Treating axial spondyloarthritis via the gut microbiome

Background: Axial spondyloarthritis (axSpA) is a common immune-mediated arthritis affecting primarily the spine and sacroiliac joints of the pelvis.

Available therapies suppress the immune system and are associated with risks, a significant proportion (~30-40%) of patients respond inadequately to them, and they are expensive and do not induce remission in the disease. There is thus a substantial remaining unmet therapeutic need in this disease.

There is strong evidence that the disease is driven by interaction between the gut bacterial microbiome and the host immune system.

Recolonising the gut microbiome by fecal microbiota transplantation (FMT) has been demonstrated to be effective in inflammatory bowel disease, a condition with overlapping pathogenesis to axSpA.

Aims and Purpose: We propose to perform a phase 1a/2b clinical trial of FMT in axSpA patients to determine its tolerability and safety, the extent and duration of gut microbiome alteration following therapy, and to explore clinical, biomarker and imaging evidence of efficacy of the treatment. This preliminary data will be used to design larger definitive studies.

Experimental Plan: 45 patients with active non-radiographic axSpA will be recruited.

Inclusion criteria will be meeting ASAS classification criteria for axSpA, with significant symptoms (BASDAI >4.0), having objective evidence of inflammation (sacroiliac MRI positive, elevated CRP), age 18-45-years, on stable medications.

Exclusion criteria will include pregnancy, co-existent inflammatory bowel disease, oral or parenteral antibiotic use in past 3 months, treatment with sulphasalazine or biologic agents (TNF- or IL-17-inhibitors), or other major illness.

Patients will be recruited from axSpA clinical services at Guy's and King's College Hospital, and following consent and assessment will be randomised to receive either FMT by oral capsule delivery (50g/dose, n=30), or placebo (n=15), in a double-blind manner. Two doses will be given, at baseline and at 2 months.

FMT will be derived from healthy volunteers who have undergone full screening and testing, produced by the St Thomas' Hospital MHRA licensed FMT donor program.

Stool samples collected before and after FMT for shotgun sequencing to assess extent and duration of normalisation of axSpA-associated microbiome changes towards that of the healthy donor. axSpA disease activity will be assessed at baseline, 2 weeks, and 1, 2 and 4 months, using established outcome measures including patient reported outcome measures of disease activity (ASDAS-CRP, BASDAI, BASFI), fatigue (TACIT-F), acute phase reactants (ESR, CRP), and by MRI-imaging at baseline and 4 months (using the Berlin Ankylosing Spondylitis spine Magnetic Resonance Imaging-activity index).

Relevance to Versus Arthritis and Potential Patient Benefit: This trial will pave the way for full scale therapeutic studies of an innovative treatment for a common rheumatic disease, axSpA.

The goal of this treatment is to reduce inflammation in axSpA patients by normalising the gut microbiome, thereby reducing pain and fatigue in axSpA patients.

The therapeutic approach involved is novel in this disease, and offers the possibility of benefit for patients not responding to biological therapies, or where such therapies are contraindicated.

If this treatment is successful in axSpA this would support trials in aetiopathogenically related conditions such as psoriatic arthritis.