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.

Register-based incidence of multiple sclerosis in Brittany (north-western France), 2000-2001.

OBJECTIVES: To report on multiple sclerosis (MS) incidence in Brittany, north-western France. MATERIALS & METHODS: From 2000, we set up a population-based register for patients presenting a putative incident MS (PIMS), that is first symptoms compatible with MS onset. We used 3 medical sources of case ascertainment (neurologists, CSF, regional MS-Clinic). Eligibility criteria required both clinical onset and being permanent resident of Brittany in 2000 or 2001. From 2010, all medical records were tracked, the 10-year follow-up allowing previously reported data to be updated. RESULTS: Of 313 eligible PIMS, there were 208 definite MS (both McDonald and Poser criteria), 41 CIS-probable MS (Poser criteria), 32 CIS-possible MS and 32 non-MS. Our incident cohort of 249 MS cases with definite/probable MS (sex ratio 2.95) gave a crude annual incidence of 4.28 per 100,000 inhabitants (6.22 for women, 2.23 for men), and age-standardized rates (adjustment to the European population) of 4.41 [3.32-5.51], 6.68 [4.75-8.60], and 2.21 [1.12-3.31], respectively. Age-specific rates by gender and initial course showed that attack onset MS peaked at 25-29 years and progressive onset MS at 40-44 years in women (20-24 years and 45-49 years in men, respectively). CONCLUSIONS: Brittany is confirmed a high-risk region for MS. Our data show marked differences in sex-specific pattern of MS incidence by clinical course and point out 25- to 29-year-old women as having the highest MS risk. While temporal variations cannot be excluded, comparison with overall French data suggests that other factors rather than latitude may influence the MS risk in France.

'Clinically definite benign multiple sclerosis', an unwarranted conceptual hodgepodge: evidence from a 30-year observational study.

BACKGROUND: Benign multiple sclerosis (BMS) is a controversial concept which is still debated. However identification of this kind of patients is crucial to prevent them from unnecessary exposure to aggressive and/or long term medical treatments. OBJECTIVES: To assess two definitions of 'clinically definite benign multiple sclerosis' (CDBMS) using long-term follow-up data, and to look for prognostic factors of CDBMS. METHODS: In 874 patients with definite relapsing-remitting MS, followed up for at least 10 years, disability was assessed using the Disability Status Scale (DSS). CDBMS was defined by either DSS score≤2 (CDBMS1 group) or DSS score≤ 3 (CDBMS2 group) at 10 years. We estimated the proportion of patients who were still benign at 20 and 30 years after clinical onset. RESULTS: CDBMS frequency estimates were 57.7% and 73.9% when using CDBMS1 and CDBMS2 definitions, respectively. In the CDBMS1 group, only 41.7% (105/252) of cases were still benign 10 years later, and 41.1% (23/56) after an additional decade, while there were 53.8% (162/301) and 59.5% (44/74) respectively in the CDBMS2 group. CONCLUSIONS: This 30-year observational study, which is one of the largest published series, indicates that favourable 10-year disability scores of DSS 2 or 3 fail to ensure a long-term benign course of multiple sclerosis. After every decade almost half of the CDBMS were no longer benign. CDBMS, as currently defined, is an unwarranted conceptual hodgepodge. Other criteria using new biomarkers (genetic, biologic or MRI) should be found to detect benign cases of MS.

MGAT5 alters the severity of multiple sclerosis.

Multiple Sclerosis (MS) is a genetically complex immune mediated, demyelinating disease of the central nervous system. To date no genetic variants have been unambiguously linked to disease severity. We have conducted a genome wide screen, using Affymetrix Genechip 500K technology, for severity in 1040 MS patients. Two markers within MGAT5, a gene coding for a glycosylation enzyme, were found to be significantly associated with outcome in the screening as well as in an independent population (combined p-values: 2.8 x 10(-6) and 1.5 x 10(-7)).

Season of birth and not vitamin D receptor promoter polymorphisms is a risk factor for multiple sclerosis.

