A Systematic Review and Network Meta‑Analysis:Dental Management Strategies for Methotrexate‑Associated Oral Mucositis
Methotrexate (MTX) is a cornerstone therapy for rheumatoid arthritis and graft-versus-host disease prophylaxis but is frequently complicated by oral mucositis. This systematic review and network meta-analysis, registered in PROSPERO (CRD420251048475) and conducted in accordance with PRISMA 2020 and PRISMA-NMA guidelines, evaluated the comparative effectiveness of preventive interventions for MTX-associated mucositis. PubMed, Embase, Cochrane CENTRAL, Scopus, and Web of Science were searched from 2000 to July 2025 without language restrictions. Randomised controlled trials involving adults or children receiving MTX were included if they assessed cryotherapy, low-level laser therapy (LLLT), palifermin, folinic acid rescue, or high-dose leucovorin versus standard care or placebo. Two reviewers independently extracted data and assessed risk of bias. Random-effects pairwise meta-analyses and a frequentist network meta-analysis were performed. Of 1,432 records screened, six trials including 321 participants met the inclusion criteria. LLLT (OR 0.30; 95% CI 0.17–0.54) and palifermin (OR 0.39; 95% CI 0.22–0.68) substantially reduced the risk of severe mucositis compared with standard care. Cryotherapy and high-dose leucovorin demonstrated modest benefit, while folinic acid rescue showed no protective effect. Indirect comparisons between active interventions were imprecise. Overall, LLLT and palifermin appear to be the most effective preventive strategies for MTX-associated oral mucositis, although larger, well-designed head-to-head trials are required to strengthen the evidence base.