Long-term follow-up of patients with multiple sclerosis over age 60: Comparing clinical and radiological outcomes in disease-modifying therapy continuers and discontinuers

Abstract

Background

Relapse prevention in multiple sclerosis (MS) is accomplished with disease-modifying therapy (DMT). Relapse rates typically decrease with age while DMT-associated risks increase, complicating treatment of older persons with MS (PwMS).

Objectives

This follow-up study aims to guide treatment decisions by evaluating clinical and patient-reported outcomes among older PwMS who discontinue DMT.

Methods

This study included PwMS aged ≥60 evaluated at the Cleveland Clinic from 2010 to 2016, categorized as DMT continuers or discontinuers. Follow-up timeframe was February 2018–April 2024. Outcomes included relapses, magnetic resonance imaging (MRI) activity, and Neuro-QoL and MS Performance Test scores. Mixed-effects regression and survival models were used.

Results

In total, 600 PwMS were included. Median follow-up time was 10.5 years (interquartile range 7.7–13.4), 66.0% discontinued DMT, and 3.3% had ≥1 relapse. Relapse risk did not differ significantly between groups (hazard ratio for discontinuers vs. continuers, 1.80, 95% confidence interval 0.51–6.39, p = 0.365). T2 lesions developed in 37.5% of continuers and 36.6% of discontinuers. Gadolinium-enhancing lesions developed in 10.1% and 7.9%, respectively. Neuro-QoL Fatigue T-scores slightly worsened for discontinuers over time.

Conclusion

Findings demonstrate low relapse risk among PwMS over age 60, however, MRI changes were common. DMT discontinuation may be considered in this population, though further studies are needed to better understand radiological disease activity.

Keywords

Multiple sclerosis multiple sclerosis relapsing-remitting chronic progressive immunomodulation aged disease progression follow-up studies

Introduction

Multiple sclerosis (MS) is an immune-mediated disorder commonly characterized by relapses resulting from inflammation in the central nervous system. The mainstay of relapse prevention is disease-modifying therapy (DMT). DMTs have been shown to reduce annualized relapse rates (ARRs) and magnetic resonance imaging (MRI) activity.¹ Relapse frequency generally decreases with age and disease duration, which is the result of immunosenescence, or a decline in immune response with age.^2–4 Disability can still accumulate in the form of progression independent of relapse activity (PIRA). While some DMTs may modestly slow PIRA, their primary impact is on relapse-associated worsening.⁵

The utility of DMTs in older persons with MS (PwMS) without relapses remains unclear. This is complicated by DMT-associated risks, such as infection and cancer.⁶ Determining an optimal approach to treating these individuals is critical, as the average age of PwMS and age at diagnosis are increasing.^7–10 Several retrospective studies showed that discontinuation of DMTs in older patients with stable MS does not significantly increase risk of relapse.^11–20 The first multi-center prospective study that investigated this was DISCOMS.²¹ DISCOMS aimed to evaluate whether discontinuation of DMT was non-inferior to continuation in stable patients with MS over the age of 55. Non-inferiority was not demonstrated, but it remains unclear whether the outcome might differ with an older age cutoff.

To date, no additional large-scale prospective discontinuation studies focusing specifically on adults 55 or older have been published. Some studies included younger adults, such as the DOT-MS trial with a median age of 54.0 (interquartile range (IQR) = 49.0–59.0). DOT-MS was terminated early due to new disease activity among some participants (median follow-up time of 15.3 months).²²

In a previous paper, we described a cohort of PwMS over age 60, showing that most were able to discontinue DMT, with only one relapse occurring and 10.7% reinitiating over a median follow-up of 7.3 years after age 60.¹² Here, we present long-term follow-up of this cohort. To the best of our knowledge, this is the longest-term follow-up study investigating DMT discontinuation in patients over 60.

