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ObjectivesThis study aimed to: 1) Analyze the circulating inflammatory profile of Rheumatoid Arthritis (RA) patients, in order to recognize distinctive clinical phenotypes associated with CV risk; 2) Evaluate modulatory effects of TNF inhibitors (TNFi), JAK-STAT inhibitors (JAKInibs) and IL-6R inhibitors (IL6Ri); 3) Characterize underlying molecular mechanisms involved in endothelial dysfunction.MethodsTwo hundred and eight RA patients and 45 healthy donors (HD) were recruited. Serum inflammatory profile was assessed by analyzing 27 cytokines/chemokines -Luminex assays-, and biomolecules related to NETosis and oxidative stress -by base-plate kits-. Parallel extensive clinical analyses were performed. TNFi, JAKinibs and IL-6Ri effects were evaluated, respectively, in 45, 20 and 17 RA patients after 6 months. Lastly, mechanisticin vitrostudies were developed in cultured endothelial cells (ECs) and changes in protein expression were evaluated in cell lysates by proximity extension assay technology, analyzing a panel of 88 proteins related to CV disease.ResultsUnsupervised-clustering identified 3 clusters representing specific molecular profiles. Clinically, even in the presence of similar disease score (DAS28) and positivity for autoantibodies, cluster 1 (C1) identified RA-patients expressing high inflammatory mediators’ levels, the highest CV-risk score, and a preponderance of atheroma plaques. Conversely, RA-patients conforming C3 showed the lowest inflammatory profile and the lowest CV-risk score. Lastly, C2 characterized an intermediate phenotype. Comparative analyses with a cohort of 98 RA patients presenting previous CV events, demonstrated that their inflammatory profile mimicked that found in C1, supporting the association of this altered shape with the CV status.In vivo, both biological and targeted-synthetic DMARDs’ therapy reduced DAS28-score and re-established normal levels of several altered biomolecules, reflecting a key role in the CV-risk control.In vitro, RA patients’ serum pool from cluster 1 promoted in cultured ECs increased expression of several CV-related proteins, further prevented-albeit in an specific way- by the pre-incubation with TNFi (Etanercept), JAKinibs (Baricitinib) and anti-IL6Ri (Tocilizumab).Conclusion:1. The systemic inflammatory profile of RA identified patients’ subgroups with enhanced CV-risk, not associated with their disease activity status.2. Both biological and targeted-synthetic DMARDs re-established normal levels of circulating inflammatory biomolecules, reducing the CV-risk in RA.3.In vitrostudies revealed that RA-serum inflammatory mediators directly induced endothelial damage which might be prevented by effect of both, biological and targeted-synthetic DMARDs’ therapy.Thus, the analysis of the RA patients circulating molecular profile might contribute to improve the personalized clinical management of these patients and their CV risk.AcknowledgementsSupported by ISCIII (PI21/0591, CD21/00187 and RICOR-RD21/0002/0033), and Junta de Andalucía (P20_01367) co-financed by FEDER; Fundacion Andaluza de Reumatología (FAR).Disclosure of InterestsNone Declared.

