877810 research-article20192019 MSJ0010.1177/1352458519877810Multiple Sclerosis JournalM Tintore, G Arrambide MULTIPLE SCLEROSIS MSJ JOURNAL Original Research Paper The long-term outcomes of CIS patients in the Multiple Sclerosis Journal 2020, Vol. 26(13) 1658­–1669 Barcelona inception cohort: Looking back to DOI: 10.1177/ https://doi.org/10.1177/1352458519877810 1352458519877810 https://doi.org/10.1177/1352458519877810 recognize aggressive MS © The Author(s), 2019. Article reuse guidelines: sagepub.com/journals- Mar Tintore, Georgina Arrambide, Susana Otero-Romero, Pere Carbonell-Mirabent, permissions Jordi Río, Carmen Tur, Manuel Comabella, Carlos Nos, María Jesús Arévalo, Elisenda Anglada, Rebeca Menendez, Luciana Midaglia, Ingrid Galán, Angela Vidal-Jordana, Joaquin Castilló, Patricia Mulero, Ana Zabalza, Breogan Rodríguez-Acevedo, Marta Rodriguez, Carmen Espejo, Joao Sequeira, Raquel Mitjana, Andrea de Barros, Deborah Pareto, Cristina Auger, Santiago Pérez-Hoyos, Jaume Sastre-Garriga, Alex Rovira and Xavier Montalban Abstract Correspondence to: M Tintore Objective: To explore the long-term outcomes of patients with clinically isolated syndromes from the Centre d’Esclerosi Múltiple Barcelona cohort. de Catalunya (Cemcat), Servei de Neurologia/ Methods: We selected patients with a follow-up longer than 10 years to (1) estimate the risks of multiple Neuroimmunologia, Vall d’Hebron Institut de Recerca sclerosis (MS) and disability accumulation according to the baseline number of T2 lesions and to compare (VHIR), Hospital Universitari treated versus untreated patients and early versus delayed treatment, and (2) to study baseline features of Vall d’Hebron, Universitat Autònoma de Barcelona, patients with aggressive MS (Expanded Disability Status Scale (EDSS) ⩾6.0 at 10 years). Pg. Vall d’Hebron 119-129, Results: In all, 401 patients were included (mean follow-up of 14.4 (standard deviation of 2.9) years). A Barcelona 08035, Spain. mtintore@cem-cat.org higher number of T2 lesions was associated with an earlier MS diagnosis and an earlier risk of irrevers- Mar Tintore ible disability. Early treatment was associated with a decreased risk of EDSS of 3.0: adjusted hazard Georgina Arrambide Pere Carbonell-Mirabent ratio = 0.4, 95% confidence interval = (0.2, 0.7). Patients with aggressive MS differed in their baseline Jordi Río brain magnetic resonance images: The median (interquartile range) number of T2 lesions and contrast- Manuel Comabella Carlos Nos enhancing lesions (CEL) was 71 (28–95) versus 7 (1–19) and 3 (1–24) versus 0 (0–1), respectively. The María Jesús Arévalo Elisenda Anglada cut-offs that better classified patients with aggressive MS were 20 for T2 lesions and 2 for CEL. Rebeca Menendez Conclusion: Although MS natural history is changing, a high lesion load at onset is helpful to identify Luciana Midaglia Ingrid Galán patients at risk of presenting an aggressive MS. Angela Vidal-Jordana Joaquin Castilló Patricia Mulero Ana Zabalza Keywords: Clinically isolated syndromes, multiple sclerosis, MRI, prognosis, disease-modifying Breogan Rodríguez- treatment, prediction Acevedo Marta Rodriguez Carmen Espejo Date received: 8 March 2019; accepted: 6th August 2019. Joao Sequeira Jaume Sastre-Garriga Centre d’Esclerosi Múltiple Introduction disability early in the disease course. Although there de Catalunya (Cemcat), Servei de Neurologia/ Multiple sclerosis (MS) is a chronic disease. Classical is no established definition of aggressive MS, the Neuroimmunologia, Vall natural history studies have shown that more than early identification of this population would be of d’Hebron Institut de Recerca (VHIR), Hospital Universitari 50% of patients will develop severe disability after utmost importance for establishing an accurate and Vall d’Hebron, Universitat 15–30 years.1–4 However, when considering inception personalized treatment strategy.6 Autònoma de Barcelona, Barcelona, Spain cohorts of patients seen from their very first attack, Susana Otero-Romero the rates of disability accumulation seem to be milder. The aim