And/or Anti-citrullinated Protein Antibody Research Articles

Rheumatoid Arthritis from Easy to Complex Disease: From the "2022 GISEA International Symposium".

Rheumatoid Arthritis (RA) is a systemic disease with many different clinical phenotypes. RA could be classified according to disease duration, seropositivity for rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA), joint subtype, clinical behaviourbehavior and many other subgroups. In this review, we summarize and discuss the multifaceted aspects of RA, focusing on the relationship between autoimmunity status and clinical outcome, achievement of remission and influence on treatment response, from the 2022 International GISEA/OEG Symposium.

Presence of autoantibodies in \u201cseronegative\u201d rheumatoid arthritis associates with classical risk factors and high disease activity

BackgroundRheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative.MethodsAnti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets.ResultsAutoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined “seronegative” RA, associated with worse clinical outcome.Conclusions“Seronegative” RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2−/IgM RF− patients with a high need for active treatment.

Rheumatoid Arthritis: Seropositivity versus Seronegativity; A Comparative Cross-sectional Study Arising from Moroccan Context.

Rheumatoid arthritis (RA) is biologically marked by a positive serum rate of rheumatoid factor (RA) and/or anti-citrullinated protein antibodies (ACPA). Nevertheless, 20% of RA cases remain seronegative. The main purpose of this study, is to bring out the clinical, biological, imaging, therapeutic, and evolutionary distinctions between seropositive RA and seronegative one. This is an observational cross-sectional study that involves patients with RA admitted in the rheumatology department, from the period between January 2012 and January 2018. RA seronegativity is described as the absence of both RF and ACPA, while seropositivity is recognized by the presence of at least one of the two antibodies. 294 patients were included, of which 90% were seropositive and 10% seronegative. Therefore, RA in this study is seropositive most often. The bivariate analysis underscored plenty of differences, statistically notable, according to the RA immune status. In fact, patients with seropositive RA had more synovitis (p=0.049), more deformities (p=0.01), and more bone destruction on radiographs (p=0.04). Furthermore, RA in this Moroccan study was quite severe (p=0.006) and got more complicated by systemic manifestations (p=0.02). Whereas, no distinction was brought up between the two groups, concerning the use of biotherapy. As for the multivariate study, seropositive RA in these patients, had greater severity (p=0.009, OR=4.53) and was more deforming (p=0.03 OR=2.45). RA in our Moroccan context is dominated by the seropositive form. This seropositivity is often coupled with clinical severity and joint destruction, resulting in more deformities.

Lung cancer in rheumatoid arthritis. Is there a need for better risk assessment and screening?

Extra-articular manifestations are common in rheumatoid arthritis (RA), with lung involvement being one of the commonest. Apart from interstitial lung disease which is a well-recognized manifestation, it seems that lung cancer has also increased frequency in RA. In fact, recent meta-analyses have suggested that in RA compared with the general population, lymphomas and lung malignancy are more frequent. For the latter, male gender, seropositivity for rheumatoid factor and/or anti-citrullinated protein antibody (ACPA), as well as older age, has been suggested, among others, as risk factors. Several hypotheses have been formulated to explain the increased frequency of lung cancer in RA. These include smoking and/or interstitial lung as common risk factors for both RA and lung cancer and chronic inflammation predisposing to malignant diseases. Numerous questions remain to be answered. For example, are there any risk factors (e.g., positivity for rheumatoid factor or anti-citrullinated peptide antibodies) that would predict the development of lung cancer in these patients? Are there any screening procedures appropriate for early diagnosis and therefore better outcome? Data from large registries are needed to better define the profile of these patients.

Impact of the combined presence of erosions and ACPA on rheumatoid arthritis disease activity over time: results from the METEOR registry

ObjectiveTo investigate associations between baseline presence of erosions and/or anti-citrullinated protein antibodies (ACPA) on functional ability, disease activity and treatment survival over time.MethodsReal life data from newly diagnosed rheumatoid arthritis...

Combination of anti-citrullinated protein antibodies and rheumatoid factor is associated with increased systemic inflammatory mediators and more rapid progression from preclinical to clinical rheumatoid arthritis

The development of rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPAs) can be observed years prior to clinical diagnosis of rheumatoid arthritis (RA). Nevertheless, the interaction between these two autoantibodies and their combined effect on development of RA is unclear. We measured RF, cytokines, and ACPA subtypes in serial pre-clinical serum samples collected from 83 US veterans who all developed RA. Levels of cytokines and ACPAs were compared between the following groups: anti-cyclic citrullinated peptide (anti-CCP)-/RF- (double negative), anti-CCP+/RF-, anti-CCP-/RF+, or anti-CCP+/RF+ (double-positive). The double-positive subgroup had significantly higher levels of 20 inflammatory cytokines and 29 ACPA reactivities, and the shortest interval, 1.3 years, between the preclinical sample timepoint and diagnosis of RA. Thus, the combined presence of ACPAs and RF is associated with a more rapid progression to RA, suggesting that anti-CCP+/RF+ individuals have a more advanced preclinical disease state and that the onset of RA may be imminent.

