Treatment Of Relapsing-remitting Multiple Sclerosis Research Articles

Cost-utility analysis of alemtuzumab in comparison with interferon beta, fingolimod, and natalizumab treatment for relapsing-remitting multiple sclerosis in Austria

Background: Multiple sclerosis (MS), a chronic progressive, demyelinating, inflammatory disease, affects 2.5 million people worldwide. Approximately 63% of cases are classified as relapsing–remitting MS (RRMS) at the time of diagnosis. The aim of this cost-utility analysis is to evaluate alemtuzumab vs interferon beta (intramuscular [IM] interferon beta-1a, subcutaneous [SC] interferon beta-1a, SC interferon beta-1b, and SC pegylated interferon beta-1a) in previously treated, and vs SC interferon beta-1a, fingolimod, and natalizumab in untreated RRMS patients to determine the incremental cost-effectiveness ratio among the treatment alternatives as prices, the route, and the frequency of administration of considered products vary significantly.Methods: The primary outcome was the modeled incremental cost-effectiveness ratio (ICER; €/quality-adjusted life-year [QALY] gained). Markov modeling with a 10-year time horizon was carried out. During each 3-month cycle, patients maintained the Expanded Disability Status Scale (EDSS) score or experienced progression, developed secondary progressive MS (SPMS), or showed EDSS progression in SPMS; experienced relapses; suffered from an adverse event (AE); changed treatment; or died. A published network meta-analysis (NMA) was used for indirect comparison. The possibility of a therapy switch was considered. Clinical input data and resource utilization data were derived from the literature. Costs were extracted from price lists published in Austria and were calculated from the payer’s perspective.Results: In treatment naïve patients, alemtuzumab is associated with costs of €132,663 and 5.25 QALYs in a 10-year time horizon. Costs for SC interferon beta amount to €164,159 and generate 4.85 QALYs. Also, in the pre-treated patients, alemtuzumab dominated comparators by accumulating higher total QALYs (4.88) and lower total costs (€137.409) compared to interferon beta-1a (€200.133), fingolimod (€240.903), and natalizumab (€247.758).Conclusion: The analysis shows that alemtuzumab is a cost-saving alternative to treat RRMS in pre-treated and therapy naïve patients. From the patient perspective, alemtuzumab improves quality-of-life.

Benefit evaluation in multiple sclerosis relapse treatment from the patients’ perspective – Development and validation of a new questionnaire

BackgroundLittle is known on how to measure patient-relevant benefit of relapse treatment in relapsing-remitting multiple sclerosis (MS). The objective of this study was to develop and validate a new method for monitoring recovery from MS relapses and patient-relevant treatment benefits. MethodsA 27-item questionnaire was developed using a multi-step approach comprising open item collection, multidisciplinary expert panel and cognitive debriefing. It was evaluated regarding psychometric properties and feasibility in a longitudinal validation study with 100 patients with MS undergoing relapse treatment. Construct validity was tested by correlations with patient and physician global impressions of change as well as disease-specific and generic health-related quality of life (HRQoL) measures. ResultsResults of the feasibility survey indicated high patient acceptance. Reliability was high (Cronbach's α = 0.90). While the Expanded Disability Status Scale (EDSS) was not sensitive to change, Patient Benefit Index for Multiple Sclerosis (PBI-MS) showed a high correlation cross-sectionally with patient global impression of change (PaGIC) (r = 0.60, p < 0.001). Significant moderate to high correlations were found with change in generic HRQoL (r = 0.55–0.61, p < 0.001) and lower correlations with change in disease-specific HRQoL (r = −0.36, p < 0.01). ConclusionThe PBI-MS is a reliable and valid instrument for ascertaining patient-relevant benefits of acute relapse treatment; it appears suited for use in routine care and in clinical or health care studies.

Safety and efficacy of autologous hematopoietic stem-cell transplantation following natalizumab discontinuation in aggressive multiple sclerosis.

Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting multiple sclerosis (MS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease-modifying treatments (DMTs) are administered. In this study, for the first time, the safety and efficacy of autologous hematopoietic stem-cell transplantation (aHSCT) performed following NTZ discontinuation were retrospectively compared with conventional DMTs. Patients with relapsing-remitting MS treated with NTZ who discontinued the drug after at least six administrations and with at least 6months of follow-up were included. Patients underwent aHSCT after a minimum of 6months following NTZ withdrawal, receiving meanwhile cyclophosphamide or corticosteroids, or other DMTs approved for MS (control group) after an adequate wash-out period. Both hematological and neurological follow-up were assessed according to standard policies. A total of 52 patients were included, 11 who received aHSCT and 41 who received DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life-threatening complications, including progressive multifocal leukoencephalopathy, were observed. At 3years following NTZ discontinuation, no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared with 11.5% of those in the DMT group (P=0.0212). Disease reactivation in the patients with aHSCT was observed only during wash-out/bridging therapy and 100% of the cases were free from disease activity after aHSCT. These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash-out period. aHSCT after 6months from NTZ withdrawal appears to be safe.

Cost-Effectiveness Analysis of Peginterferon Beta-1a in the Treatment of Relapsing-Remitting Multiple Sclerosis in Italy: Results of an Updated Analysis

Cost-Effectiveness Analysis of Peginterferon Beta-1a in the Treatment of Relapsing-Remitting Multiple Sclerosis in Italy: Results of an Updated Analysis

Cost-effectiveness of alemtuzumab and natalizumab for relapsing-remitting multiple sclerosis treatment in Iran: decision analysis based on an indirect comparison

Background: Alemtuzumab and natalizumab are approved as second-line therapies for relapsing-remitting multiple sclerosis (RRMS) patients in Iran who have shown an inadequate response to other disease-modifying therapy (DMT). In the absence of head-to-head trials, evaluations based on decision analytic modeling may be a suitable alternative to compare alemtuzumab and natalizumab in RRMS.Purpose: To evaluate the cost-effectiveness of alemtuzumab compared with natalizumab in RRMS in Iran, based on an indirect comparison of clinical trial data.Methods: A cost-utility analysis was conducted using a cohort-based Markov model to analyze cost-utility in a cohort of 1,000 RRMS patients treated with alemtuzumab or natalizumab who had failed at least one previous DMT. Costs were measured in 2018 US Dollars, and were estimated from both the societal and National Healthcare Service (NHS) perspective over a 20-year time horizon in Iran. One-way deterministic sensitivity analyses were carried out to investigate the impact of individual variables on model results.Results: Alemtuzumab dominated natalizumab in both NHS and societal perspective analyses. From the NHS perspective, the total discounted costs per patient were estimated at $147,417 and $150,579 for alemtuzumab and natalizumab, respectively, over 20 years. The discounted quality-adjusted life years were estimated to be 7.07 and 6.05, respectively. Results were similar for the societal perspective analysis. Results were most sensitive to acquisition costs and the time horizon, while no sensitivity was observed for Expanded Disability Status Scale (EDSS) health-states utility, relapse relative risk, adverse event or EDSS-related costs, and laboratory/monitoring costs.Conclusion: Alemtuzumab was dominant in the treatment of RRMS compared with natalizumab due to lower total cost, greater efficacy and slowing of disease progression, and lower rate of relapses over a 20-year time horizon in Iran. Comparative head-to-head trials and long-term follow-up are needed to confirm these results.

Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation

Natalizumab (NTZ) was the first approved monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite proven and sustained efficacy, its use is limited by the risk of progressive multifocal leukoencephalopathy (PML). Moreover, some patients show ongoing disease activity under NTZ, requiring a switch to another disease-modifying treatment (DMT). However, evidence regarding the optimal DMT for treatment of active RRMS after NTZ-cessation is still scarce. To evaluate efficacy and safety outcomes of ALEM vs FTY treatment after cessation of NTZ. We retrospectively identified patients at 12 German neurology centers and analyzed risks for disease activity, adverse events, disability progression, and treatment discontinuation. 195 patients were identified and 144 underwent final analysis (FTY: 101; ALEM: 42). The hazard ratio for clinical relapses was 2.24 favoring ALEM (95% CI 1.12-4.50; p = 0.015). The hazard ratio for adverse events was 7.78 (95% CI 1.04-57.95; p = 0.006) and 2.41 for MRI progression (95% CI 1.26-4.60; p = 0.004). The odds ratio for disability progression after 12months was 4.84 (95% CI 1.74-13.47, p = 0.003). Differences remained after adjusting for possible confounders (e.g., age, sex, baseline disability, NTZ treatment duration, washout time). Our findings indicated particular advantages of ALEM compared to FTY in patients stopping NTZ.

Are there any clinical and electrocardiographic predictors of heart rate reduction in relapsing- remitting multiple sclerosis patients treated with fingolimod?

BackgroundFingolimod, a sphingosine-1-phosphate receptor agonist, is used for treatment of relapsing-remitting multiple sclerosis (RRMS). S1P receptors that fingolimod acts upon have also been shown to be expressed on atrial myocytes. This expression pattern has been linked with the drug's cardiovascular effects, such as bradycardia. We aimed to evaluate the clinical and electrocardiographic predictors of heart rate (HR) reduction in patients receiving first-dose fingolimod. MethodsWe retrospectively analyzed subjects diagnosed with RRMS who were allocated to fingolimod treatment. HR, systolic and diastolic blood pressure values and electrocardiography during the first dose of fingolimod were accessed. ResultsA total of 114 RRMS patients (65.8% female, 33.58 ± 8.63 years) were included. After the initial dose of fingolimod, the heart rate decreased significantly at each hour (each p < 0.001). Nadir heart rate was reached at 4 h. The multivariate binary logistic regression analysis revealed that BMI (OR: 0.878, p = 0.045), optic nerve involvement (OR: 3.205, p = 0.018), baseline HR (OR: 1.079, p = 0.002) and T-peak-T-end interval (OR: 1.046, p = 0.030) were independent predictors of greater HR reduction. During 6-h monitorization, none of the patients had relevant adverse reactions. ConclusionOur findings provide an insight on clinical and electrocardiographic predictors of HR reduction that occurs in RRMS patients receiving first dose of fingolimod.

Glatiramer acetate persists at the injection site and draining lymph nodes via electrostatically-induced aggregation

Glatiramer acetate (GA) is widely prescribed for the treatment of relapsing-remitting multiple sclerosis, however, the mechanism of action is still not fully understood. We investigated the structural properties of GA and examined alterations to the drug upon injection into the subcutaneous space. First, a variety of biophysical characterization techniques were employed to characterize GA in solution. GA was found to exist as alpha helices in solution with a hydrodynamic radius of ~3 nm in size. To simulate GA behavior at the site of injection, GA was injected into a solution of 1.5 MDa hyaluronic acid (HA). Visible aggregates were observed immediately upon injection and subsequent testing indicated aggregation was driven by electrostatic interactions between the positively-charged GA and negatively-charged HA. In vivo testing confirmed GA formed spherical particles in the nano- to micrometer size range, suggesting this mechanism contributes to persistence at the injection site and in draining lymph nodes. The aggregates were found to associate with glycosaminoglycans, suggesting an electrostatic mechanism of induced aggregation like the simulated injection. These novel observations may help explain the complex immunomodulatory mechanisms of GA and adverse injection site reactions seen in patients.

Multi-centre validation of a flow cytometry method to identify optimal responders to interferon-beta in multiple sclerosis

