Reduction in experimental autoimmune thyroiditis by IgG Fc fragments bearing regRF epitopes.

Previously, we identified a new immunoregulatory factor, the production of which provides rats with resistance to certain experimental autoimmune diseases. It has been named regulatory rheumatoid factor (regRF). RegRF inhibits the expansion of CD4 T lymphocytes by killing activated cells. CD4 T cells are essential for antibody production against a majority of antigens and for the generation of cytotoxic T cells; therefore, regRF is an attractive therapeutic biotarget for T-cell and antibody-mediated autoimmune diseases. RegRF is anti-idiotypic antibodies that have a shared paratope in addition to an individual paratope. Epitopes specific to the shared regRF paratope (regRF epitopes) can be obtained on conformers of IgG Fc fragments. Immunization with Fc fragments carrying regRF epitopes reduces rat collagen-induced arthritis and diminishes experimental autoimmune encephalomyelitis. The aim of this study was to determine whether IgG Fc fragments bearing regRF epitopes suppress experimental autoimmune thyroiditis (EAT). Four weeks after EAT induction, rats were immunized with IgG Fc fragments exhibiting regRF epitopes. Histology studies of the thyroid were performed 4 weeks later. Thyroid function and other parameters were also evaluated. Treatment of rats with Fc fragments bearing regRF epitopes decreased the number of rats affected by EAT, significantly decreased the extent of thyroid damage, prevented thyroid metaplasia, and restored normal thyroid hormone production. Therefore, RegRF is a promising biotarget in autoimmune thyroiditis, and Fc fragments bearing regRF epitopes are a potential therapeutic agent for that condition.

Association between rheumatoid factors and proinflammatory biomarkers with implant health in rheumatoid arthritis patients with dental implants.

OBJECTIVE: To evaluate the levels of crevicular fluid rheumatoid factors (RFs), and other proinflammatory cytokines including interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-ɑ) and correlate these biomarkers with the clinical peri-implant parameters among rheumatoid arthritis (RA) patients with or without concomitant connective tissue disorder (CTD). PATIENTS AND METHODS: Three groups of 14 participants each [Group-I: healthy, Group-II: RA without CTD, and Group-III: RA with CTD] were selected. The clinical parameters observed were bleeding on probing (BOP), plaque scores (PS), pocket depth (PD) and alveolar bone loss (ABL). RFs, IL-6 and TNF-α were Enzyme-linked immunosorbent assay (ELISA) was incorporated to quantify RFs, IL-6 and TNF-α. RESULTS: BOP was significantly higher in Groups II and III as compared with Group I. Alveolar bone loss was significantly higher in Group III followed by Group II and least in Group I. Patients with RA with CTD presented with statistically higher levels of RF, IL-6 and TNF-α followed by Group II compared with Group I (p<0.05). A positive correlation existed between BOP and all the three biomarkers RF (r=0.0562; p=0.0039), IL-6 and TNF-α for Group-II patients. Similarly, a significant positive correlation existed between BOP and all the three biomarkers RF, IL-6 and TNF-α for Group-III patients. In addition, a positive correlation was also seen between ABL and RF, PD, and IL-6 in Group-III patients. CONCLUSIONS: RF might influence peri-implant inflammation in RA patients with CTD. Moreover, the increased RF levels are indicative of diagnostic marker for peri-implant complications in RA.

The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis.

Differences in clinical presentation, response to treatment, and long-term outcomes between autoantibody-positive and -negative rheumatoid arthritis (RA) highlight the need for a better comprehension of the immunopathogenic events underlying the two disease subtypes. Whilst the drivers and perpetuators of autoimmunity in autoantibody-positive RA have started to be disclosed, autoantibody-negative RA remains puzzling, also due its wide phenotypic heterogeneity and its possible misdiagnosis. Genetic susceptibility appears to mostly rely on class I HLA genes and a number of yet unidentified non-HLA loci. On the background of such variable genetic predisposition, multiple exogeneous, endogenous, and stochastic factors, some of which are not shared with autoantibody-positive RA, contribute to the onset of the inflammatory cascade. In a proportion of the patients, the immunopathology of synovitis, at least in the initial stages, appears largely myeloid driven, with abundant production of proinflammatory cytokines and only minor involvement of cells of the adaptive immune system. Better understanding of the complexity of autoantibody-negative RA is still needed in order to open new avenues for targeted intervention and improve clinical outcomes.

