G. Leroux

Determinants of Hydroxychloroquine Blood Concentration Variations in Systemic Lupus Erythematosus

Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations.

Four-year longitudinal study of clinical and functional endpoints in sporadic inclusion body myositis: Implications for therapeutic trials

Natural history studies in sporadic inclusion body myositis are of fundamental interest for future therapeutic trials. Previous works have demonstrated the particular relevance of knee extension strength in the follow-up of this disease. This work aimed to extend a preceding natural history over 9 months to a four year period. Thirteen patients were assessed using clinical and functional scales and dynamometry. Except wrist extension torque and manual muscle testing composite score, all the measurements presented a significant decline. The most important changes were observed for knee extension and ankle flexion and extension. The relative change in knee extension strength correlated with the level of strength at baseline. A non-linear correlation was found between 6-minute walk distance and knee extension strength. This study confirms that knee extension strength is particularly relevant to follow patients with sporadic inclusion body myositis. It also shows that a strength loss does not have linear consequences on motor ability. Finally strength and motor ability are complementing each other in the understanding of disease progression.

Dermatomyositis With or Without Anti-Melanoma Differentiation-Associated Gene 5 Antibodies: Common Interferon Signature but Distinct NOS2 Expression.

The anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is specifically associated with dermatomyositis (DM). Nevertheless, anti-MDA5(+)-patients experience characteristic symptoms distinct from classic DM, including severe signs of extramuscular involvement; however, the clinical signs of myopathy are mild or even absent. The morphological and immunological features are not yet described in adulthood. Data concerning the pathophysiology of anti-MDA5 DM are sparse; however, the importance of the interferon (IFN) type I pathway involved in DM has been shown. Our aim was to define morphological alterations of the skeletal muscle and the intrinsic immune response of anti-MDA5-positive DM patients. Immunohistological and RT-PCR analysis of muscle biopsy specimens from anti-MDA5 and classic DM were compared. Those with anti-MDA5 DM did not present the classic features of perifascicular fiber atrophy and major histocompatibility complex class I expression. They did not show significant signs of capillary loss; tubuloreticular formations were observed less frequently. Inflammation was focal, clustering around single vessels but significantly less intense. Expression of IFN-stimulated genes was up-regulated in anti-MDA5 DM; however, the IFN score was significantly lower. Characteristic features were observed inxa0anti-MDA5 DM and not in classic DM patients. Only anti-MDA5 DM showed numerous nitric oxide synthase 2-positive muscle fibers with sarcoplasmic colocalization of markers of regeneration and cell stress. Anti-MDA5-positive patients demonstrate a morphological pattern distinct from classic DM.

Relapsing Polychondritis Can Be Characterized by Three Different Clinical Phenotypes: Analysis of a Recent Series of 142 Patients.

Relapsing polychondritis (RP) is a rare condition characterized by recurrent inflammation of cartilaginous tissue and systemic manifestations. Data on this disease remain scarce. This study was undertaken to describe patient characteristics and disease evolution, identify prognostic factors, and define different clinical phenotypes of RP.

Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a French nationwide study of thirty-three patients

Objectives To assess efficacy and safety of rituximab (RTX) as induction therapy, maintenance of remission and treatment of relapses in a cohort of IgG4-related disease (IgG4-RD) patients. Methods Nationwide retrospective multicenter study of IgG4-RD patients treated with at least one course of RTX. Clinical, biological and radiological response, relapse rate and drug tolerance were analyzed. Kaplan-Meier curves were plotted and risk factors for relapse studied with a Cox regression model. Results Among 156 IgG4-RD patients included in the French database, 33 received rituximab. Clinical response was noted in 29/31 (93.5%) symptomatic patients. Glucocorticoids withdrawal was achieved in 17 (51.5%) patients. During a mean follow-up of 24.8 ±21 months, 13/31 (41.9%) responder patients relapsed after a mean delay of 19 ±11 months after RTX. Active disease, as defined by an IgG4-RD Responder Index >9 before RTX, was significantly associated with relapse (HR = 3.68, 95% CI: 1.1, 12.6) (P = 0.04), whereas maintenance therapy with systematic (i.e. before occurrence of a relapse) RTX retreatment was associated with longer relapse-free survival (41 versus 21 months; P = 0.02). Eight severe infections occurred in 4 patients during follow-up (severe infections rate of 12.1/100 patient-years) and hypogammaglobulinemia ≤5 g/l in 3 patients. Conclusion RTX is effective for both induction therapy and treatment of relapses in IgG4-RD, but relapses are frequent after B-cell reconstitution. Maintenance therapy with systematic RTX infusions is associated with longer relapse-free survival and might represent a novel treatment strategy. Yet, the high rate of infections and the temporary effect of RTX might be hindrances to such strategy.

