Anti-citrullinated Protein Antibodies Positive Patients Research Articles

Prognostic value of serum protein electrophoresis constituents for arthritis development in anti-citrullinated protein antibody-positive patients with musculoskeletal pain

Objective Predictors of arthritis development in patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms are needed for risk stratification and to improve clinical outcomes. The aim of this study was to assess the relationship between serum protein electrophoresis (SPE) constituents and the development of clinical arthritis in ACPA-positive patients with musculoskeletal pain. Method We prospectively followed 82 ACPA-positive patients with musculoskeletal pain but no baseline arthritis during a median of 72 months (interquartile range 57–81 months). The primary outcome was arthritis development, as judged by clinical examination. SPE constituents were evaluated in baseline sera by immunoturbidimetric methods. Serum levels of the analysed proteins (albumin, orosomucoid, α1-anti-trypsin, haptoglobin, and immunoglobulins IgA, IgG, and IgM) were related to arthritis development by Cox regression analyses. Results During the follow-up period, 39/82 patients (48%) progressed to arthritis. Median baseline levels of orosomucoid and α1-anti-trypsin were higher in patients who developed arthritis than in those who did not (p = 0.04), while median albumin levels were significantly lower (p = 0.03). Immunoglobulin levels did not differ between the groups. Univariable analysis demonstrated a significantly increased risk of arthritis with elevated baseline haptoglobin [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.32–4.85, p = 0.005] and orosomucoid levels (HR 2.63, 95% CI 1.09–6.31, p = 0.03). However, neither remained significant in multivariable analysis adjusting for elevated C-reactive protein (CRP) levels. Conclusion SPE does not add prognostic value for arthritis development in ACPA-positive patients with musculoskeletal pain.

The trajectory of clinical responses in patients with early rheumatoid arthritis who achieve sustained remission in response to abatacept: subanalysis of AVERT-2, a randomized phase IIIb study

BackgroundAVERT-2 (a phase IIIb, two-stage study) evaluated abatacept + methotrexate versus methotrexate alone, in methotrexate-naive, anti-citrullinated protein antibody-positive patients with early (≤ 6 months), active RA. This subanalysis investigated whether individual patients who achieved the week 24 Simplified Disease Activity Index (SDAI) remission primary endpoint could sustain remission to 1 year and then maintain it following changes in therapy.MethodsDuring the 56-week induction period (IP), patients were randomized to weekly subcutaneous abatacept 125 mg + methotrexate or abatacept placebo + methotrexate. Patients completing the IP who achieved SDAI remission (≤ 3.3) at weeks 40 and 52 entered a 48-week de-escalation (DE) period. Patients treated with abatacept + methotrexate were re-randomized to continue weekly abatacept + methotrexate, or de-escalate and then withdraw abatacept (after 24 weeks), or receive abatacept monotherapy. Proportions of patients achieving sustained SDAI and Boolean remission, and Disease Activity Score in 28 joints using C-reactive protein (DAS28 [CRP]) < 2.6, were assessed. For patients achieving early sustained SDAI remission at weeks 24/40/52, flow between disease activity categories and individual trajectories was evaluated; flow was also evaluated for later remitters (weeks 40/52 but not week 24).ResultsAmong patients treated with abatacept + methotrexate (n/N = 451/752) at IP week 24, 22% achieved SDAI remission, 17% achieved Boolean remission, and 42% achieved DAS28 (CRP) < 2.6; of these, 56%, 58%, and 74%, respectively, sustained a response throughout IP weeks 40/52. Among patients with a sustained response at IP weeks 24/40/52, 82% (14/17) on weekly abatacept + methotrexate, 81% (13/16) on abatacept monotherapy, 63% (12/19) who de-escalated/withdrew abatacept, and 65% (11/17) on abatacept placebo + methotrexate were in SDAI remission at end of the DE period; rates were higher than for later remitters in all arms except abatacept placebo + methotrexate.ConclusionsA high proportion of individual patients achieving clinical endpoints at IP week 24 with abatacept + methotrexate sustained their responses through week 52. Of patients achieving early and sustained SDAI remission through 52 weeks, numerically more maintained remission during the DE period if weekly abatacept treatment continued.Trial registrationNCT02504268 (ClinicalTrials.gov), registered July 21, 2015.

Antibodies against citrullinated proteins of IgA isotype are associated with progression to rheumatoid arthritis in individuals at-risk

ObjectiveEvents triggering disease outbreak in individuals at-risk for rheumatoid arthritis (RA at-risk) remain unclear, and the role of the various anticitrullinated protein antibody (ACPA) isotypes in this process is still...

