Study Highlights Factors Linked to Clinical Response to FMT in Patients With PsA

Torkell Ellingsen

Credit: University of Southern Denmark

Results from an exploratory study are providing an overview of the association between intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate-treated active psoriatic arthritis (PsA) with clinical response to sham or fecal microbiota transplantation (FMT).

“Compared with healthy individuals, patients with PsA have decreased stool bacterial diversity with a distinct bacterial compositional signature and subclinical gut inflammation characterized by increased expression of antimicrobial peptides and up-regulation of interleukin-17 (IL-17), IL-22, and IL-9,” wrote investigators.¹ “However, at present, the underlying mechanisms linking these structural and compositional changes with PsA pathogenesis and its functional implications for disease severity and response to therapy remain to be investigated.”

A chronic, inflammatory disease of the joints and entheses, management approaches for PsA range from oral medications for reducing inflammation and swelling to biologic therapies targeting parts of the immune system to combat symptoms and slow joint damage.²

To examine the association between functional permeability of the small intestine and fecal, plasma, and urine metabolomic profiles with treatment failure, senior investigator Torkell Ellingsen, clinical professor and head of research at Odense University Hospital in Denmark, and a team of investigators conducted an exploratory study among patients with moderate-to-high peripheral PsA disease activity despite at least 3 months of methotrexate-treatment from the FLORA trial cohort. A 26-week, double-blind, randomized, sham-controlled trial, FLORA evaluated the efficacy of FMT in reducing disease activity in patients with psoriatic arthritis.^1,3

To be included in the trial, patients were required to have a diagnosis of psoriatic arthritis, active peripheral psoriatic arthritis defined as ≥ 3 swollen joints, and methotrexate ≥ 15mg/week for a minimum of 3 months prior to study inclusion. In total, 31 participants were enrolled with a mean age of 50.7 (standard deviation [SD], 13.6) years and 20 (65%) were female.¹

Participants were randomly assigned 1:1 to receive either a healthy donor FMT (n = 15) or sham (n = 16) via gastroscopy. The primary endpoint was the proportion of treatment failures through 26 weeks, defined as the need for treatment escalation because of insufficient improvement of current symptoms or disease worsening.¹

Investigators performed a lactulose-to-mannitol ratio (LMR) test at baseline and at week 26 to assess small intestinal permeability. Of note, LMR results were expressed as median values, with additional interest in detailing the minimum and maximum values among the cohort. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1H Nuclear Magnetic Resonance. Investigators used K-fold cross-validation to assess the quality of models, with results summarized by the value of R2 and Q2 parameters for the goodness of the fit and the predictability of the model, respectively.¹

Upon analysis, intestinal permeability and fecal and plasma metabolomic profiles of patients with PsA were associated with clinical response. The LMR increased significantly from baseline to week 26 in the 16 sham-treated patients (0.0046; −0.012 to 0.088; P = .032), but not in the 10 FMT-treated patients (0.0020; −0.27 to 0.32; P = .92). Investigators pointed out trial failures (n = 7) had significantly higher LMR compared with responders (n = 19) at week 26 (0.027; 0.017 to 0.33 vs 0.012; 0-0.064; P = .013), indicating increased intestinal permeability.¹

Multivariate analysis revealed a significant model for responders (n = 19) versus failures (n = 12) at all time points based on their fecal (R2 = 0.613, Q2 = 0.220, P < .0001) and plasma (R2 = 0.514; Q2 = 0.121; P = .005) metabolomic profiles, whereas urine metabolomic profiles did not differ between groups (R2 = 0.115, Q2 = −0.274, P = 1). When stratified for intervention type, the models continued to show significant separation between the FMT arm (R2 = 0.766, Q2 = 0.383, P < .0001) and the sham arm (R2 = 0.790, Q2 = 0.260, P = .002). In both the FMT and sham models, plasma glucose (r = 0.67 and r = 0.63) correlated with failure, whereas lysine (r = −0.83 and r = −0.65) correlated with responder.¹

Investigators also pointed out fecal N-acetyl glycoprotein GlycA correlated with Health Assessment Questionnaire Disability Index (coefficient = 0.50; P = .03) and fecal propionate correlated with American College of Rheumatology 20 response at week 26 (coefficient = 27, P = .02).¹

“The results of this exploratory study reinforce the relationship between PsA and host-microbiota crosstalk and the possibilities for therapies aimed at restoring the microbiota ecosystem and/or modulating specific metabolites/microbiota-host pathways in PsA,” investigators concluded.¹

References:

1. Kragsnaes MS, Miguens Blanco J, Mullish BH, et al. Small Intestinal Permeability and Metabolomic Profiles in Feces and Plasma Associate With Clinical Response in Patients With Active Psoriatic Arthritis Participating in a Fecal Microbiota Transplantation Trial: Exploratory Findings From the FLORA Trial [published online ahead of print, 2023 Sep 22]. ACR Open Rheumatol. 2023;10.1002/acr2.11604. doi:10.1002/acr2.11604
2. National Psoriasis Foundation. About Psoriasis. September 29, 2023. Accessed October 3, 2023. https://www.psoriasis.org/about-psoriatic-arthritis/
3. Clinicaltrials.gov. Efficacy and Safety of Fecal Microbiota Transplantation in Peripheral Psoriatic Arthritis (FLORA). December 7, 2020. Accessed October 3, 2023. https://www.clinicaltrials.gov/study/NCT03058900