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.

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.

STAT1 deficiency underlies a proinflammatory imprint of naive CD4+ T cells in spondyloarthritis.

Introduction: In spondyloarthritis (SpA), an increased type 3 immune response, including T helper cells (Th) 17 excess, is observed in both human and SpA animal models, such as the HLA-B27/human ß2-microglobulin transgenic rat (B27-rat). Methods: To investigate this unexplained Th17-biased differentiation, we focused on understanding the immunobiology of B27-rat naive CD4+ T cells (Tn). Results: We observed that neutrally stimulated B27-rat Tn developed heightened Th17 profile even before disease onset, suggesting an intrinsic proinflammatory predisposition. In parallel with this observation, transcriptomic and epigenomic analyses showed that B27-rat Tn exhibited a decreased expression of Interferon/Th1- and increased expression of Th17-related genes. This molecular signature was predicted to be related to an imbalance of STAT1/STAT3 transcription factors activity. Stat1 mRNA and STAT1 protein expression were decreased before disease onset in Tn, even in their thymic precursors, whereas Stat3/STAT3 expression increased upon disease establishment. Confirming the relevance of these results, STAT1 mRNA expression was also decreased in Tn from SpA patients, as compared with healthy controls and rheumatoid arthritis patients. Finally, stimulation of B27-rat Tn with a selective STAT1 activator abolished this preferential IL-17A expression, suggesting that STAT1-altered activity in B27-rats allows Th17 differentiation. Discussion: Altogether, B27-rat Tn harbor a STAT1 deficiency preceding disease onset, which may occur during their thymic differentiation, secondarily associated with a persistent Th17 bias, which is imprinted at the epigenomic level. This early molecular phenomenon might lead to the persistent proinflammatory skew of CD4+ T cells in SpA patients, thus offering new clues to better understand and treat SpA.

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.

Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14+ monocytes and CD4+ and CD8+ T cells show disease-specific differences at the RNA level, epigenomic differences are only apparent upon multi-omics integration. The latter reveals enrichment at disease-associated loci in monocytes. We link putative functional SNPs to genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1, and show how disease-specific functional genomic data can be integrated with GWASs to enhance therapeutic target discovery. This study combines epigenetic and transcriptional analysis with GWASs to identify disease-relevant cell types and gene regulation of likely pathogenic relevance and prioritize drug targets.

Influenza-like illness in individuals treated with immunosuppressants, biologics, and/or systemic corticosteroids for autoimmune or chronic inflammatory disease: A crowdsourced cohort study, France, 2017-2018.

BACKGROUND: Influenza-like illness (ILI) incidence estimates in individuals treated with immunosuppressants and/or biologics and/or corticosteroid for an autoimmune or chronic inflammatory disease are scarce. We compared the ILI incidence among immunocompromised population and the general population. METHOD: We conducted a prospective cohort study during the 2017-2018 seasonal influenza epidemic, on the GrippeNet.fr electronic platform, which allows the collection of epidemiological crowdsourced data on ILI, directly from the French general population. The immunocompromised population were adults treated with systemic corticosteroids, immunosuppressants, and/or biologics for an autoimmune or chronic inflammatory disease, recruited directly on GrippeNet.fr and also among patients of the departments of a single university hospital that were asked to incorporate GrippeNet.fr. The general population consisted of adults reporting none of the above treatments or diseases participating in GrippeNet.fr. The incidence of ILI was estimated on a weekly basis and compared between the immunocompromised population and the general population, during the seasonal influenza epidemic. RESULTS: Among the 318 immunocompromised patients assessed for eligibility, 177 were included. During the 2017-2018 seasonal influenza epidemic period, immunocompromised population had 1.59 (95% CI: 1.13-2.20) higher odds to experience an ILI episode, compared to the general population (N = 5358). An influenza vaccination was reported by 58% of the immunocompromised population, compared to 41% of the general population (p < 0.001). CONCLUSION: During a seasonal influenza epidemic period, the incidence of influenza-like illness was higher in patients treated with immunosuppressants, biologics, and/or corticosteroids for an autoimmune or chronic inflammatory disease, compared to the general population.

