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ObjectivesTo investigate the clinical value of detecting anti–mutated citrullinated vimentin (anti-MCV), anti-citrullinated peptide (anti-CCP), red-blood-cell distribution width (RDW), and 25-hydroxyvitamin D (25-[OH]D) in the diagnosis of rheumatoid arthritis (RA).MethodsWe enrolled 119 patients with RA, 114 control individuals without RA (disease controls), and 40 healthy controls in our study (Han Chinese). Anti-CCP and anti-MCV were detected by enzyme-linked immunosorbent assay (ELISA), 25-(OH)D was detected by electrochemical luminescence, and RDW was calculated by erythrocyte parameters detected via the electric resistance method.ResultsThe serum levels of anti-CCP and anti-MCV in RA were higher than those in disease controls and healthy controls (P ConclusionsAnti-CCP and anti-MCV are ideal indices for RA diagnosis. Also, in combination with RDW and 25-(OH)D, the diagnostic level will be improved, as well as the sensitivity and specificity, which is significant for the differential diagnosis of RA.

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.

ObjectivesLittle is known about the likelihood of developing inflammatory arthritis (IA) in individuals who screen autoantibody positive (aAb+) in a non-clinical research setting.MethodsWe screened for serum cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor isotype aAbs in subjects who were at increased risk for rheumatoid arthritis (RA) because they are a first-degree relative of an individual with classified RA (n=1780). We evaluated combinations of aAbs and high titre aAbs, as defined by 2-times (2 x) the standard cut-off and an optimal cut-off, as predictors of our two outcomes, aAb+ persistence and incident IA.Results304 subjects (17.1%) tested aAb+; of those, 131 were IA-free and had at least one follow-up visit. Sixty-four per cent of these tested aAb+ again on their next visit. Anti-CCP+ at levels ≥2 x the standard cut-off was associated with 13-fold higher likelihood of aAb +persistence. During a median of 4.4 years (IQR: 2.2–7.2), 20 subjects (15.3%) developed IA. Among subjects that screened anti-CCP+ at ≥ 2 x or ≥an optimal cut-off, 32% and 26% had developed IA within 5 years, respectively. Both anti-CCP cut-offs conferred an approximate fourfold increased risk of future IA (HR 4.09 and HR 3.95, pConclusionsThese findings support that aAb screening in a non-clinical setting can identify RA-related aAb+ individuals, as well as levels and combinations of aAbs that are associated with higher risk for future IA. Monitoring for the development of IA in aAb+ individuals and similar aAb testing approaches in at-risk populations may identify candidates for prevention studies in RA.

Introduction Idiopathic inflammatory myopathies (IIM) have long been diagnosed using a defined number of clinical criteria (Bohan and Peter). The emergence of new myositis specific antibodies (MSAs) and their relation to specific disease phenotypes may be useful in establishing a new clinical-serological diagnostic criteria for different disease presentations and thus help to determine management and prognosis. We present a case of dermatomyositis (DM) where limb subcutaneous oedema; a rare manifestation of the disease, and severe dysphagia were prominent clinical features in addition with the presence of anti-small ubiquitin-like modifier activating enzyme (SAE) antibodies. Case description A 63-year-old Pakistani male presented with weight loss, anorexia, odynophagia, and a rash over his scalp, chest, face and flexor surfaces. Initial blood results revealed hypoalbuminaemia, CRP 7mg/L and ESR 37mm/h. A CT chest revealed an anterior mediastinum soft tissue mass suggestive of necrosis, with multiple ill-defined nodes throughout the lungs. An endoscopy revealed severe gastritis. Oropharyngeal examination revealed pooling of saliva and mucositis. Ceftriaxone was commenced for a presumed infective aetiology. Video fluoroscopy confirmed pharyngeal dysphagia with aspiration. Examination demonstrated a non-fatigable bulbar sounding dysarthria. There was no tongue wasting or fasciculations. Power was globally reduced, with marked proximal upper and lower limb weakness. Nerve conduction studies revealed normal sensation, and most motor nerves had normal conduction velocities with small nerve responses. Electromyography showed areas with denervation. With no improvement in the patient’s condition, anti-tuberculosis and anti-fungal therapy were commenced, with pulsed methylprednisolone for three days followed by 80mg daily to cover for an organizing pneumonia. Subsequent cultures were negative. Progressive weight loss with muscle wasting ensued and later, facial hyperpigmentation was noted in addition to the development of facial, lip and arms swelling. He was rheumatoid factor positive >500 iu/ml, with a raised IgE 2912 g/L and IgG 37.6 g/L. A CT-PET scan revealed intense uptake in the muscles posterior of the neck, tongue and masticators. An MRI scan of his arms revealed several abnormal signals around the shoulder girdle, long muscles of the back, and upper arm, which guided the site for muscle biopsy. This revealed highly abnormal skeletal muscle with frequent atrophic and necrotic fibres overrun by macrophages and T-cell rich inflammation. These findings in addition to serology reporting the presence of anti-SAE antibodies confirmed the diagnosis. Pulsed methylprednisolone, immunoglobulin therapy, and azathioprine were initiated with reducing prednisolone dose. Discussion This case of DM with a generalised rash, severe dysphagia and limb subcutaneous oedema were salient features in addition to the presence of anti-SAE antibodies. Anti-SAE has been shown to be present exclusively in DM patients where rash and severe dysphagia are common clinical findings. Our patient presented with severe dysphagia, which can be difficult to manage requiring enteral feeding. Video fluoroscopy was particularly useful in this case helping to stratify the severity of dysphagia and we would urge other clinicians to use this tool when investigating patients with suspected dermatomyositis to avoid potential complications of poor swallow including aspiration pneumonia. The additional imaging modality of PET-CT in our case confirmed the involvement of the muscles of mastication thus could prove a useful tool when investigating involvement of swallowing muscles in patients with anti-SAE DM. Skin features are another common finding in the anti-SAE group and our patient had a heliotrophic rash and shawl sign, which responded poorly to treatment. We describe the additional feature of severe subcutaneous limb and facial oedema, a rare manifestation of the disease, described in only a few other cases. Limb subcutaneous oedema is thought to reflect underlying severe muscle disease, is difficult to treat, and often is unresponsive to conventional treatment. Our case, and several other cases with the presence of limb oedema as reported in a literature search, required treatment with intravenous immunoglobulin and glucocorticoids, in addition with azathioprine and methotrexate. This is the first reported case to our knowledge of a patient with positive ANA, RF, anti-ccp, and anti-small ubiquitin-like modifier activating enzyme (anti-SAE) antibodies. Key learning points The finding of anti-SAE in our case where severe dysphagia was present provides further weight to this antibody being a useful serological marker to identify this subgroup of DM patients. Identifying this antibody may be helpful in creating management strategies for these patients and determining disease progression and prognosis. The presence of limb and facial oedema may be an overlying feature of the anti-SAE group; however, previous cases of limb oedema have not identified this antibody as the SAE test was unavailable. The presence of severe dysphagia and subcutaneous oedema suggests the presence of anti-SAE lends itself to a clinical phenotype of DM that is particularly severe and requires multidisciplinary input. Conflicts of interest The authors have declared no conflicts of interest.

