Presence Of Anti-citrullinated Peptide Antibodies Research Articles

A Clinical Evaluation of the Role of Autoimmunity in the Relation Between Erosions and Bone Mineral Density in Rheumatoid Arthritis.

Background/objectives: Both erosions and osteoporosis in rheumatoid arthritis (RA) have common mechanisms. The aim of this study was to evaluate the relationship between erosion and bone mineral density (BMD) in RA and whether it can be driven by autoimmunity. Methods: Patients fulfilling the ACR 1987- or ACR/EULAR 2010-criteriae for RA. performed radiographs (erosions evaluated by the modified Sharp/van der Heidje erosion score) and biology for anti-citrullinated peptide antibodies (ACPAs), rheumatoid factors (RFs) and anti-nuclear antibodies (ANAs) at intervals of less than 2 years from dual-energy X-ray absorptiometry (DXA) for BMD assessment. Results: A total of 149 patients were included, (75.8% women, mean age of 62 y.o (SD 9.61) and a median disease duration of 132 months [60; 240]). A total of 61.1% patients were ACPA positive, 79.9% were erosive and 10.7% had a hip or spine T-score ≤ -2.5. A higher erosion score was associated with a lower BMD (value: -0.222; p = 0.009) and T-score (value -0.397; p < 0.0001) in the hip. ACPA status was associated with a higher erosion score (63.0 (53.2) vs. 45.5 (44.1) for ACPA- (p = 0.04)). ACPA titers were associated with a lower BMD in the hip (value -0.216; p = 0.01). In linear regression, erosion and BMD were still associated, but this association is not driven by ACPA status or titer. Conclusions: In RA patients, erosions and BMD are inversely associated but this relationship does not seem to be driven by autoimmunity only. However, the presence of ACPA or erosion should lead to osteoporosis screening.

Genetic Variants in RANK and OPG Could Influence Disease Severity and Bone Remodeling in Patients with Early Arthritis.

The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in bone remodeling-related genes associated with disease severity and bone mineral density (BMD) in early arthritis (EA) patients. For this purpose, the genotyping of 552 SNPs located in gene regions of semaphorins 4b, 4d, 4f, DKK1, 2 and 3, sclerostin, OPG, RANK and RANKL was performed using Immunochip from Illumina Inc. in 268 patients from the Princesa Early Arthritis Register Longitudinal (PEARL) study. Measurements of BMD and disease activity were chosen as outcome variables to select SNPs of interest. The relationships of SNPs with the BMD of the forearm, lumbar spine and hip (Hologic-4500 QDR) were analyzed by linear regression adjusted for age, sex, body mass index and presence of anti-citrullinated peptide antibodies (ACPAs). The association of each SNP with activity variables was analyzed by linear regression, logistic regression or ordered logistic regression according to the variable, and multivariate models were adjusted for potentially confounding variables, such as age, sex and presence of ACPAs. These analyses showed that four SNPs located in the genes coding for RANK (TNFRSF11A) and OPG (TNFRSF11B) were significantly associated with clinical variables of severity. SNP rs1805034 located in exon 6 of TNFRSF11A, which causes a non-synonymous (A/V) mutation, showed significant association with BMD and therefore may be considered as a possible biomarker of severity in RA patients. SNPs in the OPG gene showed an association with serum OPG levels and predicted disease activity after two years of follow-up.

Abatacept versus tumor necrosis factor inhibitors on mortality and medical utilizations in the treatment of rheumatoid arthritis associated interstitial lung disease: a large-scale real-world retrospective cohort study

