Evaluation of drivers of treatment switch in relapsing multiple sclerosis: a study from the Italian MS Registry.

BACKGROUND: Active relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as "relapsing MS" (RMS). The aim of this cross-sectional study was to assess drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD). METHODS: RRMS and SPMS patients with at least one relapse in a time window of 2 years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT's class [moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs]. RESULTS: A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (p < 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02-0.37), Natalizumab (0.48, 0.30-0.76), Ocrelizumab (0.1, 0.02-0.45) and Rituximab (0.23, 0.06-0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31-0.59), especially anti-CD20 drugs (0.14, 0.05-0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs. CONCLUSIONS: More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch.

Retrospectively acquired cohort study to evaluate the long-term impact of two different treatment strategies on disability outcomes in patients with relapsing multiple sclerosis (RE.LO.DI.MS): data from the Italian MS Register.

BACKGROUND: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies. OBJECTIVE: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings. METHODS: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register. RESULTS: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-ß1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-ß1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48-2.04), p = 0.98 and 0.81 (0.42-1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00-2.12), p = 0.05]. CONCLUSION: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-ß1a to FTY.

Metabolic response to glatiramer acetate therapy in multiple sclerosis patients.

Glatiramer acetate (GA; Copaxone) is a random copolymer of glutamic acid, lysine, alanine, and tyrosine used for the treatment of patients with multiple sclerosis (MS). Its mechanism of action has not been already fully elucidated, but it seems that GA has an immune-modulatory effect and neuro-protective properties. Lymphocyte mitochondrial dysfunction underlines the onset of several autoimmune disorders. In MS first diagnosis patients, CD4+, the main T cell subset involved in the pathogenesis of MS, undergo a metabolic reprogramming that consist in the up-regulation of glycolysis and in the down-regulation of oxidative phosphorylation. Currently, no works exist about CD4+ T cell metabolism in response to GA treatment. In order to provide novel insight into the potential use of GA in MS treatment, blood samples were collected from 20 healthy controls (HCs) and from 20 RR MS patients prior and every 6 months during the 12 months of GA administration. GA treated patients' CD4+ T cells were compared with those from HCs analysing their mitochondrial activity through polarographic and enzymatic methods in association with their antioxidant status, through the analysis of SOD, GPx and CAT activities. Altogether, our findings suggest that GA is able to reduce CD4+ T lymphocytes' dysfunctions by increasing mitochondrial activity and their response to oxidative stress.

Long-term adherence of patients with relapsing-remitting multiple sclerosis to subcutaneous self-injections of interferon ß-1a using an electronic device: the RIVER study.

OBJECTIVES: The BRIDGE study has previously shown a high short-term (12 weeks) adherence rate (>85%) of patients with relapsing-remitting multiple sclerosis (RRMS) to subcutaneous self-injections of interferon ß-1a using an electronic auto-injection device (RebiSmart®). The primary goal of the RIVER study was to investigate in a real-life setting the long-term adherence to the use of RebiSmart among patients enrolled in the parent BRIDGE study. METHODS: The RIVER study was designed as a real-life extension study of the BRIDGE trial. RRMS patients who completed BRIDGE and still had an indication for treatment were included. Data were collected prospectively through the RebiSmart device, and analyzed retrospectively. Long term adherence (administration of ≥ 80% of injections) to and safety of RebiSmart were assessed. The expected follow-up period ranged from 19 to 26 months. RESULTS: A total of 57 RRMS patients participated in the follow-up study. The mean observation period was 20.5 ± 5.7 months. The overall adherence to the use of RebiSmart in the entire study cohort was 79.8% (median = 85.2%, range = 16-100%). There were 36 patients (63.2%) who completed at least 80% of the scheduled injections. No statistically significant differences were found between adherent and non-adherent patients in terms of age, sex, duration of the observation period, and occurrence of relapses. No serious treatment-related adverse events occurred. CONCLUSIONS: This study showed a high level of long-term adherence to the use of RebiSmart, with 63.2% of participants meeting the criterion for adherence to treatment.

A lipidomic approach to the study of human CD4(+) T lymphocytes in multiple sclerosis.

