Anti-citrullinated Protein Antibodies Titers Research Articles

Elderly-Onset Rheumatoid Arthritis: Characteristics and Treatment Options.

Elderly-onset rheumatoid arthritis (EORA) is a distinct clinical entity defined as the onset of rheumatoid arthritis (RA) in individuals aged over 60 years. EORA presents unique clinical features, including a more equitable distribution of sexes, a potential predilection for male involvement, a higher incidence of acute onset characterized by constitutional symptoms, a propensity for systemic manifestations, elevated sedimentation rates at disease onset, a reduced occurrence of rheumatoid factor positivity, increased titers of anti-citrullinated protein antibodies, a preference for involvement of large joints, elevated disease activity, the presence of bone erosions, and heightened patient disability. RA is recognized to consist of three partially overlapping subsets. One subset mirrors the classical RA clinical presentation, while the remaining subsets exhibit either a polymyalgia rheumatica-like phenotype or present with remitting seronegative symmetrical synovitis accompanied by pitting edema syndrome. In the initial stages of EORA management, non-steroidal anti-inflammatory drugs (NSAIDs) are not typically the first-line treatment choice, because seniors are much more prone to develop side effects due to NSAIDs, and the use of NSAIDs is in reality contraindicated to the majority of seniors due to comorbidities. Disease-modifying antirheumatic drugs (DMARDs), frequently methotrexate, are introduced immediately after the diagnosis is made. In cases where elderly patients demonstrate resistance to conventional DMARD therapy, the introduction of biological or targeted synthetic DMARDs becomes a viable treatment option. EORA presents a unique clinical profile, necessitating tailored treatment strategies. Our study emphasizes the challenges of NSAID use in seniors, highlighting the imperative shift toward DMARDs such as methotrexate. Future research should explore personalized DMARD approaches based on disease activity, comorbidities, and safety considerations, aiming to optimize treatment outcomes and minimize glucocorticoid reliance, thereby enhancing the quality of care for EORA patients.

Factors associated with interstitial lung disease in patients with rheumatoid arthritis: A systematic review and meta-analysis.

Interstitial lung disease (ILD) is frequent in patients with rheumatoid arthritis (RA) and is a potentially life-threatening complication with significant morbidity and mortality. This meta-analysis aims to systematically determine the factors associated with the development of rheumatoid arthritis-related interstitial lung disease (RA-ILD). All primary studies which reported the factors associated with of RA-ILD were eligible for the review except case reports. The Cochrane Library, PubMed, Embase, Web of Science, Chinese Biological Medicine Database (CBM), China National Knowledge Infrastructure (CNKI), and WANFANG electronic databases were searched through to December 30, 2022, for studies investigating the factors associated with RA-ILD. The methodological quality assessment of the eligible studies was performed using the Newcastle-Ottawa Scale (NOS). 2 reviewers extracted relevant data independently. Then, weighed mean differences (WMDs) or pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were obtained for the relationships between the factors and RA-ILD. The statistical meta-analysis, subgroup and sensitivity analyses were performed using the Review Manager 5.3, and publication bias with Egger's test were performed using the Stata12.0 software. A total of 22 articles were screened for a meta-analysis which involved 1887 RA-ILD patients and 8066 RA without ILD patients. Some identified factors that were associated with an increased risk of RA-ILD included male sex (OR = 1.92, 95% CI: 1.54-2.39; P < 0.00001), older age (WMD = 5.77 years, 95% CI: 3.50-8.04; P < 0.00001), longer duration of RA (WMD = 0.80 years, 95% CI 0.12-1.47; P = 0.02), older age at onset of RA (WMD = 6.41 years, 95% CI: 3.17-9.64; P = 0.0001), smoking (OR = 1.69, 95% CI: 1.30-2.18; P < 0.0001). Five factors of laboratory items associated with the development of RA-ILD were evaluated in the meta-analysis. Compared with RA without ILD patients, positive rheumatoid factor (RF) (OR = 1.72, 95% CI: 1.47-2.01; P < 0.00001) and positive anti-citrullinated protein antibodies (ACPA) (OR = 1.58, 95% CI: 1.31-1.90; P < 0.00001) increased the risk of RA-ILD. Meanwhile, RF titer (WMD = 183.62 (IU/mL), 95% CI: 66.94-300.30; P = 0.002) and ACPA titer (WMD = 194.18 (IU/mL), 95% CI: 115.89-272.47; P < 0.00001) were significantly associated with increased risk of RA-ILD. Elevated erythrocyte sedimentation rate (ESR) (WMD = 7.41 (mm/h), 95% CI: 2.21-12.61; P = 0.005) and C-reactive protein (CRP) (WMD = 4.98 (mg/L), 95% CI: 0.76-9.20; P = 0.02) were also significantly associated with the development of the RA-ILD, whereas antinuclear antibody (ANA) positive status was not significantly associated with increased risk of RA-ILD (OR = 1.27, 95% CI: 1.00-1.60; P = 0.05). This meta-analysis showed that male gender, older age, longer duration of RA, older age at onset of RA, smoking, positive RF, positive ACPA, elevated RF titer, elevated ACPA titer, higher ESR and higher CRP were associated with RA-ILD.

