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Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, multiplexed imaging and spatial transcriptomics along with in vitro modeling of cell-extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell-derived cytokines, TNF, IFN-γ, IL-1β or lack thereof, drive four distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium. Smith et al. present a resource detailing drivers of transcriptional heterogeneity of synovial fibroblasts cell states in the inflamed joints of human patients with rheumatoid arthritis.

Droplet-based single-cell RNA-seq has emerged as a powerful technique for massively parallel cellular profiling. While this approach offers the exciting promise to deconvolute cellular heterogeneity in diseased tissues, the lack of cost-effective and user-friendly instrumentation has hindered widespread adoption of droplet microfluidic techniques. To address this, we developed a 3D-printed, low-cost droplet microfluidic control instrument and deploy it in a clinical environment to perform single-cell transcriptome profiling of disaggregated synovial tissue from five rheumatoid arthritis patients. We sequence 20,387 single cells revealing 13 transcriptomically distinct clusters. These encompass an unsupervised draft atlas of the autoimmune infiltrate that contribute to disease biology. Additionally, we identify previously uncharacterized fibroblast subpopulations and discern their spatial location within the synovium. We envision that this instrument will have broad utility in both research and clinical settings, enabling low-cost and routine application of microfluidic techniques. Droplet-based single-cell RNA-seq is a powerful tool for cellular heterogeneity profiling in disease but is limited by instrumentation required. Here the authors develop a 3D printed microfluidic platform for massive parallel sequencing of rheumatoid arthritis tissues.

The immune mechanisms that mediate synovitis and joint destruction in rheumatoid arthritis (RA) remain poorly defined. Although increased levels of CD8 + T cells have been described in RA, their function in pathogenesis remains unclear. Here we perform single cell transcriptome and T cell receptor (TCR) sequencing of CD8 + T cells derived from anti-citrullinated protein antibodies (ACPA)+ RA blood. We identify GZMB + CD8 + subpopulations containing large clonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while a GZMK + CD8 + memory subpopulation comprises smaller clonal expansions that express effector T cell transcriptional programs. We demonstrate RA citrullinated autoantigens presented by MHC class I activate RA blood-derived GZMB + CD8 + T cells to expand, express cytotoxic mediators, and mediate killing of target cells. We also demonstrate that these clonally expanded GZMB + CD8 + cells are present in RA synovium. These findings suggest that cytotoxic CD8 + T cells targeting citrullinated antigens contribute to synovitis and joint tissue destruction in ACPA+ RA. The immune mechanisms underlying synovitis and joint tissue destruction in rheumatoid arthritis (RA) remain incompletely defined. Here, the authors demonstrate that ACPA+ RA patients have activated clonally expanded cytotoxic GZMB + CD8+ T cells in blood and synovium that target and are activated by citrullinated antigens to mediate cell killing.

Objective Racial and ethnic disparities in arthroplasty utilization are evident, but the reasons are not known. We aimed to identify concerns that may contribute to barriers to arthroplasty from the patient’s perspective. Methods We identified patients’ concerns about arthroplasty by performing a mixed methods study. Themes identified during semi-structured interviews with Black and Hispanic patients with advanced symptomatic hip or knee arthritis were used to develop a questionnaire to quantify and prioritize their concerns. Multiple linear and logistic regression analyses were conducted to determine the association between race/ethnicity and the importance of each theme. Models were adjusted for sex, insurance, education, HOOS, JR/KOOS, JR, and discussion of joint replacement with a doctor. Results Interviews with eight participants reached saturation and provided five themes used to develop a survey answered by 738 (24%) participants; 75.5% White, 10.3% Black, 8.7% Hispanic, 3.9% Asian/Other. Responses were significantly different between groups ( p  < 0.05). Themes identified were “Trust in the surgeon” “Recovery”, “Cost/Insurance”, “Surgical outcome”, and “Personal suitability/timing”. Compared to Whites, Blacks were two-fold, Hispanics four-fold more likely to rate “Trust in the surgeon” as very/extremely important. Blacks were almost three times and Hispanics over six times more likely to rate “Recovery” as very/extremely important. Conclusion We identified factors of importance to patients that may contribute to barriers to arthroplasty, with marked differences between Blacks, Hispanics, and Whites.