Synovial IgG-expressing B cells from patients with rheumatoid arthritis show specificity for citrullinated autoantigens., Antibodies targeting citrullinated proteins (ACPAs [anticitrullinated protein antibodies]) are commonly found in patients with rheumatoid arthritis (RA), strongly associate with distinct HLA-DR alleles, and predict a more aggressive disease course as compared with seronegative patients. Still, many features of these antibodies, including their site of production and the extent of MHC class II–driven T cell help, remain unclarified. To address these questions, we have used a single B cell–based cloning technology to isolate and express immunoglobulin (Ig) genes from joint-derived B cells of active RA patients. We found ∼25% of synovial IgG-expressing B cells to be specific for citrullinated autoantigens in the investigated ACPA+ RA patients, whereas such antibodies were not found in ACPA− patients. The citrulline-reactive monoclonal antibodies did not react with the unmodified arginine peptides, yet several reacted with more than one citrullinated antigen. A role for active antigen selection of the citrulline-reactive synovial B cells was supported by the strong bias toward amino acid replacement mutations in ACPA+ antibodies and by their loss of reactivity to citrullinated autoantigens when somatic mutations were reverted to the corresponding germline sequences.

We studied the diagnostic value of high-frequency color Doppler ultrasonography (HCDU) examination in combination with anti-cyclic citrullinated peptide (anti-CCP) antibody testing in rheumatoid arthritis (RA) patients with finger joint damage. From January 2015 to December 2015, 80 patients diagnosed with RA with finger joints damage were enrolled in this study. Patients were examined with HCDU. Serum anti-CCP antibody level was tested using ELISA, and results were compared with the healthy control group. Results obtained by ELISA demonstrated that the positive rate of anti-CCP antibodies was 73.8% in the study group, and 10% in the control group. The negative rate was 26.2% in the study group, and 90% in the control group. HCDU examination suggested that the predominantly affected joint by bone erosion of RA with finger joint damage was MCP3 (16.7%), followed by PIP3 (14.1%), MCP2 (13.5%) and PIP2 (12.8%). The slightest affected joint was thumb metacarpophalangeal joint, followed by thumb, little finger metacarpophalangeal joint and proximal interphalangeal joint. The sensitivity of diagnosis of RA with finger joints damage with both HCDU and CCP antibody examination showed a significantly lower level compared with examination with each one of the methods alone, while specificity showed a significantly higher level. Thus, a combination of HCDU examination and anti-CCP antibody testing can be considered useful to improve the early diagnostic rate of RA. HCDU examination is a sensitive, secure, atraumatic and easily-operated diagnostic method for early RA patients with finger joint damage. When combined with anti-CCP antibody testing, it will provide a better chance for RA patients, and give them hope for a better treatment and improved prognosis.

