"For half of these patients, the disease begins in their teens and twenties…It is particularly satisfying to be part of the research effort to develop therapies that help these young people avoid surgery and ileostomy."
William Sandborn, M.D.

Richard Johannsen's passion is robotics technology. His burden is Crohn's disease, a painful and debilitating condition that causes chronic inflammation of the digestive tract. Diagnosed in his 20s, he underwent so many small bowel resections that further surgery would put him at risk for malabsorbtion of nutrients. Since coming to Mayo Clinic in 1997, Johannsen has never looked back. Now 55, his energy has been dramatically restored. Though he is not about to go off and conquer Rome , Johannsen's figurative crossing of the Rubicon has allowed him to renew the pursuit of his passion.

Johannsen is building a full-sized, remote-controlled 4x4 vehicle to race in the Defense Advanced Research Projects Agency (DARPA) Grand Challenge—a 142-mile field test in the Mohave Desert . DARPA, the research arm of the U.S. Department of Defense, is developing remote-controlled vehicles to save lives on the battlefield. The race is an avenue for inventors to contribute their ideas. Johannsen, of Houston , Texas , is able to participate because the clinical research conducted by William Sandborn, M.D., has given him access to experimental therapies that have relieved his symptoms.

"Coming to Mayo turned my life around," says Johannsen. "Before coming here, most days I couldn't even get out of bed. I couldn't sleep, couldn't eat, and had night sweats. It's a miserable disease that affects your work, your social life, your vacations—every aspect of your life—all of it planned around restroom availability. Now my disease is in remission, I'm off steroids, I've recovered my positive attitude and I can spend long periods in the desert working on my vehicle."

Helping Patients Return from a Personal Hell

Pouchitis

Pouchitis is an inflammation of the intestinal wall of a surgically-constructed pouch. Surgeons form the pouch to improve the quality of life for patients who need to have their diseased large intestine removed. The ileo-anal pouch connects the small bowel to the anus and forms a reservoir for stool. This allows patients to eliminate waste normally rather than through a colostomy. Mayo Clinic has done more of these procedures than any other institution.

Ironically, Mayo's success with the procedure has created the need for a practice to treat the rising incidence of pouchitis, a complication of the surgery. "We've now done more than 3000 pouch surgeries and up to half of patients have an episode of pouchitis within 10 years of their surgery," says Dr. Sandborn. "So it's become a third IBD for our center."

Dr. Sandborn established diagnostic criteria to accurately diagnose and measure pouchitis. He conducted studies to better understand the risk factors for developing pouchitis and to evaluate its treatment. The treatment for pouchitis is antibiotics, and occasionally a safer steroid called budesinide.

Dr. Sandborn, a gastroenterologist and clinical researcher who heads the Inflammatory Bowel Disease (IBD) Clinical Research Unit, has a different passion—helping patients return from the personal hell caused by IBD. Crohn's disease, ulcerative colitis and pouchitis (see sidebar) are the most common IBDs. Although not considered deadly diseases, patients who have them frequently feel so wretched that death sometimes seems a welcome release. That's why Dr. Sandborn is excited by the knowledge that his research has contributed to an array of new treatments.

"I started out by focusing on the clinical pharmacology of drugs that we use in IBD," says Dr. Sandborn. "That evolved into how I now spend most of my time—designing and administering multi-center trials. Over the last 14 years, we've introduced therapies that have made considerable progress in the management of IBD."

Dr. Sandborn holds nine patents and has published 37 peer-reviewed articles about IBD treatments. His expert consultation is sought by 34 pharmaceutical companies. Besides working with the U.S. Food and Drug Administration to determine the best design for making drugs safe and effective, his expertise is also sought as a reviewer or editorial board member for a number of medical journals including the New England Journal of Medicine, Inflammatory Bowel Disease, and Clinical Gastroenterology & Hepatology. In addition, Dr. Sandborn chairs the Crohn's and Colitis Foundation of America (CCFA) task force, "Challenges in IBD Research Update" and is scientific secretary for the International Organization of Inflammatory Bowel Disease (IOIBD).

Dr. Sandborn's studies made significant contributions to determining the optimum dose and dosing schedule of azathioprine and 6-mercapto-purine—two important immunosuppressant drugs in IBD. Now his focus has turned to the new biotechnology therapies.

