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Brain volume loss and physical and cognitive impairment in naïve multiple sclerosis patients treated with fingolimod: prospective cohort study in Buenos Aires, Argentina

Perda de volume cerebral e comprometimento físico e cognitivo em pacientes recém-diagnosticados com esclerose múltipla tratados com fingolimode: estudo de coorte prospectivo em Buenos Aires, Argentina

Juan Ignacio Rojas Liliana Patrucco Agustín Pappolla Francisco Sánchez Edgardo Cristiano About the authors

Abstract

Background

The percentage of brain volume loss (PBVL) has been classically considered as a biomarker in multiple sclerosis (MS).

Objective

The objective of the present study was to analyze if the PBVL during the 1st year after the onset of the disease predicts physical and cognitive impairment (CI).

Methods

Prospective study that included naïve patients without cognitive impairment who initiated MS treatment with fingolimod. Patients were followed for 3 years and relapses, expanded disability status scale (EDSS) progression (defined as worsening of 1 point on the EDSS), the annual PBVL (evaluated by structural image evaluation using normalization of atrophy [SIENA]), and the presence of CI were evaluated. Cognitive impairment was defined in patients who scored at least 2 standard deviations (SDs) below controls on at least 2 domains. The PBVL after 1 year of treatment with fingolimod was used as an independent variable, while CI and EDSS progression at the 3rd year of follow-up as dependent variables.

Results

A total of 71 patients were included, with a mean age of 35.4 ± 3 years old. At the 3rd year, 14% of the patients were classified as CI and 6.2% had EDSS progression. In the CI group, the PBVL during the 1st year was-0.52 (± 0.07) versus-0.42 (± 0.04) in the no CI group (p < 0.01; odds ratio [OR] = 2.24; 95% confidence interval [CI]: 1.72–2.44). In the group that showed EDSS progression, the PBVL during the 1st year was - 0.59 (± 0.05) versus - 0.42 (± 0.03) (p < 0.01; OR = 2.33; 95%CI: 1.60-2.55).

Conclusions

A higher PBVL during the 1st year in naïve MS patients was independently associated with a significant risk of CI and EDSS progression.

Keywords:
Multiple Sclerosis; Cognitive Dysfunction; Disabled Persons; Biomarkers; Fingolimod Hydrochloride; Argentina

Resumo

Antecedentes

A porcentagem de perda de volume cerebral (PPVC) é um biomarcador na esclerose múltipla (EM).

Objetivo

Analisar se a PPVC durante o 1° ano após o início da doença prediz deterioração física (DF) e cognitiva (DC) em pacientes com EM.

Métodos

Estudo de coorte prospectivo que incluiu pacientes recém-diagnosticados sem comprometimento cognitivo que iniciaram tratamento com fingolimode. Os pacientes foram acompanhados por 3 anos, sendo avaliados a presença de recidivas, progressão da Escala Expandida do Estado de Incapacidade (EDSS, na sigla em inglês) (definida como agravamento de 1 ponto na EDSS), o PPVC anual (avaliado pela avaliação de imagem estrutural de atrofia normalizada [SIENA, na sigla em inglês) e a presença de DC (avaliada no início do estudo e nos 2° e 3° anos). O PPVC no 1° ano de tratamento com fingolimode foi utilizado como variável independente.

Resultados

foram incluídos 71 pacientes com idade média de 35,4 ± 3 anos. No 3° ano, 14% dos pacientes tiveram DC e 6,2% tiveram progressão de EDSS. No grupo DC, o PPVC durante o 1o ano foi - 0,52 (± 0,07) versus - 0,42 (± 0,04) no grupo sem DC (p<0,01; razão de probabilidades [OR, na sigla em inglês] =2,24; intervalo de confiança [IC] de 95%: 1,72-2,44). No grupo que apresentou progressão da EDSS, o PPVC durante o 1° ano foi de - 0,59 (± 0,05) versus - 0,42 (± 0,03) (p < 0,01; OR = 2,33; IC95%: 1,60-2,55).

Conclusões

Um maior PPVC durante o 1° ano foi associado a um risco significativo de progressão de DC e EDSS durante o seguimento.

