Figure - available from: Frontiers in Neurology
This content is subject to copyright.
Roving expanded disability status scale (EDSS) progression overall and unrelated to concurrent relapse (EDSS worsening is related to a relapse if at least one relapse occurred between 30 days before start of EDSS worsening and 30 days after confirmation of EDSS worsening).

Roving expanded disability status scale (EDSS) progression overall and unrelated to concurrent relapse (EDSS worsening is related to a relapse if at least one relapse occurred between 30 days before start of EDSS worsening and 30 days after confirmation of EDSS worsening).

Source publication
Article
Full-text available
Background: Fingolimod (Gilenya®) is approved for adult and pediatric patients with highly active relapsing–remitting multiple sclerosis (RRMS). Objectives: The objective was to describe the effectiveness of fingolimod in young adults compared to older patients in clinical practice. Methods: PANGAEA is the largest prospective, multi-center, non-int...

Similar publications

Article
Full-text available
Background Pediatric-onset Multiple Sclerosis (POMS) patients show more inflammatory disease compared with adult-onset MS. However, highly effective treatments are limited with only fingolimod being approved in Italy and natalizumab prescribed as off-label treatment. Objectives to compare the efficacy of natalizumab versus fingolimod in POMS. Met...

Citations

... Overall, the results of this retrospective registry study are consistent with previous studies of natalizumab 13,22,[24][25][26][27][28] and fingolimod in patients with POMS and therefore entirely expected. 21,[41][42][43][44][45] Specifically, consistent results of the analyses of relapse risk in these 2 treatment groups suggests that natalizumab may be more effective than fingolimod on relapse outcomes. These effectiveness results are also generally consistent with comparative studies of natalizumab and fingolimod in adult patients with MS, 37,[46][47][48] in concordance with the general agreement that pediatric-onset and adult-onset MS have similar underlying pathophysiology 14 and that outcomes for patients younger than 18 years are not fundamentally different than those for patients older than 18 years, although data supporting this point are limited. ...
Article
Background and objectives: Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. Methods: This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. Results: A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. Discussion: Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. Classification of evidence: This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.
... In young adults, MS is a major cause of non-traumatic disability [2], placing a substantial burden on individuals and society due to the long-term loss of productivity, physical and cognitive disability, fatigue, comorbidity, assistance with daily living, and multidisciplinary healthcare requirements [3]. Patients with early-onset MS are reported to relapse more frequently, with higher disease activity compared with their adult counterparts; although disability accumulation occurs at a slower rate, younger patients eventually have significant disability at an earlier age [4][5][6][7]. These features suggest that younger patients with MS experience a more inflammatory disease course than older patients [6,8]. ...
... Patients with early-onset MS are reported to relapse more frequently, with higher disease activity compared with their adult counterparts; although disability accumulation occurs at a slower rate, younger patients eventually have significant disability at an earlier age [4][5][6][7]. These features suggest that younger patients with MS experience a more inflammatory disease course than older patients [6,8]. As a heterogeneous chronic disease, treatment goals for MS among younger patients therefore include prompt intervention for prevention of relapses and disability accumulation [2,9]. ...
... Patient details for DEFINE and CONFIRM were reported previously [21]. In this report, young adult patients were defined as adults aged 18--29 years [6]. ...
Article
Full-text available
IntroductionDimethyl fumarate (DMF) showed favorable benefit-risk in patients with relapsing-remitting multiple sclerosis (MS) in phase 3 DEFINE and CONFIRM trials and in the ENDORSE extension study. Disease activity can differ in younger patients with MS compared with the overall population.Methods Randomized patients received DMF 240 mg twice daily or placebo (PBO; years 0–2 DEFINE/CONFIRM), then DMF (years 3–10; continuous DMF/DMF or PBO/DMF; ENDORSE); maximum follow-up (combined studies) was 13 years. This integrated post hoc analysis evaluated safety and efficacy of DMF in a subgroup of young adults aged 18–29 years.ResultsOf 1736 patients enrolled in ENDORSE, 125 were young adults, 86 treated continuously with DMF (DMF/DMF) and 39 received delayed DMF (PBO/DMF) in DEFINE/CONFIRM. Most (n = 116 [93%]) young adults completed DMF treatment in DEFINE/CONFIRM. Median (range) follow-up time in ENDORSE was 6.5 (2.0–10.0) years. Young adults entering ENDORSE who had been treated with DMF in DEFINE/CONFIRM had a model-based Annualized Relapse Rate (ARR; 95% CI) of 0.24 (0.16–0.35) vs. 0.56 (0.35–0.88) in PBO patients. ARR remained low in ENDORSE: 0.07 (0.01–0.47) at years 9–10 (DMF/DMF group). At year 10 of ENDORSE, EDSS scores were low in young adults: DMF/DMF, 1.9 (1.4); PBO/DMF, 2.4 (1.6). At ~ 7 years, the proportion of young adults with no confirmed disability progresion was 81% for DMF/DMF and 72% for PBO/DMF. Patient-reported outcomes (PROs) (SF-36 and EQ-5D) generally remained stable during ENDORSE. The most common adverse events (AEs) in young adults during ENDORSE were MS relapse (n = 53 [42%]). Most AEs were mild (n = 20 [23.3%], n = 7 [17.9%]) to moderate (n = 45 [52.3%], n = 23 [59.0%]) in the DMF/DMF and PBO/DMF groups, respectively. The most common serious AE (SAE) was MS relapse (n = 19 [15%]).Conclusion The data support a favorable benefit-risk profile of DMF in young adults, as evidenced by well-characterized safety, sustained efficacy, and stable PROs.Clinical Trial InformationClinical trials.gov, DEFINE (NCT00420212), CONFIRM (NCT00451451), and ENDORSE (NCT00835770).
... Overall, the results of this retrospective registry study are consistent with previous studies of natalizumab 13,[22][23][24][25][26][27][28][29][30] and fingolimod in patients with POMS, and therefore entirely expected. 21,[42][43][44][45][46] The results are also generally consistent with comparative studies of natalizumab and fingolimod in adult patients with MS, in concordance with the general agreement that pediatric-and adult-onset MS have similar underlying pathophysiology 14 and that outcomes for patients <18 years are not fundamentally different than those for patients >18 years, although data supporting this point are limited. ...
Preprint
Full-text available
Background and Objectives Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses and reach irreversible disability at a younger age than adult-onset patients. There have been few randomized placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. Methods This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021 (N=1218). The primary outcome was the time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years post baseline; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. Results Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMT (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29–0.83; P =0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMT (HR, 0.15; 95% CI, 0.07–0.31; P <0.001) or fingolimod (HR, 0.37; 95% CI, 0.14–1.00; P =0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting–adjusted patient populations were confirmed in multiple sensitivity analyses. Discussion Our results suggest that natalizumab and fingolimod have broadly equivalent therapeutic efficacies in patients with POMS, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. However, analyses of relapse outcomes suggest natalizumab is superior to fingolimod in the control of relapses in this population with high rates of new inflammatory activity. Classification of Evidence This study provides Class III evidence that natalizumab may provide better disease control than fingolimod in patients with POMS.
... This trend is also indicated in the prospective, multicenter, longitudinal PANGEA study, which reported higher ARRs in younger fingolimod-treated patients with RRMS compared with older ones (B 20 years: 2.0, [ 20 to B 30 years: 1.7, [ 30 years: 1.4.) [25]. Furthermore, DMDs of increased efficacy (e.g., fingolimod) have no additional effect on disability progression compared to more modest/moderate-efficacy DMDs (e.g., interferon beta) in PwMS aged [ 40 years [26]. ...
Article
Full-text available
Introductions: Therapy switches in patients with multiple sclerosis (MS) receiving treatment with fingolimod occur frequently in clinical practice but are not well represented in real-world data. The aim of this study was to identify and characterize treatment switches and reveal sociodemographic/clinical changes over time in fingolimod-treated people with MS (PwMS). Methods: Data on 2536 fingolimod-treated PwMS extracted from the German MS Registry during different time periods were analyzed (2010–2019). Results: Overall, 28.3% of PwMS were treatment-naïve before fingolimod initiation. Interferon beta (30.7%) was the most common pre-fingolimod treatment. Ocrelizumab (19.8%) was the most frequent subsequent treatment in the 944 patients on fingolimod who switched. Between 2010 and 2019, median disease duration at fingolimod initiation decreased from 8.5 to 7.1 years (p < 0.001), and patients taking fingolimod for ≥ 1 year after treatment initiation decreased from 89.6 to 80.5% (p < 0.001). Females (p < 0.001) and young patients (p = 0.003) showed a shorter time on fingolimod. The most frequent reason for switching was disease activity (relapse/MRI) despite treatment. The annualized relapse rate increased from 0.37 in patients on fingolimod to 0.47 after treatment cessation, decreasing to 0.19 after treatment with a subsequent disease-modifying drug (DMD) was initiated. Conclusion: Treatment switches from fingolimod to subsequent DMDs currently occur after shorter treatment durations than 10 years ago, possibly due to the growing treatment spectrum. Planning adequate washout periods is essential and should be done on an individualized basis.