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 presence of anti-citrullinated protein antibodies (ACPAs) in primary Sjögren’s syndrome (pSS) ranges from 3% to 9.9%; however, there is no agreement about their clinical significance. Our aim was to systematically review the literature regarding the association of arthritis and ACPAs in pSS and their role in the development of rheumatoid arthritis (RA). Method: A comprehensive search of MEDLINE, ISI Web of Knowledge, and Cochrane Library from inception until June 2016 was undertaken using the combination of two or three of the keywords: primary Sjögren’s syndrome, Sjögren’s syndrome, arthritis, synovitis, arthropathy, anti-cyclic citrullinated peptide antibodies, and anti-citrullinated protein antibody–ACPA. No language restriction was used. Studies were included if they: assessed the association of arthritis and ACPAs, had sufficient data to construct a two-by-two table, tested immunoglobulin G ACPA by any method, and included patients with pSS according to a validated set of classification criteria. We used a random effects model and evaluated the heterogeneity and publication bias. Results: Ten studies were included (involving 1322 patients). We found a pooled odds ratio of 4.42 (95% confidence interval 1.15–16.94, p = 0.03). The test for heterogeneity was I 2 = 0.87. Publication bias was not observed. Based on data from three studies, 33 of 58 pSS patients with ACPAs (57%) developed RA compared with none of 598 pSS patients with negative ACPA (p and lt; 0.000001). Conclusion: Patients with pSS disclosing ACPAs are prone to arthritis as part of the clinical spectrum of the disease, but are also at risk of developing RA. © 2019, © 2019 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation.

Objective To investigate the risk of progression to rheumatoid arthritis (RA) in patients who were cyclic citrullinated peptide (CCP) antibody positive without RA at initial presentation. Methods We performed a retrospective cohort study of CCP+ individuals seen at a US tertiary care system between 2009 and 2018 who were without RA or other systemic rheumatic disease by medical record review at the time of CCP antibody positivity. Progression to classifiable RA was determined through medical record review. We investigated the risk of progression to RA overall and stratified by CCP antibody level (low: >1 to 2× the upper limit of normal [ULN]; medium: >2 to 3× ULN; high: >3× ULN). Multivariable Cox regression estimated the hazard ratio (HR) and 95% confidence interval (95% CI) for RA by CCP antibody level. Results We identified 340 CCP+ patients who were without RA or other rheumatic disease at baseline. During 1,047 person-years of follow-up, 73 patients (21.5%) developed RA. The risk of progression to RA increased with CCP antibody level, with 46.0% (95% CI 34.7-55.3) of patients with high-level CCP antibodies progressing to RA by 5 years. Compared to low CCP antibody level, medium (HR 3.00 [95% CI 1.32-6.81]) and high (HR 4.83 [95% CI 2.51-9.31]) CCP antibody levels were strongly associated with progression to RA, adjusting for age, sex, body mass index, smoking, family history of RA, and rheumatoid factor level. Conclusion Among CCP+ patients without RA, the risk for progression to RA increased substantially with increasing CCP antibody level. This study provides further support for close monitoring for development of RA among CCP+ patients and identifying strategies to mitigate this risk.

It was with interest that we read the article by Belkhir et al 1 in the recent Annals of Rheumatic Disease . The article described the first report of rheumatoid arthritis (RA) and polymyalgia rheumatica developing after the use of immune checkpoint inhibitors to treat a variety of cancers. We found the article interesting and informative but noted that in all of their 10 reported cases, the patients seroconverted from rheumatoid factor (RF) or cyclic citrullinated peptide antibody (CCP) negative to positive, supporting their claim that ‘rheumatoid arthritis’ may develop after immune checkpoint inhibitor treatment. The report by Belkhir et al is in contrast to our experience managing …

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.

Objective To investigate the reactivity of monoclonal anti–citrullinated protein antibody (ACPA) obtained from peripheral blood B cells of rheumatoid arthritis (RA) patients with human autoantigens as well as environmental proteins by determining the essential epitope for the ACPA. Methods A human monoclonal ACPA (cyclic citrullinated peptide antibody 1 [CCP-Ab1]) was obtained by screening peripheral blood lymphocytes from 31 patients with RA using a novel monoclonal antibody–secreting cell (ASC) screening system, the immunospot-array assay on a chip. The essential epitope for CCP-Ab1 was determined using epitope mapping. Then, human, microbial, and plant proteins that share the essential epitope identified were searched using BLAST. Finally, representative proteins identified by the search were produced in vitro, and their reactivity with CCP-Ab1 was examined. Results CCP-Ab1 bound CCP in a citrulline-indispensable manner. In CCP, the 6 amino acid residues required for CCP-Ab1 binding were identified. In the BLAST search, 38 human, 56 viral, 1,383 fungal, 547 bacterial, and 1,072 plant proteins were found to share the essential epitope, and CCP-Ab1 reacted with all of the recombinant citrullinated proteins tested, which included the various environmental factors, such as various plant proteins that are part of the daily diet. Conclusion Our findings demonstrate, for the first time, that a monoclonal ACPA (CCP-Ab1) derived from RA patients cross-reacts not only with various autoantigens but also with numerous plant and microbial proteins. We propose that countless environmental factors, including microbes and diet, may trigger the generation of ACPAs that then cross-react with various citrullinated human autoantigens through molecular mimicry to induce RA.

