Biomechanics in the onset and severity of spondyloarthritis: a force to be reckoned with.

Increasing evidence suggests that there is a pivotal role for physical force (mechanotransduction) in the initiation and/or the perpetuation of spondyloarthritis; the review contained herein examines that evidence. Furthermore, we know that damage and inflammation can limit spinal mobility, but is there a cycle created by altered spinal mobility leading to additional damage and inflammation?Over the past several years, mechanotransduction, the mechanism by which mechanical perturbation influences gene expression and cellular behaviour, has recently gained popularity because of emerging data from both animal models and human studies of the pathogenesis of ankylosing spondylitis (AS). In this review, we provide evidence towards an appreciation of the unsolved paradigm of how biomechanical forces may play a role in the initiation and propagation of AS.

Causality of occupational exposure on rheumatoid arthritis and ankylosing spondylitis: a two-sample mendelian randomization study.

Objective: This study aimed to explore the potential causal link between three specific types of occupational exposure on rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Method: A Two-sample Mendelian randomization (TSMR) analysis, comprising univariate MR (UVMR) and multivariate MR (MVMR) analyses, was performed to investigate the potential causal association between three types of occupational exposures, jobs involving mainly walking or standing (JWS), jobs involving heavy manual or physical work (JMP), and jobs involving shift work(JSW) on RA and AS. Genetic variants for genome-wide association studies (GWAS) of occupational exposure and AS were obtained from the UK Biobank. GWAS summary data for RA were obtained from FinnGen Biobank analysis. For UVMR, six methods of Inverse Variance Weighted (IVW), MR-Egger, Weighted Mode, Weighted Median, Simple Mode, MR pleiotropy residual sum, and outlier (MR-PRESSO) were used for the analysis. The MVMR was analyzed using the IVW model as well as the MR-Egger model. Results: The UVMR suggested no causal relationship between the three occupational exposure and RA [IVW: P=0.59,0.21,0.63] or AS [IVW: P=0.43,0.57,0.04], as did the bidirectional MR [IVW: P=0.73,0.70,0.16], [IVW: P=0.65,0.68,0.74]. Although unadjusted MVMR suggested a causal relationship between JMP and AS [IVW: OR = 1.01, 95% CI = 1.00- 1.02, p = 0.02], the adjusted MVMR denied this relationship and concluded that there was no causal relationship between the other occupational exposure and either RA or AS. Conclusion: Our MR analysis did not establish a direct causal relationship between certain occupational exposures and either RA or AS.

Spondyloarthritides.

The spondyloarthritides are a diverse group of distinct yet interrelated disease processes with overlapping clinical features. They are ankylosing spondylitis, reactive arthritis, inflammatory bowel disease-associated arthritis, and psoriatic arthritis. Genetically, these disease processes have been linked by the presence of HLA-B27. They manifest with axial and peripheral symptoms, such as inflammatory back pain, enthesitis, oligoarthritis, and dactylitis. The onset of symptoms can begin before the age of 45; however, because of the wide range of signs and symptoms, diagnosis can be delayed, leading to unchecked inflammation, structural damage, and later, restriction in physical mobility.

Joint together: The etiology and pathogenesis of ankylosing spondylitis.

Spondyloarthritis (SpA) refers to a group of diseases with inflammation in joints and spines. In this family, ankylosing spondylitis (AS) is a rare but classic form that mainly involves the spine and sacroiliac joint, leading to the loss of flexibility and fusion of the spine. Compared to other diseases in SpA, AS has a very distinct hereditary disposition and pattern of involvement, and several hypotheses about its etiopathogenesis have been proposed. In spite of significant advances made in Th17 dynamics and AS treatment, the underlying mechanism remains concealed. To this end, we covered several topics, including the nature of the immune response, the microenvironment in the articulation that is behind the disease's progression, and the split between the hypotheses and the evidence on how the intestine affects arthritis. In this review, we describe the current findings of AS and SpA, with the aim of providing an integrated view of the initiation of inflammation and the development of the disease.

