Do immunosuppressive treatments influence immune responses against adenovirus-based COVID-19 vaccines in patients with multiple sclerosis? An Argentine multicenter study.

Introduction: There are no reports in LATAM related to longitudinal humoral and cellular response to adenovirus based COVID-19 vaccines in people with Multiple Sclerosis (pwMS) under different disease modifying therapies (DMTs) and neutralization of the Omicron and Wuhan variants of SARS-COV-2. Methods: IgG anti- SARS-COV-2 spike titer were measured in a cohort of 101 pwMS under fingolimod, dimethyl fumarate, cladribine and antiCD20, as well as 28 healthy controls (HC) were measured 6 weeks after vaccination with 2nd dose (Sputnik V or AZD1222) and 3nd dose (homologous or heterologous schedule). Neutralizing capacity was against Omicron (BA.1) and Wuhan (D614G) variants and pseudotyped particles and Cellular response were analyzed. Results: Multivariate regression analysis showed anti-cd20 (ß= -,349, 95% CI: -3655.6 - -369.01, p=0.017) and fingolimod (ß=-,399, 95% CI: -3363.8 - -250.9, p=0.023) treatments as an independent factor associated with low antibody response (r2 adjusted=0.157). After the 2nd dose we found a correlation between total and neutralizing titers against D614G (rho=0.6; p<0.001; slope 0.8, 95%CI:0.4-1.3), with no differences between DMTs. Neutralization capacity was lower for BA.1 (slope 0.3, 95%CI:0.1-0.4). After the 3rd dose, neutralization of BA.1 improved (slope: 0.9 95%CI:0.6-1.2), without differences between DMTs. A fraction of pwMS generated anti-Spike CD4+ and CD8+ T cell response. In contrast, pwMS under antiCD20 generated CD8+TNF+IL2+ response without differences with HC, even in the absence of humoral response. The 3rd dose significantly increased the neutralization against the Omicron, as observed in the immunocompetent population. Discussion: Findings regarding humoral and cellular response are consistent with previous reports.

Cladribine use trend in Latin America: the changes in patient profile impact in the drug effectiveness.

INTRODUCTION: Cladribine was approved for Multiple Sclerosis (MS) in our country in 2018. A previous study by our group showed that its use among high efficacy therapies options has been increasing along the years. OBJECTIVE: to analyze the cladribine use trend across time since its approval. METHOD: A retrospective cohort study was performed. People with MS (pwMS) treated with cladribine were included. Two periods were defined: P1 = 2018 - 2020 and P2 = 2021 - 2023. A comparative analysis was carry out between P1 and P2 to assess the trend of use, clinical/demographic characteristics, and effectiveness. RESULTS: One hundred ninety- seven people with MS (pwMS) were included, mean EDSS: 2.2 ± 3.08, 72.6% female, mean age: 35.2 ± 9 years, mean disease duration: 6.6 ± 5.6 years, mean time lapse under cladribine: 26.1 ± 12.4 months. Regarding patient profile, we found significant differences between P1 and P2 in the MS evolution (p = 0.001) and EDSS ( p = 0.018) prior to initiation of cladribine. In the individualized analysis by year, we found a decrease in relapse number in the year prior to starting cladribine (p = 0.02). A higher proportion of No Evidence of Disease Activity (NEDA) was found in patients treated at P2 compared to those treated at P1 (p < 0.001). CONCLUSION: An earlier use of cladribine achieved a significant increase in reaching NEDA. This learning curve in the use of cladribine allows a better identification of the candidate patient and influences the treatment effectiveness.

Traditional first-line treatment failure rates in neuromyelitis optica spectrum disorder patients included in the Argentinean registry (RelevarEM).