Objectives RA is an articular chronic inflammatory disease that in a subgroup of patients can also present with extra-articular manifestations (EAMs). Despite intense investigation on this topic, reliable biomarkers for EAMs are lacking. In recent years several ACPAs, including those targeting anti-citrullinated alpha enolase peptide-1 (anti-CEP-1), have been identified in patients with RA. Data about the ability of anti-CEP-1 to predict the development of erosive disease are confliciting and no evidence concerning their possible association with EAMs in RA is currently available. The aim of this study was to investigate the prevalence and significance of anti-CEP-1 with regard to the association with erosive disease and EAMs in a large cohort of patients with RA. Methods Anti-CCP and anti-CEP-1 antibodies have been assessed on serum samples of RA patients, healthy donors and patients with SpA using commercially available ELISA kits. Results Anti-CEP-1 antibodies are detectable in over 40% of RA patients and are associated with erosive RA and with RA-associated interstitial lung disease (ILD). Conclusion Anti-CEP-1 antibodies may represent a useful biomarker for RA-associated ILD and erosive disease to be employed in clinical practice.

Background: Interleukin (IL)-17 is the main Th-1 cytokine, produced by activated T-lymphocytes. The potential IL-17 value in rheumatoid arthritis (RA) pathogenesis consists of its independent inflammatory response induction and mediated stimulation of proinflammatory factors synthesis resulting in joint destruction. The aim of study was to determine the role of IL-17 in immuno-inflammatory/autoimmune reactions development and to reveal IL-17 serum level associations with clinical and immunological characteristics of RA. Methods: 50 patients with early RA (disease duration >, Russia), anti-CCP antibodies (Axies-Shield Diagnostic, UK) were revealed using ELISA immunoassay. Results: On the base of IL-17 serum level patients were divided in two groups: group1 (n = 28) were patients with normal IL-17 serum level and group2 (n = 22) were those with high IL-17 serum level. In the group2, the rate of patients' pain assessment by visual analogue scale (67.3 ± 7.2 vs 32.8 ± 4.6; P

Background Both Peptydil arginine deiminase of P. gingivalis (pPAD), and the human enzyme (hPAD), could citrullinarize peptides from the bacteria and human host in Rheumatoid Arthritis patients (RA). Chronic periodontitis (CP) could be associated with a constant generation of citrullinated proteins, and it lead to a proportional hPAD enzymatic production. Objectives The aim was to demonstrate the association between serum levels of hPAD4 and severe Periodontitis in patients with rheumatoid arthritis. Methods Patients with RA (n=127) matched with healthy controls (n=120) were studied in a cross-sectional study. Levels of human recombinant antigens for hPAD4; cyclic citrullinated peptide antibody (CCP3, IgG), Rheumatoid factor (IgM) and C-reactive protein (CRP); determined by ELISA test. The CP was classified according to the recommendations of the International Workshop for Classification of Periodontal Diseases and Conditions. Bivariate analysis to demonstrate the associations, and non-parametric analyzes were used according to the case. Results There were no significant demographic diffrences between the two groups. The median hPAD4 level was 1.21 (95% CI 1.4–1.7) in RA and 0.75 (95% CI 0.94–1.26) ng/ml in controls, (p The frequency of CP was higher in patients with RA than in controls (66.9 vs 43%, p A significant correlation was found between levels of hPAD4 with the DAS28 ESR score (p 2.0) correlated with hPAD4 levels (P Conclusions hPAD4 levels correlate with the severity of CP independent of the RA presence and in RA subjects with high score of disability and activity disease. The hPAD4 could be proposed as a serological marker of clinical severity in chronic diseases such as CP and RA. References Rose, H.M., C. Ragan, and et al., Differential agglutination of normal and sensitized sheep erythrocytes by sera of patients with rheumatoid arthritis. Proc Soc Exp Biol Med, 1948. 68(1): p. 1–6. Girbal-Neuhauser, E., et al., The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol, 1999. 162(1): p. 585–94. Lundberg, K., et al., Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum, 2008. 58(10): p. 3009–19. Mikuls, T.R., et al., Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis Rheumatol, 2014. 66(5): p. 1090–100. Disclosure of Interest None declared

Objective To analyze indirect immunofluorescence (IIF) patterns and autoantibodies identified by line immunoassay (LIA) in rheumatoid arthritis (RA) patients, and to compare the autoantibody profiles with serological markers to determine their relevance. Methods A total of 153 specimens were obtained from RA patients for diagnostic or monitoring purposes. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP) were measured, and autoantibody testing using IIF and LIA was performed. Frequencies of IIF patterns and autoantibodies identified by LIA were analyzed and compared with each other and with serologic markers of RF, including anti-CCP, ESR, and CRP. Results The overall positivity of IIF and LIA results was 49.7% and 34.0%, respectively. The most frequent IIF pattern in RA was homogenous (20.9%), followed by dense fine speckled (DFS) pattern (17%). Anti-SS-A and/or anti-Ro-52 were most frequently detected in RA irrespective of the observed IIF pattern. Positive rates and intensities of autoantibodies detected did not differ by therapeutic regimen or disease activity, as reflected by CRP levels or ESR. Only anti-CCP showed a tendency to increase depending on IIF intensity. Conclusions RA patients did not display a specific or dominant IIF pattern or autoantibody presence, as identified by LIA. RA patients had lower frequencies of anti-SS-A and anti-Ro-52 compared with other systemic autoimmune diseases (serologically characteristic of RA). IIF and LIA appear insufficient for diagnosing RA and monitoring disease activity yet can be useful for screening and differentiating major systemic autoimmune diseases. * RA : rheumatoid arthritis RF : rheumatoid factor anti-CCP : anti-cyclic citrullinated peptide APF : antiperinuclear factor AKA : antikeratin antibodies AFA : antifilaggrin antibodies ACR/EULAR : American College of Rheumatology/European League Against Rheumatism CRP : C-reactive protein ESR : erythrocyte sedimentation ratio IIF : indirect immunofluorescence LIA : line immunoassay ANA : antinuclear antibodies SPRA : seropositive rheumatoid arthritis ULN : upper limit of normal DFS : dense fine speckled DS : discrete speckled nRNP : nuclear ribonucleoprotein PCNA : proliferating cell nuclear antigen CENP-B : centromere protein B dsDNA : double-stranded DNA AMA-M2s : antimitochondrial antibodies ANOVA : analysis of variance LEDGF : lens epithelium-derived growth factor SLE : systemic lupus erythematosus SSC : systemic sclerosis NSAIDs : non-steroidal anti-inflammatory agents DMARD : disease modifying antirheumatic drugs ESR : erythrocyte sedimentation rate WBC : white blood cell nRNP/SM : nuclear ribonucleoprotein CENP-B : centromere protein B Scl-70 : topoisomerase I

