This systematic review aims to relate intestinal microbiota to SLE in activity. This study will be conducted and reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)(10). See Additional file 1 for the completed PRISMA-P checklist. The review will adopt the PECO structure (11) (Population, Exposure, Comparator, and Outcome) recommended for systematic reviews. The PECO structure will be defined as ‘P’ (individuals with SLE), ‘E’ (intestinal microbiota composition), ‘C’ (SLE in remission and healthy control group), and ‘O’ (SLE in activity).
Eligibility criteria
This review will include observational studies (cross-sectional, cohort, and case-control) which analyzed the intestinal microbiota composition in patients with SLE. Publications concerning cases with SLE, with no restriction of age or sex, which fulfilled the classification criteria of either Systemic Lupus International Collaborating Clinic (SLICC)(12), European League Against Rheumatism (EULAR) or American College of Rheumatology (ACR) (13) and considered the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (14) to classify disease in activity or in remission will be included. Researches that evaluated intestinal microbiota composition in SLE from stool samples, colon tissue or intestinal biopsies through a method accepted by the scientific community will be considered. There will be no restriction on language and publication year.
Ecological studies, case reports or case series, literature reviews, randomized clinical trials, dissertation, thesis and conference summaries, as well as duplicate articles and unavailable data even after contacting the authors will be excluded. Researches in patients with intestinal and metabolic diseases that somehow affect intestinal microbiota, in addition to articles that do not provide measures for microbiota composition will also be excluded.
Databases
Searches will be carried out using the following databases: Medline via PubMed, Scopus, and EMBASE. The search strategy will apply Medical Subject Headings (MeSH) terms in PubMed, Emtree terms in EMBASE, and both terms in Scopus. Relevant keywords about SLE and microbiota will also be used, aiming to encompass all articles on this issue. The search will be adapted for each database. The strategy for PubMed is presented in Table 1.
Review process
The search will be performed by two independent researchers (JRPV and ATOR) and a third senior reviewer (MRF), then articles will be grouped and the duplicated ones will be deleted using Mendeley software. The authors who will participate in the eligibility criteria will be appropriately trained concerning the study inclusion/exclusion criteria and will perform a pilot test to reduce the risk of bias by reading the title and abstract of 5 articles before starting the selection process.
Subsequently, reviewers (JRPV and ATOR) will independently select the articles using Rayyan software (15). Reviewers will read the titles, then the abstracts and, finally, the entire article, according to the eligibility criteria, and so articles will be included. Disagreements about inclusion will be discussed and resolved by the third reviewer (MRF), and agreement between reviewers will be measured using Kappa de Cohen statistic (16). Finally, the studies considered eligible will be included in the systematic review. A flowchart of the planned review process is shown in Figure 1.
Data extraction
Data will be extracted from articles that presented information related to intestinal microbiota and SLE in activity or remission and, then, they will be inserted in a standardized form prepared by the authors. The following aspects were considered: author/year, country where the study was carried out, type of study, participants, microbiota analysis method, disease activity index, and outcomes.
In order to assess the risk of bias, Downs&Black Scale (17) will be used, it consists of an instrument with 27 items, however only 19 items are applicable to observational studies (questions 1–3, 5–7, 9–12, 15–18, 20, 21, 25–27). Each manuscript will receive a punctuation according to the number of items considering the total percentage (0 to 19 points). Low bias risk will be defined for punctuation >70%. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE)(18) will be applied to assess the quality of the evidence of the selected studies.