Influence of anti-carbamylated protein antibodies on disease activity and joint erosions in seronegative and seropositive rheumatoid arthritis.

Anti-carbamylated protein (anti-CarP) antibodies are promising biomarkers in rheumatoid arthritis (RA), although their significance in seronegative disease (SNRA) remains uncertain. To assess the influence of anti-CarP antibodies on disease activity and erosive joint damage in SNRA patients. In RA patients, rheumatoid factor (RF), anti-citrullinated protein antibodies, and anti-CarP antibodies were measured. Disease activity was assessed using DAS28-CRP and SDAI indices, while musculoskeletal ultrasound identified bone erosions. A total of 77 patients were enrolled, comprising 49 with seropositive RA (SPRA) and 28 with SNRA. Notably, 28% of SPRA and 10% of SNRA patients were positive to anti-CarP antibodies. Anti-CarP-positive patients exhibited elevated C-reactive protein (median 10.6, interquartile range 4.6-20.0 vs. 3.4, 1.7-9.9 mg/L; p = 0.005), erythrocyte sedimentation rate (34, 19-46 vs. 16, 7-25 mm/h; p = 0.002), DAS28-CRP (3.2, 2.6-4.2 vs. 2.6, 1.9-3.5; p = 0.048), and SDAI (19.9, 6.3-32.1 vs. 10.9, 5.5-18.1; p = 0.034) indices. Multivariate analysis revealed RF positivity as the sole predictor for anti-CarP antibodies (odds ratio [OR] = 5.9). Musculoskeletal ultrasound revealed bone erosions in 36% of RA patients; 35% among anti-CarP-negative patients and 40% among anti-CarP-positive patients. Notably, RF presence (OR = 44.3) and DAS28-CRP index (OR = 2.4) emerged as predictors of musculoskeletal ultrasound-confirmed erosive joint disease. Anti-CarP antibodies are detected at similar frequencies among both SPRA and SNRA patients. While associated with increased disease activity, these antibodies did not correlate with increased erosive joint damage.

Anti-Ro52/TRIM21 antibodies are associated with aberrant inflammatory circuits in patients with systemic autoimmune rheumatic diseases.

INTRODUCTION: Anti-Ro52/TRIM21 antibodies are markers for several systemic autoimmune rheumatic diseases (SARD). OBJECTIVE: To assess whether anti-Ro52/TRIM21 antibodies are related to abnormalities in inflammatory circuits. METHODS: Cross-sectional study of consecutive outpatients with SARD. Anti-Ro52/TRIM21 antibodies and serum amyloid A protein were measured by ELISA; panels for 18 cytokines and nine chemokines were analyzed on a Luminex reading platform, while high-sensitivity C-reactive protein (hs-CRP) and complement were measured by nephelometry. RESULTS: Among 167 included patients, 143 had systemic lupus erythematosus (SLE), 16 had primary Sjögren's syndrome and eight had systemic sclerosis; 41 (24%) were positive for anti-Ro52/TRIM21 antibodies. Patients with anti-Ro52/TRIM21 antibodies had higher serum levels of IL-2, IL-4, IL-6, GM-CSF, IL-21, IL-22, hs-CRP and chemokines CCL4, CXCL8, CXCL10 and CXCL12, but lower levels of complement C4. Anti-Ro52/TRIM21 antibody titers were positively correlated with IL-2, IL-4, IL-6, IL-10, IL-21, IL-22, CXCL10, and hs-CRP, and negatively with complements C3 and C4. When only SLE patients were included, no association was identified between anti-Ro52/TRIM21 antibodies and disease activity or organ-specific involvement. CONCLUSIONS: Anti-Ro52/TRIM21 antibodies are associated with aberrant cytokine circuits and elevated levels of angiogenic molecules and neutrophil and monocyte chemoattractants, which suggests an active role for these antibodies in SARD.

