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MS Center Amsterdam, Radiology & Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The NetherlandsQueen Square Institute of Neurology and Centre for Medical Image Computing, University College London, United Kingdom
The most frequent reason for discontinuation of therapy was side effects.
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Sixty percent of the participants showed disease activity after discontinuation.
•
Higher age was associated with a lower risk of MRI activity after discontinuation.
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Higher age was also associated with a lower risk of relapses after discontinuation.
Abstract
Background
It is not known if and when first-line disease modifying therapy (DMT) can safely be discontinued in relapse onset multiple sclerosis (MS) patients.
Objectives
To investigate the characteristics of patients who discontinued first-line DMT, and the occurrence of clinical and radiological inflammatory disease activity after discontinuation.
Methods
We collected clinical and MRI parameters from patients with relapse onset MS in the MS Center Amsterdam and Rijnstate Hospital Arnhem who discontinued first-line DMT with no intention of restarting or switching treatment.
Results
In total, 130 patients were included in the analyses. After discontinuation, 78 patients (60%) experienced disease activity. Sixty-three patients (48.5%) showed MRI activity after DMT discontinuation, 40 patients (30.8%) experienced relapse(s), and 29 patients (22.3%) restarted DMT. Higher age at DMT discontinuation was associated with a lower risk of MRI activity (45 -55 vs. <45 years: OR 0.301, p = 0.007, >55 vs. <45 years, OR: 0.296, p = 0.044), and with a lower risk of relapse(s) after discontinuation (45–55 vs. <45 years: OR=0.495, p = 0.106, >55 vs. <45 years: OR=0.081, p = 0.020).
Conclusion
Higher age at first-line DMT discontinuation is associated with lower risk and severity of radiological disease activity in MS, and a lower risk of relapse(s) after discontinuation.
1. Introduction
Over the years, the number of disease-modifying therapies (DMTs) for multiple sclerosis (MS) has increased rapidly, resulting in more complex treatment decisions (
. Nowadays, people with relapsing-remitting multiple sclerosis (RRMS) are often advised to start DMT in an early phase of the disease, with the aim to prevent or minimize the occurrence of inflammatory disease activity, monitored by clinical relapses, new T2-lesions and/or presence of contrast enhancing lesions (CELs) on brain magnetic resonance imaging (MRI) (
Although treatment is often started early in the disease course, it is still not fully known if and when patients can safely discontinue these DMTs. A number of retrospective studies have been conducted investigating the clinical consequences of discontinuation of DMT in MS. Several studies suggest that a higher age of the patient is associated with a lower risk of recurrent inflammatory disease activity after DMT discontinuation (
. Another possible predictor of recurrent inflammatory disease activity after DMT discontinuation, is duration of inflammatory stable disease before DMT discontinuation (
. Recently, Bsteh et al. published an article introducing the VIAADISC score, a risk score for disease reactivation after DMT discontinuation, that could be used as a valuable tool in the process of decision making regarding discontinuation of injectable first-line DMTs. They reported that age at DMT discontinuation, presence of MRI activity at discontinuation, and duration of clinical stability before discontinuation were predictors of disease reactivation after DMT discontinuation (
Most of these studies have focused on the impact of DMT discontinuation on clinical relapses. Less is known about the return of radiological inflammatory disease activity, i.e. new T2-lesions and/or presence of CELs on MRI. The aim of this study was to investigate the characteristics of patients that discontinued first-line DMT in our cohort, reasons for DMT-discontinuation, and the occurrence of inflammatory disease activity after DMT discontinuation, with a focus on radiological disease activity. Furthermore, we investigated differences in patient characteristics between patients with and without recurrent (radiological and clinical) disease activity after DMT discontinuation, to provide more insight into possible predictors of the occurrence of inflammatory disease activity after DMT discontinuation.
