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Uveitis is the most frequent extra-articular manifestation of axial spondyloarthritis (SpA), occurring in up to one-third of the patients. In the majority of patients, uveitis is acute, anterior and unilateral and presents with photosensitivity, sudden onset of pain and blurred vision. Topical steroids are an effective treatment; however, recurrent or refractory cases may need conventional disease-modifying antirheumatic drugs or biological treatment with monoclonal tumor necrosis factor (TNF) inhibitors, thus also influencing treatment strategy of the underlying SpA. Though the exact pathogenesis of SpA and uveitis remains unknown, both seem to result from the interaction of a specific, mostly shared genetical background (among other HLA-B27 positivity), external influences such as microbiome, bacterial infection or mechanical stress and activation of the immune system resulting in inflammation. Up to 40% of patients presenting with acute anterior uveitis (AAU) have an undiagnosed SpA. Therefore, an effective referral strategy for AAU patients is needed to shorten the diagnostic delay of SpA and enable an early effective treatment. Further, the risk for ophthalmological manifestations increases with the disease duration in SpA; and patients presenting with ocular symptoms should be referred to an ophthalmologist. Thus, a close collaboration between patient, rheumatologist and ophthalmologist is needed to optimally manage ocular inflammation in SpA.

Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer’s disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system. Autoantibodies are implicated in autoimmunity, but may also be present in healthy individuals. Here the authors find that the autoantibody specificity signatures against various G protein-coupled receptors are associated with multiple parameters, including disease states, to imply a physiological function in maintaining immune homeostasis.

Background Radiographs of the sacroiliac joints are commonly used for the diagnosis and classification of axial spondyloarthritis. The aim of this study was to develop and validate an artificial neural network for the detection of definite radiographic sacroiliitis as a manifestation of axial spondyloarthritis (axSpA). Methods Conventional radiographs of the sacroiliac joints obtained in two independent studies of patients with axSpA were used. The first cohort comprised 1553 radiographs and was split into training ( n  = 1324) and validation ( n  = 229) sets. The second cohort comprised 458 radiographs and was used as an independent test dataset. All radiographs were assessed in a central reading session, and the final decision on the presence or absence of definite radiographic sacroiliitis was used as a reference. The performance of the neural network was evaluated by calculating areas under the receiver operating characteristic curves (AUCs) as well as sensitivity and specificity. Cohen’s kappa and the absolute agreement were used to assess the agreement between the neural network and the human readers. Results The neural network achieved an excellent performance in the detection of definite radiographic sacroiliitis with an AUC of 0.97 and 0.94 for the validation and test datasets, respectively. Sensitivity and specificity for the cut-off weighting both measurements equally were 88% and 95% for the validation and 92% and 81% for the test set. The Cohen’s kappa between the neural network and the reference judgements were 0.79 and 0.72 for the validation and test sets with an absolute agreement of 90% and 88%, respectively. Conclusion Deep artificial neural networks enable the accurate detection of definite radiographic sacroiliitis relevant for the diagnosis and classification of axSpA.

ObjectiveTo evaluate the association of nociplastic (NoP) and neuropathic pain (NP) components with residual symptoms in patients with radiographic axial spondyloarthritis (r-axSpA) receiving biological disease-modifying antirheumatic drugs (bDMARDs).Methods78 patients with r-axSpA from the GErman SPondyloarthritis Inception Cohort receiving a bDMARD for at least 3 months were included in this analysis. The Widespread Pain Index (WPI) and the PainDETECT (PD) questionnaire were used to quantify the NoP and the NP components, respectively. Axial Spondyloarthritis Disease Activity Score (ASDAS) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were used as measures of residual symptoms. C reactive protein (CRP) was used as a measure of systemic inflammatory activity. Univariable and multivariable regression analyses of disease activity were performed. The regions of the WPI score and items of the PD score were used for cluster analyses.ResultsLinear multivariable regression analysis showed that WPI and PD were independently associated with ASDAS (b=0.1, 95% CI 0.04 to 0.17, and b=0.05, 95% CI 0.02 to 0.08, respectively) and BASDAI (b=0.24, 95% CI 0.08 to 0.39, and b=0.17, 95% CI 0.1 to 0.25, respectively) in r-axSpA patients receiving stable treatment with bDMARDs. Furthermore, WPI and PD were found to be significantly associated with the presence of relevant residual symptoms as defined by BASDAI ≥4 (OR 1.93, 95% CI 1.09 to 4.15, and OR 1.32, 95% CI 1.04 to 1.85, respectively). The effects were present also in patients with normal level of CRP. Cluster analysis revealed three distinct pain distribution profiles and four specific sensory symptom constellations allowing differentiation of different pain subtypes.ConclusionBoth NoP and NP components seem to be associated with residual symptoms in patients with r-axSpA receiving treatment with bDMARDs.

