Altered serum metabolome as an indicator of paraneoplasia or concomitant cancer in patients with rheumatic disease.

OBJECTIVES: A timely diagnosis is imperative for curing cancer. However, in patients with rheumatic musculoskeletal diseases (RMDs) or paraneoplastic syndromes, misleading symptoms frequently delay cancer diagnosis. As metabolic remodelling characterises both cancer and RMD, we analysed if a metabolic signature can indicate paraneoplasia (PN) or reveal concomitant cancer in patients with RMD. METHODS: Metabolic alterations in the sera of rheumatoid arthritis (RA) patients with (n=56) or without (n=52) a history of invasive cancer were quantified by nuclear magnetic resonance analysis. Metabolites indicative of cancer were determined by multivariable regression analyses. Two independent RA and spondyloarthritis (SpA) cohorts with or without a history of invasive cancer were used for blinded validation. Samples from patients with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, non-invasive (NI) precancerous lesions and non-melanoma skin cancer and systemic lupus erythematosus and samples prior to the development of malignancy were used to test the model performance. RESULTS: Based on the concentrations of acetate, creatine, glycine, formate and the lipid ratio L1/L6, a diagnostic model yielded a high sensitivity and specificity for cancer diagnosis with AUC=0.995 in the model cohort, AUC=0.940 in the blinded RA validation cohort and AUC=0.928 in the mixed RA/SpA cohort. It was equally capable of identifying cancer in patients with PN. The model was insensitive to common demographic or clinical confounders or the presence of NI malignancy like non-melanoma skin cancer. CONCLUSIONS: This new set of metabolic markers reliably predicts the presence of cancer in arthritis or PN patients with high sensitivity and specificity and has the potential to facilitate a rapid and correct diagnosis of malignancy.

Janus kinase inhibitors and tumour necrosis factor inhibitors show a favourable safety profile and similar persistence in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: real-world data from the BIOBADASER registry.

OBJECTIVES: To compare the safety of Janus kinase inhibitors (JAKi) with that of tumour necrosis factor inhibitors (TNFi) and determine drug persistence among patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). METHODS: We analysed data from patients included in BIOBADASER 3.0 and treated with JAKi or TNFi from 2015 to 2023 and estimated the incidence rate ratio (IRR) of adverse events and persistence. RESULTS: A total of 6826 patients were included. Of these, 52% had RA, 25% psoriatic arthritis and 23% axial SpA. Treatment was with TNFi in 86%. The mean duration of treatment was 2.2±2.0 years with TNFi versus 1.8±1.5 with JAKi. JAKis were prescribed in older patients with longer term disease, greater comorbidity and later treatment lines and more frequently as monotherapy. The IRR of all infections and gastrointestinal events was higher among patients with RA treated with JAKi. Drug persistence at 1, 2 and 3 years was 69%, 55% and 45% for TNFi and 68%, 54% and 45% for JAKi. Multivariate regression models showed a lower probability of discontinuation for JAKi (HR=0.85; 95% CI 0.78-0.92) and concomitant conventional synthetic disease-modifying antirheumatic drugs (HR=0.90; 95% CI 0.84-0.96). The risk of discontinuation increased with glucocorticoids, comorbidities, greater disease activity and later treatment lines. CONCLUSIONS: Infections, herpes zoster and gastrointestinal adverse events in patients with RA tended to be more frequent with JAKi. However, prognosis was poor in patients receiving JAKi. Persistence was similar for TNFi and JAKi, although factors associated with discontinuation differed by diagnostic group.

Risk of cardiovascular disease with high-dose versus low-dose use of non-steroidal anti-inflammatory drugs in ankylosing spondylitis.