Background and objectivesPercentages of blood CD19+CD5+ B cells and CD8+perforin+ T lymphocytes can predict response to Interferon (IFN)-beta treatment in relapsing-remitting multiple sclerosis (RRMS) patients. We aimed to standardize their detection in a multicenter study, prior to their implementation in clinical practice. MethodsFourteen hospitals participated in the study. A reference centre was established for comparison studies. Peripheral blood cells of 105 untreated RRMS patients were studied. Every sample was analyzed in duplicate in the participating centre and in the reference one by flow cytometry. When needed, participating centres corrected fluorescence compensations and negative cut-off position following reference centre suggestions. Concordance between results obtained by participating centres and by reference one was evaluated by intraclass correlation coefficients (ICC) and Spearman correlation test. Centre performance was measured by using z-scores values. ResultsAfter results review and corrective actions implementation, overall ICC was 0.86 (CI: 0.81–0.91) for CD19+CD5+ B cell and 0.89 (CI: 0.85–0.93) for CD8+ perforin+ T cell quantification; Spearman r was 0.92 (0.89–0.95; p <0.0001) and 0.92 (0.88–0.95; p <0.0001) respectively. All centres obtained z-scores≤0.5 for both biomarkers. ConclusionHomogenous percentages of CD19+CD5+ B cells and CD8 perforin+ T lymphocytes can be obtained if suitable compensation values and negative cut-off are pre-established.

The unintended consequences of NICE

The UK Department of Health’s (DoH) risk-sharing scheme (RSS) was set up as a political solution to protect NICE (National Institute for Health and Care Excellence) from a legal challenge....

Natalizumab Treatment for Relapsing-Remitting Multiple Sclerosis: The Experience From Saudi Arabia.

Natalizumab is the first targeted humanized monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Natalizumab appears to be more effective than current first-line disease-modifying therapies. In our study, we aimed to evaluate the outcome of Saudi patients with active RRMS treated with natalizumab and compare the results with other outcomes in the Gulf and international trials. We conducted a retrospective single-center observational study involving 32 patients with RRMS at King Abdulaziz Medical City in Jeddah, Saudi Arabia. The inclusion criteria included all patients diagnosed with RRMS according to the revised McDonald criteria who are currently receiving or received natalizumab treatment in the past for a minimum of 6 months. The mean baseline Expanded Disability Status Scale score was 4.50 ± 1.80 (range, 1.5-6; median, 5), whereas the mean Expanded Disability Status Scale at the follow-up was 4.02 ± 2.08 (range, 1-6; median, 4.25) (P = 0.3274). The mean annualized relapse rate was significantly reduced from 2.41 ± 2.48 at baseline to 0.16 ± 0.37 at the last follow-up (P < 0.0001). Twenty-seven patients (84.4%) had no relapses since the treatment with natalizumab was started, whereas 5 patients (15.6%) had only 1 relapse. In addition to clinically measurable improvement, radiological improvement was observed through magnetic resonance imaging. Magnetic resonance imaging activity was significantly improved at follow-up magnetic resonance imaging studies when compared with baseline. Our single-center study in Saudi Arabia provides further support for the efficacy of natalizumab in the clinical practice setting. The sharp decrease in relapse rate and progression of disability following the initiation of natalizumab treatment was similar to other observational studies conducted in different countries across the globe. Natalizumab was a satisfactory therapy for the management of our MS population, both from the patients' and the physicians' perspectives.