Assessment of local carotid stiffness in seronegative and seropositive rheumatoid arthritis

Objectives: Rheumatoid arthritis (RA) is a chronic, inflammatory disease associated with increased risk of cardiovascular (CV) disease. Arterial stiffness (AS) is an independent predictor of CV events. This study aimed to analyse local carotid AS parameters in seronegative and seropositive RA patients. Design: Of 347 consecutive RA patients, we selected specifically those who were free of established CV diseases and risk factors. As a result, 140 patients (126 women, 52.2 ± 10 years) and 140 healthy controls (122 women, 52.7 ± 8.0 years) were enrolled into this study. The common carotid AS was evaluated using radio frequency echo-tracking system to determine the local carotid pulse wave velocity (cPWV) and carotid intima-media thickness (cIMT). Based on rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positivity, RA patients were categorized into seronegative and seropositive subgroups. Results: Carotid PWV was determined to be significantly higher in all patients and subgroups than controls (p < .001 for all). Although cIMT was similar between the patients, controls and seropositive subgroup, seronegative patients had significantly higher cIMT compared to controls (p = .035) and seropositive group (p = .010). Moreover, a significant positive correlation was found between cPWV and age (r: 0.603, p < .001), ESR (r: 0.297, p = .004), ACPA (r: 0.346, p = .001) and cIMT (r: 0.290, p = .005) in seropositive patients. Conclusions: RA per se is sufficient to cause arteriosclerosis in the absence of classical CV risk factors. However, arterial hypertrophy is only increased in seronegative patients but not in seropositive group.

ОЦЕНКА ЭФФЕКТИВНОСТИ ВЛИЯНИЯ ПОДКОЖНОЙ ФОРМЫ МЕТОТРЕКСАТА НА УРОВЕНЬ ПРОВОСПАЛИТЕЛЬНОЙ ЦИТОКИНЕМИИ И МОРФО-ФУНКЦИОНАЛЬНОЕ СОСТОЯНИЕ СОСУДИСТОЙ СТЕНКИ У БОЛЬНЫХ РЕВМАТОИДНЫМ АРТРИТОМ

Objective: To assess the effect of the subcutaneous form of methotrexatum (metoject) on the level of pro-inflammatory cytokinemia and the morphofunctional characteristics of the vascular wall in patients with rheumatoid arthritis. Methods: The level of pro-inflammatory cytokinemia and the morphofunctional characteristics of carotid arteries were studied in 94 patients with rheumatoid arthritis (RA) positive for RF-IgM and/or anti-citrullinated protein antibody (ACPA). Results: It has been established that in patients with RA as a result of an increase in the serum concentration of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) the subclinical lesion of the major arteries, manifested by an increase in the thickness of the intima-media complex (IMC) and the stiffness index of the common carotid artery (CCA) was observed, the magnitude of which was correlated with the duration of RA, the activity index of DAS28, the level of RF and the concentration of ACPA. The use of metoject in RA patients led to a statistically significant decrease in the DAS28 index, a decrease in pro-inflammatory cytokinemia with attainment of control values in the early stages of the disease, a decrease in the thickness of IMC of the CCA, and local (carotid) rigidity of the vascular bed, which is more pronounced with RA duration less than 2 years. It was demonstrated that metoject therapy along with high anti-inflammatory activity, possesses a vasoprotective effect, which is characterized by a decrease in remodeling signs of CCA. Conclusion: The results of the study confirm not only the high clinical efficiency and good tolerancy of the subcutaneous form of metoject, but also show that it possesses a high anti-inflammatory activity, which provides a vasoprotective effect on large vessels of the elastic type (aorta and common carotid arteries). Keywords: Rheumatoid arthritis, methotrexatum, metoject, thickness of intima-media complex, common carotid artery, pro-inflammatory cytokines.

Serum Vaspin Levels Are Associated with the Development of Clinically Manifest Arthritis in Autoantibody-Positive Individuals.

