Progression independent of relapse activity in relapsing multiple sclerosis: impact and relationship with secondary progression.

OBJECTIVES: We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and transition to secondary progression (SP) in relapsing multiple sclerosis (MS). METHODS: Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively. RESULTS: Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120-0.577, p = 0.003). DISCUSSION: In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase.

Risk of secondary progression in patients with highly active multiple sclerosis treated with natalizumab: a real-life study.

BACKGROUND: one of the most important therapeutic goals in relapse-onset multiple sclerosis is to preclude conversion to secondary progression. Our objective was to determine the risk of progression associated with natalizumab treatment in an registry-based cohort of patients and to identify determinant factors. METHODS: Patients with relapse-onset multiple sclerosis from the Registre Lorrain des Scléroses en Plaques (ReLSEP) were included if they had received one infusion of natalizumab between 2002 and 2021. The risk of secondary progression was determined using a standardized definition and a multi-state estimator to account for the possibility of stopping natalizumab before progression, and analyzed with multivariate Cox models. RESULTS: 574 patients were followed up for a median of 6.7 years. Of the 304 who stopped NTZ before progression onset, the probabilities (95% confidence interval) to convert to progression after 1, 2, 5 and 10 years were 3.2% (2.0-4.8%), 5.3% (3.6-7.3%), 17.5% (14.3-21.3%) and 28.3% (23.7-33.7%), respectively. Discontinuation of NTZ during follow-up was significantly associated with an increased risk of conversion in case of no resumption of a highly active treatment thereafter (adjusted hazard ratio = 2.7; 95% confidence interval 1.5-4.9; p = 0.001). The use of such a treatment was associated with a lower risk of progression (adjusted hazard ratio = 0.42; 95% confidence interval 0.23-0.79; p = 0.007). CONCLUSION: the risk of conversion to secondary progression associated with natalizumab treatment is relatively low but increases in case of natalizumab discontinuation in the absence of switch to highly active immunosuppressant.

High temperature requirement A1 and macrophage migration inhibitory factor in the cerebrospinal fluid; a potential marker of conversion from relapsing-remitting to secondary progressive multiple sclerosis.

BACKGROUND: Predictive and prognostic biomarkers for multiple sclerosis (MS) remain a significant gap in MS diagnosis and treatment monitoring. Currently, there are no timely markers to diagnose the transition to secondary progressive MS (SPMS). OBJECTIVE: This study aims to evaluate the discriminatory potential of the High temperature requirement serine protease (HTRA1)/Macrophage migration inhibitory factor (MIF) cerebrospinal fluid (CSF) ratio in distinguishing relapsing-remitting (RRMS) patients from SPMS patients. METHODS: The MIF and HTRA1 CSF levels were determined using ELISA in healthy controls (n = 23), RRMS patients before (n = 22) and after 1 year of dimethyl fumarate treatment (n = 11), as well as in SPMS patients before (n = 11) and after 2 years of mitoxantrone treatment (n = 7). The ability of the HTRA1/MIF ratio to discriminate the different groups was determined using receiver operating curve (ROC) analyses. RESULTS: The ratio was significantly increased in treatment naïve RRMS patients while decreased again in SPMS patients at baseline. Systemic administrated disease modifying treatment (DMT) only significantly affected the ratio in RRMS patients. ROC analysis demonstrated that the ratio could discriminate treatment naïve RRMS patients from SPMS patients with 91% sensitivity and 100% specificity. CONCLUSION: The HTRA1/MIF ratio is a strong candidate as a MS biomarker for SPMS conversion.

Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression.

BACKGROUND: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. METHODS: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. RESULTS: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + TEMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. CONCLUSIONS: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

Effectiveness of first generation disease-modifying therapy to prevent conversion to secondary progressive multiple sclerosis.

BACKGROUND: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden. METHODS: We included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975-1994 (n = 2161), before DMT availability, and 1995-2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups. RESULTS: The risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups. CONCLUSION: The incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS incidence in higher age appeared in both treated and untreated strata. While first generation DMT delayed conversion to SPMS, their long-term effect was only moderate.

