Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. 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.

Rheumatoid arthritis: prediction of future clinically-apparent disease, and prevention.

PURPOSE OF REVIEW: This review discusses updates in the prediction and prevention of future rheumatoid arthritis (RA). RECENT FINDINGS: In individuals with musculoskeletal symptoms and elevated antibodies to citrullinated proteins (ACPA) without clinical inflammatory arthritis (IA), a 'simple' score has a positive predictive value (PPV) of ∼28% for clinical IA/RA within 1 year, and a comprehensive score (including ultrasound) has a PPV of ∼71% for clinical RA within 5 years. Controlled clinical trials in individuals at-risk for future RA have been performed using corticosteroids, rituximab, atorvastatin, methotrexate, hydroxychloroquine and abatacept. Abatacept modestly reduced rates of incident clinical RA and imaging inflammation within the trials, rituximab delayed clinical IA, and methotrexate improved function, symptoms and imaging inflammation. Vitamin D with or without omega 3 fatty acids reduced incidence of autoimmune diseases, including RA. While not proven in controlled clinical trials, observational studies suggest exercise, weight loss and smoking cessation may reduce progression to clinical RA. SUMMARY: Prediction and prevention of RA is advancing although there are no currently approved interventions for prevention. Future studies should include deeper evaluation of the pathophysiology of RA development to improve prediction and identify key pathways to target in future clinical trials, as well as develop infrastructure to support prevention-related research.

Short peripheral blood leukocyte telomere length in rheumatoid arthritis-interstitial lung disease.

Shortened telomere lengths (TLs) can be caused by single nucleotide polymorphisms and loss-of-function mutations in telomere-related genes (TRG), as well as ageing and lifestyle factors such as smoking. Our objective was to determine if shortened TL is associated with interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This is the largest study to demonstrate and replicate that shortened peripheral blood leukocytes-TL is associated with ILD in patients with RA compared with RA without ILD in a multinational cohort, and short PBL-TL was associated with baseline disease severity in RA-ILD as measured by forced vital capacity percent predicted.

Rheumatoid Arthritis: The Continuum of Disease and Strategies for Prediction, Early Intervention, and Prevention.

Rheumatoid arthritis (RA) is known to include a pre-RA stage that can be defined as the presence of familial or genetic risk factors, biomarker abnormalities (eg, anticitrullinated protein antibodies [ACPA]), symptoms, and even abnormal imaging findings prior to the development of the onset of clinical RA with inflammatory arthritis that is apparent on physical examination. Indeed, there are multiple completed or ongoing retrospective case-control as well as prospective observational studies to identify the key biologic drivers of disease. Further, building on the predictive ability of combinations of biomarkers, symptoms, and imaging for future RA, there are multiple clinical trials completed, underway, or in development to identify approaches that may prevent, delay, or ameliorate future clinical RA in at-risk individuals. Importantly, however, although an effective preventive intervention has not yet been identified, at-risk individuals are being increasingly identified in clinical care; this presents a challenge of how to manage these individuals in clinical practice. This review will discuss the current understanding of the biology and natural history of RA development, nomenclature, and current models for prediction of future RA, as well as evaluate the current and ongoing clinical prevention trials with the overall goal to provide insights into the challenges and opportunities in the field of RA prevention. Moreover, this review will provide up-to-date options for clinical management of individuals at risk for RA.

Analysis of Complement Gene Expression, Clinical Associations, and Biodistribution of Complement Proteins in the Synovium of Early Rheumatoid Arthritis Patients Reveals Unique Pathophysiologic Features.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and inflammation. The finding of autoantibodies in seropositive RA suggests that complement system activation might play a pathophysiologic role due to the local presence of immune complexes in the joints. Our first objective was to explore the Pathobiology of Early Arthritis Cohort (PEAC) mRNA sequencing data for correlations between clinical disease severity as measured by DAS28-ESR (disease activity score in 28 joints for erythrocyte sedimentation rate) and complement system gene expression, both in the synovium and in blood. Our second objective was to determine the biodistribution using multiplex immunohistochemical staining of specific complement activation proteins and inhibitors from subjects in the Accelerating Medicines Partnership (AMP) RA/SLE study. In the PEAC study, there were significant positive correlations between specific complement gene mRNA expression levels in the synovium and DAS28-ESR for the following complement genes: C2, FCN1, FCN3, CFB, CFP, C3AR1, C5AR1, and CR1 Additionally, there were significant negative correlations between DAS28-ESR and Colec12, C5, C6, MASP-1, CFH, and MCP In the synovium there were also significant positive correlations between DAS28-ESR and FcγR1A, FcγR1B, FcγR2A, and FcγR3A Notably, CFHR4 synovial expression was positively correlated following treatment with the DAS28-ESR at 6 mo, suggesting a role in worse therapeutic responses. The inverse correlation of C5 RNA expression in the synovium may underlie the failure of significant benefit from C5/C5aR inhibitors in clinical trials performed in patients with RA. Multiplex immunohistochemical analyses of early RA synovium reveal significant evidence of regional alterations of activation and inhibitory factors that likely promote local complement activation.