BackgroundIgA vasculitis (IgAV) and IgA nephropathy (IgAN) are inflammatory conditions that share pathophysiological mechanisms, being B-cells crucial players in both diseases [1]. In this regard, some authors have suggested that IgAV and IgAN may represent different outcomes of a continuous spectrum of a disease [2]. In addition,CD40, BLKandBANK1are relevant genes involved in the development and signalling of B-cells and are also identified as susceptibilitylocifor several immune-mediated diseases [3-6].ObjectivesTo determine whether IgAV and IgAN may be different outcomes of a single disease, by assessing theCD40, BLKandBANK1genetic pattern.MethodsThree genetic variants withinCD40(rs1883832, rs1535045, rs4813003), three genetic polymorphisms withinBLK(rs2254546, rs2736340, rs2618476) as well as twoBANK1genetic variants (rs10516487, rs3733197) were genotyped in 380 Caucasian patients diagnosed with IgAV, 90 patients diagnosed with IgAN and 1,012 ethnically matched healthy controls. The eight polymorphisms selected were previously associated with several inflammatory diseases [3-6].ResultsSimilar genotype and allele frequencies were observed in IgAV patients when compared to those with IgAN, whenCD40, BLKandBANK1variants were analyzed independently (Table 1). In addition, no statistically significant differences were observed between patients with IgAV and healthy controls as well as between patients with IgAN and healthy controls, whenCD40, BLKandBANK1genetic variants were analyzed independently (Table 1). Similar results were disclosed when haplotype frequencies ofCD40, BLKandBANK1were compared between patients with IgAV and those with IgAN, as well as between patients with IgAV and healthy controls and between IgAN and healthy controls.ConclusionOur results reveal a similarCD40, BLKandBANK1genetic distribution in IgAV and IgAN, supporting that IgAV and IgAN may represent different outcomes of a single disease.References[1] N Engl J Med 2013;368:2402-14;[2] Am J Kidney Dis 1988;12:373-7;[3] Nat Genet 2009;41:824-8;[4] Ann Rheum Dis 2012;71:136-42;[5] Nat Genet 2012;44:517-21;[6] Nat Genet 2012;44:522-5.Table 1.Genotype and allele frequencies ofCD40, BLKandBANK1in patients with IgAV, patients with IgAN and healthy controls.ChangeGenotypes, % (n)Alleles, % (n)Polymorphism1/2Data set1/11/22/212CD40rs1883832C/TIgAV54.0 (204)37.0 (140)9.0 (34)72.5 (548)27.5 (208)IgAN56.5 (48)36.5 (31)7.0 (6)74.7 (127)25.3 (43)Healthy controls52.9 (532)40.4 (409)6.7 (68)73.1 (1,479)26.9 (545)CD40rs1535045C/TIgAV53.6 (200)39.4 (147)7.0 (26)73.3 (547)26.7 (199)IgAN51.8 (44)41.2 (35)7.1 (6)72.4 (123)27.6 (47)Healthy controls56.7 (574)36.2 (366)7.1 (72)74.8 (1,514)25.2 (510)CD40rs4813003C/TIgAV78.0 (291)20.1 (75)1.9 (7)88.1 (657)11.9 (89)IgAN76.6 (59)20.8 (16)2.6 (2)87.0 (134)13.0 (20)Healthy controls74.9 (758)22.7 (230)2.4 (24)86.3 (1,746)13.7 (278)BLKrs2254546G/AIgAV74.5 (278)22.3 (83)3.2 (12)85.7 (639)14.3 (107)IgAN64.7 (55)31.8 (27)3.5 (3)80.6 (137)19.4 (33)Healthy controls71.3 (722)26.8 (271)1.9 (19)84.7 (1,715)15.3 (309)BLKrs2736340C/TIgAV62.8 (236)31.9 (120)5.3 (20)78.7 (592)21.3 (160)IgAN67.5 (52)31.2 (24)1.3 (1)83.1 (128)16.9 (26)Healthy controls59.9 (606)35.8 (362)4.3 (44)77.8 (1,574)22.2 (450)BLKrs2618476T/CIgAV60.2 (227)34.2 (129)5.6 (21)77.3 (583)22.7 (171)IgAN68.2 (58)24.7 (21)7.1 (6)80.6 (137)19.4 (33)Healthy controls57.9 (586)37.3 (377)4.8 (49)76.5 (1,549)23.5 (475)BANK1rs10516487G/AIgAV52.8 (200)39.8 (151)7.4 (28)72.7 (551)27.3 (207)IgAN50.6 (42)38.6 (32)10.8 (9)69.9 (116)30.1 (50)Healthy controls50.8 (514)41.8 (423)7.4 (75)71.7 (1,451)28.3 (573)BANK1rs3733197G/AIgAV50.0 (187)39.0 (146)11.0 (41)69.5 (520)30.5 (228)IgAN47.1 (40)37.6 (32)15.3 (13)65.9 (112)34.1 (58)Healthy controls49.5 (501)41.6 (421)8.9 (90)70.3 (1,423)29.7 (601)AcknowledgementsThis study has been funded by Instituto de Salud Carlos III (ISCIII) through the project PI18/00042 and PI21/00042, co-funded by European Regional Development Fund (ERDF), `Investing in your future´; VP-C: PI18/00042 from ISCIII, co-funded by ERDF; MSM-G is supported by funds of TRANSVAL22/01 from IDIVAL; RL-M: Miguel Servet type II programme fellowship from the ISCIII, co-funded by the European Social Fund (`Investing in your future´) [CPII21/00004].Disclosure of InterestsVerónica Pulito-Cueto: None declared, Fernanda Genre Romero: None declared, Sara Remuzgo Martinez: None declared, Belén Sevilla: None declared, Norberto Ortego: None declared, Maite Leonardo: None declared, Ana Peñalba: None declared, J. Narváez: None declared, Luis Martín-Penagos: None declared, Lara Belmar-Vega: None declared, Cristina Gomez-Fernandez: None declared, María Sebastián Mora-Gil: None declared, LUIS CAMINAL MONTERO: None declared, PAZ COLLADO: None declared, Antonio Fernandez-Nebro: None declared, Gisela Diaz-Cordobes: None declared, Secundino Cigarrán: None declared, Jesús Calviño: None declared, Carmen Cobelo: None declared, Diego de Argila: None declared, Javier Sanchez Perez: None declared, Miren Uriarte-Ecenarro: None declared, Esteban Rubio-Romero: None declared, MANUEL LEON LUQUE: None declared, Juan María Blanco-Madrigal: None declared, E. Galíndez-Agirregoikoa: None declared, Javier Martin Ibanez: None declared, Santos Castañeda: None declared, Miguel A González-Gay Speakers bureau: Abbvie, Pfizer, Roche, Sanofi, Lilly, Celgene, MSD and GSK, Grant/research support from: Abbvie, MSD, Jansen and Roche, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Raquel López-Mejías: None declared.

BackgroundSeveral mucosal immune defence polymorphisms have an impact on IgA production by plasma cells in the mucosa [1]. In this regard, these genetic variants have been previously reported as susceptibilitylocifor IgA nephropathy [1]. Given the pathophysiological similarities described between IgA nephropathy and Immunoglobulin-A vasculitis (IgAV) [2, 3], mucosal immune defence polymorphisms may also be implicated in the pathogenesis of IgAV.ObjectivesTo determine whether mucosal immune defence polymorphisms represent novel genetic risk factors for the pathogenesis of IgAV.Methods6 mucosal immune defence polymorphisms previously described as susceptibilitylocifor IgA nephropathy (ITGAM-ITGAXrs11150612,VAV3rs17019602,CARD9rs4077515,CFHR3.1-delrs6677604,DEFArs2738048 andHORMAD2rs2412971) were selected. These 6 genetic variants were genotyped in 300 unrelated Caucasian patients with IgAV (the largest series of Caucasian IgAV patients assessed for genetic studies) and 1,012 matched healthy controls. 36.1% of the IgAV patients developed renal manifestations.ResultsNo statistically significant differences were observed in the genotype and allele frequencies of mucosal immune defence polymorphisms when IgAV patients and healthy controls were compared (Table 1). Moreover, no statistically significant differences were disclosed in the genotype and allele frequencies of the 6 polymorphisms selected when patients with IgAV were stratified according to the presence/absence of renal manifestations (Table 1). Likewise, similar genotype and allele frequencies of these polymorphisms were disclosed in patients with IgAV stratified according to the age at disease onset and to the presence/absence of gastrointestinal manifestations.ConclusionOur