Anti-citrullinated Protein Antibody Positivity Research Articles

Plasma mtDNA as a possible contributor to and biomarker of inflammation in rheumatoid arthritis

ObjectivesNeutrophil extracellular trap formation and cell-free DNA (cfDNA) contribute to the inflammation in rheumatoid arthritis (RA), but it is unknown if mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) is more abundant in the circulation. It is unclear if DNA concentration measurements may assist in clinical decision-making.MethodsThis single-center prospective observational study collected plasma from consecutive RA patients and healthy blood donors. Platelets were removed, and mtDNA and nDNA copy numbers were quantified by polymerase chain reaction (PCR).ResultsOne hundred six RA patients and 85 healthy controls (HC) were recruited. Circulating median mtDNA copy numbers were increased 19.4-fold in the plasma of patients with RA (median 1.1 x108 copies/mL) compared to HC (median 5.4 x106 copies/mL, p<0.0001). Receiver operating characteristics (ROC) curve analysis of mtDNA copy numbers identified RA patients with high sensitivity (92.5%) and specificity (89.4%) with an area under the curve (AUC) of 0.97, p <0.0001 and a positive likelihood ratio of 8.7.Demographic, serological (rheumatoid factor (RF) positivity, anti-citrullinated protein antibodies (ACPA) positivity) and treatment factors were not associated with DNA concentrations. mtDNA plasma concentrations, however, correlated significantly with disease activity score-28- erythrocyte sedimentation rate (DAS28-ESR) and increased numerically with increasing DAS28-ESR and clinical disease activity index (CDAI) activity. MtDNA copy numbers also discriminated RA in remission (DAS28 <2.6) from HC (p<0.0001). Also, a correlation was observed between mtDNA and the ESR (p = 0.006, R= 0.29). Similar analyses showed no significance for nDNA.ConclusionIn contrast to nDNA, mtDNA is significantly elevated in the plasma of RA patients compared with HC. Regardless of RA activity, the abundance of circulating mtDNA is a sensitive discriminator between RA patients and HC. Further validation of the diagnostic value of mtDNA testing is required.

Reproductive Effect by Rheumatoid Arthritis and Related Autoantibodies.

Rheumatoid arthritis (RA) is a common inflammatory arthritis in women. The effects of RA on the reproductive system are usually overlooked, as RA is not diagnosed until later in reproductive age. Whether RA itself or its related rheumatoid antibodies have an impact on female reproductive function has long been a thought-provoking issue. In brief, relevant epidemiological evidence has shown that women affected by RA are more likely to have coexisting reproductive disorders, including infertility, endometriosis, and premature ovarian insufficiency (POI), or to subsequently develop them. Furthermore, linkage between RA and pregnancy loss (PL) as well as polycystic ovary syndrome (PCOS) is also well known, albeit controversial in available evidence. RA and reproductive disorders appear to share a similar inflammatory immune response and genetic background. The stress experienced by patients with RA may affect their reproductive choices to some extent. Notably, few studies have explored the impact of rheumatoid antibodies such as rheumatoid factors (RFs) and anti-citrullinated protein antibodies (ACPAs) on reproductive disorders. Although it has been mentioned that the rate of RF and/or ACPA positivity is higher in women with a history of PL and POI, the clinical relevance of this relationship and underlying mechanisms still need to be further clarified.

Alteration of Gut Microbiota in Individuals at High-Risk for Rheumatoid Arthritis Associated With Disturbed Metabolome and the Initiation of Arthritis Through the Triggering of Mucosal Immunity Imbalance.

In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis. Fecal samples were collected from 38 healthy individuals and 53 high-risk RA individuals with anti-citrullinated protein antibody (ACPA) positivity (Pre-RA), 12 of 53 Pre-RA individuals developed RA within 5 years of follow-up. The differences in intestinal microbial composition between the healthy controls and Pre-RA individuals or among Pre-RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic-pretreated mice that received GM from the healthy control or Pre-RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen-induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre-RA individuals on arthritis severity in mice. Stool microbial diversity was lower in Pre-RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre-RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre-RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre-RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre-RA group increased intestinal permeability in FMT mice and zonula occludens-1 expression in the small intestine and Caco-2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre-RA feces compared to healthy controls. The changes in intestinal permeability and Th17-cell activation prior to arthritis induction enhanced CIA severity in PreRA-FMT mice compared with HC-FMT mice. Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis.