of this study was to explore the long-term Centre d’Esclerosi Múltiple In this sense, the clinically isolated syndromes (CIS) outcomes of CIS patients from the Barcelona incep- de Catalunya (Cemcat), Servei de Neurologia/ cohort from the National Hospital for Neurology and tion cohort. For this objective, we selected patients Neuroimmunologia, Vall Neurosurgery, Queen Square, showed that only 25% with a follow-up longer than 10 years to (1) estimate d’Hebron Institut de Recerca (VHIR), Hospital had reached an Expanded Disability Status Scale the risks of MS and disability accumulation according Universitari Vall d’Hebron, (EDSS) of 6.0 after 20 years of follow-up.5 Despite to baseline T2 lesion number and to compare treated Universitat Autònoma de Barcelona, Barcelona, Spain/ these figures, there is still a subgroup of MS patients versus untreated patients and early treatment versus Department Preventive with an aggressive disease who develop severe delayed treatment, and (2) study the prevalence and Medicine and Epidemiology, 1658 journals.sagepub.com/home/msj M Tintore, G Arrambide et al. Vall d’Hebron Institut de baseline features of patients with an aggressive MS MRI protocol Recerca (VHIR), Hospital phenotype, defined as patients with an EDSS ⩾6.0 at The baseline brain MRI was performed 3–5 months Universitari Vall d’Hebron, Universitat Autònoma de 10 years. after the CIS and repeated at 12 months and every Barcelona, Barcelona, Spain 5 years thereafter. Baseline spinal cord MRIs were Carmen Tur systematically performed since 2007 and therefore Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Patients and methods were not considered in this study. Brain MRI was per- Servei de Neurologia/ formed using a 1.5 or 3.0 T magnet and included the Neuroimmunologia, Vall d’Hebron Institut de Study data and inclusion criteria following sequences: transverse proton density and Recerca (VHIR), Hospital This is a retrospective analysis based on a prospective T2-weighted conventional or fast spin-echo, trans- Universitari Vall d’Hebron, Universitat Autònoma and open CIS cohort initiated in 1995. The cohort verse and sagittal T2 FLAIR, and un-enhanced and de Barcelona, Barcelona, includes patients younger than 50 years who presented contrast-enhanced (0.1–2.0 mmol/kg; scan delay, Spain/Queen Square MS Centre, Department of with a CIS suggestive of MS within 3 months of our 5–10 minutes) T1-weighted spin-echo. All sequences Neuroinflammation, UCL first assessment. At baseline, we recorded the demo- were obtained using a contiguous 3–5 mm slice thick- Queen Square Institute of Neurology, University graphics, CIS topography and disability according to ness covering the entire brain. Having a normal brain College London, London, the EDSS score. The EDSS score and the occurrence MRI was not an exclusion criterion, since patients UK/Luton and Dunstable University Hospital, of relapses were evaluated every 3–6 months or annu- were included based solely on their clinical features if University College London, ally depending on each patient’s characteristics. For they were suggestive of MS (i.e. patients with optic London, UK the purpose of this analysis, the database was locked neuritis and normal baseline brain MRIs are included). Raquel Mitjana Andrea de Barros on 15 February 2016. For the main analysis of the Deborah Pareto study, we included patients with a CIS before 15 Cristina Auger Alex Rovira February 2006 and with at least 10 years of follow-up. Definition of the outcomes Section of Neuroradiology IgG oligoclonal bands (OB) were examined within The 2017 McDonald criteria were applied to patients and Magnetic Resonance Unit, Department of the first 3 months of disease onset via agarose isoelec- included after 2002 as lesion topography was not Radiology (IDI), Vall tric focusing combined with immunoblotting.7 OB assessed individually before this date. For patients d’Hebron Institut de Recerca, Hospital Universitari Vall were considered positive when at least two discrete included from 1995 to 2002, the 2005 McDonald