Background Rates of total knee arthroplasty (TKA) in the United States have risen in patients of a wide age range. Although rates of postoperative TKA complications have decreased, they remain a significant concern. In this study, we aim to determine how the risk of adverse TKA outcomes changes dynamically with age and explore the optimal ages with the lowest risk for adverse outcomes. Methods This retrospective cohort study included patients who underwent elective primary TKA from 2012 to 2018 in the Pennsylvania Health Care Cost Containment Council Database. We trained (70% train:30% test) an explainable boosting machine (EBM), a modern generalized additive model, to predict risk for 90-day mortality, 90-day readmission, 1-year revision, and longer length of stay (LOS). This “glass box” model allowed us to measure and visualize feature importance using mean absolute scores and determine the role of age in the model. We then ran EBM models that allowed two-way interactions between age and patient-level covariates. Results In our cohort of 227,959 patients, 90-day readmission was observed in 7.5%, 90-day mortality in 0.2%, and 1-year revision in 0.8%. The median LOS was 2 days (IQR [2, 3]). Age was among the most important factors for predicting all outcomes, and these were nonlinear relationships. The risk for 90-day mortality increased substantially at 76.5 years, and for 90-day readmission and longer LOS at 73.5 years. Risk for 1-year revision was greater before 63.5 years. Conclusions We determined that there is a nonlinear relationship between age and risk for adverse TKA outcomes, and it changes dramatically at specific time points. Our data suggests that the optimal age for lower risk of 90-day mortality, 90-day readmission, and longer LOS is below 73.5 years, and above 63.5 years for 1-year revision. These findings can help in decision-making when trying to quantify risks related to aging.

Background Moving Well is a behavioral intervention for patients with knee osteoarthritis (KOA) scheduled for a total knee replacement (TKR). The objective of this intervention is to help patients with KOA mentally and physically prepare for and recover from TKR. Methods This is an open-label pilot randomized clinical trial that will test the feasibility and effectiveness of the Moving Well intervention compared to an attention control group, Staying Well , to reduce symptoms of anxiety and depression in patients with KOA undergoing TKR. The Moving Well intervention is guided by Social Cognitive Theory. During this 12-week intervention, participants will receive 7 weekly calls before surgery and 5 weekly calls after surgery from a peer coach. During these calls, participants will be coached to use principles of cognitive behavioral therapy (CBT), stress reduction techniques, and will be assigned an online exercise program, and self-monitoring activities to complete on their own time throughout the program. Staying Well participants will receive weekly calls of similar duration from research staff to discuss a variety of health topics unrelated to TKR, CBT, or exercise. The primary outcome is the difference in levels of anxiety and/or depression between participants in the Moving Well and Staying Well groups 6 months after TKR. Discussion This study will pilot test the feasibility and effectiveness of Moving Well , a peer coach intervention, alongside principles of CBT and home exercise, to help patients with KOA mentally and physically prepare for and recover from TKR. Trial registration Clinicaltrials.gov. NCT05217420; Registered: January 31, 2022.