MIF in the cerebrospinal fluid is decreased during relapsing-remitting while increased in secondary progressive multiple sclerosis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate and adaptive immune systems and in neuroprotection and has recently been implicated in multiple sclerosis (MS). OBJECTIVES: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct subtypes of MS and the cellular localization of MIF in human brain tissue. METHODS: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS) (n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS cohorts were examined. Cellular distribution of MIF in the human brain was studied using immunochemistry and the newly available OligoInternode database. RESULTS: MIF was significantly decreased in treatment-naïve CIS and RRMS patients compared to HCs but was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly lower in women with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes, and oligo5 oligodendrocytes but not in microglia. CONCLUSION: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor expression that affects the overall MIF signaling in the brain and may represent a protective mechanism that eventually fails.

Patient-reported outcomes associated with transition to secondary progressive multiple sclerosis.

PURPOSE: To investigate patient-reported outcome (PRO) measures in patients with relapsing-remitting multiple sclerosis (RRMS) who transition to secondary progressive multiple sclerosis (SPMS). METHODS: Subjects enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) who completed PRO measures in the RRMS and SPMS phases were identified (n = 52). The PRO measures were Medical Outcomes Study Short-Form 36 Health Survey (SF-36), the Modified Fatigue Impact Scale (MFIS), and the Center for Epidemiologic Studies Depression Scale (CESD). Two control groups of RRMS CLIMB patients who did not progress to SPMS were identified based on different matching criteria related to age, sex, disease duration and Expanded Disability Status Scale (EDSS). Summary statistics for each PRO were calculated at the last RRMS measurement and first SPMS measurement, and the change over this transition was calculated using a paired t-test. Patients who transitioned were compared to the control groups using linear regression to adjust for age, disease duration and EDSS and a mixed model to further account for the matching with a random effect for matched group. RESULTS: Patients who transitioned from RRMS to SPMS had noticeable deficits in terms of Quality of Life (QOL) and fatigue at the visit prior to the transition. Patients worsened in terms of SF-36 Role Physical (- 3.6 [- 6.6, - 0.7]), Social Functioning (- 3.7 [- 6.4, - 1.0]), and Physical Component Summary (- 2.3 [- 4.5, - 0.1]) during the transition from RRMS to SPMS. When patients who transitioned were compared to the matched subjects, they had worse scores on several outcomes, including Physical Functioning (adjusted mean difference = - 10.8 [- 14.1, - 7.5]), Physical Component Summary (- 5.2 [- 9.3, - 1.0]), fatigue (8.9 [1.7, 16.1]), and depression (3.1 [0.3, 5.9]). CONCLUSIONS: Patients in the period closely preceding transition from RRMS to SPMS have worse physical QOL and fatigue compared to subjects who remain RRMS.

Clinical and radiological activity of secondary progressive multiple sclerosis in a population-based cohort.

BACKGROUND AND PURPOSE: Patients with secondary progressive multiple sclerosis (SP MS) and clinical and/or radiological activity could be the more likely to benefit from disease-modifying treatments. To evaluate the proportions each year after progression onset, patients with SP MS onset between 2002 and 2012 from a population-based multiple sclerosis registry in northeastern France were studied. METHODS: Progression onset was first identified by the neurologist's diagnosis (N cohort), and then by using an automated data-driven definition (D cohort). In a given year after onset of progression, clinical activity was defined as at least one relapse, and radiological activity as at least one new T2 and/or gadolinium-enhancing lesion. A multivariate mixed logistic regression was used to assess factors associated with activity during the year. RESULTS: In the N cohort, amongst 833 patients with SP MS with a median follow-up of 8 years, 10.0%-14.8% had at least one relapse in a year during the first 5 years of progression. Including both clinical and radiological activity increased these proportions to 11.9%-23.7%, with the proportion having a magnetic resonance imaging scan in the year ranging from 29.8% to 40.5%. The first year of progression, a young age and a high relapse rate during the 5 years before progression were associated with activity in a given year. The D cohort results confirmed these findings. CONCLUSIONS: A substantial proportion of patients with SP MS present disease activity. Further studies should evaluate the impact of disease-modifying treatments on the disease course of these patients.

