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Background/Aims The effects of antinuclear antibodies (ANA) in rheumatoid arthritis (RA) are not fully characterised. Studies investigating the effect of ANA on disease activity in RA have yielded mixed results. The presence of ANA has been correlated with higher levels of CRP and joint inflammation in RA. Evidence suggests that ANA positivity at baseline may predict poor response to both traditional disease modifying agents and biologic therapy. ANA may also be associated with higher incidences of ocular disease, Felty’s syndrome, vasculitis and subjective pain in RA patients. On the other hand, other studies showed a lack of correlation between ANA status and joint inflammation in RA. Our study investigates the relationship between ANA positivity and joint erosions in rheumatoid patients. Methods This is a cross-sectional study of patients attending the early arthritis clinic at Northwick Park Hospital in London over a five year period (2014-2019). A total of 631 patients were identified of whom 261 had RA. We collected data on the age, gender, ANA positivity, the presence of anti-CCP (anti cyclic-citrullinated peptide) antibodies and rheumatoid factor (RF) at presentation as well as the presence of erosive disease on radiological reports of hand X-rays. Positive ANA was defined as having a titre of 1:80 or greater. Patients with missing ANA result or hand X-ray reports were excluded, leaving 228 patients. Two-tailed Chi-square tests for categorical data and two-tailed student’s t-tests for continuous data were performed to determine the statistical significance of comparisons made between the ANA positive and negative groups. Results Of the 228 patients, 49 (21.5%) were male and 179 (78.5%) were female. The mean age was 58 years. 84 (36.8%) patients were ANA positive (group 1) and 144 (63.2%) were ANA negative (group 2). In group 1, 23/84 (27.4%) patients had erosive disease. In group 2, erosions were found in 25/144 patients (17.4%). This difference was not statistically significant (p = 0.073). The number of patients who were RF positive in groups 1 and 2 were 79.5% and 73.6% respectively (p = 0.317); 75/84 (89.3%) patients in group 1 and 113/143 (79.0%) in group 2 were anti-CCP antibody positive (p = 0.048). The means of the age of patients were 53 and 62 years in group 1 and group 2 respectively (p < 0.0001); the ANA positive group was significantly younger. The male:female ratio was 13:71 in group 1 and 36:108 in group 2 (p = 0.091). Conclusion Our study showed no significant association between ANA status and erosive disease in RA, although a greater proportion of patients had erosions in the ANA positive group. Larger observational studies may better study this relationship. Disclosure T. Guruparan: None. M. Hutchinson: None. R. Hayward: None. H. Penn: None. P. Kalia: None.

Background In anti-cyclic citrullinated peptide antibody-positive (ACPA+) individuals without clinical synovitis (at-risk), to define the critical ultrasound (US) features sufficiently predictive for inflammatory arthritis (IA) to enable logical initiation of therapy. Methods In a single centre prospective cohort, at risk ACPA+ individuals with a new musculoskeletal symptoms underwent an US scan of 38 joints and 18 tendons at first visit. The predictive value of US abnormalities (Power Doppler (PD), Grey Scale (GS), erosion or tenosynovitis (TSV)) for progression to IA was analysed and the best predictive joints determined by Multivariable Cox Regression, adjusted for confounders. The US results were combined with clinical symptoms/findings to produce predictive models. Results Consecutive at-risk ACPA+ individuals (n = 457, mean age 50.3 years old, 74.2% women) were followed up for median of 15.4 months (range 0.1-127.4), a complete dataset with follow-up of at least 6 months was available for 319 of them. 135 (29.5%) developed IA after a median of 11.3 months (range 0.1-111.7). The negative predictive value of a US scan without any abnormality was 82%. In multivariable Cox regression, both PD and TSV were predictive of progression, with respectively hazard ratios of 1.2 (9=0.026) and 1.13 (p = 0.025). All US abnormalities had a high specificity (spec) but only moderate sensitivity (sens), PD was the most specific with a spec/sens of 0.94/0.23, followed by TSV with a spec/sens of 0.91/0.26 but the best area under the curve (AUC) of 0.599 (P = 0.0015). The addition ACPA titre (high compared to low), but not GS, improved spec/sens up to 0.92/0.34 and AUC to 0.964 (p < 0.001). A selection of US and clinical data of 14 joints also improved prediction, with an AUC of 0.670 (p < 0.001) and a spec/sens of 0.65/0.62. A selection of the 34 most predictive features reached the same sens/spec as the ACR/EULAR 2010 classification criteria for RA, showing a spec/sens of 0.80/0.56. Conclusion In at-risk ACPA+ individuals, the presence of sub-clinical US abnormalities are highly specific for progression to IA. The only moderate sensitivity can be improved by using joints or features selection in combination with clinical examination. These results are the first step in providing guidance for which at-risk ACPA+ individuals to treat. Disclosures L.M. Duquenne None. K. Mankia None. L. Garcia Montoya None. A. Di Matteo None. J. Nam None. P. Emery None.

Background Anti-citrullinated peptide antibodies (ACPA) are important biomarkers in rheumatoid arthritis (RA) and can predict arthritis development in at-risk individuals. ACPA are conventionally detected using the second-generation or third generation IgG anti-CCP antibody (Ab) assays. Although the value of anti-CCP2 Ab for predicting progression to RA in at-risk individuals is well understood, very little knowledge exists for anti-CCP3.The objectives of this study were: i) To evaluate the prevalence of serum anti-CCP3 Ab in serum anti-CCP2 Ab positive at-risk individuals (CCP2+ at-risk); ii)) To study the incremental value of anti-CCP3 Ab in CCP2+ at-risk subjects for predicting progression to clinical inflammatory arthritis (IA). Methods Anti-CCP3 Ab were tested on stored serum samples obtained from 347 CCP2 + (BioRad, USA) at-risk individuals from the Leeds CCP study. Anti-CCP2 and anti-CCP3 tests positivity threshold was >2.99 IU/ml and >20 units, respectively. Moreover, anti-CCP2 and anti-CCP3 titres were categorised according to manufacturer’s cut-off: low (LT) and high (HT) for anti-CCP2, negative/weak/moderate/strong for anti-CCP3. Progression to IA was defined as the development of clinical synovitis in at least one joint. Only subjects with at least one follow-up visit were included in the progression analysis (n = 317). Results Anti-CCP3 Ab were negative in 138/347 (39.7%) CCP2+ individuals, and weakly, moderately, and strongly positive in 15/347 (4.3%), 5/347 (1.4%) and 189/347 (54.4%) individuals, respectively. LT and HT anti-CCP2 Ab were found in 103/347 (29.7%) and in 244/347 (70.3%) individuals, respectively. Eighty-eight/317 subjects (28%) developed IA. The rate of progression of LT and HT anti-CCP2, when anti-CCP3 was negative, decreased from 6.5% to 2.7%, and from 36.6% to 9.4%, respectively. Progression in anti-CCP2 HT increased from 36.6% to 45.6% when anti-CCP3 was positive (Table 1). Conclusion Our results support an important role for anti-CCP3 Ab in improving prediction of IA in CCP2+ at-risk individuals. Disclosures A. Di Matteo None. K. Mankia None. L. Duquenne None. M. Mahler Other; Inova Diagnostic. D. Corscadden None. K. Mbara None. L. Garcia-Montoya None. J. Nam None. P. Emery Honoraria; AbbVie, BMS, Bristol-Myers Squibb, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Samsung, Samsung Bioepis Co., Ltd.

