Key Points
Question
What proportion of disability worsening happens in conjunction with relapses vs independent of relapse activity in pediatric-onset multiple sclerosis (POMS), and how does this differ from adult-onset disease?
Findings
This multicenter cohort study of 16 130 patients with MS found that although progression independent of relapse activity (PIRA) was rarely detectable before 18 years of age, pediatric onset was not protective against PIRA. Progression independent of relapse was observed in 40.4% of patients with POMS even while they were still young (ie, approximately a single decade of follow-up), and delay in disease-modifying therapy initiation and less time receiving therapy were both associated with a higher risk of PIRA in POMS.
Meaning
This study suggests that POMS is not protective against disability worsening even in the absence of relapses.
This cohort study assesses the occurrence of progression independent of relapse activity and relapse-associated worsening in pediatric and adult patients with multiple sclerosis.
Abstract
Importance
Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability because of greater capacity for repair.
Objective
To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS).
Design, Setting, and Participants
This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73 564 patients from 120 MS centers were available in the register.
Main Outcomes and Measures
The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors.
Exposures
Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT.
Results
After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median [IQR] age at onset, 28.7 [22.8-36.2 years]; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001).
Conclusions and Relevance
PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study’s findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.
Introduction
Over the past few years, analyses from randomized clinical trials and observational studies1,2,3,4,5,6 have provided consistent evidence that disability accrual in multiple sclerosis (MS) can derive from 2 distinct mechanisms: relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). Progression independent of relapse activity occurs in approximately one-quarter of patients with early relapsing MS (RMS) and represents the main driver of disability accumulation, particularly when it develops within the first 5 years of disease.3,4,5,6 It becomes predominant in older patients,5 suggesting that aging, via different immunologic and pathophysiologic mechanisms, may increase neural susceptibility, amplify tissue damage, and decrease resilience to injury.7,8,9,10
Age has emerged as the main risk factor associated with the occurrence of PIRA, as RAW is prominent in younger and PIRA in older patients.3,4,5 Furthermore, in most studies, currently available disease-modifying treatments (DMTs) are protective, reducing at least in part disability accumulation deriving from both PIRA and RAW.3,4,5 However, information on the relative contribution to disability accrual of PIRA vs RAW in pediatric-onset MS (POMS) is extremely limited and mainly based on short-term data sets from clinical trials. Data on factors associated with PIRA in this young population and long-term evolution of disability accrual from childhood into adulthood are also missing.
On the basis of the Italian MS Register (IMSR),11 we explored the occurrence of the first PIRA and RAW events and the role of DMT in a large cohort of patients with RMS classified as having POMS, adult-onset MS (AOMS), or late-onset MS (LOMS). Moreover, in a subgroup of patients visited every 6 months, we calculated the cumulative incidence of PIRA and RAW events across the entire patient age spectrum.
Methods
Design
This cohort study using prospectively acquired data from the IMSR was performed from June 1, 2000, to September 30, 2021. The IMSR has been described elsewhere.11 At the time of data extraction, longitudinal data of 73 564 patients from 120 MS centers were available in the IMSR. This study was approved by the ethics committees of the Policlinico of Bari and of participating centers. Written informed consent was obtained from all patients. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.
Patients
Patients with a clinically isolated syndrome and relapsing-remitting course at the first neurologic evaluation, 3 or more Expanded Disability Status Scale (EDSS) evaluations, and 5 years or more of follow-up were included. We excluded patients with a primary or secondary progressive course at the first evaluation and those enrolled in randomized clinical trials. Patients were grouped based on their age at disease onset: 18 years or younger (POMS), 19 to 50 years (AOMS), or older than 50 years (LOMS). In a subgroup of patients with a first visit within 1 year of disease onset and 1 visit or more every 6 months, we assessed different rates of PIRA and RAW and associated factors across the entire age spectrum. In case of multiple visits in the 6-month period, the last visit was considered.
Variables included in the data set were date of birth, sex, date of disease onset, dates of relapses, dates of EDSS evaluations, and start and end dates of all the administered DMTs. Quality assurance through online certification of EDSS competency is required at each participating site. Baseline was defined as the first EDSS evaluation. If the first evaluation occurred within 30 days of a relapse, baseline was defined as the following assessment with EDSS scoring outside a relapse and within 1 year of the first visit. When no additional EDSS evaluations were available within 1 year of the first visit, patients were excluded. The duration of MS was calculated from the first clinical event. The follow-up time was defined as the time between the first and last available EDSS entry.