Rheumatoid arthritis is a chronic inflammatory disease, and interstitial lung disease is one of the important extra-articular manifestations. There is limited evidence comparing abatacept (ABA) and tumor necrosis factor inhibitors (TNFi) regarding the risk of mortality among patients with rheumatoid arthritis associated interstitial lung disease (RA-ILD). The aim of this study is to investigate the risk of mortality in patients with RA-ILD treated with ABA compared to TNFi. This retrospective cohort study utilized TriNetX electronic health record database. We enrolled patients who were diagnosed with RA-ILD and had received a new prescription for either ABA or TNFi. Patients were categorized into two cohorts based on their initial prescription. The primary outcome was all-cause mortality, and secondary outcomes were healthcare utilizations, including hospitalization, critical care services, and mechanical ventilation. Subgroup analyses were performed on age, presence of anti-citrullinated peptide antibodies (ACPA), and cardiovascular risk. Among 34,388 RA-ILD patients, 895 were selected for each group (ABA and TNFi) following propensity score matching. The ABA group exhibited a higher all-cause mortality risk. (HR 1.296, 95% CI 1.006–1.671). Subgroup analysis showed a heightened risk of receiving mechanical ventilation in ABA-treated patients aged 18–64 years old (HR 1.853, 95% CI 1.002–3.426), and those with cardiovascular risk factors (HR 2.015, 95% CI 1.118–3.630). Another subgroup analysis indicated a higher risk of mortality among ABA-treated patients with positive-ACPA. (HR 4.138 95% CI 1.343–12.75). This real-world data research demonstrated a higher risk of all-cause mortality in RA-ILD patients treated with ABA compared to TNFi, particularly those aged 18–64 years, lacking cardiovascular risk factors, and positive-ACPA. ABA was associated with an increased risk of mechanical ventilation in patients aged 18–64 years and those with cardiovascular risk factors.

Tumor necrosis factor alpha induced protein 3, interleukin 10, tumor necrosis factor alpha, and interleukin 17F genes polymorphisms in Algerian patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic inflammation. Its pathogenesis involves immunological, genetic, and environmental factors. We investigate the association between Tumor Necrosis Factor α Protein 3 (TNFAIP3), Interleukin 10 (IL10), Tumor Necrosis Factor α (TNF α), and Interleukin 17F (IL17F) polymorphisms with susceptibility to RA. 191 patients with RA diagnosed according to the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) classification and 190 healthy subjects were recruited. Rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), and C-reactive protein (CRP) were measured. Genotyping of the polymorphisms was performed by real-time PCR. Analysis of the allelic frequencies of TNFAIP3 showed a positive association OR (95% CI) = 1.46 (1.01-2.09); p = 0.04, but failed to meet the criteria of significance after Bonferroni Correction. The genotypic and allelic distribution of the IL10, IL17F, and TNFα showed no significant difference when comparing the RA group with controls. Furthermore, the genotype codominant model shows a moderate positive association in the presence of ACPA (OR (95% CI) = 2.82 (1.22-6.24); p = 0.01. None of the polymorphisms studied was associated with RF and CRP production. Our results show that there is a tendency for the AG genotype of IL10-1082 to be associated with the production of ACPA in patients with RA. None of the variants studied were associated with RA susceptibility in Algerians.

Recurrent ACPA-positive pericarditis, would it be a pre-clinical manifestation of RA?

Abstract Introduction Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with an autoimmune component that preferentially affects the small joints of the hands and feet. Extra-articular manifestations may be associated with it. These are rather long-term complications compared to the inaugural forms of the disease. Observation We report the observation of a 62-year-old female patient with a history of high blood pressure under monotherapy by a conversion enzyme inhibitor, followed for recurrent pericarditis for three years, who was initially treated with anti-bacillary drugs without improvement. She presented two years ago an episode of pericarditis of great abundance requiring a pericardial drainage. The pericardial biopsy was non-specific. The etiological work-up revealed the presence of anti-citrullinated peptide antibodies (ACPA) and a rheumatoid factor (RF) at very high levels. The patient did not present any other systemic signs, especially articular ones. Joint imaging was normal. The evolution was marked by the persistence of a pericardial effusion of a small to medium size. RA could not be retained according to the American College of Rheumatology/ European League Against Rheumatism’s (ACR/EULAR) 2010 criteria. Glucocorticoids therapy at a dose of 0.5 mg/kg/day allowed the resolution of the pericarditis without recurrence, with a six-month follow-up period. Conclusion This is an extra-articular manifestation that would be inaugural of RA. It is an atypical presentation in the usual history of the disease. The inclusion of extra-articular involvement in the classification criteria and in the groups at risk of developing RA would be useful in these cases.

Factors associated to long-term retention rate of Janus kinase inhibitors in a multi-failure rheumatoid arthritis population.