Myocardial T1 mapping by cardiac magnetic resonance imaging shows early myocardial changes in treatment-naive patients with active rheumatoid arthritis and positive autoantibodies.

We aimed to study whether myocardial changes are already detectable by cardiac magnetic resonance (CMR) imaging at the time of rheumatoid arthritis (RA) diagnosis. This single-centre prospective study included 39 treatment-naive patients with early rheumatoid arthritis (ERA, symptom duration <1 year) without any history of heart disease, and 38 age- and sex-matched healthy volunteers. The disease severity was assessed with clinical evaluation (Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) score) and serological testing (rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA)). The ERA patients were classified into group A (DAS28-CRP score ≥3.2, positive RF and ACPA; n=17) and group B (not fulfilling the group A criteria). The ERA patients and healthy controls underwent 1.5T CMR. Group A patients had significantly higher myocardial global T1 relaxation times than the healthy controls, 987 [965, 1003] ms vs. 979 [960, 991] ms (median [IQR]; p=0.041). A significant difference in T1 was found in the basal, mid inferior and mid anterolateral segments. In a multivariate analysis, prolonged global T1 relaxation time was independently associated with female sex (95% CI [5.62, 51.31] ms, p=0.016), and group A status (95% CI [4.65, 39.01] ms p=0.014). At the time of diagnosis, ERA patients with a higher disease activity (DAS28-CRP score ≥3.2) and both positive RF and ACPA showed prolonged T1 relaxation times in basal myocardial segments. These segments could be most susceptible to the development of myocardial fibrosis, and a segmental reporting style could be useful when estimating the first signs of myocardial fibrosis.

A new serum biochemical marker of synovium turnover predicts radiographic progression in patients with early arthritis.

To investigate whether serum Col 3-4, a new biochemical marker of synovial tissue turnover, was associated with progression of joint damage in patients with early arthritis. A total of 788 early arthritis patients (<6 months of symptoms, 82% diagnosis of RA, 18% undifferentiated arthritis) from the prospective ESPOIR study were investigated. Progression was defined as an increase of 1 or 5 unit(s) in radiographic van der Heijde modified Sharp score between baseline and 1 or 5 years, respectively. Associations between baseline Col 3-4 and progression were assessed by logistic regression. Each standard deviation increase of baseline Col 3-4 levels was associated with an increased 5-yr total damage progression with an odds ratio (OR, 95% CI) of 1.51 (1.21, 1.88), which remained significant when DAS28, C-reactive protein and anti-citrullinated protein antibodies positivity were included in the model [OR (95% CI): 1.34 (1.01, 1.76)]. Further adjustment for bone erosion did not modify the association. Patients with both Col 3-4 in the highest quintile and bone erosion had a >2-fold higher risk of progression [OR (95% CI): 7.16 (2.31, 22)] than patients with either high Col 3-4 [2.91 (1.79, 4.73)] or bone erosion [2.36 (2.38, 3.70)] alone. Similar associations were observed for prediction of 12 months progression. Increased serum Col 3-4 is associated with a higher risk of structural progression, independently of major risk factors. Col 3-4 may be useful in association with bone erosion to identify patients with early arthritis at higher risk.

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

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

Diagnostic role of minor salivary glands biopsy in Sjögren's syndrome: correlations between histology and autoimmunity in a large, monocentric cohort.

Based on ACR/EULAR classification criteria, minor salivary glands biopsy (MSGB) is a useful diagnostic tool for the diagnosis of primary Sjögren's syndrome (SS). The main objective of our study was to evaluate the diagnostic role of MSGB, as well as to highlight correlations between histological findings and autoimmune profiles. We retrospectively evaluated histological and autoimmunity data from patients who underwent MSGB in our department in cases of suspected SS, from March 2011 to December 2018. Salivary gland samples were evaluated using Chisholm and Mason (CM) grading and the focus score (FS). A total of 1,264 patients (108 males, 1,156 females) were included. The median age was 55.22 ±13.51 years (range: 15-87). In univariate binary logistic regression, CM ≥ 3 and FS ≥ 1 were significantly predicted by antinuclear antibodies (ANA), anti-extractable nuclear antigens (ENA) and anti-Ro/SSA titer as well as anti-La/SSB, anti-Ro/SSA, rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) positivity. In multivariate analysis, CM ≥ 3 and MSGB positivity were significantly associated with ANA titer; FS ≥ 1 was not associated with laboratory findings. A positive biopsy was associated with laboratory findings, as ANA and ENA titers, anti-Ro/SSA, anti-La/SSB, RF and ACPA positivity may discriminate patients with SS-related histological findings. Minor salivary glands biopsy is a useful tool to diagnose SS in cases of highly suggestive clinical symptoms but in the absence of a specific autoimmunity.

