Annals of the Rheumatic Diseases最新文献

Objectives: Vasculopathy and fibrosis are central to the pathogenesis of systemic sclerosis (SSc) and their genetic underpinnings are largely unknown. Here, we sought to examine the aetiology of severe vascular phenotypes and poorer outcomes in African American (AA) patients with SSc.

Methods: The study focuses on AA patients with SSc who have more severe vascular phenotypes and poorer outcomes and combines genetics, single-cell RNA sequencing, functional assays, and a mouse model to explore the role of NOTCH4 in SSc vasculopathy and the potential for NOTCH4-directed therapies.

Results: Gene-based testing identified NOTCH4 association at an exome-wide significance with SSc (P = 1.6 × 10^-7) and patients with severe vascular disease (P = 3.5 × 10^-7). The risk haplotype defined by the missense (c.2824C>T) and promoter (c.-117G>A) variants was enriched in AAs with SSc (11%) vs controls, and the population attributable risk due to this haplotype in AAs with SSc was 2.6%, which was 52-fold higher than in European Americans. The SSc-associated NOTCH4 variants increased NOTCH4 expression and signalling, leading to decreased angiogenesis and increased endothelial-to-mesenchymal transition (EndoMT). Nailfold capillary abnormalities, decreased angiogenesis, and fibrosis of the vascular lumen are commonly seen in SSc. Genetic, chemical, antibody, or Food and Drug Administration-approved drug inhibition of NOTCH4 signalling rescued angiogenesis and returned EndoMT to baseline.

Conclusions: NOTCH4 variants are associated with SSc pathogenesis and vasculopathy, partly explaining the increased prevalence of SSc in AAs. The study highlights the need for further research and clinical trials in the inhibition of the NOTCH4 pathway as a strategy to treat the vascular and fibrotic manifestations of SSc.

Objectives: In our previously reported trial of intra-articular tolerogenic dendritic cells (tolDC) as a treatment to restore immune tolerance in autoimmune arthritis, high doses of cells appeared to stabilise knee symptoms, although no systemic clinical or immunomodulatory effects were observed. We therefore sought to understand how tolDC affected the local synovial immune landscape.

Methods: Synovial biopsies were taken at baseline and 14 days after intra-articular injection of tolDC or, as a control, saline washout. Histopathological analyses (Krenn evaluation and pathotype) and multiparametric imaging mass cytometry (IMC) were performed on paired synovial tissues from 7 participants (5 tolDC-treated and 2 controls), selected based on tissue availability at both time points. The IMC panel included 27 antibodies defining lymphoid, myeloid, and stromal cells.

Results: We observed no changes in the histopathology or the overall distribution of broadly classified cell populations (myeloid, lymphoid, and stromal) before and after tolDC administration. Furthermore, the proportions of CD4⁺ and CD8⁺ T cells were not altered, with no indication that tolDC had induced regulatory T cells within the synovium. However, we found a significant increase in a subset of myeloid cells expressing high levels of the inflammation resolution marker Mer tyrosine kinase (MerTK^High), which positively correlated with tolDC dose. Moreover, the percentages of total MerTK⁺ myeloid cells inversely correlated with arthroscopic synovitis scores at both time points.

Conclusions: The tolDC-induced increase in synovial Myeloid MerTK^High cells may have local immune modulatory effects and provide promising evidence for an effect of tolDC treatment on the synovial immune landscape.

Objectives: Early treatment is critical for improving outcomes in rheumatoid arthritis (RA), with patient-initiated delays being a key barrier. Socioeconomic status (SES) influences health behaviour, but its role in the timing of first general practitioner (GP) contact after RA symptom onset remains unclear. This study examined the association between SES and time to help-seeking in people newly diagnosed with RA.

Methods: Data on incident RA were collected from the Danish Rheumatology Database. Patients' self-reported time from symptom onset to first GP contact was collected via questionnaire data. Responses were linked to national registries for SES information, including education, wealth, cohabitation status, and occupation. Median delays and IQRs were calculated overall, and by SES strata. Multiple logistic regression provided adjusted odds ratios (aOR) and 95% CIs. Selection bias was investigated by comparing the SES between responders and nonresponders.

Results: Median patient delay was 59 days (IQR 15-182). Medium education level was associated with longer delay compared to high level (aOR 1.96 [CI: 1.01-3.79]); low occupational status showed a tendency towards longer delay (aOR 1.58 [CI: 0.47-5.33]). No consistent associations were found for wealth or cohabitation. Delays were longer among younger patients, those without comorbidities, and those with lower disease activity. Significantly lower SES was seen among nonresponders.

Conclusions: Educational level showed the strongest socioeconomic association with patient delay. The nonresponse analysis highlighted a possible overrepresentation of socially vulnerable patients among nonresponders, reinforcing the need to address equity in early RA care pathways.

Objectives: The aim of the study was to determine the frequency of adverse pregnancy outcomes in women with spondyloarthritis (SpA) in comparison to controls from the French general population, and to identify factors associated with these adverse pregnancy outcomes.

Methods: This French prospective multicentre cohort study included pregnant women with SpA (both axial and peripheral) according to their treating rheumatologist between December 2015 and June 2021. Maternal characteristics, disease activity, treatments, and pregnancy outcomes were analysed. Outcomes of pregnancies in women with SpA were compared to that of matched (1:4) general population women from the 2016 and 2021 French National Perinatal Surveys, including pregnancy, neonatal, and maternal outcomes. For adverse pregnancy outcomes that are significantly more frequent in patients with SpA, logistic regression analysis was performed to identify potential risk factors.

Results: A total of 135 SpA pregnancies in 124 women were analysed: they have a mean age of 32.1 years, a mean disease duration of 6.3 years, and 50.4% were nulliparous. Small for gestational age (SGA) was the most common adverse pregnancy outcome and occurred more frequently in women with SpA compared to controls (17.4% vs 9.8%, odds ratios = 1.94, 95% CI 1.09-3.39). Other adverse pregnancy outcomes rates, including preterm birth and caesarean delivery, were comparable to the general population. No predictor of SGA was identified in women with SpA.

Conclusions: In this contemporary cohort, compared to the general population, SpA was associated with a higher risk of SGA, but no other adverse pregnancy outcomes, providing reassurance for most pregnant women with SpA.