John Petkau

Defining the clinical course of multiple sclerosis The 2013 revisions

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

Association Between Use of Interferon Beta and Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis

CONTEXT Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. OBJECTIVE To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. DESIGN, SETTING, AND PATIENTS Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. MAIN OUTCOME MEASURES The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. RESULTS The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. CONCLUSION Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.

Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis

The identification of factors that can affect the efficacy of immunomodulatory drugs in relapsing-remitting multiple sclerosis (MS) is important. For the available interferon-beta products, neutralising antibodies (NAb) have been shown to affect treatment efficacy. In June, 2009, a panel of experts in MS and NAbs to interferon-beta therapy convened in Amsterdam, Netherlands, under the auspices of the Neutralizing Antibodies on Interferon beta in Multiple Sclerosis consortium, a European-based project of the 6th Framework Programme of the European Commission, to review and discuss data on NAbs and their practical consequences for the treatment of patients with MS on interferon beta. The panel believed that information about NAbs and other markers of biological activity of interferons (ie, myxovirus resistance protein A [MxA]) can be integrated with clinical and imaging indicators to guide individual treatment decisions. In cases of sustained high-titre NAb positivity and/or lack of MxA bioactivity, a switch to a non-interferon-beta therapy should be considered. In patients who are doing poorly clinically, therapy should be switched irrespective of NAb or MxA bioactivity.

MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability.

Background: Previous studies have shown only modest correlation between multiple sclerosis (MS) lesions on MRI and clinical disability. Objective: To investigate the relationship between proton density/T2-weighted (T2) burden of disease (BOD) quantitatively measured on MRI scans and clinical determinants including disability. Methods: Using the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database, the authors studied baseline T2 BOD data from a pooled subsample of 1,312 placebo MS patients from 11 randomized controlled trials. Univariate comparisons guided development of multiple regression models incorporating the most important clinical predictors. Results: Significant, although weak to moderate, correlations were found between T2 BOD and age at disease onset, disease duration, disease course, disability (as measured by the Expanded Disability Status Scale [EDSS]), relapse rate, certain presenting symptoms, and gadolinium enhancement. An unexpected but key finding that persisted in the multiple regression analyses was a plateauing relationship between T2 BOD and disability for EDSS values above 4.5. Conclusions: This study confirmed the limited correlation between clinical manifestations and T2 burden of disease (BOD) but revealed an important plateauing relationship between T2 BOD and disability.

Neutralizing antibodies during treatment of secondary progressive MS with interferon β-1b

Objective: To investigate the relationship between neutralizing antibodies (NAB) and disease progression, relapses, and MR measures of MS. Methods: Sequential serum samples from all 718 patients of the European Study Group in Interferon β-1b in Secondary Progressive MS were analyzed to investigate relations between NAB and disease progression, relapses, and MR measures. Results: This study showed no attenuating effect of NAB development on progression in disability. The effects of NAB on relapse rate showed substantial variation, depending on the statistical approach and definition of positivity, though analyses comparing low- and high-NAB+ periods with NAB− periods suggested a titer-related effect. MR T2 lesion volume changes from baseline were significantly higher for NAB+ patients but remained lower than for placebo patients. A substantial proportion of NAB+ patients became NAB−. No untoward effect of NAB development on safety was observed. Conclusion: These results support the conclusion that even though high NAB titers appear to have impact on treatment efficacy with respect to relapses, treatment decisions should be based primarily on clinical grounds.

Air Pollution and Cardiac Arrhythmias in Patients with Implantable Cardioverter Defibrillators

Epidemiological studies have demonstrated associations between short-term increases in outdoor air pollution concentrations and adverse cardiovascular effects, including cardiac mortality and hospitalizations. One possible mechanism behind this association is that air pollution exposure increases the risk of developing a cardiac arrhythmia. To investigate this hypothesis, dates of implantable cardioverter defibrillator (ICD) discharges were abstracted from patient records in patients attending the two ICD clinics in Vancouver, BC, for the years 1997–2000. Daily outdoor air pollutant concentrations and daily meteorological data from the Vancouver region were obtained for the same 4-yr period. Generalized estimating equations were used to assess the association between short-term increases in air pollutant concentrations and ICD discharges while controlling for temporal trends, meteorology, and serial correlation in the data. Air pollution concentrations in the Vancouver region were relatively low from 1997 to 2000, as expected. In the 50 patients who resided within the Vancouver region and who experienced at least 1 ICD discharge during the period of follow-up, no significant associations between increased air pollution concentrations and increased ICD discharges were present. When the patient sample was restricted to the 16 patients who had at least 6 months of follow-up and experienced a rate of at least 2 days with ICD discharges per year, there was a statistically significant association between increased sulfur dioxide (SO2) concentration and ICD discharge 2 days after the SO2 increase. When stratified by season, no associations between increased air pollutant concentrations and increased risk of ICD discharge were observed in the summer, although for several pollutants, concentration increases were associated with a decrease in ICD discharges. In the winter, increased SO2 concentrations again were seen to be associated with increased risk of ICD discharge, at both 2 and 3 days following increases in SO2 concentrations. These findings provide no compelling evidence that short-term increases in relatively low concentrations of outdoor air pollutants have an adverse effect on individuals at risk of cardiac arrhythmias. The findings regarding SO2 are difficult to interpret. They may be chance findings. Alternatively, given the very low concentrations of SO2 that were present in Vancouver, SO2 may have been serving as a surrogate measure of other environmental or meteorological factors.

MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials

Over the past 15 years, MRI lesion activity has become the accepted surrogate primary outcome measure in proof-of-concept placebo-controlled clinical trials of new immunomodulating therapies in relapse-onset multiple sclerosis (MS). In parallel, the number of patients that are available for the placebo arm of trials has declined, and more-aggressive drugs are being developed. A critical review is warranted to ensure efficient MRI—and patient—resource utilization. Recently, an international panel reviewed the methodology for efficient use of MRI-monitored trials in relapse-onset MS. In this article, we provide up-to-date recommendations for scan acquisition, image analysis, outcome-measure definition and standards of reporting. Factors to consider for optimizing trial design, such as outcome measure selection and the unique requirements of phase II and phase III trials, including active-comparator studies, are outlined. Finally, we address safety considerations in the use of MRI in MS trials, and the safety-related responsibilities of the various parties involved in conducting such trials.

A Case-Crossover Analysis of Particulate Air Pollution and Cardiac Arrhythmia in Patients with Implantable Cardioverter Defibrillators

We investigated the relationship between air pollution and incidence of cardiac arrhythmia in a study of patients with implantable cardioverter defibrillators (ICDs). Thirty-four patients (ages 15–85 yr, 80% male) with ICDs residing in the Vancouver, Canada, area were included in the analyses, representing all patients attending the 2 ICD clinics in the study region who had recorded at least 1 ICD discharge during the 14 February to 31 December 2000 study period. Air pollutant (PM2.5, PM10, SO42−, elemental carbon [EC], organic carbon [OC], O3, SO2, NO2, and CO) concentrations on days for which ICD discharges were observed (“case days”) were compared to concentrations on control days in case-crossover analyses. Control days were selected symmetrically, 7 days before and after each case day. ICD discharges occurring within 72 h of 1 another were grouped and considered as 1 discharge event. Temperature, relative humidity, barometric pressure, rainfall, and wind speed were included simultaneously as covariates. Sensitivity analyses examined the effect of grouping ICD discharges, of including meteorological variables, and of excluding discharges that were considered inappropriate by a cardiologist. As in previous studies, mean concentrations and interquartile ranges of air pollutants in Vancouver were low (e.g., PM2.5 mean = 8.2 ug/m3). Although in general there were no statistically significant results, there were trends that might indicate associations between pollutants and ICD discharges. Odds ratios (OR) were consistently higher in summer than in winter (e.g., lag 0 per interquartile range increase in EC: 1.09 [0.86–1.37] vs. 0.61 [0.31–1.18]) and, in general, the highest ORs were observed for same-day effects. The one major exception was the observation of high ORs for ozone in winter (e.g., lag 1: 2.27 [0.67–7.66]). While an OR of 1.55 (0.51–4.70) was observed in summer at lag 0 for PM10, no indications of positive associations were observed for PM2.5 or SO42−. For indicators of local combustion-source pollution, EC, OC, CO, and SO2, ORs were elevated at all lags (0–3 days) in summer. In summary, this study provides little evidence that specific components of PM affect risk of cardiac arrhythmias, although power limited the ability of the study to detect small effects.

ETHICS OF PLACEBO-CONTROLLED CLINICAL TRIALS IN MULTIPLE SCLEROSIS: A REASSESSMENT

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in “resource-restricted” environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes. GLOSSARY: EET = established effective therapy; MS = multiple sclerosis; PPMS = primary progressive MS; SPMS = secondary progressive MS.

Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome.

Objective: To determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon β-1b (IFNβ-1b). Methods: In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study, patients were randomly assigned to 250 μg IFNβ-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNβ-1b for up to 5 years. NAb status was assessed every 6 months by the myxovirus protein A induction assay. A titer >20 NU/mL was considered NAb-positive, with low (≥20–100 NU/mL), medium (≥100–400 NU/mL), and high (≥400 NU/mL) titer categories. Here we examine early-treated patients, who received IFNβ-1b for up to 5 years. Results: NAbs were measured in 277 of 292 early-treated patients and detected at least once in 88 (31.8%) patients, with 53 (60.2%) reverting to NAb negativity by year 5. Time to CDMS, time to confirmed disability progression, and annualized relapse rate did not differ between NAb-positive and NAb-negative patients or between periods of NAb positivity vs NAb negativity within patients. Increases in newly active lesion number and T2 lesion volume and conversion to McDonald MS were associated with NAb positivity and were more pronounced with higher titers. Conclusions: Although NAb positivity was associated with increased brain MRI activity, no discernible effects on clinical outcomes were found. This finding may reflect the greater power of MRI compared with clinical outcomes to detect the treatment effects of IFNβ-1b and may also result from temporal changes in NAb titers and biology.