Dyadic coping strategies and quality of care experience: An original study of patients living with multiple sclerosis and their caregivers.

BACKGROUND AND OBJECTIVE: Multiple sclerosis has a major impact on the lives of patients and their caregivers. Measuring their experience is essential for improving the quality of care. Based on a sample of patient-informal caregiver dyads we examine whether coping strategies they implemented influenced their self-experience of quality of care. METHODS: One hundred and eighty three dyads were involved in this cross-sectional study. Self reported data included experience with the quality of care (Musicare) and coping strategies (Brief Cope) for patients and their caregivers. An actor-partner interdependence model (APIM) analysis was performed to assess the dyadic effects of coping strategies on experience of quality of care. RESULTS: Positive coping strategies were the most used by patients and caregivers alike. They were associated with a better experience of relationships with healthcare professionals, information about the disease and patient reception at the sites providing care. APIM analyses confirmed most of these results and identified one "partner" effect. CONCLUSION: The experience of the quality of the care of patients living with MS is related to the use of positive coping strategies.

Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis.

BACKGROUND: Natalizumab and fingolimod are used as high-efficacy treatments in relapsing-remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. METHODS: Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. RESULTS: Overall, 5,148 relapsing-remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. CONCLUSIONS: This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

Developing tools to evaluate quality of care management for patients living with multiple sclerosis: An original French initiative.

INTRODUCTION: Assessing the quality of care management for patients with a chronic disease such as multiple sclerosis (MS) is a major challenge for healthcare systems around the world. It needs to be carried out using tools that are recognized by professionals and patients alike, and should concern practices, systems, and scientific data. No such tools are currently available in Europe. The purpose of the present study was to develop indicators to contribute to assess the quality of care management for patients with MS in France. METHODS: An expert panel comprising 25 professionals from well known teams across France selected the indicators on the basis of consensus. In accordance with the Rand/UCLA Appropriateness Method, each expert had to agree with the recommendations, and there had to be agreement among the experts. RESULTS: The expert panel selected 48 indicators representing seven domains of care management for patients with MS: physical and rehabilitation medicine, disease progression, access to care, magnetic resonance imaging (MRI) management, relapse management, management of disease-modifying treatments, and management of the symptoms of disability progression. Some of these quality indicators (notably pertaining to MRI management) had not previously been identified in the literature. CONCLUSION: These indicators may allow professionals to comprehensively assess and compare their practices and cooperation, thereby contributing to improve the quality of care management for patients with MS in France.

Ten-year follow-up after mitoxantrone induction for early highly active relapsing-remitting multiple sclerosis: An observational study of 100 consecutive patients.

BACKGROUND: Six monthly courses of mitoxantrone were approved in France in 2003 for patients with highly active multiple sclerosis (MS). OBJECTIVE: To report the 10-year clinical follow-up and safety of mitoxantrone as an induction drug followed by maintenance therapy in patients with early highly active relapsing-remitting MS (RRMS) and an Expanded Disability Status Scale (EDSS) score<4, 12months prior to mitoxantrone initiation. METHODS: In total, 100 consecutive patients with highly active RRMS from the Rennes EDMUS database received monthly mitoxantrone 20mg combined with methylprednisolone 1g for 3 (n=75) or 6months (n=25) followed by first-line disease-modifying drug (DMD). The 10-year clinical impact was studied through clinical activity, DMD exposure, and adverse events. RESULTS: Twenty-four percent were relapse-free over 10years and the mean annual number of relapses was 0.2 at 10years. The mean EDSS score remained significantly improved for up to 10years, changing from 3.5 at mitoxantrone initiation to 2.7 at 10years. The probability of disability worsening and improvement from mitoxantrone initiation to 10years were respectively 27% and 58%, and 13% converted to secondary progressive MS. Patients only remained untreated or treated with a first-line maintenance DMD for 6.5years in average. In our cohort, mitoxantrone was generally safe. No leukemia was observed and six patients developed neoplasms, including 4 solid cancers. CONCLUSION: Monthly mitoxantrone for 3 or 6months, followed by maintenance first-line treatment, may be an attractive therapeutic option for patients with early highly active RRMS, particularly in low-income countries.

Cost-utility of oral methylprednisolone in the treatment of multiple sclerosis relapses: Results from the COPOUSEP trial.

