Background

Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects the white matter of the central nervous system. MS is known to be classified into Relapsing-Remitting MS (RRMS) and Primary Progressive MS (PRMS). RRMS is defined as a type of MS in which patients experience relapse and remission over time whereas PRMS is defined as a type of MS in which patients experience gradual and chronic progression of their symptoms from the onset of the disease, which often results in severe disability in patients [1]. In Japan, compared to Western countries, the prevalence of MS is significantly lower, and the current estimated prevalence is 10/100,000 [2, 3]. The advent of disease-modifying drugs (DMDs) has made it possible to prevent relapse and suppress the progression of physical disabilities [4]. The DMDs that have been approved in Japan include subcutaneous interferon beta-1b (IFNβ-1b; approved in 2000), intramuscular interferon beta-1a (IFNβ-1a; 2006), fingolimod (FTY; 2011), natalizumab (NTZ; 2014), glatiramer acetate (GA; 2015), and dimethyl fumarate (DMF; 2016). For diagnosis of MS, the globally accepted diagnostic criteria proposed by McDonald has been widely used [5]. This criteria set, featured by the use of MRI findings for demonstrating the temporal and spacial multiplicity of inflammatory demyelinating lesions in the central nervous system, was first reported in 2001 and subsequently revised, mainly in MRI criteria, in 2005 and 2010 [5,6,7,8,9]. In Japan, an original criteria set is available for diagnosing MS as a designated intractable disease, which includes MRI criteria developed based on the 2010 revised McDonald criteria [10]. Healthcare system of Japan exempts a major financial burden of patients treated with DMDs if they satisfy both diagnostic criteria for MS as a designated intractable disease and other certain conditions. This requires precise understanding of MS diagnostic criteria and diagnosing of MS in accordance with these in physicians treating MS, suggesting a wide acknowledgement of the McDonald criteria. In terms of the selection of DMDs, since few head-to-head clinical trials assessing a prognosis as an endpoint have been conducted, the Treatment Guidelines for Multiple Sclerosis 2010 [9], as well as treatment response, safety, disease severity, and history of DMD use are used as the basis for drug selection.

In this study, we conducted a questionnaire survey involving neurologists across Japan to investigate the current practices of diagnosing and determining the treatment strategy for MS in Japan.

Methods

This was a cross-sectional survey, conducted through the Internet from April 11 to 18, 2016 by M3 Inc. (Tokyo, Japan). M3 Inc. (Tokyo, Japan) conducted the survey using their healthcare professional panel. A total of 3743 registered neurologists were screened in a preliminary survey and 376 (10.0%) of them fully responded, and 269 (7.2%) neurologists who were treating MS patients with DMDs at the time of survey were included in the questionnaire survey. The questionnaire used was basically the Japanese-translated version of the one used in previous studies conducted in the U.S. [11, 12], and it consisted mostly of the same questions as the English version. After responses were collected, de-identified data were provided by M3, Inc. for the analysis, so that no individual responses were known to us or anyone else involved in data analysis or manuscript development.

Consent to the use and publication of survey results was obtained from all respondents along with the completed questionnaires.

Data analysis

Respondents with valid responses to the questionnaire were included in the analysis. The survey results were summarized descriptively, and a response concordance rate of ≥75% was considered to indicate consensus [11, 12]. Respondents were stratified by tertiles of the number of MS patients under care at the time of survey as a measure of recent experience with MS treatment. This measurement was employed because the treatment paradigm of MS in a clinical setting could have been shifted during 2 years before the survey due to the launch of 2 DMDs in Japan; therefore, the current number of MS patients under care could capture an up-to-date MS treatment experience of the respondents. Respondents were classified into groups 1 (1–3 patients); n = 69, 2 (4–9); n = 58 and 3 (≥10); n = 78, and treatment experience with MS was assessed in relation to survey results. Intergroup comparison was performed using the one-way analysis of variance (ANOVA) for continuous variables and the chi-square test for categorical variables. For the intergroup comparison of trend with increasing treatment experience, the Cochran-Armitage test was used for binary variables and the Cochrane-Mantel-Haenszel test for other variables [13]. All tests were exploratory and not adjusted for differences in demographic factors between groups or multiplicity of analysis. All tests were performed at a two-sided significance level of 5% using SAS Release 9.3 (SAS Institute).