Lung inflammation in the pathogenesis of rheumatoid arthritis.

The primary manifestation of rheumatoid arthritis (RA) is articular disease; however, extra-articular disease can also occur. In particular, pulmonary disease is a leading cause of morbidity and mortality in individuals with RA. Herein, we will review the types, prevalence, risk factors, and potential pathophysiology of lung disease in individuals with established RA. We will also discuss the emerging understanding of potential role of the lung in the generation of RA-related autoantibodies during a period of disease development termed "pre-RA." Finally, we will discuss a research agenda outlining the next steps to improve our understanding and management of lung inflammation and lung disease throughout the natural history of RA.

A potential role for chlamydial infection in rheumatoid arthritis development.

OBJECTIVES: To assess the relationship between self-reported and serologic evidence of prior chlamydial infection, rheumatoid arthritis (RA)-related autoantibodies and risk of RA-development. METHODS: This is a nested study within a prospective Swiss-based cohort including all first-degree relatives of RA patients (RA-FDR) who answered a question on past chlamydial infections. Primary outcome was systemic autoimmunity associated with RA (RA-autoimmunity) defined as positivity for anti-citrullinated peptide antibodies (ACPA) and/or rheumatoid factor (RF). Secondary outcomes were high levels of RA-autoimmunity, RA-associated symptoms and RA-autoimmunity, and subsequent seropositive RA diagnosis. We conducted a nested case-control analysis by measuring the serological status against Chlamydia trachomatis' major outer membrane protein. We replicated our analysis in an independent United States-based RA-FDR cohort. RESULTS: Among 1231 RA-FDRs, 168 (13.6%) developed RA-autoimmunity. Prevalence of self-reported chlamydial infection was significantly higher in individuals with RA-autoimmunity compared with controls (17.9% vs 9.8%, OR = 2.00, 95%CI: 1.27-3.09, p < 0.01). This association remained significant after adjustments (OR = 1.91, 95%CI: 1.20-2.95). Stronger effect sizes were observed in later stages of RA development. There was a similar trend between a positive C. trachomatis serology and high levels of RA-autoimmunity (OR = 3.05, 95% CI: 1.10-8.46, p= 0.032). In the replication cohort, there were significant associations between chlamydial infection and RF positivity and incident RA, but not anti-CCP positivity. CONCLUSIONS: Self-reported chlamydial infections are associated with elevated RA-autoimmunity in at risk individuals. The differing association of chlamydial infections and ACPA/RF between cohorts will need to be explored in future studies but is consistent with a role of mucosal origin of RA-related autoimmunity.

Experiences of initiating rapid antiretroviral therapy among people newly diagnosed with HIV in East London: a qualitative study.

OBJECTIVES: We aimed to explore the experiences of people who initiated rapid antiretroviral therapy (ART) within 7 days of HIV diagnosis, as part of routine care in London. METHODS: Using purposive sampling, 18 in-depth, semistructured interviews were conducted between December 2020 and September 2021 with people who started rapid ART at Barts Health NHS Trust. Participants aged 22-69 years included 15 cisgender men and three cisgender women. Five identified as heterosexual and 13 as gay and bisexual and other men who have sex with men. Ethnic identities: six White Non-UK, five White UK, three Black Caribbean, two South Asian and two East Asian. Interviews explored feelings about the new HIV diagnosis, attitudes to rapid ART including barriers to and facilitators of starting. Thematic analysis of transcribed interviews was undertaken. RESULTS: Four themes were identified: (1) being offered rapid ART is acceptable; (2) it is a way of taking control of their health; (3) the need for information and support and (4) an individualised approach to care. Reasons for starting included getting well, staying well and reducing the likelihood of passing on HIV. Facilitators included being given comprehensive information about treatment and managing potential side-effects and a supportive clinical team. Support specified included a non-judgemental attitude, approachability, reassurance, encouragement and information about peer support. Most participants expressed they could not understand why people would not begin treatment, but suggested needing more time to decide and denial of diagnosis as possible barriers. CONCLUSIONS: To our knowledge, this is the first qualitative study exploring the experiences of people initiating rapid ART in the UK. It was deemed acceptable to an ethnically diverse, predominantly male sample of people newly diagnosed with HIV. Future research should include strategies to recruit a more gender diverse sample and those who declined or stopped rapid ART.

