Simón Cárdenas-Robledo

Clinically silent MRI lesions occur frequently in people with relapsing-remitting multiple sclerosis (RRMS) despite disease modifying therapy (DMT). Guidelines only routinely recommend DMT escalation after multiple silent lesions, and adherence is variable. We explored outcomes and the effect of treatment escalation following single and multiple on-treatment silent lesions. This cohort study and emulated target trial used MSBase registry data from 99 clinics in 26 countries between 2007 and 2025. Clinically stable participants receiving any DMT for RRMS with silent lesions versus without silent lesions were compared. Among participants with silent lesions while taking platform or moderate-efficacy DMTs, outcomes following treatment escalation within 6 months versus no treatment escalation (unless a post-MRI clinical event occurred) were compared. The primary outcome was an MS relapse, and the secondary outcome was 6-month confirmed disability worsening. A total of 10,232 participants met inclusion criteria (71.7% female, mean age 41 [SD 11]). The 2-year cumulative incidence of relapse was 27.8% (95% CI: 25.7%-29.9%) in participants with silent lesions versus 14.3% (95% CI: 13.5%-15.2%) without (adjusted hazard ratio [aHR] 1.76 [95% CI: 1.57-1.97]). The 2-year cumulative incidence of disability worsening was 13.8% (95% CI: 12.2%-15.5%) in participants with silent lesions versus 11.4% (95% CI: 10.7%-12.2%) without (aHR 1.38 [95% CI: 1.18-1.62]). Rates of relapse and disability worsening were higher following single and multiple silent lesions versus no silent lesions. The emulated trial included 2,264 participants with ≥1 silent lesion on platform or moderate efficacy DMTs, 286 of whom escalated DMT within 6 months following silent lesions. The 4-year cumulative incidence of relapse was lower following treatment escalation (16.8% [95% CI: 12.4%-23.4%]) versus continuation (38.9% [95% CI: 35.8%-42.1%]), aHR 0.34 (95% CI: 0.23-0.47), with similar aHRs following single and multiple silent lesions. The 4-year cumulative incidence of disability worsening was similar following treatment escalation (16.0% [95% CI: 10.8%-22.2%]) versus continuation (17.7% [95% CI: 15.3%-20.1%]), aHR 0.89 (95% CI: 0.56-1.33). People with RRMS with single or multiple on-treatment silent MRI lesions have higher subsequent risks of relapse and disability worsening than people without silent lesions. DMT escalation mitigates the relapse risk, though disability worsening continues at a similar rate over 4 years. Contrary to guidelines, DMT escalation should be considered after single or multiple silent lesions.

Background: Left-truncation is an unrecorded interval between multiple sclerosis (MS) onset and initial data in observational studies. This delay may bias estimates of disease-modifying therapy (DMT) effectiveness, especially when determined by patient or disease characteristics. Objectives: To examine whether causal effect estimates of DMTs over the full disease course can be reliably derived from left-truncated registry data. Methods: We analysed data from MSBase (144 centres, 41 countries) to assess the impact of left-truncation on causal treatment effect estimates. Cox marginal structural models (MSMs) estimated hazard ratios (HRs) for relapses, disability worsening and improvement, considering left-truncation at random and not-at-random. Fixed-time truncation and multivariable adjustment were applied to remediate bias. Results: The study included 5588 patients tracked from true MS onset. The null model, without left-truncation, estimated the DMT effect on relapse risk (HR = 0.64; 95% confidence interval (CI) = 0.54–0.77). Left-truncation inflated this estimate. Shorter random truncation (1 year) produced greater bias (HR = 0.34), decreasing with longer durations (3-year HR = 0.48). Truncation not-at-random biased relapse estimates (HR = 0.37). Disability outcomes were less sensitive. Conclusion: MSMs can reliably estimate DMT effectiveness in left-truncated MS registry data, although accuracy depends on truncation mechanism and duration. Both random and not-at-random truncation impact relapse estimates. Disability outcomes appear less sensitive. Fixed-time truncation and covariate adjustment mitigated bias.

Background: Ocrelizumab, a monoclonal antibody targeting CD20+ B cells, is a high-efficacy therapy for multiple sclerosis (MS). Methods: Patients with relapse-onset MS treated with ocrelizumab, fingolimod, natalizumab or alemtuzumab for ≥6 months were identified from three registries: MSBase, OFSEP and Danish MS Registry. Pairwise comparisons were performed in the overall cohort and 14 predefined clinicodemographic subgroups based on sex, disease activity, MS duration, Expanded Disability Status Scale, prior therapy and reason for prior treatment cessation. Relapses, progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) were compared in pairwise-censored groups. Results: Fingolimod was associated with a higher annualised relapse rate (ARR) (0.14 vs 0.06, p<0.001), relapse risk (HR 2.26, 95% CI 1.98 to 2.58), RAW (1.62, 1.08 to 2.43) and lower risk of disability improvement (0.78, 0.63 to 0.96) than ocrelizumab. Superiority of ocrelizumab over fingolimod on relapses was maintained in all subgroups. Natalizumab was associated with marginally higher ARR (0.10 vs 0.07, p<0.001), relapse risk (1.35, 1.16 to 1.57) and RAW (1.77, 1.07 to 2.94) than ocrelizumab. Alemtuzumab was associated with higher ARR (0.18 vs 0.12, p<0.001) and relapse risk (1.48, 1.25 to 1.76) than ocrelizumab, but there was no evidence for a difference in risk of RAW. There was no evidence for a difference on PIRA in any comparisons. Ocrelizumab was superior to natalizumab and alemtuzumab on relapses in patients who were not treatment-naïve, experienced disease activity on the prior therapy or stopped prior therapy due to lack of efficacy. Conclusions: Ocrelizumab provides superior control of relapses and RAW, especially among patients with prior on-treatment disease activity. Treatment of PIRA remains an unmet need.