Baseline serum levels of cross-linked carboxy-terminal telopeptide of type I collagen predict abatacept treatment response in methotrexate-naive, anticitrullinated protein antibody-positive patients with early rheumatoid arthritis

ObjectiveTo investigate correlations between biomarkers of bone remodelling and extracellular matrix turnover with baseline disease activity and treatment response in patients with early rheumatoid arthritis (RA).MethodsAssessing Very Early Rheumatoid arthritis...

Imbalance of Th17, Treg, and helper innate lymphoid cell in the peripheral blood of patients with rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory disease involving a variety of immune cells, including adaptive T and B cells and innate lymphoid cells (ILCs). Understanding the pathogenic role of these immune cells in RA provides new insights into the intervention and treatment of RA.MethodsA total of 86 patients with RA (RA group) and 50 healthy controls (HC) were included in the study. The immune cells of CD4+, CD19+ B, NK, Th17, Treg, ILCs, and their subsets (i.e., ILC1s, ILC2s, and ILC3s) were characterized in peripheral blood mononuclear cells by flow cytometry. Cytokines (i.e., IFN-γ, IL-4, IL-10, IL-17A, IL-22, and IL-33) in sera were detected using ELISA. The above immune cells and cytokines were analyzed in patients with different disease activity status and positive ( +) or negative ( −) rheumatoid factor (RF)/anti-citrullinated protein antibodies (ACPA).ResultsPatients with RA had higher percentages of CD4+ T, CD19+ B, Th17, ILC2s, and ILC3s and lower percentages of Treg and ILC1s than HC. Patients with RA had elevated levels of IFN-γ, IL-4, IL-17A, and IL-22 and decreased level of IL-10. Compared with HC, patients with high disease activity had higher percentages of Th17, ILC2s, and ILC3s; lower percentages of ILC1s; and lower level of IL-10. The percentage of Treg cells in remission, low, moderate, and high disease activities decreased, whereas the level of IL-17A increased compared with HC. Furthermore, RF+ or ACPA+ patients exhibited elevated percentages of CD19+ B, ILC2s, and ILC3s and had decreased percentage of ILC1s and Treg cells than HC. The percentage of Th17 cells increased in RF−/ACPA− and RF+/ACPA+ patients. However, the above immune cells between RF or ACPA positive and negative patients were not significantly different.ConclusionTh17, Treg, and ILC subset dysregulations are present in patients with RA but may not be associated with conventionally defined seropositive RF and ACPA.Key Points• Th17, Treg, and ILC subset dysregulations are present in patients with RA but may reflect inflammation rather than specific diseases and stages.• No difference for the distribution of Th17, Treg, and ILC subsets between RF+and RF− patients and between ACPA+and ACPA− patients. The screening spectrum of RF and ACPA serology should be expanded to elucidate the role of immune cells in RA pathogenesis.

Efficacy of Abatacept Versus Tumor Necrosis Factor Inhibitors in Anti-citrullinated Protein Antibody-Positive Patients with Rheumatoid Arthritis: Results from a Korean Nationwide Biologics Registry.

Introduction To compare the efficacy of abatacept and tumor necrosis factor inhibitor (TNFi) in patients with anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) and identify those who benefit most from abatacept over TNFi.MethodsThis observational study identified RA patients who were ACPA-positive and initiated abatacept or TNFi from the Korean College of Rheumatology Biologics and Targeted therapy registry. Propensity score (PS) matching was performed to balance baseline confounding in abatacept- or TNFi-treated patients. The major endpoints were changes in Clinical Disease Activity Index (CDAI) and achievement of CDAI remission/low disease activity after 1 year of treatment. Subgroup analysis was mainly performed stratified by prior biologics use.ResultsA total of 291 PS-matched, ACPA-positive RA patients who initiated abatacept (n = 97) and TNFi (n = 194) were included. From baseline CDAI scores of 26.52 in the abatacept group and 26.38 in the TNFi group, the mean changes after 1 year were − 16.78 and − 13.61, respectively (difference − 3.17, p = 0.020). The proportion of patients achieving CDAI remission/low disease activity was 68.0% with abatacept and 52.6% with TNFi (p = 0.013). In the subgroup analysis, patients that were biologics-naïve had better improvement in CDAI after treatment with abatacept than TNFi (difference − 3.35, p = 0.021).ConclusionsThis real-world study suggests that abatacept may have better clinical response compared to TNFi in patients with established ACPA-positive RA, especially in those that were biologics-naïve.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00467-4.