Evaluating HIV policy: a gender analysis of the representation of women and men in UNAIDS HIV-prevention guidelines.

Gender inequalities have long been recognised as one of the most significant factors influencing the dynamics of the HIV epidemic in sub-Saharan Africa (SSA). However, it remains unclear how men and women are discussed in HIV-prevention initiatives and if certain representations of men and women impact prevention guidance. This research aimed to understand how men and women are portrayed in HIV-prevention guidelines produced by UNAIDS for the SSA region, and how these influence the different types of interventions targeted at women and men. Thirty-four UNAIDS prevention documents were included in the study. The policy documents were analysed to ascertain the frequency of different interventions suggested, the extent to which they were targeted at men and women, and a textual analysis of the way that men and women were represented. Due to a lack of information regarding other gender identities, the research was aimed at cis-gender men and women only. The analysis revealed that most policy documents focused on women, that there were differences in the types of interventions targeted at men and women, with few social interventions targeted at men, and that the language used to describe men and women repeats traditional gender stereotypes and cements simplistic dualisms. The lack of social interventions targeted at men suggests that behaviour change among men is not highly prioritised in current prevention initiatives. Instead, current UNAIDS policy focuses on women as the key site for intervention and empowerment. UNAIDS should therefore provide more details and examples about how best to engage men and boys in prevention efforts, as well as to include more nuanced conceptions of gender in policy guidance.

Malaria prevention interventions beyond long-lasting insecticidal nets and indoor residual spraying in low- and middle-income countries: a scoping review.

BACKGROUND: Significant progress in malaria prevention during the past two decades has prompted increasing global dialogue on malaria elimination. Recent reviews on malaria strategies have focused mainly on long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS), with little emphasis on other prevention methods. This article is a scoping review of literature on malaria prevention methods beyond LLINs and IRS in low- and middle-income countries (LMICs). METHODS: This scoping review found articles published between from 1994 to 2020. Studies were obtained from a search of the PubMed, the Cochrane Library and Social Science abstracts. Grey literature and manual search of secondary references was also done. The search strategy included all study designs but limited only to English. Three independent reviewers performed the selection and characterization of articles, and the data collected were synthesized qualitatively. RESULTS: A total of 10,112 studies were identified among which 31 met the inclusion criteria. The results were grouped by the 3 emerging themes of: housing design; mosquito repellents; and integrated vector control. Housing design strategies included closing eves, screening of houses including windows, doors and ceilings, while mosquito repellents were mainly spatial repellents, use of repellent plants, and use of plant-based oils. Integrated vector control included larvae source management. Evidence consistently shows that improving housing design reduced mosquito entry and malaria prevalence. Spatial repellents also showed promising results in field experiments, while evidence on repellent plants is limited and still emerging. Recent literature shows that IVM has been largely ignored in recent years in many LMICs. Some malaria prevention methods such as spatial repellents and IVM are shown to have the potential to target both indoor and outdoor transmission of malaria, which are both important aspects to consider to achieve malaria elimination in LMICs. CONCLUSION: The scoping review shows that other malaria prevention strategies beyond LLINs and IRS have increasingly become important in LMICs. These methods have a significant role in contributing to malaria elimination in endemic countries if they are adequately promoted alongside other conventional approaches.

Occupational trichloroethylene exposure and antinuclear antibodies: a cross-sectional study in China.

