Objectives: To study the effect of serum PCSK9 on major cardiovascular adverse events (MACEs) in Chinese patients with systemic lupus erythematosus (SLE).

Methods: Consecutive patients who fulfilled ≥4 1997 ACR criteria for SLE and consented for a biomarker study between 2009 and 2012 were included. Stored serum samples from these patients were assayed for the levels of PCSK9 using a commercial ELISA kit (OKBB00903, Lot# 1344, Aviva Systems Biology, San Diego, US). New MACEs (acute coronary syndrome, ischemic stroke, peripheral vascular disease) documented by imaging and angiographic studies over time was evaluated. Patients were stratified into high/low PCSK9 groups according to the best cut-off level by ROC analysis for the prediction of these events. The cumulative incidence of new MACEs and mortality over time was studied by Kaplan-Meier’s analysis and compared between the high and low PCSK9 subgroups. Cox regression was performed to study the effect of the PCSK9 subgroups on new MACEs and mortality, adjusted for other confounding factors.

Results: 539 SLE patients were studied (93% women, age 41.9±14.0 years; disease duration 106±90.4 months at entry). The mean PCSK level at baseline was 265±158ng/ml and a cut-off of 243.25ng/ml best predicted a new vascular event by the maximum Youden’s index (ROC analysis: AUC 0.63[0.51-0.74]; sensitivity 69%; specificity 61%). 220 SLE patients had baseline PCSK9 level of ≥243.25ng/ml (high PCSK9) and 319 patients had level below 243.25ng/ml (low PCSK9). Patients with high PCSK9 (n=220) had more active SLE than those with low PCSK9 (n=319) (p<0.001). PCSK9 level was highest in active renal SLE patients and correlated with SLE disease activity index (r=0.55; p<0.001). No significant difference in SLE manifestations and autoantibody profile was observed between the high and low PCSK9 groups except the former had a significantly higher prevalence of lupus nephritis. Over 91.3±18.6 months, 31 new MACEs (13 ischemic stroke, 13 acute coronary syndrome and 5 peripheral vascular disease) developed in 29 patients. Patients with a new MACE had a significantly higher baseline PCSK9 level than those without (350±225 vs 260±153ng.ml; p=0.02). The cumulative incidence of a first MACE at 5 years from study entry was 7.8% in the high PCSK9 group and 1.9% in the low PCSK9 group (log rank test; p=0.003, univariate hazard ratio [HR] 3.08[1.39-6.80]). At last follow-up, 40 patients succumbed (10 due to vascular event [vascular death]). Kaplan-Meier’s analysis showed that the high PCSK9 group had a significant higher cumulative risk of all-cause mortality (log rank test p=0.003; HR2.68[1.39-5.14]) and vascular mortality (log rank test p=0.002; HR12.4[1.56-98.4]) over time than the low PCSK9 group. Cox regression analyses showed that high PCSK9 was significantly associated with new MACEs (HR2.74[1.16-6.52]; p=0.02) independent of age, sex, SLE duration, history of nephritis, traditional atherosclerotic risk factors, antiphospholipid antibody, past history of vascular events, and the use of statins, aspirin/warfarin and immunosuppressive drugs (hydroxychloroquine, prednisolone, mycophenolate mofetil, azathioprine and the calcineurin inhibitors) at baseline. High PCSK9 was also independently associated with all-cause (HR2.55[1.27-5.12]; p=0.008) and vascular mortality (HR13.0[1.49-114]; p=0.02).

Conclusion: High circulating levels of PCSK9 increase the risk of MACEs and vascular mortality in patients with SLE.

Disclosure of Interests: None declared