Search

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/., 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.

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.

Introduction Axial spondyloarthritis (AxSpA) is an inflammatory disorder that affects the joints, entheses, and bone tissues and is sometimes associated with psoriasis, anterior uveitis, and gut inflammation. Its pathogenesis is not wholly understood and treatment strategies require optimization. Data concerning AxSpA pathogenesis support a critical role of abnormal CD4+ T cell differentiation and exacerbated type 3 immune response. This knowledge boosted the development of interleukin (IL)-17 and Janus kinase inhibitors for AxSpA treatment beyond tumor necrosis factor-α inhibition. Areas covered Emerging drug targets in animal and cellular models and with phase-II clinical trials have been evaluated. We also reflect on key issues for preclinical and clinical research going forward. Expert opinion Some of the most promising approaches include: (i) modulation of transforming growth factor-β family that could exert a specific role on bone formation; (ii) blockade of granulocyte-macrophage colony-stimulating factor that could reduce type 3 immune responses, and (iii) rebalancing of biased immune response by cytokines such as IL-2 or IL-27 that could favor anti-inflammatory response and sustained drug-free remission. Multiomics tools and artificial intelligence could contribute to identification of optimal targets and help stratify patients for the most appropriate treatment options.

International audience

Purpose of review The well-established link between intestinal inflammation and spondyloarthritis (SpA) remains largely unexplained. Recent sequencing technologies have given access to a thorough characterization of the gut microbiota in healthy and disease conditions. This showed that inflammatory bowel disease (IBD) is associated with dysbiosis - i.e., disturbed gut microbiota composition - which may contribute to disease pathogenesis. Whether gut dysbiosis exists in SpA and could contribute to disease development or be a bystander consequence of chronic inflammation is a question of major interest. Recent findings Several metagenomic studies have been performed in SpA. Most of them concerned faecal samples and showed dysbiosis consisting in a reduction of microbial biodiversity in a way similar to what has been described in IBD. They also highlighted changes in microbial taxa composition that could contribute to the inflammatory process. Likewise, healthy carriers of human leukocyte antigen (HLA)-B27 exhibited gut dysbiosis, indicating that this predisposing allele could exert its pathogenic effect by influencing microbiota composition, and possibly by driving antigen-specific cross-reactive immune response. On the other hand, SpA treatments were associated with a reduction of dysbiosis, showing that it is at least in part a consequence of inflammation. Summary Recent insights from metagenomic studies warrant further investigations to identify the mechanisms by which microbial dysbiosis could contribute to SpA development. This would bring novel therapeutic opportunities aiming at correcting detrimental changes.

We undertook this study to examine the functional basis for epistasis between endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 in experimental spondyloarthritis (SpA).ERAP1-knockout rats were created using genome editing and bred with HLA-B27/human βERAP1 deficiency increased the ratio of folded to unfolded (βERAP1 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.

International audience; La spondyloarthrite (SpA) est un rhumatisme inflammatoire chronique d’étiologie inconnue dont la survenue résulte de l’interaction de facteurs de prédisposition environnementaux et génétiques. Malgré des avancées récentes, une large fraction de la prédisposition génétique à la SpA demeure inexpliquée. Plusieurs mécanismes ont été proposés pour expliquer cette part d’héritabilité manquante, tels que l’épigénétique, qui peut jouer un rôle à l’interface entre facteurs génétiques et environnementaux de susceptibilité. L’épigénétique se réfère aux variations de l’expression génique qui n’impliquent aucun changement de la séquence d’ADN. Les mécanismes épigénétiques comprennent principalement la méthylation de l’ADN, les modifications des histones et les ARN non codants. La perturbation de l’un de ces systèmes peut conduire à une altération de l’expression génique susceptible de favoriser le développement de la maladie. Grâce aux récents progrès technologiques, on observe un intérêt croissant pour le domaine de l’épigénétique dans le contexte des maladies complexes comme la SpA. Cependant, les études épigénétiques sont confrontées à des obstacles méthodologiques qui limitent l’interprétation de leurs résultats : petite taille des échantillons, absence de confirmation des résultats, choix inapproprié des témoins, choix inadéquat du type cellulaire/tissulaire. Dans le futur, l’association de l’épigénétique aux autres données « -omiques » permettra de mieux comprendre la pathogénie de la SpA. Ces problématiques doivent être résolues avant d’envisager l’utilisation des marques épigénétiques en routine clinique, en tant que biomarqueurs ou cibles médicamenteuses.

