The objective of the current study was to assess baseline characteristics, treatment responses and safety for patients with MS aged above 40, sub-grouped as either 41–50 or > 50 years, to better define the MS disease course and treatment outcomes in patients from middle age onwards. The proportion of patients with RRMS or SPMS diagnoses at baseline was 96.3 and 3.7 % for those aged 41–50 years and 94.9 and 5.1 % for those aged > 50 years, respectively. Moreover, the mean age at onset of symptoms was 50.7 years in the > 50 years age group, suggesting the presence of late-onset MS in this group. Both the 41–50 and > 50 years age groups had active disease: ≥2 relapses during last 2 years: 55.6 and 52.7 %, respectively; EDSS ≥ 3, 41.6 and 52.0 %, respectively; percentage of contrast-enhancing lesions, 28.8 and 22.7 %, respectively. On average, during a patient’s fifth decade they transition from RRMS to progressive disease , and this period is also associated with other changes such as an accelerated accumulation of physical disability, and a shift from active inflammatory lesions to ‘smoldering’ (chronically active or slowly expanding) plaques in the brain . The fact that older patients with MS tend to have an inflammatory milieu different from their younger counterparts has given rise to a logical view that older patients might not respond to immunomodulatory agents in the same manner as younger patients . Many factors other than inflammation may also influence outcomes for older patients with MS, including increased number of comorbid conditions and polypharmacy in older patients, as well as age-related immunological changes [11, 27, 28]. Furthermore, when deciding to start or continue to treat patients with DMTs, the risks as well as the benefits of any therapeutic intervention must be considered, and these choices have become increasingly complex given the lack of information and complex pathophysiological changes associated with older patients with MS. However, in the present study, it was notable that the proportion of patients taking multiple additional medications (≥4 medications in addition to IFNB-1b) was similar in the two age groups studied (32.3 and 41.2 % of patients aged 41–50 years and > 50 years, respectively), and not dissimilar to other studies. For example, Frahm et al. found that 30.3 % of outpatients with RRMS were taking at least 5 medications . Moreover, a recent systematic review found polypharmacy rates between 15 and 59 % for patients with MS, and that polypharmacy correlated with comorbidities, increased risk of hospitalisation, and also increased disability, cognitive deficits, higher relapse rate and lower quality of life . Cardiovascular comorbidities and diabetes have been found to increase MS disability . Higher prevalence of comorbidities in MS patients leading to worse neurological, social and economic outcomes as well as to more complex treatment decisions have been published . Compared with these figures, the frequency of cardiovascular risk factors and other prominent comorbidities was lower in the current study (see Table 4). One limitation of this study is that these data on comorbidities are derived indirectly from comedication records, and thus should be interpreted with caution. Undertreatment and therefore missed comorbidities may be possible in some patients.
The proportion of patients of Asian ethnicity was higher among the > 50 years population (16.2 %) compared with the 41–50 years age group (8.9 %). We can only speculate about potential reasons for this. Firstly, we would like to clarify that this was a global study that included sites in the Asia Pacific region such as China, Taiwan and South Korea. Higher percentages of Asians in the older age group may suggest a different prescription behaviour in patients above 50 years in Asia, or may be also related to a greater life expectancy in some countries included (e.g. in South Korea) than in the other regions. Finally, as the > 50 years age group is fairly small (n = 154), this makes the likelihood of an ethnically representative sample less likely than for the larger 41–50 years age group (n = 327).
Little is known about the response of older adults with MS to DMTs, despite trends towards the increased age of patients living with MS [9, 10, 12, 14], though the clinical phenotype and course of MS are known to be age dependent . Whilst there have been a few studies that have described the characteristics and/or prognoses for older patients with MS, typically concerned with late-onset MS (LOMS), there is a lack of studies concerning the response to DMTs in this age group . One observational study has been conducted in a small group of older patients with LOMS and RRMS (aged ≥ 50 years) treated with a DMT (n = 90), but this did not show any significant reductions in disability compared with historical controls . Thus, data on the safety and efficacy of DMTs in older patients with MS are missing, indicating the need for further studies in this age group .
Given the current lack of data concerning the effectiveness of DMT use in older patients, decisions on whether to continue or discontinue DMT regimens in this group have become difficult, particularly in those with a stable disease course, and to date no randomised controlled trials have addressed this question. However, a prospective observational study evaluated patients who were clinically stable and taking a DMT for at least 5 years, of whom 485 stopped and 854 continued treatment . Time to first relapse among between groups was similar (hazard ratio [HR] 1.07, 95 % confidence interval [CI] 0.84–1.37; p = 0.584), whilst there was a longer time to disability progression in patients who continued treatment than in those who discontinued (HR 1.47, 95 % CI 1.18–1.84; p = 0.001). This study informed subsequent guidelines from the European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) on whether to continue or discontinue DMTs, as these state “Consider continuing a DMD if a patient is stable (clinically and on MRI) and shows no safety or tolerability issues” . Nevertheless, randomised controlled trials are needed to investigate the effect of discontinuing DMTs in older stable patients, and several are ongoing but have not yet reported results, such as the DISCO-MS trial (NCT03073603) and the STOP-I-SEP study (NCT03653273).
Within the context of the data regarding ongoing treatment with DMTs in older patients, the results of the present study indicate that IFNB-1b appears to be effective and well tolerated in MS patients aged 41–50 or those older than 50 years. For example, the observed decrease in relapse rates for both age sub-groups during the study compared favourably with the number of relapses in the 2 prior years, and was also similar in the two age groups. For example, the ARR (SD) during the 2 years before study start was 0.93 (0.48) and 0.86 (0.54) for the 41–50 and > 50 years groups, respectively, and during the study period the ARR was 0.20 (1.09) and 0.07 (0.37), respectively. Reducing risk of relapse is particularly important in older patients as the ability to recover from relapse seems to decline with age . Disease progression was stable in the two age groups over the course of the study. For example, the proportion of patients who were relapse free and disease-progression free throughout the study was 75.7 and 71.1 % for the 41–50 and > 50 years groups, respectively. Furthermore, neuropsychological measures of anxiety and depression showed overall stability in both age groups over the 2-year study. At last visit, mean (SD) HADS anxiety scores were 8.0 (4.5) and 7.5 (4.2) in the 41–50 and > 50 years age groups, respectively, and likewise HADS depression scores were 6.4 (4.0) and 7.0 (4.1), respectively. No unexpected adverse events were reported in this study for either age sub-group.
Given the outcomes for MS patients aged 41–50 or those older than 50 years in this real-world evidence current study, it seems that these patients benefitted from ongoing use of IFNB-1b during this 2-year observational period, with no evidence of particular increases in safety risks with greater age. These findings from a real-world setting are promising and demonstrate the positive benefit–risk ratio for IFNB-1b in this study population of middle-aged and older MS patients. However, randomised controlled trials are needed to better inform treatment decisions in this understudied age group.