Palavras-chave:
Esclerose Múltipla; Disfunção Cognitiva; Pessoas com Deficiências; Biomarcadores; Cloridrato de Fingolimode; Argentina

INTRODUCTION

Multiple sclerosis (MS) is a chronic degenerative disease that affects mostly young adults between 18 and 40 years old and is the first cause of physical disability of nontraumatic origin in several countries.11 Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. N Engl J Med 2018;378(02):169–180,22 Comi G, Radaelli M, Soelberg Sørensen P. Evolving concepts in the treatment of relapsing multiple sclerosis. Lancet 2017;389 (10076):1347–1356 Multiple sclerosis is characterized histopathologically by the presence of inflammatory plaques associated with the presence of axonal damage.11 Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. N Engl J Med 2018;378(02):169–180,33 Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338(05):278–285

In MS, axonal degeneration is thought tobeone important cause responsible for the irreversible progression of the disability seen in affected patients.44 Sormani MP, Kappos L, Radue EW, et al. Defining brain volume cutoffs to identify clinically relevant atrophy in RRMS. Mult Scler 2017;23(05):656–664, 55 Moccia M, de Stefano N, Barkhof F. Imaging outcome measures for progressive multiple sclerosis trials. Mult Scler 2017;23(12): 1614–1626, 66 Kappos L, De Stefano N, Freedman MS, et al. Inclusion of brain volume loss in a revised measure of ’no evidence of disease activity’ (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler 2016;22(10):1297–1305

Brain atrophy occurs faster in MS patients than in healthy control subjects,77 Eshaghi A, Marinescu RV, Young AL, et al. Progression of regional grey matter atrophy in multiple sclerosis. Brain 2018;141(06): 1665–1677 and the atrophy is the result of gray (GM) and white matter (WM) atrophy.77 Eshaghi A, Marinescu RV, Young AL, et al. Progression of regional grey matter atrophy in multiple sclerosis. Brain 2018;141(06): 1665–1677,88 Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64(03): 255–265 The annualized rates of whole-brain and GM atrophy increased with the stage of the disease, from < 0.2% in patients with clinically isolated syndromes converting to relapsing-remitting MS (RRMS) to almost 0.4% in patients with secondary progressive MS.88 Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64(03): 255–265 Interestingly, GM atrophy is not uniform, being the limbic system, the temporal cortex, and deep GM the regions that showed the fastest annual rate of tissue loss in RRMS.77 Eshaghi A, Marinescu RV, Young AL, et al. Progression of regional grey matter atrophy in multiple sclerosis. Brain 2018;141(06): 1665–1677,99 Preziosa P, Pagani E, Mesaros S, et al. Progression of regional atrophy in the left hemisphere contributes to clinical and cognitive deterioration in multiple sclerosis: A 5-year study. Hum Brain Mapp 2017;38(11):5648–5665

The percentage of brain volume loss (PBVL) has been classically considered as a biomarker present in severe or advanced stages of the disease; however, evidence showed that brain volume loss occurs early in MS.55 Moccia M, de Stefano N, Barkhof F. Imaging outcome measures for progressive multiple sclerosis trials. Mult Scler 2017;23(12): 1614–1626,1010 De Stefano N, Stromillo ML, Giorgio A, et al. Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis. J Neurol Neurosurg Psychiatry 2016;87(01):93–99 As a consequence, the PBVL has been identified as an early prognostic factor of the clinical and cognitive progression of MS.1111 Schoonheim MM, Hulst HE, Brandt RB, et al. Thalamus structure and function determine severity of cognitive impairment in multiple sclerosis. Neurology 2015;84(08):776–783, 1212 Yildiz M, Tettenborn B, Radue EW, Bendfeldt K, Borgwardt S. Association of cognitive impairment and lesion volumes in multiple sclerosis–a MRI study. Clin Neurol Neurosurg 2014; 127:54–58, 1313 Yaldizli Ö, Penner IK, Frontzek K, et al. The relationship between total and regional corpus callosum atrophy, cognitive impairment and fatigue in multiple sclerosispatients. Mult Scler 2014;20(03): 356–364, 1414 Feinstein A, Lapshin H, O’Connor P, Lanctôt KL. Sub-threshold cognitive impairment in multiple sclerosis: the association with cognitive reserve. J Neurol 2013;260(09):2256–2261, 1515 Amato MP, Hakiki B, Goretti B, et al; Italian RIS/MS Study Group. Association of MRI metrics and cognitive impairment in radio-logically isolated syndromes. Neurology 2012;78(05):309–314

