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Early intervention has been the cornerstone of improving outcomes in patients with rheumatoid arthritis. Over the past decade, the boundaries have been pushed in an attempt to achieve effective prevention strategies in those who are at high risk of developing rheumatoid arthritis. Core risk factors including the presence of serum anti-citrullinated protein antibodies, arthralgia and subclinical inflammation on imaging are highly predictive of arthritis development. The influence of air pollution, diet and the role of microbiome on disease progression are less clear. In turn, therapeutic focus has shifted to an earlier pre-arthritis phase of the disease continuum where the clinically apparent arthritis may potentially be intercepted. Seven proof-of-concept interventional trials in at-risk individuals have been conducted so far. Whether true prevention of rheumatoid arthritis is possible remains elusive. Promising signals towards permanent disease modulation and improvement in symptom burden were seen with some immunomodulatory therapies, whilst others were unsuccessful. Long-term follow-up is required to ascertain a true effect. Looking forward, a better understanding of the natural history and underlying biological mechanisms of arthritis development and more accurate, validated risk stratification is needed., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Subsets of CD21 -/low memory B cells (MBCs), including double-negative (DN, CD27 - IgD - ) and Tbet + CD11c + cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21 -/low MBCs correlate with joint destruction. However, whether this is due to the Tbet + CD11c + subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21 -/low Tbet + CD11c + MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA)., Methods: Clinical observations were combined with flow cytometry (n = 36) and single-cell RNA sequencing (scRNA-seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating Tbet + CD11c + MBCs was compared with scRNA-seq data of synovial B cells. In vitro coculture of Tbet + CD11c + B cells with T cells was used to assess costimulatory capacity., Results: CD21 -/low Tbet + CD11c + MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet + CD11c + MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up-regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin-mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet + CD11c + B cells induced retinoic acid receptor-related orphan nuclear receptor γT expression in CD4 + T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction., Conclusion: This study suggests that Tbet + CD11c + MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Rheumatoid arthritis (RA) is a prevalent autoimmune disorder with a significant global economic burden. Epigenetic modifications, particularly DNA methylation, play a crucial role in RA. This study conducted a bibliometric analysis to explore the evolving trends and predominant themes in RA and DNA methylation research over the past two decades. A total of 1800 articles met the inclusion criteria, and the analysis revealed consistent growth in the literature, with a notable increase in output after 2019. The research involved 70 countries, 2139 academic institutions, 23,365 unique authors, and 58,636 co-cited authors. The United States emerged as a dominant contributor in this research domain. The significance of DNA methylation in shaping research directions for RA management is increasingly evident. Recent investigations have shed light on the pivotal role of DNA methylation in RA, particularly in characterizing synovial tissue and exploring the underlying mechanisms of disease pathogenesis. This study provides valuable insights into the landscape of DNA methylation research in RA and highlights the importance of epigenetics in autoimmune diseases., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Loss of tolerance to self-antigens is considered to be one of the initial reasons for the onset of rheumatoid arthritis (RA). Identification of self-antigens and evaluation of autoreactive antibodies can foster understanding of the pathogenesis of the disease and the development of new therapeutics. By detection of responses to a particular self-antigen, such as α-enolase, keratin, fibrinogen, fibronectin, collagen, or vimentin, in patient- and animal model-derived samples, high-affinity T-cell receptor-dependent activation of autoreactive T cells to self-antigens can be elucidated. This chapter introduces a simple method to estimate T-cell-autoreactive responses to type II collagen (CII) in a murine collagen-induced arthritis model. A limiting dilution system is established in order to assess CII-dependent T-cell responses, which are reflected by the level of cytokine release., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have different effects on bones, cartilage and joints, sometimes destroying the spine and joints, and other times causing new bone formation. This study aimed to evaluate the effects of RA and AS on the types (radiolucent, radiopaque and mixed) of periapical lesions in jaw bones., Methods: This study included 708 individuals (97 with AS, 327 with RA and 284 healthy controls (C)) and a total of 17,118 teeth (AS: 2,442; RA: 7,638; C: 7,038). The number of teeth, extracted teeth and teeth with root canal treatment and the presence of radiopaque, radiolucent and mixed periapical lesions were recorded from dental panoramic radiographs. Kruskal-Wallis and chi-square tests were used for statistical analysis., Results: The frequency of radiopaque lesions in the AS and RA groups was similar (p > 0.05) and significantly higher than in the C group (p < 0.05) (AS: 13.4%; RA: 6.1%; C: 2%). Mixed lesions (AS: 3.1%; RA: 4.0%; C: 0.4%) were statistically significantly higher for the RA group compared to the C group (p < 0.05), while the AS-C and AS-RA groups were similar (p > 0.05). There was no significant difference in terms of radiolucent lesions among groups (p > 0.05)., Conclusion: Radiopaque apical lesions were frequent in RA and AS patients, while mixed lesions were significantly higher in RA patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background and Objective: Studies of autoimmunity and anti-citrullinated protein antibodies (ACPA) in idiopathic pulmonary fibrosis (IPF) have been confined to investigations of anti-cyclic citrullinated peptide (anti-CCP) antibodies which utilize synthetic peptides as surrogate markers for in vivo citrullinated antigens. We studied immune activation by analysing the prevalence of in vivo anti-modified protein antibodies (AMPA) in IPF., Methods: We included patients with incident and prevalent IPF (N = 120), sex and smoking-matched healthy controls (HC) (N = 120) and patients with RA (N = 104). Serum (median time: 11 months [Q1-Q3: 1-28 months] from diagnosis) was analysed for presence of antibodies towards native and posttranslational modified (citrullinated [Cit, N = 25]; acetylated [Acet, N = 4] and homocitrullinated [Carb, N = 1]) peptides derived from tenascin (TNC, N = 9), fibrinogen (Fib, N = 11), filaggrin (Fil, N = 5), histone (N = 8), cathelicidin (LL37, N = 4) and vimentin (N = 5) using a custom-made peptide microarray., Results: AMPA were more frequent and in increased levels in IPF than in HC (44% vs. 27%, p < 0.01), but less than in RA (44% vs. 79%, p < 0.01). We specifically observed AMPA in IPF towards certain citrullinated, acetylated and carbamylated peptides versus HC: tenascin (Cit (2033) -TNC 2025-2040 ; Cit (2197) -TNC 2177-2200 ; Cit (2198) -TNC 2177-2200 ) , fibrinogen (Cit (38,42) -Fibα 36-50 ; Cit (72) -Fibβ 60-74 ) and filaggrin (Acet-Fil 307-324 , Carb-Fil 307-324 ). No differences in survival (p = 0.13) or disease progression (p = 0.19) between individuals with or without AMPA was observed in IPF. However, patients with incident IPF had better survival if AMPA were present (p = 0.009)., Conclusion: A significant proportion of IPF patients present with specific AMPA in serum. Our results suggest autoimmunity as a possible characteristic for a subgroup of IPF that may affect disease outcome., (© 2023 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Objective: In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis., Methods: Fecal samples were collected from 38 healthy individuals and 53 high-risk RA individuals with anti-citrullinated protein antibody (ACPA) positivity (Pre-RA), 12 of 53 Pre-RA individuals developed RA within 5 years of follow-up. The differences in intestinal microbial composition between the healthy controls and Pre-RA individuals or among Pre-RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic-pretreated mice that received GM from the healthy control or Pre-RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen-induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre-RA individuals on arthritis severity in mice., Results: Stool microbial diversity was lower in Pre-RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre-RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre-RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre-RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre-RA group increased intestinal permeability in FMT mice and zonula occludens-1 expression in the small intestine and Caco-2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre-RA feces compared to healthy controls. The changes in intestinal permeability and Th17-cell activation prior to arthritis induction enhanced CIA severity in PreRA-FMT mice compared with HC-FMT mice., Conclusion: Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis., (© 2023 American College of Rheumatology.)

