Association entre le variant rs35705950 du promoteur de <i>MUC5B</i> et la pneumopathie interstitielle diffuse associée à la polyarthrite rhumatoïde

Background: given phenotypic similarities between rheumatoid arthritis–associated interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF), we hypothesized that the strongest risk factor for the development of IPF, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD in patients with RA. Methods: using a discovery population and multi-ethnic validation case series, we tested the association of the MUC5B promoter variant in RA-ILD (N=620), RA without ILD (N=614), and unaffected controls (N=5448). Results: the discovery population revealed an association of the MUC5B rs35705950 minor allele with RA-ILD when compared to unaffected controls (OR=3.8 95%CI[2.8-5.2]; P=9.7x10-17). Similar to the discovery population, MUC5B rs35705950 was significantly over-represented among the RA-ILD cases in the multi-ethnic study case series when compared to unaffected controls (OR=5.5 95%CI[4.2-7.2]; P=4.7x10-35), and when the discovery population and the multi-ethnic case series were combined (ORcombined=4.7 95%CI[3.9-5.8]; P=1.3x10-49). Additionally, MUC5B rs35705950 was found to increase the risk of ILD among patients with RA (ORcombined=3.1 95%CI[1.8-5.4]; P=7.4x10-5), however, no statistical association with MUC5B rs35705950 was observed for RA alone. The association of MUC5B rs35705950 with RA-ILD increased significantly when restricted to usual interstitial pneumonia (UIP) pattern by high-resolution computed tomography (ORcombined=6.1 95%CI[2.9-13.1]; P=2.5x10-6). In exploratory analyses, we found that other IPF risk variants (TOLLIP rs5743890 and IVD rs2034650) were also preliminarily associated with RA-ILD. Conclusion: our findings demonstrate that MUC5B rs35705950 is a risk factor for RA-ILD specifically associated with radiologic evidence of UIP.Introduction : la pneumopathie interstitielle diffuse (PID) associée à la polyarthrite rhumatoïde (PR) et la fibrose pulmonaire idiopathique (FPI) partagent de nombreuses caractéristiques phénotypiques. Nous avons supposé que MUC5B rs35705950, principal facteur de susceptibilité génétique à la FPI, pourrait également être associé à la PR-PID. Méthodes : à l’aide d’une étape de découverte suivie d’une réplication multi-ethnique, nous avons testé l’association entre rs35705950 et la PR-PID en génotypant 620 patients atteints de PR-PID, 614 patients atteints PR sans PID (PR-non PID) et 5448 individus témoins. Résultats : une association entre l’allèle mineur de rs35705950 et la PR-PID comparé aux individus témoins était observée dans l’étape découverte (OR=3,8 IC95 [2,8-5,2] ; P=9,7x10-17), dans l’étape de réplication multi-ethnique (OR=5,5 IC95 [4,2-7,2] ; P=4,7x10-37) et en combinant les deux populations (OR =4,7 IC95 [3,9-5,8] ; P=1,3x10-49). De plus, rs35705950 était associé à la présence d’une PID parmi les patients atteints de PR (OR =3,1 IC95 [1,8-5,4] ; P=2,5x10-5). Aucune association n’était observée en comparant la PR-non PID et la population témoin. Cette association semblait limitée à l’aspect de pneumopathie idiopathique commune (PIC) (OR =6,1 IC95 [2,9-13,1] ; P=2,5x10-6). L’analyse histologique de biopsies pulmonaires de patients PR-PID retrouvait des anomalies rencontrées dans la FPI. Enfin une étude exploratoire détectait une association entre PR-PID et deux autres variants associés à la FPI (TOLLIP rs5743890 et IVD rs2034650). Conclusion : l’association observée dans notre étude entre MUC5B rs35705950 et la PR-PID confirme l’existence de caractéristiques communes entre PR-PID et FPI

[Study of the determinism of diffuse interstitial lung disease associated with rheumatoid arthritis] : [genetic and environmental susceptibility factors]