Liver diseases and pregnancy

Liver disease can be observed in pregnant women whether or not related to pregnancy. Liver disorders can be revealed by pruritus, vomiting, jaundice or abnormal liver blood tests during pregnancy. These liver manifestations can lead to the diagnosis of liver disease specifically associated to pregnancy as intrahepatic pregnancy, intrahepatic cholestasis of pregnancy, Hyperemesis gravidarum, acute fatty liver of pregnancy and preeclampsia-induced liver injury. Pregnancy may also be a risk factor for other liver diseases coincident with pregnancy as viral hepatitis, thrombosis, drug toxicity or gallstone. Finally, pre-existing liver disease must be taken into account given the risk of fœto-maternal transmission risk as well as the risk of decompensation of underlying cirrhosis secondary to the hemodynamic changes caused by pregnancy. The aim of this revue is to perform an update on the various situations that can be observed, the principles of management of these liver diseases, in order to reduce the risk of complications and to ensure the best maternal and fetal prognosis.

A Prospective International Study on Adherence to Treatment in 305 Patients With Flaring SLE: Assessment by Drug Levels and Self‐Administered Questionnaires

Nonadherence to treatment is a major cause of lupus flares. Hydroxychloroquine (HCQ), a major medication in systemic lupus erythematosus, has a long half-life and can be quantified by high-performance liquid chromatography. This international study evaluated nonadherence in 305 lupus patients with flares using drug levels (HCQ <200u2009ng/ml or undetectable desethylchloroquine), and self-administered questionnaires (MASRI <80% or MMAS-8 <6). Drug levels defined 18.4% of the patients as severely nonadherent. In multivariate analyses, younger age, nonuse of steroids, higher body mass index, and unemployment were associated with nonadherence by drug level. Questionnaires classified 39.9% of patients as nonadherent. Correlations between adherence measured by questionnaires, drug level, and physician assessment were moderate. Both methods probably measured two different patterns of nonadherence: self-administered questionnaires mostly captured relatively infrequently missed tablets, while drug levels identified severe nonadherence (i.e., interruption or erratic tablet intake). The frequency with which physicians miss nonadherence, together with underreporting by patients, suggests that therapeutic drug monitoring is useful in this setting. (Trial registration: ClinicalTrials.gov: NCT01509989.).

Cholécystite alithiasique révélatrice d'une hépatite aiguë secondaire au virus de l'hépatite C

es hépatites virales aiguës s’accompagnent de multiples manifestations extra-hépatiques et de rares cas de cholécystites alithiasiques ont été rapportés. Ces cholécystites ont un mode de présentation typiquement chirurgical et peuvent conduire à tort à une cholécystectomie en urgence, le diagnostic d’hépatite aiguë virale étant alors ignoré ou différé de façon péjorative. Cependant, si le tableau clinique est trompeur, les tests biologiques et surtout les constatations radiologiques (échographie et/ou scanner abdomino-pelvien) permettent de redresser rapidement le diagnostic. Nous rapportons ici un cas exceptionnel de cholécystite alithiasique lié à une primo-infection par le virus de l’hépatite C et dont le diagnostic a été établi avec succès grâce à la collaboration entre radiologues, médecins internistes et chirurgiens.

Polychondrite atrophiante : actualités en 2017

Relapsing polychondritis (RP) is a rare condition characterized by recurrent inflammation of cartilaginous tissue and systemic manifestations. Data on pathophysiology are scarce and suggest an autoimmune mechanism. Recently, the possibility of dividing patients with RP into three distinct clinical phenotypes has been suggested: the hematological form representing less than 10% of patients, essentially older men with associated myelodysplasia and poor prognosis, the respiratory form representing about 25% of patients with predominant tracheobronchial involvement, and the mild and most frequent form, representing 65% of patients, with a good prognosis. Recent data on survival shows an improvement of overall prognosis compared to historical series. Reported poor prognosis factors are male gender, associated haemopathies and cardiac involvement. Few recent series suggest an interest for positron emission tomography for the diagnosis and the follow-up of treatment. Due to the lack of randomized therapeutic trial, treatment remains empirical and is mainly based on oral corticosteroids sometimes associated with immunosuppressive agents. The use of biologic agents has recently been reported in small retrospective series with different outcome. Finally, some selected patients with mild and occasional peripheral chondritis might justify a treatment with colchicine or a therapeutic abstention with occasional short-term corticosteroids therapy.