Cladribine Tablets for the First-Line Treatment of Relapsing-Remitting Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal process, the National Institute for Health and Care Excellence invited Merck to submit evidence for the clinical and cost effectiveness of cladribine tablets (cladribine) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Rapidly evolving severe (RES) and sub-optimally treated (SOT) RRMS were specified by the National Institute for Health and Care Excellence as subgroups of interest. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group. This article summarises the Evidence Review Group’s review of the company’s evidence submission for cladribine and the Appraisal Committee’s final decision. The final scope issued by the National Institute for Health and Care Excellence listed the following disease-modifying treatments as comparators: alemtuzumab, daclizumab, fingolimod and natalizumab. At the time of the company submission, a licence was anticipated for low-dose cladribine. The main clinical evidence (the CLARITY trial) in the company submission focused on the efficacy of low-dose cladribine vs. placebo. The CLARITY trial showed a statistically significant reduction in relapse rate for cladribine in the RES-RRMS subgroup (n = 50) but not in the SOT-RRMS subgroup (n = 19). Cladribine showed a numerical, but not a statistically significant, advantage in delaying disability progression at 6 months in the RES-RRMS subgroup. Disability progression benefits could not be estimated for those in the SOT-RRMS subgroup because of few events. The Evidence Review Group’s main concern regarding the clinical evidence was the small sample size of the subgroups. To compare the effectiveness of cladribine to other disease-modifying treatments, the company conducted network meta-analyses, which showed cladribine and its comparators to be equally effective. The Evidence Review Group considered the results of the disease-modifying treatments to be unreliable because few trials were in the network. The company’s cost-effectiveness evidence showed cladribine to be cheaper and more effective than other disease-modifying treatments in the RES-RRMS arm and the SOT-RRMS arm. The results were most sensitive to treatment effect on disability progression at 6 months. The Evidence Review Group was concerned that there was insufficient evidence to conclude that cladribine was superior to placebo in delaying disability progression. The Evidence Review Group amended the company’s economic model to allow alternative estimates for the treatment effect of cladribine and its comparators on relapse rate and disability progression at 6 months. The Evidence Review Group made other changes to the company model. After implementing all the amendments, cladribine remained cost effective in the RES-RRMS and SOT-RRMS subgroups. The Appraisal Committee recognised the uncertainty in the available data but concluded that cladribine could be considered a cost-effective use of National Health Service resources.

PND33 - PAYER AND SOCIETAL BENEFIT OF PEGINTERFERON BETA-1A VERSUS GLATIRAMER ACETATE IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS IN ITALY

To evaluate the clinical and economic benefits of treatment with peginterferon beta-1a (PEG-IFN) vs. glatiramer acetate (GA) for relapsing-remitting multiple sclerosis (RRMS) patients in Italy. A Markov model with a 10-year time horizon and 3-month cycles was used to compare the outcomes of treating patients with PEG-IFN vs. GA from a societal perspective in Italy. The model estimates clinical and economic consequences of initiating treatment with PEG-IFN among patients who would receive GA based on current GA market share (including GA 20 mg/mL and GA 40 mg/mL). Costs, resource utilization, and baseline Expanded Disability Status Scale (EDSS) distribution are specific to Italy. Costs of relapse and disability status are from a cross-sectional cost of illness study. Hazard and risk ratios for clinical outcomes of PEG-IFN vs. GA 20 mg/mL were estimated from an indirect treatment comparison. The number of RRMS patients treated with GA was 7,014. Within the model, across 10 years, the use of PEG-IFN in place of GA would reduce the number of relapses by 11,208 and relapse costs by €26.5 million. PEG-IFN was shown to slow disability worsening, with 18.1% fewer patients progressing to EDSS ≥ 6.0 and 11.7% more patients remaining in EDSS levels ≤ 3. Costs associated with disability would be reduced by about €120.3 million. Averted inpatient care represents €28.1 million of EDSS state cost savings which reflects 1,126 fewer inpatient admissions. Total direct cost savings for the cohort would exceed €63.7 million (€9,083/patient). Total indirect cost savings would be about €276.9 million (€39,470/patient). The results of this model suggest that use of PEG-IFN compared with GA in the treatment of RRMS in Italy is a potential cost-saving strategy that could moderate healthcare resource use and improve patient outcomes. Additional research using real-world comparative effectiveness studies should be conducted.

A randomized double-blind trial of comparative efficacy and safety of Avonex and CinnoVex for treatment of relapsing-remitting multiple sclerosis.

Interferon beta is currently the first line treatment of relapsing-remitting multiple sclerosis (RRMS). Different formulations of interferon beta are available. Avonex and CinnoVex are two interferon beta-1a being prescribed by neurologists in Iran. The aim of this study was to compare the four and half year outcome of Avonex and CinnoVex in patients with RRMS. A total 186 of patients with definite RRMS diagnosis were followed for four and half years. Patients were randomly assigned to receive either Avonex or CinnoVex. Patients were subsequently visited every 6months, and MRI was also undertaken prior each visit. The efficacy end points were to compare mean scores of expanded disability status scale (EDSS) and the proportion of patients with MRI and clinical activity in follow-up visits between Avonex and CinnoVex. Safety end point was to compare the percentage of adverse events between two groups. One hundred and eighty-two patients completed the study. The population of study experienced a steady increase in EDSS during follow-up with a mean increase of 1.03. Repeated measures ANOVA revealed no statistically significant difference between Avonex and CinnoVex (p = 0.78). The most common adverse events were headache, myalgia, fatigue, fever, flu symptoms, injection site pain, and depression. Direct comparison of each adverse events revealed no meaningful difference between two groups except for only a few adverse events. There was no statistically significant difference in MRI activity and clinical activity between two groups. Avonex and CinnoVex showed similar efficacy and safety outcome in patients with RRMS.

