Reduced expression of miRNAs as potential biomarkers in axial spondyloarthritis.

OBJECTIVE: This study aimed to investigate the value of miR-29a-3p, miR-27a, miR126-3p, miR-146a-5p, miR-625-3p, miR-130a, miR-32, miR-218, miR-131, and miR5196 in the diagnosis of axial spondyloarthritis and to determine whether there is a difference in miRNA expression levels between radiographic axial spondyloarthritis and non-radiographic axial spondyloarthritis, as well as the relationship between miRNA expression levels, disease activity, and uveitis history. METHODS: This study included 50 patients with axial spondyloarthritis (25 with radiographic axial spondyloarthritis and 25 with non-radiographic axial spondyloarthritis) and 25 healthy individuals. The fold change of miRNA expression for each miRNA was calculated using the 2-ΔΔCt method. RESULTS: The expression of all miRNAs except miR-130a was downregulated in axial spondyloarthritis patients (miR-27a: fold regulation: -11.21, p<0.001; miR-29a-3p: fold regulation: -2.63, p<0.001; miR-32: fold regulation: -2.94, p=0.002; miR-126-3p: fold regulation -10.94, p<0.001; miR-132: fold regulation: -2.18, p<0.001; miR-146-5p: fold regulation: -9.78, p<0.001; miR-218: fold regulation: -2.65, p<0.001; miR-625-3p: fold regulation: -2.01, p=0.001; miR-5196-3p: fold regulation: -7.04, p<0.001). The expression levels of these miRNAs did not differ significantly between non-radiographic axial spondyloarthritis and radiographic axial spondyloarthritis patients (p>0.05 for all). CONCLUSION: Particularly, miR-27a, miR-126-3p, miR-146-5p, and miR-5196-3p were found to be substantially downregulated in both non-radiographic axial spondyloarthritis and radiographic axial spondyloarthritis patients, suggesting their potential as diagnostic biomarkers for axial spondyloarthritis.

[HLA genotypes associated with gastrointestinal symptoms in patients with spondyloarthritis without inflammatory bowel disease]. / Genotipos HLA asociados a síntomas gastrointestinales en pacientes con espondiloartritis sin enfermedad inflamatoria intestinal.

OBJECTIVE: This study aimed to establish the association between HLA-A, B, DR genotypes and gastrointestinal variables in patients with SpA without inflammatory bowel disease (IBD). METHODS: Retrospective study of 91 patients with SpA and 401 healthy controls, with typing by Illumina Sequencing/PacBio and LIFECODES HLA-PCR/SSO multiplex sequencing technology. The presence of gastrointestinal symptoms was evaluated by administering a survey, and those who presented 2 or more symptoms were taken for clinical evaluation by rheumatology and gastroenterology, colonoscopy and histopathological study. (Ethics committee approval). RESULTS: The 59,3% of the patients were men, with a mean age of 43,9±11.4 years; 80,2% were classified as ankylosing spondylitis. 14, 28 and 19 genotypes for the HLA-A*, HLA-B* and HLA-DR* loci were identified in both groups, of which a relationship with gastrointestinal symptoms was identified: A*26, A*29 and B*27 were associated to abdominal pain, DRB1*11 and DRB1*16 with abdominal distention, A*30, B*38, DRB1*13 and DRB1*14 with weight loss, B*40 with diarrhea >4 weeks, and presence of mucus in the stools with A*02 and DRB1*11 (p<0.05). Furthermore, the presence of B*15 had a statistical relationship with intolerance to some food, highlighting the B*27 genotype in relation to grains and dairy products, A*23 with grains, vegetables and meats, and B*49 with vegetables and dairy (p<0.05). Regarding the endoscopic variables, macroscopic changes were found in the ileum mucosa related to A*02, B*48, DRB1*14 and the relationship between B*27 and ulcers at this level should be highlighted. Macroscopic changes in the sigmoid colon with B*48 and the rectum with A*30. In microscopic changes, inflammatory alterations of the ileum are mentioned with genotypes DRB1*07, DRB1*13 and DRB1*14, a genotype that is related to changes in the ileum both endoscopically and histologically (p<0.05). CONCLUSIONS: These findings indicate a potential genetic predisposition related to HLA genotypes that may increase the likelihood of food intolerance, gastrointestinal symptoms, and even visible and microscopic changes, specifically in the ileal tissue. The study highlights the presence of B*27 and other noteworthy HLA class I and class II genes (such as DRB1*14) in the diverse Colombian population.

