Anneke Neuhaus

The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability.

The relationship of relapses to long-term disability in multiple sclerosis is uncertain. Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation. We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort. Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing–remitting phase. Survival was compared among groups stratified by (i) early relapses—number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing–remitting phase. Early clinical features can predict hard disability outcomes. Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints. Attack frequencies, in the first 2 years, of 1 versus ≥3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively. Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10. In contrast, neither total number of relapsing–remitting phase attacks nor of relapses experienced during the relapsing–remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints. The failure of a regulatory mechanism tied to neurodegeneration is suggested. Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome. These appear to be separated by a watershed within the relapsing–remitting phase, just a few years after clinical onset. Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression. They increase the probability of its occurrence, its latency and influence—to a lesser degree—its slope. The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing–remitting patients.

Age and disability accumulation in multiple sclerosis

Objectives: We tested the hypothesis that age is a prognostic factor with respect to long-term accumulation of disability in multiple sclerosis (MS). Methods: Kaplan-Meier analysis and binary logistic regression models determined the effect of age at disease onset, age at onset of progression, and current age on attainment of severe disability levels (Disability Status Scale [DSS] 6–8–10) from the London, Ontario, database (n = 1,023). Results: Older age at relapsing-remitting (RR) phase onset was associated with higher risk of reaching advanced DSS scores. This was independent of disease duration and early relapse frequency but secondary to increased risk of conversion to secondary progressive (SP) MS. Onset at age 40 (odds ratio [OR] = 4.22) and at age 50 (OR = 6.04) doubled and tripled risks of developing SP, compared to age 20 (OR = 2.05). Younger age at conversion to SPMS was associated with shorter times to high DSS scores from disease onset. The progressive course, unaffected by age at RR onset, was only modestly affected by age at SP onset. Among primary progressive and RR/SP patients, median ages at attainment of DSS scores were strikingly similar: DSS = 6, 49 vs 48 years; DSS = 8, 58 vs 58 years; and DSS = 10, 78 years for both (p = NS for all comparisons). Conclusions: Development of SP is the dominant determinant of long-term prognosis, independent of disease duration and early relapse frequency. Age independently affects disability development primarily by changing probability and latency of SP onset, with little effect on the progressive course.

Onset of secondary progressive phase and long-term evolution of multiple sclerosis

Objectives To assess factors affecting the rate of conversion to secondary progressive (SP) multiple sclerosis (MS) and its subsequent evolution. Methods Among 806 patients with relapsing remitting (RR) onset MS from the London Ontario database, we used Kaplan–Meier, Cox regression and multiple logistic regression analyses to investigate the effect of baseline clinical and demographic features on (1) the probability of, and the time to, SP disease, (2) the time to bedbound status (Disability Status Scale (DSS 8)) from onset of progression. Results The risk of entering the SP phase increased proportionally with disease duration (OR=1.07 for each additional year; p<0.001). Shorter latency to SP was associated with shorter times to severe disability. The same association was found even when patients were grouped by number of total relapses before progression. However, the evolution of the SP phase was not influenced by the duration of the RR phase. Male sex (HR=1.41; p<0.001), older age at onset (age ≤20 and 21–30 vs >30 HR=0.52 (p<0.001), 0.65 (p<0.001), respectively) and high early relapse frequency (1–2 attacks vs ≥3 HR=0.63 (p<0.001), 0.75 (p=0.04), respectively) predicted significantly higher risk of SP MS and shorter latency to progression. Times to DSS 8 from onset of progression were significantly shorter among those with high early relapse frequency (≥3 attacks), and among those presenting with cerebellar and brainstem symptoms. Conclusions The onset of SP MS is the dominant determinant of long-term prognosis, and its prevention is the most important target measure for treatment. Baseline clinical features of early relapse frequency and age at onset can be used to select groups at higher risk of developing severe disability based on the probability of their disease becoming progressive within a defined time period.

MRI as an outcome in multiple sclerosis clinical trials.