OBJECTIVES: There has been concern over the possible risk of autoimmune diseases from exposure to trichloroethylene (TCE), an industrial solvent and common pollutant near hazardous waste sites. Studies of TCE-exposed lupus-prone mouse strains have reported increases in serum antinuclear antibodies (ANAs), a marker of autoimmunity, and autoimmune pathologic changes, while epidemiologic studies have provided limited support for an association between TCE exposure and scleroderma. To investigate exposure-related biologic evidence of autoimmunity in humans, we measured ANA levels in sera from a cross-sectional study of TCE-exposed (n=80) and TCE-unexposed (n=96) workers in Guangdong, China. METHODS: Full-shift personal air exposure measurements for TCE were taken prior to blood collection. Serum ANAs were detected by immunofluorescence on HEp-2 cells. We calculated ORs and 95% CI relating levels of TCE exposure (categorised using tertiles as cut-points) and ANA positivity (1+ intensity at 1:320 dilution) using multivariable logistic regression. RESULTS: Samples from 16 of 176 participants were ANA-positive. We found higher levels of TCE exposure (concentrations>17.27 ppm) to be associated with an elevated odds of ANA positivity (OR 4.7, 95% CI 1.3 to 16.8) compared with unexposed controls. This association remained after excluding two subjects with diagnosed autoimmune disease (OR 4.5, 95% CI 1.2 to 16.2). We did not observe an association with ANAs at lower exposure levels. CONCLUSIONS: Our findings, to our knowledge the first direct human evidence of an association between TCE exposure and systemic autoimmunity, provide biologic plausibility to epidemiologic evidence relating TCE and autoimmune disease.

HIV testing attitudes and practices amongst 'wealthy men': qualitative evidence from Tanzania.

Evidence from nationally representative surveys conducted in sub-Saharan Africa shows that significant proportions of men in the wealthiest quintile report never having tested for HIV. Despite high prevalence rates in this quintile, no research has been conducted on the HIV testing attitudes and practices of wealthier men. This article reports findings from qualitative research conducted with 23 wealthy men in Tanzania. Whilst wealthy men reported barriers to and enablers of HIV testing previously reported by the general population, concerns around loss of social status and community standing were amplified for members of this demographic. Furthermore, HIV stigma among members of this group remains high. However, enhanced access to HIV testing through private clinics, regular healthcare appointments, health insurance schemes and the means to travel to other countries enables wealthy men to avoid stigma. In settings such as the workplace, wealthy men were able to test in public in their roles as 'leaders' to encourage others to test. Future interventions to increase testing amongst men should target settings in which these leadership roles can be taken advantage of. HIV services also need integrating into the health system to remove the need for testing and treatment to be accessed at separate clinics.

Methotrexate and rheumatoid arthritis associated interstitial lung disease.

QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.

Factors associated with progression to inflammatory arthritis in first-degree relatives of individuals with RA following autoantibody positive screening in a non-clinical setting.

OBJECTIVES: Little is known about the likelihood of developing inflammatory arthritis (IA) in individuals who screen autoantibody positive (aAb+) in a non-clinical research setting. METHODS: We screened for serum cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor isotype aAbs in subjects who were at increased risk for rheumatoid arthritis (RA) because they are a first-degree relative of an individual with classified RA (n=1780). We evaluated combinations of aAbs and high titre aAbs, as defined by 2-times (2 x) the standard cut-off and an optimal cut-off, as predictors of our two outcomes, aAb+ persistence and incident IA. RESULTS: 304 subjects (17.1%) tested aAb+; of those, 131 were IA-free and had at least one follow-up visit. Sixty-four per cent of these tested aAb+ again on their next visit. Anti-CCP+ at levels ≥2 x the standard cut-off was associated with 13-fold higher likelihood of aAb +persistence. During a median of 4.4 years (IQR: 2.2-7.2), 20 subjects (15.3%) developed IA. Among subjects that screened anti-CCP+ at ≥ 2 x or ≥an optimal cut-off, 32% and 26% had developed IA within 5 years, respectively. Both anti-CCP cut-offs conferred an approximate fourfold increased risk of future IA (HR 4.09 and HR 3.95, p<0.01). CONCLUSIONS: These findings support that aAb screening in a non-clinical setting can identify RA-related aAb+ individuals, as well as levels and combinations of aAbs that are associated with higher risk for future IA. Monitoring for the development of IA in aAb+ individuals and similar aAb testing approaches in at-risk populations may identify candidates for prevention studies in RA.

Circulating blood metabolite trajectories and risk of rheumatoid arthritis among military personnel in the Department of Defense Biorepository.

