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BackgroundThere are muliple potential therapeutic a gents under development for sstemic sclerosis (SSc). Given that SSc is uncommon, there is interest in cohort enrichment to maximize the potential of identifying a drug effect, One area of interest is a modified Rodnan skin score (mRSS) cut-off as an inclusion criterion in early diffuse SSc trials. Autoantibody profiles of SSc patients vary by geographical region. Given that the mRSS differs between autoantibody groups and that many trials are multinational, it is important to understand the differences in mRSS patterns between autoantibodies to choose optimal mRSS cut-off points that facilitates enrichment for patients likely to develop skin progression.ObjectivesWe sought to determine the baseline mRSS to maximally predict progressive skin involvement over one year in US patients with early diffuse SSc, and assess if this differed by autoantibody.MethodsWe examined a US single-center cohort of prospectively followed early diffuse SSc patients seen for an initial visit between 1980 and 2014. To reflect modern early diffuse SSc clinical trial design, early was defined as <3 years of symptoms and diffuse SSc as proximal skin thickening. Eligible patients had ≥2 mRSS within one year of the first SSc center visit, for a minimum of 3 mRSS over one year. The outcome of interest was mRSS progression at any time over that year, defined as an increase of 5 points or more and a 25% increase in the mRSS from baseline. Autoantibodies were confirmed by immunodiffusion for Scl-70, immunofluorescence for anti-centromere and immunoprecipitation for RNA polymerase III (RNAP) and all other SSc-associated antibodies. Descriptive statistics using Receiver Operating Curve (ROC) analysis were used with mRSS progression as the state variable to determine cut-off points for mRSS.ResultsAmong 317 eligible patients the mean age was 50.8±13.5 years, 74% were female and 92% Caucasian. The median disease duration was 0.90 years (IQR 0.63, 1.46). The mean baseline mRSS was 23±11. 25% (n=79) were scl-70 positive, 56% n=178) RNAP positive, 54 (17%) other SSc-associated antibody and 2% (n=6) missing. The median baseline mRSS (IQR) for RNAP was 24 (17,33), compared to 18 (13,25) for Scl-70 and 20 (13,28) for other antibodies (p=0.0004). In total, 163 patients (51%) developed progressive skin disease over one year. 59% of RNAP positive patients progressed, versus 48% of Scl-70 and 33% of other antibody positive patients (p=0.004). The mean time to peak mRSS was 0.51±0.23 years overall. The baseline mRSS below which there was the maximal likelihood of predicting progressive skin disease, with the greatest area under the curve (AUC) in Scl-70 positive patients was ≤24 (AUC 0.72; 95%CI 0.64, 0.80). This contrasted with RNAP patients, for which the maximal AUC occurred at ≤29 (AUC 0.74;95% CI 0.67, 0.80). Patients with other autoantibodies had a much lower baseline mRSS of ≤17 for optimal prediction (AUC 0.67; 95%CI 0.53, 0.80).ConclusionsThe mRSS cut-off that predicted skin progression over one year was different between RNAP, Scl-70 and other SSc antibodies. his supports the concept that cohort enrichment in clinical trials may be enhanced by modifying the mRSS cut-off point for the major autoantibody groups. A lower cut-off point will exclude some US patients who are likely to progress.Disclosure of InterestR. Domsic Consultant for: Biogen-Idec, M. Lucas: None declared, V. Steen: None declared, R. Lafyatis Grant/research support from: Regeneron, Consultant for: Regeneron, T. Medsger: None declared

Annals of the rheumatic diseases, 2016-06, Vol.75 (Suppl 2), p.542

FRI0296 The Optimal Modified Rodnan Skin Score To Predict Skin Progression over One Year Differs between Autoantibody Subsets

