The impact of cigarette smoking on cognitive processing speed and brain atrophy in multiple sclerosis.

BACKGROUND: Smoking is associated with an increased risk of multiple sclerosis (MS) and disability worsening. The relationship between smoking, cognitive processing speed, and brain atrophy remains uncertain. OBJECTIVE: To quantify the impact of smoking on processing speed and brain volume in MS and to explore the longitudinal relationship between smoking and changes in processing speed. METHODS: A retrospective study of MS patients who completed the processing speed test (PST) between September 2015 and March 2020. Demographics, disease characteristics, smoking history, and quantitative magnetic resonance imaging (MRI) were collected. Cross-sectional associations between smoking, PST performance, whole-brain fraction (WBF), gray matter fraction (GMF), and thalamic fraction (TF) were assessed using multivariable linear regression. The longitudinal relationship between smoking and PST performance was assessed by linear mixed modeling. RESULTS: The analysis included 5536 subjects of whom 1314 had quantitative MRI within 90 days of PST assessment. Current smokers had lower PST scores than never smokers at baseline, and this difference persisted over time. Smoking was associated with reduced GMF but not with WBF or TF. CONCLUSION: Smoking has an adverse relationship with cognition and GMF. Although causality is not demonstrated, these observations support the importance of smoking cessation counseling in MS management.

Age of hypertension onset in multiple sclerosis patients.

BACKGROUND/OBJECTIVE: Hypertension (HTN) is common in multiple sclerosis (MS), and it is associated with poorer outcomes. We sought to characterize HTN age at onset (AAO) by MS status. METHODS/RESULTS: There were 130,050 incident HTN patients, among whom there were 892 MS patients. We conducted multivariable linear regression adjusting for patient attributes. Sex- and race-stratified models were conducted. HTN AAO did not differ in patients with and without MS (p = 0.17). Similar null associations were observed in the sex- and race-specific analyses. CONCLUSION: While there are complex relationships between HTN and MS, there are no differences in HTN AAO by MS status.

Patient reported outcomes and performance metrics at diagnosis of secondary progressive multiple sclerosis.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) usually evolves into secondary progressive multiple sclerosis (SPMS). Recognition of SPMS is important because of prognostic and treatment implications. OBJECTIVE: The objective of this study is to determine distributions of patient-reported outcomes (PROs) and the Timed 25-Foot Walk (T25FW) at SPMS diagnosis and describe the evolution of these metrics in patients with SPMS. METHODS: A tertiary MS center clinical database was queried to identify patients with RRMS and SPMS. PRO data including performance scales (PS), Patient Health Questionnaire-9 (PHQ-9), European Quality of Life-5-Dimensions (EQ-5D), and the T25FW were extracted. Descriptive statistics were calculated at SPMS diagnosis, and score trajectories were modeled. Cox proportional hazards modeling was used to estimate hazard ratios for time to SPMS diagnosis. RESULTS: Among 5,558 patients identified, 164 were diagnosed with SPMS between January 2008 and June 2016. At SPMS diagnosis, the mean outcome values were T25FW = 12.5 seconds (standard deviation, SD = 10.7), PS = 15.6 (SD = 6.5), PHQ-9 = 6.8 (SD = 4.2), and EQ-5D = 0.63 (SD = 0.20). Distinct patterns were observed in the measures leading up to SPMS diagnosis. Higher age, male gender, longer disease duration, and greater disability were associated with an increased hazard of SPMS diagnosis. CONCLUSION: Longitudinal monitoring of PROs and performance metrics may help identify those at higher risk of near-term SPMS.

Influence of hypertension, diabetes, hyperlipidemia, and obstructive lung disease on multiple sclerosis disease course.

