AB1109 DOUBLE FILTRATION PLASMAPHERESIS REDUCES TYPE I INTERFERON BIOAVAILABILITY AND INDUCING ACTIVITY IN PLASMA FROM PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: T. Saito, G. Murayama, M. Kusaoi, K. Yamaji, N. Tamura
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Systemic lupus erythematosus (SLE) is a chronic, progressive autoimmune disease characterized by the loss of immune tolerance and the persistent production of autoantibodies. Type I interferon (IFN-I) plays a significant role in the pathogenesis of SLE, with its production being linked to the activation of the Stimulator of Interferon Genes (STING) pathway in monocytic cells. The significance of IFN-I in the maintenance therapy of SLE has been recently acknowledged, as exemplified by the regulatory approval of anifrolumab, a therapeutic agent targeting IFN-I. In Japan and other parts of Asia, apheresis treatment has been employed since the 1970s, and its efficacy in inducing remission therapy is well-documented. Despite the availability of new drugs that have expanded treatment options for SLE, regular double filtration plasmapheresis (DFPP) remains a staple in maintenance therapy in Japan. However, the specific therapeutic mechanisms within the body have not been fully elucidated, even though DFPP is designed to remove antibody-containing fractions from plasma. <h3>Objectives:</h3> Our study aimed to elucidate the therapeutic mechanisms of DFPP in the context of maintaining SLE therapy, with a particular focus on investigating changes in IFN-I using patient plasma. <h3>Methods:</h3> We collected plasma samples from patients with SLE (n=11) who regularly underwent DFPP at Juntendo University Hospital in Tokyo, Japan. These samples were then analyzed using a cell-based reporter system that allows the detection of IFN-I bioavailability and inducing activity. Additionally, we examined the Stimulator of STING pathway through reporter cells in which STING had been knocked out. We also measured the concentration of plasma double-stranded DNA (dsDNA) using the Pico Green method. Western blot analysis was employed to assess the phosphorylation of STING and Interferon Regulatory Factor (IRF) 3. <h3>Results:</h3> Patients with SLE exhibited higher IFN-I bioavailability in their plasma compared to that of healthy controls (HCs). This heightened bioavailability decreased after undergoing DFPP. Similarly, IFN-I-inducing activity was more pronounced in patients compared to HCs and decreased after undergoing DFPP. The reduction in IFN-I-inducing activity was particularly prominent in patients with higher disease activity. Notably, this reduction was not observed in STING-knockout reporter cells. Additionally, plasma dsDNA levels decreased after DFPP, suggesting that the inhibition of the STING pathway was responsible for the observed decrease in activity. To further support this, we conducted Western blot analysis, which revealed a suppression of STING and IRF3 phosphorylation following DFPP. <h3>Conclusion:</h3> Our findings provide evidence that DFPP effectively reduces IFN-I bioavailability and IFN-I-inducing activity in patients with SLE. This reduction in IFN-I-inducing activity is likely attributable to the inhibition of the STING pathway achieved through the elimination of dsDNA from the bloodstream. Importantly, our study represents the first report to acknowledge the reduction of IFN-I bioavailability and IFN-I-inducing activity as a therapeutic effect of DFPP. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> The authors are deeply grateful to Moeko Inoue for her invaluable contributions as a research assistant, which significantly enriched the quality and success of this study. The authors also thank the members of the Laboratory of Cell Biology and Laboratory of Molecular and Biochemical Research, Biomedical Research Core Facilities, Juntendo University Graduate School of Medicine for their technical assistance. <h3>Disclosure of Interests:</h3> Takumi Saito This work was supported by Asahi Kasei Medical Company Limited as a joint research course., Goh Murayama This work was supported by Asahi Kasei Medical Company Limited as a joint research course., Makio Kusaoi This work was supported by Asahi Kasei Medical Company Limited as a joint research course., Ken Yamaji This work was supported by Asahi Kasei Medical Company Limited as a joint research course., Naoto Tamura AbbVie/Abbott, Bristol-Myers Squibb(BMS), Chugai Pharmaceutical Co.,Ltd, Eisai Co.,Ltd, Eli Lilly, GlaxoSmithKlein(GSK), janssen, Mitsubisi Tanabe Pharma Corporation, Novartis.