Objective: Heart failure is the most frequent cause of death among patients affected by rheumatoid arthritis(RA), in which high prevalence is independent of traditional risk factors. An early diagnosis of subclinical heart failure may be made by assessing left ventricular diastolic dysfunction (LVDD) by Doppler Echocardiography. Our study aims to early identify LVDD in RA patients., Methods: We enrolled 207 consecutive postmenopausal women (PMW) with normal electrocardiography and physical examination with a confirmed diagnosis of RA, for over one year, 200 PMW free from RA served as the control group (CG). All women underwent M-mode and two-dimensional Doppler echocardiography., Results: A total of 72 women were affected by LVDD among 207 women with RA (34.8%), 46 among 200 women in the CG (23%), chi-squared 6.8, OR 1.8, confidence interval (CI) 95%, p < 0.009. For our RA women, the chance of being affected by LVDD has almost doubled. There were 70 women affected by LVDD among 72 hypertensive women with RA (97.2%). A total of 32 women were affected by LVDD among 98 hypertensive women in the CG (32.7%), chi-squared 72.1, OR 7.2, CI 95%, p < 0.009. Among hypertensive PMW in our population, the chance of being affected by LVDD has more than tripled. All LVDD subjects had abnormal diastolic function for all different degrees., Conclusion: We propose that PMW, affected by RA, have a significantly higher prevalence than CG of LVDD without clinical evidence of heart disease. Since the prevalence is even higher if they are hypertensive, we suggest a Doppler echocardiography examination for all women with a diagnosis of RA., (© 2023 Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Objective: This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints., Methods: We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE)., Results: Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98-100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19-26%) of early RA patients seronegative for anti-cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE., Conclusion: A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Introduction Rheumatoid arthritis (RA) is a common autoimmune disease across the globe that is chronic and systemic as well. The disease is linked with autoantibodies and is inflammatory, eventually targeting several molecules along with certain modified self-epitopes. The disease majorly affects the joints of an individual. Rheumatoid arthritis is manifested clinically by polyarthritis linked with the dysfunction of the joints. This chiefly affects the synovial joint lining and is linked with progressive dysfunction, premature death, along with socioeconomic implications. The macrophage activation, along with the activation of certain defense cells, results in a response to self-epitopes that helps in providing a better understanding of the disease pathogenesis.  Material and methodology For this review article, papers have been retrieved and reviewed from database including PubMed, Scopus and Web of science. Relevant papers were taken fulfilling the criteria for writing this review article. Results This has resulted in the establishment of several new therapeutic techniques that serve as potential inhibitors of such cells. Researchers have gained an interest in understanding this disease to provide strategies for treatment in the last two decades. This also includes recognition followed by the treatment of the disease at its early stages. Various allopathic treatment approaches often have chronic and toxic teratogenic effects. However, to avoid this issue of toxicity followed by side effects, certain medicinal plants have been used in treating RA.  Conclusion Medicinal plants possess active phytoconstituents that entail antioxidants as well as anti-inflammatory properties, making them a helpful alternative to allopathic drugs that are often linked with highly toxic effects. This review paper entails a thorough discussion of the epidemiology, pathophysiology, diagnosis, and management of RA. The paper will also focus on the use of herbal plants in the treatment of the disease to avoid the side effects that generally occur in allopathic treatment., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Patients with arthralgias who could be at risk of progressing to rheumatoid arthritis (RA) represent a clinical challenge. Recommendations for their management and treatment are lacking. The purpose of the present study was to determine how Argentinean rheumatologists deal with these patients. We developed an anonymous ad hoc survey which was sent to 522 Argentinean rheumatologists. The RA study group of our Argentinean Rheumatology National Society assisted in forwarding the surveys to its members via the internet (e-mail or WhatsApp). The findings of the collected data are presented as descriptive statistics. The questionnaires were completed by 255 rheumatologists (overall response rate of 48.9%), and 97.6% confirmed that their practices had received medical consultations to rule out RA in patients with arthralgias. Ultrasound (US) was the method of first choice (93.7%) as part of the evaluation of these patients. For those in whom US power Doppler signal was present in at least one joint, 93.7% of the participants would start treatment and methotrexate was the first choice (58.1%). In patients with tenosynovitis but no synovitis on US, most rheumatologists would start treatment (89.4%), being NSAIDs the drug of first choice (52.3%). Argentinean rheumatologists evaluate patients with imminent RA and treat them based on their clinical judgment and findings from the US evaluation of affected joints; the drug of first choice for these patients among these rheumatologists was methotrexate. Despite published data of recent clinical trials, recommendations for the management and treatment of these patients are necessary., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objectives: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by the presence of autoantibodies that are used for classification of the disease. Though routine diagnostics is commonly restricted to measuring rheumatoid factor (RF) and anti-citrullinated protein antibodies, detection of RF IgM, IgG and IgA isotypes, may increase the power of RA serodiagnosis by reducing the number of seronegative patients as well as provide prognostic information. The agglutination-based RF assays, such as nephelometry or turbidimetry, are unable to differentiate isotypes. We compared three different immunoassays used in current laboratory practice to detect RF isotypes., Methods: We tested 117 consecutive serum samples that were positive for total RF at nephelometry, from 55 RA and 62 non-RA subjects. IgA, IgG, and IgM isotypes of RF were tested by immunoenzymatic (ELISA, Technogenetics), fluoroenzymatic (FEIA, ThermoFisher) and chemiluminescence (CLIA, YHLO Biotech Co.) immunoassays., Results: Diagnostic performance differed considerably between the assays, especially with regard to RF IgG isotype. Agreement among methods by Cohen's kappa ranged from 0.05 (RF IgG CLIA vs. FEIA) to 0.846 (RF IgM CLIA vs. FEIA)., Conclusions: The poor agreement observed in this study indicates substantial lack of comparability among assays for RF isotypes. Harmonization of these tests requires further efforts before their measurement can be used in clinical practice., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Host barriers such as the skin, the lung mucosa, the intestinal mucosa and the oral cavity are crucial at preventing contact with potential threats and are populated by a diverse population of innate and adaptive immune cells. Alterations in antigen recognition driven by genetic and environmental factors can lead to autoimmune systemic diseases such rheumatoid arthritis, systemic lupus erythematosus and food allergy. Here we review how different immune cells residing at epithelial barriers, host-derived signals and environmental signals are involved in the initiation and progression of autoimmune responses in these diseases. We discuss how regulation of innate responses at these barriers and the influence of environmental factors such as the microbiota can affect the susceptibility to develop local and systemic autoimmune responses particularly in the cases of food allergy, systemic lupus erythematosus and rheumatoid arthritis. Induction of pathogenic autoreactive immune responses at host barriers in these diseases can contribute to the initiation and progression of their pathogenesis., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objective: To identify a panel of serum biomarkers that could specifically identify imminent cases of rheumatoid arthritis (RA) before diagnosis., Methods: Serum samples were collected at 4 time points from active component US military personnel, including 157 anti-citrullinated protein antibody (ACPA)-seropositive and 50 ACPA-seronegative RA subjects, 100 reactive arthritis (ReA) subjects, and 76 healthy controls. The cohorts were split into 2 phases, with samples tested on independent proteomic platforms for each phase. Classification models of RA diagnosis based on samples obtained within 6 months prior to diagnosis were developed both in univariate analyses and by multivariate random forest modeling of training sample sets and testing sample sets from each phase., Results: Increases in serum analytes, including C-reactive protein levels, serum amyloid A, and soluble programmed cell death 1 (PD-1), were observed in seropositive RA subjects at the time point closest to diagnosis, up to several years before diagnosis. Only a small fraction of RA subjects had levels above the 95th percentile of healthy control levels until the time period within 6 months of diagnosis. For classification of RA diagnosis using samples obtained within 6 months prior to diagnosis, soluble PD-1 provided superior specificity compared to ReA cases (>89%), with a sensitivity of 48% for RA classification. An 8-analyte model provided superior sensitivity (69%), with comparable specificity relative to ReA (>82%)., Conclusion: Our findings demonstrate that imminent RA diagnosis could be classified with high specificity, relative to healthy controls and ReA cases, using a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis., (© 2022 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objectives: To analyze and evaluate the effectiveness of the detection of single autoantibody and combined autoantibodies in patients with rheumatoid arthritis (RA) and related autoimmune diseases and establish a machine learning model to predict the disease of RA., Methods: A total of 309 patients with joint pain as the first symptom were retrieved from the database. The effectiveness of single and combined antibodies tests was analyzed and evaluated in patients with RA, a cost-sensitive neural network (CSNN) model was used to integrate multiple autoantibodies and patient symptoms to predict the diagnosis of RA, and the ROC curve was used to analyze the diagnosis performance and calculate the optimal cutoff value., Results: There are differences in the seropositive rate of autoimmune diseases, the sensitivity and specificity of single or multiple autoantibody tests were insufficient, and anti-CCP performed best in RA diagnosis and had high diagnostic value. The cost-sensitive neural network prediction model had a sensitivity of up to 0.90 and specificity of up to 0.86, which was better than a single antibody and combined multiple antibody detection., Conclusion: In-depth analysis of autoantibodies and reliable early diagnosis based on the neural network could guide specialized physicians to develop different treatment plans to prevent deterioration and enable early treatment with antirheumatic drugs for remission. Key Points • There are differences in the seropositive rate of autoimmune diseases. • This is the first study to use a cost-sensitive neural network model to diagnose RA disease in patients. • The diagnosis effect of the cost-sensitive neural network model is better than a single antibody and combined multiple antibody detection., (© 2022. International League of Associations for Rheumatology (ILAR).)

