Fecal Microbiota Transplantation in Axial Spondyloarthritis

Donor Versus Autologous Fecal Microbiota Transplantation for Axial Spondyloarthritis: a Double Blind, Placebo-Controlled, Randomized Trial

Although biologic therapy have revolutionized the treatment of Spondyloarthrtitis (SpA), many patients do not experience complete relief of SpA related complaints.

It has been established that patients with SpA have an altered composition of microorganisms (microbiota) in the gut compared to healthy controls, and that this correlates to disease activity and respons to therapy.

The goal of this randomized double-blind study is to evaluate the efficacy of fecal microbiota transplantation (FMT) in patients with axial SpA with a suboptimal effect of biologic therapy.

The main questions it aims to answer are:

• Can FMT reduce disease activity in axial SpA?
• Can FMT alleviate pain and reduce fatigue in axial SpA?
• Is the composition of microorganisms restored to normal in patients with SpA after a treatment with FMT?

Participants will receive a single treatment in the form of an enema with either donor FMT or placebo at baseline. The primary endpoint will be evaluated after 90 days, but efficacy and safety will be monitored from baseline until 365 days.

Axial Spondyloarthritis (axSpA) is a chronic inflammatory disease affecting the sacroiliac joints (SIJ) and the spine.

The approach to treatment of axSpA is a combination of patient education, with a focus on exercise and lifestyle, and a medical treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line medical treatment, providing symptom relief for a large portion of the patients. For patients with inadequate response, or intolerance, to NSAIDs, biological (TNFi and IL17i) or targeted synthetic (JAKi) disease modifying drugs (b/ts-DMARDs) are considered a second-line treatment option and provide excellent efficacy for many patients. However, a substantial portion of the patients experience active disease despite this second-line therapy.

The cause of the disease is multifactorial, and both genetic and environmental factors contribute in the pathogenesis. Patients with axSpA have a higher prevalence of inflammatory bowel disease (IBD) than the background population, i.e. Crohn's disease and ulcerative colitis. However, inflammation in the gut is also demonstrated in 50-70% of patients without symptoms of IBD, and this inflammation is believed to be of importance in the development of the disease.

The human gut microbiota is the collection of microbes in the intestines. The composition of the microbiota is the result of many factors and have evolved over time to form a mutually beneficial relationship to both humans and microorganisms. Normally there is a balance and a stability in this composition, but in many conditions an imbalance, termed dysbiosis, has been demonstrated. This is also the case in axSpA, and the extent of this dysbiosis also relates to disease activity and to response to therapy.

Fecal microbiota transplantation (FMT) is a method used to alter the microbiota composition by transferring microbes from a healthy individual to a recipient. In several conditions this has both proven the ability to alter the microbiota and to provide symptom relief , e.g. clostridium difficile infections, ulcerative colitis and irritable bowel syndrome.

In the Microspa study, we aim to evaluate whether fecal microbiota transplantation (FMT) can induce clinical remission and symptom relief in patients with axial spondyloarthritis who have shown an inadequate response to biologic therapy.

Microspa 2 is a parallel trial that retains the overall design of the original study, with adjustments made to the eligibility criteria and primary and secondary endpoints. All other components-including outcome measures, sample size, randomization strategy, and statistical analysis plan-remain unchanged.

In Microspa 2, eligible participants include patients who are biologic-naïve or who have previously used biologic therapy but discontinued treatment. Patients currently receiving biologic therapy are excluded. The primary endpoint is the proportion of patients in the donor FMT group compared to the autologous FMT group who initiate immunomodulatory treatment within 90 days following the intervention. An additional secondary endpoint is the proportion of patients initiating immunomodulatory treatment within 365 days post-intervention.

Inclusion Criteria:

• Axial Spondyloarthritis according to the ASAS classification criteria
• Active disease defined as ASDAS ≥2.1 with elevated CRP ≥3 OR active inflammation on MRI within the last 3 months
• Onset of axial SpA within last 10 years
• Unsatisfactory relief of NSAIDs
• On stable immunomodulatory treatment (TNFi, IL17i or JAKi) the last 3 months OR without immunomodulatory treatment last 3 months

Exclusion Criteria:

• Planned dose adjustment or change in immunomodulatory treatment the next 90 days
• Disease or disorder with life expectancy of ≤5 years
• Severe immune deficiency (acquired, congenital og du to medication)
• Previous treatment with FMT
• Regular use of opioids with the exception of codeine and tramadol
• Any specific diagnosis that could explain or contribute to the patients back pain (e.g. tumor, fracture, infection or degenerative disease)
• Inflammatory spinal disease other than axSpA
• Severe psychiatric disorder, alcohol- or drug abuse
• Active inflammatory bowel disease
• Microscopic colitis, diverticulitis or ileus
• Active psoriasis
• Fibromyalgia
• Abdominal surgery excluding appendectomy, cholecystectomy, hysterectomy, caesarian section, sapling-ooforectomy and hernia surgery
• Malignant disease excluding basalioma and melanoma stage 1
• Conditions with expected necessary treatment with antibiotics during the study period, e.g. periodontitis end ischemic digital ulcers
• Treatment with antibiotics 12 weeks prior to study entry
• Pregnancy, lactation or planned pregnancy within the next 3 months
• Contraindications for rectal catheter insertion
• Planned rehabilitation program the next 90 days
• Limited ability to comply with protocol requirements, including biobank participation