A Retrospective Study of 116 Multiple Sclerosis Patients with Dimethyl Fumarate Treatment in a Single Institution in Japan

Abstract

Objective

The global prevalence of multiple sclerosis (MS) is increasing worldwide. Although many disease-modifying therapies (DMTs) have been approved, they can cause serious adverse events, including infections. Dimethyl fumarate (DMF), an immunomodulator, has a favorable safety profile. In this era of personalized therapy, it is important to select an appropriate DMT for individual patients. This study evaluated DMF treatment outcomes in Japanese patients with MS.

Methods

The medical records of Japanese patients with MS treated with DMF at a single institution between January 6, 2013, and October 31, 2022, were reviewed retrospectively. The reasons for discontinuation of DMF, switching from other DMTs to DMF, transition of DMF to other medications, absolute lymphocyte count, disease activity assessment, comparison of DMF continuation versus discontinuation, and factors associated with the annualized relapse rate during DMF use were assessed.

Results

Of the 116 DMF-treated patients, DMF treatment was continued to prevent relapse recurrence in 54.7% of RRMS (n=86) and 23.3% of SPMS (n=30) patients. The main reasons for not continuing DMF treatment included failure to prevent relapse or disease progression (63% of patients who did not continue DMF). A lower annual recurrence rate prior to DMF initiation, lower Expanded Disability Status Scale score, shorter duration from disease onset to DMF initiation, fewer relapse recurrences during DMF therapy, and diagnosis of RRMS were associated with DMF continuation.

Conclusion

Continuous monitoring is essential after initiating DMF treatment because patients may require transition to other therapies. Overall, 47% of the MS patients were effectively managed with DMF, with favorable outcomes observed in 54.7% of the RRMS patients.

Introduction

Multiple sclerosis (MS), an autoimmune disorder with a chronic time course characterized by inflammation in the central nervous system and degeneration of white matter, is the major cause of disability among young adults, excluding trauma, and its global prevalence is increasing (1). Several disease-modifying therapies (DMTs) for the treatment of MS have been approved in Japan, including interferon beta (IFN-β)-1a, IFN-β-1b, glatiramer acetate (GA), dimethyl fumarate (DMF), fingolimod (FTY), siponimod (Sip), natalizumab (Nat), and ofatumumab (Ofa). DMTs are administered based on the patient's clinical symptoms and magnetic resonance imaging (MRI) results indicative of “activity,” such as relapses or increased lesions on MRI, or “progression,” which refers to a deterioration of symptoms without apparent relapse (2). The primary objective of DMTs is to mitigate disease activity in patients; however, controlling disease progression remains a challenge (3).

The long-term prognosis of MS has improved due to enhanced general medical treatment, early diagnoses, rapid availability of DMTs, and the introduction of new, highly effective DMTs (4-6). It has been documented that highly effective treatment initiated early during the disease can reduce relapses and disease progression (7-9), and early intensive therapy (EIT) has become the cornerstone of treatment. However, because of the potential for serious adverse events, including infection and progressive multifocal leukoencephalopathy (PML), it is imperative to select an appropriate DMT for each patient.

DMF, a methyl ester of fumaric acid that is used as DMT, has antioxidant, anti-inflammatory, and neuroprotective properties. It modulates the immune system by preventing the phosphorylation and subsequent nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) into nuclei (10) and upregulates genes related to antioxidant activity (11). It also upregulates hydroxycarboxylic acid receptor 2 (HCAR2) (12). Although abdominal symptoms and flushing may occur as side effects of DMF treatment, its relatively favorable safety profile and high acceptability have allowed its use as a first-line drug (13).

This study retrospectively evaluated Japanese patients treated with DMF at a single institution to describe their clinical characteristics and treatment outcomes with a focus on identifying patient subgroups for whom DMF may be more appropriate.

Materials and Methods

Study design and ethical approval statement

The medical records of patients with MS (PwMS) treated at Sapporo Neurology Hospital between June 1, 2013, and October 31, 2022, were reviewed retrospectively. Patients who had been treated with DMF at least once during the observation period were included in the analysis. We examined treatment patterns and clinical outcomes related to DMF use, including reasons for discontinuation, switching from other DMTs to DMF and from DMF to other medications, changes in absolute lymphocyte count, disease activity, and comparisons between patients who continued and those who discontinued DMF. Factors associated with annualized relapse rate (ARR) during DMF use were also evaluated.

This clinical study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Sapporo Neurology Hospital (protocol no.: C22D2102).

