Serum Anti-citrullinated Protein Antibodies Research Articles

Citrullination Accompanies the Development of Carotid Atherosclerotic Plaques.

Citrullination represents a post-translational modification primarily mediated by peptidylarginine deiminase (PADI) 2 and 4 and resulting in the conversion of positively charged peptidylarginine to neutrally charged peptidylcitrulline. Molecular consequences of citrullination include the generation of neoepitopes which provoke the production of autoantibodies implicated in the development of autoimmune diseases. As citrullination initiates, promotes, and is enhanced by aseptic inflammation which plays a pivotal role in atherosclerosis, we proposed that citrullination might accompany the development of atherosclerotic vascular disease. To investigate features and patterns of citrullination in atherosclerotic plaques. We collected carotid atherosclerotic plaques (n = 14) and adjacent arterial segments (n = 14) which were pairwise excised during the carotid endarterectomy. The tissues were examined employing proteomic profiling (ultra-high performance liquid chromatography-tandem mass spectrometry analysis), haematoxylin and eosin staining, Western blotting and immunofluorescence staining for peptidylcitrulline, PADI2, and PADI4, and gene expression analysis. To better explore the mechanisms of citrullination in the neointima, we have also stained excised plaques for the extracellular vesicle markers (CD9 and CD81) and assessed co-localisation of PADI2 (a citrullination marker) with CD81 (an extracellular vesicle marker). In order to study the systemic response to citrullination in an atherosclerotic vascular disease setting, we measured the level of anti-citrullinated protein antibodies in the serum of patients with ischaemic stroke and healthy volunteers. Proteomic profiling found 213 plaque-specific and 111 intact arteria-specific proteins, as well as 46 proteins and 13 proteins which have been respectively upregulated or downregulated in plaques as compared with the adjacent intact segments. Among the top 20 upregulated proteins were atherogenic apolipoprotein B-100, iron-associated protein haptoglobin, and matrix metal-loproteinase-9, together indicating the advanced stage of plaque progression. In comparison with the intact arterial segments, plaques demonstrated protein signatures of innate immune response and oxidative stress, suggesting aseptic inflammation as a driver of atherosclerotic vascular disease. Both peptidylcitrulline and PADI2 have been abundant in the neointima but negligible in tunica media; further, the levels of peptidylcitrulline, PADI2, and PADI4 were elevated in plaque lysates in comparison with those from adjacent arterial segments (p = 0.025, 0.025, and 0.010, respectively). Notably, PADI2 and peptidylcitrulline were co-localised with the cells in the neointima and a considerable proportion of PADI2 was co-localised with CD81-positive extracellular vesicles (p = 0.003). Albeit citrullinated histone H3 and myeloperoxidase showed higher signal in the neointima than in tunica media (p = 0.048 and 0.023, respectively), we did not observe any signs of neutrophil extracellular traps (e.g., unwound chromatin or co-localisation of citrullinated histone H3 with neutrophil elastase) in the plaque tissue. Serum anti-citrullinated protein antibodies were not elevated in patients with ischaemic stroke (p = 0.71), suggesting that vascular citrullination likely does not trigger a generalised immune response. The development of carotid atherosclerosis is associated with citrullination, although it represents a local rather than systemic phenomenon in this clinical scenario.

Helicobacter pylori upregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis

ObjectiveHelicobacter pylori infection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism of H. pylori infection...

Possible Protective Effect of Trimetazidine Alone and in Combination with Methotrexate in Attenuating Joint Inflammation in Freund’s Adjuvants Induced Rheumatoid Arthritis in Rats

