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Purpose of Review: It is now 50 years since the concept of spondyloarthritis was introduced by Moll, Wright and co-authors from Leeds, UK. This review will review the original concept and mark significant milestones over the last 50 years while looking ahead to developments in the future., Recent Findings: While the diseases included under this rubric in the original description may have changed the core conditions remain and are still characterized by axial inflammation as a common feature. Imaging, animal models, genetics and immunology have contributed to our knowledge of the pathogenesis and classification of these diseases and have led to the development of more effective treatments., Summary: Future developments, facilitated by large research consortia, will help build on our current knowledge and will help clarify disease heterogeneity and provide insights into new therapeutic pathways., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Despite immunology and translational therapeutics advances in inflammatory arthritis over the past two decades, the enthesis, which is the epicentric of the spondyloarthritis family pathological process, retains many mysteries because of tissue inaccessibility that hampers direct immune study. As entheses are subject to almost continuous mechanical stress and spondyloarthritis is linked to microdamage or injury and joint stress, it is cardinal to understand the physiological changes occurring within the entheses not only to be able to differentiate disease from health but also to understand the transition normal physiology break down and its merges into spondyloarthritis-related disease., Recent Findings: Imaging has played a major role in understanding the enthesis in human. Remarkable insights from enthesis functioning and microdamage in normal and with ageing including those linked to body mass index is emerging. The impact of mechanical stress and degenerative conditions on the development of the secondary entheseal vascular changes is not understood. Of note, ultrasound studies in psoriasis have shown higher power Doppler changes compared to controls pointing towards a role for vascular changes in the development of enthesitis in psoriatic arthritis., Summary: The literature pertaining to normal entheses changes with age, microdamage and vascular changes in health is providing a roadmap for understanding of the enthesis and its potential role in evolution of spondyloarthritis including psoriatic arthritis.

Purpose of Review: The clinical overlap between spondyloarthritis (SpA) and inflammation of barrier tissues such as the intestine and skin indicates a role of barrier tissue immunity in the development of SpA. Herein, we review the recent advances in understanding lymphocyte populations and functions within the intestine and skin implicated in the pathophysiology of SpA., Recent Findings: A number of unique lymphocyte populations have been identified to be expanded within the gut and skin of patients with SpA, including γδ T cells, mucosa-associated invariant T (MAIT) cells, innate lymphoid cells (ILCs) and T resident memory (TRM) cells. These cells respond to microbial cues at their barrier surface causing cellular activation and generation of interleukin (IL)-17, which is hypothesized to be the mechanism by which they contribute to SpA pathogenesis., Summary: Understanding how unique lymphocyte populations expand and produce IL-17 in the development of SpA provides insights into the pathophysiology of this disease as well as potential future therapeutic avenues.

Purpose of Review: To give an overview of the recently published trials relating to IL-23/IL-17 pathway in spondyloarthritis (SpA)., Recent Findings: Recent studies in psoriasis confirmed the efficacy of targeting the IL-23/IL-17 pathway, with emerging evidence from head-to-head studies suggesting functional hierarchy of these inhibitors. In psoriatic arthritis (PsA), recent studies have indicated the efficacy of inhibiting IL-23p19, in addition to IL-23p40 and IL-17A, albeit all with lower hurdle results than those seen in psoriasis. The first head-to-head study of an IL-17A and tumour necrosis factor inhibitor in PsA has also recently been published. Recent studies have demonstrated the efficacy of the IL-17A inhibitor, ixekizumab, across the axial SpA spectrum. In contrast, inhibition of IL-12/IL-23p40 and IL-23p19 both failed in axial SpA. In inflammatory bowel disease (IBD), recent studies indicate efficacy of IL-23p40 and IL-23p19 inhibition, in contrast to the previous failed studies of IL-17 inhibition., Summary: Clinical trials of IL-23/IL-17 inhibition have been transformative in psoriasis, with more mixed results in PsA and differential responses in axial SpA and IBD. These results pose challenges to our fundamental understanding of SpA pathogenesis and further head-to-head studies and more subtle evaluation of the local tissue-specific aspects will be required.

Purpose of Review: This article aims to review recent literature linking epithelial barrier inflammation and arthritis in spondyloarthritis (SpA), with a critical view on how they are bound by genetic, immunological and environmental ties., Recent Findings: The epithelia-joint axis has become an intense area of both basic and clinical SpA research. The penultimate goal is to understand the immunopathologic links between epithelial inflammation and arthritis in SpA. Inflammatory bowel disease (IBD) and psoriasis (PsO) have strong links to SpA at several levels. Clinically, there is a strong association of IBD, PsO and SpA. Genetically, there are many shared risk factors; however, there are also distinct differences in the genetics of the respective diseases. Immunologically, type 3 immunity, especially interleukin (IL)-17 and IL-23 dysregulation, has been shown to play a central role in IBD, PsO and SpA. Environmentally, a microbial dysbiosis has been noted in each of these diseases, but whether the microbial signature is similar between diseases is not clear, nor is the effect of dysbiosis on the immune response known., Summary: It will be crucial to determine whether the relationship between epithelia inflammation and SpA is truly causal for both the understanding of pathogenesis and for future treatment strategies.

Purpose of Review: The spondyloarthopathies (SpA), which encompass related diseases that were originally viewed as autoimmune, are now known to have a strong innate immune or autoinflammatory initiation phase characterized by disease localization to tissue-specific sites based on the nuances and microanatomy and immunology of those sites. This review covers recent translational advances in the field of SpA., Recent Findings: Imaging studies in SpA continue to add support for the pivotal role of enthesitis in disease initiation and expression. Although in its infancy, there is growing evidence for microbiotal intestinal dysbiosis in ankylosing spondylitis and psoriatic arthritis. The role of cytokines beyond tumour necrosis factor (TNF) continues to grow with support for the interleukin (IL)-23/17 axis being key to disease and emergent evidence for the importance of the IL-36 pathway. The treatment of inflammatory bowel disease (IBD) with vedolizumab an α4β7-integrin blocker has been associated with arthritis flares and small molecules with Janus kinase inhibition appear to be as effective as the anti-TNFs. The disparate response of different domains in SpA points towards immunological heterogeneity even within what was considered a homogeneous disease., Summary: The clinical aspects and translational immunology and therapeutics of SpA continue to evolve and indicate the complexity of diagnosis and treatment of these conditions.

Purpose of Review: This article highlights and emphasizes how new knowledge of mechanisms linked to the interleukin-23 (IL-23)/IL-17 pathway is relevant to the pathophysiology of axial spondyloarthritis (axSpA) and demonstrates how molecules in IL-23/IL-17 pathway provide novel therapeutic targets for axSpA patients., Recent Findings: Similarly to ankylosing spondylitis (AS), the increased frequency of Th17 cells in nr-axSpA patients underscores the concept that these disorders can be viewed on a spectrum. Recent findings suggest that the contribution of IL-23/IL-17 signaling pathways possibly differs in male and female AS patients. The finding that IL-17 and IL-22 secreting-type 3 innate lymphoid cells are increased in AS patients point to their potential role in the pathogenesis of axSpA. Reports of dysbiosis in the gut microbiome of AS patients support previous work indicating a possible causal relationship between altered gut flora, ileocolonic inflammation and axSpA. Of important clinical relevance are results from clinical trials supporting the efficacy and safety of agents that block IL-12/23 (ustekinumab) and IL-17 (secukinumab and ixekizumab) in AS patients., Summary: Recent studies further establish the central position of the IL-23/IL-17 pathway in the pathogenesis of axSpA. Targeting the IL-23/IL-17 pathway appears to be a safe and effective strategy for treatment of axSpA patients.

