Rare Germline Variants in Complement Regulatory Genes in Antiphospholipid Antibody Positive Patients: Prospective Results from AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository (“Registry”)

Cécile Yelnik¹, shruti chaturvedi², Julien Labreuche³, Xiang-Zuo Pan², H Michael Belmont⁴, Nina Kello⁵, Paul Fortin⁶, David Branch⁷, Yu Zuo⁸, Rohan Willis⁹, Robert Brodsky², Jane Salmon¹⁰, Maria Laura Bertolaccini¹¹, Hannah Cohen¹², Michelle Petri¹³ and Doruk Erkan¹⁰, and on behalf of APS ACTION, ¹lille university, Lille, France, ²John Hopkins University, Baltimore, MD, ³Lille University Hospital, Lille, France, ⁴NYU Langone Health, New York, NY, ⁵Northwell Health, Brooklyn, NY, ⁶Centre ARThrite - CHU de Québec - Université Laval, Quebec, QC, Canada, ⁷University of Utah and Intermountain Healthcare, Salt Lake City, UT, ⁸University of Michigan, Ann Arbor, MI, ⁹University of Texas Medical Branch, Galveston, TX, ¹⁰Hospital for Special Surgery, New York, NY, ¹¹King's College London, London, United Kingdom, ¹²University College London Hospitals NHS Foundation Trust, London, United Kingdom, ¹³Johns Hopkins University School of Medicine, Timonium, MD

Meeting: ACR Convergence 2024

Keywords: antiphospholipid syndrome, complement, genetics

Session Information

Date: Saturday, November 16, 2024

Title: Antiphospholipid Syndrome Poster

Session Type: Poster Session A

Session Time: 10:30AM-12:30PM

Background/Purpose: We previously reported that markers of complement activation, specifically elevated C4d levels and positive modified HAM (mHAM) test, are associated with a higher risk of new thrombosis in our multi-center cohort of antiphospholipid antibody (aPL)-positive patients (Arthritis Rheumatol 2023; 75 [suppl 9]). This follow-up study aimed to evaluate the prevalence of rare germline variants in complement regulatory genes in these aPL-positive patients with or without new (first or recurrent) thrombosis, given that another cohort analysis previously demonstrated high rates of rare germline variants in catastrophic APS patients (60%), compared with APS patients (22%) or normal controls (24%) (Chatuverdi et al Blood. 2020;135:239).

Methods: APS ACTION registry inclusion criteria are positive aPL based on the Revised Sapporo APS Classification Criteria, tested at least twice within one year prior to enrollment. Patients are prospectively followed every 12±3m with clinical data and blood collection. Among North American APS ACTION centers, we identified patients with new thrombosis during follow-up, and controls without new thrombosis, matched (1:1) for gender, age (±5 years), history of thrombosis, and associated systemic autoimmune rheumatic disease. Complement split product assessments and functional analysis of complement activation based on mHam assay were previously described. As a follow-up, we performed a genetic analysis of complement regulatory genes by next generation sequencing, using a custom panel of genes (ADAMTS13, VWF, CFH, CFB, CFI, CFD, CFP, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, C3, C5, MCP, THBD, CR1, and DGKE), based on baseline registry samples.

Results: As of May 2022, 365 aPL-positive patients from North American APS ACTION centers were included in the registry; 27 (7%) patients had a new thrombosis during the prospective follow-up, and were matched with 25 patients without new thrombosis. Among 52 patients, 48 had available samples for genetic analysis; at least one rare germline variant in complement regulatory genes was identified in 15 (31%) patients (2/15 had two different variants). These variants were located on ADAMTS13 gene (n:5), CR1 (n:3), C5 (n:2), CFP (n:2), CFHR4 or 5 (n:2), CFI (n:1), DGKE (n:1), and THBD (n:1). When we compared aPL-positive patients with (n:15) or without (n:33) germline variants, we found no difference among baseline characteristics (Table), the frequency of new thrombosis during the follow-up [6 (40%) vs 17 (52%), p:0.45], complement split products plasma levels (C4d, Bb, sC5b-9), and the number of patients with positive mHAM (3 [20%] vs 5 [15%], p:0.69].