Spondyloarthritis (SpA) is a chronic inflammatory disorder resulting from a combination of genetic predisposition and environmental factors. Despite recent advances, a substantial fraction of its genetic basis remains poorly understood. Several mechanisms have been proposed to account for this unexplained heritability, including epigenetics which can play a role at the interface between genetic and environmental susceptibility factors. Epigenetics refers to changes in gene expression that are not encoded in the DNA sequence itself. Such mechanisms may include DNA methylation, histone modifications and non-coding RNAs. Disruption of one of these systems can lead to inappropriate gene expression, which in turn might favour the development of disease. Thanks to recent technological progress, there has been a growing interest in the field of epigenetics in complex diseases, including SpA. However, epigenetic studies face some methodological limitations that hamper interpretation of their results: small sample size, absence of biological replication, lack of adequate controls for potential confounders, studies not performed in the most relevant cell/tissues. In the future, integration of epigenetics with other "omics" data will probably be necessary to improve our understanding of SpA pathogenesis. These issues need to be addressed before considering the use of epigenetic marks in clinical routine, as biomarkers or as drug targets.

We gratefully acknowledge the kind contribution of Mrs. Nabila Yasmine Domingo-Saidji from the Clinical Research Unit of Paris Ile-de-France Ouest (URCPO), who supervised the administrative paperwork and helped us to manage ethical issues related to the study.; International audience; 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

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.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.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.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.

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 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.

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.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.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, plt;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%.ΔBASDAI appeared as a suitable variable to monitor occurrence and resolution of patient-reported flare in axSpA.

Objectives The optimal treatment target in axial spondyloarthritis (axSpA) is remission; however, a consensual definition of remission is lacking. Our objective was to explore rheumatologists’ perception of remission using vignette cases and a priority exercise. Methods A cross-sectional survey of rheumatologists’ perceptions of remission in axSpA was performed in 2020 using (i) 36 vignette cases, with a single clinical picture and three varying parameters [axial pain (ranging from 2 to 5 on a 0–10 scale)], fatigue (2–8), and morning stiffness ( Results Overall, 200 French rheumatologists participated in 2400 vignette evaluations. Of these, 463 (19%) were classified as remission. The six vignette cases representing 56% of all remission cases had Conclusions When conceptualizing remission in axSpA, rheumatologists took into account morning stiffness and axial pain as expected; the link between remission and fatigue was much weaker. Furthermore, rheumatologists also included EAMs and NSAID use in the concept of remission. Consensus is needed for definition of remission in axSpA.

International audience; ObjectifL’effet des facteurs environnementaux sur le cours de la spondyloarthrite (SpA) est encore mal caractérisé. Nous avons rapporté précédemment la possibilité que des poussées de la maladie soient déclenchées par des événements stressants et par la vaccination. L’objectif de la présente étude était de spécifier les types de vaccin et d’événements de la vie pouvant avoir une influence sur l’activité de la maladie.MéthodesUne cohorte prospective d’adultes atteints de SpA a été suivie pendant deux ans. Les patients se sont connectés chaque mois à un site Web sécurisé pour répondre à un autoquestionnaire normalisé. Ils ont indiqué s’ils avaient subi des événements stressants, été vaccinés ou avaient été exposés à d’autres facteurs environnementaux. Ils ont été invités à noter l’angoisse provoquée par ces événements sur une échelle numérique (EN : 0-10). La principale variable d’évaluation était l’indice d’activité de la maladie BASDAI (Bath Ankylosing Spondylitis Disease Activity) enregistré lors de deux connexions consécutives. Les mois où un événement s’était produit ont été comparés aux mois sans événement. Une valeur seuil de 1 a été définie comme la variation minimale cliniquement importante pour le score BASDAI.RésultatsLes 272 patients atteints de SpA recrutés ont rempli 3 388 questionnaires. Les mois durant lesquels un événement traumatisant brutal et inattendu s’était produit ont été associés à une augmentation significative du score BASDAI de 0,57 (IC 95 % 0,29–0,85) (p < 0,001). Plus la note d’angoisse était élevée, plus l’impact sur le score BASDAI était important, atteignant une hausse cliniquement pertinente de 0,99 (0,17-1,82) pour une ENV ≥ 9. L’effet des événements stressants sur le score BASDAI a persisté pendant une durée médiane de trois mois. Aucun autre facteur environnemental n’a été associé de manière significative à des variations du score BASDAI.ConclusionLa survenue brutale et inattendue d’événements stressants a été associée à une dégradation transitoire de l’activité de la SpA, dont l’augmentation était cliniquement pertinente lorsque l’angoisse générée était notée comme maximale. L’association entre vaccins et poussées n’a pas été confirmée.