Background This study aims to estimate the influence of air pollution ambients using the Air Quality Index (AQI) to Rheumatoid Arthritis (RA) disease activity. Disease Activity Score with 28 examined joints (DAS-28) and Clinical Disease Activity Index (CDAI) considered as disease activity indices for RA patients in the state of Kuwait. Methods Data for patients with RA disease were collected from Kuwait Registry for Rheumatic Diseases (KRRD) from 2013 to 2017. Moreover, data on air pollution obtained from The Kuwait Environmental Public Authority (K-EPA) during the same period. Statistical analysis was conducted using STATA to highlight the significant association between study variables. Descriptive statistics, correlation analysis and linear regression model techniques were employed to estimate the significant associations between RA disease activity represented by DAS-28 and CDAI; with air pollution components (PM10, NO2, SO2, O3, and CO). Multiple Imputation by Chained Equations (MICE) algorithm was also employed to tackle the value of the missing data for air pollution data. Results Total of 9,875 patients visits included in the analysis that matching with air pollution information from K-EPA database according to date and patient living address governorate. The study found SO2 and NO2 were significantly associated with RA disease activity using DAS-28 index, also, for CDAI index as well. For the score of RA disease activity using DAS-28 index, the correlation results show a positive significant correlation with exposure of SO2 using AQI (rp = 0.07), also the same results with the with the exposure of NO2 using AQI (rp = 0.07). The final model is demonstrating the effect from air-pollutants gaseous with RA factors (Swollen, RF, anti-CCP, ESR, CRP) on RA disease activity. The AQI of NO2 and SO2 still showed positive associations with disease activity performance of RA. The linear regression model shows a positive effects of NO2 (beta = 0.003, 95% CI: 0.002-0.005) and (beta = 0.048, 95\% CI: 0.030-0.066) for DAS-28 and CDAI respectively, where for SO2, the results shows positive significant effect with (beta = 0.003, 95% CI: 0.0004-0.005) and (beta = 0.044, 95% CI: 0.018-0.070) for DAS-28 and CDAI respectively. Conclusion In conclusion, our study showed that air ambients were significantly correlated to RA disease activity scores and should be considered as a possible risk factor for RA activity. Disclosures A.R. Alsaber None. J. Pan None. A. Al-Herz None. D.S. Alkandary None. A. Al-Hurban None. P. Setiya None.

Background The presence of antibodies against cyclic citrullinated proteins (anti-CCP) precede the development of rheumatoid arthritis (RA) and both anti-CCP antibody and RF positivity indicate more severe disease. This characteristic makes Anti-CCP best biomarker candidate for the prevention of debilitating joint disease. Almost 70% of RA patients are positive for anti-CCP IgG, while only 2% of control subjects are positive for anti-CCP. Understanding the origins of anti-CCP is critical in unraveling the etiology of RA, so we further evaluated the association of the other autoimmune tests/biomarkers with Anti-CCP to describe other comorbid autoimmune diseases/syndrome. Methods We conducted a retrospective analysis of patient data from April 18, 2016, to May 29, 2019, in Texas. The study protocol was approved by the ethics review committee and patients consented for sharing their demographics, clinical information and lab values for diagnostic and research purposes. The study population was described by descriptive statistics. Demographic characteristics and laboratory parameters were compared using chi-square tests. We analyzed blood tests/parameters conducted at the clinics and explored their association with the presence of ACCP. logistic regression models were utilized to calculate the odds ratio to delineate the strength of association of different blood parameters with ACCP. IgG anti-CCP was determined according to the manufacturer’s instruction. Results Eleven thousand, four hundred fifty-nine tests were performed on 7,200 patients with a mean age of 52 years (range 0-98). Almost half (54%) of study individuals were females, two-third (63%) were White, (29%) Hispanic and (7%) African American. Four hundred and six patients (3.5%) were positive for AntiCCP3.1. Among those who were positive for AntiCCP3.1, (22%) were Rh factor IgA (RhIgA) positive, (11%) RhIgG positive, and (9%) RhIgM. Univariate logistic regression showed that the female gender was positively associated (OR = 3.19) with ACCP presence while patients older than 50 had a positive gradient of ACCP positivity with each age category. Compared to White, African Americans were more likely (OR = 3.19) and Hispanics were less likely (OR = 0.44) to be associated with AntiCCP positivity. After controlling for age, gender and ethnicity the presence of RhIgM and RhIgA antibodies were positively associated with positive ACCP. (OR = 13.3, OR = 5.2). antiphosphatidylserine IgM and anticardiolipin IgM antibodies were positively associated with ACCP (OR = 2.1, OR = 3.4). Similarly, the presence of antimitochondrial M2 antibodies and anti-topoisomerase antibodies (SCL-70) were very significantly associated with ACCP (OR = 16.1, OR = 37.8). Conclusion The Anti-CCP antibodies are highly specific for the early diagnosis of RA and with early initiation of treatment, progression to irreversible and destructive diseases can be prevented. Association of Anti-CCP antibodies with other autoimmune antibodies highlights the importance of screening RA patients for primary biliary sclerosis and scleroderma. Similarly, a biomarker's strength of interaction with another biomarker helps in the prognostic utility of these test for preventing co-existing diseases. Disclosures M. Ayass: Other; Physician at Ayass Bioscience. K. Zhu: Other; Employee at Ayass Bioscience. S. Naveed: None. L. Mosleh: Other; Employee at Ayass Bioscience. K. Viswanathan: Other; Employee at Ayass Bioscience. G. Nowshad: Other; Employee at Ayass Bioscience.

