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Study timeline The anticipated timeline for conducting this systematic review and meta-analysis is outlined below: ► Development and finalisation of search strategy: by December 2025. ► Title and abstract screening: by February 2026. ► Full-text review and data extraction: by June 2026. ► Statistical analysis and synthesis of results: by October 2026. ► Manuscript preparation and dissemination of find- ings: by December 2026. PATIENT AND PUBLIC INVOLVEMENT A patient partner (NG) was involved in the design, conduct, reporting and dissemination plans of this research. ETHICS AND DISSEMINATION No ethical approval will be needed because we will be using data from previously published studies. The results will be disseminated through presentations at scientific conferences and publication in a peer-reviewed journal. When interpreting the knowledge arising from the systematic review, we will evaluate possible limitations at both the study level, such as risk of bias relating to rando- misation and allocation to treatment groups or missing data, and the review level, such as selection bias due to different inclusion criteria and potential heterogeneity resulting from differences in disease, intervention, treat- ment comparators, outcome and follow-up points. DISCUSSION By conducting this systematic review and meta-analysis, we aim to synthesise the existing evidence from RCTs on the clinical efficacy and safety of microbiota-targeted therapies in AIRDs. This includes interventions capable of modulating the human microbiota, such as probiotics, synbiotics, FMT, biotherapeutic products and antibiotics with immunomodulatory properties. 81 While antibiotics are well-defined drug classes, microbial-based therapies lack standardisation due to regulatory and manufacturing variations, 64 82–84 which may limit direct comparisons across trials. By systematically extracting and analysing trial data—including intervention characteristics, dosage, administration and outcomes—we will provide quantita- tive estimates of effect for both primary and secondary endpoints. This approach will enable a rigorous evalu- ation of the evidence base, clarify knowledge gaps and inform future clinical guidance on microbiota-targeted therapies in patients with AIRD. Despite great variability in genetic dispositions, disease type as well as disease stage (preclinical phase, early manifest disease and chronic disease stages), which have been associated with different alterations in micro- bial composition and function in AIRDs, a common denominator across these distinct disease entities seems
to be a reduction in bacterial diversity and a low abun- dance of microbes producing short-chain fatty acids (SCFAs). SCFAs are microbiota-derived metabolites that are involved in many physiological pathways, including the strengthening of the gut barrier integrity. 85 Notably, several studies have documented increased intestinal permeability in both RA, 86 SpA, 87 psoriatic arthritis 88 and SLE, 18 89–91 which seems to be related to disease activity. These shared microbiota-related features are the main reason for including all AIRDs in one system- atic review. Still, we acknowledge that randomised trials encompassing patients with relatively rare AIRDs, such as relapsing polychondritis and cryopyrinopathies, may be limited. Although mode(s) of action of microbiota-targeted interventions in AIRD are still not clear, one of the primary aims of these interventions is to reduce systemic inflam- mation by boosting healthy microbial diversity, increasing the number of microbes producing SCFA, 85 and/or elimi- nating proposed disease-causing, pathogenic ones. Other effects of microbiota-targeted therapies may be medi- ated through pharmacomicrobiomic interactions, where changes in the intestinal microbiota directly modulate drug disposition, action and/or toxicity. 92 Interestingly, gut bacterial compositions in patients prior to treatment instigation have been shown to relate to clinical response to conventional therapies such as methotrexate, sulfas- alazine and biological drugs. 93–96 Therefore, the current review will also present data on any concurrent immuno- modulatory drugs used in combination with the experi- mental microbiota-targeted therapeutic. While exposure to most antibiotics reduces the overall bacterial diversity both in the short and long term 97 — and its use has been associated with the development of arthritis 98 99 (but also resolution in rare cases) 100 — some antibiotics have been attributed immunomodula- tory effects, 101 102 which have motivated trials evaluating their potential disease-modifying effects in AIRDs. In addition, some microbiota-targeted strategies encom- pass pre-conditioning with antibiotics aiming at reset- ting the recipient’s microbiota before the application of probiotics and/or FMT. Even though this approach may adversely affect microbiota at mucosal sites, without the possibility for subsequent restoration of healthy micro- biota (eg, pulmonary microbiota), trials evaluating such combinations of microbiota-targeted therapies will also be included. People living with AIRDs often experience that the disease impacts their lives in multiple ways. Consequently, the core outcome set in rheumatology represents the minimum set of domains and measurement instruments that should be reported in every trial of a specific condi- tion. 103 Therefore, we will not only extract data on the predefined primary endpoint of each trial, but also collect and present data on available outcomes from preselected OMERACT core domain sets addressing both disease control, the physician and patient global assessment of disease, quality of life, fatigue, pain and inflammation.
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Kragsnaes MS, et al . BMJ Open 2025; 15 :e101593. doi:10.1136/bmjopen-2025-101593
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