INTRODUCCIÓN: Los anticuerpos anti-Ro52/TRIM21 son marcadores de varias enfermedades reumáticas autoinmunes sistémicas (ERAS). OBJETIVO: Evaluar si los anticuerpos anti-Ro52/TRIM21 están relacionados con anomalías en los circuitos inflamatorios. MÉTODOS: Estudio transversal de pacientes consecutivos y ambulatorios con ERAS. Los anticuerpos anti-Ro52/TRIM21 y la proteína amiloide sérica se midieron mediante ELISA; los paneles para 18 citocinas y nueve quimiocinas se analizaron en una plataforma de lectura Luminex; la proteína C reactiva (hs-CRP) y el complemento se midieron mediante nefelometría. RESULTADOS: Se incluyeron 167 pacientes, 143 con lupus eritematoso sistémico (LES), 16 con síndrome de Sjögren primario y ocho con esclerosis sistémica; 41 fueron positivos para anticuerpos anti-Ro52/TRIM21 (24 %). Los pacientes con anticuerpos anti-Ro52/TRIM21 tuvieron niveles séricos más altos de IL-2, IL-4, IL-6, GM-CSF, IL-21, IL-22, hs-CRP y quimiocinas CCL4, CXCL8, CXCL10 y CXCL12; y más bajos de complemento C4. Los títulos de anticuerpos anti-Ro52/TRIM21 correlacionaron positivamente con IL-2, IL-4, IL-6, IL-10, IL-21, IL-22, CXCL10 y hs-CRP; y negativamente con complemento C3 y C4. Al incluir solo LES, no se identificó asociación entre los anticuerpos anti-Ro52/TRIM21 y la actividad de la enfermedad o la afectación específica de órganos. CONCLUSIONES: Los anticuerpos anti-Ro52/TRIM21 se asocian a circuitos aberrantes de citocinas y niveles elevados de moléculas angiogénicas y quimioatrayentes de neutrófilos y monocitos, lo que sugiere un papel activo de esos anticuerpos en las ERAS.

Los anticuerpos anti-Ro52/TRIM21 están asociados a circuitos inflamatorios aberrantes en pacientes con enfermedades reumáticas autoinmunes sistémicas / Anti-Ro52/TRIM21 antibodies are associated with aberrant inflammatory circuits in patients with systemic autoimmune rheumatic diseases

Resumen Introducción: Los anticuerpos anti-Ro52/TRIM21 son marcadores de varias enfermedades reumáticas autoinmunes sistémicas (ERAS). Objetivo: Evaluar si los anticuerpos anti-Ro52/TRIM21 están relacionados con anomalías en los circuitos inflamatorios. Métodos: Estudio transversal de pacientes consecutivos y ambulatorios con ERAS. Los anticuerpos anti-Ro52/TRIM21 y la proteína amiloide sérica se midieron mediante ELISA; los paneles para 18 citocinas y nueve quimiocinas se analizaron en una plataforma de lectura Luminex; la proteína C reactiva (hs-CRP) y el complemento se midieron mediante nefelometría. Resultados: Se incluyeron 167 pacientes, 143 con lupus eritematoso sistémico (LES), 16 con síndrome de Sjögren primario y ocho con esclerosis sistémica; 41 fueron positivos para anticuerpos anti-Ro52/TRIM21 (24 %). Los pacientes con anticuerpos anti-Ro52/TRIM21 tuvieron niveles séricos más altos de IL-2, IL-4, IL-6, GM-CSF, IL-21, IL-22, hs-CRP y quimiocinas CCL4, CXCL8, CXCL10 y CXCL12; y más bajos de complemento C4. Los títulos de anticuerpos anti-Ro52/TRIM21 correlacionaron positivamente con IL-2, IL-4, IL-6, IL-10, IL-21, IL-22, CXCL10 y hs-CRP; y negativamente con complemento C3 y C4. Al incluir solo LES, no se identificó asociación entre los anticuerpos anti-Ro52/TRIM21 y la actividad de la enfermedad o la afectación específica de órganos. Conclusiones: Los anticuerpos anti-Ro52/TRIM21 se asocian a circuitos aberrantes de citocinas y niveles elevados de moléculas angiogénicas y quimioatrayentes de neutrófilos y monocitos, lo que sugiere un papel activo de esos anticuerpos en las ERAS.