Abstract Rheumatoid Arthritis is a complex chronic auto-immune systemic illness. It is primarily characterized by synovial hyperplasia and localized pro-inflammatory cytokine production that causes chronic synovitis and a long-lasting inflammation of the joints and bones. The study's goal was to look into the potential anti-arthritic effects of trimetazidine in a rat model of Freund’s complete adjuvant (FCA)-induced arthritis, which has many clinical and biochemical similarities to rheumatoid arthritis (RA). The underlying antirheumatoid arthritis mechanism, as well as its impact on TLR4/NFKB pathway were investigated to understand and confirm its potential efficacy in RA treatment. Our study was based on 4 groups, control group received saline injections, trimetazidine (7.2 mg/kg/day) treated group, methotrexate (0.75 mg/kg/week) treated group and combination group that received both medications in the same doses for 21 days. The degree of ipsilateral paw swelling, ankle diameter, body weight, tissue expression levels of TLR4(toll like receptor) and NFKB (nuclear factor kappa b) in paw, and serum ACPA (anticitrullinated protein antibodies) were all measured. With a slight but not statistically significant impact on ankle diameter, trimetazidine and methotrexate considerably reduced the arthritic symptoms as indicated by ipsilateral paw volume. It had no discernible impact on body weight. Together with the overall improved synovial hyperplasia and cartilage disarrangements, TLR4 and NFKB expression in synovial tissue were reduced. In a rat model of CFA-induced arthritis, trimetazidine displays a considerable anti- inflammatory impact that is even better than methotrexate and has the potential to be anti-arthritic. Additionally, there is a large additive effect between the two medications.

Prevention of Rheumatoid Arthritis in At-Risk Individuals: Current Status and Future Prospects.

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.

Ameliorative effects of undifferentiated and differentiated BM-MSCs in MIA-induced osteoarthritic Wistar rats: roles of NF-κB and MMPs signaling pathways.

Osteoarthritis (OA) is a degenerative joint condition that is persistent. OA affects millions of people throughout the world. Both people and society are heavily economically burdened by osteoarthritis. There is currently no medication that can structurally alter the OA processes or stop the disease from progressing. Stem cells have the potential to revolutionize medicine due to their capacity to differentiate into chondrocytes, capacity to heal tissues and organs including osteoarthritic joints, and immunomodulatory capabilities. Therefore, the goal of the current investigation was to determine how bone marrow-derived mesenchymal stem cells (BM-MSCs) and chondrogenic differentiated mesenchymal stem cells (CD-MSCs) affected the treatment of OA in rats with monosodium iodoacetate (MIA)-induced osteoarthritis. Male Wistar rats were injected three times with MIA (1 mg)/100 µL isotonic saline to induce osteoarthritis in the ankle joint of the right hind leg. Following the MIA injection, the osteoarthritic rats were given weekly treatments of 1 × 106 BM-MSCs and CD-MSCs into the tail vein for three weeks. The obtained results showed that in osteoarthritic rats, BM-MSCs and CD-MSCs dramatically decreased ankle diameter measurements, decreased oxidized glutathione (GSSG) level, and boosted glutathione peroxidase (GPx) and glutathione reductase (GR) activities. Additionally, in rats with MIA-induced OA, BM-MSCs and CD-MSCs dramatically boosted interleukin-10 (IL-10) serum levels while considerably decreasing serum anticitrullinated protein antibodies (ACPA), tumour necrosis factor-α (TNF-α), and interleukin-17 (IL-17) levels as well as ankle transforming growth factor-β1 (TGF-β1) expression. Analysis of histology, immunohistochemistry, and western blots in osteoarthritic joints showed that cartilage breakdown and joint inflammation gradually decreased over time. It is possible to conclude from these results that BM-MSCs and CD-MSCs have anti-arthritic potential in MIA-induced OA, which may be mediated via inhibitory effects on oxidative stress, MMPs and inflammation through suppressing the NF-κB pathway. In osteoarthritis, using CD-MSCs as a treatment is more beneficial therapeutically than using BM-MSCs.