The retrospective diagnosis of patients with MS was established using the McDonald criteria (2017) by neurologists specializing in MS (14). SPMS was diagnosed using the objective definition proposed by Lorscheider et al. (15), which requires progression confirmed over three months in the absence of relapse, a minimum Expanded Disability Status Scale (EDSS) score of 4, and a pyramidal Functional System score ≥2. Progression was operationally defined using three strata: an increase in EDSS by 1.5 points if the baseline EDSS was 0, 1 point if between 1.0 and 5.5, or 0.5 points if it was above 5.5. However, nine cases with EDSS ＜4 exhibiting clinically evident relapse-independent worsening were also classified as SPMS by the consensus of MS specialists. The rebound phenomenon is characterized by recurrence or imaging activity occurring within six months following the cessation of FTY, as described in previous studies (16,17).

Statistical analyses

Patient demographics were compared between the relapsing-remitting MS (RRMS) and SPMS cohorts using the Mann-Whitney U-test. The assessment of ARR before and after DMT modification was performed using the Wilcoxon signed-rank test. A chi-square test was conducted to examine sex differences as reasons for discontinuation of disease-modifying drugs. A point-biserial correlation was used to evaluate the relationship between the interval from FTY cessation to DMF initiation, and the occurrence of rebound events. The Mann-Whitney U-test was performed to investigate associations between DMF continuation and various biomarkers, and the chi-square test was performed to explore associations between sex differences, oligoclonal bands (OCB), and MS disease types. The association between biomarkers and ARR during DMF treatment was assessed using t-tests for categorical variables (sex) and Spearman's rank correlation coefficient for continuous variables (age). Patients lacking endpoint data were excluded from the analysis. Python (version 3.9.13) and the SciPy library (Version 1.9.1) were used for all statistical analyses. Statistical significance was considered when p values were ＜0.05.

Results

Proportion of PwMS by treatment with DMF

Fig. 1 shows the enrollment process for PwMSs undergoing DMF treatment. In total, 138 patients with MS who received DMF treatment were initially screened. After the exclusion of patients participating in clinical trials and those seeking a second opinion, 126 patients with MS treated with DMF were identified. This cohort comprised 86 RRMS patients and 40 SPMS patients. The median ages at the initiation of DMF treatment for patients with RRMS and SPMS were 43 and 46 years, respectively (p=0.008). The percentage of female patients was 80% in the RRMS group and 78% in the SPMS group (p=0.814). The median EDSS score was 0.0 for RRMS and 6.0 for SPMS (p＜0.005). The median disease duration was 9.57 years for RRMS and 15.03 years for SPMS patients (p=0.003) (Table 1).

Figure 1.

Overview of the Patient Selection Process. RRMS: relapsing-remitting multiple sclerosis, SPMS: secondary progressive multiple sclerosis

Table 1.

Patient Background.

	RRMS		SPMS		p value	Total
Age, median (IQR)	43	(34-48)	46	(41-53)	0.008*	44	(37-49)
Female patients, n (%)	69	(80)	31	(78)	0.814**	100	(78)
EDSS at baseline, median (IQR)	0.0	(0.0-1.0)	6.0	(3.5-7.0)	<0.005*	1.0	(0.0-2.1)
Disease duration, years, median (IQR)	9.57	(4.04-16.26)	15.03	(8.59-24.48)	0.003*	10.58	(5.33-18.78)

Group comparisons were conducted using the Mann-Whitney U-test (*), and categorical variables (sex) were analyzed using Fisher’s exact test (**).

EDSS: Expanded Disability Status Scale, IQR: interquartile range, RRMS: relapsing-remitting multiple sclerosis, SPMS: secondary progressive multiple sclerosis

Duration of DMF treatment

The overall median duration of DMF treatment was 983 [interquartile range (IQR): 335-1,516, 25-75%] days, 949 (287-1,483) days for RRMS patients, and 1,115 (345-1,606) days for SPMS patients. The shortest treatment duration recorded was 1 days for RRMS and 20 days for SPMS, whereas the longest duration was 2,063 days for RRMS and 2,032 days for SPMS. Among the patients who discontinued DMF, the median treatment duration was 490 days (range, 160-1,137 days). Specifically, the median duration for those who discontinued treatment because of insufficient drug efficacy leading to relapse or disease progression was 904 (370-1,158) days, whereas those who discontinued treatment because of adverse effects had a median duration of 55 (16-289) days.

