Multiple sclerosis (MS) is an immune-mediated neurodegenerative disorder of the central nervous system with a lifetime risk of 1 in 400 in Caucasians in industrialized society [1]. The disease course is highly heterogeneous and includes a subgroup of patients with benign MS (BMS) who demonstrate little disease progression and minimal disability, even decades after clinical onset [2–5]. However, there is no universally agreed upon definition of BMS, as multiple patient profiles are associated with this disease course [2].

In 1996, an international survey conducted by the National Multiple Sclerosis Society (NMSS) defined BMS as a disease in which patients remain fully functional across neurologic systems 15 years after disease onset [6, 7]. Unfortunately, the term “fully functional” was not clearly defined, resulting in considerable variations in the estimated frequency of BMS [8–10].

Benign MS is a retrospective diagnosis that can only be made 10 years or more after disease onset. Despite consensus recommendations for immediate treatment following diagnosis, there is still a difference of opinion among physicians regarding this issue because of the paucity of efficacy data with disease modifying therapies (DMTs) in patients with BMS [11–15].

The New York State MS Consortium (NYSMSC) has assembled a centralized registry of demographic and clinical information from more than 7000 patients with clinically definite MS from across New York State (NYS), providing a robust dataset to study the frequency and characteristics of BMS. [16, 17] This study aimed to (a) retrospectively estimate the prevalence of BMS based on the NYSMSC registry using the 3 most commonly used BMS criteria [2, 3, 18]; (b) evaluate prognostic factors associated with BMS; (c) investigate the course of BMS prospectively over time [2, 8, 19]; and (d) explore whether DMT use correlated with maintaining a benign status in patients classified as having BMS at time of study enrollment.

Although various definitions for the classification have been proposed, BMS is generally characterized by the lack of disease progression and minimal disability 10 years or more after disease onset [2, 19, 22]. The considerable variation in the estimated frequency of BMS has the potential to influence treatment decisions because, historically, some clinicians were reluctant to prescribe DMTs for patients with little evidence of physical disability [10]. Our own data supports this observation. At time of enrollment into the study cohort, only 40.8 % of benign MS patients were on DMTs, whereas 81.8 % of non-BMS patients (more than twice the rate of BMS patients, p < 0.0001) were on DMTs (Table 2). Current recommendations propose DMTs for patients with MS from date of diagnosis without waiting to determine whether they meet the criteria for benign disease [11, 13, 23].

This large study, which included 6258 patients enrolled in the NYSMSC registry, evaluated the frequency and characteristics of BMS in a prevalence cohort including patients from 18 centers across NYS accrued over a 6-year time period. Patients receiving investigational DMTs were included in the study to maintain the completeness of the dataset. The large sample size of this prevalence cohort allowed us to identify the prevalence of BMS and compare demographic and clinical characteristics of BMS according to the 3 most commonly used classification criteria [2, 3, 18], as well as to identify prognostic factors associated with the disease course of BMS. Based on the classification criteria used, the overall percentage of patients with BMS at enrollment was 19.8 % to 33.3 % at baseline, which is in accordance with previous studies [2, 10].

Our data suggest that patients with SPMS, PRMS, and PPMS disease course are less likely to remain benign over time than those with RRMS disease course, which is consistent with results previously reported in the literature [10, 18, 24]. Both baseline and follow-up data support the recommendations of others that the term “benign” MS should be reserved for patients with RRMS disease course [2, 3, 7, 8, 18, 22]. In cross-sectional baseline analyses, several demographic, clinical, and treatment factors increased the likelihood of being classified as benign. However, in exploratory Cox model analyses of benign patients over time, use of DMT and longer DD were the only significant prognostic factors for continued BMS. The data surrounding the use of DMTs suggest that there are benefits of early preventive treatment even in the absence of signs of physical disability. However, while follow-up analyses were limited to patients with baseline EDSS ≤2.0 after 10 or more years of disease duration, correlation between EDSS score and DMT use was not directly studied herein. Nevertheless, these novel findings support the consensus statements issued by the NMSS in 2008 and the Consortium of Multiple sclerosis Centers (CMSC) in 2014 regarding early initiation of DMTs upon definitive MS diagnosis for patients and continuing treatment in those who are appropriate candidates for these agents [11, 12]. Use of DMTs early in the MS disease course has been supported by pharmacoeconomics studies that indicate early vs. delayed treatment with IFN-β, in particular, may be more cost-effective in the long term, as reduction of relapses, hospitalizations, and indirect costs, and gains in quality of life, and appear to outweigh the costs of DMTs [14, 15, 25].

