Search

1 reported a positive association between allele 2 of the interleukin-1 receptor antagonist (IL- 1ra) gene which maps to 2q13-14 and multiple sclerosis (MS). Our data, based on a larger set of cases and controls and on French MS families, lessen the strength of their argument favouring the IL-1ra gene as functionally important in the susceptibility to MS. In the course of a French collaborative research project on MS genetic susceptibility, our team also listed IL-1ra among candidate genes. We first investigated the penta-allelic polymorphism of the IL-1ra gene in 77 sporadic MS patients who originated from Brittany and 168 unrelated ethnically matched controls. Although homozygosity for allele 2 was two-fold higher in MS patients than in controls, the relative excess of patients carrying allele 2 yielded an odds ratio of only 1·18 (95% CI 0·77-2·13). Moreover, the frequency of allele 2 among MS patients was not significantly different from that observed in controls (38·9% vs 30·9%, χ 2 -test), leading to the conclusion that IL-1ra alleles and the disease were randomly associated. The discordant results reported by Crusius et al 1 prompted us to extend our work on IL-1ra by use of alternative methods based on family data rather than randomly ascertained cases and controls. Our second study focused on 92 unrelated nuclear families (47 from Brittany, and 45 from south-west France) ascertained for the presence of only one affected child who did not belong to the first group of 77 patients studied, and each consisting of the proband and his/her parents. The ascertainment scheme of the families allowed parental alleles not transmitted to the proband to be used as unbiased control alleles, whereas those inherited by the proband were considered as diseased alleles. 2

Cultures of human thyroid follicles embedded in collagen gel were performed to investigate certain functional properties under bovine thyrotropin (TSH) stimulation. Follicles obtained from normal glands responded to increasing concentrations of TSH administered on day 4 in culture and for 3 days by increased amounts of cyclic AMP (cAMP), thyroglobulin (Tg) and triiodothyronine (T3) and by decreased levels of thyroxine (T4). Effect was maximal at 2000 microU/ml TSH (cAMP) or 200 microU/ml (Tg, T3, T4). When methimazole or propylthiouracil (PTU) were added, the T3 levels decreased. Follicle lumens contained a periodic acid-Schiff substance which was identified by immunoreaction as Tg. Thyroid follicles obtained from Graves' disease glands gave modified results with an earlier and intensified T3 response and no increase in Tg. These data show that (1) Tg and T3 are secretory products of functional follicles giving a cAMP-mediated response to TSH. (2) The detected T3 also derives from T4 5'-deiodination inhibited by PTU. (3) Intensified T3 response in Graves' follicles is probably due to enhanced conversion of T4 to T3.

HLA A and B antigens were determined in two groups of patients: 38 patients with idiopathic hemochromatosis (IH) and 22 patients with iron overload accompanying alcoholic liver disease (AH). As previously described, HLA A3 and HLA B14 antigens appeared more frequently in the IH group (76.3 and 28.9%, respectively) than in a control group of 204 subjects (27 and 3.4%). In the AH group the frequency of A3 (22.7%) and B14 (13.6%) was not significantly different from that observed in controls. The frequency of A3 was significantly lower in the AH group than in the IH group (P less than 0.001). On this basis a clear difference appears between the two conditions with iron overload, and genetic analysis of the results rules out the hypothesis that AH would be a heterozygous form of IH exposed by alcohol.