Rheumatoid factor and anti-citrullinated protein antibodies (ACPA) in psoriatic arthritis (PsA), and skin psoriasis: Relevance and clinical implications

Aim of the workAnti-citrullinated protein antibodies (ACPAs), is a highly specific markers for rheumatoid arthritis, can also be found in psoriatic arthritis (PsA). This work aimed to look into the frequency of rheumatoid factor (RF) and ACPA in PsA and psoriasis patients without clinical evidence of arthritis (PSO), and to correlate findings with demographics, disease characteristics, laboratory findings, and radiological damage in PsA. Patients and methods: The study included 78 PsA patients, 47 PSO patients, and 69 normal controls. Full clinical assessments, RF and ACPA assays, and modified radiological Steinbroker score (Mss) for PsA were performed. Results: The age of the patients was 45.6 ± 8.7 years and the M:F 59:66 (M:F 0.9:1). Positive RF was not significantly different between PsA and PSO groups (p = 0.35), but positive ACPA was significantly more common in PsA patients (p < 0.001) than in PSO and controls. No significant difference was observed between the PSO and controls (p = 0.08). In PsA, RF titers correlated significantly with ESR (p = 0.002), swollen joint count (SJC)(p = 0.02), tender joint count (TJC)(p = 0.02), and mSS (p = 0.001), while in the PSO RF correlated significantly with ESR (p = 0.011) and CRP levels (p = 0.02). In the PsA, ACPA titer significantly correlated with CRP levels (p < 0.001), SJC (p = 0.002), TJC (p = 0.003), mSS (p < 0.001) and PASI (p < 0.001), but with none of these in the PSO. Conclusion: PsA patients have more frequent positive RF and ACPA than PSO patients. ACPA values are significantly correlated with markers of inflammation, swollen and tender joint count and radiological damage in PsA and not in PSO patients.

Clinical significance of Galectin-1 and Galectin-4 in rheumatoid arthritis patients and their potential role as diagnostic markers

Aim of the workTo investigate the utility of serum Galectin-1 (Gal-1) and Galectin-4 (Gal-4) as potential markers for diagnosis of rheumatoid arthritis (RA) and to explore their relationship with disease activity. Patients and methodsSerum Gal-1 and Gal-4 of 60 RA patients were compared to 30 age and sex-matched controls. Potential relationship of both markers with disease activity assessed using Disease activity score-28 joints (DAS-28), seropositivity (Rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA)), functional classification assessed using modified health assessment questionnaire (MHAQ), radiographic progression assessed using Larsen score and treatment was investigated. ResultsThe study included 60 patients; 54 (90 %) females and 6 (10 %) males with a mean age of 42.6 ± 10.1 years and disease duration of 7.5 ± 6.4 years. Their mean DAS-28 was 4.6 ± 1.0, their MHAQ was 1 ± 0.5 and their Larsen score was 41.3 ± 9.9. The mean of Gal-1 and Gal-4 were both significantly lower in RA patients in comparison to control group (4.4 ± 1.5 ng/ml vs 38.1 ± 25.5 ng/ml and 1.2 ± 0.7 ng/ml; p < 0.001vs 8.1 ± 7.0 ng/ml; p < 0.001 respectively. At a cut off value ≤7.7 for Gal-1 and ≤2.3 for Gal-4 was successfully able to differentiate between RA patients and control group. There was no correlation between both Gal-1 & Gal-4 and DAS-28, MHAQ, Larsen score, RF or ACPA titres. ConclusionGal-1 & 4 serum levels have a potential role as diagnostic markers in patients with RA. Both markers however cannot be regarded as disease activity or severity markers.

