Notes how a female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients has been demonstrated in many countries around the world, but without a direct comparison of sex ratio ...time-trends among MS populations from different geographical areas. Assesses and compares sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas. Includes a cohort with definite MS, and birth years ranging from 1930 to 1989, extracted from the New Zealand MS database. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multiple Sclerosis is more common in women than men and females have more relapses than men. In a large international cohort we have evaluated the effect of gender on disability accumulation and ...disease progression to determine if male MS patients have a worse clinical outcome than females.
Using the MSBase Registry, data from 15,826 MS patients from 25 countries was analysed. Changes in the severity of MS (EDSS) were compared between sexes using a repeated measures analysis in generalised linear mixed models. Kaplan-Meier analysis was used to test for sex difference in the time to reach EDSS milestones 3 and 6 and the secondary progressive MS.
In relapse onset MS patients (n = 14,453), males progressed significantly faster in their EDSS than females (0.133 vs 0.112 per year, P<0.001,). Females had a reduced risk of secondary progressive MS (HR (95% CI) = 0.77 (0.67 to 0.90) P = 0.001). In primary progressive MS (n = 1,373), there was a significant increase in EDSS over time in males and females (P<0.001) but there was no significant sex effect on the annualized rate of EDSS change.
Among registrants of MSBase, male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of ...secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0) versus non-progressive patients 1.8 (1.2, 1.9). This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.
Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of ...individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.
Objective
To identify predictors of 10‐year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse‐onset multiple sclerosis.
Methods
Using data obtained ...from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease‐modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10‐year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.
Results
We identified 2,466 patients followed up for at least 10 years reporting post‐baseline disability scores. Patients were treated an average 83% of their follow‐up time. EDSS scores increased by a median 1 point (interquartile range = 0–2) at 10 years post‐baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10−22). On‐therapy relapses carried greater burden than off‐therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = −0.86, p = 1.3 × 10−9). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10‐year observation period (coeff = −0.36, p = 0.009).
Interpretation
We provide evidence of long‐term treatment benefit in a large registry cohort, and provide evidence of long‐term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on‐treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89–100
The prescription of generic (non-proprietary) compared to brand-name drugs is increasing worldwide. In many developing and emerging countries, generics companies market products at similar costs as ...brand-name competitors benefiting from more flexible compliance rules and regulations for marketing their products in the health system. Together, this phenomenon may influence prescriber's behavior (e.g., maintaining the same treatment despite guideline's recommendations or despite evidence of disease progression).
To compare the prevalence of therapeutic inertia (TI) between primary prescription of brand-name vs. generic drugs in the management of MS in Argentina.
We conducted a population-based online study comprising 117 neurologists with expertise in MS. Participants answered questions regarding their clinical practice, most commonly prescribed disease modifying agents, and therapeutic choices of 10 simulated case-scenarios that assessed TI. Inertia was defined as the lack of treatment initiation or escalation despite evidence of clinical and radiological activity (8 case-scenarios, 720 individual responses). We created the generic-brand name score (GBS) according to the 5 most frequently prescribed generic (
= 16) vs. brand-name (
= 9) drugs for MS, where scores higher than 1 indicated higher prescription of generic drugs and scores lower than 1 indicated higher prescription of brand-name agents. Candidate predictors of prescribing generic drugs included demographic data, MS specialist vs. general neurologist, practice setting, years of practice, volume of MS patients, risk preferences, costs of annual treatment.
population-based prospective study using including neurologists who care for patients with multiple sclerosis across Argentina.
prescription of generic vs. brand-name MS drugs
Therapeutic inertia (TI), defined as lack of treatment escalation when goals are unmet. Secondary outcomes included factors associated with generic drug prescription and costs of MS treatment.
Ninety participants completed the study (completion rate 76.9%). TI was observed in 153 (21.3%) of participants' responses. The evaluation of aggregate responses revealed a mean GBS score (SD) of 3.44 (2.1), with 46 (51.1%) participants having a GBS equal to or higher than 1. Older age (OR 1.19; 95% CI 1.00-1.42), being a general neurologist (OR 3.91; 95% CI 1.19-12.8), and being more willing to take risks in multiple domains (SOEP score OR 1.06, 95% CI 1.01-1.12) were associated with higher prescription of generic drugs in MS care. Costs of treatment were not associated with prescribing generic drugs. There was no difference in the annual costs of MS treatment for primary prescribers of brand-name vs. generic drugs (67,500 US$ vs. 67,496 US$;
= 0.99). The evaluation of individual responses revealed that participants with higher prescription of generics-reflected by a higher GBS-had higher incident risk of TI (mean GBS 3.61 for TI vs. 2.96 for no TI;
< 0.001). Multivariate analysis revealed that a prescription of generic agents was associated with an increased incident risk of TI (OR 1.56; 95%CI 1.07-2.29). There was no difference in the annual costs of MS treatment for participants that exhibited TI vs. those without TI (67,426 US$ vs. 67,704 US$;
= 0.66).
General neurologist, older age, and willingness to take risks were associated with increased prescription of generic drugs despite similar costs compared to brand-name agents. In our study, the prescription of generic-MS drugs was associated with a higher incident risk of therapeutic inertia.
Objective
Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region ...studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude.
Methods
The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak.
Results
A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10° of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29–53.71, p = 0.028).
Interpretation
We demonstrate for the first time that there is a latitude‐dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location‐specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta‐analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere. Ann Neurol 2014;76:880–890
Objective:
We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients ...with multiple sclerosis (MS).
Methods:
MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset (n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence.
Results:
A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p<0.001) while more patients switched to fingolimod than any other therapy (42.3% of switches). Patients switched to fingolimod due to convenience. Patients treated with fingolimod were less likely to discontinue treatment compared with other therapies (p<0.001). Female sex, country of residence, younger age, a high Expanded Disability Status Scale score and relapse activity were all independently associated with higher rates of treatment discontinuation.
Conclusion:
Following the availability of fingolimod, patients were more likely to discontinue injectable treatments. Those who switched to fingolimod were more likely to do so for convenience. Persistence was improved on fingolimod compared to other medications.
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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