Managing multiple sclerosis in individuals aged 55 and above: a comprehensive review.

Multiple Sclerosis (MS) management in individuals aged 55 and above presents unique challenges due to the complex interaction between aging, comorbidities, immunosenescence, and MS pathophysiology. This comprehensive review explores the evolving landscape of MS in older adults, including the increased incidence and prevalence of MS in this age group, the shift in disease phenotypes from relapsing-remitting to progressive forms, and the presence of multimorbidity and polypharmacy. We aim to provide an updated review of the available evidence of disease-modifying treatments (DMTs) in older patients, including the efficacy and safety of existing therapies, emerging treatments such as Bruton tyrosine kinase (BTKs) inhibitors and those targeting remyelination and neuroprotection, and the critical decisions surrounding the initiation, de-escalation, and discontinuation of DMTs. Non-pharmacologic approaches, including physical therapy, neuromodulation therapies, cognitive rehabilitation, and psychotherapy, are also examined for their role in holistic care. The importance of MS Care Units and advance care planning are explored as a cornerstone in providing patient-centric care, ensuring alignment with patient preferences in the disease trajectory. Finally, the review emphasizes the need for personalized management and continuous monitoring of MS patients, alongside advocating for inclusive study designs in clinical research to improve the management of this growing patient demographic.

Narrative Review on the Use of Cladribine Tablets as Exit Therapy for Stable Elderly Patients with Multiple Sclerosis.

The number of ageing people with relapsing multiple sclerosis (RMS) is increasing. The efficacy of disease-modifying therapies (DMTs) for RMS declines with age. Also, older persons with MS may be more susceptible to infections, hospitalisations and malignancy. Aging people with MS have higher rates of comorbidities versus aged-matched controls, increasing the individual risk of disability. We review the therapeutic properties of cladribine tablets (CladT) in ageing people with RMS, with regard to their utility for allowing these individuals to cease continuous administration of a DMT (i.e. to act as an "exit therapy"). CladT is thought to be an immune reconstitution therapy, in that two short courses of oral treatment 1 year apart provide suppression of MS disease activity in responders that far outlasts the duration of treatment and post-treatment reductions in lymphocyte counts. Post hoc analyses, long-term follow-up of populations with RMS in randomised trials, and real-world evidence suggest that the efficacy of CladT is probably independent of age, although more data in the elderly are still needed. No clear adverse signals for lymphopenia or other adverse safety signals have emerged with increasing age, although immunosenescence in the setting of age-related "inflammaging" may predispose elderly patients to a higher risk of infections. Updating vaccination status is recommended, especially against pneumococci and herpes zoster for older patients, to minimise the risk of these infections. CladT may be a useful alternative treatment for ageing people with MS who often bear a burden of multiple comorbidities and polypharmacy and who are more exposed to the adverse effects of continuous immunosuppressive therapy.

An AluYa5 Insertion in the 3'UTR of COL4A1 and Cerebral Small Vessel Disease.

Importance: Cerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes. Objective: To identify novel genes and mechanisms associated with familial CSVD. Design, Setting, and Participants: This 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset

Torben Fog - A Danish pioneer in a multi-faceted spectrum of multiple sclerosis research.

Torben Fog was committed to multiple sclerosis (MS) research for more than four decades, starting before the defence of his thesis in 1948 and lasting until his death in 1987. His research was multi-facetted, making him one of the great pioneers in the study of essential parts of the pathology, immunology and treatment of MS. He has contributed with meticulous studies of the MS plaques, documenting the perivenous distribution of plaques in the spinal cord. He constructed a scoring system for the disability in MS and used a computer programme to calculate a total neurological deficit. Together with his co-workers, Fog in 1972 was the first to report the association between MS and the human leukocyte antigen system. Fog can be considered as the father of immunomodulatory therapy in MS, treating MS patients with the first transfer factor, and as early as 1980, he was the first to treat MS with intramuscular natural interferon.

Efficacy of dalfampridine in neuromyelitis optica spectrum disorder: A pilot study.

