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.

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.

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.

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.

Burden of treatment and quality of life in relapsing remitting multiple sclerosis patients under early high efficacy therapy in Argentina: Data from the Argentinean registry.

The objective of this study was to describe and compare the burden of treatment (BOT) and the quality of life (QoL) in early high efficacy therapy (HET) vs. escalation therapy in relapsing remitting multiple sclerosis (RRMS) patients included in RelevarEM, the Argentinean registry of MS (RelevarEM, NCT 03,375,177). METHODS: cross sectional study conducted between September and December 2022. Participating patients were adults, RRMS patients who initiated (during the last three years) their treatment with a HET (natalizumab, ocrelizumab, alemtuzumab, cladribine) or with escalation treatment (beta interferon, glatiramer acetate, teriflunomide, dimethyl fumarate or fingolimod). Clinical and demographic aspect were collected. QoL and BOT was measured with the validated to Spanish MusiQol and BOT questionnaire. Propensity score (PS)-based nearest-neighbor matching was applied to homogenize groups. Comparisons were be done using a linear regression analysis model stratified by matched pairs, with BOT and QoL assessments as main outcomes. RESULTS: 269 patients were included in the analysis, mean age 33.7 ± 5.7 years, 193 (71.7 %) were female. A total of 136 patients were on early HET while 133 were on escalation therapy. In the entire group the mean total BOT score (±SD) was 48.5 ± 15.3 while in the group of patients receiving early HET we observed that the mean BOT score (±SD) was 43.5 ± 12.2 vs. 54.3 ± 13.3 in escalation treatment (p < 0.0001). Regarding the score QoL (±SD), in the entire sample we observed a global score of 77.4 ± 11.2. When we stratified groups, in HET (±SD) it was 81.3 ± 14 vs. 74.1 ± 18.3 in escalation therapy (p = 0.0003). CONCLUSION: in this multicenter study that included 269 patients from Argentina we observed in early HET a significantly lower BOT and higher QoL than patients receiving escalation therapy.

Second Nationwide Tuberculosis Outbreak Caused by Bone Allografts Containing Live Cells - United States, 2023.

During July 7-11, 2023, CDC received reports of two patients in different states with a tuberculosis (TB) diagnosis following spinal surgical procedures that used bone allografts containing live cells from the same deceased donor. An outbreak associated with a similar product manufactured by the same tissue establishment (i.e., manufacturer) occurred in 2021. Because of concern that these cases represented a second outbreak, CDC and the Food and Drug Administration worked with the tissue establishment to determine that this product was obtained from a donor different from the one implicated in the 2021 outbreak and learned that the bone allograft product was distributed to 13 health care facilities in seven states. Notifications to all seven states occurred on July 12. As of December 20, 2023, five of 36 surgical bone allograft recipients received laboratory-confirmed TB disease diagnoses; two patients died of TB. Whole-genome sequencing demonstrated close genetic relatedness between positive Mycobacterium tuberculosis cultures from surgical recipients and unused product. Although the bone product had tested negative by nucleic acid amplification testing before distribution, M. tuberculosis culture of unused product was not performed until after the outbreak was recognized. The public health response prevented up to 53 additional surgical procedures using allografts from that donor; additional measures to protect patients from tissue-transmitted M. tuberculosis are urgently needed.

Clinical characterization of long-term multiple sclerosis (COLuMbus) patients in Argentina: A cross-sectional non-interventional study.

BACKGROUND: Most Multiple Sclerosis (MS) clinical trials fail to assess the long-term effects of disease-modifying therapies (DMT) or disability. METHODS: COLuMbus was a single-visit, cross-sectional study in Argentina in adult patients with ≥10 years of MS since first diagnosis. The primary endpoint was to determine patient disability using the Expanded Disability Status Scale (EDSS). The secondary endpoints were to evaluate the distribution of diagnoses between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS), patient demographics, disease history, and the risk of disability progression. The relationship between baseline characteristics and the current disability state and the risk of disability progression was assessed. RESULTS: Out of the 210 patients included, 76.7 % had a diagnosis of RRMS and 23.3 % had been diagnosed with SPMS, with a mean disease duration of 17.9 years and 20.5 years, respectively. The mean delay in the initial MS diagnosis was 2.6 years for the RRMS subgroup and 2.8 years for the SPMS subgroups. At the time of cut-off (28May2020), 90.1 % (RRMS) and 75.5 % (SPMS) of patients were receiving a DMT, with a mean of 1.5 and 2.0 prior DMTs, respectively. The median EDSS scores were 2.5 (RRMS) and 6.5 (SPMS). In the RRMS and SPMS subgroups, 23 % and 95.9 % of patients were at high risk of disability, respectively; the time since first diagnosis showed a significant correlation with the degree of disability. CONCLUSIONS: This is the first local real-world study in patients with long-term MS that highlights the importance of recognizing early disease progression to treat the disease on time and delay disability.

