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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Comorbidity effect on processing speed test and MRI measures in multiple sclerosis patients.

BACKGROUND: Comorbid conditions are known to affect the clinical course of multiple sclerosis (MS). Our objective was to determine the impact of comorbidities on the processing speed test (PST). METHODS: We conducted a retrospective, longitudinal analysis of all patients who completed PST testing from June 2015 - August 2019 at our center. Our electronic medical record was queried to determine the presence of the following comorbidities: diabetes mellitus (DM), hypertension (HTN), hyperlipidemia (HLD), coronary artery disease, and depression. To help address baseline PST performance and practice effect, patients were also divided into four quartiles by baseline PST scores. Brain MRIs obtained within a 90-day window from the initial clinical assessment were quantitatively analyzed via fully-automated methods to calculate whole brain fraction (WBF), T2 lesion volume (T2LV), gray matter fraction (GMF), and thalamic volume (TV). Univariable and multivariable linear regression models were used to determine the relationship between the comorbidities, PST performance and MRI metrics over time. RESULTS: A total of 4,344 patients (mean age 49.5 ± 12.4 years, 72.3% female, and 63.7% relapsing remitting MS) were included in the analysis with 13,375 individual patient encounters. Over half the cohort (52.4%) suffered from at least one comorbidity with the most common being depression (37.4%), HLD (20.9%), HTN (19.6%), and DM (6.4%). Patients with one or more comorbidity had lower baseline PST scores. Longitudinally, patients with two comorbidities lost 1.46 points on the PST per year relative to those with no comorbidities (95% CI -2.46 - -0.46, p = 0.004). Individuals with depression had lower PST scores than those without, and this difference persisted over time (ß = -2.40, 95% CI -3.08 - -1.73, p < 0.001). At baseline, HLD patients had higher PST scores than non-HLD patients (ß = 1.10, 95% CI 0.15 - 2.05, p = 0.022), but this difference did not remain over time. Individuals in the highest PST performance quartile were negatively impacted when diagnosed with depression, HTN, and DM relative to those without the comorbidities. There were no other correlations with PST scores and the remaining comorbidities. Depression was associated with lower baseline WBF (ß = -0.0043, 95% CI -0.0084 - -0.0003, p = 0.033) and GMF (ß = -0.0046, 95% CI -0.0078 - -0.0015, p = 0.004) along with larger T2LV (ß = 0.1605, 95% CI 0.0082 - 0.3128, p = 0.039). HLD patients had more favorable baseline MRI measures, including higher WBF (ß = 0.0076, 95% CI 0.0017 - 0.0135, p = 0.012) and TV (ß = 0.0002, 95% CI 0.0000 - 0.0005, p = 0.041), with a lower T2LV (ß = -0.2963, 95% CI -0.5219 - -0.0706, p = 0.010). CONCLUSIONS: Comorbidities are common within a MS cohort and adversely impact processing speed. Depression adversely impacted PST scores with worse MRI outcomes. HLD was associated with lower longitudinal PST measures but favorable quantitative MRI metrics. MS patients with faster baseline processing speeds were most sensitive to comorbid conditions. Our findings suggest a complex interplay between cognition and comorbid conditions in MS patients.

Does obesity exacerbate brain lesion volume and atrophy in patients with multiple sclerosis?

BACKGROUND: Obesity is common among patients with multiple sclerosis (pwMS) and has been shown to exacerbate central inflammation, a key factor in disease progression. The purpose of this cross-sectional study is to examine the possible relationships between obesity, as measured by body mass index (BMI), and MS-related brain changes in atrophy and lesion volume, as measured from MRI, in a large, representative sample of pwMS. METHODS: BMI and MRI data, along with demographic and disease variables, were acquired from the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) registry. Unadjusted and adjusted partial correlations, controlling for gender, race, age, education level, MS phenotype, disability and disease duration, examined the associations between BMI and MRI outcomes, which included brain parenchymal fraction, white matter fraction, gray matter fraction, thalamic volume, and T2 lesion volume. RESULTS: The sample consisted of 3,046 pwMS. Unadjusted and adjusted BMI-MRI correlations accounted for between 0.4% and 2.0% of shared variance (R2). When considering the relationship between MRI outcomes and BMI category (normal weight, overweight, obese), multiple regression analyses continued to show minimal association, with BMI category accounting for no more than 1.5% of shared variance. CONCLUSIONS: No clinically meaningful associations were found between BMI and MRI outcomes in this large, representative sample of MS patients, regardless of demographics and disease variables. These unexpected negative results will require replication with a longitudinal design using more precise measures of obesity.

Technology-enabled assessments to enhance multiple sclerosis clinical care and research.

