Alexander Musallam

Circulating MicroRNAs as biomarkers for disease staging in multiple sclerosis

MicroRNAs (miRNAs) are single‐stranded, small noncoding RNAs that regulate gene expression. Because they are stable in serum, they are being developed as biomarkers for cancer and other diseases. In multiple sclerosis (MS), miRNAs have been studied in cell populations but not in the circulation. In MS, a major challenge is to develop immune biomarkers to monitor disease. We asked whether circulating miRNAs could be identified in MS and whether they are linked to disease stage and/or disability.

Effect of gender on late-onset multiple sclerosis

Objectives: We aimed to examine the incidence and disease course of late-onset multiple sclerosis (LOMS) compared with adult-onset MS (AOMS) in our clinic cohort, stratified based on gender and race, since both have been reported as important modifiers of disease outcomes in MS. Methods: Patients with LOMS and AOMS were compared in terms of demographic characteristics and disease course characteristics. Combined effects were investigated with a logistic regression model. Time from disease onset to sustained Expanded Disability Status Scale (EDSS) score of 6 was investigated using an extension of log-rank test appropriate for interval-censored data. Results: Some 7.96% of 4273 patients studied had an onset of MS after the age of 50 years (LOMS), and 1.33% experienced an onset after age 60. Progressive onset was more common in LOMS relative to AOMS. The proportion of women with progressive-onset disease was similar in AOMS and LOMS. Time to EDSS 6 was delayed in AOMS females compared with males; however, it was similar between males and females in the LOMS group. Conclusions: Women with LOMS have a different trajectory in terms of disease progression than women with AOMS. The effect of menopause combined with race/ethnicity on the MS disease course requires further investigation.

Evaluation of an Online Platform for Multiple Sclerosis Research: Patient Description, Validation of Severity Scale, and Exploration of BMI Effects on Disease Course

Objectives To assess the potential of an online platform, PatientsLikeMe.com (PLM), for research in multiple sclerosis (MS). An investigation of the role of body mass index (BMI) on MS disease course was conducted to illustrate the utility of the platform. Methods First, we compared the demographic characteristics of subjects from PLM and from a regional MS center. Second, we validated PLM’s patient-reported outcome measure (MS Rating Scale, MSRS) against standard physician-rated tools. Finally, we analyzed the relation of BMI to the MSRS measure. Results Compared with 4,039 MS Center patients, the 10,255 PLM members were younger, more educated, and less often male and white. Disease course was more often relapsing remitting, with younger symptom onset and shorter disease duration. Differences were significant because of large sample sizes but small in absolute terms. MSRS scores for 121 MS Center patients revealed acceptable agreement between patient-derived and physician-derived composite scores (weighted kappa = 0.46). The Walking domain showed the highest weighted kappa (0.73) and correlation (rs = 0.86) between patient and physician scores. Additionally, there were good correlations between the patient-reported MSRS composite and walking scores and physician-derived measures: Expanded Disability Status Scale (composite rs = 0.61, walking rs = 0.74), Timed 25 Foot Walk (composite rs = 0.70, walking rs = 0.69), and Ambulation Index (composite rs = 0.81, walking rs = 0.84). Finally, using PLM data, we found a modest correlation between BMI and cross-sectional MSRS (rho = 0.17) and no association between BMI and disease course. Conclusions The PLM population is comparable to a clinic population, and its patient-reported MSRS is correlated with existing clinical instruments. Thus, this online platform may provide a venue for MS investigations with unique strengths (frequent data collection, large sample sizes). To illustrate its applicability, we assessed the role of BMI in MS disease course but did not find a clinically meaningful role for BMI in this setting.

Clinical and MRI phenotype of children with MOG antibodies.

Objective: To investigate the clinical and magnetic resonance imaging (MRI) features of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-seropositive pediatric demyelinating syndromes. Methods: Serum samples collected from 74 children with suspected demyelinating disorders whom were being followed at Massachusetts General Hospital were incubated with control green fluorescent protein (GFP)- and MOG-GFP-transfected Jurkat cell clones. The binding ratios were calculated using flow cytometry. Using statistical analyses, we compared the demographic, clinical and radiological features in our seropositive and seronegative patients. Results: We found that 13 out of 74 (17.5%) patients were seropositive for MOG. The MOG-seropositive patients were younger than the seronegative patients (p = 0.049). No single disease category predominated among the seropositive patients, nor was one group more likely to have a polyphasic course. There were two out of four neuromyelitis optica (NMO) patients who had MOG antibodies; both were seronegative for aquaporin −4 (AQP4) antibodies. One had monophasic disease and the other had frequent relapses. There was a bimodal distribution of the MOG-seropositive patients by age at onset, with a distinct younger group (4–8 years) having a high prevalence of encephalopathy and an older group (13–18 years), whom presented almost exclusively with optic neuritis. MRI analysis demonstrated the absence of corpus callosum lesions in the seropositive patients (p = 0.012). The annualized relapse rate (ARR) and the Expanded Disability Status Scale (EDSS) results at 2 years did not differ between the seropositive and seronegative patients. Conclusion: MOG antibodies are found across a variety of pediatric demyelinating syndromes having some distinct clinical and MRI features.

