Research JAMA Neurology | Original Investigation Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis Carmen Tur, MD, PhD; Pere Carbonell-Mirabent, MSc; Álvaro Cobo-Calvo, MD, PhD; Susana Otero-Romero, MD, PhD; Georgina Arrambide, MD, PhD; Luciana Midaglia, MD; Joaquín Castilló, MD, PhD; Ángela Vidal-Jordana, MD, PhD; Breogán Rodríguez-Acevedo, MD; Ana Zabalza, MD; Ingrid Galán, MD; Carlos Nos, MD; Annalaura Salerno, MD; Cristina Auger, MD; Deborah Pareto, PhD; Manuel Comabella, MD, PhD; Jordi Río, MD, PhD; Jaume Sastre-Garriga, MD, PhD; Àlex Rovira, MD; Mar Tintoré, MD, PhD; Xavier Montalban, MD, PhD Editorial IMPORTANCE Progression independent of relapse activity (PIRA) is the main event Supplemental content responsible for irreversible disability accumulation in relapsing multiple sclerosis (MS). OBJECTIVE To investigate clinical and neuroimaging predictors of PIRA at the time of the first demyelinating attack and factors associated with long-term clinical outcomes of people who present with PIRA. DESIGN, SETTING, AND PARTICIPANTS This cohort study, conducted from January 1, 1994, to July 31, 2021, included patients with a first demyelinating attack from multiple sclerosis; patients were recruited from 1 study center in Spain. Patients were excluded if they refused to participate, had alternative diagnoses, did not meet protocol requirements, had inconsistent demographic information, or had less than 3 clinical assessments. EXPOSURES Exposures included (1) clinical and neuroimaging features at the first demyelinating attack and (2) presenting PIRA, ie, confirmed disability accumulation (CDA) in a free-relapse period at any time after symptom onset, within (vs after) the first 5 years of the disease (ie, early/late PIRA), and in the presence (vs absence) of new T2 lesions in the previous 2 years (ie, active/nonactive PIRA). MAIN OUTCOMES AND MEASURES Expanded Disability Status Scale (EDSS) yearly increase rates since the first attack and adjusted hazard ratios (HRs) for predictors of time to PIRA and time to EDSS 6.0. RESULTS Of the 1128 patients (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]) included in the study, 277 (25%) developed 1 or more PIRA events at a median (IQR) follow-up time of 7.2 (4.6-12.4) years (for first PIRA). Of all patients with PIRA, 86 of 277 (31%) developed early PIRA, and 73 of 144 (51%) developed active PIRA. Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than Author Affiliations: Multiple those without PIRA. Older age at the first attack was the only predictor of PIRA (HR, 1.43; Sclerosis Centre of Catalonia, 95% CI, 1.23-1.65; P < .001 for each older decade). Patients with PIRA had steeper EDSS yearly Department of Neurology/ increase rates (0.18; 95% CI, 0.16-0.20 vs 0.04; 95% CI, 0.02-0.05; P < .001) and an 8-fold Neuroimmunology, Hospital Universitari Vall d’Hebron, Universitat greater risk of reaching EDSS 6.0 (HR, 7.93; 95% CI, 2.25-27.96; P = .001) than those without Autònoma de Barcelona, Barcelona, PIRA. Early PIRA had steeper EDSS yearly increase rates than late PIRA (0.31; 95% CI, Spain (Tur, Carbonell-Mirabent, 0.26-0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) and a 26-fold greater risk of reaching Cobo-Calvo, Otero-Romero, Arrambide, Midaglia, Castilló, EDSS 6.0 from the first attack (HR, 26.21; 95% CI, 2.26-303.95; P = .009). Vidal-Jordana, Rodríguez-Acevedo, CONCLUSIONS AND RELEVANCE Results of this cohort study suggest that for patients with Zabalza, Galán, Nos, Comabella, Río, Sastre-Garriga, Tintoré, Montalban); multiple sclerosis, presenting with PIRA after a first demyelinating event was not uncommon Section of Neuroradiology, and suggests an unfavorable long-term prognosis, especially if it occurs early in the disease Department of Radiology, Vall course. d’Hebron University Hospital, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain (Salerno, Auger, Pareto, Rovira). Corresponding Author: Carmen Tur, MD, PhD, Multiple Sclerosis Centre of Catalonia, Department of Neurology/ Neuroimmunology, Hospital Universitari Vall d’Hebron, Passeig de la Vall d’Hebron, JAMA Neurol. doi:10.1001/jamaneurol.2022.4655 119-129, 08035, Barcelona, Spain Published online December 19, 2022. (ctur@cem-cat.org). (Reprinted) E1 Downloaded From: https://jamanetwork.com/ on 12/21/2022 Research Original Investigation Early Progression Independent of Relapse Activity and Long-term Disability After a First Demyelinating Event in MS I n multiple sclerosis (MS), the irreversible accumulation of disability may occur at any stage of the disease1-4 and Key Points through 2 main mechanisms: relapse-associated worsen- Question What are the long-term outcomes of patients ing (RAW) and progression independent of relapse activity developing progression independent of relapse activity (PIRA) (PIRA).4 Nonetheless, PIRA, associated with a predominant un- after a first demyelinating event in multiple sclerosis? derlying neurodegenerative component,2-5 seems to be the Findings In this longitudinal cohort study including 1128 patients most important mechanism even in patients with no formal with a first demyelinating event in multiple sclerosis, presenting diagnosis of secondary progressive MS.3,4 with PIRA was associated with significantly shorter times to PIRA has been studied in patients with very early MS, in- developing severe disability compared with not presenting with cluding patients after a first demyelinating attack of the cen- PIRA. Patients presenting with PIRA within the first 5 years of tral nervous system6 and patients with established MS.2,4 How- multiple sclerosis had a significantly 26-fold greater risk of ever, the clinical and neuroimaging predictors of PIRA at the developing severe disability than patients whose first PIRA appeared late in the disease. time of the first demyelinating event have not yet, to our knowl- edge, been investigated. Additionally, the long-term disabil- Meaning Results suggest that presenting with PIRA after a first ity outcomes of patients who present with PIRA are still largely demyelinating event in multiple sclerosis is an ominous prognosis, unknown. Considering that PIRA may be understood as the first especially if it occurs early in the disease course. clinical sign of progression in a relapsing-remitting