BACKGROUND: Comorbidities are known to affect multiple sclerosis (MS) patients in a number of ways, including delaying time to diagnosis and reducing health-related quality of life. OBJECTIVE: To determine the impact of hypertension, hyperlipidemia, diabetes mellitus, and obstructive lung disease on disease course in MS patients. METHODS: The Knowledge Program is a database linked to our electronic medical record allowing capture of patient and clinician reported outcomes. Through Knowledge Program query and chart review, we identified all relapsing-remitting MS patients seen between 1 January 2010 and 29 May 2012 and acquired their magnetic resonance imaging (MRI) results and comorbidities. Linear and logistic regression models with adjustment for important covariates were used to determine whether the comorbidities affected outcomes over a 3-year period. RESULTS: Hypertension, diabetes, and obstructive lung disease, but not hyperlipidemia, impacted clinical outcomes, including walking speed, self-reported disability, and depression. Hypertension had the greatest effect. The presence of multiple comorbidities had a cumulative effect on clinical outcomes. MRI outcomes were unaffected by comorbidities. CONCLUSION: This 3-year longitudinal study revealed that all comorbidities tested except hyperlipidemia impacted clinical outcomes and a cumulative effect with multiple comorbidities was observed. Consideration of comorbid conditions is essential in MS patient care.

Factors associated with clinically significant increased walking time in multiple sclerosis: results of a survival analysis of short-term follow-up data from a clinical database.

BACKGROUND: Because multiple sclerosis (MS) is variable and unpredictable, if symptom worsening could be predicted, patients may feel better prepared to manage changes in function. OBJECTIVE: The objective of this paper is to study the prediction of walking impairment in MS. METHODS: We retrieved data for all MS patients at our center (2008-2009), including baseline and follow-up timed 25-foot walk (T25FW) times. We assessed the incidence of ≥20% worsening in T25FW by developing two survival models: (1) disease course and (2) Multiple Sclerosis Performance Scales (MSPS) score. The outcome was days until ≥20% worsening in T25FW. Covariates were disease subtype, years since diagnosis, Patient Health Questionnaire-9 (PHQ-9) score, and demographics. Data were interval censored; missing data were handled with multiple imputation. RESULTS: Of 1544 patients, 309 (20%) experienced ≥20% worsening T25FW. For disease course, time to worsening was significantly shorter for secondary progressive vs. relapsing-remitting disease (p < 0.001). For MSPS, patients with lower baseline MSPS scores progressed more slowly (p = 0.001). In both models, sex, baseline T25W, and time since diagnosis were significantly associated with worsening. In the disease course model, PHQ 9 score may be related to worsening (p = 0.07). CONCLUSION: These findings suggest factors associated with worsening in T25FW and a potential approach to establishing indicators associated with clinically significant change.

The patient-reported wearing-off phenomenon with monoclonal antibody treatments for multiple sclerosis.

Background: Many patients report a wearing-off phenomenon with monoclonal antibody treatment for multiple sclerosis in which perceived benefits wear off before the next dose is due. Objectives: To determine prevalence of the wearing-off effect, symptoms experienced, impact on treatment satisfaction, and associated patient characteristics. Methods: Patients receiving natalizumab, ocrelizumab, ofatumumab, or rituximab at a tertiary multiple sclerosis center were invited to take an online survey interrogating their monoclonal antibody experience. Additional history and patient characteristic data were collected. Logistic regression was used to determine if patient characteristics predicted the wearing-off effect and linear regression to evaluate the impact of the wearing-off effect on treatment satisfaction. The models were adjusted for age, disease duration, race, sex, body mass index, education, and depression as measured by the Patient Health Questionnaire-9. Results: We received 258 qualifying responses and 141 (54.7%) patients reported the wearing-off phenomenon. The most common symptom was fatigue (47.7%). Higher Patient Health Questionnaire-9 scores were significantly associated with the wearing-off phenomenon (OR = 1.02, p = 0.005). The wearing-off effect (ß = -0.52, p = 0.04) and higher Patient Health Questionnaire-9 (ß = -0.09, p < 0.01) scores were associated with significantly reduced treatment satisfaction. Conclusion: The wearing-off phenomenon is common, associated with depression, and reduces treatment satisfaction. Research addressing mitigation strategies is needed.

Longitudinal myelin content measures of slowly expanding lesions using 7T MRI in multiple sclerosis.