La pneumopathie interstitielle diffuse (PID) est une manifestation extra-articulaire sévère de la polyarthrite rhumatoïde (PR) associée à une surmortalité importante. Près de 10% des patients atteints de PR vont développer une forme clinique avec présence de symptômes respiratoires mais la réalisation d’un scanner thoracique de haute définition peut mettre en évidence des anomalies interstitielles chez 30 à 58% des patients. Plusieurs facteurs de risque ont été associés à la PR-PID tels que le sexe masculin, l’âge, le tabagisme ou l’activité de la PR. L’impact des traitements spécifiques de la PR comme le méthotrexate (MTX) ou les anti-TNF sur la survenue d’une PID reste actuellement débattu.La PR-PID partage avec la fibrose pulmonaire idiopathique (FPI) plusieurs caractéristiques communes telles que l’aspect de pneumopathie interstitielle commune (PIC), certains facteurs de risque (le sexe masculin, l’âge, le tabagisme…) ainsi qu’une forte morbi-mortalité. Ces points communs laissent suspecter des mécanismes physiopathogéniques ainsi que des facteurs de risques génétiques communs entre PR-PID et FPI.L’objectif de cette thèse était 1) d’identifier des facteurs de risque génétiques associés à la PR-PID par une approche gène-candidat, 2) d’étudier l’impact d’une exposition par MTX sur la survenue d’une PID au cours de la PR.Par l’analyse de données du séquençage d’exome de 101 patients atteints de PR-PID et de 1010 témoins, nous avons mis en évidence dans la population PR-PID un excès de mutations au sein de gènes précédemment liés à des formes familiales de fibrose pulmonaires : TERT, RTEL1, PARN et SFTPC (OR = 3,17 ; IC95% : 1,53 – 6,12 ; P = 9,45x10-4). Dans une deuxième étude génétique d’association cas-témoins internationale incluant 620 patients PR-PID, 614 patients PR sans PID et 5448 témoins, nous avons identifié une forte association entre le facteur de risque génétique principal de la FPI, MUC5B rs35705950, et la PR-PID (ORaj = 3,1 ; IC95% : 1,8 – 5,4 ; P = 7,4x10-5). Cette association était restreinte au sous-phénotype de PIC.Dans une troisième étude rétrospective d’association cas-témoins internationale incluant 410 patients PR-PID et 673 patients PR sans PID, nous avons identifié une association inverse entre exposition au MTX et survenue d’une PID au cours de la PR (OR = 0,43 ; IC95% : 0,26 – 0,69 ; P = 0,0006). Cette association était observée quel que soit le type de PID (PIC ou autre). Enfin, au sein des patients PR-PID, l’exposition au MTX était associé à un délai de détection de la PID (différence de 3,6 ans après ajustement, P < 0,001).Nos deux premiers travaux ont confirmé l’existence d’une architecture génétique commune à la FPI et la PR-PID, notamment chez les patients présentant une PIC. Ces résultats soutiennent l’évaluation dans la PR-PID des traitements spécifiques à la FPI. Dans notre troisième étude, le MTX n’était pas un facteur de risque de survenue d’une PID au cours de la PR.En conclusion, La PR-PID est une maladie complexe multifactorielle constituée de multiples facteurs de risques génétiques et environnementaux. Une meilleure compréhension des mécanismes impliqués dans le développement d’une PR-PID permettra une meilleure identification des patients à risque ainsi que l’établissement de stratégies thérapeutiques adaptées.Interstitial lung disease (ILD) is a severe extra articular manifestation of rheumatoid arthritis (RA) associated with an increased mortality rate. A symptomatic clinical ILD is observed in about 10% of patients with RA but interstitial lung abnormalities can be observed in 30 to 58% of patients with RA using a systematic assessment by high resolution CT scan. Several RA-ILD risk factors have been identified (male sex, age, smoking history, RA disease activity…) but the impact of RA specific treatments such as methotrexate (MTX) or TNF inhibitors is still under discussion.RA-ILD and idiopathic pulmonary fibrosis (IPF) share several similarities: the usual interstitial pneumonia (UIP) pattern, some risk factors (male sex, age, smoking history) and a high morbimortality. These common characteristics suggest shared pathophysiological mechanisms and shared genetic risk factors.The objectives of this thesis were 1) to identify RA-ILD associated genetic risk factors using a candidate gene approach, 2) to study the impact of MTX exposure on ILD occurrence in patients with RA.Using exome sequencing data from 101 patients with RA-ILD and 1010 controls, we detected in the RA-ILD population an excess of mutations in genes previously linked to familial pulmonary fibrosis: TERT, RTEL1, PARN and SFTPC (OR = 3.17 ; 95%CI: 1.53 – 6.12; P = 9.45x10-4). In a second genetic case-control association study including 620 patients with RA-ILD, 614 patients with RA without ILD and 5448 controls, we identified a strong association between RA-ILD and IPF major genetic risk factor, MUC5B rs35705950 (ORadj = 3.1 ; 95%IC: 1.8 – 5.4; P = 7.4x10-5). This association was restricted to the patients with a UIP pattern.In an international retrospective case-control association study including 410 patients with RA-ILD and 673 patients with RA without ILD, we identified an inverse association between MTX exposition and ILD occurrence in RA (OR = 0.43; 95%CI: 0.26 – 0.69; P = 0.0006). This association was detected whatever the ILD pattern (UIP or non-UIP). In patients with RA-ILD, MTX exposure was associated with a delay in ILD detection (3,6 years after adjustment, P < 0.001).Our two first studies confirmed a shared genetic background between IPF and RA-ILD, particularly in patients with a UIP pattern. These results support the evaluation of IPF specific treatments in RA-ILD. In our third study, MTX was not a risk factor for ILD occurrence in patients with RA.In conclusion, RA-ILD is a multifactorial complex disease composed by multiple genetic and environmental risk factors. A better understanding of the mechanisms involved in RA-ILD development will improve identification of patients at risk to develop RA-ILD and will help to build specific therapeutic strategies