BackgroundSystemic sclerosis (SSc) is characterized by vascular damage and excessive collagen deposition in the skin and internal organs. The excessive collagen deposition results from accelerated turnover, both formation and degradation, contributing to release of extracellular matrix (ECM) fragments to the circulation, where they may be quantified as biomarkers. Skin is rich in type I and III collagen, while type IV, V and VI collagen are present in a lesser amount. Thus, the turnover of these collagens is potentially altered in SSc.ObjectivesThe objective was to investigate the level of collagen (type, I, III, IV, V and VI) turnover in early and late stage diffuse SSc patients compared to healthy controls (HC).MethodsDiffuse SSc patients (n=40) were included together with HC (n=20). Twenty patients were early diffuse (<2 years of SSc symptoms) and twenty were late diffuse (>10 years of disease with stable skin for at least six months), all without progressive lung disease. Biomarkers of type I, III, IV, V and VI collagen formation (P1NP, Pro-C3, P4NP7S, Pro-C5 and Pro-C6, respectively) and type I, III, IV and VI collagen degradation (C1M, C3M, C3A, C4M2 and C6M, respectively) were assessed in serum. Statistical differences between the groups were tested by Kruskal-Wallis test with Dunn's multiple comparisons test. The potential discrimination capacity of these biomarkers were analysed by receiver operating characteristics (ROC) area under the curve (AUC) on HC, SSc, early and late diffuse SSc versus each other.ResultsIn early diffuse SSc Pro-C3, P4NP7S, Pro-C5 and Pro-C6 (p<0.0001) levels were significantly increased compared to HC (figure). In late diffuse SSc compared to HC a significant increase in P4NP7S (p=0.005) and Pro-6 (p=0.006) levels were observed. Contrary, P1NP was significantly decreased in both early (p=0.016) and late (p=0.002) diffuse SSc compared to HC. Moreover, a significant increase in Pro-C3 (p=0.0006), Pro-C5 (p=0.003) and Pro-C6 (p=0.0043) levels were detected in early diffuse SSc compared to late diffuse SSc.The degradation biomarkers were significantly increased in early SSc compared to HC (C1M, C4M2 and C6M: p<0.0001, C3M: p=0.001 and C3A: p=0.02). Increased levels were found in late diffuse SSc compared to HC in C3M (p=0.02), C3A (p=0.006), C4M2 (p=0.005) and C6M (p=0.003). A significant difference between early and late diffuse SSc was also observed for C1M (p=0.02), C4M (p=0.022) and C6M (p=0.05).The best predictive value was found for Pro-C6 and C6M with AUC values of 0.92 and 0.93 for HC vs. SSc, 0.94 and 0.99 for HC vs. early diffuse, and 0.91 and 0.87 for HC vs. late diffuse, respectively. Pro-C6 had an AUC of 0.88 for early vs. late diffuse. In addition, C4M2, Pro-C3, P4NP7S and Pro C5 all had AUC values of more than 0.90 when assessing HC vs. early diffuse.ConclusionsThis pilot study showed that collagen turnover appears to be significantly different between HC and SSc, as well as between early and late stage diffuse patients. The discriminatory power of these biomarkers was high, especially C6M and Pro-C6. These data suggest that serological assessment of ECM turnover could be relevant in SSc, and offers an area of investigation of the pathogenesis.Disclosure of InterestP. Juhl: None declared, R. Domsic: None declared, A.-C. Bay-Jensen: None declared, M. Karsdal: None declared, A. Siebuhr: None declared, N. Franchimont Shareholder of: Biogen, Employee of: Biogen, J. Chavez Shareholder of: Biogen, Employee of: Biogen

Annals of the rheumatic diseases, 2016-06, Vol.75 (Suppl 2), p.740-741

SAT0200 Serum Biomarkers of Collagen Turnover in Early and Late Diffuse Systemic Sclerosis

BackgroundSystemic sclerosis (SSc) is a chronic disease characterized by vascular damage, immunologic activation and excessive extracellular matrix (ECM) deposition in the skin and internal organs. The excessive ECM deposition leads to the release of ECM fragments into circulation, where they may be quantified as biomarkers. Activation of macrophages is a hallmark of the immunologic activation in autoimmune diseases and the activation lead to uncontrolled ECM destruction. In addition, activated macrophages has been shown to secrete the intermediate filament vimentin, making it an ideal protein biomarker of activated macrophages.ObjectivesThe objectives were to investigate 1) if biomarkers of ECM turnover and macrophage activation could seperate diffuse SSc patients and healthy and 2) the diagnostic power of these biomarkers.MethodsDiffuse SSc patients (n=40) fulfilling the American College of Rheumatology criteria were included. Patients were divided into early and late diffuse based on disease duration (n=20 per group). Furthermore, early SSc patients were divided into intermediate and rapid skin thickness progression rate (STPR; n=10 in each). Twenty healthy controls were included. The macrophage activation biomarker citrullinated and MMP-degraded vimentin (VICM), the ECM biomarkers matrix metalloproteinase (MMP) degraded biglycan (BGM) and MMP-7 degraded elastin (ELM-7) were assessed in serum. The currently best diagnostic and prognostic biomarker (platelet factor 4; CXCL4) was furthermore investigated in serum. Statistical differences between the groups were tested by Kruskal-Wallis test with Dunn's multiple comparisons test. Diagnostic capacity was analysed by receiver operating characteristics (ROC) area under the curve (AUC) on healthy vs. diseased, healthy vs. early or late diffuse and between early and late diffuse.ResultsVICM level was significantly increased in early SSc compared to late SSc (p=0.023). The VICM level in the rapid STPR was significantly increased compared to healthy (p=0.025) and intermediate STPR (p=0.022). Of notice, the VICM level of intermediate STPR was at the level of healthy. BGM level was significantly increased in early diffuse SSc compared to healthy (p=0.0003). Both early SSc groups (rapid and intermediate STPR) was increased compared to healthy (p=0.012 and p=0.0022, respectively). There were no difference in the ELM-7 and CXCL4 levels between any groups.The diagnostic capacity of the biomarkers were assessed. VICM did not reach significance, but reached an AUC of 0.71 for diagnosing early vs. late SSc. BGM had an AUC of 0.79 for healthy vs. SSc. The diagnostic power increased when only testing early SSc (AUC=0.84) and decreased when only testing late SSc (AUC=0.74).ConclusionsVICM could identify the group with rapid STPR, whereas BGM was a possible diagnostic biomarker of early SSc. CXCL4 was in this study not a diagnostic tool of SSc as previously shownA. The current study illustrates that serological biomarkers of BGM could be a diagnostic tools in SSc and that macrophage activation (VICM) could be potential biomarkers of SSc disease activity (VICM).Disclosure of InterestA. S. Siebuhr Employee of: NORDIC BIOSCIENCE A/S, R. Domsic: None declared, P. Juhl Employee of: NORDIC BIOSCIENCE A/S, A.-C. Bay-Jensen Employee of: NORDIC BIOSCIENCE A/S, M. Karsdal Shareholder of: NORDIC BIOSCIENCE A/S, Employee of: NORDIC BIOSCIENCE A/S, N. Franchimont: None declared, J. Chavez: None declared