Conclusion: Although one-third of our persistently aPL-positive patients have rare germline variants in complement regulatory genes, we did not observe any association with APS manifestations or other markers of complement activation. Future analysis of the entire cohort, including evaluating the functional significance of these variants, may help further understand the interaction between autoantibodies, genes, and the environmental triggers in APS.

Table 1: Baseline Characteristics of Antiphospholipid Antibody (aPL)-positive Patients with or without New Thrombosis During the Follow-up

Disclosures: C. Yelnik: None; s. chaturvedi: AstraZeneca, 1, 2, BioCryst, 2, Kyowa Kirin Pharmaceuticals, 2, Novartis, 1, Sanofi, 1, 2, Sobi, 1, Takeda, 1; J. Labreuche: None; X. Pan: None; H. Belmont: None; N. Kello: None; P. Fortin: AstraZeneca, 2, 6, GlaxoSmithKlein(GSK), 2, 6, Moderna, 2; D. Branch: UCB Pharma Inc, 5; Y. Zuo: None; R. Willis: Louisville APL Diagnostics Inc, 2, 8; R. Brodsky: None; J. Salmon: UCB, 2, 5; M. Bertolaccini: None; H. Cohen: argenx, 1, GlaxoSmithKlein(GSK), 6, Roche, 1, Technoclone (paid to Univ Coll London Hosp Charity), 6, UCB (paid to Univ College London Hosp Charity), 2; M. Petri: Amgen, 2, AnaptysBio, 2, Annexon Bio, 2, Arthros-FocusMedEd, 6, AstraZeneca, 2, 5, Atara Biosciences, 2, Aurinia, 5, 6, Autolus, 2, Avoro Ventures, 2, Biocryst, 2, Boxer Capital, 2, Cabaletto Bio, 2, Caribou Biosciences, 2, CTI, 1, CVS Health, 1, Eli Lilly, 2, 5, Emergent Biosolutions, 1, Ermiium, 2, Escient Pharmaceuticals, 2, Exagen, 5, Exo Therapeutics, 2, Gentibio, 2, GlaxoSmithKlein(GSK), 2, 5, iCell Gene Therapeutics, 2, Innovaderm Research, 2, IQVIA, 1, Janssen, 5, Kira Pharmaceuticals, 2, Merck/EMD Serono, 1, Nexstone Immunology, 2, Nimbus Lakshmi, 2, Novartis, 2, PPD Development, 2, Precision Biosciences, 2, Proviant, 2, Regeneron Pharmaceuticals, 2, Sanofi, 2, Seismic Therapeutic, 2, Senti Bioscienes, 2, Sinomab Biosciences, 2, Takeda, 2, Tenet Medicines Inc, 2, TG Therapeutics, 2, UCB, 2, Vertex Pharmaceuticals, 2, Worldwide Clinical Trials, 1, Zydus, 2; D. Erkan: ACR, 5, APS ACTION, 4, Argenx, 1, Cadrenal, 2, Chugai, 1, EULAR, 5, Exagen, 5, GlaxoSmithKlein(GSK), 2, 5, 6, Kyverna, 1, NIH, 5, Otsuka/Visterra, 1, Up-To-Date, 9.

To cite this abstract in AMA style:

Yelnik C, chaturvedi s, Labreuche J, Pan X, Belmont H, Kello N, Fortin P, Branch D, Zuo Y, Willis R, Brodsky R, Salmon J, Bertolaccini M, Cohen H, Petri M, Erkan D. Rare Germline Variants in Complement Regulatory Genes in Antiphospholipid Antibody Positive Patients: Prospective Results from AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository (“Registry”) [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/rare-germline-variants-in-complement-regulatory-genes-in-antiphospholipid-antibody-positive-patients-prospective-results-from-antiphospholipid-syndrome-alliance-for-clinical-trials-and-international/. Accessed .

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