RMD Open最新文献

Objective: Cardiac involvement is a major complication of systemic sclerosis (SSc), with myocardial fibrosis as a hallmark feature. Cardiovascular magnetic resonance (CMR) is used to detect cardiac involvement. However, the prognostic value of serial CMR monitoring and the effects of immunosuppressive therapy remain unclear. This study aimed to assess the prognostic significance of CMR parameter evolution for long-term cardiovascular outcomes and to evaluate the impact of immunosuppressive treatments on myocardial fibrosis.

Methods: Patients from a single centre who underwent two CMR scans using the same protocol and equipment were included. CMR parameter evolution was compared using paired t-tests. The effects of treatments and changes in CMR parameters on the occurrence of major adverse cardiovascular events (MACE) and mortality were analysed using Kaplan-Meier curves and log-rank tests.

Results: 44 patients were included with a median (IQR) follow-up duration of 6.3 (3.1-9.2) years. The median interval between CMR scans was 1.5 (1.0-3.9) years. Seven (16%) patients had diastolic dysfunction, and 16 (36%) patients experienced MACE. Rituximab significantly decreased maximal T1 values (p=0.029), a marker of diffuse myocardial fibrosis linked to an increased risk of all-cause death (p=0.044). A significant increase in left ventricular ejection fraction (p=0.032) and a lower risk of MACE (p=0.024) were observed in patients treated with methotrexate.

Conclusion: Methotrexate was associated with reduced MACE risk, while rituximab decreased maximal T1 value, suggesting a reduction in diffuse myocardial fibrosis. These findings support the prognostic value of CMR monitoring and the potential benefit of immunosuppressive therapy in SSc-related cardiac involvement.

Objective: To develop a pragmatic model to predict total knee replacement (TKR) in knee osteoarthritis using non-imaging clinical, genetic and lifestyle data with machine learning (ML)-guided feature selection.

Methods: We analysed 3790 Osteoarthritis Initiative participants. Nested ML feature selection on the training set identified 15 informative variables. Classifiers were benchmarked, then a multivariable logistic regression was fit on the full cohort. Performance was summarised by discrimination (area under the curve (AUC) with 95% CI) and calibration (Brier score). To assess the incremental value of genetics, we refit an otherwise identical clinical model excluding the Polygenic Risk Score (PRS) and compared specificity at fixed sensitivities using Bonferroni-adjusted McNemar tests. A prespecified analysis examined performance by baseline Kellgren-Lawrence (KL) grade (KL 0-1 vs KL ≥2).

Results: On the test set, classifier AUCs ranged 0.716-0.748, with Elastic Net and XGBoost performing best. The final logistic model fit on the full cohort achieved AUC 0.765 (95% CI 0.736 to 0.793) with acceptable calibration (Brier 0.097). Performance remained robust by disease stage, with higher discrimination in pre-radiographic knees (KL 0-1: AUC 0.827) and moderate discrimination in KL ≥2 (AUC 0.720); decile plots indicated broadly aligned observed versus predicted risks. PRS added modest, statistically significant gains in specificity at several fixed sensitivities without materially changing AUC.

Conclusions: We present a pragmatic, non-imaging, ML-informed model that predicts TKR with clinically acceptable discrimination and calibration using routinely collected data. This framework provides a practical basis for individualised risk stratification and decision support without reliance on imaging.

Objectives: To assess the effectiveness of switching biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with low-inflammatory difficult-to-treat rheumatoid arthritis (D2T RA).

Methods: Using the multicentre FIRST registry, we identified D2T RA between August 2013 and March 2024. Low-inflammatory D2T RA was defined as a swollen 28-joint count ≤1 and C-reactive protein <10 mg/L. In the low-inflammatory D2T RA group, we compared those who underwent b/tsDMARD switching (the switch group) with the non-switch group. The primary outcome was the 6-month change in Clinical Disease Activity Index (CDAI).

Results: Among 3519 patients, 457 fulfilled the D2T RA criteria, and 173 were low-inflammatory D2T RA. Compared with inflammatory D2T RA, these patients had a shorter disease duration (127.4 vs 146.4 months), lower methotrexate (9.2 vs 10.5 mg/week) and glucocorticoid doses (4.3 vs 5.2 mg/day), and higher rates of fibromyalgia (2.9% vs 1.4%) and psychological disorders (5.2% vs 1.8%). The proportion receiving b/tsDMARD switching was lower in low-inflammatory than in inflammatory D2T RA (29/173 (16.8%) vs 217/284 (76.4%)). In the propensity score-matched analysis, the switch group (n=15) showed greater improvements in CDAI and pain than the non-switch group (n=30) (-6.6 vs -2.2, -15.3 vs -3.4, both p<0.05). Even among patients with low-grade sonographic activity (greyscale ≤1, power Doppler=0), b/tsDMARD switching improved CDAI (16.8 to 9.7).

Conclusions: A subset of patients with low-inflammatory D2T RA may benefit from b/tsDMARD switching, indicating that low-inflammatory status alone should not preclude consideration of treatment intensification.