cri- d’Hebron, Universitat bands were demonstrated in cerebrospinal fluid (CSF) teria were used.8,9 Clinically definite multiple sclerosis Autònoma de Barcelona, Barcelona, Spain only or when the CSF had at least two more bands (CDMS) was established when new symptoms sug- Santiago Pérez-Hoyos than serum. gestive of a relapse occurred after an interval of at Unitat d’Estadística i Bioinformatica, Vall least 1 month.10 Disability was evaluated according to d’Hebron Institut de Since 1996, disease-modifying treatment (DMT) was the EDSS at each visit during stability periods.11 The Recerca (VHIR), Universitat Autònoma de Barcelona, offered to patients presenting with at least two attacks primary disability milestones were defined as reaching Barcelona, Spain in the previous 3 years according to the Catalonian an EDSS score greater than or equal to 3.0 or 6.0 in Xavier Montalban Regulatory Agency guidelines. After 2001, patients two different evaluations. Finally, the follow-up dura- Centre d’Esclerosi Múltiple de Catalunya (Cemcat), presenting with a high-risk CIS (defined as the fulfil- tion was computed as the time elapsed between the Servei de Neurologia/ ment of three to four Barkhof criteria) were also candi- date of the CIS and the date of the most recent visit. Neuroimmunologia, Vall d’Hebron Institut de dates for treatment. Age and sex, date of the CIS, CIS Recerca (VHIR), Hospital topography, steroid treatment, date of the second attack, Universitari Vall d’Hebron, Universitat Autònoma de EDSS measurements, date of DMT initiation and date Statistical analysis Barcelona, Barcelona, Spain/ of the most recent visit were prospectively collected. Kaplan–Meier risk estimates were obtained for the Division of Neurology, University of Toronto, St The number and location of baseline T2 lesions, the times to McDonald MS, CDMS and EDSS score of Michael’s Hospital, Toronto, presence and number of contrast-enhancing lesions 3.0 and 6.0 according to the number of baseline T2 ON, Canada (CEL) and the number of new T2 lesions were recorded lesions. Instead of representing the resulting estimates during follow-up. For the purposes of this study, the using curves, we used heat maps to represent the pro- number of T2 lesions at baseline was divided into four portion of patients achieving each of the four out- categories: 0, 1–3, 4–9 and 10 or more. In addition, a comes during follow-up. In the heat maps, columns normal brain magnetic resonance imaging (MRI) was represent follow-up time in years and rows indicate defined as displaying zero T2 lesions. the number of baseline lesions. Thus, each cell of the map shows the proportion of patients (with its 95% Finally, the patients’ clinical and MRI data were confidence interval) fulfilling each outcome for each entered and updated on a regular basis. Quality con- time point according to the number of baseline lesions. trols were performed including a review of the data Heat maps offer the possibility of using colours as a using the primary sources of 10 randomly selected scoring gradient that goes from blue (low risk) to red patients every month. This study received approval (high risk). The same range of colours has been used from the local ethics committee, and all patients in the four heat maps to allow for an easier compari- signed a written informed consent form. son of risks between outcomes (Figure 2). These journals.sagepub.com/home/msj 1659 Multiple Sclerosis Journal 26(13) estimates have been computed and represented until symptoms (n = 1) and unspecified ophthalmological the last time point where an event or censoring hap- condition (n = 1). pened. Thus, the heat map stops when the population under risk remained constant. Univariable and multi- According to the database lock date, we identified variable Cox proportional-hazards (PH) regressions 562 cases with a CIS before 15 February 2006 and at were built for the progression to EDSS scores of 3.0 least one follow-up visit (Figure 1). Of these, 401 and 6.0. Covariates including age, sex, CIS topogra- (71.3%) patients had a