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Measurement of two groups of autoantibodies, rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) have gained increasing significance in the diagnosis and classification of rheumatoid arthritis (RA) over the last 65 years. Despite this rising importance of autoimmune serology in RA, there is a palpable lack of harmonization between different commercial RF and ACPA tests. While a minimal diagnostic specificity has been defined for RF tests, which almost always are related to an international reference preparation, neither of this applies to ACPA. Especially assays with low diagnostic specificity are associated with very low positive predictive values or post-test probabilities in real world settings. In this review we focus on issues of practical bearing for the clinical physician diagnosing patients who potentially have RA, or treating patients diagnosed with RA. We advocate that all clinically used assays for RF and ACPA should be aligned to a common diagnostic specificity of 98-99% compared to healthy controls. This high and rather narrow interval corresponds to the diagnostic specificity seen for many commercial ACPA tests, and represents a specificity that is higher than what is customary for most RF assays. Data on antibody occurrence harmonized in this way should be accompanied by test result-specific likelihood ratios for the target diagnosis RA on an ordinal or interval scale, which will provide the clinical physician with more granular and richer information than merely relating numerical values to a single cut-off point. As many physicians today are used to evaluate autoantibodies as positive or negative on a nominal scale, the introduction of test result-specific likelihood ratios will require a change in clinical mindset. We also discuss the use of autoantibodies to prognosticate future arthritis development in at-risk patients as well as predict severe disease course and outcome of pharmacological treatment., Competing Interests: JR has been a member of the scientific advisory board for Thermo Fisher Scientific, and has research collaboration with the diagnostic companies Thermo Fischer Scientific, Inova Diagnostics, Euroimmun and Theradiag. CT has received a research grant from Bristol-Myers Squibb, consultancy fees from Roche, and speaker’s honoraria from Abbvie, Bristol-Myers Squibb, Nordic Drugs, Pfizer and Roche. AK has received speaker’s honoraria from Werfen and was previously employed by Sanofi. The handling editor declared a past co-authorship with one of the authors, JR., (Copyright © 2021 Rönnelid, Turesson and Kastbom.)

Objects: Although the association of cigarette smoking (CS) with susceptibility to rheumatoid arthritis (RA) has been established, the impact of CS on anticitrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) levels in RA has yet been clear, especially in relation to shared epitope (SE) alleles., Methods: A total of 6239 subjects, the largest Asian study ever, from two independent Japanese cohorts were enrolled. Precise smoking histories, levels of ACPA and RF, and HLA-DRB1 allele status were withdrawn from databases. Associations between CS and high ACPA or RF levels, defined by the top quartiles, were evaluated. The effect of HLA-DRB1 alleles on the association was further investigated., Results: CS at RA onset conferred the risks of high levels of both antibodies, especially RF (OR 2.06, p=7.4×10 -14 ; ACPA, OR 1.29, p=0.012), suggesting that RF level is more sensitive to CS than ACPA level. The patients who had quitted CS before RA onset showed a trend of decreased risks of developing high levels of ACPA or RF, and the risks steadily decreased according to the cessation years. The association of CS with high ACPA level was observed only in subjects carrying SE alleles, while the association of high RF level was observed regardless of SE., Conclusions: CS confers the risks of high autoantibody levels in RA in different manners; CS interacts with SE alleles on ACPA level, while CS impacts on RF level despite SE allele. These data suggest novel distinct production mechanisms of RF and ACPA., Competing Interests: Competing interests: KI received speaker fee from fifteen pharmaceutical companies (Asahi-Kasei Pharma, Astellas Pharma, Abbvie GK Inc., AYUMI, Eisai, Otsuka, Kaken, Takeda, Mitsubishi-Tanabe, Chugai, Eli-Lilly, Bristol-Myers Squibb, Pfizer Japan Inc., Janssen and UCB Japan). MH, HI and MT belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan). TM received personal fees from fourteen pharmaceutical companies (Pfizer Japan Inc., Mitsubishi-Tanabe, Eisai, Astellas, AYUMI, Chugai, Daiichi Sankyo, Nippon Shinyaku, Takeda Pharmaceutical, Eli-Lilly, Asahi-Kasei Pharma, Sanofi, Bristol-Myers Squibb and GlaxoSmithKline). KURAMA cohort study is supported by grant from Daiichi Sankyo Co. Ltd. This study is conducted as investigator initiate study. These companies had no role in the design of the study, the collection or analysis of the data, the writing of the manuscript or decision to submit the manuscript for the publication. IORRA cohort study is supported by grant by twenty pharmaceutical companies (Daiichi Sankyo Co. Ltd., Mitsubishi-Tanabe, Chugai, Bristol-Myers Squibb, AYUMI, Astellas, Pfizer Japan Inc., Takeda Pharmaceutical, Eisai, Nippon Shinyaku, YL Biologics Ltd., AbbVie, Novartis Pharmaceutical K.K., Kaken Pharmaceutical Co., Ltd., UCB Japan, Ono Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Teijin Pharma, Torii Pharmaceutical Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd.). These sponsors were not involved in the: study design; collection, analysis and interpretation of data; writing of the paper; and/or decision to submit for publication., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: A retrospective comparison of the prevalence and diagnostic value of anti-Sa, anti-CEP-1, and anti-MCV autoantibodies relative to those of the established autoantibodies, composite RF and anti-CCP-IgG used routinely for RA diagnosis as a component of the ACR 2010 criteria, in a cohort of disease-modifying anti-rheumatic drug naïve African RA patients (n = 75)., Methods: Serum concentrations of anti-Sa, anti-CEP-1 and anti-MCV autoantibodies were measured using ELISA procedures, while anti-CCP-IgG antibodies were determined by fluorescence enzyme immunoassay, and composite RF by latex-enhanced laser nephelometry., Results: The seropositivity frequencies of anti-Sa, anti-CEP-1 and anti-MCV antibodies for the RA patients were 82, 72, 85%, respectively, while that of anti-CCP-IgG and RF was 87% for both. Overall, anti-MCV demonstrated the best specificity, positive predictive value (PPV), odds ratio and positive likelihood ratio of all the types of autoantibody tested., Conclusion: These observations in this unique cohort of RA patients indicated novel associations of all three autoantibodies in regard to HLA-SE risk alleles, disease severity and tobacco use that were not reported before. Elevated anti-Sa titers designated a propensity of higher disease and high-risk alleles in our cohort. Anti-CEP-1 association with HLA-SE homozygosity and high-risk alleles is also novel in this group. Of note, measurement of anti-MCV antibodies on presentation, either as an adjunctive or even as a stand-alone test, surpassed all other biomarkers investigated here and, therefore, may add value to clinical management.

