<i>RPA3-UMAD1</i> rs12702634 and rheumatoid arthritis-associated interstitial lung disease in European ancestry

Objective Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950.Methods In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin.Results Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 x 10-11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70).Conclusion Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.What does this mean for patients?Interstitial lung disease (ILD) can develop in 10-60% of patients with rheumatoid arthritis (RA) and is associated with an increased risk of death. We do not yet fully understand why RA-ILD occurs, but risk factors include genetics and environmental factors such as tobacco smoking. Identifying new genetic risk factors for RA-ILD may improve our understanding of how this disease occurs, help us categorize patients in terms of their risk level and help us to potentially identify new drug targets. A previous Japanese genetic study identified the RPA3-UMAD1 rs12702634 common genetic variant as a risk factor for RA-ILD. However, a second Japanese study failed to replicate these findings. In this international study including patients with European ancestry, we did not find that RPA3-UMAD1 rs12702634 contributed to the overall risk of RA-ILD. Our findings highlight the importance of conducting analyses that try to replicate the results of a study. We also emphasize that genetic associations-even those already reported-require rigorous testing in different groups of people before we can conclude that they contribute to disease risk. Ongoing collaboration and multi-ancestry genetic studies are essential in order to advance our understanding of the complex genetics underlying RA-ILD

Hypophosphatasie en milieu hospitalier français

Introduction: the prevalence of hypophosphatasemia in the rural population is 0.05%. Patients present symptoms related to adult hypophosphatasia: excess of joint, ab-articular and bone mineralization disorders. The objective is to estimate the prevalence and the recognition of this biological anomaly in 3 French tertiary care hospitals. Methods: alkaline phosphatase (ALP) assessment of three tertiary care hospitals in 2013 was reviewed. Persistent hypophosphatasemia was defined by less than = 30 IU/l without assessment> 40 IU/l. We eliminated secondary causes of hypophosphatasemia. A telephone survey was conducted among patients included in rheumatology and internal medicine. Results: in 2013, 288,851 assessment of ALP were performed in 124,044 patients. 716 patients had a value = 30 IU/l. Of these, 174 had just one assessement, 542 had several assessments, and among them 186 never had ALP> 40. 31 patients were excluded due to secondary hypophosphatasemia. The prevalence of hypophosphatasemia in this hospital population is 0.124%. Hypophosphatasemia was reported twice in the summary discharge. 34 of the 38 patients from rheumatology and internal medicine responded to a standardized telephone survey (79% of women, mean age: 44.5 years). 11 patients had a history of fracture, 2 patients a history of rickets in childhood, and 1 with known hypophosphatasia in the family. 16 patients had at least one dental abnormality. Conclusion: the prevalence of hypophosphatasemia is higher in hospital than in the general population. It is not recognized in clinical settings.Introduction : l’hypophosphatasémie, dont la prévalence serait de 0.05% en population générale peut être associée à des symptômes proches de ceux des formes adultes de l’hypophosphatasie : excès de pathologie articulaire, ab-articulaire, et de troubles de la minéralisation osseuse. L’objectif est d’estimer la prévalence et la reconnaissance de cette anomalie biologique dans 3 centres français. Méthodes : la totalité des dosages de phosphatases alcalines totales (PAL) de 3 centres hospitalo-universitaires réalisés en 2013 a été revue. L’hypophosphatasémie persistante a été définie par au moins un dosage = 30 UI/l sans aucun dosage > 40 UI/l. Nous avons éliminé les causes secondaires d’hypophosphatasémie. Un questionnaire téléphonique a été mené auprès des patients inclus issus de rhumatologie et médecine interne. Résultats : en 2013, 288 851 dosages de PAL ont été réalisés chez 124 044 patients. 716 patients avaient une valeur = 30 UI/l. Parmi eux, 174 avaient 1 seul dosage, 542 plusieurs dosages, dont 186 n’avaient jamais de valeur >40. 31 patients ont été exclus en raison d’une hypophosphatasémie secondaire. La prévalence de l’hypophosphatasémie en milieu hospitalier est de 0.124%. L’hypophosphatasémie était signalée dans le compte rendu 2 fois. 34 des 38 patients issus de rhumatologie et médecine interne ont répondu à un questionnaire téléphonique standardisé (79% de femmes, âge moyen : 44.5ans). 11 patients avaient un antécédent de fracture, 2 patients avaient des antécédents de rachitisme dans l’enfance, et 1 d’hypophosphatasie connue dans la famille. 16 patients avaient une anomalie dentaire. Conclusion : la prévalence de l’hypophosphatasémie est plus élevée en milieu hospitalier qu’en population générale. Elle n’est quasiment jamais relevée dans les dossiers

