Apr 30, 2018 - origins set at 6 consecutive landmark time-points, 12 months apart, starting at .... Nottingham University Hospitals NHS Trust Nottingham NHS.
ii34 Wednesday 26 April 2017
O15. DYNAMIC PREDICTION OF PULMONARY HYPERTENSION DEVELOPMENT IN SYSTEMIC SCLEROSIS PATIENTS USING LANDMARK ANALYSIS Svetlana I. Nihtyanova1, Voon H. Ong1, Emma C. Derrett-Smith1, Benjamin E. Schreiber2, Gerry J. Coghlan2, Bianca L. DeStavola3 and Christopher P. Denton1 1 Rheumatology, University College London Medical School, 2 Pulmonary Hypertension Service, Royal Free Hospital, and 3Centre for Statistical Methodology, London School of Hygiene & Tropical Medicine, London, UNITED KINGDOM Background: Pulmonary hypertension (PH) contributes substantially to systemic sclerosis (SSc)-related morbidity and mortality. Unlike other life-threatening organ-based complications, it tends to develop later in the disease, creating an opportunity for early risk stratification and potential development of preventative measures. Previously published prediction models for PH have been based on cross-sectional data. We present a model utilizing time-updated disease characteristics for dynamic prediction of PH development within 12 months. Methods: We used data from a large unselected longitudinal cohort of SSc patients. Information on demographic, clinical and serological characteristics, time-updated organ disease and serial pulmonary function test results were available. Sequential survival analyses with origins set at 6 consecutive landmark time-points, 12 months apart, starting at 60 months from disease onset were performed. The predictor variables included time-invariant characteristics (sex, subset and autoantibodies) and landmark-specific information (age, presence of organ disease, FVC and DLCO). Time to development of PH from the landmarks was calculated with administrative censoring at 12 months. These analyses were then combined using a stratified Cox proportional hazards model, with each landmark representing a separate stratum. Results: The study cohort consisted of 652 SSc patients. Of those 41.3% had diffuse SSc, 14.9% were male and the average age at disease onset was 48 years. Most patients (96%) either died during follow-up or were followed for over 10 years from disease onset. At the end of follow-up 13.3% of the subjects had developed PH. The final multivariable model included the values at landmark of age, presence of pulmonary fibrosis (PF), DLCO (% predicted) and antibody specifics [anti-U3RNP and anti-RNA polymerase (ARA)]. This showed that in the absence of PF, 1% lower DLCO was associated with 11% increase in the hazard of PH (HR 1.11, p < 0.001), controlling for the other variables. In the presence of PF, this effect was attenuated and 1% lower DLCO was associated with 6% increase in the hazard of PH (HR 1.06, p < 0.001). For every year of older age, the PH hazard increased by 3% (HR 1.03, p ¼ 0.066); ARA positive patients had nearly 5 times higher hazard of PH compared to ARA negative ones (HR 4.9, p ¼ 0.001); and anti-U3RNP positive patients had approximately 6 times higher hazard of PH development compared to anti-U3RNP negative patients (HR 5.97, p ¼ 0.005), controlling for the other variables. The effects did not vary between landmark strata. The model had a good discrimination performance with C-index¼0.88. Conclusion: Our results show that comparatively simple models, using only information on current age, autoantibodies and serial DLCO assessments could be used for risk stratification and prediction of PH development with good discriminating ability. After validation, preferably in an external cohort, this model could be used in clinical practice or in the design of clinical trials. Disclosure statement: The authors have declared no conflicts of interest. O16. STROMAL CELLS IN TERTIARY LYMPHOID STRUCTURES: A NOVEL PATHOGENIC PARADIGM AND ¨ GREN’S SYNDROME THERAPEUTIC TARGET IN SJO Saba Nayar1, Joana Campos1, Jorge Caamanˇo2, Benjamin Fisher1, Simon Bowman1, Sanjiv Luther3, Mark Coles4, Christopher Buckley1 and Francesca Barone1 1 Rheumatology, Institute of Inflammation and Ageing, 2Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UNITED KINGDOM, 3Department of Biochemistry, University of Lausanne, Lausanne, SWITZERLAND, and 4Centre for Immunology and Infection, University of York, York, UNITED KINGDOM Background: Tertiary lymphoid structures (TLS) are accumulations of lymphoid cells that share similar cellular compartments, organization and function as secondary lymphoid organs (SLOs). TLS provide a local hub for auto-reactive B-cell affinity maturation and proliferation which can contribute in expansion of malignant B-cell clones
