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.

Bases fisiopatológicas de la neoformación en las espondiloartritis / Physiopathological foundations of neoformation in spondyloarthritis

Una de las características patogénicas de las espondiloartritis (EspA) es la neoformación ósea. Distintos estudios han puesto de manifiesto que el origen de este proceso está en las entesis, donde algunos factores desen cadenantes, como el estrés biomecánico, en un individuo genéticamente predispuesto producirían una compleja cascada de señales que favorecería la vasodilatación local y la activación de células inmunocompetentes residentes. Estas, a su vez, provocarían una respuesta inflamatoria caracterizada por la secreción de factor de necrosis tumoral alfa e interleucina 17 (IL-17), entre otros, y reclutamiento de otras células inmunocompetentes. Además, se ha demostrado que la IL-17 y la IL-22 favorecen la proliferación de células madre mesenquimatosas del periostio perientesítico, lo que lleva a la formación de hueso nuevo en la entesis. En las EspA, la formación de hueso nuevo es principalmente ortotópica (en continuidad con el hueso existente) y se origina a partir de la entesis y del periostio. Al parecer, la mayoría de la neoformación ósea se produce mediante osificación endocondral. En la osificación endocondral, las células progenitoras mesenquimatosas se diferencian en condrocitos, que construyen un «molde» de cartílago, en el cual las células progresivamente maduran y evolucionan hacia condrocitos hipertróficos. Esta matriz es invadida por vasos y precursores osteoblásticos que reemplazan progresivamente el modelo por hueso maduro

One of the pathogenic characteristics of spondyloarthritis (SpA) is bone neoformation. Several studies have revealed that this process originates in the enthesis, in which triggering factors such as biomechanical stress in genetically predisposed individuals may produce a complex cascade of signals favouring local vasodilation and activation of resident immune cells. These in turn induce an inflammatory response characterised by secretion of TNF-alfa and IL-17 (among other substances) and recruitment of other immune cells. In addition, it has been demonstrated that IL-17 and IL-22 favour the proliferation of mesenchymal stem cells of the peri-enthesic periosteum, leading to the formation of new bone in the enthesis. In SpA, new bone formation is mainly orthotopic (in continuity with existing bone) and arises from the enthesis and periosteum. Most bone neoformation seems to occur through endochondral ossification. In this process, mesenchymal progenitor cells differentiate towards chondrocytes, which construct a cartilaginous "mould" in which the cells progressively mature and develop towards hypertrophic chondrocytes. This matrix is invaded by vessels and osteoblastic precursors that progressively replace the model with mature bone

[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.

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

Los inhibidores del TNFalfa (antiTNFalfa) han supuesto un avance importante en el tratamiento de las espondiloartropatías, habiendo demostrado su eficacia y seguridad, con tasas de respuesta y supervivencia incluso superiores a las observadas en pacientes con artritis reumatoide. El hecho de que los fármacos modificadores de la enfermedad (FAME) no han mostrado utilidad en el tratamiento de esta patología, especialmente en las formas axiales, les confiere mayor importancia, dado que se sabe que hasta el 30% de los pacientes no responden al tratamiento con antiinflamatorios no esteroideos. Sin embargo, hay que tener en cuenta que son fármacos caros y no exentos de efectos secundarios, por lo que es necesario un uso óptimo. Pretendemos hacer una revisión del uso de antiTNFalfa en las espondiloartropatías y se plantean las evidencias disponibles sobre estrategias que puedan ayudar a su uso racional (AU)

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 (AU)

Metrología en espondiloartritis / Measuring spondyloarthritis

Las recomendaciones del Ankylosing Spondylitis Working Group (grupo ASAS) y del Consenso de la Sociedad Española de Reumatología para el tratamiento de las espondiloartritis con inhibidores del factor de necrosis tumoral aconsejan evaluar la movilidad espinal entre las medidas de respuesta al tratamiento. Es conocida la variabilidad clínica entre los reumatólogos al realizar este tipo de determinaciones. Recientemente, el grupo GRESSER ha creado en nuestro país una escuela para mejorar entre los reumatólogos el conocimiento en el área de las espondiloartritis. Uno de sus objetivos es la estandarización en la forma de realizar las mediciones en este grupo de enfermedades. Este documento resume la actividad desarrollada en un reciente taller con una detallada descripción de los procedimientos seguidos para cumplir cada una de las mediciones importantes que afectan al esqueleto axial. Con este texto esperamos contribuir a la deseada estandarización en el campo de la metrología de las espondiloartritis (AU)

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 (AU)

[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.

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.