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, Paride Fenaroli17, Isabella Pisani17, Giacomo Garibotto15, Carlomaurizio Montecucco6, Domenico Santoro18, Francesco Scolari19, Marta Mosca20, Angela Tincani4, Giovanni Candiano1, Marco Prunotto21, Stefano Volpi22, Enrico Verrina23, Andrea Angeletti23, Angelo Ravelli22, Gian Marco Ghiggeri1,23. 1. Laboratory of Molecular Nephrology, Division of Paediatric Rheumatology and Division of Nephrology, Dialysis and Transplantation, Scientific Institute for Research and Health Care, IRCCS Istituto Giannina Gaslini, Genoa. 2. Division of Nephrology and Dialysis Fondazione, IRCCS Ca' Granda Ospedale Maggiore, Milano. 3. Department of Medicine and Surgery, University of Milan, Bicocca. 4. Rheumatology and Clinical Immunology, ASST SpedaliCivili and Università of Brescia, Brescia. 5. Nephrology and Dialysis Unit, Meyer Children's Hospital, Firenze. 6. Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Firenze, Firenze. 7. Division of Rheumatology, University and IRCCS Policlinico S. Matteo, Pavia. 8. Core Facilities-Proteomics Laboratory, Scientific Institute for Research and Health Care, IRCCS Istituto Giannina Gaslini, Genoa. 9. Clinical Immunology Unit, Department of Internal Medicine, University of Pisa, Pisa. 10. Nephrology and Dialysis, Arciospedale Santa Maria Nuova, Reggio Emilia. 11. Medical and Radiometabolic Therapy Unit, Department of Internal Medicine, University of Genoa, Genoa. 12. Unit of Internal Medicine and Immunology, IRCCS Ospedale San Raffaele, Milano. 13. Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, Pavia. 14. Department of Internal Medicine, University of Genoa, Genoa. 15. Division of Nephrology, University of Genoa and Policlinico San Martino, Genoa. 16. Lupus Clinic, Department of Biomedicine, University of Florence, University Hospital Careggi, Florence. 17. Nephrology Unit, University Hospital, University of Parma, Parma. 18. Nephrology and Dialysis Unit, University of Messina and G Martino Hospital, Messina. 19. Division of Nephrology and Dialysis, University of Brescia and Ospedale di Montichiari, Brescia. 20. Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy. 21. School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland. 22. Division of Paediatric Rheumatology. 23. Division of Nephrology, Dialysis and Transplantation, Scientific Institute for Research and Health Care, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Abstract
OBJECTIVES: Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis. METHODS: A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques. RESULTS: The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low-medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0-12 months), and high levels at T0-1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions. CONCLUSION: Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients. TRIAL REGISTRATION: The Zeus study was registered at https://clinicaltrials.gov, NCT02403115.
OBJECTIVES: Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis. METHODS: A total of 1052 SLEpatients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques. RESULTS: The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLEpatients at low-medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0-12 months), and high levels at T0-1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLEpatients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions. CONCLUSION: Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLEpatients limited to the renal complication and other SLEpatients. TRIAL REGISTRATION: The Zeus study was registered at https://clinicaltrials.gov, 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