Search

Axial Spondyloarthritis (axSpA) is a chronic, inflammatory, immune-mediated rheumatic disease that comprises two subsets, non-radiographic and radiographic axSpA, and belongs to a heterogeneous group of spondyloarthritides (SpA). Over the years, the concept of SpA has evolved significantly, as reflected in the existing classification criteria. Considerable progress has been made in understanding the genetic and immunological basis of axSpA, in studying the processes of chronic inflammation and pathological new bone formation, which are pathognomonic for the disease. As a result, new medication therapies were developed, which bring more effective ways for disease control. This review presents a brief overview of the literature related to these aspects of disease after summarising the available information on the topic that we considered relevant. Specifically, it delves into recent research illuminating the primary pathological processes of enthesitis and associated osteitis in the context of inflammation in axSpA. The exploration extends to discussion of inflammatory pathways, with a particular focus on Th1/Th17-mediated immunity and molecular signaling pathways of syndesmophyte formation. Additionally, the review sheds light on the pivotal role of cytokine dysregulation, highlighting the significance of the IL-23/17 axis and TNF-α in this intricate network of immune responses which is decisive for therapeutic approaches in the disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Background: Association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years, but still remains unexplained. We recently showed that HLA-B27 expressed in wing imaginal disc from HLA-B27/human-β2 microglobulin (hβ2m) transgenic Drosophila deregulated bone morphogenetic protein (BMP) pathway by interacting physically with type I BMP receptor (BMPR1) Saxophone (Sax), leading to crossveinless phenotype., Methods: Genetic interaction was studied between activin/transforming growth factor β (TGFβ) pathway and HLA-B27/hβ2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs. In mesenteric lymph node (mLN) T cells from HLA-B27/hβ2m rat (B27 rat), physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s, phosphorylation of small mothers against decapentaplegic (SMADs) and proteins of the non-canonical BMP/TGFβ pathways induced by its ligands, and the transcript level of target genes of the TGFβ pathway, were evaluated., Results: In HLA-B27/hβ2m transgenic Drosophila, inappropriate signalling through the activin/TGFβ pathway, involving Baboon (Babo), the type I activin/TGFβ receptor, contributed to the crossveinless phenotype, in addition to deregulated BMP pathway. We identified peptides bound to HLA-B27 with the canonical binding motif in HLA-B27/hβ2m transgenic Drosophila wing imaginal disc. We demonstrated specific physical interaction, between HLA-B27/hβ2m and mammalian orthologs of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGFβ receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFβ1 was increased in T cells from B27 rats, showing evidence for deregulated TGFβ pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFβ exposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly, Tgfb1 expression was reduced in naive T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern., Conclusions: This study shows that HLA-B27 alters the TGFβ pathways in Drosophila and B27 rat. Given the importance of this pathway in CD4 + T cells differentiation and regulation, its disturbance could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and altered regulatory T cell phenotype observed in B27 rats., (© 2024. The Author(s).)

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.)

The hallmarks of spondyloarthritis (SpA) are type 3 immunity-driven inflammation and new bone formation (NBF). Macrophage migration inhibitory factor (MIF) was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity, yet MIF-interacting molecules and networks remain elusive. Herein, we identified hypoxia-inducible factor-1 alpha (HIF1A) as an interacting partner molecule of MIF that drives SpA pathologies, including inflammation and NBF. HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG (curdlan-SKG) mice compared to the respective controls. Under hypoxic conditions in which HIF1A was stabilized, human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23, an upstream type 3 immunity-related cytokine. Similar to MIF, systemic overexpression of IL-23 induced SpA pathology in SKG mice, while the injection of a HIF1A-selective inhibitor (PX-478) into curdlan-SKG mice prevented or attenuated SpA pathology, as indicated by a marked reduction in the expression of MIF and IL-23. Furthermore, genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF, despite the presence of psoriasis-like dermatitis and blepharitis. We also found that MIF- and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice. These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification. Together, these results provide supporting evidence for an MIF/HIF1A regulatory network, and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

To evaluate tumour necrosis factor inhibitor (TNFi) drug-levels and presence of anti-drug antibodies (ADAb) in patients with inflammatory arthritis who taper TNFi compared to TNFi continuation. Patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis on stable TNFi dose and in low disease activity ≥ 12 months were randomised (2:1) to disease activity-guided tapering or control. Blood samples at baseline, 12- and 18-months were evaluated for TNFi drug-levels and ADAb. In total, 129 patients were randomised to tapering (n = 88) or control (n = 41). Between baseline and month 18, a significant shift in TNFi drug-levels were observed in the tapering group resulting in fewer patients with high drug-levels (change: - 14% [95% CI - 27 to - 1%]) and more with low drug-levels (change: 18% [95% CI 5-31%]). Disease activity was equivalent between groups at 18 months, mean difference: RA - 0.06 (95% CI - 0.44 to 0.33), PsA 0.03 (95% CI - 0.36 to 0.42), and axSpA 0.16 (- 0.17 to 0.49), equivalence margins ± 0.5 disease activity points. ADAb were detected in eight patients, all from the tapering group. TNFi drug-level category or ADAb were not predictive for achieving successful tapering at 18 months. TNFi drug-levels decreased during tapering which indicate adherence to the tapering algorithm. Despite the difference in TNFi drug-levels at 18 months, disease activity remained equivalent, and only few tapering patients had detectable ADAb. These data do not support using TNFi drug-level and/or ADAb to guide the tapering decision but future research with larger trials is needed.Trial registration: EudraCT: 2017-001970-41, December 21, 2017., (© 2024. The Author(s).)

Objectives: We aimed to determine the discriminative values of pro-inflammatory cytokines to distinguish spondyloarthritis patients from healthy subjects and to assess the association between these cytokines and spondyloarthritis characteristics., Methods: We conducted a case-control study, including 144 subjects matched for age and sex: 72 spondyloarthritis patients(G1) and 72 controls (G2). The disease activity was assessed using ASDAS-CRP and BASDAI. Structural damage was assessed using BASRI. The levels of interleukin (IL) IL-1, IL-6, IL-8, IL-17, IL-23, and tumor necrosis factor α(TNFα) were measured., Results: Each group included 57 men. The mean age was 44.84 ± 13.42 years. Except for IL-8, all cytokine levels were significantly higher in patients compared to controls (IL-1: p  = 0.05, IL-6: p  = 0.021, TNFα: p = 0.039, IL-17 and IL-23: p  < 0.001). Cutoff values of IL-17 and IL-23 distinguishing patients in G1 from those in G2 were 17.6 and 7.96 pg/mL, respectively. TNFα level correlated to BASDAI ( p  = 0.029) and BASRI ( p  = 0.002). Multivariate analysis showed that structural damage was associated with the male gender ( p = 0.017), longer disease duration ( p  = 0.038), and high disease activity ( p  = 0.044). Disease activity was associated with longer disease duration ( p  = 0.012) and increased IL-6 levels ( p  = 0.05)., Conclusion: Our study showed that IL-17 was the ablest to distinguish between spondyloarthritis patients and controls, suggesting that IL-17 may be helpful for the diagnosis of spondyloarthritis.

