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applicable to the prevention, treatment or cure of a disease or condition of human beings and (3) not be- ing a vaccine. 64 6. Antibiotics are defined as a substance able to inhibit or kill microorganisms. Studies of isolated diet interventions, prebiotics defined as substrates that are selectively utilised by host microor- ganisms conferring a health benefit (eg, fibres), 65 and probiotics within functional food are excluded. Comparator All standard comparator types for the control groups such as inactive controls and established DMARDs will be included. Studies comparing two or more microbiota- targeted therapies without the use of a no-effect compar- ator will also be included. Outcomes Primary outcome For this systematic review, we prespecify the primary outcome as the trial-level measure that best reflects the efficacy of microbiota-targeted therapies for AIRDs, consistent with our review objectives and with Grading of Recommendations Assessment, Development and Eval- uation (GRADE) guidance on defining outcomes rele- vant to the decision context. 66 67 The primary outcome for the review is therefore our choice, not determined by trial authors. Because trials may report multiple candi- date outcomes—and may label different endpoints as ‘primary’—we will use a predefined hierarchy to select the most appropriate measure from each study while limiting selective outcome reporting bias. 66 The hier- archy is: the outcome reported as informing sample size calculation (trial’s most operational ‘primary’ measure); patient global assessment of improvement (if avail- able); physician global assessment of improvement; the outcome judged by reviewers to best correspond to the review’s primary outcome domain. This approach ensures that the review-defined primary outcome is consistently extracted across heterogeneous trials while minimising indirectness. Secondary outcomes We also pre-specify the secondary outcomes for the review, reflecting domains most relevant to the effects and safety of microbiota-targeted therapies in AIRDs. Because no cross-disease core outcome measurement set exists for AIRDs, 68 and no harmonised core safety set has been finalised for rheumatology trials, 69 we draw on the Outcome Measures in Rheumatology (OMERACT)-endorsed core domain framework. 70 Secondary outcomes will therefore include rele- vant domains such as disease activity, patient global assessment, physician global assessment, quality of life, fatigue, pain, inflammation and adverse events. Trials are eligible for the review regardless of which outcomes they report. However, a study will contribute to a given meta-analysis only if it provides complete
extractable data (numerical results or sufficiently detailed figures). When outcomes are reported as composite measures, both the composite and its components will be extracted as presented. For each domain, we will extract only one pre-specified measurement instrument to avoid unit-of-analysis issues. 71 Secondary efficacy outcomes: hierarchy and definitions 1. Disease control defined as clinical remission, or alter-
natively (very) low disease activity RA: for example, DAS28(CRP) <2.6
SLE: for example, Definition Of Remission In SLE, clinical Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K)=0, lupus low disease activity state, SLEDAI-2K ≤ 4 All AIRDs: for example, a proxy for disease control such as no need to escalate guideline therapy 2. Patient global assessment of disease activity 72 For example, patient global assessment of disease activity on a visual analogue scale (VAS) 3. Physician global assessment For example, physician global assessment of disease activity on VAS 4. Health-related quality of life For example, listed in the order of preference ► The Medical Outcomes Study Short Form 36 (SF-36). ○ Physical component (SF-36 PCS). ○ Mental component (SF-36 MCS). ► EuroQol 5-domain (EQ-5D). 5. Fatigue For example, ► Multidimensional Assessment of Fatigue scale. ► Multi-dimensional Fatigue Index. ► The Fatigue Severity Scale (FSS). ► The Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) scale. ► The Brief Fatigue Inventory. ► The vitality scale of the SF-36. ► The visual analogue scale for vitality. 6. Pain 7 ► For example, pain on VAS. 7. Systemic inflammation For example, ► C reactive protein. ► Erythrocyte sedimentation rate. ► Blood cytokine levels. ► Numbers or proportions of immune cells. Safety outcomes I. Total number of withdrawals. II. Withdrawals due to adverse events. III. Number of patients with serious adverse events (SAEs). IV. Number of deaths. Timing of outcome evaluation The preferred time point of measurements is the last day of the intervention or as late as possible when the participants still receive the intervention. In trials where
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Kragsnaes MS, et al . BMJ Open 2025; 15 :e101593. doi:10.1136/bmjopen-2025-101593
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