Confirmed disability accrual (CDA) was defined as 48-week or later confirmed disability increase from study baseline, measured by EDSS (increase of ≥1.5 points if baseline EDSS score was 0, ≥1.0 point if baseline EDSS score was 1.0-5.5, and ≥0.5 point if baseline EDSS score was ≥6.0). Date of CDA was assigned at the first EDSS score when an increase was registered. Relapse-associated worsening was defined as a CDA event in which the initial disability increase from study baseline occurred 90 days or earlier after or 30 or earlier days before the onset of a relapse. Progression independent of relapse activity was defined as a CDA event occurring more than 90 days after and more than 30 days before the onset of a relapse.
Exposure to DMT was defined by the recorded starting and ending dates. Total time a patient spent receiving treatment was calculated, including any switches and gaps in treatment. We did not consider gaps less than 3 months as a therapy interruption. For long-acting DMTs, the estimated treatment effect duration was used to calculate the proportion of time that patients received therapy (6 months for mitoxantrone, rituximab, and ocrelizumab; 5 years for alemtuzumab and autologous hematopoietic stem cell transplant; 2 months for natalizumab; and 12 months for cladribine).12
As in a previous study,6 patients with PIRA were further classified into early or late PIRA, depending on whether the first PIRA event occurred within 5 years since disease onset or afterward. In a subgroup of patients with brain and spinal magnetic resonance imaging (MRI) results available within 2 years before developing PIRA, PIRA events were classified into active or nonactive, depending on the presence or absence of disease activity at MRI (T1-weighted gadolinium-enhancing lesions and/or T2-weighted new or enlarging lesions).6
Statistical Analysis
Baseline and follow-up characteristics were expressed as median (range or IQR) or number (percentage) for continuous and categorical covariates, respectively. Categorical and continuous variables were compared with analysis of variance or χ2 test, as appropriate. Factors associated with the first PIRA or RAW event were assessed using multivariable Cox proportional hazards regression. In the absence of outcome occurrence, data were censored at the latest EDSS score available. The exposure time was censored when the outcome was reached or at the last visit. The results of the Cox proportional hazards regression model were expressed as hazard ratios (HRs) and 95% CIs. The Cox proportional hazards regression models were adjusted for age at onset (POMS as reference), sex, symptoms at onset (multifocal vs monofocal), disease duration at first visit, number of relapses between the disease onset and the first visit (0 [reference category], 1, or ≥2), percentage of time spent receiving DMTs before the event, and visit frequency before the event.
In the subgroup of patients with at least 1 EDSS evaluation every 6 months, Kaplan-Meier curves were used to show different rates of PIRA and RAW cumulative incidence as a function of age. Because of the reduction in the frequency of visits beyond the fifth year of follow-up, the observation period for this subgroup of patients was right-censored at 5 years.
Factors associated with PIRA and RAW event were also estimated in this subgroup by using multivariable Cox proportional hazards regression models, including as covariates decades of age at disease onset (1-20 years [reference category], 21-30, 31-40, 41-50, 51-60, or >60 years), sex, number of relapses between the disease onset and the first visit (0 [reference category], 1, or ≥2), disease duration (in months), type of clinical onset (monofocal vs multifocal), and time from disease onset to first DMT start (<6 months [reference group] or ≥6 months).
Statistical analyses were performed with SPSS software, version 25.0 (SPSS Inc) and R, version 4.1.2 (R Foundation for Statistical Computing). A 2-sided P < .05 was considered statistically significant.
Results
Occurrence of PIRA and RAW Events
Applying the inclusion and exclusion criteria, we retrieved a cohort of 16 130 patients with MS (median [IQR] age, 28.7 [22.8-36.2] years; 68.3% female and 31.7% male) (eFigure in Supplement 1). Table 1 shows the characteristics of the cohort. The POMS group included 1383 patients with a median (IQR) age at onset of 15.8 (14.2-17.0) years. The AOMS group consisted of 14 113 patients with a median (IQR) age at onset of 29.3 (24.1-35.9) years, whereas the LOMS group included 634 patients with a median (IQR) age at onset of 52.4 (50.4-55.3) years.
