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  • Amarenco, Pierre, et al. (författare)
  • Ticagrelor Added to Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack in Prevention of Disabling Stroke : A Randomized Clinical Trial
  • 2020
  • Ingår i: JAMA Neurology. - 2168-6149 .- 2168-6157. ; 78:2, s. 177-185
  • Tidskriftsartikel (refereegranskat)abstract
    • Importance: Reduction of subsequent disabling stroke is the main goal of preventive treatment in the acute setting after transient ischemic attack (TIA) or minor ischemic stroke.Objective: To evaluate the superiority of ticagrelor added to aspirin in preventing disabling stroke and to understand the factors associated with recurrent disabling stroke.Design, Setting, and Participants: The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) was a randomized clinical trial conducted between January 22, 2018, and December 13, 2019, with a 30-day follow-up, at 414 hospitals in 28 countries. The trial included 11 016 patients with a noncardioembolic, nonsevere ischemic stroke or high-risk TIA, including 10 803 with modified Rankin Scale score (mRS) recorded at 30 days.Interventions: Ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for days 2-30) or placebo within 24 hours of symptom onset. All patients received aspirin, 300 to 325 mg on day 1 followed by 75 to 100 mg daily for days 2 to 30.Main Outcomes and Measures: Time to the occurrence of disabling stroke (progression of index event or new stroke) or death within 30 days, as measured by mRS at day 30. Disabling stroke was defined by mRS greater than 1.Results: Among participants with 30-day mRS greater than 1, mean age was 68.1 years, 1098 were female (42.6%), and 2670 had an ischemic stroke (95.8%) as a qualifying event. Among 11 016 patients, a primary end point with mRS greater than 1 at 30 days occurred in 221 of 5511 patients (4.0%) randomized to ticagrelor and in 260 of 5478 patients (4.7%) randomized to placebo (hazard ratio [HR], 0.83; 95% CI, 0.69-0.99, P = .04). A primary end point with mRS 0 or 1 at 30 days occurred in 70 of 5511 patients (1.3%) and 87 of 5478 patients (1.6%) (HR, 0.79; 95% CI, 0.57-1.08; P = .14). The ordinal analysis of mRS in patients with recurrent stroke showed a shift of the disability burden following a recurrent ischemic stroke in favor of ticagrelor (odds ratio, 0.77; 95% CI, 0.65-0.91; P = .002). Factors associated with disability were baseline National Institutes of Health Stroke Scale score 4 to 5, ipsilateral stenosis of at least 30%, Asian race/ethnicity, older age, and higher systolic blood pressure, while treatment with ticagrelor was associated with less disability.Conclusions and Relevance: In patients with TIA and minor ischemic stroke, ticagrelor added to aspirin was superior to aspirin alone in preventing disabling stroke or death at 30 days and reduced the total burden of disability owing to ischemic stroke recurrence.Trial Registration: ClinicalTrials.gov Identifier: NCT03354429.
  • Brander, Gustaf, et al. (författare)
  • Association of Tourette Syndrome and Chronic Tic Disorder With Metabolic and Cardiovascular Disorders
  • 2019
  • Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 76:4, s. 454-461
  • Tidskriftsartikel (refereegranskat)abstract
    • Importance: There are limited data concerning the risk of metabolic and cardiovascular disorders among individuals with Tourette syndrome (TS) or chronic tic disorder (CTD).Objective: To investigate the risk of metabolic and cardiovascular disorders among individuals with TS or CTD over a period of 40 years.Design, Settings, and Participants: This longitudinal population-based cohort study included all individuals living in Sweden between January 1, 1973, and December 31, 2013. Families with clusters of full siblings discordant for TS or CTD were further identified. Data analyses were conducted from August 1, 2017, to October 11, 2018.Exposures: Previously validated International Classification of Diseases diagnoses of TS or CTD in the Swedish National Patient Register.Main Outcomes and Measures: Registered diagnoses of obesity, dyslipidemia, hypertension, type 2 diabetes, and cardiovascular diseases (including ischemic heart diseases, arrhythmia, cerebrovascular diseases and transient ischemic attack, and arteriosclerosis).Results: Of the 14 045 026 individuals in the cohort, 7804 individuals (5964 males [76.4%]; median age at first diagnosis, 13.3 years [interquartile range, 9.9-21.3 years]) had a registered diagnosis of TS or CTD in specialist care. Of 2 675 482 families with at least 2 singleton full siblings, 5141 families included siblings who were discordant for these disorders. Individuals with TS or CTD had a higher risk of any metabolic or cardiovascular disorders compared with the general population (hazard ratio adjusted by sex and birth year [aHR], 1.99; 95% CI, 1.90-2.09) and sibling controls (aHR for any disorder, 1.37; 95% CI, 1.24-1.51). Specifically, individuals with TS or CTD had higher risks for obesity (aHR, 2.76; 95% CI, 2.47-3.09), type 2 diabetes (aHR, 1.67; 95% CI, 1.42-1.96), and circulatory system diseases (aHR, 1.76; 95% CI, 1.67-1.86). The risk of any cardiometabolic disorder was significantly greater