Objectives: Rheumatoid factor (RF) is a well-established marker for the diagnosis and classification of rheumatoid arthritis (RA). Most studies evaluated IgM RF or isotype-nonspecific total RF assays. We evaluated the added value of IgA RF in this context., Methods: An international sample cohort consisting of samples from 398 RA patients and 1073 controls was tested for IgA RF with 3 commercial assays. For all RA patients and 100 controls essential clinical and serological data for ACR/EULAR classification were available., Results: The sensitivity of IgA RF for diagnosing RA was lower than the sensitivity of IgM RF. Differences in numerical values between IgA RF assays were observed. With all assays, the highest IgA RF values were found in patients with primary Sjögren's syndrome. Double positivity for IgM RF and IgA RF had a higher specificity for RA than either IgM RF or IgA RF. The sensitivity of double positivity was lower than the sensitivity of either IgA RF or IgM RF. Single positivity for IgA RF was at least as prevalent in controls than in RA patients. Adding IgA RF to IgM RF and anti-citrullinated protein antibodies (ACPA) did not affect RA classification. However, combined positivity for IgA RF, IgM RF and IgG ACPA had a higher specificity and lower sensitivity for RA classification than positivity for either of the antibodies., Conclusions: IgA RF showed a lower sensitivity than IgM RF. Combining IgA RF with IgM RF and ACPA did not improve sensitivity of RA classification. Combined positivity (IgA-RF/IgM-RF/ACPA) increased specificity., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: To investigate levels and possible extramucosal formation of secretory Ig, including anti-citrullinated protein antibodies (ACPAs), in rheumatoid arthritis (RA)., Methods: Three patient groups were studied: 1) ACPA-positive patients with musculoskeletal pain without clinical arthritis, 2) patients with recent-onset RA, and 3) patients with established RA. In baseline serum samples (groups 1 and 2) and paired synovial fluid samples (group 3), we analyzed total secretory IgA, total secretory IgM, free secretory component (SC), and SC-containing ACPA. Extramucosal formation of SC-containing ACPA was investigated by preincubating RA sera and affinity-purified ACPA with recombinant free SC., Results: Compared to healthy controls, serum levels of total secretory IgA and total secretory IgM were increased both in patients with early RA and at-risk patients (P < 0.05). Patients with early RA with elevated total secretory Ig had significantly higher disease activity during the 3-year follow-up period compared to those without increased levels. At-risk patients who developed arthritis during follow-up (39 of 82) had higher baseline total secretory IgA levels compared to those who did not (P = 0.041). In established RA, total secretory IgA and total secretory IgM levels were higher in serum than in synovial fluid (P < 0.0001), but SC-containing ACPAs adjusted for total secretory Ig concentration were higher in synovial fluid (P < 0.0001). Preincubation with recombinant free SC yielded increased SC-containing ACPA reactivity in sera as well as in affinity-purified IgA and IgM ACPA preparations., Conclusion: Circulating secretory Ig are elevated before and at RA onset. In the presence of free SC, secretory Ig may form outside the mucosa, and SC-containing ACPAs are enriched in RA joints. These findings shed important new light on the mucosal connection in RA development., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Rheumatoid arthritis (RA) is an auto-immune inflammatory disorder of the synovial lining of joints marked by immune cells infiltration and hyperplasia of synovial fibroblasts which results in articular cartilage destruction and bone erosion. The current review will provide comprehensive information and results obtained from the recent research on the phytochemicals which were found to have potential anti-arthritic activity along with the molecular pathway that were targeted to control RA progression. In this review, we have summarized the scientific data from various animal studies about molecular mechanisms, possible side effects, associations with conventional therapies, and the role of complementary and alternative medicines (CAM) for RA such as ayurvedic medicines in arthritis. In the case of RA, phytochemicals have been shown to act through different pathways such as regulation of inflammatory signaling pathways, T cell differentiation, inhibition of angiogenic factors, induction of the apoptosis of fibroblast-like synoviocytes (FLS), inhibition of autophagic pathway by inhibiting High-mobility group box 1 protein (HMGB-1), Akt/ mTOR pathway and HIF-1α mediated Vascular endothelial growth (VEGF) expression. Also, osteoclasts differentiation is inhibited by down-regulating the VEGF expression by decreasing the accumulation of the ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator)-HIF-1α complex Although phytochemicals have shown to exert potential anti-arthritic activity in many animal models and further clinical data is needed to confirm their safety, efficacy, and interactions in humans., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: To assess if microstructural bone lesions in individuals at risk of developing rheumatoid arthritis (RA) are related to the spectrum of anti-modified protein antibodies (AMPAs) and affect the risk of developing RA., Methods: Cortical microchannels as well as cortical and trabecular bone mineral density (BMD) volumes (expressed as mg hydroxyapatite/cm 3 ) were analyzed by high-resolution peripheral quantitative computed tomography of the hand joints of individuals at risk of RA. AMPA response was profiled, including reactivities against citrullinated proteins (vimentin, enolase, and fibrinogen) as well as carbamylated and acetylated vimentin. All subjects were followed up for the development of RA., Results: Subjects at risk of developing RA (n = 75) who had broad-spectrum AMPAs (6-8 reactivities) had significantly more severe microstructural changes, including a higher mean ± SD number of cortical microchannels per joint (95 ± 3) and lower total volumetric BMD (vBMD; 265 ± 45), trabecular vBMD (176 ± 42), and cortical vBMD (585 ± 138), than those with moderate AMPA reactivity (3-5 reactivities) (number of cortical microchannels, 79 ± 30; total vBMD, 293 ± 33; trabecular vBMD, 195 ± 32; and cortical vBMD, 627 ± 91) and those with narrow AMPA reactivity (1-2 reactivities) (number of cortical microchannels, 47 ± 20; total vBMD, 311 ± 34; trabecular vBMD, 211 ± 30; and cortical vBMD, 674 ± 56). Progressors to RA had significantly higher numbers of cortical microchannels (103 ± 30 versus 71 ± 35) and lower bone volume (258 ± 37 versus 295 ± 34) compared to nonprogressors. Furthermore, rate of progression to RA was high in subjects with broad AMPA reactivity (48%) versus those with medium AMPA reactivity (26%) or narrow AMPA reactivity (0%), as well as in those with a high number of cortical microchannels (44%) versus those with a low number of cortical microchannels (10%)., Conclusion: Microstructural changes in individuals at risk of RA are associated with broad-spectrum autoimmunity and predict the onset of RA. These data support the concept of structural priming of joints by autoimmunity before the onset of the inflammatory phase of the disease., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

