2. Methods
2.1 Search strategy
A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) Statement (supplementary figure S1) [29]. The protocol for this study was registered on the website of PROSPERO International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/prospero/), registration number CRD42020197101. Embase, Medline, Cochrane Central, and Web of Science were searched from 1946 to June 29, 2020. The search was conducted utilizing the PICOS format (Patients, Interventions, Comparators, Outcomes and Studies) as follows: P: adult participants (age > 18 years) with IBD; I: received VDZ treatment; C: control group given placebo; O: arthralgias; S: RCTs.
Manual searches of reference citations in the reviewed literature sources was subsequently performed. A detailed description of the search strategy is provided in supplementary figure S2. Two authors (from among: JBS, MT, EI, HK) independently reviewed each of the titles and abstracts for eligible studies. All disagreements were resolved by consensus among the authors.
2.2 Eligibility criteria
Eligibility was limited to: (1) studies involving humans; (2) with> 18 year-old participants enrolled; (3) which were RCTs comparing treatment with VDZ versus placebo; (4) with atleast one case of new-onset arthralgia reported within the listed AEs. Studies were excluded if: (1) they were abstracts, case-reports, editorials, comments, letters, reviews, meta-analyses, observational studies, or open-label trials; (2) duplicate; or (3) written in languages other than English or without English translated versions available.
2.3 Study selection
Two researchers (from among: JBS, MT, EI, HK) independently performed the initial screening of each paper by title and abstract. Full texts were retrieved for all articles which were deemed potentially eligible, and were screened accordingly. Any disagreements were resolved by consensus among the researchers.
2.4 Data extraction and synthesis
The selected studies were reviewed with the data extracted independently by two researchers (JBS, MT). Conflicting data was resolved by consensus between the researchers. Information related to author, publication year, country/region, study type, sample size, age, and outcomes were put into a bibliographic database using Microsoft® Office Excel® version 14.0 software (Microsoft, Redmond, WA, USA). Corresponding authors were contacted by email to provide additional data where needed. Among papers describing the same cohort of patients, the most up-to-date study was considered for inclusion.
2.5 Assessment of risk bias and quality
The risk of bias of the RCTs was evaluated using the Cochrane Collaboration’s tool, evaluating sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias [30]. The included studies were stratified according to risk of bias. The GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach was used to rate overall quality of the evidence [31]. Two reviewers (from among: JBS, YGP, MT) independently assessed the risk of bias and evaluated the quality of each of the included papers. Disagreements were resolved by consensus among the researchers.
2.6 Data collection
A narrative synthesis of the included studies was performed around the sample size, disease population, participant demographics, baseline disease activity, length of disease, prior immunosuppressive treatments, presence of arthralgias, other side effects to treatment, odds ratio (OR), and 95% confidence interval (CI) measurements.
2.7 Ethical considerations
Due to the nature of this study, a systematic literature review, there was no need for institutional review board approval.