Étude du déterminisme des pneumopathies interstitielles diffuses associées à la polyarthrite rhumatoïde : facteurs de susceptibilité génétiques et environnementaux

Interstitial lung disease (ILD) is a severe extra articular manifestation of rheumatoid arthritis (RA) associated with an increased mortality rate. A symptomatic clinical ILD is observed in about 10% of patients with RA but interstitial lung abnormalities can be observed in 30 to 58% of patients with RA using a systematic assessment by high resolution CT scan. Several RA-ILD risk factors have been identified (male sex, age, smoking history, RA disease activity…) but the impact of RA specific treatments such as methotrexate (MTX) or TNF inhibitors is still under discussion.RA-ILD and idiopathic pulmonary fibrosis (IPF) share several similarities: the usual interstitial pneumonia (UIP) pattern, some risk factors (male sex, age, smoking history) and a high morbimortality. These common characteristics suggest shared pathophysiological mechanisms and shared genetic risk factors.The objectives of this thesis were 1) to identify RA-ILD associated genetic risk factors using a candidate gene approach, 2) to study the impact of MTX exposure on ILD occurrence in patients with RA.Using exome sequencing data from 101 patients with RA-ILD and 1010 controls, we detected in the RA-ILD population an excess of mutations in genes previously linked to familial pulmonary fibrosis: TERT, RTEL1, PARN and SFTPC (OR = 3.17 ; 95%CI: 1.53 – 6.12; P = 9.45x10-4). In a second genetic case-control association study including 620 patients with RA-ILD, 614 patients with RA without ILD and 5448 controls, we identified a strong association between RA-ILD and IPF major genetic risk factor, MUC5B rs35705950 (ORadj = 3.1 ; 95%IC: 1.8 – 5.4; P = 7.4x10-5). This association was restricted to the patients with a UIP pattern.In an international retrospective case-control association study including 410 patients with RA-ILD and 673 patients with RA without ILD, we identified an inverse association between MTX exposition and ILD occurrence in RA (OR = 0.43; 95%CI: 0.26 – 0.69; P = 0.0006). This association was detected whatever the ILD pattern (UIP or non-UIP). In patients with RA-ILD, MTX exposure was associated with a delay in ILD detection (3,6 years after adjustment, P < 0.001).Our two first studies confirmed a shared genetic background between IPF and RA-ILD, particularly in patients with a UIP pattern. These results support the evaluation of IPF specific treatments in RA-ILD. In our third study, MTX was not a risk factor for ILD occurrence in patients with RA.In conclusion, RA-ILD is a multifactorial complex disease composed by multiple genetic and environmental risk factors. A better understanding of the mechanisms involved in RA-ILD development will improve identification of patients at risk to develop RA-ILD and will help to build specific therapeutic strategies.La pneumopathie interstitielle diffuse (PID) est une manifestation extra-articulaire sévère de la polyarthrite rhumatoïde (PR) associée à une surmortalité importante. Près de 10% des patients atteints de PR vont développer une forme clinique avec