OBJECTIVE: To investigate the risk of cardiovascular disease (CVD) associated with increasing dose of a non-steroidal anti-inflammatory drug (NSAID) in patients with ankylosing spondylitis (AS). METHODS: Using the Korean National Health Insurance database, patients newly diagnosed with AS without prior CVD between 2010 and 2018 were included in this nationwide cohort study. The primary outcome was CVD, a composite outcome of ischaemic heart disease, stroke or congestive heart failure. Exposure to NSAIDs was evaluated using a time-varying approach. The dose of NSAIDs was considered in each exposure period. Cox proportional hazard regression was used to investigate the risk of CVD associated with NSAID use. RESULTS: Of the 19 775 patients (mean age, 36 years; 75% were male), 19 706 received NSAID treatment. During follow-up period of 98 290 person-years, 1663 cases of CVD occurred including 1157 cases of ischaemic heart disease, 301 cases of stroke and 613 cases of congestive heart failure. Increasing dose of NSAIDs was associated with incident CVD after adjusting for confounders (adjusted HR (aHR) 1.10; 95% CI 1.08 to 1.13). Specifically, increasing dose of NSAIDs was associated with incident ischaemic heart disease (aHR 1.08; 95% CI 1.05 to 1.11), stroke (aHR 1.09; 95% CI 1.04 to 1.15) and congestive heart failure (aHR 1.12; 95% CI 1.08 to 1.16). The association between NSAID dose and higher CVD risk was consistent in different subgroups. CONCLUSION: In a real-world AS cohort, higher dose of NSAID treatment was associated with a higher risk of CVD, including ischaemic heart disease, stroke and congestive heart failure.

Association of clinical response criteria and disease activity levels with axial spondyloarthritis core domains: results from two phase 3 randomised studies, BE MOBILE 1 and 2.

OBJECTIVE: To assess how achievement of increasingly stringent clinical response criteria and disease activity states at week 52 translate into changes in core domains in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA). METHODS: Patients in BE MOBILE 1 and 2 achieving different levels of response or disease activity (Assessment of SpondyloArthritis International Society (ASAS) and Ankylosing Spondylitis Disease Activity Score (ASDAS) response criteria, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50)) at week 52 were pooled, regardless of treatment arm. Associations between achievement of these endpoints and change from baseline (CfB) in patient-reported outcomes (PROs) measuring core axSpA domains, including pain, fatigue, physical function, overall functioning and health, and work and employment, were assessed. RESULTS: Achievement of increasingly stringent clinical efficacy endpoints at week 52 was generally associated with sequentially greater improvements from baseline in all PROs. Patients with nr-axSpA achieving ASAS40 demonstrated greater improvements (CfB) than patients who did not achieve ASAS40 but did achieve ASAS20, in total spinal pain (-5.3 vs -2.8, respectively), Functional Assessment of Chronic Illness-Fatigue subscale (12.7 vs 6.7), Bath Ankylosing Spondylitis Function Index (-3.9 vs -1.8), European Quality of Life 5-Dimension 3-Level Version (0.30 vs 0.16), Work Productivity and Activity Impairment-axSpA presenteeism (-35.4 vs -15.9), overall work impairment (-36.5 vs -12.9), activity impairment (-39.0 vs -21.0) and sleep (9.0 vs 3.9). Results were similar for ASDAS and BASDAI50. Similar amplitudes of improvement were observed between patients with nr-axSpA and r-axSpA. CONCLUSIONS: Patients treated with bimekizumab across the full axSpA disease spectrum, who achieved increasingly stringent clinical response criteria and lower disease activity at week 52, reported larger improvements in core axSpA domains.

Exploring the Effects of Ixekizumab on Pain in Patients with Ankylosing Spondylitis Based on Objective Measures of Inflammation: Post Hoc Analysis from a Large Randomized Clinical Trial.

