Therapy For Relapsing-remitting Multiple Sclerosis Research Articles

Budget impact analysis of biosimilar natalizumab in the US.

Biosimilars provide an opportunity for a more sustainable and cost-effective treatment for multiple sclerosis (MS). This study evaluated the potential financial impact of implementing a formulary change from reference to biosimilar natalizumab (NTZ) from the US commercial payer perspective. The budget impact of transitioning to biosimilar NTZ for the treatment of relapsing-remitting MS (RRMS) was estimated over a 3-year time horizon based on real-world dosing. Additional scenario analyses were conducted by varying the price differential of biosimilar NTZ. The target population was estimated from a 1-million-member hypothetical commercial health plan. Model inputs were drug acquisition costs and treatment-related and patient coinsurance costs. Budget impact and cost savings per member per year were calculated by assuming a biosimilar uptake of 10% in year 1 to 20% in year 3. Over 3 years, 255 patients were estimated to be treated with high-efficacy disease-modifying therapies for RRMS. The inclusion of biosimilar NTZ onto a formulary would result in cumulative cost savings to payers of $452,611 over 3 years, with mean savings per treated member per year of $1179, $1769, and $2359 in years 1, 2, and 3, respectively. One-way sensitivity analyses indicated that budget impact results were most sensitive to drug acquisition costs of both reference and biosimilar NTZ. Adoption of biosimilar NTZ can yield considerable cost savings to US health plans that could result in increased treatment access for patients with RRMS.

Ethnicity and deprivation negatively impact the access to disease-modifying therapy for relapsing-remitting multiple sclerosis: a retrospective, single-centre study

BackgroundA growing body of evidence suggests inequitable access to disease-modifying therapies (DMTs) for multiple sclerosis (MS) in publicly funded healthcare systems. This retrospective study examined the impact of ethnicity and...

Do efficacy results obtained from randomized controlled trials translate to effectiveness data from observational studies for relapsing-remitting multiple sclerosis?

Randomized controlled trials are considered the gold standard in regulatory decision making, as observational studies are known to have important methodological limitations. However, real-world evidence may be helpful in specific situations. This review investigates how the effect estimates obtained from randomized controlled trials compare to those obtained from observational studies, using drug therapy for relapsing-remitting multiple sclerosis as an example. A systematic review of randomized controlled trials and observational studies was conducted. The primary outcome was the annualized relapse rate. Using (network) meta-analysis together with posterior predictive distributions, the drug-specific rate ratios from the network of randomized controlled trials were compared with those from the network of observational studies. Effect estimates from 26 observational studies showed greater magnitudes and were less precise compared to estimates obtained from 21 randomized controlled trials. Twenty of the 28 treatment comparisons between designs had similar rate ratios. Seven inconsistencies in observed rate ratios could be attributed to two specific disease-modifying therapies. In this case study, estimates from observational studies predominantly agreed with estimates from randomized controlled trials given their posterior predictive distributions. Multiple observational studies together may therefore supplement additional pivotal randomized controlled trials in relapsing-remitting multiple sclerosis, for instance facilitating the extrapolation of trial results to the broader patient population.

Novel peripheral blood mononuclear cell mRNA signature for IFN-beta therapy responsiveness prediction in multiple sclerosis