Objective: To assess the efficacy of dalfampridine in patients with neuromyelitis optica spectrum disorder. Methods: We included 15 consecutive patients, who were started on a treatment of dalfampridine 10 mg twice daily for 2 weeks. Efficacy assessment was based on walking ability improvement using Timed-25-Foot Walk and 12-item Multiple Sclerosis Walking Scale tests. Results: The mean Timed-25-Foot Walk score was reduced from 14.8 (±2.4) to 11.3 (±1.9) seconds (p = 0.01). The mean score on the 12-item Multiple Sclerosis Walking Scale was reduced from 41.2 (±3.5) to 31.4 (±3.2) (p = 0.004). Conclusion: Dalfampridine seems to be useful for symptomatic treatment of walking impairment in neuromyelitis optica spectrum disorder.

Holistic, Long-Term Management of People with Relapsing Multiple Sclerosis with Cladribine Tablets: Expert Opinion from France.

Cladribine tablets (CladT) has been available for therapeutic use in France since March 2021 for the management of highly active relapsing multiple sclerosis (RMS). This high-efficacy disease-modifying therapy (DMT) acts as an immune reconstitution therapy. In contrast to most high-efficacy DMTs, which act via continuous immunosuppression, two short courses of oral treatment with CladT at the beginning of years 1 and 2 of treatment provide long-term control of MS disease activity in responders to treatment, without the need for any further pharmacological treatment for several years. Although the labelling for CladT does not provide guidance beyond the initial treatment courses, real-world data on the therapeutic use of CladT from registries of previous clinical trial participants and patients treated in routine practice indicate that MS disease activity is controlled for a period of years beyond this time for a substantial proportion of patients. Moreover, this clinical experience has provided useful information on how to initiate and manage treatment with CladT. In this article we, a group of expert neurologists from France, provide recommendations on the initiation of CladT in DMT-naïve patients, how to switch from existing DMTs to CladT for patients with continuing MS disease activity, how to manage patients during the first 2 years of treatment and finally, how to manage patients with or without MS disease activity in years 3, 4 and beyond after initiating treatment with CladT. We believe that optimisation of the use of CladT beyond its initial courses of treatment will maximise the benefits of this treatment, especially early in the course of MS when suppression of focal inflammation in the CNS is a clinical priority to limit MS disease progression.

Inhibition of CD40L with Frexalimab in Multiple Sclerosis.

BACKGROUND: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis. METHODS: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab. RESULTS: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches. CONCLUSIONS: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

Response to tibial and sacral nerve modulation in overactive bladder: Is there any correlation?

OBJECTIVES: To assess the correlation between the response to transcutaneous tibial nerve stimulation (TTNS) and subsequent response to sacral nerve modulation (SNM) to treat overactive bladder (OAB). MATERIALS AND METHODS: All patients who consecutively received TTNS followed by a two-stage SNM between January 2016 and June 2022 to treat OAB in two university hospital centers were included. The response to each therapy was evaluated with success defined by a 50% or greater improvement in one or more bothersome urinary symptoms from baseline. The primary endpoint was the statistical relationship between the response to TTNS and the response to SNM, assessed by logistic regression. Secondary endpoints were the statistical relationship between the response to TTNS and the response to SNM when controlling for gender, age (<57 years vs. >57 years), presence of an underlying neurological disease, and presence of DO, adding the factor and interaction to the previous regression model. RESULTS: Among the 92 patients enrolled in the study, 68 of them were women (73.9%), and the median age was 57.0 [41.0-69.0] years. The success was reported in 22 patients (23.9%) under TTNS and 66 patients (71.7%) during the SNM test phase. There was no statistical correlation between response to TTNS and response to SNM in the overall population (confidence interval: 95% [0.48-4.47], p = 0.51). Similarly, there was no statistical correlation when controlling for age <57 years or ≥57 years, with p = 1.0 and p = 0.69, respectively. No statistical study could be conducted for the other subpopulations due to small sample sizes. CONCLUSION: The response to TTNS does not predict the response to SNM in the treatment of OAB. TTNS and SNM should be considered as separate therapies, and the decision-making process for OAB treatment should take this into account.

Development of a predictive tool for sacral nerve modulation implantation in the treatment of non-obstructive urinary retention and/or slow urinary stream: a study from the Neuro-Urology Committee of the French Association of Urology.

