Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts.

Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leucocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesised the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms (SNPs) at genome-wide significance (p < 5 x 10-8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.

EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders.

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.

Prevalence of ultrasound and clinical findings suggestive of inflammatory arthritis in children with skin psoriasis.

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.

EULAR points to consider for minimal reporting requirements in synovial tissue research in rheumatology.

BACKGROUND: Synovial tissue research has become widely developed in several rheumatology centres, however, large discrepancies exist in the way synovial tissue is handled and, more specifically, how data pertaining to biopsy procedure, quality check and experimental results are reported in the literature. This heterogeneity hampers the progress of research in this rapidly expanding field. In that context, under the umbrella of European Alliance of Associations for Rheumatology, we aimed at proposing points to consider (PtC) for minimal reporting requirements in synovial tissue research. METHODS: Twenty-five members from 10 countries across Europe and USA met virtually to define the key areas needing evaluation and formulating the research questions to inform a systematic literature review (SLR). The results were presented during a second virtual meeting where PtC were formulated and agreed. RESULTS: Study design, biopsy procedures, tissue handling, tissue quality control and tissue outcomes (imaging, DNA/RNA analysis and disaggregation) were identified as important aspects for the quality of synovial tissue research. The SLR interrogated four databases, retrieved 7654 abstracts and included 26 manuscripts. Three OPs and nine PtC were formulated covering the following areas: description of biopsy procedure, overarching clinical design, patient characteristics, tissue handling and processing, quality control, histopathology, transcriptomic analyses and single-cell technologies. CONCLUSIONS: These PtC provide guidance on how research involving synovial tissue should be reported to ensure a better evaluation of results by readers, reviewers and the broader scientific community. We anticipate that these PtC will enable the field to progress in a robust and transparent manner over the coming years.

Cluster analysis in early axial spondyloarthritis predicts poor outcome in the presence of peripheral articular manifestations.

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.

Peripheral manifestations are major determinants of disease phenotype and outcome in new onset spondyloarthritis.

OBJECTIVES: To delineate the impact of peripheral musculoskeletal manifestations on stratification of disease phenotype and outcome in new-onset spondyloarthritis (SpA), using a prospective observational nationwide inception cohort, the BelGian Inflammatory Arthritis and spoNdylitis cohorT (Be-Giant). METHODS: Newly diagnosed adult SpA patients, fulfilling the Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral SpA, were included in Be-Giant and prospectively followed every six months. Peripheral involvement (defined as arthritis, enthesitis and/or dactylitis) was determined in relation to clinically similar patient subsets at baseline and disease activity patterns during two-year follow-up, identified through K-means cluster analysis and latent class growth analysis. RESULTS: From November 2010 to March 2020, 367 patients were enrolled in Be-Giant, of whom 162 (44%) had peripheral manifestations. Two patient clusters [A, axial predominant (n = 248) and B, peripheral predominant (n = 119)] were identified at diagnosis. Longitudinal analysis (n = 115) revealed two trajectories of disease activity in each cluster: one with persistently high disease activity over time ('High'), the other rapidly evolving to low disease activity ('Low'). In cluster A patients, peripheral manifestations predisposed to the 'High' trajectory [odds ratio (OR) = 2.0, 95% CI: 1.3, 3.1, P = 0.001], despite more rapid initiation of biologics compared with patients without peripheral manifestations (hazard ratio (HR) = 2.1, 95% CI: 1.0, 4.4, P = 0.04 - Cox proportional-hazards model). CONCLUSION: Peripheral musculoskeletal manifestations are major determinants of phenotypical diversity in new-onset SpA. Intriguingly, stratification of axial SpA according to concomitant peripheral involvement identified an endotype with an unfavorable outcome despite more prompt therapeutic intensification with biologics. These observations justify an endotype-tailored approach beyond current ASAS/EULAR management recommendations.