Interferon-beta (IFN- β ) is one of the classical drugs for immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS) patients, but the drug responsiveness of different patients varies. Currently, there is no valid model to predict IFN- β responsiveness. This research attempted to develop an IFN- β responsiveness prediction model based on mRNA expression in RRMS patient peripheral blood mononuclear cells. Peripheral blood mononuclear cell mRNA expression datasets including 50 RRMS patients receiving IFN- β treatment were obtained from GEO. Among the datasets, 24 cases from GSE24427 were included in a training set, and 18 and 9 cases from GSE19285 and GSE33464, respectively, were adopted as two independent test sets. In the training set, blood samples were collected immediately before first, second, month 1, 12, and 24 IFN- β injection, and the mRNA expression data at four time points, namely, two days, one month, one year and two years after the onset of IFN- β treatment, were compared with pre-treatment data to identify IFN-stimulated genes (ISGs). The ISGs at the one-month time point were used to construct the drug responsiveness prediction model. Next, the drug responsiveness model was verified in the two independent test sets to examine the performance of the model in predicting drug responsiveness. Finally, we used CIBERSORTx to estimate the content of cell subtypes in samples and evaluated whether differences in the proportions of cell subtypes were related to differences in IFN- β responsiveness. Among the four time points, one month was the time point when the training set GSE24427 and test set GSE33464 had the highest number of ISGs. Functional analysis showed that these one-month ISGs were enriched in biological functions such as the innate immune response, type-I interferon signalling pathway, and other IFN- β -associated functions. Based on these ISGs, we obtained a four-factor prediction model for IFN- β responsiveness including MX1, MX2, XAF1, and LAMP3. In addition, the model demonstrated favourable predictive performance within the training set and two external test sets. A higher proportion of activated NK cells and lower naive CD4/total CD4 ratio might indicate better drug responsiveness. This research developed a polygene-based biomarker model that could predict RRMS patient IFN- β responsiveness in the early treatment period. This model could probably help doctors screen out patients who would not benefit from IFN- β treatment early and determine whether a current treatment plan should be continued.

Thrombotic Microangiopathy as a Life-Threatening Complication of Long-Term Interferon Beta Therapy for Multiple Sclerosis: Clinical Phenotype and Response to Treatment-A Literature Review.

Thrombotic microangiopathy (TMA) has been observed in some patients receiving interferon beta (IFNβ) therapy for relapsing-remitting multiple sclerosis, but little is known about its clinical features and outcomes. We searched the literature to identify cases with IFNβ-related TMA and assessed their pattern of organ involvement, the presence of prodromal manifestations, the treatments used, and the outcomes. Thirty-five articles met the inclusion criteria, and data of 67 patients were collected. The median duration of IFNβ therapy before the diagnosis of TMA was 8 years, and 56/67 (84%) presented with acute kidney injury (AKI), of which 33 required acute dialysis. All but three patients had manifestations during the four weeks before TMA onset, including flu-like symptoms, headache, and worsening blood pressure control. In only two patients, ADAMTS13 activity was reduced, while 27% had low C3 levels. However, none showed causative genetic mutations associated with development of atypical hemolytic uremic syndrome. All patients discontinued IFNβ, 34 (55%) also received plasma exchange, and 12 (18%) received eculizumab. Complete renal recovery was achieved by 20 patients (30%), while 13 (20%) developed end-stage renal disease. Among those with AKI requiring dialysis, eculizumab therapy was associated with a significantly reduced risk of ESRD compared with plasma exchange. Therefore, TMA with features of aHUS mainly occurs after prolonged treatment with IFNβ and is preceded by prodromes, which may lead to an early diagnosis before life-threatening complications occur. Eculizumab appears beneficial in cases with severe kidney involvement, which supports a role of the complement system in the pathogenesis of these forms.

Risk of T2 lesions when discontinuing fingolimod: a nationwide predictive and comparative study.