context, it is important to know whether patients who develop their first PIRA event very early in the disease course show a particu- quences [DMT onset and stop dates]). EDSS scores were ob- larly unfavorable prognosis. Furthermore, the association of tained within 3 months after the first demyelinating attack and PIRA with brain inflammatory activity is still unclear.2,4 then (at least) annually. Also collected were paraclinical With this longitudinal study of a uniquely large cohort of data, ie, the presence of oligoclonal bands (OBs) in the cere- patients with a first demyelinating event,7,8 we aimed to esti- brospinal fluid (CSF) and serum at the first attack, which were mate the risk of PIRA after symptom onset and investigate its tested on agarose gel isoelectric focusing combined with potential clinical and magnetic resonance imaging (MRI) pre- immunoblotting11 and MRI data of the brain and spinal cord, dictors at the time of such first event. We also aimed to evalu- which included the number and topography of T2 lesions and ate the long-term evolution of those patients with PIRA and the presence of contrast-enhancing lesions (CELs) at the first understand the potential association between the timing of attack and the number of new brain T2 lesions on follow-up the first PIRA event or the presence of recent inflammatory ac- MRI scans. Brain MRI scans were performed within the first 5 tivity before PIRA and the long-term disability outcomes. months after symptom onset, then 12 months afterward, and at least every 5 years thereafter, for all patients. Additionally, patients could undergo a new brain MRI scan when new symp- toms were reported or before starting any new treatment.12 Methods After 2007, spinal cord MRI scans were performed systemati- Study Design and Participants cally for all patients at study baseline (ie, within 5 months of This was a retrospective analysis of data from patients pro- the first demyelinating attack), regardless of the topography spectively included in the deeply phenotyped Barcelona co- of the first attack. hort of patients with a first demyelinating attack from the Mul- tiple Sclerosis Center of Catalonia7-9 between January 1, 1994, Definition of PIRA and PIRA Subgroups and July 31, 2021. The study protocol was evaluated by the Definition of PIRA and RAW ethics committee of Vall d’Hebron Hospital. The cohort in- We defined a PIRA event as experiencing confirmed disabil- cluded patients younger than 50 years who experienced a first ity accumulation (CDA) in the EDSS scale at 6 months during demyelinating event of the central nervous system that could a period free of relapses (PFRs) (Figure 1). A PFR was the time not be attributed to other diseases. Patients were assessed at between 2 consecutive relapses, starting 3 months after a re- the Multiple Sclerosis Center of Catalonia within 3 months of lapse (or 6 months after the first demyelinating event). The first the first demyelinating attack.7 For the current study, only those EDSS score obtained at least 6 months after the first attack or patients with at least 3 Expanded Disability Status Scale (EDSS) 3 months after any other attack was referred to as the base- assessments were included. All patients provided written in- line EDSS score and rebaseline EDSS score, respectively. formed consent. This study followed the Strengthening the We set that no rebaseline EDSS score could be lower than the Reporting of Observational Studies in Epidemiology (STROBE) first recorded (baseline) EDSS score.4 CDA was defined as an reporting guidelines. increase in the EDSS score of 1.5, 1.0, or 0.5 if the baseline/ rebaseline EDSS score was, respectively, 0, 1.0 to 5.0, or greater Demographic, Clinical, and Paraclinical Data than 5.0. The date of PIRA was the date of the confirmation The included information consisted of demographics (sex, age of the CDA. Any other episodes of CDA that did not qualify at first demyelinating attack) and clinical data (date and to- for PIRA (ie, which occurred outside the PFR) were consid- pography of the first demyelinating event, presence and dates ered to be RAW events. Those patients with at least 1 CDA but of relapses [recorded at each visit], disability status accord- who did not present with any PIRA event were considered ing to the EDSS,10 and disease-modifying treatment [DMT] se- patients with RAW. E2 JAMA Neurology Published online December 19, 2022 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 12/21/2022 Early Progression Independent of Relapse Activity and Long-term Disability After a First Demyelinating Event in MS Original Investigation Research Figure 1. Patient Flowchart and 6-Month Confirmed Disability Accumulation (CDA) A Patient flowchart B 6-mo CDA 1459 Patients presented with a first demyelinating PIRA event attack at Cemcat PIRA event EDSS score 120 Excluded 58 Had alternative diagnosis 26 Exceeded the inclusion window 21 Had previous relapse 11 Did not agree to study inclusion 4 >50 y at first attack First Relapse Relapse Time 1339 Included in deeply phenotyped first demyelinating demyelinating event cohort attack ≥6 mo Free-relapse 3 mo Free-relapse 3 mo Free-relapse period 1 period 2 period 3 211 Excluded 209 Did not have enough EDSS assessments 2 Had inconsistent demographic Original study baseline EDSS score information Re-baseline EDSS score 1128 With a first demyelinating event with sufficient EDSS assessments included A, Patient flowchart from the whole deeply phenotyped cohort until the study cohort, with 1128 patients. B, Display of how the events of 6-month CDA were considered. The periods shaded in gray (6 months after the first attack and 3 months after any other event) represent the periods where any increase in Expanded Disability Status Scale (EDSS) score is considered to be associated with relapses. The time outside of these gray-shaded periods is referred to as periods free of relapses (PFRs). Any CDA within a PFR was considered a progression independent of relapse activity (PIRA) event, whereas any CDA outside a PFR was considered a relapse-associated worsening event. Patients with at least 1 CDA who had at least 1 PIRA event were considered patients with PIRA. Instead, patients with at least 1 CDA who never presented with a PIRA event