Purpose of Review: We focus on the role of killer immunoglobulin receptor (KIR) interactions with the human leukocyte antigens (HLA)-B27 ligand and the potential contribution of KIR-expressing natural killer and T cells in spondyloarthritis, more specifically in ankylosing spondylitis (AS)., Recent Findings: In AS strong epidemiological evidence of significant genetic associations with the major histocompatibility complex was convincingly identified. HLA-B27-positive first-degree relatives of AS cases are 5-16 times more likely to develop disease than HLA-B27-positive carriers in the general community. The GWAS era has enabled rapid progress in identifying non-major histocompatibility complex associations of AS., Summary: These findings show a number of important pathways in AS pathogenesis, including the IL-23-IL-17 pathway, aminopeptidases, peptide presentation, and KIR-HLA-B27 interactions. Studies using genetic markers, including KIRs may be used for a risk assessment about whom may benefit most from the various treatment protocols in spondyloarthritis, now that alternative therapeutic options have become feasible.

Purpose of Review: Inflammatory innate and adaptive immune cell responses to commensal bacteria underlie the pathogenesis of human chronic inflammatory diseases. Intestinal dysbiosis has been described in patients with spondyloarthritis (SpA) and seems to be correlated with histologic and immunologic alterations. Purpose of this review is to discuss the relationship occurring between intestinal dysbiosis and innate immune responses in patients with axial SpA., Recent Findings: Intestinal dysbiosis and differential activation of intestinal immune responses in patients with SpA have been demonstrated. Furthermore, innate cells that appear to be involved in the pathogenesis of SpA may control intestinal homeostasis through induction of apoptotic cell death and deletion of activated commensal bacteria-specific T cells., Summary: Although the evidence shows that dysbiosis occurs in SpA, it is not clear the role of dysbiosis in regulating innate immune responses in SpA. Relationships between cause and effect remain to be answered., Video Abstract: http://links.lww.com/COR/A34.

Purpose of Review: Microbial dysbiosis in the gut is emerging as a common component in various inflammatory disorders including spondyloarthritis (SpA). The depth of this influence has begun to be realized with next-generation sequencing of the gut microbiome providing unbiased assessment of previously uncharted bacterial populations., Recent Findings: Decreased numbers of Firmicutes, a major phyla of gut commensals, especially the species Faecalibacterium prausnitzii and Clostridium leptum have been found in various inflammatory disorders including SpA and inflammatory bowel disease (IBD), and could be an important link between SpA and gut inflammation. Multiple studies in ankylosing spondylitis, psoriatic arthritis, juvenile SpA, and animal models of SpA are revealing common bacterial associations among these diseases as well as IBD., Summary: We are beginning to appreciate the complex relationship between the gut microbiome and host immune regulation and dysregulation in health and disease. Potentially important differences have been revealed in SpA, but cause and effect relationships remain far from established. Many critical questions remain to be answered before we can apply new knowledge to improve therapeutics in SpA.

Purpose of Review: The association between spondyloarthritis (SpA) and inflammatory bowel disease (IBD) is well known. Additionally, about half of SpA patients show microscopic gut inflammation. Substantial progress has been made in understanding the pathogenesis of SpA and IBD, with new therapeutic targets for either of them in clinical development., Recent Findings: Microscopic gut inflammation was found in early forms of SpA in about 50% of cases and is associated with age, sex, disease activity and degree of MRI inflammation on sacroiliac joints. Although prospective follow-up data in men and murine animal studies show a parallelism between gut and joint evolution in SpA, therapeutic outcomes are not always the same in SpA and IBD. These differences can be ascribed to differences in not only the cytokine pathways and cells involved in disease, tissue localization and environmental factors but also in pharmacokinetics and biodistribution., Summary: A significant amount of data all point in the direction of arthritis and gut inflammation being pathogenetically closely linked in the SpA concept. However, when it comes to therapeutic effectiveness, the gut and the joints do not always react in the same way. These differences in therapeutic effect could be attributed to the different ways in which cytokine pathways are involved in SpA and IBD.

