Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis.

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis: An International Registry Study.

BACKGROUND AND OBJECTIVES: The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS. METHODS: This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS. RESULTS: The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (ß = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (ß = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (ß = - 0.5, 95% CI -0.6 to 0.4) and 18 years (ß = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (ß = -1.0, 95% CI -1.1 to 0.9). DISCUSSION: In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.

Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score.

BACKGROUND: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapses and magnetic resonance imaging (MRI) lesions to predict disability outcomes in relapsing-remitting multiple sclerosis (RRMS) treated with interferon-ß. OBJECTIVE: To validate the MAGNIMS score and extend to other disease-modifying therapies (DMTs). To examine the prognostic value of gadolinium contrast-enhancing (Gd+) lesions. METHODS: This RRMS MSBase cohort study (n = 2293) used a Cox model to examine the prognostic value of relapses, MRI activity and the MAGNIMS score for disability worsening during treatment with interferon-ß and three other DMTs. RESULTS: Three new T2 lesions (hazard ratio (HR) = 1.60, p = 0.028) or two relapses (HR = 2.24, p = 0.002) on interferon-ß (for 12 months) were predictive of disability worsening over 4 years. MAGNIMS score = 2 (1 relapse and ⩾3 T2 lesions or ⩾2 relapses) was associated with a greater risk of disability worsening on interferon-ß (HR = 2.0, p = 0.001). In pooled cohort of four DMTs, similar associations were seen (MAGNIMS score = 2: HR = 1.72, p = 0.001). Secondary analyses demonstrated that the addition of Gd+ to the MAGNIMS did not materially improve its prediction of disability worsening. CONCLUSION: We have validated the MAGNIMS score in RRMS and extended its application to three other DMTs: 1 relapse and ⩾3 T2 lesions or ⩾2 relapses predicted worsening of disability. Contrast-enhancing lesions did not substantially improve the prognostic score.

Preliminary Results of the FASM Study, an On-Going Italian Active Pharmacovigilance Project.

BACKGROUND AND AIM: Disease-modifying therapies (DMTs) used in multiple sclerosis (MS) have distinct safety profiles. In this paper, we report preliminary results of an on-going pharmacovigilance project (the FASM study). RESULTS: Neurologists working at involved multiple sclerosis centers collected 272 Individual Case Safety Reports (ICSRs). Adverse drug reactions (ADRs) mainly occurred in adult patients and in a higher percentage of women compared to men. No difference was found in ADRs distribution by seriousness. The outcome was reported as favorable in 61% of ICSRs. Out of 272 ICSRs, almost 53% reported dimethyl fumarate, fingolimod and IFN beta 1a as suspected. These medications were commonly associated to the occurrence of ADRs related hematological, gastrointestinal, general, infective or cancer disorders. The median time to event (days) was 177 for dimethyl fumarate, 1058 for fingolimod and 413 for IFN beta 1a. The median time to event for the remaining suspected drugs was 226. CONCLUSION: We believe that our results, together with those that will be presented at the end of the study, may bring new knowledge concerning the safety profile of DMTs and their proper use. This will provide the opportunity to draw new recommendations both for neurologists and patients.

The Association of Olfactory Dysfunction, Frailty, and Mortality Is Mediated by Inflammation: Results from the InCHIANTI Study.