BACKGROUND: Studies have shown that oral high-dose methylprednisolone (MP) is non-inferior to intravenous MP in treating multiple sclerosis relapses in terms of effectiveness and tolerance. In order to assist with resource allocation and decision-making, its cost-effectiveness must also be assessed. Our objective was to evaluate the cost-utility of per os high-dose MP as well as the cost-savings associated with implementing the strategy. METHODS: A cost-utility analysis at 28 days was carried out using data from the French COPOUSEP multicenter, double-blind randomized controlled non-inferiority trial and the statutory health insurance reimbursement database. Costs were calculated using a societal perspective, including both direct and indirect costs. An incremental cost-effectiveness ratio was calculated and bootstrapping methods assessed the uncertainty surrounding the results. An alternative scenario analysis in which MP was administered at home was also carried out. A budgetary impact analysis was carried at five years. RESULTS: In the conditions of the trial (hospitalized patients), there was no significant difference in utilities and costs at 28 days. The incremental cost-effectiveness ratio was €15,360 per quality-adjusted life-year gained. If multiple sclerosis relapses were treated at home, oral MP would be more effective, less costly and associated with annual savings up to 25 million euros for the French healthcare system. CONCLUSIONS: Oral MP is cost-effective in the treatment of multiple sclerosis relapses and associated with major savings.

Evaluation of the quality of the care pathway for patients with multiple sclerosis in France: Results of an original study of a cohort of 700 patients.

INTRODUCTION: Evaluating the quality of the care pathway for patients with chronic diseases, such as multiple sclerosis (MS), is an important issue. Process indicators are a recognized method for evaluating professional practices. However, these tools have been little developed in the field of MS, and few data are available. The aim of this study was to describe, retrospectively, with validated indicators, the quality of the care pathway in a population-based cohort of 700 patients with the first manifestations of the disease occurring between January 1, 2000 and December 31, 2001 and during the first 10 years of disease. METHOD: This assessment was based on 48 indicators specific to MS. The information required for the calculation of each indicator was collected from the source files of the 700 patients of the cohort. RESULTS: Data for the 10 years of follow-up were collected for 80% of the patients. In total, 36 indicators were calculated. These results reveal that there is room for improvement, particularly in terms of the initial assessment, access to ophthalmological evaluation, employment, obtaining an evaluation of the need for rehabilitation and access to such care. CONCLUSION: The results of this survey provide access to unprecedented new data in France, that professionals and patients can appropriate to improve the targeting of actions, to improve the quality of care further for patients with MS in France. We propose to continue this process by submitting, for discussion, a targeted list of updated indicators relating to changes in guidelines, and in issues concerning the quality of patient management.

SMILE: a predictive model for Scoring the severity of relapses in MultIple scLErosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), relapse severity and residual disability are difficult to predict. Nevertheless, this information is crucial both for guiding relapse treatment strategies and for informing patients. OBJECTIVE: We, therefore, developed and validated a clinical-based model for predicting the risk of residual disability at 6 months post-relapse in MS. METHODS: We used the data of 186 patients with RRMS collected during the COPOUSEP multicentre trial. The outcome was an increase of ≥ 1 EDSS point 6 months post-relapse treatment. We used logistic regression with LASSO penalization to construct the model, and bootstrap cross-validation to internally validate it. The model was externally validated with an independent retrospective French single-centre cohort of 175 patients. RESULTS: The predictive factors contained in the model were age > 40 years, shorter disease duration, EDSS increase ≥ 1.5 points at time of relapse, EDSS = 0 before relapse, proprioceptive ataxia, and absence of subjective sensory disorders. Discriminative accuracy was acceptable in both the internal (AUC 0.82, 95% CI [0.73, 0.91]) and external (AUC 0.71, 95% CI [0.62, 0.80]) validations. CONCLUSION: The predictive model we developed should prove useful for adapting therapeutic strategy of relapse and follow-up to individual patients.

Inaugural tumor-like multiple sclerosis: clinical presentation and medium-term outcome in 87 patients.