The effect of a multidisciplinary lifestyle program for patients with rheumatoid arthritis, an increased risk for rheumatoid arthritis or with metabolic syndrome-associated osteoarthritis: the \u201cPlants for Joints\u201d randomized controlled trial protocol

Low-grade inflammation and metabolic syndrome are seen in many chronic diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). Lifestyle interventions which combine different non-pharmacological therapies have shown synergizing effects in improving outcomes in patients with other chronic diseases or increased risk thereof, especially cardiovascular disease. For RA and metabolic syndrome-associated OA (MSOA), whole food plant-based diets (WFPDs) have shown promising results. A WFPD, however, had not yet been combined with other lifestyle interventions for RA and OA patients. In this protocol paper, we therefore present Plants for Joints, a multidisciplinary lifestyle program, based on a WFPD, exercise, and stress management. The objective is to study the effect of this program on disease activity in patients with RA (randomized controlled trial [RCT] 1), on a risk score for developing RA in patients with anti-citrullinated protein antibody (ACPA) positive arthralgia (RCT 2) and on pain, stiffness, and function in patients with MSOA (RCT 3), all in comparison with usual care.We designed three 16-week observer-blind RCTs with a waiting-list control group for patients with RA with low to moderate disease activity (2.6 ≤ Disease Activity Score [DAS28] ≤ 5.1, RCT 1, n = 80), for patients at risk for RA, defined by ACPA-positive arthralgia (RCT 2, n = 16) and for patients with metabolic syndrome and OA in the knee and/or hip (RCT 3, n = 80). After personal counseling on diet and exercise, participants join 10 group meetings with 6–12 other patients to receive theoretical and practical training on a WFPD, exercise, and stress management, while medication remains unchanged. The waiting-list control group receives usual care, while entering the program after the RCT. Primary outcomes are: difference in mean change between intervention and control groups within 16 weeks for the DAS28 in RA patients (RCT 1), the RA-risk score for ACPA positive arthralgia patients (RCT 2), and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) score for MSOA patients (RCT 3). Continued adherence to the lifestyle program is measured in a two-year observational extension study.

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.

Structural Analysis of Variable Domain Glycosylation of Anti-Citrullinated Protein Antibodies in Rheumatoid Arthritis Reveals the Presence of Highly Sialylated Glycans

Recently, we showed the unexpectedly high abundance of N-linked glycans on the Fab-domain of Anti-Citrullinated Protein Antibodies (ACPA). As N-linked glycans can mediate a variety of biological functions, we now aimed at investigating the structural composition of the Fab-glycans of ACPA-IgG to better understand their mediated biological effects. ACPA-IgG and noncitrulline specific (control) IgG from plasma and/or synovial fluid of nine ACPA positive rheumatoid arthritis patients were affinity purified. The N-linked glycosylation of total, Fc and F(ab′)2 fragments, as well as heavy and light chains of ACPA-IgG and control IgG were analyzed by UHPLC and MALDI-TOF mass spectrometry. The Fc-glycosylation of ACPA-IgG and IgG was analyzed at the glycopeptide level using LC-MS. The structural analyses revealed that ACPA-IgG molecules contain highly sialylated glycans in their Fab-domain. Importantly, Fab-glycans were estimated to be present on over 90% of ACPA-IgG, which is five times higher than in control IgG isolated from the same patients. This feature was more prominent on ACPA isolated from synovial fluid compared with peripheral blood. These observations provide the first evidence pointing to the ability of ACPA-IgG to mediate novel immunological activities, for example through binding specific lectins via hyper-sialylated Fab-glycans.

Economic Burden of Rheumatoid Arthritis in Italy: Possible Consequences on Anti-Citrullinated Protein Antibody-Positive Patients.

Rheumatoid arthritis (RA) is an autoimmune disease with a substantial medical and economic burden. In Italy, it affects approximately 280,000 people, therefore representing the musculoskeletal disease with the highest economic impact in terms of costs for the National Health Service and the social security system. The aim of this study was to estimate the annual economic burden of RA in Italy and determine the potential cost reduction considering the most effective biologic treatment for early rapidly progressing RA (ERPRA) patients. The model developed considers both direct costs that are mainly due to the pharmacological treatments, and indirect costs, which also include the productivity lost because of the disease. A systematic literature review provided the epidemiological and economic data used to inform the model. A one-way probabilistic sensitivity analysis based on 5000 Monte Carlo simulations was performed. Furthermore, specific scenario analyses were developed for those patients presenting an ERPRA, with the aim of evaluating the effectiveness of different biologic treatments for this subgroup of patients and estimating potential cost reduction. The total economic burden associated with RA was estimated to be €2.0billion per year (95%confidence interval [CI] €1.8-2.3billion). Forty-five percent of the expenditure was due to indirect costs (95% CI €0.8-1.0billion); 45% depended on direct medical costs (95%CI €0.7-1.1billion), and the residual 10% was determined by direct non-medical costs (95%CI €0.16-0.25billion). In particular, the costs estimated for ERPRA patients totalled €76,171,181, of which approximately €18million was associated with patients with a high level of anti-citrullinated protein antibodies (ACPA). The results of the analysis outline how it is possible to obtain a cost reduction for ERPRA patients of between €1 and €3million by varying the number of patients with a high level of immunoglobulinG treated with the most effective biologic drug. In fact, the latter may determine higher efficacy outcomes, especially for poor prognostic ERPRA patients, ensuing higher levels of productivity. This study presents a pioneering approach to estimate the direct and indirect costs of RA. The model developed is a useful tool for policy makers as it allows to understand the economic implications of RA treatment in Italy, identify the most effective allocation of resources, and select the most appropriate treatment for ERPRA patients.