Materials and methods

Patients included in this study were over age 60 with an MS diagnosis made prior to age 60, who were seen at a Cleveland Clinic MS center (Cleveland, Ohio; Las Vegas, NV; Weston, Florida) between 2010 and 2016, and for whom Knowledge Program (KP) data were available. The KP was developed at the Cleveland Clinic to capture clinical information from the electronic health record and collect patient-reported outcomes at each visit. Additional details about the KP are included in the original publication.¹² The KP has since been replaced by the MS performance test (MSPT), which allows for the collection of objective data relating to neurological functioning.^23,24 MSPT components were administered during clinic visits by trained clinical staff using standardized protocols, and results were recorded in the electronic health record at the time of testing. For patients categorized as “discontinuers,” DMT must have been used for ≥ 2 years prior to discontinuing and discontinuation must have occurred after age 60. The study was approved by our Institutional Review Board as a minimal risk study using data collected from routine clinical practice.

Additional data were collected from retrospective chart review from February 2018 to April 2024. Updated values included disease duration, phenotype, relapse history, treatment duration, DMTs used, new T2 and gadolinium-enhancing (GdE) lesions on MRI, and brain volume loss (subjectively categorized as none, mild, moderate, or severe). From the MSPT, we obtained Contrast Sensitivity Test (CST), Processing Speed Test (PST), Manual Dexterity Test (MDT), and Walking Speed Test (WST). We also reviewed quality of life (Neuro-QoL) data.

Statistical analysis

Descriptive statistics summarized the cohort, stratified by discontinuation status. Mean with standard deviation (SD) or median with IQR was used for continuous variables and frequency with percentage was used for categorical variables. Comparisons were made using the two-sample t-test or Wilcoxon rank sum test for continuous variables and chi-square test for categorical variables.

To examine factors associated with discontinuation of DMT, we fit cause-specific Cox proportional hazard models where time from age 60 to DMT discontinuation was the outcome. Death was treated as a competing risk. Patients who died before discontinuing DMT were censored at their date of death. Surviving patients who did not discontinue DMT were censored at last follow-up. We examined the same patient and clinical factors as was previously done: sex, baseline MS phenotype (relapsing remitting vs. primary progressive) disease duration, DMT duration, most recent DMT used (glatiramer acetate (GA), interferons, IV therapies, oral, and unapproved therapies), and number of DMTs used. Interactions between phenotype and each of DMT duration and number of DMTs were also examined.

Among patients who discontinued DMT, we examined factors associated with time from DMT discontinuation to DMT reinitiation using cause-specific Cox proportional hazard modeling, with death treated as a competing risk. The predictors in this model included sex, MS phenotype at discontinuation, DMT duration, age at discontinuation, most recent DMT, provider vs. patient-initiated discontinuation, and independent ambulation status at discontinuation.

For clinical and patient-reported outcomes, we fit mixed-effects models. For continuous outcomes (Neuro-QoL, performance tests, and quantitative MRI variables), we fit mixed-effects linear regression models. For the number of new T2 lesions (1 + vs. 0) and the number of GdE lesions (1 + vs. 0), we used mixed-effects logistic regression. For T2 burden of disease and volume loss, we fit cumulative link mixed-effects models. In all models, the independent variables of interest, treated as fixed effects, were time from age 60 and a treatment group variable comparing DMT continuers and discontinuers consisting of three categories: Continuers, discontinuers before discontinuation (DBD), and discontinuers after discontinuation (DAD). The DBD and DAD groups consist of the same patients (those who discontinued DMT), but the level of the variable changes according to whether the outcome was collected before or after DMT discontinuation. To determine if outcome trajectories differ by treatment group over time, we included an interaction term between the time and treatment group variables. The following fixed-effect covariates were included in all models: age at MS diagnosis, sex, phenotype at diagnosis (primary progressive vs. relapsing remitting), proportion of time on DMT, baseline DMT, and ambulation status at age 60 (no assistance vs. cane/walker/wheelchair/bedbound). To account for the correlation among repeated measures within each patient, we included a subject-specific random intercept.

To examine relapse data, we used descriptive statistics (frequency and percentage) to summarize relapses overall and by DMT discontinuation status. A cause-specific Cox proportional hazards model was fit where time from age 60 until first relapse was the dependent variable, and death was again treated as a competing risk. The independent variable was DMT discontinuation, which was treated as a time-varying covariate. Due to the relatively low rate of relapse, we did not include any covariates in this model.

