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Frontiers in Immunology 2021
Topics: Adaptive Immunity; Animals; Anti-Inflammatory Agents; Cost of Illness; Humans; Immunity, Innate; Quality of Life; Sacroiliac Joint; Spine; Spondylitis, Ankylosing
PubMed: 35003143
DOI: 10.3389/fimmu.2021.822582 -
Nature Reviews. Rheumatology Jul 2021Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a... (Review)
Review
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.
Topics: Animals; Autoimmune Diseases; Hereditary Autoinflammatory Diseases; Humans; Spondylitis, Ankylosing
PubMed: 34113018
DOI: 10.1038/s41584-021-00625-y -
Clinical Rheumatology Aug 2021Radiographic axial spondyloarthritis (also known as ankylosing spondylitis [AS]) is a chronic immune-mediated arthritis characterized by inflammation of the axial...
Radiographic axial spondyloarthritis (also known as ankylosing spondylitis [AS]) is a chronic immune-mediated arthritis characterized by inflammation of the axial skeleton, peripheral joints, and entheses. It is estimated that 1 in every 200 people are affected by AS, making it an important healthcare and socioeconomic issue. In this review, we aim to explore the current understanding of AS risk factors and provide a comprehensive update. Multiple search strings were used to identify articles of interest published in PubMed between January 1, 2013, and February 1, 2021. On the basis of the literature review and analysis, we present up-to-date information on the risk factors of developing AS and our viewpoints on disease onset and progression. Multiple genetic and nongenetic risk factors have been suggested in the onset of AS. HLA-B27 is known to have a strong association with the disease, but other genes have been implicated in disease development. Aside from genetics, other factors are thought to be involved; up to 70% of patients with AS have subclinical intestinal inflammation, suggesting that the origin of the disease may be in the gut. The exact mechanism by which AS onset begins is most likely complex and multifactorial. Key Points • It remains unclear how interactions between genes, microbes, mechanical stress, gender, and other environmental and lifestyle factors predispose patients to the development of ankylosing spondylitis (AS). • The exact mechanisms of AS are complex and multifactorial which will require much future research • Recognizing the risk factors, as well as understanding gene-environment interactions, may offer valuable insights into the etiology of AS and have important implications for diagnosis and treatment strategies.
Topics: HLA-B27 Antigen; Humans; Inflammation; Risk Factors; Spondylarthritis; Spondylitis, Ankylosing
PubMed: 33754220
DOI: 10.1007/s10067-021-05679-7 -
Immunology and Allergy Clinics of North... Aug 2023The spondyloarthritides are a diverse group of distinct yet interrelated disease processes with overlapping clinical features. They are ankylosing spondylitis, reactive... (Review)
Review
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.
Topics: Humans; Spondylarthritis; Spondylitis, Ankylosing; Arthritis, Psoriatic; Arthritis, Reactive; Inflammatory Bowel Diseases
PubMed: 37394262
DOI: 10.1016/j.iac.2022.10.001 -
Rheumatology (Oxford, England) Oct 2020In recent years, significant progress has been made in improving the early diagnosis of spondyloarthritides (SpA), including axial SpA. Nonetheless, there are still... (Review)
Review
In recent years, significant progress has been made in improving the early diagnosis of spondyloarthritides (SpA), including axial SpA. Nonetheless, there are still issues related to the application of classification criteria for making the primary diagnosis of SpA in the daily practice. There are substantial conceptional and operational differences between the diagnostic vs classification approach. Although it is not possible to develop true diagnostic criteria for natural reasons as discussed in this review, the main principles of the diagnostic approach can be clearly defined: consider the pre-test probability of the disease, evaluate positive and negative results of the diagnostic test, exclude other entities, and estimate the probability of the disease at the end. Classification criteria should only be applied to patients with an established diagnosis and aimed at the identification of a rather homogeneous group of patients for the conduction of clinical research.
Topics: Diagnosis, Differential; Humans; Magnetic Resonance Imaging; Spondylarthritis; Spondylitis, Ankylosing; Tomography, X-Ray Computed
PubMed: 33053191
DOI: 10.1093/rheumatology/keaa250 -
Frontiers in Immunology 2021The term spondyloarthritis pertains to both axial and peripheral arthritis including ankylosing spondylitis (AS) and psoriatic arthritis (PsA), which is strongly linked... (Review)
Review
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.
