Prognostic Markers of Ocrelizumab Effectiveness in Multiple Sclerosis: A Real World Observational Multicenter Study.

Pivotal trials showed the effectiveness of the monoclonal antibody ocrelizumab in relapsing and progressive multiple sclerosis (MS). However, data on everyday practice in MS patients and markers of treatment effectiveness are scarce. We aimed to collect real-world data from ocrelizumab-treated MS patients, relapsing-remitting (RR) and progressive MS patients (PMS), including active secondary progressive MS (aSPMS) and primary progressive MS (PPMS) patients, and to explore potential prognostic factors of clinical outcome. Patients were enrolled at MS centres in the Campania region, Italy. We collected clinic-demographic features retrospectively one year before ocrelizumab start (T−1), at ocrelizumab start (T0), and after one year from ocrelizumab start (T1). We explored possible clinical markers of treatment effectiveness in those patients receiving ocrelizumab treatment for at least one year using multilevel-mixed models. We included a total of 383 MS patients (89 RRMS and 294 PMS; 205 females, mean age: 45.8 ± 11.2, disease duration: 12.7 ± 11.6 years). Patients had a mean follow-up of 12.4 ± 8.2 months, and 217 patients completed one-year ocrelizumab treatment. Overall, EDSS increased from T−1 to T0 (coeff. = 0.30, 95% coefficient interval [CI] = 0.19−0.41, p < 0.001) without a further change between T0 and T1 (p = 0.61). RRMS patients did not show an EDSS change between T−1 and T0 nor between T0 and T1. Conversely, PMS patients showed EDSS increase from T−1 to T0 (coeff. = 0.34, 95% CI = 0.22−0.45, p < 0.001) without a further change between T0 and T1 (p = 0.21). PMS patients with a time from conversion shorter than 2 years showed increased EDSS from T−1 to T0 (coeff. = 0.63, 95% CI = 0.18−1.08, p = 0.006) without a further change between T0 and T1 (p = 0.94), whereas PMS patients with a time from conversion longer than 2 years showed increased EDSS from T0 to T1 (coeff. = 0.30, 95% CI = 0.11−0.49, p = 0.002). Naïve patients showed an EDSS decrease between T0 and T1 (coeff. = −0.30, 95% CI = −0.50−−0.09, p = 0.004). In conclusion, our study highlighted that early ocrelizumab treatment is effective in modifying the disability accrual in MS patients.

Management of hepatitis B virus prophylaxis in patients treated with disease-modifying therapies for multiple sclerosis: a multicentric Italian retrospective study.

BACKGROUND: Patients with multiple sclerosis (MS) often receive disease-modifying therapies (DMTs) that can expose them to reactivation of potential occult hepatitis B virus (HBV) infection (pOBI). We aimed to evaluate the MS Centers behavior regarding HBV screening and prophylaxis in a large cohort of MS patients receiving anti-CD20 or cladribine. METHODS: Retrospective, multicentric study recruiting Italian MS patients treated with rituximab, ocrelizumab and cladribine. RESULTS: We included 931 MS patients from 15 centers. All but 38 patients performed a complete HBV screening. Patients' age > 50 years was significantly associated with no history of vaccination and HBsAb titres < 100 mIU at baseline (p < 0.001). No significant correlation was found between post-vaccination HBsAb titres and type of treatment (p = 0.5), pre-or post-therapy vaccination (p = 0.2) and number of previous DMTs (p = 0.2). Among pOBI patients (n = 53), 21 received antiviral prophylaxis, while only 13 had HBV DNA monitoring and 19 patients neither monitored HBV DNA nor received prophylaxis. CONCLUSIONS: Baseline HBV screening in patients receiving anti-CD20 and cladribine is a consolidated practice. Nonetheless, HBV vaccination coverage is still lacking in such population and age is a significant factor associated with low HBV protection. Rituximab, ocrelizumab and cladribine did not impair HBV vaccine response. Almost 35% of pOBI patients fail to receive HBVr prevention. Management of HBV prophylaxis could be improved in MS patients and further prospective studies are needed to assess the effectiveness of prophylactic strategies in such patients.