Cardiometabolic multimorbidity may identify a more severe subset of rheumatoid arthritis, results from a “real-life” study

This "real-life" cross-sectional study has been designed to describe disease features of rheumatoid arthritis (RA) participants affected by cardiometabolic multimorbidity than those without. Our purpose was also the identification of possible associations between these cardiometabolic diseases and RA clinical characteristics. Consecutive RA participants with and without cardiometabolic multimorbidity were assessed and their clinical characteristics were recorded. Participants were grouped and compared by the presence or not of cardiometabolic multimorbidity (defined as ≥ 2 out of 3 cardiovascular risk factors including hypertension, dyslipidemia, and type 2 diabetes). The possible influence of cardiometabolic multimorbidity on RA features of poor prognosis was assessed. The positivity of anti-citrullinated protein antibodies, presence of extra-articular manifestations, lack of clinical remission, and biologic Disease-Modifying anti-Rheumatic Drugs (bDMARDs) failure were considered as RA features of poor prognosis. In the present evaluation, 757 consecutive RA participants were evaluated. Among them, 13.5% showed cardiometabolic multimorbidity. These were older (P < .001) and characterized by a longer disease duration (P = .023). They were more often affected by extra-articular manifestations (P = .029) and frequently displayed smoking habit (P = .003). A lower percentage of these patients was in clinical remission (P = .048), and they showed a more frequent history of bDMARD failure (P < .001). Regression models showed that cardiometabolic multimorbidity was significantly correlated with RA features of disease severity. They were predictors of anti-citrullinated protein antibodies positivity, of extra-articular manifestations, and of lack of clinical remission, in both univariate and multivariate analyses. Cardiometabolic multimorbidity was significantly associated with a history of bDMARD failure. We described disease features of RA participants with cardiometabolic multimorbidity, identifying a possible more difficult to treat subset, which may need a new management approach to achieve the treatment goal.

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

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

Baseline erythrocyte sedimentation rate level predicts long-term inhibition of radiographic progression by tocilizumab: the KURAMA cohort

The short-term effect of tocilizumab (TCZ) on the radiographic progression of rheumatoid arthritis has been reported; however, reports on its long-term effects are scarce. In this study, we aimed to evaluate its long-term effects on joint destruction in patients who had been treated with TCZ for at least two years and for whom X-rays were available. Radiographic progression was evaluated with modified Total Sharp Score (mTSS), and structural remission was defined as the mean annual change in mTSS ≤0.5. Of the 59 patients included in this study (median age, 62 years; female, 81.4%), 34 patients (57.6%) achieved structural remission. Patients who achieved structural remission were relatively younger (59 years vs. 64 years, p = .06), had relatively higher proportion of anti-citrullinated protein antibody positivity (91.2% vs. 72.0%, p = .08), relatively lower C-reactive protein level (0.6 mg/dL vs. 2.2 mg/dL, p = .05), and significantly lower erythrocyte sedimentation rate (ESR) level (28.0 mm/h vs 65.5 mm/h, p = .003) than those who did not. Multivariate logistic regression analysis demonstrated that the baseline ESR level was significantly associated with structural remission (odds ratio, 0.98; 95% confidence interval: 0.96–0.99, p = .049). The baseline ESR level is a critical determinant of the long-term effect of TCZ on joint destruction.

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...

Added value of multiple autoantibody testing for predicting progression to inflammatory arthritis in at-risk individuals

BackgroundPredicting progression to clinical arthritis in individuals at-risk of developing rheumatoid arthritis is a prerequisite to developing stratification groups for prevention strategies. Selecting accurate predictive criteria is the critical step...

Clinical characteristics of rheumatoid arthritis patients complicated with pulmonary nontuberculous mycobacterial disease: A cross-sectional case series study.

