Showing papers by "Madelon C. Vonk published in 2016"

The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis

Abstract: Background Interferon (IFN) signature has been reported in definite systemic sclerosis (SSc) but it has not been characterised in early SSc (EaSSc). We aim at characterising IFN type I signature in SSc before overt skin fibrosis develops. Methods The expression of 11 IFN type I inducible genes was tested in whole-blood samples from 30 healthy controls (HCs), 12 subjects with primary Raynaud9s phenomenon (RP), 19 patients with EaSSc, 7 patients with definite SSc without cutaneous fibrosis, 21 limited cutaneous SSc and 10 diffuse cutaneous SSc subjects. The correlation between IFN activity in monocytes, B cell activating factor (BAFF) mRNA expression and type III procollagen N-terminal propeptide (PIIINP) serum levels was tested. Results In all the SSc groups, higher IFN scores were observed compared with HC. An IFN score ≥7.09 discriminated HCs from patients with SSc (sensitivity=0.7, specificity=0.88, area under receiving operating characteristic (AUROC)=0.82); the prevalence of an elevated IFN score was: HC=3.3%; RP=33.3%, EaSSc=78.9%, definite SSc=100%, limited cutaneous SSc=42.9%, diffuse cutaneous SSc=70.0%. In monocytes an IFN score ≥4.12 distinguished HCs from patients with fibrotic SSc (sensitivity=0.62, specificity=0.85, AUROC=0.76). Compared with IFN-negative subjects, IFN-positive subjects had higher monocyte BAFF mRNA levels (19.7±5.2 vs 15.20±4.0, p=2.1×10 −5 ) and serum PIIINP levels (median=6.0 (IQR 5.4–8.9) vs median=3.9 (IQR 3.3–4.7), p=0.0004). Conclusions An IFN type I signature is observed in patients with SSc from the earliest phases of the disease, even before overt skin fibrosis. The presence of IFN type I signature in monocytes is correlated with BAFF mRNA expression and serum PIIINP levels, supporting a contribution in the pathogenesis and progression of SSc.

Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross‐Disease Meta‐Analysis of Genome‐Wide Association Studies

Abstract: Objective: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc–RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc–RA loci through an interdisease meta–genome-wide association (meta-GWAS) strategy. Methods: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case–control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10−6) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc–RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10−12). Analysis of the biologic relevance of the known SSc–RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. Conclusion: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.

Survival and organ involvement in patients with limited cutaneous systemic sclerosis and anti-topoisomerase-I antibodies: determined by skin subtype or auto-antibody subtype? A long-term follow-up study

Abstract: OBJECTIVE: LcSSc is associated with ACAs and a mild course, whereas dcSSc is associated with anti-topoisomerase antibodies (ATAs) and a more severe course. However, ATAs are also present in lcSSc. Little is known about survival and organ involvement in this subgroup. The aim of this study is to determine whether survival and organ involvement of lcSSc ATA-positive patients differs from lcSSc ATA-negative or dcSSc ATA-positive patients. Furthermore, transition from lcSSc to dcSSc was evaluated. METHODS: Data from The Nijmegen Systemic Sclerosis cohort were used, with up to 15 years of follow-up. Kaplan-Meier analysis was performed for survival and organ involvement, including interstitial lung disease, pulmonary arterial hypertension, cardiac involvement and Scleroderma Renal Crises. Cox proportional hazard modelling was performed to adjust for confounders. RESULTS: A total of 460 patients were included: 58 (13%) lcSSc ATA-positive patients, 237 (52%) lcSSc ATA-negative patients and 78 (17%) dcSSc ATA-positive patients. Cumulative survival in lcSSc ATA-positive patients was 75%, in lcSSc ATA-negative patients 58% and in dcSSc ATA-positive patients 53%. Interstitial lung disease was more prevalent in lcSSc ATA-positive patients (49%) than in lcSSc ATA-negative patients (25%), but less than in dcSSc ATA-positive patients (60%). Forty-eight patients developed dcSSc: 24 ATA-negative and 24 ATA-positive (P < 0.001). CONCLUSION: LcSSc ATA-positive patients differ from lcSSc ATA-negative patients and dcSSc ATA-positive patients concerning survival and organ involvement. LcSSc patients who are ATA-positive are more likely to develop dcSSc than lcSSc patients who are ATA negative.

