This single-center, open-label, prospective cohort study demonstrated that MMF effectively prevents NMOSD relapse and may safely enable steroid reduction. It is notable that 77.8% of enrolled patients achieved the primary endpoint for treatment protocol including MMF administration and prednisolone dose reduction. Although the 95% CI (40–97%) was wide due to the limited sample size, it clearly exceeded the 10% threshold. In addition, the patients with NMOSD in our study were older than those reported in a recent study [26], and their risk of osteoporosis and subsequent bone fractures would increase due to long-term steroid administration.
The efficacy of MMF in the treatment of NMOSD has been reported in several studies, including one by Jacob et al. in 2009 [9]. However, most studies were retrospective [26, 27], and no study has aimed to evaluate the possibility of steroid reduction under MMF. Oral prednisolone is frequently used along with other immunosuppressive drugs, including MMF, AZA, and rituximab, not only for NMOSD but also for other autoimmune diseases. MMF is reported to be better tolerated than other drugs [28–30], indicating its applicability for older patients.
Previous studies reported a decrease in the ARR with the initiation of MMF, consistent with our findings. Our cohort had a lower baseline ARR (0.72) than those reported previously, suggesting that this study included patients with less disease activity. As NMOSD is a chronic disease, EDSS scores may reflect residual sequelae from previous attacks, and the patients’ scores did not change during MMF treatment in this study. Although there have been reports of EDSS scores improving after MMF initiation [10, 21, 31], it should be noted that those studies may have included patients still affected by their most recent attacks, and that their EDSS scores before MMF initiation may have been overestimated. Recently, several studies on OCT findings in NMOSD have been reported, including comparisons with MS (e.g., changes in RNFL) [32–34]. Our study did not show any remarkable changes on RNFL thickness over the treatment protocol period, and long-term follow-up is needed. In this study, PASAT1 scores improved after MMF initiation; however, to our knowledge, no report has shown that MMF improves cognitive function, which may be a secondary effect of prednisolone dose reduction. In this study, serum cytokine levels were measured to assess the immune backgrounds of the treated patients. Although no significant change was observed, probably due to the small sample size, a trend of reduction in pro-inflammatory cytokines after MMF initiation was observed that corresponded to the reduction in the ARR.
In practice, each clinician makes individualized and integrated decisions regarding each patient’s long-term treatment plan. The practice involves complex decision-making (e.g., steroid reduction rate) considering various parameters, including disease activity (based on the frequency of relapses), the severity of neurological disabilities, imaging findings, comorbidities, and background lifestyle. Recently, a study showed that the risk of relapse is higher in patients with NMOSD who are in the cluster phase [35]; the steroid dose may not be reduced in some cases due to several clinical issues. We believe that the strength of our study is that the primary endpoint was achieved, even with a protocol aimed at steroid reduction in all patients. A few prospective studies have implemented steroid reduction in their protocols [21, 22]; however, their protocols for MMF initiation with high-dose oral prednisolone (1 mg/kg/day) were not intended to target steroid reduction.
This study has several limitations. First, it was a single-center, single-arm study with a small sample size. However, we believe that the prospective design and analysis of a one-sample proportion test demonstrated the efficacy of MMF for steroid reduction. It is controversial whether a randomized controlled trial is necessary for MMF, which has been on the market for decades and is widely used [36]. Second, long-term evaluation of each parameter was challenging in our 48-week trial period but would be preferable in future studies.