2. Methods
2.1 Study design
We collected data from people with MS that discontinued first-line DMT in two medical centers in The Netherlands: the MS Center Amsterdam and the Rijnstate Hospital Arnhem. We included all patients ≥18 years old with relapse onset multiple sclerosis that received DMT ≥6 months, discontinued first-line DMT with no intention of restarting treatment or switching to another DMT, and of whom a minimum radiological follow-up of 3 months after DMT discontinuation was available. We obtained written informed consent from all patients. We collected the following patient characteristics: age, sex, date of MS onset, and date of MS diagnosis. In addition, we collected data on DMT use, including type of DMT used, treatment duration, and reason(s) for DMT start and discontinuation. Regarding follow-up, we extracted data on the presence of relapses and MRI activity (T2 lesions and CELs) from the clinical notes and radiology reports. New T2 lesions on MRI were detected by visual comparison of FLAIR and T2 images with the previous time-point.
2.2 Definitions
First-line DMTs included all interferons, glatiramer acetate, teriflunomide and dimethyl fumarate. We defined the primary endpoint as occurrence of inflammatory disease activity after DMT discontinuation, measured as either new T2 lesions or CELs on brain MRI, or clinical relapses. Secondary endpoints were clinical characteristics of patients who discontinued DMT and reasons of DMT discontinuation. In addition, we investigated possible predictors of recurrence of inflammatory disease activity.
2.3 Statistical analysis
We analyzed baseline characteristics using Pearson chi-square test or Fisher's exact test for categorical variables and independent-samples T tests or Mann-Whitney U tests for continuous variables. To investigate predictors of inflammatory disease activity after DMT discontinuation, we performed binary logistic regression analyses and negative binomial analyses. Candidate predictors were age at discontinuation, sex, MS subtype and type of DMT that was discontinued. For all analyses a p-value <0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics 26.
3. Results
3.1 Baseline characteristics
Baseline characteristics are depicted in Table 1. In total, 130 patients matched the inclusion criteria and were included in the analyses. Most patients (67.7%) were female. At baseline, 114 patients (87.7%) had a diagnosis of RRMS, and 16 (12.3%) of SPMS. Mean age at the moment of DMT discontinuation was 45.3 years (SD 9.46), and the most frequent reason of DMT discontinuation was side effects of the medication (33.1%). Median follow-up duration after DMT discontinuation was 59.5 months (IQR 26.5–99.9). The median number of MRI-scans after DMT discontinuation was 3.0 (IQR 2.0–5.0).
Table 1Baseline characteristics.
Baseline characteristics
n = 130
Sex, n (%) female
88 (67.7)
MS subtype, n (%)
RRMS
114 (87.7)
SPMS
16 (12.3)
Age at onset, mean (SD)
33.1 (8.9)
Age at diagnosis, mean (SD)
35.1 (9.0)
Age at discontinuation, mean (SD)
45.3 (9.5)
Age at discontinuation, n (%)
< 45 years
51 (39.2)
45 – 55 years
62 (47.7)
> 55 years
17 (13.1)
Type of DMT discontinued, n (%)
Interferon (all types)
76 (58.5)
Glatiramer acetate
42 (32.3)
Dimethyl fumarate
10 (7.7)
Teriflunomide
2 (1.5)
Reason for DMT discontinuation, n (%)
Side effects
43 (33.1)
Secondary progression
13 (10.0)
No/insufficient effect
6 (4.6)
Patient's wish
29 (22.3)
Pregnancy (wish)
9 (6.9)
Anti-interferon antibodies
3 (2.3)
Other
6 (4.6)
Unknown/missing
21 (16.2)
Follow-up duration after DMT discontinuation, months, median (IQR)
59.5 (26.5–99.0)
Duration of stable MRI before DMT discontinuation, months, median (IQR)
32.0 (11.8–69.3)
MRI activity < 6 months before discontinuation, yes, n (%)
18 (13.8)
Type of MRI activity < 6 months before discontinuation, n (%)
New T2-lesions
13 (67.2)
Both new T2-lesions and CELs
5 (27.8)
Time since last relapse until DMT discontinuation, months, median (IQR)
After discontinuation of DMT, 78 patients (60.0%) experienced inflammatory disease activity, i.e. one or more relapse and/or MRI activity. Of these patients, 63 patients (48.5%) showed inflammatory disease activity on cerebral MRI, i.e. either new T2-lesions (50 patients (38.5%)) or CELs (42 patients (32.3%)) on any of the follow-up scans, of whom 38 did not have a clinical relapse. Median time to new inflammatory disease activity on cerebral MRI was 24 months (IQR 8.3–54.0). In 48 patients (36.9%), a spinal cord MRI had been conducted after DMT discontinuation, of whom 9 (6.9%) showed new spinal cord lesions. Forty patients (30.8%) experienced one or more relapses after DMT discontinuation, of whom 25 also showed MRI activity. Median time to first relapse after DMT discontinuation was 30.5 months (IQR 19.3–44.8). Information on recurrence of disease activity after DMT discontinuation is also depicted in Table 2.