Abstract Introduction: Anti-Ro52/TRIM21 antibodies are markers for several systemic autoimmune rheumatic diseases (SARD). Objective: To assess whether anti-Ro52/TRIM21 antibodies are related to abnormalities in inflammatory circuits. Methods: Cross-sectional study of consecutive outpatients with SARD. Anti-Ro52/TRIM21 antibodies and serum amyloid A protein were measured by ELISA; panels for 18 cytokines and nine chemokines were analyzed on a Luminex reading platform, while high-sensitivity C-reactive protein (hs-CRP) and complement were measured by nephelometry. Results: Among 167 included patients, 143 had systemic lupus erythematosus (SLE), 16 had primary Sjögren's syndrome and eight had systemic sclerosis; 41 (24%) were positive for anti-Ro52/TRIM21 antibodies. Patients with anti-Ro52/TRIM21 antibodies had higher serum levels of IL-2, IL-4, IL-6, GM-CSF, IL-21, IL-22, hs-CRP and chemokines CCL4, CXCL8, CXCL10 and CXCL12, but lower levels of complement C4. Anti-Ro52/TRIM21 antibody titers were positively correlated with IL-2, IL-4, IL-6, IL-10, IL-21, IL-22, CXCL10, and hs-CRP, and negatively with complement C3 and C4. When only SLE patients were included, no association was identified between anti-Ro52/TRIM21 antibodies and disease activity or organ-specific involvement. Conclusions: Anti-Ro52/TRIM21 antibodies are associated with aberrant cytokine circuits and elevated levels of angiogenic molecules and neutrophil and monocyte chemoattractants, which suggests an active role for these antibodies in SARD.

Patients with seronegative rheumatoid arthritis have a different phenotype than seropositive patients: A clinical and ultrasound study.

Introduction: Rheumatoid arthritis (RA) is an inflammatory disease whose clinical phenotype largely depends on the presence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). Seronegative RA appears to be a less severe disease, but this remains controversial. This study aimed to assess whether seronegative patients show a less severe disease than seropositive patients. Methods: A cross-sectional study was conducted on RA outpatients from a single center. Clinical activity scales, laboratory evaluations, and cardiovascular risk scores were assessed. Musculoskeletal ultrasound (US) examinations were performed. Results: One hundred and fourteen patients were enrolled. Eighty-five were seropositive (76% women) and 29 seronegative (93% women). Seropositive patients had a younger age at disease onset (43 ± 14 vs. 54 ± 11; p = 0.001) and used sulfasalazine (47 vs. 17%; p = 0.004) and glucocorticoids (36 vs. 10%; p = 0.007) more frequently. No differences in clinical activity scales and in 10-year cardiovascular risk were observed. Pathological US data were found more frequently in seropositive patients in the 2nd metacarpophalangeal (MCP) joint, both in grayscale (71 vs. 38%; p = 0.008) and in power Doppler (PD; 53 vs. 9%; p < 0.001); erosions (36 vs. 9%; p = 0.020) were also more frequent. We found greater severity of PD signals in the 2nd MCP and 3rd MCP joints of the seropositive patients, while synovitis severity was higher only in the 2nd MCP joints. The percentage of total joints with erosions (9 vs. 1%; p < 0.001) and 2nd MCP joints with erosions (25 vs. 7%; p < 0.001) was higher in seropositive patients. Conclusion: RA patients show a differentiated phenotype according to their ACPA and RF status. In seronegative patients, RA begins later in life and has a lower requirement for antirheumatic therapies. On US evaluation, seropositive patients show more joint damage, especially in MCP joints. Despite this, long-term cardiovascular risk is similar among RA patients, regardless of their RF and ACPA status.

Bioprosthesis in aortic valve replacement: long-term inflammatory response and functionality.