Anti-Citrullinated Protein Antibody Titers Are Independently Modulated by Both Disease Activity and Conventional or Biologic Anti-Rheumatic Drugs.

This study aimed to analyze the factors that influence anti-citrullinated protein antibody (ACPA) titers in a seropositive early arthritis (EA) population under non-protocolized treatment with disease-modifying anti-rheumatic drugs (DMARDs). A total of 130 ACPA-positive patients from the PEARL (Princesa Early Arthritis Longitudinal) study were studied along a 5-year follow-up. Sociodemographic, clinical, and therapeutic variables, along with serum samples, were collected at five visits by protocol. Anti-cyclic citrullinated peptide 2 (CCP2) ACPA titers were measured by ELISA. The effect of different variables on anti-CCP2 titers was estimated using longitudinal multivariate analysis models, nested by visit and patient. Data from 471 visits in 130 patients were analyzed. A significant decrease in anti-CCP2 titers was observed at all time-points, compared to baseline, following the decline of disease activity. In the multivariate analysis, active or ever smoking was significantly associated with the highest anti-CCP2 titers while reduction in disease activity was associated with titer decline. After adjusting for these variables, both conventional synthetic (cs) and biologic (b) DMARDs accounted for the decline in anti-CCP2 titers as independent factors. Conclusion: In patients with EA, an early and sustained reduction in ACPA titers can be detected associated with the decline in disease activity, irrespective of the treatment used.

Methotrexate induced lung diseases in rheumatoid arthritis patients

Abstract Background Rheumatoid arthritis (RA) is a progressive, systemic autoimmune disorder characterized by articular and extra-articular manifestations. The lung is commonly a site of extra-articular disease. The lung manifestations of RA vary and may include airways, parenchymal, vascular, and pleural disease. Manifestations of lung disease in RA typically follow the development of articular disease. Methotrexate (MTX)has shown efficacy for the treatment of several diseases, especially RA. Methotrexate has also been implicated as a causative agent in interstitial lung disease. Objective to find any association between MTX intake and lung abnormalities in RA patients. Patients and Methods This study included sixty adult RA patients, recruited from Ain Shams University Hospitals. Patients were divided into thirty patients on MTX therapy, and another thirty patients on non-methotrexate therapy. All underwent history, clinical examination, chest examination, evaluation of RA by modified disease activity score 28 (DAS 28) and pulmonary function tests(PFT). Results The age of patients receiving MTX ranged from 35-65 years and the non-MTX group was 35-57 years with a mean ±SD of 47.733±5.265 and 40.700 ±5.187, respectively. Male to female ratio of MTX group was about 1:3, while Non MTX group was about 1:9.There was no significant difference regarding age and sex. There was no difference between both group regarding modified DAS score and chest manifestations. There was no difference in PFT findings between patients on high or low dose of MTX therapy .Similarly, no association was found between disease activity score and PFT findings in both groups. On the other hand, a significant association between chest symptoms and PFT, P value&amp;lt;0.05 . Also a strong significant association was found between anticitrullinated protein antibodies (ACPA) status and PFT in both group, p value &amp;lt;0.05. Conclusion MTX treatment was not associated with an increased risk of RA-ILD diagnosis. On the contrary, evidence showed that MTX may delay the onset of ILD. There seems no reason to confuse the association of MTX and hypersensitivity pneumonitis with the onset of RAILD.ACPA antibody is considered a major risk factor in RA-ILD, ACPA titers constitute an independent factor associated not only with the presence but also with the severity of RA-ILD

Pathogenic Role of Circulating Citrullinated Antigens and Anti-Cyclic Monoclonal Citrullinated Peptide Antibodies in Rheumatoid Arthritis.