Results

Demographics of respondents

Valid responses were obtained from 205 of the 269 neurologists to whom the questionnaire was sent, yielding a response rate of 76.2%. The demographics of the 205 respondents are summarized in Table 1. The mean number of MS patients under care was 8.78, with 70.3% of the respondents having more than 10 years of experience with MS treatment. The most common affiliation was hospitals in general (38.5%), although there was a significant difference in the distribution of affiliations among 3 groups, with hospitals in general being the most common in group 1 (40.6%) and group 2 (46.6%) while university hospitals being the most common in group 3 (42.3%) (p = 0.019). The percentages of respondents who have prescribed NTZ or GA, DMDs launched in 2014 or after, were low at 15.6 and 17.6%, respectively, whereas those of respondents who have prescribed subcutaneous IFNβ-1b, intramuscular IFNβ-1a and FTY were high at 97.1, 87.8 and 83.4%, respectively. The percentages of respondents who have prescribed FTY and NTZ were the highest in group 3 (94.9 and 26.9%, respectively), with significant differences among 3 groups (FTY: p < 0.001, NTZ: p = 0.009).

Table 1 Respondent characteristics
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Diagnosis of relapsing remitting MS (RRMS) based on McDonald criteria

To determine the acknowledgement of the 2010 revised McDonald diagnostic criteria, we used a question “Can dissemination in time and space be determined for the purpose of diagnosing relapsing remitting MS (RRMS) in the presence of 1 clinical attack with a single MRI scan?” (Table 2). To this question, 86.3% of the respondents answered “yes”, indicating that the 2010 revised McDonald diagnostic criteria are used as the consensus criteria. The percentage of respondents answering “yes” also significantly increased with increasing number of patients under care (trend test p = 0.014).

Table 2 Diagnosis of RRMS based on the McDonald criteria
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Determination of clinical relapse and use of MRI scan

The survey results on the determination of clinical relapse and use of MRI scan are summarized in Table 3. There was consensus in diagnosing clinical relapse based on “new/worsening symptoms lasting ≥24 hours in the absence of comorbidities, such as acute infection” and “worsening neurological exam” (98.0%). In contrast, “new/worsening symptoms lasting ≥24 hours” was not a consensus criterion for diagnosing clinical relapse if either “no neurological exam was performed” or “no change in neurological exam” applied (47.8 and 51.7%, respectively). We then asked the question “In a patient presenting with a clinical relapse based on your definition of a relapse, do you usually order an MRI scan?” To this question, all respondents answered “yes”. In addition, 63.4% of respondents answered yes to the question “Does the appearance of new asymptomatic MRI activity constitute the equivalent of a clinical relapse?”, although consensus was not achieved. No significant intergroup difference was observed in any of these questions.

Table 3 Criteria for a clinical relapse and application of MRI for judgement for a relapse
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Timing of starting DMD treatment and timing of MRI scan after start of DMD treatment

We presented case scenarios 1, 2 and 3 where untreated patients have different levels of disease activity (the lowest in case 1 and the highest in case 3) and investigated when physicians decide to start treatment in case scenarios 1 and 2 (Table 4). There was consensus in starting DMD treatment in both case scenarios (91.2 and 96.6%, respectively). Performing follow-up MRI scans within 6 months after the start of DMD treatment in cases 1 and 3 also reached consensus (85.6 and 88.3%, respectively).

Table 4 Timing for initiation of DMD treatment and follow-up MRI for the case scenarios
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Relationship between the number of clinical relapses or new MRI lesions after start of DMD treatment and switching of DMDs

The question “Assuming a patient is currently receiving treatment, what is the minimum number of clinical relapses over 6 months or 12 months that would prompt you to suggest a change in DMD?” was asked (Table 5). There was consensus in considering switching from one DMD to another after 1 to 2 clinical relapses either within 6 or 12 months after the start of treatment (96.5 and 77.1%, respectively). There was no significant difference among groups in all cases. In the next question, we assumed 2 case scenarios, where a patient has been receiving the same treatment for 2 years, and no changes in MRI were observed on scans after 1 year of treatment, but activity was observed on a routine MRI performed after 2 years of treatment (case 1), or no changes in MRI were observed on scans at 1 and 2 years, but activity was observed on a routine MRI performed after 3 years of treatment (case 2), and asked “what is the lowest number of new T2 or gadolinium-enhanced (Gd+) lesions that would prompt you to suggest a change in DMD?” (Table 5). In terms of the number of new T2 lesions, the most frequent answer was “2” or “3–4” in both cases (32.7 and 33.2% in case 1; 33.7 and 31.2% in case 2, respectively). In terms of the number of new Gd + lesions, the most frequent answer was “1” followed by “2” in both cases (47.3 and 34.6% in case 1; 46.3 and 30.7% in case 2, respectively). Thus, there was consensus in considering change of DMDs after 1–2 new Gd + lesions were detected. No significant difference was observed among groups.

