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Background Primary‐progressive multiple sclerosis (PPMS) and relapsing‐remitting multiple sclerosis (RRMS) are two frequent multiple sclerosis (MS) subtypes that involve 10%–15% of patients. PPMS progresses slowly and is diagnosed later in life. Both subtypes are influenced by genetic and environmental factors such as smoking, obesity, and vitamin D insufficiency. Although there is no cure, ocrelizumab can reduce symptoms and delay disease development. RRMS is an autoimmune disease that causes inflammation, demyelination, and disability. Early detection, therapy, and lifestyle changes are critical. This study delves into genetics, immunology, biomarkers, neuroimaging, and the usefulness of ocrelizumab in the treatment of refractory patients of PPMS. Method In search of published literature providing up‐to‐date information on PPMS and RRMS, this review conducted numerous searches in databases such as PubMed, Google Scholar, MEDLINE, and Scopus. We looked into genetics, immunology, biomarkers, current breakthroughs in neuroimaging, and the role of ocrelizumab in refractory cases. Results Our comprehensive analysis found considerable advances in genetics, immunology, biomarkers, neuroimaging, and the efficacy of ocrelizumab in the treatment of refractory patients. Conclusion Early detection, timely intervention, and the adoption of lifestyle modifications play pivotal roles in enhancing treatment outcomes. Notably, ocrelizumab has demonstrated potential in symptom control and mitigating the rate of disease advancement, further underscoring its clinical significance in the management of MS.

Background Patients With Multiple Sclerosis (MS) Have Higher Mortality Than Matched Background Populations. We Compare Relative and Excess Mortality in MS Over the Matched Background Populations Between Primary Progressive MS (PPMS), relapsing Onset MS (ROMS), and Secondary Progressive MS (SPMS). Methods We included all patients from the nationwide and complete Danish MS Registry with onset 1994–2022 and compared the extra mortality of the MS phenotypes in terms of relative and excess mortality, with adjustment for sex, age at onset, disease‐modifying treatment, and number of recorded relapses. We calculated the adjusted ratios of relative and excess mortalities between PPMS and ROMS and between PPMS and SPMS. Results The initial course was unknown in 221, leaving 1412 cases with PPMS (which includes progressive relapsing MS) and 12,449 cases with ROMS. 627 had died during follow‐up by the end of 2022. After adjustment, both ratios between PPMS and ROMS came close to unity, indicating that the excess mortality is equal for PPMS and ROMS in the long run. The adjusted relative and additive mortalities were factors 6.05 (95% CI 4.42–8.27) and 1.90 (95% CI 1.65–2.18) higher in SPMS than in PPMS. Conclusions Compared with the matched population, the adjusted relative and excess mortalities are the same for PPMS and ROMS. However, SPMS had a higher relative and excess mortality than PPMS, probably in part owing to the burden of disease carried over from the pre‐progressive phase. This underlines the need for effective treatment in this later stage of the disease and more attention to comorbidity.

Background Relapsing–remitting (RR) and primary progressive (PP) multiple sclerosis (MS) have distinct clinical courses, but underlying pathophysiological differences remain unclear. We compared pathological components between RRMS, PPMS, and other inflammatory and neurodegenerative disorders, leveraging soluble biomarkers and post‐mortem pathology. Methods Serum and cerebrospinal fluid (CSF) of people diagnosed with (pw) PPMS (n = 104), RRMS (n = 38), Alzheimer's disease (AD, n = 22), neuromyelitis optica spectrum disorder (NMOSD, n = 10), and myelin oligodendrocyte glycoprotein–associated disease (MOGAD, n = 10) were collected. B‐cell maturation antigen (BCMA), soluble CD27 (sCD27), osteopontin (OPN), chitinase‐3‐like‐1 (CHI3L1), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and synaptosomal‐associated protein‐25 (SNAP25) were measured. Lymphocytes (CD20+, CD138+, CD3+) and pyramidal‐tract axonal density in RR‐onset (n = 86) and PPMS (n = 45) post‐mortem brain tissue were quantified. Results Soluble and post‐mortem tissue biomarkers did not differ between pwRRMS and pwPPMS. Compared to AD, MS had higher CSF sCD27 (p < 0.001) but lower serum CHI3L1 and GFAP, and CSF OPN and SNAP25 (all p < 0.05). Serum OPN was lower in RRMS than NMOSD (p = 0.013). Principal component analyses and K‐means clustering showed substantial overlap of RRMS and PPMS biomarkers, distinct from AD. In all pwMS, serum NfL and CSF BCMA correlated with clinical/radiological disease activity, CSF BCMA and sCD27 with inflammatory parameters, and serum GFAP, CSF GFAP, and CSF NfL with Expanded Disability Status Scale (EDSS) score. Conclusions Serum and CSF soluble biomarker profiles and post‐mortem pathology do not differentiate RRMS from PPMS diagnoses but reflect the extent of inflammation and tissue damage. Detailed assessment of MS‐associated inflammation and tissue damage may enhance classification and therapeutic strategies.