Purpose of Review: Janus kinase-signal transducers and activators of transcription cell signaling proteins (JAK-STATs) play a key regulatory role in functioning of several inflammatory cytokines. JAK-STAT signaling proteins are the key regulators of the cytokine/cytokine receptor system involved in the pathogenesis of various autoimmune disease including spondyloarthritis (SpA). This article mainly highlights the JAK-STAT signaling system, its association with the relevant cytokine/cytokine-receptor system, and its regulatory role in pathogenesis of SpA. Also, we have briefly addressed the principle for the use JAKi in SpA and the current status of use of JAK inhibitors (JAKi) in SpA., Recent Findings: Recent developments with newer JAK molecules as well as other molecules beyond JAK inhibitors are now an exciting field for the development of novel therapies for autoimmune diseases and various malignant conditions. In this article, we have provided a special emphasis on how various cell signaling systems beyond JAK/STAT pathway are relevant to SpA and have provided a comprehensive review on this upcoming field in respect to the novel TYK2 inhibitors, RORγT inhibitors, mTOR inhibitors, NGF inhibitors, and various STAT kinase inhibitors. SpA are a group of autoimmune diseases with multifactorial etiologies. SpA is linked with genetic predisposition, environmental risk factors, and the immune system-mediated systemic inflammation. Here, we have provided the regulatory role of JAK/STAT pathway and other intracellular signaling system in the pathogenesis of SpA and its therapeutic relevance., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Spondylarthritis (SpA) is a chronic inflammatory condition that encompasses damage to the axial or peripheral skeleton, accompanied by specific extra-articular symptoms. Within this group, Ankylosing Spondylitis stands out as the hallmark member. Although the heritability of Ankylosing Spondylitis is estimated to be over 95%, only a portion of the heritability has been explained, with HLA-B27 accounting for 20.1% of it; therefore, ongoing research endeavors are currently concentrated on investigating the potential participation of different entities in the development of the disease. Genome-wide association studies have led to significant advances in our understanding of the genetics of SpA. In this descriptive review, we delve into the pathogenesis of Spondylarthritis beyond HLA-B27. We summarize the latest research on the potential participation of various entities in the development of the disease, including other genetic loci, immune dysregulation, microbiota, and environmental factors. The multifactorial nature of SpA and the complex interplay of genetic, immunological, and environmental factors are being increasingly recognized; therefore, it is of paramount importance to consider a holistic approach to comprehend the pathogenesis of SpA in order to identify novel therapeutic targets.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

The gut microbiota plays a pivotal role in regulating host immunity, and dysregulation of this interaction is implicated in autoimmune and inflammatory diseases, including spondyloarthritis (SpA). This review explores microbial dysbiosis and altered metabolic function observed in various forms of SpA, such as ankylosing spondylitis (AS), psoriatic arthritis (PsA), acute anterior uveitis (AAU), and SpA-associated gut inflammation. Studies on animal models and clinical samples highlight the association between gut microbial dysbiosis, metabolic perturbations and immune dysregulation in SpA pathogenesis. These studies have received impetus through next-generation sequencing methods, which have enabled the characterization of gut microbial composition and function, and host gene expression. Microbial/metabolomic studies have revealed potential biomarkers and therapeutic targets, such as short-chain fatty acids, and tryptophan metabolites, offering insights into disease mechanisms and treatment approaches. Further studies on microbial function and its modulation of the immune response have uncovered molecular mechanisms underlying various SpA. Understanding the complex interplay between microbial community structure and function holds promise for improved diagnosis and management of SpA and other autoimmune disorders., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Immuno-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis, spondyloarthritis, and inflammatory bowel disease are characterised by pathophysiological mechanisms wherein the immune system erroneously targets the body's own tissues. This review explores the heightened vulnerability of women with IMIDs, influenced by hormonal modulators like estrogen and progesterone. The challenges this poses are multifaceted, encompassing the impact of active disease and medical treatments throughout life stages, including family planning, fertility, and menopause. From the perspectives of rheumatologists and gastroenterologists, we review current management strategies and underscore the need for a multidisciplinary and life-cycle approach to healthcare for women with IMIDs., Competing Interests: Declaration of Competing Interest L.A. and M.P. received an honorarium from Pfizer in connection with the development of this manuscript. G.P. and I.G. are Pfizer employees., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Tumor necrosis factor alpha (TNF alpha) blockers such as infliximab (IFX) and adalimumab (ADA) had significantly changed the course of inflammatory diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and Crohn's disease (CD). However, about 30% of patients do not respond to these treatments. This lack of response may be due to the formation of antibodies against these drugs (anti-drug antibodies: ADAbs). The aim of this study was to determine the prevalence of ADAbs against IFX and ADA, and the trough serum concentration of IFX and ADA in RA, SpA or CD patients and to assess their impact on the therapeutic response., Methods: A cross sectional, multi-centric study was conducted, including patients with RA, SpA or CD treated with IFX or ADA as a first biotherapy for at least 6 months. ADAbs and trough levels were measured by an Enzyme Linked Immunosorbent assay (ELISA)., Results: 197 patients were included (57 RA, 73 SpA and 67 CD). ADAbs were positive in 40% of cases for IFX and 25% for ADA. They were positive in 40% of SpA, 35% of RA, and 21% of CD. The presence of ADAbs was inversely correlated to the trough levels of IFX and ADA during RA (p = 0.01 and p < 0.0001), SpA (p < 0.01 and p < 0.0001) and CD (p = 0.001 and p = 0.04). For all pathologies, the presence of ADAbs was not correlated with disease activity. Concomitant methotrexate significantly reduced immunogenicity., Conclusion: In our study, the presence of ADAb and low trough levels seem to not affect the therapeutic response in patients on TNF alpha antagonists. Other tracks more than immunogenicity should be investigated to explain the loss of response to these biotherapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: To assess the kinetics of humoral response after the first and second dose of messenger RNA (mRNA) vaccines in patients with inflammatory joint diseases compared with healthy controls (HC). To analyse factors influencing the quantity of the immune response., Methods: We enrolled patients with rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA), excluding those receiving B-cell depleting therapies and assessed the humoral response to mRNA vaccines after the first and the second dose of the vaccine in terms of seroconversion rate and titre. We compared the results to a HC group and analysed the influence of therapies as well as other characteristics on the humoral response., Results: Samples from 53 patients with RA, 46 patients with SpA and 169 healthy participants were analysed. Seroconversion rates after the first immunisation were only 54% in patients with inflammatory arthritis compared with 98% in the HC group. However, seroconversion rates were 100% in all groups after second immunisation. Patients developed reduced antibody titres after the first vaccination compared with HC, but there was no difference after the second dose. While disease modifying anti-rheumatic drug (DMARD) monotherapy did not affect antibody levels, seroconversion rates as well as titre levels were reduced in patients receiving a combination of DMARDs compared with HC., Conclusions: Patients with inflammatory joint diseases under DMARD therapy show impaired humoral responses to the first vaccine dose but excellent final responses to vaccination with mRNA vaccines. Therefore, the full course of two immunisations is necessary for efficient vaccination responses in patients with inflammatory arthritis under DMARD therapy., Competing Interests: Competing interests: PM reports speaker fees from AbbVie, Janssen and Novartis and research grants from AbbVie, BMS, Novartis, Janssen, MSD and UCB. HH received grants from Glock Health, BlueSky Immunotherapies and Neutrolis. JS is the President of the Austrian Society of Rheumatology and Rehabilitation (unpaid position). HB received consulting fees from MSD, Pfizer, Takeda and Gilead, speaker fees from Shionogi, Pfizer and MSD, advisory boards for Valneva, MSD and Gilead. DA reports grants from AbbVie, Amgen, Lilly, Novartis, Roche, SoBi and Sanofi, other from AbbVie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche and Sandoz, outside the submitted work. SB reports personal fees from AbbVie and personal fees from Novartis, outside the submitted work. ES reports support for meeting attendances from Pfizer and Bristol Myers Squibb., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Spondyloarthritis (SpA) is a systemic inflammatory arthritis mediated mainly by interleukin (IL)-17. The vitronectin-derived bioactive peptide, VnP-16, exerts an anti-osteoporotic effect via β1 and αvβ3 integrin signaling. SpA is associated with an increased risk of osteoporosis, and we investigated the effect of VnP-16 in mice with SpA., Methods: SpA was induced by curdlan in SKG ZAP-70W163C mice, which were treated with vehicle, celecoxib, VnP-16, or VnP-16+celecoxib. The clinical score, arthritis score, spondylitis score, and proinflammatory cytokine expression of the spine were evaluated by immunohistochemical staining. Type 17 helper T cell (Th17) and regulatory T cell (Treg) differentiation in the spleen was evaluated by flow cytometry and in the spine by confocal staining. Splenocyte expression of signal transducer and activator of transcription (STAT) 3 and pSTAT3 was evaluated by in vitro Western blotting., Results: The clinical score was significantly reduced in the VnP16+celecoxib group. The arthritis and spondylitis scores were significantly lower in the VnP-16 and VnP16+celecoxib groups than the vehicle group. In the spine, the levels of IL-1β, IL-6, tumor necrosis factor-α, and IL-17 expression were reduced and Th17/Treg imbalance was regulated in the VnP-16 alone and VnP-16+celecoxib groups. Flow cytometry of splenocytes showed increased polarization of Tregs in the VnP-16+celecoxib group. In vitro, VnP-16 suppressed pSTAT3., Conclusions: VnP-16 plus celecoxib prevented SpA progression in a mouse model by regulating the Th17/Treg imbalance and suppressing the expression of proinflammatory cytokines., Competing Interests: The authors have declared that no competing interests exist.