Emphysematous aortitis is a form of septic aortitis. It is a rare disease with a high mortality rate, necessitating prompt diagnosis and aggressive treatment. We present the computed tomography features of emphysematous aortitis leading to esophageal rupture and esophageal-pleural fistula in a 76-year-old female with rheumatoid arthritis. © SAGE Publications.

Objectives: To determine factors influencing the age at onset of rheumatoid arthritis (RA). Methods: A sample of 152 Colombian patients was investigated. Hazard ratios (HRs) that measured the effect size of risk factors on the age at RA onset were computed by using Cox regression models. Results: Positive anti-CCP antibodies were associated with an increased risk of early RA onset (HR=1.60; 95% confidence interval, [1.06, 2.4]), whereas the presence of the protective 70DERAA74 sequence was associated with a delayed onset (HR=0.55; [0.33, 0.92]). After controlling for both anti-CCP antibodies and the 70DERAA74 sequence, the following variables did not influence significantly the age at RA onset: gender, ever cigarette smoking, family RA history, the TNF-308 A polymorphism, HLA shared epitope, and the presence of rheumatoid factor. Conclusion: Anti-CCP antibodies and the HLA-DRB1 70DERAA74 sequence influence the age at onset of RA. © 2010 Société française de rhumatologie.

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.

Anti-cyclic citrullinated peptide antibodies (anti-CCP) are highly considered to indicate disease severity and be predictive markers in rheumatoid arthritis (RA). RA patients who are positive for anti-CCP tend to progress more frequently to joint deformity and functionally deteriorate more than negative patients. A study concerning the presence of anti-CCP in Japanese patients with psoriatic arthritis (PsA) has been published. Our aim was to clarify that anti-CCP could be a potentially useful marker in PsA patients. We herein describe a PsA patient with presence of anti-CCP. We examined anti-CCP in 15 patients with PsA, and compared with 18 controls who had other types of psoriasis. Three PsA patients were positive for anti-CCP, but no controls showed positive. The anti-CCP-positive patients had higher counts of radiographic erosion, higher prevalence rates of polyarticular disease, use of disease-modifying anti-rheumatic drugs, and the human leukocyte antigen DRB1*04 shared epitope than negative patients. Our study demonstrated that anti-CCP was potentially both predictive and a severity marker of joint involvement in PsA, the same as in RA.

The probability of one patient has ankylosing spondylitis (AS) and rheumatoid arthritis (RA) is low. It is usually difficult to diagnose the association, indeed we require a careful diagnostic process and more tests are needed. A 21-year-old female patient with coexisting AS and RA was reported here. 9 months later, she developed peripheral polyarthritis, erosion changes on the radiography of Metatarso-phalangeal (MTP), rheumatoid factor and cyclic citrullinated peptide antibody (anti-CCP) were positives. Here, we describe the diagnostic process that we followed.

Rheumatoid arthritis is both common and chronic, with significant consequences for multiple organ systems. Better understanding of its pathophysiology has led to the development of targeted therapies that have dramatically improved outcomes. The key to therapeutic success lies in identifying individuals who will have severe destructive disease as early as possible, so that effective treatment can be initiated before irreversible damage occurs. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing is particularly useful in the diagnosis of rheumatoid arthritis, with high specificity, presence early in the disease process, and ability to identify patients who are likely to have severe disease and irreversible damage. However, its sensitivity is low, and a negative result does not exclude disease. Anti-CCP antibodies have not been found at a significant frequency in other diseases to date, and are more specific than rheumatoid factor for detecting rheumatoid arthritis. We discuss anti-CCP antibody testing in rheumatoid arthritis, with an emphasis on diagnostic performance, prognostic capability, and relevance to pathogenesis and new treatment paradigms in rheumatoid arthritis.