OBJETIVO: Establecer la asociación entre genotipos HLA-A, B, DR y variables gastrointestinales en pacientes con EspA, sin enfermedad inflamatoria intestinal (EII). MÉTODOS: Estudio retrospectivo de 91 pacientes con EspA y 401 controles sanos, con tipificación por tecnología de secuenciación Illumina Sequencing/PacBio, y LIFECODES HLA-PCR/SSO multiplex. Se evaluó la presencia de síntomas gastrointestinales por aplicación de una encuesta, y, aquellos que presentaran dos o más síntomas, fueron llevados a valoración clínica por reumatología y gastroenterología, colonoscopia y estudio histopatológico. (Aprobación del Comité de Ética, HMC, 2022 - 2020). RESULTADOS: El 59,3% de los pacientes fueron hombres, con edad media de 43,9 ± 11,4 años. El 80,2% se clasificó como espondilitis anquilosante. Se identificaron en ambos grupos 14, 28 y 19 genotipos para los loci HLA-A*, HLA-B* y HLA-DR*, de los cuales se identificó relación con síntomas gastrointestinales: A*26, A*29 y B*27, con dolor abdominal; DRB1*11 y DRB1*16, con distensión abdominal; A*30, B*38, DRB1*13 y DRB1*14, con pérdida de peso; B*40, con diarrea >4 semanas y presencia de moco en las deposiciones con A*2 y DRB1*11 (p<0,05). Además, la presencia de B*15, tuvo relación estadística con intolerancia a algún tipo de alimento, a resaltar el genotipo B*27, en relación con granos y lácteos; A*23 con granos, verduras y carnes; y el B*49, con verduras y lácteos (p<0,05). Frente a las variables endoscópicas, se encontraron cambios macroscópicos en la mucosa de íleon relacionados con A*02, B*48, DRB1*14 y, a destacar, la relación B*27 con úlceras a este nivel. Cambios macroscópicos en colon sigmoides con B*48 y en recto con A*30. En cambios microscópicos, se mencionan alteraciones inflamatorias de íleon con genotipos DRB1*07, DRB1*13 y DRB1*14, genotipos que se relaciona a cambios en íleon tanto endoscópica e histológicamente (p<0,05). CONCLUSIONES: Estos resultados sugieren una posible susceptibilidad genética asociada al HLA, con genotipos que pueden predisponer a intolerancia alimentaria, síntomas gastrointestinales, e incluso, a cambios macroscópicos e histológicos, particularmente en tejido de íleon, entre los cuales está presente el B*27, pero resaltan otros interesantes en HLA clase I, como clase II (DRB1*14), en una población de alto mestizaje como la colombiana.

Investigation of the acute pathogenesis of spondyloarthritis/HLA-B27-associated anterior uveitis based on genome-wide association analysis and single-cell transcriptomics.

BACKGROUND: Patients with spondyloarthritis (SpA)/HLA-B27-associated acute anterior uveitis (AAU) experience recurring acute flares, which pose significant visual and financial challenges. Despite established links between SpA and HLA-B27-associated AAU, the exact mechanism involved remains unclear, and further understanding is needed for effective prevention and treatment. METHODS: To investigate the acute pathogenesis of SpA/HLA-B27-associated AAU, Mendelian randomization (MR) and single-cell transcriptomic analyses were employed. The MR incorporated publicly available protein quantitative trait locus data from previous studies, along with genome-wide association study data from public databases. Causal relationships between plasma proteins and anterior uveitis were assessed using two-sample MR. Additionally, colocalization analysis was performed using Bayesian colocalization. Single-cell transcriptome analysis utilized the anterior uveitis dataset from the Gene Expression Omnibus (GEO) database. Dimensionality reduction, clustering, transcription factor analysis, pseudotime analysis, and cell communication analysis were subsequently conducted to explore the underlying mechanisms involved. RESULTS: Mendelian randomization analysis revealed that circulating levels of AIF1 and VARS were significantly associated with a reduced risk of developing SpA/HLA-B27-associated AAU, with AIF1 showing a robust correlation with anterior uveitis onset. Colocalization analysis supported these findings. Single-cell transcriptome analysis showed predominant AIF1 expression in myeloid cells, which was notably lower in the HLA-B27-positive group. Pseudotime analysis revealed dendritic cell terminal positions in differentiation branches, accompanied by gradual decreases in AIF1 expression. Based on cell communication analysis, CD141+CLEC9A+ classic dendritic cells (cDCs) and the APP pathway play crucial roles in cellular communication in the Spa/HLA-B27 group. CONCLUSIONS: AIF1 is essential for the pathogenesis of SpA/HLA-B27-associated AAU. Myeloid cell differentiation into DCs and decreased AIF1 levels are also pivotal in this process.