Aim - to identify deviations in immune parameters in patients with reactive chlamydial spondyloarthritis, allowing more targeted correction of immune status and improve the quality of treatment of these patients. A comparative immunological examination of 14 patients with reactive spondyloarthritis of chlamydial etiology before and after specific treatment and practically healthy people was carried out. CIC, lymphocytotoxic and granulocytotoxic antibodies, including autoimmune, LIF including autoantigens (cartilage, bone, sinewy), neutrophilic leukocytes, lymphocytes, IL-1, IL-4, IL-6, TNF-α, CD-3, CD-4, CD-8, CD-25, Ig A, G, M. The immune status of patients before treatment was characterized by a perverse immune response, which was characterized by hyperactivation of the T-lymphocytic link of immunity, impaired suppressive link of the immune system, a tendency to autoimmune aggression, incomplete anti-infectious immunity, and chronic inflammatory process. Antichlamydial treatment with the eradication of the pathogen within 1 month led to a partial normalization of the immune response, normalization of the neutrophilic / lymphocytic ratio and the amount of granulocytotoxic and lymphocytotoxic antibodies. Desensitization of the organism to autoantigens (cartilage and synovial tissue) was observed. Comprehensive analysis of immunological parameters before and after treatment in patients with reactive spondyloarthritis of chlamydial etiology allows monitoring the effectiveness of the treatment and increases its effectiveness.

Objective: IL-17A plays a major role in the pathogenesis of spondyloarthritis (SpA). Here we assessed the impact of inhibition of RAR related orphan receptor-γ (RORC), the key transcription factor controlling IL-17 production, on experimental SpA in HLA-B27 transgenic (tg) rats., Methods: Experimental SpA was induced by immunization of HLA-B27 tg rats with heat-inactivated Mycobacterium tuberculosis . Splenocytes obtained at day 7, 14 and 21 after immunization were restimulated ex vivo to assess the induction of pro-inflammatory cytokines. Rats were then prophylactically treated with a RORC inhibitor versus vehicle control. The biologic effect of RORC inhibition was assessed by pro-inflammatory cytokine expression in draining lymph nodes. Arthritis and spondylitis were monitored clinically, and the degree of peripheral and axial inflammation, destruction and new bone formation was confirmed by histology., Results: Ex vivo mRNA and protein analyses revealed the rapid and selective induction of IL-17A and IL-22 production by a variety of lymphocyte subsets upon disease induction in HLA-B27 tg rats. Prophylactic RORC inhibition in vivo suppressed the expression of IL-17A, IL17F, and IL-22 without affecting the expression of other T helper cell subset related genes. This biological effect did not translate into clinical efficacy as RORC inhibition significantly accelerated the onset of arthritis and spondylitis, and aggravated the clinical severity of arthritis. This worsening of experimental SpA was confirmed by histopathological demonstration of increased inflammation, destruction, and new bone formation., Conclusion: Despite a significant suppression of the IL-17 axis, RORC inhibitor treatment accelerates and aggravates experimental SpA in the HLA-B27 tg rat model., Competing Interests: ML and GN are employees of Boehringer-Ingelheim Pharmaceuticals Inc. MS received consultancy fees from Novartis and Abbvie and research grants from Janssen, Novartis and Eli Lilly. DB is an employee of UCB. The authors declare that this study received funding from Boehringer-Ingelheim Pharmaceuticals Inc. The funder shared in study design, data analysis and data collection. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van Tok, Mandour, Wahle, Labadia, van de Sande, Nabozny, Baeten and van Duivenvoorde.)