Fingolimod is a frequently used disease-modifying therapy in relapsing-remitting multiple sclerosis. However, case reports and small observational studies indicate a highly increased risk of disease reactivation after discontinuation. We aimed to investigate the risk of radiological disease reactivation in patients discontinuing fingolimod. We performed a nationwide cohort study in Denmark, including patients who discontinued fingolimod between January 2014 and January 2023. Eligibility was a diagnosis with relapsing-remitting multiple sclerosis and two MRIs performed respectively within 1 year before and after discontinuing fingolimod. The included patients were compared with those discontinuing dimethyl fumarate with the same eligibility criteria in an unadjusted and matched propensity score analysis. Matching was done on age, sex, Expanded Disability Status Scale, MRI data, cause for treatment discontinuation, treatment duration and relapse rate. The main outcome was the presence of new T2 lesions on the first MRI after treatment discontinuation. To identify high-risk patients among those discontinuing fingolimod, we made a predictive model assessing risk factors for obtaining new T2 lesions. Of 1324 patients discontinuing fingolimod in the study period, 752 were eligible for inclusion [mean age (standard deviation), years, 41 (10); 552 females (73%); median Expanded Disability Status Scale (Q1-Q3), 2.5 (2.0-3.5); mean disease duration (standard deviation), years, 12 (8)]. Of 2044 patients discontinuing dimethyl fumarate in the study period, 957 were eligible for inclusion, presenting similar baseline characteristics. Among patients discontinuing fingolimod, 127 (17%) had 1-2 new T2 lesions, and 124 (17%) had ≥3 new T2 lesions compared with 114 (12%) and 45 (5%), respectively, for those discontinuing dimethyl fumarate, corresponding to odds ratios (95% confidence interval) of 1.8 (1.3-2.3) and 4.4 (3.1-6.3). The predictive model, including 509 of the 752 patients discontinuing fingolimod, showed a highly increased risk of new T2 lesions among those with disease activity during fingolimod treatment and among females under 40 years. This nationwide study suggests that discontinuing fingolimod in some cases carries a risk of developing new T2 lesions, emphasizing the importance of clinical awareness. If feasible, clinicians should prioritize the prompt initiation of new disease-modifying therapies, particularly among young females.

Rates of John Cunningham virus seroconversion greatly reduced in natalizumab-treated patients during COVID-19-related lockdowns.

This study was undertaken to retrospectively compare rates of John Cunningham virus (JCV) seroconversion in natalizumab-treated patients before and during COVID-19-related community restrictions. Natalizumab is highly effective therapy for relapsing-remitting multiple sclerosis. Prolonged exposure to natalizumab in JCV-positive patients can cause progressive multifocal leukoencephalopathy, a potentially fatal brain infection. Serial assessment of JCV status is required for patients receiving natalizumab. Patients receiving natalizumab at the Royal Melbourne Hospital were assessed for change in JCV serostatus and duration of exposure to natalizumab in two discrete time periods: from 1 February 2012 until 1 February 2017 ("pre-COVID"; n = 128) and from 1 April 2020 until 12 October 2022 ("COVID"; n = 214). A Poisson regression model adjusted for age at natalizumab commencement and sex was used to model seroconversion rate between the two time periods. The pre-COVID JCV seroconversion rate among natalizumab-treated patients at the Royal Melbourne Hospital was 9.08%. Conversely, we found a precipitous decline in JCV seroconversion during COVID lockdown. Annualized seroconversion during COVID-19-related restrictions was 2.01%. The annualized seroconversion rate was 4.7 times higher during the pre-COVID-19 period (95% confidence interval = 2.96-7.45, p < 0.0001) compared to the annualized seroconversion rate during COVID lockdown. Males had a 2× higher rate of seroconversion compared to females. JCV seroconversion among natalizumab-treated patients was markedly lower during COVID-19-related community restrictions. Restrictions observed in Melbourne were among the longest and most comprehensive implemented worldwide. This suggests the presence of modifiable risk factors that could lower rates of JCV seroconversion among natalizumab-treated patients.

Comparative analysis of dimethyl fumarate and teriflunomide in relapsing-remitting multiple sclerosis.

In relapsing-remitting multiple sclerosis (RRMS), analyses from observational studies comparing dimethyl fumarate (DMF) and teriflunomide showed conflicting results. We aimed to compare the effectiveness of DMF and teriflunomide in a real-world setting, where both drugs are licensed as first-line therapies for RRMS. We included all patients who initiated DMF or teriflunomide between 2013 and 2022, listed in the Swiss National Treatment Registry. Coarsened exact matching was applied using age, gender, disease duration, baseline Expanded Disability Status Scale (EDSS) score, time since last relapse, and relapse rate in the previous year as matching variables. Time to relapse and time to 12-month confirmed EDSS worsening were compared using Cox proportional hazard models. In total, 2028 patients were included in this study, of whom 1498 were matched (DMF: n = 1090, 69.6% female, mean age 45.1 years, median EDSS score 2.0; teriflunomide: n = 408, 68.9% female, mean age 45.1 years, median EDSS score 2.0). Time to relapse and time to EDSS worsening was longer in the DMF than the teriflunomide group (hazard ratio 0.734, p = 0.026 and hazard ratio 0.576, p = 0.003, respectively). Analysis of real-world data showed that DMF treatment was associated with more favorable outcomes than teriflunomide treatment.

