Annals of the Rheumatic Diseases最新文献

Objectives: To investigate the association between joint involvement pattern (JIP) subgroups and treatment responses to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biological disease-modifying antirheumatic drugs (bDMARDs), and to compare the impact of JIP subgroups with other clinical parameters in treatment-naïve patients with early rheumatoid arthritis (RA).

Methods: An individual patient data meta-analysis was conducted using 2 randomised controlled trials, NOrdic Rheumatic Diseases Strategy Trials And Registries (NORD-STAR) and Behandel-Strategieën (BeSt), including 1250 treatment-naïve patients with early RA. JIP subgroup assignment was based on 4 previously identified subgroups defined by baseline clinical characteristics, primarily joint involvement in the 66/68 joint scheme. Treatment outcomes were measured using the longitudinal Clinical Disease Activity Index (CDAI) and other disease activity indices through week 48. Associations of the JIP subgroups and other clinical predictors were evaluated using a mixed-model analysis.

Results: Patients with a hand-dominant JIP (JIP-Hand) showed significantly better CDAI scores after treatment (Beta for CDAI = -1.4 [95% CI, -2.3 to -0.55]; p = .0016), whereas those with a polyarthritis pattern (JIP-Poly) exhibited worse outcomes (Beta = 0.95 [95% CI, 0.064-1.8]; p = .035). Female sex was also associated with worse CDAI scores (Beta = 1.2 [95% CI, 0.40-2.0]; p = .0031), whereas anticitrullinated protein antibodies did not show a significant association (Beta = 0.19 [95% CI, -0.69 to 1.1]; p = .67). When compared across groups, csDMARDs and combined bDMARDs were similarly effective in the respective JIP subgroups (interaction p > .10).

Conclusions: In early RA, csDMARD and bDMARD treatments resulted in the greatest improvement in disease activity in JIP-Hand and the least improvement in JIP-Poly.

Objectives: This study aimed to evaluate the prevalence of suspected fibromyalgia using the Fibromyalgia Rapid Screening Tool (FiRST) and its impact on disease burden, disability, TNF inhibitor (TNFi) initiation, and treatment retention over 10 years in patients with axial spondyloarthritis (axSpA) from the DESIR cohort.

Methods: The FiRST questionnaire was administered annually from year 7 to year 10. Missing FiRST data were imputed using longitudinal multiple imputation. Patients were classified as suspected fibromyalgia-positive at baseline if they were FiRST-positive (FiRST ≥5/6) at least twice after multiple imputation. Associations with disease outcomes over the 10-year period were assessed using mixed models for repeated measures, adjusted for TNFi use. TNFi initiation and retention over 10 years were compared using Kaplan-Meier analyses.

Results: The estimated prevalence of suspected fibromyalgia was 21.7% (144/663; 95% CI: 18.6-25.1). At baseline, suspected fibromyalgia was associated with a lower prevalence of HLA-B27 positivity and radiographic sacroiliitis, but similar rates of magnetic resonance imaging sacroiliitis and elevated C-reactive protein. Over 10 years, suspected fibromyalgia was consistently associated with higher self-reported disease activity, poorer health-related quality of life, and greater disability. Permanent disability at 10 years occurred more frequently in patients with suspected fibromyalgia (26.4% vs 9.4%; P < .001). TNFi initiation was more frequent (64.4% vs 46.1%), but treatment persistence at 1 year was significantly lower (42.0% vs 64.2%) in this group.

Conclusions: Suspected fibromyalgia is common and clinically relevant in axSpA. It is associated with higher disease burden, increased biologic use, and poorer treatment persistence.

Objectives: Human leukocyte antigen (HLA) alleles, particularly of HLA-B and HLA-C, are associated with the susceptibility to and the expression of psoriatic arthritis (PsA). We aimed to identify HLA alleles and haplotypes associated with dactylitis and the time to resolution of tender dactylitis.

Methods: We retrieved longitudinal data on 1216 patients with PsA followed at an observational cohort. We screened HLA-B and -C alleles with >5% frequency in our sample for association with dactylitis by employing logistic regression fitted using generalised estimating equations. We also analysed common haplotypes. We then used Cox regression, adjusted for confounders, to explore the association between these alleles and haplotypes with the time to resolution of the first tender dactylitis episode.

Results: Dactylitis was observed in 584 (48%) patients over a median follow-up of 12.0 years (IQR: 5.7-20.1). HLA-B*27 (odds ratio [OR] 1.94, 95% CI 1.49-2.53), HLA-C*02 (OR 1.63, 95% CI 1.17-2.25), and HLA-B*27/C*02 (OR 1.88, 95% CI 1.32-2.67) were associated with a higher risk of dactylitis, whereas HLA-B*15 was associated with a lower risk (OR 0.72, 95% CI 0.54-0.98). A weaker association was observed for HLA-C*12 (OR 1.25, 95% CI 0.97-1.62) and HLA-B*27/C*01 (OR 1.40, 95% CI 0.99-2.00). Notably, HLA-B*27 was associated with slower resolution of tender dactylitis (hazard ratio 0.74, 95% CI 0.57-0.96).