MRI AS AN OUTCOME IN MULTIPLE SCLEROSIS CLINICAL TRIALS To the Editor: We read with interest the retrospective study of Daumer et al.,1 who analyzed the placebo arms of several randomized clinical trials (RCTs) to establish the relationship of T2-weighted and gadolinium-enhanced T1-weighted MRI lesions with clinical endpoints. The results showed no correlation between clinical and MRI markers and were interpreted as an indication that MRI adds little, if anything, to clinical measures. If confirmed, this should lead us to reconsider the use of MRI measures as surrogates of clinical endpoints in multiple sclerosis (MS) clinical trials. However, we believe that the study has important methodologic flaws, which limit the validity of the results and the consequent conclusions. The concept of clinical surrogacy should always be related to a treatment effect. Indeed, the Prentice criteria have been developed to validate surrogate markers in the context of individual RCTs or metaanalysis of several complete RCTs. The clinical/MRI correlation performed by Daumer et al. using only placebo arms of different trials does not meet an established validation procedure and might be misleading. In contrast, a previous analysis of complete data sets of RCTs revealed that a clinical/MRI correlation does exist, providing preliminary evidence of the validity of MRI surrogates.2,3 Another recent study confirmed this by demonstrating that the reduction in MRI lesions across different treatment trials correlated with the effect of reducing relapses.4 Using the same database, it was shown that the main source of variability of MRI lesion counts in placebo arms of different RCTs is the MRI center where data were analyzed.5 Therefore, reporting the correlation of MRI lesions and clinical endpoints using individual data from different trials necessarily dilutes the correlation. In a highly variable disease such as MS, the low individual level of correlation between MRI markers and clinical variables is likely due to the high variability of both measures rather than to the lack of a biologically meaningful relationship. The well-documented capability of the brain to reorganize after tissue injury makes this relationship even more difficult to prove with the authors’ simplified approach. In addition, the known limitations of any retrospective analysis based on data from old and heterogeneously evaluated trials should prompt a more cautious interpretation of the results.

Early Relapses, Onset of Progression, and Late Outcome in Multiple Sclerosis

OBJECTIVES To investigate the relationship among attacks in the first 2 years (early relapses), secondary progression (SP), and late disability in multiple sclerosis (MS). DESIGN Cohort study with follow-up of 28 years. SETTING Referral MS center. PATIENTS Patients (N=730) with relapsing-remitting MS diagnosed according to Poser criteria, from the database of the London Multiple Sclerosis Clinic, London, Ontario, Canada. MAIN OUTCOME MEASURE Long-term evolution of patients with high (≥ 3 attacks) and early (within the first 2 years of the disease) frequency of relapses. In the total SP population and in patients grouped by numbers of early relapses, we assessed the predictive effect of latency to progression (time to SP) on times to attain cane requirement (Disability Status Scale score of 6 [DSS 6]) and bedridden status (DSS 8). RESULTS Among the group with frequent early relapses (n=158), outcomes were variable. Although 103 (65.2%) experienced rapid conversion to SP MS (median duration, 5 years) and rapidly attained DSS 6 and DSS 8 scores (7 and 17 years, respectively), the remainder (n=55) did not enter the SP phase, despite adverse early relapse features. Among the total SP population, longer latency to progression was associated with lower probability of attaining DSS 6 (odds ratio, 0.76 [95% CI, 0.69-0.84] and 0.44 [95% CI, 0.37-0.52] for 5- and 15-year latency, respectively) and longer times to severe disability. The same association between time to onset of SP and late outcomes was observed even in patients matched by number of early attacks. However, duration of the relapsing-remitting phase did not influence the times from SP onset to DSS levels. CONCLUSIONS Our results indicate dissociation between early inflammatory attacks and onset of the SP phase and further question the validity of relapse frequency as a surrogate marker for late disability. Among the group with frequent early relapses, we observed a large variability of outcomes, ranging from one extreme to the opposite.

Prognosis of the individual course of disease: the elements of time, hetereogeneity and precision

There is no gold standard in monitoring disease activity for clinical trials in multiple sclerosis. Various outcome measures, including relapses, disability and magnetic resonance imaging (MRI) measures have been used to demonstrate the efficacy of the different available therapies for multiple sclerosis. Recently, the potential limitations of these measures have received increasing attention, and these have stimulated research into more appropriate and sensitive outcome measures for clinical trials. For example, it has been shown that widely-used MRI measures add little, if any, independent information to that provided by more clinically relevant measures such as relapses and disability. Similarly, the Expanded Disability status Scale (EDSS), which is the most widely-used measure of disability related to multiple sclerosis, is insufficiently sensitive to detect robust changes in disability over the timeframes usually used in clinical trials. An alternative to the EDSS is the Multiple Sclerosis Severity Score (MSSS), a severity scale which relates clinical disability to disease duration. The MSSS was originally developed from a database of nearly ten thousand patients from eleven European countries and Australia and has since been reproduced in an independent dataset of 1134 patients from the placebo arms of randomised clinical trials. Based on the MSSS score, disease severity can be defined, which shows stability over time and may provide evidence-based decision support for patient management. Another alternative to measure disability is the objective quantification of physical activity. There is evidence that recent developments in pervasive computing using tiny accelerometers may have the potential to increase the reliability and precision of motor assessment, especially in the mid-range of the EDSS. The outcome measures discussed have potential use as online tools for evidence-based decision support which are increasingly being used in medical research and clinical decision-making.