Patients with Systemic Sclerosis/polymyositis Overlap Have a Worse Survival Rate Than Patients Without It

Abstract: Objective Studies on mortality associated with patients with systemic sclerosis (SSc) and myopathy have been limited by heterogeneous definitions of muscle involvement. The objective of this study is to determine whether homogeneous-defined SSc/polymyositis overlap (SSc-PM overlap) is associated with a worse survival rate compared with SSc without PM. Methods Data from the Nijmegen Systemic Sclerosis cohort were used. Incidence rates were calculated from the observed number of deaths and followup time. Survival analysis using Cox proportional hazard modeling was performed to compare survival among patients with SSc and patients with SSc-PM overlap, including controlling for confounders. All patients with SSc-PM fulfilled the Bohan and Peter criteria for PM. Results There were 24 patients with SSc-PM (5.7%) and 396 patients with SSc (94.2%). The 5- and 10-year cumulative survival rates from diagnosis were 82% and 68% for the SSc-PM group and 93% and 87% for the SSc group, respectively. Multivariate survival analysis revealed an adjusted HR of 2.34 (95% CI 1.09–5.02) for SSc-PM compared with SSc, with age at diagnosis, modified Rodnan skin score, diffuse cutaneous subtype, and male sex included as confounders. The most common cause of death among patients with SSc-PM overlap was cardiopulmonary involvement (63%), which was similar to the patients with SSc (51%). Conclusion Patients with SSc-PM overlap have a worse survival rate compared with patients with SSc.

Low heme oxygenase-1 levels in patients with systemic sclerosis are associated with an altered Toll-like receptor response: another role for CXCL4?

Abstract: Objective. SSc is a disease characterized by inflammation and fibrosis. Heme Oxygenase-1 (HO-1) is a haem-degrading enzyme that mediates resolution of inflammation and is induced upon mediators abundantly present in SSc. We aimed to assess whether HO-1 expression/function is disturbed in SSc patients and could therefore be contributing to the ongoing inflammation. Methods. In total, 92 SSc patients and 48 healthy controls were included. By measuring total bilirubin in plasma in vivo, HO-activity was assessed. HO-1 expression levels were determined with western blot in monocytes before and after induction of HO-1 with cobalt protoporphyrin (CoPP) with or without CXCL4. Monocyte-derived dendritic cells (DCs) were stimulated with several Toll-like receptor (TLR) ligands with or without pre-stimulation with CoPP for 24 h. Cytokine levels were measured in the supernatants using the Luminex Bead Array. Results. SSc patients have lower plasma levels of bilirubin, suggestive of an aberrant HO-1 function. We demonstrated low HO-1 expression in immune cells from SSc patients, whereas induction with CoPP was able to restore HO-1 levels in DCs from SSc patients, almost normalizing the increased TLR response observed in SSc. Co-exposure to CXCL4 completely abrogated CoPP-induced HO-1 expression, suggesting that the high CXCL4 levels present in SSc patients block the normal induction of HO-1 and its function. Conclusion. We demonstrate that HO activity in SSc patients is decreased and show its functional consequences. Since CXCL4 blocks the induction of HO-1 expression, neutralization of CXCL4 in SSc patients could have clinical benefits by diminishing overactivation of immune cells and other antiinflammatory effects of HO-1.

An easy prediction rule for diffuse cutaneous systemic sclerosis using only the timing and type of first symptoms and auto-antibodies: derivation and validation.

