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potential application in AIRD disease management to facil- itate evidence-based recommendations for clinical use and to guide future research priorities. Current interventions include personalised diets, prebiotics, probiotics, synbi- otics, postbiotics, live biotherapeutic products, faecal micro- biota transplantation (FMT), bacteriophages, microbiome mimetics and antibiotics, 28 29 although not all have been explored in AIRDs. Among these, bacteriophages and micro- biome mimetics represent emerging modalities under early investigation, while dietary interventions and prebiotics are considered beyond the scope of this review. The proposed therapeutic effects of microbiota-targeted therapies in AIRDs are thought to involve direct and indirect immunomodula- tory mechanisms, including modulation of microbial compo- sition and metabolites, restoration of the gut barrier integrity and/or alterations of host-drug interactions (pharmacomi- crobiomics). 30 31 Growing evidence of clinical benefits from probiotics 32 and FMT 33 in patients with IBD, alongside the overlapping gut microbiota alterations in AIRDs, 10 14 15 has further encouraged clinical trials investigating the safety and efficacy of microbiota-targeted therapies in rheumatology. 34–36 Rationale This review protocol is a collaborative initiative of the European Alliance of Associations of Rheumatology research study group on Microbiota and Mucosal Barrier Research in Rheumatic and Musculoskeletal Diseases (the MICMUC group). Established in 2022, the MICMUC group brings together patient partners, clinicians, transla- tional scientists, statisticians and bioinformaticians in an international network dedicated to advancing research on microbial and mucosal barrier mechanisms in rheu- matic diseases. Its main objectives include promoting multidisciplinary collaboration, identifying novel micro- bial biomarkers and therapeutic targets and evaluating the clinical potential of microbiota-targeted interventions and pharmacomicrobiomics. To establish the need for a systematic review, we performed a pragmatic but systematic search of PubMed on 9 December 2024 to identify existing systematic reviews and meta-analyses. Of 1160 references identified, 246 were of potential interest based on title screening, excluding studies on unrelated diseases (eg, prosthetic joint, septic arthritis, osteoarthritis, gout) or interventions (eg, diet or prebiotics alone). After abstract screening, only 18 needed further scrutiny. 37–54 Most of these reviews evaluated the efficacy of probiotics in RA. 37–40 49 50 52 The most recent and comprehensive review/meta-analyses on probiotics in inflammatory arthritis was based on reviews conducted in June 2020 40 and May 2022, 52 respectively. We also identified one meta-analysis on antibiotics for anti-neutrophil cytoplasmic antibody-associated vascu- litis 44 and a few systematic reviews on non-pharmacologic therapies in patients with SLE. 41–43 46–48 52 Only one review from 2022 evaluated efficacy and safety of FMT in AIRDs. 51 Consequently, we decided that a comprehensive, updated investigation is warranted to guide patients and health professionals within this rapidly expanding research field.
withdrawals due to adverse events, number of patients with serious adverse events, disease flares and deaths. A meta-analysis will be performed for each outcome domain separately. Depending on the type of outcome, the quantitative synthesis will encompass both ORs and standardised mean differences with corresponding 95% CIs. Ethics and dissemination No ethics approval will be needed for this systematic review. We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to disseminate the study results through a peer-reviewed publication. PROSPERO registration number CRD42025644244. INTRODUCTION Within the last 25 years, the growing portfolio of biological agents and small molecule drugs that target specific cyto- kines and signalling pathways involved in the dysregulated immunological cascade of autoimmune and inflammatory rheumatic diseases (AIRDs) has greatly expanded the phar- macological toolbox. 1 However, despite these breakthroughs in the management of AIRDs, current immunosuppressive therapies may still not be successful in achieving and/or maintaining long-standing disease control in a high propor- tion of treated patients. 2–4 Suboptimal responses may reflect unknown environmental mediators of beneficial clinical responses despite maximal dose, tolerability issues and/or drug-related toxicity. Moreover, targeting several different cytokines or immune-related molecular pathways in combi- nation may adversely affect host defence. Therefore, iden- tification of new therapeutic targets that are central to the initiation and/or progression of AIRDs—but that do not require blocking of immunological pathways critical for host defence—is highly needed. The human microbiota is one such promising therapeutic target. Although causality has yet to be established for most microbes associated with AIRDs, modulation of the intes- tinal microbiota is increasingly being recognised as a poten- tial novel complementary therapy to immunomodulatory drugs. 5 Many AIRDs are associated with gut microbial imbal- ances in both early and chronic disease stages, 6–10 some of which have been mechanistically linked to disease patho- genesis. 11–13 A systematic review of gut microbiota alterations in rheumatoid arthritis (RA), spondyloarthritis (SpA) and inflammatory bowel diseases (IBD) revealed reduced intes- tinal bacterial diversity and common features such as dimin- ished Bacillota (formerly Firmicutes) abundance. 14 Similarly, patients with systemic lupus erythematosus (SLE) exhibit overlapping features with IBD-associated microbiota. Addi- tional changes include lower Ruminococcaceae , outgrowth of Lactobacillus , autoantigen cross-reactive pathobionts, as well as translocation of Enterococcus gallinarum and enrichment of Ruminococcus gnavus —the latter associated with lupus nephritis and SpA. 15–22 In RA, disease-associated microbial expansions include Segatella copri (formerly Prevotella copri ) in the gut and citrullination-promoting pathobionts in the oral cavity and intestine. 23–26 Collectively, these findings under- score that perturbations across microbial taxa may influence autoimmune pathways and disease activity. Research on gut microbiota modulation to promote human health is increasing. 27 This systematic review focuses on gut microbiota-targeted therapeutic strategies and their
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Kragsnaes MS, et al . BMJ Open 2025; 15 :e101593. doi:10.1136/bmjopen-2025-101593
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