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.

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.

Development and Validation of a Self-Administered Questionnaire Measuring Essential Knowledge in Patients With Axial Spondyloarthritis.

OBJECTIVE: To develop and validate a patient knowledge questionnaire regarding axial spondyloarthritis (axSpA). METHODS: Knowledge considered essential for patients with axSpA was identified through Delphi rounds among rheumatologists, healthcare professionals (HCPs), and patients, then reformulated to develop the knowledge questionnaire. Cross-sectional validation was performed in 14 rheumatology departments to assess internal validity (Kuder-Richardson coefficient), external validity, acceptability, reproducibility (Lin concordance correlation coefficient), and sensitivity to change (knowledge score before vs after patient education sessions and effect size). RESULTS: The Spondyloarthritis Knowledge Questionnaire (SPAKE) is a self-administered 42-item questionnaire with a 32-item short form, both scored 0 to 100, assessing knowledge of disease, comorbidities, pharmacological treatments, nonpharmacological treatments, self-care, and adaptive skills. In the validation study (130 patients; 67 [51.5%] male, mean age 43.5 [SD 12.9] yrs), the mean (SD) score of the long-form questionnaire was 71.6 (15.4), with higher scores (better knowledge) in nonpharmacological treatments and adaptive skills and lower scores in cardiovascular comorbidity and pharmacological treatments. Acceptability was good, with no missing data; the internal validity coefficient was 0.85. Reproducibility was good (0.81, 95% CI 0.72-0.89). SPAKE showed good sensitivity to change; scores were 69.2 (15.3) then 82.7 (14.0) after patient education sessions (Hedges effect size = 0.92, 95% CI 0.52-1.31). CONCLUSION: SPAKE is a knowledge questionnaire for patients with axSpA, developed with the involvement of HCPs and patients and reflecting current recommendations for the management of axSpA. SPAKE will be useful in assessing knowledge acquisition and self-management strategies in routine care and research.

Identification of Symptom Phenotypes of Hand Osteoarthritis Using Hierarchical Clustering: Results From the DIGICOD Cohort.

OBJECTIVE: We aimed to delineate phenotypes in hand osteoarthritis (HOA) based on cardinal symptoms (pain, functional limitation, stiffness, and aesthetic discomfort). METHODS: With data from the Digital Cohort Design (DIGICOD), we performed a hierarchical agglomerative clustering analysis based on Australian/Canadian Osteoarthritis Hand Index (AUSCAN) subscores for pain, physical function, stiffness, and visual analog scale for aesthetic discomfort. Kruskal-Wallis and post hoc analyses were used to assess differences between clusters. RESULTS: Among 389 patients, we identified 5 clusters: cluster 1 (n = 88) and cluster 2 (n = 91) featured low and mild symptoms; cluster 3 (n = 80) featured isolated aesthetic discomfort; cluster 4 (n = 42) featured a high level of pain, stiffness, and functional limitation; and cluster 5 (n = 88) had the same features as cluster 4 but with high aesthetic discomfort. For clusters 4 and 5, AUSCAN pain score was >41 of 100, representing only one-third of our patients. Aesthetic discomfort (clusters 3 and 5) was significantly associated with erosive HOA and a higher number of nodes. The highly symptomatic cluster 5 was associated but not significantly with metabolic syndrome, and body mass index and C-reactive protein level did not differ among clusters. Symptom intensity was significantly associated with joint destruction as well as with physical and psychological burden. Patients' main expectations differed among clusters, and function improvement was the most frequent expectation overall. CONCLUSION: The identification of distinct clinical clusters based on HOA cardinal symptoms suggests previously undescribed subtypes of this condition, warranting further study of biological characteristics of such clusters, and opening a path toward phenotype-based personalized medicine in HOA.

Correspondence between patient-reported flare and disease activity score variation in axial spondyloarthritis: A 12-months web-based study.

