“What are we talking about with ‘out-of-the-box’ therapy? Really, these are things we can lean on or gravitate towards when our patients are not doing well or not responding to standard therapies,” said Dr Jessica Allegretti in her presentation with at the Advances in Inflammatory Bowel Disease (AIBD) regional meeting on September 25.

Jessica Allegretti, MD, is associate director of the Crohn's and Colitis Center and director of the Fecal Microbiota Transplant program at Brigham and Women's Hospital in Boston, Massachusetts.

Dr Allegretti explained some of the out-of-the-box therapies in discussion would be cannabis and CBD, hyperbaric oxygen, and combining biologics.

 “So, let’s start with cannabis. Cannabis is a plant of the Cannabaceae family and contains more than 80 biological active chemical compound,” Dr Allegretti explained, with CBD the component that is felt to be anti-inflammatory.

“Now there has been interest in the pharmacology of marijuana since the discovery of the cannabinoid receptors (CB1 and CB2), and both of these receptors can be found in the gut. And in inflammation, animal models have shown that in activation of CB1 may in fact reduce peripheral inflammation,” Dr Allegretti explained.

“And so, what’s really the science behind looking at this therapeutic in Crohn’s disease? Well, there were several preclinical studies in animal models that suggested that it may slow gastrointestinal motility, decrease abdominal pain and visceral hyperalgesia, and again has potential for an anti-inflammatory response,” she said. “Our group decided, when the law changed in Massachusetts to legalize medicinal use of marijuana, we surveyed all of the patients who came through our center, and we found that 39% admitted to lifetime use of marijuana, 12% were currently using, and 16.4% of patients used cannabis to relieve symptoms of IBD—the majority felt it was very helpful."

She also explained that of those surveyed, younger age and chronic abdominal pain were associated with current use, and half of those who never used marijuana reported an interested in using it for abdominal pain if it were legal.

“When the law changed 4 years later to legalize recreational use in our state, we actually resurveyed our patients and found there was a significant increase in marijuana use from 12.3% in 2012 to 22.8% 2017;  however, there was no significant increase in medicinal use,” Dr Allegretti explained.

She displayed results from a randomized placebo-controlled trial of cannabis for Crohn disease, including 21 patients with Crohn’s disease who failed at lease 1 form of therapy. The cannabis BID vs placebo trial utilized cigarettes containing 115mg of THC, and cigarettes containing cannabis flower with the THC removed, over 8 weeks of treatment with 2 weeks of follow-up. The primary outcome of the study was induction of remission.

“Overall, again with small numbers, they did not meet their primary outcome of statistically significant induction of remission; however, you can see numerically, there were higher numbers of patients who achieved remission in the treatment arm,” Dr Allegretti reported. There was no significant change in C-reactive protein (CRP) or other objective markers of inflammation, with very minimal adverse effects.

Dr Allegretti discussed some risks of cannabis, including addiction, acute effects on cognition and reaction times, respiratory effects, cardiovascular toxicity, and cannabinoid hyperemesis. She also detailed the increasing legalization of cannabis throughout the United States, as it is still a Schedule 1 drug with no medical use and a high potential for abuse.

“So, what do we as physicians need to know? Currently patients must have a qualifying condition, which in all states with medical marijuana includes cancer, HIV/AIDS, nausea, vomiting, seizures, severe pain, and several have Crohn’s, but not ulcerative colitis (UC) listed. Physicians cannot prescribe marijuana, rather patients obtain this on the basis of a recommendation or referral.” Dr Allegretti reported.

Before recommending medical marijuana for Crohn disease, she said, more data are needed, including proof that medical marijuana is effective in treating Crohn’s disease and specifically, evidence it improves inflammation. Questions also need to be answered, such as whether the specific cannabinoids are effective in the treatment of Crohn disease; if there is an optimal dose and delivery method; and whether cannabis use is safe long-term.

Hyperbaric oxygen (HBOT), which is breathing 100% oxygen while under increased atmospheric pressure, offers another alternative therapy, Dr Allegretti said. Blood is hyperoxygenated by dissolving oxygen within the plasma, she explained. “That’s really how this works. And we know that you don’t need hemoglobin to deliver oxygen to tissues when using this therapy.”

The rationale for using hyperbaric oxygen therapy for IBD, Dr Allegretti said, is based on several factors, including:

• Improvement of oxygen delivery to tissues
• Promotion of tissue neovascularization by hyperoxia/hypoxia cycles neovascularization
• Bactericidal effects, especially against anaerobes, potentiate effects of antibiotics
• Increase of stem cells in intestinal mucosa, aiding in tissue repair
• Stimulates proliferation of fibroblasts
• Improves collagen synthesis

“And so, this has been assessed in several studies,” Dr Allegretti explained, referencing results from a systematic review. “In both UC and Crohn’s disease, there was very high response rates, and lower rates of adverse effects.”

Dr Allegretti discussed the results of a Phase IIB trail of hospitalized patients with UC who were treated with HBO, including no colectomies or readmissions, and 100% steroid-free remission.

“What are the limitations to this therapy? Accessibility (access to a hyperbolic chamber and insurance), role as induction agent only, and positions—do we use this before, during, after IV steroids, anti-TNF, cyclosporine?”

Dr Allegretti also discussed dual biological therapy (DBT), which is expressed as multiple pathways driving the immune-mediated inflammatory process. “We know there are low remission rates for biologic agents in clinical trials for both induction and maintenance when used as single agents, and we also know that biologics used in succession can be less effective—those who are treatment-naive always do better than those who are treatment-exposed. So, what are the potential combinations to consider? Well, we don’t really know, there are countless combinations to consider,” she said.

In a study of dual biologic therapy from a 2-center experience in Canada, she said, “If we look at the data, … notably 79% of the patients receiving DBT used a biologic with prior secondary nonresponse, whereas 29% of patients receiving DBT used a biologic that had not previously been given. So, when you look at the outcomes of this study, again we see a significant decrease in SES-CD scores.”

Dr Allegretti also explained the important factors to consider when optioning DBT, including a patient’s prior history of response or nonresponse to biologics, disease phenotype, risks of infection, and costs and insurance coverage.

“I think it’s important to remember or at least confirm you have utilized everything you have available in your tool kit,” Dr Allegretti explained, discussing what clinicians should do before considering out-of-the-box therapies. She also said physicians should try to identify what “failed” in previous treatment, treat moderate to severe disease with appropriate agents only, optimize modifiable variables, monitor high-risk patients closely, move ahead with necessary surgery, and utilize treat to target.

“Identify timepoints for response and re-evaluate if the end point isn’t achieved.” Dr Allegretti concluded.

—Angelique Platas

Reference

Allegretti J, Outside-the-box therapeutic options. Presented at: Advances in Inflammatory Bowel Disease regional meeting. September 25, 2021. Virtual.