Osteoporosis and risk of fracture in heart transplant patients

IntroductionSignificant bone loss occurs after heart transplantation, predominantly in the first year, with increased risk of incident fractures. The goal of this study was to evaluate the prevalence of fragility fractures in a population of heart transplantation patients and to identify the independent risk factors for fractures.MethodsThis was a prospective monocentric study that included patients with heart transplantation occurring &lt; 10 years who were undergoing heart transplantation monitoring. All patients underwent bone mineral density evaluation by dual-energy X-ray absorptiometry and radiographies to establish the presence of vertebral fractures.ResultsWe included 79 patients (61 men); the mean age was 56.8 ± 10.8 years. The mean time between transplantation and inclusion was 32.3 ± 35.0 months. Incident fractures were diagnosed in 21 (27%) patients after heart transplantation. Vertebral fractures were the most frequent (30 vertebral fractures for 15 patients). Osteoporosis was confirmed in 22 (28%) patients. Mean bone mineral density at the femoral neck and total hip was lower with than without fracture (femoral neck: 0.777 ± 0.125 vs 0.892 ± 0.174 g/cm2, p&lt;0.01; total hip: 0.892 ± 0.165 vs 0.748 ± 0.07 g/cm2, p&lt;0.001), with a significant result on multivariate analysis. The mean time from transplantation to the first fracture was 8.0 ± 7.6 months.DiscussionOur study confirmed a high vertebral fracture risk in heart transplant patients, especially during the first year after transplantation

Ultrasound evaluation in follow-up of urate-lowering therapy in gout: the USEFUL study

International audienc

UltraSound Evaluation in Follow-up of Urate-Lowering therapy in gout phase 2 (USEFUL-2): duration of flare prophylaxis

OBJECTIVES: To determine whether changes in ultrasonography (US) features of monosodium urate crystal deposition is associated with the number of gouty flares after stopping gout flare prophylaxis. METHODS: We performed a 1-year multicentre prospective study including patients with proven gout and US features of gout. The first phase of the study was a 6-month US follow-up after starting urate-lowering therapy (ULT) with gout flare prophylaxis. After 6 months of ULT, gout flare prophylaxis was stopped, followed by a clinical follow-up (M6 to 12) and ULT was maintained. Outcomes were the proportion of relapsing patients between M6 and M12 according to changes of US features of gout and determining a threshold decrease in tophus size according to the probability of relapse. RESULTS: We included 79 gouty patients (mean [± SD] age 61.8 ± 14 years, 91% males, median disease duration 4 [IQR 1.5; 10] years). Among the 49 completers at M12, 23 (47%) experienced relapse. Decrease in tophus size ≥ 50% at M6 was more frequent without than with relapse (54% vs 26%, P= 0.049). On ROC curve analysis, a threshold decrease of 50.8% in tophus size had the best sensitivity/specificity ratio to predict relapse (AUC 0.649 [95% confidence interval 0.488 ; 0.809]). Probability of relapse was increased for patients with a decrease in tophus size <50% between M0 and M6 (OR 3.35 [95% confidence interval 0.98; 11.44]). CONCLUSION: A high reduction in US tophus size is associated with lower probability of relapse after stopping gout prophylaxis. US follow-up may be useful for managing ULT and gout flare prophylaxis

A Risk Score to Detect Subclinical Rheumatoid Arthritis\textendashAssociated Interstitial Lung Disease

International audienc

Methotrexate and rheumatoid arthritis associated interstitial lung disease

Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

International audienceBACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7x10(-17)). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7x10(-35)) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3x10(-49)). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4x10(-5)), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5x10(-6)). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Societe Francaise de Rhumatologie and others.)

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

BackgroundGiven the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA.MethodsUsing a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls.ResultsAnalysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone.ConclusionsWe found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.)