Objectives: Rheumatoid factor (RF) and anti-cyclic citrullinated protein/peptide antibodies (ACPA) are integrated in the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for rheumatoid arthritis (RA). The objectives of this study were to evaluate the technical and diagnostic performance of different RF and ACPA assays and to evaluate whether differences in performance impact RA classification., Methods: Samples from 594 consecutive patients who for the first time consulted a rheumatologist (44 of whom were diagnosed with RA) and 26 extra newly diagnosed patients with RA were analysed with six different RF assays (Menarini, Thermo Fisher, Inova, Roche, Abbott, Euroimmun) and seven different ACPA assays (Menarini, Thermo Fisher, Inova, Roche, Abbott, Euro Diagnostica, Euroimmun)., Results: We found differences in analytical performance between assays. There was poor numerical agreement between the different RF and ACPA assays. For all assays, the likelihood ratio for RA increased with increasing antibody levels. The areas under the curve of receiver operating characteristic analysis of the RF (range 0.676-0.709) and ACPA assays (range 0.672-0.769) only differed between some ACPA assays. Nevertheless, using the cut-off proposed by the manufacturer, there was a large variation in sensitivity and specificity between assays (mainly for RF). Consequently, depending on the assay used, a subgroup of patients (13% for RF, 1% for ACPA and 9% for RF/ACPA) might or might not be classified as RA according to the 2010 ACR/EULAR criteria., Conclusion: Due to poor harmonisation of RF and ACPA assays and of test result interpretation, RA classification according to 2010 ACR/EULAR criteria may vary when different assays are used., Competing Interests: Competing interests: XB has received lecture fees from Thermo Fisher, Inova and Menarini and has been a consultant for Inova., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aim: Patients with rheumatoid arthritis (RA) and co-existent bronchiectasis (BRRA) have a five-fold increased mortality compared to rheumatoid arthritis alone. Yet previous studies have found no difference in clinical and serological markers of RA disease severity between BRRA patients and RA alone. However, RA disease activity measures such as Disease Activity Score of 28 joints - C-reactive protein (DAS28-CRP) and anti-cyclic citrullinated peptide antibodies (anti-CCP) have not been studied, so we assessed these parameters in patients with BRRA and RA alone., Methods: BRRA patients (n = 53) had high-resolution computed tomography proven bronchiectasis without any interstitial lung disease and ≥ 2 respiratory infections/year. RA alone patients (n = 50) had no clinical or radiological evidence of lung disease. DAS28-CRP, rheumatoid factor (immunoglobulin M) and anti-CCP were measured in all patients, together with detailed clinical and radiology records., Results: In BRRA, bronchiectasis predated RA in 58% of patients. BRRA patients had higher DAS28 scores (3.51 vs. 2.59), higher levels of anti-CCP (89% vs. 46%) and rheumatoid factor (79% vs. 52%) (P = 0.003) compared to RA alone. Where hand and foot radiology findings were recorded, 29/37 BRRA (78%) and 13/30 (43%) RA alone had evidence of erosive change (P = 0.003). There were no significant differences between groups in smoking history or disease-modifying anti-rheumatic drug/biologic therapy., Conclusions: Increased levels of RA disease activity, severity and RA autoantibodies are demonstrated in patients with RA and co-existent bronchiectasis compared to patients with RA alone, despite lower tobacco exposure. This study demonstrates that BRRA is a more severe systemic disease than RA alone., (© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Aim: To investigate the presence of the 'shared epitope' (SE) in the HLA-DRB1 alleles in patients with RA and to ascertain the frequency of the HLA-DRB1 alleles with autoantibodies (anti-cyclic citrullinated peptide [anti-CCP] rheumatoid factor [RF]) and disease severity., Methods: A total of 200 RA patients and 200 apparently healthy subjects participated in the study. HLA-DRB1 were genotyped using polymerase chain reaction with sequence-specific primer (PCR-SSP). Anti-CCP and RF in serum were determined by in vitro quantitative enzyme-linked immunosorbent assay (ELISA) method. Erythrocyte sedimentation rate (ESR) was measured by Westergren method. Disease activity was assessed by using the disease activity score-28 (DAS-28). Chi-square test and Student's t-test were used in the statistical analysis., Results: A significant increase in the frequency of HLA-DRB1*01, *04, *10 and *14 were identified in RA patients and showed a strong association with the disease susceptibility. While the frequencies of HLA-DRB1*03, *07, *11 and *13 were significantly lower in RA patients than in controls. The other HLA-DRB1 alleles *08, *09, *12, *15 and *16 showed no significant difference. The frequency of anti-CCP and RF antibodies did not showed significant difference in SE-positive patients compared with SE-negative patients. DAS-28 values of RA patients showed no significant difference between SE-positive and SE-negative groups., Conclusion: Our results indicate that HLA-DRB1*01, *04, *10 and *14 alleles are related with RA, while HLA-DRB1*03, *07, *11 and *13 protect against RA in our population. On the other hand, we failed to provide evidence for the association of the autoantibodies and DAS-28 with SE-positive RA patients., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Viruses are common and are involved in the etiology of idiopathic rheumatological diseases. Hepatitis B virus (HBV), a member of the family Hepadnaviridae and hepatitis C virus (HCV), play an important role in the undetermined etiology of arthritis. The clinical manifestations of hepatitis B and C show similarities with various diseases, such as rheumatic diseases. Anti-cyclic citrullinated peptide (anti-CCP) is a specific serological marker for rheumatoid arthritis., Objectives: The aim of this study was to analyze anti-CCP and rheumatoid factor (RF) levels in patients with a hepatitis B and C infection., Material and Methods: Forty-four patients with hepatitis B, 43 patients with hepatitis C, 25 patients with rheumatoid arthritis, and 46 healthy control serums and their RF and anti-CCP levels were compared. RF was measured by the nephelometer, which detects IgM-RF. Anti-CCP was measured using enzymelinked immunosorbent assay (ELISA) that is included in the second-generation anti-CCP antibody assays (anti-CCP2)., Results: The anti-CCP positivity levels were 20.5%, 32.5%, 72.4% and 10.9% for HBV, HCV and RA groups and healthy control group, respectively. When the groups were compared based on their RF positivity and anti-CCP positivity while the values for HBV and HCV group and healthy control group were the same, in RA group there is a significant difference to the rest of the groups (p < 0.01)., Conclusions: Anti-CCP may be positive for HBV and HCV as well, but it is a sensitive and specific immunological marker for RA diagnosis, especially in high-titres.

ACPA (anti-citrullinated protein antibody) tests are today systematically added to clinical and radiological investigations when diagnosing rheumatoid arthritis (RA), and the inclusion of ACPA positivity in the new 2010 RA criteria underlines their importance. The aim of this study was to determine the sensitivity and specificity of different ACPA assays and IgA, IgG and IgM isotypes of rheumatoid factor (RF) in a cohort of patients with early RA in order to assess the value of combining the tests. The serum samples were obtained from 46 RA patients, 80 patients with systemic rheumatic disease, and 20 blood donors. ACPAs were measured using five different commercial kits. The receiver operating characteristic (ROC) curves of the anti-ACPA tests had area under the curve (AUC) values of 0.60-0.83. The diagnostic accuracy of the Bio-Rad multiplex flow immunoassay, a new technology for ACPA testing, was very similar to that of the other widely used commercial immunoassays. The EliA CCP-Phadia test was the most specific, and had the best positive likelihood ratio and positive predictive values, whereas the anti-CCP Inova 3.1 test was the most sensitive, and had the best negative likelihood ratio and negative predictive values. The best combination to use for early RA screening was an ACPA test together with IgM and IgA RF., (Published by Elsevier B.V.)

Owing to limited usefulness of Rheumatoid Factor and anti-CCP in rheumatoid arthritis, there is a need to identify a more sensitive and specific biomarker to detect rheumatoid arthritis (RA), particularly seronegative RA cases. Tenascin-C is an extracellular matrix glycoprotein, which has been implicated in the pathophysiology of RA. The objective of our study was to evaluate the diagnostic utility of serum Tenascin-C in seropositive and seronegative rheumatoid arthritis patients. We conducted a cross-sectional case control study. Sixty patients who fulfilled the ACR 2010 criteria for rheumatoid arthritis were included in the study. Thirty patients were found to be positive for RF and/or anti-CCP and 30 were negative for both RF and anti-CCP. Thirty age and gender-matched healthy subjects were taken as controls. Serum Tenascin-C was measured by quantitative sandwich enzyme immunoassay technique. The mean serum concentration of Tenascin-C in controls, seronegative and seropositive cases was 0.66 ng/ml, 20.54 ng/ml and 23.42 ng/ml, respectively. Tenascin-C levels were significantly higher in RA cases compared to controls (p < 0.0001). There was no significant difference in Tenascin-C between seropositive and seronegative cases (p = 0.603). ROC curve analysis showed a sensitivity of 96.6% and specificity of 100% with AUC of 0.98 at 2.21 ng/ml as cut-off value for diagnosing RA. Tenascin-C is elevated in both seronegative and seropositive RA, which indicates that it can be used as a sensitive marker for RA. The addition of Tenascin-C to the existing RF and anti-CCP may help in identifying a large number of patients with RA, particularly seronegative rheumatoid arthritis cases. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the Human Leukocyte Antigen (HLA) class II (DRB1 and DQB1) alleles and haplotype frequency in Rheumatoid Arthritis (RA) in the Sudanese population. The frequency of HLA-DRB1 and -DQB1 alleles and DRB1-DQB1 haplotypes were determined in 122 RA patients and 100 controls. HLA alleles were genotyped by the polymerase chain reaction-sequence specific primers (PCR-SSP) method. In RA patients, HLA-DRB1*04 and *10 alleles were high in frequency (9.6% vs 14.2%, P = 0.038 and P = 0.042, respectively), and dependently on anti-citrullinated protein antibodies (ACPAs) seropositivity (P = 0.044 and P = 0.027, respectively). In contrast, the frequency of the HLADRB1* 07 allele was significantly low in patients than in controls (11.7% vs 5.0%, P = 0.010). Moreover, the HLA-DQB1*03 allele was strongly associated with RA risk (42.2%, P = 2.2x10-8), whereas, HLA-DQB1*02 and *06 showed protective effects against RA (23.1% and 42.2%, P = 0.024 and P = 2.2x10-6, respectively). Five different HLA haplotypes, DRB1*03-DQB1*03 (P = 0.00003), DRB1*04-DQB1*03 (P = 0.00014), DRB1*08-DQB1*03 (P = 0.027), DRB1*13-DQB1*02 (P = 0.004), and DRB1*13-DQB1*03 (P = 3.79x10-8) were significantly associated with RA risk, while 3 protective haplotypes, DRB1*03-DQB1*02 (Pc = 0.008), DRB1*07-DQB1*02 (Pc = 0.004), and DRB1*13-DQB1*06 (Pc = 0.02) were identified. This is the first study determining the association between HLA class II alleles and haplotypes and RA risk in our population. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is an autoimmune disorder associated with a chronic inflammation, which can cause joint damage and extra-articular complications. Anti-citrullinated protein antibody (ACPA) positivity is accompanied by poor prognosis in RA, and testing for ACPA has become traditional practice in the context of RA diagnosis. Objective: The aim of the study was to estimate the prevalence of low bone mineral density (BMD) among female patients with RA using dual energy x-ray absorptiometry (DEXA), and to study the correlation between BMD & levels of anti-cyclic citrullinated peptide (anti-CCP) and RF in the studied cases. Patients and methods: The present study was a cross-section descriptive study that was conducted on eighty female patients with RA. All patients were subjected to assessment to the levels of anti-CCP and RF using ELISA. BMD was measured by DEXA. Results: Osteopenia and Osteoporosis at lumbar spine, femoral neck and distal end of radius showed statistically significant increase in +ve anti-CCP patients when compared to -ve anti-CCP patients. BMD at the lumbar spine, femoral neck and lower end of radius showed statistically significant decrease in +ve anti-CCP patients when compared to -ve anti-CCP patients. History of fragility fracture showed statistically significant increase in RA patients with +ve RF when compared to -ve RF patients. Conclusion: Bone loss and fragility fracture are common in RA and increased in seropositive RA, post-menopausal state and corticosteroids use. The presence of ACPA and RF are strongly predictive for the development of osteoporosis and erosions in RA patients. It would be a more appropriate approach to carefully monitor osteoporosis in seropositive RA. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the Human Leukocyte Antigen (HLA) class II (DRB1 and DQB1) alleles and haplotype frequency in Rheumatoid Arthritis (RA) in the Sudanese population. The frequency of HLA-DRB1 and -DQB1 alleles and DRB1-DQB1 haplotypes were determined in 122 RA patients and 100 controls. HLA alleles were genotyped by the polymerase chain reaction-sequence specific primers (PCR-SSP) method. In RA patients, HLA-DRB1*04 and *10 alleles were high in frequency (9.6% vs 14.2%, P = 0.038 and P = 0.042, respectively), and dependently on anti-citrullinated protein antibodies (ACPAs) seropositivity (P = 0.044 and P = 0.027, respectively). In contrast, the frequency of the HLA-DRB1*07 allele was significantly low in patients than in controls (11.7% vs 5.0%, P = 0.010). Moreover, the HLA-DQB1*03 allele was strongly associated with RA risk (42.2%, P = 2.2x10-8), whereas, HLA-DQB1*02 and *06 showed protective effects against RA (23.1% and 42.2%, P = 0.024 and P = 2.2x10-6, respectively). Five different HLA haplotypes, DRB1*03-DQB1*03 (P = 0.00003), DRB1*04-DQB1*03 (P = 0.00014), DRB1*08-DQB1*03 (P = 0.027), DRB1*13-DQB1*02 (P = 0.004), and DRB1*13-DQB1*03 (P = 3.79x10-8) were significantly associated with RA risk, while 3 protective haplotypes, DRB1*03-DQB1*02 (Pc = 0.008), DRB1*07-DQB1*02 (Pc = 0.004), and DRB1*13-DQB1*06 (Pc = 0.02) were identified. This is the first study determining the association between HLA class II alleles and haplotypes and RA risk in our population.