Pulmonary nontuberculous mycobacterial disease (pNTM) is a common pulmonary complication of rheumatoid arthritis (RA), but their association has rarely been researched. We aimed to reveal the clinical characteristics of RA with pNTM. Among all the RA patients who visited Tenri hospital from April 2017 to March 2018, we enrolled those fulfilling the 2007 ATS/IDSA diagnostic criteria of pNTM, and sex- and age- matched control group at a ratio of 1:5. Demographic characteristics were compared between the two groups. Among 865 RA patients, 35 (4.0%) patients were complicated with pNTM. RA patients with pNTM had significantly lower BMI and higher rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity. Bronchiectasis was the most frequent lesion, followed by clusters of small nodules, patchy consolidation and cavity. Multivariable logistic regression analysis revealed bronchiectasis as a strong independent associated factor of pNTM. Treatment for pNTM was needed in 14 of the 35 (40%) RA patients with pNTM and sputum negative conversion was accomplished in 11 of the 14 cases (78.6%). RA patients with lower BMI, RF/ACPA positivity, and bronchiectasis were associated with pNTM. Treatment for pNTM may attain sputum negative conversion and radiological improvement in patients with RA.

Preferences and Insights for Participation in a Rheumatoid Arthritis Clinical Prevention Trial: A Mixed-Methods Study.

In rheumatoid arthritis (RA), anti-citrullinated protein antibodies (ACPA) can be elevated prior to inflammatory arthritis (IA). The potential to intervene in people with ACPA positivity underpins the development of prevention trials in RA. The Research Participation Influences Study examined factors influencing the decisions of individuals who are ACPA(+) to participate in a prevention trial using qualitative and quantitative methods. Individuals with ACPA positivity without IA were provided information regarding their risk for future RA, were provided a description of a clinical prevention trial using hydroxychloroquine, and were asked if they would participate in the trial. After agreeing to or declining participation, they were surveyed on what influenced their decision using Likert scales and open-response questions. Thirty-nine individuals who agreed to trial participation (enrollees) and 31 individuals who declined (nonenrollees) completed surveys. Enrollees expressed greater perceived risk for RA and greater perception of benefit to themselves or others than nonenrollees. Nonenrollees expressed greater concern about medication effects and less personal or family experience with RA than enrollees. There was a higher proportion of first-degree relatives (FDRs) of people with RA in enrollees versus nonenrollees (54% vs. 23%, P = 0.01). Enrollees were more likely than nonenrollees to be FDRs, exhibit stronger concern for personal risk for RA, and have less concern about adverse effects. Further exploration is needed to determine why these differences were present, including exploration of symptoms and the role of family history. Understanding these issues will better inform researchers and individuals who are candidates for prevention.

Cerebrovascular reactivity depending on rheumatoid factor and anticitrullinated protein antibody positivity in hypertensive patients with rheumatoid arthritis

Objective – to investigate cerebrovascular reactivity (CVR) depending on rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in hypertensive patients with rheumatoid arthritis (RA).Subjects and methods. A single cross-sectional study included 61 patients (mean age 59.8±7.7 years; 6 men and 55 women) with combined RA and grade 1–2 hypertension (HTN). The duration of RA was 11.2±7.4 years. The duration of HTN was 12.1±8.6 years. All patients were treated with methotrexate. RA patients were categorized into RF/ACPA seronegative and RF/ACPA seropositive subgroups. CVR was evaluated by bilateral transcranial Doppler sonography of the middle cerebral arteries (MCA) in a hyperoxic test (O2 CVR) and in a hypercapnic test (CO2 CVR). We measured MCA mean blood flow velocity (Vmn), time average maximal blood flow velocity (TAMX), peak systolic velocity (Vps) at baseline, within 2 minutes of 100% oxygen inhalation and within 3 minutes of recovery phase (hyperoxic test). We calculated the following indicators for assessing CVR: index changes of flow velocity mean (IFVm), speed modification of velocity (SMFVm) and normalized answer of reserve (NAR). Then, according to the same scheme, we performed a hypercapnic test with the inhalation of a 4% mixture of carbon dioxide with air. Values are presented as Me [Q1 ; Q3 ].Results and discussion. Hypertensive patients with RA had a decrease in response power of MCA blood flow to hyperoxia. RF-seropositive RA patients had a more pronounced decrease in the power of the response to hyperoxia compared with RF-seronegative RA patients. The values of IFVm in the hyperoxic test were –13.4 [–19.9; –0.9] versus –16.2 [–22.7; –13.4]% (р=0.0453), respectively. ACPA-seropositive RA patients had not only a more pronounced decrease in the power of the response of MCA blood flow to hyperoxia, but also a more pronounced slowdown in the response velocity of MCA blood flow to hyperoxia compared with ACPA-seronegative RA patients. The values of IFVm in the hyperoxic test were –9.74 [–15.9; 2.84] versus –20.9 [–25.0; –14.7]% (р=0.0062), the values of SMFVm were –0.05 [–0.09; 0.02] versus –0.09 [–0.20; –0.05] sm/s2 (р=0.0488) respectively. Combined RA and HTN patients had a decrease in response power of MCA blood flow to hypercapnia. However, no statistical differences were found in the state of CO2 CVR between patients with seropositive RA and seronegative RA.Conclusion. Hypertensive patients with seropositive RA have a more pronounced O2 CVR disorder in compared to seronegative RA patients.