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial

BackgroundSimultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly...

Simple parameters from complete blood count predict lymphopenia, adverse effects and efficacy in people with MS treated with dimethyl fumarate.

Dimethyl fumarate (DMF) is a first-line oral therapy for relapsing-remitting multiple sclerosis (RRMS). This retrospective study aims to determine the utility of routine complete blood counts (CBC) in predicting lymphopenia, adverse effects and efficacy in a real-world clinical setting. The Calgary Multiple Sclerosis (MS) Clinic manages over 1800 people with MS on disease-modifying therapies (DMT). Data of patients with relapsing-remitting MS (pwMS) who initiated DMF between July 1, 2013 and December 31, 2014 were included. Patients were followed for one year. DMT use is carefully monitored and pwMS need a screening CBC and have regular CBCs done at follow-up. Demographic, clinical, MRI and relapse information are collected prospectively in a clinic database. We analyzed CBCs at baseline and month 3. We identified 139 pwMS in the study period who started DMF. Median follow-up time on-drug was 12 (0.16-12) months. In our study, 15.8% of pwMS developed lymphopenia grade 2 or higher. Baseline lymphocyte counts and older age were significant predictors of lymphopenia. Higher baseline eosinophil counts predicted flushing/gastrointestinal adverse effects, and higher baseline monocyte counts were predictive of breakthrough disease activity. Neutrophil and platelet to lymphocyte ratios, markers that have been associated with overall mortality in the general population, were increased at month 3. Routinely obtained CBCs during the screening and monitoring of people with MS starting DMF offer clinically useful information and generate interesting hypotheses. Age and baseline lymphocyte counts are reinforced as clinically useful predictors of lymphopenia. Our novel findings that baseline eosinophil and monocyte counts could offer insights into usual adverse effects and efficacy, respectively, should be further investigated as a potentially new set of biomarkers.

Cost Per Relapse Avoided for Ozanimod Versus Other Selected Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis in the United States.

This study assessed the cost-effectiveness of ozanimod compared with commonly used disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS). Annualized relapse rate (ARR) and safety data were obtained from a network meta-analysis (NMA) of clinical trials of RRMS treatments including ozanimod, fingolimod, dimethyl fumarate, teriflunomide, interferon beta-1a, interferon beta-1b, and glatiramer acetate. ARR-related number needed to treat (NNT) relative to placebo and annual total MS-related healthcare costs was used to estimate the incremental annual cost per relapse avoided with ozanimod vs each DMT. ARR and adverse event (AE) data were combined with drug costs and healthcare costs to manage relapses and AEs in order to estimate annual cost savings with ozanimod vs other DMTs, assuming a 1million USD fixed treatment budget. Treatment with ozanimod was associated with lower incremental annual healthcare costs to avoid a relapse, ranging from $843,684 vs interferon beta-1a (30μg; 95% confidence interval [CI] - $1,431,619, - $255,749) to $72,847 (95%CI - $153,444, $7750) vs fingolimod. Compared with all other DMTs, ozanimod was associated with overall healthcare cost savings ranging from $8257 vs interferon beta-1a (30μg) to $2178 vs fingolimod. Compared with oral DMTs, ozanimod was associated with annual cost savings of $6199 withteriflunomide 7mg, $4737 withteriflunomide 14mg, $2178 withfingolimod, and $2793 withdimethyl fumarate. Treatment with ozanimod was associated with substantial reductions in annual drug costs and total MS-related healthcare costs to avoid relapses compared with other DMTs. In the fixed-budget analysis, ozanimod demonstrated a favorable cost-effective profile relative to other DMTs.