Analyses were conducted in R, version 4.3.1. All tests were two-sided and p-values <.05 were considered statistically significant. For the analyses of MSPT outcomes, Neuro-QoL outcomes, and MRI outcomes, we corrected for multiple testing using Holm's method.

Results

In this updated analysis, median follow-up time after age 60 was 10.5 years (IQR = 7.7–13.4), compared to 7.3 years in the original analysis (IQR = 4.5–10.0). For DMT discontinuers, the median time to discontinuation was 6.9 years (IQR = 4.3–9.7 years) and the median time from discontinuation to last follow-up was 4.3 years (IQR = 1.5–6.5 years). A total of 396/600 (66.0%) discontinued DMT, compared to 178/600 (29.7%) in the original analysis. In this update, 38/396 (9.6%) DMT discontinuers later reinitiated DMT, compared to 19/178 (10.7%) originally. Of note, 101/600 (16.8%) patients died during the study period, compared with 20/600 (3.3%) originally. The percentage of patients who were independently ambulatory did not significantly differ between groups at baseline or at last follow-up. See Table 1 for patient characteristics stratified by discontinuation status.

Table 1.

Patient characteristics by DMT discontinuation status.

Variable	Continuers	Discontinuers	All	P-value
N	204 (34.0%)	396 (66.0%)	600
Current age, mean (SD)	73.7 (3.5)	74.2 (3.6)	74.0 (3.6)	0.112
Age at diagnosis, mean (SD)	46.4 (9.1)	46.1 (8.1)	46.2 (8.4)	0.679
Male	68 (33.3%)	98 (24.7%)	166 (27.7%)	0.033
White	174 (85.3%)	354 (89.4%)	528 (88.0%)	0.376
Missing	3 (1.5%)	0 (0.0%)	3 (0.5%)
Married	150 (73.5%)	297 (75.0%)	447 (74.5%)	0.838
Missing	3 (1.5%)	4 (1.0%)	7 (1.2%)
Phenotype at diagnosis
Primary progressive	21 (10.3%)	40 (10.1%)	61 (10.2%)	1.000
Relapsing remitting	183 (89.7%)	356 (89.9%)	539 (89.8%)	1.000
Independently ambulatory at baseline	106 (52.0%)	195 (49.2%)	301 (50.2%)	0.384
Missing	44 (21.6%)	80 (20.2%)	124 (20.7%)
Independently ambulatory at last follow-up	77 (37.7%)	143 (36.1%)	220 (36.7%)	0.614
Missing	8 (3.9%)	7 (1.8%)	15 (2.5%)
Number of medications used, mean (SD)	2.2 (1.1)	2.2 (1.3)	2.2 (1.3)	0.961
Number of DMT starts, mean (SD)	2.4 (1.4)	2.4 (1.6)	2.4 (1.5)	0.815
Disease duration in years, median (IQR)	21.4 (15.3, 27.3)	19.6 (14.6, 26.3)	20.3 (14.7, 26.3)	0.064
DMT treatment duration in years, median (IQR)	18.7 (13.2, 22.0)	16.2 (12.2, 19.5)	16.9 (12.5, 20.5)	< 0.001
DMT proportion, median (IQR)^a	0.93 (0.74, 0.99)	0.92 (0.68, 0.99)	0.92 (0.70, 0.99)	0.383
Deaths	42 (20.6%)	59 (14.9%)	101 (16.8%)	0.099

DMT: disease-modifying therapy; SD: standard deviation; IQR: interquartile range.

DMT proportion is calculated as the total DMT treatment duration divided by the disease duration.

Table 2 shows most recent DMT and overall DMT use. Interferons and GA were the most widely used DMTs among continuers and discontinuers (77.8% of the cohort used interferons and 42.2% used GA). The proportion of continuers vs. discontinuers that used each DMT did not differ significantly, with the exception of B-cell therapies as most recent DMT (9.3% vs. 4.0%, p = 0.015).

