Objective
To evaluate the effect of discontinuation of different disease-modifying therapies (DMTs) before pregnancy with respect to the occurrence of relapses and pregnancy outcomes.
Methods
Women ...with multiple sclerosis who desire to bear children were followed prospectively. Demographic data, clinical characteristics, and the information on the use of DMTs were collected. A multivariate analysis was used to assess the relationship between relapses and the prior use of different DMTs.
Results
The present study assessed 75 consecutive pregnancy plans (66 women), 65 of which resulted in pregnancy. The mean age of the participants was 32.1 ± 4.2 years, and the mean disease duration was 6.1 ± 4.2 years. No relapses before pregnancy were reported in the group of women who maintained their DMT until pregnancy confirmation, while 14 relapses were reported in 12/42 women (29%) who discontinued DMT before pregnancy. During pregnancy, patients on natalizumab or fingolimod before pregnancy had a higher rate of relapses. Most women restarted their previous DMT after delivery within the first trimester. The relapse rate in postpartum was 0.07.
Conclusions
Disease-modifying therapies received influences the risk of relapse and disease progression from women who are planning pregnancy. The risk of relapse during pregnancy was significantly higher in the group of women treated with natalizumab or fingolimod compared to the group of women treated with interferon beta or glatiramer acetate. The postpartum risk of relapses was lower than that found in previous reports.
Background and purpose
The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short‐term treatment ...effects on disability. This study aimed to define criteria for 6‐month confirmed disability progression events of MS with a high probability of resulting in sustained long‐term disability worsening.
Methods
In total, 14,802 6‐month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6‐month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long‐term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial.
Results
The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29–0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score ˃1.5).
Conclusions
Clinicodemographic characteristics of 6‐month confirmed disability progression events identify those at high risk of sustained long‐term disability. This knowledge will allow future trials to better assess the effect of therapy on long‐term disability accrual.
Using 13,321 confirmed disability progression events from the MSBase registry, a sustained progression score was developed based on patients' characteristics at the time of progression. The sustained progression score helps identify those confirmed progression events that will be sustained over at least 5 years. This score allows randomized trials to establish the effect of therapy not only on short‐term but also on long‐term disability accrual, as demonstrated in our reanalysis of the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial data.
Background and purpose
This study assessed the effect of patient characteristics on the response to disease‐modifying therapy (DMT) in multiple sclerosis (MS).
Methods
We extracted data from 61,810 ...patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow‐up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12‐month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics.
Results
Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio HR = 0.52, 95% confidence interval CI = 0.45–0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41–0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09–1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity.
Conclusions
DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.
Marine reserves: size and age do matter Claudet, Joachim; Osenberg, Craig W; Benedetti-Cecchi, Lisandro ...
Ecology letters,
20/May , Letnik:
11, Številka:
5
Journal Article
Recenzirano
Marine reserves are widely used throughout the world to prevent overfishing and conserve biodiversity, but uncertainties remain about their optimal design. The effects of marine reserves are ...heterogeneous. Despite theoretical findings, empirical studies have previously found no effect of size on the effectiveness of marine reserves in protecting commercial fish stocks. Using 58 datasets from 19 European marine reserves, we show that reserve size and age do matter: Increasing the size of the no-take zone increases the density of commercial fishes within the reserve compared with outside; whereas the size of the buffer zone has the opposite effect. Moreover, positive effects of marine reserve on commercial fish species and species richness are linked to the time elapsed since the establishment of the protection scheme. The reserve size-dependency of the response to protection has strong implications for the spatial management of coastal areas because marine reserves are used for spatial zoning.
To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients.
We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct ...sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing.
A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported.
Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
Ocrelizumab, an antiCD-20 antibody, is the only drug approved to treat patients with primary progressive multiple sclerosis (pwPPMS). Not all candidates receive this treatment due to ...prescription limitations. Rituximab, another antiCD-20 antibody, has been used off-label in pwPPMS before and after ocrelizumab approval. However, studies comparing effectiveness of both drugs are lacking.
Objective
To evaluate effectiveness of rituximab and ocrelizumab in pwPPMS under real-life conditions.