OBJECTIVE--To determine the optimal duration of antithyroid drug treatment by monitoring serum thyroid stimulating antibody values in patients with Graves' disease. DESIGN--Prospective longitudinal trial of patients with Graves' disease followed up for 24 months after withdrawal of treatment. SETTING--Tertiary referral centre. PATIENTS--A total of 64 consecutive patients with untreated Graves' disease, eight of whom were subsequently excluded. Fifty six patients completed the study. INTERVENTIONS--All patients were treated initially with carbimazole 40 mg, then with decreasing doses that maintained a euthyroid state. Treatment was scheduled to continue for 18 months but was withdrawn earlier if serum thyroid stimulating antibody became undetectable. END POINT--Serum values of thyroid stimulating antibody (assayed by stimulation of human thyroid cells in vitro) and thyroid hormones and thyroid state every three months during treatment and afterwards every six months for 24 months. MEASUREMENTS AND MAIN RESULTS--In 44 patients serum thyroid stimulating antibody became undetectable during treatment and treatment was withdrawn (median duration of treatment nine months, range 3-18 months). In 12 patients the antibody could be detected during 18 months of treatment. Among the first group of 44 patients initial values of the antibody before treatment were significantly lower than in the second group of 12 patients (median 225% (range 138-1236%) v 570% (250-1480%), p less than 0.001); the incidence of relapse was also lower (41% v 92%, p less than 0.001); and among those who did relapse the disease free interval after treatment was longer (median 12 months v 1 month, p less than 0.001). Moreover, the initial median serum values of thyroid stimulating antibodies were not related to the occurrence of relapse or remission as these did not differ between patients who did and did not have a relapse (median 267% (range 139-1480%) v 220% (range 138-1236%). CONCLUSION--Monitoring of serum thyroid stimulating antibody was a good guide to the duration of treatment as it allowed the treatment period to be considerably shortened in a large group of patients with no loss of efficiency.

International audience

International audience; Magnetization transfer ratio (MTR) imaging is sensitive to tissue integrity in MS lesions and normal-appearing tissue. Previous studies including patients with well-established MS have shown a significant and disability-related reduction in MTR values in the spinal cord (SC). However, early damage and its predictive utility have yet to be investigated.

Multiple sclerosis (MS) is a chronic neurological disease starting in early adulthood. Relapsing-onset MS is the most common phenotype and defined as occurrence of relapses, a relapse being defined as apparition or worsening of new symptoms. At long term, symptoms get worst and lead to irreversible disability. Since the mid-1990s, the arsenal of specific MS disease-modifying drugs has evolved, leading to different therapeutic strategies based on patient’s characteristics and benefit/risk profile of treatment. The main objective of this PhD thesis was to assess the effectiveness of treatments and therapeutic strategies in real-life on disability progression. The secondary objective was to explore the propensity score methods used to control indication bias. This work was based upon observational data from the “Observatoire Français de la Sclérose en plaques” (OFSEP), mainly collected at consultations in MS expert center. This work was organized around three axes. The evaluation of the effect of first-line injectable treatments led to the use of a method based on a time-dependent propensity score. No benefit was shown on long-term outcome, but this result was probably altered by residual confusion. Comparison of second-line treatments (natalizumab and fingolimod) confirmed the superiority of natalizumab on disability progression and provided the opportunity to explore the impact of methods using propensity scores on results. Finally, the different usual therapeutic strategies were described in France, and preliminary results on their effectiveness were proposed., La sclérose en plaques (SEP) est une maladie neurologique chronique affectant le jeune adulte. Dans sa forme la plus fréquente, la forme rémittente, elle évolue par poussée. A long-terme, celles-ci peuvent laisser des séquelles et conduire à un handicap irréversible. Depuis le milieu des années 90, le répertoire des traitements de fond spécifiques de la SEP ne cesse d’évoluer faisant émerger différentes stratégies thérapeutiques, définies à partir des caractéristiques des patients et du profil bénéfice/risque des traitements. L’efficacité des traitements de fond en vie réelle a déjà été explorée mais a conduit à des résultats controversés. L’objectif principal de cette thèse est d’évaluer l’efficacité des traitements et des stratégies thérapeutiques en vie réelle sur la progression du handicap. L’objectif secondaire était d’explorer les méthodes de score de propension, utilisées dans le but de contrôler le biais d’indication. Ce travail a été réalisé à partir des données de l’Observatoire Français de la Sclérose en Plaques (OFSEP), principalement collectées au cours des consultations en centre expert SEP. Ce travail a été organisé autour de trois axes. L’évaluation de l’effet des traitements de première ligne injectables a mené à utiliser une méthode basée sur un score de propension dépendant du temps, conduisant à ne pas montrer de bénéfice à long terme, résultat probablement altéré par de la confusion résiduelle. La comparaison de deux traitements de deuxième ligne, natalizumab et fingolimod, a conduit à confirmer la supériorité du natalizumab sur la progression du handicap et a offert l‘opportunité d’explorer l’impact des méthodes utilisant les scores de propension sur les résultats. Enfin, les différentes stratégies thérapeutiques ont été décrites en France, des résultats préliminaires sur leur efficacité ont été proposés.

