Browsing by Author "Kalincik, Tomas"

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Bayesian Network to Generate Representative Longitudinal Data in Multiple Sclerosis
(Sage Publications Ltd, 2025) Qiang, Zhe; Iqbal, Hassam; Sharmin, Sifat; Ozakbas, Serkan; Zakaria, Magd Fouad; Etemadifar, Masoud; Kalincik, Tomas
Cladribine as an Exit Strategy in People with MS Over the Age of 50
(Sage Publications Ltd, 2025) Roos, Izanne; Sharmin, Sifat; Mueller, Jannis; Horakova, Dana; Havrdova, Eva; Ozakbas, Serkan; Kalincik, Tomas
Comparative Effectiveness of Rituximab and Immunosuppressants in Neuromyelitis Optica Spectrum Disorder: a Retrospective Analysis of International Registry Data
(Sage Publications Ltd, 2025) Huang, Yishi; Engels, Daniel; Shaygannejad, Vahid; Horakova, Dana; Havrdova, Eva; Ozakbas, Serkan; Kalincik, Tomas
Citation - WoS: 12
Citation - Scopus: 8
Disease Activity in Pregnant and Postpartum Women With Multiple Sclerosis Receiving Ocrelizumab or Other Disease-Modifying Therapies
(Lippincott Williams & Wilkins, 2024) Yeh, Wei Z.; van der Walt, Anneke; Skibina, Olga G.; Kalincik, Tomas; Alroughani, Raed; Kermode, Allan G.; Fabis-Pedrini, Marzena J.
Background and Objectives Women with multiple sclerosis (MS) are at risk of disease reactivation in the early postpartum period. Ocrelizumab (OCR) is an anti-CD20 therapy highly effective at reducing MS disease activity. Data remain limited regarding use of disease-modifying therapies (DMTs), including OCR, and disease activity during peripregnancy periods. Methods We performed a retrospective cohort study using data from the MSBase Registry including pregnancies conceived after December 31, 2010, from women aged 18 years and older, with relapsing-remitting MS or clinically isolated syndrome. Women were classified by preconception exposure to DMTs, including OCR, rituximab (RTX), natalizumab (NAT), stratified into active (NAT-A; continued >= 28 weeks of gestation, restarted <= 1 month postpartum) or conservative (NAT-C; continued <= 4 weeks of gestation, restarted >1 month postpartum) strategies, dimethyl fumarate (DMF) or low-efficacy DMTs (interferon-beta, glatiramer acetate). Annualized relapse rates (ARRs) were calculated for 12-month prepregnancy, pregnancy, and 6-month postpartum periods. Results A total of 2,009 live births from 1,744 women were analyzed, including 73 live births from 69 women treated with preconception OCR. For OCR, no within-pregnancy relapse was observed and 3 women (4.1%) experienced 1 relapse in the postpartum period (ARR 0.09 [95% CI 0.02-0.27]). For NAT-A, 3 (3.7%) of 82 women relapsed during pregnancy (0.05 [0.01-0.15]) and 4 (4.9%) relapsed during postpartum (0.10 [0.03-0.26]). However, for NAT-C, 13 (15.9%) of 82 women relapsed within pregnancy (0.32 [0.20-0.51]) and 25 (30.5%) relapsed during postpartum (0.74 [0.50-1.06]). In the low-efficacy DMT group, 101 (7.6%) of 1,329 women experienced within-pregnancy relapse (0.12 [0.10-0.14]), followed by an increase in postpartum relapse activity with 234 women (17.6%) relapsing (0.43 [0.38-0.48]). This was similarly seen in the DMF group with 13 (7.9%) of 164 women experiencing within-pregnancy relapse (0.12 [0.06-0.20]) and 25 (15.2%) of 164 relapsing postpartum (0.39 [0.26-0.57]). Our RTX cohort had 0 of 24 women experiencing within-pregnancy relapse and 3 (12.5%) of 24 experiencing postpartum relapse. Discussion Women treated with OCR or NAT-A were observed to have low relapse rates during pregnancy and postpartum. NAT-C was associated with increased risk of relapses. There was no within-pregnancy relapse in our RTX cohort, although we caution overinterpretation due to our sample size. An effective DMT strategy with a favorable safety profile for the mother and infant should be discussed and implemented well in advance of planning a family. Classification of Evidence This study provides Class III evidence that for women with relapsing-remitting MS or clinically isolated syndrome who become pregnant, ocrelizumab, rituximab, and natalizumab (continued >= 28 weeks of gestation and restarted <= 1 month postpartum) were associated with reduced risk of relapses, compared with other therapeutic strategies.