We aimed to retrospectively evaluate retention rate and causes of discontinuation of JAKi in rheumatoid arthritis (RA) patients with particular regards to difficult-to-treat subgroups. The diffusion of Janus kinase inhibitors (JAKi) for the treatment of RA has rapidly increased in recent years due to their effectiveness, even in difficult-to-treat subgroups of patients. After the publication of the Oral Surveillance study, the labelling of JAKi was modified, advising against their use in elderly patients and those at risk for cardiovascular events and malignancies. Demographic, clinical, serological and therapeutic characteristics of RA patients treated with JAKi were recorded, including smoking habit and comorbidities. Three hundred and thirty consecutive RA patients were enrolled in the study. Among them, 50.3% patients had previously failed at least two biologic DMARDs. Risk factors for the use of JAKi were reported in 75.5% of patients, 41.5% of them were older than 65 years, 37.6% had smoked, while 48.8% had increased cardiovascular or cancer risk. Anticitrullinated peptide antibodies (ACPA) and combination therapy with conventional synthetic DMARDs were associated with a longer drug persistence and ACPA remained independently associated to a higher retention rate of JAKi also in the subgroup of difficult-to-treat patients. In conclusion, our study supports the clinical effectiveness of JAKi in RA, even in the multi-failure subgroup of patients, where the risk/benefit ratio overcomes the safety risk. The presence of ACPA and the concurrent use of + cs-DMARD may increase the survival on JAKi in the long term.

Risk stratification using anti-citrullinated peptide antibodies (ACPA) in polyarticular subtypes of juvenile idiopathic arthritis in adulthood.

Polyarticular juvenile idiopathic arthritis (pJIA) is a subset of juvenile idiopathic arthritis (JIA), divided into two subtypes according to the presence of rheumatoid factor : pJIA without rheumatoid factor (pJIA RF-) and pJIA with positive rheumatoid factor (pJIA RF+), this latter is characterised with more structural damage. Anti-citrullinated peptide antibodies (ACPA) are often associated with RF. The respective performance of ACPA versus RF in structural outcome in pJIA, and in particular in adulthood pJIA remains unknown. Therefore, the aim of this study was to determine whether ACPA could be of value to assess structural damage in pJIA persisting in adulthood. Patients with pJIA and available data for ACPA, RF and X-ray were included retrospectively. Structural damage was assessed by two independent blinded investigators using Sharp Van Der Heijde scores. 56 pJIA adult patients were included : 62% (35/56) had pJIA RF+ and 38% (21/56) pJIA RF-. ACPA positivity in pJIA was significantly associated with presence of RF (96% vs 26%, p<0.001 ). RF positivity was significantly associated with higher Sharp van Der Heijde erosion and total scores (respectively p< 0.01 and p< 0.05 ). There were higher Sharp Van Der Heijde erosion, joint space narrowing and total scores in the pJIA ACPA+ subgroup than in the pJIA ACPA- subgroup, although there was no statistical significance. However, when adjusted on disease duration, pJIA ACPA+ patients had significantly higher erosion and total scores than pJIA ACPA- patients (p<0.05), and pJIA ACPA+ patients required more bDMARDs than pJIA ACPA- patients (p<0.05). Moreover, pJIA patients with high Sharp van Der Heijde joint space narrowing and total scores had significantly higher ACPA levels (p<0.01). A correlation was identified between ACPA levels and Sharp van Der Heijde total score ( r=0.54, p<0.05). In the pJIA RF+ subgroup the presence of ACPA was associated with additional structural damage compared to no ACPA: sharp Van Der Heijde erosion, joint space narrowing and total scores were higher in the pJIA RF+ ACPA+ subgroup than in the pJIA RF+ ACPA- subgroup although these results did not reach significance. Our results suggest that pJIA RF+ ACPA+ adult patients may have a more severe articular phenotype than pJIA RF+ ACPA- patients. ACPA could bring an additional value to RF for pJIA patients regarding structural damage. Altogether our results show that RF and ACPA are associated with structural damage measured by Sharp Van Der Heijde score in pJIA persisting in adulthood.

Using Treg, Tr1, and Breg Expression Levels to Predict Clinical Responses to csDMARD Treatment in Drug-naive Patients With Rheumatoid Arthritis.