BACKGROUND: Lipids play different important roles in central nervous system so that dysregulation of lipid pathways has been implicated in a growing number of neurodegenerative disorders including multiple sclerosis (MS). MS is the most prevalent autoimmune disorder of the central nervous system, with neurological symptoms caused by inflammation and demyelination. In this study, a lipidomic analysis was performed for the rapid profile of CD4(+) T lymphocytes from MS patient and control samples in an untargeted approach. METHODS: A matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry based approach was used for the analysis of lipid extracts using 9-aminoacridine as matrix. Lipids were analyzed in negative mode and selected species fragmented using MALDI tandem mass spectrometry for their structural assignments. RESULTS: The analysis reveals some modifications in the phospholipid pattern of MS CD4(+) T lymphocytes with respect to healthy controls with a significant increase of cardiolipin species in MS samples. CONCLUSIONS: These results demonstrate the feasibility of a MALDI-TOF approach for the analysis of CD4(+) lipid extracts and suggest how alterations in the lipid metabolism characterized lymphocytes of MS patients.

Bioenergetics profile of CD4(+) T cells in relapsing remitting multiple sclerosis subjects.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. There are four clinical forms of MS, the most common of which is characterized by a relapsing remitting course (RRMS). The etiology of MS is unknown, but many studies suggested that genetic, environmental and infectious agents may contribute to the development of this disease. In experimental autoimmune encephalomyelitis (EAE), the animal model for MS, it has been shown that CD4(+) T cells play a key role in MS pathogenesis. In fact, these cells are able to cross the blood-brain barrier and cause axonal damage with neuronal death. T cell activation critically depends on mitochondrial ATP synthesis and reactive oxygen species (ROS) production. Interestingly, lots of studies linked the oxidative damage arising from mitochondrial changes to neurodegenerative disorders, such as MS. Based on these evidences, this work focused on the metabolic reprogramming of CD4(+) T cells in MS subjects, being this cell population directly implicated in pathogenesis of disease, paying attention to mitochondrial function and response to oxidative stress. Such aspects, once clarified, may open new opportunities for a therapeutic metabolic modulation of MS disorder.

ExtaviJect® 30G device for subcutaneous self-injection of interferon beta-1b for multiple sclerosis: a prospective European study.

BACKGROUND: The ExtaviJect® 30G autoinjector was developed to facilitate parenteral self-administration of interferon beta-1b (Extavia®), a first-line disease-modifying therapy in patients with multiple sclerosis. Our aim was to assess patient compliance with treatment when using the autoinjector, patients' and nurses' experiences of using the device, its tolerability, and patient satisfaction. METHODS: This was a 12-week, real-world, prospective, observational, noninterventional study conducted in nine European countries. Questionnaires were used to measure patient compliance and to assess patients' and nurses' experiences. All adverse events were recorded by severity, including injection site reactions or pain. Patient satisfaction and health-related quality of life were assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) and EuroQol-5 Dimension (EQ-5D) instruments, respectively. RESULTS: Of 582 patients enrolled, 568 (98%) received at least one injection and attended the first follow-up visit at 6 weeks, and 542 (93%) attended the second follow-up visit at 12 weeks. For the whole study, 548 of 568 (97%) patients were compliant with treatment. Among the various questions assessing whether the device was easy and quick to use accurately, without fear of the needle, 56%-98% of patients and 59%-98% of nurses were in agreement. There were nine serious adverse events (four disease-related) reported among the 227 (39%) patients reporting adverse events. Scores increased in the TSQM-9 convenience domain between weeks 6 and 12 (P=0.0009), and in the EQ-5D visual analog scale between baseline and week 12 (P<0.0001), indicating improvement in health-related quality of life. CONCLUSION: ExtaviJect 30G was convenient to use and was associated with high levels of compliance.

A case report of double filtration plasmapheresis in an acute episode of multiple sclerosis.