Table 1. Demographic and Clinical Characteristics of the Entire Relapsing Multiple Sclerosis Cohort and the 3 Subgroups Stratified by Age at Onseta.
| Variable | Overall (N = 16 130) | POMS (n = 1383) | AOMS (n = 14 113) | LOMS (n = 634) | P value |
|---|---|---|---|---|---|
| Age at onset, median (IQR), y | 28.7 (22.8-36.2) | 15.8 (14.2-17.0) | 29.3 (24.1-35.9) | 52.4 (50.4-55.3) | <.001 |
| Age at baseline, median (IQR), y | 34.8 (27.8-43.1) | 21.1 (17.1-29.3) | 35.2 (28.8-42.6) | 55.8 (52.6-59.5) | <.001 |
| Sex | |||||
| Female | 11 013 (68.3) | 944 (68.3) | 9626 (68.2) | 443 (69.9) | .68 |
| Male | 5117 (31.7) | 439 (31.7) | 4487 (31.8) | 191 (30.1) | |
| Disease duration, median (IQR), y | 2.83 (0.66-8.42) | 5.59 (1.14-14.64) | 2.72 (0.64-8.14) | 1.68 (0.47-4.00) | <.001 |
| Type of clinical onset | |||||
| Monofocal | 14 068 (87.2) | 1204 (87.1) | 12 296 (87.1) | 568 (89.6) | .19 |
| Multifocal | 2062 (12.8) | 179 (12.9) | 1817 (12.9) | 66 (10.4) | |
| No. of relapses between the disease onset and the first clinic visit | |||||
| 0 | 6806 (42.2) | 478 (34.6) | 5953 (42.2) | 375 (59.1) | <.001 |
| 1 | 4146 (25.7) | 339 (24.5) | 3656 (25.9) | 151 (23.8) | |
| ≥2 | 5178 (32.1) | 566 (40.9) | 4504 (31.9) | 108 (17.0) | |
| Baseline EDSS score, median (IQR) | 2.00 (1.00-3.00) | 2.00 (1.00-2.50) | 2.00 (1.00-3.00) | 2.00 (1.50-3.50) | <.001 |
| Time spent with DMT exposure, median (IQR), % | 85.8 (45.9-98.7) | 87.4 (55.6-98.7) | 85.7 (46.0-98.6) | 82.2 (6.4-99.0) | <.001 |
| Classification of first DMTb | |||||
| METc | 13 933 (94.2) | 1236 (94.3) | 12 226 (94.3) | 471 (90.9) | .005 |
| HETd | 859 (5.8) | 75 (5.7) | 737 (5.7) | 47 (9.1) |
Abbreviations: AOMS, adult-onset multiple sclerosis; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; HET, high-efficacy treatment; LOMS, late-onset multiple sclerosis; MET, moderate-efficacy treatment; POMS, pediatric-onset multiple sclerosis.
Data are presented as number (percentage) of patients unless otherwise indicated.
The percentages of MET and HET DMT exposure were calculated using as denominator the number of patients who received at least 1 DMT prescription during the follow-up.
The MET group is composed of interferon beta products, glatiramer acetate, teriflunomide, dimethyl fumarate, and azathioprine.
The HET group is composed of natalizumab, fingolimod, mitoxantrone, rituximab, cladribine, and cyclophosphamide.
Median (IQR) disease duration was longer in the POMS group (5.59 [1.14-14.64] years) than in the AOMS (2.72 [0.64-8.14] years) and LOMS (1.68 [0.47-4.00] years) groups (P < .001); a lower number of patients with LOMS (259 [40.8%]) reported at least 1 relapse in the period between disease onset and the first visit compared with the patients with AOMS (8160 [57.8%]) and POMS (905 [65.4%]; P < .001). The baseline median (IQR) EDSS score was higher in the LOMS group (2.00 [1.50-3.50]) compared with the POMS (2.00 [1.00-2.50]) and AOMS (2.00 [1.00-3.00]) groups (P < .001).
