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.

Real-life evaluation of the 2017 McDonald criteria for relapsing-remitting multiple sclerosis after a clinically isolated syndrome confirms a gain in time-to-diagnosis.

BACKGROUND: Previous cohort studies evaluating the performances of the McDonald criteria suffered from bias regarding real-life conditions. We aimed to evaluate the probability of diagnosing relapsing-remitting multiple sclerosis (MS) at several timepoints from the first medical evaluation and the gain in time-to-diagnosis with the 2017 McDonald criteria compared with the 2001, 2005 and 2010 versions in real life. METHODS: Patients with a first demyelinating event suggestive of MS between 2002 and 2020 were included in the ReLSEP, an exhaustive and prospectively incremented registry of MS patients in North-Eastern France. We estimated the probability of being positive at the first medical evaluation and at five timepoints according to the four versions of criteria using Kaplan-Meier estimators and Cox models. RESULTS: A total of 2220 patients were followed up for a median of 7.1 years. At baseline, 31.7%, 32.1%, 36.6% and 54.0% of patients, respectively, fulfilled the 2001, 2005, 2010 and 2017 McDonald criteria. Using the 2017 criteria, the gain in time-to-diagnosis was 3.7 months compared with the 2010 criteria. The presence of intrathecal synthesis of immunoglobulin G in the McDonald 2017 criteria led to a 1.8-month reduction in median time-to-diagnosis compared to a version of McDonald 2017 without this criteria. CONCLUSIONS: In real-life, the 2017 McDonald criteria revision undoubtedly shortened time-to-diagnosis.

Long-term analysis of patients with benign multiple sclerosis: new insights about the disability course.

OBJECTIVE: To describe the course of disability in patients with benign multiple sclerosis-i.e., with an expanded disability status scale score < 3 10 years after disease onset-for up to 30 years after disease onset. We evaluated the proportion of patients remaining in the benign state on the long term and the factor associated with this favorable outcome and determined the pattern of disability course after the loss of the benign status. METHODS: Patients were selected from the ReLSEP, a French population-based registry. We studied the probability (Kaplan-Meier method) and predictors (multivariate Cox model) of remaining < 3 after year 10, and the course of disability after score 3 according to the duration of the benign phase in patients with ≥ 30 years of follow-up (graphs of the course of the mean expanded disability status scale scores in subgroups of patients). RESULTS: 2295/3440 patients had benign multiple sclerosis (66.7%). The probability of remaining benign at year 30 was 0.26 (95% CI 0.26-0.32). A young age at disease onset and a good recovery after the first relapse were associated with remaining benign. Graphs illustrate that those who lost their benign status between years 10 and 30 follow a two-stage course. Beyond score 3, disability accumulation is similar in all but lower disability scores at advanced age are associated with longer benign periods. CONCLUSION: The longer a patient remains in the benign state, the lower the final EDSS at advanced age.

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.

Effect of familial clustering in the genetic screening of 235 French ALS families.

OBJECTIVES: To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved. METHODS: We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed. RESULTS: Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years. CONCLUSION: Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.

Discontinuation of disease-modifying treatments for multiple sclerosis in patients aged over 50 with disease Inactivity.

BACKGROUND: Treatments may become redundant in older patients with multiple sclerosis (MS). Our aim was to explore whether stopping treatments might be possible in patients aged over 50 with disease inactivity. METHODS: Patients over 50 were included from the population-based MS Lorraine registry if they had a relapsing-remitting course at onset and had experienced no relapse for ≥ 3 years. Patients who stopped treatments were defined as "stoppers", and the others as "stayers". The outcomes were the time to first relapse, to first disability progression, and to the occurrence of EDSS score of 6, assessed by multivariate analysis using a propensity score. RESULTS: 132 stoppers and 366 stayers had a median follow-up of 7 years. There was no difference in Log-rank tests for the times to first relapse (p = 0.61) and to first disability progression (p = 0.22). In Cox models, stopping treatments was not associated with an increased risk of relapse (adjusted Hazard ratio (aHR) = 0.92 [0.72-1.16; p = 0.47]) or of an increase in EDSS score (aHR = 0.89 [0.71-1.13; p = 0.34]). However, stopping was associated with a higher risk of occurrence of EDSS score of 6 (aHR = 3.29 [2.22-4.86; p < 0.0001]), with a significant difference for the time to occurrence of EDSS score of 6 (p = 0.003). CONCLUSION: Our study suggests that stopping injectable disease-modifying treatments, in patients over 50 with disease inactivity, is not associated with an increased risk of relapse or EDSS progression, but there might be a higher risk of reaching EDSS 6. These results have to be confirmed by interventional studies.