INTRODUCTION: The objective of this analysis is to evaluate the improvement in spinal pain with ixekizumab, placebo, and adalimumab based on objective measures of inflammation response in patients with ankylosing spondylitis (AS). METHODS: The COAST-V 52-week, double-blind, placebo-controlled, randomized phase III trial examined the efficacy of ixekizumab in patients with active AS; adalimumab was used as an active reference arm. Treatment effects on reduction in pain were assessed by objective measures of controlled and persisting inflammation (defined by magnetic resonance imaging [MRI], C-reactive protein [CRP], or MRI + CRP status). Pathway analysis was used to analyze treatment effect that was not attributable to reduction in inflammation biomarkers. RESULTS: In patients with AS, when inflammation was controlled as assessed by MRI, patients treated with ixekizumab experienced a reduction in spinal pain at night (SP-N, numeric rating scale, ixekizumab mean = - 3.9, p < 0.001, adalimumab mean = - 2.6, p < 0.05) compared to placebo (mean = - 1.6) at week 16. When inflammation was controlled as assessed by MRI + CRP, ixekizumab and adalimumab had numerically greater reductions at week 16 in SP-N versus placebo. All ixekizumab groups had further improvements at week 52. When inflammation was persisting as assessed by MRI + CRP, ixekizumab-treated patients had significant reduction in SP-N (mean = - 3.7, p < 0.001) versus placebo (mean = - 1.7), improvement with adalimumab did not reach significance (mean = - 2.6, p = 0.06). In the pathway analysis at week 16, ixekizumab had a greater effect on pain outcomes compared to adalimumab. CONCLUSION: This post hoc analysis is supportive of the hypothesis that ixekizumab reduces pain in AS by additional mechanisms other than the reduction of measurable inflammation. TRIAL REGISTRATION NUMBER: NCT02696785.

MRI-based synthetic CT: a new method for structural damage assessment in the spine in patients with axial spondyloarthritis - a comparison with low-dose CT and radiography.

OBJECTIVE: To investigate the ability of MRI-based synthetic CT (sCT), low-dose CT (ldCT) and radiography to detect spinal new bone formation (NBF) in patients with axial spondyloarthritis (axSpA). METHODS: Radiography of lumbar and cervical spine, ldCT and sCT of the entire spine were performed in 17 patients with axSpA. sCT was reconstructed using the BoneMRI application (V.1.6, MRIGuidance BV, Utrecht, NL), a quantitative three-dimensional MRI-technique based on a dual-echo gradient sequence and a machine learning processing pipeline that can generate CT-like MR images. Images were anonymised and scored by four readers blinded to other imaging/clinical information, applying the Canada-Denmark NBF assessment system. RESULTS: Mean scores of NBF lesions for the four readers were 188/209/37 for ldCT/sCT/radiography. Most NBF findings were at anterior vertebral corners with means 163 on ldCT, 166 on sCT and 35 on radiography. With ldCT of the entire spine as reference standard, the sensitivity to detect NBF was 0.67/0.13 for sCT/radiography; both with specificities >0.95. For levels that were assessable on radiography (C2-T1 and T12-S1), the sensitivity was 0.61/0.48 for sCT/radiography, specificities >0.90. For facet joints, the sensitivity was 0.46/0.03 for sCT/radiography, specificities >0.94. The mean inter-reader agreements (kappa) for all locations were 0.68/0.58/0.56 for ldCT/sCT/radiography, best for anterior corners. CONCLUSION: With ldCT as reference standard, MRI-based sCT of the spine showed very high specificity and a sensitivity much higher than radiography, despite limited reader training. sCT could become highly valuable for detecting/monitoring structural spine damage in axSpA, not the least in clinical trials.

Persistence and safety of anti-TNF biosimilars versus originators in immune-mediated inflammatory diseases: an observational study on the French National Health Data System.

