Efficacy and Safety of Cyclophosphamide for the Treatment of Graves’ Ophthalmopathy: A Meta-Analysis

Abstract

Background: Graves’ ophthalmopathy (GO) is a complicated autoimmune disease. Cyclophosphamide (CTX) is an alkylant agent with highly potent immunosuppressive effects. Some case reports and recent randomized controlled trials (RCTs), have reported numerous patients with GO have benefited from CTX. However, its practical application value is still unclear. Therefore, we performed a meta-analysis to investigate the efficacy and safety of CTX for patients with GO. Methods: A literature search in the Embase, Cochrane, PubMed, China Network Knowledge Infrastructure (CNKI) and Chinese Scientific Journal Database (VIP) databases was undertaken through October 2020, looking for the open published RCTs related to CTX for the treatment of GO. The Cochrane bias risk assessment tool conducts the evaluation of included studies, and meta-analysis was performed using Revman 5.3 software. Subgroup analyses and sensitivity analyses were also performed. Findings: A total of twelve RCTs with 654 patients were included in the meta-analysis. CTX therapy brought about a higher response rate compared with non-CTX treatments (RR: 1.20; 95% CI: 1.10 to 1.31). Compared with the non-CTX group, considerable proptosis reduction was also observed in the CTX group (SMD: 1.35; 95% CI: 0.60 to 2.10), Subgroup meta-analysis showed that cumulative doses ≥4g of intravenous CTX (SMD: 1.86; 95% CI: 1.41 to 2.30) had a higher efficacy in the treatment of exophthalmos than non-CTX group, but when cumulative doses ≤4g of intravenous CTX (SMD: 0.04; 95% CI: ﹣0.29 to 0.37) there was no significant differences. The CTX group and the non-CTX group had no statistically significant difference in the proportion of adverse events (RR:0.74; 95% CI: 0.54 to 1.01). Furthermore, the above results were robust to sensitivity analysis. Interpretation: This review found that CTX is a relatively safe and viable treatment for patients with GO. Cumulative doses ≥4g of intravenous CTX appeared to show a superior ability in the treatment of exophthalmos. Nevertheless, large sample, multi-center, reasonable design, and high-quality clinical studies are still needed for further verification. Funding Statement: This work was supported by the Government and School Cooperation Program of Nanchong, Sichuan, China. Declaration of Interests: We declare no conflict of interests in this work.