Annals of the Rheumatic Diseases最新文献

Many people with chronic inflammatory arthritis (IA) experience significant disease impact, even with well-controlled disease activity. For rheumatoid arthritis (RA), 20% to 50% of patients in remission still report pain, disability, fatigue, or negative illness perceptions, leading to poorer long-term outcomes. However, evidence shows that long-term patient-reported outcomes improve when remission is achieved early, and that this is at least partly explained by a positive influence on psychological factors like illness perceptions. Based on these insights and a narrative literature review, we propose a conceptual framework to support clinical practice and further research in the prevention of the long-term impact of chronic IA, using the example of RA. Building on Leventhal's Model of Self-Regulation, the 'positive perspective paradigm' postulates that the early stages of a chronic inflammatory disease present an optimal time window where appropriate intervention might positively influence one's health perspective, in turn contributing to reduced long-term disease impact. Through the model, we discuss how pharmacological control of inflammation can be integrated with patient education and psychosocial support, emphasising early intervention and positive communication whenever possible. We hypothesise that these interventions have both direct effects on the long-term impact of chronic IA and indirect effects through a positive influence on the patient's health perspective. Fostering a positive perspective is thus the focal point of the model. By proposing this paradigm, we aim to provide a foundation for further validation in independent cohorts or other chronic inflammatory conditions, with the ultimate goal of implementing it to reduce long-term disease impact and promote well-being.

Objectives: This study aims to evaluate the efficacy and safety of IM19, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell, in patients with refractory systemic lupus erythematosus (SLE), with a particular focus on lupus nephritis (LN).

Methods: This is an open-label, single-arm clinical trial. IM19 was administered following lymphodepletion. Repeated renal biopsies were performed at day 180. Single-cell RNA sequencing on peripheral blood mononuclear cells was performed pre- and 180-day post-CAR-T infusion. A literature search on the efficacy of CAR T-cell therapy in LN in PubMed database was conducted.

Results: Six patients with refractory SLE and renal involvement were enrolled. IM19 therapy was well tolerant, with mild cytokine release syndrome occurring in 4 patients. The median Systemic Lupus Erythematosus Disease Activity Index-2000 score decreased from 12 (range, 10-24) to 4 (range, 2-8) at day 90, and remained stable at 5 (range, 2-6) at day 180. The renal responses were heterogeneous with 2 complete responders, 2 partial responders, and 2 nonresponders. Repeated renal biopsies showed no B-cell infiltration, but dominant chronic changes and podocytopathies post-CAR-T therapy. A mini-review demonstrated that the renal complete response rate of CAR-T therapy was 72.4%, and advanced age was associated with suboptimal response. Single-cell analysis confirmed B-cell reconstitution in 3/6 patients.

Conclusions: IM19 CAR T-cell therapy demonstrated a favourable safety profile and clinically meaningful systemic improvement. Responses to CAR-T therapy in LN were variable. Chronic renal manifestations, podocytopathy, and ageing were associated with suboptimal therapeutic outcome.

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.