Introduction: MS patients are at increased risk of comorbidities and use more healthcare resources. Multimorbidity approached as the number of conditions is flawed by classifying patients with different needs as equal. We aimed to explore how comorbidities cluster and their impact on healthcare resource usage. Methods: We used latent‐class models of up to 10 clusters in a population‐based sample of MS patients. The optimal number of clusters was determined using model metrics and similarity/entropy measures, and cluster stability was assessed by bootstrapping. Sociodemographic characteristics and healthcare‐resource usage according to the clusters assigned were compared to each other and to patients without comorbidities using univariable and adjusted linear regression models. Results: In 5548 MS cases, of which 60% had comorbidities, the optimal number of comorbidity clusters was two, comprising a high frequency of cardiovascular comorbidities and psychiatric disorders. Patients in the cardiovascular cluster were older, and in the psychiatric cluster were more frequently female. After adjusting for sociodemographic variables, healthcare resource usage was higher for patients with comorbidities, particularly for nurse (1.1 more average yearly visit; [95% CI 0.41–1.8]; p = 0.002), primary care (1.8 more visits; [95% CI 1.4–2.1]; p < 0.001), and medication dispensation (336 more dosage units; [95% CI 260–402]; p < 0.001) in the cardiovascular cluster, and annual sick‐leave days (3.8 more days; [95% CI 0.25–7.3]; p = 0.036) in the psychiatric cluster. Discussion: We observed clustering of comorbidities around cardiovascular comorbidities and mental disorders, which impacted healthcare resource usage differently. Further research is needed to assess the influence of these clusters on the prognosis of MS.

In the treatment of relapsing-remitting multiple sclerosis, autologous haematopoietic stem cell transplant (AHSCT) and immune-reconstitution therapies show several similarities. These treatment strategies have not yet been compared head-to-head. This study emulated pairwise trials of comparative effectiveness of stem cell transplant versus immune-reconstitution therapies cladribine and alemtuzumab. This cohort/registry study of comparative treatment effectiveness included data from seven specialist multiple sclerosis centres with AHSCT programmes (RESCUE-MS) and international MSBase registry during 2006–2023. The study included patients with relapsing-remitting multiple sclerosis treated with AHSCT, cladribine or alemtuzumab, with a minimum of 2-months follow-up before commencing study therapy and ≥2 disability assessments after commencing the study therapy. Patients were matched on a propensity score derived from their clinical and demographic characteristics. The matched groups were compared according to annualized relapse rates, freedom from relapses and 6-month confirmed disability worsening and improvement (measured with the Expanded Disability Status Scale). The matching of 143 (stem cell) to 283 cladribine-treated patients and 134 (stem cell) to 562 alemtuzumab-treated patients reduced the measured differences between the groups by 98% and 96%, respectively. The matched patients had high mean disease activity (>0.8 relapses in the prior 2 years), mean Expanded Disability Status Scale scores of 3–4, and were followed-up for a mean of 3.8–3.9 (stem cell), 1.9 (cladribine) or 4.5 years (alemtuzumab). Compared with cladribine, stem cell transplant was associated with a lower risk of relapse [mean annualized relapse rate ± standard deviation (SD): 0.05 ± 0.28 versus 0.16 ± 0.39, respectively; hazard ratio: 0.24; 95% confidence interval (CI): 0.15–0.41], similar risk of disability worsening (hazard ratio: 0.70; 95% CI: 0.34–1.43) and higher probability of disability improvement (hazard ratio: 2.19; 95% CI: 1.31–3.66). Compared with alemtuzumab, stem cell transplant was associated with a lower risk of relapses (mean annualized relapse rate ± SD: 0.04 ± 0.23 versus 0.09 ± 0.21, respectively; hazard ratio: 0.52; 95% CI: 0.29–0.93), similar risk of disability worsening (hazard ratio: 0.95; 95% CI: 0.53–1.72) and higher probability of disability improvement (hazard ratio: 2.03; 95% CI: 1.23–3.34). Thirty-four per cent of patients treated with stem cell transplant experienced delayed complications, mainly infections. No treatment-associated deaths were reported. Among patients with active relapsing-remitting multiple sclerosis and moderate disability, AHSCT is superior to cladribine and alemtuzumab at suppressing relapses and enabling recovery of neurological function. The high effectiveness of stem cell transplant is likely attributable to a complex interplay between immune suppression and reconstitution.