ObjectivesRadiography and MRI of the sacroiliac joints (SIJ) are relevant for the diagnosis and classification of patients with axial spondyloarthritis (axSpA). This study aimed to evaluate the impact of clinical information (CI) on the accuracy of imaging interpretation.MethodsOut of 109 patients referred because of suspicion of axSpA with complete imaging sets (radiographs and MRI of SIJ), 61 were diagnosed with axSpA (56%). Images were independently evaluated by three radiologists in four consecutive reading campaigns: radiographs and radiographs+MRI without and with CI including demographic data, SpA features, physical activity and pregnancy. Radiographs were scored according to the modified New York criteria, and MRIs for inflammatory and structural changes compatible with axSpA (yes/no). The clinical diagnosis was taken as reference standard. The compatibility of imaging findings with a diagnosis of axSpA (precision) before and after the provision of CI and radiologists’ confidence with their findings (0–10) were evaluated.ResultsThe precision of radiographs evaluation without versus with CI increased from 70% to 78% (p=0.008), and for radiographs+MRI from 81% to 82% (p=1.0), respectively. For CR alone, the sensitivity and specificity of radiologic findings were 51% and 94% without and 60% and 100% with CI, while, for radiographs+MRI, they were 74% and 90% vs 71% and 98%, respectively. The diagnostic confidence of radiologists increased from 5.2±1.9 to 6.0±1.7 with CI for radiographs, and from 6.7±1.6 to 7.2±1.6 for radiographs+MRI, respectively.ConclusionThe precision, specificity and diagnostic confidence of radiologic evaluation increased when CI was provided.

Early treatment initiation is one of the strongest predictors of good treatment response in axial spondyloarthritis (axSpA). Recently, the Assessment in SpondyloArthritis International Society (ASAS) defined early axSpA as a diagnosis of axSpA with a duration of axial symptoms equal to or less than 2 years. Tofacitinib is a Janus kinase (JAK) inhibitor for the treatment of ankylosing spondylitis. Compare the efficacy and safety of tofacitinib versus placebo (both on non-steroidal anti-inflammatory drug (NSAID) background) in patients with active early axSpA and inadequate response to at least one NSAID. This is a phase IV, randomized, double-blind, placebo-controlled, multicenter clinical trial. The study will recruit 104 patients aged ⩾18 and ⩽45 years with active early axSpA (chronic back pain ⩽2 years), inadequate response to at least one NSAID, and objective signs of active inflammation (on magnetic resonance imaging (MRI) of sacroiliac joints (SIJs) or elevated C-reactive protein). Patients will be randomized 1:1 to receive tofacitinib 5 mg twice daily or placebo, with background naproxen 500 mg twice daily for 16 weeks. Patients not meeting early treatment response criteria at week 4 will receive open-label tofacitinib until week 16. Primary and key secondary endpoints at week 16 will be the proportion of patients achieving disease remission (Axial Spondyloarthritis Disease Activity Score <1.3) and change from baseline in MRI SIJ Spondyloarthritis Research Consortium of Canada osteitis score, respectively. Safety will be monitored up to 4 weeks after the last study drug dose. The study will be performed according to the ethical principles of the Declaration of Helsinki and will be approved by independent ethics committees of each center. This is one of the first randomized clinical trials designed to evaluate the efficacy and safety of a JAK inhibitor in the recently ASAS-defined \"early\" axSpA population. ClinicalTrials.gov: NCT06112665; CTIS: 2023-505050-18-00.

ObjectivesAnatomical variation of the sacroiliac (SI) joints is common and specific variants are associated with erosions and bone marrow oedema on imaging. Our investigation aims to evaluate whether anatomical variations influence the clinical presentation of axial spondyloarthritis (axSpA).MethodsIn this propensity score matched post hoc analysis documented clinical data from four prospective clinical cohorts was assessed. Classification of back pain as inflammatory (=IBP), human leucocyte antigen-B27 positivity, family history, disease activity according to Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), symptom duration, elevated acute phase reactants, peripheral and extramusculoskeletal manifestations were evaluated. Statistical analyses were done using (generalised) linear models, t-tests, χ2 tests and analysis of variances. Multiple testing was corrected according to Bonferroni.ResultsA total of 165 patients (86 women) were included. Atypical SI joints, defined by the presence of accessory joint facets, iliosacral complex or crescent-shaped ilii on MRI, were identified in 61 out of 165 patients with axSpA. Disease activity, assessed by BASDAI and symptom duration were similar in both groups (adjusted ß=−0.118 (95% CI -0.713, 0.476), p=0.696 and 120.0 (107.4) vs 116.5 (98.3) months, p=0.838, respectively). There was no significant difference in IBP between the groups (adjusted OR=0.614 (95% CI 0.274, 1.377), p=0.236). Sex-stratified analysis revealed no statistically significant results.ConclusionOur analysis suggests that clinical phenotypes do not significantly differ between patients with axSpA with and without atypical joints.