Table 2Disease course after DMT discontinuation.
n = 130
Relapse(s) and/or MRI activity after discontinuation, n (%)
Yes No
78 (60.0) 52 (40.0)
Brain: CELs and/or new T2-lesions after discontinuation, n (%)
Yes
63 (48.5)
No
62 (47.7)
Missing
5 (3.8)
Brain: CELs after discontinuation, n (%)
Yes
42 (32.3)
No
49 (37.7)
No contrast administered
30 (23.1)
Missing
9 (6.9)
Brain: New T2-lesions after discontinuation, n (%)
Yes
50 (38.5)
No
73 (56.2)
Missing
7 (5.4)
Brain: number of new T2-lesions after discontinuation, n (%)
0
73 (56.2)
1
11 (8.5)
2
11 (8.5)
3–5
9 (6.9)
>5
11 (8.5)
Missing
15 (11.5)
Brain: Time to new MRI activity after discontinuation, months, median (IQR)
24.0 (8.3–54.0)
One or more relapses since DMT discontinuation, n (%)
Yes
40 (30.8)
No
90 (69.2)
Time to first relapse after DMT discontinuation, months, median (IQR)
Twenty-nine patients (22.3%) restarted DMT after initial discontinuation, with a median time to DMT restart of 17 months (IQR 5.5–41.5). The most frequent reason for DMT restart was clinically active disease (15/29 patients, 51.7%), and the type of DMT that was restarted most was dimethyl fumarate (12/29 patients, 41.3%). Eleven patients restarted the same type of DMT as they initially discontinued, and 18 patients restarted another DMT. See also Table 2.
3.3 Differences between patients with and without disease activity after DMT discontinuation
Differences between patients with and without inflammatory disease activity after DMT discontinuation are depicted in Table 3. Age at DMT discontinuation was higher in patients without inflammatory disease activity on MRI after discontinuation (p = 0.002), and in patients without relapses after DMT discontinuation (p<0.001). Additionally, age at onset and age at diagnosis were higher in patients without relapses after DMT discontinuation (p = 0.005). Duration of stable MRI before DMT discontinuation was longer in patients without MRI activity or clinical relapses after discontinuation, and the number of patients with radiological disease activity <6 months before discontinuation was lower in patients without MRI activity or clinical relapses after discontinuation. However, both of these findings were not statistically significant. No other statistically significant differences were found between the patient groups.
Table 3Differences between patients with and without disease activity after DMT discontinuation.