Objectives Autophagy may represent a functional processing event that creates a substrate for autoreactivity. In particular, autophagy may play a role in the pathogenesis of RA, since autophagy is a key cellular event involved in the generation of citrullinated peptides, with consequent breakage of tolerance. Thus, in RA, autophagy may be the common feature in several situations (including smoking, joint injury and infection) that may drive the adaptive responses to citrullinated self-proteins. The aim of this study was the analysis, in vitro, of the role of autophagy in the generation of citrullinated peptides and, in vivo, of the relationship between autophagy and the production of anti-CCP antibodies (Abs). Methods For autophagy induction, fibroblast-like synoviocytes, primary fibroblasts and monocytes were stimulated with tunicamycin or rapamycin. Peptidyl arginine deiminase activity was tested by enzyme-linked immunosorbent assay, and protein citrullination was evaluated by western blotting. The main citrullinated RA candidate antigens, vimentin, α-enolase and filaggrin, were demonstrated by immunoprecipitation. The relationship between autophagy and anti-CCP Abs was analysed in 30 early-active RA patients. Results Our results demonstrated in vitro a role for autophagy in the citrullination process. Cells treated with tunicamycin or rapamycin showed peptidyl arginine deiminase 4 activation, with consequent protein citrullination. Immunoblotting and immunoprecipitation experiments, using specific Abs, identified the main citrullinated proteins: vimentin, α-enolase and filaggrin. In vivo, a significant association between levels of autophagy and anti-CCP Abs was observed in treatment-naive early-active RA patients. Conclusion These findings support the view that the processing of proteins in autophagy generates citrullinated peptides recognized by the immune system in RA.

Objective. To evaluate, firstly, all published data on baseline and annual progression rates of radiographic damage from all longitudinal observational cohorts, and secondly, the association of standard clinical and laboratory parameters with long-term radiographic joint damage. Methods. A comprehensive search of the literature from 1975 to 2014, using PubMed, SCOPUS and Cochrane databases, identified a total of 28 studies that investigated long-term radiographic progression, and 41 studies investigating predictors of long-term radiographic progression. This was submitted and approved by PROSPERO in February 2014 (Registration Number: CRD42014007589). Results. Meta-analysis indicated an overall baseline rate of 2.02%, and a yearly increase of 1.08% of maximum damage. Stratified analysis found that baseline radiographic scores did not differ significantly between cohorts recruiting patients pre- and post-1990 (2.01% vs 2.03%; P > 0.01); however, the annual rate of progression was significantly reduced in the post-1990 cohorts (0.68% vs 1.50%; P < 0.05). High levels of acute phase markers, baseline radiographic damage, anti-CCP and RF positivity remain consistently predictive of long-term radiographic joint damage. Conclusion. Critical changes in treatment practices over the last three decades are likely to explain the reduction in the long-term progression of structural joint damage. Acute phase markers and presence of RF/anti-CCP are strongly associated with increased radiographic progression.

Objective. The aim of this study was to investigate omega-3 fatty acid (FA) supplement use and omega-3 FAs in erythrocyte membranes [omega-3 FA % in erythrocyte membranes (RBC)] and their association with anti-CCP autoantibodies in a population without RA, but who are at genetic risk for RA. Methods. The multicentre Studies of the Etiology of RA (SERA) cohort includes RA-free subjects who are first-degree relatives of RA probands or are enriched with the HLA-DR4 allele. In a nested case-control study, 30 SERA cases were identified who were anti-CCP2 antibody positive. We further identified 47 autoantibody negative controls, frequency matched to cases on age at study visit, sex, race and study site. Anti-CCP2 status, self-reported omega-3 FA supplement use and omega-3 FA % in RBCs were obtained from a single visit. Results. Anti-CCP2 positive cases were less likely than controls to report omega-3 FA supplement use (odds ratio: 0.14; 95% CI 0.03, 0.68). In addition, the likelihood of anti-CCP2 positivity was inversely associated with total omega-3 FA % in RBCs (odds ratio: 0.47; 95% CI 0.24, 0.92, for a s.d. increase). Conclusion. The inverse association between anti-CCP2 positivity and self-reported omega-3 FA supplement use and omega-3 FA % in RBCs suggests that omega-3 FAs may protect against the development of RA-related autoimmunity in pre-clinical RA.

