Long-term effectiveness of natalizumab in secondary progressive multiple sclerosis: A propensity-matched study

Introduction: MRI activity is less frequent among secondary progressive multiple sclerosis (SPMS) patients. In the current study, we aimed to identify SPMS patients with higher radiological disease activity (RDA) and determine their clinical characteristics. Methods: We evaluated the occurrence of RDA in SPMS patients followed at the Sheba Multiple Sclerosis Center between January 1, 2015, and December 31, 2020. All patients underwent brain and spinal cord MRI examinations as a routine follow-up unrelated to clinical disease activity. Patients were subdivided into RDA and non-RDA MRI groups based on the presence of active gadolinium-enhancing T1 lesions and/or new/enlarging T2 lesions. Demographic variables and disease-related data were compared. Results: One hundred consecutive SPMS patients, 74 females, median age of 50 years, disease duration of 19.5 years, and neurological disability by the Expanded Disability Status Scale (EDSS) score of 6.0, were included in the study. The RDA group comprised 35 patients (35%), of them 65.7% (n = 23) exhibited only brain MRI activity, 22.8% (n = 8) only spinal cord MRI activity, and 11.4% (n = 4) had both. Patients in the RDA group were diagnosed at a younger mean (SD) age of 28.2 (8.9) versus 33.7 (10.1) years and were younger with a mean (SD) age of 47.8 (9.9) versus 53.4 (10.1) years, as compared with the non-RDA group. No significant differences were found in relation to disease duration, EDSS, exposure to immunomodulatory treatments, and duration of immunomodulatory treatments. Conclusions: RDA unrelated to clinical symptomatology was more frequent in a subgroup of young SPMS patients.

To evaluate whether the effects on potential surrogate endpoints, such as MRI markers and relapses, observed in trials of experimental treatments are able to predict the effects of these treatments on disability progression as defined in relapsing-remitting multiple sclerosis (RRMS) trials. We used a pooled analysis of all the published randomized controlled clinical trials in RRMS reporting data on Expanded Disability Status Scale (EDSS) worsening and relapses or MRI lesions or both. We extracted data on relapses, MRI lesions, and the proportion of progressing patients. A regression analysis weighted on trial size and duration was performed to study the relationship between the treatment effect observed in each trial on relapses and MRI lesions and the observed treatment effect on EDSS worsening. A set of 19 randomized double-blind controlled trials in RRMS were identified, for a total of 44 arms, 25 contrasts, and 10,009 patients. A significant correlation was found between the effect of treatments on relapses and the effect of treatments on EDSS worsening: the adjusted R(2) value of the weighted regression was 0.71. The correlation between the treatment effect on MRI lesions and EDSS worsening was slightly weaker (R(2) = 0.57) but significant. These findings support the use of commonly used surrogate markers of EDSS worsening as endpoints in multiple sclerosis clinical trials. Further research is warranted to validate surrogate endpoints at the individual level rather than at the trial level, to draw important conclusions in the management of the individual patient.

Introduction: Secondary progressive multiple sclerosis (SPMS) represents a disabling stage of multiple sclerosis (MS) with limited treatment options. The evidence regarding the effectiveness of disease-modifying therapies (DMTs) in SPMS remains uncertain. This study evaluated the comparative efficacy and safety of DMTs in SPMS using a network meta-analysis (NMA). Methods: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases was conducted from January 2000 to May 2025 to identify randomized controlled trials (RCTs) involving adults with SPMS. The outcomes of interest were confirmed disability progression (CDP) and serious adverse events (SAEs). A frequentist random-effects NMA was performed to estimate odds ratios (ORs) and rank treatments using surface under the cumulative ranking (SUCRA) values. Results: Seven RCTs involving 5,872 patients with SPMS were included in the final analysis. Approximately 60% of participants were women, with a mean age ranging from 39.9 to 48.9 years and a baseline Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5. Tolebrutinib (OR 0.66, 95% confidence interval [CI] 0.50–0.87; SUCRA 0.713) and siponimod (OR 0.72, 95% CI 0.57–0.92; SUCRA 0.606) significantly reduced 6-month CDP compared with placebo. At 3 months, interferon beta-1b (OR 0.64, 95% CI 0.43–0.97; SUCRA 0.663), tolebrutinib (OR 0.73, 95% CI 0.56–0.96; SUCRA 0.554), and siponimod (OR 0.76, 95% CI 0.61–0.96; SUCRA 0.497) showed significant benefits. In terms of safety, tolebrutinib was associated with a higher risk of SAEs (OR 1.53, 95% CI 1.04–2.25), whereas the other agents had safety profiles comparable to placebo. Conclusion: This NMA found that tolebrutinib, IFN-β-1b, and siponimod delay disability progression in SPMS, with IFN-β-1b and siponimod remaining the most practical options. The conclusions should be interpreted cautiously given bias risk, moderate evidence certainty, limited safety data, and clinical heterogeneity.