Objectives: Female sex and anticitrullinated protein antibodies (ACPA) are associated with higher disease activity in rheumatoid arthritis (RA). Since disease-related inflammation is linked to cardiovascular risk, we explored whether sex and ACPA influenced the association between disease activity at study entry and cardiovascular risk in established RA.

Methods: We evaluated 4008 patients with prevalent RA from an international observational cohort enrolled between 1985 and 2012. Outcomes included major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction and stroke) and ischaemic cardiovascular events (iCVE: MACE, angina, revascularisation, transient ischaemic attack and peripheral arterial disease). Follow-up accrued from enrolment until the first event or censoring. Multivariable Cox models stratified by centre risk evaluated disease activity, sex, ACPA and their interactions.

Results: We documented 193 MACE and 299 iCVE. Disease activity and sex were associated with MACE (all p≤0.017) and iCVE (p≤0.005) but ACPA was only associated with MACE (p=0.043). A three-way interaction on MACE (p=0.034) but not iCVE was noted. Among ACPA-negative patients, disease activity was associated with MACE in males (HR 1.57 (95% CI 1.14 to 2.16)) but not females (p-for-interaction=0.022). Among ACPA-positive patients, neither the disease activity x sex interaction (p=0.929), nor main effect of disease activity on MACE (p=0.124) was significant, but male sex was (HR 1.61 (95% CI 1.15 to 2.27)). Among females, neither disease activity x ACPA interaction (p=0.523) nor disease activity (p=0.319) was significant for MACE, but ACPA was (HR 1.57 (95% CI 1.02 to 2.42)).

Conclusions: The effect of disease activity at enrolment on cardiovascular risk in prevalent RA varies across patient groups with different sex and ACPA characteristics.

Objectives: This prespecified interim analysis of the PRO-SPIRIT observational study compares the effectiveness and persistence of ixekizumab (IXE) with other biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) among patients with psoriatic arthritis (PsA) after 12 months of real-world treatment.

Methods: Data were collected from a multinational cohort (n=1192) initiating IXE or other b/tsDMARDs. Comparative effectiveness between IXE and other b/tsDMARDs was assessed using frequentist model averaging, with multiple imputation for missing data. Pairwise comparisons were performed between IXE and tumour necrosis factor inhibitors (TNFi), secukinumab (SEC), Janus kinase inhibitors and pooled interleukin (IL)-12/23i & IL-23i groups.

Results: At month 12, IXE-treated patients displayed improvement in clinical Disease Activity in PsA index (cDAPSA) and body surface area (BSA) and the highest remission rate (cDAPSA score≤4; 18.8%). Versus pooled IL-12/23i and IL-23i, IXE patients were more likely to achieve cDAPSA remission (OR 2.0 (95% CI 1.2 to 6.0)) or very low disease activity (VLDA; OR 2.5 (1.1 to 13.6)), with greater pain reduction (least squares mean (LSM) (95% CI) -7.3 (-13.2 to -0.7)). Compared with TNFi, IXE patients exhibited greater BSA improvement (LSM (95% CI) -0.9 (-1.4 to -0.1)). IXE and SEC results were similar; most SEC patients received the 300 mg dose. Persistence rates were similar across groups, with varying reasons for discontinuation.

Conclusions: IXE patients had significantly greater odds of achieving cDAPSA remission and VLDA, plus greater pain reduction versus the pooled IL-12/23i and IL-23i group, with significant improvements in BSA versus TNFi. Treatment persistence was similar among all b/tsDMARDs.

Objectives: To assess the impact of rheumatoid factor (RF) levels and previous inadequate responses/intolerance to tumour necrosis factor inhibitors (TNFi-IR) on the efficacy of certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA) through a post hoc analysis of the RA Evaluation in Subjects Receiving TNF Inhibitor CZP (REALISTIC) trial.

Methods: In the phase IIIb REALISTIC trial, patients with RA were randomised to CZP (400 mg at weeks 0, 2 and 4, then 200 mg every 2 weeks) or placebo (PBO) for 12 weeks, followed by open-label CZP (minimum 16 weeks). Outcomes reported to week 36 include Disease Activity Score 28 C-reactive protein (DAS28-CRP) and Clinical Disease Activity Index (CDAI) scores, rates of DAS28-CRP <2.6 and CDAI remission (CDAI ≤2.8) and components of each. Data were stratified by baseline RF level (≤3rd quarter (≤Q3; <180 kU/L) vs 4th quarter (Q4; 'high RF'; ≥180 kU/L)) and prior TNFi use (TNFinaïve vs TNFi-IR).

Results: A total of 930 patients were included: 751 CZP-randomised and 179 PBO-randomised. At week 12, CZP-randomised patients experienced marked and similar improvements in disease activity, irrespective of RF level and prior TNFi use, while PBO-randomised patients did not. Responses generally improved through week 36 in CZP-treated patients (including PBO-randomised switchers), with similar efficacy across subgroups.