Conclusions: HLA-B*27 and -C*02 and the HLA-B*27/C*02 haplotype are associated with PsA dactylitis. HLA-B*27 may also influence the resolution of tender dactylitis. These alleles are thus associated with PsA dactylitis susceptibility and severity; replication studies are required.

Objectives: This study aims to estimate the extent of the reduction in healthy working life expectancy (HWLE), from age 50, for people with rheumatic and musculoskeletal diseases (RMDs) in 19 countries across Europe and highlight the need to target extending working lives through interventions and policy.

Methods: Data were from 2 longitudinal studies (Survey of Health, Ageing and Retirement in Europe [2004-2022], English Longitudinal Study of Ageing [2002-2023]) that collect information in people aged 50 years and over. 'Healthy' and 'working' were defined as no limiting long-standing illness and employment/self-employment, respectively. RMDs were identified from self-report of ever having received a doctor diagnosis of arthritis or rheumatism. Age-adjusted discrete time 3-state models were fitted using IMaCh software, a maximum likelihood modelling programme using interpolation of Markov Chains, to estimate HWLE from transition probabilities between each healthy and working state based on RMD status (overall, by sex, education, and physical activity), stratified by 19 countries.

Results: In 6 countries, HWLE in the population with RMDs was around 50% or less than for the population without RMDs. The lowest HWLE for populations with RMDs was in Austria 2.60 (1.49, 3.71) years which was 42.9% of HWLE for the population without RMDs. HWLE was lower in populations with RMDs with lower than upper secondary education in all countries and in populations with RMDs categorised as physically inactive in 16 countries.

Conclusions: The differences observed in HWLE demonstrate the substantial societal burden associated with RMDs. However, differences by country, sex, education and physical activity indicate that there are opportunities for interventions and policies to increase HWLE.

Objectives: Understanding the molecular events underlying systemic lupus erythematosus (SLE) onset and progression can facilitate early intervention strategies. We explored transcriptomic changes during progression from preclinical to clinical and advanced SLE, and assessed their potential reversibility by targeted agents.

Methods: This includes multicentre prospective study of individuals with nondiagnostic features suggestive of SLE. Baseline blood RNA-sequencing was performed in groups who progressed to classifiable SLE or not (n = 36 each), and compared with healthy (n = 42) and early SLE (n = 43). Transcriptome analysis included supervised methods, gene module-based clustering, and drug reversibility/repurposing pipelines with publicly available data. An independent at-risk cohort (n = 15 progressors, n = 20 nonprogressors) was used to validate molecular classifiers.

Results: At-risk individuals exhibited deregulated metabolic, cytokine signalling, haematologic, and stress-response pathways. Progressors vs nonprogressors showed heightened interferon (IFN)-alpha (α)/gamma (γ) and inflammatory cytokine activity, corroborated by Gene Set Enrichment Analysis and coexpression analysis, and intensified during SLE classification. Unsupervised modelling of gene module-eigengene patterns revealed molecular heterogeneity among progressors, differing in p53/insulin activity and Toll-like receptor (TLR) signalling. Importantly, we characterised a 17-gene susceptibility signature that predicted transition with an area under the curve 0.80 of the receiver operating characteris (95% CI: 0.65-0.94) in the external cohort. Analysis across the continuum-from healthy and at-risk states to early SLE and lupus nephritis-revealed stepwise upregulation of IFN-α/γ, haem metabolism, and oxidative phosphorylation pathways, with additional IFN-related genes activated in established disease. SLE susceptibility and progression signatures demonstrated in silico reversibility by anifrolumab and belimumab.

Conclusions: IFN-α/γ and inflammatory cytokine signatures characterise evolving/early SLE, whereas amplification of IFN signalling and oxidative phosphorylation denotes severity. Blood molecular profiling may aid risk stratification and rationalise early biologic approaches.

Objectives: This study aims to evaluate the safety, biological activity, and exploratory clinical effects of CD19-directed T-cell engagement with blinatumomab in patients with severe, treatment-refractory antitopoisomerase I-positive systemic sclerosis (SSc).

Methods: We conducted an exploratory case series of 5 patients with refractory SSc who received a 14-day continuous intravenous infusion of blinatumomab (9 µg/d for 7 days, escalated to 28 µg/d for 7 days) in 2 tertiary hospitals. Safety assessments included cytokine release syndrome (CRS), neurotoxicity, infections, and serum immunoglobulin levels. Exploratory efficacy outcomes comprised modified Rodnan skin score (mRSS), pulmonary function tests, and patient-reported outcomes. Immunologic endpoints included serial peripheral CD19⁺ B-cell counts, B-cell subset phenotyping, and a 6-gene type I interferon signature. Patients' follow-up was a median of 8 months (range: 6-12).

