There have recently been substantial advances in the treatment of relapsing-remitting multiple sclerosis (RRMS). Numerous disease-modifying therapies (DMTs) are currently available for early aggressive interventions in patients with RRMS. Although general conclusions have been drawn about the efficacy of DMTs from randomized controlled trials, observational studies in real-world settings are essential for documenting the long-term impact of DMT in the wider population. Such studies can provide insight into the predictors of a response to treatment for MS, which will be useful for daily treatment decision-making. Numerous observational studies of MS patients receiving DMTs in Western countries have shown long-term treatment benefits and identified several predictors of a poor prognosis.1,2,3,4,5 The prevalence of MS is lower in Asia than in Western countries, and there is less data available about the long-term treatment outcomes of DMTs and predictors of a treatment response in Asian MS patients.

MS is considered to be a rare disease in Korea.6 All Korean MS patients are eligible to receive financial support for medical care from the government. The treatment era for RRMS began in 1993, and 11 DMTs have been approved by the Korean Food and Drug Administration in line with the global expansion of therapeutic options for MS. However, the effect of these drugs in Korean patients, the remission of disease activity, and the long-term benefits with respect to disabilities are not fully understood. The present study therefore aimed to determine the long-term impact of DMTs on the remission of disease activity and the prevention of disability progression in Korean MS patients. We also estimated 1) how many patients achieve a status of no evidence of disease activity (NEDA), as measured by relapses, disability, and magnetic resonance imaging (MRI) over 2 years, 2) whether the loss of NEDA within 2 years can predict long-term disability progression, 3) how many patients require treatment escalation following first-line treatment, and 4) predictors of a poor response to first-line treatment.

This study enrolled 160 patients: 3 with CIS, 152 with RRMS, and 5 with secondary progressive multiple sclerosis (SPMS). At the initiation of DMT, 13 had CIS and 147 had RRMS. The baseline characteristics of subjects are summarized in Table 1. Their age at the onset of MS was 29.2±9.7 years, the female-to-male ratio was 2.07, and the disease duration from clinical onset to the last visit was 8.2±5.2 years. Treatment was started at a median of 1 year (range, 0–22 years) after the clinical onset of MS, and the treatment duration was 5.7±3.3 years. Of 47 patients for whom treatment was initiated at the first attack, 12 (26%) had progressed to clinically definite MS. Compared to the pretreatment phase, the annualized relapse rate (ARR) was significantly reduced during the treatment (from 1.0±0.8 to 0.2±0.4, p<0.001). The median MSSS at the time of the initiation of DMTs was 4.27 (range, 0.24–8.64) in 89 patients for whom at least 1 year had elapsed between disease onset and treatment, with a median MSSS of 1.77 (range, 0.04–9.08) at the last follow-up. Globally, significant worsening in EDSS score during the treatment period was observed in 29 patients (18%). Of the 106 and 35 patients who were treated for at least 5 and 10 years, respectively, 26 patients (25%) and 14 patients (40%) experienced disability progression. At the last follow-up, 30 patients (19%) had an EDSS score of ≥3 and 9 patients (6%) had an EDSS score of ≥6.0. Among 60 patients with a disease duration of at least 10 years, 5 (8%) progressed to SPMS and 8 (13%) had an EDSS score of ≥6.

Most of the patients were initially treated with interferon β (IFNβ) (n=152) [91 with subcutaneous (s.c.) IFNβ-1b, 51 with s.c. IFNβ-1a, and 10 with intramuscular (i.m.) IFNβ-1a), while 6 were started on glatiramer acetate, and 2 on teriflunomide (Fig. 1A). During the follow-up, 81 patients (51%) had remained on their first treatment regimen, while 79 patients (49%) had changed their treatment regimen due to lack of efficacy (n=53, 67%), side effects (n=23, 29%), or other reasons (n=3, 4%). Thirty-four (21%) patients escalated to a second-line DMT [natalizumab (n=4), alemtuzumab (n=17), fingolimod (n=8), or mitoxantrone (n=7)]. In patients switching DMTs due to lack of efficacy, the median time to the first switch (including lateral switching or escalation) was 2 years (range, 3–17 years), and the median time to the second switch was 1.4 years (range, 5–8 years). The first drug switch due to a lack of efficacy was observed after a median of 2 attacks (range, 0–25 attacks) during first-line treatment.

