High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS.

Importance: A recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity. Objective: To determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET. Design, Setting, and Participants: This observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022. Exposures: Natalizumab, fingolimod, rituximab, and ocrelizumab. Main Outcomes and Measures: Time to first relapse. Results: Of 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P < .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy. Conclusion and Relevance: As in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

A cross-sectional study on infectious health risks regarding freshwater sports practice in Brittany, France.

Freshwater sports expose practitioners to pathogens in the water environment and may result in infection. In French Brittany, these infections are particularly worrying, especially since 2016 with an increase in the incidence of leptospirosis reaching 1 case per 100,000 inhabitants, which represents the highest incidence observed since 1920. We aimed to estimate the prevalence of infectious diseases related to freshwater sports practice and to identify the factors associated with these infections among freshwater sports licensees in Brittany, France. From March 18, 2019, to May 8, 2019, we interviewed freshwater sports licensees (online study) and club presidents and instructors (phone study) in Brittany. Licensee participants were 18 years old or more and practiced at least one freshwater sport in one of the 79 Brittany clubs. We used logistic regression models to study the association between our variables of interest and potential risk factors. In total, 551 licensees (20.3% of the total number of licensees) and 38 clubs (48.1%) were surveyed. Among the licensees, 29 (5.3%) reported being diagnosed with leptospirosis, of which 12 (41.3%) occurred in the last 5 years. The most reported symptoms were skin irritation/itchy skin (24.3%) and 39 individuals (7.1%) reported at least one hospitalization in their lifetime for a disease related to freshwater sports. The occurrence of leptospirosis was negatively associated with boarding from a pontoon (odds ratio (OR)=0.20, 95% confidence interval (95% CI) 0.06-0.56), practicing for less than 4 years (OR=0.17, 95% CI 0.04-0.56) compared to more than 10 years, and the occurrence of leptospirosis was positively associated with taking a soapy shower after practice (OR=4.38, 95% CI 1.90-10.51). Eskimo roll was positively associated with the occurrence of otitis and conjunctivitis (OR=3.22, 95% CI 1.82-6.03), and skin irritation/itchy skin (OR=1.66, 95% CI 0.99-2.84). Otitis, conjunctivitis, and skin irritation/itchy skin are the most commonly reported freshwater sport-related diseases in French Brittany. Despite a good level of knowledge of prevention measures, their implementation by licensees and clubs remains low. Further studies are needed to identify practices associated with infectious risk in freshwater sports.

Disease modifying therapies and disease activity during pregnancy and postpartum in a contemporary cohort of relapsing Multiple Sclerosis patients.

BACKGROUND: In Multiple Sclerosis (MS) women, therapeutic management for pregnancy planning and during pregnancy still represents a challenge regarding timing of disease-modifying therapies (DMT) stop, risk of disease reactivation and potential fetal toxicity. The objective of this study was to describe disease activity during pregnancy and postpartum depending on treatment status before conception in women with MS. METHODS: 339 MS patients who have achieved a pregnancy between 2007 and 2017 were included. Women were classified according to their exposure to DMT in the 18 months period prior to pregnancy (untreated / first- / second/third-line treatment). RESULTS: 122 women were not exposed to DMT prior to conception, whereas 147 were exposed to first-line DMT and 70 to second/third line DMT (73% to natalizumab and 23% to fingolimod) before conception. In the first-line group, the ARR decreased from 0.39 during the year before conception to 0.21 during pregnancy, whereas it increased in the second/third-line group from 0.59 to 0.78. 47.1% of the second/third-line group faced at least one relapse during pregnancy and the time from conception to first relapse was significantly shorter in this group (p < 10-4). The risk of relapse during pregnancy and postpartum was associated with occurrence of pre-conception relapses and second/third line DMT exposure before pregnancy. CONCLUSION: Careful consideration should be given to natalizumab and fingolimod exposed patients before conception as they are at higher risk of reactivation of MS during pregnancy.

COPP-MS: COrticosteroids during the Post-Partum in relapsing Multiple Sclerosis patients.

BACKGROUND: No specific treatment has demonstrated its effectiveness to prevent post-partum relapses for multiple sclerosis (MS) women. OBJECTIVE: To assess the effectiveness of preventive high-dose corticosteroids in the post-partum period by comparing two strategies: (1) no preventive treatment and (2) standardized preventive treatment. METHODS: We selected five French Multiple Sclerosis centers using the same post-partum strategy for their patients-either high-dose steroids (treating centers TC) or no treatment (non-treating centers NTC). We included relapsing-remitting multiple sclerosis women who delivered between January 2007 and January 2017. Our primary outcomes were the time from delivery to first relapse, EDSS progression and MRI activity between patients of treating centers and non-treating centers, after propensity-score weighting. RESULTS: 350 patients were included (116 from treating centers, 234 from non-treating centers). For both groups, the annualized relapse rate decreased during pregnancy (0.28 in treating centers and 0.34 in non-treating centers during the third trimester) and increased during the first post-partum trimester (0.45 and 0.69, respectively) with 11% and 14% (NS) of patients facing at least one relapse, respectively. Our primary outcomes were not statistically different between both groups. CONCLUSION: This study provides class III evidence that systematic high-dose corticosteroids are not associated with a reduced inflammatory activity during the post-partum period in multiple sclerosis patients.