BACKGROUND: The evaluation of long-term inflammatory response and function in postoperative patients with aortic valve replacement (AVR) deserves special analysis because it is important to try to prevent reoperation and improve durability and functionality of the prostheses. It is our objective METHODS: In this study, we included a cohort of patients with aortic valve damage treated by AVR with mechanical prosthesis, bio prosthesis and we included a control group. RESULTS: We found that IL-4 and osteopontin levels were higher in patients with mechanical vs biological prostheses (p=0.01 and p=0.04, respectively), osteoprotegerin (OPG) levels were decreased (p=0.01), women had lower levels of ET-1 and IL-6, (p=0.02) (p=0.04), respectively. Patients older than 60 years had decreased levels of IL-1ß p<0.001) and a higher concentration of IL-4 p<0.05). IL-1ß, OPG and TNFα were higher in patients with less than 5 years of evolution vs more than 10 years (p=0.004, p=0.02 and p=0.03, respectively). Factors such as age, gender, prosthetic and elevated IL-1B and ET-1 levels are associated with valve dysfunction prosthetic. These results indicate that the inflammatory involvement present prior to valve replacement may be perpetuated by various factors in the long term. CONCLUSIONS: The findings provide us with the opportunity to effectively treat patients with AVR in the postoperative period, which could prolong the functionality of the bio prostheses. TRIAL REGISTRATION NUMBER: NCT04557345.

Modification of Serum Natriuretic Peptide Profile and Echocardiographic Parameters After Surgical Left Atrial Appendage Exclusion/Resection During Mitral Valve Surgery.

BACKGROUND: Being a well-recognised source of cardiac embolism, the left atrial (LA) appendage (LAA) is frequently excluded during mitral valve (MV) surgery. However, the LAA is also a source of cardiac hormones and a new drug (sacubitril), which beneficially interferes with hormonal imbalance during heart failure, leads to re-evaluation of the LAA for the maintenance of adequate hormone production in the heart. We compared the effects of LAA surgical resection/exclusion in patients with MV replacement (MVR) on natriuretic peptides (NPs) and related enzymes versus similar patients, in whom the LAA was preserved. A comparison of clinical response was also carried out. METHOD: Haemodynamically stable patients scheduled for MV surgery with or without elimination of the LAA were studied before and 3 months after surgery. Serum NPs, furin, corin, and neprilysin were determined. A transthoracic echocardiogram was also performed before and after surgery. RESULTS: Patients in the LAA intervention group exhibited lower levels of atrial natriuretic peptide (ANP) 3 months after surgery than patients with intact LAAs. There were no differences in NP and related enzyme levels pre- or postsurgery. The echocardiograms indicated a similar decrease in the diameters and volumes of the LA, and normal pulmonary arterial pressure values, in both groups. The indexed LA volume showed a positive correlation with postoperative brain natriuretic peptide. CONCLUSIONS: Surgical resection or exclusion of the LAA in patients with MVR promotes a decrease in ANP production at 3 months postsurgery. Echocardiography is useful when evaluating surgical replacement of the MV with elimination of the LAA.

Plasma let-7i, miR-16, and miR-221 levels as candidate biomarkers for the assessment of ankylosing spondylitis in Mexican patients naïve to anti-TNF therapy.

Novel biomarkers are needed for the diagnosis and clinical assessment of ankylosing spondylitis (AS). Our objective was to investigate plasma microRNAs differentially expressed between AS patients and controls and to evaluate their potential as biomarkers in Mexican subjects. A cross-sectional study including 15 AS patients naïve to anti-TNF therapy and 13 controls was performed. Disease activity, physical function, and global well-being were evaluated by the AS Disease Activity Score (ASDAS-CRP), the Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), and the AS Quality of Life Questionnaire (ASQoL), respectively. Total RNA was isolated from plasma of participants and relative expression of let-7i, miR-16, and miR-221 was evaluated. Serum levels of C-reactive protein (CRP), matrix metalloproteinase-1 (MMP-1), MMP-9, and intercellular adhesion molecule-1 (ICAM-1) were also measured. Expression of let-7i was higher in patients than in controls (1.8, 0.9 to 3.4 versus 0.6, 0.4 to 1.2; P = 0.033) with an AUC/ROC of 0.74 (0.54 to 0.93; P = 0.032). Levels of miR-16 and miR-221 were unable to discriminate between patients and controls. Notably, plasma miR-16 levels were inversely correlated with the ASDAS-CRP score (rho - 64, - 0.87 to - 0.18; P = 0.011), the BASFI score (rho - 0.78, - 0.93 to - 0.43; P = 0.001), and serum MMP-1 levels (rho - 0.59, - 0.85 to - 0.09; P = 0.022). No other associations were found. Plasma let-7i levels may serve as a biomarker for the diagnosis of AS in Mexican individuals. Additionally, plasma miR-16 levels are associated with disease activity and physical functionality in patients naïve to anti-TNF therapy.