Both genetic and environmental factors contribute to multiple sclerosis, the most common neurodegenerative disorder with onset in young adults. The objective of the current study is, based on the hypothesis that environmentally predisposed individuals are at risk for multiple sclerosis, to investigate whether they also carry genetic variants within the vitamin D machinery. Using medical files and DNA samples from 583 trios (a patient and both parents) of the French Multiple Sclerosis Genetics Group as well as data from the French Statistics Bureau, we aimed to assess whether: (1) a seasonality of birth was observed in French multiple sclerosis patients; (2) three single nucleotide polymorphisms within the promoter region of the vitamin D receptor were associated with multiple sclerosis susceptibility; and (3) the combination of a high risk month of birth and vitamin D receptor polymorphisms were correlated to multiple sclerosis incidence. We observed a significantly reduced number of individuals born in November who were later diagnosed as multiple sclerosis patients. However, we found no association between the three studied vitamin D receptor polymorphisms and multiple sclerosis. In conclusion, our data suggest that high levels of vitamin D during the third trimester of pregnancy could be a protective factor for multiple sclerosis.

HLA-DRB1*15 allele influences the later course of relapsing remitting multiple sclerosis.

Most of the published works so far have aimed at finding genes associated with multiple sclerosis (MS) susceptibility. Very few studies have attempted to correlate disease features with DNA variants. In a well-characterized sample (651 patients) representative of multiple sclerosis natural history, we engaged a comprehensive study of the role of human leukocyte antigen (HLA) in the course of the disease. We investigated the role of HLA-DRB1*15 allele in samples stratified according to severity evaluated by the Multiple Sclerosis Severity Score (MSSS), time to reach EDSS 6.0 and disease type. We found that HLA-DRB1*15 genotype does not influence MS severity even among patients presenting with a given type of the disease. However, we show for the first time that HLA-DRB1*15 allele modulates the course of MS for relapsing-remitting (RR) onset patients likely by precipitating the secondary progressive (SP) phase.

IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations.

Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.

Long-term survival of patients with multiple sclerosis in West France.

In France no data have been published about comparing survival in multiple sclerosis (MS) patients with the general French population. We estimated survival probabilities in MS patients from a major centre for MS in West France. We also compared MS survival with the general population and assessed prognostic parameters. All patients with MS onset after January 1976 and classified as dead or alive on 1 January 2004 were included. One thousand eight-hundred and seventy-nine patients (sex ratio W: M 2.3; relapsing/progressive onset 77.4%/22.6%) fulfilled these criteria, disease duration ranged from one to 28 years. By 2004, 68 patients died (51 due to MS) and the 15 and 25-year survival probabilities were 96% and 88%. Male gender, progressive course (either primary or secondary), polysymptomatic onset, and increased annual relapse rate during the first two years of MS were related to a worse prognosis. After a mean follow-up duration of 12.7 years since clinical onset, MS increased the number of deaths compared with the general population. However taking into account disability status, we found that less disabled MS patients had a better survival and highly disabled patients a worse survival (eight-fold increase of mortality) compared with the French population.

A second-generation genomic screen for multiple sclerosis.

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder. Despite substantial evidence for polygenic inheritance of the disease, the major histocompatibility complex is the only region that clearly and consistently demonstrates linkage and association in MS studies. The goal of this study was to identify additional chromosomal regions that harbor susceptibility genes for MS. With a panel of 390 microsatellite markers genotyped in 245 U.S. and French multiplex families (456 affected relative pairs), this is the largest genomic screen for MS conducted to date. Four regions met both of our primary criteria for further interest (heterogeneity LOD [HLOD] and Z scores >2.0): 1q (HLOD=2.17; Z=3.38), 6p (HLOD=4.21; Z=2.26), 9q (HLOD; Z=2.71), and 16p (HLOD=2.64; Z=2.05). Two additional regions met only the Z score criterion: 3q (Z=2.39) and 5q (Z=2.17). Further examination of the data by country (United States vs. France) identified one additional region demonstrating suggestive linkage in the U.S. subset (18p [HLOD=2.39]) and two additional regions generating suggestive linkage in the French subset (1p [HLOD=2.08] and 22q [HLOD=2.06]). Examination of the data by human leukocyte antigen (HLA)-DR2 stratification identified four additional regions demonstrating suggestive linkage: 2q (HLOD=3.09 in the U.S. DR2- families), 6q (HLOD=3.10 in the French DR2- families), 13q (HLOD=2.32 in all DR2+ families and HLOD=2.17 in the U.S. DR2+ families), and 16q (HLOD=2.32 in all DR2+ families and HLOD=2.13 in the U.S. DR2+ families). These data suggest several regions that warrant further investigation in the search for MS susceptibility genes.