Background and purpose Newly appearing lesions in multiple sclerosis (MS) may evolve into chronically active, slowly expanding lesions (SELs), leading to sustained disability progression. The aim of this study was to evaluate the incidence of newly appearing lesions developing into SELs, and their correlation to clinical evolution and treatment. Methods A retrospective analysis of a fingolimod trial in primary progressive MS (PPMS; INFORMS, NCT 00731692) was undertaken. Data were available from 324 patients with magnetic resonance imaging scans up to 3 years after screening. New lesions at year 1 were identified with convolutional neural networks, and SELs obtained through a deformation‐based method. Clinical disability was assessed annually by Expanded Disability Status Scale (EDSS), Nine‐Hole Peg Test, Timed 25‐Foot Walk, and Paced Auditory Serial Addition Test. Linear, logistic, and mixed‐effect models were used to assess the relationship between the Jacobian expansion in new lesions and SELs, disability scores, and treatment status. Results One hundred seventy patients had ≥1 new lesions at year 1 and had a higher lesion count at screening compared to patients with no new lesions (median = 27 vs. 22, p = 0.007). Among the new lesions (median = 2 per patient), 37% evolved into definite or possible SELs. Higher SEL volume and count were associated with EDSS worsening and confirmed disability progression. Treated patients had lower volume and count of definite SELs (β = −0.04, 95% confidence interval [CI] = −0.07 to −0.01, p = 0.015; β = −0.36, 95% CI = −0.67 to −0.06, p = 0.019, respectively). Conclusions Incident chronic active lesions are common in PPMS, and fingolimod treatment can reduce their number.

Primary progressive multiple sclerosis (PPMS), the least frequent type of multiple sclerosis (MS), is characterized by a specific course and clinical symptoms, and it is associated with a poor prognosis. It requires extensive differential diagnosis and often a long-term follow-up before its correct recognition. Despite recent progress in research into and treatment for progressive MS, the diagnosis and management of this type of disease still poses a challenge. Considering the modern concept of progression “smoldering” throughout all the stages of disease, a thorough exploration of PPMS may provide a better insight into mechanisms of progression in MS, with potential clinical implications. The goal of this study was to review the current evidence from investigations of PPMS, including its background, clinical characteristics, potential biomarkers and therapeutic opportunities. Processes underlying CNS damage in PPMS are discussed, including chronic immune-mediated inflammation, neurodegeneration, and remyelination failure. A review of potential clinical, biochemical and radiological biomarkers is presented, which is useful in monitoring and predicting the progression of PPMS. Therapeutic options for PPMS are summarized, with approved therapies, ongoing clinical trials and future directions of investigations. The clinical implications of findings from PPMS research would be associated with reliable assessments of disease outcomes, improvements in individualized therapeutic approaches and, hopefully, novel therapeutic targets, relevant for the management of progression.

Approximately 15% of multiple sclerosis (MS) patients develop a progressive form of disease from onset; this condition (primary progressive-PP) MS is difficult to diagnose and treat, and is associated with a poor prognosis. Extracellular vesicles (EVs) of brain origin isolated from blood and their protein cargoes could function as a biomarker of pathological conditions. We verified whether MBP and MOG content in oligodendrocytes-derived EVs (ODEVs) could be biomarkers of MS and could help in the differential diagnosis of clinical MS phenotypes. A total of 136 individuals (7 clinically isolated syndrome (CIS), 18 PPMS, 49 relapsing remitting (RRMS)) and 70 matched healthy controls (HC) were enrolled. ODEVs were enriched from serum by immune-capture with anti-MOG antibody; MBP and MOG protein cargoes were measured by ELISA. MBP concentration in ODEVs was significantly increased in CIS (p < 0.001), RRMS (p < 0.001) and PPMS (p < 0.001) compared to HC and was correlated with disease severity measured by EDSS and MSSS. Notably, MBP concentration in ODEVs was also significantly augmented in PPMS compared to RRMS (p = 0.004) and CIS (p = 0.03). Logistic regression and ROC analyses confirmed these results. A minimally invasive blood test measuring the concentration of MBP in ODEVs is a promising tool that could facilitate MS diagnosis.

