ABSTRACT
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.
Subject(s)
Animals, Genetically Modified , HLA-B27 Antigen , Signal Transduction , Spondylarthritis , Transforming Growth Factor beta , Animals , Signal Transduction/physiology , Spondylarthritis/metabolism , Spondylarthritis/immunology , Humans , HLA-B27 Antigen/genetics , HLA-B27 Antigen/metabolism , HLA-B27 Antigen/immunology , Transforming Growth Factor beta/metabolism , Rats , Drosophila , Drosophila melanogaster , Wings, Animal/metabolismABSTRACT
The progress observed over the last 30 years in the field of axial spondyloarthritis (axSpA) has not made it possible to answer all the current questions. This manuscript represents the proceedings of the meeting of the French spondyloArthitiS Task force (FAST) in Besançon on September 28 and 29, 2023. Different points of discussion were thus individualized as unmet needs: biomarkers for early diagnosis and disease activity, a common electronic file dedicated to SpA nationwide, a better comprehension of dysbiosis in the disease, a check-list for addressing to the rheumatologist, adapt patient reported outcomes thresholds for female gender, implementation of comorbidities screening programs, new imaging tools, in research cellular and multi omics approaches, grouping, at a nationwide level, different cohorts and registries, therapeutic strategy studies, consensual definition of difficult to treat disease and management, preclinical stage of the disease, mastering AI as a tool in the various aspects of research. These elements may represent a framework for the research agenda in axSpA for the years to come.
ABSTRACT
OBJECTIVES: Spondyloarthritis (SpA) and psoriatic arthritis (PsA) represent two frequent inflammatory rheumatic disorders, characterized by an increased burden on quality of life, due to the association of several comorbidities, especially cardiovascular diseases (CVD). The estimated prevalence of CVD ranges from 12-19% and differ between the two diseases, however, its incidence is not completely known. We aimed to systematically review the literature (SLR) and perform a meta-analysis of controlled observational studies to assess the incidence rate of CVD over time, separately in SpA and PsA. METHODS: We performed a SLR of longitudinal studies with a study period of at least 5 years, including SpA/PsA patients and general population. The main outcome was the occurrence of CVD, including ischemic heart disease, stroke, and death from CV cause. We then performed a random-effect model for meta-analysis. RESULTS: The SLR included 34 articles, mainly focused on the association between SpA/PsA and CVD. Twenty-four articles were then selected for the meta-analysis. The overall incidence of CVD was increased in PsA (HR: 1.28, 95%CI: 1.15-1.43), and in SpA (HR: 1.45, 95%CI: 1.22-1.72) compared with the general population, with consistency across the different types of CVD; Interestingly the incidence tended to decrease over time in PsA, but not in SpA. CONCLUSION: The SLR and meta-analysis confirmed the increased incidence of CVD in both SpA and PsA patients compared with the general population during the last years, although such increase seems to be less prominent in PsA than in SpA. Future studies are needed to confirm such tendence.
ABSTRACT
Spondyloarthritis (SpA) is characterized by a strong genetic predisposition evidenced by the identification of up to 50 susceptibility loci, in addition to HLA-B27, the major genetic factor associated with the disease. These loci have not only deepened our understanding of disease pathogenesis but also offer the potential to improve disease management. Diagnostic delay is a major issue in SpA. HLA-B27 testing is widely used as diagnostic biomarker in SpA but its predictive value is limited. Several attempts have been made to develop more sophisticated polygenic risk score (PRS). However, these scores currently offer very little improvement as compared to HLA-B27 and are still difficult to implement in clinical routine. Genetics might also help to predict disease outcome including treatment response. Several genetic variants have been reported to be associated with radiographic damage or with poor response to TNF blockers, unfortunately with lack of coherence across studies. Large-scale studies should be conducted to obtain more robust findings. Genetic and genomic evidence in complex diseases can be further used to support the identification of new drug targets and to repurpose existing drugs. Although not fully driven by genetics, development of IL-17 blockers has been facilitated by the discovery of the association between IL23R variants and SpA. Development of recent approaches combining GWAS findings with functional genomics will help to prioritize new drug targets in the future. Although very promising, translational genetics in SpA remains challenging and will require a multidisciplinary approach that integrates genetics, genomics, immunology, and clinical research.