Positive association of the HLA DMB1*0101-0101 genotype with rheumatoid arthritis.

OBJECTIVE: HLA DM is a non-classical major histocompatibility complex (MHC) class II molecule that has been shown to facilitate peptide loading with classical class II molecules. METHODS: In this study, we analysed the polymorphism in exon 3 of HLA DMA and DMB genes by a polymerase chain reaction-sequence-specific oligonucleotide probe method in 163 rheumatoid arthritis (RA) patients and 146 ethnically matched controls. The HLA-DRB1 genotype was also analysed by a reverse-dot blot method. RESULTS: Our results show in RA patients a significant increase in the HLA DMB*0101 allele frequency (83% vs 72.3% of the controls, P < 1.6 x 10(-3), significance at P < 0.0125) and in the HLA DMB*0101-0101 homozygote genotype frequency [70.8% vs 50% of the controls, P < 4.2 x 10(-4), significance at P < 0.00625, odds ratio (OR) = 2.4, 95% confidence interval (CI): 1.43-4]. The increase in DMB*0101 allele and homozygote genotype frequencies was independent of a linkage disequilibrium between DMB and DRB1 alleles. The analysis of non-random associations between the HLA-DM and DRB1 alleles only revealed a significant association in controls between DMB*0104 and DRB1*07 alleles (delta = 0.01, P < 7 x 10(-4), significance at P < 9.6 x 10(-4)). On the other hand, the DMB*0101-0102 genotype frequency was increased in DRB1*0401-negative RA patients as compared to controls (11% vs 2%, P < 0.011, significance at P < 0.015, OR = 6.2, 95% CI: 1.2-30). CONCLUSION: Our data suggest that HLA-DM alleles could play a role in the genetic susceptibility to RA.

Familial factors influence disability in MS multiplex families. French Multiple Sclerosis Genetics Group.

BACKGROUND: Both genetic and environmental factors play a role in the pathophysiology of MS and may influence the clinical expression of the disease. OBJECTIVE: To determine the contribution of familial factors to the clinical expression of MS. METHODS: The French Multiple Sclerosis Genetics Group identified 87 sibling pairs. For each patient, sex, age at onset, duration of the disease, and disease course from onset were recorded. Disability was determined by the progression index (PI), defined as the ratio of the Expanded Disability Status Scale (EDSS) score disease duration when the latter exceeded 5 years. Statistical analyses were performed either with a group of patients (clinical features, relation between human leukocyte antigen and clinical features) or with a group of sibpairs (concordance for clinical features). RESULTS: The mean age at onset was 29.6 years, the ratio of women to men was 59:28, and the mean PI was 0.27. There was no correlation for disease course and age at onset between sibs with MS. In contrast, we observed a weak but significant correlation of the PI in MS sibpairs (r = 0.234, p = 0.03). CONCLUSION: This study revealed a concordance in MS sibling pairs for the disease severity, supporting the hypothesis that the degree of disability might be partly influenced by familial factors (environmental or genetic).

Non-C282Y familial iron overload: evidence for locus heterogeneity in haemochromatosis.

Haemochromatosis (HC) is an autosomal recessive disease with progressive iron overload leading to midlife onset of clinical complications. The causal gene (HFE) maps to 6p, in close linkage with the HLA class I genes. An HFE candidate gene recently identified has two missense mutations (C282Y and H63D) associated with the disease. Here we document the phenotypic and genetic analysis of a nuclear family comprising two sibs with symptomatic and massive iron overload before the age of 25. The disease seemed to be recessively transmitted and fitted the agreed criteria for haemochromatosis, but was neither associated with the C282Y and H63D mutations nor linked with HLA markers. Our data strongly support locus heterogeneity in haemochromatosis by showing evidence that the gene responsible for juvenile haemochromatosis (JH) does not map to 6p. In the absence of clear cut phenotypic distinction from typical haemochromatosis, patients below 30 years of age and C282Y negative should be considered as putative juvenile cases. This has practical implications in genetic counselling and family management.