in males than in females (aHR, 2.13; 95% CI, 2.01-2.26 vs aHR, 1.79; 95% CI, 1.64-1.96), as was the risk of obesity (aHR, 3.24; 95% CI, 2.83-3.70 vs aHR, 1.97; 95% CI, 1.59-2.44). The risks were already evident from childhood (the groups were significantly different by age 8 years) and were significantly reduced with the exclusion of individuals with comorbid attention-deficit/hyperactivity disorder (aHR, 1.52; 95% CI, 1.42-1.62), while excluding other comorbidities did not significantly affect the results. Compared with patients with TS or CTD who were not taking antipsychotics, patients with a longer duration of antipsychotic treatment (>1 year) had significantly lower risks of metabolic and cardiovascular disorders.Conclusions and Relevance: The findings of this study suggest that TS and CTD are associated with a substantial risk of metabolic and cardiovascular disorders. The results highlight the importance of carefully monitoring cardiometabolic health in patients with TS or CTD across the lifespan, particularly in those with comorbid attention-deficit/hyperactivity disorder.
  • Bridel, Claire, et al. (författare)
  • Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis.
  • 2019
  • Ingår i: JAMA neurology. - : American Medical Association. - 2168-6157 .- 2168-6149. ; 76:9, s. 1035-1048
  • Tidskriftsartikel (refereegranskat)abstract
    • Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.The cNfL levels adjusted for age and sex across diagnoses.Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
  • Bäckström, David C, et al. (författare)
  • Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease
  • 2015
  • Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 72:10, s. 1175-1182
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE: Alterations in cerebrospinal fluid (CSF) have been found in Parkinson disease (PD) and in PD dementia (PDD), but the prognostic importance of such changes is not well known. In vivo biomarkers for disease processes in PD are important for future development of disease-modifying therapies. OBJECTIVE: To assess the diagnostic and prognostic value of a panel of CSF biomarkers in patients with early PD and related disorders. DESIGN, SETTING, AND PARTICIPANTS: Regional population-based, prospective cohort study of idiopathic parkinsonism that included patients diagnosed between January 1, 2004, and April 30, 2009, by amovement disorder team at a university hospital that represented the only neurology clinic in the region. Participants were 128 nondemented patients with new-onset parkinsonism (104 with PD, 11 with multiple system atrophy, and 13 with progressive supranuclear palsy) who were followed up for 5 to 9 years. At baseline, CSF from 30 healthy control participants was obtained for comparison. MAIN OUTCOMES AND MEASURES: Cerebrospinal fluid concentrations of neurofilament light chain protein, Aβ1-42, total tau, phosphorylated tau, α-synuclein, and heart fatty acid-binding protein were quantified by 2 blinded measurements (at baseline and after 1 year). Follow-up included an extensive neuropsychological assessment. As PD outcome variables, mild cognitive impairment and incident PDD were diagnosed based on published criteria. RESULTS: Among the 128 study participants, the 104 patients with early PD had a different CSF pattern compared with the 13 patients with progressive supranuclear palsy (baseline area under the receiver operating characteristic curve, 0.87; P < .0001) and the 30 control participants (baseline area under the receiver operating characteristic curve, 0.69; P = .0021). A CSF biomarker pattern associated with the development of PDD was observed. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PDD as analyzed by Cox proportional hazards regression models. Combined, these early biomarkers predicted PDD with high accuracy (hazard ratio, 11.8; 95% CI, 3.3-42.1; P = .0001) after adjusting for possible confounders. CONCLUSIONS AND RELEVANCE: The analyzed CSF biomarkers have potential usefulness as a diagnostic tool in patients with parkinsonism. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein were related to future PDD, providing new insights into the etiology of PDD.
  • Chohan, Muhammad O., et al. (författare)
  • Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease : A Review
  • 2019
  • Ingår i: JAMA Neurology. - : AMER MEDICAL ASSOC. - 2168-6149 .- 2168-6157. ; 76:4, s. 492-500
  • Forskningsöversikt (refereegranskat)abstract
    • IMPORTANCE: Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality.OBSERVATIONS: We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies that provide insight into CCM pathogenesis and indicate molecular mechanisms as potential therapeutic targets. These studies report dysregulated cellular pathways shared between CCM, cardiovascular diseases, and cancer. They also suggest the potential effectiveness of proper drug repurposing in association with, or as an alternative to, targeted interventions.CONCLUSIONS AND RELEVANCE: We propose methods to exploit specific molecular pathways to design patient-tailored therapeutic approaches in CCM, with the aim to alter its natural progression. In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need.