The median (IQR) percentage of time spent receiving DMT exposure was lower in the LOMS group (82.2% [6.4%-99.0%]) than in the AOMS (85.7% [46.0%-98.6%]) and POMS (87.4% [55.6%-98.7%]) groups (P < .001); a greater number of patients in the LOMS group (47 of 518 [9.1%]) started with a high-efficacy treatment (HET) compared with the AOMS (737 of 12 963 [5.7%]) and POMS (75 of 1311 [5.7%]) groups (P = .005) (Table 1). A first 48-week CDA event occurred in 8896 patients (55.2%). Progression independent of relapse activity events accounted for 7176 of all 8896 CDA events (80.7%) that occurred in the whole population, 558 (74.4%) of those that occurred in POMS, 6258 (80.8%) of those that occurred in AOMS, and 360 (90.5%) of those occurred in LOMS.
In the multivariable Cox proportional hazards regression models, PIRA was associated with AOMS (HR, 1.42; 95% CI, 1.30-1.55; P < .001) and LOMS (HR, 2.98; 95% CI, 2.60-3.41; P < .001), male sex (HR, 1.12; 95% CI, 1.06-1.17; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001) (Table 2). Patients with AOMS (HR, 0.88; 95% CI, 0.79-0.98; P = .02) and LOMS (HR, 0.69; 95% CI, 0.55-0.87; P = .001) were at lower risk of having a RAW event compared with patients with POMS. Relapse-associated worsening was associated with higher relapse activity, shorter disease duration (HR, 0.98, 95% CI, 0.98-0.99; P < .001), and shorter DMT exposure (HR, 0.54; 95% CI, 0.49-0.60; P < .001). Early PIRA was observed in 229 patients with POMS (41.0%), 2815 patients with AOMS (45.0%), and 196 patients with LOMS (54.4%) (P < .001). In 4881 patients with PIRA (68.0%), brain MRI results were available within 2 years of their first PIRA; spinal MRI results were also available in 3290 patients with PIRA (45.8%). Active PIRA accounted for 82 PIRA events (20.8%) in the POMS group, 949 (22.3%) in the AOMS groups, and 52 (23.2%) in the LOMS group (P = .75). Progression independent of relapse and MRI activity (true PIRA) was associated with AOMS (HR, 1.38; 95% CI, 1.22-1.54; P < .001) and LOMS (HR, 2.84; 95% CI, 2.35-3.44; P < .001), male sex (HR, 1.14; 95% CI, 1.06-1.22; P < .001), multifocal onset (HR, 1.13; 95% CI, 1.03-1.24; P = .01), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), higher number of relapses before baseline, and shorter DMT exposure (HR, 0.75; 95% CI, 0.68-0.84; P < .001) (eTable in Supplement 1).
Table 2. Multivariable Cox Proportional Hazards Regression Model Parameters to Estimate Risk of Reaching the First PIRA and RAW Events.
| Parameter | PIRA | RAW | ||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Sex | ||||
| Female | 1 [Reference] | NA | 1 [Reference] | NA |
| Male | 1.12 (1.06-1.17) | <.001 | 0.98 (0.91-1.05) | .59 |
| Classes of age at onseta | ||||
| POMS | 1 [Reference] | NA | 1 [Reference] | NA |
| AOMS | 1.42 (1.30-1.55) | <.001 | 0.88 (0.79-0.98) | .02 |
| LOMS | 2.98 (2.60-3.41) | <.001 | 0.69 (0.55-0.87) | .001 |
| No. of clinical relapses in the period between disease onset and the first clinical visit | ||||
| 0 | 1 [Reference] | NA | 1 [Reference] | NA |
| 1 | 0.97 (0.91-1.03) | .24 | 1.28 (1.17-1.39) | <.001 |
| ≥2 | 1.01 (0.95-1.06) | .87 | 1.60 (1.48-1.73) | <.001 |
| Disease duration, y | 1.04 (1.04-1.05) | <.001 | 0.98 (0.98-0.99) | <.001 |
| Type of clinical onset | ||||
| Monofocal | 1 [Reference] | NA | 1 [Reference] | NA |
| Multifocal | 1.07 (1.00-1.14) | .06 | 1.00 (0.91-1.10) | .95 |
| Percentage of DMT exposure | 0.69 (0.64-0.74) | <.001 | 0.54 (0.49-0.60) | <.001 |
| Visit frequency | 1.42 (1.40-1.44) | <.001 | 1.53 (1.51-1.55) | <.001 |
Abbreviations: AOMS, adult-onset multiple sclerosis; DMT, disease-modifying therapy; HR, hazard ratio; LOMS, late-onset multiple sclerosis; NA, not applicable; PIRA, progression independent of relapse activity; POMS, pediatric-onset multiple sclerosis; RAW, relapse-associated worsening.