were called patients with a relapse-associated worsening event. CDA was considered when a minimum EDSS increase was observed: 1.5, 1.0, or 0.5 points, with respect to a baseline/rebaseline EDSS score of 0, 1.0 to 5.0, or greater than 5.0, respectively. PIRA Subgroups of total follow-up). eTable 1 in the Supplement shows the high- All patients with PIRA were classified into early PIRA or late efficacy drugs prescribed to our patients. For all survival mod- PIRA groups, depending on whether the first PIRA event oc- els, the proportional hazard assumption was assessed through curred within the first 5 years since their first attack or after- visual inspection of scaled Schoenfeld residuals and through ward, respectively; the choice of a 5-year cutoff is taken from scaled Schoenfeld residuals test from Stata/SE, version 14.2 previous longitudinal studies of primary progressive MS, which (StataCorp). considered early disease to be disease with a duration less than 5 years.13-16 Patients with PIRA were further classified into Long-term Clinical Outcomes active PIRA or nonactive PIRA groups, depending on the pres- Comparisons across groups (ie, PIRA vs no PIRA, PIRA vs RAW, ence or absence, respectively, of new T2 lesions observed in or PIRA subgroups) were made with respect to different lon- the 2 years before developing PIRA. The latter classification gitudinal outcomes: (1) the yearly rates of EDSS increase since was applied on a subcohort of patients with a brain MRI scan the first demyelinating attack and (2) the risk of reaching available within the 2 years before developing PIRA. 6-month confirmed EDSS 6.0 from the first demyelinating attack. Statistical Analyses The yearly rates of EDSS increase since the first demyelin- Descriptive Statistics and Baseline Comparisons ating attack were evaluated through linear mixed models. In We assessed the proportion of patients developing PIRA and such models, the EDSS score at each time point was consid- compared clinical/paraclinical characteristics across groups ered as the dependent variable, and time (in years) was the (PIRA vs no PIRA, PIRA vs RAW, PIRA subgroup comparisons) main explanatory variable. Moreover, we included, as a co- at the time of the first demyelinating event using parametric variate, a quadratic term for time in order to account for a non- or nonparametric tests as appropriate. linear behavior of the EDSS increase over time. To assess Kaplan-Meier and Cox regression models were built to as- differences between groups, a binary indicator of group sess, respectively, the risk of PIRA and the association of base- (eg, PIRA/no PIRA) and an interaction term such as time X line (first attack) characteristics (age, sex, topography of first binary group indicator were also included as covariates. When- attack, brain and spinal cord lesion number categories, brain ever the interaction term was significant, we assumed that CEL number category, and OBs) with such risk. Cox models the 2 groups differed in terms of EDSS changes over time. were also adjusted for (binary) DMT exposure (treated as a time- All these models were adjusted for the following first at- varying covariate, assuming that treatment exposure started tack–related covariates: age, sex, topography of first attack, when the first DMT started and finished at the end of follow- brain and spinal cord lesion number categories, brain CEL num- up) and for percentage time receiving high-efficacy drugs (out ber category, and OBs. Models were also adjusted for the pro- jamaneurology.com (Reprinted) JAMA Neurology Published online December 19, 2022 E3 Downloaded From: https://jamanetwork.com/ on 12/21/2022 Research Original Investigation Early Progression Independent of Relapse Activity and Long-term Disability After a First Demyelinating Event in MS portion of time receiving DMTs and the proportion of time information, 73 (51%) developed new T2 lesions before devel- receiving high-efficacy DMTs (out of total follow-up in both oping PIRA. For patients with PIRA who had (n = 144) and did cases). Mixed models had random intercept (for patient) not have (n = 133) recent pre-PIRA MRI information, MRI and and random slope (for time), with unstructured covariance clinical data were similar at baseline (data not shown). structure. At baseline, patients with PIRA had more T2 lesions in the The risk of reaching 6-month confirmed EDSS 6.0 from the brain and were more likely to have CSF OB than patients with- first demyelinating attack was evaluated with Kaplan-Meier out PIRA (Table 1). Patients with early PIRA were older (mean and Cox regression models, including a binary indicator of [SD] age, 34.8 [7.9] years vs 32.1 [8.3] years) and had more spi- group (eg, PIRA/no IRA) as an explanatory variable. Kaplan- nal cord lesions (≥4 lesions, 5 of 57 [8.8%] vs 7 of 97 [7.2%]) Meier estimates were compared across groups through log- than those with late PIRA. Patients with active PIRA were rank tests. Cox models were adjusted for first attack–related younger (mean [SD] age, 31.1 [8.3] years vs 35.2 [8.3] years) and covariates: age, sex, first attack topography, brain and spinal more likely to have CSF OBs (51 of 63 [81.0%] vs 35 of 60 cord lesion number categories, brain CEL number category, [58.3%]) than those with nonactive PIRA and had more brain and OBs. Models were also adjusted for DMT exposure: bi- T2 lesions (≥9 lesions, 49 of 72 [68.1%] vs 26 of 69 [37.7%]) nary time-varying covariate (for any DMT) plus adjustment (Table 1). for the percentage of time receiving high-efficacy drugs (out of total follow-up). Adjusted hazard ratios (HRs) for predic- Risk of PIRA After a First Demyelinating Attack tors of time to EDSS 6.0 were obtained. Our Kaplan-Meier analysis revealed that an estimated 8% of all patients (86 of 1128) who present with a first demyelinat- Sensitivity Analyses ing attack may develop PIRA within the first 5 years of the In order to understand to what extent our results could be disease, and an estimated 50% (564 of 1128) may do so within influenced by the presence of a large proportion of patients the first 22 years (Figure 2). Regarding all potential predictors with a first demyelinating attack who most likely would of PIRA at the time of the first attack, only older age was