OBJECTIVES: We sought to identify metabolic changes potentially related to rheumatoid arthritis (RA) pathogenesis occurring in the blood prior to its diagnosis. METHODS: In a US military biorepository, serum samples collected at two timepoints prior to a diagnosis of RA were identified. These were matched to controls who did not develop RA by subject age, race and time between sample collections and RA diagnosis time to stored serum samples. Relative abundances of 380 metabolites were measured using liquid chromatography-tandem mass spectrometry. We determined whether pre-RA case versus control status predicted metabolite concentration differences and differences over time (trajectories) using linear mixed models, assessing for interactions between time, pre-RA status and metabolite concentrations. We separately examined pre-RA and pre-seropositive RA cases versus matched controls and adjusted for smoking. Multiple comparison adjustment set the false discovery rate to 0.05. RESULTS: 291 pre-RA cases (80.8% pre seropositive RA) were matched to 292 controls, all with two serum samples (2.7±1.6 years; 1.0±0.9 years before RA/matched date). 52.0% were women; 52.8% were White, 26.8% Black and 20.4% other race. Mean age was 31.2 (±8.1) years at earliest blood draw. Fourteen metabolites had statistically significant trajectory differences among pre-RA subjects versus controls, including sex steroids, amino acid/lipid metabolism and xenobiotics. Results were similar when limited to pre seropositive RA and after adjusting for smoking. CONCLUSIONS: In this military case-control study, metabolite concentration trajectory differences in pre-RA cases versus controls implicated steroidogenesis, lipid/amino acid metabolism and xenobiotics in RA pathogenesis. Metabolites may have potential as biomarkers and/or therapeutic targets preceding RA diagnosis.

EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis.

BACKGROUND: Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA). METHODS: An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1-10) for each PTC. RESULTS: Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants' knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach. CONCLUSION: These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.

Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis.

OBJECTIVES: Literature suggests that neutrophils of patients with rheumatoid arthritis (RA) are primed to respond to N-formyl methionine group (formylated peptides). Animal models indicate that formylated peptides contribute to joint damage via neutrophil recruitment and inflammation in joints. Non-steroidal anti-inflammatory drugs are also known to inhibit formyl peptide-induced neutrophil activation. The predominant source of formylated peptides in sterile inflammatory conditions like RA is mitochondria, organelles with prokaryotic molecular signatures. However, there is no direct evidence of mitochondrial formyl peptides (mtNFPs) in the circulation of patients with RA and their potential role in neutrophil-mediated inflammation in RA, including their clinical significance. METHODS: Levels of mtNFPs (total fMet, MT-ND6) were analyzed using ELISA in plasma and serum obtained from patients in 3 cross-sectional RA cohorts (n = 275), a longitudinal inception cohort (n = 192) followed for a median of 8 years, and age/gender-matched healthy controls (total n = 134). Neutrophil activation assays were done in the absence or presence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporine H. RESULTS: Elevated levels of total fMet were observed in the circulation of patients with RA as compared to healthy controls (p < 0.0001) associating with disease activity and could distinguish patients with the active disease from patients with inactive disease or patients in remission. Baseline levels of total fMet correlated with current and future joint involvement, respectively and predicted the development of rheumatoid nodules (OR = 1.2, p = 0.04). Further, total fMet levels improved the prognostic ability of ACPA in predicting erosive disease (OR of 7.9, p = 0.001). Total fMet levels correlated with markers of inflammation and neutrophil activation. Circulating mtNFPs induced neutrophil activation in vitro through FPR1-dependent mechanisms. CONCLUSIONS: Circulating mtNFPs could be novel biomarkers of disease monitoring and prognosis for RA and in investigating neutrophil-mediated inflammation in RA. We propose, FPR1 as a novel therapeutic target for RA.

Subjects at-risk for future development of rheumatoid arthritis demonstrate a PAD4-and TLR-dependent enhanced histone H3 citrullination and proinflammatory cytokine production in CD14hi monocytes.

The presence of anti-citrullinated protein/peptide antibodies (ACPA) and epitope spreading across the target autoantigens is a unique feature of rheumatoid arthritis (RA). ACPA are present in the peripheral blood for several years prior to the onset of arthritis and clinical classification of RA. ACPA recognize multiple citrullinated proteins, including histone H3 (H3). Intracellular citrullination of H3 in neutrophils and T cells is known to regulate immune cell function by promoting neutrophil extracellular trap formation and citrullinated autoantigen release as well as regulating the Th2/Th17 T cell phenotypic balance. However, the roles of H3 citrullination in other immune cells are not fully elucidated. We aimed to explore H3 citrullination and cytokine/metabolomic signatures in peripheral blood immune cells from subjects prior to and after the onset of RA, at baseline and in response to ex vivo toll-like receptor (TLR) stimulation. Here, we analyzed 13 ACPA (+) subjects without arthritis but at-risk for future development of RA, 14 early RA patients, and 13 healthy controls. We found significantly elevated H3 citrullination in CD14hi monocytes, as well as CD1c+ dendritic cells and CD66+ granulocytes. Unsupervised analysis identified two distinct subsets in CD14hi monocytes characterized by H3 modification and unique cytokine/metabolomic signatures. CD14hi monocytes with elevated TLR-stimulated H3 citrullination were significantly increased in ACPA (+) at-risk subjects. These cells were skewed to produce TNFα, MIP1ß, IFNα, and partially IL-12. Additionally, they demonstrate peptidyl arginine deiminase 4 (PAD4) mediated upregulation of the glycolytic enzyme PFKFB3. These CD14hi monocytes with elevated H3 citrullination morphologically formed monocyte extracellular traps (METs). Taken together, dysregulated PAD4-driven cytokine production as well as MET formation in CD14hi monocytes in ACPA (+) at-risk subjects likely plays an important role in the development of RA via promoting and perpetuating inflammation and generation of citrullinated autoantigens.