Topics: Animals; Biomarkers; Diagnosis, Differential; Disease Management; Disease Susceptibility; Genetic Predisposition to Disease; Humans; Interleukin-17; Interleukin-23; Molecular Targeted Therapy; Signal Transduction; Spondylitis, Ankylosing; Treatment Outcome
PubMed: 33815371
DOI: 10.3389/fimmu.2021.614255 -
RMD Open Jul 2022Long-term safety and efficacy of upadacitinib in patients with active ankylosing spondylitis (AS) has not been previously reported. (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Long-term safety and efficacy of upadacitinib in patients with active ankylosing spondylitis (AS) has not been previously reported.
METHODS
In SELECT-AXIS 1, patients receiving placebo were switched to upadacitinib 15 mg once daily at week 14 while patients initially randomised to upadacitinib continued their regimen through week 104. Efficacy was assessed using as-observed (AO) and non-responder imputation (NRI).
RESULTS
Of 187 patients randomised, 144 patients (77%) completed week 104. Among patients receiving continuous upadacitinib, 85.9% (AO) and 65.6% (NRI) achieved Assessment of SpondyloArthritis international Society 40 response (ASAS40) at week 104. Similar magnitude of ASAS40 responses were observed among patients who switched from placebo to upadacitinib (88.7% and 63.8%, respectively). The mean change from baseline to week 104 in Spondyloarthritis Research Consortium of Canada MRI spine and sacroiliac joint inflammation scores were -7.3 and -5.3, respectively, in the continuous upadacitinib group and -7.9 and -4.9 in the placebo-to-upadacitinib switch group. The mean (95% CI) change from baseline to week 104 in the modified Stoke Ankylosing Spondylitis Spine Score was 0.7 (0.3, 1.1) in the total group. Adverse event rate was 242.7/100 patient-years. No serious infections, adjudicated major adverse cardiovascular events, lymphoma, non-melanoma skin cancer, or gastrointestinal perforations were observed.
CONCLUSIONS
Upadacitinib 15 mg once daily showed sustained and consistent efficacy over 2 years for ASAS40 and other clinically relevant endpoints. A low rate of radiographic progression was observed and no new safety findings were observed.
Topics: Antirheumatic Agents; Heterocyclic Compounds, 3-Ring; Humans; Spondylarthritis; Spondylitis, Ankylosing; Treatment Outcome
PubMed: 35896281
DOI: 10.1136/rmdopen-2022-002280 -
BMJ (Clinical Research Ed.) Jan 2021Axial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton associated with significant pain and disability. Previously, the diagnosis of ankylosing... (Review)
Review
Axial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton associated with significant pain and disability. Previously, the diagnosis of ankylosing spondylitis required advanced changes on plain radiographs of the sacroiliac joints. Classification criteria released in 2009, however, identified a subset of patients, under the age of 45, with back pain for more than three months in the absence of radiographic sacroiliitis who were classified as axSpA based on a positive magnetic resonance imaging or HLAB27 positivity and specific clinical features. This subgroup was labeled non-radiographic (nr)-axSpA. These patients, compared with those identified by the older New York criteria, contained a larger percentage of women and demonstrated less structural damage. However, their clinical manifestations and response to biologics were similar to radiographic axSpA. The discovery of the interleukin (IL) IL-23/IL-17 pathway revealed key molecules involved in the pathophysiology of axSpA. This discovery propelled the generation of antibodies directed toward IL-17A, which are highly effective and demonstrate treatment responses in axSpA that are similar to those observed with anti-TNF agents. The finding that agents that block IL-23 were not effective in axSpA came as a surprise and the potential underlying mechanisms underlying this lack of response are discussed. New agents with dual inhibition of the IL-17A and F isoforms and some oral small molecule agents that target the Jak-STAT pathway, have also shown efficacy in axSpA.
