December 8, 2015

Fighting a Fire Within: New treatments for IBD aim to provide personalized solutions

By Editor

As featured in Women magazine.

By Sharon Reynolds

When she was in college, Brooke Abbott began experiencing a range of mild but persistent symptoms: fatigue, back pain, and scalp sensitivity. Sometimes she would have to go to the bathroom immediately after eating. Some days she found blood in her stool.

“I just thought I was stressed from school, and then once I had left school and went into the workplace, I thought I was stressed from the workplace,” Brooke recalls. After college she had immediately begun a high-pressure job in the entertainment industry.

One day on the set of her first big television show, she remembers sitting next to a cameraman, beginning the countdown. “I don’t remember the rest, but he said my voice kept getting lower and lower, and then he couldn’t hear me. And then I fell over.”

After weeks of rest, during which her gastrointestinal symptoms only worsened and she rapidly lost weight, she finally saw a digestive specialist, who diagnosed her with inflammatory bowel disease (IBD).

IBD comes in two varieties: Crohn’s disease and ulcerative colitis. In Crohn’s disease damaging inflammation can occur anywhere along the lining of the digestive tract, from the mouth to the anus. In ulcerative colitis it is mostly confined to the colon and rectum.1

Over the seven years since the ulcerative colitis diagnosis, Brooke has experienced the full rollercoaster ride of IBD, from getting the inflammation under control and giving birth to her son, now six, to relapses and eventually an emergency hospitalization that ended in a colectomy—the removal of her entire colon.

Brooke now blogs about parenting with a chronic illness at crazycreolemommy.com and has traded television production for patient advocacy at the national level. “It is so hard being a mom with a [chronic] disease, but I can say that if I didn’t have my son, I probably wouldn’t be as much of a fighter,” she says.

Targeting Treatment

IBD is a type of autoimmune disease, where the immune system attacks the body’s own tissues. The immune system is normally finely tuned to distinguish friend from foe. This is vital in the gut, where trillions of friendly bacteria[1]—called the gut microbiome—normally reside, helping us digest food and producing nutrients that we need.

Scientists still don’t understand the exact causes of IBD but believe it begins when the immune cells in the intestines overreact to an environmental trigger, which could be anything from an infectious agent to a medication or a normal component of the diet,[2] and once “turned on” to attack mode cannot turn themselves off. The resulting chronic inflammation can damage the lining of the digestive tract (the mucosa), sometimes severely, leading to the pain, bloating, bowel problems, and bleeding associated with IBD. The disease likely has a genetic component, where some inherited gene variations make a person more susceptible to developing IBD.

In some cases, the inflammation can be severe. In Crohn’s disease it can lead to strictures (narrowing of the bowels, which can cause obstructions), fistulas (abnormal connections between the bowels and other organs such as the vagina or bladder), or abscesses. In ulcerative colitis it can increase the risk of colorectal cancer. The disease is not considered curable, but it can be managed.

Traditionally, treatment for IBD began with drugs with relatively mild side effects and moved to more-aggressive drugs that modify the immune system as the disease progresses, a so-called step-up approach. For many patients this started to change after 1998, with the approval of the first targeted, biologic drug for IBD. Biologic drugs are designed in the laboratory to attack specific proteins that play a role in a disease. For IBD this has been proteins that ramp up the inflammatory process.[3]

“Biologics have truly revolutionized the field of IBD,” says Susan Kais, MD, a gastroenterologist with special interest and training in IBD, in private practice at GastroHealth in Florida. For some patients with aggressive IBD, “We now start off with a more aggressive approach called the top-down approach,” where biologics, immunomodulators, or both are used up front to promote early remission, she explains. The idea is not just to make patients feel better—which is vital—but to promote complete healing of the mucosa.[4]

“By achieving mucosal healing, we believe that we can actually alter the natural history of the disease and prevent complications down the road,” and clinical trials are under way to test this, she adds.

“I’ve seen the change from before the biologic era to after,” says Daniel Hommes, MD, PhD, director of the Center for Inflammatory Bowel Diseases at the University of California, Los Angeles, who helped lead one of the large trials testing the top-down approach to IBD.[5] “The number of people who can be weaned off steroids, the number of people who have avoided hospitalizations and surgeries…has been phenomenal,” he says.