Effectiveness of Autologous Haematopoietic Stem Cell Transplant in Comparison With Anti-CD20 Therapies in Relapsing-Remitting Multiple Sclerosis
(Sage Publications Ltd, 2025) Kalincik, Tomas; Sharmin, Sifat; Roos, Izanne; Freedman, Mark S.; Atkins, Harold; Massey, Jennifer; Snowden, John
Effectiveness of Autologous Haematopoietic Stem Cell Transplantation in Comparison With Immune-Reconstitution Therapies in Relapsing-Remitting MS
(Sage Publications Ltd, 2024) Kalincik, Tomas; Sharmin, Sifat; Roos, Izanne; Freedman, Mark S.; Atkins, Harold; Massey, Jennifer; Snowden, John
Citation - WoS: 1
Citation - Scopus: 2
Explainable Time-To Predictions in Multiple Sclerosis
(Elsevier Ireland Ltd, 2025) D'hondt, Robbe; Dedja, Klest; Aerts, Sofie; Van Wijmeersch, Bart; Kalincik, Tomas; Reddel, Stephen; MSBase Study Grp, MSBase Study
Background: Prognostic machine learning research in multiple sclerosis has been mainly focusing on black-box models predicting whether a patients' disability will progress in a fixed number of years. However, as this is a binary yes/no question, it cannot take individual disease severity into account. Therefore, in this work we propose to model the time to disease progression instead. Additionally, we use explainable machine learning techniques to make the model outputs more interpretable. Methods: A preprocessed subset of 29,201 patients of the international data registry MSBase was used. Disability was assessed in terms of the Expanded Disability Status Scale (EDSS). We predict the time to significant and confirmed disability progression using random survival forests, a machine learning model for survival analysis. Performance is evaluated on a time-dependent area under the receiver operating characteristic and the precision-recall curves. Importantly, predictions are then explained using SHAP and Bellatrex, two explainability toolboxes, and lead to both global (population-wide) as well as local (patient visit-specific) insights. Results: On the task of predicting progression in 2 years, the random survival forest achieves state-of-the-art performance, comparable to previous work employing a random forest. However, here the random survival forest has the added advantage of being able to predict progression over a longer time horizon, with AUROC > 60% for the first 10 years after baseline. Explainability techniques further validated the model by extracting clinically valid insights from the predictions made by the model. For example, a clear decline in the per-visit probability of progression is observed in more recent years since 2012, likely reflecting globally increasing use of more effective MS therapies. Conclusion: The binary classification models found in the literature can be extended to a time-to-event setting without loss of performance, thus allowing a more comprehensive prediction of patient prognosis. Furthermore, explainability techniques proved to be key to reach a better understanding of the model and increase validation of its behaviour.
FloRank: Adaptive Structured Personalization in Federated Learning for Predicting Disability Progression in Multiple Sclerosis
(Sage Publications Ltd, 2025) Pirmani, Ashkan; Arany, Adam; Kalincik, Tomas; Ozakbas, Serkan; Van Wijmeersch, Bart; Gouider, Riadh; Moreau, Yves
Machine Learning-Generated Longitudinal Synthetic International Data in Multiple Sclerosis
(Sage Publications Ltd, 2025) Iqbal, Hassam; Qiang, Zhe; Sharmin, Sifat; Ball, Gareth; Brankovic, Aida; Horakova, Dana; Kalincik, Tomas
Managing Reactivation of Multiple Sclerosis During Treatment with Natalizumab
(Sage Publications Ltd, 2026) Lizak, Nathaniel; Sharmin, Sifat; Horakova, Dana; Havrdova, Eva Kubala; Eichau, Sara; Van Der Walt, Anneke; Kalincik, Tomas
Background: Following natalizumab failure, it is unknown whether switching to alternative high-efficacy therapies offers superior effectiveness over continuing natalizumab. Objective: To compare different treatment strategies following natalizumab failure. Methods: Patients suffering a relapse during natalizumab treatment with adequate follow-up were identified from the MSBase registry. Following natalizumab failure, natalizumab continuation was compared to switching to anti-CD20 therapies/alemtuzumab/lower-efficacy therapies and treatment discontinuation. The primary outcome was the risk of further relapses. Secondary outcomes included risk of subsequent magnetic resonance imaging (MRI) activity, confirmed disability worsening and disease-activity-free survival. Multivariable proportional hazards models compared outcomes during time-varying therapy exposures. Four sensitivity analyses were conducted with varied inclusion criteria and treatment failure definitions. Results: Of 1553 patients experiencing a relapse during natalizumab treatment, 1037 met the inclusion criteria. Following natalizumab failure, switch to anti-CD20 therapy was associated with a lower relapse risk (heart rate (HR) = 0.48, 95% confidence interval (CI) = 0.27-0.84) compared to continuing natalizumab; no differences were observed in MRI or disability outcomes. Treatment de-escalation or cessation was associated with increased relapse risk (HR = 1.46, 95% CI = 1.15-1.85; HR = 2.08, 95% CI = 1.22-3.55, respectively). We did not find evidence of a difference for switching to alemtuzumab. Sensitivity analyses replicated primary findings. Conclusion: This exploratory study indicates that switching to anti-CD20 therapies following natalizumab failure is associated with a >50% reduction in relapse risk. No differences were seen in secondary outcomes, despite consistent trends. Clinicians may consider anti-CD20 therapies following natalizumab failure, noting further research is needed to confirm differences in MRI and disability outcomes.