Subject(s)
Spondylarthritis , Spondylitis, Ankylosing , Humans , Spondylitis, Ankylosing/genetics , HLA-B27 Antigen/genetics , Delayed Diagnosis , Spondylarthritis/diagnosis , Spondylarthritis/genetics , Genetic Predisposition to DiseaseABSTRACT
Introduction: In spondyloarthritis (SpA), an increased type 3 immune response, including T helper cells (Th) 17 excess, is observed in both human and SpA animal models, such as the HLA-B27/human ß2-microglobulin transgenic rat (B27-rat). Methods: To investigate this unexplained Th17-biased differentiation, we focused on understanding the immunobiology of B27-rat naive CD4+ T cells (Tn). Results: We observed that neutrally stimulated B27-rat Tn developed heightened Th17 profile even before disease onset, suggesting an intrinsic proinflammatory predisposition. In parallel with this observation, transcriptomic and epigenomic analyses showed that B27-rat Tn exhibited a decreased expression of Interferon/Th1- and increased expression of Th17-related genes. This molecular signature was predicted to be related to an imbalance of STAT1/STAT3 transcription factors activity. Stat1 mRNA and STAT1 protein expression were decreased before disease onset in Tn, even in their thymic precursors, whereas Stat3/STAT3 expression increased upon disease establishment. Confirming the relevance of these results, STAT1 mRNA expression was also decreased in Tn from SpA patients, as compared with healthy controls and rheumatoid arthritis patients. Finally, stimulation of B27-rat Tn with a selective STAT1 activator abolished this preferential IL-17A expression, suggesting that STAT1-altered activity in B27-rats allows Th17 differentiation. Discussion: Altogether, B27-rat Tn harbor a STAT1 deficiency preceding disease onset, which may occur during their thymic differentiation, secondarily associated with a persistent Th17 bias, which is imprinted at the epigenomic level. This early molecular phenomenon might lead to the persistent proinflammatory skew of CD4+ T cells in SpA patients, thus offering new clues to better understand and treat SpA.
Subject(s)
Arthritis, Rheumatoid , Spondylarthritis , Animals , Humans , Rats , Arthritis, Rheumatoid/metabolism , CD4-Positive T-Lymphocytes , Rats, Transgenic , RNA, Messenger/metabolism , STAT1 Transcription Factor/metabolismABSTRACT
OBJECTIVE: To evaluate the prevalence of clinical and ultrasound (grey-scale and Doppler) abnormalities in joints, periarticular structures and nails of children affected by skin psoriasis (PsO). METHODS: Cross-sectional study including consecutive children affected by PsO. A systematic clinical and ultrasound evaluation of joints, entheses, tendons and nails were performed by independent examiners blinded to each other assessment. RESULTS: 57 Children: 26 girls (46%), mean age of 9 ± 4 years, divided into two groups, asymptomatic (Asy, 42 children) and symptomatic (Sy, 15 children) according to musculoskeletal pain. Differences were observed between the two groups in relation to age (9 ± 3 in Asy vs 11 ± 4 yrs in Sy, p< 0.05), PsO duration (2.4 ± 2.4 vs 5.4 ± 3.9 yrs, p< 0.001), systemic treatment (23 [54.8%] vs 2 [13.3%], p< 0.01), tender joint count (0 vs 12 children [80%], p< 0.001), swollen joint count (0 vs 3 [20%], p< 0.01) and entheseal pain (0 vs 10 [66.7%], p< 0.001). Ultrasound evaluation showed statistically significant differences between Asy and Sy groups for the presence of ultrasound abnormalities (16/42 [38%] vs 12/15 [80%]), synovitis (1/42 [2%] vs 4/15 [25%]) and enthesitis (4/42 [9.5%] vs 5/15 [33%]). Three children in the Sy group were classified with juvenile psoriatic arthritis (JPsA). CONCLUSIONS: Ultrasound abnormalities were higher in the Sy group with synovitis and enthesitis as the most prevalent findings. Asy patients were more frequently under systemic treatment. Ultrasound and a systematic clinical evaluation are useful tools for detecting subclinical JPsA in children with PsO and musculoskeletal symptoms.