Periodontal Treatment for Chronic Periodontitis With Rheumatoid Arthritis

BackgroundHistory of rheumatoid arthritis (RA) increases risk of periodontal diseases. A pro-inflammatory condition noted in periodontitis is considered a trigger for RA. Thus, periodontal treatment aimed at attenuating the pro-inflammatory state could aid in potentially reducing the risk of RA. AimsThe objective of this research was to assess the effect of periodontal therapy on rheumatoid factor, Disease Activity Score-28, anti-citrullinated protein antibody, and C-reactive protein levels in patients with chronic periodontitis (CP) and RA. Materials and methodsThe sample consisted of 28 patients with CP and RA. The study was designed to be a double-blind, randomised controlled clinical study. The samples were randomly categorised to either the treatment group (n = 13) or the control group (n = 15). CP status (plaque index, bleeding on probing, probing pocket depth, clinical attachment loss), clinical rheumatologic status (Disease Activity Score), and biochemical status (C-reactive protein, anti-citrullinated protein antibody, and rheumatoid factor) were assessed at baseline and at follow-up at 8 to 12 weeks. ResultsThe treatment group showed a highly statistically significant reduction in bleeding on probing (P < .005), probing pocket depth (P < .001), plaque index (P < .001), and C-reactive protein (P < .001); a gain in the clinical attachment loss (P < .001) and an improvement in Disease Activity Score-28 (P = .001) were observed at reassessment following nonsurgical periodontal treatment as compared to the control group. However, blood serum anti-citrullinated protein antibody (P = .002) and rheumatoid factor levels (P = .351) were found to increase from baseline to 8 to 12 weeks following subgingival scaling and root planing. ConclusionsReduction of inflammation in the periodontium by nonsurgical periodontal therapy did not reduce anti-citrullinated protein antibody and rheumatoid factor levels. However, it has shown improvement in periodontal conditions, and remarkable changes were observed in the clinical Disease Activity Score and C-reactive protein levels of individuals with RA.

Antibodies against citrullinated proteins in relation to periodontitis with or without rheumatoid arthritis: a cross-sectional study

BackgroundPrevious studies have reported conflicting findings between serum anti-citrullinated protein antibodies (ACPA) levels in rheumatoid arthritis (RA) participants with and without periodontitis (Pd). This study aimed to analyse possible correlations between serum ACPA levels and clinical parameters in Pd and RA participants.MethodsFull mouth periodontal examination (probing pocket depth, clinical attachment levels, gingival bleeding index, visual plaque index) was conducted and serum samples obtained from 80 participants comprising RA, Pd, both RA and Pd (RAPd) and healthy individuals (HC). Erythrocyte sedimentation rates (ESR) and periodontal inflamed surface area (PISA) were obtained. Serum samples were analysed for ACPA quantification using enzyme-linked immunosorbent assay (ELISA).ResultsMedian levels (IU/mL) of ACPA (interquartile range, IQR) in RAPd, RA, Pd and HC groups were 118.58(274.51), 102.02(252.89), 78.48(132.6) and 51.67(91.31) respectively. ACPA levels were significantly higher in RAPd and RA as compared to HC group (p < 0.05). However, ACPA levels of any of the groups were not correlated with any clinical periodontal and RA parameters within the respective groups.ConclusionsAt individual level, the amount of serum ACPA seem to have an increasing trend with the diseased condition in the order of RAPd > RA > Pd > HC. However, lack of any significant correlation between the serum ACPA levels with the clinical Pd and RA parameters warrants further studies to investigate the causal link between RA and Pd for such a trend. Further studies involving more inflammatory biomarkers might be useful to establish the causal link between Pd in the development and progression of RA or vice versa.

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.

Anti-peptidylarginine deiminase-4 antibodies at mucosal sites can activate peptidylarginine deiminase-4 enzyme activity in rheumatoid arthritis

BackgroundMucosal sites are hypothesized to play a role in the development of rheumatoid arthritis (RA). Since serum anti-peptidylarginine deiminase (PAD)4 antibodies, including a subset that cross-react with PAD3 (PAD3/4), are specific for RA and associate with severe disease, we sought to examine whether anti-PAD4 and anti-PAD3/4 antibodies were present in the lung and oral mucosa of subjects with RA and “at-risk” for RA.MethodsWe included 37 RA, 25 healthy control, and 46 subjects “at-risk” for RA based on familial RA and/or serum anti-citrullinated protein antibody (ACPA) positivity. Paired serum, sputum, and saliva were evaluated for anti-PAD4 and anti-PAD3/4 using immunoprecipitation and ACPA using ELISA. Immunoglobulins (Ig) were purified from representative samples, and their effect on citrullination of histone H3 by recombinant human PAD4 was measured by anti-citH3 immunoblot.ResultsAnti-PAD4 antibodies were detected in the serum of 6/37 (16.2%), sputum of 3/37 (8.1%), and saliva of 3/33 (9.1%) RA subjects and in the serum and sputum of 1/46 (2.2%) at-risk subjects. None of the healthy controls had anti-PAD4 antibodies at any site. Serum, sputum, and salivary anti-PAD4 antibodies were more prevalent in RA subjects with RA duration >2 years. Purified antibodies from representative anti-PAD4-positive and anti-PAD3/4-positive sputum were primarily of the IgA isotype and able to increase PAD4 enzymatic activity.ConclusionsAnti-PAD4 antibodies are present in the sputum and saliva of a portion of RA patients and are infrequent in at-risk subjects. Importantly, the ability of anti-PAD4, and particularly anti-PAD3/4, antibodies in the sputum to enhance PAD4 enzymatic activity suggests that anti-PAD4 may play an active role in the RA lung.

POS0441 DEVELOPMENT OF RHEUMATOID ARTHRITIS AMONG ANTI-CITRULLINATED PROTEIN ANTIBODIES POSITIVE ASYMPTOMATIC INDIVIDUALS: A PROSPECTIVE OBSERVATIONAL STUDY

Background:In the idividuals with genetic and enviromental risk factors, immune events at mucosal surfaces occur and may precede systemic autoimmunity. Anti-citrullinated protein antibodies (ACPA) are present in the serum for an average of 3-5 years prior to the onset of rheumatoid arthritis (RA) during an asymptomatic period. In ACPA-positivite individuals, the additional presence of RA-related risk factors appears to add significant power for the development of RA. To date, there have been few reports in which clinical courses of ACPA-positive asymptomatic individuals were investigated prospectively.Objectives:To observe the clinical time course of ACPA-positive healthy population for the development of RA.Methods:Healthy volunteers without joint pain or stiffness, who attended the comprehensive health screening of our hospital, were enrolled in this prospective observational study. The serum ACPA levels were quantified by Ig-G anti-cyclic citrullinated peptide enzyme-linked immunosorbent assay with levels &gt; 4.4 U/mL considered positive. ACPA-positive subjects were followed by rheumatologists of our department clinically or a questionnaire sent by mail for screening to detect arthritis.Results:5,971 healthy individuals without joint symptons were included. Ninty-two (1.5%) were positive for ACPA. Of these, 19 (20.7%) developed RA and two were suspected as RA by mail questionnaire. Their average age were 58-years, and women were 68%. The average duration between the date of serum sampling and diagnosis was 10.7 months. ACPA-positive individuals who developed to RA had higher serum ACPA and Ig-M rheumatoid factor levels than ACPA-positive individuals who did not (P value by Mann-Whitney U test: 0.002, 0.005, respectively).Conclusion:Among ACPA-positive asymptomatic individuals, 20% developed RA. The higher titer of ACPA and Ig-M rheumatoid factor levels are risk factors for devoloping RA.Disclosure of Interests:None declared

Immunogenic and inflammatory responses to citrullinated proteins are enhanced following modification with malondialdehyde-acetaldehyde adducts

Background/ObjectiveMalondialdehyde-acetaldehyde adducts (MAA) act as potent immune adjuvants and co-localize with citrullinated antigens in tissues effected by rheumatoid arthritis (RA). We sought to examine the role of MAA-adducts in promoting RA-related autoimmunity and inflammation. MethodsDBA/J1 mice were immunized with human serum albumin (HSA), HSA-MAA, citrullinated HSA (HSA-Cit), or HSA-MAA-Cit with subsequent measurement of serum anti-citrullinated protein antibody (ACPA) and anti-Cit T cell responses. Cellular binding of the same antigens was examined using THP-1 monocytes and Chinese Hamster Ovary (CHO) cells transfected with specific scavenger receptors (SRs: TLR4, SR-B2, SREC-1). The effects of these antigens on THP-1 activation were then examined by quantifying plate adherence, pro-inflammatory (TNFα, IL-1β, IL-10) cytokine release, and SR (CD14, SR-B2)/co-stimulatory molecule (CD80, HLA-DR) expression. Comparisons were completed using one-way ANOVA with Tukey’s post-hoc test. ResultsMice immunized with co-modified HSA produced significantly higher ACPA concentrations than all other groups whereas T cell responses to citrullinated proteins were highest following immunization with HSA-MAA. Both transfected CHO and THP-1 cells demonstrated significantly higher binding of HSA-MAA-Cit vs. HSA or HSA-Cit. THP-1 cells exposed to HSA-MAA-Cit expressed significantly higher concentrations of TNFα, IL-1β, and IL-10 vs. all other groups. Furthermore, THP-1 cells demonstrated significantly increased plate adherence and higher expression of CD14, SR-B2, and HLA-DR following incubation with HSA-MAA-Cit vs. HSA or HSA-Cit. ConclusionThese studies demonstrate that MAA-adduction of citrullinated antigen greatly enhances immune and cellular responses, potentially acting as a key co-factor in RA pathogenesis.

The Association Between MUC5B Mutations and Clinical Outcome in Patients with Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Retrospective Exploratory Study in China.

BackgroundPatients with rheumatoid arthritis (RA) who develop interstitial lung disease (RA-ILD), show features of usual interstitial pneumonia (UIP) on high-resolution computed tomography (HRCT). This retrospective exploratory clinical study aimed to investigate the association between mutations in the MUC5B gene and clinical outcome in patients with RA, with or without RA-ILD, using whole-exome sequencing (WES).Material/MethodsWES was performed using peripheral blood samples for mutations in the MUC5B gene in 51 patients diagnosed with RA without ILD, and 45 patients with RA-ILD. The cumulative incidence in acute exacerbations of RA-ILD and variables associated with acute exacerbations of RA-ILD were analyzed.ResultsIn patients with RA-ILD, the main genetic variants of MUC5B were identified, with an odds ratio (OR) of 3.410 (p=0.013). Nine patients with RA without ILD (17.6%) and 19 patients with RA-ILD (42.2%) expressed MUC5B variants. Patients with RA-ILD carrying MUC5B variants had a significantly increased duration of RA-ILD (p=0.03) and showed a UIP pattern on lung HRCT (p=0.01). Acute exacerbations of RA-ILD occurred in 25 patients during follow-up, including 13 patients with mutant MUC5B and 12 patients with wildtype MUC5B. Univariate analysis showed that MUC5B mutations (p=0.043), older age of onset of RA (p=0.041), increased serum anti-citrullinated protein antibodies (ACPAs) (p=0.033), and a UIP imaging pattern on HRCT (p=0.015) were significantly correlated with acute exacerbations of RA-ILD. However, these findings were not supported by multivariate analysis (p=0.065).ConclusionsThe carrier status of MUC5B variants was an indicator of reduced prognosis and increased exacerbations of RA-ILD.

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.

An assessment of anti-citrullinated protein antibody in systemically healthy individuals with or without chronic periodontitis: A case-control study.

Background:Periodontitis has been implicated as a risk factor for rheumatoid arthritis (RA).Aim:This study aimed to assess the relationship between RA and chronic periodontitis (CP) by evaluating the serum levels of the anti citrullinated protein antibody (ACPA) which is a marker of RA in systemically healthy individuals with and without CP.Materials and Methods:This case–control study enrolled 40 systemically healthy individuals. Participants were divided into two groups, i.e., CP group Systemically healthy chronic periodontitis (CPSH) (n = 20) and control group Systemically healthy (SH) (n = 20), matched for age and gender. The CP patients were evaluated for periodontal parameters, namely probing pocket depth, clinical attachment loss, percentage of the site involved with attachment loss, and number of teeth present. A volume of 5 ml of venous blood was collected from both the groups and centrifuged; the separated serum was stored at − 70°C before being analyzed. Later, serum samples were tested for levels of ACPA in both the groups and compared.Results:The mean serum ACPA levels were higher in CPSH patients compared to SH (131.38 RU/ml vs. 34.54 RU/ml, P = 0.001), which was statistically highly significant. In addition, we found a significant elevation of serum ACPA levels in severe generalized CP patients compared to moderate generalized CP patients (175.47 RU/ml vs. 95.31 RU/ml, P = 0.001), and the difference was statistically highly significant.Conclusion:The results of the study confirmed that CP can be a risk factor for RA. Moreover, the severity of periodontitis appeared to be related to elevated serum levels of ACPA.