Table 2.

Most recent and historical disease-modifying therapy (DMT) use by discontinuation status.

DMT	Most recent DMT			Overall DMT use
	Continuers	Discontinuers	P-value	Continuers	Discontinuers	P-value
	(N = 204)	(N = 396)	P-value	(N = 204)	(N = 396)	P-value
Interferons	76 (37.3%)	170 (42.9%)	0.190	156 (76.5%)	311 (78.5%)	0.604
Glatiramer acetate	41 (20.1%)	79 (19.9%)	1.000	85 (41.7%)	168 (42.4%)	0.930
Natalizumab^a	7 (3.4%)	13 (3.3%)	1.000	27 (13.2%)	38 (9.6%)	0.212
Mitoxantrone^a	1 (0.5%)	4 (1.0%)	0.666	8 (3.9%)	25 (6.3%)	0.260
Teriflunomide^b	5 (2.5%)	7 (1.8%)	0.553	7 (3.4%)	10 (2.5%)	0.605
Fumarates^b	20 (9.8%)	54 (13.6%)	0.192	40 (19.6%)	76 (19.2%)	0.913
S1PR modulators^b	15 (7.4%)	18 (4.5%)	0.185	28 (13.7%)	34 (8.6%)	0.065
B cell therapies/rituximab^b	19 (9.3%)	16 (4.0%)	0.015	19 (9.3%)	20 (5.1%)	0.054
IVIG^b	0 (0.0%)	1 (0.3%)	1.000	0 (0.0%)	2 (0.5%)	0.550
Unapproved therapies^b,c	20 (9.8%)	34 (8.6%)	0.652	42 (20.6%)	72 (18.2%)	0.510

All figures presented as frequency (percentage)

Grouped as intravenous therapies in multivariate analyses.

Grouped as oral or unapproved therapies in multivariate analyses.

Azathioprine, methotrexate, mycophenolate acid, cyclophosphamide, or investigational products.

DMT discontinuation

Median age at discontinuation was 66.9 (IQR = 64.3–69.7). Figure 1(A) shows the cumulative incidence of DMT discontinuation or death. The probability of DMT discontinuation at age 62, 65, 70, and 80 was 7.0%, 21.0%, 56.2%, and 86.3%, respectively. Table 3 shows the results of the multivariable cause-specific Cox proportional hazards model for time to DMT discontinuation. As in the original analysis, GA use was associated with greater likelihood of discontinuation (hazard ratio (HR) = 1.31, 95% confidence interval (CI) = 1.03–1.67, p = 0.029). Unlike the original analysis, a larger proportion of time on DMT was associated with greater likelihood of discontinuation (per 10% increase HR = 1.07, 95% CI = 1.02–1.12, p = 0.005), and longer MS duration was associated with greater likelihood of discontinuation (per 10-year HR = 1.29, 95% CI = 1.11–1.52, p = 0.001). The interactions between phenotype and number of DMTs used and proportion of time on DMT were not significant. Regarding phenotype at time of discontinuation, 204/396 (51.5%) were relapsing-remitting, 128 (32.3%) secondary progressive, 27 (6.8%) primary progressive, and 20 (5.1%) progressive-relapsing. Phenotype data were missing for 17 (4.3%).

Figure 1.

(A) Cumulative incidence for time to discontinuation and the competing risk of death. (B) Cumulative incidence for time to reinitiation and the competing risk of death.

Table 3.

Results of multivariable cause-specific cox proportional hazards model for time from age 60 to disease-modifying therapy discontinuation (N = 600).

