Targeting inflammatory pathways in axial spondyloarthritis.
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ABSTRACT:
SUBMITTER: Furst DE
PROVIDER: S-EPMC6549293 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
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Project description: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.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.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.
| S-EPMC5777167 | biostudies-literature
Project description:The IL-23/IL-17 pathway has been implicated in the etiopathogenesis of axial spondyloarthritis through studies of genetic polymorphisms associated with disease, an animal model with over-expression of IL-23 that resembles human disease, and observations that cytokines in this pathway can be found at the site of disease in both humans and animal models. However, the most direct evidence has emerged from clinical trials of agents targeting cytokines in this pathway. Monoclonal antibodies targeting IL-17A have been shown to ameliorate signs and symptoms, as well as MRI inflammation in the spine and sacroiliac joints, in patients with radiographic and non-radiographic axial spondyloarthritis. This was evident in patients refractory to non-steroidal anti-inflammatory agents as well as patients failing treatment with tumor necrosis factor inhibitor therapies. Treatment with a bispecific antibody targeting both IL-17A and IL-17F was also effective in a phase II study. Post-hoc analyses have even suggested a potential disease-modifying effect in reducing development of spinal ankylosis. However, benefits for extra-articular manifestations were limited to psoriasis and did not extend to colitis and uveitis. Conversely, trials of therapies targeting IL-23 did not demonstrate any significant impact on signs, symptoms, and MRI inflammation in axial spondyloarthritis. These developments coincide with recent observations that expression of these cytokines is evident in many different cell types with roles in innate as well as adaptive immunity. Moreover, evidence has emerged for the existence of both IL-23-dependent and IL-23-independent pathways regulating expression of IL-17, potentially associated with different roles in intestinal and axial skeletal inflammation.
| S-EPMC8446672 | biostudies-literature
Project description:Axial spondyloarthritis (AxSpA) is an inflammatory spondyloarthritis (SpA) that has significant impact on a patient's life. Symptoms, including fatigue, sleep problems, depression, and sexual dysfunction, can profoundly impact health-related quality of life (HRQoL) and limit work, leisure, and daily activities. Available therapies effectively manage pain and inflammation in early-stage disease, but patients often continue to experience impaired HRQoL. Thus, there remains a need for new therapies with novel mechanisms that can stop disease progression, potentially reverse damage caused by AxSpA and improve HRQoL in patients with AxSpA. Newer biologic agents, such as those targeting the interleukin 17-interleukin 23 axis, have promising efficacy and may improve HRQoL for patients with AxSpA. The AxSpA has many negative effects on HRQoL. By targeting disease pathways responsible for the development of AxSpA, approved and emerging therapies potentially reduce disease activity and improve the functional status of patients with AxSpA. This narrative review reflects on the findings of studies evaluating HRQoL of individuals with AxSpA and the role of newer therapies.
| S-EPMC5617559 | biostudies-other
Project description:Current studies concentrate on the cytokine network and its role in the pathogenesis of spondyloarthritis (SpA). In this study, we analyzed whether the serum cytokine profile (interleukins: IL-10, IL-11, IL-12, IL-15, IL-17, IL-23 and IL-33) correlates with demographic data, clinical manifestations, disease activity and treatment outcome in a group of patients with axial spondyloarthritis.Forty-nine patients with an established diagnosis of axial spondyloarthritis (aSpA) and 19 healthy volunteers as controls were enrolled in the study. Clinical evaluation included patient's medical history, 44 joint count, back pain intensity and global disease activity in the preceding week (VAS), the duration of morning stiffness and blood tests. Disease activity was assessed using BASDAI and ASDAS-CRP. Serum concentration of IL-10, IL-11, IL-12, IL-15, IL-17, IL-23 and IL-33 was determined.In patients with aSpA, elevated serum concentration of IL-10, IL-15, IL-17 and IL-23 was detected. In the aSpA group we detected higher values of serum concentration of IL-23 and IL-33 in the subgroup with anterior uveitis (83.1 ±184.0 pg/ml vs. 14.0 ±17.1 pg/ml, p < 0.0001 and 45.5 ±71.9 pg/ml vs. 18.4 ±14.3 pg/ml, p < 0.0001, respectively). Additionally, in the subgroup with peripheral arthritis, elevation of serum concentration of IL-12 (249.3 ±246.9 pg/ml vs. 99.9 ±105.9 pg/ml, p = 0.0001) was detected. Patients with preradiological SpA had higher serum concentration of IL-17 than patients with established diagnosis of AS (6.37 ±8.50 pg/ml vs. 2.04 ±2.98 pg/ml, p = 0.0295). No differences in serum concentration of analyzed cytokines were found between the subgroup with low to moderate disease activity and the subgroup with high to very high disease activity.We report that in aSpA patients, compared to controls, elevated serum concentrations of IL-10, IL-15, IL-17 and IL-23 were observed. Some cytokines may predispose to a more severe course of aSpA.