Cognitive trajectories in multiple sclerosis: a long-term follow-up study.

BACKGROUND: Cognitive impairment occurs in multiple sclerosis (MS) and undergoes a progressive worsening over disease course. However, clinicians still struggle to predict the course of cognitive function. To evaluate baseline clinical and imaging predictors of cognitive abilities worsening over time, we performed a latent trajectory analysis for cognitive performances in MS patients, up to 15 years from disease onset. METHODS: We collected age, sex, education, dominant and non-dominant 9-hole peg test (9HP) and timed 25-foot walk (T25-FW) as well as MRI measures (grey matter volume and lesion load) within 6 months from disease diagnosis for relapsing-remitting MS (RR-MS) patients. At diagnosis and over the follow-up, we also assessed cognitive status through the symbol digit modalities test (SDMT). Cognitive impairment was defined by applying age-, gender- and education-adjusted normative values. Group-based trajectory analysis was performed to determine trajectories, and the predictive value of clinical and imaging variables at baseline was assessed through multinomial logistic regression. RESULTS: We included 148 RR-MS (98 females and 50 males). Over 11 ± 4 year follow-up, 51.4% remained cognitively stable whereas 48.6% cognitively worsened. Cognitively worsening patients had a higher T25FW time (p = 0.004) and a reduced hippocampal volume at baseline (p = 0.04). CONCLUSION: Physical disability as well as hippocampal atrophy might depict patients at risk of cognitive worsening over the disease course. Therefore, using such predictors, clinicians may select patients to carefully evaluate for cognitive impairment as to eventually introduce cognitive rehabilitation treatments.

Digital Technology in Clinical Trials for Multiple Sclerosis: Systematic Review.

Clinical trials in multiple sclerosis (MS) have been including digital technology tools to overcome limitations in treatment delivery and disease monitoring. In March 2020, we conducted a systematic search on pubmed.gov and clinicaltrials.gov databases (with no restrictions) to identify all relevant published and unpublished clinical trials, in English language, including MS patients, in which digital technology was applied. We used "multiple sclerosis" and "clinical trial" as the main search words, and "app", "digital", "electronic", "internet" and "mobile" as additional search words, separately. Digital technology is part of clinical trial interventions to deliver psychotherapy and motor rehabilitation, with exergames, e-training, and robot-assisted exercises. Digital technology has been used to standardise previously existing outcome measures, with automatic acquisitions, reduced inconsistencies, and improved detection of symptoms (e.g., electronic recording of motor performance). Other clinical trials have been using digital technology for monitoring symptoms that would be otherwise difficult to detect (e.g., fatigue, balance), for measuring treatment adherence and side effects, and for self-assessment purposes. Collection of outcome measures is progressively shifting from paper-based on site, to internet-based on site, and, in the future, to internet-based at home, with the detection of clinical and treatment features that would have remained otherwise invisible. Similarly, remote interventions provide new possibilities of motor and cognitive rehabilitation.

Physical Exercise Moderates the Effects of Disability on Depression in People with Multiple Sclerosis during the COVID-19 Outbreak.

Physical disability impacts psychosocial wellbeing in people with multiple sclerosis. However, the role of physical activity in this context is still debated. By taking advantage of a previous survey, conducted online from 22 April to 7 May 2020, we performed a post-hoc analysis with the aim to assess the associations between disability, physical exercise, and mental health in multiple sclerosis. We retrieved the following data: (i) sociodemographic information, (ii) changes in lifestyle (including exercise), (iii) physical disability, as measured with the Patient-Determined Disease Steps scale, and (iv) anxiety feelings and depressive symptoms assessed via the items included in the Quality of Life in Neurological Disorders measurement system. Examination of the interaction plot showed that the effect of disability on depression, but not on anxious symptoms, was significant for all levels of physical exercise (low: b = 1.22, 95% C.I. 0.85, 1.58, p < 0.001; moderate: b = 0.95, 95% C.I. 0.66, 1.24, p < 0.001; and high: b = 0.68, 95% C.I. 0.24, 1.13, p = 0.003). Based on these data, we can conclude that disability significantly impacted depression during the COVID-19 pandemic, with physical activity playing a moderating role. Our results suggest that favoring exercise in multiple sclerosis (MS) would ameliorate psychological wellbeing regardless of the level of physical disability.