Background This review outlines current knowledge of diagnosis, assessment, treatment and risk factors for early rheumatoid arthritis (RA). Methods Selective review of current literature was obtained by searching the terms 'rheumatoid arthritis' and 'early'. Results Three issues dominate the current views on early RA. First, its recognition may be difficult. Many experts consider that early inflammatory arthritis should only be classified as RA after several months' of observation. Secondly, there is emphasis on early intensive treatment with conventional disease-modifying drugs or biologics, especially tumour necrosis factor inhibitors. Thirdly, there is a debate on the risk factors with evidence of genetic risks and environmental factors like smoking that may trigger RA. Developing citrullinated proteins followed by anti-cyclic citrullinated peptide antibodies, specific for RA, appears to be a crucial pathogenetic step. Discussion Early RA needs immediate specialist assessment and review. Early intensive therapy is effective but needs to be focussed on patients mostly at risk of severe progressive disease.

Objective: To explore the value of rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibody, C-reactive protein (CRP), and the erythrocyte sedimentation rate (ESR) in the diagnosis of rheumatoid arthritis (RA). Methods: Using rate nephelometry, chemiluminescence microparticle immunoassay (CMIA), and Westergren sedimentation rate testing, we detected RF, anti-CCP antibody, CRP, and ESR in 134 patients with RA and 50 healthy control individuals. Results: We observed significant differences in RF, anti-CCP antibody, CRP, and ESR concentrations between the RA and control groups ( P

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.

Our aim is to assess the prevalence and associated clinical features of anti-CCP (cyclic citrullinated peptide) antibodies for RF (rheumatoid factor)-positive and RF-negative rheumatoid arthritis (RA) and psoriatic arthritis (PsA). In a prospective, cross-sectional, multi-centre study, we determined the titres of anti-CCP antibodies in 208 RA patients (129 RF-positive, 79 RF-negative), 56 PsA patients and 39 healthy controls (HC). Clinical parameters including disease activity (disease activity score 28-DAS28), physical disability (health assessment questionnaire-HAQ), functional capacity (functional class) and radiological erosions were investigated in patients with RA. In PsA patients, clinical and radiological features were determined. Anti-CCP2 antibodies were measured using a second-generation anti-CCP enzyme-linked immunosorbent assay (Euro-Diagnostica, Netherlands). One-hundred four of 129 RF-positive RA (81%), 16 of 79 RF-negative RA (20%), seven of 56 PsA patients (12.5%) and none of the HC had anti-CCP antibodies. RA patients with anti-CCP antibodies had significantly higher disease activity, greater loss of function and more frequent erosive disease than anti-CCP antibody-negative group. In subgroup analysis, anti-CCP antibodies in RF-negative patients were also associated with erosive disease. All PsA patients with anti-CCP antibodies had symmetric arthritis with higher number of swollen joints. The prevalence of anti-CCP antibodies in RF-positive RA patients was significantly higher than in RF-negative RA and PsA patients. Anti-CCP antibodies were also associated with erosive disease in RF-negative RA patients. Both anti-CCP and RF tests were negative in 30% of the patients. Anti-CCP positivity was a frequent finding in PsA and associated with symmetrical polyarthritis.

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

Objectives To determine the prevalence and the predictive factors of autoimmune hypothyroidism (AH) within a systemic lupus erythematosus (SLE) cohort and to analyse the current information concerning the prevalence and impact of autoimmune thyroid disease (AITD) and thyroid autoimmunity in patients with SLE. Methods A total of 376 patients with SLE were assessed for the presence of the following: (i) confirmed AH, (ii) positive thy-roperoxidase/thyroglobulin antibodies [TPOAb/TgAb] without hypothyroidism, (iii) nonautoimmune hypothyroidism and (iv) SLE patients with neither. Multivariate analysis and a classification and regression tree model were used to analyse data. The current information was discussed through a systematic literature review (SLR). Results In our cohort, the prevalence of confirmed AH was 12%. However, in euthyroid patients with SLE, TPOAb and TgAb were observed in 21% and 10%, respectively. Patients with confirmed AH were significantly older and had later age at onset of the disease. Smoking (adjusted odds ratio (AOR) 6·93, 95% CI 1·98-28·54, P = 0·004), Sjögren's Syndrome (SS) (AOR 23·2, 95% CI 1·89-359·53, P = 0·015) and positivity for anticyclic citrullinated peptide (anti-CCP) (AOR 10·35, 95% CI 1·04-121·26, P = 0·047) were associated with AH-SLE, regardless of gender and duration of the disease. Smoking and SS were confirmed as predictors of AH-SLE. In the SLR, the prevalence of AITD ranged from 1% to 60%. The factors associated with this polyautoimmunity were female gender, older age, smoking, certain autoantibodies, SS, and cutaneous and articular involvement. Conclusions AITD is frequent in SLE and does not affect the severity of SLE. Identified risk factors will assist clinicians in the search for AITD. Our results encourage smoke-free policies in patients with SLE. © 2014 John Wiley and Sons Ltd.