Evaluation of thiol-disulfide homeostasis in active ankylosing spondylitis patients / Evaluación de la homeostasis de tiol-disulfuro en pacientes con espondilitis anquilosante activa

Introduction and objectives: The etiopathogenesis of ankylosing spondylitis (AS), which is a chronic, progressive, inflammatory, systemic disease, has not been fully elucidated yet. Thiol-disulfide homeostasis, a component of antioxidant defense, is thought to play a role in the etiology of inflammatory diseases. We aimed to evaluate the existence of oxidative stress in active AS patients with thiol-disulfide homeostasis. Materials and methods: Patients who were found to have high (n: 27) and very-high (n: 18) activity levels with ASDAS-ESR and 40 healthy controls participated in the study. Serum native-thiol (NT), total-thiol (TT), and disulfide levels were analyzed by an automated colorimetric method. Results: While TT and NT levels were significantly decreased in patients compared to the control group, the disulfide levels were increased. There was a significant negative correlation between ESR, and NT, TT in both groups and also between hsCRP and NT, TT in very-high active AS patients.TT and NT levels were significantly higher in the nonsteroidal anti-inflammatory drug (NSAID) users compared to those using biological agents. Conclusions: The deterioration of thiol-disulfide homeostasis in favor of disulfide; correlations between ESR, CRP, and NT, TT support the use of thiol-disulfide variables in determining the disease activity level.(AU)

Introducción y objetivos: La etiopatogenia de la espondilitis anquilosante (EA), que es una enfermedad crónica, progresiva, inflamatoria y sistémica, aún no se ha dilucidado por completo. Se cree que la homeostasis del tiol-disulfuro, un componente de la defensa antioxidante, desempeña un papel en la etiología de las enfermedades inflamatorias. Nuestro objetivo fue evaluar la existencia de estrés oxidativo en pacientes con EA activa con homeostasis de tiol-disulfuro. Materiales y métodos: Participaron en el estudio pacientes que tenían niveles de actividad altos (n: 27) y muy altos (n: 18) con ASDAS-ESR y 40 controles sanos. Los niveles séricos de tiol nativo (NT), tiol total (TT) y disulfuro se analizaron mediante un método colorimétrico automático. Resultados: Si bien los niveles de TT y NT disminuyeron significativamente en los pacientes en comparación con el grupo de control, los de disulfuro aumentaron. Hubo una correlación negativa significativa entre ESR y NT, TT en ambos grupos y también entre hsCRP y NT, TT en pacientes con EA muy alta activa. Los niveles de TT y NT fueron significativamente más altos en los usuarios de medicamentos antiinflamatorios no esteroideos (AINE) en comparación con los que utilizan agentes biológicos. Conclusiones: El deterioro de la homeostasis tiol-disulfuro a favor del disulfuro y las correlaciones entre ESR, CRP y NT, TT apoyan el uso de variables de tiol-disulfuro para determinar el nivel de actividad de la enfermedad.(AU)

Association Between Infections and Risk of Ankylosing Spondylitis: A Systematic Review and Meta-Analysis.

Background: Previous literature on the association between infections and the risk of developing ankylosing spondylitis (AS) presented controversial results. This meta-analysis aimed to quantitatively investigate the effect of infections on the risk of AS. Methods: We searched the PubMed, Embase, and Web of Science databases until March 26, 2021 for analytical epidemiological studies on the association between infections and the risk of AS. Fixed or random effect models were used to calculate total risk estimates based on study heterogeneity. Subgroup analysis, and sensitivity analysis were also performed. Publication bias was estimated using funnel plots and Begg's test. Results: Six case-control articles (n=1,296,239) and seven cohort articles (n=7,618,524) were incorporated into our meta-analysis. The pooled odds ratio (OR) from these case-control studies showed that infections were associated with an increased risk of AS (OR=1.46, 95% confidence interval [CI], 1.23-1.73), and the pooled relative risk (RR) from the cohort studies showed the same findings (RR=1.35, 95% CI, 1.12-1.63). Subgroup analysis showed that infections in participants with unadjusted comorbidities (OR=1.66, 95% CI, 1.35-2.03), other types of infection (OR=1.40, 95% CI, 1.15-1.70), and infection of the immune system (OR=1.46, 95% CI, 1.42-1.49) were associated with the risk of AS in case-control studies. In cohort studies, infections with adjusted comorbidities (RR=1.39, 95% CI, 1.15-1.68), viral infection (RR=1.43, 95% CI, 1.22-1.66), other types of infection (RR=1.44, 95% CI, 1.12-1.86), and other sites of infection (RR=1.36, 95% CI, 1.11-1.67) were associated with an increased risk of AS. Conclusions: The findings of this meta-analysis confirm that infections significantly increase the risks of AS. This is helpful in providing an essential basis for the prevention of AS via the avoidance of infections.