EULAR recommendations for the reporting of ultrasound studies in rheumatic and musculoskeletal diseases (RMDs).

OBJECTIVE: To produce European League Against Rheumatism (EULAR) recommendations for the reporting of ultrasound studies in rheumatic and musculoskeletal diseases (RMDs). METHODS: Based on the literature reviews and expert opinion (through Delphi surveys), a taskforce of 23 members (12 experts in ultrasound in RMDs, 9 in methodology and biostatistics together with a patient research partner and a health professional in rheumatology) developed a checklist of items to be reported in every RMD study using ultrasound. This checklist was further refined by involving a panel of 79 external experts (musculoskeletal imaging experts, methodologists, journal editors), who evaluated its comprehensibility, feasibility and comprehensiveness. Agreement on each proposed item was assessed with an 11-point Likert scale, grading from 0 (total disagreement) to 10 (full agreement). RESULTS: Two face-to-face meetings, as well as two Delphi rounds of voting, resulted in a final checklist of 23 items, including a glossary of terminology. Twenty-one of these were considered 'mandatory' items to be reported in every study (such as blinding, development of scoring systems, definition of target pathologies) and 2 'optional' to be reported only if applicable, such as possible confounding factors (ie, ambient conditions) or experience of the sonographers. CONCLUSION: An EULAR taskforce developed a checklist to ensure transparent and comprehensive reporting of aspects concerning research and procedures that need to be presented in studies using ultrasound in RMDs. This checklist, if widely adopted by authors and editors, will greatly improve the interpretability of study development and results, including the assessment of validity, generalisability and applicability.

Patient-based reliability of the Outcome Measures in Rheumatology (OMERACT) ultrasound scoring system for salivary gland assessment in patients with Sjögren's syndrome.

BACKGROUND: To assess the reliability of the consensually agreed US definitions of major salivary gland lesions and the US scoring system for salivary gland assessment in patients with SS. METHODS: Nine experienced sonographers scanned and read the US images of both parotid glands (PGs) and submandibular glands (SMGs) in eight patients with primary and secondary SS in two rounds. A consensually agreed four-grade semi-quantitative scoring was applied in B-mode for morphological lesions: grade 0, normal; grade 1, mild inhomogeneity without anechoic or hypoechoic areas; grade 2, moderate inhomogeneity with focal anechoic or hypoechoic areas; grade 3, severe inhomogeneity with diffuse an- or hypoechoic areas occupying the entire gland or fibrous gland. The presence or absence of typical SS lesions, i.e. the Sjögren's signature, was scored binary. Intra- and interreader reliabilities were computed using weighted and unweighted Cohen's and Light's κ coefficients. RESULTS: The mean prevalence of grades 0-3 in PG were 43, 17, 23 and 31% and 28, 14, 33 and 32% for the SMGs, respectively. The weighted κ for intrareader reliability ranged from 0.44 to 1 for grading and 0.64 to 1 for the Sjögren's signature of PG and 0.59 to 1 and -0.09 to 0.6 for SMGs, respectively. The interreader reliability κ for grading in PG was 0.62 (95% CI 0.47, 0.74) and for Sjögren's signature it was 0.36 (95% CI 0, 0.43); in SMG it was 0.62 (95% CI 0.47, 0.72) and 0.03 (95% CI 0, 0.07) respectively. CONCLUSIONS: The consensually agreed novel US scoring system for major salivary gland lesions showed substantial intra- and interreader reliability in patients with SS. The reliability of the Sjögren's signature was moderate.

A family-based genome-wide association study reveals an association of spondyloarthritis with MAPK14.

OBJECTIVE: More than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA. METHODS: 906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations. RESULTS: 43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1×10-4). In the extension studies, association was replicated at a nominal p value of p<0.05 for 16 SNPs in the second cohort and for three SNPs in the third cohort. Combined analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=3.5×10-7). Such association appeared to be independent of HLA-B27. CONCLUSIONS: We report here for the first time a family-based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association.