BACKGROUND AND PURPOSE: Slowly expanding lesions (SELs) are thought to represent a subset of chronic active lesions and have been associated with clinical disability, severity, and disease progression. The purpose of this study was to characterize SELs using advanced magnetic resonance imaging (MRI) measures related to myelin and neurite density on 7 Tesla (T) MRI. METHODS: The study design was retrospective, longitudinal, observational cohort with multiple sclerosis (n = 15). Magnetom 7T scanner was used to acquire magnetization-prepared 2 rapid acquisition gradient echo and advanced MRI including visualization of short transverse relaxation time component (ViSTa) for myelin, quantitative magnetization transfer (qMT) for myelin, and neurite orientation dispersion density imaging (NODDI). SELs were defined as lesions showing ≥12% of growth over 12 months on serial MRI. Comparisons of quantitative measures in SELs and non-SELs were performed at baseline and over time. Statistical analyses included two-sample t-test, analysis of variance, and mixed-effects linear model for MRI metrics between lesion types. RESULTS: A total of 1075 lesions were evaluated. Two hundred twenty-four lesions (21%) were SELs, and 216 (96%) of the SELs were black holes. At baseline, compared to non-SELs, SELs showed significantly lower ViSTa (1.38 vs. 1.53, p < .001) and qMT (2.47 vs. 2.97, p < .001) but not in NODDI measures (p > .27). Longitudinally, only ViSTa showed a greater loss when comparing SEL and non-SEL (p = .03). CONCLUSIONS: SELs have a lower myelin content relative to non-SELs without a difference in neurite measures. SELs showed a longitudinal decrease in apparent myelin water fraction reflecting greater tissue injury.

Common Social and Health Disparities Contribute to Racial Differences in Ambulatory Impairment in Multiple Sclerosis.

BACKGROUND: We previously reported more rapid accrual of ambulatory impairments in Black compared to White individuals with relapsing remitting multiple sclerosis (RRMS) and higher body mass index (BMI). Hypertension and lower neighborhood socioeconomic status (SES) were associated with greater impairment, irrespective of race. We hypothesize that these common social and health inequities may explain a substantial portion of the racial differences in ambulation in American individuals with RRMS. METHODS: Causal mediation analyses investigated baseline and change-over-time mediators of ambulatory impairment differences between 1795 Black and White individuals with RRMS using a retrospective cohort study comprised of electronic health record data from 8491 clinical encounters between 2008 and 2015 where Timed 25-Foot Walk (T25FW) speeds without assistive devices were recorded. The hypothesis was that BMI, neighborhood SES, and hypertension were possible mediators. RESULTS: At baseline, Black individuals with RRMS (n = 175) had significantly slower T25FW speeds (5.78 vs 5.27 ft/s), higher BMI, a higher prevalence of hypertension, and they were more likely to live in lower-income neighborhoods than White individuals (n = 1,620). At baseline, a significant proportion (33.7%; 95% CI, 18.9%-59.4%) of the T25FW difference between Black and White individuals was indirectly due to a higher BMI (12.5%), hypertension burden (9.5%), and living in lower-income neighborhoods (11.2%). Once baseline mediation relationships were accounted for, there were no significant longitudinal mediation relationships. CONCLUSIONS: The findings implicate social and health disparities as prominent drivers of ambulatory differences between Black and White individuals with RRMS, suggesting that wellness and health promotion are essential components of MS care, particularly for Black individuals.

Progressive Encephalomyelopathy in an Older Man: A Case Report From the National Multiple Sclerosis Society Case Conference Proceedings.

We present a case of subacute onset progressive encephalomyelopathy in a 77-year-old man with symmetric lateral column signal abnormalities on spinal MRI. We discuss the differential and presumptive final diagnosis along with a review of the postulated disease immunopathogenesis.

A 2-stage model of heterogenous treatment effects for brain atrophy in multiple sclerosis utilizing the MS PATHS research network.

