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.

Clinical relevance of thymic and bone marrow outputs in multiple sclerosis patients treated with alemtuzumab.

Thymic and bone marrow outputs were evaluated in 13 sequential samples of 68 multiple sclerosis patients who initiated alemtuzumab and were clinically followed for 48 months. Three months after alemtuzumab infusions, the levels of new T lymphocytes were significantly reduced, but progressively increased reaching the highest values at 36 months, indicating the remarkable capacity of thymic function recovery. Newly produced B cells exceeded baseline levels as early as 3 months after alemtuzumab initiation. Heterogeneous patterns of new T- and B-cell recovery were identified, but without associations with age, sex, previous therapies, development of secondary autoimmunity or infections, and disease re-emergence. Trial registration version 2.0-27/01/2016.

Impact of Dimethylfumarate on Sleep in Multiple Sclerosis Patients: An Actigraphic Study.

BACKGROUND: Sleep disorders in multiple sclerosis (MS) patients are common. Dimethylfumarate is an oral disease-modifying drug (DMT), whose impact on sleep is unknown. OBJECTIVE: The aim of this study was to characterize actigraphic patterns in MS patients treated with dimethylfumarate. METHODS: Twenty relapsing-remitting MS patients with low to a mild disability, aged 20-50y, treated with dimethylfumarate for more than 6 months, were enrolled. All subjects had no history of sleep disorders. Actigraphy was used to study sleep patterns during a seven-day period. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Twenty healthy subjects served as controls. RESULTS: Our results showed statistically significant differences between some actigraphic patterns in MS patients treated with dimethylfumarate and healthy subjects, but the values for patients were still within normal limits. PSQI score was higher in MS patients compared to controls. CONCLUSION: Our findings suggest that dimethylfumarate, an oral DMT with a favourable benefit-risk profile, does not strongly alter sleep patterns in MS patients with low to mild disability and with no history of sleep disorders. Actigraphy is a simple diagnostic tool, able to support an objective measure of sleep parameters. The simplicity of application may allow considering its use for a screening of sleep disorders in MS patients.

Potential prognostic value of circulating inflamma-miR-146a-5p and miR-125a-5p in relapsing-remitting multiple sclerosis.

BACKGROUND: Inflamma-miRs are a group of microRNAs involved in the regulation of innate and adaptive immune responses. Increasing evidence support the contribution of dysregulated inflamma-miRs in the pathogenesis of multiple sclerosis. The aim of this study was to evaluate the expression of selected inflamma-miRs, i.e., miR-34a-5p, -125a-5p, -146a-5p, and -155, in relapsing-remitting multiple sclerosis (RRMS) and their modulation after treatment with dimethyl fumarate (DMF). METHODS: Circulating levels of microRNAs involved in inflammatory response (inflamma-miRs) were compared between healthy controls (CTRs, n=21) and patients with RRMS (n=24) who started treatment with DMF. RESULTS: Plasma levels of miR-34a (p<0.001) and miR-125a-5p (p=0.034) were higher, whereas miR-146a-5p levels were lower (p=0.041) in RRMS patients compared to CTRs. Circulating miR-125a-5p (p=0.001), miR-146a-5p (p<0.001), and miR-155 (p=0.013) were reduced after 4-month treatment with DMF. Among these, baseline and 4-month follow up miR-125a-5p (p=0.028) and miR-146a-5p (p=0.042) levels were related to disability progression. CONCLUSION: Circulating inflamma-miRs could represent candidate tools to predict MS clinical course and evaluate the effectiveness of disease-modifying treatments in RRMS.

Nabiximols discontinuation rate in a large population of patients with multiple sclerosis: a 18-month multicentre study.

INTRODUCTION: Delta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation. MATERIALS AND METHODS: This prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline. RESULTS: A total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, p<0.01) and higher differences of NRS between T0 and T1 (OR 2.11, 95% CI 1.08 to 8.26, p<0.05) were associated with an increased probability to continue therapy after 18 months. DISCUSSION: THC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events.

Sleep in multiple sclerosis patients treated with interferon beta: an actigraphic study.

OBJECTIVE: Sleep disorders in multiple sclerosis (MS) patients are common and complex. Some evidences suggest that interferon beta (IFN-ß), a first line disease modifying therapy can be involved in the induction of sleep architecture changes. The aim of this study was to evaluate and characterize actigraphic patterns in MS patients treated with IFN-ß. METHODS: Ten relapsing remitting MS patients with low to mild disability (Expanded Disability Status Scale<2.5), aged 20-50y treated with IFN-ß for more than 6 months were enrolled. Actigraphy was used to study sleep pattern. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Ten sex-and age-matched healthy subjects served as controls. In patients, a comparison between drug free nights and nights following drug administration was made. RESULTS: Patients had significantly higher PSQI (p = 0.006), sleep onset latency (p = 0.029), sleep efficiency percentage (p = 0.001) and number of wake episodes (p = 0,0001) values, when compared with controls. When comparing the actigraphic results acquired in the nights after treatment with those acquired in the free-drug nights, the only significant difference (p = 0.038) was detected for time in bed that was higher after IFN-ß administration. CONCLUSIONS: Our results, besides confirming the presence of alterations in sleep patterns in MS patients, suggest that IFN-ß may contribute to promote alteration in sleep architecture. Actigraphy is a simple diagnostic tool, able to support an objective measure of sleep parameters. The relative simplicity of application and low costs may allow considering its use for an adequate screening of sleep disorders in MS patients.