Cognitive impairment (CI) is frequently observed in MS patients even in the early stages of the disease1515 Amato MP, Hakiki B, Goretti B, et al; Italian RIS/MS Study Group. Association of MRI metrics and cognitive impairment in radio-logically isolated syndromes. Neurology 2012;78(05):309–314 and may reflect damages to brain structures, usually detected too late to implement an effective preventive therapy.1515 Amato MP, Hakiki B, Goretti B, et al; Italian RIS/MS Study Group. Association of MRI metrics and cognitive impairment in radio-logically isolated syndromes. Neurology 2012;78(05):309–314

Considering the relevance of identifying early biomarkers of disease progression in terms of clinical and cognitive aspects, the objective of the present study was to analyze if the PBVL during the 1st year after the onset of MS predicts physical impairment and CI over 3 years in MS patients in a prospective cohort study in Buenos Aires, Argentina.

METHODS

Patients were prospectively included during January 2014 and January 2017. Consecutive, not random patients with a diagnosis of MS, defined according to 2010 validated diagnosis criteria, were considered for inclusion in the study.1616 Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69(02):292–302 Once RRMS was diagnosed and the decision to start with fingolimod was indicated, patients were invited to participate and those who accepted were included in the study. Only patients who started the treatment with fingolimod were included to homogenize the sample and avoid the possibility of the confounding factor of different treatments over brain volume measurements. In Argentina, fingolimod is available since 2010 for RRMS independently of the activity of the disease and of the duration of the disease, so it is possible to use it from the moment the patients are diagnosed.1717 Cristiano E, Rojas JI, Alonso R, et al. Consensus recommendations on the management of multiple sclerosis patients in Argentina. J Neurol Sci 2020;409:116609

Once included, patients were followed longitudinally for at least 3 years with evaluations of clinical aspects (relapses and progression of the disease as measured by EDSS). Magnetic resonance imaging (MRI) evaluation was done 6 months (range: 4 to 7 months) after fingolimod initiation (baseline MRI), and then at the 1st, 2nd, and 3rd years after the first MRI. Cognitive evaluation was performed at study entry to exclude CI in selected patients, and then again at the 2nd and 3rd years.

Clinical parameters evaluated at baseline

Demographic and clinical characteristics of the disease were collected at the initiation of fingolimod. Age and sex data were extracted, as well as disease characteristics including age at onset, disease duration, number of relapses, EDSS scores prior exposure tofingolimod, andMRI activitydefined by T2 lesion/gadolinium-enhancing lesions (pretreatment).

Follow-up evaluation

Patients were followed-up prospectively and during at least 3 years for the analysis. Evaluations collected information about a) clinical relapses, defined as the appearance of a new neurological symptom that lasts > 24 hours, in the absence of clinical intercurrence, followed by a period of clinical stability or improvement of at least 30 days; b) progression of physical disability, evaluated through clinical evaluation by applying the EDSS scale. This variable was dichotomized for analysis inpatients who progressedin EDSS and inthosewho did not progress. Progression was defined as a worsening of 1 point on the scale between one measurement and another with an interval of at least 6 months between them. To consider progression, in the case of presenting a clinical relapse, the patient must have been 3 months away from the relapse regardless of whether steroid treatment was received for the management of the acute episode; and c) new lesions in MRI. Magnetic resonance imaging included the use of 1.5 Tesla equipment,with cuts of 1.5 to 3 mm wide, obtaining sequences of T1, T2, FLAIR, and T1 with intravenous contrast. The images obtained and stored in standard storage format (DICOM) were subsequently included and processed in a semiautomated way by JIM synapse software to identify new or enlarging lesions. Magnetic resonance imaging scans were obtained from each patient at baseline (month 6 after initiation of the treatment) and at the 1st, 2nd, and 3rd years after initiation of the treatment.