Citation - Scopus: 1
Persistent Progression Independent of Relapse Activity in Multiple Sclerosis
(Oxford Univ Press, 2025) Zhu, Chao; Zhou, Zhen; Kalincik, Tomas; Roos, Izanne; Buzzard, Katherine; Skibina, Olga; Butzkueven, Helmut
Patients with relapsing-remitting multiple sclerosis (RRMS) may experience disability progression independent of relapse activity (PIRA), which can be an early sign of secondary progressive MS (SPMS). We defined persistent PIRA as ongoing sustained disability over the entire available follow-up period. However, PIRA events can regress over time. Identifying factors that predict PIRA persistence is of great interest as they can refine the definition of RRMS to SPMS transition. Equally, factors associated with the non-persistence of PIRA have potential treatment implications for patients suffering from a PIRA event. We conducted a study to examine risk factors for PIRA persistence and risk differences in long-term disability progression between persistent and non-persistent PIRA. In this cohort study, we included only patients who had already experienced a PIRA event and investigated the persistence of disability progression following their first PIRA event. Therefore, PIRA occurrence time was set as the baseline. Data were collected from the MSBase registry between April 1995 and January 2024, with a median follow-up of 8.7 years. The primary outcome was time to 6-month confirmed non-persistence of PIRA. Secondary outcomes comprised time to 6-month confirmed Expanded Disability Status Scale (EDSS) 6 and time to SPMS. A stratified Cox regression model was used to identify risk factors associated with non-persistent PIRA. We then matched persistent PIRA patients with non-persistent PIRA patients in a 1:1 ratio using propensity scores, and compared their risk of reaching EDSS 6 using the Cox regression model. We re-matched patients with complete Kurtzke Functional Systems Scores to compare their risks of reaching SPMS. We included 4713 RRMS patients with PIRA, of whom around one-third experienced a post-PIRA disability improvement, over a relatively long period (median of 2.6 years to improvement). Use of high-efficacy disease-modifying therapies (DMT) at baseline [hazard ratio, 1.22; 95% confidence interval, (1.08-1.38); P = 0.0015], lower baseline EDSS [hazard ratio, 0.73 (0.69-0.78); P < 0.0001] and younger age [per 10 years; hazard ratio, 0.84 (0.80-0.89); P < 0.0001] were associated with non-persistent PIRA. Patients with non-persistent PIRA had a hazard ratio of 0.19 [95% confidence interval, (0.15-0.25); P < 0.0001] for reaching EDSS 6 and 0.18 [(0.11-0.29); P < 0.0001] for reaching SPMS compared to patients with persistent PIRA. PIRA events slowly regress in one-third of patients. Patients with persistent PIRA had a substantially higher risk of reaching EDSS 6 and SPMS than those with non-persistent PIRA. Younger age, lower baseline EDSS, and use of high-efficacy DMT during PIRA events were associated with PIRA regression.