Radiographic sacroiliitis develops predictably over time in a cohort of familial spondyloarthritis followed longitudinally.

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.

Prevalence of ultrasound synovial inflammatory findings in healthy subjects.

OBJECTIVE: To evaluate the prevalence of joint inflammatory abnormalities and erosions detected by grey-scale and Doppler ultrasound (US) in the small joints of hands and feet in healthy subjects. METHODS: US of the dorsal surface of 32 joints (10 metacarpophalangeal, 10 proximal interphalangeal, 10 metatarsophalangeal (MTP) and 2 wrists) was performed in 207 healthy subjects without joint symptom. Synovial effusion (SE), synovial hypertrophy (SH) and power Doppler (PD) signal were scored using a semiquantitative grading scale (0-3) and erosion binary. RESULTS: One-hundred and eighty-two subjects had at least one US abnormality: 52% of the subjects had SE alone, 13% SH alone (5% with and 8% without PD) and 35% both SH and SE. US findings were detected in 9% of the total joints examined, mostly in the feet, and in particular in the MTP1 (33% of the positive joints). SE was the most frequently detected finding (68% of the positive joints), followed by SH (31%). Severity was mild (grade 1 in average) whatever the finding recorded (SH, SE or PD). Four erosions were detected (MTP1). CONCLUSIONS: This study describes for the first time, in a large cohort of healthy subjects, the prevalence and location of US signs of joint inflammation and of structural damage in small joints of hands and feet. US abnormalities were quite common, and mostly located in the feet. Further studies are needed to define which US components may allow to discriminate between pathological and physiological findings in the joints commonly affected by inflammatory arthritis conditions.

Whole-genome single nucleotide polymorphism-based linkage analysis in spondyloarthritis multiplex families reveals a new susceptibility locus in 13q13.

OBJECTIVE: Spondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. Apart from HLA-B27, most of the underlying genetic components remain to be identified. We conducted a whole-genome high-density non-parametric linkage analysis to identify new genetic factors of susceptibility to SpA. METHODS: 914 subjects including 462 with SpA from 143 multiplex families were genotyped using Affymetrix 250K microarrays. After quality control, 189 368 single nucleotide polymorphisms (SNPs) were kept for further analyses. Both non-parametric and parametric linkage analyses were performed using Merlin software. Association was tested with Unphased. RESULTS: Non-parametric linkage analysis identified two regions significantly linked to SpA: the major histocompatibility complex (LODmax=24.77) and a new 13q13 locus (LODmax=5.03). Additionally, eight loci achieved suggestive LOD scores, including the previously identified SPA2 locus at 9q33 (LODmax=3.51). Parametric analysis supported a codominant model in 13q13 with a maximum heterogeneity LOD, 'HLOD' score of 3.084 (α=0.28). Identification of meiotic recombination events around the 13q13 linkage peak in affected subjects from the 43 best-linked families allowed us to map the disease interval between 38.753 and 40.040 Mb. Family-based association analysis of the SNPs inside this interval in the best-linked families identified a SNP near FREM2 (rs1945502) which reached a p value close to statistical significance (corrected p=0.08). CONCLUSION: We report here for the first time a significant linkage between 13q13 and SpA. Identification of susceptibility factor inside this chromosomal region through targeted sequencing in linked families is underway.

Prevalence of spondyloarthritis in reference to HLA-B27 in the French population: results of the GAZEL cohort.