Background: Antibodies that react with citrullinated proteins (anti-mutated citrullinated vimentin [anti-MCV] and second-generation anti-cyclic citrullinated peptide antibodies [anti-CCP2]) are markers for rheumatoid arthritis. Recent studies have demonstrated that these antibodies are present in other arthropathies including the spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Arthritis associated with inflammatory bowel disease (IBD) takes various forms, with some shared similarities with classic spondylarthropathies. Our objective was to investigate the role of anti-MCV and anti-CCP2 as potential biomarkers in IBD and related arthritis. Methods: In all, 125 IBD patients (71 males, 54 females) were compared to 81 age- and sex-matched healthy controls. Anti-MCV and Anti-CCP2 IgG were measured using an enzyme linked immunosorbent assay. Results: In the 125 IBD patients (mean age 32.6 ± 12.3 years), 44 (35.2%) had ulcerative colitis and 81 (64.8%) had Crohn's disease. Forty-four (35.2%) IBD patients developed arthritic manifestations. Antibody positivity was observed in 24/125 (19.2%) IBD patients and in 18/81 (22.2%) healthy subjects. The proportion of anti-MCV positivity among IBD patients and healthy individuals were similar: 16.8% vs. 16.0%, P = 0.887. Anti-CCP2 positivity among IBD patients and healthy individuals was also comparable: 6.4% vs. 6.2%, P = 0.948. Similarly, the presence of anti-MCV and anti-CCP2 antibodies was not different among IBD patients with and without arthritis. The mean titers of antibodies were low: anti-MCV (29.6 ± 7.5 U/mL) and anti-CCP2 (27.6 ± 4.0 U/mL) in IBD patients with arthritis. Conclusions: Autoantibodies to citrullinated proteins were low in IBD-related arthritis. These findings suggest that these antibodies are not useful biomarkers in IBD to predict who may develop IBD-related arthropathy. (Inflamm Bowel Dis 2012)

OBJECTIVES: The anti-CCP antibodies are specific serological markers of RA, especially the aggressive course of joint disease. It has been postulated that the chronic inflammatory state is underlain by cardiovascular (CV) disease and that a higher level of anti-CCP antibodies is implicated in CV risk. The aim of the study was to assess: (i) the possible impact of anti-CCP antibodies on left ventricular diastolic dysfunction ; and (ii) the possible differences in the effects of DASs on diastolic dysfunction. METHODS: The study included 80 RA patients (70 females and 10 males) with no clinically evident CV disease, or concomitant diseases, and 80 matched healthy controls. Upon clinical and laboratory evaluation, all subjects underwent M-mode, two-dimensional and colour Doppler echocardiographic examination. RESULTS: Isovolumetric relaxation time (IVRT) prolongation as the first sign of diastolic dysfunction was present in 36.25% of RA patients and in 15% of control subjects. IVRT was found to correlate with anti-CCP antibody titre (r = 0.382, P = 0.002) and modified DAS including CRP [DAS-28-CRP(4v)] (r = 0.204, P = 0.039). On multivariate linear regression analysis, anti-CCP antibody titre showed significant correlation with IVRT, while the ratio of early and late transmitral wave (E/A ratio) independently correlated with age and DAS-28-CRP(4v). CONCLUSIONS: Anti-CCP antibody is an important marker, independently associated with impaired left ventricular relaxation and the DAS-28-CRP(4v) is a more sensitive predictor of cardiac involvement in the RA than the DAS-28 variant including the ESR.

Recently, a number of studies have pointed to a potential relationship between periodontitis (PO) and RA and vice versa. Both diseases are characterized by chronic inflammation, osseous destruction, damage of the supporting soft tissues, similar cellular immune responses and common immunogenetic findings. Although a definite, methodological report associating these diseases is missing from the literature, it is possible that both diseases share a common aetiopathogenic background. This background includes the post-translation modification citrullination, which guides the conversion of the amino acid arginine to citrulline in certain self-proteins, generating neo-epitope structures. This results in reduced self-tolerance, development of autoimmunity and the production of ACPAs. The current hypothesis suggests that certain oral bacteria induce the citrullination of proteins under the action of the enzyme peptidyl arginine deiminase (PAD), which exists in both Porphyromonas gingivalis and inflammatory cells. Antibodies against citrullinated proteins and peptides constitute a common serological finding in both RA and PO. The aim of this review is to map the immunological and serological profiles of PO, and to unveil the parameters that connect PO with the appearance of RA at clinical, prognostic and pathogenetic levels. Until now, there have been no reports sufficiently mapping the immunological profile of PO and defining its aetiopathogenic connection with RA, although a similarity between the immunological profile of PO and RA is highly expected.

Objective.Cyclic citrullinated peptide antibody (anti-CCP)-positive and anti-CCP-negative rheumatoid arthritis (RA) have been suggested as 2 distinctive disease subsets with respect to disease activity and prognosis. Previously, we proposed that anti-CCP antibodies might have a chondrocyte-suppressive effect. We aimed to compare circulating cartilage oligomeric matrix protein (COMP), a marker of cartilage turnover, in untreated anti-CCP-positive and anti-CCP-negative RA, and to study the temporal pattern of COMP through 4 years of treatment, including the relationship to imaging and clinical findings.Methods.A total of 160 patients with newly diagnosed RA who were naive to disease-modifying antirheumatic drugs were included in the CIMESTRA trial. Ninety healthy blood donors served as controls. Demographic and disease measures including Disease Activity Score in 28 joints, IgM rheumatoid factor, anti-CCP, Health Assessment Questionnaire, visual analog scale scores for pain and global and physician assessment, and magnetic resonance imaging (MRI) of the nondominant hand were recorded at baseline. COMP in serum was measured by ELISA at inclusion and serially through 4 years.Results.Median baseline COMP was higher in patients with RA [9.8 U/l (interquartile range 8.96, 10.5)] compared with controls [8.3 U/l (IQR 7.84, 8.9); p < 0.001] and remained elevated at 4 years [10.8 U/l (IQR 10.2, 11.7); p < 0.001]. At baseline, anti-CCP-positive patients had lower COMP than anti-CCP-negative patients (p = 0.048). In anti-CCP-positive patients, COMP exhibited a parabolic course over 4 years, while COMP in anti-CCP-negative patients had an almost linear course. In anti-CCP-positive patients, COMP was associated with MRI edema and erosion score, while COMP was correlated with synovitis score in anti-CCP-negative individuals.Conclusion.Our study provides additional evidence for the existence of different disease pathways in anti-CCP-positive and anti-CCP-negative subsets of RA, and evidence that anti-CCP antibodies may be implicated in the disease process by modifying cartilage metabolism.