Real-World Effectiveness of Natalizumab Extended Interval Dosing in a French Cohort.

Natalizumab, a therapy for relapsing-remitting multiple sclerosis (RRMS), is associated with a risk of progressive multifocal leukoencephalopathy (PML). Over the last several years, practitioners have used off-label extended interval dosing (EID) of natalizumab to reduce PML risk, despite the absence of a large-scale efficacy evaluation. We conducted a retrospective, multicenter cohort study among adults with RRMS receiving stable standard interval dosing (SID), defined as a ≥ 12-month consecutive period of ≥ 11 natalizumab infusions/year in France. We compared the 12-month risk difference of remaining relapse-free (primary endpoint) between patients who switched to EID (≤ 9 natalizumab infusions) and those who remained on SID, with a noninferiority margin of - 11%. We used propensity score methods such as inverse probability treatment weighting (IPTW) and 1:1 propensity score matching (PSM). Secondary endpoints were annualized relapse rate, disease progression, and safety. Baseline characteristics were similar between patients receiving EID (n = 147) and SID (n = 156). The proportion of relapse-free patients 12months postbaseline was 142/147 in the EID (96.6%) and 144/156 in the SID group (92.3%); risk difference (95% CI) 4.3% (- 1.3 to 9.8%); p < 0.001 for non-inferiority. There were no significant differences between relapse rates (0.043 vs. 0.083 per year, respectively; p = 0.14) or Expanded Disability Status Scale mean scores (2.43 vs. 2.72, respectively; p = 0.18); anti-JC virus index values were similar (p = 0.23); and no instances of PML were reported. The comparisons using IPTW (n = 306) and PSM (n = 204) were consistent. These results support the pertinence of using an EID strategy for RRMS patients treated with natalizumab. gov identifier (NCT04580381).

Efficacy and safety of repeated low-dose rituximab therapy in relapsing-remitting multiple sclerosis: A retrospective case series study.

Rituximab (RTX) is an extensively used off-label drug for multiple sclerosis (MS), whereas the induction and maintenance regimens vary widely among studies. Few data are available on efficacy and safety of repeated low-dose RTX therapy in MS patients. This study aimed to evaluate the efficacy and safety of repeated low-dose RTX therapy for relapsing-remitting MS (RRMS), the most common form of MS affecting approximately 85% of patients. Nine RRMS patients were enrolled and the medical records were retrospectively reviewed. RTX at 100mg per week for three consecutive weeks was used as induction therapy. Maintenance therapy was reinfusions of RTX at 100mg every 6 months during the first year, followed by 100mg every 6 to 12 months. Main outcome measures included annualized relapse rate (ARR), expanded disability status scale (EDSS) score, and T2 lesion burden on MRI for evaluating the efficacy of low-dose RTX regimen. Meanwhile, adverse events (AEs) were recorded to assess the safety of repeated RTX infusions. All patients were females with an average onset age of 25.4±6.7 years. The median disease duration before the first RTX infusion was 56 (range, 3-108) months and the median follow-up period was 30 (range, 15-40) months. No relapses were recorded in all patients after RTX therapy. Repeated low-dose RTX therapy resulted in a dramatic reduction of median ARR (pre-RTX vs post-RTX, 1.1vs 0, p=0.012), median EDSS score (2.0vs 0, p=0.007), and the number of T2 lesions on MRI (35.6±18.0vs 29.4±18.1, p=0.001). A total of 35 episodes of AEs occurred during repeated low-dose RTX therapy, and all of them were mild and transient. Repeated low-dose RTX therapy is cost-effective for RRMS patients and shows a good safety profile. It may be a promising option for those having no access or poor response to first-line disease-modified drugs (DMDs), particularly in low- or middle-income countries.