Objectives. To evaluate the prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and RF in RA patients and their relatives from Southern Brazil. Methods. Anti-CCP2 and IgM-RF were evaluated in 156 RA patients and 200 relatives. Sera from 100 healthy unrelated individuals were used as control. The anti-CCP2 was detected by ELISA and the IgM-RF using the latex agglutination test. Results. We identified 117 anti-CCP2 (75%)-positive and 106 RF (67.9%)-positive patients. Anti-CCP2 was increased in relatives (5.5%; 11/200) when compared with unrelated individuals (1%; P = 0.050). Titre of anti-CCP2 in RA patients did not differ from relatives [140.4 (75.7) vs 115.6 (84.2) U, respectively; P = 0.30]. Positive relatives were younger than patients for anti-CCP2 (P = 0.0081), RF (P < 0.001) and both concomitantly (P = 0.012), and although there was no difference for anti-CCP2 positivity according to gender, increased RF positivity and concomitant anti-CCP2/RF were observed in the female relatives (P = 0.067 and 0.082, respectively). No difference regarding the relative degree of tobacco use in relatives was detected. Among the 11 anti-CCP2-positive relatives, 2 females had RA diagnosis established and 6 individuals presented with joint symptoms suggestive of RA. Conclusion. The results demonstrate a significant positivity of anti-CCP2 in relatives of RA patients from Brazil and reinforce the importance of serological tools to identify undiagnosed RA.

Objective To evaluate antibodies against cyclic citrullinated peptide (anti-CCP antibodies) for their predictive value for severe joint destruction in rheumatoid arthritis (RA) and to examine their relationship to shared epitope (SE)-positive DRB1 alleles. Methods Concentrations of anti-CCP antibodies were determined in sera from 126 patients with recent onset RA who had been followed prospectively for 6 yr. Progression of joint destruction was evaluated according to Larsen by scoring radiographs from the hand and feet taken at baseline and after 1, 2, 4 and 6 yr of observation. In addition to clinical parameters, the presence of SE-positive DRB1 alleles and of rheumatoid factor IgM and IgA was determined. Results Anti-CCP antibodies were found more frequently and in higher concentrations in both DRB1*01-positive and in DRB1*04-positive SE-positive patients compared with SE-negative patients. Severe joint destruction as defined by a Larsen score in the upper third of the study population was predicted by positivity for anti-CCP antibodies, by the presence of SE-positive DRB1*04 alleles and by the presence of erosive disease at initial presentation. Multiple logistic regression analysis revealed that SE-positive DRB1*04 alleles and anti-CCP antibodies exerted a significant influence on the progression of joint destruction. Conclusion The association of anti-CCP antibodies with DRB1*01 and with SE-positive DRB1*04 alleles implies a functional role for the SE sequence motif. The determination of SE-positive DRB1*04 alleles and of anti-CCP antibody positivity facilitates the prediction of disease course and prognosis at the time of initial presentation.

Objectives. Antibodies recognizing a cyclic citrullinated peptide (anti-CCP) are highly specific for rheumatoid arthritis (RA) but their role in psoriatic arthritis (PsA) remains unclear. The aim of this study was therefore to investigate the prevalence of anti-CCP antibodies in PsA and assess their clinical and genetic associations. Methods. One hundred and twenty-six patients with PsA, 40 patients with seropositive RA and 40 controls were tested for the presence of anti-CCP antibodies, rheumatoid factor (RF) and the HLA-DRB1 shared epitope. Clinical and radiological data were collected prospectively on all patients and compared between anti-CCP-positive and -negative patients. Results. Seven (5.6%) patients with PsA were positive for anti-CCP antibodies compared with 0% of controls and 97% of patients with seropositive RA. The presence of anti-CCP antibodies in PsA was significantly associated with the HLA-DRB1 shared epitope (P