To evaluate the association between TGFB1 + 869 T > C (rs1800470) and TGFB1-509 C > T (rs1800469) variants with susceptibility for rheumatoid arthritis (RA), disease activity, presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) and TGF-β1 plasma levels. A total of 262 patients with RA and 168 control individuals were tested for the TGFB1 variants using a TaqMan genotyping assay. Disease activity score in 28 joints (DAS28) classified RA patients into two groups of disease activity: remission/mild (DAS28 < 3.2) and moderate/severe (DAS28 ≥ 3.2). TGFB1 + 869 T > C and -509 C > T variants, independently or in haplotype combination, were not associated with RA's susceptibility. Patients with the TGFB1-509 TT genotype had a higher frequency of DAS28 ≥ 3.2 (OR 2.58, 95% CI 1.04-6.42, p = 0.041). The TGFB1 + 869 CC genotype in seropositive patients for RF or anti-CCP was associated with decreased TGF-β1 levels (p = 0.032 and p = 0.039, respectively). Patients with the TGFB1 + 869 C allele and elevated RF titles demonstrated a higher frequency of DAS28 ≥ 3.2 (p = 0.037). The TGFB1 + 869 T > C variant was associated with diminished TGF-β1 plasma levels and moderate/severe activity disease only in seropositive RF patients. This is the first study showing that TGF-β1 plasma levels can be modulated by the interaction between the TGFB1 + 869 T > C variant and autoantibodies. However, the TGFB1-509 C > T variant was associated with moderate/severe activity disease, independently of autoantibodies positivity. Thus, our findings suggest that TGFB1 + 869 T > C and -509 C > T variants can predict activity disease in different RA patient subgroups., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects small joints. The impaired chemokine and cytokine responses are essential pathological mechanisms for the RA clinical presentation. Given the role of chemokines and inflammatory reactions in RA pathogenesis, we evaluate the association between the plasma concentration of CCL20 with the clinical and laboratory parameters in newly diagnosed RA patients., Material and Methods: Forty-five newly diagnosed RA patients and forty-five healthy subjects were enrolled in this study. The plasma levels of CCL20, rheumatoid factor, and anti-citrullinated peptide antibodies were measured using the enzyme-linked immunosorbent assay (ELISA) technique., Result: The plasma levels of CCL20 were increased significantly in RA patients compared to the healthy controls (p < 0.0001). There was a positive correlation between CCL20 and RF, anti-CCP, ESR, and DAS-28 (p < 0.0001, r = 0.669; p < 0.015, r = 0.358; p < 0.0001, r = 0.586; p < 0.0001, r = 0.769)., Conclusion: The increased plasma levels of CCL20 in newly diagnosed RA patients may contribute to RA pathogenesis, and it is in association with clinical and laboratory parameters. Key Points • CCL20 has a contribution to the early phase of RA., (© 2021. International League of Associations for Rheumatology (ILAR).)