BACKGROUND: Immunosuppressive therapies as azathioprine (AZA), mycophenolate mofetil (MMF) and rituximab (RTX) are widely prescribed as first-line treatment to prevent relapses in NMOSD. However, the rate of response to these traditional therapies is unknown in Argentina. We aimed to describe and compare treatment failure rates in NMOSD patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). METHODS: A retrospective cohort study was conducted in NMOSD patients included in RelevarEM (a nationwide, longitudinal, observational, non-mandatory registry of MS and NMOSD in Argentina). NMOSD patients were defined based on validate diagnostic criteria. Only NMOSD patients who received AZA or MMF for at least 6 months or RTX for at least 1 month were included. Patients who were receiving AZA, MMF, or RTX and then switched to another 1 of these 3 therapies were included if the above-mentioned criteria for each drug were fulfilled. Data on patient demographics, clinical, neuroradiological findings, and treatments administered were collected. Treatment failure was defined as any new attack/relapse that occurred despite immunosuppressive treatment. RESULTS: We included 139 NMOSD patients who were receiving AZA (n = 105), MMF (n = 5) or RTX (n = 29) with a mean follow-up time of 41.3 ± 11.4 months and median of EDSS at treatment initiation of 3. We observed a reduction in the annualized relapse rate from pre-treatment to post-treatment of 51.1 %, 48.4 %, and 79.1 % respectively with a Hazard Risk relative to RTX (95 % CI) of 1.67 (1.34-3.54, p = 0.01) for AZA and 2.01 (1.86-4.43, p = 0.008) for MMF. AZA, MMF and RTX failure was observed in 45/105 (42.8 %), 2/5 (40 %) and 3/29 (10.3 %) patients, respectively. CONCLUSIONS: Treatment failure rates were higher for AZA and MMF than RTX in Argentinean NMOSD patients in a real-world setting. High-efficacy treatment increases the opportunity to prevent attacks of NMOSD.

Clinical effectiveness of dimethyl fumarate in multiple sclerosis patients from Argentina.

BACKGROUND: We assessed the effectiveness, safety and patient-reported outcomes (PROs) of dimethyl fumarate (DMF) in real-world clinical practice in patients with multiple sclerosis (PwMS) from Argentina. METHODS: We conducted a multicenter ambispective cohort study in Argentina between September 2020 and March 2023. Changes in annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, magnetic resonance imaging (MRI), no evidence of disease activity (NEDA), PROs (depression, anxiety, fatigue, burden of treatment and quality of life), and safety data were collected at clinical visits performed every 6 months for at least 24 months. RESULTS: We included 161 PwMS (64% female). DMF treatment was associated with a significant reduction in ARR from baseline after 24 months of treatment (from 0.87 to 0.23, p < 0.001). Disability progression was observed in 27.9% vs. 9.3% pre- and post-DMF, and disability improvement was found in 13% of patients from baseline to month 24. MRI activity was significantly reduced compared with baseline. Fatigue, depression, and quality of life scores were significantly improved from baseline to 24 months. Flushing was the most frequent adverse event reported in 19.2%. No significant reduction was observed in the hospitalization rate pre- and post-DMF (19.8% vs. 5.6%, p = 0.32). During follow-up, 135 (83%) patients were relapse-free, 110 (68.3%) were MRI free activity (Gad + lesion) and 108 (67%) reached NEDA. CONCLUSIONS: DMF significantly reduced disease activity in PwMS from Argentina with a good safety profile in real-world settings. A significant impact on the quality of life during follow-up was found.

Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina.