We examined whether it is possible to directly detect citrullinated antigens in the serum of rheumatoid arthritis (RA) patients using a monoclonal antibody (mAb) designed to be specific for citrullinated peptides. In order to confirm the potential of the mAb as a direct arthritis-inducing substance through experimental model of RA, a monoclonal antibody (mAb) 12G1 was generated using by immunization of mice with a challenging cyclic citrullinated peptide. Immunohistochemical analysis of RA-affected synovial tissue showed that our mAb 12G1 could indeed detect citrullinated proteins in target tissues. Subsequently, serum levels of citrullinated type II collagen and filaggrin were measured in healthy volunteers, patients with RA, ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE) using a 12G1-based sandwich ELISA. This showed that citrullinated filaggrin showed 78.9% sensitivity and 85.9% specificity for RA diagnosis with a cutoff optical density (OD) value of 1.013, comparable with the results from a second-generation anti-citrullinated protein antibody (ACPA) test. Circulating citrullinated collagen and filaggrin were detected even in sera of RA patients who were negative for both rheumatoid factor (RF) and ACPA. ELISA results also showed that RF and ACPA titers showed significantly positive correlation with both citrullinated collagen and filaggrin OD values in sera of RA patients. 12G1 challenging aggravated the severity of murine arthritis. In summary, mAb 12G1 can directly detect citrullinated proteins in RA target tissue and in sera of RA patients and 12G1 showed direct arthritogenic potential in vivo. This, 12G1 might be useful for diagnosis of RA including seronegative RA and may help to elucidate the pathophysiological role of citrullination in RA.

Serum anti-citrullinated protein antibodies and rheumatoid factor increase the risk of rheumatoid arthritis-related interstitial lung disease: a meta-analysis.

This meta-analysis aims to determine the association between antibodies including anti-citrullinated protein antibodies (ACPA) and rheumatoid factors (RF) and risk of rheumatoid arthritis-related interstitial lung disease (RA-ILD). PubMed, Embase, and Cochrane were searched up to September 13, 2020, for studies investigating the risk of RA-ILD in ACPA-positive patients. The statistical meta-analysis and sensitivity analysis were performed using the Review Manager 5.4 and Stata16.0 software, respectively. Total 1 double-blind randomized controlled study and 16 observational studies, including 992 RA-ILD patients and 2223 RA-non ILD patients, met the inclusion criteria of the meta-analysis. Compared with ACPA-negative patients, positive serum ACPA increased the risk of RA-ILD (OR = 2.51; 95% CI: 1.35-4.68; P = 0.004) and serum ACPA titer was significantly correlated with risk of RA-ILD (SMD = 0.39; 95% CI: 0.17-0.62; P = 0.0006). In a region-based subgroup analysis, ACPA titer in Asian, European, and African populations was significantly related to the risk of RA-ILD, while there was no significant correlation in the Americans (SMD = - 0.03; 95% CI: - 0.89-0.83; P = 0.95), especially in the USA (SMD = 0.37; 95% CI: - 0.26-0.99; P = 0.25). In addition, serum positive RF increased the risk of RA-ILD (OR = 2.85; 95% CI: 2.19-3.71; P < 0.00001) and serum RF titer was significantly correlated with the risk of RA-ILD (SMD = 0.35; 95% CI: 0.23-0.46; P < 0.00001). However, for the analysis of RF dichotomous data, the funnel shape was asymmetric and the p value of egger test was less than 0.05, which indicated potential publication bias. ACPA and RF positive patients have greater risk of RA-ILD, and RA patients positive for ACPA should be paid more attention. • Autoantibodies ACPA and RF increase the risk of RA-ILD. • Regions may be related to RA-ILD.

Predictors of Progression and Mortality in Patients with Prevalent Rheumatoid Arthritis and Interstitial Lung Disease: A Prospective Cohort Study.