Rheumatoid arthritis (RA) is an extremely painful autoimmune disease characterized by chronic joint inflammation leading to the erosion of adjacent cartilage and bone. Rheumatoid arthritis pathology is primarily driven by inappropriate infiltration and activation of immune cells within the synovium of the joint. There is no cure for RA. As such, manifestation of symptoms entails lifelong management via various therapies that aim to generally dampen the immune system or impede the function of immune mediators. However, these treatment strategies lead to adverse effects such as toxicity, general immunosuppression, and increased risk of infection. In pursuit of safer and more efficacious therapies, many emerging biomaterial-based strategies are being developed to improve payload delivery, specific targeting, and dose efficacy, and to mitigate adverse reactions and toxicity. In this review, we highlight biomaterial-based approaches that are currently under investigation to circumvent the limitations of conventional RA treatments., (© 2021. Controlled Release Society.)

Introduction: Autoantibodies such as IgM rheumatoid factor (RF) and anti-citrullinated proteins/peptides antibodies (ACPA) have previously been incriminated in systemic bone loss in rheumatoid arthritis (RA). There are, however, no data describing association of IgA RF and IgG RF with systemic bone loss., Objective: This study was aimed to investigate the association of RF isotypes with systemic bone loss among patients with RA., Methods: RF isotypes and ACPA were measured by enzyme-linked immunosorbent assay among 153 patients with RA. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry., Results: Ninety-four (61.4%) patients had positive IgA RF, 89 (58.2%) had positive IgG RF, 109 (71.2%) had positive IgM RF, whereas 122 (80.3%) RA patients tested positive for ACPA. Compared to the IgA RF-negative patients, IgA RF-positive patients exhibited higher disease activity and had higher RF titers. Seven (4.6%) patients had low BMD at femoral neck, 12 (7.8%) at total femur, and 47 (30.7%) at lumbar spine. IgA RF was found to be associated with protection against low BMD at spine (OR = 0.47, 95% CI = 0.23-0.95, p = 0.034). This association was further confirmed in the multivariate regression analysis taking into account several potential confounding factors (OR = 0.21, 95% CI = 0.06-0.65, p = 0.039). No association between low BMD and the presence of IgG RF or IgM RF or ACPA was found., Conclusion: IgA RF for the first time ever was shown to be associated with BMD preservation at spine in RA. Key points • IgA RF was associated with protection against low spinal BMD. • No association between low BMD and the presence of IgG RF or IgM RF was found., (© 2021. International League of Associations for Rheumatology (ILAR).)