Disability Progression in Multiple Sclerosis Patients using Early First-line Treatments.

BACKGROUND: Therapeutic management of relapsing-remitting multiple sclerosis (RRMS) has evolved towards early treatment. The objective was to assess the impact of early treatment initiation on disability progression among RRMS first-line treated patients. METHODS: This study included all incident RRMS cases starting interferon or glatiramer acetate for the first time from 1996/01/01 to 2012/31/12 (N=5,279) from ten MS expert OFSEP centers (Observatoire Français de la Sclérose en Plaques). The delay from treatment start to attain an irreversible Expanded Disability Status Scale score of 3.0 were compared between "Early" group (N= 1,882; treated within 12 months following MS clinical onset) and "Later" group using propensity score weighted Kaplan-Meier methods, overall and stratified by age. RESULTS: Overall, the restricted mean time before reaching EDSS 3.0 (RMST) from treatment start was 11 years and two months for patients treated within the year following MS clinical onset and 10 years and seven months for patients treated later. Thus, early treated patients gained 7 months (95% CI: [4-11] months) in the time to reach EDSS 3.0 compared to patients treated later (treatment start delayed by 28 months). The difference in RMST was respectively six months (95% CI: [1-10] months) and 14 months (95% CI: [4-24] months) in the "≤40 years" age group and in the ">40 years" age group, in favour of early group. . CONCLUSIONS: Early treatment initiation resulted in a significant reduction of disability progression among patients with RRMS, and also among older patients.

Trends in disease-modifying therapy use in patients with multiple sclerosis using a 10-year population-based cohort study in France.

BACKGROUND: The availability of new disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS) provides an opportunity for improving outcomes but makes disease management more complex. Our study aimed to describe changes in therapeutic practices over the period 2009-2018 and measure the impact of the arrival of oral DMTs on the use of injectable DMTs. METHODS: Data were extracted from a representative 1/97 sample of the French population covered by the healthcare insurance system. Study period was set from 1 January 2009 to 31 December 2018. Four periods of MS identification were defined (before 2009, 2009-2011, 2012-2015, and 2016-2018). RESULTS: Overall, 1,508 patients with MS were included, of whom 876 (58.1%) were treated at least once over the study period. Untreated patients were older and had more comorbidities than treated ones. First-line DMTs were the most frequent initial DMT (78.5%), and a shift has operated from injectable to oral drugs over time. The proportion of patients receiving several DMTs increased with the number of available drugs. End 2018, relative parts of all DMTs were almost equal. CONCLUSIONS: This study provides valuable insights into the real-world use of DMTs and changes that have operated over time.

Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts.

INTRODUCTION: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined. OBJECTIVE: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest. METHODS: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients' sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed with weighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score. RESULTS: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15-41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65-0.88); in those aged ≤ 38 years (0.64; 0.54-0.76); in those with disease duration ≤ 7 years (0.63; 0.53-0.76); in those with EDSS score < 4 (0.75; 0.64-0.88), < 6 (0.80; 0.70-0.91), and ≥ 6 (0.52; 0.31-0.86); and in patients with pre-baseline relapses (0.74; 0.64-0.86). A higher probability of confirmed disability improvement on natalizumab versus fingolimod (hazard ratio [HR]; 95% CI) was observed among women (1.36; 1.10-1.66); those aged > 38 years (1.34; 1.04-1.73); those with disease duration > 7 years (1.33; 1.01-1.74); those with EDSS score < 6 (1.21; 1.01-1.46) and ≥ 6 (1.93; 1.11-3.34); and patients with no new MRI lesion (1.73; 1.19-2.51). CONCLUSIONS: Overall, in women, younger patients, those with shorter disease durations, and patients with pre-treatment relapses, natalizumab was associated with a lower frequency of multiple sclerosis relapses than fingolimod. It was also associated with an increased chance of recovery from disability among most patients, particularly women and those with no recent MRI activity.

The effectiveness of natalizumab vs fingolimod-A comparison of international registry studies.

BACKGROUND: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. METHODS: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. RESULTS: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. CONCLUSION: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.

Long-term effect of first-line injectable multiple sclerosis treatments: Input of a time-dependent propensity score.