minimum follow-up of 10 years phy, OB, baseline number of T2 lesions, MRI criteria (Figure 1). Compared to these, patients with a shorter and DMT status were considered. This last variable follow-up (n = 161, 28.6%) were similar in age but was first considered a time-dependent exposure and were more likely to have a normal baseline MRI and modelled later as an indicator of whether the DMT negative OB (Supplementary Table 1). was initiated before or after the second attack. Possible interactions between age, sex, CIS topography, pres- Ultimately, 401 patients were included in this analy- ence of OB, number of baseline T2 lesions and DMT sis. Of these, one died during follow-up due to an were also evaluated (Figure 3). We defined the aggres- acute myeloid leukaemia with a complex karyotype sive MS phenotype as reaching an EDSS ⩾6.0 at not related to MS treatment. 10 years. We compared patients who presented this phenotype to those who did not in terms of sex, age at Table 1 shows the baseline characteristics of this CIS, CIS topography, OB status, and number of T2 long-term cohort: as expected, two out of three were lesions and CEL at baseline (Figure 4). Next, we cal- females, the mean age at onset was 30 years and one- culated the cut-off number of baseline T2 lesions and third presented with an optic neuritis. The mean clini- CEL that best predicted the development of an aggres- cal follow-up duration was 14.4 (standard deviation sive MS (Figure 4(b)). Both cut-offs were defined as (SD) 2.9) years. Of the total cohort, 334 patients those with the best balance between sensitivity and underwent a CSF tap, of whom 221 (66.2%) had posi- specificity rates. Finally, we combined both MRI var- tive OB. The baseline brain MRI was normal in 20.5% iables to estimate the positive predictive values (PPV) of the patients, almost half of the patients displayed of developing aggressive MS (Table 3). 10 or more T2 lesions, and one-third showed at least one CEL. Out of the entire cohort, 190 (47.4%) A p-value of 0.05 was considered statistically signifi- patients received no DMT; 55 (13.7%) initiated a cant. All analyses were performed using SPSS 22.0 DMT prior to their second attack and 156 (38.9%) (SPSS Inc. Chicago, IL, USA) and R 3.5.1 (R Foundation after their second attack. for Statistical Computing). The median time from CIS onset to drug prescription was 23.5 months (interquartile range (IQR): 8.3–63.2). Results Study population Long-term outcomes: CDMS, McDonald MS, and From January 1995 to 15 February 2016, 1207 EDSS of 3.0 and 6.0 patients were enrolled in the prospective CIS cohort; Figure 2 shows the proportion of patients reaching 70 (5.8%) were ultimately excluded for various rea- each of the four outcomes according to the number of sons: previous attack (n = 13), age above 50 (n = 4), baseline T2 lesions. A higher number of T2 lesions exceeded entry window (n = 26) and alternative diag- was associated with an earlier second attack and an noses (n = 27). These alternative diagnoses included earlier McDonald MS diagnosis. In addition, the risk acute disseminated encephalomyelitis (n = 1), neuro- of irreversible disability was especially worrisome in myelitis optica spectrum disorder (n = 5), chronic patients with at least 10 baseline lesions: 30% of them relapsing inflammatory optic neuritis associated with reached an EDSS of 3.0, and 7% needed a cane before anti-MOG antibodies (n = 1), brain tumour (n = 5), 10 years. These numbers rose to 39% and 9% within ischemic stroke (n = 2), cerebral autosomal dominant the first 15 years of the disease, respectively. arteriopathy with subcortical infarcts and leukoen- cephalopathy (CADASIL; n = 1), anterior ischemic optic neuropathy (n = 3), Leber’s hereditary optic neu- Long-term outcomes: treated versus not treated ropathy (n = 1), central nervous system vasculitis patients (n = 1), atypical brainstem lesions (n = 2), alcoholic Patients who were treated had clearly a more aggres- polyneuropathy with vitamin B deficiency (n = 1), sive phenotype (Supplementary Table 2). It is