BACKGROUND: Tumefactive demyelinating lesions of the central nervous system can be the initial presentation in various pathological entities [multiple sclerosis (the most common), Balo's concentric sclerosis, Schilder's disease and acute disseminated encephalomyelitis] with overlapping clinical presentation. The aim of our study was to better characterize these patients. METHODS: Eighty-seven patients (62 women and 25 men) from different MS centers in France were studied retrospectively. Inclusion criteria were (1) a first clinical event (2) MRI showing one or more large demyelinating lesions (20 mm or more in diameter) with mass-like features. Patients with a previous demyelinating event (i.e. confirmed multiple sclerosis) were excluded. RESULTS: Mean age at onset was 26 years. The most common initial symptoms (67% of the patients) were hemiparesis or hemiplegia. Aphasia, headache and cognitive disturbances (i.e. atypical symptoms for demyelinating diseases) were observed in 15, 18 and 15% of patients, respectively. The mean largest diameter of the tumefactive lesions was 26.9 mm, with gadolinium enhancement in 66 patients (81%). Twenty-one patients (24%) had a single tumefactive lesion. During follow-up (median time 5.7 years) 4 patients died, 70 patients improved or remained stable and 12 worsened. 86% of patients received initial corticosteroid treatment, and 73% received disease-modifying therapy subsequently. EDSS at the end of the follow-up was 2.4 ± 2.6 (mean ± SD). CONCLUSION: This study provides further evidence that the clinical course of MS presenting with large focal tumor-like lesions does not differ from that of classical relapsing-remitting MS, once the noisy first relapsing occurred.

Induction or escalation therapy for patients with multiple sclerosis?

The concept of induction followed by a long-term maintenance treatment has attracted much attention for the treatment of multiple sclerosis over the 30 past years. It was first demonstrated by the combination of induction therapy with mitoxantrone (six-monthly courses) followed by maintenance therapy with an immunomodulatory treatment such as an interferon-ß or glatiramer acetate. Long-term observational studies confirmed that this therapeutic regimen provides a rapid reduction in disease activity and sustained disease control up to at least five years in 60% of patients. A better treatment response was observed in patients with early signs of aggressive disease, as shown in randomised studies (using six-monthly 12mg/m2 of mitoxantrone intravenously at a cumulative dose of 72mg/m2, followed by an interferon-ß) as well as in long-term observational studies. But the safety profile of mitoxantrone make it more particularly suitable for young patients with frequent early relapses with incomplete recovery and multiple gadolinium-enhancing T1 lesions or spinal cord lesions on magnetic resonance imaging. More recently approved, the second candidate for an induction strategy is alemtuzumab: phases II and III randomised studies showed the superiority of alemtuzumab 12mg per day given intravenously for only five days and repeated for 3 days one year later, compared with interferon-ß three times a week. Like with mitoxantrone, results supported the concept of long-term benefit after a short induction rather than escalation, in a subset of patients with early very active MS, with a sustained control of the disease for up to 7 years in 60% of patients in the phase III extension studies and in a long-term observational study. On the contrary, when alemtuzumab was first studied later in the disease course, results were disappointing. However, the risk of developing manageable but potentially severe systemic autoimmune diseases within the years following the last course of alemtuzumab make it, like mitoxantrone, more suitable for patients with early aggressive MS. More recently, cladribine an oral immunosuppressant, showed interesting results in a phase III study extension suggesting its potential induction effect, since after two cycles of treatment (5 days repeated 1 month later) at one year of interval, the remained low up to 4 years of follow-up, in the absence of any new treatment. However, today other immunosuppressive drugs have proved to be strongly and rapidly efficacious in treating highly active MS patients but through a mechanism of continuous immunosuppression (i.e., natalizumab and ocrelizumab). Indeed, disease activity can reappear rapidly after stopping these drugs, sometimes associated with a rebound of the inflammatory process, which is the contrary of a mechanism of induction that is associated with a remnant effect. Taking into account advantages and disadvantages of the different DMDs, which enriched the today therapeutic arsenal for MS, we propose in this paper some algorithms summarizing our reflexion about using an escalation strategy or an induction strategy according to disease course and activity.

Survey of diagnostic and treatment practices for multiple sclerosis (MS) in Europe. Part 2: Progressive MS, paediatric MS, pregnancy and general management.

