Modulating the Gut
“Our next question was: Can we modulate the gut microbiome to improve methotrexate efficacy?” Dr. Blank said.
They considered probiotics and prebiotics as possible means for modulating gut microbiota, but evidence of efficacy for these agents has been decidedly mixed, she noted.
Instead, the investigators focused on short-chain fatty acids, gut microbial fermentation byproducts of indigestible carbohydrates, which have been demonstrated to help improve gut mucosal barrier integrity and promote a more tolerant immune response.
One such short-chain fatty acid, butyrate, is produced through microbial fermentation of dietary fiber in the colon; it is available in various foods and in supplement form.
Butyrate has been shown to ameliorate inflammatory arthritis in a collagen-induced arthritis model, and in this model, methotrexate efficacy was increased with the addition of butyrate or butyrate-producing bacterial species.
Dr. Blank and colleagues compared patients with new-onset RA treated with methotrexate alone or methotrexate plus butyrate for 4 months and looked at up to 2 months of methotrexate plus butyrate treatment in patients who had suboptimal response to methotrexate alone.
In preliminary analyses, they found that at baseline, fecal butyrate was significantly elevated in methotrexate responders compared with in nonresponders. In addition, in the new-onset RA cohort, they saw that the 4-month responsiveness rate was 52.6% for those treated with methotrexate compared with 64.7% for those treated with methotrexate plus butyrate.
“Although this difference was not statistically significant, it’s exciting to think we may have an impact. What’s more, we were really excited to find that oral butyrate can lead to increased microbial diversity,” she said.
What Are You Measuring?
In the Q & A following the presentation, Clifton O. Bingham III, MD, director of the Johns Hopkins Arthritis Center in Baltimore, Maryland, commented that “the definitions of response and nonresponse are quite variable, depending on the studies that you use, and I think this is potentially a real problem for this entire line of investigation.”
Johns Hopkins Medicine, Johns Hopkins Division of Rheumatology
Dr. Clifton O. Bingham III
He noted that the DAS28, as used by Dr. Blank and colleagues, was developed in 1993, and that American College of Rheumatology response criteria, employed by other investigators who also presented during the session, were developed in 1990.
“It was a very different world when those criteria and those response indices were developed for patients with a very different disease from what we know as RA today,” he said.
He added that “I see a tremendous need for the rheumatology community to reevaluate what we define as responders and nonresponders, so that in all of these studies that are being done around the world, there is one definition that we understand [for] someone who is doing better, responding, or not responding.”
Dr. Blank’s work is supported by NYU, the Arthritis Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. She reported having no conflicts of interest to disclose. Dr. Bingham had no relevant conflicts of interest to disclose.
A version of this article appeared on Medscape.com.