IgA rheumatoid factor in rheumatoid arthritis.

Rheumatoid factor (RF) is a well-established marker for the diagnosis and classification of rheumatoid arthritis (RA). Most studies evaluated IgM RF or isotype-nonspecific total RF assays. We evaluated the added value of IgA RF in this context. An international sample cohort consisting of samples from 398 RA patients and 1073 controls was tested for IgA RF with 3 commercial assays. For all RA patients and 100 controls essential clinical and serological data for ACR/EULAR classification were available. The sensitivity of IgA RF for diagnosing RA was lower than the sensitivity of IgM RF. Differences in numerical values between IgA RF assays were observed. With all assays, the highest IgA RF values were found inpatients with primary Sjögren's syndrome. Double positivity for IgM RF and IgA RF had a higher specificity for RA than either IgM RF or IgA RF. The sensitivity of double positivity was lower than the sensitivity of either IgA RF or IgM RF. Single positivity for IgA RF was at least as prevalent in controls than in RA patients. Adding IgA RF to IgM RF and anti-citrullinated protein antibodies (ACPA) did not affect RA classification. However, combined positivity for IgA RF, IgM RF and IgG ACPA had a higher specificity and lower sensitivity for RA classification than positivity for either of the antibodies. IgA RF showed a lower sensitivity than IgM RF. Combining IgA RF with IgM RF and ACPA did not improve sensitivity of RA classification. Combined positivity (IgA-RF/IgM-RF/ACPA) increased specificity.

Rheumatic?-A Digital Diagnostic Decision Support Tool for Individuals Suspecting Rheumatic Diseases: A Multicenter Pilot Validation Study.

IntroductionDigital diagnostic decision support tools promise to accelerate diagnosis and increase health care efficiency in rheumatology. Rheumatic? is an online tool developed by specialists in rheumatology and general medicine together with patients and patient organizations. It calculates a risk score for several rheumatic diseases. We ran a pilot study retrospectively testing Rheumatic? for its ability to differentiate symptoms from existing or emerging immune-mediated rheumatic diseases from other rheumatic and musculoskeletal complaints and disorders in patients visiting rheumatology clinics.Materials and MethodsThe performance of Rheumatic? was tested using in three university rheumatology centers: (A) patients at Risk for RA (Karolinska Institutet, n = 50 individuals with musculoskeletal complaints and anti-citrullinated protein antibody positivity) (B) patients with early joint swelling [dataset B (Erlangen) n = 52]. (C) Patients with early arthritis where the clinician considered it likely to be of auto-immune origin [dataset C (Leiden) n = 73]. In dataset A we tested whether Rheumatic? could predict the development of arthritis. In dataset B and C we tested whether Rheumatic? could predict the development of an immune-mediated rheumatic diseases. We examined the discriminative power of the total score with the Wilcoxon rank test and the area-under-the-receiver-operating-characteristic curve (AUC-ROC). Next, we calculated the test characteristics for these patients passing the first or second expert-based Rheumatic? scoring threshold.ResultsThe total test scores differentiated between: (A) Individuals developing arthritis or not, median 245 vs. 163, P < 0.0001, AUC-ROC = 75.3; (B) patients with an immune-mediated arthritic disease or not median 191 vs. 107, P < 0.0001, AUC-ROC = 79.0; but less patients with an immune-mediated arthritic disease or not amongst those where the clinician already considered an immune mediated disease most likely (median 262 vs. 212, P < 0.0001, AUC-ROC = 53.6). Threshold-1 (advising to visit primary care doctor) was highly specific in dataset A and B (0.72, 0.87, and 0.23, respectively) and sensitive (0.67, 0.61, and 0.67). Threshold-2 (advising to visit rheumatologic care) was very specific in all three centers but not very sensitive: specificity of 1.0, 0.96, and 0.91, sensitivity 0.05, 0.07, 0.14 in dataset A, B, and C, respectively.ConclusionRheumatic? is a web-based patient-centered multilingual diagnostic tool capable of differentiating immune-mediated rheumatic conditions from other musculoskeletal problems. The current scoring system needs to be further optimized.