BACKGROUND: Comprehensive and efficient assessments are necessary for clinical care and research in chronic diseases. Our objective was to assess the implementation of a technology-enabled tool in MS practice. METHOD: We analyzed prospectively collected longitudinal data from routine multiple sclerosis (MS) visits between September 2015 and May 2018. The MS Performance Test, comprising patient-reported outcome measures (PROMs) and neuroperformance tests (NPTs) self-administered using a tablet, was integrated into routine care. Descriptive statistics, Spearman correlations, and linear mixed-effect models were used to examine the implementation process and relationship between patient characteristics and completion of assessments. RESULTS: A total of 8022 follow-up visits from 4199 patients (median age 49.9 [40.2-58.8] years, 32.1% progressive course, and median disease duration 13.6 [5.9-22.3] years) were analyzed. By the end of integration, the tablet version of the Timed 25-Foot Walk was obtained in 89.0% of patients and the 9-Hole Peg Test in 94.8% compared with 74.2% and 64.3%, respectively before implementation. The greatest increase in data capture occurred in processing speed and low-contrast acuity assessments (0% prior vs 78.4% and 36.7%, respectively, following implementation). Four PROMs were administered in 41%-98% of patients compared with a single depression questionnaire with a previous capture rate of 70.6%. Completion rates and time required to complete each NPT improved with subsequent visits. Younger age and lower disability scores were associated with shorter completion time and higher completion rates. CONCLUSIONS: Integration of technology-enabled data capture in routine clinical practice allows acquisition of comprehensive standardized data for use in patient care and clinical research.

Is Obesity Related to Processing Speed Impairment in Patients with Multiple Sclerosis: Results of a Large-Scale, Multicenter Study.

BACKGROUND: Obesity is linked to greater physical disability and increased comorbidities among patients with multiple sclerosis (MS). Its contribution to cognition in this group is unclear. This observational study examines the link between obesity and processing speed in a large sample of patients with MS (PwMS). METHODS: As part of routine clinical care at our center, PwMS completed the Processing Speed Test (PST), an electronic implementation of the Symbol Digit Modalities Test (SDMT). Height and weight were used to calculate body mass index (BMI). Bivariate correlations were conducted to examine the association between PST and BMI in the group overall and in subgroups based on demographic and clinical variables. A one-way ANOVA examined differences in PST by BMI categories (normal weight, overweight, obese). RESULTS: The sample included 8,713 patients. No association between PST and BMI was found in the entire sample (r = .01), nor within subgroups based on demographic and disease variables. No difference in PST score was found between BMI categories. CONCLUSIONS: No association between BMI and processing speed was found among PwMS regardless of demographic or disease-specific patient characteristics.

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.

Technology-enabled comprehensive characterization of multiple sclerosis in clinical practice.

BACKGROUND: Objective and longitudinal measurements of disability in patients with multiple sclerosis (MS) are desired in order to monitor disease status and response to disease-modifying and symptomatic therapies. Technology-enabled comprehensive assessment of MS patients, including neuroperformance tests (NPTs), patient-reported outcome measures (PROMs), and MRI, is incorporated into clinical care at our center. The relationships of each NPT with PROMs and MRI measures in a real-world setting are incompletely studied, particularly in larger datasets. OBJECTIVES: To demonstrate the utility of comprehensive neurological assessment and determine the association between NPTs, PROMs, and quantitative MRI measures in a large MS clinical cohort. METHODS: NPTs (processing speed [PST], contrast sensitivity [CST], manual dexterity [MDT], and walking speed [WST]) and physical disability-related PROMs (Quality of Life in Neurological Disorders [Neuro-QoL], Patient Determined Disease Steps [PDDS], and Patient-Reported Outcomes Measurement Information System Global-10 [PROMIS-10] physical) were collected as part of routine clinical care. Fully-automated MRI analysis calculated T2-lesion volume (T2LV), whole brain fraction (WBF), thalamic volume (TV), and cervical spinal cord cross-sectional area (CA) for brain MRIs completed within 3 months of a clinic visit during which NPTs and PROMs were assessed. Spearman's rank correlation coefficients evaluated the cross-sectional associations of NPTs with PROMs and MRI measures. Linear regression was utilized to determine which combination of clinical characteristics, patient demographics, MRI measures, and PROMs best cross-sectionally explained each NPT result. RESULTS: 997 unique patients (age 47.7 ±â€¯11.4 years, 71.8% female) who underwent assessments over a 2-year period were included. Correlations among NPTs and PROMs were moderate. PST correlations were strongest for Neuro-QoL upper extremity (NQ-UE) (Spearman's rho = 0.43) and lower extremity (NQ-LE) (0.47). CST correlations were strongest for NQ-UE (0.33), NQ-LE (0.36), and PDDS (-0.31). MDT correlations were strongest for NQ-UE (-0.53), NQ-LE (-0.54), and PDDS (0.53). WST correlations were strongest for PDDS (0.64) and NQ-LE (-0.65). NPTs also had moderate correlations with MRI metrics, the strongest of which were observed with PST (with T2LV (-0.44) and WBF (0.49)). Spearman's rho for other NPT-MRI correlations ranged from 0.23 to 0.36. Linear regression identified age, disease duration, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV and WBF as significant cross-sectional explanatory variables for PST (adjusted R2=0.46). For CST, significant variables included age and NQ-LE (adjusted R2 = 0.30). For MDT, significant variables included PDDS, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV, and WBF (adjusted R2=0.37). For WST, significant variables included sex, PDDS, NQ-LE, T2LV, and CA (adjusted R2=0.39). CONCLUSIONS: Impaired performance on NPTs correlated with worse physical disability-related PROMs and MRI disease severity, but the strongest cross-sectional explanatory variables for each NPT component varied. This study supports the use of comprehensive, objective quantification of MS status in clinical and research settings. Future longitudinal analyses can determine predictors of treatment response and disability worsening.