Sequence of Events in the Pathogenesis of Axial Spondyloarthritis: A Current Review-2023 SPARTAN Meeting Proceedings.

PURPOSE OF REVIEW: Over the past two decades, significant progress has been made to untangle the etiology of inflammation and new bone formation (NBF) associated with axial spondyloarthritis (axSpA). However, exact mechanisms as to how the disease initiates and develops remain elusive. RECENT FINDINGS: Type 3 immunity, centered around the IL-23/IL-17 axis, has been recognized as a key player in the pathogenesis of axSpA. Multiple hypotheses associated with HLA-B*27 have been proposed to account for disease onset and progression of axSpA, potentially by driving downstream T cell responses. However, HLA-B*27 alone is not sufficient to fully explain the development of axSpA. Genome-wide association studies (GWAS) identified several genes that are potentially relevant to disease pathogenesis leading to a better understanding of the immune activation seen in axSpA. Furthermore, gut microbiome studies suggest an altered microbiome in axSpA, and animal studies suggest a pathogenic role for immune cells migrating from the gut to the joint. Recent studies focusing on the pathogenesis of new bone formation (NBF) have highlighted the importance of endochondral ossification, mechanical stress, pre-existing inflammation, and activated anabolic signaling pathways during the development of NBF. Despite the complex etiology of axSpA, recent studies have shed light on pivotal pieces that could lead to a better understanding of the pathogenic events in axSpA.

Causal association of gut microbiota on spondyloarthritis and its subtypes: a Mendelian randomization analysis.

Background: Despite establishing an association between gut microbiota and spondyloarthritis (SpA) subtypes, the causal relationship between them remains unclear. Methods: Gut microbiota data were obtained from the MiBioGen collaboration, and SpA genome-wide association study (GWAS) summary data were obtained from the FinnGen collaboration. We conducted a two-sample Mendelian randomization (MR) analysis using the inverse-variance-weighted method supplemented with four additional MR methods (MR-Egger, weighted median, simple mode, and weighted mode). Pleiotropy and heterogeneity were also assessed. Reverse MR analysis was used to detect reverse causal relationships. Results: We identified 23 causal links between specific gut microbiota taxa and SpA levels. Of these, 22 displayed nominal causal associations, and only one demonstrated a robust causal connection. Actinobacteria id.419 increased the risk of ankylosing spondylitis (AS) (odds ratio (OR) = 1.86 (95% confidence interval (CI): 1.29-2.69); p = 8.63E-04). The family Rikenellaceae id.967 was associated with a reduced risk of both AS (OR = 0.66 (95% CI: 0.47-0.93); p = 1.81E-02) and psoriatic arthritis (OR = 0.70 (95% CI: 0.50-0.97); p = 3.00E-02). Bacillales id.1674 increased the risk of AS (OR = 1.23 (95% CI: 1.00-1.51); p = 4.94E-02) and decreased the risk of enteropathic arthritis (OR = 0.56 (95% CI: 0.35-0.88); p = 1.14E-02). Directional pleiotropy, or heterogeneity, was not observed. No reverse causal associations were observed between the diseases and the gut microbiota. Conclusion: Our MR analysis suggested a genetic-level causal relationship between specific gut microbiota and SpA, providing insights into the underlying mechanisms behind SpA development mediated by gut microbiota.

How to translate genetic findings into clinical applications in spondyloarthritis?

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.

Mendelian randomization analysis reveals causal associations of inflammatory bowel disease with Spondylarthritis.

