Intérêt du dosage des chaînes légères libres des immunoglobulines dans la sclérodermie systémique (étude prospective contrôlée chez 134 malades)

Contexte : La synthèse des chaînes lourdes et légères des immunoglobulines par les lymphocytes B (LB) se fait avec un excès de chaînes légères, libérées dans la circulation sanguine sous forme libre (serum Free Light Chains, sFLC). Leur étude dans les situations de stimulation immunitaire chronique polyclonale est en plein essor. Dans le lupus, la polyarthrite rhumatoïde, et le syndrome de Gougerot-Sjögren, il a été démontré que leur taux est plus élevé que chez les sujets sains, et qu il est corrélé à l activité de ces maladies. Aucune donnée n existe à ce sujet dans la sclérodermie systémique (SSc), Méthode : 134 patients SSc ont été inclus prospectivement. Les données suivantes ont été recueillies : date de diagnostic, forme clinique, atteintes viscérales, score d activité et association à d autres maladies auto-immunes. Le dosage des sFLC (Combylite , The Binding Site, Birmingham, RU), et des autres marqueurs d activation lymphocytaire B (gammaglobulines, facteur rhumatoïde, b2-microglobuline, B-cell Activating Factor of the TNF Family BAFF) ont été réalisés à l inclusion. Les taux de sFLC des patients ont été comparés à ceux de 401 sujets donneurs de sang appariés par le sexe et par tranche d âge. Résultats : Les taux moyens et médians de sFLC sont significativement plus élevés chez les patients SSc (médiane 19,99 mg/l, moyenne 24,03 mg/l) comparativement aux contrôles (médiane 15,43 mg/l, moyenne 17,50 mg/l). En analyse univariée, il existe une corrélation significative entre le taux de sFLC et le score de Rodnan modifié (p=0,0099), les antécédents d ulcérations digitales (UD) (p=0,0426), la pression artérielle pulmonaire systolique (p=0,0369), la DLCO (p=0,0063), ainsi qu avec les scores d activité EUSTAR (p=0,009) et de gravité MEDGSER (p=0,0001), la vitesse de sédimentation (p<0,0001), la CRP (p=0,0002), et tous les marqueurs d activation B. L analyse multivariée a mis en évidence une relation forte et indépendante entre le taux de sFLC et l existence d une atteinte pulmonaire interstitielle et sa sévérité, les antécédents d UD, et tous les marqueurs B à l exception du taux d IgM. Conclusion : Notre étude montre pour la première fois que le taux de sFLC est plus élevé chez les patients SSc que chez les sujets sains. Ce taux est corrélé à la présence d atteintes fibrosantes de la SSc, à leur sévérité et à l activité de la maladie. Ces résultats constituent des arguments supplémentaires pour évoquer la participation active des LB à la physiopathologie de la SSc.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Neuralgic amyotrophy triggered by hepatitis E virus: a particular phenotype

International audienceObjective: The neuralgic amyotrophy may be of difficult diagnosis, due to phenotypic variability, with different initial presentations (upper plexus multiple mononeuropathy, lumbosacral involvement, distal reached, phrenic involvement). To date, there is little guidance on these patients’ therapeutic management, especially those for which neuralgic amyotrophy is triggered by hepatitis E virus (HEV-NA). The study aims to identify specific features that characterize patients bearing the neuralgic amyotrophy triggered by HEV. Methods: We first describe a new case report of HEV-neuralgic amyotrophy, with delayed diaphragmatic reach. Then, the literature was searched for reports of HEV-NA (n=39), and neuralgic amyotrophy with phrenic paresis (n=42) from 1999 to June 2016. Relevant data were retrieved, analyzed and compared with the parameters of idiopathic neuralgic amyotrophy (n=199) of the largest cohort, described by Van Alfen and Van Engelen in 2006. Results: Compared to the published cohort, HEV-NA patients were more likely to be men (M/F 34/5 versus 136/ 63, p=0.017), with more frequent bilateral symptoms (86.8% cases versus 28.5%, p<0.0001) as well as phrenic paresis (18.0% versus 6.6%, p=0.028). The clinical improvement is poor, with 15.6% of cases with remission only. Conclusions: A particular phenotype characteristic of the HEV-induced neuralgic amyotrophy has arisen. Our findings call for action in validating the above mentioned features that illustrate the HEV-NA cases as an early diagnosis would prevent complications, especially the phrenic damage often associated with a worse functional outcome

Familial and syndromic lupus share the same phenotype as other early-onset forms of lupus.