THU0510 Igg ACPA Level Increase Drives Rheumatoid Factor Response Maturation in Patients before Onset of Clinically Apparent Rheumatoid Arthritis

BackgroundIn Rheumatoid Arthritis (RA) the pathophysiological role of both rheumatoid factor (RF) and anti citrullinated protein antibodies (ACPA) is still subject of debate. Since the antigen for RF is the...

Clinical correlation between Anti-CCP antibody, rheumatoid factor and clinical parameters of patients with rheumatoid arthritis

BACKGROUND: The main clinically useful serological markers in patients with Rheumatoid Arthritis are Rheumatoid Factor and Anti-citrullinated Protein Antibodies (ACPA) for both diagnosis and prediction of functional and radiographic outcomes. We do not have data from Nepalese patients about gender differences and association of these antibodies with disease nature. OBJECTIVE: To identify the difference in nature of disease in relation to ACPA and gender. METHODS: A cross sectional open labeled study including consecutive patients who were diagnosed as RA according to ACR/EULAR 2010 attending the rheumatology OPD from October 2010 to October 2012 at Alka Hospital, Nepal. Data collection was done by direct patient interview and all data were recorded electronically in a predesigned performa. ACPA and RF were tested in the serum samples of 184 patients. RESULTS: Out of 184 patients, 114 of them were ACPA positive and 54 were Rheumatoid factor positive. The median duration of symptoms was 30.3±7.0 months lesser in ACPA positive patients as compared to negative ones. Mean age of females was 10.7 years less than male patients. No other significant differences were noted between male and female patients. Also, 52.3%ofRF negative patients were found to have ACPA positivity. CONCLUSION: Anti cyclic citrullinated peptide antibodies are excellent serological markers of rheumatoid arthritis, which shows good diagnostic value. This can increase the diagnostic value in addition to rheumatoid factor and its use in clinical practice may contribute to increased ability of rheumatologists to make judicious treatment decisions. DOI: http://dx.doi.org/10.3126/jucms.v1i4.9566 Journal of Universal College of Medical Sciences (2013) Vol.1 No.04: 13-16

AB1263 Higher prevalence of anti-citrullinated protein antibodies (ACPA) without impact on prognosis in patients with aggressive B-non-hodgkin lymphoma (DLCBL)

BackgroundThe complex processes of citrullination presents an ubiquitous pathophysiological procedure during inflammation. However, anti-citrullinated protein antibodies (ACPA) are highly specific for the rheumatoid arthritis (RA). In order to a variety...

AB0371 In RA patients with very strongly positive serology there is a striking discordance in presentation between those with very strongly positive ACPA levels associated with negative or low-positive rf levels and those with very strongly positive RF levels

BackgroundRA has been viewed for many years as a heterogeneous collection of rheumatic diseases. Previously rheumatoid factor (RF) positive and negative patients were regarded as distinct clinical subtypes. Additionally, within...

FRI0094 Outcomes of two years of remission steered treatment in early arthritis patients

ObjectivesTo evaluate the 2 year clinical outcomes of remission steered therapy in early arthritis patients in the IMPROVED study.Methods610 patients with early rheumatoid or undifferentiated arthritis (RA or UA) started...

AB0336 Clinical significance of serial measurement of anti-citrullinated protein antibodies (ACPA) in patients with palindromic rheumatism

BackgroundAnti-citrullinated protein antibodies (ACPA), the most specific markers of rheumatoid arthritis (RA), are found in approximately 50% of patients with palindromic rheumatism (PR). A significant proportion of these patients may...

Lung changes detected by high resolution tomography are present in ACPA positive RA patients already at disease onset

Background/purposeThe authors have previously shown that smoking increases citrullination in the lungs of healthy smokers and hypothesised that this process is an important step in the early development of rheumatoid...

Lung changes are present in ACPA positive RA patients already at disease onset

ObjectiveWe have previously shown that smoking increases citrullination in the lungs of healthy smokers and hypothesised that this process is an important step in the early development of rheumatoid arthritis...