ObjectivesWe have previously shown that overweight may increase the risk of developing rheumatoid arthritis (RA) in autoantibody positive individuals. Adipose tissue could contribute to the development of RA by production of various bioactive peptides. Therefore, we examined levels of adipokines in serum and synovial tissue of subjects at risk of RA.MethodsFifty-one individuals positive for immunoglobulin M rheumatoid factor (IgM-RF) and/or anti-citrullinated protein antibodies (ACPA), without arthritis, were included in this prospective study. Levels of adiponectin, vaspin, resistin, leptin, chemerin and omentin were determined in baseline fasting serum samples (n = 27). Synovial tissue was obtained by arthroscopy at baseline and we examined the expression of adiponectin, resistin and visfatin by immunohistochemistry.ResultsThe development of clinically manifest arthritis after follow-up was associated with baseline serum vaspin levels (HR1.5 (95% CI 1.1 to 2.2); p = 0.020), also after adjustment for overweight (HR1.7 (95% CI 1.1 to 2.5); p = 0.016). This association was not seen for other adipokines. Various serum adipokine levels correlated with BMI (adiponectin r = -0.538, leptin r = 0.664; chemerin r = 0.529) and systemic markers of inflammation such as CRP levels at baseline (adiponectin r = -0.449, omentin r = -0.557, leptin r = 0.635, chemerin r = 0.619, resistin r = 0.520) and ESR (leptin r = 0.512, chemerin r = 0.708), p-value<0.05. Synovial expression of adiponectin, resistin and visfatin was not associated with development of clinically manifest arthritis.ConclusionsIn this exploratory study, serum adipokines were associated with an increased inflammatory state in autoantibody-positive individuals at risk of developing RA. Furthermore, serum vaspin levels may assist in predicting the development of arthritis in these individuals.

IgG Subclass Specificity Discriminates Restricted IgM Rheumatoid Factor Responses From More Mature Anti-Citrullinated Protein Antibody-Associated or Isotype-Switched IgA Responses.

To investigate the presence and patterns of specific IgG subclass recognition by IgM rheumatoid factor (IgM-RF) and IgA-RF with a newly developed enzyme-linked immunosorbent assay (ELISA), which can discriminate between polyspecific and restricted RF responses. Polyspecific and restricted RF responses were determined with our ELISA, which uses individually coated recombinant IgG subclasses instead of polyclonal IgG as target antibodies. Fine specificity was determined using target antibodies with single amino acid mutations in the Fc region. In a screening panel of 93 sera that were previously found to be IgM-RF positive in a conventional RF assay, we were able to discriminate between sera with polyspecific IgM-RF responses (i.e., RF responses directed against all 4 IgG subclasses) and those with restricted IgM-RF responses, with low or absent relative reactivity against IgG2, IgG3, or IgG4. We found the largest variation for anti-IgG3 reactivity. Samples without detectable anti-IgG4 reactivity formed an independent group from the other restricted RF responses and the polyspecific RF responses. The specificity of these anti-IgG4-negative sera could be pinpointed to single amino acid differences between IgG1 and IgG4. Polyspecific RF responses more often showed signs of RF response maturation, with more isotype switching to IgA-RF, as compared to restricted RF responses. In a cohort of IgM-RF+ and/or anti-citrullinated protein antibody (ACPA)-positive arthralgia patients, we found restricted RF responses in 35% (49 of 140) of RF+/ACPA- patients, while RF+/ACPA+ patients, who have a much higher risk of developing rheumatoid arthritis, virtually always (123 of 128 [96%]) showed a polyspecific RF response. IgG subclass-specific RF distinguishes between immature restricted RF responses and potentially more pathogenic, ACPA-associated polyspecific responses.

Diagnostic performance of a new vimentin-derived ACPA (CCP high sensitive) in patients with rheumatoid arthritis.

Autoantibodies are a common feature of rheumatoid arthritis (RA), and their detection is used as a diagnostic tool in medical practice. Rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA) detection in patients' sera are now included in 2010 ACR/EULAR criteria for RA diagnosis. In this study, we evaluated a new vimentin-derived ACPA ELISA, the anti-cyclic citrullinated peptide high sensitive (CCP hs) test, and we compared its performance with the RF IgM and anti-CCP3 tests on a French multicenter cohort of 84 RA patients, 107 non-RA patients and 100 healthy controls. Sensitivities for RA diagnosis were 71.4, 84.5 and 64.3 % and specificities were 88.4, 86.9 and 87.3 % for CCP hs, CCP3 and RF IgM, respectively. There was a moderate correlation between CCP hs and CCP3 titers (Pearson's r = 0.43; p < 0.0001). These results support the contention that anti-CCP hs antibodies are new reliable ACPA with high specificity for RA.

