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.

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.

Significance of structural changes in the axial skeleton in patients with axial spondyloarthritis: how important are lesions in the sacroiliac joint?

Inflammatory back pain (IBP) is a characteristic clinical symptom of patients with axial spondyloarthritis (axSpA) that is caused by inflammation in the axial skeleton. In early disease stages the sacroiliac joints (SIJ) are most often affected, the spine usually at later stages. In many but clearly not all cases of axSpA new bone formation in form of syndesmophytes and ankylosis occur in the further course of the disease. Function and mobility may be impaired by both, inflammation and structural changes. In clinical trials outcome parameters most often used refer to pain, disease activity, function, mobility and global health but many researchers are also interested in radiographic progression in the axial skeleton of patients with axSpA. This viewpoint discusses the relevance of structural changes in the SIJ in comparison to the spine and in relation to functional outcomes and mobility.

Musculoskeletal manifestations in a Portuguese cohort of 235 inflammatory bowel disease patients.

BACKGROUND: Musculoskeletal symptoms represent the most common extraintestinal manifestations of inflammatory bowel disease (IBD) and a major cause of impaired quality of life in these patients. Spondyloarthritis (SpA) is classically associated with IBD, but other rheumatic manifestations may occur. OBJECTIVE: To characterize musculoskeletal symptoms and rheumatic diseases in an IBD cohort. METHODS: Retrospective monocentric descriptive study including all the patients with IBD consecutively referred from Gastroenterology to the Reumatology Department (from January of 2013 to April of 2021) in a Portuguese tertiary university hospital. Demographic and clinical data were collected and musculoskeletal symptoms and rheumatic diseases diagnosed in the Rheumatology outpatient center were registered. RESULTS: A total of 235 patients were included: 177 (75.3%) with Crohn´s disease (CD) and 58 (24.7%) with ulcerative colitis. Musculoskeletal symptoms were observed in 142 (60.4%) patients and 105 (44.7%) had some rheumatic condition. Regarding spondyloarthritis, 46 (19.6%) patients fulfilled ASAS (Assessment of SpondyloArthritis international Society) criteria for axial SpA and 5 (2.1%) for peripheral SpA. Osteoarthritis (n=70, 29.8%) and osteoporosis (n=33, 14%) were the most frequent non-inflammatory rheumatic conditions observed, mostly previously undiagnosed. No significant differences were observed between CD and UC. CONCLUSION: Rheumatic conditions are frequent in IBD patients and are not limited to SpA features. They remain mostly undiagnosed and the collaboration between gastroenterologists and rheumatologists is important for their best management.

Dual Blockade of TNF and IL-17A Inhibits Inflammation and Structural Damage in a Rat Model of Spondyloarthritis.

The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human ß2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.

The Role of the IL-23/IL-17 Axis in Disease Initiation in Spondyloarthritis: Lessons Learned From Animal Models.

Spondyloarthritis (SpA) is a spectrum of chronic inflammatory joint diseases that frequently presents with inflammation of the axial skeleton, peripheral joints, entheses, skin, and gut. Understanding SpA pathogenesis has been proven challenging due to the limited availability of human target tissues. In recent years, the interleukin (IL)-23/IL-17 pathway has been implicated in the pathogenesis of SpA, in addition to the Tumor Necrosis Factor Alpha (TNF-α) cytokine. The underlying molecular mechanisms by which the IL-23/IL-17 pathway triggers disease initiation, both in the joints as well as at extra-musculoskeletal sites, are not precisely known. Animal models that resemble pathological features of human SpA have provided possibilities for in-depth molecular analyses of target tissues during various phases of the disease, including the pre-clinical initiation phase of the disease before arthritis and spondylitis are clinically present. Herein, we summarize recent insights gained in SpA animal models on the role of the IL-23/IL-17 pathway in immune activation across affected sites in SpA, which include the joint, entheses, gut and skin. We discuss how local activation of the IL-23/IL-17 axis may contribute to the development of tissue inflammation and the onset of clinically manifest SpA. The overall aim is to provide the reader with an overview of how the IL-23/IL-17 axis could contribute to the onset of SpA pathogenesis. We discuss how insights from animal studies into the initiation phase of disease could instruct validation studies in at-risk individuals and thereby provide a perspective for potential future preventive treatment.

