Baptiste Coustet

Independent Replication and Metaanalysis of Association Studies Establish TNFSF4 as a Susceptibility Gene Preferentially Associated with the Subset of Anticentromere-positive Patients with Systemic Sclerosis

Objective. Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk. Methods. Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and metaanalysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry. Results. Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12–1.66)], with significant intra-cohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15–1.54) and TT genotype p = 0.00046; OR 2.02 (1.36–2.98)]. Conclusion. We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype.

Positron emission tomography and computed tomography angiography for the diagnosis of giant cell arteritis: A real-life prospective study.

AbstractThe use of 18F-fluoro-deoxyglucose positron emission tomography scan (FDG-PET) and computed tomography angiography (CTA) to improve accuracy of diagnosis of giant cell arteritis (GCA) is a very important clinical need. We aimed to compare the diagnostic performance of FDG-PET and CTA in patients with GCA.FDG-PET and CTA were acquired in all consecutive patients suspected for GCA. Results of FDG-PET and CTA were compared with the final diagnosis based on clinical judgment, temporal artery biopsy (TAB) findings, and ACR criteria. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for each method.Twenty-four patients suspected for GCA were included. Fifteen (62.5%) were ultimately diagnosed as having GCA. Among them, all fulfilled ACR criteria and 6 had biopsy-proven GCA. Strong FDG uptake in large vessels was found in 10 patients who all had GCA. Mean maximal standard uptake values (SUVmax) per patient measured at all the arterial territories were of 3.7 (range: 2.8–4.7). FDG uptake was negative in 14 patients including 9 and 5 patients without and with GCA, respectively. Mural thickening suggestive of aortitis or branch vessel arteritis was observed on CTA in 11 patients with and 2 patients without GCA. No mural thickening was observed in 11 patients including 7 patients without and 4 patients with GCA. Overall, sensitivity was 66.7% and 73.3%, specificity was 100% and 84.6%, NPV was 64.3% and 64.6%, and PPV was 100% and 84.6% of FDG-PET and CTA, respectively.Both FDG-PET and CTA have a strong diagnostic yield for the diagnosis of GCA. FDG-PET appeared to have a higher PPV as compared to CTA and may be the preferred noninvasive technique to explore patients with suspected GCA.

Identification of secreted phosphoprotein 1 gene as a new rheumatoid arthritis susceptibility gene

OBJECTIVE To evaluate the contribution of the SPP1 rs11439060 and rs9138 polymorphisms, previously reported as autoimmune risk variants, in the rheumatoid arthritis (RA) genetic background according to anti-citrullinated protein antibodies (ACPAs) status of RA individuals. METHODS We analysed a total of 11,715 RA cases and 26,493 controls from nine independent cohorts; all individuals were genotyped or had imputed genotypes for SPP1 rs11439060 and rs9138. The effect of the SPP1 rs11439060 and rs9138 risk-allele combination on osteopontin (OPN) expression in macrophages and OPN serum levels was investigated. RESULTS We provide evidence for a distinct contribution of SPP1 to RA susceptibility according to ACPA status: the combination of ≥3 SPP1 rs11439060 and rs9138 common alleles was associated mainly with ACPA negativity (p=1.29×10(-5), ORACPA-negative 1.257 (1.135 to 1.394)) and less with ACPA positivity (p=0.0148, ORACPA-positive 1.072 (1.014 to 1.134)). The ORs between these subgroups (ie, ACPA-positive and ACPA-negative) significantly differed (p=7.33×10(-3)). Expression quantitative trait locus analysis revealed an association of the SPP1 risk-allele combination with decreased SPP1 expression in peripheral macrophages from 599 individuals. To corroborate these findings, we found an association of the SPP1 risk-allele combination and low serum level of secreted OPN (p=0.0157), as well as serum level of secreted OPN correlated positively with ACPA production (p=0.005; r=0.483). CONCLUSIONS We demonstrate a significant contribution of the combination of SPP1 rs11439060 and rs9138 frequent alleles to risk of RA, the magnitude of the association being greater in patients negative for ACPAs.

Association Study of ITGAM, ITGAX, and CD58 Autoimmune Risk Loci in Systemic Sclerosis: Results from 2 Large European Caucasian Cohorts

Objective. Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations. Methods. SNP harboring associations with autoimmune diseases, ITGAM rs9937837, ITGAX rs11574637, and CD58 rs12044852, were genotyped in 2 independent cohorts of European Caucasian ancestry: 1031 SSc patients and 1014 controls from France and 1038 SSc patients and 691 controls from the USA, providing a combined study population of 3774 individuals. ITGAM rs1143679 was additionally genotyped in the French cohort. Results. The 4 polymorphisms were in Hardy-Weinberg equilibrium in the 2 control populations, and allelic frequencies were similar to those expected in European Caucasian populations. Allelic and genotypic frequencies for these 3 SNP were found to be statistically similar in SSc patients and controls. Subphenotype analyses for subgroups having diffuse cutaneous subtype disease, specific autoantibodies, or fibrosing alveolitis did not reveal any difference between SSc patients and controls. Conclusion. These results obtained through 2 large cohorts of SSc patients of European Caucasian ancestry do not support the implication of ITGAM, ITGAX, and CD58 genes in the genetic susceptibility of SSc, although they were recently identified as autoimmune disease risk genes.

Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD. We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls. Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53–6.12; p=9.45×10−4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10−2). Our results support the contribution of FPF-linked genes to RA-ILD susceptibility. Contribution of TERT, RTEL1, PARN and SFTPC mutations to rheumatoid interstitial lung disease susceptibility http://ow.ly/SXEm30a98Ic

Epistatic Interaction between BANK1 and BLK in Rheumatoid Arthritis: Results from a Large Trans-Ethnic Meta-Analysis

Background BANK1 and BLK belong to the pleiotropic autoimmune genes; recently, epistasis between BANK1 and BLK was detected in systemic lupus erythematosus. Although BLK has been reproducibly identified as a risk factor in rheumatoid arthritis (RA), reports are conflicting about the contribution of BANK1 to RA susceptibility. To ascertain the real impact of BANK1 on RA genetic susceptibility, we performed a large meta-analysis including our original data and tested for an epistatic interaction between BANK1 and BLK in RA susceptibility. Patients and Methods We investigated data for 1,915 RA patients and 1,915 ethnically matched healthy controls genotyped for BANK1 rs10516487 and rs3733197 and BLK rs13277113. The association of each SNP and RA was tested by logistic regression. Multivariate analysis was then used with an interaction term to test for an epistatic interaction between the SNPs in the 2 genes. Results None of the SNPs tested individually was significantly associated with RA in the genotyped samples. However, we detected an epistatic interaction between BANK1 rs3733197 and BLK rs13277113 (Pinteraction = 0.037). In individuals carrying the BLK rs13277113 GG genotype, presence of the BANK1 rs3733197 G allele increased the risk of RA (odds ratio 1.21 [95% confidence interval 1.04–1.41], P = 0.015. Combining our results with those of all other studies in a large trans-ethnic meta-analysis revealed an association of the BANK1 rs3733197 G allele and RA (1.11 [1.02–1.21], P = 0.012). Conclusion This study confirms BANK1 as an RA susceptibility gene and for the first time provides evidence for epistasis between BANK1 and BLK in RA. Our results illustrate the concept of pleiotropic epistatic interaction, suggesting that BANK1 and BLK might play a role in RA pathogenesis.

Electrocardiographic Changes During Exercise in Acute Hypoxia and Susceptibility to Severe High-Altitude Illnesses

Background— The goals of this study were to compare ECG at moderate exercise in normoxia and hypoxia at the same heart rate, to provide evidence of independent predictors of hypoxia-induced ECG changes, and to evaluate ECG risk factors of severe high-altitude illness. Methods and Results— A total of 456 subjects performed a 20-minute hypoxia exercise test with continuous recording of ECG and physiological measurements before a sojourn above 4000 m. Hypoxia did not induce any conduction disorder, arrhythmias, or change in QRS axis. The amplitude of the P wave in V1 was lower in hypoxia than in normoxia. The amplitudes of the R, S, and T waves and the Sokolow index decreased in hypoxia. Under hypoxia, the amplitude of the ST segment decreased in II and V6 and increased in V1, the ST slope rose in V5 and V6, and the J point was lower in II, V5, and V6. Multivariate regression of hypoxic/normoxic ratios of electrophysiological parameters and clinical characteristics showed a correlation between the decrease in Sokolow index and T-wave amplitude in V5 with desaturation at exercise. Trained status and low body mass index were associated with a smaller decrease in T-wave amplitude in V5 and V6. Comparison of ECG between subjects suffering or not suffering from severe high-altitude illness failed to show any difference. Conclusions— During a hypoxia exercise test, a dose-dependent hypoxia-induced decrease in the amplitude of the P/QRS/T waves was observed. No standard ECG characteristic predicted the risk of developing severe high-altitude illness. Further studies are required to clarify the cause of these electric changes and their potential predictive role in cardiac events.

Hip Gout Arthritis Revealed by Sonography.