Objectives: To describe a prospective cohort of patients with rheumatoid arthritis associated with interstitial lung disease (RA-ILD) and identify risk factors associated with disease progression and mortality in this cohort. Patients and methods: We performed a multicenter, prospective, observational study of patients with RA-ILD receiving disease-modifying antirheumatic drugs (DMARDs) between 2015 and 2020. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline and at 60 months. The main endpoint was “Progression to ILD at the end of follow-up” in terms of the following outcomes: (1) improvement (i.e., improvement in forced vital capacity (FVC) ≥10% or diffusing capacity of the lungs for carbon monoxide (DLCO) ≥15% and absence of radiological progression); (2) nonprogression (stabilization or improvement in FVC ≤10% or diffusing capacity of the lungs for carbon monoxide (DLCO) <15% and absence of radiological progression); (3) progression (worsening of FVC >10% or DLCO >15% and radiological progression); or (4) death. We recorded demographic and clinical characteristics, lung function, and the incidence of adverse events. A Cox regression analysis was performed to identify factors associated with the worsening of ILD. Results: After 60 months, lung disease had stabilized in 66 patients (56.9%), improved in 9 (7.8%), and worsened in 23 (19.8%). Eighteen patients (15.5%) died, with a mean survival of 71.8 (1.9) months after diagnosis of ILD. The Cox multivariate analysis revealed the independent predictors of worsening of RA-ILD to be usual interstitial pneumonia (hazard ratio (HR), 2.6 (95%CI, 1.0–6.7)), FVC <80% (HR, 3.8 (95%CI, 1.5–6.7)), anticitrullinated protein antibody titers (HR, 2.8 (95%CI, 1.1–6.8)), smoking (HR, 2.5 (95%CI, 1.1–6.2)), and treatment with abatacept, tocilizumab, or rituximab (HR, 0.4 (95%CI, 0.2–0.8)). During follow-up, 79 patients (68%) experienced an adverse event, mostly infection (61%). Infection was fatal in 10/18 patients (55.5%) during follow-up. Conclusions: Lung function is stable in most patients with RA-ILD receiving treatment with disease-modifying anti-rheumatic drugs (DMARDs), although one-third worsened or died. Identifying factors associated with worsening in RA-ILD is important for clinical management.

The Subgingival Plaque Microbiome, Systemic Antibodies Against Bacteria and Citrullinated Proteins Following Periodontal Therapy.

Periodontitis (PD) shows an association with rheumatoid arthritis (RA) and systemic inflammation. Periodontal pathogens, namely Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, are proposed to be capable of inducing citrullination of peptides in the gingiva, inducing the formation of anti-citrullinated protein antibodies (ACPAs) within susceptible hosts. Here, we sought to investigate whether periodontal treatment influenced systemic inflammation and antibody titres to P. gingivalis, A. actinomycetemcomitans, Prevotella intermedia and ACPA in 42 systemically health patients with periodontal disease. Subgingival plaque and serum samples were collected from study participants before (baseline) and 90 days after treatment to analyse the abundance of specific bacteria and evaluate anti-bacterial antibodies, C-reactive protein (CRP), tumour necrosis factor α (TNF-α), interleukin 6 (IL-6) and ACPA in serum. Following treatment, all patients showed reduced periodontal inflammation. Despite observing a weak positive correlation between CRP and IL-6 with periodontal inflammation at baseline, we observed no significant reductions in any indicators of systemic inflammation 90 days after treatment. In contrast, anti-P. gingivalis IgG significantly reduced post-treatment (p < 0.001, Wilcoxon signed rank test), although no changes were observed for other antibody titres. Patients who had detectable P. gingivalis in subgingival plaques had significantly higher anti-P. gingivalis IgG and ACPA titres, suggesting a potential association between P. gingivalis colonisation and systemic antibody titres.

Anti-citrullinated protein antibodies are associated with neutrophil extracellular trap formation in rheumatoid arthritis.

