Fecal microbiota transplantation safe in patients with psoriatic arthritis
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Fecal microbiota transplantation is safe in patients with psoriatic arthritis, according to data from the first preliminary, randomized trial of the procedure in immune-mediated arthritis.
However, data from the albeit small study of 31 patients suggests that fecal microbiota transplantation is inferior to sham surgery, leading the researchers to call for more trials.
“Overall, we think that the results are very interesting and that the feasibility and safety aspects, as well as the clinical results of the trial, may encourage more research into the potential of fecal microbiota transplantation in the treatment of inflammatory arthritis and may help guide the direction of future trials within the field,” researchers Maja S. Kragsnaes, MD, PhD, and Torkell Ellingsen, MD, PhD, both from Odense University Hospital and the University of Southern Denmark, told Healio Rheumatology in a joint statement.
According to the researchers, previous data have found PsA to be associated with decreased intestinal bacterial diversity, displaying both disease-specific patterns and microbial abnormalities similar to those seen in other subtypes of spondyloarthritis, rheumatoid arthritis and inflammatory bowel disease. This has in turn led to research into the relationship between host-microbiota and the dysregulated immunological consequences involved with immune-mediated arthritis, and the potential of treatments that target the microbiome.
“Fecal microbiota transplantation (FMT) is currently considered the most efficient method to restore a healthy diversity of the gastrointestinal microbiota,” Kragsnaes and colleagues wrote in Annals of the Rheumatic Diseases. “Indeed, the transfer of feces containing minimally manipulated communities of micro-organisms from a donor to a recipient has revolutionized the treatment of Clostridioides difficile infection. FMT may also induce beneficial responses in patients with IBD, thereby demonstrating local therapeutic immune-modulating abilities.”
“However, whether manipulation of the intestinal microbiota can treat extraintestinal, immune-mediated disorders remains to be established,” they added. “This is the first exploratory, randomized trial to assess the safety and efficacy of FMT in patients with active, peripheral PsA.”
To examine the safety and efficacy of fecal microbiota transplantation in patients with PsA, the researchers conducted a double-blind, parallel-group, placebo-controlled, superiority, proof-of-concept trial. Participants included Danish adults aged 18 to 75 years with active peripheral PsA despite ongoing treatment with methotrexate for at least 3 months prior to enrollment.
Among the 97 total patients screened, 31 were randomized, with 15 receiving gastroscopic-guided fecal microbiota transplantation into the duodenum while the remainder underwent a sham procedure. The stool transplants were obtained from four healthy donors recruited from a nonprofit public stool bank, at the local blood and tissue transplant service.
The primary efficacy endpoint was the proportion of participants who demonstrated treatment failure — defined as requiring treatment intensification — through 26 weeks. Important secondary endpoints included change in Health Assessment Questionnaire Disability Index (HAQ-DI) and ACR20 response at week 26. A total of 30 randomized participants completed the 26-week evaluation.
According to the researchers, there were no serious adverse events. However, treatment failure occurred in 60% of patients who received the fecal transplant, compared with 19% in the sham group (RR = 3.2; 95% CI, 1.06-9.62). HAQ-DI improvements between the groups differed by 0.23 points in favor of those who received the sham surgery (95% CI, 0.02-0.44). Additionally, there was no difference in the proportion of ACR20 responders between the groups, with 47% for those who received the transplant, compared with 50% for the control.
“The most important findings from this trial are that FMT appears to be safe in patients with PsA, and that the patients find the treatment acceptable, and support future research into the therapeutic potential of FMT in PsA,” Kragsnaes and Ellingsen said in their joint statement. “Extrinsic factors that may influence the effectiveness of FMT in PsA needs further investigation, however. From FMT trials in patients with active ulcerative colitis, higher dose and repeated administration appear to be effective and safe in inducing remission.”
The pair added that the procedure’s success in IBD appears to be driven by “super donors,” characterized by the presence or absence of specific bacteria species.
“Our team will continue our research into the effect mechanisms of FMT in immune-mediated diseases, including the characterization of potential ‘super donors,’” they said. “We will conduct new randomized trials using different FMT strategies — by changing the type of administration form, dose and treatment frequency — to explore whether microbial dysbiosis or specific bacteria are common or decisive mediators of disease activity in inflammatory diseases and whether this proposed relation can be modified without exacerbating the disease.”
Perspective
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Evan L. Siegel, MD, FACP, FACR
This proof-of-concept trial provides a foray into a totally novel therapeutic modality for psoriatic arthritis. Based on the concept of the role of dysbiosis of the microbiome in inflammatory and autoimmune disease, the authors provided fecal microbiota transplantation (FMT) or a sham procedure to 30 patients with active psoriatic arthritis.
Healthy stool donations were delivered to the third part of the duodenum endoscopically. There is good precedent for such procedures which normalizes and increases diversity of the microbiome which is lost in the pathologic state; FMT has been essentially curative for C. difficile enterocolitis and has shown variable promise in inducing remission in a proportion of patients with ulcerative colitis. While it has been demonstrated that the decreased diversity of the microbiome promotes multiple inflammatory pathways, as noted by the authors, it is unknown whether manipulation of intestinal flora can have any effect on extra intestinal immune mediated manifestations.
Unfortunately, this trial failed to meet its primary outcome. Significantly more patients receiving FMT proceeded to treatment failure (requiring additional rescue treatments) than those receiving the sham procedure. In fact, the sham group did better in almost all outcome measures including HAQ-DI, ACR 20 and SPARCC indices. While this is disappointing, there were no significant safety signals with this therapy and the concept remains intriguing. It is unfortunate that the authors did not characterize the microbiota environment before and after the fecal transplants.
Prior attempts at therapy with FMT in ulcerative colitis have met with very mixed results and have raised questions as to efficacy based on multiple variables that will need to be explored. Donor characteristics may be important. There have been reports of a single donor’s stool causing significant improvement in multiple patients with UC. Single versus pooled donor stools may make a difference.
Mode of administration, particularly endoscopic duodenal delivery vs. colonoscopic infusion with subsequent enema boosters increasing the delivered dose may be important and seemed to be more effective in ulcerative colitis. Finally, recipient characteristics including baseline pre-transfusion microbiota characteristics and previous biologic exposure may change responsiveness to this therapy.
Of course, based on the results of this trial, it is possible that infusion of bacteria into the gut of patients with PsA may actually exacerbate their disease. However, given the exploding knowledge of the effects of the microbiome on inflammatory diseases, this novel and apparently safe approach needs further study in larger trials using different treatment approaches, careful evaluation of donor characteristics and better characterization of recipient microbial communities before and after transplantation.
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