These drugs can also be used as part of a step-up approach for milder disease and for patients like Brooke, who have had surgery to remove the damaged part of their digestive system but still experience inflammation from their disease elsewhere in the body.

Six biologic drugs are currently approved for IBD treatment by the US Food and Drug Administration. Unfortunately, biologics do not work for all patients with IBD, and for some they may stop working over time; however, many new targeted drugs for IBD are under development and being tested in clinical trials.4

Taking Care of the Gut’s Residents

Increasingly, the idea of manipulating the gut microbiome to help treat IBD is coming under scrutiny. Though every person’s collection of helpful bacteria is different, a broad trend can be observed in patients with IBD: their gut bacteria are out of balance one way or another, a state called dysbiosis.[6]

Whether this is a cause or an effect of IBD is not understood, but researchers want to know “if there are ways we can manipulate the gut flora to go back [to normal] from this state of dysbiosis, and by doing that reduce inflammation,” says Dr. Kais.

Some promising ideas in this field have unfortunately not lived up to initial expectations. Fecal microbiota transplantation,[7] in which stool from a healthy donor is infused into a patient’s colon to “reset” the microbiome, induced remission in less than one-quarter of IBD patients in the largest clinical trial published to date.[8]

Small studies of probiotics—cultures of live microorganisms that are usually taken in pill form—and prebiotics, nutrients that feed these microorganisms, have also shown mixed results.2 Some patients feel symptom relief, but others gain no benefit.

Researchers continue to study these and other ways of targeting the gut microbiome. Because IBD is so individualized, certain groups of patients can likely be helped if they can be identified.5

Rebooting the Immune System

For some patients with severe IBD, all the available drugs stop working over time. This can make finding an effective new treatment a life-or-death matter, especially for people with Crohn’s disease, where the inflammation and resulting fistulas and strictures can occur all along the digestive tract. “You just have to keep cutting and cutting,” says Dr. Hommes.

Dr. Hommes and his colleagues, as well as researchers at other hospitals around the country, are testing10 a drastic but promising treatment option for these patients with Crohn’s disease: autologous stem cell transplantation. “We often describe the process as a ‘Control-Alt-Delete’ of your immune system,” explains Dr. Hommes. The procedure provides a reboot of the overreacting immune cells in the gut.

Immune cells found throughout the body are produced by specialized stem cells in the bone marrow. For autologous stem cell transplantation, some of these stem cells are first harvested from a patient. Then the patient receives chemotherapy, similar to—though not as intense as—that used for cancer, which kills the existing immune cells in the body.

The harvested stem cells are then put back, and they produce new immune cells that have never been exposed to the gut environment—and have no cellular memory of attacking it. Though inflammation can develop again over the years, explains Dr. Hommes, the procedure buys time—in some cases, decades.

And these patients can be carefully monitored so that aggressive top-down treatment can be started at the first sign of inflammation. “Transplantation puts you back to the first stage of that disease course, and you can introduce more-effective medications up front much sooner than normal,” Dr. Hommes says.

Autologous stem cell transplantation is an extreme option for severe cases. For other IBD patients, researchers are trying to harness another type of stem cell found in the adult body as a new potential treatment. Mesenchymal stem cells produce bone cells, fat cells, and other types of supportive cells for the body. Through mechanisms not totally understood,11 “these cells [also] have fantastic immunomodulatory properties. That means they can decrease inflammation,” explains Dr. Hommes.

In a recently published clinical trial, he and his colleagues delivered mesenchymal stem cells directly into fistulas in the perianal region in 21 patients with Crohn’s disease. The results were excellent; in one group in the trial, up to 90 percent of patients experienced healing of their fistulas.12

“They’re very harmless cells, and these fistulas reacted dramatically; it’s a very, very exciting field,” says Dr. Hommes.

“The goal of research is to cure ulcerative colitis and Crohn’s disease,” concludes Dr. Kais. “Unfortunately, we’re not there yet, but we’re making huge strides on many fronts.”

IBD and Nutrition

“Patients with IBD are superinterested in nonpharmacological approaches to managing the disease,” says Dr. Kais. “They want a sense of having control of the disease, and many feel that by altering their diet they can have some control.”

Myriad diets are being tried by patients with IBD, explains Dr. Kais, though these diets have not been tested in controlled clinical trials. They vary widely, in what they both include and disallow, in keeping with the individualized nature of IBD.