Conversion to Secondary Progressive Multiple Sclerosis: Patient Awareness and Needs. Results From an Online Survey in Italy and Germany.

Background: Few studies have investigated the experiences of patients around the conversion to secondary progressive multiple sclerosis (SPMS). ManTra is a mixed-method, co-production research project conducted in Italy and Germany to develop an intervention for newly-diagnosed SPMS patients. In previous project actions, we identified the needs and experiences of patients converting to SPMS via literature review and qualitative research which involved key stakeholders. Aims: The online patient survey aimed to assess, on a larger and independent sample of recently-diagnosed SPMS patients: (a) the characteristics associated to patient awareness of SPMS conversion; (b) the experience of conversion; (c) importance and prioritization of the needs previously identified. Methods: Participants were consenting adults with SPMS since ≤5 years. The survey consisted of three sections: on general and clinical characteristics; on experience of SPMS diagnosis disclosure (aware participants only); and on importance and prioritization of 33 pre-specified needs. Results: Of 215 participants, those aware of their SPMS diagnosis were 57% in Italy vs. 77% in Germany (p = 0.004). In both countries, over 80% of aware participants received a SPMS diagnosis from the neurologist; satisfaction with SPMS disclosure was moderate to high. Nevertheless, 28-35% obtained second opinions, and 48-56% reported they did not receive any information on SPMS. Participants actively seeking further information were 63% in Germany vs. 31% in Italy (p < 0.001). Variables independently associated to patient awareness were geographic area (odds ratio, OR 0.32, 95% CI 0.13-0.78 for Central Italy; OR 0.21, 95% CI 0.08-0.58 for Southern Italy [vs. Germany]) and activity limitations (OR 7.80, 95% CI 1.47-41.37 for dependent vs. autonomous patients). All pre-specified needs were scored a lot or extremely important, and two prioritized needs were shared by Italian and German patients: "physiotherapy" and "active patient care involvement." The other two differed across countries: "an individualized health care plan" and "information on social rights and policies" in Italy, and "psychological support" and "cognitive rehabilitation" in Germany. Conclusions: Around 40% of SPMS patients were not aware of their disease form indicating a need to improve patient-physician communication. Physiotherapy and active patient care involvement were prioritized in both countries.

Palatability and oral cavity tolerability of THC:CBD oromucosal spray and possible improvement measures in multiple sclerosis patients with resistant spasticity: a pilot study.

AIM: Complaints about Δ9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex®; GW Pharma Ltd, Salisbury, UK) in the management of multiple sclerosis spasticity include unpleasant taste and oral mucosal anomalies. This pilot study assessed the use of sugar-free chewing gum and/or a refrigerated bottle of THC:CBD oromucosal spray to mitigate these effects. MATERIALS & METHODS: Patients with multiple sclerosis spasticity (n = 52) at six sites in Italy who were receiving THC:CBD oromucosal spray and had associated oral mucosal effects were randomized into Group A (chewing gum; n = 15); Group B (cold bottle; n = 20); and Group C (cold bottle + chewing gum; n = 17). RESULTS: Taste perception in patients receiving chewing gum ± cold bottle intervention (Groups A and C combined) was significantly (p = 0.0001) improved from baseline to week 4 while maintaining spasticity control. CONCLUSION: Patient comfort, satisfaction and treatment adherence may benefit from these interventions.

Sativex in resistant multiple sclerosis spasticity: Discontinuation study in a large population of Italian patients (SA.FE. study).

BACKGROUND: The approval of Sativex for the management of multiple sclerosis (MS) spasticity opened a new opportunity to many patients. In Italy, the healthcare payer can be fully reimbursed by the involved pharma company with the cost of treatment for patients not responding after a 4 week (28 days) trial period (Payment by Results, PbR), and 50% reimbursed with the cost of 6 weeks (42 days) treatment for other patients discontinuing (Cost Sharing, CS). The aim of our study was to describe the Sativex discontinuation profile from a large population of spasticity treated Italian MS patients. METHODS: We collected data of patients from 30 MS centres across the country starting Sativex between January 2014 and February 2015. Data were collected from the mandatory Italian Medicines Agency (AIFA) web-registry. Predictors of treatment discontinuation were assessed using a multivariate Cox proportional regression analysis. RESULTS: During the observation period 631 out of 1597 (39.5%) patients discontinued Sativex. The Kaplan-Meier estimates curve showed that 333 patients (20.8%) discontinued treatment at 4 weeks while 422 patients (26.4%) discontinued at 6 weeks. We found after adjusted modeling that a higher NRS score at T1 (adjHR 2.23, 95% 2.07-2.41, p<0.001) and a lower baseline NRS score (adjHR 0.51 95% CI 0.46-0.56, p<0.001) were predictive of treatment discontinuation. CONCLUSION: These data show that the first 6 weeks are useful in identifying those patients in which Sativex could be effective, thus avoiding the cost of longer term evaluation.