OBJECTIVE: Inflammatory bowel disease (IBD) is strongly associated with Spondylarthritis (SpA), but the causal relationship remains unclear. This study explores the causal associations between IBD (Crohn's disease [CD] and ulcerative colitis [UC]) and several common subtypes of SpA (Ankylosing Spondylitis [AS], Psoriatic Arthritis [PsA], and Reactive Arthritis [ReA]), using bidirectional two-sample Mendelian randomization (TSMR). METHODS: The causal effects of genetically predicted IBD on AS, PsA, and ReA were firstly investigated in this forward study. The causal effects from AS, PsA, and ReA on IBD were analyzed in the reverse MR. Inverse variance weighted, weighted median, and MR-Egger were applied in the MR analyses. The pleiotropic effects, heterogeneity, and leave-one-out sensitivity analysis were also evaluated. RESULTS: The forward MR analysis demonstrated that IBD increased risk for AS (OR:1.278; P = 1.273 × 10-5), PsA (OR:1.192; P = 1.690 × 10-5), and ReA (OR:1.106; P = 1.524 × 10-3). Among them, CD increased risk of AS (OR:1.196; P = 3.424 × 10-4), PsA (OR:1.101; P = 1.537 × 10-3), ReA (OR:1.079; P = 6.321 × 10-3) whereas UC increased risk of AS (OR:1.166; P = 2.727 × 10-2), PsA (OR:1.110; P = 1.944 × 10-2), and ReA (OR:1.091; P = 1.768 × 10-2). The reverse-direction MR disclosed no notable association; neither was any evidence of pleiotropy detected. CONCLUSION: Our study verifies a causal effect of IBD to AS, PsA as well as ReA, but not vice versa. This might bring new insights for the management of IBD and SpA in clinical practice.

[The role of HLA-B27 in the pathogenesis and diagnosis of axial spondyloarthritis : 50 years after discovery of the strong genetic association]. / Zur Rolle von HLA-B27 in der Pathogenese und Diagnostik der axialen Spondyloarthritis : 50 Jahre nach Entdeckung der starken genetischen Assoziation.

BACKGROUND: The association of the human lymphocyte antigen B27 (HLA-B27) with ankylosing spondylitis (AS), also now called axial spondylarthritis (axSpA), was first described 50 years ago. OBJECTIVE: This article gives an overview of the available knowledge on the topic. MATERIAL AND METHODS: This is a narrative review based on the experience of the authors. RESULTS: The HLA-B27 is a member of the HLA class I family of genes of the major histocompatibility complex (MHC). The prevalence of HLA-B27 in the central European population is approximately 8 %, i.e., the vast majority of carriers of HLA-B27+ remain healthy. The frequency of HLA-B27 shows a decline from north to south. The HLA-B27 explains only 30 % of the genetic burden of axSpA. The prevalence of the disease correlates with the frequency of HLA-B27 in the population, i.e., there are geographic differences. Approximately 60-90 % of patients with axSpA worldwide are HLA-B27+. Some 200 subtypes of HLA-B27 can be differentiated using the polymerase chain reaction (PCR). In Thailand and Sardinia two subtypes were found that are not associated with axSpA. The physiological function of HLA class I molecules is the defence of the organism against microbes. Microbial peptides are presented to the immune system, which can be specifically attacked by CD8+ T­cells. Genetic polymorphisms of the enzyme endoplasmic reticulum aminopeptidase 1 (ERAP1), which breaks down peptides in the endoplasmic reticulum, are associated only with HLA-B27+ diseases. DISCUSSION: The pathogenesis of axSpA is unclear but a major hypothesis is that of the arthritogenic peptides. In this it is assumed that potentially pathogenic foreign or autologous peptides can be presented by HLA-B27. If nothing else, HLA-B27 plays an important role in the diagnosis, classification and determination of the severity of axSpA.

Causal relationship between spondylarthritis and stroke in a European population: a two sample Mendelian randomization study.