ObjectivesThe Steroid PRO is a treatment-specific patient-reported outcome questionnaire which measures the impact of glucocorticoids on health-related quality of life. It has 15 items grouped into 4 domains (Social impact, Impact on Appearance, Psychological Impact and Treatment Concerns). Initially developed and validated in rheumatic diseases, the Steroid PRO demonstrates potential for broader application in patients with other inflammatory conditions. The objective of this study was to assess face validity, content validity and feasibility of the Steroid PRO in (1) patients treated with glucocorticoids for inflammatory respiratory, dermatological and gastroenterological conditions and (2) clinicians working within these specialties in the UK and USA.DesignQualitative study with semistructured cognitive interview methods.SettingOnline or face-to-face interviews with participants from seven departments across three secondary care hospitals in the UK and USA.ParticipantsInclusion criteria: (1) Adult patients with inflammatory respiratory, gastroenterological and dermatological conditions treated with glucocorticoids and (2) healthcare professionals (HCPs) working in respiratory, dermatology and gastroenterology departments in the UK and USA.ResultsPurposive sampling to ensure a range of patient and HCP participants. A total of 42 patient participants were recruited, from respiratory/pulmonology (n=14, 33.3%), dermatology (n=13, 31.0%) and gastroenterology (n=15, 35.8%) medical departments; 32 in the UK and 10 from the USA. Mean age 48.2 years (range 22–71) and 19 (45.2%) were female. Patient participants had a range of inflammatory lung, skin and bowel conditions, with a spectrum of demographics and patterns of glucocorticoid use. 14 HCPs participated from the UK (9) and USA (5). Face validity: 97% (30/31) patients and 100% (14/14) HCPs reported the Steroid PRO was ‘relevant or very relevant’ to them and their disease. Feasibility: 97% (30/31) patients and 100% (14/14) HCPs reported the Steroid PRO was ‘easy or very easy to complete’. Patients reported that the four domains of the Steroid PRO had relevance to them and that it was validating to see their concerns represented: ‘It’s obvious you guys know what you’re talking about—these are my issues. It’s very validating when you realise it’s not just you. These problems are real and they matter.… These are not questions my doctor asks me about. Doctors never ask about psychosocial aspects. It would be really great if they used this’ (female patient with asthma). Patients and clinicians felt the Steroid PRO would be suitable for use in clinical practice within their specialties and would aid in understanding of the impact of glucocorticoids.ConclusionsThe Steroid PRO demonstrated face validity and content validity for assessing the impact of glucocorticoids in patients with inflammatory respiratory, gastroenterological and dermatological conditions. Additionally, the feasibility of using the Steroid PRO with both patients and HCPs has been established. Future work should include quantitative testing of the Steroid PRO as an outcome measure within clinical trials in these conditions.Trial registration numberNCT06314451.

Total hip and total knee arthroplasty) remain important interventions to treat symptomatic knee and hip damage in patients with rheumatoid arthritis, with little change in utilisation rates despite the increasingly widespread use of potent conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and targeted DMARDs including Janus kinase inhibitors and biologics. The majority of patients are receiving these immunosuppressing medications and glucocorticoids at the time they present for arthroplasty. There is minimal randomised controlled trial data addressing the use of DMARDs in the perioperative period, yet patients and their physicians face these decisions daily. This paper reviews what is known regarding perioperative management of targeted and csDMARDs and glucocorticoids.

Objective Mixed‐methods research is valuable in health care to gain insights into patient perceptions. However, analyzing textual data from interviews can be time‐consuming and require multiple analysts for investigator triangulation. This study aims to explore a novel approach to investigator triangulation in mixed‐methods research by employing a large language model (LLM) for analyzing data from patient interviews. Methods This study compared the thematic analysis and survey generation performed by human investigators and ChatGPT‐4, which uses GPT‐4 as its backbone model, using data from an existing study that explored patient perceptions of barriers to arthroplasty. The human‐ and ChatGPT‐4–generated themes and surveys were compared and evaluated based on their representation of salient themes from a predetermined topic guide. Results ChatGPT‐4 generated analogous dominant themes and a comprehensive corresponding survey as the human investigators but in significantly less time. The survey questions generated by ChatGPT‐4 were less precise than those developed by human investigators. The mixed‐methods flowchart proposes integrating LLMs and human investigators as a supplementary tool for the preliminary thematic analysis of qualitative data and survey generation. Conclusion By utilizing a combination of LLMs and human investigators through investigator triangulation, researchers may be able to conduct more efficient mixed‐methods research to better understand patient perspectives. Ethical and qualitative implications of using LLMs should be considered.

Total hip (THA) and total knee arthroplasty (TKA) are widely used, successful procedures for symptomatic end stage arthritis of the hips or knees, but patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and spondyloarthritis (SPA) including ankylosing spondylitis (AS) and psoriatic arthritis (PSA) are at higher risk for adverse events after surgery. Utilization rates of THA and TKA remain high for patients with RA, and rates of arthroplasty have increased for patients with SLE and SPA. However, complications such as infection are increased for patients with SLE, RA, and SPA, most of whom are receiving potent immunosuppressant medications and glucocorticoids at the time of surgery. Patients with SLE and AS are also at increased risk for perioperative cardiac and venous thromboembolism (VTE), while RA patients do not have an increase in perioperative cardiac or VTE risk, despite an overall increase in VTE and cardiac disease. This narrative review will discuss the areas of heightened risk for patients with RA, SLE, and SPA, and the perioperative management strategies currently used to minimize the risks.