Background: Posterior scleritis is a potentially vision threatening condition which is often underdiagnosed due to varied clinical presentation, several non-infectious inflammatory diseases can cause this disorder, although infectious diseases should be ruled out. Case presentation: A 56 years-old-female with acute unilateral decreased vision in right eye and positive history for rheumatoid arthritis (RA) was referred, based on ophthalmic examination the diagnosis of posterior scleritis was considered. The only positive inflammatory marker was found is high serum titer of Anti-Cyclic Citrullinated Peptide (Anti-CCP). Conclusion: This is the first case of posterior scleritis with only positive Anti-CCP. Elevated serum Anti-CCP titer may be considered as risk factor for inflammatory scleritis in patient with RA. [ABSTRACT FROM AUTHOR]

Abstract Background There is a need for biomarker to identify patients “at risk” for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers. Methods Using protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models. HnRNP-DL expression in cultivated cells and synovial tissue was analysed by indirect immunofluorescence, immunoblot and immunohistochemistry. Results HnRNP-DL was highly expressed in stress granules, citrullinated in the rheumatoid joint and targeted by autoantibodies either as native or citrullinated proteins in patient subsets with different developed RA disease. Structural citrullination dependent epitopes (SCEs) of hnRNP-DL were detected in 58% of the SLE patients although 98% of these sera were α-CCP-2-negative. To obtain a specific citrullinated signal value, we subtracted the native antibody value from the citrullinated signal. The citrullinated/native index of autoantibodies against hnRNP-DL (CNDL-Index) was identified as a new value for an “individual window of treatment success” in early RA and for the detection of RF IgM/α-CCP-2 seronegative RA patients (24–46%). Negative CNDL-index was found in SLE patients, risk-RA and early RA cohorts such as EIRA where the majority of these patients are DAS28-responders to methotrexate (MTX) treatment (87%). High positive CNDL-values were associated with more severe RA, shared epitope and parenchymal changes in the lung. Specifically, native α-hnRNP-DL is TLR7/9-dependent, associated with pain and ROC analysis revealed an association to initial MTX or etanercept treatment response, especially in seronegative RA patients. Conclusion CNDL-index defines people at risk to develop RA and the “window of treatment success” thereby closing the sensitivity gap in RA.

Rheumatoid arthritis (RA) is a multifactorial disease which can be triggered by gene-environment interactions. Numerous risk factors have been acknowledged in varied ethnicities, but their generalizability is vague. Hence, proposed to identify impact of etiology on citrullination and how both interact with peptidyl arginine deiminase 4 (PADI4) polymorphism in RA onset among South Indian Tamil RA cases. Studied 207 RA cases and 186 healthy controls for C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP), anti-Sa (citrullinated vimentin), anti-citrullinated α-enolase peptide-1 (CEP-1) and diseases activity score-28 (DAS-28). Past exposure to studied etiological risk factors obtained through questionnaire. Family history of RA (FHRA), surgery/injury and chikungunya virus (CHIKV) infection significantly contributed to RA (p < 0.05) particularly CHIKV (OR = 6.66, 95% CI 3.92-11.32, p = 0.001). Strikingly, 67.1% of surgery/injury and 80% of CHIKV exposed patients had RA onset within a year. RA cases with tooth decay had impact on RF, anti-CCP, anti-Sa freequeny and anti-CEP-1 level (p < 0.05).Since CHIKV infected cases showed significant anti-Sa (p = 0.04) level and frequency (p = 0.01), they were genotyped for polymorphism in PADI4_92 (rs874881), 104 (rs1748033) and 94 (rs2240340) by Sanger's sequencing which demonstrated that PADI4 confers risk (p < 0.05) for the onset of CHIKV induced RA. This is the initial report that CHIKV may contribute to RA development via vimentin citrullination. FHRA, surgery/injury, CHIKV and smoking posed a key RA risk. [ABSTRACT FROM AUTHOR]

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

Objective: Autoantibodies such as rheumatoid factor, anti-nuclear antibody, anti-Ro/SSA, and anti-La/SSB have an important role in the diagnosis of primary Sjogren’s syndrome (PSS), but are not essential in seronegative PSS when there is at least one focus in minor salivary gland biopsy. The aim of this study was to compare the clinical and serological differences between patients with seropositive and seronegative PSS. Materials and Methods: The study included 273 patients with PSS who were followed up at Kayseri City Training and Research Hospital, a tertiary hospital, between June 2018 and July 2021. The diagnosis of PSS was based on the 2016 American College of Rheumatology/European League Against Rheumatism PSS classification criteria. Autoantibodies were not detected in 45 (16.5%) patients, and they were evaluated as having seronegative PSS. Clinical and laboratory parameter data of all the patients were collected retrospectively from the hospital database, and compared between the patients with seronegative PSS and patients with seropositive PSS. Results: Females constituted 93.9% (n=214) of the seropositive group and 91.1% (n=41) of the seronegative group. The mean age at diagnosis was 47.87±9.07 years in the seropositive group and 44.34±11.48 years in the seronegative group (p=0.026). No statistically significant differences were determined between the groups in terms of sex distribution, clinical features, and the rate of patients with leukopenia, lymphopenia, thrombocytopenia, hypergammaglobulinemia, hypocomplementemia, and increased acute phase reactant. The median C4 value was lower, and the median IgG value was higher in the seropositive PSS group. Conclusion: Clinical findings in patients with seronegative PSS overlapped with those of patients with seropositive PSS, but diagnosis was made later in patients with seronegative PSS. [ABSTRACT FROM AUTHOR]