Telomeres: New players in immune-mediated inflammatory diseases?

Telomeres are repetitive DNA sequences located at the ends of linear chromosomes that preserve the integrity and stability of the genome. Telomere dysfunctions due to short telomeres or altered telomere structures can ultimately lead to replicative cellular senescence and chromosomal instability, both mechanisms being hallmarks of ageing. Chronic inflammation, oxidative stress and finally telomere length (TL) dynamics have been shown to be involved in various age-related non-communicable diseases (NCDs). Immune-mediated inflammatory diseases (IMIDs), including affections such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, spondyloarthritis and uveitis belong to this group of age-related NCDs. Although in recent years, we have witnessed the emergence of studies in the literature linking these IMIDs to TL dynamics, the causality between these diseases and telomere attrition is still unclear and controversial. In this review, we provide an overview of available studies on telomere dynamics and discuss the utility of TL measurements in immune-mediated inflammatory diseases.

Testing if Micro-CT Is Capable of Quantitating the Extent of Proteoglycan-Aggrecan Induced Axial Spondyloarthritis in Mice.

Objective: Injections of proteoglycan aggrecan (PGA) have been reported to induce axial spondyloarthritis (ax-SpA) in BALB/c mice. It is considered to be a model for radiographic ax-SpA. However, evaluation of the extent of axial disease by histopathological assessment of every intervertebral space is labor-intensive. The objective of our paper is to test the feasibility of Micro Computed Tomography (Micro-CT) in rapidly enumerating the number of intervertebral spaces affected in each mouse. Methods: Arthritis was induced in BALB/c mice by intraperitoneal injections of PGA. Involvement of several spinal segments, and selected sacroiliac and hip joints were evaluated by histopathology. The involvement of all intervertebral spaces, sacroiliac and hip joints was evaluated by Micro-CT. Results: BALB/c mice injected with PGA developed histopathology of SpA-like axial lesions, including spondylitis, sacroiliac joint arthritis and hip joint arthritis. Micro-CT allowed us to clearly enumerate the number of lesions in each mouse. Conclusion: Micro-CT allows quantitative assessment of the extent of axial involvement in PGA-induced mouse spondylitis. This can be a useful tool in assessing therapeutic interventions.

Axial and peripheral spondyloarthritis triggered by sars-cov-2 infection: a report of two cases.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can show musculoskeletal symptoms such as peripheral arthritis. In rare cases, peripheral arthritis can develop after the resolution of SARS-CoV-2. We present two cases of spondyloarthritis induced by SARS-CoV-2; one case with axial and peripheral spondyloarthritis and the other with peripheral spondyloarthritis. Both cases refer to Lebanese patients who were HLA-B27 positive. These two cases highlight the possible predisposition of HLA-B27 positive patients to the development of spondyloarthritis symptoms triggered by SARS-CoV-2.

The gut-joint axis in spondyloarthritis: immunological, microbial, and clinical insights.