Suppression of experimental autoimmune encephalomyelitis by IgG Fc fragments bearing regRF epitopes.

Previously we identified a rheumatoid factor, the production of which provides rats with resistance to experimental autoimmune diseases. It has been named regulatory rheumatoid factor (regRF). Immunization with conformers of IgG Fc fragments carrying epitopes specific to regRF reduces rat collagen-induced arthritis. The aim of this study was to determine whether IgG Fc fragments bearing regRF epitopes suppress experimental autoimmune encephalomyelitis, and to evaluate the potential of a strategy of stimulating production of regRF to treat multiple sclerosis. Two days after myelin basic protein injection, rats were immunized with Fc fragments exhibiting regRF epitopes, as well as with Fc fragments without those epitopes. The effect of Fc immunization on clinical signs of EAE and immunological parameters was evaluated. Stimulation of regRF production by IgG Fc fragments bearing regRF epitopes diminished EAE symptoms in rats, while immunization with Fc fragments without those epitopes worsened EAE. The improvement of EAE symptoms in rats treated with Fc fragments bearing regRF epitopes was associated with regRF production and with the relatively low number of blood CD4 T lymphocytes during disease development. In experiments involving immunizing intact rats and lymph node mononuclear cell cultures, Fc fragments bearing regRF epitopes decreased the CD4 T lymphocyte population indirectly, via regRF production. RegRF is a promising biotarget in MS, and Fc fragments bearing regRF epitopes are a potential therapeutic agent for MS.

Differences in autoimmunity factors based on the activity of thromboangiitis obliterans.

OBJECTIVE: The treatment of Buerger's disease (BD) presents a medical problem as its etiology is still unclear. In this study, our objective was to evaluate the serum levels of autoimmune markers in patients with different clinical features of BD. METHODS: In this study, 80 BD patients were categorized in three groups using a cross-sectional design: migratory thrombophlebitis, cold sensitivity, and skin discoloration (mild symptoms); chronic ulcers, claudication, and burning pain of the feet at night (moderate symptoms); pain at rest and spontaneous gangrene (severe symptoms). Enzyme-linked immunosorbent assay was performed to measure antibodies against immunoglobulin M rheumatoid factor (IgM RF), anti-nuclear antibodies (ANA), antibodies against cyclic citrullinated peptide (anti-CCP), antiphospholipid antibodies (APA), anti-cardiolipin antibodies (ACLA), anti-double stranded DNA (anti-dsDNA), and extractable nuclear antigen (ENA) profile. RESULTS: Patients with severe symptoms showed the lowest age (p=0.031), ESR (p<0.001), and highest prevalence of ischemia (p<0.001). In all the patients, the serum levels of ANA and IgM RF were higher than 1 U and 15 IU/mL, respectively. However, the progression of the disease from mild to moderate did not affect these markers significantly (p>0.05). Other markers were negative in patients with BD. CONCLUSION: The findings of this study indicate that BD may closely be correlated to transient autoimmune phenomena, despite the fact that further research is required to investigate how transient unspecific autoimmune reactions contribute to the BD pathogenesis.

Preclinical models of arthritis for studying immunotherapy and immune tolerance.

Increasingly earlier identification of individuals at high risk of rheumatoid arthritis (RA) (eg, with autoantibodies and mild symptoms) improves the feasibility of preventing or curing disease. The use of antigen-specific immunotherapies to reinstate immunological self-tolerance represent a highly attractive strategy due to their potential to induce disease resolution, in contrast to existing approaches that require long-term treatment of underlying symptoms.Preclinical animal models have been used to understand disease mechanisms and to evaluate novel immunotherapeutic approaches. However, models are required to understand critical processes supporting disease development such as the breach of self-tolerance that triggers autoimmunity and the progression from asymptomatic autoimmunity to joint pain and bone loss. These models would also be useful in evaluating the response to treatment in the pre-RA period.This review proposes that focusing on immune processes contributing to initial disease induction rather than end-stage pathological consequences is essential to allow development and evaluation of novel immunotherapies for early intervention. We will describe and critique existing models in arthritis and the broader field of autoimmunity that may fulfil these criteria. We will also identify key gaps in our ability to study these processes in animal models, to highlight where further research should be targeted.