Cerebrospinal fluid chitinase-3-like protein 1 level is not an independent predictive factor for the risk of clinical conversion in radiologically isolated syndrome.

BACKGROUND: Younger age, male sex and presence of spinal cord lesion(s) increase the risk of conversion from radiologically isolated syndrome (RIS) to relapsing-remitting multiple sclerosis (RRMS). Elevated cerebrospinal fluid (CSF) chitinase-3-like protein 1 (CHI3L1) levels predict conversion from clinically isolated syndrome (CIS) to RRMS. OBJECTIVE: To evaluate the prognostic value of CSF CHI3L1 in RIS patients for conversion to RRMS. METHODS: We compared CSF CHI3L1 concentrations in RIS, CIS, RRMS and symptomatic controls (SCs). We analysed the influence of epidemiological, radiological and CSF parameters on the risk of clinical event. RESULTS: A total of 211 patients (71 RIS, 48 CIS, 50 RRMS and 42 SC) were included. CSF CHI3L1 levels were lower in RIS than in RRMS and higher in RIS with positive CSF versus negative CSF and SC. The presence of at least one spinal cord lesion was the only independent predictor of faster conversion to RRMS. Association of high CSF CHI3L1 levels, positive CSF (presence of oligoclonal bands and/or an elevated IgG index) or four Barkhof criteria with any spinal cord lesion showed a tendency for reduced mean conversion time. CONCLUSION: CSF CHI3L1 correlates with positive CSF but is not an independent predictor of the risk of conversion from RIS to RRMS.

Generational changes in multiple sclerosis phenotype in North African immigrants in France: A population-based observational study.

BACKGROUND: The incidence of multiple sclerosis (MS) changes from generation to generation in ethnically different immigrants compared with native-born people. We aimed to determine whether there are generational changes in MS phenotypes among North African immigrants in France. METHODS: Cohort study with data from a population-based MS registry to compare the clinical characteristics of 80 first (NAG1) and 167 second (NAG2) generation North Africans with MS living in France with 5200 native-born Europeans. Adjusted Cox models were used to test the association between scores of 3 and 6 on the expanded disability status scale (EDSS) and the "origin/generation" variable. RESULTS: Cox models for EDSS scores 3 and 6 showed a higher risk of score 3 (hazard ratio = 1.738, 95% confidence interval 1.237 to 2.444; P = .002) and 6 (hazard ratio = 2.372, 95% confidence interval 1.626 to 3.462; P<.0001) for NAG1 than Europeans. Being NAG2 was not significantly associated with higher hazards of scores 3 and 6. CONCLUSIONS: We found two different phenotypes among NAG1 and NAG2 MS patients in France. NAG1, but not NAG2, have a higher risk of disability than Europeans. This raises the question of environmental factors in MS expression, and advocates appropriate patient management according to generation in immigrants.

Physical dimension of fatigue correlated with disability change over time in patients with multiple sclerosis.

To determine the value of fatigue in predicting the change in disability status in patients with multiple sclerosis (MS), we realized a prospective population-based cohort study of 196 patients with clinically definite MS. In 2002, baseline data were collected on fatigue (Modified Fatigue Impact Scale), health-related quality of life (SF-36), and disability status (EDSS score). The EDSS scores were determined again at least three years later. Univariate and multivariate analysis were performed to determine the predictive value of different dimensions of fatigue and other variables (depression and SF- 36) on the change in disability status. Of the 196 patients, 106 (54%) patients had an unchanged status or improvement and 90 (46%) showed a worsening of disability. After three years, with control for gender, age, and baseline disability status, a high baseline level of physical fatigue was associated with a worsening of disability status, whereas a low baseline level of physical fatigue was associated with the absence of worsening of the EDSS score. Other dimensions of fatigue, depression and SF-36 were not associated with a worsening of disability.A patient's perceived fatigue may be not only a clinically and psychosocially meaningful outcome but also a predictor of objective outcomes such as changes in disability status at three years.