Background: Observational studies have found an increased risk of stroke in patients with spondyloarthritis, but the results are susceptible to reverse causality and confounders. Therefore, the study aimed to further explore the association between spondyloarthritis and different subtypes of stroke by using a two sample Mendelian randomization (MR) analysis. Methods: Genetic instrumental variables for spondyloarthritis were identified using summary level data from a genome-wide association study involving 201,581 people. Summary statistics from the Multiancestry Genome-wide Association Study of Stroke Consortium were used to obtain genetic data on stroke. There was no sample overlap between the exposure and outcome datasets. Inverse-variance weighted was considered the primary MR method for causal analysis. Heterogeneity, pleiotropy and sensitivity analyses were performed to ensure robustness, and single nucleotide polymorphism (SNP) with potential confounders was further screened in the PhenoScanner database to better evaluate the stability of our study. Results: One SNP (rs1065045) was excluded due to schizophrenia. After excluding SNP (rs1065045), results of the second MR analysis were slightly different from the first, which were considered as the final result: a significant positive causality between spondyloarthritis and cardioembolic stroke (OR=1.296, 95% CI:1.094-1.534, p=0.003); a possible positive causality between spondyloarthritis and any stroke (OR=1.082, 95% CI:1.016-1.152, p=0.013)/any ischemic stroke (OR=1.086, 95% CI:1.013-1.163, p=0.020); no significant/possible causality between spondyloarthritis and small vessel stroke (OR=1.168, 95% CI:0.993-1.375, p=0.061). Insufficient power may be one possible reason why a causality was not observed between spondyloarthritis in our study. Conclusions: This study suggests that the possible causative effects of spondyloarthritis predicted by genetics on stroke may be limited to any stroke, any ischemic stroke, and cardioembolic stroke, especially the last.

HLA-B27, axial spondyloarthritis and survival.

INTRODUCTION: Ankylosing spondylitis (AS), and carriage of HLA-B27 gene in otherwise healthy individuals, are reportedly associated with increased mortality. We evaluated this hypothesis, using data from both a 35-year AS follow-up study and UK Biobank data. METHODS: In 1985, 363 members of the Swiss AS Patient Society and 806 relatives were screened clinically and then radiographically for AS/axial spondyloarthritis (axSpA). Life expectancy was analysed in 377 axSpA patients having available pelvic radiographs and HLA-B27 status, comparing with matched Swiss population data. Survival in relation to HLA-B27 status in the general population was studied in UK Biobank European-ancestry participants (n=407 480, n=30 419 deaths). RESULTS: AS patients have increased standardised mortality rate (SMR) compared with the general population (1.37, 95% CI 1.11 to 1.62). This increase was significant for HLA-B27-positive AS (SMR 1.38, 95% CI 1.11 to 1.65). Shortened life expectancy was observed among both HLA-B27-positive AS women (SMR 1.77, 95% CI 1.09 to 2.70) and men (SMR 1.31, 95% CI 1.02 to 1.59). Patients with non-radiographic axSpA (nr-axSpA) had significantly lower SMR: 0.44 (95% CI 0.23 to 0.77), compared with the general population. In the UK Biobank European-ancestry population cohort, HLA-B27 carriage was not significantly associated with any change in mortality (HR 1, 95% CI 0.97 to 1.1, p=0.349, adjusted by sex), in either males (HR 1, 95% CI 0.98 to 1.1, p=0.281) or females (HR 0.96, 95% CI 0.9 to 1, p=0.232), and no increase in vascular disease mortality was observed. DISCUSSION: AS patients, but not nr-axSpA patients, have a significantly shortened life expectancy. Increased mortality is particularly significant among women with HLA-B27-positive AS. HLA-B27 carriage in the European-ancestry general population does not influence survival, or the risk of death due to vascular disease.

Transcriptome-wide association study identifies new susceptibility genes and pathways for spondyloarthritis.

BACKGROUND: Spondyloarthritis (SpA) is a group of multifactorial bone diseases influenced by genetic factors, the environment and lifestyle. However, current studies have found a limited number of SpA-related genes, and the genetic and pathogenic mechanisms of SpA are still unclear. METHODS: A tissue-specific transcriptome-wide association study (TWAS) of SpA was performed using GWAS (including 3966 SpA patients and 448,298 controls) summary data and gene expression weights of whole blood and skeletal muscle. The SpA-associated genes identified by TWAS were further compared with the differentially expressed genes (DEGs) identified in the SpA gene expression profile acquired from the Gene Expression Omnibus database (GEO, GSE58667). Finally, functional enrichment and annotation analyses of the identified genes were performed. RESULTS: The TWAS detected 499 suggestive genes associated with SpA in whole blood and skeletal muscle, such as CTNNAL1 (PSM = 3.04 × 10-2, PWB = 9.58 × 10-3). The gene expression profile of SpA identified 20 candidate genes that overlapped in the TWAS data, such as MCM4 (PTWAS = 1.32 × 10-2, PDEG = 2.75 × 10-2) and KIAA1109 (PTWAS = 3.71 × 10-2, PDEG = 4.67 × 10-2). Enrichment analysis of the genes identified by TWAS identified 93 significant GO terms and 33 KEGG pathways, such as mitochondrion organization (GO: 0007005) and axon guidance (hsa04360). CONCLUSION: We identified multiple candidate genes that were genetically related to SpA. Our study may provide novel clues regarding the genetic mechanism, diagnosis, and treatment of SpA.

