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Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction 1 . There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity 1 , 2 . Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments. Single-cell transcriptomic and proteomic data from synovial tissue from individuals with rheumatoid arthritis classify patients into groups based on abundance of cell states that can provide insights into pathology and predict individual treatment responses.

Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA. Activated B cells and T cells accumulate within joints of patients with rheumatoid arthritis. Here, the authors use single-cell transcriptome and repertoire profiling to identify clonally expanded synovial B cells and T cells and define their phenotypes and predicted cell-cell interactions.

ObjectivesTranscriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven approaches to define clinically relevant subgroups.MethodsRNASeq was performed on 74 samples, with disease activity data collected at inclusion. Principal components analysis (PCA) and unsupervised clustering were used to define patient clusters based on expression of the most variable genes, followed by pathway analysis and inference of relative abundance of immune cell subsets. Histological assessment and multiplex immunofluorescence (for CD45, CD68, CD206) were performed on paraffin sections.ResultsPCA on expression of the (n=894) most variable genes across this series did not divide samples into distinct groups, instead yielding a continuum correlated with baseline disease activity. Two patient clusters (PtC1, n=52; PtC2, n=22) were defined based on expression of these genes. PtC1, with significantly higher disease activity and probability of response to methotrexate therapy, showed upregulation of immune system genes; PtC2 showed upregulation of lipid metabolism genes, described to characterise tissue resident or M2-like macrophages. In keeping with these data, M2-like:M1-like macrophage ratios were inversely correlated with disease activity scores and were associated with lower synovial immune infiltration and the presence of thinner, M2-like macrophage-rich synovial lining layers.ConclusionIn this large series of early, untreated RA, we show that the synovial transcriptome closely mirrors clinical disease activity and correlates with synovial inflammation. Intriguingly, lower inflammation and disease activity are associated with higher ratios of M2:M1 macrophages, particularly striking in the synovial lining layer. This may point to a protective role for tissue resident macrophages in RA.

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn’s disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases. In this Resource, Buckley and colleagues profile patients with Crohn’s disease and ulcerative colitis before and after adalimumab therapy. Specific pretreatment differences in the epithelial and myeloid compartments were associated with remission outcomes in both diseases. The authors also describe the cellular circuitry in nonremission patients following treatment.

Background:Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA). Previous studies have suggested pathophysiological links between ILD and the presence of anti-cyclic citrullinated peptide antibodies (anti-CCP antibodies). The main aim of our study was to evaluate the prevalence and features of RA-associated ILD (RA-ILD) and to explore a possible association between the presence of anti-CCP antibodies and the development of ILD.Objectives:Examine the relationship between anti-CCP antibodies and diffuse interstitial pneumonia in rheumatoid arthritis, aiming to enhance strategies for early detection and effective management.Methods:We conducted a prospective study that included 180 patients diagnosed with RA according to the ACR/EULAR 2010 criteria, from January 2022 to January 2023. Screening for RA-ILD and characterization of the ILD pattern were performed using high-resolution computed tomography, which was centrally interpreted by expert radiologists and pulmonologists.Results:Of the 180 RA patients, 87.9% were female, with a median age of 56 years (interquartile range: 31 to 89 years). The median duration of RA was 8 years (interquartile range: 1 to 32 years). Erosive lesions were observed in 58% of patients on standard radiographs, anti-CCP antibodies were positive in 72% of cases, and rheumatoid factor (RF) was present in 62.9% of patients. The mean DAS28-CRP score was 4.48 ± 1.24. About 91% of patients had received at least one csDMARDs treatment, and nearly 59.8% were on biologic therapies. Moreover, 90.7% of patients had been treated with glucocorticoids. RA-ILD was present in 24.7% of patients, with a distribution of usual interstitial pneumonia (UIP) in 54% of cases, non-specific interstitial pneumonia (NSIP) in 43.18% of cases, and organized pneumonia (OP) in one patient. Factors associated with the presence of RA-ILD were male gender (p < 0.001) and a significant correlation with the presence of anti-CCP antibodies (p = 0.004).Conclusion:Interstitial lung disease associated with rheumatoid arthritis requires special attention from rheumatologists due to its high prevalence, often asymptomatic nature, and tendency to progress to fibrosis. This study contributes to a better understanding of the relationship between RA and ILD, emphasizing the importance of early detection and management of this potentially severe complication.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Joint inflammation of RA is closely related to infiltration of immune cells, synovium hyperplasia, and superfluous secretion of proinflammatory cytokines, which lead to cartilage degradation and bone erosion. The joint synovium of RA patients contains a variety of immune cellular types, among which monocytes/macrophages and T cells are two essential cellular components. Monocytes/macrophages can recruit and promote the differentiation of T cells into inflammatory phenotypes in RA synovium. Similarly, different subtypes of T cells can recruit monocytes/macrophages and promote osteoblast differentiation and production of inflammatory cytokines. In this review, we will discuss how T cell-monocyte/macrophage interactions promote the development of RA, which will provide new perspectives on RA pathogenesis and the development of targeted therapy.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in joints, associated with synovial hyperplasia and with bone and cartilage destruction. Although the primacy of T cell-related events early in the disease continues to be debated, there is strong evidence that autoantigen recognition by specific T cells is crucial to the pathophysiology of rheumatoid synovitis. In addition, T cells are key components of the immune cell infiltrate detected in the joints of RA patients. Initial analysis of the cytokines released into the synovial membrane showed an imbalance, with a predominance of proinflammatory mediators, indicating a deleterious effect of Th1 T cells. There is nonetheless evidence that Th17 cells also play an important role in RA. T cells migrate from the bloodstream to the synovial tissue via their interactions with the endothelial cells that line synovial postcapillary venules. At this stage, selectins, integrins, and chemokines have a central role in blood cell invasion of synovial tissue, and therefore in the intensity of the inflammatory response. In this review, we will focus on the mechanisms involved in T cell attraction to the joint, the proteins involved in their extravasation from blood vessels, and the signaling pathways activated. Knowledge of these processes will lead to a better understanding of the mechanism by which the systemic immune response causes local joint disorders and will help to provide a molecular basis for therapeutic strategies.