Regulatory T cells (Treg) play a crucial role in maintaining immune tolerance and preventing autoimmune diseases. Recent data also indicate that type 1 regulatory T (Tr1) and regulatory B (Breg) cells play an inhibitory (i.e., protective) role in autoimmune diseases. Conventional synthetic disease-modifying antirheumatic drugs (csDMARD) are a first-line therapy for rheumatoid arthritis (RA), and our aim was to predict clinical responses of this treatment using immunophenotyping. We first detected the presence of immune cells in fresh blood from 16 healthy controls (HC) and 26 patients with RA (14 drug-naive and 12 csDMARD-experienced). Then, we recorded immunophenotypic changes in 14 drug-naive RA (naive RA) patients prior to csDMARD treatment (i.e., day 0) and after receiving treatment for 6 months. The observed changes were also compared with other clinical indicators, including the presence of anti-citrullinated peptide antibodies (anti-CCP), rheumatoid factor (RF) levels, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. Naive RA patients had significantly lower Tregs than HC and csDMARD-experienced patients (both p<0.0001) and the number of Tregs correlated with the diagnosis of RA and therapeutic efficacy of csDMARD treatment. Furthermore, lower baseline levels of Treg, memory Treg, Tr1, and higher PD-1+ Marginal B, Breg cells were significantly associated with decreased development of the 28-joint Disease Activity Score (DAS28) (all p<0.05), revealing better medical response. Multiple regression and principal component analysis identified Treg, Tr1, and Breg as potential predictors of csDMARD responses (Area under curve: 0.9; Accuracy: 92.86%). Furthermore, elevated Treg, Tr1, and Breg cells were associated with decreased DAS28, ESR, and CRP (all p<0.05); changes in Treg and Breg cell expression were also more pronounced among double negative anti-CCP and RF in RA patients with better outcomes (p<0.05). Immunophenotyping can be an adjunct clinical tool to identify patients who are poor candidates for csDMARD therapy. Alternative therapeutic interventions in the early stages of disease should be formulated for these patients.

Association of anti-citrullinated peptide antibodies with the progression of aortic stenosis

Abstract Background/Purpose Aortic stenosis (AS) is common in an aging population, but disease activity biomarkers are lacking. The pathophysiology of calcific AS shares many similarities with atherosclerosis, including lipid deposition, inflammation, and calcification. Citrullination is a part of many chronic inflammatory processes and citrullinated proteins have been found within atherosclerotic plaque. Thus, we investigated whether the presence of anti-citrullinated peptide antibody, especially anti-CCP antibody, might be associated with AS. Methods A retrospective observational study was conducted for 678 patients who underwent echocardiography and anti-CCP antibody test between April 2004 and July 2020. Anti-CCP antibody status was regarded as positive when concentrations exceeded the upper limit of normal (ULN), and any lower value was considered negative. The anti-CCP antibody-positive group was subdivided into two groups: low-positive for ≥ ULN but &amp;lt; the median, and high-positive ≥ the median value (Figure 1A). Also, aortic valve (AV) tissues were obtained from the patients with AS or not at the time of surgical aortic valve replacement or heart transplantation, who did not have rheumatoid arthritis. We analyzed the presence of citrullinated proteins in the AV by immunohistochemistry and Western blotting. Results 241 (35.5%) subjects showed AV degeneration in baseline echocardiography. They had a higher anti-CCP antibody positivity rate (42.7% vs. 34.6%, p=0.035) than the subjects without AV degeneration. Of total patients, 331 (48.8%) subjects underwent follow-up echocardiography (median follow-up duration 4.6 years [interquartile range 2.0–8.0 years]). AS progression, which was defined as an increase of at least one grade in AS severity classification on follow-up echocardiography, was observed in 34 (10.3%) patients. The progression of AS occurred more in the high-positive group than in the low-positive or negative group (19.0% vs. 11.3% vs. 8.4%, respectively; p=0.041) (Figure 1B). In multivariate analysis, the high-positivity of anti-CCP antibody was an independent predictor of AS progression (Odds ratio: 2.312; 95% confidence interval: 1.006–5.310; p=0.048) (Figure 1C). Increased citrullination was visualized in areas with diseased AV compared with normal AV tissue by immunohistochemistry (Figure 2A, 2B) and Western blotting (Figure 2C, 2D). These results suggested the possible association with the citrullinated peptide-related inflammation process and the pathophysiology of AS. Conclusion A positive result of anti-CCP antibody, especially with a high titer, was associated with AV degenerative change at baseline echocardiography. Also, anti-CCP antibody positivity was an independent factor for predicting the progression of AS. These findings suggest that citrullination can be a part of the pathophysiology of AS. Furthermore, the anti-CCP antibody can be a biomarker predicting AS progression. Further research will be needed. Funding Acknowledgement Type of funding sources: None.

Clinical Implications of Shared Epitope and Anti-citrullinated Peptide Antibody in Patients With Rheumatoid Arthritis.