To further evaluate treatment persistence, a Kaplan-Meier survival analysis was performed (Fig. 2). No statistically significant difference in DMF continuation was observed between the RRMS and SPMS patients (log-rank test, p=0.11).

Figure 2.

Kaplan-Meier Curves of DMF Continuation. DMF: dimethyl fumarate, RRMS: relapsing-remitting multiple sclerosis, SPMS: secondary progressive multiple sclerosis

Pre-treatment of DMF

Overall, 22 patients (17%) were treatment naïve. In the cohort of patients with RRMS, the most prevalent previous treatment was IFN-β-1b, with 19 (22%) patients transitioning to DMF. In the cohort of patients with SPMS, the most common previous treatment was IFN-β-1a, with 12 patients (30%) transitioning. The overall proportion of patients who switched from Nat to DMF was 2%, and there were no instances of switching from Ofa to DMF (Table 2).

Table 2.

Previous DMTs Used Before DMF.

Pre DMT	RRMS (%)		SPMS (%)		Total (%)
Naïve	17	(20)	5	(13)	22	(17)
IFN-β-1a	17	(20)	12	(30)	29	(23)
IFN-β-1b	19	(22)	10	(25)	29	(23)
GA	11	(13)	1	(3)	12	(10)
FTY	17	(20)	10	(25)	27	(21)
Nat	2	(2)	0	(0)	2	(2)
Sip	1	(1)	0	(0)	1	(1)
DMF	2	(2)	1	(3)	3	(2)
PSL	0	(0)	1	(3)	1	(1)
Total	86		40		126

Instances in which pre-DMT was recorded as DMF indicated patients who discontinued DMF but subsequently resumed it without transitioning to another DMT.

DMF: dimethyl fumarate, DMT: disease-modifying therapy, FTY: fingolimod, GA: glatiramer acetate, IFN-β: interferon beta, Nat: natalizumab, PSL: prednisolone, RRMS: relapsing-remitting multiple sclerosis, SPMS: secondary progressive multiple sclerosis

Among those transitioning from IFN-β-1a, 16 of the 29 patients (55%) opted for DMF because of the inadequate efficacy of IFN-β-1a. Similarly, 6 of the 29 patients (21%) switched from IFN-β-1b, and 7 of the 12 patients (58%) switched from GA for the same reason. Conversely, some patients elected to switch to DMF despite the satisfactory efficacy of their previous treatment, with the intention of discontinuing injectable medications: 3 of 29 patients (10%) for IFN-β-1a, 14 of 29 patients (48%) for IFN-β-1b, and 5 of 12 patients (42%) for GA.

Discontinuation of DMF

The primary reasons for the discontinuation of DMF during the first year of treatment were gastrointestinal symptoms (eight patients) and inadequate response (eight patients), followed by lymphopenia (four patients). DMF was continued in 58 patients (47 with RRMS and 11 with SPMS) and discontinued in 68 (39 with RRMS and 29 with SPMS).

Changes attributable to challenges in suppressing disease activity

The primary reason for discontinuing DMF was relapse or MRI activity in the RRMS and SPMS cohorts, accounting for 30 cases (44%), or approximately half of the total number of cases (Fig. 3). In addition, DMF was discontinued in 10 patients (15%) due to disease progression, with 31% of SPMS patients requiring a change in therapy for this reason.

Figure 3.

Reasons for DMF Discontinuation. The “Ineffective” category encompasses cases where discontinuation was due to relapses or MRI-detected disease activity. RRMS: relapsing-remitting multiple sclerosis, SPMS: secondary progressive multiple sclerosis

DMF discontinuation due to adverse effects

Adverse effects of DMF include gastrointestinal symptoms, lymphopenia, and flushing. Discontinuation due to gastrointestinal symptoms occurred in nine cases (13%), all within the RRMS cohort. DMF was discontinued when persistent grade 2 lymphopenia [absolute lymphocyte count (ALC) 500 to ＜800/μL] was observed.

The lymphocyte count trends for each patient are shown in Fig. 4. Five patients had grade 2 lymphopenia and two had grade 3 lymphopenia (ALC 200 to ＜500/μL), with no instances of grade 4 lymphopenia (ALC ＜200/μL). Following DMF discontinuation, the patients were transitioned to immunomodulatory drugs (four to IFN-β-1a and two to GA). Patient 7 was diagnosed with SPMS, and as the disease activity had stabilized, no DMT was administered after the discontinuation of DMF. The median duration for lymphocyte counts to fall below 800/μL was 61.0 (47.0-159.5) days. Excluding one patient whose lymphocyte count recovered before DMF discontinuation, the median duration for recovery to a lymphocyte count ≥800/μL after DMF discontinuation was 77.5 (58.0-101.5) days. In all patients, lymphocyte counts improved to ≥800/μL after discontinuing DMF, with the longest recovery period of 126 days. Discontinuation due to flushing occurred in only one patient. In addition, one patient discontinued treatment because of pregnancy during the DMF treatment. No cases of PML were observed. Overall, there were no sex differences in the reasons for discontinuing DMF (p=0.48).