| S-EPMC4847310 | biostudies-literature
Project description:ObjectivesTo explore differences in axial spondyloarthritis (axSpA) clinical phenotype around the world in a large sample of patients included in the International Map of Axial Spondyloarthritis (IMAS).MethodIMAS was a cross-sectional online survey (2017-2022) of 5557 unselected axSpA patients from 27 countries. We analysed across five geographic regions the age at symptom onset, diagnostic delay, gender, HLA-B27, family history, extra-musculoskeletal manifestations, presence of comorbidities, disease activity (BASDAI), level of spinal stiffness and treatments.ResultsOf 5557 IMAS participants, 3493 were from Europe, 770 from North America, 600 from Asia, 548 from Latin America and 146 from South Africa. Age at symptom onset ranged between 25 and 30 years and was higher in Latin America. Diagnostic delay was longest in South Africa and lowest in Asia. The lowest HLA-B27 positivity was observed in Latin America and the highest in Asia. Extra-musculoskeletal manifestations were the lowest in Europe. Mean disease activity (BASDAI) was 5.4, with highest values in South Africa and lowest in Asia. Most of the patients had used NSAIDs for their condition and less than half had ever taken conventional synthetic DMARDS; both were more frequent in Latin America and South Africa. Almost half of the patients had ever taken biologic DMARDs, more frequent use being in the Americas.ConclusionThere is great heterogeneity of axSpA clinical phenotype presentation around the world. AxSpA manifests differently in different regions, so further understanding of these differences of phenotypes is needed to achieve early diagnosis and initiation of optimal disease treatment in axSpA in the different regions.
| S-EPMC11371368 | biostudies-literature
Project description:The axial SpAs (axSpAs) are clearly clinically a heterogeneous set of diseases with markedly varying extra-articular features. These diseases are all highly heritable and have overlapping but differing genetic origins. Shared features include association with HLA class I alleles and genes of the IL-23 pathway, among other things. Significant differences do exist however, both in the genetic loci involved and at specific loci in the individual genetic variants associated with each disease. These similarities and differences are of great interest in regards to disease pathogenesis and treatment development, although individually they are too small in effect to be of prognostic or diagnostic value. Polygenic risk scores, which capture a high proportion of the genetic variation between disorders, have been shown to have clinically useful discriminatory capacity in axSpA. This suggests they have the potential to enable improved disease classification, incorporating basic pathogenic features such as genomics, and ultimately benefitting clinical care. The aim of this article is to review the genetic characteristics of the spectrum of axSpAs and to discuss how this influences our understanding of the disease pathogenesis and the clinical implications of this understanding.
| S-EPMC7566537 | biostudies-literature
Project description:Axial spondyloarthritis (axial-SpA) is a multifactorial disease characterized by inflammation in sacroiliac joints and spine, bone reabsorption, and aberrant bone deposition, which may lead to ankylosis. Disease pathogenesis depends on genetic, immunological, mechanical, and bioenvironmental factors. HLA-B27 represents the most important genetic factor, although the disease may also develop in its absence. This MHC class I molecule has been deeply studied from a molecular point of view. Different theories, including the arthritogenic peptide, the unfolded protein response, and HLA-B27 homodimers formation, have been proposed to explain its role. From an immunological point of view, a complex interplay between the innate and adaptive immune system is involved in disease onset. Unlike other systemic autoimmune diseases, the innate immune system in axial-SpA has a crucial role marked by abnormal activity of innate immune cells, including γδ T cells, type 3 innate lymphoid cells, neutrophils, and mucosal-associated invariant T cells, at tissue-specific sites prone to the disease. On the other hand, a T cell adaptive response would seem involved in axial-SpA pathogenesis as emphasized by several studies focusing on TCR low clonal heterogeneity and clonal expansions as well as an interindividual sharing of CD4/8 T cell receptors. As a result of this immune dysregulation, several proinflammatory molecules are produced following the activation of tangled intracellular pathways involved in pathomechanisms of axial-SpA. This review aims to expand the current understanding of axial-SpA pathogenesis, pointing out novel molecular mechanisms leading to disease development and to further investigate potential therapeutic targets.