présence de symptômes respiratoires mais la réalisation d’un scanner thoracique de haute définition peut mettre en évidence des anomalies interstitielles chez 30 à 58% des patients. Plusieurs facteurs de risque ont été associés à la PR-PID tels que le sexe masculin, l’âge, le tabagisme ou l’activité de la PR. L’impact des traitements spécifiques de la PR comme le méthotrexate (MTX) ou les anti-TNF sur la survenue d’une PID reste actuellement débattu.La PR-PID partage avec la fibrose pulmonaire idiopathique (FPI) plusieurs caractéristiques communes telles que l’aspect de pneumopathie interstitielle commune (PIC), certains facteurs de risque (le sexe masculin, l’âge, le tabagisme…) ainsi qu’une forte morbi-mortalité. Ces points communs laissent suspecter des mécanismes physiopathogéniques ainsi que des facteurs de risques génétiques communs entre PR-PID et FPI.L’objectif de cette thèse était 1) d’identifier des facteurs de risque génétiques associés à la PR-PID par une approche gène-candidat, 2) d’étudier l’impact d’une exposition par MTX sur la survenue d’une PID au cours de la PR.Par l’analyse de données du séquençage d’exome de 101 patients atteints de PR-PID et de 1010 témoins, nous avons mis en évidence dans la population PR-PID un excès de mutations au sein de gènes précédemment liés à des formes familiales de fibrose pulmonaires : TERT, RTEL1, PARN et SFTPC (OR = 3,17 ; IC95% : 1,53 – 6,12 ; P = 9,45x10-4). Dans une deuxième étude génétique d’association cas-témoins internationale incluant 620 patients PR-PID, 614 patients PR sans PID et 5448 témoins, nous avons identifié une forte association entre le facteur de risque génétique principal de la FPI, MUC5B rs35705950, et la PR-PID (ORaj = 3,1 ; IC95% : 1,8 – 5,4 ; P = 7,4x10-5). Cette association était restreinte au sous-phénotype de PIC.Dans une troisième étude rétrospective d’association cas-témoins internationale incluant 410 patients PR-PID et 673 patients PR sans PID, nous avons identifié une association inverse entre exposition au MTX et survenue d’une PID au cours de la PR (OR = 0,43 ; IC95% : 0,26 – 0,69 ; P = 0,0006). Cette association était observée quel que soit le type de PID (PIC ou autre). Enfin, au sein des patients PR-PID, l’exposition au MTX était associé à un délai de détection de la PID (différence de 3,6 ans après ajustement, P < 0,001).Nos deux premiers travaux ont confirmé l’existence d’une architecture génétique commune à la FPI et la PR-PID, notamment chez les patients présentant une PIC. Ces résultats soutiennent l’évaluation dans la PR-PID des traitements spécifiques à la FPI. Dans notre troisième étude, le MTX n’était pas un facteur de risque de survenue d’une PID au cours de la PR.En conclusion, La PR-PID est une maladie complexe multifactorielle constituée de multiples facteurs de risques génétiques et environnementaux. Une meilleure compréhension des mécanismes impliqués dans le développement d’une PR-PID permettra une meilleure identification des patients à risque ainsi que l’établissement de stratégies thérapeutiques adaptées

Cardiometabolic risk factors in primary centred and rotator cuff-related shoulder osteoarthritis: a comparative study

