Annals of the Rheumatic Diseases最新文献

Objectives: Systemic lupus erythematosus (SLE) is a complex autoimmune disease strongly associated with the major histocompatibility complex (MHC) region, but precisely pinpointing the risk variants remains challenging. This study aimed to comprehensively profile SLE-driving variants using a newly developed East Asian MHC imputation reference panel, capable of simultaneously imputing diverse MHC variants, including multilevel human leukocyte antigen (HLA) variants and copy number variations (CNVs) of C4 elements, such as C4A, C4B, and human endogenous retrovirus (HERV).

Methods: Using the whole-genome-sequencing (WGS) data from ∼2000 Korean samples, we genotyped and phased MHC variants, including HLA variants and C4-related CNVs, to construct an MHC reference panel. Imputation performance of the panel was assessed through leave-one-out cross-validation and validated using WGS and droplet digital polymerase chain reaction methodology. The panel was applied to 2 independent SLE genome-wide association study datasets, followed by stepwise conditional analyses, fine-mapping, and model comparisons.

Results: The MHC panel achieved high imputation accuracies of 95% for HLA and 94% for C4 at the haploid-level. Independent contributions to SLE risk were identified from 6 amino acid positions altering the epitope-binding surfaces of HLA-DRB1 and HLA-C. Reduced C4A copy numbers and increased HERV copy numbers, collectively lowering C4 protein levels, were associated with increased SLE risk, independent of HLA variants. Our refined MHC-SLE association model provided superior explanations for SLE risk over previous association models in an independent Korean population.

Conclusions: This study enhanced the understanding of HLA and C4 in SLE pathogenesis and holds promise for advancing MHC association studies for immune-mediated inflammatory disorders in East Asians using our MHC panel, accessible via https://coda.nih.go.kr/usab/kis/intro.do.

Objectives: Despite advances in rheumatoid arthritis (RA) treatment, a significant proportion of patients fail to achieve adequate remission. The dynamic cellular and architectural changes within the synovium that underpin therapeutic success remain poorly understood. This study aimed to unravel the synovial landscape during effective RA treatment, identifying key cellular networks and molecular pathways associated with remission.

Methods: We performed high-dimensional imaging mass cytometry on synovial tissues from healthy controls, patients with osteoarthritis, and patients with early RA longitudinally before and after 6 months of conventional synthetic disease-modifying antirheumatic drugs (csDMARD) therapy. Findings were validated using whole-tissue RNA-sequencing and immunofluorescence in larger patient cohorts, and integrated with ligand-receptor analyses from public single-cell RNA-seq datasets and in vitro functional coculture assays.

Results: Our deep spatial profiling pinpointed a critical LYVE1⁺CD206⁺tissue-resident macrophage network, localised within perivascular niches alongside fibroblasts and vascular cells. This homeostatic network was disrupted in active RA but restored in patients responding well to csDMARDs. This restoration correlated with the re-establishment of specific cell-cell interactions and was governed by distinct molecular pathways, including chemokines, annexins, and TAM (TYRO3, AXL, MERTK) receptors. Functionally, LYVE1⁺ macrophages demonstrated a regulatory, anti-inflammatory phenotype in vitro, contrasting with proinflammatory myeloid cells.

Conclusions: This study provides an unprecedented spatial and dynamic blueprint of the RA synovium's response to therapy. We identify the LYVE1⁺ macrophage network as a pivotal component of synovial homeostasis and its restoration as a hallmark of clinical remission. These findings unveil novel cellular and molecular targets, paving the way for more active therapeutic strategies.

Objectives: This study aims to quantify the impact of population ageing on the global burden and healthcare costs of musculoskeletal (MSK) disorders across 204 countries and territories from 1990 to 2021, stratified by geographic region, sociodemographic index (SDI), sex, and major MSK subcategories.

Methods: The global burden of MSK disorders attributed to population ageing was evaluated using decomposition analysis, while related healthcare costs were estimated through an extrapolation approach.