PURPOSE: This study aimed to seek predictive factors and develop a predictive tool for sacral nerve modulation (SNM) implantation in patients with non-obstructive urinary retention and/or slow urinary stream (NOUR/SS). METHODS: This study was designed as a retrospective study including all patients who have undergone a two-stage SNM for NOUR/SS between 2000 and 2021 in 11 academic hospitals. The primary outcome was defined as the implantation rate. Secondary outcomes included changes in bladder emptying parameters. Univariate and multivariable logistic regression analysis were performed and determined odds ratio for IPG implantation to build a predictive tool. The performance of the multivariable model discrimination was evaluated using the c-statistics and an internal validation was performed using bootstrap resampling. RESULTS: Of the 357 patients included, 210 (58.8%) were finally implanted. After multivariable logistic regression, 4 predictive factors were found, including age (≤ 52 yo; OR = 3.31 CI95% [1.79; 6.14]), gender (female; OR = 2.62 CI95% [1.39; 4.92]), maximal urethral closure pressure (≥ 70 cmH2O; OR: 2.36 CI95% [1.17; 4.74]), and the absence of an underlying neurological disease affecting the lower motor neuron (OR = 2.25 CI95% [1.07; 4.76]). Combining these factors, we established 16 response profiles with distinct IPG implantation rates, ranging from 8.7 to 81.5%. Internal validation found a good discrimination value (c-statistic, 0.724; 95% CI 0.660-0.789) with a low optimism bias (0.013). This allowed us to develop a predictive tool ( https://predictivetool.wixsite.com/void ). CONCLUSION: The present study identified 4 predictive factors, allowing to develop a predictive tool for SNM implantation in NOUR/SS patients, that may help in guiding therapeutic decision-making. External validation of the tool is warranted.

Tolerability of subcutaneous ofatumumab with long-term exposure in relapsing multiple sclerosis.

Background: Ofatumumab is approved for treating relapsing multiple sclerosis (RMS). Examining tolerability will enable understanding of its risk-benefit profile. Objective: Report the tolerability profile of ofatumumab in RMS during treatment of up to 4 years and the effect of pre-medication. Methods: Cumulative data from the overall safety population included patients taking continuous ofatumumab or being newly switched from teriflunomide. Injection-related reactions (IRRs) by incidence and severity, and post-marketing surveillance data, with an exposure of 18,530 patient-years, were analyzed. Results: Systemic IRRs affected 24.7% of patients (487/1969) in the overall safety population; most (99.2% [483/487]) were mild (333/487) to moderate (150/487) in Common Terminology Criteria for Adverse Events severity; most systemic IRRs occurred after first injection. Local-site IRRs affected 11.8% (233/1969) and most (99.6% [232/233]) were mild/moderate. Incidence and severity of systemic and localized IRRs were similar between continuous and newly switched patients across repeated injections. Systemic IRR incidence and severity were not substantially affected by steroidal or non-steroidal pre-medication. Post-marketing surveillance identified no new tolerability issues. Conclusion: Ofatumumab is well tolerated, displays a consistent safety profile during continuous use or after switching from teriflunomide and does not require pre-medication. This enables home management of RMS with a high-efficacy treatment.

Summary of Research: Collaboration Between Healthcare Professionals and People with Multiple Sclerosis to Develop Communication Tools to Improve the Standard of Multiple Sclerosis Care.

This is a summary of a previously published paper: Joint Healthcare Professional and Patient Development of Communication Tools to Improve the Standard of MS Care. It describes a collaboration between people with multiple sclerosis (PwMS) and healthcare professionals (HCPs) to identify challenges in multiple sclerosis (MS) care and design tools to improve communication during consultations.

Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial.

Importance: Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system. Objective: To determine the time to onset of symptoms consistent with MS. Design, Setting, and Participants: From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144. Interventions: Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred. Main outcomes: Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs. Results: Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant. Conclusion and Relevance: Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum. Trial Registration: ClinicalTrials.gov Identifier: NCT03122652.

The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice.

Expert Narrative Review of the Safety of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis.