Objectives: Antibodies against anti-CD74 are related to axial spondyloarthritis (axSpA). The objectives were (i) to study IgA anti-CD74 in radiographic (r)-axSpA patients in the Backbone cohort and to calculate the sensitivity and specificity of anti-CD74, (ii) to study the fluctuation of IgA anti-CD74 levels in prospectively collected samples, and (iii) to explore the relation between IgA anti-CD74 and radiographic spinal changes., Methods: IgA anti-CD74 was analysed by ELISA in 155 patients with r-axSpA and age- and sex-matched controls. BASDAI, ASDAS, BASFI and BASMI were assessed and spinal radiographs were scored for r-axSpA-related changes with mSASSS. Previously donated samples, before inclusion in the Backbone study, were identified in the Medical Biobank of Northern Sweden., Results: A total of 155 patients comprising 69% men and 31% women, age [mean (s.d.)] 55.5 (11.4) years and 152 (98.1%) HLA-B27 positive, were included. The plasma level of IgA anti-CD74 was significantly higher in the patients [median (interquartile range), 12.9 (7.9-17.9) U/ml] compared with controls [10.9 (7.2-14.6) U/ml, P = 0.003]. IgA anti-CD74 was above the cut-off level of 20 U/ml in 36/155 (23.2%) patients and in 15/151 (9.9%) controls (P = 0.002). Multivariable logistic regression analyses revealed ≥1 syndesmophyte associated with IgA anti-CD74 (odds ratio 5.64; 95% CI: 1.02, 35.58; P = 0.048) adjusted for hsCRP, smoking, BMI, sex and age. No distinct pattern of IgA anti-CD74 over time was revealed., Conclusion: Plasma levels of IgA anti-CD74 were increased in r-axSpA and independently associated with radiographic spinal changes, which suggests that IgA anti-CD74 could play a role in the pathogenies of r-axSpA., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Spondyloarthritis (SpA) is mainly characterized by bone erosion, new bone formation, inflammation and potential disability. Epigallocatechin gallate (EGCG) has been proved to be closely related with the regulation of inflammation and bone metabolism. However, whether EGCG could improve SpA remains unclear., Methods: SpA animal model was established using proteoglycan. Cell proliferation were measured by CCK-8 assay. The mRNA expression levels of genes were detected using qRT-PCR, protein levels were assessed via western blotting and immunohistochemistry. ELISA assay was performed to examined the inflammatory cytokine release. Lesions in spine cartilage tissues were observed using hematoxylin-eosin (HE) and Safranin O staining. Alkaline phosphatase (ALP) assay and Alizarin Red S staining was used to investigate osteoblast mineralization., Results: We found that EGCG could inhibit inflammation and new bone formation in SpA mice. Besides, inflammatory factor expression and osteogenic differentiation in osteoblasts isolated from SpA mice were also decreased by EGCG. Further, EGCG treatment suppressed the activation of Wnt/β-Catenin/COX-2 pathway and the activator of this pathway partially reversed the effects of EGCG on inflammation and osteoblast differentiation., Conclusions: EGCG repressed inflammatory responses and new bone formation, and further improved SpA through Wnt/β-Catenin/COX-2 pathway. Our findings may provide a new thought for the prevention and treatment of SpA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To describe characteristics of children with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (PsA) who were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry., Methods: All children with ERA and those with juvenile PsA were identified. Demographic characteristics, clinical characteristics, and treatments were described. The children with sacroiliitis and those without sacroiliitis were compared. In the children with sacroiliitis, the first visit with clinically active sacroiliitis (which came first in 72% of cases) was compared to the first visit without clinically active sacroiliitis., Results: A total of 902 children with ERA or juvenile PsA were identified. Children with ERA were older at diagnosis (ages 10.8 years versus 8.2 years; P < 0.01) and were more likely to be male (56% versus 38%; P < 0.01). Polyarticular involvement was reported in 57% of children with ERA and in 72% of those with juvenile PsA. Of the children tested, HLA-B27 was positive in 38% of those in the ERA group and in 12% of those in the juvenile PsA group. At least 1 biologic was taken by 72% of those with ERA and 64% of those with juvenile PsA. Sacroiliitis (diagnosed clinically and/or by imaging) was reported in 28% of the children (40% of those with ERA and 12% of those with juvenile PsA). Of these, 54% of the children were female, 36% were HLA-B27 positive, and 81% took at least 1 biologic. In children with sacroiliitis, scores according to the physician global assessment of disease activity, parent/patient global assessment of well-being, and clinical Juvenile Arthritis Disease Activity Score 10 were all significantly worse at the first visit with clinically active sacroiliitis versus the first visit without active sacroiliitis., Conclusion: In this registry, there are more than 900 children with ERA or juvenile PsA. There was high biologic use in this population, especially in those with sacroiliitis. Further, there was equal sex representation in those children with sacroiliitis., (© 2020, American College of Rheumatology.)

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., Competing Interests: MS: Consultancy fees/speaker fees from Abbvie, Novartis and Eli Lilly, MSD. Research support from Novartis, Eli Lilly, UCB, Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mandour, Chen and van de Sande.)

Objectives: Peripheral SpA (pSpA) is comprised of ReA, PsA, enteritis-associated arthritis and undifferentiated pSpA (upSpA). ReA and upSpA share T cell oligotypes and metabolomics in serum and SF. We investigated HLA-B27 subtypes and cytokines in serum and SF that were compared between ReA and upSpA., Methods: ReA and upSpA were compared in two cohorts. In cohort I (44 ReA and 56 upSpA), HLA-B27 subtyping was carried out. In cohort II (17 ReA and 21 upSpA), serum and SF cytokines were compared using a multiplex cytokine bead assay (27 cytokines). A total of 28 healthy controls with similar age and sex to cohort II were included for comparison of serum cytokine levels., Results: In cohort I, HLA-B27 was positive in 81.8% (36/44) of ReA and 85.71% (48/56) of upSpA patients. HLA-B27 typing was successful in 70 patients (30 ReA and 40 uSpA). HLA-B*2705 was the most common, followed by HLA-B*2704 and HLA-B*2707. Frequencies were the same between ReA and upSpA. In cohort II, 14 cytokines were detectable in the serum of patients. The levels of eight cytokines were higher than in the controls. The cytokine levels of ReA and upSpA were similar. Sixteen cytokines were detectable in the SF of patients. There was no statistical difference in the levels between ReA and upSpA. The cytokine profiles in sera and SF were also similar among HLA-B27-positive and negative patients., Conclusion: ReA and upSpA have similar HLA-B27 subtype associations and similar cytokine profiles. They should be considered as a single entity during studies as well as clinical management., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

B-cells have received little attention in axial spondyloarthritis (axSpA) and for this reason their role in pathogenesis remains unclear. However, there are indications that B-cells may be involved in the disease process. Our objective was to obtain insights into the composition of the peripheral B-cell compartment of axSpA patients compared to healthy donors (HD) and patients with primary Sjögren's syndrome (pSS), a typical B-cell-associated autoimmune disease. Special emphasis was given to CD27-negative B-cells expressing low levels of CD21 (CD21 low B-cells), since this subset is implicated in autoimmune diseases with strong involvement of B-cells. Transitional B-cells (CD38 hi ) were excluded from the analysis of the CD27 - CD21 low B-cell compartment. This study included 45 axSpA patients, 20 pSS patients and 30 HDs. Intriguingly, compared to HDs the frequency of CD27 - CD38 low CD21 low B-cells was significantly elevated in both axSpA and pSS patients (P<0.0001 for both comparisons). The frequency of CD27 - CD38 low CD21 low B-cells expressing the activation-induced immune markers T-bet and CD11c was decreased in axSpA patients compared to HDs. A higher proportion of CD27 - CD38 low CD21 low B-cells expressed the chemokine receptor CXCR3 in axSpA compared to HDs, suggestive for active involvement of these cells in an inflammatory process. The frequency of CD27 - CD38 low CD21 low B-cells in axSpA patients correlated positively with age and erythrocyte sedimentation rate. Furthermore, axSpA patients with extra-skeletal manifestations (ESM) showed increased frequencies of CD27 - CD38 low CD21 low B-cells compared to patients without ESM. In conclusion, our findings are suggestive of active B-cell involvement in the pathogenesis of axSpA, against prevailing dogma., Competing Interests: AS has received grant/research support from Abbvie, Pfizer, Union Chimique Belge (UCB), Novartis and acted as a consultant for Abbvie, Pfizer, MSD, UCB, Lilly and Novartis. SA has received grant/research support from Pfizer. KG has received a speaker fee from Roche. EB has received consultancy and speaker fees from Roche. HB has received unrestricted grants from Bristol Myers Squibb (BMS) and Roche, consultant for BMS, Roche, Novartis, MedImmune, UCB, speaker for BMS and Novartis. FK has received unrestricted grants from BMS, is consultant for BMS, speaker for BMS Roche and Jannsen-Cilag. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wilbrink, Spoorenberg, Arends, van der Geest, Brouwer, Bootsma, Kroese and Verstappen.)

Bone marrow adipose tissue (BMAT) has recently been recognized as a distinct fat depot with endocrine functions. However, if and how it is regulated by chronic inflammation remains unknown. Here, we investigate the amount of white fat and BMAT in HLA-B27 transgenic rats and curdlan-challenged SKG mice, two well-established models of chronic inflammatory spondyloarthritis (SpA). Subcutaneous and gonadal white adipose tissue and BMAT was reduced by 65-70% and by up to 90% in both experimental models. Consistently, B27 rats had a 2-3-fold decrease in the serum concentrations of the adipocyte-derived cytokines adiponectin and leptin as well as a 2-fold lower concentration of triglycerides. The bone marrow of B27 rats was further characterized by higher numbers of neutrophils, lower numbers of erythroblast precursors, and higher numbers of IL-17 producing CD4 + T cells. IL-17 concentration was also increased in the serum of B27 rats. Using a cell culture model, we show that high levels of IL-17 in the serum of B27 rats negatively impacted adipogenesis (-76%), an effect that was reversed in the presence of neutralizing anti-IL-17 antibody. In summary, these findings show BMAT is severely reduced in two experimental models of chronic inflammatory SpA and suggest that IL-17 is involved in this process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Furesi, Fert, Beaufrère, Araujo, Glatigny, Baschant, von Bonin, Hofbauer, Horwood, Breban and Rauner.)

