1053001 research-article20212021 MSJ0010.1177/13524585211053001Multiple Sclerosis JournalS Otero-Romero, P Carbonell-Mirabent MULTIPLE SCLEROSIS MSJ JOURNAL Original Research Paper Oral contraceptives do not modify the risk Multiple Sclerosis Journal 2022, Vol. 28(6) 950­–957 of a second attack and disability accrual in a DOI: 10.1177/ https://doi.org/10.1177/13524585211053001 13524585211053001 https://doi.org/10.1177/13524585211053001 prospective cohort of women with a clinically © The Author(s), 2021. isolated syndrome and early multiple sclerosis Article reuse guidelines: sagepub.com/journals- permissions Susana Otero-Romero, Pere Carbonell-Mirabent, Luciana Midaglia, María Zuluaga, Ingrid Galán, Alvaro Cobo-Calvo , Jordi Rio , Georgina Arrambide , Angela Vidal-Jordana , Joaquín Castillo, Breogán Rodríguez-Acevedo , Manuel Comabella, Marta Rodríguez, Carmen Tur , Cristina Auger, Alex Rovira , Jaume Sastre-Garriga , Xavier Montalban and Mar Tintoré Abstract Correspondence to: S Otero-Romero Objective: To evaluate whether oral contraceptive (OC) use is associated with the risk of a second attack Servicio de Medicina Preventiva y Epidemiología, and disability accrual in women with a clinically isolated syndrome (CIS) and early multiple sclerosis Antigua Escuela de (MS). Enfermeria, Hospital Universitari Vall d’Hebron, Methods: Reproductive information from women included in the Barcelona CIS prospective cohort was Vall d’Hebron Institut de collected through a self-reported cross-sectional survey. We examined the relationship of OC exposure Recerca (VHIR), Universitat Autònoma de Barcelona, Psg with the risk of a second attack and confirmed Expanded Disability Status Scale of 3.0 using multivariate de la Vall d’Hebron 119-129, 08035 Barcelona, Spain. Cox regression models, adjusted by age, topography of CIS, oligoclonal bands, baseline brain T2 lesions, sotero@cem-cat.org body size at menarche, smoking, and disease-modifying treatment (DMT). OC and DMT exposures were considered as time-varying variables. Findings were confirmed with sensitivity analyses using propensity Susana Otero-Romero Centro de Esclerosis Múltiple score models. de Catalunya (Cemcat), Results: A total of 495 women were included, 389 (78.6%) referred to ever use OC and 341 (68.9%) Department of Neurology and Neuroimmunology, Hospital started OC before the CIS. Exposure to OC was not associated with a second attack (adjusted hazard ratio Universitari Vall d’Hebron, Vall d’Hebron Institut de (aHR) = 0.73, 95% confidence interval (CI) = 0.33–1.61) or disability accrual (aHR = 0.81, 95% CI = 0.17– Recerca (VHIR), Universitat 3.76). Sensitivity analyses confirmed these results. Autònoma de Barcelona, Barcelona, Spain/Servicio Conclusion: OC use does not modify the risk of second attack or disability accrual in patients with CIS de Medicina Preventiva y Epidemiología, Antigua and early MS, once considered as a time-dependent exposure and adjusted by other potential confounders. Escuela de Enfermeria, Hospital Universitari Vall d’Hebron, Vall d’Hebron Keywords: Clinically isolated syndrome, multiple sclerosis, oral contraceptives, second relapse, Institut de Recerca (VHIR), Universitat Autònoma de disability, cohort study Barcelona, Barcelona, Spain Pere Carbonell-Mirabent Date received: 17 May 2021; revised: 29 July 2021; accepted: 23 August 2021. Luciana Midaglia María Zuluaga Ingrid Galán Alvaro Cobo-Calvo Jordi Rio Introduction still conflicting. Different population-based case–con- Georgina Arrambide Angela Vidal-Jordana Hormonal exposures and environmental factors could trol or cohort studies conclude protective,3,4 neutral,5 Joaquín Castillo play a role in multiple sclerosis (MS) risk and progno- or even negative6 effects of OC exposure on the risk of Breogán Rodríguez-Acevedo Manuel Comabella sis. High doses of estrogen seem to be protective in the MS. Studies focusing on patients with confirmed MS Marta Rodríguez animal model of MS and in patients during pregnancy, report no effect on clinical and magnetic resonance Carmen Tur Jaume Sastre-Garriga when the disease activity decreases significantly.1,2 imaging (MRI) activity7–9 and inconsistencies with Xavier Montalban Therefore, other