Purpose of Review: Thirty years ago, the concept of microscopic gut inflammation in spondyloarthritis (SpA) was established. Over the past decade, there has been tremendous progress in the earlier diagnosis of SpA. In addition, it has been suggested that, because of improved hygiene over the past years, exposure to microorganisms has changed, leading to a shift in diseases, for example, a decreased incidence of reactive arthritis. It is therefore necessary to re-establish the role of gut inflammation in SpA., Recent Findings: The prevalence of microscopic gut inflammation could be confirmed in c. 50% of patients with early axial and/or peripheral SpA. More importantly, a predictive model could be developed linking gut inflammation with clinical factors, that is, higher disease activity, extensive sacroiliac bone marrow edema, and progressive disease. In addition, there is increasing evidence indicating that the presence or absence of gut inflammation in SpA may influence therapeutic decision-making in the future. A clear demonstration of this is the different efficacy of IL-17 blockade in Crohn's disease versus SpA., Summary: Microscopic gut inflammation is present in almost 50% of SpA patients and appears relevant for prognosis and therapeutic decision-making. SpA patients with the chronic type of gut inflammation seem to have a less favorable disease course. It is therefore conceivable that assessment of gut inflammation should be included in future models for risk stratification of SpA.

Purpose of Review: Various novel therapies for spondyloarthritis (SpA) are currently under development. In this review, we discuss the scientific rational to target the interleukin (IL)-23/IL-17 axis in SpA and give an overview of the proof-of-concept trials with drugs directed towards this axis., Recent Findings: Cumulative evidence from genetics (e.g. the strong genetic association with the IL-23 receptor gene), in-vitro models (e.g. the increased IL-23 production upon HLA-B27 misfolding), human expression studies (e.g. the expansion of IL-17 producing innate cells in SpA) and animal models (e.g. the increased IL-17 production in HLA-B27 transgenic rats) strongly supports the involvement of the IL-23/IL-17 axis in the pathogenesis of SpA. Ustekinumab (a monoclonal antibody directed against the common p40 subunit of IL-23 and IL-12), secukinumab, ixekizumab (both monoclonal antibodies directed against IL-17A), and brodalumab a monoclonal antibody against the IL-17RA receptor) have been recently used in proof-of-concept and randomized trials in the ankylosing spondylitis and/or psoriatic arthritis subforms of SpA, with overall very promising clinical efficacy., Summary: The first results for novel drugs blocking key cytokines in the IL-23/IL-17 axis are promising in SpA and more novel compounds are upcoming. This will teach us more on the role of the IL-23/IL-17 axis in the pathophysiology of SpA.

Purpose of Review: The spondyloarthropathies (SpAs) are a group of interrelated inflammatory disorders with overlapping clinical features. Current SpA treatments only provide partial symptomatic and functional relief in a subgroup of patients. Consequently, there is a need to better understand the pathophysiology of SpA to develop more specific and effective treatments for these conditions., Recent Findings: Genetic and mechanistic evidence links SpA with inflammatory bowel disease (IBD) and psoriasis, and the symptoms of these diseases partially overlap. Regulatory T cells (Tregs) and dendritic cells control the adaptive immune response, and failures in their functions are likely to contribute to the establishment of chronic inflammation. The contributions of Tregs and dendritic cells to IBD and SpA have been assessed in both animal models of disease and patients., Summary: Although defects in Tregs are important in psoriasis and in animal models of IBD, there is little evidence that they are important in SpA. However, data from animal models indicate that dendritic cells drive pathogenic T-cell responses, partly through the production of interleukin-23 (IL-23). Dendritic cells from SpA patients may also contribute to disease by producing IL-23, therefore supporting the differentiation of the Th17 cells that contribute to inflammation. The driving forces in SpA pathophysiology are now becoming clear; these data may lead to the development of novel therapies to target SpA and related inflammatory disorders.

Purpose of Review: HLA-B27 is associated with low viral load and long-term nonprogression in HIV infection as well as spontaneous clearance of hepatitis C virus (HCV) infection. This review summarizes mechanisms that have been suggested to be involved in this protective effect of HLA-B27, and highlights possible lessons for the role of HLA-B27 in spondyloarthritis., Recent Findings: Recent studies linked protection by HLA-B27 in HIV and HCV infection to virological mechanisms such as a complicated pathways of viral escape from immunodominant HLA-B27-restricted virus-specific CD8+ T-cell epitopes. In addition, several immunological mechanisms have been proposed, including CD8+ T-cell polyfunctionality and functional avidity, thymic selection of CD8+ T-cell precursors, specific T-cell receptor repertoires and clonotypes, efficient antigen processing, and evasion from regulatory T-cell-mediated suppression., Summary: Multiple virological and immunological mechanisms have been suggested to contribute to HLA-B27-mediated protection in HIV and HCV infection. Some of these mechanisms may also be involved in HLA-B27-associated pathogenesis in spondyloarthritis.

