Pierre Duquette

A population-based study of multiple sclerosis in twins.

Results from studies of twin concordance in multiple sclerosis have not conclusively differentiated between environmental and genetic factors that determine susceptibility to the disease. Published studies that have been based on case finding by public appeal have been characterized by difficulties in ascertainment. The data reported here are from a large population-based study of multiple sclerosis in twins, in which ascertainment has been relatively unbiased and the cooperation of patients nearly complete. A total of 5463 patients attending 10 multiple sclerosis clinics across Canada were surveyed. Twenty-seven monozygotic and 43 dizygotic twin pairs were identified, and the diagnosis of multiple sclerosis was verified by examination and laboratory investigation. Seven of 27 monozygotic pairs (25.9 percent) and 1 of 43 dizygotic pairs (2.3 percent) were concordant for multiple sclerosis. The concordance rate for 4582 nontwin siblings of patients at two multiple sclerosis clinics was 1.9 percent, closely paralleling the concordance rate in dizygotic twins. To the extent that the difference in concordance rates between monozygotic and dizygotic twins indicates genetic susceptibility, the results of this study show a major genetic component in susceptibility to multiple sclerosis.

Preferential recruitment of interferon-γ-expressing TH17 cells in multiple sclerosis

There is substantial evidence supporting the role of interferon (IFN)‐γ–producing T helper (TH) 1 and interleukin (IL)‐17–expressing TH17 lymphocytes in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). However, to date little is known about the potential cooperative interplay between these 2 cytokines. In the current study, we sought to evaluate the frequency of IFN‐γ–expressing TH17 lymphocytes in MS and EAE, and study their recruitment into the central nervous system (CNS).

Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial

To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis.

Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis.

The cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients is characterized by increased concentrations of immunoglobulin (Ig), which on electrophoretic analysis shows restricted heterogeneity (oligoclonal bands). CSF Ig is composed of both serum and intrathecally produced components. To examine the properties of intrathecal antibody-producing B cells, we analyzed Ig heavy-chain variable (V(H)) region genes of B cells recovered from the CSF of 12 MS patients and 15 patients with other neurological diseases (OND). Using a PCR technique, we could detect rearrangements of Ig V(H) genes in all samples. Sequence analysis of complementarity-determining region 3 (CDR3) of rearranged VDJ genes revealed expansion of a dominant clone or clones in 10 of the 12 MS patients. B cell clonal expansion was identified in 3 of 15 OND. The nucleotide sequences of V(H) genes from clonally expanded CSF B cells in MS patients demonstrated the preferential usage of the V(H) IV family. There were numerous somatic mutations, mainly in the CDRs, with a high replacement-to-silent ratio; the mutations were distributed in a way suggesting that these B cells had been positively selected through their antigen receptor. Our results demonstrate that in MS CSF, there is a high frequency of clonally expanded B cells that have properties of postgerminal center memory or antibody-forming lymphocytes.

Conjugal multiple sclerosis: Population-based prevalence and recurrence risks in offspring

From a population‐based sample of 15,504 patients attending Canadian multiple sclerosis (MS) clinics, we have determined the frequency of conjugal MS and have estimated the recurrence risk in offspring of such matings. Twenty‐three MS cases were found among 13,550 spouses of study probands for a crude conjugal rate of 0.17% (95% CI of 0.10%–0.24%). Despite ascertainment bias that expectedly inflates this number, this is a frequency intermediate between the point prevalence (0.1%) and lifetime risk (0.2%) for the general population and close to an order of magnitude less than reported for half siblings reared apart (1.06%) from the same population. Six of the 49 offspring of conjugal pairs also had MS, and age conversion gives a rate similar to the concordance rate for Canadian monozygotic twins. However, this correction may not be appropriate in this special case. Despite an ascertainment bias in favor of recognizing affected spouses and a large population sample, the common environment in adulthood shared by spousal pairs could not be shown to increase the risk of conjugal MS. Although the high recurrence rate in offspring is similarly subject to an upward bias, the low risk for MS spouses and the high risk for offspring support other data indicating that familial risk is genetically determined. Furthermore, these results imply that susceptibility alleles are shared by unrelated individuals with the disease. Ann Neurol 2000;48:927–931