ABSTRACT
Spondyloarthritis (SpA) is an immune-mediated disease characterized by a high heritability, reflected by strong familial aggregation. Therefore, family studies are a powerful tool for elucidating the genetic basis of SpA. First, they helped to assess the relative importance of genetic and environmental factors and established the polygenic character of the disease. Family-based designs were also historically used to identify genetic factors of susceptibility through linkage analyses. In SpA, three whole-genome linkage studies were published in the 1990's, unfortunately with few consistent results. After having been put aside for several years in favour of case-control GWAS, there is a renewed interest in family-based designs in particular to detect rare variant associations. This review aims at summarizing what family studies have brought to the field of SpA genetics, from genetic epidemiology studies to the most recent rare variant analyses. It also highlights the potential interest of family history of SpA to help diagnosis and detection of patients at high risk to develop the disease.
Subject(s)
Spondylarthritis , Spondylitis, Ankylosing , Humans , Spondylarthritis/diagnosis , Spondylarthritis/epidemiology , Spondylarthritis/genetics , Severity of Illness Index , Spondylitis, Ankylosing/diagnosisABSTRACT
The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.
Subject(s)
Behcet Syndrome , Spondylarthritis , Uveitis , Humans , Genetic Predisposition to Disease , Behcet Syndrome/genetics , Histocompatibility Antigens Class I/genetics , Aminopeptidases/genetics , Minor Histocompatibility Antigens/geneticsABSTRACT
OBJECTIVE: We undertook this study to examine the functional basis for epistasis between endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 in experimental spondyloarthritis (SpA). METHODS: ERAP1-knockout rats were created using genome editing and bred with HLA-B27/human ß2 -microglobulin-transgenic (HLA-B27-Tg) rats and HLA-B7-Tg rats. The effects of ERAP1 deficiency on HLA allotypes were determined using immunoprecipitation and immunoblotting, flow cytometry, allogeneic T cell proliferation assays, and gene expression analyses. Animals were examined for clinical features of disease, and tissue was assessed by histology. RESULTS: ERAP1 deficiency increased the ratio of folded to unfolded (ß2 m-free) HLA-B27 heavy chains, while having the opposite effect on HLA-B7. Furthermore, in rats with ERAP1 deficiency, HLA-B27 misfolding was reduced, while free HLA-B27 heavy chain dimers on the cell surface and monomers were increased. The effects of ERAP1 deficiency persisted during up-regulation of HLA-B27 and led to a reduction in endoplasmic reticulum stress. ERAP1 deficiency reduced the prevalence of arthritis in HLA-B27-Tg rats by two-thirds without reducing gastrointestinal inflammation. Dendritic cell abnormalities attributed to the presence of HLA-B27, including reduced allogeneic T cell stimulation and loss of CD103-positive/major histocompatibility complex class II-positive cells, were not rescued by ERAP1 deficiency, while excess Il23a up-regulation was mitigated. CONCLUSION: ERAP1 deficiency reduced HLA-B27 misfolding and improved folding while having opposing effects on HLA-B7. The finding that HLA-B27-Tg rats had partial protection against SpA in this study is consistent with genetic evidence that loss-of-function and/or reduced expression of ERAP1 reduces the risk of ankylosing spondylitis. Functional studies support the concept that the effects of ERAP1 on HLA-B27 and SpA may be a consequence of how peptides affect the biology of this allotype rather than their role as antigenic determinants.