Background: RA is a systemic inflammatory condition characterized by chronic arthritis and often associated with irreversible joint damage. Objectives: To assess the significance of serum level of 14-3-3η in RA and its association with clinical and serological features of the disease. Methods: This is a case-control study done on 80 participants. They were divided into 2 groups. Group 1: 40 rheumatoid arthritis patients compared to group 2: 40 healthy participants matched for age and sex. Laboratory investigations including complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPAs), and serum 14-3-3η were done to all participants. Radiological examination in the form of plain X-ray for hands and feet was done to all patients. Results: Serum levels of 14-3-3η were significantly higher in RA patients compared to the control group (p < 0.001). Serum 14-3-3η was the only predictor of high Larsen's score (p = 0.013) on using linear regression analysis. Serum 14-3-3η can predict RA in healthy controls in univariate (p = 0.001) and multivariate (p = 0.004) analyses. The receiver operating characteristic (ROC) curve of 14-3-3η was constructed for discrimination between RA and control subjects. The best cut-off value was 61.9 ng/mL, with fair AUC (0.773, p < 0.001), 95% CI (0.656–0.889), and the sensitivity and specificity of 14-3-3η for RA diagnosis as 65% and 95% respectively. Also, we constructed ROC curves for RF, ACPA, 14-3-3η, and their combinations; we found that the highest test sensitivity of 95.7% appeared on adding the 3 markers together, and the highest test specificity of 100% was detected on adding RF to ACPA, 14-3-3η to ACPA or the 3 molecules together. Conclusion: 14-3-3η could be a valuable marker for the diagnosis of RA patients and it may have prognostic value. Key Points • 14–3-3η is a valuable marker for the diagnosis of RA patients. • 14–3-3η reflects disease severity and joint damage in RA patients. [ABSTRACT FROM AUTHOR]

Measurement of two groups of autoantibodies, rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) have gained increasing significance in the diagnosis and classification of rheumatoid arthritis (RA) over the last 65 years. Despite this rising importance of autoimmune serology in RA, there is a palpable lack of harmonization between different commercial RF and ACPA tests. While a minimal diagnostic specificity has been defined for RF tests, which almost always are related to an international reference preparation, neither of this applies to ACPA. Especially assays with low diagnostic specificity are associated with very low positive predictive values or post-test probabilities in real world settings. In this review we focus on issues of practical bearing for the clinical physician diagnosing patients who potentially have RA, or treating patients diagnosed with RA. We advocate that all clinically used assays for RF and ACPA should be aligned to a common diagnostic specificity of 98-99% compared to healthy controls. This high and rather narrow interval corresponds to the diagnostic specificity seen for many commercial ACPA tests, and represents a specificity that is higher than what is customary for most RF assays. Data on antibody occurrence harmonized in this way should be accompanied by test result-specific likelihood ratios for the target diagnosis RA on an ordinal or interval scale, which will provide the clinical physician with more granular and richer information than merely relating numerical values to a single cut-off point. As many physicians today are used to evaluate autoantibodies as positive or negative on a nominal scale, the introduction of test result-specific likelihood ratios will require a change in clinical mindset. We also discuss the use of autoantibodies to prognosticate future arthritis development in at-risk patients as well as predict severe disease course and outcome of pharmacological treatment.

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affect 1-2% of people worldwide. Inflammation is an important factor in the pathogenesis of RA. Anti- Cyclic Citrullinated Peptid (Anti-CCP) antibody and Rheumatoid Factor (RF) are autoantibodies that promotes inflammatory reactions and have a crucial role in RA pathogenesis. Treg cells are necessary for the maintenance of immune homeostasis and prevention of autoimmunity. FoxP3 is essential transcription factor for development of these regulatory cells. In this study, we surveyed the effects of FoxP3 gene expression in peripheral blood on plasma levels of Anti-CCP and RF. Methods: Peripheral blood samples were collected from 47 patients and 44 healthy subjects. Then plasma levels of Anti-CCP have been evaluated using ELISA method. Also RF was detected with latex agglutination test, and gene expression of FoxP3 analyzed by real time PCR . Results: The amount of Anti-CCP and RF were significantly higher in our patients in comparison with healthy subjects (P

Aim: To investigate anti‐cyclic citrullinated peptide (anti‐CCP) and rheumatoid factor (RF) in relation to ultrasound‐detected joint inflammation and bone erosion in patients with rheumatoid arthritis (RA) as previous studies have mainly utilized radiographic damage as imaging outcomes. Method: In this cross‐sectional study, patients were grouped based on their Disease Activity Score at 28 joints (DAS28 < 3.2, DAS28 ≥ 3.2). Ultrasound variables (power Doppler and gray scale joint inflammation graded 0‐3 semi‐quantitatively; bone erosion graded Yes = 1/No = 0 dichotomously) were correlated with antibodies levels using Pearson correlation. Simple linear regression was used to characterize relationships between variables. Receiver operating characteristic (ROC) analysis was performed to determine statistically optimal cut‐off values for identifying patient subgroups with ultrasound erosion scores >25th, >50th and >75th percentiles. Results: One thousand and eighty joints and 1800 joint recesses from 36 peripheral joint sites were scanned in 30 adult RA patients (mean disease duration, 70.3 months; 93.3% female; 93.3% anti‐CCP positive; 93.3% RF positive). In the DAS28 < 3.2 group, no significant correlations were found between antibody levels and ultrasound variables. In the DAS28 ≥ 3.2 group, anti‐CCP levels correlated significantly (r = 0.46, P =.048) and were predictive (P =.048) of ultrasound erosion scores. Area under the ROC curve based on cut‐off anti‐CCP level of ≥95.2 to identify patients with ultrasound erosion scores >7 (75th percentile) was 0.72 (sensitivity = 83.3%, specificity = 53.8%). Conclusion: The association of anti‐CCP and RF with joint damage appears to differ in RA. Among patients with at least moderate disease activity (DAS28 ≥ 3.2), anti‐CCP—but not RF—is associated with joint damage, being moderately correlated with ultrasound‐detected bone erosion. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is an autoimmune disorder that is highly prevalent, leading to gradual cartilage distraction, and therefore is important to diagnose in the early stage. This study aimed to estimate the level of rheumatoid factor (RF) and Anticitrullinated protein (Anti-ccp) in the serum of female patients. We also investigated several female reproductive hormones in the patients and compared their levels in the premenopausal and postmenopausal phases. The study included 88 female subjects, 50 suffering from signs of rheumatoid arthritis who were attending ALYarmouk teaching hospital, Baghdad, Iraq, and 38 without clinical signs of RA as a control group. The ELISA technique was used to estimate all the studied parameters. The results showed a significant elevation in the levels of RF (103.6 ± 227.0 vs. 22.1 ± 111.0 U/ml) and Anti-ccp (158.0 ± 170.0 vs. 0.51 ± 1.69 U/ml) in patient’s serum as compared to the control. The percentage of overweight and obese patients was higher than that of those with normal weight. Also, the current results showed significant differences in the serum concentrations of the reproductive hormones between the premenopausal and postmenopausal phases in the patients group. The level of FSH in postmenopausal female patients was higher than that in premenopausal ones (33.5 ± 17.9 vs. 9.01 ± 9.31 U/ml). Also, the level of luteinizing hormone (LH) in the postmenopausal patients was higher than that in the premenopausal patients (26.4 ± 12.3 vs. 12.7 ± 10.2 U/ml). While the level of prolactin (PRL) in RA postmenopausal female patients was lower than that in the premenopausal patients (8.60 ± 7.07 vs. 14.8 ± 10.6 ng/ml). In addition, the level of Anti-mullerian hormone (AMH) in post-menopausal patients was lower than that in the pre-menopausal ones (0.034 ± 0.023 vs. 0.635 ± 0.683 ng/ml). Finally, the concentration of estradiol (E2) in the post-menopausal female patients was lower than that in the pre-menopausal ones (32.9 ± 18.6 vs. 76.5 ± 43.6 ng/ml). [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) are small non-coding RNAs, whose role in regulating diverse immune functions, suggests they might play a role as biomarkers for immune mediated disorders. Studies showed that miRNA-146a (miR-146a) expression is increased by proinflammatory cytokines and is an important modulator of differentiation and function of cells of innate and adaptive immunity. Aim of the work: The current study aimed to evaluate the expression of miR-146a as a potential biomarker for diagnosis of rheumatoid arthritis (RA) and to explore its association with disease activity. Subjects and methods: The study enrolled 50 Egyptian subjects divided into a patient group, which comprised 25 RA patients, and a control group which comprised 25 healthy individuals. The disease activity for the patients’ group was determined by simplified disease activity index. Relative quantification of miR-146a expression in whole blood was determined using reverse transcriptase quantitative real time polymerase chain reaction. Results: There were highly significant statistical differences between patients and healthy controls as regards miR-146a relative expression, erythrocyte sedimentation rate (ESR) and anti-cyclic citrullinated peptide (anti-CCP) (p