OBJECTIVE: The aims of this study were to determine thresholds of variations of BASDAI and pain associated with patient-reported outbreak or resolution of flare and to test performance of ASAS preliminary definitions of flare. METHODS: SpA patients registered on the Spondy+platform were invited to fill BASDAI and global pain on numeric rating scales every week during one year and to tell if they experienced flare since last week. Performance of BASDAI and pain variations (ΔBASDAI and Δpain) to detect occurrence and resolution of flare was determined with receiver operator characteristic (ROC) curves. RESULTS: Ninety-one of the 99 axSpA patients included reported at least one episode of flare. Area under the ROC curve was significantly higher for ΔBASDAI than for Δpain to predict outbreak of flare (0.81 vs. 0.77, p<0.05) without statically significant difference to predict flare resolution (0.78 vs. 0.80). Best sensitivity/specificity compromise was obtained for ΔBASDAI of 0.2 and 0.4 points to predict flare outbreak or resolution, respectively. All the ASAS definitions obtained a specificity higher than 95% whereas sensitivity was lower than 40%. CONCLUSION: ΔBASDAI appeared as a suitable variable to monitor occurrence and resolution of patient-reported flare in axSpA.

Targeted resequencing of the 13q13 spondyloarthritis-linked locus identifies a rare variant in FREM2 possibly associated with familial spondyloarthritis.

OBJECTIVES: The strong heritability of spondyloarthritis remains poorly explained, despite several large-scale association studies. A recent linkage analysis identified a new region linked to SpA on 13q13. Here we searched for variants potentially explaining this linkage signal by deep-sequencing of the region. METHODS: Re-sequencing of the 1.4 Mb target interval was performed in 92 subjects from the 43 best-linked multicases families (71 spondyloarthritis and 21 unaffected relatives), using hybridization capture-based protocol (Illumina Nextera®). Variants of interest were then genotyped by TaqMan and high resolution melting to check their co-segregation with disease in the same families and to test their association with spondyloarthritis in an independent cohort of 1,091 unrelated cases and 399 controls. Expression of FREM2 was assessed by immunostaining. RESULTS: Of the 7,563 variants identified, 24 were non-synonymous coding single-nucleotide variants. Two of them were located in the FREM2 gene on a haplotype co-segregating with the disease, including one common variant (R1840W, minor allele frequency=0.11) and one rare variant (R727H, minor allele frequency=0.0001). In the case-control analysis, there was no significant association between R1840W and spondyloarthritis (P-value=0.21), whereas R727H was not detected in any of the genotyped individuals. Immunostaining experiments revealed that FREM2 is expressed in synovial membrane, cartilage and colon. CONCLUSIONS: Targeted re-sequencing of a spondyloarthritis-linked region allowed us to identify a rare non-synonymous coding variant in FREM2, co-segregating with spondyloarthritis in a large family. This gene is expressed in several tissues relevant to spondyloarthritis pathogenesis, supporting its putative implication in spondyloarthritis.

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.

Impact of synovial biopsy procedures and disease-specific aspects on synovial tissue outcome: a systematic literature review informing the EULAR points to consider for the minimal reporting requirements in synovial tissue research in rheumatology.

BACKGROUND: The aim of this work was to summarise the literature evaluating the impact of biopsy procedures, tissue handling, tissue quality and disease-specific aspects including joint biopsied and disease stage, on synovial tissue outcome. METHODS: Two reviewers independently identified eligible studies according to the Patients, Intervention, Comparator and Outcome framework obtained for five research questions formulated during the first EULAR task force meeting to produce points to consider (PtC) for minimal reporting requirements in synovial tissue studies. The databases explored were Medline, Embase, CENTRAL and Cinhal. The risk of bias of each study was evaluated using an adapted version of the Joanna Briggs Institute checklist for analytical cross-sectional studies. RESULTS: Of the 7654 records yielded, 75 full texts were assessed, leading to the inclusion of 26 manuscripts in the systematic literature review (SLR). Two papers assessed the impact of biopsy procedures on the quality and quantity of tissue retrieved alongside patient tolerability; six papers focused on synovial tissue variability. Four papers studied the impact of sample handling or randomisation and 14 assessed the impact of disease stage and state, namely early or established active rheumatoid arthritis and remission on histopathological and transcriptomic results. CONCLUSIONS: This SLR informs the EULAR PtC for minimal reporting requirements in synovial tissue research in rheumatology. Characteristics related to the study design, population, sample handling, randomisation and analysis can affect the final synovial tissue outcome in the studies reviewed. Thus, accurate reporting of these factors is required in order to ensure the scientific validity of manuscripts describing synovial tissue outcomes.