“Almost every patient has a trigger food” that can aggravate IBD symptoms, says Laura Scaviola, an ulcerative colitis patient. In Laura’s case, the disease emerged out of nowhere when she was 26, with a severe flare that put her in the hospital, her entire colon inflamed. The first thing she remembers asking her doctor upon waking up from anesthesia and getting her diagnosis was “What can I eat?”

Laura, who blogs about IBD and her diet at mangiapaleo.com, started off with the paleo diet, which excludes grains and focuses on unprocessed foods, but she quickly learned that just because a food is labeled “paleo” didn’t mean she could eat it without consequences. “I tell people that though I seemingly promote the paleo diet, I’m actually on the Laura diet. Although there are labels on all of these diets, I really take them as just suggestions on healthier eating and getting to know your body,” she explains to people with IBD who e-mail her for advice about what to eat.

Table 1: Biologic Drugs Approved to Treat IBD13

Drug Brand Name Approved for Crohn’s Disease or Ulcerative Colitis?
Infliximab Remicade® Both
Adalimumab Humira® Both
Certolizumab pegol Cimzia® Crohn’s disease
Golimumab Simponi® Ulcerative colitis
Natalizumab Tysabri® Crohn’s disease
Vedolizumab Entyvio® Both

 

References

[1]. Fakhoury M, Negrulj R, Mooranian A, Al-Salami H. Inflammatory bowel disease: Clinical aspects and treatments. Journal of Inflammation Research, 2014;7:113-20. doi: 10.2147/JIR.S65979.

  1. Ghouri YA, Richards DM, Rahimi EF, Krill JT, Jelinek KA, DuPont AW. Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease. Clinical and Experimental Gastroenterology. 2014;7:473-87. doi: 10.2147/CEG.S27530.
  2. Ananthakrishnan AN. Environmental triggers for inflammatory bowel disease. Current Gastroenterology Reports. 2013;15(1):302. doi: 10.1007/s11894-012-0302-4.
  3. Löwenberg M, D’Haens G. Next-generation therapeutics for IBD. Current Gastroenterology Reports. 2015;17(6):21. doi: 10.1007/s11894-015-0444-2.
  4. D’Haens GR, Sartor RB, Silverberg MS, Petersson J, Rutgeerts P. Future directions in inflammatory bowel disease management. Journal of Crohn’s & Colitis. 2014;8(8):726-34. doi: 10.1016/j.crohns.2014.02.025.
  5. D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: An open randomised trial. Lancet. 2008;371(9613):660-67. doi: 10.1016/S0140-6736(08)60304-9.
  6. Matsuoka K, Kanai T. The gut microbiota and inflammatory bowel disease. Seminars in Immunopathology. 2015;37(1):47-55. doi: 10.1007/s00281-014-0454-4.
  7. Colman RJ, Rubin DT. Fecal microbiota transplantation as therapy for inflammatory bowel disease: A systematic review and meta-analysis. Journal of Crohn’s & Colitis. 2014;8(12):1569-81. doi: 10.1016/j.crohns.2014.08.006.
  8. Moayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015;149(1):102-109.e6. doi: 10.1053/j.gastro.2015.04.001.
  9. Autologous Hematopoietic Stem Cell Transplantation for Crohn’s Disease Treatment (HSCT). Clinical Trials.gov website. Available at: https://clinicaltrials.gov/ct2/show/NCT01932658. Accessed October 26, 2015.
  10. van der Marel S, Majowicz A, van Deventer S, Petry H, Hommes DW, Ferreira V. Gene and cell therapy based treatment strategies for inflammatory bowel diseases. World Journal of Gastrointestinal Pathophysiology. 2011;2(6):114-22. doi: 10.4291/wjgp.v2.i6.114.
  11. Molendijk I, Bonsing BA, Roelofs H, et al. Allogeneic bone marrow-derived mesenchymal stromal cells promote healing of refractory perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2015;149(4):918-27.e6. doi: 10.1053/j.gastro.2015.06.014.
  12. Biologic Therapies. Crohn’s & Colitis Foundation of America website. Available at: http://www.ccfa.org/resources/biologic-therapies.html. Accessed October 26, 2015.

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CONDITIONS OF THE GI TRACT