ObjectivesWe evaluated the associations of anti‐citrullinated protein antibodies (ACPAs) and serological and cytological levels of neutrophil extracellular trap (NET) formation in rheumatoid arthritis (RA) patients.MethodsSerum levels of myeloperoxidase‐DNA and elastase‐DNA complexes (NET remnants) were examined in 51 patients with RA and 40 healthy controls using a modified enzyme‐linked immunosorbent assay. Neutrophils were isolated by density gradient centrifugation. IgG antibodies were purified by affinity chromatography. NET formation in RA and control neutrophils was assessed by microscopy in vitro. NETs were purified and co‐incubated with fibroblast‐like synoviocyte (FLS) cells. Interleukin (IL)‐6 and IL‐8 mRNA expression and protein levels in FLS cells were determined by real‐time polymerase chain reaction and enzyme‐linked immunosorbent assay, respectively.ResultsIn RA patients, NET remnants in the peripheral circulation were higher in extremely high ACPA titers when compared to in moderate ACPA titers. And IgG antibodies containing ACPA can stimulate neutrophils to form NETs in a concentration‐dependent manner. Furthermore, significantly higher expression of the pro‐inflammatory cytokines IL‐6 and IL‐8 is detected after FLS cells interacted with NETs which derived from neutrophils stimulated with ACPA‐containing IgG antibodies.ConclusionsAnti‐citrullinated protein antibodies may enhance NET formation and contribute to inflammation development in RA by stimulating NET formation, such as by subsequent activation of FLS cells by NETs.

Autoantibody Seropositivity and Risk for Interstitial Lung Disease in a Prospective Male-Predominant Rheumatoid Arthritis Cohort of U.S. Veterans

Rationale: Prior studies investigating associations of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) seropositivity with risk for rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) have mostly used cross-sectional or case-control designs.Objectives: To determine whether combined autoantibody seropositivity and higher individual autoantibody concentrations were associated with increased risk for RA-ILD in a prospective RA cohort.Methods: Within the Veterans Affairs Rheumatoid Arthritis prospective registry, we performed a cross-sectional study of prevalent ILD and a retrospective cohort study of incident ILD (diagnosed after at least 12 mo of longitudinal follow-up). We used logistic and Cox regression methods to determine whether combined RF/ACPA seropositivity and higher autoantibody concentrations were independently associated with greater risk for prevalent and incident ILD, respectively.Results: Among 2,328 participants (median age 64 yr, 89.3% male), 100 (4.3%) subjects had prevalent ILD at enrollment. During 14,281 patient-years of follow-up, 83 (3.7%) of the remaining 2,228 were subsequently diagnosed with incident ILD (5.8 cases per 1,000 person-years). Patients with combined RF/ACPA seropositivity had a higher probability of prevalent ILD compared with seronegative subjects (odds ratio [OR], 2.90; 95% confidence interval [CI], 1.24-6.78). RF titers demonstrated a monotonic association with prevalent ILD (OR, 2.69; 95% CI, 1.11-6.51 for low-positive [15-45 IU/ml] titers; OR, 3.40; 95% CI, 1.61-7.18 for high-positive [>45 IU/ml] titers; P for trend 0.01). Patients with high-positive (>15 U/ml) ACPA titers were also at higher risk for prevalent ILD (OR, 1.91; 95% CI, 1.04-3.49) compared with ACPA-negative subjects. Combined RF/ACPA seropositivity was not associated with increased risk for incident ILD, nor were high- or low-positive RF or ACPA titers. In a piecewise linear spline model, however, RF titers greater than 90 IU/ml independently correlated with increased risk for incident ILD (hazard ratio, 1.68, 95% CI, 1.02-2.77).Conclusions: Combined RF/ACPA seropositivity and individual autoantibody concentrations were strongly associated with prevalent but not incident RA-ILD. Only patients with RF concentrations >90 IU/ml were observed to be at higher risk of incident RA-ILD.

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease.