Increased Risk of Rheumatoid Arthritis-Related Pulmonary Disease as a Results of Serum Anticitrullinated Protein Antibody Positivity

Background: there is increasing evidence to indicate that autoimmunity as well as inflammatory reactions occur systemically before development of any clinical sign of joint disease in patients with anti–citrullinated protein antibody (ACPA)–positive rheumatoid arthritis (RA). Objective: The aim of the work was to investigate the potential predictive value of anti-ccp3 for interstitial lung disease association with RA and to discriminate RA patient who are at potential risk to develop methotrexate (MTX) induced pulmonary toxicity. Patients and methods: This cross-sectional study included a total of 50 RA patients who were diagnosed according to the 2010 American College of Rheumatology / the European League Against Rheumatism classification criteria for Rheumatoid Arthritis (ACR/EULAR 2010 criteria) for detection of pulmonary manifestations attending at Physical medicine, Rheumatology and Rehabilitation Outpatient Clinics of Al-Azhar University Hospitals. Results: there was statistically significant difference between patients with and without interstitial lung disease (ILD), in high-resolution computed tomography (HRCT) as regards to Tiffeneau-Pinelli index (FEV1/FVC ratio), except for FEV1/FVC between patients with and without ILD in HRCT, forced expiratory volume in first second (FEV1), and forced vital capacity (FVC) are often decreased because of the reduction in lung volume, but the FEV1- to-FVC ratio is maintained or increased in ILD. Conclusion: RA patients without chest symptoms should not be neglected, pulmonary function testing and HRCT should be done routinely to pick up early ILD cases.

Increased Risk of Rheumatoid Arthritis-Related Pulmonary Disease as a Results of Serum Anticitrullinated Protein Antibody Positivity

Background: there is increasing evidence to indicate that autoimmunity as well as inflammatory reactions occur systemically before development of any clinical sign of joint disease in patients with anti–citrullinated protein antibody (ACPA)–positive rheumatoid arthritis (RA). Objective: The aim of the work was to investigate the potential predictive value of anti-ccp3 for interstitial lung disease association with RA and to discriminate RA patient who are at potential risk to develop methotrexate (MTX) induced pulmonary toxicity. Patients and methods: This cross-sectional study included a total of 50 RA patients who were diagnosed according to the 2010 American College of Rheumatology / the European League Against Rheumatism classification criteria for Rheumatoid Arthritis (ACR/EULAR 2010 criteria) for detection of pulmonary manifestations attending at Physical medicine, Rheumatology and Rehabilitation Outpatient Clinics of Al-Azhar University Hospitals. Results: there was statistically significant difference between patients with and without interstitial lung disease (ILD), in high-resolution computed tomography (HRCT) as regards to Tiffeneau-Pinelli index (FEV1/FVC ratio), except for FEV1/FVC between patients with and without ILD in HRCT, forced expiratory volume in first second (FEV1), and forced vital capacity (FVC) are often decreased because of the reduction in lung volume, but the FEV1- to-FVC ratio is maintained or increased in ILD. Conclusion: RA patients without chest symptoms should not be neglected, pulmonary function testing and HRCT should be done routinely to pick up early ILD cases.

Complement and its environmental determinants in the progression of human rheumatoid arthritis

Rheumatoid arthritis (RA) is a complex autoimmune disease with an etiology that is not yet well understood, disproportionally affects women and also varies in incidence and prevalence by population. The presence of anti-citrullinated protein antibodies (ACPA) is a highly specific biomarker for the diagnosis of clinically apparent RA. ACPA are also present in the serum for an average of 3–5 years prior to the onset of RA during an asymptomatic period characterized by mucosal inflammation and local ACPA production at these sites. We hypothesized that systemic complement activation products might be generated during the pre-clinical initiation of RA and/or provide a second hit that promotes subsequent arthritis development in the joints. In addition, we evaluated which demographic and genetic features and environmental exposures could influence the complement activation process. We analyzed plasma from healthy subjects, subjects at-risk for the development of RA based on serum ACPA positivity in absence of inflammatory arthritis (IA), and ACPA positive RA subjects by Multiplex Assay and ELISA for eighteen complement system components, factors and activation products belonging to the classical, lectin and alternative pathways. By using regression models, associations between complement proteins and various demographic, genetic, and environmental factors previously found to be associated with RA, including sex, smoking, shared epitope, and oral contraceptive use, were examined. We found no evidence of systemic complement activation in ACPA positive subjects without IA, but in contrast found evidence of systemic involvement of the both classical and alternative pathways during the stage of the disease where classified RA is present, (i.e. during joint inflammation and damage). With regard to the demographic, genetic, and environmental variables, females who reported current or past oral contraceptive use and subjects with current tobacco exposure demonstrated alterations of the alternative pathway of complement. Furthermore, RA subjects with established disease who have a body mass index categorized as obese demonstrated higher levels of C2 compared to RA subjects who are not considered obese. In sum, the complement system may be involved in the pathogenesis of RA, with only localized mucosal effects during the preclinical period in those at-risk for RA but in the joint as well as systemically in those who have developed clinically apparent arthritis.