variations in estrogen levels during a respect to disability accumulation, with a reduced Mar Tintoré Centro de Esclerosis Múltiple woman’s lifetime, such as the use of oral contracep- risk8,10 or an increased risk in patients with progressive de Catalunya (Cemcat), tives (OC), could potentially have an effect on the risk onset.11 The lack of consistency between results could Department of Neurology and Neuroimmunology, Hospital of developing MS and its prognosis, but their role is be partially explained by the influence of potential Universitari Vall d’Hebron, 950 journals.sagepub.com/home/msj S Otero-Romero, P Carbonell-Mirabent et al. clinical,12 reproductive,13 and environmental con- lesions (CEL), and the number of new T2 lesions on Vall d’Hebron Institut de Recerca (VHIR), founders14,15 that affect disease evolution and also follow-up MRIs). The information collected within Universitat Autònoma determine the patient’s decision to take OC leading to the MS&Gender questionnaire included exposure to de Barcelona, Barcelona, Spain a possible selection bias. Moreover, there is a lack of any composition of OCs (estrogen, progestogen, or Cristina Auger evidence on the role of oral contraceptives in the tran- combination), pregnancy history (number of pregnan- Alex Rovira Sección de sition to confirmed MS in women with a clinically iso- cies, date, and outcome), smoking habits (recorded as Neuroradiologia, Servei lated syndrome (CIS), which represents an important yes/no and year of smoking onset), and body size self- de Radiologia, Hospital Universitari Vall target population for clinical counseling, as the time of perception (1 of 9 body silhouettes on the Stunkard d’Hebron, Universitat first exposure to OC usually overlaps with the average figure rating scale).18 Autònoma de Barcelona, Barcelona, age at CIS. In this study, we assess whether exposure Spain to OC in patients with CIS is associated with the risk We studied the association of OC exposure with the of (1) experiencing the clinically definite MS (CDMS) following outcomes: (1) time to MS diagnosis by and (2) reaching a confirmed Expanded Disability presence of a second attack (new symptoms sugges- Status Scale (EDSS) of 3.0 using a time-dependent tive of relapse occurring after an interval of at least multivariable approach with relevant confounders. 1 month) and (2) time to confirmed EDSS score of 3.0 This study is framed within the Barcelona MS&Gender (EDSS score ⩾ 3.0 in two evaluations over the course Project aimed at studying the role of hormonal factors of the disease, performed during stable periods). in the modulation of MS prognosis.16,17 Data management and statistical analysis Methodology For the purpose of this study, women were catego- rized with respect to their OC exposure in “never- Study design and data collection users” or “ever-users.” The “ever-users” category was The Barcelona MS&Gender Project is an observa- also subdivided into those who started the OC expo- tional study based on an ongoing prospective CIS sure before or after their CIS, respectively. For DMT cohort that includes patients aged below 50 years who modeling, we considered the first drug exposure of exhibit a CIS suggestive of central nervous system the patient and date of its initiation (any disease-mod- demyelination. Patients are seen on a regular basis ifying drug). The total number of T2 lesions was cat- and demographic, clinical, cerebrospinal fluid (CSF), egorized in four levels: 0, 1–3, 4–9, and 10 or more and MRI information is prospectively collected using and CEL was categorized into 0, 1, or >1 lesions. a pre-specified protocol that has been previously Body size self-perception was categorized into under- described.12 Female patients belonging to this cohort weight 1–3, normal weight 4–6, and overweight 7–9. were invited to participate in the Barcelona MS&Gender Project16 by signing an informed con- The association between OC use with the diagnosis sent and completing a self-administered survey on and prognosis was evaluated with Cox proportional reproductive information, external hormonal expo- hazards (PH) regression models in which OC expo- sures, and other environmental risk factors. The sur- sure