International audienceStudies of early-onset systemic lupus erythematosus (SLE) have identified monogenic forms of the disease. The primary objective of this study was to compare the clinical and laboratory features of the first patients included in the GENIAL/LUMUGENE cohort to those reported in previous publications. The secondary objective was to determine whether subgroups with a distinctive pattern of clinical and biological features are seen in predominantly genetic forms of SLE

Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts

International audienceBackgroundSystemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice, while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE.MethodsFor this genetic panel analysis we designed a next-generation sequencing panel comprising 147 genes, including all known lupus-causing genes in humans, and potentially lupus-causing genes identified through GWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteria for SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these data with those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREX Consortium.FindingsAfter filtering, mendelian genotypes were confirmed in eight probands, involving variants in C1QA, C1QC, C2, DNASE1L3, and IKZF1. Seven additional patients carried heterozygous variants in complement or type I interferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9 recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in the childhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified to harbour at least one rare, predicted damaging variant (p=2·98 × 10 −11). Inborn errors of immunity were estimated to account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the main monogenic contribution.InterpretationAn accumulation of rare variants that are predicted to be damaging in SLE-associated genes might contribute to disease expression and clinical heterogeneity

Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients

International audienceObjectives: There is little known about the impact of SARS-CoV-2 on patients with inflammatory rheumatic and musculoskeletal diseases (iRMD). We examined epidemiological characteristics associated with severe disease, then with death. We also compared mortality between patients hospitalised for COVID-19 with and without iRMD.Methods: Individuals with suspected iRMD-COVID-19 were included in this French cohort. Logistic regression models adjusted for age and sex were used to estimate adjusted ORs and 95% CIs of severe COVID-19. The most significant clinically relevant factors were analysed by multivariable penalised logistic regression models, using a forward selection method. The death rate of hospitalised patients with iRMD-COVID-19 (moderate-severe) was compared with a subset of patients with non-iRMD-COVID-19 from a French hospital matched for age, sex, and comorbidities.Results: Of 694 adults, 438 (63%) developed mild (not hospitalised), 169 (24%) moderate (hospitalised out of the intensive care unit (ICU) and 87 (13%) severe (patients in ICU/deceased) disease. In multivariable imputed analyses, the variables associated with severe infection were age (OR=1.08, 95% CI: 1.05-1.10), female gender (OR=0.45, 95% CI: 0.25-0.80), body mass index (OR=1.07, 95% CI: 1.02-1.12), hypertension (OR=1.86, 95% CI: 1.01-3.42), and use of corticosteroids (OR=1.97, 95% CI: 1.09-3.54), mycophenolate mofetil (OR=6.6, 95% CI: 1.47-29.62) and rituximab (OR=4.21, 95% CI: 1.61-10.98). Fifty-eight patients died (8% (total) and 23% (hospitalised)). Compared with 175 matched hospitalised patients with non-iRMD-COVID-19, the OR of mortality associated with hospitalised patients with iRMD-COVID-19 was 1.45 (95% CI: 0.87-2.42) (n=175 each group).Conclusions: In the French RMD COVID-19 cohort, as already identified in the general population, older age, male gender, obesity, and hypertension were found to be associated with severe COVID-19. Patients with iRMD on corticosteroids, but not methotrexate, or tumour necrosis factor alpha and interleukin-6 inhibitors, should be considered as more likely to develop severe COVID-19. Unlike common comorbidities such as obesity, and cardiovascular or lung diseases, the risk of death is not significantly increased in patients with iRMD

Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients

International audienceObjectives: There is little known about the impact of SARS-CoV-2 on patients with inflammatory rheumatic and musculoskeletal diseases (iRMD). We examined epidemiological characteristics associated with severe disease, then with death. We also compared mortality between patients hospitalised for COVID-19 with and without iRMD.Methods: Individuals with suspected iRMD-COVID-19 were included in this French cohort. Logistic regression models adjusted for age and sex were used to estimate adjusted ORs and 95% CIs of severe COVID-19. The most significant clinically relevant factors were analysed by multivariable penalised logistic regression models, using a forward selection method. The death rate of hospitalised patients with iRMD-COVID-19 (moderate-severe) was compared with a subset of patients with non-iRMD-COVID-19 from a French hospital matched for age, sex, and comorbidities.Results: Of 694 adults, 438 (63%) developed mild (not hospitalised), 169 (24%) moderate (hospitalised out of the intensive care unit (ICU) and 87 (13%) severe (patients in ICU/deceased) disease. In multivariable imputed analyses, the variables associated with severe infection were age (OR=1.08, 95% CI: 1.05-1.10), female gender (OR=0.45, 95% CI: 0.25-0.80), body mass index (OR=1.07, 95% CI: 1.02-1.12), hypertension (OR=1.86, 95% CI: 1.01-3.42), and use of corticosteroids (OR=1.97, 95% CI: 1.09-3.54), mycophenolate mofetil (OR=6.6, 95% CI: 1.47-29.62) and rituximab (OR=4.21, 95% CI: 1.61-10.98). Fifty-eight patients died (8% (total) and 23% (hospitalised)). Compared with 175 matched hospitalised patients with non-iRMD-COVID-19, the OR of mortality associated with hospitalised patients with iRMD-COVID-19 was 1.45 (95% CI: 0.87-2.42) (n=175 each group).Conclusions: In the French RMD COVID-19 cohort, as already identified in the general population, older age, male gender, obesity, and hypertension were found to be associated with severe COVID-19. Patients with iRMD on corticosteroids, but not methotrexate, or tumour necrosis factor alpha and interleukin-6 inhibitors, should be considered as more likely to develop severe COVID-19. Unlike common comorbidities such as obesity, and cardiovascular or lung diseases, the risk of death is not significantly increased in patients with iRMD

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study

International audienceBackground: Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.Methods: In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609.Findings: Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66-6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46-0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55-3·19, p=0·53).Interpretation: Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases