Circulating anti-Ro/Sjögren’s syndrome-related antigen A antibodies and risk of heart rate-corrected QT interval prolongation: a meta-analysis

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. This meta-analysis aims at pooling the available data to provide clarity on this clinically relevant issue.

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. Twenty-five studies were included, pooling 2122 anti-Ro/SSA-positive and 8865 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 more than two times higher risk of QTc prolongation [OR = 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 connective tissue disease, QTc absolute values are higher [SMD = 0.56 (0.20–0.93), P = 0.0026] and QTc prolongation occurs more frequently [OR = 6.99 (2.35–20.75), P < 0.001] than in negative patients; furthermore, QTc prolongation is also more common in systemic lupus erythematosus 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].

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.