Any disease activity
MRI activity
Relapses
Yes N = 78
No N = 52
p-value
Yes N = 63
No N = 62
p-value
Yes N = 40
No N = 90
p-value
Sex, n (%) female
52 (66.7)
36 (69.2)
0.849
43 (68.3)
42 (67.7)
0.95
28 (70.0)
60 (66.7)
0.839
MS subtype, n (%)
0.180
0.549
0.775
RRMS
71 (91.0)
43 (82.7)
57 (90.5)
54 (87.1)
36 (90.0)
78 (86.7)
SPMS
7 (9.0)
9 (17.3)
6 (9.5)
8 (12.9)
4 (10.0)
12 (13.3)
Age at onset, mean (SD)
31.8 (8.4)
35.2 (9.4)
0.041*
31.7 (8.7)
34.0 (9.1)
0.159
29.8 (7.6)
34.7 (9.1)
0.005*
Age at diagnosis, mean (SD)
33.6 (8.9)
37.3 (8.7)
0.023*
33.5 (9.4)
36.1 (8.6)
0.109
31.8 (8.2)
36.6 (9.0)
0.005*
Age at discontinuation, mean (SD)
42.4 (9.6)
49.5 (7.4)
<0.001*
42.5 (10.3)
47.8 (8.1)
0.002*
40.0 (9.2)
47.6 (8.7)
<0.001*
Age at discontinuation, n (%)
<0.001*
0.004*
0.013*
< 45 years
42 (53.8)
9 (17.3)
35 (55.6)
16 (25.8)
23 (57.5)
28 (31.1)
45 – 55 years
30 (38.5)
32 (61.5)
22 (34.9)
35 (56.5)
16 (40.0)
46 (51.1)
> 55 years
6 (7.7)
11 (21.2)
6 (9.5)
11 (17.7)
1 (2.5)
16 (17.8)
Duration of stable MRI before DMT discontinuation, months, median (IQR)
30.5 (9.0–65.3)
44.5 (17.5–76.5)
0.166
30.0 (7.0–64.0)
47.0 (17.0–77.0)
0.109
30.0 (9.5–71.5)
35.0 (13.0–66.5)
0.648
Duration of stable MRI before DMT discontinuation, n (%)
0.190
0.091
1.000
< 4 years
49 (62.8)
26 (50.0)
40 (63.5)
31 (50.0)
23 (57.5)
52 (57.8)33
≥ 4 years
25 (32.1)
22 (42.3)
19 (30.2)
28 (45.2)
14 (35.0)
33 (36.7)
MRI activity < 6 months before discontinuation, yes, n (%)
13 (16.7)
5 (9.6)
0.266
12 (19.0)
6 (9.7)
0.115
4 (10.3)
14 (15.6)
0.438
Time since last relapse until DMT discontinuation, months, median (IQR)
3.4 Predictors of recurrent inflammatory disease activity after DMT discontinuation
Regarding predictors of inflammatory disease activity, higher age at DMT discontinuation was associated with a lower risk of MRI activity after discontinuation (45 −55 vs. <45 years: OR 0.301, p = 0.007, >55 vs. <45 years, OR: 0.296, p = 0.044). Higher age at discontinuation was also associated with a lower total number of new T2-lesions after discontinuation (45–55 vs. <45 years: rate ratio(RR)=0.621, p = 0.097, >55 vs. <45 years: RR=0.249, p = 0.012). In addition, age at DMT discontinuation was associated with the occurrence of one or more relapse after discontinuation (45–55 vs. <45 years: OR=0.495, p = 0.106, >55 vs. <45 years: OR=0.081, p = 0.020), and with combined disease activity (radiological activity or relapses) after DMT discontinuation (45–55 years old vs. <45 years old: OR=0.227, p = 0.002, >55 years old vs. <45 years old: OR=0.135, p = 0.002). Furthermore, age at DMT discontinuation was associated with DMT restart, although not statistically significant (45–55 years old vs. <45 years old: OR=0.431, p = 0.059, >55 years old vs. 45–55 years old: OR=0.126, p = 0.054). No other statistically significant predictors of inflammatory disease activity after DMT discontinuation were found in our cohort. See also Table 4 and Fig. 1.
Table 4Prediction models regarding disease activity after DMT discontinuation.
Any disease activity
MRI activity
Relapses
OR
p-value
95% CI
OR
p-value
95% CI
OR
p-value
95% CI
Sex
0.918
0.843
0.40–2.13
1.031
0.943
0.45–2.36
1.047
0.918
0.44–2.50
Age at DMT discontinuation
< 45 years
Reference
Reference
Reference
45 – 55 years
0.227
0.002*
0.09–0.57
0.301
0.007*
0.13–0.72
0.495
0.106
0.21–1.16
> 55 years
0.135
0.002*
0.04–0.47
0.296
0.044*
0.09–0.97
0.081
0.020*
0.01–0.67
MRI activity < 6 months before DMT discontinuation
2.112
0.329
0.61–7.40
2.668
0.112
0.79–8.96
0.645
0.508
0.18–2.63
> 4 years of stable MRI before DMT discontinuation
Fig. 1Age vs. inflammatory disease activity after DMT discontinuation.