Association of FOXO3a gene polymorphisms and ankylosing spondylitis susceptibility in Eastern Chinese Han population.

OBJECTIVE: To investigate the association of FOXO3a polymorphisms and ankylosing spondylitis (AS) susceptibility in Eastern Chinese Han population. METHODS: FOXO3a polymorphisms rs12206094, rs12212067, rs2253310, rs3800232, and rs4946933 were genotyped in 650 AS patients and 646 controls by the improved Multiple Ligase Detection Reaction. RESULTS: The distribution of genotype in rs12212067 polymorphism was significantly different between AS patients and controls (P = 0.020), especially in male population (P = 0.009). There was significant difference of the genotype frequency distribution at rs3800232 between patients and controls in male population. The results of binary regression analysis showed that the rs12212067 GG genotype and rs3800232 TT genotype were obviously correlated with elevated AS risk, and the associations were still significant after being adjusted by age and gender (all P < 0.05). Interestingly, rs12212067 and rs3800232 genotypes were associated with disease activity of patients. Additionally, haplotype block rs12212067G- rs3800232T (OR = 1.403, 95%CI = 1.011-1.949) was further shown to confer promoting effect on developing AS. CONCLUSION: Among Eastern Chinese Han population, FOXO3a polymorphism rs12212067 and rs3800232 may contribute to increased risk of developing AS, but well-designed multicenter studies are needed to further confirm these preliminary findings in the future.

Ankylosing spondylitis: an autoimmune or autoinflammatory disease?

Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a dominant role characterized by aberrant activity of innate and innate-like immune cells, including γδ T cells, group 3 innate lymphoid cells, neutrophils, mucosal-associated invariant T cells and mast cells, at sites predisposed to the disease. The intestine is involved in disease manifestations, as it is at the forefront of the interaction between the mucosal-associated immune cells and the intestinal microbiota. Similarly, biomechanical factors, such as entheseal micro-trauma, might also be involved in the pathogenesis of the articular manifestation of AS, and sentinel immune cells located in the entheses could provide links between local damage, genetic predisposition and the development of chronic inflammation. Although these elements might support the autoinflammatory nature of AS, studies demonstrating the presence of autoantibodies (such as anti-CD74, anti-sclerostin and anti-noggin antibodies) and evidence of activation and clonal expansion of T cell populations support an autoimmune component to the disease. This Review presents the evidence for autoinflammation and the evidence for autoimmunity in AS and, by discussing the pathophysiological factors associated with each, aims to reconcile the two hypotheses.

Rheumatic manifestations of Chikungunya virus infection: Prevalence, patterns, and enthesitis.

Chikungunya virus (CHIKV) is an arthropod-borne virus transmitted by mosquitoes of the genus Aedes. CHIKV infection causes various rheumatic symptoms, including enthesitis; however, these effects are rarely investigated. The aim of this study was to describe the rheumatic manifestations in CHIKV infection, estimate the prevalence of enthesitis in CHIKV-infected patients, and determine the factors associated with CHIKV-induced enthesitis. We conducted a prospective, observational study in patients with CHIKV infection confirmed by positive RT-PCR or IgM assay from October 2019 to March 2020. Patients with pre-existing inflammatory rheumatic diseases were excluded. A rheumatologist evaluated the demographic and clinical characteristics of the patients, including the number of inflamed joints, enthesitis sites, tendinitis, and tenosynovitis. The Leeds enthesitis index (LEI) and the Maastricht ankylosing spondylitis enthesis score (MASES) were used to evaluate enthesitis sites. Factors associated with enthesitis were determined using logistic regression analysis. One hundred and sixty-four participants diagnosed with CHIKV infection were enrolled. The mean (SD) age of the patients was 48.2 (14) years. The most common pattern of rheumatic manifestations was polyarthritis with or without enthesitis. Enthesitis was observed in 63 patients (38.4%). The most common site of enthesitis was the left lateral epicondyle as assessed by LEI and the posterior superior iliac spine as assessed by MASES. Multivariate analysis indicated that the number of actively inflamed joints and Thai-HAQ score at the initial evaluation were significantly associated with the presence of enthesitis. The main rheumatic manifestations of CHIKV infection were arthritis/arthralgia, with enthesitis as a prominent extraarticular feature. CHIKV infection can cause enthesitis at peripheral and axial sites. We found that enthesitis was associated with a high number of inflamed joints and reduced physical function. These results indicate that the assessment of enthesitis should be considered when monitoring disease activity and as a treatment response parameter in CHIKV-infected patients.