To measure PBVL between the baseline MRI and the MRI obtained in the 1st year after initiation of the treatment, the structural image evaluation using normalization of atrophy (SIENA) fully automated longitudinal analysis method was used. SIENA software was used to measure cross-sectional volumes.1818 Smith SM, De Stefano N, Jenkinson M, Matthews PM. Normalized accurate measurement of longitudinal brain change. J Comput Assist Tomogr 2001;25(03):466–475, 1919 Smith SM, Zhang Y, Jenkinson M, et al. Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 2002;17(01):479–489 The PBVL was also estimated at the 2nd and 3rd years of follow-up. Regarding the neuropsychological evaluation, subjects underwent a comprehensive set of tests at study entry and then at the 2nd and 3rd years. Evaluations included the Brief Repeatable Battery of Neuropsychological tests,2020 Rao SM. A Manual for the Brief Repeatable Battery of Neuropsy-chological Tests in Multiple Sclerosis: Medical College of Wisconsin. Milwaukee: Medical College of Wisconsin; 1990 the Stroop color-word test, and the memory comparison test (MCT). Z scores were calculated based on the mean and standard deviations (SDs) of healthy people for executive functioning (computerized self test [CST], word list generation), verbal memory (selective reminding test [SRT]), information processing speed (symbol digit modalities test [SDMT]), visuospatial memory (spatial recall test), working memory (MCT), attention (Stroop), and psychomotor speed (CST, SDMT) domains. Tests were performed by an experienced group of neurologists and a neuropshychologist (Neuropsychlogy Team, Neurology Service, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina) who were unaware of the MRI results, using validated translations of the neuropsychological tests.

Statistical analysis plan

Continuous data were expressed with their means and SDs. Categorical data were expressed in percentages. Demographic and clinical variables were described. At study entry, all patients had no CI after the neuropsychological assessment. The cohort was followed and reassessed at the 2nd and 3rd years. After reassessment, the cohort was subdivided into two groups representing patients with CI and patients without CI (noCI), using cognitive domain Z scores. All patients who scored at least 2 SDs below controls on at least 2 domains were designated as CI.1414 Feinstein A, Lapshin H, O’Connor P, Lanctôt KL. Sub-threshold cognitive impairment in multiple sclerosis: the association with cognitive reserve. J Neurol 2013;260(09):2256–2261 The remaining patients (scoring > 2 SDs below controls) were designated as noCI.The Z scores from all cognitive domains were also averaged to form one summary statistic of average cognition. This was used to explore relations between MRI metrics and cognition but not to form patient groups. The same analysis was performed for progression of physical disability. The PBVL after 1 year of treatment with fingolimod was used as an independent variable, while CI and EDSS progression at the 3rd year follow-up were used as dependent variables. A stepwise logistic regression analysis was performed between independent and dependent variables, adjusted by age, sex, EDSS at study entry, and years of education. Forward and backward stepwise analyses were conducted using the Wald statistic as a criterion, with p = 0.05 for entry and p = 0.10 for removal. We also performed a receiver operating characteristic (ROC) curve analysis to determine the optimal sensitivity and specificity of PBVL after 1 year of treatment and CI and EDSS progression. The data analysis was performed with Stata 15 software (StataCorp, College Station, TX, USA).

The Institutional Review Board of the Hospital Italiano of Buenos Aires approved the present study (approval protocol number 2047, date of approval August 8, 2013). Informed consent was obtained from all included patients.

RESULTS

A total of 71 patients were included, 69% of whom were female (n = 49), with a mean age of 35.4 ± 3 years old, a mean EDSS 1.5 ± 1, a mean follow-up time of 43 ± 5 months, and mean years of education 12 ± 3. In 7 cases, fingolimod was switched due to treatment failure based on the decision by the principal investigators. The rest of the baseline characteristics are shown in ►Table 1.

Table 1
Patient demographics and baseline clinical characteristics

Volumetric analysis was performed on the included sample.

Patients were identified according to CI and physical disability progression during the follow-up, as previously described. A total of 9 (14%) patients were classified as CI, 4 (6.2%) patients had physical disability progression, and 6 (9.3%) had relapse activity at the 3rd year.

Volumetric description according to cognitive and physical disability progression

Patients who changed the treatmentduetotreatment failure were excluded from the analysis.

In the CI group, a significant reduction during the 1st-year PBVL was observed compared with the noCI group after accounting for the influence of demographics and clinical variables (p < 0.01; odds ratio [OR] = 2.11; 95% confidence interval [CI]: 1.53–2.41) (►Figure 1).

