran, prednisone, methotrexate, or sulfasalazine. For patients seeking the next line of medical therapy, the agents of choice would be the so-called "biologics" such as Remicade. Two studies called ACT 1 & ACT 2 (Active Ulcerative Colitis Trials) were published in 2005 examining the efficacy of Remicade as a maintenance therapy for UC patients losing response to their current medications. Of the 364 patients enrolled in the studies, 65-70% had a clinical response to Remicade as compared to 29-37% of those who received placebo. Remicade is given as a 2 hour infusion at an infusion clinic or hospital. Initially, a patient receives doses at 1,2, and 6 weeks to build up the medication in the body. Thereafter, it is typically given every 8 weeks.

Another drug in the same category as Remicade is Humira. Its mechanism of action is similar to Remicade, however, it is a "humanized form" (Remicade is made from a combination of mouse and human antibodies and Humira is made from human antibodies). Humira has usually been reserved as a second line agent for people who fail Remicade therapy. It is administered as an injection done under the skin every 2 weeks.

There are several new treatments for IBD that are in the process of being developed. Many large centers and those affiliated with university hospitals can provide patients an option to try new therapies through being in a clinical trial. Patients considering this avenue can contact regional centers to find out if they may qualify to participate in a study.

Marylou also asked about the prospect of surgery in UC. The indications for surgery would include disease refractory to medicines, acute massive bleeding that cannot be stopped, a sick colon that perforates (break open), or cancer. Historically, is has been quoted that 30% of patients who develop severe disease will ultimately require a colectomy. Advances in surgical techniques over the last several decades have provided surgeons with a way to reconnect the small bowel to the rectum after the colon is removed, so appropriate UC patients may not need to wear a permanent ostomy (bag for stool collection). Surgery is a viable and reasonable option for patients suffering from porly controlled disease or ill-toward effects of medications. Patients considering surgery should seek consultation with a colorectal surgeon who is familiar with surgical techniques in IBD patients.

Ted recently wrote into the blog querying the use of fecal biotherapy in UC and a common bacterial gastrointestinal infection known as Clostridium difficle (C. diff).Fecal biotherapy refers to the process of taking stool from a healthy donor and administering it to another individual either by colonoscopy, enema, or a tube inserted from the nose into the intestine. The concept behind this is that the gut theoretically becomes colonized with the bacteria from the healthy donor's stool in the hopes of healing a gastrointestinal malady. This is an extension of probiotic therapy discussed in prior blogs.

There have been at least 3 or 4 published studies regarding the use of fecal biotherapy in UC showing some degree of benefit. In these studies, patients with severe UC or UC losing response to other therapies were given retention enemas of stool from donors. On average, the enemas were administered daily for approximately 5 days. The authors of these studies have suggested that many patients had improved symptoms or achieved remission of UC for 6 months to 13 years. A few caveats to this research are that: 1) the numbers of patients studied were small, 2) none were randomized control trials (the "gold standard" study design for assessing efficacy of treatment), and 3) they are possibly limited by publication bias (ie; studies that show a positive treatment result get published and those that show a treatment doesn't work are less likely to get published).

As Ted noted, this has typically been reported as a last resort type of therapy. A major fear regarding the use of donated human feces is the potential for transmission of viral, bacterial, and parasitic infections among individuals. There are no guidelines as what kind of an individual is an appropriate donor. Furthermore, there is no consensus as to appropriate preparation and administration of fecal contents for biotherapy.

One of the major limitations of our understanding of the bacteria of the intestine has been our inability to grow many of the bacteria outside of the GI tract for experimentation. New molecular methods designed in the last few years, however, have provided scientists with the ability to identify different strains of bacteria in stool. The advent of these tools may help investigators understand more about how fecal biotherapy works and utilize these principles to design more mainstream therapy.

The following biologic therapies have recent or ongoing studies in UC. Some are more promising than others.

Basiliximab is an antibody which binds to the interleukin-2 (IL-2) receptor on activated white blood cells (T-lymphocytes). Antibody binding prevents IL-2 from binding to the receptor and activating the lymphocyte. This process impairs immune system responses. Basiliximab was initially studies in the late 1990s and approved for prevention of organ rejection after kidney transplant. A study of 20 patients with steroid resistant UC showed promising results after a single dose of Basiliximab. Thirteen of 20 patients were in remission after 24 weeks, while had undergone colectomy.

Visilizumab is an antibody to the CD3 antigen, a receptor intimately related to the immune response, with the ability to induce cell death (apoptosis) selectively in activated T cells. Preliminary studies were performed in bone marrow transplant. A single open label phase I (safety) study of 32 steroid refractory patients showed a possible benefit of therapy with an acceptable safety profile. Follow-up studies are currently underway.

Daclizumab is an antibody to the IL-2 receptor similar to basiliximab. It is also used for the prevention of acute rejection of transplanted kidneys. The only study in ulcerative colitis involved 159 patients with moderate disease and did not show a benefit over placebo.

In a recent blog regarding UC and fecal biotherapy, mention was made about a gastrointestinal infection known as Clostridium difficile or C. diff for short. I wanted to expand on this topic as patients with IBD, and particularly UC, have a predilection for becoming ill with C. diff infections.

C. diff is a bacterium that commonly resides in the gut. The population of C. diff in the gut is usually small because other bacteria in the intestine keep it in check. At times, however, the balance of bacterial populations in the gut can be thrown off allowing the C. diff type of bacteria to overgrow. Overgrowth of C. diff results in severe diarrhea that may or may not be bloody and abdominal pain. Precipitants that can disrupt this balance of bacteria include antibiotics, proton pump inhibitor medication (ie; omeprazole, rabeprazole), immunocompromise, and exposure to hospitalized settings or nursing homes. It is easily diagnosed through collection of 2-3 stool specimens. The infection is treated with antibiotics such as metronidazole and vancomycin that restore the appropriate bacterial balance.

A study published in 2007 showed that IBD patients who are hospitalized are 3 times as likely to have a C. diff infection as other hospitalized individuals without IBD. Furthermore, when patients were sub-divided into those with Crohn's vs. UC, hospitalized individuals with UC were found to be 4 times as likely to have C. diff compared to hospitalized individuals without IBD. As we learn more about C. diff, we are finding that it is not only a problem in hospitalized patients, but also for those living everyday life in the community. As such, it is important that IBD patients are educated about this infection because it can be a cause if flare symptoms. Any patient experiencing worsening diarrhea and abdominal pain should review their risk factors for the infection with their doctor and consider stool analysis for the bacteria.