BACKGROUND AND PURPOSE: The European Charcot Foundation supported the development of a set of surveys to understand current practice patterns for the diagnosis and management of multiple sclerosis (MS) in Europe. Part 2 of the report summarizes survey results related to secondary progressive MS (SPMS), primary progressive MS (PPMS), pregnancy, paediatric MS and overall patient management. METHODS: A steering committee of MS neurologists developed case- and practice-based questions for two sequential surveys distributed to MS neurologists throughout Europe. RESULTS: Respondents generally favoured changing rather than stopping disease-modifying treatment (DMT) in patients transitioning from relapsing-remitting MS to SPMS, particularly with active disease. Respondents would not initiate DMT in patients with typical PPMS symptoms, although the presence of ≥1 spinal cord or brain gadolinium-enhancing lesion might affect that decision. For patients considering pregnancy, respondents were equally divided on whether to stop treatment before or after conception. Respondents strongly favoured starting DMT in paediatric MS with active disease; recommended treatments included interferon, glatiramer acetate and, in John Cunningham virus negative patients, natalizumab. Additional results regarding practice-based questions and management are summarized. CONCLUSIONS: Results of part 2 of the survey of diagnostic and treatment practices for MS in Europe largely mirror results for part 1, with neurologists in general agreement about the treatment and management of SPMS, PPMS, pregnancy and paediatric MS as well as the general management of MS. However, there are also many areas of disagreement, indicating the need for evidence-based recommendations and/or guidelines.

Survey of diagnostic and treatment practices for multiple sclerosis in Europe.

BACKGROUND AND PURPOSE: Up-to-date information is needed on the extent to which neurologists treating multiple sclerosis (MS) in Europe are integrating rapidly evolving diagnostic criteria, disease-modifying therapies and recommendations for monitoring disease activity into their clinical practice. METHODS: A steering committee of MS neurologists used a modified Delphi process to develop case- and practice-based questions for two sequential surveys distributed to MS neurologists throughout Europe. Case-based questions were developed for radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS) and RRMS with breakthrough disease. RESULTS: Multiple sclerosis neurologists from 11 European countries responded to survey 1 (n = 233) and survey 2 (n = 171). Respondents agreed that they would not treat the patients in the RIS or CIS cases but would treat a patient with a relatively mild form of RRMS. Choice of treatment was evenly distributed among first-line injectables and oral treatments for mild RRMS, and moved to second-line treatment as the RRMS case increased in severity. Additional results on RRMS with breakthrough disease are presented. CONCLUSIONS: Although there was general agreement on some aspects of treatment, responses to other management and clinical practice questions varied considerably. These results, which reflect current clinical practice patterns, highlight the need for additional MS treatment education and awareness and may help inform the development of MS practice guidelines in Europe.

Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis?

BACKGROUND AND PURPOSE: The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS. METHODS: We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified. RESULTS: Mean treatment duration was 60.4 ± 39.3 months, and mean follow-up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal [0.09, 95% confidence interval (CI), 0.05-0.17 and 0.07, 95% CI, 0.05-0.11, respectively], relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09-0.16). Sixteen patients experienced a relapse and 19 had a gadolinium-positive MRI scan without relapse during follow-up. A gadolinium-positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of <6 were positively associated with relapse and/or MRI activity after discontinuation (P = 0.0004 and P = 0.03, respectively). CONCLUSION: In this retrospective study, including a limited number of patients with SPMS, the annualized relapse rate remained stable after treatment withdrawal, relative to before treatment withdrawal. Further prospective studies are needed to confirm this result and provide evidence-based guidelines for daily practice.

[Rapid improvement in visual function after high-dose oral corticosteroids in patients with inflammatory optic neuropathy]. / Amélioration rapide de la fonction visuelle après corticothérapie orale à forte dose chez des patients atteints de neuropathie optique inflammatoire.

PURPOSE: To study the progression of visual acuity and visual function parameters in patients with optic neuritis (ON) treated with high-dose oral corticosteroid therapy. METHODS: This retrospective descriptive monocentric study included nine patients with ON treated with orally administered methylprednisolone at 1000 mg per day for three to five days. The follow-up visits were performed on day 4 (D4), day 15 (D15), day 30 (D30) and day 90 (D90) after treatment was begun. The initial examination (D0) and the follow-up visits included a visual acuity (VA) assessment according to the Early Treatment Diabetic Retinopathy Study scale, a contrast sensitivity test and a 30.2 automated visual field (Visual Field Index [VFI]). The overall subjective tolerance of the treatment was assessed by patients on a scale from 0 to 10. RESULTS: We observed an improvement of all parameters from D4. From D0 to D4, the average VA increased from 40.1 letters to 57.9 letters, the average VFI from 40.9% to 70.3% and the overall average contrast sensitivity from 7.7 dB to 11.3 dB. From D15 to D90, the average VA increased from 77 letters to 80.3 letters, the average VFI from 91.2% to 97.9% and the overall average contrast sensitivity from 15.4 dB to 16.7 dB. Four patients rated tolerance at 10 (excellent), three between 8 and 9, and two at 6. CONCLUSION: We demonstrated rapid improvement of visual function parameters in patients with ON after high-dose oral corticosteroids.