Immunologic Responses in Biological and Mechanical Valve Prostheses: Inflammation and Functionality Are Not Always Related.

BACKGROUND AND AIM OF THE STUDY: The aim of this retrospective study was to evaluate the inflammatory response in patients with aortic and/or mitral prostheses, and to correlate the level of inflammatory markers with prosthesis functionality. METHODS: A total of 48 patients with biological or mechanical prostheses was included in the study, in which levels of tumor necrosis factor-alpha (TNFα), interleukin (IL)-1, -4, and -6, interferon-gamma (IFNγ), osteopontin (OPN), intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), endothelin-1 and C-reactive protein were analyzed. Functionality of the prosthesis was evaluated using transthoracic echocardiography at three years after surgery. RESULTS: The mean period from the date of surgery was seven years. High levels of IL-1 were found in patients with mechanical prostheses compared to those with bioprostheses (p = 0.04). Patients with aortic bioprostheses and stenosis had higher levels of OPN and endothelin-1, those with aortic mechanical prostheses with stenosis had increased levels of matrix metalloproteinase (MMP)-9, OPN and ICAM, and those with aortic mechanical leakage had increased levels of MMP-1 and endothelin-1. In mitral bioprostheses with leakage of endothelin-1, ICAM and MMP-9 levels were increased, while in mechanical prostheses with leakage there were increases of ICAM and endothelin-1. Tricuspid bioprostheses with double lesions had increased levels of OPN and endothelin-1. CONCLUSIONS: Valvular dysfunction was similar across the types of prosthesis material. IL-1 was increased in subjects with mechanical prostheses independently of dysfunction, while in biological prostheses there were increases in OPN and endothelin-1, and these were related to valvular dysfunction. Given that in the analysis of durability and functionality there were no significant differences between biological and mechanical prostheses, biological prostheses may represent the first treatment option in patients with low economic resources, the elderly, and even young patients.

Serum levels of adipokines in patients with idiopathic inflammatory myopathies: a pilot study.

Adipokines are cytokines not only regulating metabolic and endocrine activities, but also modulating inflammatory and immune responses in several clinical settings, including autoimmunity. This study was aimed to evaluate whether serum adipokine levels may be useful as markers of disease activity in patients with idiopathic inflammatory myopathies (IIM). Adiponectin, leptin, chemokine C-C motif ligand-2 (CCL2), interleukin (IL)-6, and tumor necrosis factor (TNF) were measured in the serum of all participants. For each adipokine, we evaluate the area under the ROC curve (AUC) and its correlation with creatine kinase (CK) levels. Thirteen patients with IIM and 13 age- and gender-matched healthy individuals were studied. In patients, the levels of CK (273 ± 321 versus 54 ± 29 U/L; P < 0.0001), leptin (1994 ± 1355 versus 818 ± 738 pg/mL; P = 0.024), and IL-6 (32.4 ± 24.1 versus 13.9 ± 3.5 pg/mL; P = 0.003) were significantly higher than in controls. As a result, CK (AUC = 0.929, 0.833-1.00; P = 0.0002), leptin (AUC = 0.783, 0.588-0.977; P = 0.025), and IL-6 (AUC = 0.846, 0.680-1.00; P = 0.005) significantly discriminated between patients and controls. Neither CCL2 (3256 ± 4585 versus 1118 ± 399 pg/mL; P = 0.319) nor TNF (85.1 ± 83.3 versus 58.2 ± 16.8 pg/mL; P = 0.809) levels were different. Additionally, only serum levels of CCL2 were significantly correlated with CK titers (Spearman´s rho coefficient 0.620, 0.087-0.877; P = 0.023). The levels of CCL2 are in parallel with CK activity in the serum of patients with IIM, suggesting a potential utility as markers of disease activity. Elevated levels of leptin and IL-6 also support a role for adipokines in IIM.