Gout usually involves inferior limbs and particularly the first metatarsophalangeal joint and knees.1 Hip localization of gout is uncommon. The reference standard for gout diagnosis is the presence of monosodium urate crystals (MSU) in synovial fluid.2 However, in some patients, the diagnosis is more difficult, and sonography could help the physician.3 We report a case of hip gout arthritis revealed by sonography. A 54-year-old man was admitted for acute polyarthritis with fever. His medical history included chronic alcohol consumption and arthritis of the knees, feet, and elbows, which suggested crystal-related disease. On clinical examination, swelling of the left elbow, wrists, knees, and ankles was noted. Blood tests revealed an increased C-reactive protein level (420 mg/L) and an increased serum uric acid level (479 μM). Knee synovial fluid analyses by optic microscopy showed MSU crystals. Colchicine (1.5 mg/d) was started, with no improvement, and the patient began to have pain in the left hip. Radiography of the hips revealed only osteoarthritis without fracture. Sonography (MyLab 70, 5–10-MHz linear probe; Esaote SpA, Genoa, Italy) of the hip revealed a double-contour sign, which strongly suggested gout (Figure 1), and synovitis of the left hip. Aspiration of the hip joint confirmed gouty arthritis (20,000 cells/mm3 and MSU crystals). Anakinra (100 mg/d for 5 days) was added to the colchicine, with marked improvement of symptoms and a decreased C-reactive protein level (32 mg/L). Gout is a common form of arthritis caused by deposition of MSU crystals within joints secondary to chronic hyperuricemia. Gout commonly affects joints of the lower limbs, such as the first metatarsophalangeal joints, ankles, and knees. Hip gout is rare. Only a few cases of hip involvement, with a documented presence of urate crystal, have been reported.4–7 In these patients, hip involvement was Clinical Letters

Arthritis secondary to meningococcal disease: A case series of 7 patients

Abstract Arthritis secondary to invasive meningococcemia is rare and has been described as a direct result of bacteremia or as immunoallergic-type arthritis, related to the immune complex. Only a few case series have been reported. This multicenter study aimed to describe the clinical characteristics and therapeutic outcomes of arthritis secondary to meningococcal infection. We performed a 5-year retrospective study. We included all patients with inflammatory joint symptoms and proven meningococcal disease defined by the identification of Neisseria meningitidis in blood, cerebrospinal fluid, or synovial fluid. Septic arthritis was defined by the identification of N meningitidis in joint fluid. Immune-mediated arthritis was considered to be arthritis occurring after at least 1 day of invasive meningococcal disease without positive joint fluid culture. A total of 7 patients (5 males) with joint symptoms and meningococcal disease were identified. The clinical presentation was mainly oligoarticular and the knee was the most frequent joint site. Five patients had septic arthritis and 4 had immune-mediated arthritis; 2 had septic arthritis followed by immune-mediated arthritis. Immune-mediated arthritis occurred 3 to 7 days after meningococcal meningitis, and treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) led to improvement without complications. Physicians must be vigilant to the different clinical presentations in patients with arthritis associated with invasive meningococcal disease. If immune-mediated arthritis is suspected, NSAIDs are usually efficient.

Enthesopathy in rheumatoid arthritis and spondyloarthritis: An ultrasound study

OBJECTIVE We aimed to compare the prevalence of enthesopathy seen on ultrasonography (US) in spondyloarthritis (SpA) and rheumatoid arthritis (RA) and compared it to healthy controls. METHODS All included patients with RA (2010 ACR/EULAR criteria) and SpA (ASAS criteria) and healthy controls underwent clinical and US evaluation of enthesis at seven sites (quadriceps, proximal and distal patellar, Achilles and triceps tendons, plantar aponeurosis and lateral epicondyle enthesis). The Glasgow Ultrasound Enthesitis Scoring System (GUESS) and the Madrid Sonographic Enthesitis Index (MASEI) scores were determined by two sonographers blinded to clinical data. RESULTS We included 30 patients with RA (mean age: 55.7±14.8 years, mean disease duration 10.5±7.9years); 41 with SpA (mean age: 45.3±15.4 years, mean disease duration 9.2±8.7years) and 26 healthy controls (HC) (mean age: 50.4±17.3years). Patients with SpA and RA had similar prevalence of painful enthesis of examined sites (17% vs. 14%, non-significant [ns]), but more than among in healthy controls (3%, P<0.05 for RA and SpA comparison). Comparison between SpA and RA patients revealed that at least one US enthesis abnormality was found with similar frequency (46% and 48% sites [ns]) but both rheumatic diseases had higher frequency of US enthesis abnormality than HC (31%, P<0.05 for RA and SpA comparison). The mean MASEI score was 8.5±7.3 for RA patients, 7.8±6.5 for SpA patients (ns) and 3.4±2.8 for healthy controls (P<0.05 for RA and SpA comparison). Overall, 6 RA (20%) and 4 SpA (10%) patients had a MASEI score≥18 (ns). None of the healthy controls had a MASEI score≥18 (P<0.05 for RA and SpA comparison). The mean GUESS score was 5.8±3.1 and 6.3±3.9 for RA and SpA patients (ns), and 4.0±3.1 for healthy controls (P<0.01 vs. SpA and <0.05 vs. RA). CONCLUSIONS RA and SpA patients did not differ in entheseal abnormalities seen on US. Such US features may have low specificity in inflammatory conditions affecting joints and enthesis such as SpA and RA.