A Retrospective Exploratory Analysis on Cardiovascular Risk and Cognitive Dysfunction in Multiple Sclerosis.

BACKGROUND: Cardiovascular comorbidities have been associated with cognitive decline in the general population. OBJECTIVES: To evaluate the associations between cardiovascular risk and neuropsychological performances in MS. METHODS: This is a retrospective study, including 69 MS patients. For all patients, we calculated the Framingham risk score, which provides the 10-year probability of developing macrovascular disease, using age, sex, diabetes, smoking, systolic blood pressure, and cholesterol levels as input variables. Cognitive function was examined with the Brief International Cognitive Assessment for MS (BICAMS), including the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-II (CVLT-II), and the Brief Visuospatial Memory Test-Revised (BVMT-R). RESULTS: Each point increase of the Framingham risk score corresponded to 0.21 lower CVLT-II score. Looking at Framingham risk score components, male sex and higher total cholesterol levels corresponded to lower CVLT scores (Coeff = -8.54; 95%CI = -15.51, -1.57; and Coeff = -0.11; 95%CI = -0.20, -0.02, respectively). No associations were found between cardiovascular risk and SDMT or BVMT-R. CONCLUSIONS: In our exploratory analyses, cardiovascular risk was associated with verbal learning dysfunction in MS. Lifestyle and pharmacological interventions on cardiovascular risk factors should be considered carefully in the management of MS, given the possible effects on cognitive function.

MRI activity and extended interval of Natalizumab dosing regimen: a multicentre Italian study.

BACKGROUND: To minimize the risk of Progressive Multifocal Leukoencephalopathy and rebound in JCV-positive multiple sclerosis (MS) patients after 24 natalizumab doses, it has been proposed to extend the administrations interval. The objective is to evaluate the EID efficacy on MRI activity compared with the standard interval dosing (SID). METHODS: Observational, multicentre, retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Three hundred and sixteen patients were enrolled. The median dose interval (MDI) following the 24th infusion was 5 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Patients were grouped into 2 categories according to the mean number of weeks between doses: <5 weeks, SID; ≥5 weeks, EID. RESULTS: One hundred and eighty-seven patients were in the SID group (MDI = 4.5 weeks) and 129 in the EID group (MDI 6.1 weeks). The risk to develop active lesions on MRI is similar in SID and EID groups during the 6 and 12 months after the 24th natalizumab infusion, respectively 4.27% (95% CI:0.84-7.70) vs 4.71% (95% CI:0.16-9.25%) [p = 0.89] and 8.50% (95% CI:4.05-12.95) vs 6.55% (95% CI:2.11-11.00%) [p = 0.56]. The EID regimen does not appear to increase the occurrence of MRI activity during follow-up. CONCLUSION: There is no evidence of the reduced efficacy of natalizumab in an EID setting regarding the MRI activity. This observation supports the need for a bigger randomized study to assess the need to change the standard of the natalizumab dosing schedule, to better manage JCV-positive patients.

Asymptomatic bradycardia after first fingolimod dose in a pediatric patient with multiple sclerosis - a case report.

Fingolimod is currently approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of pediatric patients with relapsing-remitting multiple sclerosis (RRMS). However, transient asymptomatic bradycardia with treatment initiation has been reported in a small population of predisposed patients, which may be a result of short-term activation and internalization/desensitization of the G-protein-gated potassium channel IKACh on the atrial myocyte membrane. Asymptomatic bradycardia, with or without atrioventricular block, is generally self-limiting and has been reported within the first 6 h of administration of the first oral dose of fingolimod. Therefore, patients initiating fingolimod treatment are monitored for this initial period to identify any changes in their electrocardiogram and heart rate that may require further treatment. Here, we report a case of a 17-year-old female with RRMS who received her first fingolimod dose and showed asymptomatic bradycardia that resolved without treatment.