Figure 1
Comparative analysis of PBVL according to cognitive impairment. Abbreviations: CI, cognitive impairment; NoCI, no cognitive impairment; PBVL, percentage of brain volume loss.

Regarding physical disability, in the group that showed physical disability progression, a significant reduction during the 1st -year PBVL was also observed versus patients who did not progress (p < 0.01, OR = 2.13, 95%CI: 1.63–2.31) (►Figure 2).

Figure 2
Comparative analysis of PBVL according to progression of physical disability. Abbreviations: NoPD, no physical disability; PD, physical disability; PBVL, percentage of brain volume loss.

In the logistic regression analysis, the PBVL during the 1st year of treatment with fingolimod was independently associated with the occurrence of CI in the initial 3 years of follow-up (OR = 2.24; 95%CI; 1.72–2.44; p < 0.01). This was also observed for EDSS progression (OR = 2.33; 95%CI: 1.60–2.55; p < 0.01) (►Table 2 and 3). The optimal cutoff for PBVL 1 year of treatment and CI determined by ROC analysis was - 0.49, with a diagnostic sensitivity and specificity of 84 and 91%, respectively (correctly classified 81%), and the cutoff for EDSS progression was - 0.55, with a sensitivity and specificity of 86 and 90%, respectively (correctly classified 85%).

Table 2
Regression analysis assessing percentage of brain volume loss after the 1st year of the treatment with fingolimod in predicting cognitive impairment at the 3rd year
Table 3
Regression analysis assessing PBVL after the 1st year of treatment with fingolimod in predicting the progression of physical disability on the 3rd year

DISCUSSION

In the present study, we found that a low number of patients progressed in terms of physical and cognitive impairment during the first 3 years of follow up. We observed that patients who progressed to CI had a significant reduction in PBVL compared with patients that did not (- 0.51 versus -0.42) in the 1st year of treatment. Similar findings were observed when the dependent variable was progression of physical disability. A higher PBVL was observed in patients who progressed versus nonprogressive patients during the 1st year of treatment (- 0.59 versus - 0.42, respectively; p = 0.008). The regression analysis showed that higher PBVL during 1st first year was independently associated with CI and physical disability progression at the 3rd year. It is also worth highlighting that the included patients were naïve;however, the PBVL rate during the 1st yearof follow-up exceeded - 0.5% in the entire group follow-up (►Figures. 1 and 2), showing how the process is present since early moments of the disease and warrants a detailed identification process.

Several studies have investigated the association between brain volume and/or atrophy and physical disability in MS populations.2121 Rojas JI, PatruccoL,MiguezJ, CristianoE. Brain atrophyinmultiple sclerosis: therapeutic, cognitive and clinical impact. Arq Neuro-psiquiatr 2016;74(03):235–243 At a population level, brain volume has long been considered to have a better association with clinical disability than WM lesion volume. This is based on cross-sectional studies that showed negative correlations between wholebrainvolume/fraction andtheEDSS.2222 BermelRA, Sharma J, Tjoa CW, Puli SR, Bakshi R. A semiautomated measure of whole-brain atrophy in multiple sclerosis. J Neurol Sci 2003;208(1-2):57–65, 2323 Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol 2006;5(02):158–170, 2424 Sharma J, Sanfilipo MP, Benedict RH, Weinstock-Guttman B, Munschauer FE III, Bakshi R. Whole-brain atrophy in multiple sclerosis measured by automated versus semiautomated MR imaging segmentation. AJNR Am J Neuroradiol 2004;25(06): 985–996 Longitudinal studies, however, have demonstrated strong group-level associations between baseline brain volume and early brain atrophy, and future clinical disability.2525 Minagar A, Barnett MH, Benedict RH, et al. The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects. Neurology 2013;80(02):210–219,2626 Zivadinov R, Havrdová E, Bergsland N, et al. Thalamic atrophy is associated with development of clinically definite multiple sclerosis. Radiology 2013;268(03):831–841 Early brain atrophy has been found to be associated with the developmentof clinical disability over the medium- to long-term in multiple longitudinal studies.88 Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64(03): 255–265,2727 Fisniku LK, Chard DT, Jackson JS, et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 2008;64(03):247–254 Studies have demonstrated particularly strong associations between GM atrophy and physical disability.88 Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64(03): 255–265,2727 Fisniku LK, Chard DT, Jackson JS, et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 2008;64(03):247–254 In most of these studies, physical disability was based on the EDSS; however, in some cases, the MS Functional Composite (MSFC) was also used to assess levels of disability.88 Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64(03): 255–265,2828 Sastre-Garriga J, Ingle GT, Chard DT, Ramió-Torrentà L, Miller DH, Thompson AJ. Grey and white matter atrophy in early clinical stages of primary progressive multiple sclerosis. Neuroimage 2004;22(01):353–359 A large multicenter study in Europe that included 8 centers and 261 MS patients evaluated whether brain atrophy and lesion volumes predict subsequent 10-year clinical evolution in MS patients.2929 Popescu V, Agosta F, Hulst HE, et al; MAGNIMS Study Group. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry 2013;84(10):1082–1091 The study used MRI imaging at baseline and after 1 to 2 years. In the entire patient group, whole-brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS,anddisease-modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10-year EDSS with r2 = 0.74 in the whole group and r2 = 0.72 in the relapse onset group.2929 Popescu V, Agosta F, Hulst HE, et al; MAGNIMS Study Group. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry 2013;84(10):1082–1091 Interestingly, whole-brain atrophy was the only MRI predictor of 10-year multiple sclerosis severity score (MSSS), and the combined model explained 64.1% of the variance in MSSS.2929 Popescu V, Agosta F, Hulst HE, et al; MAGNIMS Study Group. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry 2013;84(10):1082–1091