ORAL PRESENTATIONS
responsible for lymphoma development. TLS that form within salivary glands (SGs) of patients with Sjo¨gren’s syndrome (SS) are clearly associated with poor disease outcome, the presence of systemic manifestation and development of lymphoid-malignancies. Despite clear evidence supporting B-cell contribution to SS pathogenesis, Bcell depletion has failed in double-blinded randomized clinical trials; suggesting that targeting leucocytes might not be sufficient to eradicate disease. Moreover, it has been shown that pathogenic microenvironment of SGs is responsible for disease resistance to treatment and relapse. Others and we have shown in TLS-associated diseases, resident-stromal cells can undergo changes to acquire features of SLO-stromal cells. However, the mechanisms regulating these lymphoid-like stromal cells (LLSCs) are not clear. Methods: Inducible SS mouse model of TLS formation by retrograde cannulation of SGs with a replication-deficient adenovirus was used. Cannulated SGs of C57BL/6 (wildtype;WT) and knockout mice (IL4Ra/, IL-13/, IL-22/, IL22Ra/, LTbR/, RAG2/, Bcell/, T-cell/) at different time-points and SG biopsies from SS patients were analysed by immunofluorescence, flow cytometry and RT-PCR. Results: Our work in the inducible TLS formation model in both WT and knock-out mice and in vitro experiments revealed acquisition of lymphoid phenotype by non-activated resident stroma is a multistep process, fundamentally different from signals responsible in SLO. We showed early during TLS formation, LLSC priming [i.e. up-regulation of SLO-associated stromal markers: gp38, FAP and adhesion molecules (ICAM-1/VCAM-1)] is mediated by IL-13 via IL-4Ra engagement on quiescent tissue-resident fibroblasts. Expansion/proliferation of these activated LLSCs requires IL-22R/IL-22 signalling. Impairment in any of these stromal induction/proliferation pathways resulted in defective TLS formation. Finally, we demonstrated LTb/LTbR and lymphocytes are required to maintain long-term secretion of lymphoid chemokines and cytokines from LLSCs for leucocyte retention, survival, organization and generation of humoral response. Taking advantage of in vivo targeted-deletion of LLSCs (using FAP-DTR mice) we confirmed that integrity of LLSCs is critical for TLS assembly, organization and disease persistence in SGs. Observational studies in SS SGs confirmed presence of LLSCs in human disease and engagement of pathways demonstrated in the animal model. Conclusion: Our data highlight previously unappreciated pathogenic role for stromal cells in context of TLS-associated diseases. It demonstrates that activated lymphocytes and local stromal cells cooperate in an amplificatory loop to induce TLS and are responsible for disease chronicization and persistence. We propose that treating LLSCs either directly or via modulation of the signals identified in this study could be used in combination with leucocyte depletion to increase therapeutic activity of these compounds in clinical trials. Disclosure statement: The authors have declared no conflicts of interest.
O17. THE UNITED KIGDOM AND IRELAND VASCULITIS REGISTRY: CROSS-SECTIONAL DATA ON THE FIRST 3195 PATIENTS WITH A FOCUS ON ANTI-NEUTROPHIL CYTOPLASM – ASSOCIATED VASCULITIS AND GIANT CELL ARTERITIS Raashid A. Luqmani1, Anthea Craven1, Jan Sznajd2, Neil Basu3, Joe Barrett1, David Jayne4, Peter Lanyon5, Mark Little6, Joanna Robson7, Michael Robson8, Alan Salama9 and Richard Watts10 1 NDORMS, Botnar Research Centre, University of Oxford, Oxford, 2 Department of Rheumatology, Raigmore Hospital, Inverness, 3 Institute of Applied Health Sciences, University of Aberdeen, School of Medicine and Dentistry, Aberdeen, 4Department of Medicine, University of Cambridge, Cambridge, 5Nottingham University Hospitals NHS Trust and Nottingham NHS Treatment Centre, Nottingham University Hospitals NHS Trust Nottingham NHS Treatment Centre, Nottingham, UNITED KINGDOM, 6Trinity Health Kidney Centre, Trinity College Dublin, Dublin, IRELAND, 7 Rheumatology & Faculty of Health and Applied Sciences, University of the West of England, University of Bristol, University Hospitals Bristol NHS Trust, Bristol, 8MRC Centre for Transplantation, Guy’s Hospital, 9University College London Centre for Nephrology, Royal Free Hospital, London, and 10Norwich Medical School and Department of Rheumatology, University of East Anglia, Norwich and Ipswich Hospital NHS Trust, Ipswich, Suffolk, UNITED KINGDOM
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