Objectives To estimate the number of patients with severe spondyloarthritis (SpA) in France, describe their comorbidities and document and value their healthcare resource consumption. Methods Data were retrieved from an insurance claims database covering a 1/97 random sample of the French population. All patients benefiting from full insurance coverage (“ALD”) for severe SpA in 2012 (including cases with structural damage and/or frequent flares) were identified, together with a control group frequency-matched by age and gender. Severe comorbidities were documented through ALD categories. Healthcare resource consumption was documented and valued from the payer's perspective. Rates of comorbidities and costs were compared in SpA patients versus controls using non-parametric testing. Results Overall, 827 patients with ALD status for severe SpA were identified (control group: n = 2.481), corresponding to a prevalence rate of 0.18% [0.17–0.19] for SpA with ALD in the general population. Severe comorbidities more frequent in patients with SpA than in controls included inflammatory bowel disorders (odds ratio: 15.0 [6.2–36.2]), hypertension (2.5 [1.6–3.9]), atrial fibrillation (4.3 [1.9–9.6]) and major depressive disorder (2.1 [1.3–3.6]). Mean per capita annual direct healthcare expenditure was 3.6 [3.2–4.1]-fold higher in SpA patients (€6,122 [€5,838–€6,406]) than in controls (€1,682 [€1,566–€1,798]). Extrapolating to all patients in France, total healthcare cost attributable to severe SpA patients was €391 [€355–€426] million, with medication accounting for 53.8% of this cost. Conclusions The burden of severe SpA in France is substantial, due to the high prevalence, high direct costs and associated comorbidities.

ObjectiveWe sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain.MethodsPRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI.ResultsIn people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively.ConclusionsPRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.

International audience; Understanding the complex mechanisms underlying a disorder such as spondyloarthritis (SpA) may benefit from studying animal models. Several suitable models have been developed, in particular to investigate the role of genetic factors predisposing to SpA, including HLA-B27, ERAP1, and genes related to the interleukin (IL)-23/IL-17 axis. One of the best examples of such research is the HLA-B27 transgenic rat model that fostered the emergence of original theories regarding HLA-B27 pathogenicity, including dysregulation of innate immunity, contribution of the adaptive immune system to chronic inflammation, and influence of the microbiota on disease development. Very recently, a new model of HLA-B27 transgenic Drosophila helped to expand further some of those theories in an unexpected direction involving the TGFβ/BMP family of mediators. On the other hand, several spontaneous, inducible, and/or genetically modified mouse models-including SKG mouse, TNFΔARE mouse and IL-23-inducible mouse model of SpA-have highlighted the importance of TNFα and IL-23/IL-17 axis in the development of SpA manifestations. Altogether, those animal models afford not only to study disease mechanism but also to investigate putative therapeutic targets.

International audience; 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.

A causal link between the wealth of microbes that populate our body surfaces, designated as microbiota, and inflammatory disorders, including ankylosing spondylitis and the related spondyloarthritis (SpA) has been suspected for decades. This specially concerns the gut microbiota that became only recently accessible to thorough description thanks to massive sequencing methods or metagenomics. Here, we review evidences supporting the existence of microbiota imbalance or dysbiosis in the context of SpA. We also discuss currently existing evidences for a causal relationship between such dysbiosis and disease development, as well as putative therapeutic implications.