Subject(s)
HLA-B27 Antigen , Spondylitis, Ankylosing , Animals , Humans , Rats , Aminopeptidases/genetics , Aminopeptidases/metabolism , Endoplasmic Reticulum/metabolism , HLA-B27 Antigen/genetics , HLA-B27 Antigen/metabolism , HLA-B7 Antigen , Minor Histocompatibility Antigens/genetics , Spondylitis, Ankylosing/genetics , Arthritis/genetics , Arthritis/metabolismABSTRACT
OBJECTIVE: Gut microbiome dysbiosis has previously been reported in spondyloarthritis (SpA) patients and could be critically involved in the pathogenesis of this disorder. The objectives of this study were to further characterize the microbiota structure in SpA patients and to investigate the relationship between dysbiosis and disease activity in light of the putative influence of the genetic background. METHODS: Shotgun sequencing was performed on fecal DNA isolated from stool samples from 2 groups of adult volunteers: SpA patients (n = 102) and healthy controls (n = 63). A subset of the healthy controls comprised the age-matched siblings of patients whose HLA-B27 status was known. Changes in gut microbiota composition were assessed based on species diversity, enterotypes, and taxonomic and functional differences. RESULTS: Dysbiosis was confirmed in SpA patients as compared to healthy controls. The restriction of microbiota diversity was detected in patients with the most active disease, and the abundance of several bacterial species was correlated with Bath Ankylosing Spondylitis Disease Activity Index score. Among healthy controls, significant differences in microbiota composition were also detected between the HLA-B27-positive and the HLA-B27-negative siblings of SpA patients. We highlighted a decreased abundance of several species of bacteria in SpA patients, especially those bacteria belonging to the Clostridiales order. Among the few species of bacteria showing increased abundance, Ruminococcus gnavus was one of the top differentiating species. CONCLUSION: These findings reveal that genetic background and level of disease activity are likely to influence the composition of the gut microbiota of patients with SpA. It may be appropriate for further research on chronic arthritis to focus on these key parameters.
Subject(s)
Gastrointestinal Microbiome , Microbiota , Spondylarthritis , Adult , Humans , Gastrointestinal Microbiome/genetics , HLA-B27 Antigen/genetics , Dysbiosis/microbiology , Spondylarthritis/genetics , Spondylarthritis/complicationsABSTRACT
OBJECTIVE: The aims of this study were to determine thresholds of variations of BASDAI and pain associated with patient-reported outbreak or resolution of flare and to test performance of ASAS preliminary definitions of flare. METHODS: SpA patients registered on the Spondy+platform were invited to fill BASDAI and global pain on numeric rating scales every week during one year and to tell if they experienced flare since last week. Performance of BASDAI and pain variations (ΔBASDAI and Δpain) to detect occurrence and resolution of flare was determined with receiver operator characteristic (ROC) curves. RESULTS: Ninety-one of the 99 axSpA patients included reported at least one episode of flare. Area under the ROC curve was significantly higher for ΔBASDAI than for Δpain to predict outbreak of flare (0.81 vs. 0.77, p<0.05) without statically significant difference to predict flare resolution (0.78 vs. 0.80). Best sensitivity/specificity compromise was obtained for ΔBASDAI of 0.2 and 0.4 points to predict flare outbreak or resolution, respectively. All the ASAS definitions obtained a specificity higher than 95% whereas sensitivity was lower than 40%. CONCLUSION: ΔBASDAI appeared as a suitable variable to monitor occurrence and resolution of patient-reported flare in axSpA.
