Cost-consequence analysis of ofatumumab for the treatment of relapsing-remitting multiple sclerosis in Canada.

Aim: The costs and consequences of initial and delayed ofatumumab treatment were evaluated in relapsing-remitting multiple sclerosis with active disease in Canada. Materials & methods: A Markov cohort model was used (10-year horizon, annual cycle length, 1.5% discounting). Scenario analyses examined ofatumumab as first-line treatment versus 3 and 5 years following switch from commonly used first-line therapies. Results: Ofatumumab resulted in improvements in clinical outcomes (relapses and disease progression) and productivity (employment and full-time work), and reduction of economic burden (administration, monitoring and non-drug costs) that were comparable to other high-efficacy therapies (ocrelizumab, cladribine and natalizumab). Switching to ofatumumab earlier in the disease course may improve these outcomes. Conclusion: Results highlight the value of a high-efficacy therapy such as ofatumumab as initial treatment (i.e., first-line) in newly diagnosed relapsing-remitting multiple sclerosis patients with active disease.

Translingual neurostimulation combined with physical therapy to improve walking and balance in multiple sclerosis (NeuroMSTraLS): Study protocol for a randomized controlled trial.

INTRODUCTION: Physical rehabilitation restores lost function and promotes brain plasticity in people with Multiple Sclerosis (MS). Research groups worldwide are testing the therapeutic effects of combining non-invasive neuromodulation with physical therapy (PT) to further improve functional outcomes in neurological disorders but with mixed results. Whether such devices enhance function is not clear. We present the rationale and study design for a randomized controlled trial evaluating if there is additional benefit to the synergistic pairing of translingual neurostimulation (TLNS) with PT to improve walking and balance in MS. METHODS AND ANALYSIS: A parallel group [PT + TLNS or PT + Sham], quadruple-blinded, randomized controlled trial. Participants (N = 52) with gait and balance deficits due to relapsing-remitting or progressive MS, who are between 18 and 70 years of age, will be recruited through patient registries in Newfoundland & Labrador and Saskatchewan, Canada. All participants will receive 14 weeks of PT while wearing either a TLNS or sham device. Dynamic Gait Index is the primary outcome. Secondary outcomes include fast walking speed, subjective ratings of fatigue, MS impact, and quality of life. Outcomes are assessed at baseline (Pre), after 14 weeks of therapy (Post), and 26 weeks (Follow Up). We employ multiple methods to ensure treatment fidelity including activity and device use monitoring. Primary and secondary outcomes will be analyzed using linear mixed-effect models. We will control for baseline score and site to test the effects of Time (Post vs. Follow-Up), Group and the Group x Time interaction as fixed effects. A random intercept of participant will account for the repeated measures in the Time variable. Participants must complete the Post testing to be included in the analysis. ETHICS AND DISSEMINATION: The Human Research Ethics Boards in Newfoundland & Labrador (HREB#2021.085) & Saskatchewan (HREB Bio 2578) approved the protocol. Dissemination avenues include peer-reviewed journals, conferences and patient-oriented communications.

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

BACKGROUND: Ofatumumab is a high-efficacy disease-modifying therapy (DMT) approved for first-line treatment of relapsing-remitting multiple sclerosis (RRMS) in Canada. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of ofatumumab from a Canadian healthcare system perspective. METHODS: A 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. RESULTS: Among 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. CONCLUSIONS: Ofatumumab is cost effective against all comparators and dominant against all currently approved and reimbursed first-line DMTs for RRMS, except glatiramer acetate.

Does the use of the Bruton Tyrosine Kinase inhibitors and the c-kit inhibitor masitinib result in clinically significant outcomes among patients with various forms of multiple sclerosis?

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system accompanied by chronic inflammation, axonal loss, and neurodegeneration. Traditionally, MS has been thought of as a T-cell mediated disease, but research over the past decade has demonstrated the importance of B cells in both acute demyelination and disease progression. The highly selective irreversible Bruton Tyrosine Kinase (BTK) inhibitors evobrutinib, tolebrutinib, and orelabrutinib, and the reversible BTK inhibitor fenebrutinib, all target B-cell activation and aspects of innate immunity, including macrophage and microglia biology. The c-KIT inhibitor masitinib mitigates neuroinflammation by controlling the survival, migration, and degranulation of mast cells, leading to the inhibition of proinflammatory and vasoactive molecular cascades that result from mast cell activation. This article will review and critically appraise the ongoing clinical trials of two classes of receptor tyrosine kinase inhibitors that are emerging as potential medical treatments for the varying subtypes of MS: BTK inhibitors and c-KIT inhibitors. Specifically, this review will attempt to answer whether BTK inhibitors have measurable positive clinical effects on patients with RRMS, SPMS with relapses, relapse-free SPMS, and PPMS through their effect on MRI T1 lesions; annualized relapse rate; EDSS scale; MSFC score; and time to onset of composite 12-week confirmed disability progression. Additionally, this review will examine the literature to determine if masitinib has positive clinical effects on patients with PPMS or relapse-free SPMS through its effect on EDSS or MSFC scores.