International audience; Objective: It was previously shown that HLA–B27 subtypes predisposing to spondyloarthritis (SpA), i.e., B*27:02, B*27:05, and B*27:07, displayed an increased propensity to form intracellular oligomers and to accumulate at a high density in cytoplasmic vesicles, as compared to the non–SpA-associated HLA–B*07:02 and HLA–B*27:06. This study was undertaken to characterize the nature and content of HLA–B–containing vesicles and to further examine their relevance to SpA predisposition. Methods: Vesicles containing HLA–B proteins were detected in transfected HeLa cells and in cells from SpA patients or HLA–B27/human β2-microglobulin (hβ2m)–transgenic rats, by microscopy. The nature and content of HLA–B–containing vesicles were characterized in colocalization experiments with appropriate markers. Results: The SpA-associated HLA–B*27:04 subtype accumulated at higher levels (P < 10−5) in cytoplasmic vesicles compared to HLA–B*27:06, from which it differs only by 2 substitutions, reinforcing the correlation between vesicle formation and SpA predisposition. Colocalization studies showed that those vesicles contained misfolded HLA–B heavy chain along with β2m and endoplasmic reticulum (ER) chaperones (calnexin, calreticulin, BiP, glucose-regulated protein 94-kd) and belonged to the ER but were distinct from the peptide-loading complex (PLC). Similar vesicles were observed in immune cells from HLA–B27+ SpA patients, in greater abundance than in healthy controls (P < 0.01), and in dendritic cells from HLA–B27/hβ2m transgenic rats, correlating with SpA susceptibility. Conclusion: Accumulation of misfolded HLA–B heavy chain along with β2m and ER chaperones into ER-derived vesicles distinct from the PLC is a characteristic feature of HLA–B27 subtypes predisposing to SpA. This phenomenon could contribute to HLA–B27 pathogenicity, via a noncanonical mechanism.

Background:Treat-to-target in axial spondyloarthritis (axSpA) aims to achieve and maintain clinical remission/inactive disease or alternatively, low disease activity [1]. However, there is no consensual definition of remission in axSpA: the T2T international task force has proposed Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease, but this definition is not widely accepted [1, 2].Objectives:To explore rheumatologists’ perception of remission in axSpA, using vignette cases and a priority exercise.Methods:A steering group of 7 rheumatologists designed a national cross-sectional survey during two face-to-face meetings in 2019-2020. The survey comprised 36 vignette cases: fixed elements included the clinical picture (34 year-old-male with confirmed axSpA, normal C-reactive protein (CRP), without synovitis, enthesitis, dactylitis or extra-articular manifestations) and there were 3 varying parameters (axial pain (0-10) [ranging 2 to 5], fatigue (0-10) [2 to 8], and morning stiffness [Results:Overall, 200 French rheumatologists participated between June and September 2020. Out of 2,400 vignette evaluations (mean of 66 evaluations per vignette), 463 (19%) were classified as remission by rheumatologists. Six vignette cases constituted 56% of all remission cases (Figure 1): these comprised a short duration of morning stiffness (In priority ratings, 4 items were selected as important by 68-75% of rheumatologists: morning stiffness and axial pain (both included in the vignettes), as well as extra-articular manifestations and NSAID use, whereas only 18% selected fatigue. BASDAI was cited as the 1st priority criteria by 24% of rheumatologists and ASDAS as the 2nd by 16% of rheumatologists.Figure 1.Frequencies of the declared remission states by rheumatologists for each of the 36 vignette casesConclusion:Morning stiffness, axial pain, NSAIDs use, and extra-articular manifestations seem to impact the physicians’ perception of remission in axSpA, whereas fatigue has less impact on remission for rheumatologists. Consensus is needed on remission in axSpA.References:[1Smolen JS et al. Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. Ann Rheum Dis 2018;77:3–17.[2]Wendling D et al. 2018 update of French Society for Rheumatology (SFR) recommendations about the everyday management of patients with spondyloarthritis. Joint Bone Spine 2018;85:275–84.Funding:This study was funded and organized by Novartis FranceDisclosure of Interests:Krystel Aouad: None declared, Daniel Wendling: None declared, Anne BAGLIN Employee of: Novartis, Maxime Breban: None declared, sabrina DADOUN: None declared, Christophe Hudry: None declared, Anna Moltó: None declared, Edouard Pertuiset: None declared, Laure Gossec: None declared

Objectives Radiographic sacroiliitis is an important outcome in SpA and is considered a hallmark to ascertain the diagnosis of AS. The aim of the current study was to investigate factors associated with the presence of radiographic sacroiliitis at baseline and the predictors of progression to AS in a family cohort of SpA. Methods A total of 953 patients fulfilling the Assessment of SpondyloArthritis international Society criteria for SpA and having at least one first- or second-degree SpA-affected relative were included. Pelvic X-rays were examined blindly and independently by two qualified examiners using the modified New York criteria. Of the 446 cases without definite sacroiliitis at inclusion, 145 patients were followed up with new pelvic X-rays for 3-15 years. Regression analysis was used to assess factors associated with definite radiographic sacroiliitis. Results Factors independently associated with radiographic sacroiliitis at inclusion were male sex, younger age at disease onset, longer disease duration, inflammatory back pain, uveitis and lack of enthesitis. During the follow-up, 27.3% of the patients with axial SpA developed definite sacroiliitis, whereas there was no progression in patients with peripheral SpA. After 15 years of follow-up, a Kaplan-Meier estimate of the proportion of patients with definite radiographic sacroiliitis reached 68.5%. Factors associated with progression to definite sacroiliitis were a low-grade radiographic sacroiliitis at inclusion, occurrence of buttock pain and the absence of peripheral arthritis during the follow-up period. Conclusions These data confirm that progression to radiographic disease occurs most often over time in axial SpA patients.