  • Cronberg, Tobias, et al. (författare)
  • Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33 degrees C vs 36 degrees C After Out-of-Hospital Cardiac Arrest A Randomized Clinical Trial
  • 2015
  • Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 72:6, s. 634-641
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS Targeted temperature management at 33 degrees C vs 36 degrees C. MAIN OUTCOMES AND MEASURES Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33 degrees C group (interquartile range [IQR], 0-28) vs 17 in the 36 degrees C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33 degrees C and 36 degrees C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33 degrees C group median, 28; IQR, 26-30; vs 36 degrees C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33 degrees C group median, 79.5; IQR, 78.0-85.9; vs 36 degrees C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33 degrees C group vs 61.8% in the 36 degrees C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33 degrees C or 36 degrees C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales.
  • Fogh, Isabella, et al. (författare)
  • Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis
  • 2016
  • Ingår i: JAMA Neurology. - 2168-6149 .- 2168-6157. ; 73:7, s. 812-820
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. OBJECTIVE To identify gene variants influencing survival in ALS. DESIGN, SETTING, AND PARTICIPANTS This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. MAIN OUTCOMES AND MEASURES Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed bymeta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. RESULTS Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 x 10(-9)) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 x 10(-8)). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 x 10(-9)), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 x 10(-8)), corresponding to a 4-month reduction in survival compared with TT carriers. CONCLUSIONS AND RELEVANCE This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.
  • Freischmidt, Axel, et al. (författare)
  • Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
  • 2017
  • Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 74:1, s. 110-113
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative syndromes that occur sporadically or have been associated with mostly dominant inheritance of mutations in more than 30 genes. A critical issue is whether all reported mutations are disease causing or are coincidental findings. In this review we analyze the pathogenicity of nonsynonymous variants in the newly discovered gene encoding TANK-binding kinase 1 (TBK1). The available data suggest that mutations in TBK1 that cause a 50% reduction of TBK1 protein levels are pathogenic. In most cases, the almost complete loss of expression of the mutated TBK1 allele is due to loss-of-function mutations creating a premature termination codon and the degradation of the mutated messenger RNA by nonsense-mediated messenger RNA decay. In addition, TBK1 protein levels reduced by 50% have been proven for specific in-frame deletions of 1 or several amino acids, probably due to increased degradation of the mutated protein. Evaluation of many of the TBK1 missense mutations found in patients with ALS or FTD is prevented by missing data demonstrating cosegregation of the variants and incomplete knowledge about the TBK1 functions relevant for neurodegeneration. These findings suggest that haploinsufficiency of TBK1 is causative for ALS and FTD regardless of the type of mutation. Evaluation of TBK1 variants that do not cause haploinsufficiency is not possible without data demonstrating cosegregation.
  • Grande, Giulia, et al. (författare)
  • Association Between Cardiovascular Disease and Long-term Exposure to Air Pollution With the Risk of Dementia
  • 2020
  • Ingår i: JAMA Neurology. - 2168-6149 .- 2168-6157. ; 77:7, s. 801-809
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Emerging yet contrasting evidence associates air pollution with incident dementia, and the potential role of cardiovascular disease (CVD) in this association is unclear.OBJECTIVE To investigate the association between long-term exposure to air pollution and dementia and to assess the role of CVD in that association.DESIGN, SETTING, AND PARTICIPANTS Data for this cohort study were extracted from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. Of the 5111 randomly selected residents in the Kungsholmen district of Stockholm 60 years or older and living at home or in institutions, 521 were not eligible (eg, due to death before the start of the study or no contact information). Among the remaining 4590 individuals, 3363 (73.3%) were assessed. For the current analysis, 2927 participants who did not have dementia at baseline were examined, with follow-up to 2013 (mean [SD] follow-up time, 6.01 [2.56] years). Follow-up was completed February 18, 2013, and data were analyzed from June 26, 2018, through June 20, 2019.EXPOSURES Two major air pollutants (particulate matter <= 2.5 mu m [PM2.5] and nitrogen oxide [NOx]) were assessed yearly from 1990, using dispersion models for outdoor levels at residential addresses.MAIN OUTCOMES AND MEASURES The hazard of dementia was estimated using Cox proportional hazards regression models. The potential of CVD (ie, atrial fibrillation, ischemic heart