Results: Between 1990 and 2021, population ageing was the largest contributor to the increases in incident cases, prevalent cases, and disability-adjusted life-years (DALYs) in 33.3%, 37.7%, and 35.8% of countries and territories, respectively. Inverted U-shaped associations were observed between SDI and the proportions of incident cases, prevalent cases, and DALYs attributed to population ageing, with middle SDI countries exhibiting the highest proportions. Declines in incidence rates have partially offset the increase in incident cases due to population ageing globally. However, population ageing contributed more to the increases in prevalent cases and DALYs than increases in epidemiological rates. Males were more affected by population ageing globally, particularly in high and high-middle SDI countries, whereas females were more impacted in low-to-middle SDI countries. Osteoarthritis was the MSK disorder most influenced by population ageing globally, followed by gout and rheumatoid arthritis. In 2021, population ageing contributed US$96.0 billion to global healthcare costs for MSK disorders, equivalent to 0.10% of global gross domestic product.

Conclusions: Over the past 3 decades, the global burden of MSK disorders attributed to population ageing has consistently increased. Public health strategies, tailored to SDI level, sex, and specific MSK subcategories, should not only enhance prevention efforts but also strengthen long-term management to mitigate the rising global burden and economic impact of MSK disorders driven by population ageing.

Objectives: Entheseal inflammation (ligament and tendon insertions) and subclinical intestinal inflammation are both hallmarks of the seronegative spondyloarthropathy (SpA) diseases. While regulatory T cells (Tregs) are key to intestinal homeostasis, entheseal homeostatic mechanisms are poorly understood in humans.

Methods: Single-cell RNA sequencing of entheseal tissue, comparative transcriptomic analysis with intestinal tissue datasets, and functional analysis of entheseal stromal populations were undertaken. Functional immunomodulation by entheseal mesenchymal stromal cells (MSCs) was evaluated via coculture with activated T cells. CD39/CD73 pathway involvement was confirmed using pharmacological inhibition and transcriptional profiling.

Results: Single-cell RNA sequencing of 27,348 entheseal cells revealed a lower frequency of Tregs in the T cells of the enthesis (2.60% ± 0.36%) compared to those of the ileum (7.37% ± 4.47%) and colon (18% ± 8.59%). We found that entheseal fibroblasts expressed key immunomodulatory markers, including CD39 (ENTPD1) and CD73 (NT5E), which were further upregulated upon coculture with activated T cells. Entheseal MSCs significantly suppressed T cell proliferation (up to 89%, P < .0001) in an adenosine-dependent manner. Transcriptional profiling revealed that entheseal MSC cocultured with activated T cells upregulated genes of known functional importance in Treg, including IL10, IDO1, PTGS2, HLA-G, and CD274. In this assay, dual CD39/CD73 inhibition restored T cell proliferation by ∼48% (P = .0004), confirming that entheseal MSC-mediated immunomodulation acts in part through an adenosine-mediated mechanism.

Conclusions: The normal spinal enthesis harbours an immunoregulatory cellular environment related to entheseal MSCs that utilises the CD39/CD73 adenosine ectonucleotidase axis that may help maintain local immune homeostasis, while the same adenosine ectonucleotidase immunoregulatory pathway is likely dependent on Treg function in the intestine. This has broad implications for understanding the cellular bases of immune dysregulation in the gut-joint axis and could help guide tissue-specific therapy in SpA.

Objectives: The lack of effective biomarkers for relapsing polychondritis (RP) poses a significant challenge in its early diagnosis and treatment. This study aimed to identify novel autoantibodies and elucidate the pathogenesis and molecular heterogeneity of RP.

Methods: Plasma samples from 467 RP patients, 164 healthy controls (HCs), and 186 disease controls (DCs) were analysed using 2 sequential microarrays and enzyme-linked immunosorbent assay to sequentially discover, validate, and verify new autoantibodies. Machine learning and differential analysis were used to identify diagnosis-specific autoantibodies and their correlation with disease activity, recurrence, and remission.

Results: The RP group had 1344 elevated autoantibodies, discriminating RP patients from HCs. These antigenic targets were associated with pathways involving autoimmune responses, infections, and cardiovascular lesions. Two molecular subtypes characterised by distinct organ involvement and prognosis highlighted the heterogeneity of RP. Notably, 14 new autoantibodies were identified, which differentiated RP versus HCs and DCs with a sensitivity of 41% and 49.7% and a specificity of 91.7% and 90.5%, respectively. Among them, 6 autoantibodies showed better diagnostic performance and were consistently verified. Specifically, anti-C4B was positively correlated with disease activity, and increased anti-KRT16 predicted RP recurrence within 1 year. In addition, anti-C4B, anti-FNBP4, and anti-KRT10 decreased from acute attack to remission. Furthermore, the deposition of C4B protein in tracheal tissues, coupled with its reduction in plasma of RP patients, indicated that abnormal complement activation might be related to the pathological mechanism of RP.