Therapy with either recombinant beta-1a or beta-1b interferons (IFNs) is worldwide approved for Relapsing Remitting Multiple Sclerosis (RRMS). A major unanswered question is whether this treatment is able to safely reverse or retard the progressive phase of the disease. The main objective was to verify whether IFNs treatment in Secondary Progressive Multiple Sclerosis (SPMS) is more effective than placebo in reducing the number of patients who experience disability progression. We searched the Cochrane Multiple Sclerosis Group's Trials Register (1995 to 15 February 2011), the reference lists of relevant articles and conference proceedings. Regulatory agencies were used as additional sources of information. We included all randomised, double or single blind, placebo-controlled trials (RCTs) evaluating the efficacy of IFNs versus placebo in SPMS patients. Two review authors independently assessed all reports retrieved from the search. They independently extracted clinical, safety and MRI data, using a predefined data extraction form, resolving disagreements after discussion with a third reviewer. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using Risk Ratio (RR) with 95% confidence intervals (CI) for the binary outcomes and Standard Mean Difference with 95% CI for the continuous outcomes. Five RCTs met the inclusion criteria, from which 3122 (1829 IFN and 1293 placebo) treated patients contributed to the analysis. Included population was heterogeneous in terms of baseline clinical characteristics of the disease, in particular the percentage of patients affected by secondary progression with superimposed relapse ranging from 72% to 44%. IFN beta 1a and 1b did not decrease the risk of progression sustained at 6 months (RR, 95% CI: 0.98, [0.82-1.16]) after three years of treatment. A significant decrease of the risk of progression sustained at 3 months (RR, 95% CI: 0.88 [0.80, 0.97]) and of the risk of developing new relapses at three years (RR 0.91, [0.84-0.97]) were found. The risk of developing new active brain lesions decreased over time but this data was obtained from single studies on Magnetic Resonance Imaging (MRI), performed in subgroups of patients; in spite of no effect on progression, the radiological data supported an effect on MRI parameters. The safety profile reflects what is commonly reported in MS IFN-treated patients. Well designed RCTs, evaluating a high number of patients were included in the review. Recombinant IFN beta does not prevent the development of permanent physical disability in SPMS. We were unable to verify the effect on cognitive function for the lack of comparable data. This treatment significantly reduces the risk of relapse and of short -term relapse-related disability.Overall, these results show that IFNs' anti-inflammatory effect is unable to retard progression, when established. In the future, no new RCTs for IFNs versus placebo in SPMS will probably be undertaken, because research is now focusing on innovative drugs. We believe that this review gives conclusive evidence on the clinical efficacy of IFNs versus placebo in SPMS.

Introduction. The study was driven by the prevalence of secondary progressive multiple sclerosis (SPMS) in Russia and the lack of data on siponimod in the real clinical practice (RCP).Aim. To collect and analyze data on the administration of siponimod in SPMS patients within Russia’s RCP as part of the EMBOSSES study (rEtrospective Multicenter oBservatiOnal Study Siponimod rEal-world Spms).Materials and methods. The study encompassed data of 606 SPMS patients from 11 centers who received siponimod for at least 6 months. The analysed data included demographic and clinical characteristics of patients, changes in the Expanded Disability Status Scale (EDSS) scores over time, percentage of patients with 6-month confirmed disability progression (6mCDP), annualized relapse rate (ARR) for MS, radiological signs of the disease activity and adverse events (AEs).Results. Among the study patients, women predominated (64.9%), while men accounted for 35.1%. The median age of patients was 49.5 (±8.9) years. 143 (23.6%) patients reported relapses during 2 years, whereas relapse-free SPMS was observed in 463 (76.4%) patients. The average EDSS scores remained stable, demonstrating minimal changes from 5.44 (±0.998) to 5.58 (±1.028) scores during the 2-year therapy. The percentage of patients free from 6mCDP was 85.5%. The KaplanMeier analysis revealed that 25% of patients achieved 6mCDP by Month 27 of therapy. The average ARR decreased from 0.14 to 0.032 at 12 months and remained low (0.062) after 2 years of treatment. The MRI showed a decrease in the percentage of patients with Gd+ T1 lesions to their complete absence over 2 years of therapy. Main AEs: lymphopenia, bradycardia, and elevated liver enzymes; serious AEs were observed in 3.3% of all cases.Conclusions. Siponimod demonstrated efficacy in controlling disability progression and inflammatory activity, as well as a favourable safety profile in patients with SPMS in the RCP setting. The results confirm the feasibility of using siponimod in patients with SPMS.