The levels of the serine protease HTRA1 in cerebrospinal fluid correlate with progression and disability in multiple sclerosis.

BACKGROUND: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease. OBJECTIVE: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue. METHODS: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map. RESULTS: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons. CONCLUSION: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.

Long-term MS secondary progression: Derivation and validation of a clinical risk score.

OBJECTIVE: The risk of progression of multiple sclerosis (MS) related to the association of prognostic factors present at disease onset has rarely been explored. We aimed to construct a clinical risk score for MS long-term progression that could be easily applied in clinical practice. PATIENTS AND METHODS: Among 432 patients with MS, 288 patients were selected as a derivation sample for identification of the knowledge prognostic factors more associated with long-term progression. One point was given to each risk factor identified as statistically significant by the adjusted model, and the sum of the points gave the overall risk score. Subsequently the score was applied to the remaining 144 patients to confirm if those with higher scores had reached MS secondary progression. RESULTS: The prognostic factors identified as independently associated with long-term progression were: no specific MS treatment before EDSS 3, age of onset older than 30 years, pyramidal and cerebellar impairment as the first manifestation of disease, time interval between the first and second relapses less than 2 years, and African ancestry. There was no significant difference between expected and observed number of patients in progression (44 vs. 31, p = 0.966), indicating that the score was able to predict the progression in the validation sample. There was no significant difference between patients with low risk (≤ 2 points) (p = 0.98) and high risk (≥ 3 points) (p = 0.48) in the derivation versus validation samples. In the derivation sample, the patients with three or more points had a 2.8-fold increased risk of progression [hazard ratio (HR): 2.8; 95 % confidence interval (CI): 1.2-6.3; p = 0.014). CONCLUSION: The score proposed was capable of predicting long-term MS progression.

Pediatric Multiple Sclerosis in Rio de Janeiro: Secondary Progression and Disability.

BACKGROUND: The onset of multiple sclerosis (MS) in 2% to 10% of cases occurs prior to 18 years of age. Early age onset appears to affect some aspects of multiple sclerosis. The objective of our study was to evaluate the prevalence, the clinical and demographic characteristics, and the disease progression in a sample of pediatric multiple sclerosis patients from a mixed population. METHODS: In a cross-sectional design, the prevalence, demographic characteristics, and initial clinical forms were compared between 75 cases of pediatric multiple sclerosis (PMS) and 689 adults with MS. Sixty-five PMS patients with complete data and 260 randomly selected adults with relapsing-remitting multiple sclerosis were compared. A Kaplan-Meier analysis was conducted to compare the age at and time to Expanded Disability Status Scale (EDSS) 3, EDSS 6, and secondary progressive multiple sclerosis (SPMS). RESULTS: A total of 9.8% of all MS cases with available data were PMS. All cases of PMS consisted of relapsing-remitting multiple sclerosis. Brazilians of African descent comprised 34.6% of the sample, and the female-to-male ratio was 2.4:1. At the first attack, motor alterations were more common. Benign forms were more common in PMS (84.6% versus 62.2%). Fewer PMS patients reached EDSS 6 (11.6% versus 25.4%) (P = 0.0017) and SPMS (11.1% versus 28.1%) (P = 0.005). PMS patients took longer to reach EDSS 3 (P = 0.017), EDSS 6 (P = 0.001), and SPMS (P < 0.001); however, they reached EDSS 3 earlier (P < 0.001). CONCLUSIONS: In this mixed cohort, the prevalence of PMS was similar to that reported in other studies, and the pediatric patients had a more benign course than adults with MS.

Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS. Indeed, S1PR modulation by FTY720 in murine and human astrocytes suppressed neurodegeneration-promoting mechanisms mediated by astrocytes, microglia, and CNS-infiltrating proinflammatory monocytes. Genome-wide studies showed that FTY720 suppresses transcriptional programs associated with the promotion of disease progression by astrocytes. The study of the molecular mechanisms controlling these transcriptional modules may open new avenues for the development of therapeutic strategies for progressive MS.