Ocrelizumab is a recombinant humanized monoclonal antibody selectively targeting CD20-expressing B cells. The effect of ocrelizumab on primary progressive multiple sclerosis (PPMS) has been evaluated during phase 3 trials that enrolled patients under 55 years with a maximum Expanded Disability Status Scale (EDSS) of 6.5. However, little is known on older disabled patients with longer disease duration. We aimed to assess the clinical effectiveness of ocrelizumab in PPMS patients out of the ORATORIO eligibility criteria. This multicenter retrospective study collected data about the effectiveness of ocrelizumab in PPMS patients who received treatment between May 2017 and June 2022 in the Italian MS centers contributing to the Italian MS Registry who adhered to the Compassionate Use Program. The confirmed EDSS worsening (CEW) (defined as either a ≥ 1-point or ≥ 2-point increase in EDSS score from baseline that was confirmed at T12 and T24) was calculated. At the date of data extraction, out of 887 PPMS patients who had received ocrelizumab, 589 (mean age 49.7 ± 10.7 years, 242 (41.1%) females) were enrolled. The mean follow-up period was 41.3 ± 12.3 months. A total of 149 (25.3%) received ocrelizumab according to the ORATORIO criteria (ORATORIO group) and 440 (74.7%) outside the ORATORIO criteria (non-ORATORIO group). No differences in terms of cumulative probabilities of 12 and 24 months of CEW of ≤ 1 point were found between ORATORIO and non-ORATORIO groups. Cox regression analyses showed that age older than 65 years (HR 2.51, 25% CI 1.07–3.65; p = 0.01) was associated with higher risk of CEW at 24 months. Patients not responding to ORATORIO criteria for reimbursability may benefit from ocrelizumab treatment, as disease activity, disease duration, and EDSS seem to not impact the disability outcome. Our results may suggest to extend the possible use of this powerful agent in selected patients under the age of 65 years.

BackgroundClinical trials in primary progressive MS (PPMS) generally use the Expanded Disability Status Scale (EDSS) as their primary outcome measure, although different clinical outcomes may be more useful. Disability worsening in PPMS trials may be influenced by baseline factors, such as age, sex, and contrast-enhancing lesions.MethodsWe used the dataset of PROMISE, a large randomized controlled trial of glatiramer acetate (GA) versus placebo, to compare the clinical outcomes EDSS, timed 25-foot walk (T25FW), and nine-hole peg test (NHPT). We used Cox regression analyses to investigate the association of the baseline factors age, sex, treatment arm, contrast-enhancing lesions (CELs), and EDSS on the time to 3-month confirmed disability worsening (3MCDW) on the EDSS and the T25FW.ResultsPROMISE included 943 participants. Worsening on the T25FW or EDSS or occurred much more frequently than on the NHPT. Having CELs at baseline was associated with a shorter time to 3MCDW on both the EDSS and T25FW. An additional resampling experiment using the PROMISE dataset showed that increasing representation of participants with CELs at baseline increases the likelihood of having a positive trial result in favor of GA treatment.ConclusionOur investigation suggests that the T25FW may be a more useful primary outcome measure than the EDSS in PPMS trials, and that its use may shorten clinical trials. Our findings on the impact of CELs at baseline on disability outcomes inform the critical appraisal of clinical trials in PPMS.

BackgroundSmoking and obesity are recognized modifiable risk factors associated with a higher MS incidence, but their impact on physical and cognitive disability worsening is less clear.ObjectiveTo investigate the impact of smoking and obesity on disability worsening in primary progressive MS (PPMS).MethodsWe used data from INFORMS (clinicaltrials.gov identifier: NCT00731692), a large randomized-controlled trial in PPMS to compare significant worsening on the EDSS, T25FW, NHPT, and PASAT between smokers and non-smokers, and between BMI groups, at 12, 24, and 33 months of follow-up. We investigated the association of smoking and BMI at screening and the risk of disability worsening with logistic regression models.ResultsSmokers had significantly higher EDSS scores throughout the trial. EDSS was not significantly different between BMI categories. No other outcome measure was significantly different between smokers and non-smokers and between BMI categories throughout the trial. Neither smoking status nor BMI were associated with significant worsening on any outcome measure at any time point during follow-up.ConclusionDespite the known effects on MS incidence, smoking and BMI were not associated with the risk of physical and cognitive disability worsening over 3 years in this well-characterized PPMS trial cohort.

BackgroundOcrelizumab was found to decrease brain atrophy rate in primary progressive multiple sclerosis (PPMS), but no data are currently available on the effect of ocrelizumab on retinal layer thicknesses in the PPMS population.ObjectiveTo assess retinal layer changes in ocrelizumab-treated PPMS and test their possible application as biomarkers of therapy response.Methods36 PPMS patients, treated with ocrelizumab for at least 6 months, and 39 sex- and age-matched healthy controls (HC) were included in a blind, longitudinal study. Spectrum-domain optical coherence tomography (SD-OCT) was performed at study entry (T0) and after 6 (T6) and 12 months (T12). At month 24 (T24), patients were divided into responders (no evidence of 1-year confirmed disability progression, 1y-CDP) and non-responders (evidence of 1y-CDP).ResultsAt T24, 23/36 (64%) patients were considered responders and 13/36 (36%) non-responders. At T0, peripapillary retinal nerve fiber layer (pRNFL) thickness, macular ganglion cell–inner plexiform layer (GCIPL) and inner retinal layer (IRL) volume were significantly lower in PPMS compared to HC (p = 0.001 for all comparisons). At T6 and T12, non-responders significantly differed in the inner nuclear layer (INL) thinning rate compared to responders (p = 0.005 at both time-points).ConclusionsOcrelizumab significantly slows down INL thinning rate in PPMS responders. The longitudinal analysis of retina layer changes by means of OCT may be a promising prognostic test, and merits further investigations.