In Rheumatoid Arthritis Patients, HLA-DRB1*04:01 and Rheumatoid Nodules Are Associated With ACPA to a Particular Fibrin Epitope.

Objectives: Rheumatoid arthritis (RA) is associated with HLA-DRB1 genes encoding the shared epitope (SE), a 5-amino acid motive. RA is usually preceded by the emergence of anti-citrullinated protein/peptide antibodies (ACPAs). Citrulline is a neutral amino acid resulting from post-translational modification of arginine involved in peptidic bounds (arginyl residue) by PeptidylArginine Deiminases (PADs). ACPAs recognize epitopes from citrullinated human fibrin(ogen) (hFib) and can be specifically detected by the AhFibA assay. Five citrullinated peptides derived from hFib together represent almost all of the epitopes recognized by patients with ACPA-positive RA, namely: α36-50cit, α171-185cit, α501-515cit, α621-635cit, and ß60-74cit. The use of antibody fine specificities as markers of clinical phenotypes has become a major challenge. Our objective was to study whether RA clinical characteristics and HLA-DRB1 genetic background were associated with a specific reactivity against the epitopes borne by the five peptides. Methods: 184 ACPA-positive RA patients fulfilling the 2010 ACR/EULAR criteria were studied. Patient characteristics including HLA-DRB1 genotype, were collected from their medical files. Anti-CCP2 antibodies, AhFibA, and antibodies against the five citrullinated hFib (hFib-cit) peptides were analyzed by ELISA. Results: Anti-α505-515cit antibodies were associated with HLA-DRB1*04:01 (OR = 5.52 [2.00 - 13.64]; p = 0.0003). High level anti-α505-515cit antibodies were associated with rheumatoid nodules (OR = 2.71 [1.00 - 7.16], p= 0.044). Conclusion: Immune complexes containing anti-α501-515cit antibodies and rheumatoid factors might be involved in the development of rheumatoid nodules on the HLA-DRB1*04:01 background. Apheresis of these epitope-specific antibodies might be a new therapeutic opportunity for patients with rheumatoid nodules.

Increased disease activity in early arthritis patients with anti-carbamylated protein antibodies.

The initial management of rheumatoid arthritis (RA) has a high impact on disease prognosis. Therefore, we need to select the most appropriate treatment as soon as possible. This goal requires biomarkers of disease severity and prognosis. One such biomarker may be the presence of anti-carbamylated protein antibodies (ACarPA) because it is associated with adverse long term outcomes as radiographic damage and mortality. Here, we have assessed the ACarPA as short-term prognostic biomarkers. The study was conducted in 978 prospective early arthritis (EA) patients that were followed for two years. Our results show the association of ACarPA with increased levels of all the disease activity measures in the first visit after arthritis onset. However, the associations were more significant with the high levels in local measures of inflammation and physician assessment than with the increases in systemic inflammation and patient-reported outcomes. More notably, disease activity was persistently increased in the ACarPA positive patients during the two years of follow-up. These differences were significant even after accounting for the presence of other RA autoantibodies. Therefore, the ACarPA could be considered short-term prognostic biomarkers of increased disease activity in the EA patients.

Relationships of Rheumatoid Factor with Thickness of Retina and Choroid in Subjects without Ocular Symptoms Using Swept-Source Optical Coherence Tomography.

PURPOSE: Researches have confirmed that the retinal and choroidal thickness in patients with autoimmune disease-associated uveitis displays significant changes. However, the relationships between rheumatoid factor (RF) and thickness of the retina and choroid in individuals without ocular manifestations remain unclear. The aim of this study is to assess the associations of RF with retinal and choroidal thickness. METHODS: The individuals enrolled in the cross-sectional research received full ocular examinations. The participants were classified as the RF (+) group (RF ≥ 15.0 IU/ml) and the RF (-) group (RF < 15.0 IU/ml) according to the serum RF titers. The thickness of the retina and choroid was measured by swept-source optical coherence tomography (SS-OCT). RESULTS: The study covered 65 right eyes of 65 individuals that are RF-positive and 130 right eyes of 130 age- and sex-matched individuals that are RF-negative. The RF (+) group showed decreased choroidal thickness that achieved statistical significance only in the outer inferior and outer temporal sectors, as compared to the RF (-) group. There was no statistically significant difference regarding the retinal thickness between the two groups. Pearson's correlation analysis revealed that the RF was significantly negatively related to the choroidal thickness in all areas. However, there was no significant correlation between the RF and the retinal thickness. CONCLUSIONS: Serum RF titers are closely linked with choroidal thickness before the emergence of ocular symptoms. Research into the relationships may improve our understanding of the role of serum RF in the pathogenesis of uveitis.