P282 ANA seroconversion during prior anti-TNF therapy abolishes anti-CCP antibody positivity as a predictor of abatacept retention in rheumatoid arthritis

Abstract Background/Aims Few long-term drug survival analyses have been reported for patients with rheumatoid arthritis (RA) treated with abatacept. Here we report a machine learning approach to investigate drug-survival of abatacept over 5 years in RA patients. Methods We performed a retrospective observational study on a tertiary hospital dataset of RA patients who started abatacept between January 2008 and December 2020. Time to abatacept discontinuation over 5 years was estimated using Kaplan-Meier survival analyses. A multivariate cox-proportional hazard model to predict abatacept discontinuation was chosen by random survival forest and partial least regression. Results A total of 112 RA patients (81% female, mean age 58.1 [SD 13.5] years) received abatacept. Mean disease duration was 18.3 months (SD 13.6). More than half (65/112) were co-prescribed at least one conventional synthetic DMARD (csDMARD). Methotrexate was the most frequently concomitant csDMARD (n = 37), followed by hydroxychloroquine (n = 23), sulfasalazine (n = 15), and leflunomide (n = 7). 42 (37.5%) patients were treated with glucocorticoids (intermittent or continuous) with abatacept. Abatacept was mostly used as 4th (n = 29) and 3rd line (n = 24) bDMARD, but 19 patients received abatacept as their first line bDMARD. 75 (67%) patients were rheumatoid factor (RF) positive and 73 (65.2%) were anti-citrullinated protein antibody (ACPA) positive. Anti-nuclear antibody (ANA) was positive (≥1:80) in 25 patients (pre-biologics) and 18 seroconverted to previously exposed anti-TNF (ANA seroconversion group). Abatacept was discontinued in 54 patients (48.2%); 19 (35.2%) due to an adverse event and 35 (64.8%) due to loss of efficacy. Overall, the median time to discontinuation of abatacept was 3.8 years. Multivariate cox-proportional hazard model revealed that ACPA positivity was associated with reduced risk of abatacept discontinuation with HR of 0.56 (95% CI 0.32-0.95,p=0.03) compared to the ACPA-negative group. In contrast, the ANA seroconversion group demonstrated worse retention of abatacept with HR of 2.67 (95% CI 1.39-5.16, p = 0.0033) compared to ANA-negative patients. Kaplan-Meier analysis demonstrated that in the ANA seroconversion group, retention of abatacept was significantly inferior to pre-anti-TNF ANA positive patients (p = 0.0084) and ANA-negative patients (p = 0.0041). ACPA positivity was associated with better survival only in the non-ANA seroconverted group with HR of 0.54 (95% CI 0.29-0.92, p = 0.041), after adjusted by propensity score. Combining abatacept with any csDMARDs reduced the risk of abatacept discontinuation with HR of 0.57 (95% CI 0.33-0.98, p = 0.043) after adjusting by propensity score. No statistical difference was found between first-line, second-line, or any subsequent chronology of use of abatacept. Conclusion Our data suggest that previous ANA seroconversion occurring whilst on anti-TNF therapy reduces subsequent abatacept retention and cancels out the protective effect of anti-CCP positivity. The mechanism through which this occurs is unclear and further prospective and mechanistic studies are needed to validate these findings. Disclosure J. Kimpton: None. M. Shipa: Grants/research support; MS is funded by Versus Arthritis. S. Yeoh: Grants/research support; SY is funded by the Royal College of Physicians, Rosetrees Trust, NIHR University College London Hospitals Biomedical Research Centre, UCLH Charities, and Versus Arthritis. E. Hawkins: None. M. Ehrenstein: Grants/research support; ME is supported (in part) by the University College London Hospital Biomedical Research Centre.