was considered as a dichotomous time-depend- vey was completed from February 2015 until ent variable (considering the date of OC initiation as November 2015 during the patient’s regular clinical the beginning of the exposure). For these models, we assessments, using a tablet device or by email. A selected women who were never exposed to OC and reminder email was sent up to three times if the patient women who were exposed after their CIS. This was did not fill out the survey after the first email invita- done to avoid a potential overrepresentation of expo- tion. Any missing or ambiguous data were confirmed sure to OC in the cohort, as the time-dependent mod- during clinical visits or by telephone call. eling of OC assumes an ongoing exposure during the complete observation period. For those women who Data prospectively collected in the Barcelona CIS start OC early (before the CIS), it is unclear whether cohort include demographics (date of birth and sex), they would still be on OCs after disease onset and baseline clinical data (age at CIS, topography of the their exclusion allows minimizing the risk of classifi- CIS, previous history of neurological abnormalities, cation bias. Two main PH Cox models were built for disability according to the EDSS) and follow-up clini- each outcome: (1) univariate model and (2) multivari- cal information (disease-modifying treatment (DMT) ate model adjusted by the age at CIS, topography of and date of its initiation, relapses, and annual EDSS), the CIS, presence of OB in CSF, baseline number of presence of oligoclonal bands (OB) in CSF, and MRI brain T2 lesions, CEL at baseline, and DMT initia- information (number and topography of T2 lesions, tion. Body size at menarche and smoking at the time the presence of contrast gadolinium-enhancing of the CIS were also included in the multivariable journals.sagepub.com/home/msj 951 Multiple Sclerosis Journal 28(6) adjustment. In the latter approach, DMT exposure “ever use” OC of whom 341 (68.9%) started OC was modeled as a dichotomous time-dependent before their CIS. Patients who started OC before CIS covariate. were older at CIS, had a smaller body size at menarche, and a shorter follow-up. No differences were found in Additionally, we confirmed our findings by fitting a other clinical or radiological characteristics (see Table propensity score model for OC use at any time using 1). From the 495 responders, 208 (42%) fulfill inverse probability weighting. These models control McDonald 2017 criteria at baseline and 352 (71.1%) for the possible selection bias given that women who at the time of responding the questionnaire. A total of decided to use OC could exhibit different prognoses. 266 (54%) women experienced a second attack The weights were estimated using a logistic regres- (CDMS) during their follow-up and 66 (13%) reached sion to estimate the probability of starting OC use confirmed EDSS 3.0. At the time when the question- including age at CIS, parity, displaying ⩾10 T2 brain naire was administered, 143 (28.9%) women were lesions at baseline, presence of CEL, presence of OB CIS patients not fulfilling McDonald 2017 criteria. in CSF, presenting an optic neuritis at CIS, and being However, the percentage of patients who reported OC treated before the CDMS. Standardized mean differ- use was similar among women who were and were ences (SMD) were estimated to examine the balance not diagnosed at the time they responded to the ques- of covariate distribution according to the exposure of tionnaire (77.3% vs 81.8%) and also between those OC after weighting. who had and had not reached EDSS 3.0 (77.3% vs 78.8%). Finally, a sensitivity analysis was conducted includ- ing also the group of women who started OC before The proportionality assumption was held both for the the CIS into the univariable and multivariable Cox univariate PH Cox models (p = 0.601 of Schoenfeld regression models, in order to confirm the robustness residuals test for CDMS; 0.314 for EDSS 3.0) and the of the previous findings. multivariate models (p = 0.501 for CDMS; p = 0.480 for EDSS 3.0). The univariate time-dependent analy- In all PH Cox models, the proportionality assumption sis showed no association between OC exposure nei- was diagnosed via a statistical significance of the test ther with the risk of experiencing CDMS (hazard ratio of time independence of the Schoenfeld residuals. (HR) = 0.65, 95% confidence interval (CI) = 0.32– Analyses were performed using R software (3.6.0 1.32) nor for EDSS 3.0 (HR = 0.50, 95% CI = 0.14– version). 