Enhanced NETosis generation in radiographic axial spondyloarthritis: utility as biomarker for disease activity and anti-TNF-α therapy effectiveness.

BACKGROUND: Radiographic axial spondyloarthritis (r-axSpA) is a chronic inflammatory form of arthritis in which tumor necrosis factor (TNF)-α, a potent inducer of inflammatory response and a key regulator of innate immunity and of Th1 immune responses, plays a central role. NETosis is a mechanism of innate immune defense that is involved in diverse rheumatology diseases. Nevertheless, spontaneous NETosis generation in r-axSpA, its association to disease pathogenesis, and the NETosis involvement on anti-TNF-α therapy's effects has never been explored. METHODS: Thirty r-axSpA patients and 32 healthy donors (HDs) were evaluated. Neutrophil extracellular trap (NET) formation, mediators of signal-transduction cascade required for NETosis induction and cell-free NETosis-derived products were quantified. An additional cohort of 15 r-axSpA patients treated with infliximab (IFX) for six months were further analyzed. In vitro studies were designed to assess the effects of IFX in NETosis generation and the inflammatory profile triggered. RESULTS: Compared to HDs, neutrophils from r-axSpA patients displayed augmented spontaneous NET formation, elevated expression of NET-associated signaling components, nuclear peptidylarginine deiminase 4 translocation and increased citrullinated histone H3. Furthermore, patients exhibited altered circulating levels of cell-free NETosis-derived products (DNA, nucleosomes and elastase). Additional studies revealed that cell-free NETosis-derived products could be suitable biomarkers for distinguish r-axSpA patients from HDs. Correlation studies showed association between cell-free NETosis-derived products and clinical inflammatory parameters. Besides, nucleosomes displayed potential as a biomarker for discriminate patients according to disease activity. IFX therapy promoted a reduction in both NETosis generation and disease activity in r-axSpA patients. Mechanistic in vitro studies further unveiled the relevance of IFX in reducing NET release and normalizing the augmented inflammatory activities promoted by NETs in mononuclear cells. CONCLUSIONS: This study reveals that NETosis is enhanced in r-axSpA patients and identifies the NETosis-derived products as potential disease activity biomarkers. In addition, the data suggests the potential role of NET generation analysis for assessment of therapeutic effectiveness in r-axSpA.

Assessment of the relationship between estimated cardiovascular risk and structural damage in patients with axial spondyloarthritis.

AIMS: To evaluate the association of estimated cardiovascular (CV) risk and subclinical atherosclerosis with radiographic structural damage in patients with axial spondyloarthritis (axSpA). METHODS: Cross-sectional study including 114 patients axSpA from the SpA registry of Córdoba (CASTRO) and 132 age- and sex-matched healthy controls (HCs). Disease activity and the presence of traditional CV risk factors were recorded. The presence of atherosclerotic plaques and carotid intima media thickness (cIMT) were evaluated through carotid ultrasound and the SCORE index was calculated. Radiographic damage was measured though modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The association between mSASSS and SCORE was tested using generalized linear models (GLM), and an age-adjusted cluster analysis was performed to identify different phenotypes dependent on the subclinical CV risk. RESULTS: Increased traditional CV risk factors, SCORE, and the presence of carotid plaques were found in axSpA patients compared with HCs. The presence of atherosclerotic plaques and SCORE were associated with radiographic structural damage. The GLM showed that the total mSASSS was associated independently with the SCORE [ß coefficient 0.24; 95% confidence interval (CI) 0.10-0.38] adjusted for disease duration, age, tobacco, C-reactive protein, and non-steroidal anti-inflammatory drugs (NSAID) intake. Hard cluster analysis identified two phenotypes of patients. Patients from cluster 1, characterized by the presence of plaques and increased cIMT, had a higher prevalence of CV risk factors and SCORE, and more structural damage than cluster two patients. CONCLUSION: Radiographic structural damage is associated closely with increased estimated CV risk: higher SCORE levels in axSpA patients were found to be associated independently with mSASSS after adjusting for age, disease duration, CRP, tobacco and NSAID intake.

Tumour necrosis factor-alpha levels in aqueous humour and serum from patients with uveitis: the involvement of HLA-B27.

OBJECTIVE: To study the local and systemic levels of the tumour necrosis factor-alpha in patients with active uveitis and to determine the implication of TNF-alpha in rheumatological uveitis and to observe if this relationship is more significant in the B27 positive patients. PATIENTS AND METHODS: Patients were selected on the basis of a diagnosis of uveitis of any aetiology. Data from 23 patients were stratified into two categories according to the presence or absence of systemic rheumatic disease. The first group comprised nine patients with rheumatic disease; the second group contained 14 patients without rheumatic disease. The patients were also sub-classified into those who were HLA-B27 positive (14 patients) and those who were not. TNF-alpha levels in serum and aqueous humour from a group of 16 patients with uncomplicated cataracts were analysed as a control group. RESULTS: In the control group (n = 16) the serum TNF-alpha concentration was 13.1 +/- 2.9 pg/ml and the aqueous humour concentration of TNF-alpha was 0.56 +/- 1.53 pg/ml. In uveitis patients (n = 23) the serum TNF-alpha concentration was 35.35 +/- 26.77 pg/ml and the aqueous humour concentration of TNF-alpha was 15.1 +/- 1.70 pg/ml (p < 0.01). In HLA-B27 positive patients (n = 9) the serum TNF-alpha concentration was 45.56 +/- 34.17 pg/ml and the aqueous humour concentration of TNF-alpha was 15.89 +/- 0.93 pg/ml. In HLA-B27 negative patients (n = 14) the serum TNF-alpha concentration was 28.79 +/- 19.38 pg/ml and aqueous humour concentration of TNF-alpha was 14.57 +/- 1.91 pg/ml (p < 0.01). CONCLUSIONS: The concentration of TNF-alpha in aqueous humour in patients who are HLA-B27 positive is significantly greater than in those who are B27 negative. No significant differences in the concentrations of TNF-alpha in serum or aqueous humour in patients with or without rheumatic diseases were detected. TNF-alpha is a cytokine that may participate actively in the pathogenesis of clinical uveitis.

[How to optimize the antiTNF alpha therapy in spondylitis?]. / Cómo optimizar la terapia antiTNFalfa en las espondiloartritis?

TNFalpha inhibitors have been a major advance in the treatment of spondyloarthropathies, having demonstrated their safety and efficacy, with higher response and survival rates than those observed in patients with rheumatoid arthritis. The fact that disease modifying anti-arthritic drugs (DMARD) have shown utility in the treatment of this disease, especially in the axial forms, gives them greater importance, since it is known that up to 30%of patients do not respond to treatment with non-steroidal anti-inflammatory drugs. However, we must take into account that these drugs are expensive and not without side effects, so it is necessary to optimize their use. We intend to review the use of antiTNF alpha in spondyloarthropathies and review the available evidence on strategies that can help with their rational use.

[Measuring spondyloarthritis]. / Metrología en espondiloartritis.

The ASAS group recommendations as well as those from the SER consensus for the treatment of spondyloarthritis with TNF inhibitors advise for the performance of spinal motility tests among the response to treatment measures. The clinical variability between rheumatologists when performing these types of measurements is well documented. Recently, the GRESSER group in our country has created a school to improve knowledge in the area of spondyloarthritis among rheumatologists. One of their objectives is the standardization in the ways measurements are performed in this group of diseases. This document summarizes the activities developed in a recent workshop with a detailed description of the procedures followed to perform each one of the important measurements affecting the axial skeleton. With this we hope to contribute to the much desired standardization in the field of metrology in spondyloarthritis.