Rheumatoid arthritis (RA) is an autoimmune disease of complex etiopathogenic origin and traditionally characterized by chronic synovitis and articular erosions. Furthermore, there is strong evidence that infectious agents, including those that become dormant within the host, play a major role in much of the etiology of RA and its hallmark of inflammation. A combination of genetic predisposition, environmental exposure, and presence of infectious agents may therefore lead to a loss of immune tolerance to citrullinated proteins, which present as self-antigens to the human immune system. This results in generation of highly RA-specific autoantibodies, known as anti-citrullinated protein antibodies (ACPAs). Protein citrullination occurs via posttranslational deamination of arginine residues by peptidylarginine deiminase enzymes, which have confirmed sources of both endogenous and infectious origins. A recognized plasma protein target of citrullination and RA autoantibody generation is fibrin and its soluble precursor fibrinogen, both key components of hemostasis and acute phase reaction. Increased titers of ACPAs that accompany rapid progression to clinical RA disease have been shown to drive a variety of proinflammatory processes, and therefore results in aberrant fibrin clot formation and increased cardiovascular risk. However, the full extent to which hemostasis is affected in RA remains controversial, owing to the differential impact that citrullinated fibrin(ogen) and concurrent systemic inflammation may have on resulting hemostatic outcome. This review highlights key events in initiation of autoimmune-driven inflammatory events, including the role of bacterial infectious agents, which subsequently result in clinical RA disease and associated secondary cardiovascular disease risk, with specific focus on plasma proteins that are heavily involved throughout the immunopathological progression process.

Oral Microbiota Perturbations Are Linked to High Risk for Rheumatoid Arthritis.

Oral microbial dysbiosis is known to increase susceptibility of an individual to develop rheumatoid arthritis (RA). Individuals at-risk of RA may undergo different phases of disease progression. In this study, we aim to investigate whether and whereby the oral microbiome communities alter prior to symptoms of RA. Seventy-nine saliva samples were collected from 29 high-risk individuals, who were positive for anti-citrullinated protein antibodies (ACPA) and have no clinical arthritis, 27 RA patients and 23 healthy controls (HCs). The salivary microbiome was examined using 16S ribosomal RNA gene sequencing. Alpha and beta diversity analysis and the linear discriminant analysis were applied to examine the bacterial diversity, community structure and discriminatory taxa between three groups, respectively. The correlation between salivary bacteria and autoantibodies were analyzed. In the “pre-clinical” stages, salivary microbial diversity was significantly reduced comparing to RA patients and HCs. In contrast to HCs, like RA patients, individuals at high-risk for RA showed a reduction in the abundance of genus Defluviitaleaceae_UCG-011 and the species Neisseria oralis, but an expansion of Prevotella_6. Unexpectedly, the relative abundance of Porphyromonas gingivalis, reported as opportunistic pathogens for RA development, was significantly decreased in high-risk individuals. Additionally, we identified four genera in the saliva from high-risk individuals positively correlated with serum ACPA titers, and the other two genera inversely displayed. In summary, we observed a characteristic compositional change of salivary microbes in individuals at high-risk for RA, suggesting that oral microbiota dysbiosis occurs in the “pre-clinical” stage of RA and are correlated with systemic autoimmune features.

Peptidyl arginine deiminase inhibition suppresses arthritis via decreased protein citrullination in joints and serum with the downregulation of interleukin-6

Objective: To explore the relevance of citrullinated proteins and anti-citrullinated protein antibodies (ACPA) via protein arginine deiminase (PAD) inhibition in peptide glucose-6-phosphate isomerase-induced arthritis (pGIA).Methods: Cl-amidine, a PAD inhibitor, was injected into pGIA. Clinical scores and histopathological findings of ankle joints were assessed. Serum ACPA titers were analyzed using ELISA. Citrullinated protein expression in joints and sera were examined with immunohistochemistry and Western blot analysis, respectively. Serum levels of IL-6, TNFα, and IL-1β were measured with cytometric bead array (CBA). Gene expression levels of IL-6 and TNFα in joints, lymph nodes, and spleens were analyzed with quantitative PCR. GPI-specific productions of IFNγ and IL-17 from T cells in lymph nodes were evaluated.Results: Cl-amidine treatment significantly reduced arthritis severity while ACPA titers tended to be lower, but not significantly different compared to the control. Citrullinated proteins in joints and sera from treated mice were clearly decreased. With Cl-amidine treatment, serum IL-6 levels were significantly decreased, and IL-6 and TNFα gene expression were significantly reduced in joints. IL-17 production from GPI-specific T cells tended to be lower in Cl-amidine-treated mice, but not significantly different.Conclusion: Our results suggested that PAD-mediated citrullinated protein was involved in the pathogenesis of arthritis via IL-6.