1.77). The same association was seen in the multivariate time-dependent analyses, showing no association Standard protocol approvals, registrations, and between OC exposure with the risk of CDMS (adjusted patient consents. This study was performed with the hazard ratio (aHR) = 0.73, 95% CI = 0.33–1.61) or for approval of the Ethics Committee of Hospital Univer- EDSS 3.0 (aHR = 0.81, 95% CI = 0.17–3.76). The sitari Vall d’ Hebron. All patients signed a written results of the HR estimates for the covariates included informed consent form. in the multivariate time-dependent model are shown in Table 2. This absence of association was supported by Data availability. Anonymized data will be shared the multivariable HR calculated within the propensity by request from any qualified investigator. score sensitivity analyses (aHR = 1.44, 95% CI = 0.59– 3.54 for CDMS and aHR = 0.92, 95% CI = 0.16–5.09 for EDSS3) (Figure 1). Finally, the same results were Results obtained in the sensitivity analysis when considering A total of 1137 patients were enrolled in the prospec- the whole study cohort (no OC use, OC use before the tive CIS cohort up to February 2016, of whom 764 CIS, and OC use after the CIS), showing no associa- (67.2%) were female and 496 responded the question- tion between OC use and the risk of second attack naire (65% response rate). As compared with those (HR: 0.91 (0.69, 1.18), p = 0.471 and aHR: 1.08 (0.82, who did not participate, patients who filled out the 1.41), p = 0.5832) or the risk of EDSS 3.0 (HR: 1.09 survey had a similar age at CIS (31.6 vs 31.5 years, (0.62, 1.92), p = 0.775 and aHR: 1.13 (0.61, 2.08), p = 0.971) but were more prone to exhibit an abnormal p = 0.6969). baseline MRI (49.4% vs 34.4%, p < 0.001), were more frequently on DMT (54% vs 16%, p < 0.001), and had a longer follow-up (9.7 vs 5.2 years, Discussion p < 0.001). One patient was excluded for not provid- Exposure to OCs is not associated neither with the ing information regarding the date of OC initiation. risk of second attack or with disability accumulation From the 495 responders, 389 (78.6%) referred to in CIS patients, once considered as time-dependent 952 journals.sagepub.com/home/msj S Otero-Romero, P Carbonell-Mirabent et al. Table 1. Patients’ characteristics according to oral contraceptive use. Never OC OC before CIS OC after CIS N = 106 N = 341 N = 48 Age at CIS, mean (SD) 31.0 (7.9) 32.7 (7.5) 24.4 (6.8) CIS topography, n (%) Optic nerve 35 (33.0) 109 (32.0) 14 (29.2) Brainstem 34 (32.1) 82 (24.0) 20 (41.7) Spinal cord 29 (27.4) 105 (30.8) 9 (18.8) Other 8 (7.5) 45 (13.2) 5 (10.4) Positive OB, n (%) 56 (61.5) 189 (64.7) 25 (64.1) Baseline MRI T2 lesions 0 lesions 20 (19.6) 74 (22.6) 10 (21.3) 1–3 lesions 13 (12.7) 47 (14.4) 9 (19.1) 4–9 lesions 16 (15.7) 50 (15.3) 2 (4.3) ⩾10 lesions 53 (52.0) 156 (47.7) 26 (55.3) Baseline MRI CEL lesions 0 lesions 44 (54.3) 163 (64.7) 15 (53.6) 1 lesion 13 (16.0) 35 (13.9) 5 (17.9) >1 lesion 24 (29.6) 54 (21.4) 8 (28.6) Body size at CIS, n (%) Underweight (1–3) 57 (53.8) 199 (58.4) 21 (43.8) Normal weight (4–6) 41 (38.7) 128 (37.5) 20 (41.7) Overweight (7–9) 8 (7.5) 14 (4.1) 7 (14.6) Parity, n (%) 0 45 (42.5) 93 (27.3) 19 (39.6) ⩾1 61 (57.5) 248 (72.9) 29 (60.4) Smoking status at CIS Smoker 66 (62.3) 233 (68.3) 26 (54.2) EDSS at questionnaire, median (IQR) 1.5 (1–2) 1.5 (1–2) 1 (1–2) Confirmed MSa at questionnaire 80 (75.5) 235 (68.9) 37 (77.1) DMTs at questionnaire First lineb 40/45 (88.9) 102/134 (76.1) 17/25 (68) Second linec 5/45 (11.1) 29/134 (21.6) 8/25 (32) Follow-up years, mean (SD) 10.1 (5.6) 9.2 (5.4) 12.9 (4.3) OC: oral contraceptives; CIS: clinically isolated syndrome; SD: standard deviation; OB: oligoclonal bands; MRI: magnetic resonance imaging; CEL: contrast gadolinium-enhancing lesions; EDSS: Expanded Disability Status Scale; IQR: interquartile range; MS: multiple sclerosis; DMT: disease-modifying treatment. A total of 3/341 (0.9%) patients starting OC before the CIS were enrolled in a clinical trial at the time of the questionnaire. aAccording to McDonald 2017 criteria. bFirst line: interferons, glatiramer acetate, teriflunomide, and dimethyl fumarate. cSecond line: natalizumab, S1P receptors, cladribine, alemtuzumab, and anti-CD20. covariates and adjusted for other confounders. The indicating no increase in relapse rate.7 It would also absence of effect on MS activity (second attack) be consistent with the neutral effect of OC exposure would support the idea that low doses of estrogen on MS risk reported in studies performed in unaf- (alone or in combination with progestin) contained in fected populations.5 contemporary OCs might not be high enough to play an anti-inflammatory role in CIS patients.19 There is We did not find a protective effect on disability accu- not specific data focusing on CIS patients, but this mulation as suggested by other authors8,10 possibly due lack of association would be in line with previous to the different outcomes used. Previous studies studies looking at the potential effects of OC in focused on the mean EDSS between groups while in patients with relapsing-remitting MS (RRMS), the present work we used the time to confirmed EDSS journals.sagepub.com/home/msj 953 Multiple Sclerosis Journal 28(6) Table 2. HR estimates of the adjusting variables of the multivariate time-dependent Cox models. Time to second attack Time to confirmed EDSS 3.0 HR 95% CI p-value HR 95% CI p-value Age at CIS 0.96 0.93–0.99 0.0098 1.04 0.99–1.1 0.143 CIS topography Optic nerve Ref. Ref. Brainstem 0.68 0.36–1.26 0.2161 2.11 0.33–13.49 0.429 Spinal cord 1.31 0.72–2.39 0.3752 3.55 0.57–22.05 0.175 Other 0.68 0.28–1.61 0.3785 4.64 0.53–40.68 0.166 OB Negative Ref. Ref. Positive 1.62 0.90–2.91 0.1058 1.44 0.32–6.4 0.635 Unknown 1.01 0.48–2.12 0.9711 3.13 0.69–14.12 0.138 MRI T2 lesions <10 lesions Ref. Ref. ⩾10 lesions 2.85 1.61–5.02 0.0003 2.24 0.57–8.77 0.248 MRI CEL lesions 0 lesions Ref. Ref. >0 lesions 1.88 1.12–3.18 0.0178 1.6 0.45–5.61 0.467 Unknown 0.53 0.31–0.91 0.0225 0.65 0.11–3.78 0.630 Body size, n (%) Underweight (1–3) Ref. Ref. Normal weight (4–6) 0.8 0.49–1.30 0.3708 0.63 0.18–2.22 0.475 Overweight (7–9) 1.12 0.58–2.17 0.7449 2.47 0.31–19.47 0.390 Smoking status at CIS Non-smoker Ref. Ref. Smoker 0.95 0.60–1.49 0.8156 1 0.31–3.24 0.998 Treatment initiation No initiation Ref. Ref. Treated 0.48 0.25–0.92 0.0270 0.9 0.26–3.17 0.875 HR: hazard ratio; EDSS: Expanded Disability Status Scale; CI: confidence interval; CIS: clinically isolated syndrome; OB: oligoclonal bands; MRI: magnetic resonance imaging; CEL: contrast gadolinium-enhancing lesions. The values highlighted in bold are those with statistical significance (p < 0.05). 3.0 which we believe to be a more robust disability out- those who had enough time to start using OC given that come. Moreover, in our study, clinical and radiological their CIS occurred at older ages. These results lead us to characteristics were similar between groups at baseline emphasize the importance of being aware of this phe- and an additional adjustment was performed analyzing nomenon and to be cautious when considering associa- OC and DMT as time-changing exposures. This was tion and causality in observational studies. not the case in previous studies where women with less severe disease were more frequently exposed to OC The present study has two major strengths: the after CIS8,9 and the protective effect of OC could be in study population characteristics and the analytical part confounded by a “healthy user” bias. In this situa- approach. The patients of this study belong to a large tion, the adjustment for other confounders is crucial. and deeply phenotyped prospective cohort of CIS patients with a long follow-up in which demographic, We found that the use of OC before the CIS was associ- clinical, MRI, and biological data have been col- ated with a later age at onset of the disease as compared lected under strict protocols and quality controls. to women who were never exposed to OC and women This valuable information allows for a multivariable who started the exposure after their