Introducción: la esclerosis múltiple es una enfermedad crónica, neurodegenerativa y autoinmune del sistema nervioso central. En Colombia, se considera como la enfermedad huérfana-rara más común, con 3224 casos reportados entre los años 2016 y 2021. El tratamiento se basa en una variedad de terapias modificadoras de la enfermedad que busca reducir las recaídas, disminuir la actividad en imágenes y retrasar la progresión de la discapacidad; sin embargo, el manejo clínico presenta desafíos debido a la falta de definiciones claras sobre el fallo de las terapias modificadoras y la falta de guías claras para el cambio de tratamiento. Objetivo: elaborar una definición de fallo terapéutico y diseñar un algoritmo para su manejo en pacientes con esclerosis múltiple recurrente en Colombia. Materiales y métodos: se llevó a cabo un consenso de expertos mediante la metodología Delphi en dos rondas virtuales con diez expertos. Además, se hizo una revisión de la literatura para obtener información destinada al diseño de la definición y al algoritmo del fallo terapéutico. Resultados: se elaboró una definición de fallo terapéutico compuesta por una introducción y la descripción de las variables clínicas que se utilizarán para determinar si un paciente presenta fallo terapéutico, y también se diseñó un algoritmo con una estrategia de optimización terapéutica, considerando las necesidades individuales de cada paciente según la definición diseñada previamente. Conclusiones: se desarrolló una definición y un algoritmo de manejo específico para Colombia basados en evidencia, experiencia clínica y recomendaciones de expertos. Estas herramientas facilitarán la toma de decisiones, el seguimiento y la eficiencia de los tratamientos, y se actualizarán periódicamente para reflejar avances científicos y mejores prácticas.

Effective interventions for Multiple Sclerosis require timely treatment optimization which usually involves switching disease modifying therapies. The patterns of prescription and the reasons for changing treatment in people with MS, especially in low prevalence populations, are unknown. To describe the persistence, reasons of DMT switches and prescription patterns in a cohort of Colombian people with MS. We conducted a retrospective observational study including patients with confirmed MS with at least one visit at our centre. We estimated the overall incidence rate of medication changes and assessed the persistence on medication with Kaplan–Meier survival estimates for individual medications and according to efficacy and mode of administration. The factors associated with changing medications were assessed using adjusted Cox proportional-hazards models. The reasons for switching medication changes were described, and the prescription patterns were assessed using network analysis, with measures of centrality. Seven hundred one patients with MS were included. Mean age was 44.3 years, and 67.9% were female. Mean disease duration was 11.3 years and 84.5% had relapsing MS at onset, with median EDSS of 1.0. Treatment was started in 659 (94%) of the patients after a mean of 3 years after MS symptom onset. Among them, 39.5% maintained their initial DMT, 29.9% experienced a single DMT change, while 18.7% went through two, and 11.9% had three or more DMT changes until the final follow-up. The total number of treatment modifications reached 720, resulting in an incidence rate of 1.09 (95% confidence interval: 1.01–1.17) per patient per year The median time to change after the first DMT was 3.75 years, and was not different according to the mode of administration or efficacy classification. The main reasons for changing DMT were MS activity (relapses, 56.7%; MRI activity, 18.6%), followed by non-serious adverse events (15.3%) and disability (11.1%). Younger age at MS onset, care under our centre and insurer status were the main determinants of treatment change. Network analysis showed that interferons and fingolimod were the most influential DMTs. A majority of patients switch medications, mostly due to disease activity, and in association with age and insurer status.

Background Multiple sclerosis is a chronic disease of the central nervous system characterized by autoimmune demyelination. Various immunomodulatory medications are available for its treatment, among which anti-CD20 monoclonal antibodies have demonstrated superior efficacy compared to other disease-modifying therapies. However, there is a lack of direct comparison between the four available anti-CD20 monoclonal antibodies. Therefore, this study aims to systematically assess the relative efficacy and safety of anti-CD20 monoclonal antibodies for treating relapsing multiple sclerosis. Materials and Methods We will conduct a systematic review of phase IIb and phase III clinical trials of anti-CD20 monoclonal antibodies for the treatment of relapsing multiple sclerosis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A comprehensive review of the Cochrane Central Register of Controlled Trials; MEDLINE; Embase; ClinicalTrials; International Clinical Trials Registry Platform; OpenGray; and MedRxiv will be performed. Two independent reviewers will select titles, abstracts, and eligible full texts to execute the data extraction. The risk of bias will be assessed with the Cochrane RoB 2 tool. Data on pre-specified outcomes will be analyzed for the selected articles using a random-effects network meta-analysis with a frequentist framework. Summary statistics, along with 95% confidence intervals will be presented, and the effectiveness and safety of each intervention will be ranked using the surface under the cumulative ranking curve. A missing data and a sensitivity analysis will be conducted. We will use the GRADE approach to assess the certainty of the direct, indirect, and network estimate for all outcomes. Results and Conclusion The results will provide evidence of the relative efficacy and safety of anti-CD20 monoclonal antibodies for the treatment of relapsing multiple sclerosis. Systematic review registration PROSPERO registration number CRD42023437996