Topics: Antibodies, Monoclonal, Humanized; Exercise Therapy; HLA-B27 Antigen; Humans; Interleukin-17; Interleukins; Magnetic Resonance Imaging; Spondylitis, Ankylosing
PubMed: 33397652
DOI: 10.1136/bmj.m4447 -
Annals of Medicine Dec 2021Hook (TWH) has significant anti-inflammatory and immunosuppressive properties and is widely used for treating autoimmune and inflammatory diseases. However, the...
BACKGROUND
Hook (TWH) has significant anti-inflammatory and immunosuppressive properties and is widely used for treating autoimmune and inflammatory diseases. However, the multi-target mechanism of TWH on ankylosing spondylitis (AS) remains to be elucidated.
METHODS
Active components and their target proteins were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Meanwhile, AS-related targets were obtained from the Genecards Database. After overlapping, the targets of TWH against AS were collected. Then protein-protein interaction (PPI) network and core targets analysis were conducted through STRING network platform and Cytoscape software. Moreover, molecular docking methods were utilized to confirm the high affinity between TWH and targets. Finally, DAVID online tool was used to perform gene ontology (GO) and Kyoto encyclopaedia of genes and genome (KEGG) pathway enrichment analysis of overlapping targets.
RESULTS
The TCMSP Database results showed that there were11 active components of TWH against AS. PPI network and core targets analysis suggested that ESR1, VEGF, ICAM-1, and RELA were key targets against AS. Moreover, molecular docking methods confirmed the high affinity between bioactive molecular of TWH and their targets in AS. At last, enrichment analysis indicated that TWH participates in various biological processes, such as cell-cell adhesion, regulation of cell-matrix adhesion, acute inflammatory response, via TNF-α, NF-κB and so forth signalling pathways.
CONCLUSION
Verified by network pharmacology approach based on data mining and molecular docking methods, multi-target drug TWH may serve as a promising therapeutic candidate for AS but still needs further / experiments.
Topics: Drugs, Chinese Herbal; Humans; Medicine, Chinese Traditional; Molecular Docking Simulation; Network Pharmacology; Spondylitis, Ankylosing
PubMed: 34259096
DOI: 10.1080/07853890.2021.1918345 -
Pharmacology 2022Janus kinase (JAK) inhibitors and secukinumab have been demonstrated to be effective treatments for ankylosing spondylitis (AS). However, there have been no head-to-head... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Janus kinase (JAK) inhibitors and secukinumab have been demonstrated to be effective treatments for ankylosing spondylitis (AS). However, there have been no head-to-head trials comparing the effectiveness and safety characteristics of JAK inhibitors with secukinumab. This study aimed to evaluate the relative effectiveness and safety of JAK inhibitors and secukinumab in patients with active AS.
SUMMARY
A Bayesian network meta-analysis was conducted using direct and indirect data from randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib 5 mg, upadacitinib 15 mg, filgotinib 200 mg, and secukinumab 150 mg in patients with active AS who had a poor response or intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs) and were tumor necrosis factor (TNF) inhibitor-naïve. Data from six RCTs comprising 937 patients were analyzed. The Assessment of SpondyloArthritis International Society 20 (ASAS20) response rates were significantly higher in the JAK inhibitors and secukinumab groups than in the placebo group. The surface under the cumulative ranking curve (SUCRA)-based ranking probability based on the ASAS20 response rate suggested that tofacitinib 5 mg had the highest likelihood of being the best treatment for achieving the ASAS20 response rate, followed by filgotinib 200 mg, upadacitinib 15 mg, secukinumab 150 mg, and placebo. The SUCRA-based ranking probability based on the ASAS20 response rate suggested that tofacitinib 5 mg had the highest likelihood of being the best treatment for achieving the ASAS40 response rate, followed by upadacitinib 15 mg, secukinumab 150 mg, filgotinib 200 mg, and placebo.
KEY MESSAGES
Tofacitinib 5 mg was the most effective treatment for AS, whereas JAK inhibitors and secukinumab 150 mg were effective treatments in patients with active AS who had a poor response or intolerance to NSAIDs and were TNF inhibitor-naïve.
Topics: Humans; Janus Kinase Inhibitors; Spondylitis, Ankylosing; Antirheumatic Agents; Treatment Outcome; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 35817017
DOI: 10.1159/000525627