A7.7 Synovial tissue profiling in autoantibody positive individuals without arthritis reveals gene signatures associated with subsequent development of rheumatoid arthritis

Background Previous work has suggested subtle infiltration of synovial T cells in the absence of overt synovial inflammation in individuals at risk of developing rheumatoid arthritis (RA). Objective To study the molecular changes in synovial tissue preceding arthritis development in preclinical RA. Materials and methods Sixty-one individuals who were IgM rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positive and without any evidence of arthritis were included. All individuals underwent mini-arthroscopic synovial biopsy sampling of a knee joint at inclusion and were prospectively followed. An explorative genome-wide transcriptional profiling study was performed on synovial biopsies obtained from 13 individuals using Agilent arrays (test cohort). Survival analysis within the software package Significance Analysis of Microarrays was used to identify transcripts with a significant association with arthritis development. The expression level of differentially expressed genes was validated using quantitative real-time PCR in the total cohort. Results Six of the 13 individuals in the explorative study developed RA after a median follow up time of 20 months (IQR 2 – 44). The 7 individuals who did not develop RA had a median follow up time of 56 months (IQR 56 – 60). Using a False Discovery Rate of Conclusion This study clearly shows molecular changes appearing in synovial tissues before onset of arthritis in the absence of overt synovitis and demonstrates preclinical synovial activation of immune response genes associated with development of arthritis.

Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis.

ObjectiveFindings from previous studies have suggested that subclinical inflammation of the synovium does not coincide with the appearance of rheumatoid arthritis (RA)–specific autoantibodies. This study was undertaken to examine the relationship between the presence of autoantibodies, changes in the synovium, and development of arthritis over time in a markedly larger, prospective study.MethodsFifty-five individuals who were IgM rheumatoid factor positive and/or anti–citrullinated protein antibody (ACPA) positive (detected by the anti–cyclic citrullinated peptide antibody test) and who were without any evidence of arthritis upon physical examination were included in the study. ACPAs were subsequently also detected using a multiplex chip-based assay. All individuals underwent magnetic resonance imaging and mini-arthroscopic synovial biopsy sampling of a knee joint at inclusion and were prospectively followed up. Proportional hazards regression analysis was performed to investigate whether changes in the synovium were associated with the onset of arthritis.ResultsFifteen individuals (27%) developed arthritis after a median followup time of 13 months (interquartile range 6–27 months; range 1–47 months). No overt synovial inflammation was observed, but CD3+ T cell numbers in the biopsy tissue showed a borderline association with subsequent development of clinically manifest arthritis (hazard ratio 2.8, 95% confidence interval [95% CI] 0.9–9.1; P = 0.088). In addition, the presence of CD8+ T cells was associated with ACPA positivity (odds ratio [OR] 16.0, 95% CI 1.7–151.1) and with the total number of ACPAs present (OR 1.4, 95% CI 1.0–1.8).ConclusionThese findings confirm and extend previous results showing the absence of clearcut synovial inflammation in individuals having systemic autoimmunity associated with RA. However, subtle infiltration by synovial T cells may precede the signs and symptoms of arthritis in preclinical RA.

No evidence of accelerated atherogenesis in the preclinical and very early phase of rheumatoid arthritis

Backgroundand objectivesThe increased risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) has been largely ascribed to the chronic inflammatory state. Whether the CVD risk is restricted to...

Mannan Binding Lectin (MBL) genotypes coding for high MBL serum levels are associated with rheumatoid factor negative rheumatoid arthritis in never smokers

IntroductionPrevious studies have provided inconsistent results on whether variants in the MBL2 gene, coding for the complement-activating mannan-binding lectin (MBL) protein, associate with rheumatoid arthritis (RA). We re-evaluated this in context of the main environmental and genetic risk factors (smoking, HLA-DRB1 'shared epitope' (SE), PTPN22*620W), which predispose to rheumatoid factor (RF) and/or anti-citrullinated-protein antibody (ACPA)-positive RA.MethodsIn this population-based EIRA study, rheumatoid factor (RF), ACPA, smoking, SE and PTPN22*620W status was determined in incident RA cases and matched controls. MBL-high (n = 1330) and MBL-low (n = 1257) genotypes predicting MBL levels were constructed from four promoter and exon-1 polymorphisms in the MBL2 gene. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated by logistic regression. In extended families (n = 316), previously reported data were re-analyzed, considering RF and smoking.ResultsMBL-high genotypes tended to be associated with RF-negative (OR = 1.20, 95% CI 0.96-1.51) but not RF-positive (OR = 1.00, 95% CI 0.83-1.20) RA. Results divided by ACPA status did not differ. When stratified for smoking, MBL-high genotype was strongly associated with RF-negative RA in never smokers (OR = 1.82, 95% CI 1.24-2.69) but not in ever smokers (OR = 0.96, 95% CI 0.73-1.30). In never smokers, the association was observed in both the RF-negative/ACPA-negative (OR = 1.67, 95% CI 1.10-2.55) and RF-negative/ACPA-positive subgroups (OR = 3.07, 95% CI 1.37-6.89), and remained on an SE/PTPN22*620W negative background. In the extended families, the reported association between high MBL and RA was in fact confined to never smokers.ConclusionsHigh MBL may predispose to RF-negative RA but only in individuals who have never smoked. This illustrates the importance of phenotypic subgrouping in genetic studies.