| S-EPMC10095023 | biostudies-literature
Project description:Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease that predominantly affects the axial skeleton. The advent of biologic drugs has transformed the management of patients with axSpA. However, non-steroidal anti-inflammatory drugs remain the first-line drug treatment for axSpA. The optimal management of patients with axSpA requires a combination of pharmacological and non-pharmacological treatment modalities, namely exercise and physical therapy. This review looks at novel therapeutic options in patients with axSpA. It also summarises current evidence regarding radiographic progression and treat-to-target in axSpA.
| S-EPMC7359748 | biostudies-literature
Project description:The Assessment of Spondyloarthritis International Society (ASAS) health index (HI) is a novel tool for approaching disability, health, and functioning in spondyloarthritis (SpA). In the present study we compared ASAS HI between patients with ankylosing spondylitis (AS) and those with nonradiographic axial SpA (nr-axSpA). In addition, we identified predictors of ASAS HI. We designed this cross-sectional study using data from the Catholic Axial Spondyloarthritis COhort (CASCO), a prospective cohort from a single tertiary hospital. We compared baseline characteristics, including ASAS HI, between AS and nr-axSpA, and determined the frequency of each item constituting the ASAS HI. We used linear regression analysis to identify factors associated with ASAS HI. Total of 357 patients with axSpA-261 with AS and 96 with nr-axSpA-were included in analysis. AS patients were older and had higher ASAS HI than nr-axSpA. Among ASAS HI items, pain (item No. 1) and energy/drive (item No. 5) were the most common areas for which axSpA patients experienced discomfort. ASAS HI correlated with other SpA-related parameters such as BASDAI, ASDAS, and BASFI. Multivariable regression analysis of the axSpA group showed that high NSAID intake and mSASSS were positively associated with ASAS HI, whereas higher economic status and alcohol consumption were negatively associated with ASAS HI. Results were consistent in the AS group on subgroup analysis, whereas alcohol consumption was the only factor significantly associated with ASAS HI in the nr-axSpA group. In the present cohort study, patients with AS had poorer health status (higher ASAS HI) than those with nr-axSpA. Items proposed by AS patients (items No. 1 and 5) were the most frequently checked areas as axSpA patients feel discomfort, and this support that ASAS HI could practically assess actual discomfort of axSpA patient. ASAS HI was well correlated with known disease parameters, including activity, function, and quality of life; therefore, ASAS HI could be used in the future to represent the health status of SpA in a systematic way. Spinal structural damage (higher mSASSS), high NSAID intake, alcohol consumption, and economic status were predictors of ASAS HI in patients with axSpA, especially those with AS.
| S-EPMC6518358 | biostudies-literature
Project description:BackgroundAxial spondyloarthritis (axSpA) has strong connections with intestinal inflammation as occurs in Crohn's disease (CD). However, the immunologic mechanisms that distinguish axSpA, CD, and those with features of both diseases (CD-axSpA) are unknown. This study aimed to address this question by initial unbiased single cell RNA-sequencing (scRNAseq) on a pilot cohort followed by validating findings using flow cytometry and ELISA in a larger cohort.MethodsTwo individuals each with CD, axSpA, CD-axSpA, and healthy controls (HC) were recruited for a pilot discovery scRNAseq cohort, and the validation cohort consisted of 18 axSpA, 24 CD, 13 CD-axSpA, and 17 HC that was evaluated by flow cytometry on PBMCs and ELISAs for plasma cytokines.ResultsUniquely, PBMCs from subjects with CD-axSpA demonstrated a significant increase in granzyme B+ T cells of both CD4+ and CD8+ lineages by both scRNAseq and flow cytometry. T cell maturation was also greater in those with CD-axSpA, particularly the CD4+ granzyme B+ population. Pathway analysis suggested increased interferon response genes in all immune cell populations within CD-axSpA. Although IFN-γ was elevated in the plasma of a subset of subjects with CD-axSpA, IL-6 was also significantly elevated.ConclusionsOur findings support the presence of a chronic interferonopathy in subjects with CD-axSpA characterized by interferon signaling by pathway analysis and an expansion of mature, cytotoxic T cells. These data indicate fundamental immunological differences between CD-axSpA and both of the putative "parent" conditions, suggesting that it is a distinct disease with unique natural history and treatment needs.
| S-EPMC8140495 | biostudies-literature