BackgroundThe diagnosis of primary Sjögren Disease (SjD) is currently based on a combination of clinical, histological and biological findings [1]. Current thinking supports anti-Ro60 antibodies as the most specific serum marker, while the impact of anti-Ro52 remains unclear [2].ObjectivesThe aim of this study was to characterize the clinical, serological, biological, transcriptomic and interferon profiles of SjD patients according to their anti-Ro52 status and discuss the role of anti-Ro52 in the prognosis of SjD.MethodsSjD patients were recruited from the European PRECISESADS (378 patients) [3] and the independant Brittany DIApSS cohorts (160 patients) [4]. Four groups were defined: double negative (Ro52-/Ro60-), isolated anti-Ro52 positive (Ro52+), isolated anti-Ro60 positive (Ro60+), and double positive (Ro52+/Ro60+) patients. Clinical information, disease activity, and biological markers linked to disease severity were evaluated. Transcriptome data on whole blood by RNAseq and Type I and type II interferon signatures [5,6] were analyzed for PRECISESADS SjD patients.ResultsIn both cohorts, arthritis, parotidomegaly, and biological markers (hypergammaglobulinemia, rheumatoid factor and inflammation) [7] were significantly more frequent in the double positive group as compared to other groups. ESSDAI, a score representing systemic activity [8], was also significantly higher in double positive patients compared to the others. Transcriptome analysis demonstrated that anti-Ro52 positivity was associated with a strong interferon pathway activation as the lead cause to explain the clinical associations.ConclusionTaken together, these results suggest that SjD patients with anti-Ro52 positivity adopt a more severe phenotype as compared to their negative counterparts, independently of anti-Ro60 positivity.References[1]Brito-Zerón P, Baldini C, Bootsma H, Bowman SJ, Jonsson R, Mariette X, et al. Sjögren syndrome. Nat Rev Dis Primer. 2016 Jul 7;2(1):1–20.[2]Decker P, Moulinet T, Pontille F, Cravat M, De Carvalho Bittencourt M, Jaussaud R. An updated review of anti-Ro52 (TRIM21) antibodies impact in connective tissue diseases clinical management. Autoimmun Rev. 2022 Mar;21(3):103013.[3]Soret P, Le Dantec C, Desvaux E, Foulquier N, Chassagnol B, Hubert S, et al. A new molecular classification to drive precision treatment strategies in primary Sjögren’s syndrome. Nat Commun. 2021 Jun 10;12(1):3523.[4]Cornec D, Jousse-Joulin S, Pers JO, Marhadour T, Cochener B, Boisramé-Gastrin S, et al. Contribution of salivary gland ultrasonography to the diagnosis of Sjögren’s syndrome: toward new diagnostic criteria? Arthritis Rheum. 2013 Jan;65(1):216–25.[5]Kirou KA, Lee C, George S, Louca K, Papagiannis IG, Peterson MGE, et al. Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus. Arthritis Rheum. 2004 Dec;50(12):3958–67.[6]Chiche L, Jourde-Chiche N, Whalen E, Presnell S, Gersuk V, Dang K, et al. Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheumatol Hoboken NJ. 2014 Jun;66(6):1583–95.[7]Baldini C, Pepe P, Quartuccio L, Priori R, Bartoloni E, Alunno A, et al. Primary Sjögren’s syndrome as a multi-organ disease: impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients. Rheumatology. 2014 May 1;53(5):839–44.[8]Brito-Zerón P, Kostov B, Solans R, Fraile G, Suárez-Cuervo C, Casanovas A, et al. Systemic activity and mortality in primary Sjögren syndrome: predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients. Ann Rheum Dis. 2016 Feb;75(2):348–55.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
BackgroundAnti-SSA/Ro autoantibodies are among the most frequently detected extractable nuclear antigen autoantibodies and have mainly been associated with primary Sjögren’s syndrome (pSS), systemic lupus erythematosus (SLE) and undifferentiated connective tissue disease (UCTD).ObjectivesIs there a common signature to all patients expressing anti-Ro60 autoantibodies regardless of their disease phenotype?MethodsUsing high-throughput multi-omics data collected within the cross-sectional cohort from the PRECISESADS IMI project [1] (genetic, epigenomic, transcriptomic, combined with flow cytometric data, multiplexed cytokines, classical serology and clinical data), we assessed by machine learning the integrated molecular profiling of 520 anti-Ro60-positive (anti-Ro60+) compared to 511 anti-Ro60-negative (anti-Ro60-) patients with pSS, SLE and UCTD, and 279 healthy controls (HCs).ResultsThe selected features for RNA-Seq, DNA methylation and GWAS data allowed a clear separation between anti-Ro60+ and anti-Ro60- patients. These results demonstrate that the different features selected by machine learning from the anti-Ro60+ patients constitute specific signatures when compared to anti-Ro60- patients and HCs. Remarkably, the gene transcript z-score of three genes (ATP10A, MX1 and PARP14), presenting an overexpression associated with a hypomethylation and genetic variation, and independently identified by the Boruta algorithm, was clearly higher in anti-Ro60+ patients compared to anti-Ro60- patients in all the diseases (Figure 1). Finally, we demonstrate that these signatures, enriched in interferon stimulated genes, were also found in anti-Ro60+ patients with rheumatoid arthritis and systemic sclerosis.Figure 1.Three genes common to RNA-Seq, DNA methylation and GWAS analysis characterize anti-Ro60+ patients. (A) ATP10/MX1/PARP14 z-score analyses were performed for 731 patients and 254 HCs according to anti-Ro60 expression. (B) ATP10/MX1/PARP14 z-score analyses were performed for 286 pSS, 351 SLE and 94 UCTD patients and 254 HCs. Two-tailed pairwise Wilcoxon-rank sum test results are shown. Plots show median, with error bars indicating ± interquartile range. (pSS: primary Sjögren’s syndrome, SLE: systemic lupus erythematosus, UCTD: undifferentiated connective tissue disease, HCs: healthy controls).ConclusionAnti-Ro60+ patients present a specific inflammatory signature regardless of their disease suggesting that a dual approach targeting both Ro-associated RNAs and anti-Ro60 autoantibodies should be considered.References[1]Barturen G, Babaei S, Català-Moll F, Martínez-Bueno M, Makowska Z, Martorell-Marugán J, et al. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases. Arthritis Rheumatol Hoboken NJ. 2021 Jun;73(6):1073–85FundingThe research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under the Grant Agreement Number 115565 (PRECISESADS project), resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007–2013) and EFPIA companies’ in-kind contribution.AcknowledgementsThe study has been conducted thank to the contribution of the PRECISESADS clinical consortium and the PRECISESADS flow cytometry consortium.Disclosure of InterestsNone declared.
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