Eugénie Koumakis

Increased risk of osteoporosis and fracture in women with systemic sclerosis: A comparative study with rheumatoid arthritis

To investigate whether women with systemic sclerosis (SSc) have an increased risk of osteoporosis (OP) and related fractures compared to a high‐risk population with rheumatoid arthritis (RA) and also healthy controls, and to determine putative specific OP and fracture risk factors.

Identification of NF-κB and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis

IntroductionSystemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. Furthermore, both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. The present study was undertaken to investigate whether single-nucleotide polymorphisms (SNPs) identified by a large genome-wide association study (GWAS) in PBC might contribute to SSc susceptibility.MethodsSixteen PBC susceptibility SNPs were genotyped in a total of 1,616 patients with SSc and 3,621 healthy controls from two European populations (France and Italy).ResultsWe observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, Padj = 7.22 × 10−5), nuclear factor-kappa-B (NF-κB) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, Padj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, Padj = 2.49 × 10−4) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (Padj = 4.45 × 10−4 and Padj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (Padj = 0.003). Genotype-mRNA expression correlation analysis revealed that the IRF8 protective allele was associated with increased interferon-gamma (IFN-γ) expression (P = 0.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (P = 0.02). In addition, we found an epistatic interaction between NF-κB and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P = 4 × 10−4) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-κB susceptibility allele.ConclusionsAn analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-κB and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-κB gene variants that might play a role in SSc susceptibility.

Performance of the Assessment in Spondyloarthritis International Society Classification for Axial and Peripheral Spondyloarthritis in an Established Clinical Cohort: Comparison with Criteria Sets of Amor and the European Spondylarthropathy Study Group

Objective. To evaluate the performance of the Assessment in Spondyloarthritis International Society (ASAS) criteria (axial or peripheral) against the Amor and European Spondylarthropathy Study Group criteria in established spondyloarthritis (SpA). Methods. Rheumatologist-diagnosed patients with SpA were retrospectively classified according to the different criteria sets. Clinical characteristics of patients fulfilling all 3 criteria were compared with those who did not, by nonparametric statistics. Results. ASAS classified 90% of the 231 patients, with 169 (73%) fulfilling all 3 criteria sets. Multivariate analysis showed the 62 patients not fulfilling all criteria sets were older at symptom onset (p < 0.001) and less likely to have inflammatory back pain (p < 0.001), peripheral arthritis (p < 0.001), or elevated C-reactive protein levels (p = 0.034). Conclusion. ASAS criteria can be used in established disease.

Trabecular Bone Score in Female Patients with Systemic Sclerosis: Comparison with Rheumatoid Arthritis and Influence of Glucocorticoid Exposure

Objective. Systemic sclerosis (SSc) is associated with an increased risk of osteoporosis and fractures. To date, the etiology of bone loss in SSc is unclear. Trabecular bone score (TBS) provides an indirect measurement of bone microarchitecture, independent of areal bone mineral density (aBMD). The aims were to assess bone involvement in SSc using TBS in comparison with a “high-risk” population with rheumatoid arthritis (RA) and controls, and to investigate the determinants of a low TBS. Methods. This was a cross-sectional study of 65 women with SSc, 138 age-matched female patients with RA, and 227 age-matched female controls. Spine and hip aBMD were assessed using dual-energy X-ray absorptiometry. TBS was calculated from the anteroposterior image of the spine aBMD. Results. TBS was significantly lower in SSc compared to controls (p < 0.0001) and did not differ from RA (p = 0.128), despite lower cumulative and daily glucocorticoid (GC) dose (p < 0.0001). Further, patients with SSc receiving GC ≥ 5 mg/day had a significantly lower TBS than those receiving GC < 5 mg/day (p = 0.001). Multivariate analysis revealed that a low TBS was independently associated with daily GC dose (OR 5.6, 95% CI 1.7–19.2) and a T score ≤ −2.5 SD (OR 5.0, 95% CI 1.5–7.0) in SSc. No association between GC and TBS was found in RA. Conclusion. Our results support the development of a combined approach using both TBS and aBMD for the assessment of bone microarchitecture in inflammatory rheumatic diseases. Our study showed that SSc-related bone involvement is characterized by an impairment in bone quality in addition to reduced bone quantity, and highlights that TBS can identify the negative effect of GC on bone microarchitecture.

Brief Report: A Regulatory Variant in CCR6 Is Associated With Susceptibility to Antitopoisomerase‐Positive Systemic Sclerosis

OBJECTIVE Recognition of the well-known pleiotropism of autoimmune genes supports the concept of a shared pathogenesis across autoimmune diseases such as rheumatoid arthritis (RA) and systemic sclerosis (SSc). Studies have reproducibly demonstrated an association between susceptibility to RA and polymorphisms of the CCR6 gene, a surface marker for Th17 cells, and the causal variant was recently identified. The present study was thus undertaken to investigate whether CCR6 polymorphisms could also be associated with susceptibility to SSc. METHODS Twelve tag single-nucleotide polymorphisms (SNPs) of CCR6, including the known RA-associated SNP rs3093023, were genotyped in a total of 2,411 SSc patients and 7,084 healthy individuals from 3 European populations (France, Italy, and Germany). Meta-analyses of the data were performed to assess whether an association exists between CCR6 polymorphisms and susceptibility to SSc or its main subtypes. Direct sequencing of DNA was performed to ascertain whether the functional dinucleotide polymorphism of CCR6 previously identified in RA (CCR6DNP) was also present in SSc. RESULTS Combined analyses revealed an association between the rs10946216 SNP and SSc susceptibility (odds ratio [OR] 1.13, 95% confidence interval [95% CI] 1.05-1.21, adjusted P [P(adj)] = 0.026). The rs3093023 A allele and rs10946216 T allele were in high linkage disequilibrium, and both were found to confer disease susceptibility in the antitopoisomerase-positive subset of SSc patients (OR 1.27, 95% CI 1.13-1.42, P(adj) = 1.5 × 10(-3) and OR 1.32, 95% CI 1.17-1.48, P(adj) = 9.0 × 10(-5), respectively, relative to healthy controls). Direct sequencing of the DNA of 78 individuals supported the hypothesis that the regulatory dinucleotide CCR6DNP could be the causal variant in SSc. CONCLUSION The results of this study establish CCR6 as a new susceptibility factor for antitopoisomerase-positive SSc, as demonstrated in 3 European Caucasian populations, confirming the notion that SSc and RA could conceivably share autoimmune risk alleles. The results also suggest a potential role of the interleukin-17 pathway in SSc.

Familial Autoimmunity in Systemic Sclerosis - Results of a French-based Case-control Family Study

Objective. To assess the prevalence of autoimmune diseases in first-degree relatives of patients with systemic sclerosis (SSc), and to compare those results with control families in order to identify patterns of autoimmune diseases in relatives. Methods. A retrospective case-control postal questionnaire survey was performed in France to recruit patients with SSc belonging to an association of patients with SSc and unrelated age-matched and sex-matched controls. Each participant was asked to self-report on the existence of autoimmune diseases in their first-degree relatives. The prevalence of autoimmune diseases in the families of patients with SSc was compared with the corresponding prevalence in the families of controls. Results. A total of 121 families out of 373 (32.4%) with a member having SSc reported at least 1 autoimmune disease in 1 or more first-degree relatives. The most frequent autoimmune diseases in SSc families when adjusted for family size were autoimmune thyroid disease (AITD; 4.9%), rheumatoid arthritis (4.1%), psoriasis (3.9%), and type 1 diabetes mellitus (2.9%). Compared with control families, AITD and connective tissue diseases (SSc, systemic lupus erythematosus, or Sjögren’s syndrome) were more likely to occur in families with SSc (p = 0.01 and p = 0.01, respectively), with OR of 3.20 (95% CI 1.25–8.18) and 5.20 (95% CI 1.22–21.8). In contrast, inflammatory bowel disease was less likely to occur within families with SSc (p = 0.02, OR 0.29, 95% CI 0.11–0.80). In addition, the coexistence of more than 1 autoimmune disease in the index SSc case was associated with familial aggregation of autoimmune diseases. Conclusion. Our results show that autoimmune diseases cluster within families of patients with SSc. This supports the notion that these diseases might arise on a shared genetic basis underlying several autoimmune phenotypes.

A Regulatory Variant in CCR6 Is Associated With Susceptibility to Antitopoisomerase-Positive Systemic Sclerosis

OBJECTIVE Recognition of the well-known pleiotropism of autoimmune genes supports the concept of a shared pathogenesis across autoimmune diseases such as rheumatoid arthritis (RA) and systemic sclerosis (SSc). Studies have reproducibly demonstrated an association between susceptibility to RA and polymorphisms of the CCR6 gene, a surface marker for Th17 cells, and the causal variant was recently identified. The present study was thus undertaken to investigate whether CCR6 polymorphisms could also be associated with susceptibility to SSc. METHODS Twelve tag single-nucleotide polymorphisms (SNPs) of CCR6, including the known RA-associated SNP rs3093023, were genotyped in a total of 2,411 SSc patients and 7,084 healthy individuals from 3 European populations (France, Italy, and Germany). Meta-analyses of the data were performed to assess whether an association exists between CCR6 polymorphisms and susceptibility to SSc or its main subtypes. Direct sequencing of DNA was performed to ascertain whether the functional dinucleotide polymorphism of CCR6 previously identified in RA (CCR6DNP) was also present in SSc. RESULTS Combined analyses revealed an association between the rs10946216 SNP and SSc susceptibility (odds ratio [OR] 1.13, 95% confidence interval [95% CI] 1.05-1.21, adjusted P [P(adj)] = 0.026). The rs3093023 A allele and rs10946216 T allele were in high linkage disequilibrium, and both were found to confer disease susceptibility in the antitopoisomerase-positive subset of SSc patients (OR 1.27, 95% CI 1.13-1.42, P(adj) = 1.5 × 10(-3) and OR 1.32, 95% CI 1.17-1.48, P(adj) = 9.0 × 10(-5), respectively, relative to healthy controls). Direct sequencing of the DNA of 78 individuals supported the hypothesis that the regulatory dinucleotide CCR6DNP could be the causal variant in SSc. CONCLUSION The results of this study establish CCR6 as a new susceptibility factor for antitopoisomerase-positive SSc, as demonstrated in 3 European Caucasian populations, confirming the notion that SSc and RA could conceivably share autoimmune risk alleles. The results also suggest a potential role of the interleukin-17 pathway in SSc.

Clinical characteristics of anterior chest wall pain in spondyloarthritis: An analysis of 275 patients

OBJECTIVES Anterior chest wall pain is a common but little studied feature of spondyloarthritis. The objectives of our study were to assess the prevalence of anterior chest wall pain and to describe its clinical characteristics in a cohort of spondyloarthritis patients in a tertiary care center. METHODS STUDY DESIGN retrolective single center observational study in 2010 (COSPA). Consecutive patients with definite spondyloarthritis according to Amors criteria were included. DATA COLLECTION each patient underwent direct interview by a physician. Prevalence of anterior chest wall pain, according to spondyloarthritis subtype and its date of appearance, localization and nature were collected. RESULTS In all, 275 consecutive spondyloarthritis patients were assessed. Among them, 102 patients (37.1%) suffered from spondyloarthritis-associated anterior chest wall pain. It was the first symptom of spondyloarthritis in 3.6% of cases. The prevalence after 5 and 10 years following the diagnosis of spondyloarthritis was 26.0% and 35.5%, respectively. Pain was usually in the upper chest and acute, increased by respiratory movements and movements of the arm; pain during the night was less frequent (41.0%). A flare lasted on average 5 weeks; recurrences were frequent (75%). Non-steroidal anti-inflammatory drugs and anti-tumor necrosis factor agents were reported as effective in 49.3% and 80.0% of cases, respectively. CONCLUSION Anterior chest wall pain was a frequent manifestation in spondyloarthritis. It occurred early in the disease course, but the risk persisted after disease onset. Better knowledge of the clinical characteristics of this symptom may help physicians for diagnosis and follow-up.

TGFβ receptor gene variants in systemic sclerosis-related pulmonary arterial hypertension: results from a multicentre EUSTAR study of European Caucasian patients

Introduction Systemic sclerosis (SSc)-related pulmonary arterial hypertension (PAH) has emerged as a major mortality prognostic factor. Mutations of transforming growth factor beta (TGFβ) receptor genes strongly contribute to idiopathic and familial PAH. Objective To explore the genetic bases of SSc–PAH, we combined direct sequencing and genotyping of candidate genes encoding TGFβ receptor family members. Materials and methods TGFβ receptor genes, BMPR2, ALK1, TGFR2 and ENG, were sequenced in 10 SSc–PAH patients, nine SSc and seven controls. In addition, 22 single-nucleotide polymorphisms (SNP) of these four candidate genes were tested for association in a first set of 824 French Caucasian SSc patients (including 54 SSc–PAH) and 939 controls. The replication set consisted of 1516 European SSc (including 219 SSc–PAH) and 3129 controls from the European League Against Rheumatism Scleroderma Trials and Research group network. Results No mutation was identified by direct sequencing. However, two repertoried SNP, ENG rs35400405 and ALK1 rs2277382, were found in SSc–PAH patients only. The genotyping of 22 SNP including the latter showed that only rs2277382 was associated with SSc–PAH (p=0.0066, OR 2.13, 95% CI 1.24 to 3.65). Nevertheless, this was not replicated with the following result in combined analysis: p=0.123, OR 0.79, 95% CI 0.59 to 1.07. Conclusions This study demonstrates the lack of association between these TGFβ receptor gene polymorphisms and SSc–PAH using both sequencing and genotyping methods.

Interleukin 6 Blockade in Spondyloarthritis

To the Editor: We read with interest the case report by Cohen, et al on sustained clinical improvement under tocilizumab [a humanized monoclonal antiinterleukin 6 (IL-6) receptor antibody] in a patient with HLA-B27-positive ankylosing spondylitis (AS)1. The patient had not responded after 3 anti-tumor necrosis factor (TNF-α) agents. There are still few but promising reports of successful treatment of spondyloarthritis (SpA) with tocilizumab. Here we add our experience. A 61-year-old woman had a 19-year history of HLA-B27-positive AS. At onset, radiographic imaging showed multilevel spondylodiscitis with acquired vertebral blocks and grade IV bilateral sacroiliitis. Due to insufficient response to nonsteroidal antiinflammatory drugs, she was prescribed etanercept from 2003 to 2010. In 2010, etanercept was switched to adalimumab because of multiple side effects including recurrent urinary tract infections, rhinosinusitis, furunculosis, and patient-reported shortness of breath after etanercept injections. Despite its efficacy on axial symptoms, adalimumab was withdrawn after 8 months because of the recurrence of infectious episodes including herpes zoster, rhinosinusitis, persistent furunculosis, and a dengue virus after traveling to the West … Address correspondence to Dr. Y. Allanore, Service de Rhumatologie A, Hopital Cochin, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France. E-mail: yannick.allanore{at}cch.aphp.fr