Ocrelizumab depletes T-lymphocytes more than rituximab in multiple sclerosis.

BACKGROUND: We aim to directly compare changes in lymphocyte subpopulations between chimeric (rituximab) and humanised (ocrelizumab) anti-CD20 antibodies in multiple sclerosis (MS). METHODS: In this retrospective analysis of prospectively collected data, we included 88 patients with MS, treated with rituximab (n=50) or ocrelizumab (n=38). We used flow cytometry in the peripheral blood to count total lymphocytes and lymphocytes expressing different phenotypic markers (CD4, CD8, CD19, CD20, CD4/CD8 ratio), before treatment and after 1, 3 and 6 months. RESULTS: On linear mixed effect regression models, after 1, 3 and 6 months, patients treated with rituximab and with ocrelizumab were similar in total lymphocyte count, CD19 lymphocytes, CD20 lymphocytes and CD4/CD8 ratio. However, patients treated with ocrelizumab presented with lower CD4 T lymphocytes and CD8 T lymphocytes after 1, 3 and 6 months (all p<0.05). No between-treatment difference in EDSS progression was found. DISCUSSION: B-cell levels in the peripheral blood were equally decreased by rituximab and ocrelizumab. On the contrary, CD4 and CD8 T lymphocyte reduction was more pronounced in ocrelizumab, when compared with rituximab, suggesting a broader immunomodulatory effect for the humanised antibody to be confirmed and correlated with clinical efficacy in the long term.

COVID-19 pandemic and mental distress in multiple sclerosis: Implications for clinical management.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), disease-related factors and dysfunctional coping might favor the development of mental distress induced by COVID-19 containment measures. Aim of this study was exploring the relationship between disability, coping strategies, daily life reorganization and neuropsychiatric symptoms in an Italian MS population during the COVID-19 lockdown, in order to identify potentially modifiable factors that could inform clinical management of mental distress in people with MS. METHODS: We explored the relationship between mental distress, disability and coping strategies in the Italian MS population under lockdown. Structural equation modeling was applied to information collected via web survey to identify modifiable factors that could account for mental distress. RESULTS: A total of 845 participants (497 with MS and 348 controls) were included in the study. The MS group had higher scores than the control group for depression (p = 0.005), but not for anxiety, emotional dyscontrol or sleep disturbances. The structural equation modeling explained 74% of the variance observed in depression score. Within the model, three latent factors were characterized from measured variables: motor disability and cognitive dysfunction contributed to disability (ß = 0.509 and ß = 0.836; p < 0.001); positive attitude and exercise contributed to active attitude (ß = 0.386 and ß = 0.297; p < 0.001); and avoidance, social support and watching television contributed to passive attitude (ß = 0.301, ß = 0.243 and ß = 0.212; p < 0.001). With regard to the relationship between latent factors and their influence on depression, disability contributed to passive attitude (ß = 0.855; p < 0.001), while both passive and active attitude significantly influenced depression (ß = 0.729 and ß = -0.456; p < 0.001). CONCLUSION: As a practical implication of our model, favoring exercise would enhance active attitude and its positive impact on mental well-being while, at the same time, reducing the negative impact of disability on depression, representing a valuable tool in facing COVID-19-related mental distress.

The Framingham cardiovascular risk score and 5-year progression of multiple sclerosis.