BACKGROUND: Two-stage models of heterogenous treatment effects (HTE) may advance personalized medicine in multiple sclerosis (MS). Brain atrophy is a relatively objective outcome measure that has strong relationships to MS prognosis and treatment effects and is enabled by standardized MRI. OBJECTIVES: To predict brain atrophy outcomes for patients initiating disease-modifying therapies (DMT) with different efficacies, considering the patients' baseline brain atrophy risk measured via brain parenchymal fraction (BPF). METHODS: Analyses included patients enrolled in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network who started DMT and had complete baseline data and ≥ 6-month brain MRI follow-up. All brain MRIs were acquired using standardized acquisition sequences on Siemens 3T scanners. BPF change risk was derived by linear mixed effects models using baseline covariates. Model performance was assessed by predicted versus actual BPF change R2. Propensity score (PS) weighting was used to balance covariates between groups defined by DMT efficacy (high: natalizumab, alemtuzumab, ocrelizumab, and rituximab; moderate: dimethyl fumarate, fingolimod, and cladribine; low: teriflunomide, interferons, and glatiramer acetate). HTE models predicting 1 year change in BPF were built using a weighted linear mixed effects model with low-efficacy DMT as the reference. RESULTS: Analyses included 581 high-, 183 moderate-, and 106 low-efficacy DMT-treated patients. The mean and median number of brain MRI observations per treatment period were 2.9 and 3.0, respectively. Risk model performance R2=0.55. After PS weighting, covariate standardized mean differences were <10 %, indicating excellent balance across measured variables. Changes in BPF between baseline and follow-up were found to be statistically significant (p < 0.001), suggesting a pathological change. Patients with low brain atrophy risk had a similar outcome regardless of DMT selection. In patients with high brain atrophy risk, high- and moderate-efficacy DMTs performed similarly, while a 2-fold worse BPF change was predicted for patients selecting low-efficacy DMTs (p < 0.001). Similar results were observed in a sensitivity analysis adjusting for pseudoatrophy effects in a sub-population of patients treated with natalizumab. CONCLUSIONS: The relative benefit of selecting higher efficacy treatments may vary depending on patients' baseline brain atrophy risk. Poor outcomes are predicted in individuals with high baseline risk who are treated with low-efficacy DMTs.

Predicting disability and mortality in CV2/CRMP5-IgG associated paraneoplastic neurologic disorders.

BACKGROUND: We aimed to investigate the prognostic factors associated with clinical outcomes in CV2/Collapsin response-mediator protein 5 (CRMP5)-IgG paraneoplastic neurologic disorders (PND). METHODS: This is a retrospective study of patients with CV2/CRMP5-IgG PND evaluated between 2002-2022. We examined the association of clinical variables (including age, clinical phenotype [autoimmune encephalopathy, myelopathy, polyneuropathy/radiculopathy, MG, cerebellar ataxia, chorea, optic neuropathy], cancer) with three clinical outcomes (wheelchair dependence, modified Rankin Scale [mRS], mortality) using univariate logistic regression and Cox proportional hazards modeling. Kaplan-Meier estimates were used to determine the probability of survival. RESULTS: Twenty-seven patients (56% female) with CV2/CRMP5-IgG PND were identified with a median follow-up of 54 months (IQR = 11-102). An underlying tumor was identified in 15 patients (56%) including small cell lung cancer (SCLC) (8, [53%]), thymoma (4, [27%]), and other histologies (3, [20%]). At last follow-up, 10 patients (37%) needed a wheelchair for mobility and this outcome was associated with myelopathy (HR = 7.57, 95% CI = 1.87-30.64, P = 0.005). Moderate-severe mRS = 3-5 was associated with CNS involvement (encephalopathy, myelopathy, or cerebellar ataxia) (OR = 7.00, 95% CI = 1.18-41.36, P = 0.032). The probability of survival 4 years after symptom onset was 66%. Among cancer subtypes, SCLC (HR = 18.18, 95% CI = 3.55-93.04, P < 0.001) was significantly associated with mortality, while thymoma was not. INTERPRETATION: In this retrospective longitudinal study of CV2/CRMP5-IgG PND, patients with CNS involvement, particularly myelopathy, had higher probability of disability. SCLC was the main determinant of survival in this population.

Long term benefit of multiple sclerosis treatment: an investigation using a novel data collection technique.