worth musculoskeletal disorders (n = 2), unspecified sensory highlighting that covariates were not balanced across 1660 journals.sagepub.com/home/msj M Tintore, G Arrambide et al. Figure 1. Flowchart: patient’s disposition. CIS: clinically isolated syndrome. Table 1. Baseline characteristics of patients with at least treated and untreated groups. Thus, time-dependent 10 years of follow-up. variables could not control for this unbalance, and no Baseline clinical n = 401 further analyses comparing treated and untreated and demographic patients were performed. characteristics Females: n (%) 287 (71.6) Mean (SD) age in years 30.0 (8.1) Long-term outcomes in treated patients: DMT CIS topography: n (%) before or after the second attack ON 142 (35.4) Table 2 compares the baseline characteristics of BS 112 (27.9) patients who received an early treatment (median SC 110 (27.4) time: 4 months) and patients starting treatment after Other 37 (9.2) the second attack (median time: 36 months). Although +OB: n (%) 221/334 (66.2) patients who received an early treatment had a higher Baseline number of T2 lesions on brain and SC MRI: number of T2 and CEL lesions at baseline, univaria- n (%) ble and multivariable analyses showed that treatment 0 80/391 (20.5) before the second attack was associated with a 1–3 67/391 (17.1) decreased risk (adjusted hazard ratio (aHR) = 0.4 (0.2, 4–9 56/391 (14.3) 0.7)) of reaching an EDSS score of 3.0 (Figure 3). When analysing EDSS of 6.0 as the outcome, the haz- ⩾10 188/391 (48.1) ards proportionality assumption was violated (p-value CEL: n (%) 97/239 (40.6) Median (IQR) time of 14.0 (11.9–16.7) of 0.2 in the log-rank test), and therefore no further follow-up in years research on this outcome was performed. SD: standard deviation; CIS: clinically isolated syndrome; ON: optic neuritis; BS: brainstem; SC: spinal cord; OB: Aggressive MS: EDSS of 6.0 at 10 years oligoclonal bands; MRI: magnetic resonance imaging, CEL: We compared the baseline characteristics of patients contrast-enhancing lesions; IQR: interquartile range. who presented with this aggressive phenotype to journals.sagepub.com/home/msj 1661 Multiple Sclerosis Journal 26(13) Figure 2. Heat maps showing the proportion of patients reaching McDonald MS, CDMS, and EDSS of 3.0 and 6.0 according to the number of baseline T2 lesions. those who did not. There were no differences in sex the median number of CEL was 3 (1–24) compared (76.9% of aggressive MS vs 72.7% of non-aggres- to 0 (0–1) (p < 0.0001 for both tests) (Figure 4). sive MS, p = 1) and age at CIS (mean (SD) of 27.3 (5.5) vs 30.1 (8.2) years, p = 0.1). Positive OB were In addition, presenting at least 20 T2 lesions at base- more common in patients with aggressive MS (90.0% line was the cut-off that best discriminated patients vs 65.4%, p = 0.174), although these differences were with aggressive MS from those who did not present not statistically significant. On the contrary, treat- this phenotype, with a sensitivity of 0.85 and a speci- ment was clearly more frequent on the aggressive ficity of 0.76. Performing the same analysis for base- cohort (92.3% vs 50.9%, p = 0.003). In terms of the line CEL, the best cut-off was at least two lesions, MRI characteristics, all patients with aggressive MS with a sensitivity of 0.73 and a specificity of 0.79 presented 10 or more T2 lesions at baseline (100.0% (Figure 4). Table 3 shows the PPVs for developing vs 45.9%, p = 0.02) and more frequently presented aggressive MS for several combinations of baseline at least one CEL (92.3% vs 50.9%, p = 0.003). T2 lesions and CEL. If MRI information was not con- Furthermore, the median (IQR) number of baseline sidered, the risk of having aggressive MS for patients T2 lesions was 71 (28–95) compared to 7 (1–19), and in our cohort was 4.7% (Table 3). For patients having 1662 journals.sagepub.com/home/msj M Tintore, G Arrambide et al. Table 2. Baseline characteristics of patients according to early versus delayed treatment. Baseline characteristics DMT after CDMS DMT before p-value (n = 156) CDMS (n = 55) Females: n (%) 112 (71.8) 39 (70.9) 1 Mean (SD) age in years 28.3 (7.3) 29.1 (7.7) 0.553 CIS topography: n (%) ON 47 (30.1) 14 (25.5) 0.320 BS 50 (32.1) 16 (29.1) SC 47 (30.1) 16 (29.1) Other 12 (7.7) 9 (16.4) +OB: n (%) 115/137 (83.9) 32/38 (84.2) 1.0 Baseline T2 brain lesions: n (%) 0 2/154 (1.3) 0/52 (0) 0.053 1–3 22/154 (14.3) 2/52 (3.9) 4–9 29/154 (18.8) 6/52 (11.5) ⩾10 101/154 (65.6) 44/52 (84.6) CEL: n (%) 50/110 (45.4) 31/47 (66.0) 0.029 Median(IQR) time to start 36 (16–72) 4 (1–6) <0.001 treatment in months Median (IQR) time of 14.6 (12.8–16.8) 12.0 (11–12.9) <0.001 follow-up in years Outcomes DMT after CDMS DMT before p-value (n = 156) CDMS (n = 55) CDMS 156 (100.0) 40 (72.7) < 0.001 2005 McDonald MS 156 (100.0) 43 (78.2) < 0.001 2017 McDonald MS 66/66 (100.0) 43/46 (93.5) 0.067 Confirmed EDSS of 3.0 74 (47.4) 11 (20.0) < 0.001 Confirmed EDSS of 6.0 11 (7.1) 4 (7.3) 1.0 DMT: disease-modifying treatment; CDMS: clinically definite multiple sclerosis; SD: standard deviation; CIS: clinically isolated syndrome; ON: optic nerve; BS: brainstem; SC: spinal cord; OB: oligoclonal bands; CEL: contrast-enhancing lesions; MS: multiple sclerosis; EDSS: Expanded Disability Status Scale. IQR: Interquartile range. All tests are Fisher’s exact and chi-square tests, except for age (Student’s t-test) and follow-up time (Mann–Whitney test). more than 20 T2 lesions and more than 2 CEL, this Nevertheless, a higher proportion of OB, a lower pro- probability increased to 19.0% (10.4%, 28.1%). The portion of optic neuritis and a higher proportion of probability further increased to 40% for patients with spinal cord CIS were observed. Comparing patients more than 20 T2 lesions and more than 10 CEL with an aggressive phenotype to those with a more (14.3%, 71.4%). standard evolution, the former mainly differed in their baseline brain MRIs: the median number of baseline T2 lesion was 71 (28–95) compared to 7 (1–19), and Discussion the median for CEL was 3 (1–24) compared to 0 (0–1). Our study confirmed that when the baseline MRI is The cut-offs that better classified patients with aggres- abnormal, a high proportion of patients with CIS pre- sive MS were 20 for T2 lesions and 2 for CEL. It is sented a second attack in the long term. Moreover, important to note that both the number and activity of almost all patients developed McDonald MS. The the lesions seem to contribute to better predict patients heat maps show that a higher number of lesions is with an aggressive MS phenotype. Also, we would associated with an earlier outcome. Less than 5% of like to highlight that there is no consensus on the defi- our patients developed an aggressive MS (reaching an nition of aggressive MS, and specific guidelines for EDSS status of 6.0 at 10 years). It is worth highlight- its treatment are also lacking. ing that in patients with an aggressive phenotype, baseline characteristics such as sex, age and OB were A high proportion of our patients received DMT during not helpful in identifying them as patients at risk. their follow-up, but for the majority of them, there was journals.sagepub.com/home/msj 1663 Multiple Sclerosis Journal 26(13) Figure 3. Multivariable Cox model results for reaching an EDSS of 3.0 in treated patients: initiation of DMT before or after CDMS. EDSS: Expanded Disability Status Scale; DMT: disease-modifying treatment; CDMS: clinically definite multiple sclerosis; OB: oligoclonal bands; HR: hazard ratio; CI: confidence interval. a long time between the first clinical event and treat- more than 10 T2 lesions at baseline, compared to the ment initiation. These data reflect our clinical practice London cohort, we found similar rates of patients pre- two decades ago when the concept of early treatment senting a second attack (80% vs 85% at 10 years).13,14 was in its infancy. Treated patients had a more aggres- Although a small proportion of our patients started sive disease phenotype than untreated patients, and for DMT before their second attack (n = 55), compared to this reason we were unable to match both populations. the largely