Four patients switched to mitoxantrone due to the progression of disability without clinical relapse when receiving the first-line injectable treatment. Since alemtuzumab and natalizumab were launched in Korea in 2015, the median time from the initiation of the first-line drug to these higher potency drugs was 4 years (range, 1.3–17 years), and the median treatment duration was 15 months. Fingolimod was not eligible for reimbursement until 2017, but 8 patients started this treatment in 2013 via the Drug-Free Communities Support Program. Among them, one switched to natalizumab due to persistent lymphopenia and one switched to alemtuzumab due to lack of efficacy. Of 29 patients who switched to fingolimod, natalizumab, or alemtuzumab, ongoing disease activity (i.e., clinical relapse or MRI activity) was observed in 10 patients (34%), and significant disability worsening was found in only 1 patient (3%) during a median of 18 months of treatment with these higher potency drugs. All 4 patients treated with natalizumab achieved an NEDA3 during a median of 18 months (range, 18–20 months), and no progressive multifocal leukoencephalopathy occurred. Of the 23 patients who switched drugs due to side effects such as flu-like symptoms, injectionsite reactions, or laboratory abnormalities, 11 switched from s.c. IFNβ-1b or IFNβ-1a to i.m. IFNβ-1a, 8 switched from injectable drugs to oral first-line agents, and 4 switched from s.c. IFNβ-1b or IFNβ-1a to glatiramer acetate. The treatment at the last follow-up consisted of first-line injectable therapies (n=104), first-line oral therapies (n=23), second-line oral therapies (n=6), second-line injectable therapies (n=21), or no therapy (n=6) (Fig. 1B). At the follow-up there were no reports of serious adverse clinical events leading to treatment discontinuation.

In our cohort, 97 patients were eligible for an NEDA3 evaluation during the initial 2 years, and this resulted in NEDA3 being found in 37 of the patients (38%). To evaluate the utility of NEDA3 at 2 years as a predictor of long-term disease progression, we conducted subgroup analysis in patients who were treated for at least 5 years (n=106). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value of EDA3 at 2 years for disability progression over a median of 7 years of treatment were 96%, 48%, 38%, and 97%, respectively. In univariable analyses, disease duration [odds ratio (OR)=1.194, 95% confidence interval (CI)=1.080–1.320, p=0.001] and EDA3 at 2 years were associated with progression of the EDSS score over a median of 7 years of treatment (OR=20.167, 95% CI=2.573–158.058, p=0.004) (Table 2). In multivariable analyses, EDA3 at 2 years (OR=14.444, 95% CI=1.770–117.819, p=0.013) was independently associated with disability progression.

Our cohort included 54 patients (34%) classified as poor responders to first-line treatment. Multivariable logistic regression analyses revealed that poor responses were independently associated with time (per year longer) from the disease onset to treatment (OR=1.238, 95% CI=1.001–1.533, p=0.049) and the presence of 10 or more brain lesions in the initial MRI (OR=3.648, 95% CI=1.018–13.071, p=0.047) (Table 3).

The main aim of this study was to determine the long-term outcomes of DMTs in a cohort of Korean patients with MS and the predictors of a poor response to first-line treatment. Most of the patients (82%) achieved long-term stabilization of their disability (based on the EDSS scores) during 6 years of treatment. DMTs reduced the ARR by 80%. Escalation to higher potency therapy was observed in 21% of the patients, which stabilized the disease activity in most of them. Among 158 patients who started first-line injectable treatments, 23 patients (15%) switched their drug treatment regimens to low-frequency administration, other types of injectable drugs, or oral agents due to their simplicity and convenience.

Our previous report on the clinical characteristics of 105 Korean MS patients demonstrated that the clinical pattern of MS in Korea did not differ fundamentally from that seen in Western countries.13 Before 2015, mitoxantrone was the only second-line treatment for which reimbursement was provided in Korea. This meant that our previous study could only evaluate the efficacy of IFNβ treatment, and 14 of 88 patients (16%) showed disability progression during approximately 3 years. Alemtuzumab and natalizumab were launched in Korea in 2015, while fingolimod was approved for reimbursement from the government in 2017. Eight of the patients in the present cohort started fingolimod in 2013 via the Drug-Free Communities Support Program. Although the treatment duration was longer in the present study (mean, 6 years) than in our previous study, the proportion of patients with disability progression was similar (18% of 160 patients), which may be attributed to the effect of escalation with these therapies. Of the patients with a disease duration longer than 10 years (n=60), the proportions of patients who progressed to SPMS (8%) and reached an EDSS score of 6 (13%) were lower than those found in Western patients for the natural history of MS, with approximately 60% of the patients who were followed for 11–25 years from onset showing these outcomes.14

It could be argued that the more-favorable outcome in the present cohort is due to the effect of racial differences in MS disease activity, and is only partially explained by treatment effects. Piccolo et al.15 reported that the median MSSS was significantly lower in Japanese patients (3.34) than in patients from the UK (5.87). MS may indeed be associated with less disability in Japan than in the UK, but because of differences in the number of patients (104 in Japan vs. 1,148 in the UK), the proportion of primary progressive MS patients (3% in Japan vs. 12.9% in the UK), and the proportion of patients receiving DMTs (83.7% in Japan vs. 17% in the UK) between the two cohorts, it is difficult to conclude that the MS disease activity is milder in Japanese patients than in UK patients.