Conclusions: Patients with high and low RF levels experienced similar clinical responses to CZP treatment, irrespective of previous inadequate responses or intolerance to TNFis. These findings expand previous observations, supporting CZP as an effective treatment for patients with RA who have high RF levels and prior inadequate responses to TNFis.

Trial registration number: NCT00717236.

Objectives: To identify clusters of highly correlated genes enriched in biological functions and specific molecular pathways involved in the pathogenesis of radiographic damage in axial spondyloarthritis (axSpA) and to discover molecular biomarkers of radiographic progression and disease severity.

Methods: A total of 144 patients with axSpA were included. First, RNA from peripheral blood mononuclear cells was sequenced in a cohort of 24 patients with axSpA. Hub genes were measured in a n=60 validation cohort through microfluidic PCR. A 5-year follow-up enabled the classification of the patients into fast/moderate or slow progressors. Machine learning approaches were applied to identify a predictive biomarker of progression by integrating gene expression data with clinical variables. An independent cohort of 60 patients with axSpA, with spine radiographs taken 5 years prior, underwent serum proteomic analysis using a Proximity Extension Assay.

Results: Unsupervised clustering analysis using transcriptomics revealed two distinct groups of patients with axSpA, differentiated by their clinical profiles. Weight gene correlation network analysis identified six gene modules differentially expressed between the two clusters. Patients in cluster 2 exhibited higher disease activity, greater functional impairment and more structural damage. Molecular alterations linked to structural damage revealed a specific circulating inflammatory proteome profile associated with disease severity. A predictive model composed of two genes and basal total modified Stoke Ankylosing Spondylitis Spinal Score emerged as a key biomarker for identifying moderate-to-fast radiographic progression.

Conclusions: This study identified molecular pathways involved in radiographic damage and discovered potential proteomic biomarkers of disease severity and transcriptomic predictors of radiographic progression in axSpA.

Objective: Studies of dermatomyositis (DM) are frequently limited to single-centre cohorts. We used two large nationally representative US cohorts to conduct a descriptive epidemiological study of the characteristics, treatments and outcomes of patients with incident DM.

Methods: This retrospective study identified two DM inception cohorts using (1) commercial claims and (2) electronic health record (EHR) data from the Excellence Network in Rheumatology to Innovate Care and High-impact research (ENRICH), a community rheumatology practice-based research network. Patient characteristics, treatments and healthcare utilisation were assessed using the 18 months before and 12 months after diagnosis in claims and the 12 months before and after diagnosis in EHR data.

Results: We identified 2475 patients (claims) and 1196 patients (EHR) with incident DM. Among 998 patients in the EHR cohort with available laboratory data, 472 had available myositis panel results, with 165 (35.0%) having a positive myositis-specific antibody. Glucocorticoid use was common, 68.7% and 73.8% in the two cohorts, respectively, with initial doses most often >20 mg/day; among glucocorticoid users, mean cumulative dose was 1407 mg in the claims cohort. Hydroxychloroquine, methotrexate and mycophenolate were the most commonly used immunomodulatory therapies. During follow-up in the claims data cohort, incidence per 1000 person-years was 92.2, 15.3, 6.4, 2.9 and 2.1 for all-cause hospitalisation, malignancy, interstitial lung disease, gastrostomy tube placement and myocarditis, respectively.

Conclusion: Administrative claims and EHR data can be leveraged to assess treatment patterns and longitudinal outcomes/disease manifestations in incident dermatomyositis cohorts. This study highlights a high burden of glucocorticoid exposure, significant heterogeneity in treatment and high healthcare utilisation in this population.

Background: Existing proteomic studies have primarily focused on gout flares or symptomatic hyperuricaemia, and few have comprehensively investigated circulating proteomic profiles in serum urate (SU) concentration as a continuous quantitative trait. This cross-sectional study investigated the association between SU concentration and serum proteomic profiles.

Methods: We enrolled 176 Japanese individuals aged ≥50 years and measured serum proteins using the Olink Explore 3072. To analyse the association between SU concentration and serum proteins, we applied linear regression adjusting for age, sex, renal function and insulin resistance with a false discovery rate threshold of 5%. Tissue-specific and gene set enrichment analyses were conducted based on the regression results.

Results: A total of 2886 proteins were analysed, among whom 63 showed significant associations with SU concentration; uromodulin demonstrated the strongest association (adjusted p=2.21×10^-5). These 63 SU-associated proteins were significantly enriched in the liver, kidneys and duodenum by tissue-specific enrichment analysis. We further examined p.Q141K-a dysfunctional variant of adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2). Among p.Q141K minor allele carriers (n=91), 11 SU-associated proteins were identified, whereas no significant SU-associated proteins were detected in wild-type homozygotes (n=85). Gene set enrichment analysis highlighted xenobiotic metabolism in wild-types and additional inflammation- and disease-related gene sets in minor allele carriers.

Conclusions: To the best of our knowledge, this is the first study to report a proteomic signature of SU concentration. These findings suggest that SU-associated proteomic signatures vary according to ABCG2 genotypes, highlighting the genetic contribution to pathophysiological processes associated with SU concentration variation.

Trial registration number: NCT00262691.