CIS. This result approach to understand the potential impact of OC in could be clearly affected by the reverse causality,20 indi- the presence of other relevant explanatory variables. cating that women exposed to OC before their CIS were The time-dependent approach takes into account that 954 journals.sagepub.com/home/msj S Otero-Romero, P Carbonell-Mirabent et al. Figure 1. Proportional hazard Cox model estimates of the oral contraceptive exposure associated with the risk of (a) second relapse and (b) moderate disability (confirmed EDSS of 3.0). *Adjusted by age at CIS, topography of CIS, presence of OB in CSF, baseline number of T2 lesions, baseline CEL, body size at menarche, and treatment initiation. **Propensity score (PS) model for the OC use at any time using inverse probability weighting. OC: oral contraceptives; HR: hazard ratio. real time when exposure begins rather than assuming our cohort is slightly higher than other cohorts of it is present since the beginning of the follow-up. In RRMS patients and the numbers are similar regardless addition, we performed a propensity score analysis of the time when the questionnaire was completed for the OC use to address the possible selection bias (before or after the outcomes were met). Additionally, as women with a milder disease could more likely be being a relatively young cohort can reduce the risk of engaged in sexual activity and thus exposed to con- recall bias. Finally, our study sample has an underrep- traceptives as compared to women with a more resentation of patients belonging to the CIS inception severe course of the disease. cohort with normal baseline MRI who are not on DMT, as they are not regularly seen in the clinic and did not However, we are also aware of certain limitations. We respond the MS&Gender questionnaire despite several selected the subgroup of women who were never email reminders. However, the study cohort does not exposed to OC and women who were exposed after substantially differ from other available CIS cohorts in their CIS to avoid a potential overrepresentation of terms of baseline clinical and MRI characteristics.21,22 exposure to OC and minimizing the risk of classifica- Finally, the resulting cohorts after weighting for the tion bias. The studied cohort is similar in terms of clini- propensity of OC exposure still presented slight imbal- cal and MRI characteristics to the excluded patients ances (Supplementary Table 2). Therefore, estimates of and, therefore, the risk of selection bias is unlikely. the HRs associated with OC exposure were obtained This was further confirmed in the sensitivity analysis within adjusted models. with consistent results for the whole cohort. However, reducing the study sample can have an impact on the This multivariate time-dependent analysis provides precision of our estimates and larger numbers are evidence that OC use after the CIS is not significantly needed to confirm our findings. Other potential limita- associated with the risk of second attack or disability tions are the lack of information about the OCs hormo- accumulation. These findings are relevant for clinical nal composition and the duration of the exposure. counseling for young women with CIS and/or recent Nevertheless, none of the previous studies found a dose MS diagnosis. effect,3,5,6 which favors our results of a non-impact of OC, or a difference in the course of the disease depend- Author Contributions ing on the OC formulation used.8 Also, a possible recall S.O.-R. designed and conceptualized the study, ana- bias could potentially underestimate the exposure, but lyzed the data, and drafted the manuscript for intellec- the percentage of patients reporting to ever use OC in tual content. P.C.-M. played a major role in the analysis journals.sagepub.com/home/msj 955 Multiple Sclerosis Journal 28(6) of the data, interpreted the data, and revised the manu- Pharmaceuticals, Sanofi-Aventis, and Novartis. M.R. script for intellectual content. L.M. played a major role declares that there is no conflict of interest. C.A. has in the acquisition of data, interpreted the data, and received speaking honoraria from Novartis, Biogen, revised the manuscript for intellectual content. A.R. and Stendhal. J.S.