Objects: Although the association of cigarette smoking (CS) with susceptibility to rheumatoid arthritis (RA) has been established, the impact of CS on anticitrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) levels in RA has yet been clear, especially in relation to shared epitope (SE) alleles.Methods: A total of 6239 subjects, the largest Asian study ever, from two independent Japanese cohorts were enrolled. Precise smoking histories, levels of ACPA and RF, and HLA-DRB1 allele status were withdrawn from databases. Associations between CS and high ACPA or RF levels, defined by the top quartiles, were evaluated. The effect of HLA-DRB1 alleles on the association was further investigated.Results: CS at RA onset conferred the risks of high levels of both antibodies, especially RF (OR 2.06, p=7.4×10-14; ACPA, OR 1.29, p=0.012), suggesting that RF level is more sensitive to CS than ACPA level. The patients who had quitted CS before RA onset showed a trend of decreased risks of developing high levels of ACPA or RF, and the risks steadily decreased according to the cessation years. The association of CS with high ACPA level was observed only in subjects carrying SE alleles, while the association of high RF level was observed regardless of SE.Conclusions: CS confers the risks of high autoantibody levels in RA in different manners; CS interacts with SE alleles on ACPA level, while CS impacts on RF level despite SE allele. These data suggest novel distinct production mechanisms of RF and ACPA. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic T cell-mediated autoimmune disease. Serum autoantibodies against cyclic citrullinated peptides (anti-CCP) are significant markers for diagnosis and prognosis of this disease. Induction of immune tolerance as therapeutic approach for RA constitutes a current research focal point. In this sense, we carried out a phase I clinical trial in RA patients with a new therapeutic candidate (called CIGB-814); which induced mechanisms associated with restoration of peripheral tolerance in preclinical studies. CIGB 814 is an altered peptide ligand (APL), derived from a CD4+ T cell epitope of human heat-shock protein 60 (HSP60), an autoantigen involved in the pathogenesis of RA. Twenty patients with moderate disease activity were included in this open label trial. Sequential dose-escalation of 1, 2.5 and 5 mg of CIGB-814 was studied. Consecutive groups of six, five, and nine patients received a subcutaneous dose weekly of the peptide during the first month and one dose monthly during the next 5 months. The peptide was well tolerated and reduced disease activity. Here, we reported the quantification of anti-CCP antibodies during the treatment with this APL and in the follow-up stage. Anti-CCP antibodies were quantified in the plasma from patients by a commercial enzyme immunoassay at baseline (T0) and at weeks 28 and 48. Results showed that CIGB-814 induced a significant reduction of anti-CCP antibodies. In addition, this decrease correlated with clinical improvement in patients assessed by Disease Activity Score in 28 joints (DAS28) criteria. These findings reinforce the therapeutic potential of CIGB-814. [ABSTRACT FROM AUTHOR]

Abstract Background The diagnosis of early rheumatoid arthritis (RA) is challenging. B-cell chemokine (CXCL13) plays a critical role in the disease pathogenesis. Aim of the work To assess the diagnostic value of serum CXCL13 in early RA and compare it with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Patients and methods The study included 60 RA patients; 30 early, 30 established RA and 30 healthy controls. The modified health assessment questionnaire (MHAQ), modified Sharp-van der Heijde score (MSS) and disease activity score (DAS28) were assessed in RA patients. RF, anti-CCP and serum level of CXCL13 were measured. Results Patients had a mean age of 39 ± 7.4 years and disease duration of 4.4 ± 5.7 years; they were 46 females and 12 males (F:M 3.8:1). Serum CXCL13 was significantly higher in early (191.7 ± 74.4 pg/ml) compared to established (136.4 ± 79 pg/ml) RA (p = 0.007) which were not observed with RF and anti-CCP; both were higher than in control (30.4 ± 13.5 pg/ml) (p < 0.001). In early RA, the frequencies of CXCL13, RF and anti-CCP positivity were 90%, 73.3% and 56.7% while in the established cases the frequencies were 36.7%, 66.7% and 63.3% respectively. CXCL13 significantly correlated with DAS28 (early: 0.49, p = 0.006; established: r = 0.38, p = 0.04) but not with MHAQ or MSS. The CXCL13 significantly correlated with both the RF and anti-CCP in both early and established cases (p < 0.001). Conclusion CXCL13 is an important for the diagnosis of early RA with a superior diagnostic performance compared to RF and anti-CCP. It may also be considered a potential biomarker of disease activity. [ABSTRACT FROM AUTHOR]

Purpose: A retrospective comparison of the prevalence and diagnostic value of anti-Sa, anti-CEP-1, and anti-MCV autoantibodies relative to those of the established autoantibodies, composite RF and anti-CCP-IgG used routinely for RA diagnosis as a component of the ACR 2010 criteria, in a cohort of disease-modifying anti-rheumatic drug naïve African RA patients (n = 75).Methods: Serum concentrations of anti-Sa, anti-CEP-1 and anti-MCV autoantibodies were measured using ELISA procedures, while anti-CCP-IgG antibodies were determined by fluorescence enzyme immunoassay, and composite RF by latex-enhanced laser nephelometry.Results: The seropositivity frequencies of anti-Sa, anti-CEP-1 and anti-MCV antibodies for the RA patients were 82, 72, 85%, respectively, while that of anti-CCP-IgG and RF was 87% for both. Overall, anti-MCV demonstrated the best specificity, positive predictive value (PPV), odds ratio and positive likelihood ratio of all the types of autoantibody tested.Conclusion: These observations in this unique cohort of RA patients indicated novel associations of all three autoantibodies in regard to HLA-SE risk alleles, disease severity and tobacco use that were not reported before. Elevated anti-Sa titers designated a propensity of higher disease and high-risk alleles in our cohort. Anti-CEP-1 association with HLA-SE homozygosity and high-risk alleles is also novel in this group. Of note, measurement of anti-MCV antibodies on presentation, either as an adjunctive or even as a stand-alone test, surpassed all other biomarkers investigated here and, therefore, may add value to clinical management. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate association of protein tyrosine phosphatase non-receptor type 22 (PTPN22) rs2476601 and signal transducer and activator of transcription 4 (STAT4) rs7574865 polymorphisms with rheumatoid arthritis (RA) susceptibility and to assess potential association with the status of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, serum neopterin, and disease activity. RF, anti-CCP antibodies, and neopterin were assayed in serum of 100 unrelated RA patients and 114 controls. STAT4 rs7574865 G/T and PTPN22 rs2476601 C/T polymorphisms were genotyped by the TaqMan allelic discrimination method. The frequency of STAT4 variant allele was significantly higher in RA patients than in controls ( p = 0.01), while the variant allele of PTPN22 was identified in only two RA patients, in a heterozygous form and in none of control subjects. The frequency of STAT4 variant allele carrier genotypes (GT+TT) was significantly higher among RA patients than in controls (43.7 vs. 10.5%, p = 0.02) and associated with RA under additive and dominant models. The frequency of RF and anti-CCP positivity was significantly higher among RA patients carrying T allele genotypes compared to patients carrying wild genotype ( P = 0.02 and 0.04, respectively). No significant associations between STAT4 variant and serum neopterin or disease activity parameters were identified. Our study confirmed the association of STAT4 rs7574865 polymorphism with RA and was the first to indicate an association with RF and anti-CCP antibodies positivity. We also found PTPN22 rs2476601 has no role in susceptibility to RA in Egyptian patients. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) are small non-coding RNAs, whose role in regulating diverse immune functions, suggests they might play a role as biomarkers for immune mediated disorders. Studies showed that miRNA-146a (miR-146a) expression is increased by proinflammatory cytokines and is an important modulator of differentiation and function of cells of innate and adaptive immunity. Aim of the work: The current study aimed to evaluate the expression of miR-146a as a potential biomarker for diagnosis of rheumatoid arthritis (RA) and to explore its association with disease activity. Subjects and methods: The study enrolled 50 Egyptian subjects divided into a patient group, which comprised 25 RA patients, and a control group which comprised 25 healthy individuals. The disease activity for the patients' group was determined by simplified disease activity index. Relative quantification of miR-146a expression in whole blood was determined using reverse transcriptase quantitative real time polymerase chain reaction. Results: There were highly significant statistical differences between patients and healthy controls as regards miR-146a relative expression, erythrocyte sedimentation rate (ESR) and anticyclic citrullinated peptide (anti-CCP) (p< 0.001). Highly significant statistical differences (p< 0.001) were also found between different patients' subgroups as regards miR-146a relative expression and ESR. miR-146a levels correlated positively with those of ESR, C-reactive protein and anti-CCP (p< 0.001). miR-146a illustrated best performance in diagnosing RA, showing the highest sensitivity and specificity (96% and 100%, respectively) (AUC: 0.992 at a cut off value of P2.16) compared to anti-CCP (sensitivity: 68%, specificity: 100% and AUC: 0.87 at a cut off value of P22 U/ml) and RF (sensitivity: 56%, specificity: 80% and AUC: 0.992 at a cut off value of P13 U/ml). [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction. Serologically, it can be differentiated according to rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (anti-CCP), or both. This differentiation is prognostically and therapeutically relevant. No method has been described to separate the two forms phenotypically. We hypothesize that a differentiation is possible by evaluating oscillation patterns in power Doppler sonography (PDS). In a prospective study, 20 patients with anti-CCP-positive RA and 20 patients with anti-CCP-negative RA with active wrist synovitis were examined. A PDS scan was performed, and perfusion maxima ( P ) and minima ( P ) as well as the amplitude (Δ P) were determined by a blinded study member. The amplitude was standardized (sΔ P) by dividing by P , and the anti-CCP-positive and anti-CCP-negative patients as well as the RF-positive and RF-negative were compared to each other. In the ultrasonographic evaluation, we found a highly significant difference in sΔ P between CCPp and CCPn patients (median 19.0 vs. 42.9 %, p < 0.0001). sΔ P is independent of disease activity. The absolute amplitude Δ P did not differ between the groups. Also, in anti-CCP-positive patients there was a completely linear correlation between P and P , and this was far less marked in anti-CCP-negative patients. Anti-CCP-positive and anti-CCP-negative RA display different PDS oscillation patterns. This constitutes a nonserological parameter to differentiate between the two forms. The difference in PDS oscillation patterns suggests that the underlying pathological process differs between the forms. [ABSTRACT FROM AUTHOR]