International audienceBackground Risk: factors for shoulder osteoarthritis (SOA) have been poorly studied. SOA has two anatomical subtypes: primary centred SOA (centred SOA) and rotator cuff-related OA (non-centred SOA). We examined whether cardiometabolic risk factors are preferentially associated with centred than mechanical-induced non-centred SOA.Methods: This 2004–2012 retrospective multicentric study included patients with SOA. Data on clinical characteristics, especially cardiometabolic risk factors, were collected. We compared patients with radiographic-centred and non-centred SOA and tested the association between cardiometabolic risk factors and subtypes of SOA.Results: We included 147 patients (101 women (68.7%); mean age 75.8±10 years); 99 had centred SOA. As compared with patients with non-centred SOA, those with centred SOA were older (77.5±9 vs 72.4±11 years; p=0.004) with no difference in cardiometabolic disturbances or their accumulation. Multivariable analyses indicated that older age was independently associated with centred SOA (OR 1.06;95% CI 1.02 to 1.1; p=0.004), and cardiovascular diseases were less associated with this subtype (OR 0.27; 95% CI 0.089 to 0.824; p=0.02) than with the non-centred one.Conclusion: Cardiometabolic risk factors were not more prevalent with primary centred than rotator cuff-related SOA. They may participate in the pathophysiology of both SOA subtypes through cartilage and tendon disruption

Variants of genes implicated in type 1 interferon pathway and B-cell activation modulate the EULAR response to rituximab at 24 weeks in rheumatoid arthritis

BACKGROUND: The type 1 interferon (IFN) pathway has been identified to potentially affect the response to rituximab (RTX) for rheumatoid arthritis (RA), which suggests the contribution of type 1 IFN pathway genes such as IFN regulatory factor 5 and 7 (IRF5 and IRF7), tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 4 (STAT4) and osteopontin (SPP1). Our objective was to study functional variants of these IFN pathway genes as predictors of the European League Against Rheumatism (EULAR) response to RTX for RA at week 24 (W24). METHODS: Logistic regression analysis with a stepwise multivariate model adjusted for sex, age and DAS28-CRP (Disease Activity Score in 28 joints with C reactive protein) in 115 patients from the SMART randomised studywas used to analyse the association between the candidate variants and W24 EULAR response. Because the variant TNFSF13B rs9514828 was previously found associated with RTX response in the same population, it was included in the analysis. RESULTS: The combination of IRF5 rs2004640, SPP1 rs9138 and TNFSF13B rs9514828 was strongly associated with good/moderate EULAR response to RTX at W24: p=9.34x10(-6), OR 11.37 (95% CI 4.03 to 35.28), positive predictive value 91% and negative predictive value 54%. CONCLUSION: Our results support the contribution of the IRF5, SPP1 and TNFSF13B genotypic combination in the response to RTX for RA at W24

Increased mortality in patients with RA-associated interstitial lung disease: data from a French administrative healthcare database

Objectives Interstitial lung disease (ILD) is a severe extra-articular manifestation of rheumatoid arthritis (RA). The objectives of this study were to estimate mortality rate in patients with RA-ILD and identify factors affecting mortality.Methods Data from a French national claims database (Système National des Données de Santé) from 2013 to 2018 were analysed. Adults with an RA diagnosis (International Classification of Diseases (ICD)-10 codes M05, M06.0, M06.8 and M06.9) were included. ILD diagnosis was defined with ICD-10 code J84. Mortality rates were compared between patients with RA with and without ILD, using Cox proportional hazards regression, after matching 1:1 for age, sex, age at RA-ILD onset and RA duration.Results Among 173 132 patients with RA, 4330 (3%) also had ILD (RA-ILD). After matching, RA-ILD was associated with an increased mortality rate (HR 3.4, 95% CI 3.1 to 3.9). The HR for mortality was greater for: patients aged &lt;75 years (HR 4.8, 95% CI 3.9 to 5.9) versus ≥75 years (HR 3.0, 95% CI 2.6 to 3.5); patients with ILD onset occurring before RA onset (HR 8.4, 95% CI 5.5 to 13.0) versus ILD onset occurring after RA onset (HR 2.9, 95% CI 2.6 to 3.3); and men (HR 5.2, 95% CI 4.4 to 6.2) versus women (HR 3.6, 95% CI 3.0 to 4.2).Conclusion In this nationwide cohort study, RA-ILD was associated with increased mortality rate (vs in patients with RA without ILD), notably for those aged &lt;75 years, those whose ILD preceded RA onset and men

Variants of genes implicated in type 1 interferon pathway and B-cell activation modulate the EULAR response to rituximab at 24 weeks in rheumatoid arthritis