... Except for patient 5, they experienced total or near-total disease remission. The aforementioned findings show a trend for worse response to fingolimod in younger patients, who are treatment naïve, at least for our group of POMS patients presented here, in accordance with the results of the PANGAEA study, in which younger patients treated with fingolimod had a lower overall proportion of relapsefree disease than older groups, despite the undeniable benefit with respect to the reduction of relapse activity in all age groups [14]. This lower overall proportion of relapsefree patients in the younger ages could be attributed both to the inherently high inflammatory profile of POMS at its earliest stages [1][2][3] and the role of previous DMT use in modifying disease course. ...
Article
Full-text available
Background Pediatric onset multiple sclerosis(POMS) is characterized by a highly active profile, often warranting treatment with high efficacy disease-modulating therapies (DMTs). Fingolimod, an oral sphingosine-1-phosphate receptor modulator, is the first Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved DMT for the treatment of POMS.ObjectOur aim is to present real-world data of seven fingolimod-treated POMS-patients, recruited in a single MS center in Greece.Methods Clinical and imaging/laboratory data from 7 Hellenic patients fulfilling the International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria for POMS diagnosis, who have received fingolimod treatment, were selected. Human leukocyte antigen (HLA) genotyping was performed with standard low-resolution sequence-specific oligonucleotide techniques.ResultsThree patients were treatment-naïve adolescents who received fingolimod as first-line treatment. Two experienced ongoing clinical and radiological disease activity and have been switched to natalizumab. The remaining cases were post-adolescent adults with POMS, where the vast majority experienced total/near-total disease remission. Fingolimod was generally well-tolerated. Two patients with high disease activity carried the HLA-DRB1*03 allele, while five patients were carriers of at least one of the HLA-DRB1*04, HLA-DRB1*13, and HLA-DRB1*14 alleles, which when not combined with HLA-DRB1*03 showed a trend towards a more favorable clinical course. Fingolimod responders showed a trend towards increased CD(16–56)+NK cell counts in immunophenotyping assays.Conclusions Our preliminary results support that response of POMS patients to fingolimod may be partially dependent on age and previous DMT, with younger and treatment-naïve patients presenting worse outcomes. The role of immunogenetics and immunophenotyping in personalized treatment warrants investigation in larger and more diverse populations.
... Interestingly, patients in both studies, PANGAEA and PANGAEA 2.0, had a similar mean age of 39 years with no trend towards earlier treatment initiation with respect to age. Given that fingolimod is efficacious and safe to use in the treatment of young adults [17], there is still much room for improvement regarding earlier intervention in case of disease activity. ...
Article
Full-text available
(1) Background: Fingolimod (Gilenya®) was the first oral treatment for patients with relapsing-remitting multiple sclerosis (RRMS). Since its approval, the treatment landscape has changed enormously. (2) Methods: Data of PANGAEA and PANGAEA 2.0, two German real-world studies, were descriptively analysed for possible evolution of patient profiles and treatment behavior. Both are prospective, multi-center, non-interventional, long-term studies on fingolimod use in RRMS in real life. Data of 4229 PANGAEA patients (recruited 2011–2013) and 2441 PANGAEA 2.0 patients (recruited 2015–2018) were available. Baseline data included demographics, RRMS characteristics and disease severity. (3) Results: The mean age of PANGAEA and PANGAEA 2.0 patients was similar (38.8 vs. 39.2 years). Patients in PANGAEA 2.0 had shorter disease duration (7.1 vs. 8.2 years) and fewer relapses in the year before baseline (1.2 vs. 1.6). Disease severity at baseline estimated by EDSS and SDMT was lower in PANGAEA 2.0 patients compared to PANGAEA (EDSS difference 1.0 points; SDMT difference 3.3 points). (4) Conclusions: The results hint at an influence of changes in the treatment guidelines and the label on fingolimod patients profiles over time. Patients tended to have lower disease activity at fingolimod initiation, suggesting an earlier intervention. This indicates increased experience in using fingolimod for sub-optimally treated RRMS patients and a change in mindset towards an early treatment optimization.