Low testosterone is associated with disability in men with multiple sclerosis

Background: Gonadal steroids may modulate disease course in multiple sclerosis (MS). Objective: To assess the prevalence and clinical associations of hypogonadism in men with MS. Methods: Male patients, aged 18–65 years, with relapsing–remitting MS (RRMS) or clinically-isolated syndrome (CIS) and their first symptom < 10 years prior were selected from a longitudinal clinical study. We measured their hormones in stored morning blood samples, and collected their Expanded Disability Status Scale (EDSS) scores every 6 months and their Symbol Digit Modalities Test (SDMT) results annually. Results: Our analysis included 96 men with a mean age of 40 years, EDSS of 1.1 and disease duration of 4.6 years. Of these men, 39% were hypogonadal (total testosterone < 288 ng/dL); none showed compensatory elevations in luteinizing hormone. Their low testosterone levels and testosterone:estradiol ratios were negatively correlated with body mass index (BMI) and leptin, and showed no correlation with 25-hydroxy-vitamin D levels. In our primary cross-sectional analyses, there was a negative age-adjusted correlation between total testosterone and EDSS (p = 0.044). In the age-adjusted longitudinal analyses, higher baseline testosterone levels were associated with less decline in SDMT (p = 0.012). Conclusions: Men with MS may experience hypogonadotropic hypogonadism. Low testosterone levels may be associated with worse clinical outcomes. A potential neuroprotective role for testosterone warrants further investigation.

Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years

OBJECTIVE To compare relapse rates in pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (AOMS) over the first 6-years of disease. METHODS Patients with relapsing-remitting disease onset were identified from the Partners Pediatric MS Center, Massachusetts General Hospital and Partners MS Center, Brigham and Womens Hospital. 84 POMS and 258 AOMS patients were included. Annualized relapse rates (ARR) for each individual year from year 1 to year 6, after first attack were compared using Poisson regression, as was expanded disability status scale (EDSS) score at the visit closest to each year interval. RESULTS ARR was significantly higher in POMS compared to AOMS at individual years (except year 4), and was not significantly affected by adjustment for gender, race and proportion of time on treatment. Despite a 2.30 times higher relapse rate over 6-years, EDSS between groups did not differ. ARR in years 1-5 did not impact year 5 disability measured by EDSS in POMS. CONCLUSIONS Our findings demonstrate that higher ARR in POMS relative to AOMS is sustained over 6-years, suggesting a more inflammatory nature and potential disconnect between relapses and disability measured by EDSS early in POMS. This data may be useful when designing clinical trials for POMS.

Factors associated with recovery from acute optic neuritis in patients with multiple sclerosis

Objective: To identify clinical and demographic features associated with the severity and recovery from acute optic neuritis (AON) episodes in patients with multiple sclerosis (MS). Methods: Adult (n = 253) and pediatric (n = 38) patients whose first symptom was AON were identified from our MS database. Severity measured by loss of visual acuity (mild attack ≤20/40, moderate attack 20/50–20/190, and severe attack ≥20/200) and recovery in visual acuity at 1 year after the attack (complete recovery ≤20/20, fair recovery 20/40, and poor recovery ≥20/50) were recorded. Demographic and clinical features associated with attack severity and recovery were identified using proportional odds logistic regression. For another group of patients, blood samples were available within 6 months of an AON attack. In this group, the impact of vitamin D level on the severity/recovery was also assessed. Results: Men (adjusted odds ratio [OR] = 2.28, p = 0.03) and subjects with severe attacks (adjusted OR = 5.24, p < 0.001) had worse recovery. AON severity was similar between the pediatric and adult subjects, but recovery was significantly better in pediatric subjects in the unadjusted analysis (p = 0.041) and the analysis adjusted for sex (p = 0.029). Season-adjusted vitamin D level was significantly associated with attack severity (OR for 10-U increase in vitamin D level = 0.47; 95% confidence interval: 0.32, 0.68; p < 0.001). Vitamin D level was not associated with recovery from the attack (p = 0.98) in univariate analysis or after accounting for attack severity (p = 0.10). Conclusion: Vitamin D levels affect AON severity, whereas younger age, attack severity, and male sex affect AON recovery. Underlying mechanisms and potential therapeutic targets may identify new measures to mitigate disability accrual in MS.