BACKGROUND: The Knowledge Program (KP) is an initiative to collect self-reported patient data and objective clinician assessments electronically at each outpatient clinical encounter. Available outcomes include the EuroQoL-5D (EQ5D), Patient Health Questionnaire-9 (PHQ9), Multiple Sclerosis Performance Scales (MSPS), and the timed 25-foot walk (T25FW). OBJECTIVE: This study was designed to use the KP to investigate the long-term benefits of early treatment (ET) in multiple sclerosis (MS). METHODS: The KP was queried for patients with relapsing-remitting MS or secondary progressive MS who were ≥ 5 years from symptom onset. ET was defined as treatment with an approved agent for ≥ 3 of the first five years after symptom onset. Propensity scores for ET were calculated based on early clinical characteristics. Patients were divided into propensity score quintiles and linear regression models were constructed to determine the treatment effect sizes and confidence intervals. RESULTS: From the 1082 patients that met entry criteria, 453 patients (41.9%) received ET. Those patients receiving ET showed significantly better scores on the EQ5D index, PHQ9, and MSPS, but only in the upper three propensity quintiles. For the T25FW, ET did not result in significantly better times in any quintile. CONCLUSIONS: These results suggest that ET of MS is beneficial but the effect appears modest.

The relationship between cognition, education, and employment in multiple sclerosis patients.

Background: Processing speed decline is a common manifestation of multiple sclerosis (MS). The processing speed test (PST) is a validated electronic cognitive assessment based on the Symbol-Digit Modalities Test, which is routinely administered as part of the multi-institutional Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) initiative. The longitudinal relationship between education, processing speed, and employment is unclear. Objectives: Determine the longitudinal impact of educational attainment on processing speed and employment. Methods: MS PATHS data through March 2020 were analyzed. Repeat PST assessments at 1, 2, and 3 years were classified as improved, worsened, or stable. Linear regression was used to evaluate the relationship between education and baseline PST performance and logistic regression was used to determine the odds of PST worsening by educational attainment. Employment outcomes were analyzed by PST status and educational level. Results: There were 13,732 patients analyzed. Education impacted baseline PST scores, but had a limited effect on PST performance over time. Education was protective with respect to employment in the setting of both PST worsening and improvement. Conclusion: Greater education results in better baseline processing speed and is protective with respect to employment status. Its impact on processing speed over time is marginal.

Racial disparities in hypertension management among multiple sclerosis patients.

BACKGROUND: Hypertension adversely impacts the multiple sclerosis (MS) disease course and is more common among Black Americans. Disparities in care due to structural racism may lead to suboptimal hypertension detection and control in Black American MS patients. OBJECTIVES: To determine if uncontrolled hypertension is more common in Black or White Americans with MS and whether race impacts the likelihood of receiving anti-hypertensive treatment. METHODS: A retrospective cohort study was conducted using longitudinal data from American participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) multi-institutional registry. Data was collected from 7 sites in the United States between May 2015 and November 2020. Patients with uncontrolled hypertension, defined as ≥2 blood pressure measurements ≥140/90 mmHg, were identified in the dataset. Racial differences in uncontrolled hypertension and odds of anti-hypertensive treatment were evaluated using logistic regression. Predictors of anti-hypertensive treatment in those with uncontrolled hypertension were determined by race. RESULTS: The analysis included 10,673 MS patients, of whom 1,442 (13.5%) were Black Americans. Despite a lower mean age (45.7 vs. 49.2 years), Black Americans had a 31% increased odds of uncontrolled hypertension compared to White Americans. After adjustment for relevant covariates, mean systolic blood pressure was 1.84 mmHg (95% confidence interval=1.07-2.61) higher in Black Americans than White Americans, and mean diastolic blood pressure was 1.28 mmHg (95% confidence interval=0.74-1.82) higher. Black Americans were also more likely to be on anti-hypertensive therapy (OR=1.68, 95% confidence interval=1.30-2.18) and were exposed to an adjusted average of 0.61 (95% confidence interval=0.45-0.78) more anti-hypertensive treatments than White Americans (p<0.001). Age, comorbid diabetes mellitus, and comorbid hyperlipidemia were positively associated with use of anti-hypertensive treatments in all patients with uncontrolled hypertension. CONCLUSION: Black American MS patients have significantly increased odds of uncontrolled hypertension, but also higher odds of receiving anti-hypertensive treatment.

Characterizing relapsing remitting multiple sclerosis patients burdened with hypertension, hyperlipidemia, and asthma.