Vapour, gas, dust and fume occupational exposures in male patients with rheumatoid arthritis resident in Cornwall (UK) and their association with rheumatoid factor and anti-cyclic protein antibodies: a retrospective clinical study

ObjectivesTo quantify exposure to vapour, gas, dust and fumes (VGDF) and smoking in male rheumatoid arthritis (RA) and investigate impact on rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) levels.DesignA...

Conversion to seronegative status after abatacept treatment in patients with early and poor prognostic rheumatoid arthritis is associated with better radiographic outcomes and sustained remission: post hoc analysis of the AGREE study

ObjectiveTo evaluate the effects of the T-cell costimulation blocker abatacept on anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) in early rheumatoid arthritis (RA), and associations between changes in serological...

HLA-DRB1 Analysis Identified a Genetically Unique Subset within Rheumatoid Arthritis and Distinct Genetic Background of Rheumatoid Factor Levels from Anticyclic Citrullinated Peptide Antibodies.

HLA-DRB1 is the most important locus associated with rheumatoid arthritis (RA) and anticitrullinated protein antibodies (ACPA). However, fluctuations of rheumatoid factor (RF) over the disease course have made it difficult to define fine subgroups according to consistent RF positivity for the analyses of genetic background and the levels of RF. A total of 2873 patients with RA and 2008 healthy controls were recruited. We genotyped HLA-DRB1 alleles for the participants and collected consecutive data of RF in the case subjects. In addition to RF+ and RF- subsets, we classified the RF+ subjects into group 1 (constant RF+) and group 2 (seroconversion). We compared HLA-DRB1 alleles between the RA subsets and controls and performed linear regression analysis to identify HLA-DRB1 alleles associated with maximal RF levels. Omnibus tests were conducted to assess important amino acid positions. RF positivity was 88%, and 1372 and 970 RF+ subjects were classified into groups 1 and 2, respectively. RF+ and RF- showed similar genetic associations to ACPA+ and ACPA- RA, respectively. We found that shared epitope (SE) was more enriched in group 2 than 1, p = 2.0 × 10-5, and that amino acid position 11 showed a significant association between 1 and 2, p = 2.7 × 10-5. These associations were independent of ACPA positivity. SE showed a tendency to be negatively correlated with RF titer (p = 0.012). HLA-DRB1*09:01, which reduces ACPA titer, was not associated with RF levels (p = 0.70). The seroconversion group was shown to have distinct genetic characteristics. The genetic architecture of RF levels is different from that of ACPA.

Cost Per Response for Abatacept Compared with Adalimumab In the Treatment of Patients with Rheumatoid Arthritis Based on Anti-Citrullinated Protein Antibody Titres In Italy

Cost Per Response for Abatacept Compared with Adalimumab In the Treatment of Patients with Rheumatoid Arthritis Based on Anti-Citrullinated Protein Antibody Titres In Italy

Variable domain glycosylation of ACPA-IgG: A missing link in the maturation of the ACPA response?

Anti-citrullinated Protein Antibodies (ACPA) are excellent markers for Rheumatoid arthritis (RA) and are postulated to have a pathogenic role in the disease process. A multistep model for the evolution of the ACPA response in RA was proposed in which an initial break of tolerance causes, as “first hit”, “silent” production of ACPA without any clinical symptoms. The model further proposes that the ACPA immune response matures upon a certain (unknown) trigger, a “second hit”, which leads to epitope spreading, an increase in ACPA titres and extended isotype usage before clinical RA manifestations. These occurrences are indicative of an expansion of the citrulline-specific B cell response, though ACPA remain of low avidity even in established disease. This persistence of low avidity is puzzling, as the typical signs of maturation of the immune response seem to be uncoupled from the classical process of affinity maturation. In fact, it suggests that B cells expressing ACPA could bypass selection mechanisms that otherwise control the expansion of auto-reactive B cells. In the established, chronic phase, we recently found that ACPA-IgG are extensively glycosylated in the variable (Fab) domain. More than 90% of ACPA-IgG molecules carry Fab glycans that are highly sialylated. This molecular feature is striking and may provide a missing link in our understanding of the maturation of the ACPA immune response. This review, therefore, describes the current knowledge about ACPA Fab glycosylation in the pathogenesis of RA.