Circulating anti-citrullinated protein antibodies containing secretory component are prognostic for arthritis onset in at-risk patients.

Autoantibodies related to rheumatoid arthritis (RA), such as anti-citrullinated protein antibodies (ACPA), are often detectable in the preclinical period years before arthritis onset. However, events triggering arthritis development remain incompletely known. We aimed to determine whether ACPA isotype levels are prognostic for arthritis development in patients presenting with immunoglobulin (Ig)G ACPA and musculoskeletal pain. Study participants (n = 82) had musculoskeletal pain of any sort and duration and a positive IgG ACPA test. None of the patients had arthritis upon clinical examination at baseline, but during follow-up (mean = 6 years), 48% developed at least one arthritic joint. IgG, IgA, IgM and secretory component (SC)-containing ACPA was measured in longitudinally collected serum samples. Cox regression analysis was performed to test the prognostic value of baseline antibody levels and changes over time. All analysed ACPA isotype levels were associated with arthritis development in univariable Cox regression analysis. In multivariable analysis, baseline SC ACPA levels were independently prognostic for arthritis development in multivariable analysis [hazard ratio (HR) = 1·006, 95% confidence interval (CI) = 1·001-1·010, P = 0·012]. There were no significant changes in ACPA isotype levels over time, and no significant association between changes over time and arthritis development. In this prospective longitudinal study, baseline serum SC ACPA levels, but neither IgG, IgA nor IgM ACPA are prognostic for future arthritis development. Repeated measurement of ACPA isotypes do not bring additional prognostic value. The results reinforce a mucosal connection in RA development and encourage further exploration of the mechanisms underlying secretory ACPA formation as a trigger for arthritis development.

Does smoking affect level of seropositivity in RA? A post-HOC global and inter-country analysis of COMORA cohort.

To study the association of smoking status and the level of seropositivity in RA patients from COMORA Cohort. A post hoc analysis of COMORA database included 3439 RA patients was performed. Current smokers or recently quitted (< 3 years) were initially compared to those who never smoked or stopped > 3 years (Group I vs. II) regarding their seropositivity status (high positive, low positive and negative) for Rheumatoid Factor (RF) or Anti-citrullinated antibodies (ACPA). A further comparison was made between current smokers (Group III) and never smoked patients (Group IV). Analysis was also done on the individual country level for the 17 countries included in the COMORA study. Out of 3439 RA patients, 705 (20.5%) were smokers (group I), and 2734 (79.5%) were non-smokers (group II). Significantly more patients in group I, 442 (62.7%), had high levels of seropositivity than those in group II, 1556 (56.9%), [P = 0.006, OR 1.27 (95% CI, 1.07-1.5)]. More current smoker patients (group III-286 out of 456 "62.7%") had high levels of seropositivity than never smoked patients (group IV-1236 out of 2191 "56.4%"), with significant difference [P = 0.013, OR 1.3 (95% CI, 1.06-1.6)]. In 11 countries, higher proportions of patients with high level of seropositivity in group I was found, with statistical significance in four countries. Smoking was associated with higher level of seropositivity in patients with RA in this post hoc analysis, both on a global level and in certain individual countries. As smoking is a modifiable risk factor, studying the effects of quitting smoking on level of seropositivity and other disease parameters is warranted.

Expansion of Alternative Autoantibodies Does Not Follow the Evolution of Anti-Citrullinated Protein Antibodies in Preclinical Rheumatoid Arthritis: An Analysis in At-Risk First Degree Relatives.

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.

From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease with diverse clinical presentations, prognoses and therapeutic responses. Following the first discovery of rheumatoid factors (RFs) 80 years ago, the identification of both anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. Specifically, these three RA associating auto-antibodies (autoAbs) all precede the development of RA by years. However, while the current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs. In the present review, we critically summarize the characteristics of these autoantibodies and focus on their distinct clinical applications in the early identification, clinical manifestations and prognosis prediction of RA. With the advancement of treatment options in the era of biologics, we also discuss the relevance of these autoantibodies in association with RA patient response to therapy.