Cladribine tablets (CladT) is a highly active oral disease-modifying therapy (DMT) for the management of relapsing multiple sclerosis (RMS). CladT acts as an immune reconstitution therapy, in that two short courses of treatment 1 year apart have been shown to suppress disease activity for a prolonged period in most patients, without need for continued DMT. Each course of CladT induces a profound reduction in B lymphocytes that recovers over months, and serious lymphopenia (Grade 3-4) is uncommon. Smaller reductions in levels of T lymphocytes occur slightly later: on average, these remain within the normal range and repopulate progressively. A larger effect occurs on CD8 vs. CD4 cells. Reactivation of latent or opportunistic infections (e.g. varicella zoster, tuberculosis) is mostly associated with very low lymphocyte counts (< 200/mm3). Screening and managing pre-existing infections, vaccinating non-exposed patients and delaying the 2nd year of treatment with CladT to allow lymphocytes to recover to > 800/mm3 (if necessary) are important for avoiding infections and higher-grade lymphopenia. There was no demonstrable or apparent effect of CladT on the efficacy of vaccinations, including against Covid-19. Adverse events consistent with drug-induced liver injury (DILI) represent a rare but potentially serious complication of CladT therapy in spontaneous adverse event reporting; patients should be screened for liver dysfunction before starting treatment. Ongoing hepatic monitoring is not required, but CladT must be withdrawn if signs and symptoms of DILI develop. There was a numerical imbalance for malignancies when comparing cladribine to placebo in the clinical programme, particularly in short-term data, but recent evidence shows that the risk of malignancy with CladT is similar to the background rate in the general population and to that with other DMTs. Overall, CladT is well tolerated with a favorable safety profile appropriate for the management of RMS.

Development and usability testing of your MS questionnaire: A patient-based digital tool to monitor symptoms of multiple sclerosis.

Objectives: We describe the development of Your Multiple Sclerosis Questionnaire and present the real-world usability testing results of Your Multiple Sclerosis Questionnaire. Methods: The Your Multiple Sclerosis Questionnaire tool was developed in four stages to collect feedback from people living with MS (plwMS), patient organizations, and clinicians on content, format, and applicability. To assess its usability, 13 clinicians across 7 countries completed an online survey after using the tool with plwMS in a total of 261 consultations from September, 2020 to July, 2021. Results: The initial Your Multiple Sclerosis Questionnaire version was based on findings from previous research developing MSProDiscuss™, a clinician-completed tool. Subsequently, insights from plwMS obtained during cognitive debriefing, patient councils and advisory boards led to changes including the addition of mood and sexual problems and the definition of relapse. All 13 clinicians completed the individual survey, whereas 10 clinicians completed the final survey. Clinicians "strongly agreed" or "agreed" that Your Multiple Sclerosis Questionnaire was easy to use and understand (98.5%; 257/261 patient consultations). The clinicians were willing to use the tool again with the same patient (98.1%; 256/261 patient consultations). All clinicians who completed the final survey (100%; 10/10) reported the tool to have a positive influence on their clinical practice, helped patients engage with their MS, facilitated discussion with patients, and complemented neurological assessment. Conclusion: Your Multiple Sclerosis Questionnaire benefits both plwMS and clinicians by facilitating a structured discussion and engaging the plwMS to self-monitor and self-manage. Your Multiple Sclerosis Questionnaire is compatible with telemedicine practice and integration of the tool into electronic health records would enable tracking of the disease evolution and individual monitoring of MS symptoms over time.

Masitinib for mild-to-moderate Alzheimer's disease: results from a randomized, placebo-controlled, phase 3, clinical trial.

BACKGROUND: Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer's disease (AD). METHODS: Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12-25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population. RESULTS: Masitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, -1.46 (95% CI [-2.46, -0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [-0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of -2.15 (97.5% CI [-3.48, -0.81]); p<0.001. For the ADCS-ADL primary endpoint, the between-group difference was 1.82 (97.5% CI [-0.15, 3.79]); p=0.038 (i.e., 1.01 (95% CI [-0.48, 2.50]) (representing an overall functional improvement) versus -0.81 (95% CI [-2.36, 0.74]) (representing increased functional deterioration), respectively). Safety was consistent with masitinib's known profile (maculo-papular rash, neutropenia, hypoalbuminemia). Efficacy results from the independent parallel group of titrated masitinib 6.0 mg/kg/day versus placebo (n=186 and 91 patients, respectively) were inconclusive and no new safety signal was observed. CONCLUSIONS: Masitinib (4.5 mg/kg/day) may benefit people with mild-to-moderate AD. A confirmatory study has been initiated to substantiate these data. TRIAL REGISTRATION: EudraCT: 2010-021218-50. CLINICALTRIALS: gov : NCT01872598.