In the present study, the median MSSS was 4.27 at the time of initiating DMTs, which is comparable to that of global cohorts, although the EDSS scores at the initiation of treatment may be confounded by the incomplete recovery from a prior attack in some patients. At the last follow-up, based on EDSS scores that were confirmed after ≥3 months, we observed a significantly lower median MSSS (of 1.77) than that at the time of DMT initiation. These findings suggest that the clinical course of our patients had been changed by the effectiveness of DMTs. The early initiation of treatment in our cohort (median, 1 year) may have stabilized the disease course and resulted in lower MSSSs during the ensuing years.

The subgroup analysis revealed NEDA3 at 2 years in 38% of our patients, which is slightly higher than the reported percentages (17.9–27.5%) of NEDA3 over 2 years in patients with RRMS in Western countries.2,16 The inclusion of CIS patients (8%) in the present study may have contributed to these higher rates, but this factor alone cannot explain the higher rates of NEDA3 observations in the present study. The retrospective design of our study meant that serial MRI scans were not obtained using the same MRI system and imaging protocols. In addition, a section thickness of 5 mm was used in the MRI protocols for some patients, and this is greater than that of ≤3 mm used in the standard protocol. These limitations of the MRI assessments might have resulted in low sensitivity for monitoring disease activity based on MRI findings and consequently contributed to the high rate of NEDA3 at 2 years that was observed in our study.

NEDA3 has become an important treatment goal and outcome measure in clinical trials,17 but its utility as a predictor of long-term disease progression remains unclear. In the present study, EDA3 over 2 years had a negative impact on the risk of disability progression during a median of 7 years of treatment. However, the PPV of EDA3 over 2 years was only 38%, and the presence of EDA3 over 2 years did not necessarily predict future disability progression at the individual level. This finding is in agreement with recent studies in Western countries finding that EDA3 over 1–2 years had good or moderate sensitivity but relatively low specificity for the prediction of long-term disability progression.16,18 Regarding the low specificity of EDA3, Río et al.19 recently reported that minimal disease activity [i.e., one relapse without an impact on disability, or the presence of minimal isolated radiological activity (one or two new T2-weighted lesions, or a single gadolinium-enhanced lesion)] did not confer a significant risk of the EDSS score worsening over a mean of 6.7 years of follow-up. Furthermore, the disease activity before the drug becomes effective should not be considered as EDA3 on treatment.20 Finally, even if there is significant disease activity at the beginning of treatment, switching to more efficacious therapies within an appropriate timeframe can prevent the further deterioration of disability.21

In our cohort, 34% of the patients were classified as poor responders (switching drugs due to lack of efficacy or disability progression) to first-line treatment. This poor response to first-line treatment was independently associated with delayed initiation of DMTs (per year longer) (OR=1.238, p=0.049), which is consistent with current treatment guidelines to start DMTs early in order to obtain more-favorable outcomes. The presence of at least 10 high-intensity T2-weighted brain lesions in the initial MRI (OR=3.348, p=0.047) also increased the risk of a poor response to first-line treatment. A large observational study in Spain found that the presence of at least 10 high-intensity T2-weighted brain MRI lesions at baseline is the most-robust predictive factor for the conversion to MS and disability accumulation after controlling for all of the other variables examined.4 Therefore, the presence of a large number of brain lesions at baseline may indicate high disease activity, and so these patients may require a high level of vigilance for the drug response during treatment and should be considered for early escalation if required.

The limitations of this study include its retrospective design and small sample. The small proportion of patients with SPMS or with an EDSS score of ≥6 in our cohort may have been due to selection bias. Since we included patients who had been treated for at least 2 years, patients who already had SPMS during the initiation of DMTs and did not maintain the drug for more than 2 years were likely to have been excluded from this study. Meanwhile, because the four included centers are referral centers in Korea, unintentional selection bias may have caused a greater inclusion of patients with on-going disease activity despite first-line treatment. In addition, because the use of second-line treatment with reimbursement has only been available in Korea since 2015, the duration of treatment of the higher-potency drugs may be insufficient for evaluating efficacy and safety. Nevertheless, this study is the first to provide insight into the real-world long-term benefit of DMTs in Korean patients with MS, and the proportion of patients with NEDA3 at 2 years based on an annual MRI evaluation and its prognostic value for long-term disability.

In conclusion, the real-world benefits of DMTs observed in Korean patients seem to be similar to those found in previous observational studies and clinical trials in Western countries.3,22,23,24 Starting DMTs early could therefore lead to more-favorable outcomes. Additionally, patients with a large number of brain lesions at baseline may need to be monitored more carefully to track the effects of first-line treatments. Future studies should involve longer follow-ups, have larger samples, and examine newly developed second-line treatments in greater depth.