Background: Rheumatoid arthritis is a chronic inflammatory and systemic autoimmune disease associated with synovial fluid inflammatory lesions and articular changes. The aim of the present study was to determine socioeconomic inequality in RA patients using a meta-analysis approach., Methods: A systematic search of national and international databases of SID, MagIran, Google Scholar, Cochrane, Embase, ScienceDirect, Scopus, PubMed, and Web of Science (WoS) was conducted to find articles published from 1988 to March 2020. Random effects model was used for analysis and heterogeneity of studies was investigated using I 2 index. Data analysis was then carried out using Comprehensive Meta-Analysis (Ver. 2)., Results: A total of 51 articles with a total sample size of 48,195 individuals were included in the meta-analysis in all the components. The results showed that 18.9% (95% CI: 4.9-13.25%) of patients were single patients, 70.6% (95% CI: 63.5-76.8%) were married, 31.6% (95% CI: 24.5-39.7%) had low economic status, 52.1% (95% CI: 5.8-44.53%) had moderate economic status, level of education was below diploma in 33% (95% CI: 27.1-39.5%) of cases, 36.2% (95% CI: 27.3-46.1%) were smokers, and 8.8% (95% CI: 2.8-24.1%) of patients were unemployed., Conclusion: The results of the present study indicate high socioeconomic inequality in RA patients in the main components of the study. Hence, to improve the aforementioned status and find causes and do the monitoring at all levels, appropriate solutions must be adopted by providing feedback to policy-makers., Key Points: • The results showed that 18.9% (95% CI: 4.9-13.25%) of patients were single patients. • 70.6% (95% CI: 63.5-76.8%) were married and 31.6% (95% CI: 24.5-39.7%) had low economic status. • 52.1% (95% CI: 5.8-44.53%) had moderate economic status; 36.2% (95% CI: 27.3-46.1%) were smokers., (© 2021. International League of Associations for Rheumatology (ILAR).)

Objective: To identify the predictive biomarkers for achieving remission with abatacept in patients with seropositive rheumatoid arthritis (RA)., Methods: We enrolled patients with RA who were treated with abatacept. We compared the baseline laboratory results and longitudinal immune-phenotyping data between patients who achieved remission and those who did not achieve remission at 6 months according to the clinical disease activity index., Results: One hundred and twenty RA patients were enrolled. In the seropositive patients with early RA (n = 24), high serum IgA levels, anti-citrullinated peptide (CCP) titers, and neutrophil counts before treatment were predictors of remission (area under the curve [AUC], 0.659, 0.741, and 0.704, respectively). Additionally, activated Th17 (aTh17) cells and activated Treg (aTreg) cells before treatment were found to be significantly higher in patients with remission compared to those without remission (2.9% vs 1.1%, P = 0.02; 34.3% vs 17%, P = 0.03, respectively). The measurement of longitudinal cell subpopulation revealed a decrease in the effector CD4 T cell population after abatacept treatment, which correlated with anti-CCP titers and neutrophil counts, and was associated with remission achievement. In seropositive patients with established RA (n = 79), high RF titers and low IFN-γ levels were associated with the good response to abatacept., Conclusion: Our study has shown that serum IgA levels, anti-CCP titer, and neutrophil counts are predictive biomarkers for predicting the response to abatacept in patients with seropositive and early RA and may reflect the inhibition of effector CD4 T cell subpopulations by abatacept. Key Points • Serum IgA levels and neutrophil counts are novel biomarkers for predicting the efficacy of abatacept. • Those may reflect the inhibition of effector CD4 T cell subpopulations by abatacept., (© 2021. International League of Associations for Rheumatology (ILAR).)

Background: First-degree relatives (FDRs) of people with rheumatoid arthritis (RA) have a fourfold increased risk of developing RA. The Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire was developed to document symptoms in persons at risk of RA. The aims of this study were (1) to describe symptoms in a cohort of FDRs of patients with RA overall and stratified by seropositivity and elevated CRP and (2) to determine if patient characteristics were associated with symptoms suggestive of RA., Methods: A cross-sectional study of FDRs of patients with RA, in the PREVeNT-RA study, who completed a study questionnaire, provided a blood sample measured for rheumatoid factor, anti-CCP and CRP and completed the SPARRA questionnaire. Moderate/severe symptoms and symmetrical, small and large joint pain were identified and described. Symptoms associated with both seropositivity and elevated CRP were considered suggestive of RA. Logistic regression was used to determine if symptoms suggestive of RA were associated with patient characteristics., Results: Eight hundred seventy participants provided all data, 43 (5%) were seropositive and 122 (14%) had elevated CRP. The most frequently reported symptoms were sleep disturbances (20.3%) and joint pain (17.9%). Symmetrical and small joint pain were 11.3% and 12.8% higher, respectively, in those who were seropositive and 11.5% and 10.7% higher in those with elevated CRP. In the logistic regression model, seropositivity, older age and feeling depressed were associated with increased odds of small and symmetrical joint pain., Conclusions: This is the first time the SPARRA questionnaire has been applied in FDRs of patients with RA and has demonstrated that the presence of symmetrical and small joint pain in this group may be useful in identifying people at higher risk of developing RA., (© 2021. The Author(s).)