BACKGROUND AND PURPOSE: Cardiovascular risk factors and comorbidities can affect the prognosis of multiple sclerosis (MS). The Framingham risk score is an algorithm that can estimate the 10-year risk of developing macrovascular disease. Our objectives were to evaluate the possible association between the Framingham risk score at baseline and MS relapses, disability, and disease-modifying therapy (DMT) choices over a 5-year follow-up. METHODS: This is a retrospective cohort study including 251 MS subjects. At baseline, we calculated the Framingham risk score considering the following variables: age, sex, diabetes, smoking, systolic blood pressure, and body mass index. MS outcomes including relapses, disability, and treatments were collected over 5 years. Cox proportional regression models were employed to estimate hazard ratios (HRs). RESULTS: A one-point increase in the Framingham risk score was associated with 31% higher risk of relapse (HR = 1.31; 95% confidence interval [CI] = 1.03, 1.68), 19% higher risk of reaching of EDSS 6.0 (HR = 1.19; 95% CI = 1.05, 3.01), and 62% higher risk of DMT escalation (HR = 1.62; 95% CI = 1.22, 3.01). CONCLUSIONS: Higher cardiovascular risk was associated with higher risk of relapses, disability, and DMT escalation in MS. Early identification, correction, and treatment of cardiovascular comorbidities should be carefully considered within MS management.

A Multiple N-Glucosylated Peptide Epitope Efficiently Detecting Antibodies in Multiple Sclerosis.

Diagnostics of Multiple Sclerosis (MS) are essentially based on the gold standard magnetic resonance imaging. Few alternative simple assays are available to follow up disease activity. Considering that the disease can remain elusive for years, identification of antibodies fluctuating in biological fluids as relevant biomarkers of immune response is a challenge. In previous studies, we reported that anti-N-glucosylated (N-Glc) peptide antibodies that can be easily detected in Solid-Phase Enzyme-Linked ImmunoSorbent Assays (SP-ELISA) on MS patients' sera preferentially recognize hyperglucosylated adhesin of non-typeable Haemophilus Influenzae. Since multivalency can be useful for diagnostic purposes to allow an efficient coating in ELISA, we report herein the development of a collection of Multiple N-glucosylated Peptide Epitopes (N-Glc MEPs) to detect anti-N-Glc antibodies in MS. To this aim, a series of N-Glc peptide antigens to be represented in the N-GlcMEPs were tested in competitive ELISA. We confirmed that the epitope recognized by antibodies shall contain at least 5-mer sequences including the fundamental N-Glc moiety. Using a 4-branched dendrimeric lysine scaffold, we selected the N-Glc MEP 24, carrying the minimal epitope Asn(Glc) anchored to a polyethylene glycol-based spacer (PEG) containing a 19-atoms chain, as an efficient multivalent probe to reveal specific and high affinity anti-N-Glc antibodies in MS.

Single-Center 8-Years Clinical Follow-Up of Cladribine-Treated Patients From Phase 2 and 3 Trials.

Background: Cladribine is approved for the treatment of highly-active relapsing multiple sclerosis (MS), where it is also effective on disability progression. In the present single-center study, we aim to report on the 8-years clinical follow-up of 27 patients included in phase 2 and 3 clinical trials for cladribine. Methods: We included patients exposed to cladribine (n = 13) or placebo (n = 14) in ONWARD, CLARITY, and ORACLE-MS trials, and followed-up at the same center after trial termination. Outcomes of long-term disease progression were recorded. Results: During 8-year follow-up, patients treated with cladribine presented with reduced risk of EDSS progression (HR = 0.148; 95%CI = 0.031, 0.709; p = 0.017), of reaching EDSS 6.0 (HR = 0.115; 95%CI = 0.015, 0.872; p = 0.036), and of SP conversion (HR = 0.010; 95%CI = 0.001, 0.329; p = 0.010), when compared with placebo. Conclusions: Our exploratory study provides additional evidence that cladribine may be useful to prevent or, at least, mitigate the risk of disability progression after 8 years.

Peripapillary Vessel Density as Early Biomarker in Multiple Sclerosis.