In vivo cortical glutathione response to oral fumarate therapy in relapsing-remitting multiple sclerosis: A single-arm open-label phase IV trial using 7-Tesla 1H MRS

BackgroundThis is an open-label, single-arm, single-center pilot study using 7-Tesla in vivo proton magnetic resonance spectroscopy (1H MRS) to measure brain cortical glutathione concentration at baseline before and during the use of oral fumarates as a disease-modifying therapy for multiple sclerosis. The primary endpoint of this research was the change in prefrontal cortex glutathione concentration relative to a therapy-naïve baseline after one year of oral fumarate therapy. MethodsBrain glutathione concentrations were examined by 1H MRS in single prefrontal and occipital cortex cubic voxels (2.5 × 2.5 × 2.5 cm3) before and during initiation of oral fumarate therapy (120 mg b.i.d. for 7 days and 240 mg b.i.d. thereafter). Additional measurements of related metabolites glutamate, glutamine, myoinositol, total N-acetyl aspartate, and total choline were also acquired in voxels centered on the same regions. Seven relapsing-remitting multiple sclerosis patients (4 f / 3 m, age range 28–50 years, mean age 40 years) naïve to fumarate therapy were scanned at pre-therapy baseline and after 1, 3, 6 and 12 months of therapy. A group of 8 healthy volunteers (4 f / 4 m, age range 33–48 years, mean age 41 years) was also scanned at baseline and Month 6 to characterize 1H-MRS measurement reproducibility over a comparable time frame. ResultsIn the multiple sclerosis cohort, general linear models demonstrated a significant positive linear relationship between prefrontal glutathione and time either linearly across all time points (+0.05 ± 0.02 mM/month, t(27) = 2.6, p = 0.02) or specifically for factor variable Month 12 (+0.6 ± 0.3 mM/12 months, t(24) = 2.2, p = 0.04) relative to baseline. No such effects of time on glutathione concentration were demonstrated in the occipital cortex or in the healthy volunteer group. Changes in occipital total choline were further observed in the multiple sclerosis cohort as well as prefrontal total choline and occipital glutamine and myoinositol in the control cohort throughout the study duration. ConclusionsWhile the open-label single-arm pilot study design and abbreviated control series cannot support firm conclusions about the influence of oral fumarate therapy independent of test–retest factors or normal biological variation in a state of either health or disease, these results do justify further investigation at a larger scale into the potential relationship between prefrontal cortex glutathione increases and oral fumarate therapy in relapsing-remitting multiple sclerosis.

Actual adherence to dimethyl fumarate in patients with relapsing-remitting multiple sclerosis

Multiple sclerosis is a chronic neurological disease with numerous disease-modifying treatments available, including dimethyl fumarate (DMF), a first-line therapy for relapsing-remitting multiple sclerosis. Although rates of discontinuation of DMF are generally low in clinical trials, non-adherence to treatment is associated with poorer clinical outcomes. Assessing real-world adherence and predictive factors is critical to be able to improve clinical outcomes for patients. This study evaluated adherence to DMF over 24 months in a cohort of patients treated in a Portuguese healthcare centre. A prospective, non-interventional, single-centre study with 24 months' follow-up was conducted. The study included adult patients with relapsing-remitting multiple sclerosis treated with DMF in routine clinical practice. Adherence to DMF was calculated and patients were considered to have adhered if the value was above 80%. Clinical and socio-demographic variables were compared between groups. Of the 80 patients included, 74% were women, with a mean age of 39 years and a mean age of 32 years at diagnosis. Twenty-six patients had not received any previous treatment. Adherence varied between 93, 82 and 87.5% at 6, 12 and 24 months, respectively. No differences were found between patients who had not received any prior treatment and those who had been treated. This real-world analysis showed significant adherence to DMF treatment by Portuguese patients over a period of two years. However, these results must be interpreted in the light of the substantial changes in outpatient consultations and the various periodic restrictions due to the COVID-19 pandemic, which had an important effect on patient follow-up and data collection.

From bedside to bench: how existing therapies inform the relationship between Epstein-Barr virus and multiplesclerosis.