Incidence of SARS-CoV-2 infection in patients with multiple sclerosis who received SARS-CoV-2 vaccines and are under treatment with high-efficacy therapies in Argentina.

We aimed to evaluate the incidence of SARS-CoV-2 breakthrough infection of SARS-CoV-2 vaccines in people with MS (PwMS) on high-efficacy disease-modifying therapies (HET) included in the national MS registry in Argentina (RelevarEM). METHODS: Non-interventional, retrospective cohort study that collected information directly from RelevarEM. Adult PwMS who had been treated for at least 6 months with a HET (ocrelizumab, natalizumab, alemtuzumab, cladribine) who had received at least two doses of SARS-CoV-2 vaccines available in Argentina were included. Full course of vaccination was considered after the second dose of the corresponding vaccines. Cumulative incidence of SARS-CoV-2 infection was reported for the whole cohort by Kaplan-Meier survival curves (which is expressed in percentage) as well as incidence density (which is expressed per 10.000 patients/day with 95% CI). RESULTS: Two hundred twenty-eight PwMS were included. Most frequent first and second dose received was AstraZeneca vaccine, followed by Sputnik vaccine. Most frequent HETs used in included patients were cladribine in 79 (34.8%). We found an incidence density of breakthrough COVID-19 infection of 3.5 × 10.000 patients/day (95% CI 2.3-6.7) after vaccination in Argentina. We described the incidence rate after vaccination for every HET used, it being significantly higher for ocrelizumab compared with other HETs (p = 0.005). Only five patients presented a relapse during the follow-up period with no differences regarding the pre-vaccination period. CONCLUSIONS: We found an incidence density of breakthrough COVID-19 infection of 3.5 × 10.000 patients/day (95% CI 2.3-6.7) after vaccination in Argentina.

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.

Evaluation of the use of high-efficacy treatments (HETs) in patients with relapsing-remitting multiple sclerosis in Argentina.

BACKGROUND: Disease-modifying therapies (DMTs) in multiple sclerosis (MS) can be classified according to the efficacy in which they prevent inflammatory activity. To date, there are limited data regarding the use of high-efficacy treatments (HETs) in Latin America (LATAM). We aimed to analyze the use of HETs in Argentina, focusing on the clinical and sociodemographic characteristics of the patients who use these treatments and the changes in the trend of use over the years. METHODS: A retrospective cohort study was done using the Argentina MS patient registry, RelevarEM. Patients diagnosed with relapsing-remitting MS (RRMS) according to validated diagnostic criteria and under treatment with natalizumab, alemtuzumab, cladribine, rituximab or ocrelizumab were included. RESULTS: Out of 2450 RRMS patients under a DMT, 462 (19%) were on HETs. One third of those patients (35%) received HETs as the first treatment. The most frequent reason for switching to HETs was treatment failure to previous DMT (77%). The time from MS diagnosis to the first HET in treatment-naive patients was less than one year (IQR: 0-1 year) and in treatment-experienced patients it was 5 years (IQR: 3-9 years). Between 2015 and 2017 (P1), 729 patients included in RelevarEM started a new treatment, of which 85 (11.65%) were HETs. Between 2018 and 2020 (P2), 961 patients included in RelevarEM started a new treatment, of which 284 (29.55%) were HETs. When comparing P2 with P1, a significant increase in the use of HETs was observed (p < 0.01). The most frequently used HETs were alemtuzumab (50.59%) in P1, and cladribine (45.20%) in P2. CONCLUSION: The demographic and clinical characteristics of patients under HET in Argentina were identified. Based on a real-world setting, we found a significant trend towards and a rapid increase in the use of HETs in clinical practice in patients with RRMS.

Implementation of Bedaquiline, Pretomanid, and Linezolid in the United States: Experience Using a Novel All-Oral Treatment Regimen for Treatment of Rifampin-Resistant or Rifampin-Intolerant Tuberculosis Disease.

BACKGROUND: Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring. METHODS: Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring. RESULTS: Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. CONCLUSIONS: BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

Achieving no evidence of disease activity-3 in highly active multiple sclerosis patients treated with cladribine and monoclonal antibodies.