Background: To evaluate retinal vessel density (VD) in macular and in peripapillary regions in patients with recent onset of multiple sclerosis, at initial demyelinating event (IDE) and in matched relapsing-remitting multiple sclerosis (RRMS) patients. Methods: We evaluated VD in superficial capillary plexus, deep capillary plexus, choriocapillaris and radial peripapillary capillary plexus in IDE, RRMS patients and in matched healthy controls (HCs) through Optical Coherence Tomography Angiography (OCT-A). Clinical history, including history of optic neuritis, Expanded Disability Status scale and disease duration of patients were collected. Results: Thirty patients (20 with IDE and 10 with RRMS) and 15 HCs were enrolled. IDE patients showed a lower VD in radial peripapillary capillary plexus compared with controls (coeff. ß = -3.578; p = 0.002). RRMS patients displayed a lower VD in both superficial capillary plexus and radial peripapillary capillary plexus compared with HCs (coeff. ß = -4.955; p = 0.002, and coeff. ß = -7.446; p < 0.001, respectively). Furthermore, RRMS patients showed a decreased VD in radial peripapillary capillary plexus compared with IDE patients (coeff. ß = -3.868; p = 0.003). Conclusions: Peripapillary region vessel density reduction, revealed through OCT-A, might be considered as an early event in MS, and might be relevant as a biomarker of disease pathology.

Multiple Sclerosis in the Campania Region (South Italy): Algorithm Validation and 2015-2017 Prevalence.

We aim to validate a case-finding algorithm to detect individuals with multiple sclerosis (MS) using routinely collected healthcare data, and to assess the prevalence of MS in the Campania Region (South Italy). To identify individuals with MS living in the Campania Region, we employed an algorithm using different routinely collected healthcare administrative databases (hospital discharges, drug prescriptions, outpatient consultations with payment exemptions), from 1 January 2015 to 31 December 2017. The algorithm was validated towards the clinical registry from the largest regional MS centre (n = 1460). We used the direct method to standardise the prevalence rate and the capture-recapture method to estimate the proportion of undetected cases. The case-finding algorithm including individuals with at least one MS record during the study period captured 5362 MS patients (females = 64.4%; age = 44.6 ± 12.9 years), with 99.0% sensitivity (95% CI = 98.3%, 99.4%). Standardised prevalence rate per 100,000 people was 89.8 (95% CI = 87.4, 92.2) (111.8 for females [95% CI = 108.1, 115.6] and 66.2 for males [95% CI = 63.2, 69.2]). The number of expected MS cases was 2.7% higher than cases we detected. We developed a case-finding algorithm for MS using routinely collected healthcare data from the Campania Region, which was validated towards a clinical dataset, with high sensitivity and low proportion of undetected cases. Our prevalence estimates are in line with those reported by international studies conducted using similar methods. In the future, this cohort could be used for studies with high granularity of clinical, environmental, healthcare resource utilisation, and pharmacoeconomic variables.

Predictors of Nabiximols (Sativex®) discontinuation over long-term follow-up: a real-life study.

Nabiximols is an effective treatment for spasticity in MS. However, treatment discontinuation over-time might occur and predictors of sustained treatment persistence over long-term follow-up in real-world settings are highly needed. We aim at evaluating baseline predictors of treatment persistence on Nabiximols. This is a retrospective real-world study including MS patients treated with Nabiximols. At baseline (Nabiximols prescription), we evaluated disability using the EDSS, and cognitive function using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Nabiximols discontinuation was evaluated after 4 weeks of treatment ("titration phase''), and over the follow-up ("treatment phase"). We included 396 MS patients (228 females and 168 males). After 4 weeks (titration phase), 266 MS patients (67.2%) were considered persistent on treatment, while 130 patients dropped out. After 19 ± 21 months (treatment phase), 136 out of 266 MS patients (51.1%) were still on treatment, whereas 130 patients dropped at follow-up. Higher EDSS and cognitive impairment predicted treatment discontinuation at follow-up (p = 0.04 and p = 0.005, respectively). In conclusion, higher physical and cognitive disability predicted Nabiximols treatment discontinuation over 2 years in MS patients suffering from spasticity. Nabiximols should be started earlier to decrease the likelihood of treatment discontinuation over time.

Extending the Interval of Natalizumab Dosing: Is Efficacy Preserved?

Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML). The objective is to evaluate the noninferiority of the efficacy of an extended interval dosing (EID) compared with the standard interval dosing (SID) of natalizumab. It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Three hundred and sixty patients were enrolled. Median dose interval (MDI) following 24th infusion was 4.7 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Two hundred and sixteen patients were in the SID group (MDI = 4.3 weeks) and 144 in the EID group (MDI 6.2 weeks). Annualized relapse rate was 0.060 (95% CI = 0.033-0.087) in the SID group and 0.039 (95% CI = 0.017-0.063) in the EID group. The non-inferiority of EID versus SID was satisfied. In conclusion, there is no evidence of a reduced efficacy of natalizumab in an EID setting. This observation confirms previous results and together with the emerging evidence of a reduced risk of PML associated to an EID, supports the need of a randomized study to assess the need to change the standard of the natalizumab dosing schedule.

The impact of diagnostic criteria and treatments on the 20-year costs for treating relapsing-remitting multiple sclerosis.

OBJECTIVE: To assess whether the introduction of the new diagnostic criteria and disease modifying therapies (DMTs) is associated with higher cost for treating multiple sclerosis (MS). METHODS: This is a regression-based quasi-experimental study employing interrupted time series analysis, including data from 2229 patients (age 42.1 ±â€¯11.2 years; female 63.34%), with incident diagnosis of relapsing remitting MS (RRMS) and followed up from 1997 to 2017, extracted from the database of the MS Clinical Care and Research Centre of the Federico II University Hospital of Naples (Italy). Annual healthcare costs for DMT (e.g., prescription, staff involved in DMT administration) and management (e.g., neurological consultations, other consultations related to DMT safety, MRI, laboratory exams), were calculated and inflated to the most recent value. RESULTS: Annual costs per patient for DMT prescription and management were not affected by the introduction of 2001 and 2005 criteria, but decreased by 0.4% after the introduction of 2011 criteria (PD= -0.4%; 95% C.I. -0.7%/-0.0%; p = 0.023). Annual costs per patient increased by 11.2% after the introduction of Natalizumab in 2007 (PD= 11.2%; 95% C.I.= 9.4%/13.0%; p <0.001), by 10.9% after the introduction of tablets in 2011 (Fingolimod, Teriflunomide and Dimethyl Fumarate) (PD= 10.9%; 95% C.I. 9.2%/12.7%; p<0.001), and by 10.7% after the introduction of Alemtuzumab in 2015 (PD= 10.7%; 95% C.I. 9.0%/12.4%; p< 0.001). DISCUSSION: DMTs remain the main responsible for increased medical direct costs in MS, whilst improved diagnostic skills and subsequent patient profiling can at least in part mitigate costs for MS treatment and management.

Therapeutic lag in reducing disability progression in relapsing-remitting multiple sclerosis: 8-year follow-up of two randomized add-on trials with atorvastatin.

BACKGROUND: Current treatments for relapsing remitting multiple sclerosis (RRMS) reduce inflammation, but have a partial or modest effect on disability. This effect may require a much longer follow-up than standard trial design, in particular in RRMS with relatively-preserved functional reserve. We aimed to assess the long-term clinical evolution of RRMS patients exposed to atorvastatin in two trials (ACTIVE and ARIANNA). METHODS: We retrospectively looked at 69 participants randomized with atorvastatin or placebo as add-on therapy to interferon-beta for 24 months at a single MS centre. We recorded relapses, 1-point EDSS progression and progression to EDSS 4.0. Cox regression was performed for these three questions. A Poisson regression model was used to evaluate the association between atorvastatin treatment and annualized relapse rate (ARR). RESULTS: After 8.4 ±â€¯2.3 (3.7-11.9) years from trial, the use of atorvastatin was associated with reduced risk of 1-point EDSS progression (HR = 0.440; 95%CI = 0.225-0.861; p = 0.017), and of EDSS 4.0 (HR = 0.310; 95%CI = 0.123-0.784; p = 0.013). We found no significant association between atorvastatin and relapses. DISCUSSION: These data suggest that a delayed treatment effect may be seen with atorvastatin added to interferon-beta, eight years after entering the clinical trials. Long-term follow-up of trial cohorts should be mandated.