as- never progress, we repeated all our analyses with only those sociated with a higher risk of PIRA: for each older decade at patients who fulfilled McDonald 2017 criteria at any time first attack, the risk of PIRA increased by 43% (HR for each during the follow-up. decade, 1.43; 95% CI, 1.23-1.65; P < .001) (eTable 2 in Supple- Statistical evidence was considered when 2-sided P val- ment). ues were <.05. Statistical analyses were performed with R Core team, version 3.6.0 (R Foundation Statistical Comput- Long-term Clinical Outcomes ing), and Stata/SE, version 14.2 (StataCorp). PIRA vs non-PIRA For all patients, the estimated adjusted rate of EDSS increase was 0.07 points per year (95% CI, 0.06-0.09; P < .001), al- though this increase was nonlinear because there was a flat- Results tening of the curve as time went along. Patients with PIRA Descriptive Statistics showed a significantly steeper increase in EDSS scores than Of the 1339 patients belonging to our cohort,7 1128 patients those without PIRA (Figure 2), which was maintained after ad- (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]; justing for confounders (0.18; 95% CI, 0.16-0.20 vs 0.04; 347 male individuals [30.8%]) met the inclusion criteria for this 95% CI, 0.02-0.05; P < .001) (Table 2). Additionally, Kaplan- study (Figure 1). Of all PIRA patients, 86 of 277 (31%) devel- Meier estimates showed that patients with PIRA had a greater oped early PIRA, and 73 of 144 (51%) developed active PIRA. risk of reaching EDSS 6.0 than those without PIRA (Figure 2; The median (IQR) time of follow-up was 10.5 years (5.2-17.1) Table 2). This was confirmed through adjusted Cox models years (Table 1). Patients had a median (IQR) number of visits (HR, 7.93; 95% CI, 2.25-27.96; P = .001) (Table 2). of 16 (7-36), which made a total of 27 355 EDSS assessments. Of the 1128 study patients, 419 (37%) had at least 1 episode of PIRA vs RAW CDA: 277 of 419 (66%) had at least 1 PIRA event, whereas in No significant differences were observed between patients the remaining 142 (34%), all their CDA episodes qualified for with PIRA and patients with RAW in terms of yearly EDSS in- RAW. In our patients with PIRA, who represented the 25% of crease rates. However, Kaplan-Meier analyses (Figure 3) and all patients with a first demyelinating attack, the first PIRA Cox regression models showed that patients with PIRA reached event occurred at a median (IQR) time of 7.2 (4.6-12.4) years, EDSS 6.0 at significantly faster rates than patients with RAW and 86 of patients (31%) developed PIRA within the first 5 years (HR, 4.11; 95% CI, 1.76-9.62; P = .001). of the disease. Of those 277 patients who had PIRA, 144 (52.0%) had a re- Early PIRA vs Late PIRA cent pre-PIRA MRI done within the 2 years before PIRA. The Patients with early PIRA showed significantly steeper EDSS in- median (IQR) time between this pre-PIRA MRI and the first crease rates than those with late PIRA (0.31; 95% CI, 0.26- PIRA event was 1.0 (0.1-2.0) years. The median (IQR) time be- 0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) (Table 2). Further- tween this pre-PIRA MRI scan and the previous MRI (used as more, patients with early PIRA had a greater risk of reaching reference to assess new T2 lesions in the pre-PIRA scan) was EDSS 6.0 at faster rates than those with late PIRA, according 1.7 (0-10.6) years. Of all 144 patients with recent pre-PIRA MRI to Kaplan-Meier analyses and especially multivariable Cox E4 JAMA Neurology Published online December 19, 2022 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 12/21/2022 Early Progression Independent of Relapse Activity and Long-term Disability After a First Demyelinating Event in MS Original Investigation Research Table 1. Description of All Study Patients With a First Demyelinating Event (N = 1128) All P value, P value, included P value, early active vs patients PIRA No PIRA PIRA vs Early PIRA Late PIRA PIRA vs Active PIRA Nonactive nonactive Characteristic (N = 1128) (n = 277) (n = 851) no PIRA (n = 86) (n = 191) late PIRA (n = 73) PIRA (n = 71) PIRA Age at first attack, 32.1 (8.3) 33.0 (8.2) 31.8 (8.3) .05a 34.8 (7.9) 32.1 (8.3) .01a 31.1 (8.3) 35.2 (8.3) .004a mean (SD), y Sex, No. (%) Male 347 87 (31.4) 260 (30.6) 33 (38.4) 54 (28.3) 29 (39.7) 17 (23.9) (30.8) .85b .12b .06b Female 781 (69.2) 190 (68.6) 591 (69.4) 53 (61.6) 137 (71.7) 44 (60.3) 54 (76.1) Topography of first attack, patient No. (%) Optic nerve 385 (34.1) 91 (32.9) 294 (34.5) 20 (23.3) 71 (37.2) 17/73 (23.3) 29/71 (40.8) Brainstem 283 (25.1) 74 (26.7) 209 (24.6) b 27 (31.4) 47 (24.6) b 23/73 (31.5) 15/71 (21.1) .69 .14 .14b Spinal cord 333 (29.5) 86 (31.1) 247 (29.0) 29 (33.7) 57 (29.8) 26/73 (35.6) 21/71 (29.6) Other 121 (10.7) 26 (9.4) 95 (11.2) 10 (11.6) 16 (8.4) 7/73 (9.6) 6/71 (8.5) T2 lesion No. category at first attack, patient No. (%) 0 Lesions 280/1077 54/268 226/809 15/83 (18.1) 39/185 3/72 (4.2) 21/69 (30.4) (26.0) (20.2) (27.9) (21.1) 1-3 Lesions 154/1077 34/268 120/809 7 /83 (8.4) 27/185 10/72 (13.9) 10/69 (14.5) (14.3) (12.7) (14.8) (14.6) .03b 36b <.001b 4-8 Lesions 137/1077 38/268 99/809 11 /83 (13.3) 27/185 10/72 (13.9) 12/69 (17.4) (12.7) (14.2) (12.2) (14.6) ≥9 Lesions 506/1077 142/268 364/809 50/83 (60.2) 92/185 49/72 (68.1) 26/69 (37.7) (47.0) (53.0) (45.0) (49.7) ≥1 lnfratentorial 436/836 83/188 353/648 .02b 41/70 (58.6) 64/118 .67b 39/54 (72.2) 15/49 (30.6) <.001b lesion category at (52.2) (44.2) (54.5) (54.2) first attack, patient No. (%) Spinal cord lesion category at first attack, patient No. (%) 0 Lesions 423/661 111/154 312/507 34/57 (59.6) 77/97 (79.4) 20/33 (61.1) 35/47 (74.5) (64.0) (72.1) (61.5) 1 Lesion 120 /661 20/154 100/507 12/57 (21.1) 8/97 (8.2) 4/33 (12.1) 7/47 (14.9) (18.2) (13.0) (19.7) .11b .05b .10b 2-3 Lesions 55/661 11/154 44/507 6/57 (10.5) 5/97 (5.2) 6/33 (18.2) 1/47 (2.1) (8.3) (7.1) (8.7) ≥4 Lesions 63/661 12/154 51/507 5/57 (8.8) 7/97 (7.2) 3/33 (9.1) 4/47 (8.5) (9.5) (7.8) (10.1) No. of CEL category at first attack, patient No. (%) 0 Lesions 523/804 124/190 399/614 39/66 (59.1) 85/124 36/59 (61.0) 39/47 (83.0) (65.1) (65.3) (65.0) (68.5) 1 Lesion 117/804 28/190 89 /614 14/66 (21.2) 14/124 10/59 (16.9) 2/47 (4.3) .99b .18b .03b (14.6) (14.7) (14.5) (11.3) >1 Lesions 164/804 38/190 126/614 13/66 (19.7) 25/124 13/59 (22.0) 6/47 (12.8) (20.4) (20.0) (20.5) (20.2) Presence of OBs at 577/956 158/234 419/722 .01b 50/73 (68.5) 108/161 .95b 51/63 (81.0) 35/60 (58.3) .01b first attack, No. (%) (60.4) (67.5) (58.0) (67.1) Follow-up characteristics Follow-up time, 10.46 16.95 8.65 <.001c 13.0 17.9 <.001c 17.1 14.1 .06c median (IQR), y (5.2-17.1) (11.5-20.9) (4.4-14.1) (6.8-18.7) (13.2-21.4) (11.8-21.2) (8.3-19.7) Time to first 7.22 7.22 NA NA 3.8 10.1 <.001c 6.6 6.9 .56c PIRA, median (4.6-12.4) (4.6-12.4) (3.0-4.4) (7.0-14.7) (4.4-10.8) (3.4-11.9) (IQR), y ARR considering 0.21 0.17 0.2 <.001c 0.2 (0.1-0.3) 0.2 (0.1-0.3) .10c 0.2 (0.2-0.4) 0.1 (0.1-0.3) <.001c the whole (0.1-0.4) (0.1-0.3) (0.1-0.4) follow-up, median (IQR) No. of patients 580/1109 166/274 414/835 .002b 57/84 (67.9) 109/190 .13b 64/72 (88.9) 30/71 (42.3) <.001b treated with (52.3)d (60.6)d (49.6)d (57.4) DMTs at any time during follow-up (%)d (continued) jamaneurology.com (Reprinted) JAMA Neurology Published online December 19, 2022 E5 Downloaded From: https://jamanetwork.com/ on 12/21/2022 Research Original Investigation Early Progression Independent of Relapse Activity and Long-term Disability After a First Demyelinating Event in MS Table 1. Description of All Study Patients With a First Demyelinating Event (N = 1128) (continued) All P value, P value, included P value, early active vs patients PIRA No PIRA PIRA vs Early PIRA Late PIRA PIRA vs Active PIRA Nonactive nonactive Characteristic (N = 1128) (n = 277) (n = 851) no PIRA (n = 86) (n = 191) late PIRA (n = 73) PIRA (n = 71) PIRA Proportion of time receiving DMT during whole follow-upe Median (IQR) 0.1 (0-0.8) 0.4 (0-0.9) 0 (0-0.8) 0.6 (0-0.9) 0.33 (0-0.8) 0.7 (0.5-0.9) 0 (0-0.7) .006c .05c <.001c Mean (SD) 0.4 (0.4) 0.4 (0.4) 0.4 (0.4) 0.5 (0.4) 0.4 (0.4) 0.6 (0.3) 0.3 (0.4) Abbreviations: ARR, annualized relapse rate; CEL, contrast-enhancing lesion; (n = 19) because they could have received placebo (we do not have DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; information on treatment allocation). HR, hazard ratio; IT, interaction term; NA, not applicable; OB, oligoclonal band; e In the numerator, we have only considered those periods of time outside PIRA, progression independent of relapse activity. clinical trials, since we are still blinded to treatment allocation in some (n = 51) a t Test. of those patients who have participated in clinical trials (n = 71), ie, those b χ2 Test. periods of time within a clinical trial have been considered as if the patient was c not treated. Mann-Whitney U test (comparison of medians). d We have excluded those patients who were part of a randomized clinical trial Figure 2. Long-term Outcomes: Progression Independent of Relapse Activity (PIRA) vs No PIRA Comparison and Comparison Between PIRA Subgroups A Cumulative probability of first PIRA event after first demyelinating event B Time to EDSS score of 6.0 by PIRA status 1.0 1.0 No PIRA 0.8 0.8 Patients with first Survival probability demyelinating event Survival probability PIRA 0.6 0.6 0.4 0.4 0.2 0.2 P <.001 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Time from first demyelinating event, y Time from first demyelinating event, y No. at risk No. at risk Patients with first No PIRA 851 606 372 192 76 9 demyelinating event 1128 797 471 238 86 10 PIRA 277 263 212 139 74 6 C Estimated EDSS trajectories by PIRA status D Main characteristics of PIRA subgroups 8.0 Characteristic Early PIRA Late PIRA P <.001 Age at first attack, mean (SD), ya 34.80 (7.92) 32.14 (8.26) 7.5 SC lesions, %a 40.4% 20.6% ARR, median (IQR) 0.20 (0.12-0.31) 0.15 (0.08-0.31) EDSS score Adjusted EDSS yearly rates (95% CI)b 0.31 (0.26- 0.35) 0.13 (0.10-0.16) 5.0 Adjusted HR for time to EDSS 6.0 (95% CI)b 26.21 (2.26-303.95) 1 [Reference] PIRA Characteristic Active PIRA Nonactive PIRA 2.5 Age at first attack, mean (SD), yb 31.07 (8.28) 35.15 (8.29) SC lesions, %c 38.9% 25.5% No PIRA ARR, median (IQR)b 0.23 (0.15-0.40) 0.13 (0.08-0.29) 0 0 5 10 15 20 Adjusted EDSS yearly rates (95% CI)a 0.20 (0.15-0.25) 0.12 (0.06-0.18) Time from first demyelinating event, y Adjusted HR for time to EDSS 6.0 (95% CI) 2.51 (0.58-10.85) 1 [Reference] A, Cumulative probability according to Kaplan-Meier estimations of subgroups. Early PIRA was associated with steeper EDSS trajectories over time experiencing the first PIRA event after the first demyelinating attack. and a higher risk of reaching EDSS 6.0 than late PIRA. Although patients with Our estimations show that approximately 22 years after the first demyelinating active PIRA and late PIRA (marginally) differed in terms of yearly EDSS increase event, 50% of all patients will have developed PIRA. B, Cumulative probabilities rates, no significant differences were observed in survival models after according to Kaplan-Meier estimations of reaching Expanded Disability Status adjusting for confounders. ARR indicates annualized relapse rate; Scale (EDSS) score of 6.0 in the PIRA and non-PIRA groups. C, Estimated EDSS HR, hazard ratio; SC, spinal cord. trajectories over time for patients with and without PIRA. Both panels B and C a P < .05. show that patients with PIRA presented a much worse clinical evolution over b P < .01. time than those without PIRA. D, The main characteristics for the different PIRA E6 JAMA Neurology Published online December 19, 2022 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 12/21/2022 Early Progression Independent of Relapse Activity and Long-term Disability After a First Demyelinating Event in MS Original Investigation Research regression models (HR, 26.21; 95% CI, 2.26-303.95; P = .009) nonactive PIRA P value, active (Table 2). patient reached that score for the second time; for that analysis, we did not exclude those 10 patients who PIRA vs .003 Active PIRA vs Nonactive PIRA 0.12 (0.06-0.18) .05 .22 Although (unadjusted) Kaplan-Meier analyses showed faster 38.32 (22.05-51.19) 10.46 (0-21.50) rates of reaching EDSS 6.0 among patients with active PIRA, 4.86 (0-10.09) 24.54 (12.18-35.15) 4.86 (0-10.09) Nonactive PIRA 1.52 (0-4.42) 1 [Reference] no significant differences were observed between active PIRA (n = 71) and nonactive PIRA in terms of confounder-adjusted EDSS yearly increase rates or Cox regression models (Table 2). All analyses were repeated using a