Suppressing Inflammation in IBD Patients

UH Digestive Health Institute explores new IBD treatment using IL-1 targeted therapy

UH Innovations in Digestive Health - Fall 2018

 Fabio Cominelli, MD

For 25 years, researchers have studied interleukin-1 (IL-1), a highly active proinflammatory cytokine known to lower pain thresholds, damage tissues and contribute to a growing list of diseases. While researchers have developed drugs that block IL-1 activity (Anakinra, Rilonacept and Canakinumab), no drug has been developed to treat inflammatory bowel disease (IBD).1

A team led by Fabio Cominelli, MD, PhD, Chief Scientific Officer, UH Digestive Health Institute, Chief, Division of Gastroenterology and Liver Disease, UH Cleveland Medical Center and Professor of Medicine, Case Western Reserve University School of Medicine, recently began collaboration with XBiotech to test an antibody designed to block IL-1?, one of two distinct IL-1 genes.

“We tested the antibody in mice models and it has shown a strong anti-inflammatory effect, similar to the effect of corticosteroids,” Dr. Cominelli says, adding that they plan to publish the study in the next few months.

WHY IL-1?

IL-1 binds to a cell surface receptor, IL-1RI. Once it binds, IL-1 triggers inflammatory responses. IL-1 ? is present on the cells of even healthy individuals. However, Dr. Cominelli says patients with IBD and many other diseases overproduce IL-1a, which causes the excessive inflammation that leads to disease.

Due to IL-1?'s presence on platelets, keratinocytes of the skin, epithelial cells of the mucosal membranes and cells of the liver, lung and kidney, IL-1? is associated with inflammatory responses seen in cancer, atherosclerosis, diabetes, Crohn's disease and ulcerative colitis.

XBiotech's neutralizing monoclonal antibody holds promise to treat many of these diseases. In 2015, researchers from MD Anderson Cancer Center in Houston, Texas, assessed the antibody in 52 patients with metastatic cancer. Results showed patients tolerated the drug well with minimal side effects. For 42 patients, IL-6 concentrations decreased over eight weeks.2

If UH Digestive Health Institute's study is successful, the antibody would put patients' disease in remission. It also holds promise as an effective treatment for a broader segment of the IBD population. People living with IBD have a wide range of treatments available to suppress inflammation; however, these treatments don't work for everyone.

The five main categories of medication currently used to treat IBD include:

• Aminosalicylates: These anti-inflammatory compounds contain 5-aminosalicylic acid (5-ASA). Examples are sulfasalazine, balsalazide, mesalamine and olsalazine. Aminosalicylates act to decrease inflammation at the intestinal wall. They aim to treat mild-to-moderate episodes of Crohn’s disease and ulcerative colitis. According to the Crohn's & Colitis Foundation, aminosalicylates help up to 75 percent of ulcerative colitis patients; however, they are less effective for Crohn’s disease.3
• Corticosteroids: Medications such as prednisone, prednisolone and budesonide control the inflammatory process and keep the immune system in check. They are only recommended for short-term control of flare-ups because of their side effects, which include infection, bone loss, weight gain, cataracts, skin fragility, sleep disturbance and mood swings.
• Immunomodulators: Immunomodulators control immune system activity to calm ongoing inflammation. Examples include azathioprine, 6-mercaptopurine (6-MP) and methotrexate. Doctors generally prescribe these drugs to maintain remission in patients who haven't responded to other medications.
• Antibiotics: Ciprofloxacin and metronidazole have shown modest benefit for people with Crohn’s disease that affects the colon or the area around the anus. Doctors may prescribe antibiotics when infections, such as abscesses, occur. They're generally not used to treat ulcerative colitis.
• Biologic therapies: Newly developed for IBD, biologic agents adalimumab, certolizumab pegol and infliximab target an inflammatory protein called tumor necrosis factor (TNF). Doctors recommend biologic therapies for people with moderate to severe active disease who have not responded well to conventional therapy.  All three anti-TNF medications are FDA-approved for Crohn’s disease treatment, but only infliximab is approved to treat ulcerative colitis. About 60 percent of IBD patients respond to biologic therapies; of these, about 35 percent will achieve remission at the end of one year.

Although people living with IBD have more treatments available now than ever, many still require surgery. More than half of Crohn's disease patients will require some type of surgery. Results are usually temporary.

UH Digestive Health Institute is continually pursuing research to discover new treatments and techniques to help IBD patients.

“We continue to do high-level research to offer our patients clinical trials and advanced therapies,” Dr. Cominelli says. “We are at the forefront of study and have clinical trials available. We hope to be a reference for the entire physician community.”

To refer a patient to UH Digestive Health Institute, call 216-844-8500.

References:
1. www.ncbi.nlm.nih.gov/pmc/articles/PMC3644509
2. www.ncbi.nlm.nih.gov/pubmed/24746841
3. www.crohnscolitisfoundation.org/resources/treatment-options-in-ibd.html