The shared epitope (SE) and anti-citrullinated peptide antibody (ACPA) are involved in the pathogenesis of rheumatoid arthritis (RA). This study evaluated the clinical implications of SE and ACPA in terms of disease manifestation and response to biologic disease modifying anti-rheumatic drugs (DMARDs). Patients with identified human leukocyte antigen (HLA)-DRB1 alleles were included to compare the clinical characteristics and drug survival rate of tumor necrosis factor (TNF) inhibitors or abatacept based on the presence of SE and ACPA. Of the 533 patients with identified HLA-DRB1 alleles, 329 patients (61.7%) with SE alleles showed higher disease activity and erosive changes compared to patients without SE alleles. SE-positive patients were more likely to start biologic (b-) or targeted synthetic DMARDs (tsDMARDs) within the first 5 years (p=0.020). The presence of SE, smoking, dyslipidemia, and higher erythrocyte sedimentation rate were independently associated with the initiation of b- or tsDMARDs (p=0.016, 0.028, 0.031, and 0.001, respectively). The presence of SE and ACPA did not affect the drug survival rate of TNF inhibitors, whereas the abatacept retention rate was higher in ACPA-positive patients (p=0.024). The presence of SE affected disease characteristics and prognosis in Korean patients with RA without a significant impact on drug survival rate of TNF inhibitors and abatacept. ACPA positivity was associated with abatacept drug retention, suggesting that abatacept may be helpful in ACPA-positive patients than in ACPA-negative patients.

Anti-Citrullinated Peptide Antibody Expression and Its Association with Clinical Features and Outcomes in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Background and objectives: Anti-citrullinated peptide antibody (ACPA), a characteristic antibody detected in rheumatoid arthritis, could be linked to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) via the formation of neutrophil extracellular traps. We investigated the rate of ACPA positivity in patients with AAV and evaluated the association of ACPAs with their clinical features and outcomes. Materials and Methods: A total of 168 AAV patients with both ACPA and ANCA results at diagnosis were identified. Clinical and laboratory variables, including the disease-specific indices of Birmingham Vasculitis Activity Score (BVAS) and Five-Factor Score (FFS), were investigated. All-cause mortality, relapse, and end-stage renal disease, as well as interstitial lung disease (ILD) were evaluated as outcomes of the patients, and the Kaplan–Meier survival analysis was used to compare the event-free survival rates of the groups. Results: Fifteen (8.9%) and 135 (80.4%) patients were positive for ACPA and ANCA, respectively. There were no significant differences in the baseline variables of ACPA-negative and ACPA-positive patients. The absolute titre of ACPAs also did not significantly correlate with BVAS, FFS, erythrocyte sedimentation rate, or C-reactive protein. In addition, there was no difference noted regarding overall, relapse-free, and ESRD-free survival rates between ACPA-negative and ACPA-positive AAV patients. However, when the patients were divided into four groups according to ACPA and ANCA status, differences were present in the outcomes, and the ACPA-positive ANCA-positive group exhibited the lowest cumulative relapse-free survival rate, while no significant difference was present in the relapse between the ANCA-positive ANCA-positive, ACPA-positive ANCA-negative, and ACPA-negative ANCA-positive groups. Finally, the cumulative ILD-free survival rates were comparable between ACPA-positive and ACPA-negative AAV patients. Conclusions: The detection of ACPA expression is not uncommon in AAV. However, the presence of ACPA did not influence patients’ basal characteristics and outcomes, suggesting that further exploration of the role of this antibody is needed in patients with AAV.

Detection of salivary citrullinated cytokeratin 13 in healthy individuals and patients with rheumatoid arthritis by proteomics analysis.

The immune response to citrullinated peptides in the mucosa has been suggested to play an important role in the transition from pre-onset rheumatoid arthritis (RA) to clinically evident RA. Although there are reports indicating the presence of anti-citrullinated peptide antibodies in the saliva, few studies have reported citrullinated peptide detection in human saliva. This study aimed to identify citrullinated peptides in human saliva and discuss their clinical significance. Saliva samples were collected from 11 patients with RA and from 20 healthy individuals. Citrullinated peptides were detected using an anti-modified citrulline (AMC) antibody. Saliva from the healthy individuals was subjected to two-dimensional protein electrophoresis to isolate citrullinated peptides, which were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and mass spectrometry by peptide mass fingerprinting. The results were corroborated by immunoprecipitation (IP)-western blotting. The signal intensities of the bands precipitated with anti-cytokeratin 13 (CK13) and AMC antibodies were quantified. The signal intensity ratio of the band produced by the AMC antibody was divided by that of the band produced by the anti-CK13 antibody to calculate the citrullinated CK13 (Cit-CK13) ratio. A citrullinated peptide band corresponding to a molecular weight of approximately 50 kDa was detected in the saliva of healthy individuals, and identified as CK13 via mass spectrometry and IP-western blotting. No significant difference was observed between the salivary Cit-CK13 ratios of patients with RA and healthy participants (p = 0.605). This is the first study to show that Cit-CK13 is present in human saliva, and that there is no significant difference between the Cit-CK13 ratios of patients with RA and healthy individuals, suggesting that salivary Cit-CK13 content and RA development may not be associated. The physiological and pathological roles of Cit-CK13 in the oral cavity, and its responsiveness to mucosal immunity, remain unknown and will be the subject of further investigation.