OBJECTIVES: Biosimilar-originator equivalence has been demonstrated in phase 3 trials in a few indications of infliximab, etanercept and adalimumab. The objective of our study was to compare the persistence and safety of biosimilars versus originators in all the licensed indications of these molecules. METHODS: We used data from the French National Health Data System (SNDS), covering 99% of the French population, to identify infliximab, etanercept and adalimumab initiators from biosimilar launch (January 2015, May 2016 and October 2018, respectively) to 30 June 2021. Patients were then followed for 1 year. Treatment persistence (duration without treatment discontinuation or modification) and safety (including severe infections, all-cause hospitalisation and death) were compared between originator and biosimilar users by Cox regressions weighting the populations on the inverse probability of treatment. Analyses were performed by molecule, by disease and by biosimilar product. RESULTS: From January 2015 to June 2021, 86 776 patients were included in the study: 22 670, 24 442 and 39 664 patients had initiated infliximab, etanercept and adalimumab, respectively; 49 752 (53%) were biosimilar initiators. We did not find any risk of discontinuation (HRs were below or around 1, here all pathologies and products together: infliximab 0.88 (0.80-0.97), etanercept 0.85 (0.81-0.90) and adalimumab 0.96 (0.91-1.00)) or safety event (infection: infliximab 0.97 (0.78-1.21), etanercept 1.04 (0.81-1.33) and adalimumab 0.98 (0.83-1.16); hospitalisation: infliximab 1.08 (0.96-1.23), etanercept 0.99 (0.87-1.11) and adalimumab 0.91 (0.83-0.99)) associated with biosimilar versus originator use. CONCLUSIONS: Our study shows reassuring results regarding the persistence and safety of biosimilar tumour necrosis factor-alpha inhibitors compared with originators in all licensed indications.

Impact of the time of initiation and line of biologic therapy on the retention rate of secukinumab in axial spondyloarthritis (axSpA): data from the French multicentre retrospective FORSYA study.

OBJECTIVE: To compare the 1-year retention rate of secukinumab in axial spondyloarthritis (axSpA) and its predisposing factors with regard to its time of initiation (eg, right after or remotely from its launch). METHODS: Study design: Retrospective multicentre French study of patients with axSpA. Study periods: Two cohorts were evaluated regarding the time of initiation of secukinumab: cohort 1 (C1)-between 16 August 2016 and 31 August 2018-and cohort 2 (C2)-between 1 September 2018 and 13 November 2020. STATISTICAL ANALYSIS: The 1-year retention rate of secukinumab was estimated using the Kaplan-Meier method, and the log-rank test was used to compare the retention curves of the two cohorts. Preselected factors (eg, disease characterristics, line and time of secukinumab initiation) of secukinumab retention at 1 year were analysed by univariate and multivariate Cox model regression. RESULTS: In total, 906 patients in C1 and 758 in C2 from 50 centres were included in the analysis. The 1-year retention rate was better in C2 (64% (61%-68%)) vs C1 (59% (55%-62%)) (HR=1.19 (1.02-1.39); p=0.0297). In the multivariate analysis, the line of biologic therapy was the single predictive factor of the 1-year retention rate of secukinumab picked up in both cohorts, with a better retention rate when prescribed as first-line biologic therapy. CONCLUSION: The better secukinumab retention rate remotely from its launch is explained by its use at an earlier stage of the disease, suggesting a change in the behaviour of prescribing physicians. Our results emphasise the relevance of iterative evaluations of routine care treatments.

Power Doppler signal at the enthesis and bone erosions are the most discriminative OMERACT ultrasound lesions for SpA: results from the DEUS (Defining Enthesitis on Ultrasound in Spondyloarthritis) multicentre study.

OBJECTIVES: To assess, in spondyloarthritis (SpA), the discriminative value of the Outcome Measures in Rheumatology (OMERACT) ultrasound lesions of enthesitis and their associations with clinical features in this population. METHODS: In this multicentre study involving 20 rheumatology centres, clinical and ultrasound examinations of the lower limb large entheses were performed in 413 patients with SpA (axial SpA and psoriatic arthritis) and 282 disease controls (osteoarthritis and fibromyalgia). 'Active enthesitis' was defined as (1) power Doppler (PD) at the enthesis grade ≥1 plus entheseal thickening and/or hypoechoic areas, or (2) PD grade >1 (independent of the presence of entheseal thickening and/or hypoechoic areas). RESULTS: In the univariate analysis, all OMERACT lesions except enthesophytes/calcifications showed a significant association with SpA. PD (OR=8.77, 95% CI 4.40 to 19.20, p<0.001) and bone erosions (OR=4.75, 95% CI 2.43 to 10.10, p<0.001) retained this association in the multivariate analysis. Among the lower limb entheses, only the Achilles tendon was significantly associated with SpA (OR=1.93, 95% CI 1.30 to 2.88, p<0.001) in the multivariate analyses. Active enthesitis showed a significant association with SpA (OR=9.20, 95% CI 4.21 to 23.20, p<0.001), and unlike the individual OMERACT ultrasound lesions it was consistently associated with most clinical measures of SpA disease activity and severity in the regression analyses. CONCLUSIONS: This large multicentre study assessed the value of different ultrasound findings of enthesitis in SpA, identifying the most discriminative ultrasound lesions and entheseal sites for SpA. Ultrasound could differentiate between SpA-related enthesitis and other forms of entheseal pathology (ie, mechanical enthesitis), thus improving the assessment of entheseal involvement in SpA.

