Fecal Microbiome Transplantation in Patients with Peripheral Psoriat-ic Arthritis: A 6-months Randomized, Placebo-Controlled Trial - The FLORA trial
This is a double-blind randomized placebo-controlled trial of fecal microbiome transplantation combined with subcutaneously administered methotrexate in 80 patients with psoriatic arthritis. Clinical measures of disease activity as well as adverse events will be registered. The primary outcome measure at the 6 months follow-up is the proportion of patients in each group who experience a treatment failure according to shared decision making between patient and physician. The degree of intestinal inflammation will be assessed using fecal calprotectin, intestinal permeability tests, and analyses of fecal microbiome composition, metabolomics and proteomics.
An increasing amount of data suggests a causal relationship between the intestinal microbiota and spondyloarthritis (SpA) thus linking dysbiosis with SpA pathogenesis. Psoriatic arthritis (PsA) is one of five SpA categories which also include ankylosing spondylitis, undifferentiated arthritis, reactive arthritis, and arthritis associated with inflammatory bowel disease. While the association between the gut and the latter two disorders is well established, only recently, studies evaluating the fecal microbiota and the presence of subclinical gut inflammation in PsA patients, have linked this disease to a perturbation of the intestinal microbiota composition.
PsA is a distinct, multi-faceted inflammatory disease with a diverse clinical spectrum and varied disease course. The clinical manifestations include peripheral arthritis, enthesitis and/or spondylitis combined with more or less severe psoriatic skin involvement, nail psoriasis, and dactylitis. Nearly half of the patients with both early and established PsA also present with extra-musculoskeletal manifestations which can include bowel (16 %), ocular, cardiovascular or urogenital involvement. Without disease modifying intervention, 40 % to 60 % of PsA patients will develop erosive and deforming joint damage within a few years of disease onset. Unfortunately, the PsA disease activity in peripheral disease has proven difficult to diminish, and no current treatment targets the cause of the disease.
The traditional pathophysiological concept of PsA is that it is an autoimmune disease of the skin and joints and that the pathological processes at both sites are driven by inflammatory responses involving the innate immune system, T lymphocytes, and the expression of pro-inflammatory cytokines. Nevertheless, limited data exist on the true pathophysiological factors triggering this dysregulated immunological cascade. During the years, microbial agents including dormant bacteria, bacteria products, mycobacteria, and viral antigens have been implicated as potential initiators. Also, the eruption of skin psoriasis has been associated with a decreased diversity of skin bacteria, and an abnormal response to bacteria in the skin due to genetic factors. Intriguingly, psoriasis patients and recent onset DMARD-naive PsA patients also exhibit less diverse intestinal microbiota. In addition, several studies have reported the presence of subclinical gut inflammation in PsA patients as well as an increase in intestinal lumen immunoglobulin A. Currently, the link between gut and joint inflammation, and whether the intestinal dysbiosis is causative or a consequence of systemic inflammation, remain to be elucidated. However, the intestinal microbiota and its metabolites play a complex role in shaping the immune system, and a decreased microbial diversity is likely to promote local gut inflammation and induce alterations in the epithelial and mucosal permeability. This may compromise the capacity of the intestine to provide adequate containment of luminal molecules and disturb the immune tolerance to components of the indigenous microbiota thereby promoting translocation of both activated immune cells and antigenic material to the joints and entheseal sites.
If the gut microbiota is the conductor, or at least a mediator, of the common inflammatory pathways seen in PsA, modifying the intestinal microbiota could be a novel treatment strategy for this disease. Fecal microbiota transplantation (FMT) is currently being used to restore imbalance of the intestinal flora. Based on more than 400 cases reported, and a small, open-label, randomized, controlled trial including 43 patients, FMT has demonstrated > 90 % clinical resolution of antibiotic-resistant Clostridium difficile infections.
The main objective of this study is to examine whether FMT is more effective than placebo in reducing disease activity in PsA patients with active peripheral arthritis treated with weekly s.c. metothrexate.
Description of the cohort
From January 2017 through 2020, 80 psoriatic arthritis patients presenting with active peripheral arthritis defined as at least three swollen joints despite three months treatment with subcutaneously administered methotrexate (Above or equal to 15mg/week (maximal tolerable dosage)) prior to study inclusion will be enrolled. \n
Data and biological material
Clinical measures: Height, weight, blood pressure, Psoriasis Area Severity Index, SPARCC Enthesitis Score, swollen joint count (66), tender joint count (68), doctors global (VAS 0-100 mm), and BASMI.
Patient questionnaires: Patient global (VAS), patient fatigue (VAS), patient pain (VAS), HAQ, and BASDI.
Biological material: Blood, faeces, urine, and colonic mucosae.
Collaborating researchers and departments
Department of Rheumatology, Odense University Hospital
- PhD student Maja Skov Kragsnæs, MD
- Professor Torkell Ellingsen, MD, PhD
- Consultant Jens Kristian Pedersen, MD, PhD
- Consultant Hans Christian Horn, MD
- Consultant Heidi Munk, MD, PhD
Department of Medical Gastrointestinal Diseases, Odense University Hospital
- Professor Jens Kjeldsen, Md, PhD
- Consultant Finn Møller Pedersen, MD
Department of Rheumatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg
- Senior Biostatistician Robin Christensen, BSc, MSc, PhD
Diagnostic Centre, Silkeborg Regional Hospital
- Chief consultant Ulrich Fredberg, MD, PhD
- Consultant Henning Glerup, MD PhD
- Consultant Ole Bonderup, MD, PhD
Department of Rheumatology, Odense University Hospital, Svendborg
- Consultant Inger Marie Jensen Hansen, MD PhD
Department of Clinical Microbiology, Odense University Hospital
- Consultant Hanne Marie Holt, MD PhD
Organ Centre, Hospital of Southern Jutland
- Professor Vibeke Andersen, MD PhD.