Identification of a Novel Serological Marker in Seronegative Rheumatoid Arthritis Using the Peptide Library Approach.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation mainly affecting the joints leading to cartilage and bone destruction. The definition of seropositive or seronegative RA is based on the presence or absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs). Other autoantibodies have been identified in the last decade such as antibodies directed against carbamylated antigens, peptidyl-arginine deiminase type 4 and v-Raf murine sarcoma viral oncogene homologue B. In order to identify relevant autoantigens, we screened a random peptide library (RPL) with pooled IgGs obtained from 50 patients with seronegative RA. Patients’ sera were then used in an ELISA test to identify the most frequently recognized peptide among those obtained by screening the RPL. Sera from age- and sex-matched healthy subjects were used as controls. We identified a specific peptide (RA-peptide) recognized by RA patients’ sera, but not by healthy subjects or by patients with other immune-mediated diseases. The majority of sera from seronegative and seropositive RA patients (73.8% and 63.6% respectively) contained IgG antibodies directed against the RA-peptide. Interestingly, this peptide shares homology with some self-antigens, such as Protein-tyrosine kinase 2 beta, B cell scaffold protein, Liprin-alfa1 and Cytotoxic T lymphocyte protein 4. Affinity purified anti-RA-peptide antibodies were able to cross react with these autoantigens. In conclusion, we identified a peptide that is recognized by seropositive and, most importantly, by seronegative RA patients’ sera, but not by healthy subjects, conferring to this epitope a high degree of specificity. This peptide shares also homology with other autoantigens which can be recognized by autoantibodies present in seronegative RA sera. These newly identified autoantibodies, although present also in a percentage of seropositive RA patients, may be considered as novel serum biomarkers for seronegative RA, which lacks the presence of RF and/or ACPAs.

Clinical Relevance of Autoantibodies and Inflammatory Parameters in Non-infectious Scleritis

ABSTRACT Purpose Scleritis is a potentially blinding disorder, with highly unpredictable course and outcome. We analyzed the prevalence and clinical relevance of autoantibodies and inflammatory parameters in non-infectious scleritis. Methods Retrospective analysis of laboratory findings in all consecutive patients at the department of Ophthalmology of the Erasmus MC with non-infectious scleritis. Results We included 81 patients with non-infectious scleritis. A systemic autoimmune disease was present in 46%. Positive anti-nuclear antibodies were found in 30%, anti-neutrophil cytoplasmic antibodies were positive in 19%, and the presence of rheumatoid factor was shown in 17%. The aforementioned autoantibodies, as well as inflammatory parameters, failed to show prognostic clinical value. In contrast, anti-citrullinated peptide antibodies (ACPA), found in 9% of scleritis patients, were significantly associated with the development of scleral necrosis (P = .01). Conclusions The presence of ACPA in patients with non-infectious scleritis was associated with the development of scleral necrosis.

Anti-carbamylated protein antibodies: are they useful for the diagnosis of rheumatoid arthritis?