Fig. 1. A) Age vs. inflammatory disease activity (active MRI and/or relapse) after DMT discontinuation. B) Age vs. MRI activity (new T2 lesions and/or CEL) after DMT discontinuation. C) Age vs. occurrence of one or more relapses after DMT discontinuation. D) Age vs. number of new T2 lesions on MRI after DMT discontinuation.
In 82.4% of the patients <45 years inflammatory disease activity returned during follow-up. Of the patients <45 years, 45.1% percent had a relapse, 68.6% had inflammatory disease activity on MRI, and 54.9% had new T2 lesions. On the contrary, in patients >55 years, 35.3% had recurrent inflammatory disease activity, 5.9% experienced a relapse, 35.3% had an active MRI and 17.6% had new T2 lesions, with a maximum of 2 lesions.
4. Discussion
Our study shows that age at the moment of DMT discontinuation is, in addition to clinical disease activity, a significant predictor of the occurrence of radiological disease activity after discontinuation of first-line therapy in MS. Higher age was not only associated with a lower occurrence of any inflammatory disease activity on MRI, but also with a lower total number of new T2-lesions on MRI after DMT discontinuation. In addition, we found that a higher age at DMT discontinuation was associated with a lower risk of relapses during follow-up.
Several previous studies have found an association between age and relapse risk after DMT discontinuation. For example, Kister et al. found a higher risk of post-DMT relapse in younger patients (
. Yano et al. have investigated the impact of DMT discontinuation on clinical relapses and radiological disease activity, and reported discontinuation of DMT after an age of 45 years might be associated with a stable disease course, whereas younger patients may have a higher risk of recurrent disease activity after DMT discontinuation (
). Our study confirms these findings, and adds more information on the association between age and the severity of radiological disease activity. In our cohort, the risk of inflammatory disease activity decreases with age, and patients aged >55 years have the lowest risk and lowest severity (i.e. lowest number of new T2-lesions) of radiological inflammatory disease activity, compared to patients aged <45 years. These findings are in line with previous research suggesting a decrease of focal inflammatory disease activity in relapse onset MS with higher age, and over time (
). As most currently available disease-modifying therapies are aimed at preventing or diminishing focal inflammation in MS, our data suggest that these therapies might not be cost-effective and/or necessary anymore in older patients with longer disease duration and perhaps could be safely discontinued (
Indeed, previous studies have found duration of disease stability before DMT discontinuation and the presence of inflammatory MRI activity at the moment of DMT discontinuation to be possible predictors of recurrent inflammatory disease activity after discontinuation (
. As mentioned, Bsteh et al. published an article introducing the VIAADISC score, a risk score for disease reactivation after DMT discontinuation. The VIAADISC score includes age at DMT discontinuation, presence of MRI activity at discontinuation, and duration of clinical stability before discontinuation of therapy (
). In our cohort, we confirmed that the number of patients with MRI activity at discontinuation is lower in the patient group without clinical and/or radiological disease activity after DMT discontinuation. We also found that the duration of clinically stable disease before discontinuation was higher in patients without clinical and/or radiological disease activity after DMT discontinuation. However, both of these findings were not statistically significant, and both were not statistically significant predictors of disease activity in our cohort. This might be due to the relatively small sample size of our study.
In addition to previous work, here we focused on radiological outcome measures after DMT discontinuation. MRI is a sensitive biomarkers for inflammatory disease activity in MS (
). In our cohort, we found that the proportion of patient with only radiological disease activity was substantially higher than the proportion of patients with both clinical and radiological disease activity. This confirms that MRI measurements is a sensitive marker for disease reactivation and should be included in clinical follow-up protocols. However, it remains to be seen if radiological disease activity always is clinically relevant, and should be prevented completely. In some circumstances 1 or 2 new lesions might be accepted, especially when they can be due to technical errors, artifacts or vasculoischaemic lesions in older patients.