Geographical variations in sex ratio trends over time in multiple sclerosis

Background A female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients was demonstrated in many countries around the world. So far, a direct comparison of sex ratio time-trends among MS populations from different geographical areas was not carried out. Objective In this paper we assessed and compared sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas. Methods Data of a cohort of 15,996 (F = 11,290; M = 4,706) definite MS with birth years ranging from 1930 to 1989 were extracted from the international MSBase registry and the New Zealand MS database. Gender ratios were calculated by six decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the respective national registries of births. Results Adjusted sex ratios showed a significant increase from the first to the last decade in the whole MS sample (from 2.35 to 2.73; p = 0.03) and in the subgroups belonging to the areas between 83° N and 45° N (from 1.93 to 4.55; p<0.0001) and between 45° N to 35° N (from 1.46 to 2.30; p<0.05) latitude, while a sex ratio stability over time was found in the subgroup from areas between 12° S and 55° S latitude. The sex ratio increase mainly affected relapsing-remitting (RR) MS. Conclusions Our results confirm a general sex ratio increase over time in RRMS and also demonstrate a latitudinal gradient of this increase. These findings add useful information for planning case-control studies aimed to explore sex-related factors responsible for MS development.

Fingolimod after natalizumab and the risk of short-term relapse

Objective: To determine early risk of relapse after switch from natalizumab to fingolimod; to compare the switch experience to that in patients switching from interferon-β/glatiramer acetate (IFN-β/GA) and those previously treatment naive; and to determine predictors of time to first relapse on fingolimod. Methods: Data were obtained from the MSBase Registry. Relapse rates (RRs) for each patient group were compared using adjusted negative binomial regression. Survival analyses coupled with adjusted Cox regression were used to model predictors of time to first relapse on fingolimod. Results: A total of 536 patients (natalizumab-fingolimod [n = 89]; IFN-β/GA-fingolimod [n = 350]; naive-fingolimod [n = 97]) were followed up for a median 10 months. In the natalizumab-fingolimod group, there was a small increase in RR on fingolimod (annualized RR [ARR] 0.38) relative to natalizumab (ARR 0.26; p = 0.002). RRs were generally low across all patient groups in the first 9 months on fingolimod (RR 0.001–0.13). However, 30% of patients with disease activity on natalizumab relapsed within the first 6 months on fingolimod. Independent predictors of time to first relapse on fingolimod were the number of relapses in the prior 6 months (hazard ratio [HR] 1.59 per relapse; p = 0.002) and a gap in treatment of 2–4 months compared to no gap (HR 2.10; p = 0.041). Conclusions: RRs after switch to fingolimod were low in all patient groups. The strongest predictor of relapse on fingolimod was prior relapse activity. Based on our data, we recommend a maximum 2-month treatment gap for switches to fingolimod to decrease the hazard of relapse. Classification of evidence: This study provides Class IV evidence that RRs are not higher in patients with multiple sclerosis switching to fingolimod from natalizumab compared to those patients switching to fingolimod from other therapies.

Persistence on therapy and propensity matched outcome comparison of two subcutaneous interferon beta 1a dosages for multiple sclerosis

Objectives To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. Methods Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. Results Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as “lack of efficacy” (3.3% vs. 1.7%), “scheduled stop” (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. Conclusions Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from “real-world” database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.

Intrathecal B-Cell Clonal Expansion, an Early Sign of Humoral Immunity, in the Cerebrospinal Fluid of Patients with Clinically Isolated Syndrome Suggestive of Multiple Sclerosis

The development of somatically mutated memory and plasma B cells is a consequence of T cell-dependent antigen-challenged humoral immunity. To investigate the role of B cell-mediated humoral immunity in the initiation and evolution of multiple sclerosis (MS), we analyzed Ig variable heavy chain genes of intrathecal B cells derived from patients with a first clinical manifestation suggestive of MS. Sequences of Ig variable regions showed that B cells in the cerebrospinal fluid from most of these patients were clonally expanded and carried somatic hypermutated variable heavy chain genes. The mutations showed a high replacement-to-silent ratio and were distributed in a way suggesting that these clonally expanded B cells had been positively selected through their antigen receptor. In comparison, intrathecal B-cell clonal expansion often precedes both oligoclonal IgG bands and multiple magnetic resonance imaging lesions. Clinical follow-up study showed that patients with clonally expanded intrathecal B cells had a high rate of conversion to clinically definite MS. The findings provide direct evidence of recruitment of germinal center differentiated B lymphocytes into the central nervous system during the initiation of MS. These results indicate B cell-mediated immune response in the cerebrospinal fluid is an early event of inflammatory reaction in the central nervous system of MS. This procedure also provides a more sensitive method to evaluate the association of humoral immunity in the evolution of MS.

Switch to Natalizumab versus Fingolimod in Active Relapsing-Remitting Multiple Sclerosis

In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents.