Clinical significance of the anti-Nucleolar Organizer Region 90 antibodies (NOR90) in systemic sclerosis: Analysis of the European Scleroderma Trials and Research (EUSTAR) cohort and a systematic literature review.

BACKGROUND: The anti-Nucleolar Organizer Region 90 antibodies (NOR90) are rare antinuclear antibodies (ANA) reported in systemic sclerosis (SSc). Especially due to low prevalence, the clinical relevance of NOR90 in SSc remains uncertain. OBJECTIVES: To analyze the clinical associations of NOR90 in patients with SSc in a multicentric cohort. METHODS: Post-hoc, cross-sectional study of prospectively collected data from the European Scleroderma Trials and Research (EUSTAR) database, with additional information on NOR90. Further, we performed a systematic literature search, using the terms "systemic sclerosis" and "NOR90" across three databases: Medline via PubMed, Scopus, and Thomson Reuters' Web of Science Core Collection, from inception to November 1st, 2023. RESULTS: Overall, 1318 patients with SSc were included (mean age 58.3 ± 13.7 years, 81.3 % female), of whom 44 (3.3 %) were positive for NOR90. Of these, 32 were also positive for one of the SSc-criteria antibodies: 9/44 (20.5 %) for anti-topoisomerase I, 18/42 (42.9 %) for anti-centromere, and 5/40 (12.5 %) for anti-RNA polymerase III. NOR90-positive patients were more frequently female, had lower modified Rodnan skin score (mRSS), and lower prevalence of upper and lower gastrointestinal (GI) symptoms compared to NOR90-negative patients. In multivariable analysis, NOR90 remained significantly associated with lower mRSS and less frequent GI symptoms. The literature search identified 17 articles, including a total number of 87 NOR90-positive out of 3357 SSc patients, corresponding to an overall prevalence of 2.6 %. CONCLUSION: To our best knowledge, this is the largest SSc cohort tested for NOR90 to date, confirming the NOR90 prevalence in SSc patients is around 3 %.

Case report: A successful second autologous hematopoietic stem cell transplantation in refractory systemic sclerosis, with positive effect on skin involvement, pulmonary function and microcirculation.

Background: Systemic sclerosis (SSc) is a complex autoimmune disease characterized by inflammation, vasculopathy and fibrosis of the skin and internal organs. Treatment with autologous hematopoietic cell transplantation (HCT) for progressive SSc has improved overall and event-free survival rates significantly, but unfortunately disease progression after HCT is seen in a subset of patients. Data on the efficacy and safety of second HCT is scarce. Case: We present a patient with diffuse cutaneous SSc and associated interstitial lung disease (ILD) who successfully underwent a second HCT for progressive disease five years after a first HCT. We describe changes in skin involvement and pulmonary involvement as well as the changes observed in sequential nailfold microcapillaroscopy (NCM), performed from first presentation up to this moment. Conclusion: This case adds to the current limited literature on efficacy and safety of a second HCT in SSc refractory cases. Furthermore it outlines the potential of HCT on amelioration of microvasculopathy in SSc.

Right atrial and ventricular strain detects subclinical changes in right ventricular function in precapillary pulmonary hypertension.

Right ventricular (RV) ejection fraction (EF) by cardiac magnetic resonance (CMR) correlates to outcome in precapillary pulmonary hypertension (pPH) patients, but is insensitive to early changes. Strain might provide incremental information. In this study, we compare right atrial (RA) and RV strain in pPH patients to healthy controls, and evaluate the prognostic value of strain in pPH. In this cross-sectional study, 45 pPH patients and 20 healthy controls underwent CMR, and feature-tracking derived RA and RV strain were evaluated. pPH patients had impaired RA reservoir and conduit strain, and RV longitudinal strain (LS), compared to healthy controls. In pPH patients with preserved RVEF (≥ 50%, n = 18), RA reservoir (35% ± 9 vs. 41% ± 6, p = 0.02) and conduit strain (16% ± 8 vs. 23% ± 5, p = 0.004), and RV-LS (-25% ± 4 vs. -31% ± 4, p < 0.001) remained impaired, compared to healthy controls. The association of strain with the primary endpoint (combination of all-cause death, lung transplantation, and heart failure hospitalization) was evaluated using a multivariable Cox regression model. RV-LS (HR 1.18, 95%-CI 1.04-1.34, p = 0.01) and RA strain (reservoir: HR 0.87, 95%-CI 0.80-0.94, p = 0.001; conduit: HR 0.85, 95%-CI 0.75-0.97, p = 0.02, booster: HR 0.81, 95%-CI 0.71-0.92, p = 0.001) were independent predictors of outcome, beyond clinical and imaging features. In conclusion, pPH patients have impaired RA strain and RV-LS, even when RVEF is preserved. In addition, RA strain and RV-LS were independent predictors of adverse prognosis. These results emphasize the incremental value of RA and RV strain analyses, to detect alterations in RV function, even before RVEF declines.

Physical therapy in patients with systemic sclerosis: physical therapists' perspectives on current delivery and educational needs.

OBJECTIVE: To assess the perspectives of physical therapists treating patients with systemic sclerosis (SSc) on their current practice and educational needs. METHOD: In July 2019, 405 SSc patients attending a multidisciplinary SSc programme received a survey on physical therapy. Patients who indicated having received physical therapy in the past 2 years were asked to invite their treating physical therapist to complete a questionnaire including sociodemographic characteristics, referral process, content of treatment, perceived knowledge and skills, and educational needs (mostly yes/no answers). RESULTS: Forty-eight of 80 possibly eligible physical therapists treating SSc patients returned the questionnaire [median age 44 years (interquartile range 35-58); 52% female; median number of SSc patients currently treated: 1 (range 1-4)]. Eighty-one per cent (n = 39) of physical therapists had received a referral, with 69% (n = 27/39) judging its content as insufficient. The most often provided types of exercises were range of motion (96%), muscle-strengthening (85%), and aerobic (71%) exercises, followed by hand (42%) and mouth (10%) exercises. Concerning manual treatment, 65% performed either massage or passive mobilization. Regarding competences, 65% indicated feeling capable of treating SSc patients. Nevertheless, 85% expressed the need for an information website on physical therapy in SSc, and 77% for postgraduate education on SSc. CONCLUSION: Primary care physical therapists treating patients with SSc used a wide range of treatment modalities. Although most stated that they treated very few patients, the majority felt capable of treating SSc patients. Nevertheless, the large majority expressed a need for additional information and educational activities concerning SSc.

Change of the microvascularization in systemic sclerosis, a matter of air.

Systemic sclerosis (SSc) is a rare complex disease, characterized by microvascular damage, auto-immunity, and fibrosis. Nailfold capillary microscopy (NCM), a safe and noninvasive imaging technique, can be used to visualize specific microvascular alterations in SSc. In this review, we discuss an interesting case of a patient with changes in microvascular pattern on NCM after pulmonary transplantation. We provide an overview of microvascular alterations in systemic sclerosis and the evidence in the literature about the effect of vasoactive and immunomodulation therapy on these vascular changes. We also outline the influence of pulmonal pathology, such as interstitial lung disease and pulmonary arterial hypertension, on the capillaroscopic pattern, and finally, we discuss how NCM could possibly serve as a biomarker of treatment.

Intestinal hypomotility in systemic sclerosis: a histological study into the sequence of events.

OBJECTIVES: The pathogenesis of intestinal involvement in systemic sclerosis (SSc) is thought to be a sequential process (vascular, neuronal, and consecutive muscular impairment), but understanding of the underlying histological changes and how they translate to symptoms, is still lacking. Therefore, we systematically investigated histological characteristics of SSc in the intestines, compared to controls. METHODS: Autopsy material from the small bowel and colon was used for histological semiquantitative evaluation of the vasculature, enteric nervous system, interstitial cells of Cajal (ICC), and muscle layers, using a combination of histochemical and immunohistochemical stainings, according to guidelines of the Gastro 2009 International Working Group. RESULTS: Vascular changes were most frequently encountered, represented by intima fibrosis in both arteries and small vessels, and represented by venous dilatation. Second, generalized fibrosis of the circular muscle layer was significantly more found in SSc patients than in controls. Third, reduction of submucosal nerve fibers and myenteric neurons was shown in the colon of four SSc patients, which may explain severe symptoms of intestinal dysmotility. The density of myenteric ICC network was decreased in the small bowel of SSc patients. CONCLUSIONS: The postulated sequential processes of intestinal involvement in SSc could not be supported by our histological evaluation. The interpatient diversity suggests that parallel processes occur, explaining the variety of histological features and clinical symptoms. Key Points • Histological analysis showed vascular changes, fibrosis in the muscularis propria, and reduction of the ENS and ICC network in the intestines of SSc patients. • Pathophysiological mechanisms leading to intestinal dysmotility in SSc may be parallel rather than sequential. • The interpatient diversity suggests parallel pathophysiological processes, explaining the variety of histological features and clinical symptoms.

TGFß-mediated expression of TGFß-activating integrins in SSc monocytes: disturbed activation of latent TGFß?

INTRODUCTION: The pathophysiology of systemic sclerosis (SSc) is closely linked to overactive TGFß signaling. TGFß is produced and circulates in latent form, making its activation crucial for signaling. This activation can be mediated via integrins. We investigated the balance between active and latent TGFß in serum of SSc patients and investigated if this correlates with integrin expression on monocytes. METHODS: A TGFß/SMAD3- or BMP/SMAD1/5-luciferase reporter construct was expressed in primary human skin fibroblasts. Both acidified and non-acidified sera of ten SSc patients and ten healthy controls were tested on these cells to determine total and active TGFß and BMP levels respectively. A pan-specific TGFß1/2/3 neutralizing antibody was used to confirm TGFß signaling. Monocytes of 20 SSc patients were isolated using CD14+ positive selection, and integrin gene expression was measured using qPCR. Integrin expression was modulated using rhTGFß1 or a small molecule inhibitor of TGFBR1: SB-505124. RESULTS: SSc sera induced 50% less SMAD3-reporter activity than control sera. Serum acidification increased reporter activity, but a difference between healthy control and SSc serum was no longer observed, indicating that total TGFß levels were not different. Addition of a pan-specific TGFß1/2/3 neutralizing antibody fully inhibited SMAD3-reporter activity of both acidified and not-acidified control and SSc sera. Both HC and SSc sera induced similar SMAD1/5-reporter activity, and acidification increased this, but not differently between groups. Interestingly, expression of two integrin alpha subunits ITGA5 and ITGAV was significantly reduced in monocytes obtained from SSc patients. Furthermore, ITGB3, ITGB5, and ITGB8 expression was also reduced in SSc monocytes. Stimulation of monocytes with TGFß1 induced ITGA5 and ITGAV but lowered ITGB8 expression, whereas the use of the TGFß receptor inhibitor SB-505124 had the opposite effect. CONCLUSION: Total TGFß serum levels are not different between SSc patients and controls, but TGFß activity is. This coincides with a reduced expression of TGFß-activating integrins in monocytes of SSc patients. Because TGFß regulates expression of these integrins in monocytes, a negative feedback mechanism possibly underlies these observations.

Intravenous cyclophosphamide pulse therapy in interstitial lung disease associated with systemic sclerosis in a retrospective open-label study: influence of the extent of inflammation on pulmonary function.