ACR/EULAR-2010 classification criteria for rheumatoid arthritis (RA) rely heavily on the presence of anti-citrullinated peptide antibody (ACPA). The role of anti-carbamylated protein antibodies (anti-CarP) in this context is uncertain. We aimed to investigate the value of anti-CarP for RA classification in patients with early inflammatory arthritis. Patients (n=402) were recruited from an early arthritis clinic and followed for 24 months. Healthy controls (n=95) were included. An anti-CarP ELISA was performed (aU/mL). Statistical analysis used regression and AUC analysis. The criteria for RA were met by 195/402 patients at inclusion; 28 developed RA during follow-up and 179 had other diagnosis (non-RA). 97/195 (49%) RA patients were anti-CarP+ (median 250 uA/mL [IQR 25-762]). In the group that progressed to RA, 7/28 (25%) were positive (82 uA/mL [13-235]) compared to non-RA (p=0.001) with 13/179 (7%) positive (26 uA/mL [5-80]). Being anti-CarP+ alone was observed in 17 patients of whom 7 (41%) were RA. Levels/positivity were not associated with other parameters. Anti-CarP+ had an odds ratio (OR) 6.5 for predicting RA (OR=17.1 for ACPA+ and OR=2.5 for RF+). In ACPA- patients, anti-CarP+ was also predictive of RA (OR=2.39). Being ACPA+/anti-CarP+/RF+ had a high predictive value for RA (OR=29.9 sensitivity/specificity (sen/spe) 33%/99%, positive/negative predictive values (ppv/npv) 97%/54%), however, being ACPA+/anti-CarP+ was superior (OR=36.1 sen/spe=41%/99%, ppv/npv=98%/57%) while being ACPA+/RF+ was inferior (OR=11.9, sen/spe=54%/95%, ppv/npv=94%/62%). For RA classification, anti-CarP+ was less sensitive than ACPA, but more specific than RF. Anti-CarP+ may prove useful, classifying early arthritis patients, notably ACPA- patients.

Association between levels of synovial anti‐citrullinated peptide antibodies and neutrophil response in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by the presence of anti-citrullinated peptide antibodies (ACPAs) and neutrophils infiltrating the synovial fluid (SF) of the affected joints. The aim of this work was to analyze whether the presence of ACPAs in SF is associated with neutrophil infiltration and with their phenotype in the inflamed joints of RA patients. We found that in the presence of ACPAs, the number of synovial neutrophils correlated with severe disease activity. The SF were divided according to synovial ACPA levels in negative- (<25 U/mL), low- (25-200 U/mL) and high level (˃200 U/mL; ACPAhigh ). We observed that IL-6, IL-17, and IL-8 were significantly elevated in ACPAhigh SF and that IL-8 levels correlated positively with neutrophil counts and with worse clinical manifestations. Additionally, in vitro incubation of neutrophils with ACPAhigh SF resulted in an increased ROS production and extracellular DNA release compared to neutrophils incubated with ACPA-negative SF. These exacerbated effector functions were associated with a fraction of ICAM-1-positive neutrophils, which were induced by ACPAhigh SF. Likewise, in in vivo, we could also detect this subset among neutrophils present in ACPAhigh SF. In conclusion, the data presented here shed light on the role of SF-ACPAs as inductors of a proinflammatory profile in neutrophils.

Erratum to: A novel bedside test for ACPA: the CCPoint test is moving the laboratory to the rheumatologist's office.

Rheumatoid Arthritis (RA) is an autoimmune destructive joint disease affecting 1 % of the general population. In recent years, the benefits of identifying RA at an early stage and initiating therapy before joint damage occurs have been acknowledged. An elevated anti-citrullinated peptide antibody (ACPA) level serves as a marker for the early diagnosis of RA. Often the diagnosis is delayed because conventional methods of antibody detection require referral to a specific laboratory. In the current study, we determined the diagnostic accuracy of a new lateral flow point-of-care kit available for ACPA detection in the rheumatologist office. The presence of ACPA was determined by the visually read, qualitative rapid CCPoint® test (Euro-Diagnostica, Malmo, Sweden) compared to routinely used ELISA assays (Immunoscan CCPlus®-Euro-Diagnostica, Sweden, and QuantLite® CCP3-INOVA Diagnostics Inc., USA), in the sera of 184 patients: early RA(n = 38), established RA (n = 84), inflammatory arthritis(n = 34) and systemic lupus erythematosus (SLE) (n = 28). ACPA was detected in 18/38(47 %), 53/84(63 %), 2/34(6 %) and 2/28(7 %) of patients with early RA, established RA, inflammatory arthritis and SLE, respectively. The sensitivity and specificity, negative and positive predictive values of the CCPoint® test were equivalent to the Immunoscan CCPlus® and Quanta Lite® CCP3 ELISA assays. Correlation between ACPA positive results detected in the different assays was 97 %, while negative agreement reached 98 %. Excellent correlation (100 %) was observed between CCPoint® results obtained using capillary blood versus serum. CCPoint® is a novel technology that allows for a rapid accurate analysis of ACPA and diagnosis during the patient’s visit in the rheumatologist office.

A novel bedside test for ACPA: the CCPoint test is moving the laboratory to the rheumatologist's office.