No. of events per group are as follows: POMS (n = 1383): confirmed disability accrual (CDA), n = 750 (54.2%); PIRA, n = 558 (40.4%); RAW, n = 192 (13.9%); AOMS (n = 14 113): CDA, n = 7748 (54.9%); PIRA, n = 6258 (44.3%); RAW, n = 1490 (10.6%); and LOMS (n = 634): CDA, n = 398 (62.8%); PIRA, n = 360 (56.8%); RAW, n = 38 (6.0%).
Rates of PIRA and RAW Incidence as a Function of Age
The subgroup of patients with a first visit within 1 year after disease onset and EDSS scores collected every 6 months included 3777 patients with RMS (eFigure in Supplement 1). Table 3 shows the characteristics of these patients. A first 48-week CDA event occurred in 1037 of 3777 patients (27.5%), and PIRA events accounted for 842 (81.2%) of the first CDA events. The cumulative incidence of the first PIRA and RAW events according to age is shown in panel A of the Figure. The incidence of PIRA was approximately 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and then nearly doubled for each age decade from 40 to 70 years (21.6% for 40 years of age, 39.0% for 50 years of age, 61.0% for 60 years of age, and 78.7% for 70 years of age). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years of age, 3.5% at 30 years of age, 7.8% at 40 years of age, 14.4% at 50 years of age, and 24.1% at 60 years of age); no further increase was found at 70 years of age (27.7%). The relative contribution of PIRA events to overall disability accrual increased with age as shown in panel B of the Figure, in which the relative contribution of the first PIRA and RAW events to total CDA events is stratified by decades of age.
Table 3. Demographic and Clinical Characteristics of the Subgroup of Patients With a First Visit Within 1 Year After Disease Onset and EDSS Scores Regularly Collected Every 6 Monthsa.
| Characteristic | Finding (N = 3777) |
|---|---|
| Age at onset, median (IQR), y | 31.0 (24.0-39.0) |
| Age at first prescription, median (IQR), y | 31.8 (25.8-39-8) |
| Sex | |
| Female | 2538 (67.2) |
| Male | 1239 (32.8) |
| Disease duration, mo | 3.40 (1.30-6.90) |
| Type of clinical onset | |
| Monofocal | 3144 (83.2) |
| Multifocal | 539 (14.3) |
| No. of relapses between the disease onset and the first visit | |
| 0 | 2523 (66.8) |
| 1 | 975 (25.8) |
| ≥2 | 279 (7.4) |
| Baseline EDSS score, median (IQR) | 1.50 (1.00-2.00) |
| At least 1 DMT prescription | 3654 (96.7) |
| Total DMT exposure duration, median (IQR), y | 4.37 (1.93-4.95) |
| Time from disease onset to first DMT start, mo | 6.90 (3.40-11.50) |
| Time from disease onset to first DMT start | |
| <6 mo | 1704 (45.1) |
| ≥6 mo | 2073 (54.9) |
| Classification of first DMT | |
| METb | 3233 (88.48) |
| HETc | 421 (11.52) |
| Patients who were exposed to a vertical switch during the follow-up | 1323 (39.46) |
Abbreviations: AOMS, adult-onset multiple sclerosis; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; HET, high-efficacy treatment; LOMS, late-onset multiple sclerosis; MET, moderate-efficacy treatment.
Data are presented as number (percentage) of patients unless otherwise indicated.
The MET group is composed of interferon beta products, glatiramer acetate, teriflunomide, dimethyl fumarate, and azathioprine.
The HET group is composed of natalizumab, fingolimod, mitoxantrone, rituximab, cladribine, and cyclophosphamide.
Figure. Kaplan-Meier Estimate of the Cumulative Incidence of the First Confirmed Disability Accrual (CDA), Progression Independent of Relapse Activity (PIRA), and Relapse-Associated Worsening (RAW) Events and Contribution of First PIRA and RAW Events to CDA in Different Decades of Age.