	Hazard ratio (95% CI)	P-value
Initial MS course primary progressive (vs. relapsing remitting)	0.83 (0.29, 2.42)	0.734
Male (vs. female)	0.89 (0.70, 1.13)	0.323
Proportion of disease duration on DMT at age 60 (per 10%)	1.07 (1.02, 1.12)	0.005
MS duration at age 60	1.29 (1.11, 1.52)	0.001
Number of DMT starts at age 60	1.11 (1.00, 1.24)	0.055
Most recent DMT at age 60 (vs. interferons)
Glatiramer acetate	1.31 (1.03, 1.67)	0.029
IV therapies	1.02 (0.69, 1.52)	0.910
Oral/unapproved therapies	0.96 (0.70, 1.31)	0.795
Initial MS course x Number DMT starts	0.87 (0.69, 1.09)	0.229
Initial MS course x Proportion time on DMT	1.07 (0.96, 1.20)	0.226

DMT: disease-modifying therapy; MS: multiple sclerosis; CI: confidence interval.

DMT reinitiation

Figure 1(B) shows cumulative incidence of DMT reinitiation or death. The probability of DMT reinitiation at 2, 5, and 10 years post-discontinuation was 5.6%, 11.4%, and 15.1%, respectively. Only one predictor was associated with reinitiation: age at DMT discontinuation. For each one-year increase in age at DMT discontinuation, the risk of DMT reinitiation decreased by 13% (HR = 0.87, 95% CI = 0.76–0.99, p = 0.039), which was not observed in the original analysis. In the original analysis, DMT reinitiation was more likely when discontinuation was patient-initiated, which was not observed in this analysis. Provider vs. patient-initiated discontinuation and reasons for reinitiation are shown in Tables 4 and 5, respectively.

Table 4.

Provider versus patient-initiated discontinuation among disease-modifying therapy (DMT) discontinuers.

DMT discontinuation (N = 396)
Provider vs. patient initiated	n (%)
Provider initiated	200 (50.5%)
Patient initiated	186 (47.0%)
Not specified	10 (2.5%)

Table 5.

Reasons for DMT reinitiation among DMT discontinuers.

DMT reinitiation (N = 38)
Reason	n (%)
Clinical worsening/progression	23/38 (60.5%)
New MRI activity	7/38 (18.4%)
Combination clinical and radiological worsening	3/28 (5.3%)
Patient preference with stable disease	4/38 (10.5%)
Provider preference with stable disease	3/38 (7.9%)

DMT: disease-modifying therapy; MRI: magnetic resonance imaging.

Relapse data

As presented in Table 6, 20/600 (3.3%) patients had ≥ 1 clinical relapse recorded after age 60, with 18 having 1 relapse, 1 having 2 relapses, and 1 having 3 relapses. Among the 20 that relapsed, 15 had relapses on therapy, and 5 had relapses post-discontinuation. There were 10 patients with relapses on DMT after age 60 who went on to discontinue DMT. Of these 10, only 1 had a relapse post-discontinuation (this individual had 2 relapses prior to discontinuation for a total of 3 relapses after age 60). The cause-specific Cox proportional hazard model where DMT discontinuation status was treated as a time-varying covariate revealed no significant difference between DMT discontinuers and DMT continuers with respect to relapse risk (HR discontinuers vs. continuers, 1.80, 95% CI = 0.51–6.39, p = 0.365).

Table 6.

Number of patients with ≥1 clinical relapse or new MRI lesion.

	DMT continuers n/N (%)	DMT discontinuers before discontinuation n/N (%)	DMT discontinuers after discontinuation n/N (%)
Clinical relapse	5/204 (2.5%)	10/396 (2.5%)	5/396 (1.3%)
New T2 Lesions	57/152 (37.5%)	73/286 (25.5%)	64/272 (23.5%)
New GdE Lesions	16/158 (10.1%)	18/287 (6.3%)	10/262 (3.8%)

Denominators represent the number of patients with available data for each outcome. Clinical relapse denominators reflect the full cohort in each treatment group. MRI outcome denominators reflect patients with MRI reports specifically documenting presence or absence of new T2 or GdE lesions. DMT: disease modifying therapy; MRI: magnetic resonance imaging; GdE: gadolinium-enhancing.

Neuroperformance tests

Of the 600 patients, 410 had ≥ 1 visit with MSPT data available. There were no significant differences in CST, PST, MDT, or WST scores between DMT continuers and discontinuers, and no significant differences in outcomes in DBD and DAD groups.