IntroductionThe Tysabri® Observational Program (TOP) is a 10 year, ongoing, global open-label study enrolling natalizumab-treated relapsing-remitting multiple sclerosis patients from clinical practice settings.MethodsWe analysed pre- and on-natalizumab annualised relapse rates...

The motor cortex (MC) receives an excitatory input from the cerebellum which is reduced in patients with cerebellar lesions. High-frequency repetitive transcranial magnetic stimulation (rTMS) induces cortical facilitation which can counteract the reduced cerebellar drive to the MC. Our study included 24 relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) patients with dysmetria. The patients were divided into two groups: Group A received two sessions of real MC rTMS and Group B received one session of real rTMS and one session of sham rTMS. Ten healthy volunteers formed group C. Evaluation was carried out using the nine-hole pegboard task and the cerebellar functional system score (FSS) of the expanded disability status scale (EDSS). Group A patients showed a significant improvement in the time required to finish the pegboard task (P=0.002) and in their cerebellar FSS (P=0.000) directly after the second session and 1month later. The RRMS patients showed more improvement than the SPMS patients. Group B patients did not show any improvement in the pegboard task or the cerebellar FSS. These results indicate that MC rTMS can be a promising option in treating both RRMS or SPMS patients with cerebellar impairment and that its effect can be long-lasting.

BackgroundThe recruitment of secondary progressive multiple sclerosis (SPMS) patients to the MS-STAT trial (a double-blind randomised placebo-controlled trial of high dose simvastatin) provided an opportunity to evaluate the frequency and...

The aim of this study was to investigate the shape differences in the corpus callosum (CC) and cerebellum of female relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) patients compared with healthy controls. This study was conducted using the magnetic resonance imaging scans of 15 control subjects, 26 RRMS, and 14 SPMS patients. The data obtained from the landmark coordinates were analyzed with statistical shape analysis. The landmarks that were chosen to determine the shape differences of the CC and cerebellum have been identified and used in previous studies. In addition to these landmarks, constructed landmarks were determined and used to assess regional shape differences better. The shapes of the CC and cerebellum showed statistically significant differences from the controls when compared with both the RRMS and SPMS patients. It was found that the deformation observed from controls to SPMS was greater than the deformation from controls to RRMS, both for the CC and cerebellum. In conclusion, this study revealed CC and cerebellar shape change in RRMS and SPMS, and showed that deformations both in CC and cerebellum advances with the disease progression.

To investigate the relationship between neutralizing antibodies (NAB) and disease progression, relapses, and MR measures of MS.Sequential serum samples from all 718 patients of the European Study Group in Interferon beta-1b in Secondary Progressive MS were analyzed to investigate relations between NAB and disease progression, relapses, and MR measures.This study showed no attenuating effect of NAB development on progression in disability. The effects of NAB on relapse rate showed substantial variation, depending on the statistical approach and definition of positivity, though analyses comparing low- and high-NAB+ periods with NAB- periods suggested a titer-related effect. MR T2 lesion volume changes from baseline were significantly higher for NAB+ patients but remained lower than for placebo patients. A substantial proportion of NAB+ patients became NAB-. No untoward effect of NAB development on safety was observed.These results support the conclusion that even though high NAB titers appear to have impact on treatment efficacy with respect to relapses, treatment decisions should be based primarily on clinical grounds.

Fibroblast growth factor-2 levels are elevated in the cerebrospinal fluid of multiple sclerosis patients

BackgroundMultiple sclerosis (MS) is a disease with profound heterogeneity in clinical course.ObjectiveTo analyze sources and levels of income among MS patients in relation to disease phenotype with a special focus on identifying differences/similarities between primary progressive MS (PPMS) and secondary progressive MS (SPMS).MethodsA total of 6890 MS patients aged 21−64 years and living in Sweden in 2010 were identified for this cross-sectional study. Descriptive statistics, logistic, truncated linear, and zero-inflated negative binomial regression models were used to estimate differences in income between SPMS, PPMS and relapsing-remitting MS (RRMS) patients.ResultsRRMS patients earned almost twice as much as PPMS and SPMS patients (on average SEK 204,500, SEK 114,500, and SEK 79,800 in 2010, respectively). The difference in earnings between PPMS and SPMS was not statistically significant when analyzed with multivariable regression. The estimated odds ratio for PPMS patients to have income from earnings was not significantly different from SPMS patients (95% CI 0.98 to 1.59). PPMS and RRMS patients were less likely to receive benefits when compared to SPMS patients (by 6% and 27% lower, respectively).ConclusionOur findings argue for similarities between PPMS and SPMS and highlight the socioeconomic importance of preventing RRMS patients convert to SPMS.

