Circulating anti-Ro/SSA-antibodies and risk of heart rate-corrected QT interval prolongation: a meta-analysis

Abstract Backgrounds Accumulating evidence indicates that anti-Ro/Sjögren’s syndrome-related antigen A(SSA)-antibodies, specifically the anti-Ro/SSA-52kD subtype, can promote heart rate-corrected QT interval(QTc) prolongation by inhibiting the hERG-K+ channel. However, the numerous clinical studies published over the past two decades yielded conflicting results. Objective This meta-analysis aims at pooling the available data to provide clarity on this clinically relevant issue. Methods A systematic review was performed for clinical studies comparing QTc in anti-Ro/SSA-positive vs. -negative subjects. Standardized mean differences(SMDs) and odds ratios(ORs) were compared using random effects models. The risk of bias was assessed using RoBANS2, Egger's test and contour-enhanced funnel plots. Results Twenty-five studies were included, pooling 2,122 anti-Ro/SSA-positive and 8,865 anti-Ro/SSA-negative subjects. Overall, anti-Ro/SSA-positivity is associated with a longer QTc(SMD=0.36[0.18–0.53], p<0.001), and a >2-times higher risk of QTc prolongation(2.24[1.54-3.27], p<0.001). Several sub-analyses supported and refined these findings. Specifically, in anti-Ro/SSA-positive patients with unselected CTD, QTc absolute values are higher(SMD=0.57[0.20-0.94], p=0.002) and QTc prolongation occurs more frequently(OR=7.62[2.50-23.21], p<0.001) than in negative patients; furthermore, QTc prolongation is also more common in SLE patients with circulating anti-Ro/SSA-antibodies than in those without(OR=1.86[1.19–2.90], p=0.006). Finally, in anti-Ro/SSA-52kD-positive subjects, the QTc is longer compared to the negative ones(SMD=0.43[0.15–0.71], p=0.002). Conclusions This meta-analysis supports the conclusion that circulating anti-Ro/SSA-antibodies per se represents a significant risk factor for QTc prolongation. However, the presence of several conflicting studies suggests that a more accurate investigation of specific factors, such as the impact of individual antibody subtype levels(anti-52kD/anti-60kD), will be critical to fully clarify the topic and its implications in clinical practice.