Comparative study of HO-1 expressing synovial lining cells between RA and OA.

OBJECTIVES: We aimed to clarify the characteristics of heme oxygenase (HO)-1 expressing cells in the synovium from rheumatoid arthritis (RA) and osteoarthritis (OA), and to investigate the co-expression of HO-1 and IgG-Fc/HLA-DR complex. METHODS: The characteristics of HO-1 expressing cells in the synovium were investigated by using immunohistochemistry. The co-expression of HO-1 and IgG-Fc/HLA-DR complex was examined by an in situ proximity ligation assay (PLA) with immunofluorescence. HO-1 mRNA was investigated by reverse transcription-polymerase chain reaction. RESULTS: The number of HO-1+ cells from the RA synovium is higher than that from OA synovium. The double positive cells of HO-1 and IgG-Fc/HLA-DR complex were detected by the in situ PLA with immunofluorescence in RA synovium. HO-1 mRNA was detected in both RA and OA synovium. CONCLUSION: A portion of HO-1+ cells with IgG-Fc/HLA-DR complex in lining layer of RA may be concluded as one of antigen presenting cells in RA and may be involved in production of RF.

Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthritis and in Relation to Smoking.

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 (ORadj ) 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 ORadj 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 (ORadj 2.1 [95% CI 1.5-2.9]) than for smokers (ORadj 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.

Association of a Serum Protein Signature With Rheumatoid Arthritis Development.

OBJECTIVE: The pathophysiologic events that precede the onset of rheumatoid arthritis (RA) remain incompletely understood. This study was undertaken to identify changes in the serum proteome that precede the onset of RA, with the aim of providing new insights into the pathogenic mechanisms that lead to its development. METHODS: In a cohort of first-degree relatives of Indigenous North American RA patients, the SomaScan proteomics platform was used to determine the levels of 1,307 proteins in multiple longitudinal serum samples from 17 individuals who were followed up prospectively to the time of disease onset. Proteomic signatures from this group of individuals (designated the progressor group) were compared to those in a group of individuals who were considered at risk of developing RA, stratified as either positive (n = 63) or negative (n = 47) for anti-citrullinated protein antibodies (ACPAs) (designated the at-risk group). Machine learning was used to identify a protein signature that could accurately classify those individuals at highest risk of future RA development. RESULTS: A preclinical proteomic signature that differentiated RA progressors from at-risk individuals, irrespective of ACPA status, was identified (area under the curve 0.913, accuracy 91.2%). Importantly, the predictive preclinical proteomic signature was present not only in serum samples obtained close to the onset of RA, but also in serum samples obtained a median of 30.9 months prior to onset. Network analysis implicated the activation of Toll-like receptor 2 and production of tumor necrosis factor and interleukin-1 as key events that precede RA progression. CONCLUSION: Alterations in the serum proteome in the preclinical phase of RA can emerge years prior to the onset of disease. Our findings suggest that the serum proteome provides a rich source of proteins serving both to classify at-risk individuals and to identify molecular pathways involved in the development of clinically detectable RA.

Association of Agricultural, Occupational, and Military Inhalants With Autoantibodies and Disease Features in US Veterans With Rheumatoid Arthritis.

OBJECTIVE: To determine the association of inhalant exposures with rheumatoid arthritis (RA)-related autoantibodies and severity in US veterans. METHODS: Participants in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were mailed surveys assessing occupational, agricultural, and military inhalant exposures. Demographic characteristics, disease activity, functional status, and extraarticular features were obtained from the VARA registry, while HLA-DRB1 shared epitope (SE) status, anti-cyclic citrullinated peptide (anti-CCP) antibodies, and rheumatoid factor (RF) were measured using banked DNA/serum from enrollment. Associations between inhalant exposures and RA-related factors (autoantibodies, severity, and extraarticular features) were assessed using multivariable linear and logistic regression models adjusted for age, sex, race, and tobacco use and stratified by SE status. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Questionnaires were returned by 797 of 1,566 participants (50.9%). Survey respondents were older, more often White or male, and less frequently smokers, and had lower disease activity compared to nonrespondents. Anti-CCP positivity was more common among veterans exposed to burn pits (OR 1.66 [95% CI 1.02, 2.69]) and military waste disposal (OR 1.74 [95% CI 1.04, 2.93]) independent of other factors. Among participants who were positive for SE alleles, burn pit exposure (OR 5.69 [95% CI 2.73, 11.87]) and military waste disposal exposure (OR 5.05 [95% CI 2.42, 10.54]) were numerically more strongly associated with anti-CCP positivity. Several inhalant exposures were associated with the presence of chronic lung disease, but not with the presence of RF or the level of disease activity. CONCLUSION: Military burn pit exposure and military waste disposal exposure were independently associated with the presence of anti-CCP antibodies in RA patients. These findings are consistent with emerging evidence that various inhalant exposures influence autoantibody expression and RA risk.

Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift.

Rheumatoid arthritis (RA) is currently diagnosed and treated when an individual presents with signs and symptoms of inflammatory arthritis (IA) as well as other features, such as autoantibodies and/or imaging findings, that provide sufficient confidence that the individual has RA-like IA (e.g., meeting established classification criteria) that warrants therapeutic intervention. However, it is now known that there is a stage of seropositive RA during which circulating biomarkers and other factors (e.g., joint symptoms) can be used to predict if and when an individual who does not currently have IA may develop future clinically apparent IA and classifiable RA. Indeed, the discovery of the "pre-RA" stage of seropositive disease has led to the development of several clinical trials in which individuals are studied to identify ways to delay or prevent the onset of clinically apparent IA/RA. This review focuses on several issues pertinent to understanding the prevention of RA. These include discussion of the pathogenesis of pre-RA development, prediction of the likelihood and timing of future classifiable RA, and a review of completed and ongoing clinical trials in RA prevention. Furthermore, this review discusses challenges and opportunities to be addressed to effect a paradigm shift in RA, where in the near future, proactive risk assessment focused on prevention of RA will become a public health strategy in much the same manner as cardiovascular disease is managed today.

Association Between Bone Mineral Density and Autoantibodies in Patients With Rheumatoid Arthritis.

OBJECTIVE: Autoantibodies, such as anti-citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral density (BMD). We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts. METHODS: Dual x-ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow-up and in 198 Swedish patients with early RA during 10 years of follow-up. The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations. RESULTS: In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA-positive patients compared to ACPA-negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm2 (95% confidence interval [95% CI] 0.91-0.93) versus 0.95 g/cm2 (95% CI 0.93-0.97) (P = 0.01). In line with this, significantly lower Z scores at baseline were noted in the ACPA-positive group compared to the ACPA-negative group (estimated marginal mean Z score in the left hip of 0.18 [95% CI 0.08-0.29] versus 0.48 [95% CI 0.33-0.63]) (P < 0.01). However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time. Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti-carbamylated protein antibodies). In the Swedish cohort, ACPA-positive patients tended to have a higher prevalence of osteopenia at baseline (P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time. CONCLUSION: The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients. These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well-managed.

Childhood Sjögren syndrome: features of an international cohort and application of the 2016 ACR/EULAR classification criteria.

OBJECTIVE: Sjögren syndrome in children is a poorly understood autoimmune disease. We aimed to describe the clinical and diagnostic features of children diagnosed with Sjögren syndrome and explore how the 2016 ACR/EULAR classification criteria apply to this population. METHODS: An international workgroup retrospectively collected cases of Sjögren syndrome diagnosed under 18 years of age from 23 centres across eight nations. We analysed patterns of symptoms, diagnostic workup, and applied the 2016 ACR/EULAR classification criteria. RESULTS: We identified 300 children with Sjögren syndrome. The majority of patients n = 232 (77%) did not meet 2016 ACR/EULAR classification criteria, but n = 110 (37%) did not have sufficient testing done to even possibly achieve the score necessary to meet criteria. Even among those children with all criteria items tested, only 36% met criteria. The most common non-sicca symptoms were arthralgia [n = 161 (54%)] and parotitis [n = 140 (47%)] with parotitis inversely correlating with age. CONCLUSION: Sjögren syndrome in children can present at any age. Recurrent or persistent parotitis and arthralgias are common symptoms that should prompt clinicians to consider the possibility of Sjögren syndrome. The majority of children diagnosed with Sjögren syndromes did not meet 2016 ACR/EULAR classification criteria. Comprehensive diagnostic testing from the 2016 ACR/EULAR criteria are not universally performed. This may lead to under-recognition and emphasizes a need for further research including creation of paediatric-specific classification criteria.