Placebo Cohorts in Phase-3 MS Treatment Trials - Predictors for On-Trial Disease Activity 1990-2010 Based on a Meta-Analysis and Individual Case Data

Background Annualized relapse rates (ARR) in the placebo cohorts of phase-3 randomized controlled trials (RCT) of new treatments for relapsing remitting multiple sclerosis (RRMS) have decreased substantially during the last two decades. The causes of these changes are not clear. We consider a better understanding of this phenomenon essential for valuing the effects of new drugs and by designing new trials. Objectives To identify predictive factors of on-study ARR in early and recent MS trials. Methods ARR, rate of relapse-free patients, trial start dates, baseline demographics, relapse definitions and the use of McDonald criteria were retrieved by literature research of the placebo cohorts from RRMS phase-3 trials. Predictors were estimated by univariate and multivariate regression analyses and random-effects meta-regression. In addition, regression models were calculated by the Sylvia Lawry Centres (SLC), including individual case data from clinical trials performed until 2000. The most reliable meta-analytic results can be gained from pooled individual case data. In lack of this, random-effects meta-analyses are recommended. Results Data from 12 published and one unpublished trial show a decrease of ARR from 1988 to 2012 (adjR2 = 0.807, p<0.0001). Regression models identified McDonald criteria followed by baseline mean age and the pre-study relapse rate as predictors of the ARR. The pooled individual case data (n = 505) confirmed a decrease of ARR over time. The pre-study relapse rate was the best predictor for on-study relapses. Lacking individual case data after implementation of the McDonald criteria excludes a direct comparison concerning McDonald criteria. Conclusion Pre-study relapse rate was the best predictor for on-study relapse rate but failed to explain the decrease of the ARR over time alone. Higher age at baseline and the implementation of McDonald criteria were associated as well with a lowered relapse rate in the random-effects meta-regression. These findings need further clarification based on individual case data.

Validating Predictors of Disease Progression in a Large Cohort of Primary-Progressive Multiple Sclerosis Based on a Systematic Literature Review

Background New agents with neuroprotective or neuroregenerative potential might be explored in primary-progressive Multiple Sclerosis (PPMS) - the MS disease course with leading neurodegenerative pathology. Identification of patients with a high short-term risk for progression may minimize study duration and sample size. Cohort studies reported several variables as predictors of EDSS disability progression but findings were partially contradictory. Objective To analyse the impact of published predictors on EDSS disease progression in a large cohort of PPMS patients. Methods A systematic literature research was performed to identify predictors for disease progression in PPMS. Individual case data from the Sylvia Lawry Centre (SLC) and the Hamburg MS patient database (HAPIMS) was pooled for a retrospective validation of these predictors on the annualized EDSS change. Results The systematic literature analysis revealed heterogeneous data from 3 prospective and 5 retrospective natural history cohort studies. Age at onset, gender, type of first symptoms and early EDSS changes were available for validation. Our pooled cohort of 597 PPMS patients (54% female) had a mean follow-up of 4.4 years and mean change of EDSS of 0.35 per year based on 2503 EDSS assessments. There was no significant association between the investigated variables and the EDSS-change. Conclusion None of the analysed variables were predictive for the disease progression measured by the annualized EDSS change. Whether PPMS is still unpredictable or our results may be due to limitations of cohort assessments or selection of predictors cannot be answered. Large systematic prospective studies with new endpoints are needed.

Ecological Validity of Walking Capacity Tests in Multiple Sclerosis

Background Ecological validity implicates in how far clinical assessments refer to real life. Short clinical gait tests up to ten meters and 2- or 6-Minutes Walking Tests (2MWT/6MWT) are used as performance-based outcomes in Multiple Sclerosis (MS) studies and considered as moderately associated with real life mobility. Objective To investigate the ecological validity of 10 Meter Walking Test (10mWT), 2MWT and 6MWT. Methods Persons with MS performed 10mWT, 6MWT including 2MWT and 7 recorded days by accelerometry. Ecological validity was assumed if walking tests represented a typical walking sequence in real-life and correlations with accelerometry parameters were strong. Results In this cohort (n=28, medians: age=45, EDSS=3.2, disease duration=9 years), uninterrupted walking of 2 or 6 minutes occurred not frequent in real life (2.61 and 0.35 sequences/day). 10mWT correlated only with slow walking speed quantiles in real life. 2MWT and 6MWT correlated moderately with most real life walking parameters. Conclusion Clinical gait tests over a few meters have a poor ecological validity while validity is moderate for 2MWT and 6MWT. Mobile accelerometry offers the opportunity to control and improve the ecological validity of MS mobility outcomes.

Low clinical conversion rate in clinically isolated syndrome (CIS) patients – diagnostic benefit of McDonald 2010 criteria?

New diagnostic criteria of multiple sclerosis (MS) increase the number of patients being diagnosed with MS whilst a substantial part might not convert to clinically definite MS (CDMS). The diagnostic accuracy of the McDonald 2005 and 2010 criteria for conversion to CDMS was evaluated in an unselected cohort of patients in whom an MS diagnostic work‐up was decided.