Emerging Concepts in Precision Medicine in Axial Spondyloarthritis.

PURPOSE OF REVIEW: Axial spondyloarthritis (AxSpA) is among the rheumatology's most heritable complex diseases, yet precision medicine at clinics still needs to be explored. We reviewed the emerging concepts and recent developments in polygenic risk scores, Mendelian randomization, pharmacogenomics, single-cell sequencing, and spatial transcriptomics. RECENT FINDINGS: Polygenic risk score has resulted in encouraging results with potential diagnostic utility as it appears to outperform current diagnostic tools. Its performance and generalizability vary with ethnicity. Mendelian randomization has elucidated multiple causal associations, particularly between inflammatory bowel disease and AxSpA. Single-cell transcriptomics (particularly scRNA-seq and scATAC-seq) has identified numerous cell types, including synovial and blood immunological cells, to understand the contribution of both innate and adaptative immunity in AxSpA. Current molecular tools provide an exciting opportunity to advance precision medicine for AxSpA patients. However, extensive research and implementation strategies are still required before they can have an impact in the clinic.

Clinical profile and treatment utilisation based on HLA-B*27 status in axial spondyloarthritis: results from ASAS-PerSpA study.

OBJECTIVE: We aimed to characterize differences of clinical features, extra-musculoskeletal manifestations and treatment utilizations based on the patients' HLA-B*27 status in a global axSpA cohort and identify predictors of HLA-B*27 negativity in these patients. METHODOLOGY: In post-hoc analysis of the ASAS-PerSpA study, patients fulfilling the 2009 ASAS classification criteria for axSpA and typed for HLA-B*27 were included. The patient characteristics cwere compared between the HLA-B*27(+) and HLA-B*27(-) subgroups. Multivariablete logistic regression was conducted to identify predictors of HLA-B*27 negativity. RESULTS: Of 2910 patients with axSpA from 24 countries, 2269 were tested for HLA-B*27 [1753 HLA-B*27(+) and 516 HLA-B*27(-)]. The proportion of males was higher in the HLA-B*27 (+) compared to the HLA-B*27 (-) subgroup (72.1 vs 54.3%). Patient population with HLA-B*27 (+) more often had positive family history for axSpA (29.8 vs 15.3%), and younger age at diagnosis, 31.6 years (SD 10.9) vs 37.7 years (SD 12.1). HLA-B*27 (-) patients had significantly higher peripheral arthritis (47.5 vs 42.1%, p<0.05), psoriasis (19.4 vs 10.2), enthesitis (56.6 vs 49.8%) and IBD (12.8 vs 3.4) (p<0.001). The exposure to csDMARDS in HLA-B*27 (-) patients was higher (61.2 vs 55.0%, p< 0.05). On multivariable analysis, HLA-B*27 (-) status was positively associated with enthesitis, psoriasis and IBD with an OR 1.27 (1.02-1.57), 1.84 (1.36-2.48) and 4.84 (3.23-7.30) respectively, and inversely associated with uveitis, OR 0.37 (0.27-0.50). CONCLUSION: HLA-B*27 (-) axSpA patients had a longer delay in diagnosis, more frequently had peripheral arthritis, enthesitis, IBD, psoriasis, and were more often treated with csDMARDs compared to HLA-B*27 (+) subgroup.

Family studies: A useful tool to better understand spondyloarthritis.

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.

HLA-B27 as a predictor of effectiveness of treatment with TNF inhibitors in axial spondyloarthritis: data from the Swiss Clinical Quality Management Registry.