Background and Objective: Rheumatoid arthritis (RA) is a systemic and chronic disease. Anticitrulinated anticyclic antibody (Anti-CCP) and rheumatoid factor (RF) are applied for the diagnosis of rheumatoid arthritis. This study was designed to evaluate the diagnostic value of anticitrulinated cyclic antibody and rheumatoid factor in rheumatoid arthritis patients. Materials and Methods: This laboratory study was done on 238 affected RF patients and 152 RF symptom free subjects in Gorgan, Iran. Anti-CCP and RF were measured by ELISA and Latex agglutination. Results: Out of 238 patients with rheumatoid arthritis Anti-CCP test was positive in 196 patients, and the sensivity was 82%. In control group, Anti-CCP was positive in 5 cases, and the specificity for RA was 96%. RF test was positive in 206 patients and sensitivity for RF in rheumatoid factor was 86%. In control group, RF was positive in 28 cases and specificity was 81%. Positive RF and Anti-CCP (simultaneously) showed sensitivity as 89%. Conclusion: The specificity of CCP is higher than RF and therefore can be substituted as diagnosis of rheumatoid factor.

A artrite reumatóide (AR) é uma doença crônica inflamatória, caracterizada pela produção de auto-anticorpos e participação do endotélio vascular em sua patogênese. OBJETIVOS: Analisar a correlação da molécula de adesão intercelular (ICAM-1), o fator de von Willebrand (vWF), o fator reumatóide (FR) e o anticorpo antipeptídeo citrulinado cíclico (anti-CCP) com parâmetros de atividade clínica, laboratorial e alterações radiológicas da AR. MÉTODOS: Em 38 pacientes e 24 indivíduos que não apresentavam artrite reumatóide foram dosados FR, anti-CCP, vWF e ICAM-1 no soro. A atividade da doença foi definida pelo escore do DAS-28. O Health Assessment Questionnaire (HAQ) definiu a capacidade funcional, e os critérios revisados do American College of Rheumatology, a classe funcional. Radiografias de mãos e punhos quantificaram o índice de Sharp modificado. RESULTADOS: A idade dos pacientes foi de 52 ± 12,5 anos e dos indivíduos que não apresentavam artrite reumatóide, de 49 ± 9,4 anos. O tempo de doença foi de 68 ± 66,6 meses. O vWF apresentou correlação significativa com o tempo de evolução da doença. Os auto-anticorpos tiveram correlação significativa com o índice de Sharp. A correlação do vWF e a ICAM-1 foi significativa com o DAS-28, mas apenas o vWF se correlacionou com o HAQ e com índice de Sharp. CONCLUSÃO: Esse estudo demonstrou que os auto-anticorpos não estão correlacionados com a atividade da doença, mas com seu prognóstico e sua gravidade por meio da relação destes com o índice de Sharp. O vWF apresentou correlação significativa com os parâmetros de atividade e gravidade da doença.Rheumatoid arthritis (RA) is an inflammatory chronic disease characterized by the production of antibodies and participation of the vascular endothelium in its pathogenesis. OBJECTIVES: to analyze the correlation of serum levels of the intercellular adhesion molecule 1 (ICAM-1), von Willebrand factor (vWF), Rheumatoid factor (RF), and anti-cyclic citrulinated peptide (anti-CCP) with clinical, laboratory, and radiological parameters of RA. METHODS: Serum levels of ICAM-1, vWF, RF, and anti-CCP were measured in 38 RA patients and 24 controls. Disease activity was measured by the DAS-28 score and functional capa-city was assessed using the HAQ score. The American College of Rheumatism criteria defined the functional class. Hand and fist X-rays were analyzed using the Sharp's score. Statistical analysis utilized the chi-square, Student's "t", Kolmogorov-Smirnov, and Mann-Whitney tests, as appropriate, as well as the Spearman's correlation coefficient. RESULTS: Age range was from 52 ± 12.5 and 49 ± 9.4 years-old in RA and controls, respectively. Disease duration range was 68 ± 66.6 months. Serum vWF levels had a positive significant correlation to disease evolution, whereas RF and anti-CCP correlated to the Sharp score. Serum vWF and ICAM-1 levels correlated to DAS-28, while only vWF correlated with HAQ and Sharp scores. CONCLUSION: This study shows that RF and anti-CCP autoantibody levels are correlated to disease prognosis rather than activity. Serum vWF levels are positively correlated to both activity and severity parameters of the disease.

OBJETIVOS: Avaliar a associação do anticorpo antipeptídeo citrulinado cíclico (anti-CCP) com distintos parâmetros clínicos, sorológicos e radiológicos. MÉTODOS: Anti-CCP e fator reumatóide (FR) foram pesquisados no soro de 100 pacientes com artrite reumatóide (AR). A atividade da doença foi definida por meio de um índice combinado compreendendo cinco parâmetros: número de juntas inflamadas, número de juntas doloridas, rigidez matinal, escala visual analógica (EVA) de dor e velocidade de hemossedimentação (VHS). A capacidade funcional foi medida pelo índice HAQ (Health Assessment Questionnaire) e a classe funcional foi determinada mediante aplicação dos critérios revisados do American College of Rheumatology (ACR), de 1991. Erosão e pinçamento articular foram graduados pelo índice de Sharp modificado. A análise estatística empregou os testes do Qui-quadrado, Mann Whitney e Kruskal-Wallis. RESULTADOS: Nenhum dos dois anticorpos demonstrou associação significativa com atividade da doença, sexo, idade de início da doença, presença de nódulos subcutâneos e síndrome de Sjögren. A média de idade foi significativamente menor nos pacientes com AR anti-CCP positivos. A positividade para o FR e anti-CCP foi maior nos pacientes com AR com menos de 50 anos em comparação com os pacientes com mais de 50 anos. A AR de início recente (< 2 anos) não se associou a uma maior prevalência de soropositividade para o anti-CCP e FR. O anti-CCP apresentou uma correlação positiva moderada com o FR. Houve uma correlação direta entre o anti-CCP e a VHS e a proteína C reativa (PCR). Houve também uma correlação direta entre o FR, a VHS e a PCR. A classificação funcional dos critérios revisados do ACR de 1991 não se associou a qualquer dos dois auto-anticorpos. O índice de HAQ não se correlacionou com a atividade da doença, duração da doença, positividade do FR e atividade medida pela PCR, mas associou-se nitidamente à positividade do anti-CCP e à atividade medida pelo VHS. Os índices de Sharp para erosão e pinçamento se associaram à positividade do anti-CCP. Tal associação não foi evidenciada com a positividade do FR. CONCLUSÃO: Embora o anti-CCP apresente boas propriedades diagnósticas, ele não apresenta associação com a atividade da doença, sexo, idade de início da doença, tempo de evolução de doença, presença de nódulos subcutâneos, síndrome de Sjögren ou classificação funcional do ACR de 1991. Houve associação da positividade do anti-CCP com a menor idade dos pacientes, fator reumatóide, VHS, PCR, índice de HAQ e índices de Sharp para erosão e pinçamento.OBJECTIVE: Evaluate the association of Anti-Cyclic Citrullinated Peptide Antibody (anti-CCP) with distinct clinic, serological and radiological parameters. METHODS: anti-CCP and rheumatoid factor (RF) were determined in the serum of 100 patients with rheumatoid arthritis (RA). Disease activity was defined by means of a combined index with five parameters: number of swollen joints, number of painful joints, morning stiffness, pain visual analogue scale (VAS), and erythrocyte sedimentation rate (ESR). Functional capacity was measured by (Health Assessment Questionnaire) HAQ index and the functional class was ascribed according to American College of Rheumatology criteria (1991). Articular erosion and narrowing were estimated by the modified Sharp's index. Statistical analysis was performed by chi-square, Mann-Whitney, and Kruskal-Wallis tests. A value of less 0.05 was considered significant. RESULTS: None of the two antibodies showed association with disease flare, gender, age in the time of diagnosis, secondary Sjögren's syndrome or subcutaneous nodules. The mean age was significantly lower in RA patients with positive anti-CCP. The RF and anti-CCP positivity was higher in RA patients below 50 years old than patients above 50 years old. The early RA, up to 2 years of evolution, was not associated with a higher prevalence of anti-CCP and RF reactivity. Anti-CCP showed direct moderate correlation to RF and also direct correlation to ESR and CRP. FR reactivity showed direct correlation to ESR and CRP. Functional class showed no association with neither autoantibodies. HAQ index showed correlation with anti-CCP-positive patients and activity assessed by ESR, but did not show association with disease activity, disease duration, presence of the RF and activity assessed by ESR. Sharp's erosion and narrowing index showed association to presence of anti-CCP, but not with RF positive patients. CONCLUSIONS: Although anti-CCP displays good diagnosis properties for RA, it appears not to be associated with activity disease, gender, age at the disease beginning, disease evolution, presence of the secondary Sjögren's syndrome and subcutaneous nodules or functional class. Anti-CCP reactivity showed association with early patients, RF positivity, ESR, CRP, HAQ index or Sharp'erosion and narrowing index.