Association of Polygenic Risk Scores With Radiographic Progression in Patients With Rheumatoid Arthritis.

To investigate whether polygenic risk scores obtained using data from a genome-wide association study (GWAS) of rheumatoid arthritis (RA) susceptibility can be predictors of radiographic progression. We constructed polygenic risk scores using GWAS summary data on associations of single-nucleotide polymorphisms with RA susceptibility. The polygenic risk scores were stratified into quintiles based on levels of significance (ranging from top quintile of polygenic risk scores to bottom quintile). In addition, change in the Sharp/van der Heijde score (SHS) of radiographic progression over the first 5 years after onset of RA was assessed. The change in SHS over 5 years was stratified according to quartiles, with the top quartile of change in SHS defined as severe radiographic progression (score change of >35 points) and the remaining 3 quartiles defined as nonsevere radiographic progression. Polygenic risk scores were assessed for their ability to predict the SHS status over 5 years in a training set (n = 500 RA patients) for selection of the best model, and in a testing set (n = 740 RA patients) for validation of the data. We evaluated the performance of the polygenic risk score as a predictor of severe radiographic progression in univariable and multivariable analyses with inclusion of other factors. Polygenic risk scores constructed from 43,784 single-nucleotide polymorphisms significantly differed between patients who experienced severe radiographic progression and those with nonsevere radiographic progression in both the training set (P = 0.0064) and the testing set (P = 0.017). Patients with polygenic risk scores in the top quintile had a higher risk of severe progression compared to those with polygenic risk scores in the bottom quintile (odds ratio [OR] 1.90, P = 0.0022), and the risk of severe radiographic progression was even higher when restricted to patients who were younger at disease onset (OR 5.06, P = 0.00038). The group with polygenic risk scores in the top quintile and the anti-citrullinated protein antibody (ACPA)-positive group had significantly higher proportions of patients with severe radiographic progression (P = 0.00052 and P = 0.0022, respectively) compared to the remaining groups. Multivariable analysis showed that polygenic risk score (P = 0.00019) as well as female sex (P = 0.0033), ACPA positivity (P = 0.0023), and body mass index (P = 0.024) were independent risk factors for severe radiographic progression. A polygenic risk score that is derived from GWAS data on RA susceptibility is associated with the level of severity of radiographic progression in patients with RA.

Rheumatoid arthritis, as a clinical disease, but not rheumatoid arthritis-associated autoimmunity, is linked to cardiovascular events

BackgroundRheumatoid arthritis (RA) is characterized by increased cardiovascular (CV) mortality. CV events are particularly high in patients with RA-specific autoimmunity, including rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), raising the question whether RA-specific autoimmunity itself is associated with CV events.MethodsNew CV events (myocardial infarction, stroke or death by CV cause) were recorded in 20,625 subjects of the Electricité de France – Gaz de France (GAZEL) cohort. Self-reported RA cases in the GAZEL cohort were validated by phone interview on the basis of a specific questionnaire. In 1618 subjects, in whom plasma was available, RF and ACPA were measured. A piecewise exponential Poisson regression was used to analyze the association of CV events with presence of RA as well as RA-specific autoimmunity (without RA).ResultsCV events in GAZEL were associated with age, male sex, smoking, hypertension, hyperlipidemia, and diabetes mellitus (HR from 1.06 to 1.87, p < 0.05). Forty-two confirmed RA cases were identified. Confirmed RA was significantly associated with CV risk increase (HR of 3.03; 95% CI: 1.13–8.11, p = 0.03) independently of conventional CV risk factors. One hundred seventy-eight subjects showed RF or ACPA positivity without presence of RA. CV events were not associated with ACPA positivity (HR: 1.52, 95% CI: 0.47–4.84, p = 0.48) or RF positivity (HR: 1.15, 95% CI: 0.55–2.40, p = 0.70) in the absence of RA.ConclusionsRA, as a clinical chronic inflammatory disease, but not mere positivity for RF or ACPA in the absence of clinical disease is associated with increased CV risk.