ObjectivesThe objective of this study is to investigate lipopolysaccharid-binding protein (LBP), zonulin and calprotectin as markers of bacterial translocation, disturbed gut barrier and intestinal inflammation in patients with radiographic axial spondyloarthritis (r-axSpA) during tumour necrosis factor inhibitor (TNFi) therapy and to analyze the association between disease activity, response to treatment and biomarker levels.MethodsPatients with active r-axSpA of the German Spondyloarthritis Inception Cohort starting TNFi were compared with controls with chronic back pain. Serum levels of LBP, zonulin and calprotectin were measured at baseline and after 1 year of TNFi therapy. We analysed the longitudinal association between biomarkers and disease activity, and the relationship between biomarkers and treatment response with regression analysis.Results121 patients with r-axSpA were compared with 63 controls. At baseline, patients with r-axSpA had higher levels of LBP and calprotectin than controls, which decreased significantly during TNFi treatment. LBP showed a positive association in longitudinal analyses with Axial Spondyloarthritis Disease Activity Score (ASDAS) (ß=0.08, 95% CI 0.06 to 0.10), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (ß=0.08, 95% CI 0.04 to 0.12) and C reactive protein (CRP) (ß=1.69, 95% CI 1.04 to 2.34). Calprotectin was associated with ASDAS (ß=0.04, 95% CI 0.01 to 0.07) and CRP (ß=0.82, 95% CI 0.27 to 1.37). Furthermore, LBP and calprotectin levels at baseline showed an association with a subsequent change in BASDAI. Baseline zonulin levels were not significantly associated with disease activity or treatment response.ConclusionSerum levels of LBP and calprotectin are associated with disease activity in patients with r-axSpA and decrease with TNFi response. In contrast, serum zonulin levels showed no association with disease activity or treatment response, arguing against a strict correlation between intestinal permeability and disease activity in axSpA.

ObjectiveThe assessment of inflammatory and structural lesions in the sacroiliac joint (SIJ) is crucial in axial spondyloarthritis (axSpA). HLA-B27 status plays an important role in axSpA diagnosis and has been linked to MRI lesion burden in the general population. We aimed to investigate the sex-specific influence of HLA-B27 status on inflammatory and structural MRI findings in patients with low back pain of non-inflammatory origin.MethodsThis post hoc analysis included 139 non-axSpA patients (90 women) with chronic low back pain. Two readers scored MRIs of the SIJ for the presence of sclerosis, erosion, fat metaplasia, bone marrow oedema (BMO) and ankylosis. Frequencies and extent of lesions were compared regarding the HLA-B27 status using χ2 tests and t-tests. Regression models to assess the sex-dependent influence of HLA-B27 on lesion burden were computed.ResultsHLA-B27 was positive in 33 women (36.7%) and 23 men (46.9%). The overall occurrence of all SIJ lesions did not differ in HLA-B27 negative and positive individuals. There were no significant differences in the extent of lesions considering the HLA-B27 positivity, for erosion (mean sum score (MSS) of 0.91 vs 0.48; p=0.144), sclerosis (MSS 1.65 vs 1.88; p=0.576), fat metaplasia (MSS 0.56 vs 0.27; p=0.425), BMO (MSS 0.75 vs 0.59; p=0.460) and ankylosis (MSS 0.06 vs 0.04; p=0.659).ConclusionHLA-B27 status has no significant influence on the occurrence and extent of SIJ lesions in patients with low back pain of non-inflammatory origin in either men or women.

ObjectivesIn this post-hoc analysis of ESTHER trial, we aimed to investigate the longitudinal relationship between inflammation on MRI and the achievement of inactive disease/low disease activity in patients with axial spondyloarthritis (axSpA) treated with long-term tumor necrosis factor (TNF) inhibitor etanercept.MethodsOf the 76 patients with active axSpA in the ESTHER trial, we included all patients treated with etanercept for at least 6 months for main analysis. All clinical and MRI data from 4.5 years of follow-up were used in the analysis. MRIs of the spine and sacroiliac (SI) joints were performed at baseline, week 24, week 48 and yearly thereafter and were evaluated for active inflammatory lesions according to the Berlin MRI score.ResultsLongitudinal analysis showed that higher SI joint osteitis score was associated with higher Axial Spondyloarthritis Disease Activity Score (ASDAS) at the same time point (β=0.08, 95% CI (0.05; 0.11)) and at the next time point 6 months later (β=0.05, 95% CI (0.02; 0.07)). Furthermore, resolution of osteitis in the SI joint (Berlin MRI osteitis score of ≤1) was associated with lower ASDAS at the next time point (β=−0.26, 95% CI (−0.42; −0.09)), higher odds of achieving ASDAS low disease activity (OR=5.61, 95% CI (1.06; 29.67)) and inactive disease status (OR=2.23, 95% CI (1.01; 4.94)) at the next time point.ConclusionsThe presence of inflammation on SI joints-MRI is associated with higher disease activity in axSpA. Resolution of inflammation on MRI is associated with better clinical outcomes in the long-term follow-up. Thus, achieving complete resolution of inflammation is favourable for meeting the treatment goals in axSpA.Trial registration numberNCT00844142.