Prevention is the ultimate aim for clinicians and scientists concerned with severe diseases, like many immune-mediated conditions. Here, we describe recent progress in the understanding of etiology and molecular pathogenesis of rheumatoid arthritis (RA), which make this disease a potential prototype for prevention that may include both public health measures and targeted and personalized approaches that we call "personalized prevention." Critical components of this knowledge are (i) better understanding of the dynamics of the RA-associated autoimmunity that may begin many years before onset of joint inflammation; (ii) insights into how this immunity may be triggered at mucosal surfaces after distinct environmental challenges; (iii) better understanding of which features of the pre-existing immunity may cause symptoms that precede joint inflammation and predict a high risk for imminent arthritis development; and (iv) how molecular events occurring before onset of inflammation might be targeted by existing or future therapies, ultimately by specific targeting of Major histocompatibility complex (MHC) class II restricted and RA-specific immunity. Our main conclusion is that studies and interventions in the phase of autoimmunity preceding RA offer new opportunities to prevent the disease and thereby also understand the molecular pathogenesis of its different variants., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Purpose of Review: To summarize the current understanding of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) throughout the rheumatoid arthritis (RA) disease course from preclinical to established disease., Recent Findings: ILD is a serious extra-articular manifestation of RA. Multiple studies have demonstrated a high prevalence of both subclinical and clinical ILD throughout the RA disease course. Investigations of patients without RA have demonstrated an association between RA-related autoantibodies like anticitrullinated protein antibodies (ACPA) and interstitial abnormalities on lung imaging. A significant proportion of RA-ILD patients develop ILD prior to articular manifestations, suggesting that the lung plays a central role in RA development, perhaps through ACPA production. RA-ILD also occurs in early RA, when exuberant autoantibody production and systemic inflammation may propagate pulmonary disease activity. In patients with established RA, a high burden of subclinical and clinical ILD results in significant morbidity, mortality, and healthcare expenditure. Multiple epidemiologic and genetic risk factors, as well as serum biomarkers, have been associated with RA-ILD., Summary: Subclinical and clinical ILD occur frequently in preclinical, early, and established RA and may play a key role in RA-related autoantibody production and disease progression. Further studies are needed to better understand the risk factors, prognosis, and potential therapies for RA-ILD., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Co-occurrence of autoantibodies specific for ≥1 autoimmune disease is widely prevalent in rheumatoid arthritis (RA) patients. To understand the prevalence of polyautoimmunity in preclinical RA, we performed a comprehensive autoantibody assessment in a First Nations cohort of at-risk first-degree relatives (FDR) of RA patients, a subset of whom subsequently developed RA (progressors)., Methods: Venous blood was collected from all study participants (n = 50 RA patients and 64 FDR) at scheduled visits, and serum was stored at -20°C. High-sensitivity C-reactive protein level, anti-citrullinated protein antibody (ACPA) status, and autoantibody status were determined using commercially available enzyme-linked immunosorbent assay kits. Rheumatoid factor (RF) was detected by nephelometry. Antinuclear autoantibodies (ANA) were identified using Hep-2 indirect immunofluorescence assay (IFA) and classified according to international consensus nomenclature as various anti-cell (AC) patterns., Results: Of our study cohort, 78.9% had positive ANA reactivity (≥1:80), which was either a homogenous, fine-speckled (AC-1 and AC-4) or mixed IFA pattern. Importantly, the AC-4 and mixed ANA patterns were also observed in progressors at the time of disease onset. While all of the RA patients showed a high prevalence of arthritis-associated autoantibodies, they also had a high prevalence of extractable nuclear antigen-positive autoantibodies to other autoantigens. In FDR, we did not observe any increase in serum autoreactivity to nonarthritis autoantigens, either cross-sectionally or in samples collected longitudinally from progressors prior to RA onset., Conclusion: While alternative autoimmunity and ANA positivity are widely prevalent in First Nations populations, including asymptomatic, seronegative FDR, expansion of alternative autoimmunity does not occur in parallel with ACPA expansion in FDR and is restricted to patients with established RA., (© 2021, American College of Rheumatology.)

To avoid autoimmunity, it is essential to keep the balance between the defence against pathogens and the maintenance of tolerance to self-antigens. Mucosal inflammation may lead to breakdown of tolerance and activation of autoreactive cells. Growing evidence suggests a major contribution of gut microbiota to the onset of chronic, autoimmune inflammatory diseases including rheumatoid arthritis (RA). RA patients show significant differences in the composition of gut microbiota compared to healthy controls, and in murine arthritis models certain bacteria can induce inflammatory Th17 responses or autoantibody production. The gut microbiota plays an important role in regulating the balance between immunogenic and tolerogenic immune responses. The intestinal barrier is the site of the body where most host-microbiota interaction takes place. Certain microbiota or their metabolites can cause a break in homeostasis by affecting the intestinal barrier integrity and permeability. However, an intact intestinal barrier is essential to separate the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. This review will focus on the correlation between a leaky gut and the onset of arthritis. Furthermore, it will be discussed how targeting the intestinal barrier function by dietary changes might provide an opportunity to modulate the development of RA., (© 2021 Wiley-VCH GmbH.)

Objective: The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure., Methods: Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past acute or chronic, upper or lower respiratory disease diagnoses. For each disease group, we estimated adjusted odds ratios (OR adj ) with 95% confidence intervals (95% CI) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status., Results: Respiratory disease diagnoses were associated with risk of RA, with an OR adj of 1.2 for acute upper respiratory disease (95% CI 0.8-1.7), 1.4 for chronic upper respiratory disease (95% CI 1.1-1.9), 2.4 for acute lower respiratory disease (95% CI 1.5-3.6), and 1.6 for chronic lower respiratory disease (95% CI 1.5-3.6). These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA/RF-positive than ACPA/RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (OR adj 2.1 [95% CI 1.5-2.9]) than for smokers (OR adj 1.2 [95% CI 0.9-1.5])., Conclusion: Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms., (© 2020, American College of Rheumatology.)

Objective: Rheumatoid factors (RFs), which are anti-IgG autoantibodies strongly associated with rheumatoid arthritis (RA), are also found in other diseases and in healthy individuals. RFs bind to various epitopes in the constant (Fc-) domain of IgG. Therefore, disease-specific reactivity patterns may exist. This study was undertaken in order to develop a new approach to dissecting RF epitope binding patterns across different diseases., Methods: We analyzed RF reactivity patterns in serum from patients with seropositive arthralgia, patients with RA, and patients with primary Sjögren's syndrome (SS) using bioengineered, natively folded IgG-Fc targets that demonstrated selective RF binding toward several distinct regions of the IgG-Fc domain., Results: Rheumatoid factor responses primarily bound the Fc Elbow region, with a smaller number of RFs binding the Fc Tail region, while the Fc receptor binding region was hardly targeted. A restricted reactivity against the IgG-Fc Tail region was associated with less positivity for anti-citrullinated protein antibodies (ACPAs) and less arthritis development in arthralgia, whereas combined reactivity toward IgG-Fc Tail and Elbow regions was associated with more arthritis development. Reactivity toward the IgG-Fc Tail region was observed far more frequently in RA than in primary SS., Conclusion: Bioengineered IgG targets enable serologic characterization of RF reactivity patterns, and use of this approach appears to reveal patterns associated with ACPA detection and arthritis development in patients with arthralgia. These patterns are able to distinguish RA patients from primary SS patients. This new methodology improves the clinical value of RFs and our understanding of their pathophysiologic processes., (© 2020, American College of Rheumatology.)