BACKGROUND: The type 1 interferon (IFN) pathway has been identified to potentially affect the response to rituximab (RTX) for rheumatoid arthritis (RA), which suggests the contribution of type 1 IFN pathway genes such as IFN regulatory factor 5 and 7 (IRF5 and IRF7), tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 4 (STAT4) and osteopontin (SPP1). Our objective was to study functional variants of these IFN pathway genes as predictors of the European League Against Rheumatism (EULAR) response to RTX for RA at week 24 (W24). METHODS: Logistic regression analysis with a stepwise multivariate model adjusted for sex, age and DAS28-CRP (Disease Activity Score in 28 joints with C reactive protein) in 115 patients from the SMART randomised studywas used to analyse the association between the candidate variants and W24 EULAR response. Because the variant TNFSF13B rs9514828 was previously found associated with RTX response in the same population, it was included in the analysis. RESULTS: The combination of IRF5 rs2004640, SPP1 rs9138 and TNFSF13B rs9514828 was strongly associated with good/moderate EULAR response to RTX at W24: p=9.34x10(-6), OR 11.37 (95% CI 4.03 to 35.28), positive predictive value 91% and negative predictive value 54%. CONCLUSION: Our results support the contribution of the IRF5, SPP1 and TNFSF13B genotypic combination in the response to RTX for RA at W24

Variants of genes implicated in type 1 interferon pathway and B-cell activation modulate the EULAR response to rituximab at 24 weeks in rheumatoid arthritis

BACKGROUND: The type 1 interferon (IFN) pathway has been identified to potentially affect the response to rituximab (RTX) for rheumatoid arthritis (RA), which suggests the contribution of type 1 IFN pathway genes such as IFN regulatory factor 5 and 7 (IRF5 and IRF7), tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 4 (STAT4) and osteopontin (SPP1). Our objective was to study functional variants of these IFN pathway genes as predictors of the European League Against Rheumatism (EULAR) response to RTX for RA at week 24 (W24). METHODS: Logistic regression analysis with a stepwise multivariate model adjusted for sex, age and DAS28-CRP (Disease Activity Score in 28 joints with C reactive protein) in 115 patients from the SMART randomised studywas used to analyse the association between the candidate variants and W24 EULAR response. Because the variant TNFSF13B rs9514828 was previously found associated with RTX response in the same population, it was included in the analysis. RESULTS: The combination of IRF5 rs2004640, SPP1 rs9138 and TNFSF13B rs9514828 was strongly associated with good/moderate EULAR response to RTX at W24: p=9.34x10(-6), OR 11.37 (95% CI 4.03 to 35.28), positive predictive value 91% and negative predictive value 54%. CONCLUSION: Our results support the contribution of the IRF5, SPP1 and TNFSF13B genotypic combination in the response to RTX for RA at W24

SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis.

International audienceWe recently reported an association of the SPP1 rs9138 and rs11439060 functional variants with the risk of rheumatoid arthritis (RA), the association being greater in anti-citrullinated protein autoantibody (ACPA)-negative patients. We hypothesised that SPP1 may contribute to the severity of joint destruction in RA, specifically in the ACPA-negative population.Patients with RA in the ESPOIR cohort underwent genotyping for SPP1 rs9138 and rs11439060. Radiographs of the hands and feet were obtained at the first visit and at 1- and 2-year follow-up. Association analyses were performed by ACPA status. A replication study of the relevant subset of the Leiden Early Arthritis Clinic (EAC) cohort was performed.In the ESPOIR cohort (652 patients), rs9138 was significantly associated with radiological progression of joint destruction at 2 years, the association being restricted to 358 ACPA-negative patients (p=0.034). In the replication study with the Leiden EAC cohort (273 ACPA-negative patients), rs4754, which is in complete linkage disequilibrium with rs9138, was significantly associated with joint damage progression in ACPA-negative patients at 2- and 7-year follow-up (p=0.019 and p=0.005, respectively). Combined analysis of the two cohorts revealed a 0.95-fold rate of joint destruction per year per minor allele (p=0.022).The SPP1 rs9138 variant contributes to joint damage progression in ACPA-negative RA