Preserving Neurological Function in Patients at High Risk and Low Risk of Aggressive MM
(Sage Publications Ltd, 2024) Roos, Izanne; Sharmin, Sifat; Ozakbas, Serkan; Alroughani, Raed; Ayuso, Guillermo Izquierdo; Madueno, Sara Eichau; Kalincik, Tomas
Real-World Effectiveness of Ocrelizumab in Multiple Sclerosis: A Multi-Registry Observational Cohort Study
(Sage Publications Ltd, 2025) Roos, Izanne; Sharmin, Sifat; Horakova, Dana; Ozakbas, Serkan; Libertinova, Jana; Boz, Cavit; Kalincik, Tomas
Real-World Effectiveness of Ocrelizumab in Relapsing Multiple Sclerosis: An Msbase Registry Sub-Study
(Elsevier Sci Ltd, 2026) Butzkueven, Helmut; Farr, Pamela; Ozakbas, Serkan; Boz, Cavit; Kalincik, Tomas; Taylor, Lisa; Spelman, Tim
Introduction: The MSOCR-R study evaluates the long-term effectiveness of ocrelizumab (OCR) in patients with relapsing multiple sclerosis (RMS) in real-world clinical settings. Methods: MSOCR-R is an ongoing, prospective, longitudinal, observational cohort study of people with RMS newly treated with OCR, using data from the international MSBase registry. The study started in July 2018, and data collected up to October 2023 were analyzed. Outcomes were confirmed disability worsening (CDW), progression independent of relapses (PIRA), and no evidence of disease activity (NEDA-3: absence of relapse, 24-week CDW, or imaging activity). Results: Overall, 1011 patients were enrolled (18.1% initiated OCR first-line therapy; 81.9% switched from previous treatment), with a median time of 3.4 years on OCR treatment. About 67% of patients were females. At OCR initiation, mean age was 41.9 years, median disease duration was 10.4 years, and median Expanded Disability Status Scale score was 3.0. The 4-year Kaplan-Meier probabilities of 24-week CDW or PIRA were 25.2% (95% CI 21.6-29.1) and 21.9% (95% CI 18.3-25.2), respectively. Annualized relapse rate substantially decreased from 0.58 (95% CI 0.53-0.63) before OCR to 0.05 (95% CI 0.04-0.06) after treatment initiation. NEDA-3 was assessed in 366 patients and the probability of achieving NEDA-3 was 39.7% (95% CI 36.0-43.5) at 4 years. Persistence on OCR was 88.0% (95% CI, 85.2-90.3) at 4 years. Better clinical outcomes were consistently observed among the first-line treatment cohort. Conclusion: The MSOCR-R study provides strong real-world evidence of OCR effectiveness in people with RMS.
Real-World Experience with Cladribine Tablets in the MSBase Registry 2025 Update
(Sage Publications Ltd, 2025) Spelman, Tim; van der Walt, Anneke; Ozakbas, Serkan; Horakova, Dana; Alroughani, Raed; Kalincik, Tomas; Butzkueven, Helmut
A Standardised Definition of Progression Independent of Relapse Activity in Multiple Sclerosis
(Sage Publications Ltd, 2024) Mueller, Jannis; Sharmin, Sifat; Lorscheider, Johannes; Ozakbas, Serkan; Karabudak, Rana; Horakova, Dana; Kalincik, Tomas
Citation - WoS: 14
Citation - Scopus: 11
Standardized Definition of Progression Independent of Relapse Activity (Pira) in Relapsing-Remitting Multiple Sclerosis
(Amer Medical Assoc, 2025) Muller, Jannis; Sharmin, Sifat; Lorscheider, Johannes; Ozakbas, Serkan; Karabudak, Rana; Horakova, Dana; Kalincik, Tomas
Importance Progression independent of relapse activity (PIRA) is a significant contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (MS). Prior studies have used varying PIRA definitions, hampering the comparability of study results. Objective To compare various definitions of PIRA. Design, Setting, and Participants This cohort study involved a retrospective analysis of prospectively collected data from the MSBase registry from July 2004 to July 2023. The participants were patients with MS from 186 centers across 43 countries who had clinically definite relapsing-remitting MS, a complete minimal dataset, and 3 or more documented Expanded Disability Status Scale (EDSS) assessments. Exposure Three-hundred sixty definitions of PIRA as combinations of the following criteria: baseline disability (fixed baseline with re-baselining after PIRA, or plus re-baselining after relapses, or plus re-baselining after improvements), minimum confirmation period (6, 12, or 24 months), confirmation magnitude (EDSS score at/above worsening score or at/above threshold compared with baseline), freedom from relapse at EDSS score worsening (90 days prior, 90 days prior and 30 days after, 180 days prior and after, since previous EDSS assessment, or since baseline), and freedom from relapse at confirmation (30 days prior, 90 days prior, 30 days before and after, or between worsening and confirmation). Main Outcome and Measure For each definition, we quantified PIRA incidence and persistence (ie, absence of a 3-month confirmed EDSS improvement over >= 5 years). Results Among 87 239 patients with MS, 33 303 patients fulfilled the inclusion criteria; 24 152 (72.5%) were female and 9151 (27.5%) were male. At the first visits, the mean (SD) age was 36.4 (10.9) years; 28 052 patients (84.2%) had relapsing-remitting MS, and the median (IQR) EDSS score was 2.0 (1.0-3.0). Participants had a mean (SD) 15.1 (11.9) visits over 8.9 (5.2) years. PIRA incidence ranged from 0.141 to 0.658 events per decade and persistence from 0.753 to 0.919, depending on the definition. In particular, the baseline and confirmation period influenced PIRA detection. The following definition yielded balanced incidence and persistence: a significant disability worsening compared with a baseline (reset after each PIRA event, relapse, and EDSS score improvement), in absence of relapses since the last EDSS assessment, confirmed with EDSS scores (not preceded by relapses within 30 days) that remained above the worsening threshold for at least 12 months. Conclusion and Relevance Incidence and persistence of PIRA are determined by the definition used. The proposed standardized definition aims to enhance comparability among studies.