Table 5 Change criteria of DMD by the number of relapses and lesions by case scenarios
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Selection of DMDs at start of treatment

The selection of DMDs at the start of treatment in cases 1 to 3 was asked as shown in Table 4 to investigate the relationship between disease activity and DMD selection (Fig. 1). In all cases, most of the respondents answered to choose IFNβ products or FTY (IFNβ: 70.0% in case 1, 64.7% in case 2 and 54.7% in case 3, FTY: 25.1, 27.3 and 37.1%). At the same time, increasing disease activity was associated with decreasing prescription of IFNβ and increasing prescription of FTY. This trend was especially evident in group 3. The percentage of respondents choosing IFNβ products decreased from 77.5% in case 1 to 61.8% in case 2 and then to 48.7% in case 3 while that for FTY increased from 19.7 to 31.6% and then to 48.7%. In groups 1 and 2, no substantial difference was observed in DMD selections according to disease activity. The percentages of respondents choosing FTY in case 3 were 30.4, 29.3 and 48.7% in groups 1, 2 and 3, respectively, being the highest in group 3. This indicates that respondents with greater treatment experience tend to take disease activity into consideration when choosing DMDs. As for DMDs launched in 2014 or after, the percentage of respondents choosing GA decreased with increasing disease activity from 2.7 to 2.0% and then to 1.0% while that for NTZ increased from 1.6 to 3.0% and then to 5.4% in cases negative for anti-JCV antibody.

Fig. 1
figure 1

Choice of initial treatment in patients with RRMS by case scenarios. Note: Responses of only those who reported that they would initiate DMD for each case were calculated. Case scenarios are shown in Table 5. Group 1: 1–3 MS patients under care, Group 2: 4–9 MS patients under care, Group 3: ≥10 MS patients under care. RRMS: relapsing-remitting multiple sclerosis, MS: multiple sclerosis, DMD: disease-modifying drug, SC IFNβ-1b: subcutaneous interferon beta-1b, IM IFNβ-1a: intramuscular interferon beta-1, JCV: John Cunningham virus

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Switching of DMDs

A question on switching of DMDs in cases of suboptimal response to current DMDs was asked. Respondents were allowed to select DMDs they have not used or those that have not been adopted at the affiliating institution. The results are summarized in Table 6. Non-FTY DMDs were most frequently switched to FTY, while FTY was most frequently switched to NTZ regardless of anti-JCV antibody status. The percentage of respondents switching from other DMDs to NTZ was higher in cases negative for anti-JCV antibody compared to when the anti-JCV antibody status was not taken into account (3.9% vs. 7.8, 6.3% vs. 10.2, 52.2% vs. 56.6, and 21.0% vs. 25.4%, respectively).

Table 6 DMD choice following suboptimal response to original treatment by anti-JCV antibody status (n = 205)
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Discussion

The results of the present survey study partially revealed the current practices of diagnosing and determining the treatment strategy for MS in Japan. In this section, we discuss the following four aspects:

Acknowledgements of the 2010 revised McDonald diagnostic criteria

There is consensus that RRMS can be diagnosed based on the 2010 revised McDonald criteria [7] and the percentage in favor of this notion significantly increased with increasing number of patients under care. A high accordance with the criteria was expected prior to this study because our original criteria for diagnosing MS as a designated intractable disease had been constructed based on the 2010 revised McDonald criteria [7]. Patients who are diagnosed with MS based on the original criteria and satisfy certain conditions are eligible for an application to publicly subsidized medical care. This high accordance with the 2010 revised McDonald diagnostic criteria could have been boosted by the health care system in Japan.

Determination of relapse and use of MRI scan

In the presence of new/worsening symptoms lasting ≥24 h, only about 50% of respondents diagnosed clinical relapse if no neurological examination was performed or no worsening in neurological examination was noted, whereas 98% of respondents diagnosed relapse if worsening of neurological examination was noted, suggesting that worsening of neurological examination is a key criterion for diagnosing clinical relapse. Furthermore, 63% of respondents acknowledges that the appearance of new asymptomatic MRI activity represents clinical relapse. The fact that even with clinical evidence of relapse, all respondents performed MRI scan as a key criterion for diagnosing relapse suggests that MRI scan is considered an important modality for determining relapse, regardless of treatment experience.