Objective. Serological markers are thought to be useful in predicting which patients with early inflammatory arthritis (EIA) will progress to RA. The objective of this study is to determine the per cent RF and anti-CCP seroconversion in EIA patients at 1–5 years of follow-up: 80% of established RA is RF or CCP positive. Methods. We conducted a systematic literature review of all English publications and recent abstracts from ACR and EULAR. Patients 516 years of age with at least one swollen joint and symptoms < 2 years were included. Results. Twelve publications met the criteria: 10 studies included data on RF, while only 5 addressed anti-CCP. Sample sizes ranged from 15 to 395 and follow-up was 6–60 months. There was marked heterogeneity between studies; therefore, results could not be pooled for a meta-analysis. Baseline RF and anti-CCP positivity was also highly variable: 8–55 and 4–45%, respectively. Seroconversion rates for EIA were 1.9–5.0% at up to 30 months follow-up for RF and 1.3–8.9% at up to 60 months follow-up for anti-CCP. Conclusion. There is minimal change in RF or anti-CCP positivity up to 5 years of follow-up. Prevalence data for RF in established RA is significantly higher than the baseline values reported here. The low rates of seroconversion would suggest a lower prevalence in EIA and the reason for this difference remains unknown. It is unclear whether antibody-negative patients are more likely to remit and be lost to follow-up in established RA populations.

HLA-DR [shared epitope (SE)] alleles have recently been re-classified into S1, S2, S3P and S3D groups. S2 and S3P have been associated with increased risk for RA. We assessed the impact of S1, S2, S3P and S3D alleles on anti-citrullinated protein antibody (ACPA) production. Instead of comparing allele-carriers to non-carriers, we studied each allele group individually, using the X/X (non-SE) genotype as reference.Serum and genomic DNA samples of 91 RA patients and 78 healthy controls were obtained. Various ACPAs and IgM RF were determined by ELISA. HLA-DRB1 genotyping and subtyping was performed by PCR. HLA-DRB1 alleles were re-classified as described above. Correlations between SE and ACPAs were determined.Not only S2 and S3P, but, to a lesser extent, S1 and S3D alleles also predisposed to anti-cyclic citrullinated peptide (CCP) production (P0.0001, P = 0.004, P = 0.01 and P = 0.027, respectively), with the following hierarchy of association: S2+S3PS1+S3DX/X. Similar associations were observed for anti-citrullinated vimentin. Anti-citrullinated fibrinogen (CF) exerted a different association pattern with the strongest correlation with S1 alleles [odds ratio (OR) 16.00; P = 0.05]. In addition, HLA-DRB1*15 alleles may represent a special predisposing effect for anti-CF antibody production. Finally, in this study, RF production was associated only with the HLA-DRB1*0401 SE allele (P = 0.04).Our approach of comparing individual S allele carriers with X/X genotype patients allowed us to perform unequivocal analyses and demonstrate new associations. Thus, novel subgroups of RA could be identified with potential relevance for prognosis and therapy.

Objective. The anti-cyclic citrullinated peptide (anti-CCP) antibody has been increasingly used in the field of rheumatology, and various manufacturers have developed a variety of anti-CCP assays using mainly ELISA techniques. This study evaluated the performance of recently marketed automated chemiluminescence enzyme immunoassays for anti-CCP. Methods. We investigated four anti-CCP assays (Diastat anti-CCP ELISA assay, Axsym anti-CCP assay on the Axsym system, the Architect anti-CCP assay on the Architect i2000 system and the Elecsys anti-CCP assay on the Cobas e 411 analyzer). Samples from 64 patients with RA and 152 controls, including patients with various autoimmune diseases, were studied. We assessed the clinical sensitivities and specificities, and compared the qualitative and quantitative results of each anti-CCP assay. Results. Using the manufacturers’ cut-off, diagnostic sensitivities ranged from 90.6 to 93.8% and the specificities ranged from 85.5 to 86.8%. The areas under the curve were comparable among the different assays, and qualitative agreements ranged from 97.2 to 99.1%. In the quantitative results, all anti-CCP assays were significantly correlated (P < 0.001), but the correlation coefficient ranged from 0.615 to 0.861. Especially, the correlation coefficients between the automated anti-CCP assays were higher than those between the ELISA assay (Diastat) and the automated assays. Conclusions. The overall diagnostic performance of the automated anti-CCP assays was comparable, and it provides reliable information on antibody levels, making them useful in monitoring disease activity.