subcohort of patients who Active PIRA (n = 73) developed 2017 McDonald MS at some time during the 9.11 (1.86-15.82) 2.51 (0.58-10.85) 0.20 (0.15-0.25) follow-up (n = 754), and the results were very similar, being 1.37 (0-4.00) the main messages maintained (eTables 2, 3, 4, and 5 in the Supplement). reached the outcome before the diagnosis of PIRA. P value, early Discussion late PIRA PIRA vs <.001 .009 In this cohort study, results suggest that one-fourth of all .07 patients presenting with a first demyelinating event may 16.41 (9.47-22.82) Late PIRA (n = 191) develop a first PIRA event within the first 12 years after 0.13 (0.10-0.16) 3.24 (0.65-5.76) 9.10 (4.55-3.42) symptom onset, and almost 10% may do so within the first 5 0.52 (0-1.54) 1 [Reference] years. Further, results suggest that PIRA was associated with, for most patients, a sustained accumulation of disabil- ity, which is strongly associated with unfavorable long-term outcomes. In addition, presenting PIRA early in the disease 23.93 (11.01-34.98) 23.93 (11.01-34.98) 26.21 (2.26-303.95) 12.03 (3.71-19.63) Early PIRA (n = 86) course was associated with an even worse prognosis, inde- 0.31 (0.26-0.35) pendent of the inflammatory burden at the time of the first 2.41 (0-5.67) demyelinating attack. Our data are similar to those reported by Portaccio et al6 Abbreviations: EDSS, Expanded Disability Status Scale; HR, hazard ratio; IT, interaction term; NA, not applicable; in their article investigating PIRA in early MS. Thus, it ap- The Methods section provides full details on model adjustment: outcome EDSS 6.0 was reached when the pears that a substantial proportion of patients with MS may de- P value, no PIRA PIRA vs <.001 <.001 velop progression in the absence of relapses very early in the .001 disease course. This is more typical of a progressive pheno- type than of a relapsing-remitting one.17,18 Although second- No PIRA (n = 851) 0.04 (0.02-0.05) 1.02 (0.18-1.86) 1.74 (0.42-3.03) 2.45 (0.53-4.33) ary progressive MS has been classically associated with a 0.24 (0-0.57) 1 [Reference] minimum level of disability,19 apparently a percentage of patients with relapsing MS can become progressive early in the disease course. We believe that these patients should be considered to be patients with progressive MS, with or with- 9.25 (6.23-12.19) 18.49 (12.37-24.19) out MRI inflammatory activity, independent of their disabil- 12.82 (8.18-17.23) 7.93 (2.25-27.96) 0.18 (0.16-0.20) 5.58 (2.69-8.39) ity score or their disease duration. This may have therapeutic PIRA (n = 277) 1.09(0-2.31) implications. Table 2. Prediction of Long-term Outcomes (N = 1128) At the time of the first demyelinating event, patients with PIRA were older, slightly more prone to having brain lesions, and more prone to having CSF OBs than those without PIRA. PIRA, progression independent of relapse activity. 0.07 (0.06-0.09) 0.48 (0.06-0.90) 2.54 (1.41-3.65) 6.00 (3.97-7.98) All study patients However, despite these differences, predicting which pa- tients would finally develop PIRA based only on baseline char- (N = 1128) acteristics was challenging. Among all clinical and MRI pre- dictors at the time of the first attack, only older age was NA associated with a greater risk of PIRA in the survival models, in line with previous studies.2,6 Interestingly, in the study by reaching confirmed EDSS Adjusted HR (95% CI) for reaching EDSS 6.0 from Kaplan-Meier estimates increase rates (95% CI) the first demyelinating (95% CI) of % patients Portaccio and colleagues,6 apart from older age at study base- demyelinating eventa Adjusted yearly EDSS line, PIRA could be predicted by the presence of a relapsing- 6.0 from the first remitting course, a longer disease duration, and a lower num- ber of relapses before the PIRA event.6 However, none of these Outcome 10 y 15 y 20 y eventa 5y predictors, except for older age, was immediately available at the time of the first attack. a jamaneurology.com (Reprinted) JAMA Neurology Published online December 19, 2022 E7 Downloaded From: https://jamanetwork.com/ on 12/21/2022 Research Original Investigation Early Progression Independent of Relapse Activity and Long-term Disability After a First Demyelinating Event in MS Figure 3. Long-term Outcomes: Progression Independent of Relapse Activity (PIRA) vs Relapse-Associated Worsening (RAW) Comparison A Changes in EDSS score from baseline to last follow-up Patients with PIRA Patients with RAW Patients without CDA 10 8 Difference between baseline and final EDSS score 6 4 2 0 –2 –4 B Time to EDSS score of 6.0 1.0 Patients without CDA Patients with RAW 0.8 Patients with PIRA Survival probability 0.6 0.4 0.2 Log-rank test: P <.001 PIRA vs RAW: P = .03 0 0 5 10 15 20 25 30 Time from first demyelinating event, y No. at risk Patients without CDA 709 471 269 124 51 6 Patients with PIRA 277 263 212 139 74 6 Patients with RAW 142 135 103 68 25 3 A, Crude description of nonconfirmed Expanded Disability Status Scale (EDSS) score changes between baseline EDSS and last clinical visit, for patients with PIRA, RAW, and no confirmed disability accumulation (CDA). Patients with PIRA and RAW seem to be associated with a much heavier disability burden than patients without CDA, even in this unadjusted picture. When comparing PIRA and RAW, PIRA seems to be associated with greater increases in EDSS score than RAW. These findings were then confirmed through survival models of time to EDSS 6.0 (B). B, Kaplan-Meier curves of time to EDSS 6.0 from the first demyelinating attack, for patients with PIRA, RAW, and without CDA. All 3 survival curves were very different (log-rank test, χ 22 = 44.11; P <.001). Patients with PIRA showed significantly faster rates of reaching EDSS 6.0 than patients with RAW (log-rank test, χ 12 = 4.88; P <.03). Importantly, patients with PIRA and those without PIRA This suggests that the worse prognosis of early PIRA may be, behaved very differently over time: patients with PIRA showed at least partly, independent of the inflammatory burden and much steeper EDSS increase rates than those without PIRA and older age at the first attack. This also indicates that more re- presented an almost 8-fold higher risk of reaching EDSS 6.0 search is needed not only to detect as soon as possible all who from the first