Specific Patterns of Immune Cell Dynamics May Explain the Early Onset and Prolonged Efficacy of Cladribine Tablets: A MAGNIFY-MS Substudy.

BACKGROUND AND OBJECTIVES: Cladribine tablets cause a reduction in lymphocytes with a predominant effect on B-cell and T-cell counts. The MAGNIFY-MS substudy reports the dynamic changes on multiple peripheral blood mononuclear cell (PBMC) subtypes and immunoglobulin (Ig) levels over 12 months after the first course of cladribine tablets in patients with highly active relapsing multiple sclerosis (MS). METHODS: Immunophenotyping was performed at baseline (predose) and at the end of months 1, 2, 3, 6, and 12 after initiating treatment with cladribine tablets. Assessments included lymphocyte subtype counts of CD19+ B cells, CD4+ and CD8+ T cells, CD16+ natural killer cells, plasmablasts, and Igs. Immune cell subtypes were analyzed by flow cytometry, and serum IgG and IgM were analyzed by nephelometric assay. Absolute cell counts and percentage change from baseline were assessed. RESULTS: The full analysis set included 57 patients. Rapid reductions in median CD19+, CD20+, memory, activated, and naive B-cell counts were detected, reaching nadir by month 2. Thereafter, total CD19+, CD20+, and naive B-cell counts subsequently reconstituted, but memory B cells remained reduced by 93%-87% for the remainder of the study. The decrease in plasmablasts was slower, reaching nadir at month 3. Decrease in T-cell subtypes was also slower and more moderate compared with B-cell subtypes, reaching nadir between months 3 and 6. IgG and IgM levels remained within the normal range over the 12-month study period. DISCUSSION: Cladribine tablets induce a specific pattern of early and sustained PBMC subtype dynamics in the absence of relevant Ig changes: While total B cells were reduced dramatically, T cells were affected significantly less. Naive B cells recovered toward baseline, naive CD4 and CD8 T cells did not, and memory B cells remained reduced. The results help to explain the unique immune depletion and repopulation architecture regarding onset of action and durability of effects of cladribine tablets while largely maintaining immune competence. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03364036. Date registered: December 06, 2017.

The Place of Immune Reconstitution Therapy in the Management of Relapsing Multiple Sclerosis in France: An Expert Consensus.

The treatment strategy in relapsing multiple sclerosis (RMS) is a complex decision requiring individualization of treatment sequences to maximize clinical outcomes. Current local and international guidelines do not provide specific recommendation on the use of immune reconstitution therapy (IRT) as alternative to continuous immunosuppression in the management of RMS. The objective of the program was to provide consensus-based expert opinion on the optimal use of IRT in the management of RMS. A Delphi method was performed from May 2022 to July 2022. Nineteen clinical assertions were developed by a scientific committee and sent to 14 French clinical experts in MS alongside published literature. Two consecutive reproducible anonymous votes were conducted. Consensus on recommendations was achieved when more than 75% of the respondents agreed or disagreed with the clinical assertions. After the second round, consensus was achieved amongst 16 out of 19 propositions: 13 clinical assertions had a 100% consensus, 3 clinical assertions a consensus above 75% and 3 without consensus. Expert-agreed consensus is provided on topics related to the benefit of the early use of IRT from immunological and clinical perspectives, profiles of patients who may benefit most from the IRT strategy (e.g. patients with family planning, patient preference and lifestyle requirements). These French expert consensuses provide up-to-date relevant guidance on the use of IRT in clinical practice. The current program reflects status of knowledge in 2022 and should be updated in timely manner when further clinical data in IRT become available.