Purpose of Review: Natural killer (NK) cells, gamma delta (γδ) T-cells and other innate immune cells are important lymphocyte subsets able both to produce cytokines including the pro-inflammatory cytokine IL-17 and to kill cellular targets. This review describes the features of NK cells, γδ T-cells and other innate immune cells, and outlines the evidence for their potential pathogenic roles in spondyloarthritis (SpA)., Recent Findings: NK cells and T cells both express receptors that recognize aberrantly folded human leucocyte antigen. This interaction seems to polarize towards a type 17 immunity programme which has been increasingly implicated in SpA pathology. γδ T-cells have also been shown to be polarized towards a type 17 immunity programme in SpA. Gut interactions with the microbiome can influence NK and innate lymphoid immune responses in SpA and other related diseases. A newly identified population of resident lymphoid cells at the enthesis for the first time offers an explanation for the anatomical localization of SpA., Summary: NK cells, γδ T-cells and other innate immune cells are capable of sharing expression of both transcription factors, including RORγt, and cell surface receptors, such as the killer immunoglobulin-like receptors. There is increasing genetic and functional evidence that they contribute to the RORγt-driven inflammatory type 17 immune responses, and they may link gut inflammation and joint pathology in SpA.

Purpose of Review: Spondyloarthritis (SpA) is a chronic immune-mediated inflammatory disease of unknown origin. Here we aim to review whether SpA is driven by T-cell and/or B-cell autoreactivity or by abnormal innate immune responses., Recent Findings: SpA does not share genetic risk factors, female predominance, presence of disease-specific autoantibodies and response to T-cell or B-cell-targeted therapies with prototypical autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Growing evidence indicates that increased responsiveness of innate immune cells such as macrophages, mast cells and neutrophils drives inflammation in SpA. The altered innate immune response may be related to nonantigen-presenting functions of HLA-B27, including the induction of an unfolded protein response, and can be triggered by bacterial and mechanical stress. Innate immune cells appear to be the main producers of both pro-inflammatory (tumor necrosis factor, IL-1, IL-23, IL-17) and anti-inflammatory (IL-10) cytokines in SpA., Summary: The predominance of myeloid above lymphoid alterations suggests an autoinflammatory rather than autoimmune origin of inflammation in SpA. Therefore, targeting innate cells or their inflammatory mediators may be more effective than T-cell or B-cell-directed therapies.

Purpose of Review: The management of ankylosing spondylitis and other spondyloarthritides (SpAs) such as psoriatic arthritis (PsA) is becoming more and more complex due to major advances, especially in the pharmacological therapy of these diseases. Biologics such as the anti-tumour necrosis factor agents have the potential to improve almost all outcome parameters usually assessed. The purpose of this review was to collect all available information related to the treatment of ankylosing spondylitis published in the year 2008. This was achieved by a systematic literature search in PubMed., Recent Findings: There is increasing knowledge about the short-term and long-term efficacy of anti-tumour necrosis factor agents. As it stands now, radiographic progression of ankylosing spondylitis patients is not decelerated, in contrast to PsA. One major difference between the two SpAs is that ankylosing spondylitis is more an osteoproliferative disease, whereas PsA is more osteodestructive (though it certainly has both elements). Methotrexate offers no additional benefit for the axial symptoms in ankylosing spondylitis. Other biologics such as efalizumab, which is used to treat psoriasis, seems to increase the frequency of arthritis. A whole array of potential side effects has been reported. Cardiovascular comorbidity seems to be rather important for SpA patients., Summary: In this review, we especially cover not only the following themes of new clinical studies, efficacy regarding signs and symptoms, function and quality of life but also structural damage and the link between inflammation and new bone formation. The pharmacokinetics of infliximab including the formation of antibodies and the overall and long-term safety of anti-tumour necrosis factor agents is covered.