Background: We aimed to determine the proportion of highly active multiple sclerosis patients under high-efficacy therapies (HETs) achieve no evidence of disease activity-3 (NEDA-3) at 1 and 2 years, and to identify factors associated with failing to meet no evidence of disease activity 3 at 2 years. Methods: This retrospective cohort study based on Argentina Multiple Sclerosis patient registry (RelevarEM), includes highly active multiple sclerosis patients who received HETs. Results: In total, 254 (78.51%) achieved NEDA-3 at year 1 and 220 (68.12%) achieved NEDA-3 at year 2. Patients who achieved NEDA-3 at 2 years had a shorter duration of multiple sclerosis (p < 0.01) and a shorter time between first treatment and current treatment (p = 0.01). Early high-efficacy strategy patients reached NEDA-3 more frequently (p < 0.01). Being a naïve patient (odds ratio: 3.78, 95% confidence interval 1.50-9.86, p < 0.01) was an independent predictor to reach NEDA-3 at 2 years. No association was found between type of HETs and NEDA-3 at 2 years when adjusted for potential confounders (odds ratio: 1.73; 95% confidence interval 0.51-6.06, p 0.57). Conclusion: We found a high proportion of patients who achieved NEDA-3 at 1 and 2 years. Early high-efficacy strategy patients had a higher probability of achieving NEDA-3 at 2 years.

Disability outcomes in NMOSD and MOGAD patients: data from a nationwide registry in Argentina.

The objective was to evaluate time to reach an EDSS of 4, 6, and 7 in NMOSD and MOGAD patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03,375,177). METHODS: NMOSD patients diagnosed according to 2015 criteria and with MOGAD were identified. Patients with at least 3 years of follow-up and periodic clinical evaluations with EDSS outcomes were included. AQP4-antibody and MOG-antibody status was recorded, and patients were stratified as seropositive and seronegative for AQP4-antibody. EDSS of 4, 6, and 7 were defined as dependent variables. Log rank test was used to identify differences between groups. RESULTS: Registry data was provided for a total of 137 patients. Of these, seventy-five presented AQP4-ab-positive NMOSD, 45 AQP4-ab-negative NMOSD, and 11 MOGAD. AQP4-ab status was determined by cell-based assay (CBA) in 72% of NMOSD patients. MOG-ab status was tested by CBA in all cases. Mean time to EDSS of 4 was 53.6 ± 24.5 vs. 63.1 ± 32.2 vs. 44.7 ± 32 months in seropositive, seronegative NMOSD, and MOGAD, respectively (p = 0.76). Mean time to EDSS of 6 was 79.2 ± 44.3 vs. 75.7 ± 48.6 vs. 54.7 ± 50 months in seropositive, seronegative NMOSD, and MOGAD (p = 0.23), while mean time to EDSS of 7 was 86.8 ± 54 vs. 80.4 ± 51 vs. 58.5 ± 47 months in seropositive, seronegative NMOSD, and MOGAD (p = 0.39). CONCLUSION: No differences were observed between NMOSD (seropositive and seronegative) and MOGAD in survival curves.

Four-Month High-Dose Rifampicin Regimens for Pulmonary Tuberculosis.

BACKGROUND: Shorter but effective tuberculosis treatment regimens would be of value to the tuberculosis treatment community. High-dose rifampicin has been associated with more rapid and secure lung sterilization and may enable shorter tuberculosis treatment regimens. METHODS: We randomly assigned adults who were given a diagnosis of rifampicin-susceptible pulmonary tuberculosis to a 6-month control regimen, a similar 4-month regimen of rifampicin at 1200 mg/d (study regimen 1 [SR1]), or a 4-month regimen of rifampicin at 1800 mg/d (study regimen 2 [SR2]). Sputum specimens were collected at regular intervals. The primary end point was a composite of treatment failure and relapse in participants who were sputum smear positive at baseline. The noninferiority margin was 8 percentage points. Using a sequence of ordered hypotheses, noninferiority of SR2 was tested first. RESULTS: Between January 2017 and December 2020, 672 patients were enrolled in six countries, including 191 in the control group, 192 in the SR1 group, and 195 in the SR2 group. Noninferiority was not shown. Favorable responses rates were 93, 90, and 87% in the control, SR1, and SR2 groups, respectively, for a country-adjusted absolute risk difference of 6.3 percentage points (90% confidence interval, 1.1 to 11.5) comparing SR2 with the control group. The proportions of participants experiencing a grade 3 or 4 adverse event were 4.0, 4.5, and 4.4% in the control, SR1, and SR2 groups, respectively. CONCLUSIONS: Four-month high-dose rifampicin regimens did not have dose-limiting toxicities or side effects but failed to meet noninferiority criteria compared with the standard 6-month control regimen for treatment of pulmonary tuberculosis. (Funded by the MRC/Wellcome Trust/DFID Joint Global Health Trials Scheme; ClinicalTrials.gov number, NCT02581527.)