The multivariable Cox proportional hazards regression models confirmed an increasing risk of reaching a first PIRA event with increasing decade of age at onset. There was a linear increase of the risk at each decade of age at onset (from 27% to 202%) compared with an age at disease onset younger than 20 years (Table 4, Figure, A). We found no differences for the risk of reaching a RAW event among the different decades of age at onset. The same models revealed that the number of relapses before the first visit was significantly associated with both the first PIRA and RAW events. Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001) (Table 4).
Table 4. Multivariable Cox Proportional Hazards Regression Model Parameters to Estimate Risk of Reaching the First PIRA and RAW Events in Patients With a First Visit Within 1 Year of Disease Onset and Expanded Disability Status Scale Scores Regularly Collected Every 6 Months.
| Parameter | PIRA | RAW | ||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Sex | ||||
| Female | 1 [Reference] | NA | 1 [Reference] | NA |
| Male | 0.97 (0.83-1.12) | .63 | 0.82 (0.60-1.13) | .22 |
| Decades of age at onset | ||||
| 1-20 | 1 [Reference] | NA | 1 [Reference] | NA |
| 21-30 | 1.27 (1.00-1.60) | .05 | 0.92 (0.60-1.41) | .69 |
| 31-40 | 1.31 (1.03-1.66) | .03 | 0.88 (0.57-1.38) | .58 |
| 41-50 | 1.36 (1.05-1.76) | .02 | 0.81 (0.49-1.35) | .42 |
| 51-60 | 1.51 (1.05-2.18) | .03 | 0.90 (0.41-1.97) | .80 |
| >60 | 3.02 (1.52-6.03) | .002 | 1.05 (0.14-7.71) | .97 |
| No. of clinical relapses in the period between disease onset and the first clinical visit | ||||
| 0 | 1 [Reference] | NA | 1 [Reference] | NA |
| 1 | 1.18 (1.01-1.39) | .04 | 1.63 (1.17-2.26) | .004 |
| ≥2 | 1.08 (0.83-1.42) | .57 | 1.94 (1.19-3.18) | .01 |
| Disease duration, mo | 1.00 (0.98-1.02) | .74 | 0.97 (0.93-1.01) | .17 |
| Type of clinical onset | ||||
| Monofocal | 1 [Reference] | NA | 1 [Reference] | NA |
| Multifocal | 1.12 (0.93-1.35) | .24 | 0.99 (0.67-1.48) | .97 |
| Time from disease onset to first DMT start | ||||
| <6 mo | 1 [Reference] | NA | 1 [Reference] | NA |
| ≥6 mo | 1.16 (1.00-1.34) | .04 | 1.75 (1.28-2.39) | .001 |
Abbreviations: DMT, disease-modifying therapy; NA, not applicable; HR, hazard ratio; PIRA, progression independent of relapse activity; RAW, relapse-associated worsening.
Discussion
In this observational cohort study based on the IMSR, we assessed the proportion of first PIRA and RAW events in POMS compared with patients with AOMS and LOMS. Moreover, to elucidate the association of age with disability accrual, we estimated different rates of PIRA and RAW events across the entire patient age spectrum. Because aging seems to be a critical determinant of progression, PIRA should be considerably less frequent or even absent in patients with POMS. Indeed, POMS compared with AOMS represents a more inflammatory phenotype,13 characterized by better recovery possibly due to differences in immunology and, in hypothesis, greater neuroplasticity and capability of remyelination.8 This assumption was partially met by our findings. In fact, patients with POMS had a lower frequency of early PIRA events compared with patients with AOMS and LOMS. Still, even in POMS, PIRA was detected in 40.4% of patients. In the subgroup with frequent assessments, both PIRA and RAW events were rare in childhood, and their occurrence started around the age of 18 to 20 years. The cumulative incidence of PIRA was almost absent before 18 years of age, showed a slight increase at approximately 20 years of age, rapidly increased between 21 and 30 years of age, and then nearly doubled for each age decade. The cumulative incidence of RAW followed a similar trend. The important inference from the our findings is that, although patients with MS who are younger than 18 years have a lower rate of disability, pediatric age itself is not protective. In other words, the time of injury itself is not protective against disability; rather, while the subject has a youthful immune system and a more resilient brain, less disability is manifest.