The question arises at what age to consider the discontinuation of first line DMT. In our cohort only 5.9% of the patients >55 years experienced a relapse. The occurrence of radiological activity was higher, but when present only minimally, with a maximum number of 2 new T2 lesions. Hua et al. showed that just one clinical relapse occurred in 178 MS patient aged >60 years that stopped first line DMT (
). Our study supports the consideration of discontinuation of first line DMT in patients aged >55 years with long-term stable disease.
Our study has some limitations. The design of the study is observational, which could have led to a selection bias. We predominantly included patients that self-decided to discontinue their DMT, most frequently because of side effects. Therefore, our results might not be applicable to all patients on first-line DMT. In addition, because we collected real-world data, follow-up moments and frequency were different between patients. Possibly, patients experiencing symptoms have received more frequent MRI scans than other patients. Furthermore, Expanded Disability Status Scale (EDSS) scores were available for an insufficient number of patients to reliably investigate disease progression and its possible association with the absence of inflammatory disease activity in our cohort. It is also important to note that we only investigated first-line DMT in this study, and it is very likely that our findings cannot be extrapolated to patients using high efficacy DMT. However, despite these limitations, our study provides interesting real-world data on the reasons for DMT discontinuation and the disease course after DMT discontinuation in our cohort. Ongoing and recently completed randomized controlled trials, the DISCOMS trial (NCT03073603), the STOP-I-SEP trial (NCT03653273) and the DOT-MS trial (NCT04260711), will provide more information on the impact of DMT discontinuation on radiological and clinical inflammatory disease activity and disability progression in specific patient groups.
In conclusion, in our study age was the only significant predictor of recurrent inflammatory disease activity after DMT discontinuation. Our study confirms that the occurrence of inflammatory disease activity is relatively infrequent in patients aged >55 years that discontinued DMT, and, when present, mostly radiological with a low number of T2-lesions.
Disclosures
E.M.E. Coerver reports no disclosures relevant to the manuscript; A. Bourass reports no disclosures relevant to the manuscript; M.H.J. Wessels reports no disclosures relevant to the manuscript; Z.L.E. Van Kempen reports no disclosures relevant to the manuscript; M.M.S. Jasperse reports no disclosures relevant to the manuscript; B.A.R. Tonino reports no disclosures relevant to the manuscript; F. Barkhof serves on the steering committee and is iDMC member for Biogen, Merck, Roche, EISAI. He acts as a consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. He has research agreements with Novartis, Merck, Biogen, GE, Roche. He is co-founder and share–holder of Queen Square Analytics LTD.; J. Mostert reports no disclosures relevant to the manuscript; B.M.J. Uitdehaag reports research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and Immunic Therapeutics.; J. Killestein reports grants from Biogen, Novartis, TEVA, Bayer Schering Pharma, Glaxo Smith Kline, Merck, Genzyme and Roche.; E.M.M. Strijbis reports no disclosures relevant to the manuscript.
Study funding
E.M.E. Coerver and E.M.M. Strijbis received funding from ZonMW, grant number 848043001, and Stichting MS Research, grant number 17–992. FB is supported by the NIHR biomedical research center at UCLH.
CRediT authorship contribution statement
E.M.E. Coerver: Conceptualization, Methodology, Investigation, Data curation, Writing – original draft, Visualization. A. Bourass: Investigation, Data curation, Writing – original draft, Visualization. M.H.J. Wessels: Data curation, Writing – review & editing. Z.L.E. van Kempen: Writing – review & editing. M.M.S. Jasperse: Data curation, Writing – review & editing. B.A.R. Tonino: Data curation, Writing – review & editing. F. Barkhof: Data curation, Writing – review & editing. J. Mostert: Conceptualization, Data curation, Writing – review & editing. B.M.J. Uitdehaag: Writing – review & editing. J. Killestein: Conceptualization, Methodology, Writing – review & editing, Supervision. E.M.M. Strijbis: Conceptualization, Methodology, Writing – review & editing, Supervision.
Declaration of Competing Interest
None.
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