OBJECTIVE: The aim was to evaluate patient profiles, effectiveness and safety of cladribine (CLAD) in patients with relapsing-remitting multiple sclerosis in Argentina. METHODS: This was a substudy included in RelevarEM (MS and neuromyelitis optica registry in Argentina, NCT03375177). Patients with MS who received CLAD tablets and were followed up for at least 24 months were included. Clinical evaluations every 3 months collect information about: a) clinical relapses; b) progression of physical disability, evaluated through Expanded Disability Status Scale, and c) new lesions found in the magnetic resonance imaging. Lymphopenia was evaluated during the follow-up and defined as grade 1: absolute lymphocyte count (ALC) 800-999/µL; grade 2: ALC 500-799/µL; grade 3: ALC 200-499/µL and grade 4: ALC <200/µL. RESULTS: A total of 240 patients were included from 19 centers from Argentina. The mean annualized relapse rate during the 12-month pre-CLAD initiation was 1.19 ± 0.56 versus 0.22 ± 0.18 at month 12 and 0.19 ± 0.15 at month 24 ( P < 0.001). A total of 142 (59.2%) fulfilled the criteria of disease activity during the 12 months before treatment initiation, whereas 27 (11.3%) fulfilled it at month 12 and 38 (15.8%) at month 24, P < 0.001. Regarding no evidence of disease activity (NEDA), 202 (84.2%) patients achieved NEDA status at month 12 and 185 (77%) at month 24. The most frequent incidence density of lymphopenia for course 2 observed was also for grade 1, 6.1 (95% confidence interval [CI] = 5.5-7.1). The overall incidence density of lymphopenia grade 4 was 0.1 (95% CI = 0.06-0.19). CONCLUSION: This information will help when choosing the best treatment option for Argentinean patients.

Treatment strategies and responses for attacks of neuromyelitis optica spectrum disorder: A real-world retrospective cohort study.

We aimed to assess the treatment strategies utilized in patients with neuromyelitis optica spectrum disorder (NMOSD) experiencing relapses, including their frequency, types, and response after 6 months based on the Expanded Disability Status Scale (EDSS) score. METHODS: We conducted a retrospective study involving NMOSD patients from the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). Treatment response at 6 months was categorized as "good" if the EDSS score decreased by ≥1 point after a nadir EDSS score ≤ 3, or by ≥2 points after a nadir EDSS score > 3, "poor" if the EDSS score decrease was slighter, and as "absent" if the EDSS score remained unchanged or worsened. RESULTS: We included 120 NMOSD patients (seropositive N = 75), who experienced 250 NMOSD-related relapses and received 248 treatments. At 6 months, complete recovery was achieved in 70/98 (71.4%) and 15/19 (79%) patients, respectively. Predictors of a "good" response in our regression model were a younger age at disease onset (OR:3.54, CI95% 2.45-5.01, p < 0.0001) and a short delay from onset of relapse to treatment initiation (OR:1.56, CI95% 1.22-2.13, p = 0.004). CONCLUSIONS: Approximately two-thirds of patients experienced complete recovery, and younger age and a short delay to start treatment were independent predictors of a "good" response.

Selection of disease modifying therapies in multiple sclerosis based on patient's age and disease activity: Data from a nationwide registry.

BACKGROUND: Knowledge of the safety and efficacy of disease-modifying therapies (DMTs) in older patients with Multiple Sclerosis (pwMS) is limited due to their exclusion from clinical trials. Our purpose is to evaluate the choice of DMTs in pwMS older than 50 years old in a real-world setting. METHODS: Cross-sectional study of pwMS from the Argentine MS and NMOSD Registry. We included patients under 35 and above 50 years old prescribed DMTs. Disease activity was categorized as highly active (HA) or not highly active (NHA), and DMTs were classified as low efficacy therapies (LET) or high efficacy therapies (HET). RESULTS: 1460 patients (65% females) were enrolled. The HA group comprised 241 patients, 198 young (82.2%) and 43 older (17.8%). The NHA group included 1219 patients, 893 young (73%) and 326 older (27%). In the NHA group, older patients received LET more frequently than younger patients (66% versus 44%; p < 0.01). In the HA group, older patients received LET in 61% of cases, whereas younger patients received HET in 71% (p = 0.01). CONCLUSION: The study shows the preference of LET in older patients regardless of disease activity. However it does not demonstrate a difference in disability in older patients based on low vs high efficacy DMTs used, probably due to the design of the study. Further longitudinal studies are warranted to address this issue.

