Reply

We thank Ran et al. for their comments on our work investigating the association of autoantibodies with lupus nephritis (LN) histological features and treatment response¹. As the primary aim of our study was to assess the clinical relevance of autoantibodies as biomarkers,² defining additional autoantibody mechanisms was beyond the scope of this paper. However, as speculated in our manuscript discussion, we agree that anti-C1q may inhibit apoptotic cell uptake, potentially increasing autoantigen exposure and immune complex deposition.³ Although significant work has occurred in epitope mapping and animal models,^3–5 we agree that additional mechanistic work in large cohorts of diverse SLE patients would be helpful. In addition, we agree that our findings may suggest that membranous LN involves non-antibody-dependent mechanisms or autoantibodies with specificities that were not explored in our study, as highlighted in the discussion of our manuscript.

While we appreciate Ran et al.’s insights, we have a different perspective on a couple of points. Specifically, our primary focus was on the predictive value of baseline autoantibody levels rather than changes over time. Therefore, whether the changes in autoantibody levels were driven by immunosuppression or actual disease improvement does not diminish the clinical utility of our findings. Furthermore, all patients with clinically actionable results were treated with immunosuppression, as is the standard of care. Since treatment was not protocolized, patients received different regimens according to their history at the discretion of their physician. It may be impossible to evaluate whether decreases in autoantibodies are from immunosuppression or treatment-associated disease improvement via different modes of action. This may need further investigation in clinical trials with access to deep phenotyping and repeat biopsies or in animal models.

In this study, multiple positive autoantibodies are associated with proliferative disease, but we did not observe differences in the number of positive autoantibodies based on treatment response in either proliferative or membranous LN patients. We did see that patients with a complete response were more likely to decrease their anti-Sm/anti-nRNP antibody responses by 6 to 12 months after biopsy. Given the heterogeneity of autoantibody expression in LN patients, we agree that further investigation into the role of specific autoantibody combinations in disease progression is important to the field.

Finally, we acknowledge that variability in testing methods across laboratories presents a challenge in translating these biomarkers into clinical practice. However, our findings underscore the clinical need for standardized, commercially available assays for anti-C1q to facilitate their broader clinical use across nations.