Incidence of COVID-19 after vaccination in people with multiple sclerosis in Argentina: Data from the nationwide registry RelevarEM.

The objective of the study was to evaluate the incidence of COVID-19 after complete vaccination in people with multiple sclerosis (PwMS) included in the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). METHODS: cohort study conducted between May 2021 and December 2021. The primary outcome was the appearance of infection during the follow-up time (at least three months after complete vaccination (second dose)). Data was collected through the contact between the treating physician and the patient. Specific information was requested (date, symptoms, need for hospitalization, ventilatory assistance, treatment, and evolution). The contact was made every 30 days during the period of 3 months after the full dose vaccination. A positive COVID-19 case was defined according to the definition established by the Ministry of Health in Argentina. Cumulative incidence was reported by Kaplan Meier survival curves as well as incidence density. RESULTS: A total of 576 PwMS were included, mean age 45.2 ± 13 years, 432 (75%) RRMS, 403 (70%) were female. The mean and median time of follow-up after the second dose was 91 ± 17 and 94 ± 21 days respectively. Most frequent first and second dose received was Astra-Zeneca vaccine, followed by Sputnik V vaccine. During follow-up a total of twenty COVID-19 cases were observed for a total exposure time of 39,557 days. The overall cumulative incidence for the observed period was 3.4% (SE 0.4%) with an overall incidence density of 5 × 10.000 patients/day (95%CI 0.7-12). We observed more cases in woman than men with an incidence density of 6 × 10.000 patients/day (95%CI 0.9-9) vs. 3 × 10.000 patients/day (95%CI 0.2-6) respectively, but not significantly different (IRR 1.7 95% CI 0.56-7.37 p = 0.15). CONCLUSION: we found an incidence density of breakthrough COVID-19 infection of 5 × 10.000 patients/day (95%CI 0.7-12) after vaccination in Argentina.

Rebound activity after fingolimod cessation: A case - control study.

BACKGROUND: There has been an increase in the number of reports of multiple sclerosis (MS) rebound activity (RA), which is usually defined as a severe disease reactivation after natalizumab or fingolimod withdrawal that exceeds pre-treatment baseline inflammatory activity. The frequency and risk factors that could predict RA remain unknown. Fingolimod is currently the most frequently prescribed disease modifying therapy for MS in Argentina, so that there is a need to determine possible predictors of RA. OBJECTIVES: To identify risk factors for developing RA after fingolimod cessation; to describe RA characteristics, management and evolution. METHODS: The study was a multicenter, retrospective, case-control study of patients with MS who had discontinued fingolimod and were followed up to nine months after discontinuation. Demographic, clinical and paraclinical data was extracted, including age, gender, MS phenotype, reason for discontinuation, number of relapses during the year prior to suspension, time treated with fingolimod, EDSS before, during and after rebound, MRI findings. RESULTS: 26 cases of RA were matched 1:1 with patients without RA. The median time elapsed to RA was 50 days. 68% showed worsening of the EDSS in the evaluation at 3 months of RA. When compared with the control group, no difference was found in terms of age, gender, phenotype, EDSS at the moment of suspension, reason for discontinuation, number of relapses in the previous year, and time on therapy. CONCLUSION: In this case-controlled study, no risk factors could be identified to predict RA after fingolimod cessation. Further controlled, prospective, better powered studies are needed to confirm these findings.

Clinical and demographic characteristics of male MS patients included in the national registry-RelevarEM. Does sex or phenotype make the difference in the association with poor prognosis?

BACKGROUND: In multiple sclerosis demographics there is a well-known female prevalence and male patients have been less specifically evaluated in clinical studies, though some clinical differences have been reported between sexes. OBJECTIVE: The objective of this study was to assess clinical and demographic differences between male and female patients included in the national Argentine MS Registry-RelevarEM. MATERIAL AND METHODS: This study was observational, retrospective, and was based on the data of 3099 MS patients included as of 04 April 2021. The statistical analysis plan included bivariate analyses with the crude data and also after adjustment for the MS phenotype, further categorized as progressive-onset MS or relapsing-onset MS. In the adjusted analysis, the Mantel-Haenszel odds ratio was compared to the crude odds ratio, to account for the phenotype as a confounder. RESULTS: The data from 1,074 (34.7%) men and 2,025 (65.3%) women with MS diagnosis were analysed. Males presented primary progressive disease two times more often than women (11% and 5%, respectively). In the crude analyses by sex, the presence of exclusively infratentorial lesions in the magnetic resonance imaging studies was more frequent in males than in females, but after adjustment by MS onset phenotype, such difference was only present in males with relapsing-onset MS (p = 0.00006). Similarly, worse Expanded Disability Status Scale scores were confirmed only in men with relapsing-onset disease after phenotype adjustment (p = 0.02). CONCLUSION: We did not find any statistically significant clinical or demographic difference between sexes when the progressive MS phenotype was specifically considered. However, the differences we found between the clinical phenotypes are in line with the literature and highlight the importance of stratifying the analyses by sex and phenotype when designing MS studies.