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.

Randomized Cross Over Study Assessing the Efficacy of Non-invasive Stimulation of the Vagus Nerve in Patients With Axial Spondyloarthritis Resistant to Biotherapies: The ESNV-SPA Study Protocol.

Axial spondyloarthritis (SpA), is a major cause of chronic pain and disability that profoundly alters the quality of life of patients. Nearly half of patients with SpA usually develop drug resistance. Non-pharmacological treatments targeting inflammation are an attractive alternative to drug administration. Vagus nerve stimulation (VNS), by promoting a cholinergic anti-inflammatory reflex holds promise for treating inflammatory disease. Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in animal models of endotoxemia, sepsis, colitis, and other preclinical models of inflammatory diseases. It has been proposed that vagal efferent fibers release acetylcholine (Ach), which can interact with α7-subunit-containing nicotinic receptors expressed by tissue macrophages and other immune cells to rapidly inhibit the synthesis/release of pro-inflammatory cytokines such as TNFα, IL-1ß, IL-6, and IL-18. External vagal nerve stimulation devices are now available that do not require surgery nor implantation to non-invasively stimulate the vagal nerve. This double-blind randomized cross-over clinical trial aims to study the change in SpA disease activity, according to Assessment in Ankylosing Spondylitis 20 (ASAS20) definition, after 12 weeks of non-invasive VNS treatment vs. non-specific dummy stimulation (control group). One hundred and twenty adult patients with drug resistant SpA, meeting the ASAS classification criteria, will be included in the study. Patients will be randomized into two parallel groups according to a cross over design: either active VNS for 12 weeks, then dummy stimulation for 12 weeks, or dummy stimulation for 12 weeks, then active VNS for 12 weeks. The two stimulation periods will be separated by a 4 weeks wash-out period. A transcutaneous auricular vagus nerve stimulator Tens Eco Plus SCHWA MEDICOTM France will be used in this study. The active VNS stimulation will be applied in the cymba conchae of the left ear upon the auricular branch of the vagus nerve, using low intensity (2-5 mA), once à week, during 1 h. Dummy stimulation will be performed under the same conditions and parameters as active VNS stimulation, but at an irrelevant anatomical site: the left ear lobule. This multicenter study was registered on ClinicalTrials.gov: NCT04286373.

What Have We Learned From Family-Based Studies About Spondyloarthritis?

Spondyloarthritis (SpA) is a chronic inflammatory disorder with a high familial aggregation, emphasizing the existence of genetic susceptibility factors. In the last decades, family-based studies have contributed to better understand the genetic background of SpA, in particular by showing that the most likely model of transmission is oligogenic with multiplicative effects. Coexistence of different SpA subtypes within families also highlighted the complex interplay between all subtypes. Several whole-genome linkage analyses using sib-pairs or multiplex families were performed in the 1990s to try to identify genetic susceptibility factors besides HLA-B27. Unfortunately, no consistent results were obtained and family-based studies have been progressively set aside in favor of case-control designs. In particular, case-control genome-wide association studies allowed the identification of more than 40 susceptibility regions. However, all these loci explain only a small fraction of disease predisposition. Several hypotheses have been advanced to account for this unexplained heritability, including rare variants involvement, leading to a renewed interest in family-based designs, which are probably more powerful in the detection of such variants. In this review, our purpose is to summarize what has been learned to date regarding SpA genetics from family-based studies, with a special focus on recent identification of rare associated variants through next-generation sequencing studies.

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.