Therapy for relapsing-remitting multiple sclerosis (MS) has advanced dramatically despite incomplete understanding of the cause of the condition. Current treatment involves inducing broad effects on immune cell populations with consequent off-target side effects, and no treatment can completely prevent disability progression. Further therapeutic advancement will require a better understanding of the pathobiology of MS. Interest in the role of Epstein-Barr virus (EBV) in multiple sclerosis has intensified based on strong epidemiological evidence of an association between EBV seroprevalence and MS. Hypotheses proposed to explain the biological relationship between EBV and MS include molecular mimicry, EBV immortalised autoreactive B cells and infection of glial cells by EBV. Examining the interaction between EBV and immunotherapies that have demonstrated efficacy in MS offers clues to the validity of these hypotheses. The efficacy of B cell depleting therapies could be consistent with a hypothesis that EBV-infected B cells drive MS; however, loss of T cell control of B cells does not exacerbate MS. A number of MS therapies invoke change in EBV-specific T cell populations, but pathogenic EBV-specific T cells with cross-reactivity to CNS antigen have not been identified. Immune reconstitution therapies induce EBV viraemia and expansion of EBV-specific T cell clones, but this does not correlate with relapse. Much remains unknown regarding the role of EBV in MS pathogenesis. We discuss future translational research that could fill important knowledge gaps.

Systematic review and network meta-analysis (NMA) for cladribine tablets in achieving sustained disability improvement (SDI) in multiple sclerosis.

This study was performed to compare probabilities of SDI on the Expanded Disability Status Scale (EDSS) in patients with relapsing-remitting multiple sclerosis (RRMS), treated with cladribine tablets (CT) or fingolimod (FTY), natalizumab (NAT), alemtuzumab (ALE) and ocrelizumab (OCR). Progression of neurological disability as measured by the EDSS has been a common endpoint in multiple sclerosis (MS) trials. Novel therapies can not only slow this process, but in some patients even reverse it. This effect can be measured by the sustained disability improvement (SDI) - an endpoint that seems to continuously gain importance in clinical practice. Despite that, SDI has rarely been explored as an outcome in MS clinical studies, mostly as post-hoc analyses from randomised trials or as retrospective analyses based on patient registry records. A systematic review was conducted in Medline, Embase and Cochrane to identify clinical trials (RCT or non-RCT) evaluating 6-month SDI. An indirect comparison via network meta-analysis (NMA) was performed. Bayesian inference with Markov chains Monte Carlo methods were applied. Eight trials presenting SDI results and applicable for NMA were included: six non-RCTs, with control groups selected by propensity score matching, and two RCTs. NMA results revealed that probability of achieving 6-month SDI with CT was significantly higher compared to all other high efficacy disease-modifying drugs with available data - HR (95% Crl - Bayesian Credibility Interval) vs. FTY: 4.98 (2.11-11.79); vs. NAT: 3.12 (1.31-7.27); vs. ALE: 9.29 (3.40-25.21). The main results were confirmed in the sensitivity analyses. Of all considered therapies, treatment with cladribine tablets was associated with a higher probability of sustained disability improvement in RRMS patients. As this conclusion is based on available clinical data of limited quality, future studies, as well as real-world data, would be valuable to provide further evidence regarding the comparative effectiveness of RRMS therapies.

Societal economic burden of multiple sclerosis and cost-effectiveness of disease-modifying therapies.

In an era of scarce resources, policy makers, neurologists and other stakeholders need to be aware of the economic burden of multiple sclerosis and the cost-effectiveness of disease-modifying therapies. The aim of this article is to provide a mini-review of these health economic facets of multiple sclerosis. An umbrella review was conducted by searching PubMed and Google Scholar from 2002 until June 2022 for peer-reviewed systematic and narrative literature reviews. An extensive body of evidence corroborates that multiple sclerosis is associated with a substantial economic burden within and outside the health care sector, that costs of secondary progressive multiple sclerosis exceed those of relapsing-remitting multiple sclerosis, that costs increase with disease severity and are influenced by the occurrence of relapses and therapy adherence. However, cost estimates and their breakdown into various components vary between countries. Economic evaluations show that disease-modifying therapies for relapsing-remitting multiple sclerosis are generally not cost-effective, but these results depend on the local setting. Cost-effectiveness of disease-modifying therapies improves when a societal perspective is taken and efficacy does not wane over a lifetime horizon, when oral administration forms or dosing strategies requiring less maintenance are introduced, and when generic versions enter the market. Reimbursement recommendations related to disease-modifying therapies also differ between countries. The local context matters when calculating the societal economic burden of multiple sclerosis and the cost-effectiveness of disease-modifying therapies.

