Annals of the Rheumatic Diseases最新文献

Objective: To investigate gout flare rates based on repeated serum urate (SU) measurements in a randomised controlled trial of urate-lowering therapy (ULT), accounting for dropout and death.

Methods: We performed a secondary analysis using data from Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout, which randomised participants to febuxostat or allopurinol, titrated to target SU <6 mg/dL with flare prophylaxis for 6 months. SU was categorised as ≤3.9, 4.0-5.9, 6.0-7.9, 8.0-9.9 or ≥ 10 mg/dL at each 3-6 month follow-up. The primary outcome was gout flare. Poisson regression models, adjusted for covariates and factors related to participant retention versus dropout, estimated gout flare incidence rate ratios by time-varying SU category.

Results: Among 6183 participants, the median age was 65 years and 84% were male. Peak gout flare rates for all SU categories were observed in months 0-6, coinciding with the initiation of ULT and months 6-12 after stopping prophylaxis. Flare rates were similar across SU groups in the initial year of ULT. During months 36-72, a dose-response relationship was observed between the SU category and flare rate. Lower flare rates were observed when SU ≤3.9 mg/dL and greater rates when SU ≥10 mg/dL, compared with SU 4.0-5.9 mg/dL (p for trend <0.01).

Conclusion: Gout flare rates were persistently higher when SU ≥6 mg/dL after the first year of ULT after accounting for censoring. The spike in flares in all categories after stopping prophylaxis suggests a longer duration of prophylaxis may be warranted.

Objective: Despite the strong association between gout and pre-diabetes, the role of metformin in gout among individuals with pre-diabetes remains uncertain. We compared the incidence rates of gout in adults with pre-diabetes starting metformin with those not using antidiabetic treatments.

Methods: We conducted a new-user, propensity score-matched cohort study using electronic health records from an academic health system (2007-2022). Pre-diabetes was defined based on haemoglobin A1c levels. Metformin users were identified and followed from the first metformin prescription date. Non-users of antidiabetic medications were matched to metformin users based on propensity score and the start of follow-up. The primary outcome was incident gout. Cox proportional hazards models estimated the HR for metformin. Linear regression analyses assessed the association between metformin use and changes in serum urate (SU) or C-reactive protein (CRP).

Results: We identified 25 064 individuals with pre-diabetes and propensity score-matched 1154 metformin initiators to 13 877 non-users. Baseline characteristics were well balanced (all standardised mean differences <0.1). The median follow-up was 3.9 years. The incidence rate of gout per 1000 person-years was lower in metformin users 7.1 (95% CI 5.1 to 10) compared with non-users 9.5 (95% CI 8.8 to 10.2). Metformin initiation was associated with a reduced relative risk of gout (HR 0.68, 95% CI 0.48 to 0.96). No relationship was found between metformin and changes in SU or CRP.

Conclusions: Metformin use was associated with a reduced risk of gout among adults with pre-diabetes, suggesting that metformin may be important in lowering gout risk in individuals with pre-diabetes.

Objectives: Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies.

Methods: Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose.

Results: 110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors.

Conclusions: This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.

Background: Patient research partners (PRPs) are people with a disease who collaborate in a research team as partners. The aim of this systematic literature review (SLR) was to assess barriers and facilitators to PRP involvement in rheumatology research.

Methods: The SLR was conducted in PubMed/Medline for articles on PRP involvement in rheumatology research, published between 2017 and 2023; websites were also searched in rheumatology and other specialties. Data were extracted regarding the definition of PRPs, their role and added value, as well as barriers and facilitators to PRP involvement. The quality of the articles was assessed. Quantitative data were analysed descriptively, and principles of thematic content analysis was applied to qualitative data.

Results: Of 1016 publications, 53 articles were included; the majority of these studies were qualitative studies (26%), opinion articles (21%), meeting reports (17%) and mixed-methods studies (11%). Roles of PRPs ranged from research partners to patient advocates, advisors and patient reviewers. PRPs were reported/advised to be involved early in the project (32% of articles) and in all research phases (30%), from the conception stage to the implementation of research findings. The main barriers were challenges in communication and support for both PRPs and researchers. Facilitators of PRP involvement included more than one PRP per project, training of PRPs and researchers, a supportive environment for PRPs (including adequate communication, acknowledgement and compensation of PRPs) and the presence of a PRP coordinator.

Conclusion: This SLR identified barriers and facilitators to PRP involvement, and was key to updating the European Alliance of Associations for Rheumatology recommendations for PRP-researcher collaboration based on scientific evidence.

It is quite common to investigate multiple hypotheses in a single study. For example, a researcher may want to investigate the effect on several outcome variables or at different time points, compare more than two groups or undertake separate analyses for subgroups. This increases the probability of type I errors. Different procedures for multiplicity adjustment are available to control the probability of type I errors. In the present article, we describe some methods for multiplicity adjustment, along with recommendations.

Objective: Mechanisms underpinning clinical evolution to systemic lupus erythematosus (SLE) from preceding antinuclear antibodies (ANA) positivity are poorly understood. This study aimed to understand blood immune cell transcriptional signatures associated with subclinical ANA positivity, and progression or non-progression to SLE.

Methods: Bulk RNA-sequencing of peripheral blood mononuclear cells isolated at baseline from 35 ANA positive (ANA+) subjects with non-diagnostic symptoms was analysed using differential gene expression, weighted gene co-expression network analysis, deconvolution of cell subsets and functional enrichment analyses. ANA+ subjects, including those progressing to classifiable SLE at 12 months (n=15) and those with stable subclinical ANA positivity (n=20), were compared with 15 healthy subjects and 18 patients with SLE.

Results: ANA+ subjects demonstrated extensive transcriptomic dysregulation compared with healthy controls with reduced CD4+naïve T-cells and resting NK cells, but higher activated dendritic cells. B-cell lymphopenia was evident in SLE but not ANA+ subjects. Two-thirds of dysregulated genes were common to ANA+ progressors and non-progressors. ANA+ progressors showed elevated modular interferon signature in which constituent genes were inducible by both type I interferon (IFN-I) and type II interferon (IFN-II) in vitro. Baseline downregulation of mitochondrial oxidative phosphorylation complex I components significantly associated with progression to SLE but did not directly correlate with IFN modular activity. Non-progressors demonstrated more diverse cytokine profiles.

Conclusions: ANA positivity, irrespective of clinical trajectory, is profoundly dysregulated and transcriptomically closer to SLE than to healthy immune function. Metabolic derangements and IFN-I activation occur early in the ANA+ preclinical phase and associated with diverging transcriptomic profiles which distinguish subsequent clinical evolution.