Figure 4.

Lymphocyte Trends in Multiple Sclerosis Patients Who Discontinued DMF because of Lymphopenia. The vertical line indicates the timing of DMF discontinuation. DMF: Dimethyl fumarate

Transitioning from DMF to alternative medications

Of the patients who discontinued DMF, the most prevalent transition of RRMS cases was to Nat (12 cases, 31%), and for SPMS, it was to Sip (9 cases, 31%), which was the most common transition option (Table 3). Four RRMS patients (10%) transitioned from DMF to Ofa. In 19 cases, patients transitioned from DMF to IFN-β-1a, IFN-β-1b, or GA. Most of these patients were initially transferred from IFN-β-1a, IFN-β-1b, or GA to DMF; however, they reverted to immunomodulatory drugs owing to adverse effects, such as abdominal symptoms and lymphopenia.

Table 3.

Subsequent DMTs Following DMF Discontinuation.

Post DMT	RRMS (%)		SPMS (%)		Total (%)
IFN-β-1a	6	(15)	2	(7)	8	(12)
IFN-β-1b	3	(8)	2	(7)	5	(7)
GA	4	(10)	2	(7)	6	(9)
FTY	3	(8)	1	(3)	4	(6)
Nat	12	(31)	6	(21)	18	(26)
Ofa	4	(10)	1	(3)	5	(7)
Sip	1	(3)	9	(31)	10	(15)
PSL	1	(3)	0	(0)	1	(1)
None	4	(10)	6	(21)	10	(15)
Death	1	(3)	0	(0)	1	(1)
Total	39		29		68

DMT: disease-modifying therapy, FTY: fingolimod, GA: glatiramer acetate, IFN-β: interferon beta, Nat: natalizumab, Ofa: ofatumumab, PSL: prednisolone, RRMS: relapsing-remitting multiple sclerosis, Sip: siponimod, SPMS: secondary progressive multiple sclerosis

Four patients transitioned from DMF to IFN-β-1a, IFN-β-1b, or GA, owing to the lack of efficacy of DMF. These changes were implemented prior to 2020 when CD20 monoclonal antibody agents became available. All of these cases were JC virus-positive and had a history of discontinuing FTY due to concerns about PML.

The assessment of disease activity in the year preceding and following DMF initiation

We included patients who had not altered their DMT for one year prior to and following the initiation of DMF. The ARR and disease activity, defined as the sum of the ARR and imaging activity, were evaluated. The cohort meeting these criteria included 18 of the 22 treatment-naïve patients, 21 of the 29 on IFN-β-1a, 18 of the 29 on IFN-β-1b, 5 of the 12 on GA, and 21 of the 27 on FTY. A significant improvement in the ARR was observed when patients transitioned from the treatment-naïve cohort and from IFN-β-1b to DMF. In addition, disease activity was significantly improved following the switch from treatment-naïve status and from IFN-β-1a to DMF (Fig. 5). Conversely, 14 of the 27 patients (52%) transitioning from FTY to DMF experienced a rebound phenomenon, with a significant exacerbation in disease activity. The ARR trajectories before and after switching from FTY to DMF are shown in Fig. 6. The interval between the cessation of FTY and the initiation of DMF did not correlate with the occurrence of the rebound phenomenon (Pearson's product-moment correlation coefficient=0.07, p=0.75).

Figure 5.

ARR and Disease Activity Before and After DMF Initiation. This figure shows the ARR and disease activity before and after transition to DMF. The vertical axis represents ARR or disease activity, whereas the horizontal axis represents the pre- and post-switch periods. Line thickness corresponded to the number of patients, with thicker lines indicating a larger patient cohort. The average values for each group are indicated by bold dashed black lines. ARR: annual recurrence rate, DMF: dimethyl fumarate, DMT: disease-modifying therapy, FTY: fingolimod, GA: glatiramer acetate, IFN-β: interferon beta

Figure 6.

