Abstract
Background: The efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis (RRMS) had been well verified in several large randomized controlled trials (RCTs) during the past decade. However, there are fewer systematic comparisons of different doses of fingolimod and whether the dose of 0.5 mg/d is the optimal one still remains to be solved. Objective: The objective of this systematic review was to evaluate the efficacy and safety of the four existing doses of fingolimod in the treatment of RRMS, especially the dose of 0.5 mg/d. Methods: MEDLINE, EMBASE, Cochrane Library, and clinicaltrials.gov were searched for RCTs which were performed to evaluate different doses of fingolimod and the corresponding control (placebo or DMTs) up to October 2020. Review Manager 5.3 software was used to assess the data. The risk ratio (RR) and mean difference (MD) was analyzed and calculated with a random effect model. Results: We pooled 7184 patients from 11 RCTs. Fingolimod 0.5 mg/d was superior to control group in all eight efficacy outcomes including annualized relapse rate (ARR) (MD −0.22, 95%CI −0.29 to −0.14, p < 0.00001) but surprisingly showed a higher risk of basal-cell carcinoma (RR 4.40, 95%CI 1.58 to 12.24, p = 0.004). Although 1.25 mg/d is more than twice the dose of 0.5 mg/d, the effect size was almost similar between them. Dose of 5 mg/d obtained an unsatisfactory efficacy while showing a greater risk of adverse events than other three doses (RR 1.17, 95%CI 1.05 to 1.30, p = 0.003). Additionally, fingolimod 0.25 mg/d not only showed a better performance in delaying the disease progress of magnetic resonance imaging (MRI), but also achieved a certain degree of patient treatment satisfaction. Conclusion: At present, 0.5 mg/d remains to be the optimal dose of fingolimod for RRMS patients but trials of a lower dose are still of great clinical significance and should be paid more attentions.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory disease that can induce the immune system to produce autoimmune responses against the central nervous system (CNS), involved both white and grey matter region, thereby slowly losing the patient’s physical activity (Owens, 2016)
The results showed that compared with placebo or disease-modyfing treatments (DMTs) group, the patients in fingolimod 0.5 mg/d group were more likely to have basal-cell carcinoma, which made major contribution to the high risk of serious adverse events (RR 4.40 [1.58, 12.24], p 0.004, Table 4 and Supplementary Figures S11–S14)
Several large clinical trials have shown that fingolimod with once-daily doses of 0.5, 1.25 and 5 mg could both significantly lower the ARR compared with the placebo group (Kappos et al, 2006), (Kappos et al, 2010)
Summary
Multiple sclerosis (MS) is a chronic inflammatory disease that can induce the immune system to produce autoimmune responses against the central nervous system (CNS), involved both white and grey matter region, thereby slowly losing the patient’s physical activity (Owens, 2016). Relapsing-remitting multiple sclerosis (RRMS) is the most common phenotype of MS. The process of onset-remissionrelapse can cause progressive disability in approximately 15–30% of MS patients, causing great damage to the quality of life (Thompson et al, 2018). Researches on the drugs that can effectively control the relapse and delay the progression of RRMS are still of great clinical significance. The efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis (RRMS) had been well verified in several large randomized controlled trials (RCTs) during the past decade. There are fewer systematic comparisons of different doses of fingolimod and whether the dose of 0.5 mg/d is the optimal one still remains to be solved
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