OBJECTIVE: To explore the impact of the human leucocyte antigen (HLA)-B27 on the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). METHODS: A total of 1109 patients with available HLA-B27 status (831 B27+ patients and 278 B27- patients) fulfilling the Assessment of Spondyloarthritis international Society classification criteria for axSpA from the prospective Swiss Clinical Quality Management Registry initiating a first TNFi were included. Drug retention was investigated with multiple adjusted Cox proportional hazard models with imputation of missing values. Multiple-adjusted logistic regression analyses were used to assess the proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year. RESULTS: B27+ and B27- patients differed with regard to age, sex, BASDAI, C-reactive protein (CRP), body mass index, enthesitis, uveitis, and classification status. After adjustment for potential confounders for the relationship between HLA-B27 and drug effectiveness (sex and family history of spondyloarthritis), a higher risk of drug discontinuation was found in B27- patients (HR 1.53, 95% CI 1.27-1.83). This difference decreased after additional adjustment for parameters which may act as mediators (HR 1.30, 95% CI 1.30-1.55). Male sex and elevated C-reactive protein (CRP) levels were consistently associated with longer retention. Comparable results were obtained for BASDAI50 responses. CONCLUSION: The HLA-B27 genotype is an important predictor of treatment effectiveness. Male sex and CRP seem, however, to better describe variability of response in individual patients. This data may help avoiding potential discrimination of B27- individuals with regard to TNFi initiation. Key Points • HLA-B27 is a predictor of effectiveness of TNF inhibitors in axial spondyloarthritis. • Variability of response in individual patients is better defined by sex and objective markers of disease activity, such as C-reactive protein.

Both Disease Activity and HLA-B27 Status Are Associated With Gut Microbiome Dysbiosis in Spondyloarthritis Patients.

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.

TCR repertoire profiling revealed antigen-driven CD8+ T cell clonal groups shared in synovial fluid of patients with spondyloarthritis.

Spondyloarthritis (SpA) comprises a number of inflammatory rheumatic diseases with overlapping clinical manifestations. Strong association with several HLA-I alleles and T cell infiltration into an inflamed joint suggest involvement of T cells in SpA pathogenesis. In this study, we performed high-throughput T cell repertoire profiling of synovial fluid (SF) and peripheral blood (PB) samples collected from a large cohort of SpA patients. We showed that synovial fluid is enriched with expanded T cell clones that are shared between patients with similar HLA genotypes and persist during recurrent synovitis. Using an algorithm for identification of TCRs involved in immune response we discovered several antigen-driven CD8+ clonal groups associated with risk HLA-B*27 or HLA-B*38 alleles. We further show that these clonal groups were enriched in SF and had higher frequency in PB of SpA patients vs healthy donors, implying their relevance to SpA pathogenesis. Several of the groups were shared among patients with different SpAs that suggests a common immunopathological mechanism of the diseases. In summary, our results provide evidence for the role of specific CD8+ T cell clones in pathogenesis of SpA.

Peripheral spondyloarthritis and psoriatic arthritis sine psoriase: are we dealing with semantics or clinically meaningful differences?

Diagnosing peripheral spondyloarthritis (pSpA) remains a significant challenge due to the lack of specific disease biomarkers and the overlap with other SpA subtypes, mainly psoriatic arthritis (PsA), which represents a diagnostic challenge particularly in the absence of skin psoriasis (PsA sine psoriase). This narrative review aimed to compare the epidemiology, genetic susceptibility, pathophysiology, classification criteria, disease phenotype and burden, and therapeutic guidelines between patients diagnosed with pSpA and those with PsA sine psoriase, to determine if the two entities should be considered jointly or distinctly. Globally, pSpA appears to be more inclusive compared with PsA sine psoriase Areas of similarities include age of onset, number of joints involved and prevalence of axial involvement. However, patients with pSpA have a male gender predominance, a higher prevalence of HLA-B27, enthesitis and involvement of large joints of the lower limbs, whereas patients with PsA sine psoriase have a higher prevalence HLA-Cw6, dactylitis and involvement of hand distal interphalangeal joints. Therefore, the difference between pSpA and PsA sine psoriase goes beyond semantics. The few dissimilarities should drive scientific efforts to reach a better characterisation of pSpA as an individual disease. Accordingly, randomised clinical trials should target patients with well-defined pSpA to identify effective therapies in this population.