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.

Efficacy of a mouthwash containing essential oils and curcumin as an adjunct to nonsurgical periodontal therapy among rheumatoid arthritis patients with chronic periodontitis: A randomized controlled trial

The purpose of this study was to assess the efficacy of mouthwash containing essential oils and curcumin (MEC) as an adjunct to nonsurgical periodontal therapy on the disease activity of rheumatoid arthritis (RA) among RA patients with chronic periodontitis (CP). A triple-blinded controlled trial was conducted among 45 female RA patients with CP randomized into three treatment groups as follows: Group A: scaling and root planing (SRP) with 0.2% chlorhexidine mouthwash as an adjunct (n = 15), Group B: SRP with MEC as an adjunct (n = 15), and Group C: SRP alone (n = 15). RA disease activity was assessed using erythrocyte sedimentation rate, serum C-reactive protein, serum anti-citrullinated protein antibody, and serum rheumatoid factor. Periodontal disease activity was assessed using plaque index, clinical attachment level (CAL), and pocket depth (PD). All parameters were recorded at baseline and 6 weeks thereafter. Data were assessed using one-way ANOVA and paired t-test. A significant reduction in periodontal and RA disease activity parameters was observed from baseline to 6 weeks following intervention (P < 0.05). The highest percentage of mean reduction in plaque index and RA parameters from baseline to 6 weeks was observed in Group B followed by Groups A and C. The highest percentage of mean reduction in PD and CAL was observed in Group A followed by Groups B and C (P < 0.001). This study reveals that MEC as an adjunct to SRP is effective in reducing the disease activity of RA and CP, thereby warranting the use of the same.

A cross-sectional investigation into the association between Porphyromonas gingivalis and autoantibodies to citrullinated proteins in a German population.

Background:Porphyromonas gingivalis (P.g) is unique among pathogens due to its ability to generate citrullinated proteins in an inflammatory milieu, potentially mediating the loss of immune tolerance, the production of anticitrullinated protein antibodies (ACPAs), and subsequently the development of rheumatoid arthritis (RA). Based on this hypothesis, we set out to investigate whether P.g is linked to ACPAs in a well-characterized German population.Participants and methods:A total of 600 participants (292 women and 308 men with a mean age of 67 years) of the European Prospective Investigation into Cancer and Nutrition-Potsdam study were selected in 2013, and paired saliva and serum samples were collected. Salivary P.g DNA and serum anticyclic citrullinated peptide (anti-CCP2) levels were quantified by real-time polymerase chain reaction and anti-CCP2 enzyme-linked immunosorbent assay, respectively. In selected participants, additional ACPA fine-specificities were also analysed on a custom-made multiplex peptide array.Results:Among participants with C-reactive protein greater than 3.0 mg/l, a one-unit increase in P.g DNA was associated with an almost twofold increase in anti-CCP2 levels. Moreover, participants with high P.g DNA had on average approximately 2.8-times higher anti-CCP2 levels when compared with participants with low P.g DNA, (Holm-adjusted p value = 0.01). Furthermore, citrullinated epitopes on α-enolase and vimentin were common ACPA reactivities among participants who also had high P.g DNA and elevated C-reactive protein.Conclusions:Our study suggests that in specific subgroups of individuals with systemic inflammation, higher salivary P.g DNA is associated with elevated serum ACPA. These data support a role for P.g in the development of anticitrulline immunity.