ARR Trajectory in Cases Transitioned from FTY to DMF. Solid lines represent patients without rebound and dashed lines represent patients who experienced rebound. Line thickness was proportional to the number of patients following each trajectory. “Prior year” denotes the one-year period before the switch from FTY to DMF; “First year” and “Second year” denote the first and second years after DMF initiation, respectively. ARR: annual recurrence rate, DMF: dimethyl fumarate, FTY: fingolimod

A comparison of DMF continuation versus discontinuation or modification

Clinical data pertaining to continuation of DMF therapy were also examined. The Mann-Whitney U-test revealed that a lower ARR before and during DMF treatment, lower EDSS score, lower IgG index, older age, and shorter disease duration at the initiation of DMF were significantly related to the sustained use of DMF (p＜0.005). Chi-square tests indicated that a diagnosis of RRMS was significantly related to continued DMF use (p=0.008), whereas sex and presence of OCB were not (Fig. 7). We also evaluated the biomarkers associated with ARR during DMF treatment. Categorical variables, including sex, were analyzed using t-tests, and continuous variables, including age, were assessed using the Spearman's rank correlation coefficient. Sex, age, presence of OCB, IgG index, EDSS at DMF initiation, and disease duration were not correlated with ARR during DMF therapy. However, ARR during the first year after DMF initiation correlated with ARR throughout the DMF treatment period [Spearman's rank correlation coefficient (rs)=0.69, p＜0.005] (Fig. 8).

Figure 7.

Biomarkers Associated with DMF Continuation. ARR, Annual Recurrence Rate, DIAG: diagnosis, DMF: dimethyl fumarate, EDSS: Expanded Disability Status Scale, OCB: oligoclonal bands, RRMS: relapsing-remitting multiple sclerosis, SPMS: secondary progressive multiple sclerosis

Figure 8.

Correlation Between ARR and Various Biomarkers. Each plot featured a scatter plot accompanied by a regression line with shaded confidence intervals. ARR: annual recurrence rate, DIAG: diagnosis, DMF: dimethyl fumarate, EDSS: Expanded Disability Status Scale, OCB: oligoclonal bands, RRMS: relapsing-remitting multiple sclerosis, rs: Spearman’s rank correlation coefficient, SPMS: secondary progressive multiple sclerosis

Discussion

The present study has made several important discoveries regarding the treatment of MS with DMF. This study included a detailed analysis of 126 DMF-treated patients, 86 RRMS patients, and 40 SPMS patients from an MS clinic in Japan and found that continuation of DMF treatment was effective at preventing disease worsening in 54.7% of RRMS and 27.5% of SPMS cases. In addition, in cases of failure to continue DMF treatment, 59% failed because of drug changes related to relapse or progression.

The patient cohort in this study was epidemiologically comparable to those in previous reports. MS is more prevalent in North America and Western Europe than in Asia (18). However, in Hokkaido, the prevalence of MS is higher than in other Asian regions and has been increasing annually (19-23). In 2021, the woman-to-man ratio of PwMS in Hokkaido was 4.0, which was consistent with the findings of this study. The average age at the diagnosis was 30.6 years old, which was not significantly different from the global average age at the MS diagnosis (32 years old) (24).

DMF, an oral disease-modifying therapy for MS, has high adherence rates because of its convenient administration method and relatively mild adverse effects (25). However, there are instances in which DMF is inadequate for effectively suppressing disease activity. Recently, EIT has gained prominence from the perspective of brain health (6,7). Nevertheless, careful patient selection is imperative because of the associated risks of EIT, including infection and PML.

In the present study, DMF controlled disease worsening in 58 of the 126 patients who continued treatment (Fig. 3). In the RRMS cohort, 47 of the 86 patients (54.7%) were able to control disease worsening and continue treatment (Fig. 3). In the SPMS group, 11 of the 40 patients (27.5%) were able to control disease worsening and continued treatment (Fig. 3). Roar et al. reported that of 2,448 patients with RRMS who were treated with DMF from 2013 to 2020 at Danish MS clinics (26), 49.2% who initiated treatment with DMF (n=1,205) continued treatment with DMF. The results of the study by Roar et al. indicated that the disease in some patients with MS in Japan was well controlled by DMF and that this trend was clearer for those with RRMS than SPMS.

Regarding the relationship between pretreatment with DMT and the continuation of treatment with DMF, the results suggest that it can be continued when administered to treatment-naïve patients and when switching from interferon preparations (IFN-β-1a, IFN-β-1b) (Fig. 5). However, as we previously reported, disease worsening must be considered when switching from FTY to DMF (Fig. 6) (27).