Why Inhibition of IL-23 Lacked Efficacy in Ankylosing Spondylitis.

The term spondyloarthritis pertains to both axial and peripheral arthritis including ankylosing spondylitis (AS) and psoriatic arthritis (PsA), which is strongly linked to psoriasis and also the arthritis associated with inflammatory bowel disease. The argument supporting the role for IL-23 across the spectrum of SpA comes from 4 sources. First, genome wide associated studies (GWAS) have shown that all the aforementioned disorders exhibit IL-23R pathway SNPs, whereas HLA-B27 is not linked to all of these diseases-hence the IL-23 pathway represents the common genetic denominator. Secondly, experimental animal models have demonstrated a pivotal role for the IL-23/IL-17 axis in SpA related arthropathy that initially manifests as enthesitis, but also synovitis and axial inflammation and also associated aortic root and cutaneous inflammation. Thirdly, the emergent immunology of the human enthesis also supports the presence of IL-23 producing myeloid cells, not just at the enthesis but in other SpA associated sites including skin and gut. Finally, drugs that target the IL-23 pathway show excellent efficacy for skin disease, efficacy for IBD and also in peripheral arthropathy associated with SpA. The apparent failure of IL-23 blockade in the AS which is effectively a spinal polyenthesitis but evidence for efficacy of IL-23 inhibition for peripheral enthesitis in PsA and preliminary suggestions for benefit in axial PsA, raises many questions. Key amongst these is whether spinal inflammation may exhibit entheseal IL-17A production independent of IL-23 but peripheral enthesitis is largely dependent on IL-23 driven IL-17 production. Furthermore, IL-23 blocking strategies in animal models may prevent experimental SpA evolution but not prevent established disease, perhaps pointing towards a role for IL-23 in innate immune disease initiation whereas persistent disease is dependent on memory T-cell responses that drive IL-17A production independently of IL-23, but this needs further study. Furthermore, IL-12/23 posology in inflammatory bowel disease is substantially higher than that used in AS trials which merits consideration. Therefore, the IL-23 pathway is centrally involved in the SpA concept but the nuances and intricacies in axial inflammation that suggest non-response to IL-23 antagonism await formal definition. The absence of comparative immunology between the different skeletal sites renders explanations purely hypothetical at this juncture.

Down-Regulation of LOC645166 in T Cells of Ankylosing Spondylitis Patients Promotes the NF-κB Signaling via Decreasingly Blocking Recruitment of the IKK Complex to K63-Linked Polyubiquitin Chains.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects the spine. AS is highly associated with the expression of HLA-B27. Up to 95% AS patients are HLA-B27-positive. However, only 1%-2% of the HLA-B27-positive carriers suffer from AS, implying that other factors may also govern the development of AS. Long non-coding RNAs (lncRNAs) can regulate the immune response via their binding proteins. In the present study, we have identified that the levels of lncRNA, LOC645166, in T cells of AS patients were reduced. Overexpression of LOC645166 in Jurkat cells down-regulated the IL-23p19 expression and suppressed the JAK2/STAT3 signaling in response to stimulation by phorbol 12-myristate 13-acetate. Suppression of STAT3 activation by LOC645166 was also observed when Jurkat cells or T cells of AS patient were treated with anti-CD3/CD28 antibodies. In order to explore the role of LOC645166 in the pathogenesis of AS, RNA pull-down assay plus proteomic approach and western blotting were performed and identified that LOC645166 prefers binding the K63-linked polyubiquitin chains. LOC645166 can suppress recruitment of the IKK complex to K63-linked polyubiquitin chains and diminish IKK2 activation, leading to down-regulation of NF-κB activation. Down-regulation of LOC645166 expression in T cells of AS patients up-regulates NF-kB activation via decreasingly impeding recruitment of the IKK complex to K63-linked polyubiquitin chains, allowing AS patients to exhibit more sensitivity to stimulation by the proinflammatory cytokines or by TLR ligands.