Rheumatoid Arthritis (RA) is an autoimmune destructive joint disease affecting 1% of the general population. In recent years, the benefits of identifying RA at an early stage and initiating therapy before joint damage occurs have been acknowledged. An elevated anti-citrullinated peptide antibody (ACPA) level serves as a marker for the early diagnosis of RA. Often the diagnosis is delayed because conventional methods of antibody detection require referral to a specific laboratory. In the current study, we determined the diagnostic accuracy of a new lateral flow point-of-care kit available for ACPA detection in the rheumatologist office. The presence of ACPA was determined by the visually read, qualitative rapid CCPoint® test (Euro-Diagnostica, Malmö, Sweden) compared to routinely used ELISA assays (Immunoscan CCPlus®-Euro-Diagnostica, Sweden, and QuantLite® CCP3-INOVA Diagnostics Inc., USA), in the sera of 184 patients: early RA(n=38), established RA (n=84), inflammatory arthritis(n=34) and systemic lupus erythematosus (SLE) (n=28). ACPA was detected in 18/38(47%), 53/84(63%), 2/34(6%) and 2/28(7%) of patients with early RA, established RA, inflammatory arthritis and SLE, respectively. The sensitivity and specificity, negative and positive predictive values of the CCPoint® test were equivalent to the Immunoscan CCPlus® and Quanta Lite® CCP3 ELISA assays. Correlation between ACPA positive results detected in the different assays was 97%, while negative agreement reached 98%. Excellent correlation (100%) was observed between CCPoint® results obtained using capillary blood versus serum. CCPoint® is a novel technology that allows for a rapid accurate analysis of ACPA and diagnosis during the patient's visit in the rheumatologist office.

Associations of rheumatoid factor and anti-citrullinated peptide antibody with disease progression and treatment outcomes in patients with rheumatoid arthritis.

The objective of this study was to investigate the association of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) status with disease progression and treatment outcomes in patients with rheumatoid arthritis (RA). A total of 276 adult patients who fulfilled the American College of Rheumatology 1987 classification criteria for RA were recruited from the Rheumatology clinic, Siriraj Hospital, from January 2011 to December 2012. Demographic, clinical, and laboratory data were collected at baseline and every 3months up to 1year of follow-up. RF and ACPA were measured at baseline. Radiography of the hands and feet was performed at baseline and 1year. Patients with RF+/ACPA+ had significantly more severe disease activity and impaired functional status than those who had RF-/ACPA-. Although they received more aggressive treatment with methotrexate and combination of non-biologic, disease-modifying antirheumatic drug than other groups, fewer patients in this group achieved remission at 1 year of follow-up, especially when compared to RF-/ACPA- group (12 vs. 18%). For radiographic erosion, patients with the presence of either RF or ACPA had a higher proportion of hand erosion than seronegative patients at baseline (77, 73, 83, and 32%, p<0.001 for RF+/ACPA+, RF+/ACPA-, RF-/ACPA+, and RF-/ACPA-, respectively). After 1year of follow-up, patients who developed new erosion at the hands were more prevalent in RF+/ACPA+ (32%) and RF+/ACPA- (33%) groups. However, "newly developed" feet erosion was most common in RF+/ACPA- group (40%) than in other groups. Patients with positive either RF or ACPA or both have more severe and aggressive disease that requires intensive treatment to improve outcomes.

Rheumatoid Arthritis: Clinical Manifestations and Diagnosis

The onset and course of rheumatoid arthritis (RA) can be highly variable, and the lack of a specific biologic marker can make diagnosis difficult in early disease. A careful history and physical examination and the integration of clinical and laboratory data are often required. The presence of anti-citrullinated peptide antibodies (ACPAs) is one of the best predictors of progression to establish RA. This review describes the clinical manifestations used to diagnose RA, such as physical examination of the hands and wrists, elbows and shoulders, hips, knees, ankles and feet, and cervical spine. Extra-articular manifestations related to rheumatoid nodules, eyes, lungs, heart, blood and blood vessels, and neuromuscular involvement are reviewed. Laboratory tests and differential diagnosis are also discussed. Figures show synovitis in the hand and wrist, rheumatoid nodules near the extensor surface of the elbow, a pelvic radiograph of a patient with classic seropositive RA, erosions in the metatarsal heads and phalanges of the foot of a patient with classic seropositive RA, the anterior edge of the odontoid process, and a typical rheumatoid nodule. This review contains 6 highly rendered figures and 20 references.