The association between cognitive impairment and MRI brain volumetric changes has been examined on multiple occasions in MS cohorts.2626 Zivadinov R, Havrdová E, Bergsland N, et al. Thalamic atrophy is associated with development of clinically definite multiple sclerosis. Radiology 2013;268(03):831–841,3030 Houtchens MK, Benedict RH, Killiany R, et al. Thalamic atrophy and cognition in multiple sclerosis. Neurology 2007;69(12): 1213–1223 A large number of cross-sectional studies have been performed and associations are stronger with the GM compartment,3030 Houtchens MK, Benedict RH, Killiany R, et al. Thalamic atrophy and cognition in multiple sclerosis. Neurology 2007;69(12): 1213–1223, 3131 Sanfilipo MP, Benedict RH, Sharma J, Weinstock-Guttman B, Bakshi R. The relationship between whole brain volume and disability in multiple sclerosis: a comparison of normalized gray vs. white matter with misclassification correction. Neuro-image 2005;26(04):1068–1077, 3232 Sanfilipo MP, Benedict RH, Weinstock-Guttman B, Bakshi R. Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology 2006;66(05):685–692 more specifically with deep gray matter volumes, and with cortical thickness and volume.2525 Minagar A, Barnett MH, Benedict RH, et al. The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects. Neurology 2013;80(02):210–219,3232 Sanfilipo MP, Benedict RH, Weinstock-Guttman B, Bakshi R. Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology 2006;66(05):685–692 Longitudinal studies have revealed an association between cognitive impairment and brain atrophy, particularly GM atrophy.2121 Rojas JI, PatruccoL,MiguezJ, CristianoE. Brain atrophyinmultiple sclerosis: therapeutic, cognitive and clinical impact. Arq Neuro-psiquiatr 2016;74(03):235–243 Our study is in line with previous studies in which brain atrophy measured over the 1st year after onset of the disease was a good predictor of CI ~ 5 years later, when other relevant variables (age, sex, and as being attention and information processing speed.3333 Summers M, Fisniku L, Anderson V, Miller D, Cipolotti L, Ron M. Cognitive impairment in relapsing-remitting multiple sclerosis can be predicted by imaging performed several years earlier. Mult Scler 2008;14(02):197–204 In some MS cohorts, weak correlations between brain atrophy and cognitive performance may be explained by greater cognitive reserve in earlier disease and/or higher premorbid intelligence.3434 Uher T, Blahova-Dusankova J, Horakova D, et al. Longitudinal MRI and neuropsychological assessment of patients with clinically isolated syndrome. J Neurol 2014;261(09):1735–1744