demyelinating event. When those without PIRA will develop PIRA but also to understand the mechanisms were split into RAW and no CDA groups, we observed that leading to PIRA and especially the association between age and patients with RAW and PIRA were clearly different from those early PIRA. without CDA, as expected and reported by previous authors.6 Among those patients with PIRA with recent MRI infor- Furthermore, patients with PIRA showed a 4-fold higher risk mation before the first PIRA event, one-half of them had their of reaching EDSS 6.0 than patients with RAW. All these find- first PIRA in the presence of recent MRI inflammatory activ- ings indicate that early identification of those patients who ity. Although there was some evidence suggesting that active will develop PIRA may be crucial for managing patients’ ex- PIRA might have worse long-term outcomes, this was not con- pectations and, possibly, for choosing the most appropriate firmed in adjusted models and further research is warranted. treatment options. Importantly, we conducted all our analyses on a cohort of Our analyses revealed that one-third of all patients with patients with a first demyelinating event, regardless of whether PIRA had their first PIRA event within the first 5 years after they eventually developed MS or not. However, in order to as- symptom onset. These patients with early PIRA showed steeper sess to what extent our results could have been affected by the EDSS increase rates and reached EDSS 6.0 much faster than presence of a large proportion of patients who might never de- those with late PIRA, even after adjusting for confounders. velop MS (and therefore never progress), we repeated all our E8 JAMA Neurology Published online December 19, 2022 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 12/21/2022 Early Progression Independent of Relapse Activity and Long-term Disability After a First Demyelinating Event in MS Original Investigation Research analyses on a subcohort of patients who eventually fulfilled have given slightly different results. This is particularly rel- McDonald 2017 MS diagnostic criteria at some point during evant if we consider that our PIRA group was more exposed the follow-up. The results in this subcohort were very similar to DMTs than the non-PIRA group, which may have meant (almost identical) to those observed in the whole cohort of lower annualized relapse rates and, consequently, higher prob- patients, strengthening the message of our study. ability to detect PIRA (because of the longer PFRs). Future studies in this regard are therefore warranted. A further con- Limitations sideration stems from the fact that patients underwent MRIs This study has some limitations. One possible limitation stems not only as per protocol but also because they had symptoms from the uniquely long follow-up of our cohort and its dy- or were about to change treatment, which may have altered namic nature, which means that patients have been sub- the observed proportion of patients with active PIRA. jected to different diagnostic procedures over time,9 which may have potentially affected some of our measurements. For in- stance, only after 2007 did we begin to perform systematic spi- nal cord MRI scans at the time of the first demyelinating event. Conclusions Another consideration refers to the potential effects of treat- Results of this cohort study suggest that PIRA is essentially a ment. In this study, we included the proportion of follow-up nonreversible phenomenon associated with unfavorable time during receipt of DMTs as a covariate in the mixed- long-term disability outcomes, especially if such PIRA events effects models, and a binary time-dependent covariate in the occur early in the disease course. Identifying all who will de- Cox regression models. Additionally, we adjusted all our mod- velop PIRA as soon as possible after the first demyelinating els for the proportion of follow-up time while receiving high- event, especially early PIRA, may lead to better treatment efficacy DMTs. However, other more complex models might choices, and subsequently, better long-term outcomes. ARTICLE INFORMATION steering committee member of the O’HAND trial compensation for participating on advisory boards Accepted for Publication: September 9, 2022. and the Consensus Group on Follow-on DMTs; and from Biogen-Idec, Genzyme, Merck-Serono, Mylan, being a member of the editorial board of Neurology. Novartis, Teva, Sanofi-Aventis, Roche, and Janssen. Published Online: December 19, 2022. Dr Carbonell-Mirabent reported receiving grants Dr Sastre-Garriga reported receiving personal fees doi:10.1001/jamaneurol.2022.4655 from Biogen to Fundació Privada Cemcat for for advisory board participation, speaking Open Access: This is an open access article statistical analysis. Dr Cobo Calvo reported honoraria, and travel expenses from Novartis, distributed under the terms of the CC-BY License. receiving grants from Instituto de Salud Carlos III, Biogen, Sanofi, Celgene-BMS, Merck, Bial, Teva, © 2022 Tur C et al. JAMA Neurology. Spain; JR19/00007 during the conduct of the Almirall, Genzyme, and Roche outside the Author Contributions: Dr Tur and Mr study. Dr Otero-Romero reported receiving a grant submitted work. Dr Rovira reported receiving Carbonell-Mirabent had full access to all of the data from Instituto de Salud Carlos III, Spain. advisory board fees and/or speaker honoraria from in the study and take responsibility for the integrity Dr Arrambide reported receiving personal fees from Novartis, Synthetic MRI, Biogen, Bayer, of the data and the accuracy of the data analysis. Sanofi, Merck, and Horizon Therapeutics; Merck-Serono, Bristol Myers, OLEA Medical, Roche, Dr Tur and Mr Carbonell-Mirabent are considered nonfinancial support from Roche and Novartis; a TensorMedical, Sanofi Genzyme, and Teva co–first authors. Drs Tintoré and Montalban are research grant from Instituto de Salud Carlos III, Pharmaceuticals and being a shareholder in considered co–last authors. Spain; travel support for scientific meetings from TensorMedical. Dr Tintoré reported receiving Concept and design: Tur, Carbonell-Mirabent, Galán, Novartis, Roche, and ECTRIMS; working as an editor consulting and/or speaking honoraria from Almirall, Sastre-Garriga, Tintoré. for