Efficacy and safety of monoclonal antibody therapies for relapsing remitting multiple sclerosis: A network meta-analysis

BackgroundSeveral monoclonal antibodies have been licensed for relapsing remitting multiple sclerosis (RRMS). It is still unclear which treatment regimen should be recommended due to the lack of head-to-head randomized controlled trials (RCTs). This study aims to investigate the relative efficacy and safety of existing monoclonal antibody therapies in treating RRMS. MethodsWe searched PubMed, Embase, and the Cochrane Library for RCTs of monoclonal antibodies for treatment of RRMS. We performed a network meta-analysis to identify evidence comparing monoclonal antibodies with one another, interferon beta-1a (INFβ-1a), or placebo in adult patients with RRMS. The primary efficacy outcome was annualized relapse rate and the primary safety outcome was incidence rate of serious adverse events. ResultsA total of 14 eligible studies containing 9412 patients treated with 7 regimens were analyzed. INFβ-1a was the most common comparison treatment and showed an annualized relapse rate of 45.3%. All monoclonal antibody regimens, including natalizumab, natalizumab plus INFβ-1a, alemtuzumab, daclizumab, and ocrelizumab, were associated with significant reduction in annualized relapse rate and similar risks of serious adverse events. Cluster analysis showed that natalizumab plus INFβ-1a and alemtuzumab performed best in terms of high efficacy and safety. Natalizumab and daclizumab were characterized by high efficacy but relatively high risk of serious adverse events. Ocrelizumab was differentiated by high safety but relatively poor efficacy. ConclusionThis network meta-analysis provided a comprehensive summary of efficacy and safety of monoclonal antibodies for RRMS, which might provide a reference for treatment. More direct comparison studies are warranted.

Disease-Modifying Therapies for Relapsing-Remitting and Primary Progressive Multiple Sclerosis: A Cost-Utility Analysis.

Several disease-modifying therapies (DMTs) treat relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Few comprehensive cost-effectiveness analyses exist in this area, particularly from a payer perspective, despite rapidly increasing prices of DMTs. We aimed to systematically compare cost effectiveness of all relevant DMTs for first-line treatment of RRMS, second-line treatment of RRMS, and first-line treatment of PPMS. We used a Markov model with health states based on Expanded Disability Status Score categories. Upon discontinuing first-line treatment, RRMS patients continued to second-line therapy then to supportive care, and PPMS patients moved directly to supportive care. Data was sourced from clinical trials and commercially and publicly available sources. The target population was treatment-naïve adults with RRMS or PPMS. We used a lifetime horizon from a US payer perspective, and compared DMTs for RRMS (first-line: dimethyl fumarate, glatiramer acetate, interferon β-1a, interferon β-1b, peginterferon β-1a, teriflunomide, natalizumab, fingolimod, and ocrelizumab; second-line: alemtuzumab, natalizumab, fingolimod, and ocrelizumab), ocrelizumab for PPMS, and supportive care. Outcome measures included total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). For RRMS first-line therapy, ocrelizumab dominated the other DMTs with an ICER of US$166,338/QALY compared with supportive care. For RRMS second-line therapy, alemtuzumab dominated the other three DMTs, providing more QALYs for lower costs. For PPMS, ocrelizumab had an ICER of US$648,799/QALY compared with supportive care. Wide variability in results was observed in the probabilistic sensitivity analysis. Results were sensitive to the relative risk of progression and cost of DMTs. Ocrelizumab would likely be cost effective as a first-line treatment for RRMS with a discounted price but was not cost effective for PPMS. Alemtuzumab dominated other options for second-line treatment of RRMS. Other DMTs were generally similar in terms of costs and health outcomes, providing health benefits compared to supportive care but with significant added costs. If drug prices were lowered, more DMTs could be cost effective.