Conclusions: The 14 autoantibodies promoted a noninvasive early detection of RP, predicted disease recurrence and provided new insights into the understanding of RP pathogenesis.

Objectives: To synthesise existing evidence on transitional care programmes for young people with juvenile-onset rheumatic and musculoskeletal diseases (jRMDs), focusing on their structure and implementation, the qualitative experiences and perceptions of those involved, and the quantitative outcomes associated with these programmes. Together with additional information, these insights have informed the European Alliance of Associations for Rheumatology (EULAR) Points to Consider for patient education in physical activity and self-management of pain in jRMDs during transitional care.

Methods: A systematic literature review was conducted with a broadened scope beyond patient education in physical activity and self-management of pain to provide a comprehensive overview of transitional care in rheumatology, aiming to optimise current strategies, support evidence-based approaches, and identify areas for clinical improvement. The search was conducted in PubMed and the Cochrane Library from inception until November 1, 2023. Descriptive, qualitative, and quantitative studies were included. Two researchers independently conducted the search, screening, data extraction, and quality assessment.

Results: From 31 studies, we identified 18 transitional care programmes with key approaches, including individualised and developmentally appropriate plans that often integrate educational strategies. These programmes, which generally aim to increase readiness to transfer, health-related quality of life, and continuity of care, frequently involved multidisciplinary teams and early intervention strategies. Young people with jRMDs and their families reported satisfaction with these transitional care experiences, particularly valuing early self-management support. While these programmes showed potential in promoting positive health outcomes and clinical practices, quantitative evidence supporting their effectiveness is limited, with few experimental studies confirming consistent benefits.

Conclusions: This systematic review highlights the diverse yet fragmented approaches in transitional care for jRMDs, emphasising the need for stronger quantitative evidence. Thus, it is important to conduct further experimental research to optimise existing programmes or develop new ones, ultimately contributing to a smoother transition to adult care and improved long-term outcomes.

Objectives: To assess the efficacy of new protein-based B cell depletion with glyco-engineered anti-CD20 antibody obinutuzumab (OBI) and the CD19/CD3 T cell engager blinatumomab (BLI) in patients with autoimmune diseases (AIDs) in comparison to rituximab (RTX) and CD19 chimeric antigen receptor (CAR) T cell therapy.

Methods: Sequential inguinal lymph node biopsies were taken before and after treatment with OBI-, BLI-, RTX- and CD19-CAR T cells in patients with AID. CD19+ and CD20+ B cells, plasma cells, T cells and macrophages were analysed by immunohistochemistry. Changes in follicular architecture (follicular dendritic cells, T follicular helper cells, proliferation) were also assessed.

Results: Baseline and follow-up lymph node biopsies from 24 patients with AID (OBI, 4; BLI, 4; RTX, 4; CD19-CAR T cells, 12) were analysed. B cell depletion was confirmed in all CD19-CAR T cell-treated patients but only in 1 (OBI) out of 12 protein-based B cell-treated patients. Likewise, follicular architecture was disrupted in all CD19-CAR T cell-treated patients but only in 1 (OBI) out of 12 protein-based B cell-treated patients. B cell depletion efficacy in the lymph nodes was 100% for CD19-CAR T cells, 92% for OBI, 86% for RTX and 69% for BLI. Plasma cells were reduced but not depleted in all treatment approaches. CD3+ T cells and CD68+ macrophages remained unaffected. Peripheral blood B cell depletion occurred in all but 1 BLI-treated patient. B cell depletion was associated with stable drug-free remission, whereas a reduction in B cell numbers without depletion required retreatment with immunomodulatory drugs.

Conclusions: Protein-based B cell depletion reduces but usually does not deplete B cells in lymph nodes leaving the follicular architecture intact and being associated with disease recurrence.