Subject(s)
Axial Spondyloarthritis , Spondylarthritis , Spondylitis, Ankylosing , Humans , Internet , Pain , Patient Reported Outcome Measures , Severity of Illness Index , Spondylarthritis/complications , Spondylarthritis/diagnosis , Spondylitis, Ankylosing/complicationsABSTRACT
OBJECTIVES: The strong heritability of spondyloarthritis remains poorly explained, despite several large-scale association studies. A recent linkage analysis identified a new region linked to SpA on 13q13. Here we searched for variants potentially explaining this linkage signal by deep-sequencing of the region. METHODS: Re-sequencing of the 1.4 Mb target interval was performed in 92 subjects from the 43 best-linked multicases families (71 spondyloarthritis and 21 unaffected relatives), using hybridization capture-based protocol (Illumina Nextera®). Variants of interest were then genotyped by TaqMan and high resolution melting to check their co-segregation with disease in the same families and to test their association with spondyloarthritis in an independent cohort of 1,091 unrelated cases and 399 controls. Expression of FREM2 was assessed by immunostaining. RESULTS: Of the 7,563 variants identified, 24 were non-synonymous coding single-nucleotide variants. Two of them were located in the FREM2 gene on a haplotype co-segregating with the disease, including one common variant (R1840W, minor allele frequency=0.11) and one rare variant (R727H, minor allele frequency=0.0001). In the case-control analysis, there was no significant association between R1840W and spondyloarthritis (P-value=0.21), whereas R727H was not detected in any of the genotyped individuals. Immunostaining experiments revealed that FREM2 is expressed in synovial membrane, cartilage and colon. CONCLUSIONS: Targeted re-sequencing of a spondyloarthritis-linked region allowed us to identify a rare non-synonymous coding variant in FREM2, co-segregating with spondyloarthritis in a large family. This gene is expressed in several tissues relevant to spondyloarthritis pathogenesis, supporting its putative implication in spondyloarthritis.
Subject(s)
Genetic Predisposition to Disease , Spondylarthritis , Humans , Polymorphism, Single Nucleotide , Genetic Linkage , Spondylarthritis/genetics , Genotype , Extracellular Matrix Proteins/geneticsABSTRACT
BACKGROUND: Rheumatoid arthritis (RA) is characterized by increased cardiovascular (CV) mortality. CV events are particularly high in patients with RA-specific autoimmunity, including rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), raising the question whether RA-specific autoimmunity itself is associated with CV events. METHODS: New CV events (myocardial infarction, stroke or death by CV cause) were recorded in 20,625 subjects of the Electricité de France - Gaz de France (GAZEL) cohort. Self-reported RA cases in the GAZEL cohort were validated by phone interview on the basis of a specific questionnaire. In 1618 subjects, in whom plasma was available, RF and ACPA were measured. A piecewise exponential Poisson regression was used to analyze the association of CV events with presence of RA as well as RA-specific autoimmunity (without RA). RESULTS: CV events in GAZEL were associated with age, male sex, smoking, hypertension, hyperlipidemia, and diabetes mellitus (HR from 1.06 to 1.87, p < 0.05). Forty-two confirmed RA cases were identified. Confirmed RA was significantly associated with CV risk increase (HR of 3.03; 95% CI: 1.13-8.11, p = 0.03) independently of conventional CV risk factors. One hundred seventy-eight subjects showed RF or ACPA positivity without presence of RA. CV events were not associated with ACPA positivity (HR: 1.52, 95% CI: 0.47-4.84, p = 0.48) or RF positivity (HR: 1.15, 95% CI: 0.55-2.40, p = 0.70) in the absence of RA. CONCLUSIONS: RA, as a clinical chronic inflammatory disease, but not mere positivity for RF or ACPA in the absence of clinical disease is associated with increased CV risk.
Subject(s)
Arthritis, Rheumatoid , Cardiovascular Diseases , Anti-Citrullinated Protein Antibodies , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/epidemiology , Autoantibodies , Autoimmunity , Cardiovascular Diseases/complications , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Humans , Male , Rheumatoid FactorABSTRACT
OBJECTIVE: Update the French Society for Rheumatology (SFR) recommendations on the everyday management of patients with spondyloarthritis, including psoriatic arthritis. METHODS: Following standardized procedures, a systematic literature review was done by four supervised rheumatology residents based on questions defined by a task force of 16 attending rheumatologists. The findings were reviewed during three working meetings that culminated in each recommendation receiving a grade and the level of agreement among experts being determined. RESULTS: Five general principles and 15 recommendations were developed. They take into account pharmacological and non-pharmacological measures along with treatment methods based on the dominant phenotype present (axial, articular, enthesitis/dactylitis) and the extra-articular manifestations (psoriasis, inflammatory bowel disease, uveitis). NSAIDs are the first-line pharmacological treatment in the various presentations. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are not indicated in the axial and isolated entheseal forms. If the response to conventional treatment is not adequate, targeted therapies (biologics, synthetics) should be considered; the indications depend on the clinical phenotype and presence of extra-articular manifestations. CONCLUSION: This update incorporates recent data (published since the prior update in 2018) and the predominant clinical phenotype concept. It aims to help physicians with the everyday management of patients affected by spondyloarthritis, including psoriatic arthritis.