Occurrence of area postrema syndrome during follow-up: phenotype and influence over NMOSD activity in LATAM in real-world settings.

INTRODUCTION: We aimed to assess the frequency, duration, and severity of area postrema syndrome (APS) during follow-up in neuromyelitis optica spectrum disorder (NMOSD) patients, as well as its association with inflammatory activity and prognostic factors of APS severity in a real-world setting. METHODS: We conducted a retrospective study on a cohort of Latin American (LATAM) NMOSD patients who had experienced APS during their follow-up. Patients from Mexico, Peru, Brazil, Colombia, Panama, Chile and Argentina patients who met 2015 NMOSD criteria were included. We evaluated data on symptom type (nausea, vomiting and/or hiccups), frequency, duration, severity (measured by APS severity scale), association with other NMOSD core relapses, and acute treatments (symptomatic and immunotherapy or plasmapheresis). Logistic regression was conducted to evaluate factors associated with APS severity (vs. mild-moderate). RESULTS: Out of 631 NMOSD patients, 116 (18.3%) developed APS during their follow-up. The most common APS phenotype was severe. Inflammatory activity (i.e., relapses) significantly decreased after the onset of APS. Half of the patients experienced isolated APS with a median duration of 10 days, and the most frequently used acute treatment was IV steroids. All three symptoms were present in 44.6% of the patients. APS symptoms resolved following immunotherapy. Logistic regression did not identify independent factors associated with the severity of APS. CONCLUSIONS: Our findings indicate that 18.3% of NMOSD patients developed APS during the follow-up period, with most patients fulfilling criteria for severe APS. The inflammatory activity decreased after the onset of APS compared to the previous year.

Clinical impact of gender and age at onset on disease trajectory in primary progressive multiple sclerosis patients.

BACKGROUND AND OBJECTIVES: Primary-progressive multiple sclerosis (PPMS) is characterized by gradual neurological deterioration without relapses. This study aimed to investigate the clinical impact of gender and age at disease onset on disease progression and disability accumulation in patients with this disease phenotype. METHODS: Secondary data from the RelevarEM registry, a longitudinal database in Argentina, were analyzed. The cohort comprised patients with PPMS who met inclusion criteria. Statistical analysis with multilevel Bayesian robust regression modeling was conducted to assess the associations between gender, age at onset, and Expanded Disability Status Scale (EDSS) score trajectories. RESULTS: We identified 125 patients with a confirmed diagnosis of PPMS encompassing a total of 464 observations. We found no significant differences in EDSS scores after 10 years of disease progression between genders (-0.08; credible interval (CI): -0.60, 0.42). A 20-year difference in age at onset did not show significant differences in EDSS score after 10 years of disease progression (0.281; CI: -0.251, 0.814). Finally, we also did not find any clinically relevant difference between gender EDSS score with a difference of 20 years in age at onset (-0.021; CI: -0.371, 0.319). CONCLUSION: Biological plausibility of gender and age effects does not correlate with clinical impact measured by EDSS score.

Mortality of neuromyelitis optica spectrum disorder patients in an Argentinean population: A study from the RelevarEM registry.

We aimed to evaluate mortality and causes of death among Argentinean neuromyelitis optica spectrum disorder (NMOSD) patients and identify predictors of death. Retrospective study included 158 NMOSD patients and 11 (7%) patients died after 11 years of follow-up for a total exposure time of 53,345 days with an overall incidence density of 2.06 × 10.000 patients/day (95% CI 1.75-2.68). Extensive cervical myelitis with respiratory failure (45%) was the most frequent cause of death. Older age (HR = 2.05, p = 0.002) and higher disability score (HR = 2.30, p < 0.001) at disease onset were independent predictors of death. We found an 11-year mortality rate of 7% in Argentinean NMOSD patients.