The term spondyloarthritis (SpA) encompasses a heterogeneous group of inflammatory musculoskeletal diseases with several common genetic background and clinical features, including the possible involvement of the axial skeleton with peripheral mono- or oligo- arthritis and frequently coexisting skin, eye and intestinal manifestations. When the sacroiliac joints or other parts of the spine or thoracic wall are predominantly affected at magnetic resonance or X-ray imaging with inflammatory back pain, the disease is classified as axial SpA and the therapeutic choices are significantly different compared to cases of peripheral arthritis. Moving from the narrow effectiveness and safety profiles of non-steroidal anti-inflammatory drugs, there has been a significant research effort aimed at identifying new treatments based on our better understanding of the pathogenesis of SpA. Indeed, in parallel with the solid data demonstrating that IL-17 and IL-23 are key cytokines in the development of enthesitis and spondylitis, monoclonal antibodies interfering with this pathway have been developed for the treatment of axial SpA. Furthermore, the IL-17/IL-23 axis is key to extra-articular manifestations such as inflammatory bowel disease, uveitis, and psoriasis which are frequent comorbidities of SpA. Currently available drugs act through these mechanisms recognizing IL-23 and targeting IL-17, such as secukinumab and ixekizumab. These therapeutic approaches are now envisioned in the international treatment recommendations for psoriatic arthritis with an axial phenotype as well as for ankylosing spondylitis (AS). We will provide herein a concise comprehensive overview of the clinical evidence supporting the use of these and other drugs acting on IL-23 and IL-17 in axial SpA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ceribelli, Motta, Vecellio, Isailovic, Ciccia and Selmi.)

Objectives: We aimed to explore the associations of musculoskeletal inflammation patterns with peripheral blood innate lymphoid cell (ILC) populations, serum cytokines/chemokines, and treatment response to methotrexate in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA)., Methods: We enrolled 100 patients with either RA or SpA and performed ultrasound to evaluate power Doppler signals for synovitis (52 joint regions), tenosynovitis (20 tendons), and enthesitis (44 sites). We performed clustering analysis using unsupervised random forest based on the multi-axis ultrasound information and classified the patients into groups. We identified and counted ILC1-3 populations in the peripheral blood by flow cytometry and also measured the serum levels of 20 cytokines/chemokines. We also determined ACR20 response at 3 months in 38 patients who began treatment with methotrexate after study assessment., Results: Synovitis was more prevalent and severe in RA than in SpA, whereas tenosynovitis and enthesitis were comparable between RA and SpA. Patients were classified into two groups which represented synovitis-dominant and synovitis-nondominant inflammation patterns. While peripheral ILC counts were not significantly different between RA and SpA, they were significantly higher in the synovitis-nondominant group than in the synovitis-dominant group (ILC1-3: p = 0.0007, p = 0.0061, and p = 0.0002, respectively). On the other hand, clustering of patients based on serum cytokines/chemokines did not clearly correspond either to clinical diagnoses or to synovitis-dominant/nondominant patterns. The synovitis-dominant pattern was the most significant factor that predicted clinical response to methotrexate (p = 0.0065)., Conclusions: Musculoskeletal inflammation patterns determined by ultrasound are associated with peripheral ILC counts and could predict treatment response to methotrexate., Competing Interests: The authors declare that they have no competing interests as regards this work.

Purpose of Review: Enthesitis is a cardinal feature of spondyloarthritis (SpA). Despite increasing available treatments, challenges remain in adequately controlling inflammation and subsequent new bone formation (NBF) in entheses; thus, a better understanding of the immunopathogenesis is warranted., Recent Findings: Increasing evidence has identified immune cells playing key roles in enthesitis such as γδ T cells and group 3 innate lymphoid cells (ILC3), possibly with site-specific regulatory systems. The presence of T cells producing interleukin (IL)-17 independent of IL-23 in human spinal entheses was recently reported, which may corroborate the discrepancy between recent clinical trials and pre-clinical studies. In addition, the contribution of myeloid cells has also been focused in both human and pre-clinical SpA models. Moreover, not only the IL-23/IL-17 signaling, but other key type 3 immunity mediators, such as IL-22 and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been reported as pivotal cytokines in inflammation and NBF of entheses. Immune cells demonstrating distinct features orchestrate entheses, leading to the complex landscape of enthesitis. However, recent advances in understanding the immunopathogenesis may provide new therapeutic targets and future research directions.

Objectives: Anti-cyclic citrullinated peptide (CCP) antibodies are frequently detected in the sera of patients with rheumatoid arthritis (RA). However, recent studies have revealed a potentially high prevalence rate of these antibodies in patients with other rheumatic disorders, causing confusion while diagnosing RA. Therefore, this study aimed to evaluate the positive rate of anti-CCP antibodies in other chronic arthritis diseases focusing on patients with spondyloarthritis (SpA)., Methods: A total of 109 patients who were diagnosed with SpA at Yukioka Hospital from 1993 to 2018 were included in this retrospective analysis, including patients with ankylosing spondylitis (AS); psoriatic arthritis (PsA); synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (SAPHO); undifferentiated spondyloarthritis (uSpA); reactive arthritis (ReA); and inflammatory bowel disease-associated SpA (IBD)., Results: Overall, 15.3% (16/109) of patients with SpA were positive for anti-CCP antibodies, including 2.3% (1/43) in AS, 23.1% (3/13) in SAPHO, 35.0% (7/20) in PsA, 14.8% (4/27) in uSpA, 0% (0/3) in ReA, and 33.3% (1/3) in IBD., Conclusion: PsA patients have a significantly higher prevalence rate of positive anti-CCP antibodies among SpA patients, and the positive rates in SAPHO and uSpA were also high. These findings provide insight into the heterogeneity of SpA with relevance for RA differential diagnosis.

Objective :To assess antibodies to malondialdehyde-acetaldehyde-modified low-density lipoprotein (MAA-LDL) in patients with newly diagnosed inflammatory joint disease. Method : Patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and undifferentiated arthritis (UA), participating in the Northern Savo 2010 Study, were evaluated for metabolic syndrome (MetS), metabolic and inflammatory markers, antibodies to MAA-LDL, Aggregatibacter actinomycetemcomitans , and Porphyromonas gingivalis . Results : Among 135 newly diagnosed untreated patients, of whom 53 (39%) were diagnosed to have RA, 44 (33%) SpA, and 38 (28%) UA, 49%, 30%, and 47%, respectively, had MetS. After adjusting for age and gender, anti-MAA-LDL immunoglobulin (Ig)A (p = 0.009), IgG (p = 0.031), and IgM (p = 0.001) levels differed between the diagnostic categories, but not in patients with MetS present or absent. All antibody classes to MAA-LDL correlated with erythrocyte sedimentation rate (ESR), and IgA and IgG antibodies with high-sensitivity C-reactive protein (hs-CRP). IgA antibodies to MAA-LDL correlated with rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs), fasting plasma glucose, IgA antibodies to A. actinomycetemcomitans , and in IgA and IgG antibodies to P. gingivalis. Conclusion : Among various arthritis groups, antibodies to MAA-LDL were most common in RA. Antibodies to modified lipoproteins were associated with inflammation measured by ESR and hs-CRP. IgA antibodies to MAA-LDL correlated with age, antibodies to periodontal bacteria, RF, ACPA, and fasting glucose. Associations between antibodies to MAA-LDL and antibodies to periodontal bacteria, RA-associated antibodies, inflammatory parameters, and plasma glucose already reflect cardiovascular burden in inflammatory joint diseases at diagnosis.

