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Objectives To investigate whether an SLE polygenic risk score (PRS) and an SLE DNA methylation risk score (MRS) are associated with time to lupus nephritis (LN) relapse, and whether this is influenced by the LN induction treatment.Methods Patients with biopsy-verified LN, PRS and/or MRS data, and available clinical information were recruited from University Hospitals in Uppsala, Linköping and Stockholm, Sweden. Patients were genotyped using the Illumina Global Screening Array and DNA methylation was investigated by the Illumina Human Methylation 450k BeadChip Array. For each patient, a weighted PRS was calculated including 55 non-HLA SLE risk gene variants and an MRS was calculated based on the 17 CpG sites most significantly differentially methylated in SLE compared to controls. Relapsing LN was compared with non-relapsing LN using two different Cox proportional hazard models: one including all patients receiving cyclophosphamide (Cyc group, n=64 for PRS, n=62 for MRS and n=54 for the combined model), and one including patients receiving all other induction treatments (non-Cyc group, n=72 for PRS, n=58 for MRS and n=54 for the combined model). Both models included center, gender, and year of first LN as covariates.Results A trend towards shorter time to LN relapse with higher PRS was observed in the non-Cyc group (HR=1.37, CI=0.96-2.0, P=0.084); this was not detected in the Cyc group (HR=0.81, CI=0.55-1.20, P=0.29, figure 1). A similar trend was observed for MRS and time to LN relapse, with borderline significance in the non-Cyc group (HR=1.02, CI=1.00-1.03, P=0.064) and no significance in the Cyc group (HR=1.00, CI= 0.99-1.02, P=0.893, figure 1). Combining PRS and MRS improved the model and both were significantly associated with shorter time to LN relapse in the non-Cyc group (HR=1.86, CI=1.11-3.11, P=0.018 for PRS; HR=1.02, CI=1.00-1.04, P=0.030 for MRS; figure 2), but not in the Cyc group (HR=0.77, CI=0.48-1.23, P=0.267 for PRS; HR=1.00, CI=0.99-1.02, P=0.662 for MRS). Adding MRS to the model in non-Cyc patients significantly improved its fit (LRT, P=0.021).Abstract S14:02 Figure 1Boxplots of polygenic risk score (PRS) and Lupus Nephritis (LN) relapse in relation to LN induction treatment without Cyclophosphamide (Non-Cyc) or with Cyclophosphamide (Cyc) (A). Boxplots of methylation risk score (MRS) and Lupus Nephritis (LN) relapse in relation to LN induction treatment without Cyclophosphamide (Non-Cyc) or with Cyclophosphamide Cyc) (B)Abstract S14:02 Figure 2Forest plot of polygenic risk score (PRS) and Methylation risk score (MRS) in non-cyclophosphamide treated patients, combined model with PRS and MRS. * Indicates p < 0.05Conclusions Cyclophosphamide appears to attenuate the genetic and epigenetic contribution to LN relapse risk, suggesting that genetic and epigenetic risk factors may be important for tailoring treatment decisions at LN onset.