-G. has received compensation for played a major role in the acquisition of data and participating on advisory boards, speaking honoraria, revised the manuscript for intellectual content. M.Z. and travel expenses for scientific meetings, consulting interpreted the data and revised the manuscript for services, or research support from Celgene, Novartis, intellectual content. I.G. played a major role in the Biogen, Teva, Merck, Almirall, and Genzyme. X.M. acquisition of data. J.R. interpreted the data and revised has received speaking honoraria and travel expenses the manuscript for intellectual content. G.A. interpreted for participation in scientific meetings and has been a the data and revised the manuscript for intellectual con- steering committee member of clinical trials or partici- tent. A.V.-J., J.C., B.R.-A., M.C., M.R., and C.A. pated in advisory boards of clinical trials in the past played a major role in the acquisition of data. J.S.-G. with Actelion, Almirall, Bayer, Biogen, Celgene, interpreted the data and revised the manuscript for Genzyme, Hoffmann-La Roche, Novartis, Oryzon intellectual content. X.M. interpreted the data and Genomics, Sanofi-Genzyme, and Teva Pharmaceutical. revised the manuscript for intellectual content. M.T. M.T. has received compensation for consulting ser- designed and conceptualized study, analyzed the data, vices and speaking honoraria from Bayer Schering and drafted the manuscript for intellectual content. Pharma, Merck-Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Novartis, Almirall, Declaration of Conflicting Interests Genzyme, Viela-Bio, and Roche. Go to Neurology. The author(s) declared the following potential conflicts org/N for full disclosures. of interest with respect to the research, authorship, and/ or publication of this article: S.O.-R. has received Funding speaking honoraria and consulting fees from Genzyme, The author(s) disclosed receipt of the following finan- Biogen-Idec, and MSD and research support from cial support for the research, authorship, and/or publi- Novartis. P.C.-M. declares that there is no conflict of cation of this article: This project was supported by interest. L.M. reports no disclosures relevant to the FIS PI15/0070 from Ministry of Economy and manuscript. A.R. serves on scientific advisory boards Competitiveness of Spain. for Biogen-Idec, Novartis, Genzyme, and OLEA Medical, and on the editorial boards of the American ORCID iDs Journal of Neuroradiology, Neuroradiology, and Alvaro Cobo-Calvo https://orcid.org/0000-0002- European Radiology; has received speaker honoraria 2574-0721 from Bayer, Genzyme, Sanofi-Aventis, Bracco, Merck- Jordi Rio https://orcid.org/0000-0003-4546-7627 Serono, Teva Pharmaceutical Industries Ltd., OLEA Georgina Arrambide https://orcid.org/0000-0002- Medical, Stendhal, Novartis, and Biogen-Idec; and has 2657-5510 research agreements with Siemens AG. M.Z. has Angela Vidal-Jordana https://orcid.org/0000-0002- received compensation for consulting services from 7270-5507 Novartis, Stendhal, Genzyme, Merck-Serono, and Breogán Rodríguez-Acevedo https://orcid.org/ Bayer. A.C.-C. has received grant from Instituto de 0000-0002-0314-753X Salud Carlos III, Spain; JR19/00007I. I.G. declares that Carmen Tur https://orcid.org/0000-0003-1849-3184 there is no conflict of interest. J.R. has received speak- Alex Rovira https://orcid.org/0000-0002-2132- ing honoraria and personal compensation for partici- 6750 pating on advisory boards from Almirall, Jaume Sastre-Garriga https://orcid.org/0000-0002- Bayer-Schering Healthcare, Biogen-Idec, Genzyme, 1589-2254 Merck-Serono, Novartis, Teva, and Sanofi-Aventis. Mar Tintoré https://orcid.org/0000-0001-9999-5359 G.A. has received compensation for consulting ser- vices from Biogen-Idec, research support from Supplemental Material Novartis, and speaking honoraria from Sanofi-Aventis. Supplemental material for this article is available A.V.-J. has received speaking honoraria and consulting online. fees from Novartis, Roche, and Sanofi-Aventis. J.C. reports no disclosures relevant to the manuscript. B.R.-A. declares that there is no conflict of interest. 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