Efficacy of low-dose versus high-dose intravenous cyclophosphamide in Lupus Nephritis: A systematic review and Meta-analysis.

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus. While high-dose intravenous cyclophosphamide (HDC) is standard induction therapy, concerns over toxicity have encouraged low-dose regimens (LDC). Uncertainty persists regarding their comparative efficacy and safety across diverse populations. Following PRISMA guidelines, PubMed, Embase, Scopus, Cochrane Library, and ClinicalTrials.gov were searched from inception to August 2025. Randomized controlled trials and high-quality cohort studies comparing LDC and HDC were included. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random-effects model. Risk of bias was assessed with the Cochrane RoB 2 tool and certainty of evidence with the GRADE approach. Thirteen eligible studies, including both randomized controlled trials and observational cohort studies encompassing diverse global cohorts, were included. LDC demonstrated lower rates of full remission compared with HDC (RR = 0.81, 95% CI 0.70-0.94, p = 0.008), though trials reporting complete renal remission (CRR) suggested a modest benefit for LDC (RR = 1.13, 95% CI 1.03-1.25, p = 0.01). LDC significantly reduced the risk of leukopenia (RR = 0.66, p = 0.03) and amenorrhea/gonadal toxicity (RR = 0.51, p = 0.0002), with no significant differences in renal relapse, mortality, or renal failure. Low-dose cyclophosphamide offers a safer profile, particularly for women of reproductive age, whereas high-dose regimens yield higher remission rates in severe disease. Treatment choice should be individualized according to disease severity, toxicity risk, and patient demographics.