PURPOSE: The long-term effect of beta-interferon and glatiramer acetate on multiple sclerosis (MS) disability progression has resulted in controversial results, probably due to a lack of appropriate control of biases as raised in observational studies. In particular, the time of the therapeutic decision is difficult to define when the controls are not treated. METHODS: This retrospective observational study was based on a series of patients from the MS expert center in Rennes, France. We used a time-dependent propensity score defined as the linear predictor of a Cox model estimating the hazard of being treated at each time from MS onset. The matching procedure resulted in two groups: patients matched as treated and as not yet treated. The restricted mean times (RMST) to reach a moderate level of disability or worsening of the disability were compared between the two groups in an intention-to-treat analysis. RESULTS: Of the 2383 patients included in the study, 556 were matched as treated. The matching procedure provided a good balance of both the time-fixed and the time-dependent covariates. A slight difference was observed for the time to reach a moderate level of disability, in favor of the "not yet treated" group (difference in the RMST: -0.62 [-0.91; -0.33]) while no difference was found in terms of worsening of the disability (-0.03 [-0.24; 0.33]). CONCLUSION: This unexpected result is probably due to unmeasured confounders. However, this time-dependent PS warrants consideration in long-term effectiveness studies.

Metastatic Clear-cell Renal Cell Carcinoma With a Long-term Response to Sunitinib: A Distinct Phenotype Independently Associated With Low PD-L1 Expression.

BACKGROUND: Long-term responders (LTRs) are defined by at least 18 months of response to sunitinib in metastatic clear-cell renal cell carcinoma (ccRCC). Well-described by clinical studies, the phenotype of these tumors has never been explored. PATIENTS AND METHODS: In a retrospective and multicenter study, 90 ccRCCs of patients with metastatic disease were analyzed. Immunohistochemistry (carbonic anhydrase IX, vascular endothelial growth factor, c-MET, programmed death-ligand 1 [PD-L1], and PD-1) and VHL status were performed. Progression-free survival and overall survival were calculated from sunitinib introduction and from progression. LTRs and their corresponding tumors were compared with others using univariate and multivariate analysis. RESULTS: Twenty-eight patients were LTRs. They had a median progression-free survival of 28 months versus 4 months for other patients (P < .001). Similarly, LTRs had a median overall survival of 49 months versus 14 months (P < .001), even from progression (median, 21 vs. 7 months; P = .029). They were associated with a favorable or intermediate risk (International Metastatic Renal Cell Carcinoma Database Consortium model) (P = .007) and less liver metastasis (P = .036). They experienced more frequent complete or partial responses at the first radiologic evaluation (P = .035). The corresponding ccRCCs were associated with less nucleolar International Society for Urological Pathology grade 4 (P = .037) and hilar fat infiltration (P = .006). They were also associated with low PD-L1 expression (P = .02). Only the International Metastatic Renal Cell Carcinoma Database Consortium model and PD-L1 expression remained significant after multivariate analysis (P = .014 and P = .029, respectively). CONCLUSION: Primary tumor characteristics of LTRs were studied for the first time and demonstrated a different phenotype. Interestingly, they were characterized by low expression of PD-L1, suggesting a potentially lower impact of targeted immunotherapy in these patients.

Categorical state sequence analysis and regression tree to identify determinants of care trajectory in chronic disease: Example of end-stage renal disease.

BACKGROUND: Patients with chronic diseases, like patients with end-stage renal disease (ESRD), have long history of care driven by multiple determinants (medical, social, economic, etc.). Although in most epidemiological studies, analyses of health care determinants are computed on single health care events using classical multivariate statistical regression methods. Only few studies have integrated the concept of treatment trajectories as a whole and studied their determinants. METHODS: All 18- to 80-year-old incident ESRD patients who started dialysis in Ile-de-France or Bretagne between 2006 and 2009 and could be followed for a period of 48 months after initiation of a renal replacement therapy were included (n = 5568). Their care trajectories were defined as categorical state sequences. Associations between patients' characteristics and care trajectories were assessed using a regression tree model together with a discrepancy analysis. RESULTS: On average, each patient experienced 1.56 different renal replacement therapies (min = 1; max = 5) during the 48 months of follow-up. About 55% of patients never changed treatment and only 1% tried three or more renal replacement therapy modalities. Twelve homogeneous care trajectory groups were identified. Covariates explained 12% of the discrepancy between groups, particularly age, regions and initiation of hemodialysis with a catheter. CONCLUSIONS: Regression tree analysis of categorical state sequence highlighted geographical disparities in the care trajectory of French patients with ESRD that cannot be observed when focusing on a single outcome, such as survival. This method is an original tool to visualize and characterize care trajectories, notably in the context of chronic condition like ESRD.