Europe of the Multiple Sclerosis Journal – Bayer, Schering Pharma, Biogen-Idec, Genzyme, Acquisition, analysis, or interpretation of data: Tur, Experimental, Translational and Clinical; working as Janssen, Merck-Serono, Novartis, Roche, Carbonell-Mirabent, Cobo Calvo, Otero-Romero, a member of the International Women in Multiple Sanofi-Aventis, Viela Bio, and Teva Pharmaceuticals Arrambide, Midaglia, Castillo, Vidal-Jordana, Sclerosis Network executive committee; and and being a co-editor of Multiple Sclerosis Journal – Rodríguez-Acevedo, Zabalza, Nos, Salerno, Auger, working as a member of the European Biomarkers Experimental, Translational and Clinical. Pareto, Comabella, Río, Sastre-Garriga, Rovira, in MS Consortium steering committee. Dr Montalban reported received speaking Tintoré, Montalban. Dr Vidal-Jordana reported receiving grants from honoraria, travel expenses for participation in Drafting of the manuscript: Tur, Carbonell-Mirabent, Fondo de Investigaciones Sanitarias, Instituto de scientific meetings, and/or being a steering Tintoré. Salud Carlos III, Spain; personal fees from Novartis, committee member of or participated in advisory Critical revision of the manuscript for important Roche, Merck, and Sanofi; and speaking honoraria boards for Actelion, Alexion, Almirall, Bayer, Biogen, intellectual content: All authors. and travel expenses from Novartis, Roche, Teva, Bristol Myers Squibb, Celgene, EMD Serono, Statistical analysis: Tur, Carbonell-Mirabent, Biogen, and Sanofi Genzyme. Genzyme, Hoffmann-La Roche, Immunic, Janssen, Arrambide. Dr Rodríguez-Acevedo reported receiving honoraria Medday, Merck, Mylan, Nervgen, Novartis, Oryzon Obtained funding: Tur. for consulting services from Wellspect. Dr Nos Genomics, Sanofi-Genzyme, Sandoz, Teva Administrative, technical, or material support: reported receiving steering committee fees from Pharmaceuticals, TG Therapeutics, and NMSS Arrambide, Vidal-Jordana, Rovira. Hoffmann-La Roche; consulting fees from Sanofi; outside the submitted work. No other disclosures Supervision: Tur, Galán, Río, Rovira, Tintoré, travel fees from Biogen Idec and F. Hoffmann-La were reported. Montalban. Roche; speaker honoraria from Novartis; and Funding/Support: This work was supported in part funding from Novartis for registration for scientific by the Junior Leader La Caixa Fellowship LCF/BQ/ Conflict of Interest Disclosures: Dr Tur reported meeting outside the submitted work. Dr Pareto receiving grants from “La Caixa” Foundation Junior PI20/11760008 from La Caixa Foundation; grant reported receiving grants from Biogen Idec; PI21/01860 from the Instituto de Salud Carlos III, Leader incoming fellowship, Fundación Merck Salud speaking honoraria from Novartis and Sanofi (Spain) 2021 Merck’s Award for the Investigation in Spanish Ministry of Science and Innovation; and Genzyme; and having a research contract with Ayudas Merck para la Investigación en Esclerosis MS, Instituto de Salud Carlos III, Ministerio de Biogen Idec. Dr Comabella reported receiving Ciencia e Innovación de España Proyecto de Múltiple from the Fundación Merck Salud. compensation for consulting services and speaking Investigación, ECTRIMS 2015 ECTRIMS honoraria from Bayer Schering Pharma, Merck Role of the Funder/Sponsor: The funders had no postdoctoral research fellowship, and the UK MS Serono, Biogen-Idec, Teva Pharmaceuticals, role in the design and conduct of the study; Society; speaker honoraria from Roche and Sanofi-Aventis, and Novartis. Dr Río reported collection, management, analysis, and Novartis; nonfinancial support from Biogen; being a receiving speaking honoraria and personal interpretation of the data; preparation, review, or jamaneurology.com (Reprinted) JAMA Neurology Published online December 19, 2022 E9 Downloaded From: https://jamanetwork.com/ on 12/21/2022 Research Original Investigation Early Progression Independent of Relapse Activity and Long-term Disability After a First Demyelinating Event in MS approval of the manuscript; and decision to submit relapsing multiple sclerosis in a pooled analysis of 2 Centres; North American Imaging in Multiple the manuscript for publication. randomized clinical trials. JAMA Neurol. 2020;77 Sclerosis Cooperative MRI guidelines working Meeting Presentation: This work was presented as (9):1132-1140. doi:10.1001/jamaneurol.2020.1568 group. 2021 MAGNIMS-CMSC-NAIMS consensus an abstract and oral presentation at the 37th 5. Bsteh G, Hegen H, Altmann P, et al. Retinal layer recommendations on the use of MRI in patients Congress of the European Committee for thinning is reflecting disability progression with multiple sclerosis. Lancet Neurol. 2021;20(8): Treatment and Research in Multiple Sclerosis; independent of relapse activity in multiple sclerosis. 653-670. doi:10.1016/S1474-4422(21)00095-8 October 15, 2021; virtual. Mult Scler J Exp Transl Clin. 2020;6(4): 13. Tur C, Penny S, Khaleeli Z, et al. Grey matter Additional Information: After the publication of 2055217320966344. doi:10.1177/ damage and overall cognitive impairment in this manuscript, data will be made available upon 2055217320966344 primary progressive multiple sclerosis. Mult Scler. reasonable request. All requests will need to explain 6. Portaccio E, Bellinvia A, Fonderico M, et al. 2011;17(11):1324-1332. doi:10.1177/1352458511410341 in detail the hypothesis of the study that the Progression is independent of relapse activity in 14. Tur C, Khaleeli Z, Ciccarelli O, et al. researchers want to carry out and the analysis plan. early multiple sclerosis: a real-life cohort study. Brain. Complementary roles of grey matter MTR and T2 They will be sent to the corresponding author, 2022;145(8):2796-2805. doi:10.1093/brain/awac111 lesions in predicting progression in early PPMS. who will contact the rest of the authors. 7. Tintoré M, Rovira À, Río J, et al. Defining high, J Neurol Neurosurg Psychiatry. 2011;82(4):423-428. The appropriateness of data sharing in each medium, and low impact prognostic factors for doi:10.1136/jnnp.2010.209890 particular case will be thoroughly discussed in ad developing multiple sclerosis. Brain. 2015;138(pt 7): 15. Bodini B, Cercignani M, Khaleeli Z, et al. Corpus hoc research meetings. 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