Seasonal variation in attacks of neuromyelitis optica spectrum disorders and multiple sclerosis: Evaluation of 794 attacks from a nationwide registry in Argentina.

BACKGROUND: Identification of triggers that potentially instigate attacks in neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) has remained challenging. We aimed to analyze the seasonality of NMOSD and MS attacks in an Argentinean cohort seeking differences between the two disorders. METHODS: A retrospective study was conducted in a cohort of NMOSD and MS patients followed in specialized centers from Argentina and enrolled in RelevarEM, a nationwide, longitudinal, observational, non-mandatory registry of MS/NMOSD patients. Patients with complete relapse data (date, month and year) at onset and during follow-up were included. Attack counts were analyzed by month using a Poisson regression model with the median monthly attack count used as reference. RESULTS: A total of 551 patients (431 MS and 120 NMOSD), experiencing 236 NMOSD-related attacks and 558 MS-related attacks were enrolled. The mean age at disease onset in NMOSD was 39.5 ± 5.8 vs. 31.2 ± 9.6 years in MS (p < 0.01). Mean follow-up time was 6.1 ± 3.0 vs. 7.4 ± 2.4 years (p < 0.01), respectively. Most of the included patients were female in both groups (79% vs. 60%, p < 0.01). We found a peak of number of attacks in June (NMOSD: 28 attacks (11.8%) vs MS: 33 attacks (5.9%), incidence rate ratio 1.82, 95%CI 1.15-2.12, p = 0.03), but no differences were found across the months in both disorders when evaluated separately. Strikingly, we observed a significant difference in the incidence rate ratio of attacks during the winter season when comparing NMOSD vs. MS (NMOSD: 75 attacks (31.7%) vs MS: 96 attacks (17.2%), incidence rate ratio 1.82, 95%CI 1.21-2.01, p = 0.02) after applying Poisson regression model. Similar results were observed when comparing the seropositive NMOSD (n = 75) subgroup vs. MS. CONCLUSIONS: Lack of seasonal variation in MS and NMOSD attacks was observed when evaluated separately. Future epidemiological studies about the effect of different environmental factors on MS and NMOSD attacks should be evaluated prospectively in Latin America population.

Accumulative risk of clinical event in high-risk radiologically isolated syndrome in Argentina: data from the nationwide registry RelevarEM.

INTRODUCTION: We aimed to analyze the accumulative risk of MRI and OB factors for evolution from RIS to MS in subjects included in the Argentinean MS registry (NCT03375177). METHODS: RIS subjects were identified according to RIS diagnosis criteria. Subjects were longitudinally followed with clinical and MRI at intervals of 6 months. Time from RIS identification to the first clinical event was estimated using Kaplan-Meier. Multivariable Cox regression models were created to assess the independent predictive value of demographic characteristics, as well as clinical, OB and MRI data on time to the first clinical event. The single and increased risk factor of evolution of RIS was quantified. RESULTS: A total of 88 RIS subjects, mean follow-up time 42 ± 4 months were included. 39 (44.3%) and 23 (26.1%) had a new MRI lesion or a clinical event, respectively, during the follow-up. OB (HR 5.9, 95% CI 1.29-10.1, p = 0.004), infratentorial lesions (HR 3.7, 95% CI 1.09-7.5) and spinal cord lesions (HR 5.3, 95% CI 1.4-8.2, p = 0.01) at RIS identification were independent predictors associated with a subsequent clinical event. The accumulative risk showed that when two of the three factors (OB, infratentorial or spinal cord lesions) were present the HR was 10.4, 95% CI 4.4-22, p < 0.001, and when three factors were present, it was HR 15.6, 95% CI 5.7-28, p < 0.001 for a relapse. CONCLUSION: The presence of three factors significantly increased the risk of clinical event; high-risk subjects should probably be managed by a different approach than those used for individuals without high-risk factors.