THU0244 3 YEAR FOLLOW UP OF AN AT-RISK CONNECTIVE TISSUE DISEASE COHORT: ANALYSIS OF CLINICAL, GENE EXPRESSION AND FLOW CYTOMETRIC BIOMARKERS

Abstract

Background:We previously reported results from the first 118 “At-Risk” of autoimmune connective tissue disease (AI-CTD) individuals (i.e. ANA positivity, non-specific symptoms of ≤1 year and treatment naïve). At 1 year, 16% progressed to meet classification criteria for an AI-CTD. This was predicted by high baseline interferon (IFN) Score B and family history of RMD[1].However, some may have progressed at later time points, or had clinically significant disease despite not meeting diagnostic criteria. Longer term outcomes, baseline and follow up flow cytometry biomarkers were never reported.Objectives:(i)Describe detailed analysis of 3-year follow-up data of the At-Risk cohort(ii)Evaluate flow cytometric biomarkers as predictors of these outcomes(iii)Analyse follow up biomarkersMethods:We conducted a prospective observational longitudinal study of At-Risk individuals in Leeds (n=150). Patients were assessed at baseline, then annually for 3 years. Depending on diagnostic criteria and need for therapy, patients were grouped as follows:Absolute non-progressors (no clinical diagnostic criteria)Undifferentiated CTD (U-CTD) (≥1 clinical criteria at baseline persisting at follow-up but not meeting criteria). This group was subdivided into those who required treatment with an immunosuppressant (IS) excluding antimalarials and those who did notYear 1 progressors (meeting criteria for an RMD by 1 year)Late progressors (meeting criteria for AI-CTD beyond 1 year follow-up).Bloods were analysed at baseline and 1 year for two IFN-stimulated gene expression scores previously described[2], monocytes and subsets of B and T cells using flow cytometry. Association between clinical criteria, biomarkers at baseline and long term outcomes were tested using ANOVA.Results:3 year follow up data was available in 147/150 patients. Outcomes were: Absolute non-progressors: 63/147 (43%); U-CTD: 54/147 (37%); Year 1 progressors: 21/147 (14%) [SLE=18; pSS=3]; Late progressors (in years 1-2): 9/147 (6%) [SLE=7; pSS=2]. None progressed or required IS initiation beyond the first 2 years of follow-up. In U-CTD group, 7/54 (13%) were prescribed an IS.This work describes a larger group of 36/147 (24%) At-Risk individuals who developed clinically significant disease (CSD: progressors or need for IS) versus clinically non-significant disease (CNSD: absolute non-progressors or UCTD not needing IS).Analysis of baseline biomarkers between CSD and CNSD confirmed a significant difference in IFN Score B (mean difference -0.74, p = 0.027), but not IFN Score A (mean difference -0.68, p = 0.15). In flow cytometry analysis, there was also a significant difference in percentage monocytes (mean difference -4.09, p = 0.004) but no other subset. Absence of clinical criteria at baseline did not predict clinical outcome, and no one clinical criterion had greater predictive value.In follow up samples we noted a significant reduction in expression of IFN Score B in both groups, regardless of whether they received antimalarials or IS therapy.Conclusion:Here we report findings of a larger group of 24% At-Risk individuals who developed CSD (progressors and patients who did not meet criteria but needed IS therapy). These results provide a more complex picture of IFN activity in the initiation of SLE than previously suspected. First, we confirm that a specific subset of ISGs rather than a classic IFN signature predicts progression. Second, the reduction in IFN-Score-B in both groups suggests that IFN Score B activity is a transient phenomenon, playing a greater role in disease initiation than in disease maintenance.