The strong genetic and clinical overlaps between spondyloarthritis (SpA) and inflammatory bowel disease (IBD) have placed much needed focus on the gut-joint axis of inflammation in SpA, leading to three key hypotheses that attempt to unravel this complex relationship. The arthritogenic peptide hypothesis and the aberrant cellular trafficking hypothesis have been put forth to rationalize the manner by which the innate and adaptive immune systems cooperate and converge during SpA pathogenesis. The bacterial dysbiosis hypothesis discusses how changes in the microbiome lead to architectural and immunological consequences in SpA. These theories are not mutually exclusive, but can provide an explanation as to why subclinical gut inflammation may sometimes precede joint inflammation in SpA patients, thereby implying a causal relationship. Such investigations will be important in informing therapeutic decisions which may be common to both SpA and IBD. However, these hypotheses can also offer insights for a coincident inflammatory relationship between the gut and the joint, particularly when assessing the immunological players involved. Insights from understanding how these systems might affect the gut and joint differently will be equally imperative to address where the therapeutic differences lie between the two diseases. Collectively, this knowledge has practical implications in predicting the likelihood of IBD development in SpA or presence of coincident SpA-IBD, uncovering novel therapeutic targets, and redesigning currently approved treatments. It is evident that a multidisciplinary approach between the rheumatology and gastroenterology fields cannot be ignored, when it comes to the care of SpA patients at risk of IBD or vice versa.

Recent advances on the role of cytotoxic T lymphocytes in the pathogenesis of spondyloarthritis.

Spondyloarthritis (SpA) is a chronic inflammatory disorder with complex etiology and pathogenesis. Its pathogenesis likely involves a combination of different factors. These factors include host genetics, environmental triggers, and immune and microbiota dysregulation. One of the strongest genetic associations with SpA is HLA-B27, implicating the involvement of cytotoxic T lymphocytes (CTLs) in SpA pathogenesis. Despite this discovery dating back decades ago, the CTL compartment that underlies SpA inflammation has yet to be fully defined until recently. Indeed, recent published studies support a significant role that CTLs play in contributing to chronic joint inflammation, which is a hallmark of SpA pathology. In this review chapter, we discuss emerging evidence that supports a newfound role of CTLs in SpA pathogenesis. This emerging evidence includes enrichment of CTL-related genes from genome-wide association studies, overrepresentation of pathogenic synovial CTL phenotype, clonal expansion, and immune dysregulation of CTLs. The discoveries of this mounting evidence suggest that CTL homeostasis is altered, and a disrupted adaptive immunity underlies the chronic inflammatory features seen in SpA pathology.

Novel immune cell phenotypes in spondyloarthritis pathogenesis.

Spondyloarthritis (SpA) is a heterogeneous group of chronic inflammatory diseases of unknown etiology. Over time, the plethora of cellular elements involved in its pathogenesis has progressively enriched together with the definition of specific cytokine pathways. Recent evidence suggests the involvement of new cellular mediators of inflammation in the pathogenesis of SpA or new subgroups of known cellular mediators. The research in this sense is ongoing, and it is clear that this challenge aimed at identifying new cellular actors involved in the perpetuation of the inflammatory process in AxSpA is not a mere academic exercise but rather aims to define a clear cellular hierarchy. Such a definition could pave the way for new targeted therapies, which could interfere with the inflammatory process and specific pathways that trigger immune system dysregulation and stromal cell activity, ultimately leading to significant control of the inflammation and new bone formation in a significant number of patients. In this review, we will describe the recent advances in terms of new cellular actors involved in the pathogenesis of SpA, focusing our attention on stromal cells and innate and adaptive immunity cells.

Microbial-derived antigens and metabolites in spondyloarthritis.

Spondyloarthritis (SpA) is a group of chronic, immune-mediated, inflammatory diseases affecting the bone, synovium, and enthesis. Microbiome, the community of microorganisms that has co-evolved with human hosts, plays a pivotal role in human health and disease. This invisible "essential organ" supplies the host with a myriad of chemicals and molecules. In turn, microbial metabolites can serve as messengers for microbes to communicate with each other and in the cross-talk with host cells. Gut dysbiosis in SpA is associated with altered microbial metabolites, and an accumulated body of research has contributed to the understanding that changes in intestinal microbiota can modulate disease pathogenesis. We review the novel findings from human and animal studies to provide an overview of the contribution of individual microbial metabolites and antigens to SpA.

Cytokine "fine tuning" of enthesis tissue homeostasis as a pointer to spondyloarthritis pathogenesis with a focus on relevant TNF and IL-17 targeted therapies.