A candidate gene for hemochromatosis: frequency of the C282Y and H63D mutations.

The gene whose alteration causes hereditary hemochromatosis (HFE according to the international nomenclature) was, more than 20 years ago, shown to map to 6p21.3. It has since escaped all efforts to identify it by positional cloning strategies. Quite recently, a gene named HLA-H was reported as being responsible for the disease. Two missense mutations, Cys282Tyr (C282Y) and His63Asp (H63D), were observed, but no proof was produced that the gene described is the hemochromatosis gene. To validate this gene as the actual site of the alteration causing hemochromatosis, we decided to look for the two mutations in 132 unrelated patients from Brittany. Our results indicate that more than 92% of these patients are homozygous for the C282Y mutation, and that all 264 chromosomes but 5 carry either mutation. These findings confirm the direct implication of HLA-H in hemochromatosis.

Significance of interleukin-1beta and interleukin-1 receptor antagonist genetic polymorphism in inflammatory bowel diseases.

OBJECTIVE: Genetic susceptibility to inflammatory bowel disease is well recognized. There is also increasing evidence for the activation of the mucosal immune system and the production of inflammatory cytokines, i.e., interleukin (IL)-1ra and IL-1beta in the inflammatory bowel disease. The aim of this study was to analyze the IL-1beta and IL-1ra gene polymorphism and linkage disequilibrium coefficient between the different alleles of these genes in patients with Crohn's disease (CD) or ulcerative colitis (UC), according to the severity of the disease. METHODS: Two hundred twenty-eight inflammatory bowel disease patients (87 UC and 141 CD) were included in this study and compared with 113 unrelated controls. The IL-1beta and IL-1ra gene polymorphism was studied after specific amplification of variable regions by PCR. A penta-allelic polymorphism, corresponding to a VNTR region located in intron 2 of the IL-1ra gene, was analyzed, whereas bi-allelic RFLPs displayed by two restriction enzymes (TaqI and AvaI) at position -511 of the IL-1beta gene were analyzed. RESULTS: There was no significant difference of genotype distribution between controls and CD or UC patients. However, surgically treated UC patients were characterized by a higher frequency of genotype IL-1ra 1-2 (39 vs 16%, pc < 0.01) compared with nonoperated UC patients. Moreover, nonoperated UC patients displayed a lower frequency of IL-1ra allele 2 than surgically treated UC patients (14 vs 34%, pc < 0.002) or controls (14 vs 30%, pc < 0.005). Furthermore, simultaneous analysis of the IL-1beta and IL-1ra genes that are located in the same region of chromosome 2 revealed that CD patients carrying the IL-1beta allele 2 were more often noncarriers of IL-1ra allele 2 (p < 0.005). Moreover, UC and CD patients were, characterized by a lower frequency of the association of IL-1ra allele 2 and IL-1beta allele 2 compared with controls (8.3 vs 20.3% and 10.6 vs 20.3%, p < 0.03). CONCLUSIONS: IL-1ra and IL-1beta gene polymorphism analysis from a clinical standpoint might help in defining UC prognosis. However, functional studies at both the circulating and mucosal level with stratification on allele associations, especially IL-1ra allele 2-IL-1beta allele 2 subgroups must be realized before therapeutic implications.

[Should we screen for hemochromatosis? Critical analysis of the literature]. / Faut-il dépister l'hémochromatose? Analyse critique de la littérature.

This paper focus on the main issues to evaluate before planning public health interventions which may optimise the prevention of hemochromatosis. The main indicators are considered: prevalence, morbidity and mortality of the disease, efficacy of the available treatment, sensitivity, specificity and predictive values of the screening tests; potential benefit of a national screening program in a public health perspective. These are evaluated through a critical appraisal of the clinical, epidemiologic and economic literature on hemochromatosis. The paper emphasizes how individual behavior and preferences become crucial to take into account when well-being subjects will face a population-based screening program. We conclude that further arguments are required before the implementation of a national screening program for hemochromatosis.