Clonorchis sinensis-Derived Protein Attenuates Inflammation and New Bone Formation in Ankylosing Spondylitis.

Helminth infections and their components have been shown to have the potential to modulate and attenuate immune responses. The objective of this study was to evaluate the potential protective effects of Clonorchis sinensis-derived protein (CSp) on ankylosing spondylitis (AS). Cytotoxicity of CSp at different doses was assessed by MTS and flow cytometry before performing experiments. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were obtained from AS patients. Inflammatory cytokine-producing cells were analyzed using flow cytometry. The levels of INF- γ , IL-17A, TNF-α, and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). SKG mice were treated with CSp or vehicles. Inflammation and new bone formation were evaluated using immunohistochemistry, positron emission tomography (PET), and micro-computed tomography (CT). Treatment with CSp resulted in no reduced cell viability of PBMCs or SFMCs until 24 h. In experiments culturing PBMCs and SFMCs, the frequencies of IFN- γ and IL-17A producing cells were significantly reduced after CSp treatment. In the SKG mouse model, CSp treatment significantly suppressed arthritis, enthesitis, and enteritis. Micro-CT analysis of hind paw revealed reduced new bone formation in CSp-treated mice than in vehicle-treated mice. We provide the first evidence demonstrating that CSp can ameliorate clinical signs and cytokine derangements in AS. In addition, such CSp treatment could reduce the new bone formation of AS.

Serum Metabolomics Signatures Associated With Ankylosing Spondylitis and TNF Inhibitor Therapy.

Ankylosing spondylitis (AS) is a type of spondyloarthropathies, the diagnosis of which is often delayed. The lack of early diagnosis tools often delays the institution of appropriate therapy. This study aimed to investigate the systemic metabolic shifts associated with AS and TNF inhibitors treatment. Additionally, we aimed to define reliable serum biomarkers for the diagnosis. We employed an untargeted technique, ultra-performance liquid chromatography-mass spectroscopy (LC-MS), to analyze the serum metabolome of 32 AS individuals before and after 24-week TNF inhibitors treatment, as well as 40 health controls (HCs). Multivariate and univariate statistical analyses were used to profile the differential metabolites associated with AS and TNF inhibitors. A diagnostic panel was established with the least absolute shrinkage and selection operator (LASSO). The pathway analysis was also conducted. A total of 55 significantly differential metabolites were detected. We generated a diagnostic panel comprising five metabolites (L-glutamate, arachidonic acid, L-phenylalanine, PC (18:1(9Z)/18:1(9Z)), 1-palmitoylglycerol), capable of distinguishing HCs from AS with a high AUC of 0.998, (95%CI: 0.992-1.000). TNF inhibitors treatment could restore the equilibrium of 21 metabolites. The most involved pathways in AS were amino acid biosynthesis, glycolysis, glutaminolysis, fatty acids biosynthesis and choline metabolism. This study characterized the serum metabolomics signatures of AS and TNF inhibitor therapy. We developed a five-metabolites-based panel serving as a diagnostic tool to separate patients from HCs. This serum metabolomics study yielded new knowledge about the AS pathogenesis and the systemic effects of TNF inhibitors.

Multi 'Omics Analysis of Intestinal Tissue in Ankylosing Spondylitis Identifies Alterations in the Tryptophan Metabolism Pathway.