Patients with ankylosing spondylitis present a distinct CD8 T cell subset with osteogenic and cytotoxic potential.

OBJECTIVES: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease affecting mainly the axial skeleton. Peripheral involvement (arthritis, enthesitis and dactylitis) and extra-musculoskeletal manifestations, including uveitis, psoriasis and bowel inflammation, occur in a relevant proportion of patients. AS is responsible for chronic and severe back pain caused by local inflammation that can lead to osteoproliferation and ultimately spinal fusion. The association of AS with the human leucocyte antigen-B27 gene, together with elevated levels of chemokines, CCL17 and CCL22, in the sera of patients with AS, led us to study the role of CCR4+ T cells in the disease pathogenesis. METHODS: CD8+CCR4+ T cells isolated from the blood of patients with AS (n=76) or healthy donors were analysed by multiparameter flow cytometry, and gene expression was evaluated by RNA sequencing. Patients with AS were stratified according to the therapeutic regimen and current disease score. RESULTS: CD8+CCR4+ T cells display a distinct effector phenotype and upregulate the inflammatory chemokine receptors CCR1, CCR5, CX3CR1 and L-selectin CD62L, indicating an altered migration ability. CD8+CCR4+ T cells expressing CX3CR1 present an enhanced cytotoxic profile, expressing both perforin and granzyme B. RNA-sequencing pathway analysis revealed that CD8+CCR4+ T cells from patients with active disease significantly upregulate genes promoting osteogenesis, a core process in AS pathogenesis. CONCLUSIONS: Our results shed light on a new molecular mechanism by which T cells may selectively migrate to inflammatory loci, promote new bone formation and contribute to the pathological ossification process observed in AS.

Exploring radiographic patterns of the cervical spine, including zygapophyseal joints, in axial spondyloarthritis.

INTRODUCTION: The assessment of the cervical spine (CS) in axial spondyloarthritis (axSpA) and its radiographic characteristics, including the zygapophyseal joints (ZJ), may be helpful for an accurate diagnosis, establishing a prognosis and enhancing treatment decisions. OBJECTIVES: To describe the prevalence and characteristics of CS involvement in patients with axSpA and perform a comparison between groups according to cervical radiographic damage. METHODS: Patients who fulfilled the Assessment of SpondyloArthritis International Society classification criteria were included from January 2011 to January 2021. Sociodemographic, clinical, radiographic and treatment variables were gathered. Patients were categorised into 'CS group' (Bath Ankylosing Spondylitis Radiology Index ≥2 or De Vlam score ≥3 for ZJ) and 'no CS group' as controls. ZJ fusion and interobserver reliability in ZJ scoring were analysed. RESULTS: A total of 340 patients were included, 244 (71.7%) men, with mean age 57±15 years. CS involvement was observed in 181 (53.2%) patients. Patients in the CS group, as compared with no CS group, were predominantly men, older, had a higher body mass index, higher prevalence of smoking, showed higher disease activity, worse functionality and mobility, as well as more structural damage. Sixty-nine patients with CS involvement had ZJ fusion at some level. These patients showed worse mobility and more radiographic damage. Overall, ZJ involvement was observed in 99 patients (29.1%), 20 of whom did not present with vertebral body involvement. CONCLUSION: Radiographic evaluation of CS is relevant in patients with axSpA and should be assessed routinely. Evaluation of the ZJ is particularly significant, as it is related to higher disease activity and worse function.