results reveal that mucosal immune defence polymorphisms do not contribute to the genetic background of IgAV.References[1] Nat Genet 2014, 46, 1187-96[2] N Engl J Med 2002, 347, 738-48[3] N Engl J Med 2013, 368, 2402-14.Table 1.Genotype and allele frequencies of mucosal immune defence polymorphisms in controls, patients with IgAV as well as patients with IgAV stratified according to the presence/absence of renal manifestations.ChangeGenotypes, % (n)Alleles, % (n)Polymorphism1/2Data set1/11/22/212ITGAM-ITGAXrs11150612G/AControls40.2 (407)46.3 (468)13.5 (137)63.3 (1.282)36.7 (742)IgAV39.6 (113)43.2 (123)17.2 (49)61.2 (349)38.8 (221)IgAV with nephritisIgAV without nephritis33.0 (36)43.8 (77)44.0 (48)42.6 (75)22.9 (25)13.6 (24)55.0 (120)65.0 (229)45.0 (98)35.0 (123)VAV3rs17019602A/GControls59.8 (605)35.4 (358)4.8 (49)77.5 (1,568)22.5 (456)IgAV62.1 (177)34.0 (97)3.9 (11)79.1 (451)20.9 (119)IgAV with nephritisIgAV without nephritis62.4 (68)61.9 (109)35.8 (39)33.0 (58)1.8 (2)5.1 (9)80.3 (175)78.4 (276)19.7 (43)21.6 (76)CARD9rs4077515C/TControls38.4 (389)46.1 (466)15.5 (157)61.5 (1,244)38.5 (780)IgAV35.4 (101)49.5 (141)15.1 (43)60.2 (343)39.8 (227)IgAV with nephritisIgAV without nephritis35.8 (39)35.2 (62)45.9 (50)51.7 (91)18.3 (20)13.1 (23)58.7 (128)61.1 (215)41.3 (90)38.9 (137)CFHR3.1-delrs6677604G/AControls63.5 (642)31.1 (315)5.4 (55)79.0 (1,599)21.0 (425)IgAV63.9 (182)30.9 (88)5.2 (15)79.3 (452)20.7 (118)IgAV with nephritisIgAV without nephritis67.0 (73)61.9 (109)28.4 (31)32.4 (57)4.6 (5)5.7 (10)81.2 (177)78.1 (275)18.8 (41)21.9 (77)DEFArs2738048A/GControls51.8 (524)39.8 (403)8.4 (85)71.7 (1,451)28.3 (573)IgAV46.7 (133)42.8 (122)10.5 (30)68.1 (388)31.9 (182)IgAV with nephritisIgAV without nephritis50.5 (55)44.3 (78)40.4 (44)44.3 (78)9.1 (10)11.4 (20)70.6 (154)66.5 (234)29.4 (64)33.5 (118)HORMAD2rs2412971G/AControls27.4 (277)51.2 (518)21.4 (217)53.0 (1,072)47.0 (952)IgAV29.1 (83)52.3 (149)18.6 (53)55.3 (315)44.7 (255)IgAV with nephritisIgAV without nephritis30.3 (33)28.4 (50)47.7 (52)55.1 (97)22.0 (24)16.5 (29)54.1 (118)56.0 (197)45.9 (100)44.0 (155)AcknowledgementsThis study has been funded by Instituto de Salud Carlos III (ISCIII) through the project PI18/00042 and PI21/00042, co-funded by European Regional Development Fund (ERDF), `Investing in your future´; VP-C: PI18/00042 from ISCIII, co-funded by ERDF; MSM-G is supported by funds of TRANSVAL22/01 from IDIVAL; RL-M: Miguel Servet type II programme fellowship from the ISCIII, co-funded by the European Social Fund (`Investing in your future´) [CPII21/00004].Disclosure of InterestsVerónica Pulito-Cueto: None declared, Sara Remuzgo Martinez: None declared, Fernanda Genre Romero: None declared, Belén Sevilla: None declared, Norberto Ortego: None declared, Maite Leonardo: None declared, Ana Peñalba: None declared, J. Narváez: None declared, Luis Martín-Penagos: None declared, Lara Belmar-Vega: None declared, Cristina Gomez-Fernandez: None declared, María Sebastián Mora-Gil: None declared, LUIS CAMINAL MONTERO: None declared, PAZ COLLADO: None declared, Diego de Argila: None declared, PEDRO RODRIGUEZ-JIMENEZ: None declared, Esther F. Vicente-Rabaneda: None declared, Esteban Rubio-Romero: None declared, MANUEL LEON LUQUE: None declared, Juan María Blanco-Madrigal: None declared, E. Galíndez-Agirregoikoa: None declared, Javier Martin Ibanez: None declared, Santos Castañeda: None declared, Miguel A González-Gay Speakers bureau: Abbvie, Pfizer, Roche, Sanofi, Lilly, Celgene, MSD and GSK, Grant/research support from: Abbvie, MSD, Jansen and Roche, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Raquel López-Mejías: None declared.