Epidemiology of multiple sclerosis.

Multiple sclerosis (MS) is the most frequently seen demyelinating disease, with a prevalence that varies considerably, from high levels in North America and Europe (>100/100,000 inhabitants) to low rates in Eastern Asia and sub-Saharan Africa (2/100,000 population). Knowledge of the geographical distribution of the disease and its survival data, and a better understanding of the natural history of the disease, have improved our understanding of the respective roles of endogenous and exogenous causes of MS. Concerning mortality, in a large French cohort of 27,603 patients, there was no difference between MS patients and controls in the first 20 years of the disease, although life expectancy was reduced by 6-7 years in MS patients. In 2004, the prevalence of MS in France was 94.7/100,000 population, according to data from the French National Health Insurance Agency for Salaried Workers (Caisse nationale d'assurance maladie des travailleurs Salariés [CNAM-TS]), which insures 87% of the French population. This prevalence was higher in the North and East of France. In several countries, including France, the gender ratio for MS incidence (women/men) went from 2/1 to 3/1 from the 1950s to the 2000s, but only for the relapsing-remitting form. As for risk factors of MS, the most pertinent environmental factors are infection with Epstein-Barr virus (EBV), especially if it arises after childhood and is symptomatic. The role of smoking in MS risk has been confirmed, but is modest. In contrast, vaccines, stress, traumatic events and allergies have not been identified as risk factors, while the involvement of vitamin D has yet to be confirmed. From a genetic point of view, the association between HLA-DRB1*15:01 and a high risk of MS has been known for decades. More recently, immunogenetic markers have been identified (IL2RA, IL7RA) and, in particular thanks to studies of genome-wide associations, more than 100 genetic variants have been reported. Most of these are involved in the immune response and often associated with other autoimmune diseases. Studies of the natural history of MS suggest it is a two-phase disease: in the first phase, inflammation is focal with flares; and in the second phase, disability progresses independently of focal inflammation. This has clear implications for therapy. Age may also be a key factor in the phenotype of the disease. In conclusion, France is a high-risk country for MS, but it only slightly reduces life expectancy. MS is a multifactorial disease and the implications of immunogenetics are major. Preventative approaches might be derived from knowledge of the risk factors and natural history of the disease (smoking, vitamin D).

A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

Ten-year prognosis in multiple sclerosis: a better outcome in relapsing-remitting patients but not in primary progressive patients.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) prognosis remains a challenge for both patients and physicians. Complementary to natural history studies, updated population-based data from the first event suggestive of MS, at the time of the first approved disease modifying drug (DMD), are needed. Our objective was to provide a 10-year history of MS from clinical onset at time of first approved DMDs in a population-based cohort. METHODS: A population-based cohort of patients whose first clinical event suggestive of MS had occurred in Brittany between 2000 and 2001 was prospectively selected. History of relapses, treatments and disability up to 10 years after onset were collected. RESULTS: In all, 278 patients with either attack-onset (n = 244) or progressive-onset (n = 34) were recruited. Amongst attack-onset patients, 30% remained as clinically isolated syndrome and 70% had a second relapse after a median time of 1.7 years (95% confidence interval 1.2-2.4). 80% of relapsing-remitting MS patients received DMDs for at least 6 months. 29% reached disability status scale (DSS) 3 and 8% DSS 6. Amongst progressive-onset patients, 100% reached DSS 3 and 59% DSS 6. CONCLUSION(S): Our population-based study reports a lower risk of disability progression at 10-year follow-up in the relapsing-remitting MS group than previously reported. This better prognosis was not observed in the progressive-onset MS group. This finding impacts the prognosis given to patients in clinical practice.