Abstract: OBJECTIVE: DcSSc is associated with high morbidity related to widespread skin disease and poor prognosis due to earlier and more severe organ involvement. The objective of this study is to derive and validate a simple prediction rule for identifying patients at the time of initial diagnosis of SSc who are likely to progress to dcSSc. METHODS: The Nijmegen cohort consists of 619 SSc patients. Logistic regression was used for predictive modelling. A prediction rule was created by rounding regression coefficients. Patients were stratified as being at low risk (<1) or high risk (1) of progression to dcSSc. Performance was analysed in 445 SSc patients from Madrid. RESULTS: One hundred and seventy-four out of 535 patients were classified as dcSSc. The final model consisted of gender, time between RP and non-RP, sclerodactyly (first non-Raynaud symptom) and SSc-specific auto-antibodies. The model performed well in the derivation cohort [area under the curve = 0.78 (95% CI: 0.74, 0.82)] and validation cohort [area under the curve = 0.78 (95% CI: 0.74, 0.83)]. At the optimal cut point (1) for the prediction rule, sensitivity was 87% and specificity 61% in the derivation cohort, compared with 78% and 65% in the validation cohort. Upon application of the prediction rule to 392 lcSSc patients at initial diagnosis, 32 out of 34 patients were correctly classified as dcSSc. CONCLUSION: A simple prediction rule was designed to attribute a low/high risk category for development of dcSSc.This method is suited for assigning intensified screening at the time of initial diagnosis of SSc to patients most at risk for dcSSc. It provides the opportunity for early identification of potential dcSSc patients for enrolment into clinical trials.

FRI0261 Observational Study of Outcome in Patients with Early Diffuse Cutaneous Systemic Sclerosis Treated with Immunosuppressive Therapies (ESOS Study)

Abstract: Background Early diffuse cutaneous systemic sclerosis (dcSSc) has high morbidity and mortality, and there is currently no cure. Objectives The main objective of ESOS (European Scleroderma Observational Study) was to compare the effectiveness of currently used immunosuppressant treatments. Methods ESOS was a prospective observational cohort study, capturing entry and outcome data in a standard way. Four recommended treatment protocols were decided by the steering committee: methotrexate (MTX), mycophenolate mofetil (MMF), cyclophosphamide, and “no immunosuppressant”. Patients were assessed at baseline, and then 3-monthly for 24 months or (for those entering the study subsequent to September 2013) at least 12 months. The primary outcome measure was the change in modified Rodnan skin score (mRSS – 17 sites) between 0 (baseline) and 12 months. Secondary endpoints largely reflected routine clinical practice and are not reported here. Effects of treatment on the skin score were assessed using linear regression with baseline treatments as predictors. Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights, while censoring weights adjust for bias due to patient attrition. Survival in each protocol was estimated using Kaplan-Meier curves and survival differences were tested based on the results of an IPT-weighted Cox regression model. Results Target recruitment was achieved, with 326 patients from 50 centres (median age 52.3 years, 72% female, median disease duration 11.1 months). Because this was not a randomized study, the number of patients starting on each treatment protocol differed: 65 MTX, 117 MMF, 87 cyclophosphamide, and 57 no immunosuppressant treatment. 273 patients (84%) completed 12 months follow-up and 179 (55%) 24 months follow-up. Median mRSS at baseline was 21.0 units. After 12 and 24 months, 153 (56%) and 139 (78%) of remaining patients had an improved skin score with respect to baseline. The mean change in mRSS after 12 and 24 months was -2.9 and -6.8 units. Predicted decreases in mRSS in each of the protocols are summarized in Figure 1. In both weighted and unadjusted models, the differences between the treatment groups are non-significant (p=0.27 and p=0.16). At 24 months, Kaplan-Meier predicted survival rates (adjusted for confounding) are 94% (MTX), 90% (MMF), 91% (cyclophosphamide) and 87% (no immunosuppressant). However, differences are non-significant (p=0.42). Conclusions 1. All groups showed improvement in MRSS which was not significantly different between groups although there was a trend in favour of methotrexate and MMF. 2. Survival was similar between groups although the no immunosuppressant group had lower survival (but it is important to stress that this was not a true “control” group). Disclosure of Interest None declared

AB0650 Survival and Organ Involvement in Patients with Limited Cutaneous Systemic Sclerosis and Anti-Topoisomerase Antibodies