Our findings should be considered also in context of the study limitations. The diagnosis of MS at baseline and at follow-up was not based on McDonald but on Poser criteria [21, 26, 27]. Length of follow-up included in the follow-up analyses, was not the same for each patient but varied from 1 to 8 years. With the exception of 2 patients who were exposed to DMTs in clinical trials during the follow-up period, study patients were primarily treated with first-generation DMTs. Furthermore, this was a historical study, and available data did not allow us to examine every potential prognostic factor for BMS, including MRI. For example, because data on specific symptom at onset were not available for the cohort studied (i.e. optic neuritis, sensory symptoms, and longer time intervals from onset to the second attack), some factors previously shown to be prognostic of BMS were not examined herein [10, 18, 24]. Another limitation is the missing data on cognitive status, as EDSS used within this period did not include the cognitive functional score. Similarly, additional factors may be prognostic for patient loss to follow-up, and we may not have identified all possible causes of missing follow-up data. Also, while this was an exploratory study and we evaluated factors that predicted loss to follow-up, it is still possible that bias may have been introduced due to loss to follow-up. Our finding that less than 1 % of progressive patients in the study cohort met criteria for BMS at baseline supports the notion that that progressive patients should not be classified as benign, regardless of whether they meet EDSS and DD criteria for benign classification.

Nevertheless, this study has several strengths, including the large, NYS-based, centralized dataset of patients with MS that includes almost 400 African-American patients, some of whom had BMS; a comparison of the prevalence of BMS according to 3 different definitions of benign status; and the availability of treatment data that allowed us to explore the potential effect of DMT on likelihood of continued benign status.

The results in the African-American subset of patients in our cohort are consistent with previous findings from our group and others that African-American patients with MS are likely to experience more rapid progression of disease than Caucasians [20, 28, 29]. However, while they were less likely to be classified as benign at baseline, African-American patients with BMS were just as likely to remain benign over time as Caucasians after controlling for other significant predictors of maintaining benign status. It is unlikely that this finding is the result of differential loss to follow-up or differing follow-up times because African-American race was not associated with loss to follow-up, and median follow-up years for African-Americans with BMS was not significantly different from that of other BMS patients (4.5 vs 4.0 years).

On the basis of our historical cohort study findings and those from various studies reported in the literature, we support the recommendation of Pittock and others to narrow the definition of BMS to an EDSS ≤2 after a minimum of 10 years’ DD, at least until more reliable predictors of BMS (i.e. genetic, biologic, or imaging biomarkers) have been fully developed and validated [2, 8, 22]. Many patients retrospectively classified as having BMS may ultimately transition to a non-BMS, progressive form of MS, even using these more conservative criteria [4, 5, 16, 19, 30].

Taken in context with previously reported benefits of the early initiation of DMT for patients diagnosed with MS [4, 9, 16, 25], our findings suggest that early initiation and continued treatment with DMT may increase the likelihood of maintaining BMS classification over the course of patients’ lives, thereby ameliorating disability progression, and are worth further consideration and evaluation.

BMS, Benign MS; CDMS, Clinically definite multiple sclerosis; CMSC, Consortium of Multiple sclerosis Centers; DD, Disease duration; DMTs, Disease modifying therapies; EDSS, Expanded Disability Status Scale; FDA, Food and Drug Administration; HRs, Hazard ratios; IFN-β, Interferon beta-1; IRBs, Institutional Review Boards; LR, Logistic regression; MS, Multiple sclerosis; NMSS, National Multiple Sclerosis Society; NYS, New York State; NYSMSC, New York State MS Consortium; PPMS, Primary-progressive multiple sclerosis; PRMS, Progressive-relapsing multiple sclerosis; RRMS, Relapsing-remitting multiple sclerosis; SPMS, Secondary-progressive multiple sclerosis; SPSS, Statistical Package for Social Sciences; UDSMR, Centralized data management center