Methods
We conducted a multicentric observational study of pwPPMS that started ocrelizumab or rituximab according to clinical practice, with a minimum follow-up of 1 year. Data was collected prospectively and retrospectively. Primary outcome was time to confirmed disability progression at 3 months (CDW). Secondary outcome was serum neurofilament light chain levels (sNFL) at the end of follow-up.
Results
95 out 111 pwPPMS fulfilled inclusion criteria and follow-up data availability: 49 (51.6%) received rituximab and 46 (48.4%) ocrelizumab. Rituximab-treated patients had significantly higher baseline EDSS, disease duration and history of previous disease-modifying treatment (DMT) than ocrelizumab-treated patients. After a mean follow-up of 18.3 months (SD 5.9), 26 patients experienced CDW (21.4%); 15 (30.6%) in the rituximab group; and 11 (23.9%) in the ocrelizumab group. Survival analysis revealed no differences in time to CDW
.
sNFL were measured in 60 patients and no differences between groups were found.
Interpretation
We provide real-world evidence of effectiveness of ocrelizumab and rituximab in pwPPMS. No differences in time to CDW were found between treatments. However, this study cannot establish equivalence of treatments and warrant clinical trial to confirm our findings.
Background:
In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, ...susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models.
Objective:
To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models.
Methods:
Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement.
Results:
4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 95% CI 0.62-0.80; marginal structural model: 0.71 0.62-0.80), and higher probability of disability improvement (PS matching: 1.21 1.02 -1.43; marginal structural model 1.43 1.19 -1.72). There was no evidence of a difference in the magnitude of effect between the two methods.
Conclusions:
The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.
Crucial elements for achieving optimal long-term outcomes in multiple sclerosis (MS) are patient confidence and effective physician–patient communication. Patient-reported instruments may provide the ...means to fill the gap in currently available clinician-rated measures. The SymptoMScreen (SMSS) is a brief self-assessment tool for measuring symptom severity in 12 neurologic domains commonly affected by MS. We conducted a non-interventional study to assess the dimensional structure and item characteristics of the SMSS. A total of 218 patients with relapsing–remitting MS and mild disability (median Expanded Disability Status Scale score 2.0) were studied. Symptom severity was low (SMSS score 13.5, interquartile range 4.2–27), fatigue being the domain with the highest impact. A non-parametric item response theory, i.e., Mokken analysis, found that the SMSS is a robust one-dimensional scale (overall scalability index
H
0.60) with high reliability (Cronbach’s alpha 0.94). The confirmatory factor analysis model confirmed the unidimensional structure (comparative fit index 1.0, root-mean-square error of approximation 0.001). Samejima’s model fitted well an unconstrained model with different item difficulties. The SMSS shows appropriate psychometric characteristics and may constitute a valuable and easy-to-implement addition to measure the symptom severity in clinical practice.
IMPORTANCE: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive ...MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. OBJECTIVE: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. DESIGN, SETTING, AND PARTICIPANTS: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years’ follow-up. EXPOSURES: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). MAIN OUTCOME AND MEASURE: Conversion to objectively defined secondary progressive MS. RESULTS: Of the 1555 patients, 1123 were female (mean baseline age, 35 years SD, 10). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% 49 of 407 vs 27% 58 of 213; median follow-up, 7.6 years IQR, 5.8-9.6), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% 6 of 85 vs 32% 56 of 174; median follow-up, 4.5 years IQR, 4.3-5.1); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% 16 of 82 vs 38% 62 of 164; median follow-up, 4.9 years IQR, 4.4-5.8); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% 4 of 44 vs 25% 23 of 92; median follow-up, 7.4 years IQR, 6.0-8.6). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% 16 of 235 vs 12% 46 of 380; median follow-up, 5.8 years IQR, 4.7-8.0). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% 4 of 120 vs 6% 2 of 38; median follow-up, 13.4 years IQR, 11-18.1). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% 25 of 307 vs 14% 46 of 331, median follow-up, 5.3 years IQR, 4.6-6.1). CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies’ risks, may help inform decisions about DMT selection.
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