Resume Objectifs Estimer le nombre de patients presentant une spondyolarthrite (SpA) grave en France, decrire leurs comorbidites et consigner et valoriser leur consommation de soins. Methodes Les donnees ont ete extraites de l’Echantillon generaliste des beneficiaires qui couvre 1/97e des personnes couvertes par l’assurance maladie en France. Tous les patients beneficiant d’une prise en charge a 100 % (ALD, affection de longue duree) au titre d’une SpA grave en 2012 (y compris ceux presentant des dommages structuraux et/ou des poussees frequentes) ont ete identifies et un groupe temoin apparie par frequence selon l’âge et le sexe a ete selectionne. Les comorbidites severes ont ete documentees selon les categories de l’ALD. La consommation de soins a ete consignee et valorisee du point de vue de l’organisme payeur. Les taux de comorbidites et les couts ont ete compares entre les patients atteints de SpA et les temoins par une methode de test non parametrique. Resultats Au total, 827 patients admis en ALD au titre d’une SpA grave ont ete identifies (groupe temoin n = 2 481), soit un taux de prevalence de la SpA en ALD de 0,18 % [0,17–0,19] dans la population generale. Les comorbidites severes plus frequentes chez les patients atteints de SpA que chez les temoins comprenaient : maladies inflammatoires chroniques de l’intestin (Odds Ratio 15,0 [2,2–6,6–36], hypertension (2,5 [1,6–3,9]), fibrillation auriculaire (4,3 [1,6,9]) et trouble depressif majeur (2,1 [1,3,6]). La depense de sante directe moyenne annuelle per capita etait 3,6 [1–3,3,4] fois plus elevee chez les patients atteints de SpA (6122 € [5838–6406]) que chez les temoins (1682 € [1566–1798]). L’extrapolation de ces chiffres a l’ensemble des patients en France aboutit a un cout total de soins attribuables aux SpA graves de 391 millions € [355–426], dont 53,8 % pour les medicaments. Conclusions Le fardeau considerable des spondyloarthrites graves en France resulte de la forte prevalence de cette maladie, des couts directs eleves et des comorbidites associees.

The human leucocyte antigen (HLA)-B27 confers an increased risk of spondyloarthritis (SpA) by unknown mechanism. The objective of this work was to uncover HLA-B27 non-canonical properties that could explain its pathogenicity, using a newWe produced transgenicLoss of crossveins in the wings and a reduced eye phenotype were observed after expression of HLA-B*27:04 or HLA-B*27:05 inAntagonistic interaction of HLA-B27 with ALK2, which exerts inhibitory functions on the TGFβ/BMP signalling pathway at the cross-road between inflammation and ossification, could adequately explain SpA development.