Use of natalizumab in persons with multiple sclerosis: 2022 update.

BACKGROUND: Natalizumab is a humanized monoclonal antibody used for treatment of highly active relapsing-remitting multiple sclerosis (MS). With more than 15 years of post-marketing experience with natalizumab in Canada, several real-world studies have shown the long-term efficacy and safety of natalizumab. In addition, risk stratification/mitigation strategies for progressive leukoencephalopathy (PML), an adverse effect associated with natalizumab based on the John Cunningham virus (JCV) index; treatment duration beyond 24 months; and prior exposure to immunosuppressant drugs have been developed. METHODS: A group of neurologists from various MS clinics across Canada met in September 2021 to update the 2015 Canadian practice recommendations for the use of natalizumab in persons with MS (PwMS). RESULTS: The recommendations focused on the long-term efficacy and safety data from real-world studies, patient selection according to JCV index criteria, risk management strategies for PML (including extended interval dosing), and options for switching to currently available disease-modifying therapies for MS. CONCLUSIONS: The recommendations of clinical neurologists seek to optimize the management of PwMS who may benefit from treatment with natalizumab.

Interleukin-1 receptor antagonist: An exploratory plasma biomarker that correlates with disability and provides pathophysiological insights in relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disorder. Interleukin-1 receptor antagonist (IL-1RA) is an endogenous soluble antagonist of the IL-1 receptor and blocks the pro-inflammatory effects of IL-1ß known to contribute to MS pathology. The objectives of this study were to determine whether IL-1RA is associated with disability in MS and how this correlates with neurofilament light (NfL) levels in cerebrospinal fluid (CSF). METHODS: Peripheral blood and CSF were collected from consenting MS patients. Patient demographic and clinical variables, including past relapse activity, were also collected. Circulating levels of IL-1RA, IL-18, and IL-1ß were measured in plasma; IL-1RA and NfL were measured in the CSF via Bio-plex multiplex immunoassay kits and ELISA, respectively. IL-1RA expression was investigated in vitro using primary human macrophages and microglia, and in situ using post-mortem MS tissue. RESULTS: Following a multiple regression analysis, IL-1RA levels in plasma correlated with expanded disability status scale score independent of all other variables. In a separate cohort, CSF IL-1RA significantly correlated with NfL. In vitro, induction of the NLRP3 inflammasome, a pathological hallmark within MS lesions, led to increased release of IL-1RA from primary human microglia and macrophages. In the CNS, IL-1RA+ macrophages/microglia were present at the rim of mixed active/inactive MS lesions. CONCLUSIONS: Results presented in this study demonstrate that IL-1RA is a novel exploratory biomarker in relapsing-remitting MS, which correlates with disability and provides mechanistic insights into the regulatory inflammatory responses within the demyelinated CNS.

Anti-CV2/CRMP5 antibody-associated hemorrhagic leukoencephalomyelitis treated with steroids, intravenous immunoglobulin, plasmapheresis, and cyclophosphamide.

Anti-CV2 or anti-collapsing response-mediator protein-5 (CRMP5) autoantibodies (anti-CV2/CRMP5-Ab) are associated with various paraneoplastic neurological disorders. The best therapy is typically removal of the underlying cancer. We describe a previously healthy elderly male who had no known malignancy. He presented with a demyelinating encephalomyelitis and later developed hemorrhagic changes on neuroimaging. He was treated with intravenous immunoglobulin (IVIG), intravenous steroids, and plasmapheresis; however, sustained clinical and radiographic stabilization and improvement only occurred following cyclophosphamide. He unexpectedly died of a cardiac arrest. postmortem, his serum paraneoplastic screen was found to be weakly positive for anti-CV2/CRMP5-Ab.

Nonalcoholic Wernicke's encephalopathy.

Wernicke's encephalopathy (WE) is a serious neurologic condition resulting from thiamine deficiency. The majority of cases involve alcoholism; however, nonalcohol-associated WE does occur and is under-recognized. We discuss a case of a 22-year-old man with a history of Crohn's disease who presented to our emergency department with multiple neurologic complaints related to WE.