Preclinical rheumatoid arthritis and rheumatoid arthritis prevention.

PURPOSE OF REVIEW: This review is to provide an update on the current understanding of rheumatoid arthritis (RA) development related to disease development prior to the onset clinically apparent synovitis (i.e. Pre-RA), and opportunities for disease prevention. RECENT FINDINGS: A growing number of studies have demonstrated that serum elevations of autoantibodies rheumatoid factor, antibodies to citrullinated protein/peptide antigens (ACPAs) and antibodies to other posttranslationally modified proteins (e.g. carbamylated proteins) are highly predictive of future development of inflammatory arthritis/RA during a period that can be termed Pre-RA. Other factors including genetic, environmental, symptoms and imaging findings can also enhance prediction. Moreover, several novel biomarkers and changes in autoantibodies (e.g. glycosylation of variable domains) have been identified in Pre-RA. There has also been growing evidence that initiation and propagation of RA-related autoimmunity during the Pre-RA phase may be related to mucosal processes. The discovery of Pre-RA has also underpinned the development of several clinical prevention trials in RA; specifically, the PRAIRI study demonstrated that a single dose of rituximab can delay the onset of clinically apparent IA in at-risk individuals. Additional studies are evaluating the ability of drugs including abatacept, hydroxychloroquine and methotrexate to prevent or delay future RA. SUMMARY: The results from ongoing natural history and prevention trials in RA should further inform several critical issues in RA prevention including identification and enrolment of individuals at high-risk of imminent RA, the efficacy, safety and cost-effectiveness of prevention, and potentially the identification of new targets for prevention.

Circulating plasma metabolites and risk of rheumatoid arthritis in the Nurses' Health Study.

OBJECTIVES: RA develops slowly over years. We tested for metabolic changes prior to RA onset using a large non-targeted metabolomics platform to identify novel pathways and advance understanding of RA development. METHODS: Two hundred and fifty-four incident RA cases with plasma samples drawn pre-RA onset in the Nurses' Health Study (NHS) cohorts were matched 1:2 to 501 controls on age, race, menopause/post-menopausal hormone use and blood collection features. Relative abundances of 360 unique, known metabolites were measured. Conditional logistic regression analyses assessed associations between metabolites and incidence of RA, adjusted for age, smoking and BMI, accounting for multiple comparisons. Subgroup analyses investigated seropositive (sero+) RA and RA within 5 years of sample collection. Significant metabolites were then tested in a female military pre-RA case-control study (n = 290). RESULTS: In the NHS, metabolites associated with RA and sero+RA in multivariable models included 4-acetamidobutanoate (odds ratio (OR) = 0.80/S.d., 95% CI: 0.66, 0.95), N-acetylputrescine (OR = 0.82, 95% CI: 0.69, 0.96), C5 carnitine (OR = 0.84, 95% CI: 0.71, 0.99) and C5:1 carnitine (OR = 0.81, 95% CI: 0.68, 0.95). These were involved primarily in polyamine and leucine, isoleucine and valine metabolism. Several metabolites associated with sero+RA within 5 years of diagnosis were replicated in the independent military cohort: C5 carnitine (OR = 0.55, 95% CI: 0.33, 0.92), C5:1 carnitine (OR = 0.62, 95% CI: 0.39, 0.99) and C3 carnitine (OR = 0.57, 95% CI: 0.36, 0.91). CONCLUSION: Several metabolites were inversely associated with incidence of RA among women. Three short-chain acylcarnitines replicated in a smaller dataset and may reflect inflammation in the 5-year period prior to sero+RA diagnosis.