Regarding fingolimod, once-daily oral fingolimod (Gilenya, Novartis, Basel, Switzerland) acts by reducing the number of recirculating autoreactive T-cells entering the central nervous system (CNS) and destroying the myelin sheath via reducing egress of these lymphocytes from the lymph nodes.3535 Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 2010;9(11):883–897 Fingolimod crosses the blood-brain barrier and acts directly on the S1P receptors located on these cells, leading to reduction of reactive activation of glia (which may favor naturally-occurring remyelination).3535 Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 2010;9(11):883–897 This mechanism of action might be responsible for the effects of fingolimod on slowing brain atrophy observed in previous studies (which, in turn, is possibly associated with CI).3535 Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 2010;9(11):883–897 In phase III pivotal studies, fingolimod-treated MS patients developed less brain atrophy versus patients receiving placebo both at the 1st year (- 0.50 versus -0.65%) and at the 2nd year (- 0.84 versus -1.31%) in the FREEDOMS study,3636 Kappos L, Radue EW, O’Connor P, etal; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362(05):387–401 and versus patients receiving interferon P-1a (IFN P-1a) over 1 year (- 0.31 versus - 0.45%) in the TRANSFORMS study.3737 Cohen JA, Barkhof F, Comi G, et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362(05):402–415 The effect of fingolimod on CI in patients with MS has been assessed using the Paced Auditory Serial Addition Test (PASAT) in two pivotal phase III randomized studies, FREEDOMS and TRANSFORMS. In both these studies, a trend toward a greater proportion of correct responses on the PASAT-3 was observed in patients treated with fingolimod compared with those receiving placebo (FREEDOMS) or IFN P-1a (TRANSFORMS, where the difference versus IFN P-1a was significant, with p = 0.049).3636 Kappos L, Radue EW, O’Connor P, etal; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362(05):387–401,3737 Cohen JA, Barkhof F, Comi G, et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362(05):402–415 Our study is in line with the recently published GOLDEN pilot study, which included RRMS patients with CI randomized(2:1) to fingolimod (0.5mgdaily)/ IFN β-1b (250 ug every other day).3838 Comi G, Patti F, Rocca MA, et al; Golden Study Group. Efficacy of fingolimod and interferon beta-1b on cognitive, MRI, and clinical outcomes in relapsing-remitting multiple sclerosis: an 18-month, open-label, rater-blinded, randomised, multicentre study (the GOLDEN study). J Neurol 2017;264(12):2436–2449 The objective of that study was to evaluate the stability on cognitive performance of patients with CI under fingolimod. Overall, 157 patients were randomized. Patients randomized to fingolimod showed improvements in all cognitive parameters evaluated after 18 months of follow-up.3838 Comi G, Patti F, Rocca MA, et al; Golden Study Group. Efficacy of fingolimod and interferon beta-1b on cognitive, MRI, and clinical outcomes in relapsing-remitting multiple sclerosis: an 18-month, open-label, rater-blinded, randomised, multicentre study (the GOLDEN study). J Neurol 2017;264(12):2436–2449

The main limitation of our study is that information comes from a single center. However, the prospective form of data collection and the follow-uptime (at least36 months) increase certainty regarding effectiveness and safety issues during the follow-up. Another limitation is that we only included patientsunder fingolimod; however, this limitation allows us to control the possibility of a confounding factor of brain volume loss due to a different mechanism of action of treatments used for MS.

In summary, we observed CI and disability progression during the first 3 years of follow-up were low in naïve patients who started treatment with fingolimod. In patients whoprogressed intermsof CI and physicaldisability, the rate of PBVL during the 1st year of treatment was significantly higher than that observed in patients who did not, being a useful biomarker of worse prognosis.

Our results represent one of the first postmarketing studies conducted in Argentina and its region on the use of fingolimod in a real-world setting.

  • Support
    The present research was funded by an educational grant from Novartis Argentina.

Aknowledgements

We would like to thank to the neuropsichological team, Department Neurology, Hospital Italiano de Buenos Aires.

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Publication Dates

  • Publication in this collection
    21 Nov 2022
  • Date of issue
    July 2022

History

  • Received
    16 Sept 2021
  • Accepted
    19 Oct 2021
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