Intestinal microbial dysbiosis, intestinal inflammation, and Th17 immunity are all linked to the pathophysiology of spondyloarthritis (SpA); however, the mechanisms linking them remain unknown. One potential hypothesis suggests that the dysbiotic gut microbiome as a whole produces metabolites that influence human immune cells. To identify potential disease-relevant, microbiome-produced metabolites, we performed metabolomics screening and shotgun metagenomics on paired colon biopsies and fecal samples, respectively, from subjects with axial SpA (axSpA, N=21), Crohn's disease (CD, N=27), and Crohn's-axSpA overlap (CD-axSpA, N=12), as well as controls (HC, N=24). Using LC-MS based metabolomics of 4 non-inflamed pinch biopsies of the distal colon from subjects, we identified significant alterations in tryptophan pathway metabolites, including an expansion of indole-3-acetate (IAA) in axSpA and CD-axSpA compared to HC and CD and indole-3-acetaldehyde (I3Ald) in axSpA and CD-axSpA but not CD compared to HC, suggesting possible specificity to the development of axSpA. We then performed shotgun metagenomics of fecal samples to characterize gut microbial dysbiosis across these disease states. In spite of no significant differences in alpha-diversity among the 4 groups, our results confirmed differences in gene abundances of numerous enzymes involved in tryptophan metabolism. Specifically, gene abundance of indolepyruvate decarboxylase, which generates IAA and I3Ald, was significantly elevated in individuals with axSpA while gene abundances in HC demonstrated a propensity towards tryptophan synthesis. Such genetic changes were not observed in CD, again suggesting disease specificity for axSpA. Given the emerging role of tryptophan and its metabolites in immune function, altogether these data indicate that tryptophan metabolism into I3Ald and then IAA is one mechanism by which the gut microbiome potentially influences the development of axSpA.

Aberrant antigen processing and presentation: Key pathogenic factors leading to immune activation in Ankylosing spondylitis.

The strong association of HLA-B*27 with ankylosing spondylitis (AS) was first reported nearly 50 years ago. However, the mechanistic link between HLA-B*27 and AS has remained an enigma. While 85-90% of AS patients possess HLA-B*27, majority of HLA-B*27 healthy individuals do not develop AS. This suggests that additional genes and genetic regions interplay with HLA-B*27 to cause AS. Previous genome-wide association studies (GWAS) identified key genes that are distinctively expressed in AS, including the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and ERAP2. As these gene-encoding molecules are primarily implicated in the process of peptide processing and presentation, potential pathological interaction of these molecules with HLA-B*27 may operate to cause AS by activating downstream immune responses. The aberrant peptide processing also gives rise to the accumulation of unstable protein complex in endoplasmic reticulum (ER), which drives endoplasmic reticulum-associated protein degradation (ERAD) and unfolded protein response (UPR) and activates autophagy. In this review, we describe the current hypotheses of AS pathogenesis, focusing on antigen processing and presentation operated by HLA-B*27 and associated molecules that may contribute to the disease initiation and progression of AS.

Up-regulation of TßRIII facilitates the osteogenesis of supraspinous ligament-derived fibroblasts from patients with ankylosing spondylitis.

Spinal supraspinous ligament (SL) osteogenesis is the key risk of ankylosing spondylitis (AS), with an unclear pathogenesis. We previously found that transforming growth factor ß1 (TGF-ß1), bone morphogenetic proteins (eg BMP2) and type III TGF-ß1 receptor (TßRIII) expression were markedly up-regulated in AS-SLs. However, the roles of these closely related molecules in AS are unknown. Here, we showed that BMP2, TGF-ß1, TßRIII and S100A4 (a fibroblast marker) were abundant in active osteogenic AS-SL tissues. In vitro, AS-SL fibroblasts (AS-SLFs) showed high BMP2, TGF-ß1 and TßRIII expression and auto-osteogenic capacity. We further evaluated the role of TßRIII in the osteogenesis of normal SLFs. BMP2 combined with TGF-ß1 induced the osteogenesis of TßRIII-overexpressing SLFs, but the activity was lost in SLFs upon TßRIII knockdown. Moreover, our data suggested that BMP2 combined with TGF-ß1 significantly activated both TGF-ß1/Smad signalling and BMP2/Smad/RUNX2 signalling to induce osteogenesis of SLFs with TßRIII up-regulation. Furthermore, our multi-strategy molecular interaction analysis approach indicated that TGF-ß1 presented BMP2 to TßRIII, sequentially facilitating BMP2 recognition by BMPR1A and promoting the osteogenesis of TßRIII-overexpressing SLFs. Collectively, our results indicate that TGF-ß1 combined with BMP2 may participate in the osteogenic differentiation of AS-SLF by acting on up-regulated TßRIII, resulting in excessive activation of both TGF-ß1/Smad and BMP2/BMPR1A/Smad/RUNX2 signalling.