Interstitial lung disease (ILD) is the primary cause of death in patients with systemic sclerosis (SSc). It is thought that chronic inflammation is a key component in SSc-ILD. Treatment, such as cyclophosphamide (CYC), targets this inflammation. We hypothesized that treatment with CYC might be more effective in the inflammatory phase. Therefore, we analyzed whether the extent of inflammation, as assessed by the proportion of ground glass compared to fibrosis, SSc disease duration, the extent of ILD, or baseline diffusion capacity of the lungs (DLCO) < 60%, modifies the effect of intravenous CYC pulse therapy (750 mg/m2) on pulmonary function (as measured by FVC, DLCO) in SSc-ILD patients, after 12, 24, and 36 months. Consecutive patients with SSc-ILD receiving CYC pulses between 2003 and 2015 were included. Pulmonary function tests were performed at 0, 6, 12, 24, and 36 months. There were 75 patients included. Forced vital capacity (FVC) (86% of predicted) and DLCO (42% of predicted) were stable after 12, 24 and 36 months of follow-up (p > 0.05). Forty-four patients completed 12 cycles of CYC. For the extent of ILD, proportion of ground glass compared to fibrosis, SSc disease duration, and baseline DLCO, there were no differences (all p > 0.05) in the course of FVC and DLCO. Treatment with CYC followed by maintenance therapy stabilizes pulmonary function in patients with SSc-ILD over a 3-year period. The extent of ILD, proportion of ground glass, SSc disease duration, and baseline DLCO < 60% did not influence the effect of CYC on pulmonary function.

There is a need for new systemic sclerosis subset criteria. A content analytic approach.

OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis.

There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of ≤ 1 was a significant risk factor for SSc (OR=1.55 (1.13-2.14), P=0.007) relative to CN ≥ 2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity.

The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis.

Regulatory T cells (T(regs)) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor α (IL2RA) is an important T(reg) marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P(FDR)=2.07 × 10(-4), odds ratio=1.30 (1.14-1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.

A rare polymorphism in the gene for Toll-like receptor 2 is associated with systemic sclerosis phenotype and increases the production of inflammatory mediators.

OBJECTIVE: To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc). METHODS: We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells. RESULTS: In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P=0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P=0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease (P=0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P=0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor α and interleukin-6) upon TLR-2-mediated stimulation (both P<0.0001). CONCLUSION: Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc.

Clinical prediction of 5-year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres.

OBJECTIVE: Systemic sclerosis (SSc) is associated with a significant reduction in life expectancy. A simple prognostic model to predict 5-year survival in SSc was developed in 1999 in 280 patients, but it has not been validated in other patients. The predictions of a prognostic model are usually less accurate in other patients, especially from other centres or countries. A study was undertaken to validate the prognostic model to predict 5-year survival in SSc in other centres throughout Europe. METHODS: A European multicentre cohort of patients with SSc diagnosed before 2002 was established. Patients with SSc according to the preliminary American College of Rheumatology classification criteria were eligible for the study when they were followed for at least 5 years or shorter if they died. The primary outcome was 5-year survival after diagnosis of SSc. The predefined prognostic model uses the following baseline variables: age, gender, presence of urine protein, erythrocyte sedimentation rate (ESR) and carbon monoxide diffusing capacity (DLCO). RESULTS: Data were available for 1049 patients, 119 (11%) of whom died within 5 years after diagnosis. Of the patients, 85% were female, the mean (SD) age at diagnosis was 50 (14) years and 30% were classified as having diffuse cutaneous SSc. The prognostic model with age (OR 1.03), male gender (OR 1.93), urine protein (OR 2.29), elevated ESR (1.89) and low DLCO (OR 1.94) had an area under the receiver operating characteristic curve of 0.78. Death occurred in 12 (2.2%) of 509 patients with no risk factors, 45 (13%) of 349 patients with one risk factor, 55 (33%) of 168 patients with two risk factors and 7 (30%) of 23 patients with three risk factors. CONCLUSION: A simple prognostic model using three disease factors to predict 5-year survival at diagnosis in SSc showed reasonable performance upon validation in a European multicentre study.

Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis.

OBJECTIVE: Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes. METHODS: 3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc. RESULTS: The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p(FDRcorrected)=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p(FDRcorrected)=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p(FDRcorrected)=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1). CONCLUSION: The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.

Exercise in systemic sclerosis intensifies systemic inflammation and oxidative stress.