In this study we determined the frequency, sensitivity and specificity of anti cyclic citrullinated peptides (anti-CCP) IgG antibody, total rheumatoid factor (RF-T), and RF isotypes in Iranian patients with rheumatoid arthritis (RA) and their association with age, clinical and serological parameters. Anti-CCP and RF-T and RF isotypes level were measured in 418 patients and 399 healthy controls by enzyme-linked immunosurbant assay (ELISA). Additionally, serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), visual analog scale (VAS) and disease activity score (DAS28) were evaluated in RA patients. The anti-CCP was positive in 53.1% of RA patients and 4.7% of controls. The frequency of RF-T was 61.87% and 17.66% in RA patients and controls respectively. The prevalence of RF isotypes in RA patients was 46.52% for RF-IgM, 23.47% for RF-IgA and 21.74% for RF-IgG. 31.39% of RA patients were RF-IgM positive without RF-IgA and RF-IgG and 21.9% were positive for all three RF classes. The anti-CCP positive patients showed increased number of swollen joints. On the other hand, RF-T positive patients exhibited a longer disease duration, lower age of onset and also higher ESR, CRP level and increased swollen joints. RF-T titer was significantly higher in RA patients with active disease compared to remission, low and moderate active groups. The sensitivity and specificity were 53.1, 95.3 for anti-CCP antibody and 61.8, 82.3 for RF-T. Our results support that anti-CCP and RF titer maybe valuable in estimation of disease activity and other inflammatory parameters in RA patients.

Currently the markers for the diagnosis of rheumatoid arthritis include inflammatory makers (including blood sedimentation and C-reactive protein), immune complexe and complement detection, detection of joint synovial fluid, and detection of autoantibodies. These indicators change with the activity of arthritis. Early diagnosis relies mainly on detection of autoantibodies. Anti-cyclic citrullinated peptide antibody (anti-CCP) is a kind of anti-keratin antibody, having higher sensitivity and specificity than the rheumatoid factor in diagnosis of rheumatoid arthritis. During the first year of rheumatoid arthritis, the existence of anti-CCP can be detected in the serum of most of these people. Positive anti-CCP can also be used to predict serious damage. Therefore, anti-CCP is extremely helpful in early diagnosis and prognosis assessment of rheumatoid arthritis. In this paper, the recent application of anti-CCP in the diagnosis of rheumatoid arthritis is reviewed. [ABSTRACT FROM AUTHOR]

Background Early appearance of antibodies specific for native human type II collagen (anti-CII) characterizes an early inflammatory and destructive phenotype in adults with rheumatoid arthritis (RA). The objective of this study was to investigate the occurrence of anti-CII, IgM RF, IgA RF and anti-CCP in serum samples obtained early after diagnosis, and to relate the occurrence of autoantibodies to outcome after eight years of disease in children with juvenile idiopathic arthritis (JIA). Methods The Nordic JIA database prospectively included JIA patients followed for eight years with data on remission and joint damage. From this database, serum samples collected from 192 patients, at a median of four months after disease onset, were analysed for IgG anti-CII, IgM RF, IgA RF and IgG anti-CCP. Joint damage was assessed based on Juvenile Arthritis Damage Index for Articular damage (JADI-A), a validated clinical instrument for joint damage. Results Elevated serum levels of anti-CII occurred in 3.1 %, IgM RF in 3.6 %, IgA RF in 3.1 % and anti-CCP in 2.6 % of the patients. Occurrence of RF and anti-CCP did to some extent overlap, but rarely with anti-CII. The polyarticular and oligoarticular extended categories were overrepresented in patients with two or more autoantibodies. Anti-CII occurred in younger children, usually without overlap with the other autoantibodies and was associated with high levels of C-reactive protein (CRP) early in the disease course. All four autoantibodies were significantly associated with joint damage, but not with active disease at the eight-year follow up. Conclusions Anti-CII, anti-CCP, IgA RF and IgM RF detected early in the disease course predicted joint damage when assessed after eight years of disease. The role of anti-CII in JIA should be further studied. [ABSTRACT FROM AUTHOR]

In this study we determined the frequency, sensitivity and specificity of anti cyclic citrullinated peptides (anti-CCP) IgG antibody, total rheumatoid factor (RF-T), and RF isotypes in Iranian patients with rheumatoid arthritis (RA) and their association with age, clinical and serological parameters. Anti-CCP and RF-T and RF isotypes level were measured in 418 patients and 399 healthy controls by enzyme-linked immunosurbant assay (ELISA). Additionally, serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), visual analog scale (VAS) and disease activity score (DAS28) were evaluated in RA patients. The anti-CCP was positive in 53.1% of RA patients and 4.7% of controls. The frequency of RF-T was 61.87% and 17.66% in RA patients and controls respectively. The prevalence of RF isotypes in RA patients was 46.52% for RF-IgM, 23.47% for RF-IgA and 21.74% for RF-IgG. 31.39% of RA patients were RF-IgM positive without RF-IgA and RF-IgG and 21.9% were positive for all three RF classes. The anti-CCP positive patients showed increased number of swollen joints. On the other hand, RF-T positive patients exhibited a longer disease duration, lower age of onset and also higher ESR, CRP level and increased swollen joints. RF-T titer was significantly higher in RA patients with active disease compared to remission, low and moderate active groups. The sensitivity and specificity were 53.1, 95.3 for anti-CCP antibody and 61.8, 82.3 for RF-T. Our results support that anti-CCP and RF titer maybe valuable in estimation of disease activity and other inflammatory parameters in RA patients. [ABSTRACT FROM AUTHOR]

Introduction The anti-cyclic citrullinated peptide (anti-CCP) enzyme-linked immunosorbent assay has a high sensitivity and specificity for rheumatoid arthritis (RA). It has been used in especially early diagnosis of RA, and used to discriminate from other forms of arthritis. Anti-CCP positivity is unknown in brucellosis presented with peripheric arthritis (BPA), like other rheumatic diseases. The objective of this study was to investigate the positivity of anti-CCP in patients with BPA in contrast to the patients with RA and healthy controls. Additionally, we have aimed to monitor changes of anti-CCP levels following the brucellosis treatment. Methods The study group consisted of 137 subjects. 62 brucellosis patients presented with peripheric arthritis. Additionally, 33 RA patients and 42 healthy subjects selected as control groups. The anti-CCP, rheumatoid factor and anti-nuclear antibody levels of the subjects were measured. Results Concerning the 62 BPA, 20 % (13 patients) of them had elevated anti-CCP levels. On the other side, of the 33 RA patients, 78.78 % (26 patients) of them had increased anti-CCP levels. Only one healthy subject's anti-CCP level was positive. There was statistically significant difference among the groups. After brucellosis treatment, monitorisation of the 13 patients with BPA who have the positive anti-CCP levels, were challengingly interesting because none of the patients had positive anti-CCP levels. Conclusions Anti-CCP may be positive marker in the diagnosis of BPA but clinicians need to be careful during the follow up period because it may turn into normal ranges. Additionally, patients presented with peripheric arthritis and anti-CCP positivity need to be evaluated also for the differential diagnosis of BPA. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an inflammatory multisystem disease of unknown etiology characterized by chronic destructive synovitis. It's prevalence is about 1% all over the world. Serologic markers are also important beside some clinical situations upon RA diagnosis. Today, the most commonly used laboratory test is rheumatoid factor (RF) in patients with suspected RA. RF is sensitive but not a specific biomarker for diagnosing RA. Early diagnosis of RA is essential to prevent of progressive joint damage. In recent years, anticyclic citrullinated peptide/protein antibody (anti-CCP) attracts the attention as a remarkable biomarker for early diagnosis. Anti-CCP which is a family of anti-citrullinated protein antibodies (ACPA) family, showed quite satisfactory specificity in the diagnosis of RA. Due to the prescence of ACPA was included to 2010 RA diagnostic criteria, in a manner of speaking, importance of anti-CCP was registered. [ABSTRACT FROM AUTHOR]