disease, heart failure, and stroke) to modify and mediate the association between long-term exposure to air pollution and dementia was tested using stratified analyses and generalized structural equation modeling.RESULTS At baseline, the mean (SD) age of the 2927 participants was 74.1 (10.7) years, and 1845 (63.0%) were female. Three hundred sixty-four participants with incident dementia were identified. The hazard of dementia increased by as much as 50% per interquartile range difference in mean pollutant levels during the previous 5 years at the residential address (hazard ratio [HR] for difference of 0.88 mu g/m(3)PM(2.5), 1.54 [95% CI, 1.33-1.78]; HR for difference of 8.35 mu g/m(3)NO(x), 1.14 [95% CI, 1.01-1.29]). Heart failure (HR for PM2.5, 1.93 [95% CI, 1.54-2.43]; HR for NOx, 1.43 [95% CI, 1.17-1.75]) and ischemic heart disease (HR for PM2.5, 1.67 [95% CI, 1.32-2.12]; HR for NOx, 1.36 [95% CI, 1.07-1.71]) enhanced the dementia risk, whereas stroke appeared to be the most important intermediate condition, explaining 49.4% of air pollution-related dementia cases.CONCLUSIONS AND RELEVANCE This study found that long-term exposure to air pollution was associated with a higher risk of dementia. Heart failure and ischemic heart disease appeared to enhance the association between air pollution and dementia, whereas stroke seemed to be an important intermediate condition between the association of air pollution exposure with dementia.QUESTION Does cardiovascular disease play a role in the association between long-term exposure to air pollution and dementia?FINDINGS In this cohort study of 2927 participants in the Swedish National Study on Aging and Care in Kungsholmen, air pollution exposure was associated with dementia risk despite comparatively low exposure levels. Heart failure and ischemic heart disease enhanced this association, and the development of stroke seemed to be an important intermediate condition.MEANING In this study, virtually all of the association between air pollution and dementia seemed to occur through the presence or the development of cardiovascular disease, which suggests a need to optimize treatment of concurrent cardiovascular disease and risk factor control in older adults at higher risk for dementia and living in polluted urban areas. This cohort study investigates the association of long-term exposure to air pollution with dementia and evaluates the role of cardiovascular disease in the association among participants of the population-based Swedish National Study on Aging and Care in Kungsholmen.
  • Granqvist, Mathias, et al. (författare)
  • Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis
  • 2018
  • Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 75:3, s. 320-327
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking.OBJECTIVE To assess the effectiveness and drug discontinuation rates of rituximab among patients with newly diagnosed RRMS compared with injectable DMTs, dimethyl fumarate, fingolimod, or natalizumab.DESIGN, SETTING, AND PATIENTS This retrospective cohort study used prospectively collected data to examine specialized care of 2 Swedish county-based community samples of patients with RRMS. Patients with RRMS who received diagnoses from January 1, 2012, to October 31, 2015, who resided in Stockholm or Vasterbotten Counties were identified from a Swedish multiple sclerosis registry.MAIN OUTCOMES AND MEASURES All reasons for drug discontinuation of initial treatment choice (main outcome) and specific reasons for switching (secondary outcomes) were analyzed with multivariable Cox regression, including propensity scores.RESULTS Among 494 patients (median [interquartile range] age, 34.4 [27.4-43.4] years; 158 men [32.0%]), 215 received an injectable DMT (43.5%); 86 (17.4%), dimethyl fumarate; 17 (3.4%), fingolimod; 50 (10.1%), natalizumab; 120 (24.3%), rituximab; and 6 (1.2%), other DMT. Regional preferences were pronounced, with 42 of 52 (81%) and 78 of 442 (18%) receiving rituximab in Vasterbotten and Stockholm, respectively. The annual discontinuation rate for rituximab, injectable DMTs, dimethyl fumarate, fingolimod, and natalizumab were 0.03, 0.53, 0.32, 0.38, and 0.29, respectively. Continued disease activity was the main reason for discontinuation of injectable DMTs, dimethyl fumarate, and fingolimod; positive John Cunningham virus serology results were the main reason for discontinuation of natalizumab. Rate of clinical relapses and/or neuroradiologic disease activity were significantly lower for rituximab compared with injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates also compared with natalizumab and fingolimod. The annual discontinuation rate of initial treatment choice was significantly lower in Vasterbotten compared with Stockholm (0.09 and 0.37, respectively).CONCLUSIONS AND RELEVANCE Rituximab was superior to all other DMT in terms of drug discontinuation and displayed better clinical efficacy compared with injectable DMTs and dimethyl fumarate with borderline significance compared with natalizumab and fingolimod. The county where rituximab constituted the main initial treatment choice displayed better outcomes in most measured variables. Collectively, our findings suggest that rituximab performs better than other commonly used DMTs in patients with newly diagnosed RRMS.
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