Abstract: Background In systemic sclerosis (SSc) there are two main subgroups based on skin involvement: limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc). LcSSc is associated with the presence of anti-centromere antibodies (ACA) and a more subtle disease course, whereas dcSSc is associated with anti-topoisomerase antibodies (ATA) and often a more severe disease course. Nevertheless, despite the associations between clinical subtype and autoantibodies, there are quite a number of SSc patients who have limited skin involvement and antibodies associated to diffuse skin involvement (ATA). The question is whether these patients have a disease more like lcSSc or more like dcSSc. Objectives The aim of this study is to determine whether survival and organ involvement in lcSSc patients who are ATA positive are similar to lcSSc ATA negative patients or to dcSSc ATA positive patients. Furthermore, the relation between ATA positivity and time to transition from lcSSc to dcSSc was evaluated. Methods Data from The Nijmegen Systemic Sclerosis cohort were used. Survival analysis was performed to show cumulative survival and time to event for Interstitial Lung Disease (ILD), Pulmonary Arterial Hypertension (PAH), cardiac involvement, Scleroderma Renal Crisis (SRC), and transition to lcSSc. Cox proportional hazard modelling was performed to adjust for confounders. Results Survival up to 15 years of follow-up was highest in lcSSc ATA positive patients, whereas dcSSc ATA positive patients had lowest survival (table 1). Interstitial Lung Disease (ILD) occurred more frequently in lcSSc ATA positive patients compared to lcSSc ATA negative patients. However, a higher frequency of ILD was seen dcSSc ATA positive patients. No significant differences were seen between the four (table 1) subgroups in occurrence of PAH, cardiac involvement and SRC. At the moment of diagnosis, 343 patients were classified as lcSSc and 48 of these patients evolved from lcSSc to dcSSc, 24 (9%) in the ATA negative subgroup and 24 (29%) in the ATA positive subgroup (figure 1). Conclusions This study showed that lcSSc ATA positive patients differ from lcSSc ATA negative patients and dcSSc ATA positive patients concerning both survival and occurrence of ILD. Therefore, in everyday clinical practice, the prognosis of lcSSc ATA positive patients should be considered separately. Disclosure of Interest None declared

FRI0254 The Effect of Cyclophosphamide on Lung Function in Different Stages of Interstitial Lung Disease Associated To Systemic Sclerosis

Abstract: Background The primary cause of death in patients with systemic sclerosis (SSc) is interstitial lung disease (ILD). Several retrospective studies have shown some effect of cyclophosphamide (CYC) on ILD. In one randomized controlled trial a small but significant effect on pulmonary function was shown after oral CYC (Taskin,2006). Hoyles (2006) showed a trend towards improvement of forced vital capacity after monthly CYC infusions. In our centre, intravenous CYC pulses are the first choice of therapy in SSc-ILD. Objectives To analyze 1) the effects of iv CYC pulses (750mg/m 2 ) on pulmonary function in SSc-ILD in our cohort, and 2) whether this effect is dependent on the extent of ILD. Methods Patients with SSc-ILD receiving CYC pulses between 2003 to 2015 were classified by the Goh criteria (2008) in either limited or extensive ILD, using HRCT at baseline judged by two raters. Pulmonary function tests were performed at 0, 6 and 12 months. Missing outcome data due to drop-out, but not death, were replaced by last observation carried forward. Results 79 patients were included, 42 with limited ILD, 37 with extensive ILD. There were no differences in age, gender, SSc subtype classification, disease duration or autoantibody status between the two groups. Baseline FVC (median 80% vs. 91%) and DLCO (39% vs. 50%) were lower in extensive ILD (p After 12 months, FVC (p=0.08)), and DLCO (p=0.62) did not worsen compared to baseline values. There were no differences in the degree of change in FVC and DLCO between limited and extensive ILD. Forty-eight patients completed 12 cycles of CYC. Per protocol analyses showed not significant differences between limited and extended ILD. Conclusions 1. CYC pulse therapy does not worsen pulmonary function in SSc-related ILD after 1 year. 2. The extent of ILD does not influence the effect of CYC. Disclosure of Interest None declared