Objectives: Anti-cyclic citrullinated peptide (CCP) antibody has recently been used in the classification of rheumatoid arthritis (RA). This antibody is more specific than rheumatoid factor (RF) for the diagnosis of RA. The study objectives were to determine the sensitivity, specificity, positive and negative predictive values of anti-CCP in RA diagnosis. Methodology: Eighty RA patients and 80 non-RA individuals were included in the study. Blood was collected from both arms of study subjects and tested for anti-CCP and RF antibodies. Relevant clinical information and laboratory profiles of the RA patients were evaluated using patients' medical records and Integrated Laboratory Management System (ILMS), respectively. Results: The sensitivity and specificity of anti-CCP were 35% and 100% respectively. The positive and negative predictive values were 100% and 61%, respectively. Positive anti-CCP was found significantly associated with multiple joint pain (p < 0.001) and hand's joints pain (p=0.01), symmetrical joints involvement (p=0.015) and high CRP value (p < 0.001). Anti-CCP was also found to have positive association with RF (p < 0.001). Conclusion: Anti-CCP is highly specific for the diagnosis of RA. High positive predictive value should be taken into consideration for effective treatment. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the associations between human leukocyte antigen (HLA)-DRB1 alleles with genetic susceptibility to rheumatoid arthritis (RA) and production of antibodies against cyclic citrullinated peptide (anti-CCP antibody) and rheumatoid factor (RF) in Turkish RA patients. Methods: We studied 291 RA patients and 253 controls. Genotyping was performed by polymerase chain reaction with sequence-specific oligonucleotide probes hybridization method. Serum levels of anti-CCP antibody, IgM-RF and high sensitive C-reactive protein titers were measured by commercial kits using immunological methods. Results: We found that HLA-DRB1*04 and *09 alleles were associated in anti-CCP+ and anti-CCP+ RA patients ( P < 0.0001 and P < 0.001, respectively), while DRB1*01 and *04 were determined to be higher in RF+ RA patients ( P < 0.001 and P < 0.0001, respectively). Moreover, DRB1*11 and DRB1*13 alleles were determined to be lower in RF and anti-CCP/RF+ RA patients ( P < 0.001 for both). HLA-DRB1*04 was identified as a common responsible allele for susceptibility to the disease in anti-CCP, RF and anti-CCP/RF− RA patients ( P = 0.0018, P = 0.0004 and P = 0.0023, respectively). HLA-DRB1*13 allele alone was found to be protective against to anti-CCP+ and RF− RA ( P = 0.0003 and P = 0.006, respectively). On the contrary, there was no protective allele in anti-CCP/RF− RA as well as anti-CCP− RA patients. Conclusion: This study indicates that associate and protective HLA-DRB1 allele distributions are different in autoantibody (anti-CCP or RF or anti-CCP/RF)+ RA and autoantibody− RA patients, with exceptions of DRB1*04 and DRB1*13. [ABSTRACT FROM AUTHOR]

Autoantibodies in early rheumatoid arthritis (RA) have important diagnostic value. The association between the presence of autoantibodies against cyclic citrullinated peptide and the response to treatment is controversial. To prospectively evaluate a cohort of patients with early rheumatoid arthritis (<12 months of symptoms) in order to determine the association between serological markers (rheumatoid factor (RF), anti-citrullinated protein antibodies) such as anti-cyclic citrullinated peptide antibodies (anti-CCP) and citrullinated anti-vimentin (anti-Sa) with the occurrence of clinical remission, forty patients diagnosed with early RA at the time of diagnosis were evaluated and followed for 3 years, in use of standardized therapeutic treatment. Demographic and clinical data were recorded, disease activity score 28 (DAS 28), as well as serology tests (ELISA) for RF (IgM, IgG, and IgA), anti-CCP (CCP2, CCP3, and CCP3.1) and anti-Sa in the initial evaluation and at 3, 6, 12, 18, 24, and 36 months of follow-up. The outcome evaluated was the percentage of patients with clinical remission, which was defined by DAS 28 lower than 2.6. Comparisons were made through the Student t test, mixed-effects regression analysis, and analysis of variance (significance level of 5%). The mean age was 45 years, and a female predominance was observed (90%). At the time of diagnosis, RF was observed in 50% of cases (RF IgA-42%, RF IgG-30%, and RF IgM-50%), anti-CCP in 50% (no difference between CCP2, CCP3, and CCP3.1) and anti-Sa in 10%. After 3 years, no change in the RF prevalence and anti-CCP was observed, but the anti-Sa increased to 17.5% ( P = 0.001). The percentage of patients in remission, low, moderate, and intense disease activity, according to the DAS 28, was of 0, 0, 7.5, and 92.5% (initial evaluation) and 22.5, 7.5, 32.5, and 37.5% (after 3 years). There were no associations of the presence of autoantibodies in baseline evaluation and in serial analysis with the percentage of clinical remission during follow-up of 3 years The presence of autoantibodies in early RA has no predictive value for clinical remission in early RA. [ABSTRACT FROM AUTHOR]

Abstract: Sjögren Syndrome (SS) is a systemic, autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands. Different clinical associations have been described for each of the diverse autoantibodies found in SS patients. Antibodies directed against the Ro/La ribonucleoprotein complexes have been correlated with younger age, more severe dysfunction of the exocrine glands and a higher prevalence of extraglandular manifestations. Anti-nuclear antibodies and rheumatoid factors have been associated to extraglandular manifestations and an active immunological profile, while cryoglobulins are markers of more severe disease and correlate to lymphoma development and death. Antibodies to cyclic citrullinated peptides are scarce in SS and have been linked in some cases to the development of non-erosive arthritis. Furthermore, the presence of anti-mitochondrial antibodies and anti-smooth muscle antibodies in the sera of primary SS patients is considered indicative of primary biliary cirrhosis and autoimmune hepatitis, respectively. In addition, anti-centromere antibodies have been associated with a clinical phenotype intermediate between primary SS and systemic sclerosis, while antibodies against carbonic anhydrase have been related to renal tubular acidosis. Finally, an association of anti-muscarinic antibodies with cytopenias and a higher disease activity has also been described in primary SS. In conclusion, although not all of the above mentioned antibodies are useful for predicting distinct patient subgroups in SS, knowledge of the clinical associations of the different autoantibody specificities encountered in SS can advance our understanding of the disease and improve patient management. [Copyright &y& Elsevier]

Background: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis specified by some antibodies. Although the most relevant antibody is rheumatoid factor (RF), it has little sensitivity and specificity for diagnosis of RA. Other groups of antibodies that are produced against the citrullinated epitopes have been proved to be more specific for diagnosing RA. Anti-CCP testing based on ELISA assay is the most effective test for detecting anti-filaggrin antibodies. Positive values of anti-CCP antibody a few years before the clinical signs and symptoms of RA along with high concentrations of this antibody in the synovial fluid increase the probability of citrollination in the pathogenesis of the disease. A combination of anti-CCP and RF would increase the sensitivity of both tests. Most previous studies have used RF as a gold standard for evaluating the diagnostic value of anti-CCP. However, RF is known to have a low sensitivity and specificity. Therefore, we decided to realistically evaluate the diagnostic value of anti-CCP based on American college of rheumatology (ACR) criteria as a gold standard. Methods This was a descriptive study to evaluate the diagnostic value on 49 RA patients and 49 individuals with other rheumatic diseases. Blood samples were taken to measure erythrocyte sedimentation rate (ESR), RF, anti-CCP. Disease activity was then determined by DAS28. Data analysis was performed by 2 × 2 tables, chi-square test and receiver operating characteristic (ROC) curve for trade-off points. We used SPSS15. Findings: Data analysis showed anti-CCP to have a sensitivity of 71%, a specificity of 80%, a positive predictive value of 78%, a negative predictive value of 74%, a positive likelihood ratio of 3.55 and a negative likelihood ratio of 0.36. In this study, anti-CCP and RF had a statistically significant correlation (P < 0.001). Conclusion: Anti-CCP is a test with a high predictive value for diagnosing RA. [ABSTRACT FROM AUTHOR]