Effect of vitamin D on MS activity by disease-modifying therapy class.

Objective: To determine whether vitamin D status predicts disease activity in patients with multiple sclerosis (MS) taking interferon-β (IFN), glatiramer acetate (GA), and fingolimod (FTY). Methods: Participants (n = 324) with relapsing-remitting MS on IFN (96), GA (151), or FTY (77) were identified from the Comprehensive Longitudinal Investigation of MS at Brigham and Womens Hospital (CLIMB) Study at the Partners MS Center. FTY-treated participants were analyzed separately because of differences in selection. Serum vitamin 25(OH)D concentration was adjusted for season. We evaluated the relationship between 25(OH)D tertile and time to relapse or gadolinium-enhancing lesion using a Cox model adjusted for age, sex, and disease duration. Results: Higher 25(OH)D was associated with longer time to the combined endpoint in the overall IFN/GA cohort (p for trend = 0.042; hazard ratio [HR] = 0.77) and in the IFN subgroup (HRIFN = 0.58; pIFN = 0.012), but not in GA-treated participants (p = 0.50; HR = 0.89). For gadolinium-enhancing lesions alone, there was a significant association observed in GA and IFN subgroups, although the effect was more pronounced on IFN (HRGA = 0.57; pGA = 0.039 vs HRIFN = 0.41; pIFN = 0.022). No significant associations were found for relapses. For FTY, higher 25(OH)D was associated with longer survival for the combined endpoint (HRFTY = 0.48; pFTY = 0.016) and for relapses (HRFTY = 0.50; pFTY = 0.046), but not for gadolinium-enhancing lesions. Conclusions: Disease activity generally improved with higher 25(OH)D, but this study raises the question of effect modification by treatment class.

Assessment of definitions of sustained disease progression in relapsing-remitting multiple sclerosis.

Sustained progression on the expanded disability status scale (EDSS) is a common outcome measure of disease progression in clinical studies of MS. Unfortunately, this outcome may not accurately measure long-term and irreversible disease progression. To assess the performance of definitions of sustained progression, patients with relapsing-remitting MS (RRMS) or a clinically isolated syndrome with evidence of lesions on a brain MRI were included in our study. Fifteen definitions of sustained progression using both the EDSS and the functional system (FS) scales were investigated. The impact of both relapses and changes in provider on the probability of maintaining progression was also evaluated. Although the provider scoring the EDSS sometimes changed during followup, the provider had access to previous EDSS scores. Between 15.8% and 42.2% of patients experienced sustained progression based on the definitions using EDSS as the outcome, but nearly 50% of these patients failed to maintain sustained progression for the duration of followup. When FS scales were used, progression was most common on the pyramidal and sensory scales. Unfortunately, progression on specific FS scales failed to be more sensitive to irreversible disability. Relapses or changes in provider did not explain the poor performance of the measures. Short-term changes in the EDSS or FS scores may not be an accurate marker of irreversible change in RRMS.

No sex-specific difference in disease trajectory in multiple sclerosis patients before and after age 50

BackgroundThe disease course in multiple sclerosis (MS) is influenced by many factors, including age, sex, and sex hormones. Little is known about sex-specific changes in disease course around age 50, which may represent a key biological transition period for reproductive aging.MethodsMale and female subjects with no prior chemotherapy exposure were selected from a prospective MS cohort to form groups representing the years before (38–46 years, N=351) and after (54–62 years, N=200)age 50. Primary analysis assessed for interaction between effects of sex and age on clinical (Expanded Disability Status Scale, EDSS; relapse rate) and radiologic (T2 lesion volume, T2LV; brain parenchymal fraction, BPF) outcomes. Secondarily, we explored patient-reported outcomes (PROs).ResultsAs expected, there were age- and sex- related changes with male and older cohorts showing worse disease severity (EDSS), brain atrophy (BPF), and more progressive course.There was no interaction between age and sex on cross-sectional adjusted clinical (EDSS, relapse rate) or radiologic (BPF, T2LV) measures, or on 2-year trajectories of decline.There was a significant interaction between age and sex for a physical functioning PRO (SF-36): the older female cohort reported lower physical functioning than men (p=0.002). There were no differences in depression (Center for Epidemiological Study – Depression, CES-D) or fatigue (Modified Fatigue Impact Scale, MFIS) scores.ConclusionsThere was no interaction between age and sex suggestive of an effect of reproductive aging on clinical or radiologic progression. Prospective analyses across the menopausal transition are needed.