Étude prospective internationale sur l’adhésion au traitement dans le lupus systémique : résultats préliminaires sur 307 patients en poussée

Introduction La non adhesion au traitement est une cause majeure d’echec du traitement et est difficile a diagnostiquer. Dans cette etude prospective internationale, nous avons evalue la non adhesion chez les patients ayant une poussee de lupus systemique (ClinicalTrials.govxa0: NCT01509989 ; PHRC 2012, noxa012-002-0114). Patients et methodes Nous avons inclus les patients lupiques (criteres SLICC) suivis dans 19xa0centres (dont 7xa0francais) traites par hydroxychloroquine (HCQ) depuis au moins 2xa0mois et ayant une poussee de lupus (definie selon le score composite Selena SLEDAI Flare Index). Les patients dans l’incapacite de prendre des medicaments par voie orale etaient exclus. L’adhesion au traitement par HCQ etait evaluee par des auto-questionnaires (MASRI et Morisky), par l’evaluation du medecin (EVAxa0: 0xa0a 100) et le dosage sanguin d’hydroxychloroquine [HCQ]. Les donnees manquantes (DM) etaientxa0 Resultats Trois cent sept patients (290xa0femmes), d’âge moyen 39xa0±xa012xa0ans ont ete inclus. La duree mediane d’evolution du lupus systemique etait de 12xa0ans [extremesxa0: 2–48]xa0; 110xa0patients (36xa0%) avaient des antecedents de nephropathie lupique et 32 (10,5xa0%) avaient un SAPL (2xa0DM). A l’inclusion, le score de SLEDAI median etait de 8 [3–30] et la poussee etait severe dans 42xa0% des cas (score composite Selena SLEDAI Flare Index). Le traitement de fond comportait de l’HCQ chez tous les patients (posologie de 400xa0mg/j pour 71xa0% des patients, 200xa0mg/j pour 16xa0% ou autre pour 13xa0%), des corticoides (77xa0%), et/ou un immunosuppresseur (47xa0%). La concentration mediane d’HCQ etait de 702xa0ng/mL [0–3727] (2xa0DM). La non adhesion severe definie par une [HCQ]xa0 L’EVA mediane evaluant l’adhesion du point de vue du medecin etait de 71 [3–97] chez les patients objectivement non adherents versus 87 [0–100] chez les autres patients, l’avis de du medecin investigateur etant donc dans cette etude peu informatif. Globalement, les medecins investigateurs estimaient que la prise d’HCQ etaitxa0≤xa050xa0% chez seulement 14xa0% des patientsxa0: une non adhesion severe etait alors confirmee chez 37xa0% des patients. A l’inverse, alors que leur estimation de la prise etait d’au moins 80xa0% (59xa0% des cas)xa0: 12,8xa0% de ces patients etaient neanmoins objectivement non adherents. Soixante-dix-huit pour cent des patients rapportaient une tres bonne adhesion au traitement par HCQ (definie par un MASRIxa0≥xa080xa0%). Neanmoins, selon les dosages d’HCQ et de DCQ, parmi eux, 9,1xa0% n’etaient objectivement pas adherents au traitement. Finalement, les patients non adherents definis selon les auto-questionnaires et/ou les dosages pharmacologiques, representaient 50,2xa0% de cette cohorte. Les correlations entre la non adhesion et les differentes donnees epidemiologiques et cliniques n’etaient pas disponibles lors de la soumission de cet abstract. Conclusion Ces resultats qui restent preliminaires montrent que les dosages pharmacologiques d’HCQ et de DCQ identifient une non adhesion importante chez pres d’un patient sur 5. Cette non adhesion est par ailleurs generalement meconnue du medecin, alors meme qu’il s’agit d’une etude dediee a ce sujet. Le dosage du metabolite DCQ semble interessant pour identifier les reprises recentes de traitement.