Prognostic factors associated with long-term disability and secondary progression in patients with Multiple Sclerosis.

BACKGROUND: Predicting the long-term prognosis of patients with multiple sclerosis (MS) remains an uncertain and difficult task, with most data having been obtained exclusively from Caucasian cohorts. OBJECTIVE: To investigate clinical prognostic factors in a Brazilian mixed-race cohort. METHODS: Demographic, clinical and therapeutic factors were investigated in 303 patients with relapsing-remitting MS in relation to the following outcomes: time until reaching Expanded Disability Status Scale (EDSS) 3 and EDSS 6, and until secondary progression. RESULTS: Benign course was significantly more frequent among Caucasians when compared to Afrodescendants. Patients with a malignant course had more than one relapse in the first year of the disease and reached EDSS 3 faster if treatment was not started. In the multivariate analysis, the following factors were associated with a significantly shorter time until the established outcomes: male gender, being of African descent, non-recovery after the first relapse, two or more relapses during the first year, a short interval between initial relapses, initial polysymptomatic presentation of pyramidal and cerebellar dysfunction and no treatment prior to reaching EDSS 3. CONCLUSIONS: Being of African descent was found to be an unfavorable factor for all outcomes, reinforcing the need to take ethnicity into consideration when defining treatment, particularly in mixed MS populations.

Prognostic indicators of secondary progression in a paediatric-onset multiple sclerosis cohort in Kuwait.

BACKGROUND: The frequency of paediatric-onset multiple sclerosis (POMS) and the precise risk of secondary progression of disease are largely unknown in the Middle East. This cross-sectional cohort study assessed the risk and examined prognostic factors for time to onset of secondary progressive multiple sclerosis (SPMS) in a cohort of POMS patients. METHODS: The Kuwait National MS Registry database was used to identify a cohort of POMS cases (diagnosed at age <18 years) from 1994 to 2013. Data were abstracted from patients' records. A Cox proportional hazards model was used to evaluate the prognostic significance of the variables considered. RESULTS: Of 808 multiple sclerosis (MS) patients, 127 (15.7%) were POMS cases. The median age (years) at disease onset was 16.0 (range 6.5-17.9). Of 127 POMS cases, 20 (15.8%) developed SPMS. A multivariable Cox proportional hazards model showed that at MS onset, brainstem involvement (adjusted hazard ratio 5.71; 95% confidence interval 1.53-21.30; P=0.010), and POMS patient age at MS onset (adjusted hazard ratio 1.38; 95% confidence interval 1.01-1.88; P=0.042) were significantly associated with the increased risk of a secondary progressive disease course. CONCLUSIONS: This study showed that POMS patients with brainstem/cerebellar presentation and a relatively higher age at MS onset had disposition for SPMS and warrant an aggressive therapeutic approach.

Continuous prediction of secondary progression in the individual course of multiple sclerosis.

BACKGROUND: Prediction of the course of multiple sclerosis (MS) was traditionally based on features close to onset. OBJECTIVE: To evaluate predictors of the individual risk of secondary progression (SP) identified at any time during relapsing-remitting MS. METHODS: We analysed a database comprising an untreated MS incidence cohort (n=306) with five decades of follow-up. Data regarding predictors of all attacks (n=749) and demographics from patients (n=157) with at least one distinct second attack were included as covariates in a Poisson regression analysis with SP as outcome. RESULTS: The average hazard function of transition to SPMS was 0.046 events per patient year, showing a maximum at age 33. Three covariates were significant predictors: age, a descriptor of the most recent relapse, and the interaction between the descriptor and time since the relapse. A hazard function termed "prediction score" estimated the risk of SP as number of transition events per patient year (range <0.01 to >0.15). CONCLUSIONS: The insights gained from this study are that the risk of transition to SP varies over time in individual patients, that the risk of SP is linked to previous relapses, that predictors in the later stages of the course are more effective than the traditional onset predictors, and that the number of potential predictors can be reduced to a few (three in this study) essential items. This advanced simplification facilitates adaption of the "prediction score" to other (more recent, benign or treated) materials, and allows for compact web-based applications (http://msprediction.com).