OBJECTIVE: Exercise testing can be used (i) to evaluate functional limitations of systemic sclerosis (SSc) and (ii) to study whether the inflammatory and oxidative systems are activated after a physical stimulus. The aim of this study was to determine exercise-induced inflammatory and oxidative responses in SSc compared with healthy subjects. METHODS: Eleven patients with SSc and pulmonary involvement and 10 healthy subjects underwent maximal cardiopulmonary exercise testing (CPET). Physiological responses were followed continuously during cycling. Blood samples were taken at rest, during and after maximal exercise to measure inflammatory and oxidative markers. RESULTS: In nine of the 11 SSc patients, cardiocirculatory limitation and gas exchange impairment limited exercise capacity. Basal inflammatory cells, interleukin (IL)-6, and oxidative stress were increased in SSc compared to healthy subjects and intensified after exercise. Basal and exercise-induced inflammation and oxidative stress were correlated with the modified Rodnan skin score. CONCLUSIONS: Although exercise capacity is impaired in patients with SSc, physical activity intensifies the already increased basal levels of systemic inflammation and oxidative stress. These data support the concept of a role for systemic inflammation and oxidative stress in the ongoing systemic effects of SSc.

BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians.

OBJECTIVE: To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes. METHODS: A large multicentre case-control association study including 2380 patients with SSc and 3270 healthy controls from six independent case-control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5 allelic discrimination assay. RESULTS: A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively). CONCLUSION: The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets.

Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis.

OBJECTIVES: To measure the prevalence of, and factors associated with, left ventricular (LV) dysfunction in systemic sclerosis (SSc). METHODS: The EUSTAR database was first searched. A case-control study of a patient subset was then performed to further identify independent factors associated with LV dysfunction by simple and multiple regression. RESULTS: Of 7073 patients, 383 (5.4%) had an LV ejection fraction (EF) of <55%. By multiple regression analysis, age, sex, diffuse cutaneous disease, disease duration, digital ulcerations, renal and muscle involvement, disease activity score, pulmonary fibrosis and pulmonary arterial hypertension were associated with LV dysfunction. In the second phase, 129 patients with SSc with LVEF <55% were compared with 256 patients with SSc with normal LVEF. Male sex (OR 3.48; 95% CI 1.74 to 6.98), age (OR 1.03; 95% CI 1.01 to 1.06), digital ulcerations (OR 1.91; 95% CI 1.05 to 3.50), myositis (OR 2.88; 95% CI 1.15 to 7.19) and use of calcium channel blockers (OR 0.41; 95% CI 0.22 to 0.74) were independent factors associated with LV dysfunction. CONCLUSION: The prevalence of LV dysfunction in SSc is 5.4%. Age, male gender, digital ulcerations, myositis and lung involvement are independently associated with an increased prevalence of LV dysfunction. Conversely, the use of calcium channel blockers may be protective.

Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy.

Systemic sclerosis-associated pulmonary arterial hypertension (SScPAH) has a worse prognosis and response to pulmonary arterial hypertension (PAH) therapy than idiopathic PAH (IPAH). These differences have not yet been explained. Knowledge concerning histological pulmonary vasculopathy in SScPAH is limited in contrast to IPAH. Therefore, we explored patterns of vasculopathy in SScPAH compared with IPAH. Parameters of vasculopathy were assessed from lung tissue of eight PAH patients with limited cutaneous systemic sclerosis and 11 IPAH patients. Lung tissue was obtained at autopsy (n = 15), explantation (n = 3) and biopsy (n = 1). Pulmonary arterial/arteriolar intimal fibrosis was identified in all SScPAH patients and in three IPAH patients (p = 0.003). Fibrosis of pulmonary veins/venules was found in all SScPAH patients and in three IPAH patients (p = 0.003). In four SScPAH patients, fibrosis of veins/venules was focal and associated with capillary congestion as in pulmonary veno-occlusive disease (PVOD). Of the IPAH patients, 10 had unequivocal evidence of plexogenic arteriopathy compared with none of the SScPAH patients (p = 0.001). SScPAH is characterised by small vessel intimal fibrosis, which is associated with a PVOD-like pattern in some cases. This might explain its different clinical behaviour from IPAH. Small vessel intimal fibrosis may provide clues to elucidation of differences in pathogenetic mechanisms between the groups.

The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype.

The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population [P = 1.9 x 10(-5) odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29-1.99], but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 x 10(-7) 95% CI 2.11-5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.