Objectives : Anti-carbamylated protein antibodies (anti-CarP) are reported to be associated with increased disease activity and with more severe joint damage in rheumatoid arthritis (RA) patients. The present study investigated the presence of anti-CarP in various rheumatic diseases, and their specific clinical significance in RA, in Belgian rheumatology patients. Method : We tested sera from 254 RA patients, 56 healthy controls, and 153 patients with different rheumatic conditions: juvenile idiopathic arthritis (JIA), axial spondyloarthritis, systemic sclerosis, and Sjögren's syndrome (SS). An in-house enzyme-linked immunosorbent assay was used to detect immunoglobulin G antibodies against carbamylated foetal calf serum. Results : Anti-CarP were detected in 88 RA patients (34.6%), of whom 82% were also positive for anti-citrullinated protein antibodies (ACPAs) and 81% were also rheumatoid factor (RF) positive. Of note, 11 anti-CarP single-positive patients were detected (4.3%). The previously reported association with joint erosions was not detected. However, in ACPA- and RF-negative RA patients, the presence of anti-CarP was associated with higher disease activity and disability. Fifteen per cent of JIA patients and 30% of SS patients also tested positive for anti-CarP and their antibody levels did not differ significantly from those of anti-CarP-positive RA patients. Anti-CarP levels were, however, significantly higher in ACPA- or RF-positive patients. Conclusion : Anti-CarP antibodies were detected in the sera of a cohort of Belgian RA patients. Moreover, they were also detected in primary SS patients and in JIA patients. In the seronegative subset of RA patients, anti-CarP antibodies showed prognostic value.

The complex crosstalk between the immune and the skeletal systems plays an indispensable role in the maintenance of skeletal homeostasis. Various cytokines are involved, including interleukin (IL)-17A. A variety of immune and inflammatory cells produces IL-17A, especially Th17 cells, a subtype of CD4 + T cells. IL-17A orchestrates diverse inflammatory and immune processes. IL-17A induces direct and indirect effects on osteoclasts. The dual role of IL-17A on osteoclasts partly depends on its concentrations and interactions with other factors. Interestingly, IL-17A exerts a dual role in osteoblasts in vitro . IL-17A is a bone-destroying cytokine in numerous immune-mediated bone diseases including postmenopausal osteoporosis (PMOP), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondylarthritis (axSpA). This review will summarize and discuss the pathophysiological roles of IL-17A on the skeletal system and its potential strategies for application in immune-mediated bone diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tang, Lu and Yu.)

Spondyloarthritis (SpA) is a chronic inflammatory rheumatism characterized by inflammation of sacroiliac joints, peripheral joints, and spine. The Assessment of SpondyloArthritis Society describes three disease forms: axial (axSpA), peripheral, and enthesitic SpA. Each may be associated with extra-articular manifestations: psoriasis, inflammatory bowel disease, and acute anterior uveitis. Genome-wide association studies performed in axSpA and psoriatic arthritis (PsA) have shown a shared genetic background, especially the interleukin 23 (IL-23)/IL-17 pathway, which suggests pathophysiological similarities. The convincing positive results of clinical trials assessing the effect of secukinumab and ixekizumab (anti-IL-17A monoclonal antibodies) in axSpA and PsA have reinforced the speculated crucial role of IL-17 in SpA. Nevertheless, and obviously unexpectedly, the differential efficacy of anti-IL-23-targeted treatments between axSpA (failure) and PsA (success) has profoundly disrupted our presumed knowledge of disease pathogeny. The cells able to secrete IL-17, their dependence on IL-23, and their respective role according to the clinical form of the disease is at the heart of the current debate to potentially explain these observed differences in efficacy of IL-23/IL-17-targeted therapy. In fact, IL-17 secretion is usually mainly related to T helper 17 lymphocytes. Nevertheless, several innate immune cells express IL-23 receptor and can produce IL-17. To what extent these alternative cell populations can produce IL-17 independent of IL-23 and their respective involvement in axSpA and PsA are the crucial scientific questions in SpA. From this viewpoint, this is a nice example of a reverse path from bedside to bench, in which the results of therapeutic trials allow for reflecting more in depth on the pathophysiology of a disease. Here we provide an overview of each innate immunity-producing IL-17 cell subset and their respective role in disease pathogeny at the current level of our knowledge., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rosine and Miceli-Richard.)

Objectives: This study was designed to evaluate the role of anti-CD74 antibodies in diagnosis of axial spondyloarthritis (axSpA) and their relationship to disease duration and disease activity., Methods: Fifty patients with axSpA, 15 patients with RA and 15 healthy subjects were included in the study. Clinical examination and laboratory tests were done. The ESR, CRP level and ASDAS were measured as markers of the disease activity. Quantitative determination of human CD74 IgG antibodies was done., Results: The mean age of the patients was 38.22 (S.D.12.20) years. The level of CD74 autoantibodies was significantly higher in axSpA in comparison to control groups. Most patients with positive articular and extra-articular manifestations were positive for CD74 autoantibodies. In patients with inactive disease, 33.3% were positive for CD74 autoantibodies, as were 83% with active disease. High percentages of patients with early and late axSPA were CD74 autoantibody positive. The majority of patients with positive disease activity in early and late axSpA were CD74 autoantibody positive. CD74 autoantibodies had 80% sensitivity vs both control groups with 87% specificity vs the healthy control group and 80% vs the RA control group in the diagnosis of axSpA., Conclusions: The frequency of positive anti-CD74 IgG antibodies was as high in patients with early axSpA as in those with late axSpA, with no significant differences. There was a significant difference in the frequency of positive anti-CD74 IgG antibodies between patients with positive and negative disease activity. Based on the sensitivity and specificity of anti-CD74 IgG, this is a promising diagnostic tool to support the clinical diagnosis of axSpA., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Gut microbiota has been widely reported to be involved in systemic inflammation through microbial translocation and T cell activation in several diseases. In this work we aimed to investigate bacterial infiltration and epithelial impairment in the gut of patients with IBD-associated SpA (SpA-IBD), as well as the relationship of microbial translocation with immune system activation and their putative role in the pathogenesis of joint inflammation in IBD patients., Methods: Tight-junction proteins (TJPs) occludin and claudin-1/-4 and bacteria were assessed by real-time PCR analysis and immunohistochemical staining of the ileum. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPS), soluble CD14 (sCD14), sclerostin and anti-sclerostin antibodies (anti-sclerostin-IgG) were assayed with ELISAs and peripheral mononuclear blood cells with flow cytometry. LPS and sCD14 were used in vitro to stimulate a human osteoblast cell line., Results: Compared with IBD, ileal samples from SpA-IBD patients showed bacterial infiltration, epithelial damage and downregulation of TJPs. In sera, they showed higher serum levels of I-FABP, LPS, sCD14 (the latter correlating with sclerostin and anti-sclerostin-IgG) and higher CD80+/CD163+ and lower CD14+ mononuclear cells. In vitro experiments demonstrated that only the LPS and sCD14 synergic action downregulates sclerostin expression in osteoblast cells., Conclusion: SpA-IBD patients are characterized by gut epithelium impairment with consequent translocation of microbial products into the bloodstream, immune system activation and an increase of specific soluble biomarkers. These findings suggest that gut dysbiosis could be involved in the pathogenesis of SpA-IBD and it could hopefully prompt the use of these biomarkers in the follow-up and management of IBD patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