A curious feature of axial disease in ankylosing spondylitis (AS) and related non-radiographic axial spondyloarthropathy (nrAxSpA) is that spinal inflammation may ultimately be associated with excessive entheseal tissue repair with new bone formation. Other SpA associated target tissues including the gut and the skin have well established paradigms on how local tissue immune responses and proven disease relevant cytokines including TNF and the IL-23/17 axis contribute to tissue repair. Normal skeletal homeostasis including the highly mechanically stressed entheseal sites is subject to tissue microdamage, micro-inflammation and ultimately repair. Like the skin and gut, healthy enthesis has resident immune cells including ILCs, γδ T cells, conventional CD4+ and CD8+ T cells and myeloid lineage cells capable of cytokine induction involving prostaglandins, growth factors and cytokines including TNF and IL-17 that regulate these responses. We discuss how human genetic studies, animal models and translational human immunology around TNF and IL-17 suggest a largely redundant role for these pathways in physiological tissue repair and homeostasis. However, disease associated immune system overactivity of these cytokines with loss of tissue repair "fine tuning" is eventually associated with exuberant tissue repair responses in AS. Conversely, excessive biomechanical stress at spinal enthesis or peripheral enthesis with mechanically related or degenerative conditions is associated with a normal immune system attempts at cytokine fine tuning, but in this setting, it is commensurate to sustained abnormal biomechanical stressing. Unlike SpA, where restoration of aberrant and excessive cytokine "fine tuning" is efficacious, antagonism of these pathways in biomechanically related disease may be of limited or even no value.

Do geography and ethnicity play a role in juvenile Spondyloarthritis? A multi-center binational retrospective study.

BACKGROUND: Observations among Israeli pediatric rheumatologists reveal that pediatric Juvenile Spondyloarthritis (JSpA) may present differently compared to patients from the United States (US). This study is aimed to compare the demographic and clinical variables of Israeli and US JSpA patients upon presentation. METHODS: We performed a retrospective, cross-sectional, multicenter comparison of JSpA patients among 3 large Israeli pediatric rheumatology centers and a large US pediatric rheumatology center. Patients with diagnosis of Juvenile Ankylosing Spondylitis (JAS) and/or Enthesitis-related Arthritis (ERA) were included. The demographic, clinical and radiologic features were compared. RESULTS: Overall 87 patients were included (39 Israeli, 48 US patients). Upon presentation, inflammatory back pain, sacroiliac joint tenderness and abnormal modified Schober test, were significantly more prevalent among Israeli patients (59% vs. 35.4, 48.7% vs. 16.7, and 41.2% vs. 21.5%, respectively, all p < 0.05), whereas peripheral arthritis and enthesitis were significantly more prevalent among US patients (43.6% vs. 91.7 and 7.7% vs. 39.6% in Israeli patients vs. US patients, p < 0.05). In addition, 96.7% of the Israeli patients versus 29.7% of the US patients demonstrated sacroiliitis on MRI (p < 0.001, N = 67). Less than one-third of the Israeli patients (32%) were HLA-B27 positive vs. 66.7% of US patients (p = 0.007). CONCLUSION: Israeli children with JSpA presented almost exclusively with axial disease compared to US patients who were more likely to present with peripheral symptoms. HLA B27 prevalence was significantly lower in the Israeli cohort compared to the US cohort. Further studies are needed to unravel the genetic and possibly environmental factors associated with these findings.

Sex and gender differences in axial spondyloarthritis: myths and truths.

Mounting evidence reveals evident sex differences in physiology, disease presentation and response to medication in axial SpA (axSpA). Unfortunately these data are often neglected in clinical practice and research. In this review, myths that still exist on diagnosis, disease manifestation and drug effectiveness were argued against data of the most recent literature. The aim is to increase awareness of sex differences in the clinical aspects of axSpA.