Sacroiliac radiographic progression over 10 years in axSpA: data from the DESIR inception cohort.

OBJECTIVES: To evaluate sacroiliac radiographic progression over a 10-year follow-up and determine the baseline factors associated with such progression in patients with recent-onset axial spondyloarthritis (axSpA, <3 years). METHODS: This analysis was performed in the DESIR cohort (NCT01648907). The radiographic status of the patients (radiographic axSpA (r-axSpA) vs non-radiographic axSpA (nr-axSpA)) was based on the modified New York (mNY) criteria. Information on mNY criteria on the pelvic radiographs was obtained in four reading waves over a 10-year period. Images were blinded and centrally read by 3 trained readers. The % of mNY net progressors (ie, number of 'progressors' minus number of 'regressors' divided by the total number of patients) was assessed in completers (ie, pelvic radiographs at baseline and 10 years). The yearly likelihood of mNY+ was estimated using an integrated analysis (ie, including all patients with at least one available mNY score ('intention-to-follow' population) using a generalised estimating equations model and time-varying tumour necrosis factor (TNF) use as a confounder. Baseline predictors of mNY+ during 10 years were evaluated. RESULTS: Completers included 294 patients, while intention-to-follow included 659 participants. In the completers, the net % progression (from nr-axSpA to r-axSpA) was 5.8%. In the intention-to-follow population, the probability of being mNY+ was estimated to increase 0.87% (95% CI 0.56 to 1.19) per year (ie, 8.7% after 10 years) while when introducing TNF inhibitors (TNFi) as a time-varying covariate, the probability was 0.45% (95% CI 0.09 to 0.81) (ie, 4.5% after 10 years). Baseline bone marrow oedema (BME) on MRI of the sacroiliac joints (SIJ) was associated with being mNY+ over time OR 6.2 (95% CI 5.3 to 7.2) and OR 3.1 (95% CI 2.4 to 3.9) in HLA-B27+ and HLA-B27-, respectively). Male sex, symptom duration >1.5 years, Axial Spondyloarthritis Disease Activity Score ≥2.1 and smoking (only in HLA-B27 positives) were also associated with being mNY+ over 10 years. BME was not found to be a mediator of the HLA-B27 effect on mNY+ at 10 years. CONCLUSIONS: The yearly likelihood of switching from nr-axSpA to r-axSpA in patients after 10 years of follow-up was low, and even lower when considering TNFi use.

Entry point of machine learning in axial spondyloarthritis.

Axial spondyloarthritis (axSpA) is a globally prevalent and challenging autoimmune disease. Characterised by insidious onset and slow progression, the absence of specific clinical manifestations and biomarkers often leads to misdiagnosis, thereby complicating early detection and diagnosis of axSpA. Furthermore, the high heterogeneity of axSpA, its complex pathogenesis and the lack of specific drugs means that traditional classification standards and treatment guidelines struggle to meet the demands of personalised treatment. Recently, machine learning (ML) has seen rapid advancements in the medical field. By integrating large-scale data with diverse algorithms and using multidimensional data, such as patient medical records, laboratory examinations, radiological data, drug usage and molecular biology information, ML can be modelled based on real-world clinical issues. This enables the diagnosis, stratification, therapeutic efficacy prediction and prognostic evaluation of axSpA, positioning it as an emerging research topic. This study explored the application and progression of ML in the diagnosis and therapy of axSpA from five perspectives: early diagnosis, stratification, disease monitoring, drug efficacy evaluation and comorbidity prediction. This study aimed to provide a novel direction for exploring rational diagnostic and therapeutic strategies for axSpA.