Background The course of axial spondyloarthritis (SpA) is heterogeneous, varying from mild to severe and remains to be better defined. DESIR is a French cohort of early undifferentiated axial SpA that are longitudinally followed-up, offering such opportunity. We recently performed a cluster analysis in the DESIR cohort, according to baseline characteristics and identified 2 clusters: one characterized by an isolated axial disorder (A for axial) and one by additional high frequency of peripheral manifestations (B for both)1. Those cluster-based SpA phenotypes could correspond to different levels of disease severity. Objectives To assess whether cluster-based SpA phenotypes defined at baseline are conserved over time and might predict disease outcome at follow-up. Methods We analysed longitudinal data from the 586 patients who completed all follow-up visits until 5-year (mo 6, 12, 18, 24, 36, 48 and 60) out of the 679 patients included in the DESIR cohort used to define clusters at baseline. We performed a linear mixed-effect analysis for quantitative variables (using lme4 R package) and a generalized linear mixed-effect analysis for qualitative variables (using glmer R package) with cluster and follow-up visits as fixed effects and subjects as random effect. P-values were obtained by likelihood ratio tests of the full model with cluster against the model without cluster as fixed effects. Results Over the time, both clusters continued to show sustainable consistent differences characterized by higher frequency of peripheral involvement, higher disease activity, worse patient-reported outcome, higher frequency of conventional DMARDs and TNF blockers usage in cluster B, and higher frequency of radiographic and MRI sacroiliitis at 2 and 5 years in cluster A (Table). Conclusion Cluster-based SpA phenotypes defined at baseline in the DESIR cohort were predictive of severity outcome after 5 years. Patients from cluster A were more prone to develop sacroiliitis despite lower disease activity over the time, whereas those from cluster B had poorer clinical outcome and higher need for conventional DMARDs and TNF blockers. Reference [1] Costantino F, Aegerter P, Dougados M, Breban M, D’Agostino M-A. Two Phenotypes Are Identified by Cluster Analysis in Early Inflammatory Back Pain Suggestive of Spondyloarthritis: Results From the DESIR Cohort. Arthritis & Rheumatology (Hoboken, NJ). 2016;68(7):1660–8. Disclosure of Interests Felicie Costantino: None declared, Philippe Aegerter: None declared, Anna Molto: None declared, Maxime Breban Grant/research support from: Pfizer, UCB, Novartis, MSD, Consultant for: UCB, Maria-Antonietta d’Agostino: None declared

Background The class I MHC allele, HLA-B27 is the main genetic factor predisposing to ankylosing spondylitis (AS) and related spondyloarthritis (SpA), a group of osteo-articular disorders combining inflammation with ossification. Until now, hypotheses to explain such striking association discovered 45 years have speculated either on the presentation of particular peptides to CD8+ T cells or on aberrant behaviors of the HLA-B27 molecule independent of its antigen presenting function, including slow folding and homodimers formation Objectives To unravel aberrant function(s) of HLA-B27 independent of antigen presentation that may explain its pathogenicity. Methods Drosophila transgenic for SpA-associated HLA-B*27:04 or HLA-B*27:05 or non-SpA -associated HLA-B*07:02, alone or in combination with human β2-microglobulin (hβ2m) were produced. Genetic interaction tests were used to identify altered pathway(s). Protein-protein interactions were evidenced by proximity ligation assay. Phosphorylation of Smad2/3 was tested on CD4+ T cells from HLA-B27+ SpA patients and HLA-B27-neg healthy controls (6-10/group) by PhosFlow. Results Drosophila transgenic for HLA-B*27:04 or HLA-B*27:05 but not for control HLA-B*07:02 allele, in the presence of hβ2m that allows expression of well-folded HLA-B molecules at the cell surface, developed crossveinless phenotype. This was due to a disturbance of BMP signaling by HLA-B27/hβ2m which repressed Saxophone (Sax) BMP type I receptor (BMPR1) function, resulting in widening of phosphorylated Mad, the Drosophila receptor-mediated Smad, gradient, and increased expression of its target genes dpp and omb. Consistently, HLA-B27/hβ2m well-folded conformers co-localized with Sax at the surface of Drosophila cells and also with Sax mammal ortholog ALK2, on immune cells from SpA patients. As predicted, given that Sax orthologs ALK1 and ALK2 are known to exert antagonistic function on TGFβ/BMP signaling, we found heighthened p-Smad in response to TGFβ or Activin A in CD4+ T cells from HLA-B27+ SpA patients (p Conclusion The pathogenic role of HLA-B27 in SpA may result from a TGFβ/BMP signaling misregulation due to specific antagonistic interaction with ALK1/ALK2 BMPR1, at the crosstalk between inflammation and ossification. Interestingly, ALK2 mutations are responsible for the rare mendelian disorder, Fibrodysplasia Ossifians Prgogressiva that mimicks AS (Ref). References [1] Hatsell, S. J. et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin. Science Translational Medicine7, 303ra137-303ra137 (2015). Disclosure of Interests Benjamin Grandon: None declared, Auroe Rincheval: None declared, Nadege Jah: None declared, Jean-Marc Corsi: None declared, Luiza M. Araujo: None declared, Simon Glatigny: None declared, Delphine Roche: None declared, Gilles Chiocchia: None declared, Isabelle Guenal: None declared, Sebastein Gaumer: None declared, Maxime Breban Grant/research support from: Pfizer, UCB, Novartis, MSD, Consultant for: UCB