Quality of life

The only significant interaction with Neuro-QoL scores was observed in the Fatigue score. As time from age 60 increased, Fatigue T-scores increased (i.e., worsened) for DMT discontinuers (both before and after discontinuation), and T-scores decreased (i.e., improved) for DMT continuers, as represented in Figure 2.

Figure 2.

Time from age 60 (years) vs. predicted Neuro-QoL Fatigue T-score using mixed-effects linear regression model with interaction term.

MRI data

Brain MRI data were available for 158/204 DMT continuers (77.5%) and 342/396 DMT discontinuers (86.4%). Among DMT continuers, 37.5% developed new T2 lesions and 10.1% developed GdE lesions. In the discontinuation group, 25.5% developed new T2 lesions and 6.3% developed GdE lesions while on DMT. After stopping, 23.5% had new T2 lesions and 3.8% had GdE lesions during the follow-up period (see Table 6). Our covariate-adjusted mixed-effects models found no significant between-group differences in trend of new T2 or GdE lesions over time. Volume loss did not differ significantly between groups.

Discussion

Discontinuation of DMT among older PwMS remains controversial due to uncertainty surrounding the ideal age cutoff. The DISCOMS study did not demonstrate non-inferiority of DMT discontinuation with a cutoff of 55-years-old.²¹ In contrast, our study evaluated an age cutoff of 60 and demonstrated few significant differences between DMT continuers and discontinuers. Clinical relapse risk was low in both groups.

A total of 20/600 (3.3%) patients in our study experienced a clinical relapse. Among discontinuers, 5/396 (1.3%) experienced a relapse post-discontinuation. Similarly low percentages were seen in DISCOMS (0.8% of continuers and 2.3% of discontinuers), with no relapses occurring in the DISCOMS extension trial (mean total follow-up of 40 months).^21,25 There were 4664 patient years accounted for among discontinuers and 1857 among continuers in our study, resulting in an ARR of 0.0038 and 0.0027, respectively (18/4664, 5/1857). A total of 6521 patient years were accounted for, resulting in an ARR of 0.0035 (23/6521).

Rates of new MRI activity were similar between groups, though they were higher than expected. Among DMT continuers, for example, 37.5% developed new T2 lesions and 10.1% developed GdE lesions. In contrast, DISCOMS reported new T2 lesions in 3.9% of continuers and no new GdE lesions.²¹ DOT-MS reported 0 new T2 lesions and 1 GdE lesion in continuers.²² A longer follow-up duration in our study likely contributed to these differences. Annualized rates of new MRI activity would be informative, but this is limited by highly inconsistent MRI intervals. For instance, 857 MRIs were obtained among discontinuers prior to discontinuation (average 2.85 per patient) and 1675 were obtained after stopping (average 4.75 per patient). Closer surveillance post-discontinuation possibly resulted in increased detection of MRI changes.

Lesion type was not consistently reported by radiologists and it is often challenging to distinguish demyelinating versus ischemic lesions. The prevalence of cerebral small vessel disease (CSVD) is known to be about 5% among people who are 50 years old and nearly 100% among people aged 90.²⁶ With a mean age of 74 in our study population, it is likely that a large percentage of new T2 lesions represented CSVD. One promising biomarker for differentiating CSVD from demyelinating lesions is the central vein sign, which may be useful in future studies of older PwMS.²⁷

Given the relatively high numbers of patients with GdE lesions, the possibility of missed clinical relapses cannot be excluded. Relapses could be masked by disability, as 60.8% of participants were not independently ambulatory as of last follow-up (EDSS ≥6), with 29.7% relying on wheelchair use. Low efficacy treatment use may have contributed to new MRI activity and disability accumulation. Platform therapies (i.e., interferons and GA) were the most common DMTs associated with new T2 and GdE lesions among continuers and discontinuers (61.2% of cases). Higher efficacy treatments like B-cell therapies and anti-trafficking agents (i.e., natalizumab and fingolimod) were far less commonly associated with new disease activity (18.4% of cases), despite the known risk of rebound disease following discontinuation of anti-trafficking agents.²⁸ High rates of platform therapy use are seen in other studies of older PwMS, though most reveal much lower rates of radiological disease activity. In the case of prospective DMT discontinuation studies, this is possibly influenced by the fact that patients at increased risk of disease activity are likely not enrolled.^21,22 Additional studies with consistent follow-up are needed to better understand the causes and frequency of MRI changes among this population.