We further analyzed the factors associated with continuation of DMF treatment (Fig. 7). The findings indicated that a lower ARR prior to DMF initiation, lower EDSS score, shorter duration from disease onset to DMF initiation, lower IgG index, fewer recurrences during DMF therapy, and the RRMS diagnosis were indicative of the beneficial effects of DMF treatment. In addition, a trend was observed, suggesting higher continuation rates with increasing age, potentially due to a reduced risk of relapse with advancing age (28), which consequently diminished the likelihood of considering a change in DMT. Conversely, the presence of OCB and being a man (29), which are considered markers of MS severity, were not associated with continuation rate (Fig. 7). Furthermore, a higher ARR in the first year following DMF initiation was correlated with an increased long-term relapse rate, although no significant correlation was found with other biomarkers (Fig. 8).

We also investigated the instances in which DMF was discontinued (Fig. 3). Our study revealed that 54% of patients discontinued DMF, a finding that is generally consistent with the RNDORSE trial and reports from Denmark (13,26). Difficulties in continuing DMF for reasons unrelated to disease activity or progression were observed in 28 patients, with 19 of the 39 RRMS patients and 9 of the 29 SPMS patients discontinuing DMF. Gastrointestinal symptoms were noted in 9 (13%) of the 68 patients who discontinued DMF, and flushing was observed in 2 (3%) patients, a trend that was less prevalent than that in a phase 3 study (30). Gastrointestinal symptoms and flushing can impact drug adherence (31) but can be mitigated using certain measures. At our hospital, these symptoms may have been alleviated through strategies such as initiating treatment at 120 mg/day, gradually increasing the dose (32), modifying the diet (33), and providing symptomatic treatment when necessary. Infections can pose a challenge when immunosuppressive DMTs are used. In this study, some patients discontinued DMF owing to concerns about infections related to lymphopenia, although no patient discontinued DMF due to inadequate infection control. The median time from the initiation of DMF until lymphocyte count ＜800/μL was 61.0 days, with the longest duration being approximately 1 year. Conversely, the median time to lymphocyte recovery following DMF discontinuation was 77.5 days, which was longer than that reported in the ENDORSE study (13). The interval between the blood tests ranged from one to two months, potentially resulting in a delay in detecting the actual recovery of lymphocytes.

Regarding COVID-19, DMF use was not considered a risk factor for severe disease, and there were no cases of severe COVID-19 (34). There was no association between DMT use and increased risk of cancer (35), and there were no instances of malignancy among DMF-using patients in this study. The selection of DMTs after DMF discontinuation was contingent on the patient's disease type. In the RRMS cohort, the most common motive for drug discontinuation was an inadequate response to DMF, and Nat, a high-efficacy therapy, was frequently chosen as subsequent treatment. Progression was the second-most common reason for discontinuation in the SPMS cohort, and Sip was often selected as the next treatment because of its anticipated therapeutic effect (36).

Study limitations

In Japan, the anti-CD20 antibody preparation, Ofa, was included in the insurance coverage in May 2021. However, its availability coincided with the COVID-19 pandemic, during which the properties of anti-CD20 agents in COVID-19 and the risk of severe disease are not fully understood. The study period was concluded in October 2022, and the limited availability of Ofa during this time was a contributing factor, with only a small proportion of RRMS patients: 4 (10%) transitioned from DMF to Ofa. An increasing number of reports (37) have suggested that the risk of severe COVID-19 is not significantly elevated in MS patients using Ofa, especially in RRMS cases, and that the frequency of its use has increased since the conclusion of the study period.

Furthermore, this study was conducted at a single center, which may limit the generalizability of the findings to other populations or clinical settings.

Conclusion

We examined the appropriate population of PwMSs for DMF treatment in Japan. More than half of the patients on DMF transitioned to a different DMT, and 23.3% of patients with RRMS experienced challenges in controlling disease activity, necessitating a switch to alternative agents, including high-efficacy treatment, due to drug ineffectiveness and disease progression. Continuous monitoring is essential even after initiating DMF treatment, as patients may require a transition to other therapies. Conversely, 47% of the overall MS patient cohort was effectively managed with DMF to suppress disease activity, with favorable outcomes observed in 54.7% of the RRMS patients. Possible clinical indicators for a favorable DMF response include a diagnosis of RRMS, cases that have not previously received DMT, and those with low disease activity.

The authors state that they have no Conflict of Interest (COI).

Shoki Sato and Hisashi Uwatoko contributed equally to this work.