BACKGROUND: Olfactory dysfunction might unveil the association between ageing and frailty, as it is associated with declining cognitive function, depression, reduced physical performance, reduced dietary intake, and mortality; all these conditions are characterized by increased levels of inflammatory parameters. The present study is aimed at evaluating the association between olfactory dysfunction, frailty, and mortality and whether such association might be mediated by inflammation. METHODS: We analysed data of 1035 participants aged 65+ enrolled in the "InCHIANTI" study. Olfactory function was tested by the recognition of the smells of coffee, mint, and air. Olfactory dysfunction was defined as lack of recognition of at least two smells. Considering the items "shrinking," "exhaustion," "sedentariness," "slowness," and "weakness" included in the Fried definition, frailty was defined as the presence of at least three criteria, prefrailty of one or two, and robustness of none. Serum interleukin-6 (IL-6) was measured in duplicate by high-sensitivity enzyme-linked immunosorbent assays. Logistic regression was adopted to assess the association of frailty with olfactory function, as well as with the increasing number of olfactory deficits. Cox regression was used to test the association between olfactory dysfunction and 9-year survival. RESULTS: Olfactory dysfunction was associated with frailty, after adjusting (OR 1.94, 95% CI = 1.07-3.51; P = .028); analysis of the interaction term indicated that the association varied according to interleukin-6 levels (P for interaction = .005). Increasing levels of olfactory dysfunction were associated with increasing probability of being frail. Also, olfactory dysfunction was associated with reduced survival (HR 1.52, 95% CI = 1.16-1.98; P = .002); this association varied according to the presence of frailty (P for interaction = .017) and prefrailty status (P for interaction = .046), as well as increased interleukin-6 levels (P for interaction = .011). CONCLUSIONS: Impairment of olfactory function might represent a marker of frailty, prefrailty, and consequently reduced survival in an advanced age. Inflammation might represent the possible link between these conditions.

Progression of tumefactive demyelinating lesion in a child demonstrated with MRI.

Tumefactive demyelinating lesions (TDLs) are atypical presentations of various demyelinating diseases. They can mimic brain tumors in their clinical and radiological features and usually respond favorably to corticosteroid therapy. We report a case of a 17-year-old girl with a single TDL suddenly increasing in size even under steroid therapy. She underwent very strict follow-up examinations with conventional magnetic resonance and diffusion-weighted imaging, perfusion-weighted imaging, proton-magnetic resonance spectroscopy. The behavior of the lesion during the different follow-up sessions posed a diagnostic challenge as it expanded its size during the final examination, in stark contrast to what we forecast. Diagnosis of TDL was initially hypothesized, but the aggressive behavior of the lesion required biopsy.

Longitudinal assessment of immuno-metabolic parameters in multiple sclerosis patients during treatment with glatiramer acetate.

OBJECTIVE: We investigated the effect of glatiramer acetate (GA) on the modulation of immune cell subpopulations and serum levels of multiple immune/metabolic markers in patients with relapsing-remitting multiple sclerosis (RRMS) to understand whether the treatment with GA could induce a specific change in the immunometabolic asset of patients with RRMS. MATERIAL AND METHODS: We performed an extensive peripheral blood immunophenotyping and measured serum levels of several parameters involved in the pathogenesis of RRMS and also relevant in the pathogenesis of metabolic syndrome and obesity such as leptin, soluble leptin-receptor (sLep-R), myeloperoxidase (MPO), soluble CD40 ligand (sCD40-L), soluble tumor necrosis factor-receptor (sTNF-R), monocyte chemoattractant protein 1 (MCP-1), soluble Inter-Cellular Adhesion Molecule-1 (sICAM-1) and osteoprotegerin (OPG), in 20 naïve-to-treatment RRMS patients and 20 healthy controls. We repeated these analyses over time at 6 and 12 months after starting GA treatment. RESULTS: Our analysis showed that naïve-to-treatment RRMS patients had a lower number of CD16(+)CD56(+) NK cells, CD19(+) B cells, CD4(+) T cells co-expressing the MHC class II activation marker HLA-DR (CD4(+)DR(+)) and naïve CD4(+)CD45RA(+) T cells in basal conditions. GA treatment induced a specific and significant decrease of circulating CD19(+) B cells. Naïve-to-treatment RRMS patients also showed a significantly higher number of CD4(+) T cells with a memory phenotype (CD4(+)CD45RO(+)) whose peripheral frequency was not affected by GA treatment. These changes over time associated with a higher serum concentration of leptin and lower levels of MPO. GA treatment also reduced significantly the circulating levels of sCD40-L and sTNF-R overtime. CONCLUSIONS: Our data suggest that the clinical outcome of GA treatment is associated with changes in immune cell subpopulations and modulation of specific immunometabolic markers. These data add substantial evidence of the immune modulating effect of GA during RRMS and could be of relevance in understanding the pathogenesis of disease and its follow-up.