Annals of the rheumatic diseases, 2016-06, Vol.75 (Suppl 2), p.746

SAT0214 Macrophage Activation and Biglycan as Disease Activity and Diagnostic Biomarkers in Systemic Sclerosis

BackgroundPulmonary arterial hypertension (PAH) is a leading cause of mortality in systemic sclerosis (SSc). Although medications have improved their prognosis, optimal therapy remains undefined. The goal of this study was to compare time to clinical worsening (TTCW) and survival based on initial oral PAH therapy.MethodsUsing data from the PHAROS registry (a multicenter prospective observational study enrolling SSc patients with incident pulmonary hypertension), patients with group I PAH, 6 months of initial therapy with either an endothelin-receptor antagonist (ERA), phosphodiesterase-5 inhibitor (PDE5), or a combination of ERA/PDE5 were included. Patients treated initially with prostacyclins were excluded. The starting point for all analyses was the date of therapy initiation. Outcomes were survival and TTCW, defined as the first occurrence of death, PAH-related hospitalization, lung transplant, initiation of parenteral prostacyclin, or worsening symptoms.ResultsNinety-eight patients (initial ERA=24, initial PDE5=59, initial ERA/PDE5=15) were included; no significant differences in baseline variables existed. TTCW was significantly worse in patients initially started on ERA compared to PDE5 or ERA/PDE5 (p=0.0001). Baseline factors independently associated with shorter TTCW were initial ERA (HR 2.63, p=0.009), lower DLCO (HR 0.69 per 10% change, p=0.04), and higher PVR (HR 1.10 per Wood unit change, p=0.007). Three year survival was significantly worse in the initial ERA group (52.9%) compared to the PDE5 (91.5%) or ERA/PDE5 group (92.9%, p=0.004). The only baseline factor independently associated with risk for death in this cohort was initial ERA therapy (HR 4.55, p=0.004).ConclusionsCompared to PDE5 or combination ERA/PDE5, initial therapy with an ERA in SSc-PAH patients was associated with a significantly worse TTCW and survival, even after adjustment for commonly accepted prognostic factors. Although these findings may be the result of unmeasured imbalances between groups, it is plausible that known ERA side effects such as fluid retention may have led to clinical worsening. Limitations include data collection over non-uniform points in time and limited supplementary information as well as potential selection-bias in medication assignment. Further study into the optimal initial oral therapy in patients with SSc-PAH is needed.AcknowledgementsPHAROS is supported by an investigator initiated grant from Gilead Science.Disclosure of InterestM. Lammi: None declared, L. A. Saketkoo Grant/research support from: ACR/EULAR Exchange Awardee; Gilead, S. Mathai Grant/research support from: National Heart and Blood Institute, Consultant for: Actelion Pharmaceuticals US, Bayer, R. Domsic: None declared, V. Steen Grant/research support from: Actelion Pharmaceuticals US Bayer CSL Berhing Intermune Roche Pharmaceuticals Sanofi-Aventis Pharmaceutical UCB United Therapeutics, D. Furst: None declared

Annals of the rheumatic diseases, 2015-06, Vol.74 (Suppl 2), p.828

SAT0463 Initial Therapy with an Endothelin Receptor Antagonist (ERA) is Associated with Worse Outcomes in Patients with Systemic Sclerosis and Pulmonary Arterial Hypertension: Observations from the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Cohort (Pharos)

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FRI0296 The Optimal Modified Rodnan Skin Score To Predict Skin Progression over One Year Differs between Autoantibody Subsets

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SAT0200 Serum Biomarkers of Collagen Turnover in Early and Late Diffuse Systemic Sclerosis

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SAT0214 Macrophage Activation and Biglycan as Disease Activity and Diagnostic Biomarkers in Systemic Sclerosis

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SAT0463 Initial Therapy with an Endothelin Receptor Antagonist (ERA) is Associated with Worse Outcomes in Patients with Systemic Sclerosis and Pulmonary Arterial Hypertension: Observations from the Pu...

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