Plasma exchange has been proposed as support therapy in both acute and chronic forms of multiple sclerosis (MS). For the first time, we aimed to assess whether double filtration plasmapheresis (DFPP) could be clinically efficacious. We describe the case of a patient affected by MS who developed a severe crisis refractory to conventional steroids, and immunosuppressive and immunomodulating therapy. The patient underwent 12 sessions of DFPP. In each session 3000 mL of plasma was treated. Before and immediately after each session the routine laboratory parameters were assessed. Before the apheresis cycle and one month after the end of treatment, encephalic magnetic resonance imaging (MRI) was performed. A neurological examination and assessment of the extended disability status scale (EDSS) were made once each week from the beginning of treatment until one month after the end of the cycle. No therapy was administered during the course of the apheresis cycle, with the exception of a scaled dose of steroids, that was completely withdrawn half-way through the cycle. The immunoglobulin (Ig) G, IgA and IgM values declined from 465 +/- 104 mg/dL, 69 +/- 18 mg/dL, 34 +/- 16 mg/dL, respectively, pre-apheresis to 331 +/- 76 mg/dL, 42 +/- 5 mg/dL, 15 +/- 6 mg/dL, respectively, post-apheresis; C3 and C4 decreased from 105 +/- 27 mg/dL and 21 +/- 5 mg/dL to 75 +/- 9 mg/dL and 15 +/- 4 mg/dL, respectively; fibrinogen went from 228 +/- 72 mg/dL to 128 +/- 28 mg/dL. The EDSS dropped from a value of 6 before the cycle to 5.5 one month after the end of the treatment. As compared with the pretreatment conditions, post-apheresis MRI showed stabilization of the lesions already present, the reduction of one lesion and a complete absence of enhancement of all lesions. DFPP, adopted for the first time in MS, seems to foster a short-term improvement in both the clinical and magnetic resonance images during an acute MS episode.

A whole genome screen for linkage disequilibrium in multiple sclerosis performed in a continental Italian population.

We have systematically screened the genome for evidence of linkage disequilibrium (LD) with multiple sclerosis (MS) by typing 6000 microsatellite markers in case-control and family based (AFBAC) cohorts from the Italian population. DNA pooling was used to reduce the genotyping effort involved. Four DNA pools were considered: cases (224 Italian MS patients), controls (231 healthy Italians), index (185 index cases from trio families) and parents (the 370 parents of the patient included in the Index pool), respectively. After refining analysis of the most promising 14 markers to emerge from this screening process, only marker D2S367 retained evidence for association.

Interferon beta in relapsing-remitting multiple sclerosis: an independent postmarketing study in southern Italy.

This independent, population-based surveillance study monitored the efficacy and safety of interferon beta (IFNbeta) products in 1033 patients with relapsing-remitting multiple sclerosis (RRMS) from 15 centres in Italy. Relapses, Expanded Disability Status Scale (EDSS) scores, and adverse events were evaluated for up to 24 months. Data of patients with a baseline EDSS score < or = 3.5 are reported. The proportions of relapse-free patients were similar among the groups at 12 and 24 months (P = 0.10). IFNbeta products produced significant reductions from baseline in relapse rates at 12 and 24 months (P < 0.001), with no differences among treatments (P = 0.2). There were no significant differences in mean EDSS change among groups at 12 or 24 months. The IFNbeta-1b group showed a higher incidence of adverse events during the first year of treatment (P < 0.05) than IFNbeta-1a groups, and more withdrawals (10%) compared with Avonex (5%) at 24 months. IFNbeta products are equally effective in low disability RRMS, but IFNbeta-1a may have a more favorable efficacy/tolerability ratio.

Age-related disability in multiple sclerosis.

There is evidence that the clinical course of multiple sclerosis is age related. The present study evaluated the relationship between age and rate of disability progression in a large hospital-based cohort of definite cases of multiple sclerosis (n= 1,463). Patients were followed every 6 to 12 months for a total period of observation of 11,387.8 person-years. Expanded Disability Status Scale scores increased significantly with increasing current age and longer duration of disease (p=0.007). Median times to reach Expanded Disability Status Scale scores of 4.0 and 6.0, assessed using an extended Kaplan-Meier method with age as a categorical time-varying covariate, were significantly longer among patients aged 20 to 35 years compared with patients aged 36 to 50 and 51 to 65 years (p < 0.0001). Significant associations were observed between mean Expanded Disability Status Scale scores and age at disease onset, current age, and the interaction of age at disease onset and current age (p < 0.001). Current age had a greater effect (59% of variability in the model) on disease severity than did age at disease onset. Furthermore, a multiplicative effect on Expanded Disability Status Scale score was observed for age at disease onset and current age combined, indicating a faster rate of disease progression in older patients. In conclusion, the results of the current study demonstrate the impact of age on rate of disability progression in multiple sclerosis and suggest that an age-adjusted progression index may be a more relevant criterion for defining differences between multiple sclerosis groups.