untreated London CIS cohort, these similar In our study, after excluding non-treated patients, it rates of conversion probably reflect the fact that first- appeared that treatment before the second attack could line DMTs (mainly interferons and glatiramer acetate decrease the risk of disability accumulation, highlight- in our cohort) only delay the occurrence of second ing the importance of early treatment. As a rule, patients attack in the short to medium term. Conversely, in were treated with first-line treatments. This study is in patients with at least 10 baseline T2 lesions, we found line with our previous work analysing our whole cohort lower rates of disability accumulation than the London of 1058 CIS patients followed up for a mean of cohort (30% vs 75% for EDSS of 3.0 and 7% vs 35% 6.5 years, in which we showed that MRI features (num- for EDSS of 6.0 at 10 years). Our rates of disability are ber and topography of T2 lesions) were the main prog- closer to other treated cohorts: The Betaferon® / nostic factor at disease onset and that initiation of a Betaseron® in Newly Emerging Multiple Sclerosis for DMT before a second attack could reduce the risk of Initial Treatment (BENEFIT) cohort reported 30% of disability accumulation.12 Focusing on patients with patients with an EDSS of 3.0 and 6% with an EDSS of 1664 journals.sagepub.com/home/msj M Tintore, G Arrambide et al. Figure 4. (Continued) journals.sagepub.com/home/msj 1665 Multiple Sclerosis Journal 26(13) Figure 4. Baseline MRI characteristics and cut-offs obtained at baseline for aggressive and non-aggressive MS. IQR: interquartile range; SD: standard deviation; EDSS: Expanded Disability Status Scale, sens: sensibility, spec: specificity, acc: accuracy, PPV: positive predictive value, NPV: negative predictive value; LR+: positive likelihood ratio. 1666 journals.sagepub.com/home/msj M Tintore, G Arrambide et al. Table 3. Positive predictive values for developing an treatment or changes among preparations have not aggressive MS according to the baseline number of T2 and been evaluated. We also acknowledge that this is a cul- contrast-enhancing lesions. turally and genetically homogeneous cohort, as non- T2 baseline CEL PPV (95% CI) Caucasian people were an exception in our setting. We lesions are also aware that the conclusions referring to patients with aggressive MS are based on a limited number of Unknown Unknown 4.7% (2.1%, 7.7%) patients. This could have limited the possibility of ⩾10 Unknown 8.0% (7.2%, 8.9%) finding statistically significant differences in other ⩾10 ⩾1 12.7% (8.6%, 16.9%) variables such as OB. However, this limitation also ⩾10 ⩾2 16.3% (10.2%, 22.7%) mirrors the exceptionality of this end point. ⩾10 ⩾5 18.2% (4.8%, 33.3%) ⩾10 ⩾10 36.4% (12.5%, 66.7%) The data from the long-term Barcelona cohort confirm ⩾20 Unknown 11.5% (8.6%, 13.9%) that patients with a normal baseline MRI have a low ⩾20 ⩾1 15.8% (9.8%, 22.4%) risk of developing MS after 10 or 15 years of follow- ⩾20 ⩾2 18.9% (10.6%, 28.1%) up. Conversely, patients with an abnormal MRI have a ⩾20 ⩾5 22.2% (6.3%, 41.7%) very high risk of developing further attacks or ⩾20 ⩾10 40.0% (14.3%, 71.4%) McDonald MS. In line with other cohort studies, we showed that early treatment seems to prevent disability MS: multiple sclerosis; CEL: contrast-enhancing lesions; PPV: accrual. Our long-term study confirms that MS natural positive predictive value; 95% CI: 95% confidence interval. history has changed and that aggressive MS, defined as reaching an EDSS of 6.0 at 10 years, is infrequent in the treatment era. A high lesion load (more than 20 T2 6.0 after an 11-year follow-up.15 This is also in line lesions and more than 2 CEL) at onset was helpful to with the expression/genomics, proteomics, imaging, identify patients at risk of an aggressive MS.20 and clinical (EPIC) cohort, a prospective single-centre cohort including actively managed CIS and early MS Acknowledgements patients which showed 4.7% of patients reaching an We thank Josep Graells, Rosalia Horno, Miquel Angel EDSS of 6.0 after 10 