Exploring TNFi drug-levels and anti-drug antibodies during tapering among patients with inflammatory arthritis: secondary analyses from the randomised BIODOPT trial.

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.

Illuminating the impact of γδ T cells in man and mice in spondylarthritides.

Spondylarthritides (SpA) are a group of autoinflammatory diseases affecting the spine, peripheral joints, and entheses, including axial spondyloarthritis (axSpA) and psoriatic arthritis. AxSpA has a multifactorial etiology that involves genetic predispositions, such as HLA-B27 and IL-23R. Although HLA-B27 is strongly associated with axSpA, its role remains unclear. GWAS studies have demonstrated that genetic polymorphisms related to the IL-23 pathway occur throughout the spectrum of SpA, including but not limited to axSpA and PsA. IL-23 promotes the production of IL-17, which drives inflammation and tissue damage. This pathway contributes not only to peripheral enthesitis but also to spinal inflammation. γδ T cells in axSpA express IL-23R and RORγt, crucial for their activation, although specific pathogenic cells and factors remain elusive. Despite drug efficacy in PsA, IL-23R inhibition is ineffective in axSpA. Murine models provide valuable insights into the intricate cellular and molecular interactions that contribute to the development and progression of SpA. Those models are useful tools to elucidate the dynamics of γδ T cell involvement, offering insights into disease mechanisms and potential therapeutic targets. This review aims to illuminate the complex interplay between IL-23 and γδ T cells in SpA pathogenesis, emphasizing their roles in chronic inflammation, tissue damage, and disease heterogeneity.

TGFß signaling pathway is altered by HLA-B27 expression, resulting in pathogenic consequences relevant for spondyloarthritis.

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-ß2 microglobulin (hß2m) 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 ß (TGFß) pathway and HLA-B27/hß2m 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/hß2m 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/TGFß pathways induced by its ligands, and the transcript level of target genes of the TGFß pathway, were evaluated. RESULTS: In HLA-B27/hß2m transgenic Drosophila, inappropriate signalling through the activin/TGFß pathway, involving Baboon (Babo), the type I activin/TGFß 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/hß2m transgenic Drosophila wing imaginal disc. We demonstrated specific physical interaction, between HLA-B27/hß2m and mammalian orthologs of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGFß receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFß1 was increased in T cells from B27 rats, showing evidence for deregulated TGFß pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFß 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 TGFß 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.

Exploring the role of gut microbes in spondyloarthritis: Implications for pathogenesis and therapeutic strategies.

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.

Exploring the Pathogenesis of Spondylarthritis beyond HLA-B27: A Descriptive Review.

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.

HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model.

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.

50 years of spondyloarthritis: a look back and a look ahead.

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.

Axial Spondyloarthritis: an overview of the disease.

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.

JAK-STAT Signaling and Beyond in the Pathogenesis of Spondyloarthritis and Their Clinical Significance.

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.

No Correlation between Anti-drug Antibodies and Therapeutic Response in Tunisian Patients with Chronic Inflammatory Diseases Treated by TNF Blockers.

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.

Pro-inflammatory cytokines in spondyloarthritis: a case-control study.

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.

Comprehensive reproductive healthcare for women with immune-mediated inflammatory diseases: Addressing rheumatoid arthritis, spondyloarthritis and inflammatory bowel disease through life's stages.

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.

[CHANGING IMMUNE STATUS IN PATIENTS WITH REACTIVE SPONDYLOARTHRITIS OF CHLAMIDIAL GENESIS].

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.

Vitronectin-derived bioactive peptide prevents spondyloarthritis by modulating Th17/Treg imbalance in mice with curdlan-induced spondyloarthritis.

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 ß1 and αvß3 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-1ß, 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.

Importance of the second SARS-CoV-2 vaccination dose for achieving serological response in patients with rheumatoid arthritis and seronegative spondyloarthritis.

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.

Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats.

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.