Results: Blinatumomab administration was generally well tolerated. Three patients experienced low-grade CRS (grade 1, n = 2; grade 2, n = 1), managed conservatively; no neurotoxicity or severe infections occurred. Rapid peripheral CD19⁺ B-cell depletion was achieved in all patients. B-cell repopulation occurred by 1 month in all but 1 patient and was dominated by naïve and transitional subsets. At 3 months, modest clinical improvements were observed, including a median mRSS change of -4 points (range: +1 to -8) from a baseline of 16 (range: 0-25) and a transient improvement in lung function and patient-reported outcomes. However, all patients experienced clinical relapse between months 3 and 6, leading to resumption of immunosuppressive therapy in most cases.

Conclusions: CD19-directed T-cell engagement with blinatumomab induces rapid B-cell depletion and short-term clinical improvement in refractory SSc but lacks durability after a single treatment cycle.

Objectives: Cannabidiol (CBD) is used to alleviate fibromyalgia pain despite limited evidence for efficacy. This study assessed the efficacy and safety of CBD vs placebo in patients with fibromyalgia, hypothesising that CBD would be superior to placebo in reducing pain.

Methods: In this single-centre, double-blind, randomised, placebo-controlled trial, patients diagnosed with fibromyalgia were recruited from a specialised outpatient clinic in Denmark. Eligible participants were randomised 1:1 and stratified by sex, defined as biological sex assigned at birth based on physical anatomy. Age (<45 vs ≥45), and pain level (<7 vs ≥7) on a 0 to 10 numeric rating scale (NRS) to receive 50 mg plant-derived CBD or placebo tablets. The primary outcome was change in pain intensity at week 24, assessed on the NRS pain subitem in the revised Fibromyalgia Impact Questionnaire in the intention-to-treat population. Adverse events were monitored throughout the study in the safety population.

Results: Of 273 participants screened for eligibility, 200 were included and randomised to receive CBD (n = 100) or placebo (n = 100). At week 24, mean change in pain intensity was -0.4 points (95% CI: -0.82 to 0.08) in the CBD group and -1.1 points (95% CI: -1.53 to -0.63) in the placebo group, corresponding to a between-group difference of -0.7 points (95% CI: -1.2 to -0.25; P = .0028) favouring placebo. Adverse events were generally mild and evenly distributed between groups.

Conclusions: The findings do not support CBD 50 mg daily as an analgesic supplement for patients with fibromyalgia.

Clinicaltrials: gov number: NCT04729179.

Objectives: One-third of patients diagnosed with dermatomyositis harbour an occult cancer, a rare condition named cancer-associated dermatomyositis (CAD). Emerging evidence suggests that genetic alterations in autoantibody-related genes give rise to neoantigens and specific autoantibodies that initiate an autoimmune response characteristic of CAD. This study evaluated the prevalence of such genetic alterations and elucidated molecular mechanisms that may underlie their role in triggering autoimmunity.

Methods: Fifteen patients with CAD were included in the study. We conducted genomic and transcriptomic analyses of available leukocyte (germline), muscle, skin, and tumour samples. T-cell receptor (TCR) repertoire profiling and multiplex immunophenotyping were performed to characterise immune responses in tumoural and nontumoural tissues.

Results: Somatic mutations and loss of heterozygosity (LOH) in autoantibody-related genes as tripartite motif containing 33, tripartite motif containing 66, MORC family CW-type zinc finger 3 (MORC3), Chromodomain Helicase DNA Binding Protein 4, and IFIH1, interferon-induced helicase C domain-containing protein 1-corresponding to known myositis-specific autoantibodies Anti-transcriptional intermediary factor 1 gamma, anti-nuclear matrix protein 2, (anti-transcriptional intermediary factor 1 gamma (anti-TIF1γ), anti-nuclear matrix protein 2 (anti-NXP2), anti-Mi2, antimelanoma differentiation-associated gene 5 protein), were detected in the majority of tumours from patients with CAD (75%). Tumour-specific missense mutations gave rise to highly immunogenic neoantigens, while LOH resulted in enriched allelic expression not observed in nontumoural lesions (skin and muscle). Immunophenotyping revealed a clonally expanded lymphocyte population within tumours, but not in nontumoural lesions, suggesting a distinct cellular immune response.

Conclusions: We detected highly frequent genetic alterations in autoantibody-related genes, supporting their role in the CAD pathogenic mechanisms. Moreover, our findings suggest that distinct TCR repertoire and immune signatures between tumoural and nontumoural tissues may underlie divergent cancer and dermatomyositis outcomes.