Timing of starting DMD treatment in untreated patients and selection of DMDs

In the questions about the timing of starting DMD treatment, more than 90% of respondents in all groups answered that they would start treatment in case scenarios 1 and 2, indicating consensus about the need for early treatment, regardless of treatment experience (Table 5). For treatment of untreated patients, most of the respondents chose IFNβ products or FTY, although increasing disease activity was associated with decreasing prescription of IFNβ products and increasing prescription of FTY. This trend was especially evident in group 3, while in groups 1 and 2, the same DMDs tended to be selected independent of disease activity, suggesting that physicians with greater treatment experience tend to choose DMDs according to disease activity. A previous study conducted in the U.S. in 2011 showed that increasing disease activity was associated with increased variability of prescribed DMDs; in particular, the prescription rate of NTZ, a relatively potent DMD, increased substantially (case 2: 32%, case 3: 39%) while that of FTY increased minimally (case 2: 1%, case 3: 4%) [11]. In follow-up study conducted in 2014, if the anti-JCV antibody was negative, 89% of respondents answered that NTZ was selected for Case 3 (36.6% in the case of anti-JCV antibody positive) [12]. The reasons of this discrepancy between Japan and the U.S. were considered as follows; differential demographics of respondents, where U.S. respondents were board-certified specialists in MS treatment who were treating up to 900 MS patients on average, compared with an approximate average of 9 patients treated by the respondents of our survey, the wide acceptance to use drugs with higher efficacy for patients with short MS history among MS specialists in the U.S. [11, 12], earlier launch of NTZ than FTY in the U.S., and higher prevalence of anti-JCV antibody in the Japanese population compared to the Western population [14,15,16,17,18,19].

Switch of DMDs

There was consensus that 1–2 clinical relapses over 6 months of treatment with a DMD would lead to switching from one DMD to another (96.6%). However, no consensus was achieved regarding the minimum number of clinical relapses over 1 year that would lead to treatment switch, suggesting a lack of sufficient information to determine the timing of treatment switch. The strategy for switching treatment due to suboptimal response to the current treatment was not affected by the anti-JCV antibody status, with the most common pattern being from a non-FTY DMD to FTY and from FTY to NTZ. A U.S. study conducted in 2014 showed with switching to oral drugs being the most common either from injectables (GA, IFNβ; 83.8%), oral drugs (DMF, FTY, teriflunomide; 75.5%) or IV infusion (NTZ; 89.9%) in cases positive for anti-JCV antibody [12]. In contrast, in cases negative for anti-JCV antibody, the most common patterns were switching to NTZ from injectables (46.0%) or oral drugs (69.2%) and switching to oral drugs from NTZ (83.2%) [12]. From these results of Japan and the U.S. study, it is considered that Japanese neurologists and U.S. specialists were practically choosing DMDs according to disease activity taking into account the risk of progressive multifocal leukoencephalopathy at the time of switching in the case of anti-JCV antibody positive. However, in the case of anti-JCV antibody negative, it became clear that in the United States, drugs that strongly suppress disease activity are preferred to prescribe.

Limitations of the study

There is a sampling bias in this study. First, the number of neurologists in Japan in 2016 when the present survey conducted was 4657 [20], but the present survey was conducted using a panel of 3743 neurologists. Second, only 376 neurologists from the panel responded. Third, responders might be in a biased population consisting mainly of those interested in collecting medical information from the Internet. Lastly, the population may also be biased in that the number of MS patients under care by the respondents ranged from 1 to 50 and there was no specialist treating a larger number of patients. In Japan, however, MS specialists providing more than 50 patients with treatment is extremely limited, unlike in North America, because of the significantly lower prevalence of MS in Japan [2, 3]. Members (n = 36) of the Japanese Society for Neuroimmunology could be regarded as MS specialists in Japan, because the society is focusing on MS and several intractable neurologic diseases. Therefore, we think most of the responders were typical MS neurologists in Japan in terms of the number of MS patients under care. The results should therefore be interpreted with caution, but at least, this study partially revealed the current diagnosis and therapeutic decision-making patterns for multiple sclerosis treatment in Japan and should provide some insights considering the scarcity of reports so far.

Conclusion

This survey study is meaningful in that it collected opinions from 205 neurologists engaged in MS treatment throughout Japan. This study revealed that Japanese neurologists consider both the 2010 revised McDonald diagnostic criteria and MRI scan indispensable for MS diagnosis and determination of relapse, regardless of treatment experience. Conversely, physicians with greater treatment experience tend to choose DMDs according to disease activity. Because the population includes neurologists with various levels of experience, the results are likely to reflect the current clinical practice for MS patients in Japan.

This study will contribute to improved clinical practice for MS patients in Japan by revealing some aspects of the current practice.