BACKGROUND: Hypertension, hyperlipidemia, and asthma are common in multiple sclerosis (MS) patients and adversely impact physical and mental health independent of sociodemographic and clinical attributes. Characterizing MS patients with these comorbidities is necessary for informing comorbidity screening and managed care in vulnerable patient subgroups; however, there is sparse data currently available. METHODS: We conducted cross-sectional analyses of 2,012 relapsing remitting (RR) MS patients. Separate multivariable logistic regression models were conducted for the presence of hypertension, hyperlipidemia, and asthma. Independent variables included age, sex, race, MS duration, body mass index classification, insurance payer, smoking status, median income by residence ZIP code, disease modifying therapies, and the other comorbidities. RESULTS: Hypertension was more common in RRMS patients who were older, obese/severely obese, had hyperlipidemia, were asthmatics, living in neighborhoods with the lowest income, and who were Black Americans. RRMS patients with hyperlipidemia were more likely to be male, older, overweight/obese/severely obese, hypertensive, asthmatics, and White American. Asthmatic RRMS patients were more likely to be female, obese, hypertensive, and living in neighborhood of medium/low income, and less likely to be on interferons or glatiramer acetate. CONCLUSION: We identified factors independently associated with common comorbidity burden in RRMS patients, which will inform risk-stratification efforts aimed at mitigating the adverse impact of these conditions in MS patients. Our results are consistent with what is known about the determinants of hypertension, hyperlipidemia, and asthma in the non-MS patient population, and therefore disparities that exist in screening and management in the general U.S. population may likely exist in U.S. MS patients. It is also possible that there may be unique differences in specific MS patient subgroups, which warrants further investigation and detailed characterization.

Measures of Thalamic Integrity are Associated with Cognitive Functioning in Fingolimod-treated Multiple Sclerosis Patients.

BACKGROUND: Cognitive impairment is common in relapsing-remitting multiple sclerosis (RRMS) and multiple domains are affected, including information processing speed, episodic memory, and executive function. Damage to the thalamus appears to be related to cognitive functioning in MS. Fingolimod is a disease-modifying therapy for RRMS, which has been shown to have a protective effect on thalamic volume. OBJECTIVE: To determine the relationship between cognitive measures and the thalamus in fingolimod-treated RRMS patients and healthy controls using ultra high-field magnetic resonance imaging (MRI). METHODS: Fingolimod-treated RRMS and healthy participants were recruited from a single center to undergo neuropsychological testing and 7 tesla MRI. These assessments were performed at baseline, 6 months, and 12 months. The neuropsychological testing included the Brief Visuospatial Memory Test-Revised (BVMTR), the Symbol Digit Modalities Test (SDMT), the Selective Reminding Test (SRT), and the Delis-Kaplan Executive Function System (DKEFS). MRI metrics included thalamic volume, thalamic myelin density, thalamic axon density, T2 lesion volume, brain parenchymal fraction, and cortical thickness. Mixed-effects linear regression was used to determine the relationship between MRI parameters and neuropsychological test performance over time. Rates of change in patients and controls were compared using two-sample t-tests. RESULTS: We enrolled 15 RRMS patients and 5 healthy controls. Controls performed better than patients at baseline, but this difference was only significant for the letter fluency subtest of the DKEFS and for long-term storage as assessed by the SRT. Thalamic volume and thalamic myelin density were significantly associated with visuospatial (BVMTR) and verbal memory (SRT). Thalamic volume alone was also associated with inhibitory control (Color word interference subtest of the DKEFS) and cognitive flexibility (Number letter switching subtest of the DKEFS), whereas thalamic myelin density alone was associated with semantic knowledge (Verbal fluency subtest of the DKEFS). There were no significant changes in the rates of change in neurometric test performance or MRI metrics between patients and controls from baseline to 6 months and baseline to 12 months. CONCLUSIONS: Thalamic injury is associated with cognitive performance in several domains. Fingolimod-treated RRMS patients evolved similarly to healthy controls over one year with regards to neuropsychological test performance and changes on MRI.

Integrating patient-reported outcomes and quantitative timed tasks to identify relapsing remitting multiple sclerosis patient subgroups: a latent profile analysis.