Conversion to secondary progressive multiple sclerosis (SPMS) is associated with a relatively poor prognosis, and SPMS is responsible for the majority of the social and economic costs associated with MS. Managing the Transition to SPMS (ManTra) is a mixed methods project conducted in Italy and Germany aimed to set up a user-led resource to empower and improve the quality of life of newly diagnosed SPMS patients. To assess the experiences and the needs of Italian people who recently converted to SPMS, patient significant others (SOs), neurologists and other health professionals (HPs). We conducted 15 personal semistructured interviews (PSIs) with SPMS patients who transitioned up to five years, and three focus group meetings (FGMs), one of SPMS SOs, one of neurologists, and one of other HPs. Participants were purposely selected from the three geographic areas of Italy, and varied in terms of gender, education and (for patients) disease severity. PSIs and FGMs were audiorecorded, transcribed and analyzed by two researchers using the framework analysis. One hundred sub-categories were identified, grouped into 13 categories and four themes: 'awareness of the transition', 'communication of the transition', 'dealing with symptoms worsening', and 'needs'. The major unmet needs were collected in four dimensions 'organization and management; 'empowerment training'; 'information'; and 'policies'. Two are the main findings: first, the widespread lack of awareness around the transition; second, the need to improve the quality of the care pathway in the Italian context. It was particularly stressed the need for a holistic and multidisciplinary approach (with patients and SOs as members of the team), the development of an ad hoc plan of follow up visits with easy access to MS specialists' consultation/treatment; specialized training for each stakeholders; more information on SPMS, daily management and changes at policy level.

Objective: We aimed to investigate the influence of natalizumab (NTZ) treatment on multiple sclerosis course in patients with and without spinal involvement.Methods: Annualized relapse rate (ARR), disability progression and occurrence of new brain and spinal T2 lesions (N2TL) in 68 spinal (S-P) versus 68 non-spinal matched patients (NS-P) were retrospectively collected and compared between before (2 years) and after NTZ treatment using multivariate regression models.Results: Mean duration of NTZ treatment was 31.3 ± 16.3 months in S-P and 32.1 ± 15.1 months in N-SP (p = 0.56). The mean ARR after NTZ treatment was similarly reduced in both S-P (0.07 ± 0.19) and N-SP (0.07 ± 0.16) (p < 0.001 for both). Disability progression after NTZ start was similarly low in S-P and NS-P. However, when compared to before NTZ start, disability progression was significantly reduced in S-P (p = 0.017), but not in NS-P (p = 0.68). This was largely mediated by a higher disability progression before NTZ start in S-P than N-SP. The risk of developing N2TL during NTZ was not different between S-P and NS-P (p = 0.10).Conclusions: NTZ similarly reduced the occurrence of relapses and NT2L in S-P and NS-P, whereas the effect on disability progression was particularly evident in the presence of spinal involvement. NTZ appears to be a treatment of high efficacy in both S-P and NS-P.

Natalizumab is indicated for the treatment of relapsing multiple sclerosis (MS) with insufficient response to first-line disease-modifying therapy (DMT). We studied the efficacy of natalizumab for treatment of MS in a single centre observational design. A retrospective observational study of 146 patients [66% female; mean age 37.4; 72% relapsing remitting MS (RRMS), 28% secondary progressive MS (SPMS)] referred for natalizumab treatment at St. Michael's Hospital MS Clinic between 2007 and August 2009. Data included demographic, clinical (Expanded Disability Status Scale (EDSS) and annualized relapse rate (ARR)) and patient self-report measures. The mean duration of treatment was 20 months in those treated with natalizumab and 97% had received prior DMTs. Eighty-three patients (57%) received at least 12 months of natalizumab treatment. In those who received at least 12 months of treatment, baseline ARR and EDSS were 1.6 and 2.7 in RRMS patients versus 1.0 and 5.4 in SPMS with relapses. The ARR decreased with natalizumab treatment to 0.38 (76% reduction, p<0.001) in RRMS versus 0.32 in SPMS patients (68% reduction, p=0.01). There was a treatment associated 11% reduction in EDSS to 2.4 (p=0.04) in RRMS, but no significant change in SPMS. Eighty-five percent of patients reported improved overall quality of life (QOL) and 62% indicated improved energy. There was a major reduction in relapse rate, stabilization in EDSS and improvement in QOL and energy in some patients on natalizumab, all similar to treatment effects in the pivotal trial.