Cost-Effectiveness Analysis of Ofatumumab for the Treatment of Relapsing-Remitting Multiple Sclerosis in Canada.

BackgroundOfatumumab is a high-efficacy disease-modifying therapy (DMT) approved for first-line treatment of relapsing-remitting multiple sclerosis (RRMS) in Canada.ObjectiveThe aim of this study was to evaluate the cost effectiveness of ofatumumab from a Canadian healthcare system perspective.MethodsA Markov cohort model was run over 65 years using annual cycles, 1.5% annual discount rate, and 100% treatment discontinuation at 10 years. The British Columbia database informed natural history transition probabilities. Treatment efficacy for DMTs were sourced from a network meta-analysis. Clinical trial data were used to estimate probabilities for treatment-related adverse events. Health utilities and costs were obtained from Canadian sources (if available) and the literature.ResultsAmong first-line indicated therapies for RRMS, ofatumumab was dominant (more effective, lower costs) over teriflunomide, interferons, dimethyl fumarate, and ocrelizumab. Compared with glatiramer acetate and best supportive care, ofatumumab resulted in incremental cost-effectiveness ratios (ICERs) of $24,189 Canadian dollars per quality-adjusted life-year (QALY) and $28,014/QALY, respectively. At a willingness-to-pay threshold of $50,000/QALY, ofatumumab had a 64.3% probability of being cost effective. Among second-line therapies (scenario analysis), ofatumumab dominated natalizumab and fingolimod and resulted in an ICER of $50,969 versus cladribine.ConclusionsOfatumumab is cost effective against all comparators and dominant against all currently approved and reimbursed first-line DMTs for RRMS, except glatiramer acetate.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-022-00363-1.

Risk factors for development of lymphopenia in dimethyl fumarate-treated patients with multiple sclerosis

BackgroundDimethyl fumarate (DMF, Tecfidera®) is a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis. Lymphopenia is a frequent reason for discontinuation in fumarate-treated patients. Management strategies to minimize risk of lymphopenia are warranted. ObjectiveThe aims of this study were to investigate the correlation of body mass index (BMI), baseline absolute lymphocyte count (ALC), age and sex with risk of DMF-induced lymphopenia in MS patients. MethodsThe study was a retrospective cohort study of 452 MS patients who had been prescribed DMF at six clinics in two Danish regions between May 2014 and September 2017. Data on lymphocyte counts, BMI, age, sex, and reason for discontinuation of DMF were collected through the Danish Multiple Sclerosis Registry, with follow- up to two years after treatment start. Results28.5% of patients had lymphopenia grade II or higher at some time in the first two years of DMF treatment. Increased risk of lymphopenia was observed in patients with baseline ALC of 1.00–1.49×109 cells/L (odds ratio, OR 5.48, p<0.0001) and 1.50–1.99×109 cells/L (OR 2.08, p = 0.0009). Reduced risk of lymphopenia was observed in patients with ALC of 2.00–2.49×109 cells/L (OR 0.51, p< 0.01) and ≥ 2.50×109 cells/L (0.12, p<0.0001). Patients aged ≥ 56 years had an increased risk of lymphopenia (OR 3.58, p<0.001), and patients with BMI ≥ 30 kg/m2 had a decreased risk of lymphopenia (OR 0.53, p value = 0.03). ConclusionLow baseline ALC and older age were risk factors for DMF-induced lymphopenia, while BMI ≥ 30 kg/m2 and high baseline ALC were protective factors for developing lymphopenia in MS patients treated with DMF.