Our findings also confirm the results of a clinical trial meta-analysis of PIRA and RAW that found preexisting disability and older age were the principal risk factors for further disability accumulation and incomplete relapse recovery, likely related to immunosenescence, decreased repair capacity, or neuroplasticity with aging.4 The results are also in line with data demonstrating that children recover significantly better from relapses than adults and can experience improvements in EDSS and functional system scores.8
Despite poor understanding of PIRA physiopathology, the association among PIRA, RAW, and age seems to be consistent with the presence of 2 different types of neuroinflammation described in MS.14 The first type is based on focal invasion of T- and B-lymphocytes into the central nervous system, which produces active demyelinated plaques and dominates in acute MS and RMS. Relapse-associated worsening events possibly represent the relevant clinical expression of this type of inflammation. The second type is based on slow accumulation of T- and B-cells in the connective tissue spaces of the brain, subpial demyelinated lesions in the cortex, slow expansion of preexisting lesions, and diffuse neurodegeneration in the white and gray matter. This type of smoldering inflammation has already been identified in the early stages of MS; it gradually increases with disease duration and aging and has been preliminarily associated with PIRA.15
We confirmed that relapses were associated with PIRA and RAW events in the subgroup of patients more frequently followed up. This finding is in line with previous observations showing relapses can significantly increase the hazard of all-cause disability4 as well as whole-brain and gray matter atrophy.16 Another notable finding in our study was that longer exposure to DMT was associated with a lower risk of PIRA. In this contemporary cohort, most patients received DMTs, and approximately two-thirds of the follow-up period was spent receiving treatment. This finding replicates in a population-based setting what emerged from randomized clinical trials3 and suggests that pathogenic mechanisms underlying PIRA can be, at least in part, modified by currently approved DMTs. Importantly, in the subgroup assessed every 6 months, a delayed DMT initiation was associated with higher risk of both RAW and PIRA events. Recent data also suggest that the efficacy of DMT decreases with increasing age.17,18 Because PIRA, particularly early PIRA,6 can predict worse long-term prognosis and is partially preventable by DMT, early diagnosis and treatment represent the cornerstones of MS management.
Limitations
A few limitations of our study should be considered. The definition of CDA events was based solely on the EDSS score. In a previous observational study,3 PIRA was largely driven by more sensitive quantitative assessment tools of lower and upper limb function. Therefore, we cannot exclude an underestimation of PIRA events, particularly in POMS. Furthermore, in POMS, cognitive impairment, identified using appropriate neuropsychological tools, can prevail on physical disability.19 On the other hand, compared with previous work, we used a more stringent and reliable definition of CDA, RAW, and PIRA, requiring a 48-week confirmation to assign EDSS end points.20 In our population, most of the patients were treated with moderate-efficacy treatments, so we could not distinguish between moderate-efficacy treatment and HET effects: in this regard, emerging evidence suggests that HET can be more effective than platform drugs.3 Furthermore, in the assessment of DMT effectiveness, an immortal time bias cannot be ruled out, particularly for events such as PIRA, which could take longer to occur. Last, MRI data within 2 years of PIRA were available in 68% of patients. However, it is likely that this issue had a limited impact on the main study findings. Indeed, in the subgroup with MRI data available, factors associated with true PIRA were comparable with those of PIRA in the whole cohort.
Conclusions
Our data from this cohort study add to previous observations on PIRA in early RMS and expand our understanding of the biology of MS by focusing on POMS. The availability of a large cohort of patients with POMS, mostly treated with moderate-efficacy treatment, allowed us to demonstrate that PIRA and RAW are very early events in the disease course regardless of disease duration. Moderate-efficacy treatment only partially reduces their occurrence, which calls for future evaluation of the effect of early use of HET in the pediatric population. In addition, these results provide novel information about age-related differences in rates of PIRA and RAW events, assessed during the entire patient age spectrum. Further investigation on pathologic substrates of PIRA and RAW through imaging and other potential biomarkers is required.
eFigure 1. Study Population Flowchart
eTable. Multivariable Cox Proportional Hazard Regression Model to Estimate Risk of Reaching the First True PIRA in Patients With MRI Available Within 2 Years From the Event
Nonauthor Collaborators
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure 1. Study Population Flowchart
eTable. Multivariable Cox Proportional Hazard Regression Model to Estimate Risk of Reaching the First True PIRA in Patients With MRI Available Within 2 Years From the Event
Nonauthor Collaborators
Data Sharing Statement