Subject(s)
Antirheumatic Agents , Arthritis, Psoriatic , Psoriasis , Rheumatology , Spondylarthritis , Antirheumatic Agents/therapeutic use , Arthritis, Psoriatic/diagnosis , Arthritis, Psoriatic/drug therapy , Humans , Spondylarthritis/diagnosis , Spondylarthritis/drug therapyABSTRACT
Introduction: Spondylarthritis (SpA) development in HLA-B27/human ß2-microglobulin transgenic rat (B27-rat) is correlated with altered conventional dendritic cell (cDC) function that promotes an inflammatory pattern of CD4+T cells, including a biased expansion of pro-inflammatory Th17 population and imbalance of regulatory T cells cytokine profile. Transcriptomic analysis revealed that cDCs from B27-rats under express IL-27, an anti-inflammatory cytokine which induces the differentiation of IL-10+ regulatory T cells and inhibits Th17 cells. Methods: Here, we first investigated whether in vitro addition of exogenous IL-27 could reverse the inflammatory pattern observed in CD4+ T cells. Next, we performed preclinical assay using IL-27 to investigate whether in vivo treatment could prevent SpA development in B27-rats. Results: in vitro addition of IL-27 to cocultures of cDCs and CD4+ T cell subsets from B27-rats reduced IL-17 and enhanced IL-10 production by T cells. Likewise, IL-27 inhibited the production of IL-17 by CD4+ T cells from SpA patients. Interestingly, in vivo treatment with recombinant IL-27 starting before SpA onset, inhibited SpA development in B27-rats through the suppression of IL-17/TNF producing CD4+ T cells. Discussion: Overall, our results reveal a potent inhibitory effect of IL-27 and highlight this cytokine as a promising new therapeutic target in SpA, especially for SpA patients non responders to currently approved biotherapies.
Subject(s)
Interleukin-27 , Spondylarthritis , Animals , Humans , Rats , Cytokines , Interleukin-10 , Interleukin-17 , Rats, Transgenic , Th17 CellsABSTRACT
OBJECTIVES: To assess whether two cluster analysis-based axial SpA (axSpA) endotypes (A for purely axial; B for both axial and peripheral) are stable over time and are associated with different long-term disease outcomes. METHODS: K-means cluster analysis was performed at each visit (until 5 years) on 584 patients from the DESIR cohort, who completed all planned visits, and validated in 232 consecutive axSpA patients from the BeGiant cohort. Cluster stability overtime was assessed by kappa statistics. A generalized linear mixed-effect analysis was applied to compare outcomes between clusters. Classification and regression tree (CART) analysis was performed to determine a decision rule able to assign a given patient to a definite cluster at onset. RESULTS: Both endotypes remained remarkably stable over time. In the DESIR cohort, patients in cluster B showed higher disease activity, worse functional outcome and higher need for anti-rheumatic drugs than patients in cluster A. CART analysis yielded three main clinical features (arthritis, enthesitis and dactylitis) that accurately determined cluster assignment. These results could be replicated in the Be-GIANT cohort. CONCLUSION: Cluster-based axSpA endotypes were reproducible in two different cohorts, stable over time and associated with different long-term outcome. The axSpA endotype with additional peripheral disease manifestations is associated with more severe disease and requires more intensive drug therapy. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, https://clinicaltrials.gov, NCT01648907.