"The new biologics can suppress these diseases for long periods of time without massive doses of steroids or disabling surgeries," says Dr. Sandborn. "As genes associated with IBD are discovered, more engineered therapies are likely to be developed. Approximately 50 biotechnology companies are currently developing new treatments for IBD. Ten years from now, we can look forward to having a greater range of effective therapies that will return a better quality of life to more of our patients."

Johannsen is one patient who has already reaped the benefits of the latest biotechnology.

The First of the Biotechnology Agents

Thanks to experimental treatments for Crohn's disease, Richard Johannsen feels well enough to enter his 84 Jeep, "The Grand Challenger" in a robust government project to advance robotic technology.

"Mr. Johannsen came to us with a fistula in his lower rectum—a common problem for people with Crohn's disease," explains Dr. Sandborn. "Our surgeons were able to close the fistula without major surgery. We then started him on Remicade®. It was the first biotechnology agent available for the treatment of patients with Crohn's disease who have had an inadequate response to conventional therapy. It also aids in maintaining fistula closure."

Remicade is a brand name of the drug infliximab. Dr. Sandborn and his colleagues conducted several studies to test its safety and effectiveness. Infliximab works by binding to tumor necrosis factor alpha (TNF-alpha) on the cell membrane and in the blood, which blocks its action. TNF-alpha is a monoclonal antibody—a protein produced by the immune system when there is inflammation. This is a normal part of the repair process following injury. In Crohn's disease, TNF-alpha is produced in excessive and damaging amounts.

"Because we have the largest single-center experience with the drug, we have been able to share our safety experience and make recommendations for physicians about how to use it to optimize patient care," says Dr. Sandborn. "Some patients develop antibodies to the mouse protein in Remicade that causes infusion reactions and loss of clinical effect."

Unfortunately for Johannsen, he was one of those patients so his best hope was with experimental therapies.

"He was a good candidate for one of our earliest multi-center trials on biotechnology agents," says Dr. Sandborn. "He did well with a new British drug but when the company deemed it commercially unviable, they stopped producing it and we put him back on Remicade."

This is a molecular model of Humira® (adalimumab)—the bioengineered human antibody that has turned Richard Johannsen's life around. (Image courtesy of Abbott Laboratories)

Dr. Sandborn next enrolled Johannsen in a study to test a new Swiss drug, which was reasonably effective. In the meantime, in December, 2002, adalimumab, brand name Humira®, another bioengineered monoclonal antibody with a similar action to Remicade, was approved by the FDA for the treatment of rheumatoid arthritis. Dr. Sandborn was excited that this may be just what Johannsen—and other patients who could not tolerate the mouse protein in Remicade—needed because it was a fully human protein that resembles antibodies normally found in the body.

Dr. Sandborn was on the steering committee for the first placebo-controlled trial that tested adalimumab. And in November, 2003, Johannsen began participating in Dr. Sandborn's clinical trial to show its long-term effectiveness. That's when he really started to feel great.

"To learn about the challenges my robotic vehicle would face, I recently drove four days in a conventional 4x4 over the Rubicon Trail—that's an extreme track in Nevada that crosses the Rubicon River and I never could have even thought about attempting that before," says Johannsen. "I feel blessed to have found Mayo where people look after my best interests.

Other IBD Research at Mayo

William Tremaine, M.D., also director of Mayo's Institutional Review Board, was a major investigator in the clinical research that showed budesinide is a safer steroid for treating IBD.

Edward Loftus, Jr., M.D. conducts population-based natural history studies. Mayo Clinic is a leader in North America for understanding the epidemiology of Crohn's Disease.

William Faubion, M.D., and Laurence Egan, M.D., have recently embarked on careers in basic research with interests in immunology and chronic inflammation of IBD.

Gastroenterological surgeons John Pemberton, M.D., Bruce Wolff, M.D., Eric Dozois, M.D., and David W. Larson, M.D., are involved in a variety of clinical trials to test innovations in IBD surgery, including pioneering laparoscopic techniques.

Radiologists Joel Fletcher, M.D., C.D. Johnson, M.D., and Jeff Fidler, M.D., are involved in cutting edge research with CT and MRI imaging of the colon, including virtual colonoscopy.