Sex differences in adherence to antihypertensive treatment in patients aged above 55: The French League Against Hypertension Survey (FLAHS).

Despite the availability of efficient therapies to reduce the risk of cardiovascular complications, poor adherence to antihypertensive (anti-HTN) drugs is frequent, especially during the first year of treatment and among uncontrolled/resistant hypertensive patients. The aim of the study was to identify factors associated with adherence to anti-HTN treatment and to examine whether they differ across sex. A total of 2743 treated hypertensive participants to the cross-sectional Metascope survey (France, 2015) aged 55 years or more were included. The authors measured adherence to anti-HTN treatment using the 6-item Girerd compliance test. Variations in adherence were examined using the Rao-Scott statistics and Poisson regression. Overall, 63.6% of participants were adherent to anti-HTN treatment. Adherence was more frequent among women than men (69% vs 58%, P < 10-4 ). For both sexes, level of adherence was positively associated with age (P < 10-4 ), but inversely associated with number of anti-HTN tablets, number of tablets taken for metabolic diseases, history of cardiovascular diseases, number of other chronic diseases (all P < 10-4 ). The inverse relationship between adherence and the number of anti-HTN tablets significantly differed between sexes (P < 10-4 ): Adherence decreased sharply when taking two or more anti-HTN tablets in men, whereas the decrease in women was only observed when taking three or more anti-HTN tablets. This study suggests that adherence to anti-HTN treatment is higher among women, decreases with the number of tablets prescribed, and differentially so across sex. Reducing the number of tablets for anti-HTN treatment may improve adherence, especially among men and patients with multiple comorbidities.

Hilar fat infiltration: A new prognostic factor in metastatic clear cell renal cell carcinoma with first-line sunitinib treatment.

INTRODUCTION: The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib. MATERIALS AND METHODS: In a multicentric study, we retrospectively included 90 patients and studied the corresponding ccRCC at the pathological, immunohistochemical, and molecular levels. Patient and tumor characteristics were compared using univariate and multivariate analysis. All the features were then studied by Cox models for prognostic effect. RESULTS: HFI was found in 42 patients (46.7%), who had worse prognosis (Heng criteria) (P = 0.003), liver metastases (P = 0.036), and progressive diseases at first radiological evaluation (P = 0.024). The corresponding ccRCC was associated with poor pathological prognostic factors that are well known in nonmetastatic ccRCC. For these patients, median progression-free survival was 4 months vs. 13 months (P = 0.02), and median overall survival was 14 months vs. 29 months (P = 0.006). In a multivariate Cox model integrating all the variables, only poor prognosis, according to the Heng criteria and HFI, remained independently associated with both progression-free survival and overall survival. CONCLUSION: HFI was demonstrated for the first time to be an independent poor prognostic factor. Its potential role in predicting resistance to antiangiogenic therapy warrants further investigation.

[Glioblastoma and nursing care in neurosurgery]. / Glioblastome et soins infirmiers en neurochirurgie.

Nurses in neurosurgical departments play a critical role as they are involved in the first stages of the care pathway of patients with glioblastoma. Indeed, surgery enables a definitive histopathological diagnosis to be established and the size of the tumour to be significantly reduced, thereby improving the prognosis.

Facilitating access to the renal transplant waiting list does not increase the number of transplantations: comparative study of two French regions.

BACKGROUND: In France, there are important regional disparities of access to the renal transplant waiting list and transplantation. Our objectives were to compare the characteristics of patients with end-stage renal disease (ESRD) of two French regions (Ile-de-France and Bretagne) and to identify determinants of access to the waiting list and subsequent transplantation, with a focus on temporary inactive status (TIS) periods. METHODS: All 18-80-year-old incident patients who started dialysis in Ile-de-France or Bretagne between 2006 and 2009 were included (n = 6160). Associations between patients' characteristics and placement on the waiting list or transplantation were assessed using a Fine and Gray model to take into account the competing risk of death and living donor transplantation. RESULTS: At the end of the follow-up (31 December 2013), more patients had undergone transplantation in Bretagne than in Ile-de-France (30 versus 27%), although the percentage of waitlisted patients was higher in Ile-de-France than in Bretagne (47 versus 33%). More patients were on TIS and with a longer median TIS duration in Ile-de-France. Independent of age and clinical characteristics, patients in Bretagne were less likely to be waitlisted than those in Ile-de-France [subdistribution hazard ratio 0.77 (95% confidence interval 0.7-0.9)]. After waitlisting, patients in Bretagne were four times more likely to be transplanted. CONCLUSIONS: Our study highlights clinical practice differences in Bretagne and Ile-de-France and shows that facilitating access to the waiting list is not sufficient to improve access to renal transplantation, which also depends on organ availability.