Maurizio Bruschi1, Gabriella Moroni2, Renato Alberto Sinico3, Franco Franceschini4, Micaela Fredi4, Augusto Vaglio5,6, Lorenzo Cavagna7, Andrea Petretto8, Federico Pratesi9, Paola Migliorini9, Francesco Locatelli7, Giulia Pazzola10, Giampaola Pesce11, Marcello Bagnasco11, Angelo Manfredi12, Giuseppe A Ramirez12, Pasquale Esposito13, Giuseppe Murdaca14, Simone Negrini14, Leda Cipriani15, Barbara Trezzi3, Giacomo Emmi16, Ilaria Cavazzana4, Valentina Binda2, Matteo d'Alessandro17, Paride Fenaroli18, Isabella Pisani18, Giacomo Garibotto15, Carlomaurizio Montecucco7, Domenico Santoro19, Francesco Scolari20, Stefano Volpi21, Marta Mosca22, Angela Tincani4, Giovanni Candiano1, Marco Prunotto23, Enrico Verrina17, Andrea Angeletti17, Angelo Ravelli21, Gian Marco Ghiggeri1,17. 1. Laboratory of Molecular Nephrology, Scientific Institute for Research and Health Care, IRCCS Istituto Giannina Gaslini, Genoa, Italy. 2. Division of Nephrology and Dialysis, Fondazione IRCCS Ca' Granda Ospedale Maggiore, Milano, Italy. 3. Department of Medicine and Surgery, University of Milan, Bicocca, Italy. 4. Rheumatology and Clinical Immunology, ASST SpedaliCivili and Università of Brescia, Brescia, Italy. 5. Department of Biomedical, Experimental and Clinical Sciences 'Mario Serio', University of Firenze, Firenze, Italy. 6. Nephrology and Dialysis Unit, Meyer Children's Hospital, Firenze, Italy. 7. Division of Rheumatology, University and IRCCS Policlinico S. Matteo, Pavia, Italy. 8. Core Facilities-Proteomics Laboratory, Scientific Institute for Research and Health Care, IRCCS Istituto Giannina Gaslini, Genoa, Italy. 9. Clinical Immunology Unit, Department of Internal Medicine, University of Pisa, Italy. 10. Nephrology and Dialysis, Arciospedale Santa Maria Nuova, Reggio Emilia, Italy. 11. Medical and Radiometabolic Therapy Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy. 12. Unit of Internal Medicine and Immunology, IRCCS Ospedale San Raffaele, Milano, Italy. 13. Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 14. Department of Internal Medicine, University of Genoa, Genoa, Italy. 15. Division of Nephrology, University of Genoa and Policlinico San Martino, Genova, Italy. 16. Lupus Clinic Department of Biomedicine, University of Florence, University Hospital Careggi, Florence, Italy. 17. Division of Nephrology, Dialysis and Transplantation, Scientific Institute for Research and Health Care, IRCCS Istituto Giannina Gaslini, Genoa, Italy. 18. Nephrology Unit, University Hospital, University of Parma, Parma, Italy. 19. Nephrology and Dialysis Unit, University of Messina and G Martino Hospital, Messina, Italy. 20. Division of Nephrology and Dialysis, University of Brescia and Ospedale di Montichiari, Brescia, Italy. 21. Division of Paediatric Rheumatology Scientific Institute for Research and Health Care, IRCCS Istituto Giannina Gaslini, Genoa, Italy. 22. Rheumatologu Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 23. School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
Abstract
OBJECTIVES: Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes. METHODS: Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques. RESULTS: LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T0 and presented the maximal decrement within 12 months. CONCLUSIONS: Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN. TRIAL REGISTRATION: The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).
OBJECTIVES: Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes. METHODS: Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques. RESULTS: LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T0 and presented the maximal decrement within 12 months. CONCLUSIONS: Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN. TRIAL REGISTRATION: The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).
Authors: Maurizio Bruschi; Gabriella Moroni; Renato Alberto Sinico; Franco Franceschini; Micaela Fredi; Augusto Vaglio; Lorenzo Cavagna; Andrea Petretto; Federico Pratesi; Paola Migliorini; Angelo Manfredi; Giuseppe A Ramirez; Pasquale Esposito; Simone Negrini; Barbara Trezzi; Giacomo Emmi; Domenico Santoro; Francesco Scolari; Stefano Volpi; Marta Mosca; Angela Tincani; Giovanni Candiano; Marco Prunotto; Enrico Verrina; Andrea Angeletti; Angelo Ravelli; Gian Marco Ghiggeri Journal: Front Med (Lausanne) Date: 2021-03-22
Authors: Roberta Bertelli; Francesca Schena; Francesca Antonini; Daniele Reverberi; Sara Signa; Nicoletta Pedemonte; Alessandro Consolaro; Marco Gattorno; Simone Negrini; Francesca Pupo; Stefano Volpi; Gian Marco Ghiggeri Journal: Front Med (Lausanne) Date: 2021-04-12