Validation of SPARCC MRI-RETIC e-tools for increasing scoring proficiency of MRI sacroiliac joint lesions in axial spondyloarthritis

BACKGROUND: The Spondyloarthritis Research Consortium of Canada (SPARCC) developers have created web-based calibration modules for the SPARCC MRI sacroiliac joint (SIJ) scoring methods. We aimed to test the impact of applying these e-modules on the feasibility and reliability of these methods. METHODS: The SPARCC-SIJ RETIC e-modules contain cases with baseline and follow-up scans and an online scoring interface. Visual real-time feedback regarding concordance/discordance of scoring with expert readers is provided by a colour-coding scheme. Reliability is assessed in real time by intraclass correlation coefficient (ICC), cases being scored until ICC targets are attained. Participating readers (n=17) from the EuroSpA Imaging project were randomised to one of two reader calibration strategies that each comprised three stages. Baseline and follow-up scans from 25 cases were scored after each stage was completed. Reliability was compared with a SPARCC developer, and the System Usability Scale (SUS) assessed feasibility. RESULTS: The reliability of readers for scoring bone marrow oedema was high after the first stage of calibration, and only minor improvement was noted following the use of the inflammation module. Greater enhancement of reader reliability was evident after the use of the structural module and was most consistently evident for the scoring of erosion (ICC status/change: stage 1 (0.42/0.20) to stage 3 (0.50/0.38)) and backfill (ICC status/change: stage 1 (0.51/0.19) to stage 3 (0.69/0.41)). The feasibility of both e-modules was evident by high SUS scores. CONCLUSION: The SPARCC-SIJ RETIC e-modules are feasible, effective knowledge transfer tools, and their use is recommended before using the SPARCC methods for clinical research and tria.

Male patients with inflammatory joint diseases are less likely than controls to be childless: results from a Norwegian population-based cohort study of 10 865 patients.

OBJECTIVES: To investigate the number of children per man and the proportion of childless men as a proxy of fertility in a national cohort of men with inflammatory joint diseases (IJDs), compared with matched controls from the general population. METHODS: This is a nationwide, population-based retrospective cohort study. Male patients with IJDs (n = 10 865) in the Norwegian Arthritis Registry were individually matched 1:5 on birth year and county of residence with men without IJDs obtained from the National Population Register (n = 54 325). Birth data were obtained from the Medical Birth Registry of Norway. We compared the mean number of children per man and the proportion of childless men and analysed the impact of age and year of diagnosis. RESULTS: The mean number of children per man in the patient group was 1.80 versus 1.69 in the comparison group (p <0.001), and 21% of the patients in the patient group were childless versus 27% in the comparison group (p <0.001). The finding of less childlessness and higher number of children per man remained consistent across age at diagnosis, except for those diagnosed at age 0-19 years. The difference in childlessness was most pronounced for men diagnosed after year 2000, especially when diagnosed at 30-39 years of age (22% vs 32%, p<0.001). CONCLUSION: In this large cohort study we found that patients with IJD have a higher number of children and are less likely to be childless compared with controls. Factors associated with developing or having an IJD might influence fertility and this requires further investigation.

Clinically relevant differences in spinal mobility related to daytime performance in patients with axial spondyloarthritis.

OBJECTIVE: Patients with axial spondyloarthritis (axSpA) suffer from clinical symptoms like morning stiffness and back pain. Mobility of patients with axSpA is often impaired. The aim of this study is to compare the performance of patients with axSpA regarding mobility measures including performance-based tests and objective electronic assessments with the Epionics SPINE device (ES) at different times of the day compared with healthy controls (HC). METHODS: Observational trial, consecutive inpatients with axSpA (n=100) and 20 HCs were examined in the morning (V1: before 10:00 am) and in the afternoon (V2: after 02:00 pm) by the Bath Ankylosing Spondylitis Metrology Index (BASMI), the AS physical performance index (ASPI), the Short Physical Performance Battery (SPPB) and ES measurements, including range of motion (RoM) and range of kinematics (RoK). RESULTS: The assessments of patients with axSpA performed in the morning clearly differed from those in the afternoon, especially regarding performance-based tests. Significant improvements were seen for BASMI (4.0±3.8 to 3.8±1.9; p<0.001), ASPI (36.2±18.3 to 28.8±11.9 s; p<0.001), SPPB (10.1±1.5 to 10.7±1.4 points; p<0.001) and for ES measures of speed (RoK; p<0.018) but not for RoM, except for lateral flexion (13.3±7.4 to 14.7±8.2°; p=0.002). This time of assessment-related variability was not observed in HC. CONCLUSION: The spinal mobility of patients with axSpA was worse in the morning but significantly improved in the afternoon. This was captured best by performance-based measures and was not seen in HC. The diurnal variation of mobility has implications for clinical studies, suggesting that the time of assessments needs to be standardised.

Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers.

OBJECTIVE: To explore the potential of a panel of ECM remodelling markers as endotyping tools for axial spondyloarthritis (axSpA) by separating patients into subtypes and investigate how they differ among each other in disease activity scores and response to treatment with adalimumab. METHODS: In three axSpA studies, a panel of 14 blood-based ECM biomarkers related to formation of collagen (PRO-C2, PRO-C3, PRO-C6), degradation of collagen by metalloproteinases (C1M, C2M, T2CM, C3M, C4M, C6M, C10C), matrix metalloproteinase (MMP)-degraded prolargin (PROM), MMP-degraded and citrullinated vimentin (VICM), basement membrane turnover (PRO-C4) and neutrophil activity (CPa9-HNE) were assessed to enable patient clustering (endotyping). MASH (n=41) was a cross-sectional study, while Adalimumab in Axial Spondyloarthritis study (ASIM,n=45) and Danish Multicenter Study of Adalimumab in Spondyloarthritis (DANISH, n=49) were randomised, double-blind placebo-controlled trials of adalimumab versus placebo every other week for 6 or 12 weeks, respectively, followed by active treatment. Biomarker data were log-transformed, standardised by mean centering and scaled by the SD prior to principal component analysis and K-means clustering. RESULTS: Based on all three studies, we identified two orthogonal dimensions reflecting: (1) inflammation and neutrophil activity (driven by C1M and CPa9-HNE) and (2) collagen turnover (driven by PRO-C2). Three endotypes were identified: high inflammation endotype (Endotype1), low inflammation endotype (Endotype 2) and high collagen turnover endotype (Endotype3). Endotype1 showed higher disease activity (Ankylosing Spondylitis Disease Activity Score (ASDAS)) at baseline compared with Endotype2 and Endotype3 and higher percentage of patients responding to adalimumab based on ASDAS clinical improvement at week 24. Endotype3 showed higher percentage of patients with 50% improvement in Bath Ankylosing Spondylitis Disease Activity Index response at week 24 compared with Endotype2. CONCLUSION: These endotypes differ in their tissue remodelling profile and may in the future have utility for patient stratification and treatment tailoring.

Atlas for the CT Syndesmophyte Score (CTSS) in patients with axial spondyloarthritis.

BACKGROUND: The Computed Tomography Syndesmophyte Score (CTSS) was developed as a reliable and sensitive tool to assess syndesmophytes in low-dose CT images of the entire spine in patients with axial spondyloarthritis (axSpA). The original paper provided sparce examples of the CTSS grades. OBJECTIVES: Provide an atlas tailored to assist readers in understanding and employing the CTSS method. METHODS: In this paper, illustrations of the different grades and views of the CTSS are presented. CTSS is used to measure bone formation in the spine of patients with axial spondyloarthritis (axSpA), in the form of syndesmophytes. In both the sagittal and coronal planes, syndesmophytes can be graded from 0 to 3 over 23 vertebral units starting at C2 and ending at S1. The CTSS ranges from 0 (absence of axSpA-related syndesmophytes) to 552 (total ankylosis of the spine). RESULTS: The current atlas contains low-dose CT images of the spine without lesions (for reference) and all grades of syndesmophytes in different planes used in the CTSS. Examples are arranged per spinal segment (cervical, thoracic and lumbar). CONCLUSIONS: These images can be used to assist any reader in the assessment of syndesmophytes on (low-dose) CT in patients with axSpA.