Dysregulation of SAA1, TUBA8 and Monocytes Are Key Factors in Ankylosing Spondylitis With Femoral Head Necrosis.

Introduction: The mechanism of ankylosing spondylitis with femoral head necrosis is unknown, and our study aimed investigate the effects of genetic and immune cell dysregulation on ankylosing spondylitis. Materials and Methods: The protein expression of all ligaments in ankylosing spondylitis with femoral head necrosis was obtained using label-free quantification protein park analysis of six pairs of specimens. The possible pathogenesis was explored using differential protein analysis, weighted gene co-expression network analysis, recording intersections with hypoxia-related genes, immune cell correlation analysis, and drug sensitivity analysis. Finally, routine blood test data from 502 AS and 162 healthy controls were collected to examine immune cell differential analysis. Results: SAA1 and TUBA8 were significantly expressed differentially in these two groups and correlated quite strongly with macrophage M0 and resting mast cells (P < 0.05). Routine blood data showed that monocytes were significantly more expressed in AS than in healthy controls (P < 0.05). SAA1 and TUBA8 were closely related to the sensitivity of various drugs, which might lead to altered drug sensitivity. Conclusion: Dysregulation of SAA1, TUBA8 and monocytes are key factors in ankylosing spondylitis with femoral head necrosis.

Association of homocysteine with ankylosing spondylitis: a systematic review and meta-analysis

Abstract Background: Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. Methods: Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effect model, Stata16 software. Results: Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = − 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P < 0.05) in the AS group treated with methotrexate (MTX) compared with the control group. In contrast, HCY levels were significantly (P < 0.05) lower in the AS group receiving anti-TNF-α treatment compared with the control group. No significant differences were detected between HCY levels and disease activity scores (Bath AS disease activity index, BASDAI), and methylenetetrahydrofolate reductase (MTHFR) C677T genotype. Conclusion: This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. Trial registration: This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426.(AU)

GM-CSF Primes Proinflammatory Monocyte Responses in Ankylosing Spondylitis.

Objectives: GM-CSF is a pro-inflammatory cytokine with multiple actions predominantly on myeloid cells. Enhanced GM-CSF expression by lymphocytes from patients with Ankylosing Spondylitis (AS) has recently been described, however, its potential pathogenic role(s) in AS are unknown. Methods: The effects of GM-CSF on TNF, IL-23, and CCL17 production by blood, PBMCs and isolated CD14+ monocytes from AS patients and healthy controls (HCs) were studied using ELISA. Serum CCL17 and GM-CSF and T cell GM-CSF production were studied in AS patients including pre-and on TNFi therapy. Results: GM-CSF markedly increased TNF production by LPS-stimulated whole blood, peripheral blood mononuclear cells (PBMC) and purified monocytes from AS patients, with 2 h GM-CSF exposure sufficient for monocyte "priming." Blocking of GM-CSF significantly reduced the production of TNF by whole blood from AS patients but not HCs. GM-CSF priming increased IL-23 production from LPS-stimulated AS and HC whole blood 5-fold, with baseline and stimulated IL-23 levels being significantly higher in AS whole blood. GM-CSF also stimulated CCL17 production from AS and HC blood and CCL17 levels were elevated in AS plasma. GM-CSF could be detected in plasma from 14/46 (30%) AS patients compared to 3/18 (17%) HC. Conclusion: We provide evidence that GM-CSF primes TNF and IL-23 responses in myeloid cells from AS patients and HC. We also show CCL17 levels, downstream of GM-CSF, were elevated in plasma samples of AS patients. Taken together these observations are supportive of GM-CSF neutralization as a potential novel therapeutic approach for the treatment of AS.