OBJECTIVE: To estimate the prevalence of spondyloarthritis (SpA) in reference to HLA-B27 in the French population. METHODS: In 1989, 20 625 employees of the French national gas and electricity company aged 35-50 years were enrolled in the GAZEL cohort. In 2010, 18 757 still active participants were screened by a questionnaire validated for the detection of SpA. Responders with available DNA were retained for further studies. Pelvic radiograph and HLA-B27 typing were performed in all the self-reported cases of SpA or psoriatic arthritis. Self-reported diagnosis was verified by a qualified rheumatologist. HLA-B27 determination was also performed in subjects without any SpA feature. RESULTS: The target population consisted of 6556 responders with available DNA. Their male:female ratio was 3.6 and their mean age was 65.5±3.3 years. A diagnosis of SpA was confirmed in 32 of the 72 self-reported cases, 75% of them being HLA-B27 positive. Estimated SpA prevalence adjusted for sex was 0.43% (95% CI 0.26% to 0.70%). HLA-B27 positivity rate in 2466 healthy controls was 6.9% (95% CI 5.9% to 7.9%). The relative risk of SpA in HLA-B27 positive individuals was 39 (95% CI 17 to 86). CONCLUSIONS: We estimated the prevalence of SpA in the French population in 2010 to 0.43%. With an estimated prevalence of 75.0% in SpA and 6.9% in healthy controls, HLA-B27 increased the disease risk 39-fold, as compared with HLA-B27 negative subjects.

Revisiting MHC genes in spondyloarthritis.

Spondyloarthritis (SpA) refers to a variety of inflammatory rheumatic disorders with strong heritability. Shared genetic predisposition, as shown by familial aggregation, is largely attributable to the major histocompatibility complex (MHC) locus, which was estimated to account for approximately half of the whole disease heritability. The first predisposing allele identified more than 40 years ago is HLA-B27, which is a major gene predisposing to all forms of SpA. However, despite intensive research, its pathogenesis remains uncertain. Other MHC alleles belonging to the class I and class II regions have been identified to exert additional effect. Candidate-gene approaches and genome-wide studies have recently allowed identification of several new loci residing outside of the MHC region that are involved in the predisposition to SpA. Interestingly, some of those new genes, such as ERAP1, ERAP2, and NPEPPS, code for aminopeptidases that are involved in MHC class I presentation and were shown to interact with HLA-B27.

Brief report: the IL23R nonsynonymous polymorphism rs11209026 is associated with radiographic sacroiliitis in spondyloarthritis.

OBJECTIVE: Spondyloarthritis (SpA) is a group of inflammatory articular disorders sharing a genetic background. The nonsynonymous single-nucleotide polymorphism (SNP) rs11209026 (Arg381Gln) in the IL23R gene has reproducibly been shown to be associated with ankylosing spondylitis (AS). We undertook this study to examine the association between rs11209026 and SpA as a whole, with particular attention devoted to genotype/phenotype correlation. METHODS: The SNP rs11209026 was genotyped in a French cohort of 415 patients/372 controls, with replication analysis performed in 383 "trios," each consisting of 1 patient with SpA and both parents. Association analysis was carried out in SpA as a whole group and then separately in AS and non-AS patients. Phenotype/genotype correlations were examined using logistic regression analysis. RESULTS: A significant association between rs11209026 and SpA overall was identified only in the familial data set (odds ratio 0.57, P=0.028). Strong association with AS was observed in both the case-control and familial data sets (P=4.5×10(-4) and P=4.0×10(-3), respectively). In contrast, such association was not detected in the non-AS group. Furthermore, rs11209026 frequency was significantly different between AS and non-AS patients (P=1.5×10(-3)). Phenotype/genotype correlation study revealed that both radiographic sacroiliitis and early age at onset were independently associated with a lower frequency of the rare protective rs11209026 allele A in patients (P=9×10(-3) and P=8×10(-3), respectively). CONCLUSION: Our study replicated the robust association between rs11209026 and AS in the French population. However, such association was restricted to AS, as compared to SpA without radiographic sacroiliitis. The fact that it was independently conditional on radiographic sacroiliitis and age at onset suggests that rs11209026 could affect disease severity rather than susceptibility.

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.

Unmet needs in axial spondyloarthritis. Proceedings of the French spondyloarthritis taskforce workshop.

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.