years.16 Taking all together, and Robles, Clara Oriol and Milagros Fraga for their con- considering other important factors such as the Will tinuous support. We also wish to thank our multiple Rogers phenomenon derived from diagnostic criteria sclerosis patients for their continuous enthusiasm in modifications and improvement in general health participating in clinical research studies. among others, our data seem to confirm that natural history is changing in the treated era. Others have Declaration of Conflicting Interests addressed the impact of first-line treatments on long- The author(s) declared the following potential conflicts term disability in relapsing MS patients.17,18 This pro- of interest with respect to the research, authorship, and/ tective effect is modest in patients treated with first-line or publication of this article: M.T. has received compen- drugs, with an estimated prevention of 1.0 EDSS point sation for consulting services and speaking honoraria increase for every 11.6 years of interferon-beta/glati- from Almirall, Bayer Schering Pharma, Biogen-Idec, ramer acetate exposure.19 Genzyme, Merck-Serono, Novartis, Roche, Sanofi-Aventis and Teva Pharmaceuticals. M.T. is co-editor of Multiple Limitations of our study include the following aspects: Sclerosis Journal – Experimental, Translational and MRI criteria to define MS have changed overtime, and Clinical. G.A. has received compensation for consult- therefore not all patients had the required information ing services or participation in advisory boards from to apply the 2017 McDonald criteria. To overcome this Biogen-Idec, Sanofi and Merck; research support from limitation, a combination of 2005 and 2017 criteria has Novartis; travel expenses for scientific meetings from been used. Another concern relates to the lack of spi- Novartis, Roche and Stendhal; and speaking honoraria nal cord imaging in this analysis. Unfortunately, this from Sanofi and Merck. S.O.-R. has received compen- limitation reflects our practice at a time where spinal sation for consulting services from Biogen-Idec and cord MRI was only performed in patients presenting Genzyme, and research support from Novartis. P.C. has with a myelitis. The treatments that were available at received travel expenses from Biogen. P.C.’s yearly sal- that time were mainly interferons and glatiramer ary is supported by a grant from Biogen to Fundacio acetate. The use of other treatments was restricted to privada Cemcat towards statistical analysis. J.R. has exceptional cases. Again, only an intention-to-treat received speaking honoraria and personal compensa- analysis has been performed taking into consideration tion for participating on Advisory Boards from Almirall, the date of initiation of DMT. However, time on Bayer Schering Healthcare, Biogen-Idec, Genzyme, journals.sagepub.com/home/msj 1667 Multiple Sclerosis Journal 26(13) Merck-Serono, Novartis, Teva and Sanofi-Aventis. C.T. Recerca de Catalunya’, which is sponsored by the has received a post-doctoral research ECTRIMS fel- ‘Agència de Gestió d’Ajuts Universitaris i de Recerca’ lowship (2015). C.T. has received honoraria and sup- (AGAUR) of the Generalitat de Catalunya in Spain. port for travelling from Novartis, Teva Pharmaceuticals, This work is independent of all the funding bodies, Ismar Healthcare and F. Hoffmann-La Roche, Ltd. which have played no part in any of its stages (design, M.C. has received compensation for consulting services data analysis or manuscript writing). and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Supplemental material Sanofi-Aventis and Novartis. C.N. has received funding Supplemental material for this article is available for travel from Biogen-Idec and F. Hoffmann-La Roche, online. Ltd., and speaker honoraria from Novartis. A.V.-J. receives support for contracts Juan Rodes (JR16/00024) from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain, and has received speaking hon- References oraria and travel expenses from Novartis, Roche, Teva, 1. 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