The European cohort study has indicated about CD74 IgG-autoantibodies as potential marker for axial spondyloarthritis (axSpA) diagnosis. However, multiple studies have questioned the diagnostic value of various disease-specific autoantibodies in different ethnic groups. Here, we have tried to assess the diagnostic value of anti-CD74 IgG and IgA autoantibodies in axSpA patients from Chinese Han population.The anti-CD74 IgG and IgA autoantibodies were analyzed using ELISA assay in a cohort of 97 axSpA patients, including 47 treatment-naïve axSpA patients never treated with steroids or immunosuppressants and 50 treated axSpA patients. The rheumatic disease control (RDC) group consisted of 40 rheumatoid arthritis, 25 systemic lupus erythematosus, 18 psoriatic arthritis patients, and 60 healthy controls (HC).Our data demonstrated the presence of anti-CD74 IgA auto-antibodies in 25.8% of the axSpA patients, 30.1% of the RDC group patients and none in HC. Similarly, anti-CD74 IgG autoantibodies were observed in 23.7% of the axSpA patients, 18.1% of the RDC patients and 18.3% of the HC. The sensitivity, specificity, and accuracy of IgA autoantibodies were 21.3%, 82.5%, & 67.4%, respectively, while for IgG, it was 27.7%, 81.8%, and 68.4%, in treatment-naïve axSpA patients. Furthermore, weak positive relationship between anti-CD74 IgA autoantibodies and bath ankylosing spondylitis disease activity index ( r = 0.253, P = .012) and functional index (bath ankylosing spondylitis functional index; r = 0.257, P = .011) was observed.Overall, our study demonstrated little clinical and predictive value of CD74 autoantibodies in the diagnosis of axSpA and its related manifestations, among Chinese Han population.

Objective: CD8+ T cells contribute to rheumatoid arthritis (RA) by releasing proinflammatory and cytolytic mediators, even in a challenging hypoxic and nutrient-poor microenvironment such as the synovial membrane. This study was undertaken to explore the mechanisms through which CD8+ T cells meet their metabolic demands in the blood and synovial membrane of patients with RA., Methods: Purified blood CD8+ T cells from patients with RA, patients with psoriatic arthritis (PsA), and patients with spondyloarthritis (SpA), as well as healthy control subjects, and CD8+ T cells from RA synovial membrane were stimulated in medium containing 13 C-labeled metabolic substrates in the presence or absence of metabolic inhibitors, under conditions of normoxia or hypoxia. The production of metabolic intermediates was quantified by 1 H-nuclear magnetic resonance. The expression of metabolic enzymes, transcription factors, and immune effector molecules was assessed at both the messenger RNA (mRNA) and protein levels. CD8+ T cell functional studies were performed., Results: RA blood CD8+ T cells met their metabolic demands through aerobic glycolysis, production of uniformly 13 C-enriched lactate in the RA blood (2.6 to 3.7-fold higher than in patients with SpA, patients with PsA, and healthy controls; P < 0.01), and induction of glutaminolysis. Overexpression of Warburg effect-linked enzymes in all RA CD8+ T cell subsets maintained this metabolic profile, conferring to the cells the capacity to proliferate under hypoxia and low-glucose conditions. In all RA CD8+ T cell subsets, lactate dehydrogenase A (LDHA) was overexpressed at the mRNA level (P < 0.03 versus controls; n = 6 per group) and protein level (P < 0.05 versus controls; n = 17 RA patients, n = 9 controls). In RA blood, inhibition of LDHA with FX11 led to reductions in lipogenesis, migration and proliferation of CD8+ T cells, and CD8+ T cell effector functions, while production of reactive oxygen species was increased by 1.5-fold (P < 0.03 versus controls). Following inhibition of LDHA with FX11, RA CD8+ T cells lost their capacity to induce healthy B cells to develop a proinflammatory phenotype. Similar metabolic alterations were observed in RA CD8+ T cells from the synovial membrane., Conclusion: Remodeling glucose and glutamine metabolism in RA CD8+ T cells by targeting LDHA activity can reduce the deleterious inflammatory and cytolytic contributions of these cells to the development of autoimmunity., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: This study was undertaken to identify novel autoantibodies in axial spondyloarthritis (SpA) and determine their diagnostic potential in patients with early axial SpA and controls from 2 independent cohorts., Methods: An axial SpA complementary DNA phage display library was used to screen for novel IgG antibodies in plasma from patients with early axial SpA. The presence of these antibodies against novel peptides (i.e., peptides identified in an early axial SpA cohort from Hasselt University, designated UH-axSpA) was determined by enzyme-linked immunosorbent assay in 76 patients with early axial SpA, 75 controls with nonspecific chronic low back pain, 60 patients with rheumatoid arthritis, and 94 healthy controls from the UH cohort. Antibody reactivity to these novel peptides was further validated in 174 patients with axial SpA (of whom 79 had early axial SpA) from the University Hospitals Leuven (Bio)SPAR (Spondyloarthritis [Biologics]) cohort., Results: We identified antibodies to 9 novel UH-axSpA peptides, corresponding to randomly formed peptides and to a novel axial SpA autoantigen, double homeobox protein 4. Antibodies to 3 UH-axSpA peptides with the highest positive likelihood ratio (LR) for a diagnosis of axial SpA were present in significantly more patients with early axial SpA from the UH and (Bio)SPAR cohorts (14.2% [22/155]) compared to controls with chronic low back pain (5% [4/75]), resulting in 95% specificity. The positive LR for confirming axial SpA using antibodies to these 3 UH-axSpA peptides was 2.7, which is higher than the LR obtained with the currently used laboratory marker C-reactive protein. Testing for antibodies to these 3 UH-axSpA peptides in patients with chronic low back pain increased the posttest probability of a diagnosis of axial SpA from 79% to 91%., Conclusion: Antibodies to 3 UH-axSpA peptides could provide a novel tool in the diagnosis of a subset of axial SpA patients., (© 2020, American College of Rheumatology.)