Preventing and managing dimethyl fumarate-related adverse effects in patients with multiple sclerosis may improve adherence

Flushing and gastrointestinal effects are most common adverse effects associated with the use of oral delayed-release dimethyl fumarate in the treatment of relapsing-remitting multiple sclerosis. While these adverse effects are usually transient and mild to moderate in severity, strategies to prevent and manage symptoms can help avoid treatment cessation. Management strategies should be individualized and patients given ongoing support.

Gynecological adverse effects of natalizumab administration: Case report and review of the literature

BackgroundNatalizumab is administered for the treatment of relapsing-remitting multiple sclerosis (RR-MS) with high disease activity.Natalizumab therapy has been associated with adverse effects, such as progressive multifocal leukoencephalopathy, liver damage, nasopharyngitis, urinary tract infection, urticaria, cephalgia, dizziness, fatigue, nausea, fever, rigidity, anxiety and gastroenteritis. ObjectiveTo describe a case of a woman with RR-MS who developed recurrent vaginitis on natalizumab administration. MethodsCase report and review of the literature. ResultsThe case of a 26-year-old Caucasian woman with RR-MS, who presented with recurrent vaginitis since the initiation of treatment with natalizumab, is reported. The patient had a 4-year history of RR-MS; monotherapy with natalizumab (inj. 300 mg/month) came after one year after the initial diagnosis. Since then, she had a history of persistent gynecological infections; the repeated vaginal cultures revealed a variety of underlying pathogens. The patient underwent numerous treatments with local and systematic antibiotics as well as antifungal agents. After the initiation of probiotics and local hygiene measures, recurrences resolved and the patient remains recurrence-free at one-year follow-up. ConclusionsRecurrent vaginitis should be taken into account as a possible adverse effect causing discomfort during long-term natalizumab treatment. Simple measures, such as probiotic administration and meticulous local hygiene, can provide adequate relief for such patients.

Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial

Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23-60) and the placebo group (43%, 28-59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. Novartis Pharma.

Neutralizing antibody production against Rebif® and ReciGen® in Relapsing-Remitting Multiple Sclerosis (RRMS) patients and its association with patient's disability

IntroductionHuman recombinant interferon beta (IFN-β) is one of the first line treatments for Relapsing-Remitting Multiple Sclerosis (RRMS). However, the production of neutralizing antibodies (NAb) can impair its function. The aim of this study was to investigate the production of neutralizing antibodies against Rebif® and ReciGen® (two brands of IFN-β-1a) and to evaluate its correlation with Expanded Disability Status Scale (EDSS). Materials and methodsSerum samples of 71 RRMS patients (34 in ReciGen®, 37 in Rebif® group) were collected. Neutralizing antibody was measured by Myxo-virus resistance protein A (MxA) assay using A549 cell line. The MxA concentration was measured by enzyme-linked immunosorbent assay (ELISA) kit. ResultsThe median period of treatment with IFN-β-1a was 18 months in ReciGen® and 24 months in Rebif® arms. The percentage of patients with positive titer of neutralizing antibody (NAb+) had no statistically significant difference between groups (P = 0.6). In both ReciGen® and Rebif® groups, the increase in EDSS score was significantly higher in NAb+ patients compared to NAb− patients (p ≤ 0.05). The duration of using ReciGen® or Rebif® for >24 months was influential in the NAb positivity (OR = 3.78). ConclusionReceiving interferon beta-1a for >24 months is correlated with higher possibility of NAb production. The type of IFN-β used in the study had no significant impact on NAb positivity. In addition, both groups had comparable EDSS score changes, and NAb status of patients was correlated with their EDSS score.