Multiple sclerosis (MS) is a chronic neurological disease starting in early adulthood. Relapsing-onset MS is the most common phenotype and defined as occurrence of relapses, a relapse being defined as apparition or worsening of new symptoms. At long term, symptoms get worst and lead to irreversible disability. Since the mid-1990s, the arsenal of specific MS disease-modifying drugs has evolved, leading to different therapeutic strategies based on patient’s characteristics and benefit/risk profile of treatment. The main objective of this PhD thesis was to assess the effectiveness of treatments and therapeutic strategies in real-life on disability progression. The secondary objective was to explore the propensity score methods used to control indication bias. This work was based upon observational data from the “Observatoire Français de la Sclérose en plaques” (OFSEP), mainly collected at consultations in MS expert center. This work was organized around three axes. The evaluation of the effect of first-line injectable treatments led to the use of a method based on a time-dependent propensity score. No benefit was shown on long-term outcome, but this result was probably altered by residual confusion. Comparison of second-line treatments (natalizumab and fingolimod) confirmed the superiority of natalizumab on disability progression and provided the opportunity to explore the impact of methods using propensity scores on results. Finally, the different usual therapeutic strategies were described in France, and preliminary results on their effectiveness were proposed., La sclérose en plaques (SEP) est une maladie neurologique chronique affectant le jeune adulte. Dans sa forme la plus fréquente, la forme rémittente, elle évolue par poussée. A long-terme, celles-ci peuvent laisser des séquelles et conduire à un handicap irréversible. Depuis le milieu des années 90, le répertoire des traitements de fond spécifiques de la SEP ne cesse d’évoluer faisant émerger différentes stratégies thérapeutiques, définies à partir des caractéristiques des patients et du profil bénéfice/risque des traitements. L’efficacité des traitements de fond en vie réelle a déjà été explorée mais a conduit à des résultats controversés. L’objectif principal de cette thèse est d’évaluer l’efficacité des traitements et des stratégies thérapeutiques en vie réelle sur la progression du handicap. L’objectif secondaire était d’explorer les méthodes de score de propension, utilisées dans le but de contrôler le biais d’indication. Ce travail a été réalisé à partir des données de l’Observatoire Français de la Sclérose en Plaques (OFSEP), principalement collectées au cours des consultations en centre expert SEP. Ce travail a été organisé autour de trois axes. L’évaluation de l’effet des traitements de première ligne injectables a mené à utiliser une méthode basée sur un score de propension dépendant du temps, conduisant à ne pas montrer de bénéfice à long terme, résultat probablement altéré par de la confusion résiduelle. La comparaison de deux traitements de deuxième ligne, natalizumab et fingolimod, a conduit à confirmer la supériorité du natalizumab sur la progression du handicap et a offert l‘opportunité d’explorer l’impact des méthodes utilisant les scores de propension sur les résultats. Enfin, les différentes stratégies thérapeutiques ont été décrites en France, des résultats préliminaires sur leur efficacité ont été proposés.

Introduction : Le fingolimod est un traitement de fond des formes très actives de sclérose en plaque rémittente-récurrente (SEP RR) commercialisé en France depuis 2011. Le but de notre étude est de voir l’évolution clinique et radiologique des patients de Bretagne ayant une SEP RR sous fingolimod afin d’avoir un reflet de son efficacité et de sa sécurité d’emploi en pratique courante. Matériel et méthodes. Nous avons inclus tous les patients de Bretagne de la base EDMUS ayant une SEP RR ayant reçu du fingolimod jusqu’au 31.12.2013. Le recueil de données s’est arrêté au 31.12.2014. L’ensemble des dossiers ont été relus afin de collecter les poussées, les EDSS, les IRM, les effets indésirables et les motifs d’arrêt sous fingolimod. Résultats : Nous avons inclus 219 patients. Sous fingolimod, le TAP a diminué de façon significative de 72% de 1 à 0.28, IC95%: [0.22-0.36]. Sous fingolimod, il y avait une augmentation significative à 69.41% du taux de patients ne présentant pas de poussée (p