In human autoimmune diseases, low plasma levels of complement factors C3 and C4 are commonly used as a proxy for complement activation. The measurements of C3 and C4 concentrations (the result of synthesis and consumption) however, show low sensitivity in patient follow-up. We find that the estimation of the C3dg fragment released during complement activation is a better parameter for complement activation. Available techniques for measuring the activation fragment C3dg, e.g. immune-electrophoresis or involving PEG-precipitation, are time-consuming and difficult to standardize. Here we examine the specificity and use of an antibody with mono-specificity for a neoepitope at the N-terminus of C3dg, which is only exposed after cleavage of C3. We present a stable, reproducible, and easy-to-use, time-resolved immunoassay with specificity for C3dg that can be used to directly evaluate ongoing complement activation. We demonstrate that the assay can be applied to clinical samples with a high specificity (95%) and a positive likelihood ratio of 10. It can also differentiate the complement related disease Systemic Lupus Erythematosus from controls and other immune-mediatedimmune mediated diseases like Rheumatoid Arthritis (86% specificity) and Spondyloarthritis (91% specificity). Further, we establish how the assay may also be used for experimental research in in vivo mouse models., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Targeting the interleukin 17 (IL-17) axis is efficacious in psoriasis and spondyloarthritis (SpA), but not in rheumatoid arthritis (RA). We investigated potential differences in tissue expression and function of IL-17A and IL-17F in these conditions., Methods: mRNA expression of cytokines and their receptors was assessed by quantitative PCR in psoriasis skin samples, in SpA and RA synovial tissue (ST) samples and in fibroblast-like synoviocytes (FLS). Cytokines were measured in synovial fluid (SF) and FLS supernatants by ELISA. FLS were stimulated with IL-17A or IL-17F cytokines supplemented with tumor necrosis factor (TNF), or with pooled SF from patients with SpA or RA., Results: Levels of IL-17A ( P = 0.031) and IL-17F ( P = 0.017) mRNA were lower in psoriatic arthritis ST compared to paired psoriasis skin samples. The level of IL-17A mRNA was 2.7-fold lower than that of IL-17F in skin ( P = 0.0078), but 17.3-fold higher in ST ( P < 0.0001). In SF, the level of IL-17A protein was 37.4-fold higher than that of IL-17F [median 292.4 (IQR 81.4-464.2) vs median 7.8 (IQR 7.7-8.7) pg/mL; P < 0.0001]. IL-17A and IL-17F mRNA and protein levels did not differ in SpA compared to RA synovitis samples, and neither were the IL-17 receptors IL-17RA and IL-17RC , or the TNF receptors TNFR1 and TNR2 , differentially expressed between SpA and RA ST, nor between SpA and RA FLS. SpA and RA FLS produced similar amounts of IL-6 and IL-8 protein upon stimulation with IL-17A or IL-17F cytokines, supplemented with 1 ng/ml TNF. Pooled SpA or RA SF samples similarly enhanced the inflammatory response to IL-17A and IL-17F simulation in FLS., Conclusion: The IL-17A/IL-17F expression ratio is higher in SpA synovitis compared to psoriasis skin. Expression of IL-17A and IL-17F, and the functional response to these cytokines, appear to be similar in SpA and RA synovitis.

Spondyloarthritis comprises a group of inflammatory diseases of the joints and spine, with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B*27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B*27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B*27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.

Despite the success of targeted therapies in the treatment of inflammatory arthritides, the lack of predictive biomarkers drives a 'trial and error' approach to treatment allocation, leading to variable and/or unsatisfactory responses. In-depth characterization of the synovial tissue in rheumatoid arthritis, as well as psoriatic arthritis and spondyloarthritis, is bringing new insights into the diverse cellular and molecular features of these diseases and their potential links with different clinical and treatment-response phenotypes. Such progress raises the tantalizing prospect of improving response rates by matching the use of specific agents to the cognate target pathways that might drive particular disease subtypes in specific patient groups. Innovative patient-centric, molecular pathology-driven clinical trial approaches are needed to achieve this goal. Whilst progress is clearly being made, it is important to emphasize that this field is still in its infancy and there are a number of potential barriers to realizing the premise of patient-centric clinical trials.

Spondyloarthritis (SpA) are a heterogeneous group of inflammatory chronic diseases characterized by sharing common pathogenic, clinical and radiologic features. The aim of this review is to support clinicians in understanding and managing this complex disease, from pathogenesis to therapeutic targets, through a systematic review of the current literature in accordance with PRISMA guidelines and checklist. HLA-B27 has been found to be associated with axial involvement either in SA and in PsA patients: it might be involved through presentation of an "arthritogenic peptide" to autoreactive CD8+ T cells or might accumulate in misfolded form and induce production pro-inflammatory cytokines by binding to several innate immune receptors. This genetic background in combination with mechanical stress leads to the activation of both innate and acquired immune responses as well as a possible role of autoimmunity in SpA pathogenesis. The release of IL-23 and IL-17 is relevant for their systemic and local effect on bone, inducing the activation of osteoclasts. Thus, the regulatory role of IL-17 on fibroblasts, osteoblasts and chondrocytes has an impact in both synovial inflammation and joint destruction. Innovative therapies targeting IL-12/23 and IL-17 and the use of small targeted synthetic molecules, as JAK-inhibitors, proved to be effective in SpA patients representing an alternative strategy to TNF-inhibitors., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Axial SpA (axSpA), encompassing AS, is a multifactorial disease that localizes to sites of high spinal biomechanical stress. Much has been written on T cells and adaptive immunity in axSpA, which is understandable given the very strong HLA-B27 disease association. Extra-axial disease characteristically involves the anterior uveal tract, aortic root, lung apex and terminal ileum. Under recent classification, axSpA is classified as an intermediate between autoimmunity and autoinflammatory disease, with the latter term being synonymous with innate immune dysregulation. The purpose of this review is to evaluate the 'danger signals' from both the exogenous intestinal microbiotal adjuvants or pathogen-associated molecular patterns that access the circulation and endogenously derived damaged self-tissue or damage-associated molecular patterns derived from entheses and other sites of high biomechanical stress or damage that may serve as key drivers of axSpA onset, evolution, disease flares and eventual outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

In rheumatic diseases, advances in biological molecular-targeted therapies have brought remarkable progress in treatment, but the molecular and clinical heterogeneity of the diseases can often pose a treatment challenge. In psoriatic arthritis, each patient exhibits various symptoms, and some may be resistant to treatment. It is difficult to improve all of these various symptoms simultaneously with the use of limited drugs. Therefore, precision medicine is an urgent concern that is required to overcome this problem. However, few studies focus on the precision medicine in rheumatic disease including psoriatic arthritis. We explored the potential of precision medicine in which patients with psoriatic arthritis are stratified by lymphocyte flow cytometry to select specific biologics. Selecting specific biologics according to different immunophenotypes of peripheral blood lymphocytes in psoriatic arthritis was shown to produce high therapeutic responses; in other words, the potential of precision medicine was suggested. The peripheral blood lymphocyte analysis can be applied to many other rheumatic diseases presenting various clinical features, such as spondyloarthritis and systemic lupus erythematous. We should shed light on the precision medicine not only in the psoriatic arthritis also in the other rheumatic disease.

To measure the serum levels of anticarbamylated protein (CarP) antibodies in patients with rheumatoid arthritis (RA) in China and to evaluate the association of anti-CarP antibodies with clinical parameters and disease activity. 260 Chinese patients with RA, 40 patients with osteoarthritis (OA), 88 patients with spondyloarthritis (SpA) and 77 healthy controls were included. The serum levels of anti-CarP antibodies were detected by ELISA. Blood tests to detect the anticyclic citrullinated peptide (CCP) antibody level, rheumatoid factor (RF) level, erythrocyte sedimentation rate, C reactive protein level and Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) were performed by standard methods. Bone erosion was assessed by colour Doppler ultrasonography. A total of 18.8% of patients with RA and 9.4% of anti-CCP antibody and RF-double-negative patients were positive for anti-CarP antibody. The anti-CarP antibody level was significantly higher in patients with RA than in patients with OA or SpA and in healthy controls. Univariate and multivariate analyses showed that the level of anti-CarP antibody was positively correlated with DAS28-ESR; the higher a level of serum anti-CarP antibody, the higher the DAS28-ESR score. Anti-CarP-positive patients had higher disease activity scores than anti-CarP-negative patients. Moreover, anti-CarP-positive patients had a higher risk of developing bone erosion. The anti-CarP antibody was found to play an important role in the diagnosis of RA, especially in anti-CCP antibody and RF-double-negative patients. The anti-CarP antibody is a potential marker of disease activity and bone erosion in RA., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2020. No commercial re-use. See rights and permissions. Published by BMJ.)