BACKGROUND: Multiple sclerosis (MS) patients experience wide-ranging symptoms with varied severity, and approaches that integrate patient-reported outcomes and objective quantitative measures will present opportunities for advancing clinical profiling. The primary objective of the current study was to conduct exploratory data analysis using latent variable modeling to empirically identify clusters of relapsing remitting (RR) MS patients with shared impairment patterns across three patient-reported outcomes and two timed task measures. METHODS: Latent profile analyses and impairment data for 2,012 RRMS patients identified distinct patient clusters using timed task measures of upper and lower limb performance, and patient-reported outcomes measuring quality of life, depression symptom severity, and perceived global disability. Multinomial logistic regression models were used to characterize associations between socio-demographic attributes and assignment to the patient clusters. RESULTS: There were 6 distinct clusters of RRMS patients that differed by symptom patterns, and by their socio-demographic attributes. Most notable were were no differences in age, sex, or disease duration between the least and most impaired classes, representing 14% and 4% of patients, respectively. Patients in the most impaired class were much more likely to be Black American, have a history of smoking, have a higher body mass index, and be of lower socioeconomic status than the least impaired class. There were positive relationships between age and classification to clusters of increasing moderately severe impairment but not the most severe clusters. CONCLUSION: We present a framework for discerning phenotypic impairment clusters in RRMS. The results demonstrate opportunities for advancing clinical profiling, which is necessary for optimizing personalized MS care models and clinical research.

Inverse association of PPARγ agonists use and high grade glioma development.

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have antineoplastic effects on gliomas in cell lines and animal models. In a retrospective chart review, we assessed the influence of PPARγ agonists on the odds of having a high grade glioma. We reviewed patients with a diagnosis of anaplastic astrocytoma and glioblastoma multiforme (GBM) between 1999 and 2008. Patients with hip fractures served as the control group. Multivariable unconditional logistic regression models were used to calculate the odds of diabetic hip fracture patients using a PPARγ agonist at time of diagnosis as compared to diabetic glioma patients. In addition, survival analysis was performed for all GBM patients. We identified 1602 hip fracture patients and 302 high grade glioma patients, 15 and 16% were diabetics, respectively. PPARγ agonists were used by 20% of diabetic hip fracture patients and by 6% of high grade glioma patients (chi-square P-value = 0.02) with an odds ratio of 4.081 (95% CI: 1.119-14.881). In addition, there was no difference in survival for diabetic patients with GBM compared to non-diabetic patients with GBM. The prevalence of PPARγ agonist use was lower in the diabetic high grade glioma group when compared to diabetic hip fracture patients. These findings suggest that diabetic high grade glioma patients are not given PPARγ agonists as often as diabetic hip fracture patients even though these drugs are considered standard of care and should be equally distributed throughout both groups. This indicates a possible anti-neoplastic effect of PPARγ agonists in gliomas.

Duration of natalizumab therapy and reasons for discontinuation in a multiple sclerosis population.

OBJECTIVE: To determine multiple sclerosis patient characteristics that predict a shorter duration of natalizumab treatment. METHODS: The Tysabri Outreach: Unified Commitment to Health database was reviewed to identify patients treated with natalizumab at our centers. Cox proportional hazards models were used to evaluate patient characteristics associated with shorter treatment durations on natalizumab. Associations were also assessed with respect to specific reasons for stopping natalizumab. RESULTS: We identified 554 patients who began and stopped natalizumab treatment during the observation period. The average disease duration at natalizumab initiation was 7.6 years, and the average number of infusions was 30. The multivariable Cox proportional hazards model identified greater age (P = 0.035), longer disease duration (P < 0.001), progressive relapsing multiple sclerosis phenotype (P = 0.003), current smoking (P = 0.031), and greater depression (P = 0.026) as significant predictors for natalizumab discontinuation. Greater disability levels (P = 0.022) and gadolinium-enhancing lesions on baseline magnetic resonance imaging (P < 0.001) were significantly associated with longer natalizumab treatment. Individuals with progressive relapsing multiple sclerosis had a 14-fold increased hazard of discontinuing natalizumab due to inflammatory events (P < 0.001) than those with relapsing-remitting multiple sclerosis. Smokers had an 80% increased hazard of discontinuation due to intolerance (P = 0.008). CONCLUSIONS: Our results suggest that smoking, depression, and a progressive relapsing multiple sclerosis phenotype are associated with shorter natalizumab treatment durations.