The factors associated with a greater likelihood of DMT discontinuation in this study were use of GA as most recent DMT, larger proportion of time on DMT, and longer MS disease duration. Though not entirely clear based on available data, these factors suggest that individuals with prolonged disease inactivity may have been more likely to discontinue DMT. Discontinuation may have also been influenced by the accumulation of disability and transition to progressive MS (32.3% of discontinuers were secondary progressive).

There were no significant differences in neuroperformance test scores between DMT groups. Similarly, Neuro-QoL T-scores did not differ significantly between groups except for Fatigue T-scores. Scores increased (i.e., worsened) over time in DBD and DAD groups, though the increase was by < 5 points and scores were close to average, which is not likely clinically significant. Fatigue scores decreased (i.e., improved) over time in continuers by > 10 points, which may be clinically meaningful. Whether this is the direct result of DMT use is questionable, however, as previous studies have demonstrated that DMT use has no significant impact on fatigue severity.^29,30

Our study had several limitations that deserve mention. As a single-center retrospective study from a tertiary MS center, the results may not be completely generalizable. As with most retrospective studies, there were missing data. Specifically, MSPT and MRI data were not available for all patients, which raises the possibility of selection bias. MSPT was not utilized at Cleveland Clinic MS Centers until 2015. As such, most of the initial values were obtained long after patients in this cohort turned 60 and after DMT discontinuation, limiting the ability to establish and compare baseline clinical test scores. Additionally, the majority of DMT discontinuers (76.4%) were on interferons, GA, or fumarates at the time of discontinuation, which does not align with contemporary practice of frequent use of highly effective treatments. Further research could aid in understanding the effects of discontinuing these therapies. For patients who discontinued B-cell therapies, date of the final dose was not confirmed during chart review. Residual treatment effect may have influenced rates of new disease activity. Also, phenotype data were collected at baseline and at time of discontinuation, but not at the last follow-up. These data could bring clarity to disease progression patterns among groups. Although our analyses were adjusted, it is possible that unaccounted-for variables may have influenced discontinuation versus continuation in the cohort, which could confound the results.

The optimal approach to MS treatment among older adults will likely remain a topic of discussion for the foreseeable future, though our long-term follow-up study demonstrates the feasibility of DMT discontinuation after age 60. We demonstrated a low clinical relapse risk among this patient population, though radiological changes were more common than expected. As the average age of individuals living with MS increases, ongoing investigations into DMT risk-benefit optimization in older adults will be essential.

Disclosure of previously presented unreviewed data

Preliminary data for this work was presented as a poster at the CMSC 2025 Meeting†.

†Orme DR, Matesen E, Conway DS, Thompson N, Hua LH. Long-Term Follow-up on Discontinuation of Disease-Modifying Therapy in Patients with Multiple Sclerosis over Age 60 (DMT04). Consortium of Multiple Sclerosis Centers 2025 Meeting. Phoenix, AZ

Footnotes

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Daniel R. Orme has received consulting fees from EMD Serono and Sanofi. Devon Conway has received research support paid to his institution by Biogen, Bristol Myers Squibb, EMD Serono, Horizon Therapeutics, Novartis, and the Department of Defense. He has received consulting fees from Alexion, Amgen, Biogen, Bristol Myers Squibb, and Genentech, and speaking fees from Biogen. Le H. Hua has received personal fees for speaking consulting, and advisory board activities from Alexion, EMD Serono, Genentech, Horizon, Novartis, and TG Therapeutics, and has had research support paid to her institution from Genentech outside the submitted work. Eric Matesen and Nicolas Thompson declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Daniel R Orme

Devon Conway

Nicolas Thompson

Le H Hua

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