The OMERACT-EULAR Synovitis Scoring (OESS) system is worldwide used to evaluate arthritis severity on ultrasound (US) images. Because of inter-observer and intra-observer variability, deep learning (DL) has been applied in high-quality image interpretation and analysis. Previous studies mostly focused on Doppler US (DUS) classification by convolutional neural network (CNN), which could provide objective assessment. However, the reports of DL intervention in grey scale (GS) US image automatic measurements are limited. The aim of this study was to develop an integrated multiple CNN model in precise scoring GS US images from rheumatoid arthritis (RA) patients. The standard US images from patients of RA were retrospectively selected by three 10-years US experienced rheumatologist together and were graded according to the OESS system. Six different joints data were taken, including proximal interphalangeal, metacarpophalangeal, wrist, elbow, knee and ankle joints. We conducted the DL model integrating three binary CNNs to predict four-class GS US scoring (Figure 1). The accuracy of the trained model was tested by an independent test data. Total 678 images from 447 patients of RA were used in this study. These images were divided into training (n=611) and testing (n=67) sets. The integrated multiple CNNs model could achieve a four-class accuracy of 77.6%. The individual accuracy of grades 0, 1, 2 and 3 were 68.4%, 77.3%, 73.3% and 100%, respectively (Table 1). Furthermore, we found that adding on anatomic site parameters or labeling areas of interest would establish a better average area under curve (AUC) with 92.6% and 89.0%. Our study suggests the possibility of using the integrated multiple CNNs model in grading synovial hypertrophy of RA, which is critical in RA healthcare. External validation would be required to confirm the predictive ability of this model. [1]D'Agostino MA et al. RMD Open. 2017 Jul 11;3(1):e000428. [2]Andersen JKH et al. RMD Open. 2019 Mar 30;5(1):e000891. [3]Christensen ABH et al. Ann Rheum Dis. 2020 Sep;79(9):1189-1193. [4]Shin Y et al. Ultrasonography. 2021 Jan;40(1):30-44. [5]Zhou Z et al. Patterns (N Y). 2022 Sep 29;3(10):100592. NIL. None Declared. [Display omitted] Table 1Prediction results of the integrated model for grey scale ultrasound scoresIntegrated modelAccuracyRheumatologist0123Total(%)0134201968.41417102277.32121111573.330001111100Total182314126777.6

The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal modulation by targeted treatments. We show that in treatment-naive patients, high AXL levels are associated with pauci-immune histology and low disease activity and inversely correlate with the expression levels of pro-inflammatory genes. We define the location of Axl/MerTK in rheumatoid synovium using immunohistochemistry/fluorescence and digital spatial profiling and show that Axl is preferentially expressed in the lining layer. Moreover, its ectodomain, released in the synovial fluid, is associated with synovial histopathology. We also show that Toll-like-receptor 4-stimulated synovial fibroblasts from patients with RA modulate MerTK shedding by macrophages. Lastly, Axl/MerTK synovial expression is influenced by disease stage and therapeutic intervention, notably by IL-6 inhibition. These findings suggest that Axl/MerTK are a dynamic axis modulated by synovial cellular features, disease stage and treatment. The TAM tyrosine kinases, Axl and MerTK, have been implicated in rheumatoid arthritis (RA). Here, using a synovial tissue bioresource of patients with RA, the authors describe how Axl and MerTK expression and function are linked to synovial histopathology, disease activity, and therapeutic intervention with IL-6 inhibitors.