Objective: To 1) determine the prevalence of anti-cyclic citrullinated peptide 3 (anti-CCP3) antibodies in anti-CCP2 antibody-positive (anti-CCP2+) at-risk individuals, and 2) explore the additional value of anti-CCP3 antibodies in anti-CCP2+ at-risk individuals for predicting progression to inflammatory arthritis., Methods: Stored serum samples obtained from 347 anti-CCP2+ (BioPlex 2200; Bio-Rad) at-risk individuals without clinical synovitis were tested for anti-CCP3 antibodies. Anti-CCP2 titers were categorized as low or high, and anti-CCP3 titers were categorized as negative, low, or strong. Progression to inflammatory arthritis was defined as the development of clinical synovitis in ≥1 joint. Only subjects with ≥1 follow-up visit were included in the progression analysis (n = 291)., Results: In the 347 samples included, anti-CCP3 antibody titers tended to be either negative (n = 138 [39.7%]) or strongly positive (n =189 [54.4%]), with very few subjects showing a low titer (n = 20 [5.7%]). In contrast, for anti-CCP2 antibodies, more low titers were observed (n = 103 [29.7%]). Eighty-eight of 291 subjects (30.2%) developed inflammatory arthritis. The rate of progression to inflammatory arthritis in the low-titer anti-CCP2 group and the high-titer anti-CCP2 group fell from 7.5% to 3.3% and from 38.9% to 9.8%, respectively, when anti-CCP3 was negative. Progression in the high-titer anti-CCP2 group increased from 38.9% to 48.4% when anti-CCP3 was strongly positive. The area under the curve was 0.72 for anti-CCP2 (95% confidence interval [95% CI] 0.66, 0.78) and 0.76 for anti-CCP3 (95% CI 0.70, 0.81) for assessment of progression. In the multivariable analysis, the odds ratio for the development of inflammatory arthritis in anti-CCP3+ subjects was 1.73 (95% CI 1.20, 2.51) (P < 0.01)., Conclusion: Anti-CCP3 antibodies improve the prediction of inflammatory arthritis in anti-CCP2+ at-risk individuals. The impact of anti-CCP3 antibody status for the risk stratification of individuals with high-titer anti-CCP2 is particularly notable., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Aim: To Investigate the prevalence of seroconversion to ACPA after commencement of triple disease-modifying anti-rheumatic drug (DMARD) treat-to-target therapy., Background: Anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) define 'seropositive' rheumatoid arthritis (RA). Both predict unfavourable disease course, development of extra-articular features and treatment outcomes. We investigated the prevalence of seroconversion to ACPA after commencement of triple disease-modifying anti-rheumatic drug (DMARD) treat-to-target therapy., Methods: DMARD-naïve patients with RA according to the 1987 American College of Rheumatology criteria and disease duration of <96 weeks were enrolled. RF and ACPA levels were recorded at baseline and sequentially during triple DMARD therapy., Results: A total of 368 patients were followed for a median of 272 weeks. Of 154 patients seronegative for ACPA at recruitment, 10 (6.5%) seroconverted at some point. Nine of these were positive for RF at baseline and baseline RF titre was predictive of seroconversion. Four (2.6%) patients remained seropositive. No patients seroconverted from negative to positive for both RF and ACPA. Median time to seroconversion for ACPA was 29 months., Conclusion: Persistent seroconversion of ACPA from negative to positive after diagnosis in patients with RA is uncommon. ACPA and RF double negative patients are highly unlikely to ever develop ACPA positivity with a risk <1%. It is therefore unlikely to be helpful or cost effective to perform serial ACPA measurements in patients with seronegative RA after commencement of a treat-to-target strategy., (© 2019 Royal Australasian College of Physicians.)

The current review uses rheumatoid arthritis (RA) as a prominent example for how studies on the interplay between environmental and genetic factors in defined subsets of a disease can be used to formulate aetiological hypotheses that subsequently can be tested for causality using molecular and functional studies. Major discussed findings are that exposures to airways from many different noxious agents including cigarette smoke, silica dust and more interact with major susceptibility genes, mainly HLA-DR genetic variants in triggering antigen-specific immune reactions specific for RA. We also discuss how several other environmental and lifestyle factors, including microbial, neural and metabolic factors, can influence risk for RA in ways that are different in different subsets of RA.The description of these processes in RA provides the best example so far in any immune-mediated disease of how triggering of immunity at one anatomical site in the context of known environmental and genetic factors subsequently can lead to symptoms that precede the classical inflammatory disease symptoms and later contribute also to the classical RA joint inflammation. The findings referred to in the review have led to a change of paradigms for very early therapy and prevention of RA and to efforts towards what we have named 'personalized prevention'. We believe that the progress described here for RA will be of relevance for research and practice also in other immune-mediated diseases., (© 2020 The Association for the Publication of the Journal of Internal Medicine.)

Objective: To determine the incidence of inflammatory arthritis and autoantibody prevalence in Indigenous North American people., Methods: Unaffected relatives of Indigenous North Americans with rheumatoid arthritis (RA) from central Canada and Alaska were systematically monitored from 2005 to 2017. Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) were tested at every visit, and a subset was tested for ACPA fine specificity using a custom multiplex assay. Multistate models based on all available study visits were developed to determine the likelihood of transitioning between autoantibody states, or to inflammatory arthritis., Results: Eighteen of 374 relatives (4.8%) developed inflammatory arthritis during follow-up (after a mean ± SD of 4.7 ± 2.4 years), yielding a transition rate of 9.2 cases/1,000 person-years. Thirty percent of those who developed inflammatory arthritis were seronegative at baseline, but all were seropositive at inflammatory arthritis onset. Although 30% of ACPA/RF double-seropositive individuals developed inflammatory arthritis (after 3.2 ± 2.2 years), the majority of these individuals did not develop inflammatory arthritis. Multistate modeling indicated a 71% and 68% likelihood of ACPA and RF seropositive states, respectively, reverting to a seronegative state after 5 years, and a 39% likelihood of an ACPA/RF double-seropositive state becoming seronegative. Fine specificity testing demonstrated an expansion of the ACPA repertoire prior to the development of inflammatory arthritis., Conclusion: Despite a high incidence of inflammatory arthritis in this cohort of at-risk relatives of Indigenous North Americans with RA, a large proportion of autoantibody-positive individuals do not develop inflammatory arthritis and revert back to an autoantibody-negative state., (© 2019, American College of Rheumatology.)