Anti-citrullinated Peptide Antibody Levels Research Articles

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.

Treatment resistance of rheumatoid arthritis relates to infection of periodontal pathogenic bacteria: a case–control cross-sectional study

Recent studies have shown that periodontitis is associated with rheumatoid arthritis (RA) and periodontal bacteria, such as Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg) are involved in the pathogenesis of RA via citrullinated proteins. Smoking has also been shown to be involved in the pathogenesis of RA; however, the extent of this involvement is still poorly understood. In addition, RA and polymyalgia rheumatica (PMR) are sometimes difficult to differentiate; however, the relationship between PMR and the factors from smoking and periodontal bacteria is unclear. The aim of this study was to clarify the relationship between periodontal pathogenic bacterial infections and smoking in patients with RA or PMR. This case–control study included 142 patients with untreated RA or PMR. This study evaluated the serum antibody titers against periodontal pathogenic bacterial antigens and an anti-citrullinated peptide antibody (ACPA). In patients with RA, the relationship between antibody titers and disease activity of RA and response after 3 months of treatment was also investigated. Additionally, the effects of smoking were evaluated. Although there was no significant difference in serum antibody titer against periodontal pathogenic bacteria between the ACPA-positive RA group and the ACPA-negative PMR group, we found an association between the elevated antibody titer against Pg and the degree of ACPA value, especially between negative group and high-value positive group (≥ 100 U/mL). The antibody titers against Aa and Pg did not differ depending on disease activity score 28 (DAS28) at baseline; however, patients with high antibody titers had poor RA therapeutic response as judged by DAS28 after 3 months. We could not find any association between smoking and any of these parameters. Periodontal pathogenic bacteria, especially Pg, are associated with elevated ACPA levels. Our findings suggest that Pg and Aa infections interfere with the therapeutic response of RA.

Repeat serological testing for anti-citrullinated peptide antibody after commencement of therapy is not helpful in patients with seronegative rheumatoid arthritis.

To Investigate the prevalence of seroconversion to ACPA after commencement of triple disease-modifying anti-rheumatic drug (DMARD) treat-to-target therapy. Anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) define 'seropositive' rheumatoid arthritis (RA). Both predict unfavourable disease course, development of extra-articular features and treatment outcomes. We investigated the prevalence of seroconversion to ACPA after commencement of triple disease-modifying anti-rheumatic drug (DMARD) treat-to-target therapy. DMARD-naïve patients with RA according to the 1987 American College of Rheumatology criteria and disease duration of <96 weeks were enrolled. RF and ACPA levels were recorded at baseline and sequentially during triple DMARD therapy. A total of 368 patients were followed for a median of 272 weeks. Of 154 patients seronegative for ACPA at recruitment, 10 (6.5%) seroconverted at some point. Nine of these were positive for RF at baseline and baseline RF titre was predictive of seroconversion. Four (2.6%) patients remained seropositive. No patients seroconverted from negative to positive for both RF and ACPA. Median time to seroconversion for ACPA was 29 months. Persistent seroconversion of ACPA from negative to positive after diagnosis in patients with RA is uncommon. ACPA and RF double negative patients are highly unlikely to ever develop ACPA positivity with a risk <1%. It is therefore unlikely to be helpful or cost effective to perform serial ACPA measurements in patients with seronegative RA after commencement of a treat-to-target strategy.

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.

Nicorandil and theophylline can protect experimental rats against complete Freund's adjuvant-induced rheumatoid arthritis through modulation of JAK/STAT/RANKL signaling pathway

Signaling pathways are interesting fields of study of pathogenesis and treatment trials. We elucidated the possible protective effects of nicorandil (15mg/kg/day) and theophylline (20mg/kg/day) on experimentally-induced RA, focusing on the role of JAK (Janus Kinase) / STAT (Signal Transducer and Activator of Transcription) / RANKL (Receptor Activator of Nuclear factor-Kappa B Ligand) / cytokine signaling pathway. Four sets of experiments were performed. First, effect of test agents on normal animals was evaluated. Second, effect of test agents was evaluated on Complete Freund's Adjuvant (CFA; 0.3ml, s.c.)-induced RA to investigate anti-arthritic effect. Third, effect of test agents was evaluated on growth hormone (GH; 2mg/kg/day, s.c.)-induced stimulation of JAK/STAT/RANKL/cytokine signaling pathway to investigate the role of this signaling pathway in their anti-arthritic effect. Fourth, the effect of test agents was performed on CFA/GH-induced RA. To fulfill this purpose, serum anti-citrullinated peptide antibody (ACPA), interleukin-6 (IL-6), and cartilage oligomeric matrix protein (COMP), together with tissue JAK2, STAT3, RANKL, inducible and endothelial nitric oxide synthases (iNOS and eNOS) as well as macrophage inflammatory protein (MIP1α) were estimated using ELISA, Western blotting and PCR techniques, confirmed by a histopathological study. Test agents significantly corrected JAK2, STAT3, RANKL and IL-6 values in animals receiving GH. Additionally, test agents could correct ACPA, IL-6, COMP, JAK2, STAT3, RANKL, iNOS, eNOS and MIP1α levels compared with the respective CFA or CFA/GH controls. These results conclude that nicorandil and theophylline have good anti-arthritic effects related to modulation of JAK/STAT/RANKL signaling pathway. Further clinical trials are claimed.

Preclinical lung disease in early rheumatoid arthritis.

Early detection and treatment of lung disease in patients with rheumatoid arthritis (RA) may ameliorate disease progression. The objectives of this study were to investigate the frequency of asymptomatic lung abnormalities in early RA patients and the potential association of positive RA blood reactive biomolecules with lung involvement. A prospective observational study was performed in a cohort of patients with early RA (joint symptoms < 2 years) without respiratory symptoms, who were included in a screening program for lung disease with a baseline chest radiograph (CR) and complete pulmonary function tests (PFTs). In those patients with lung abnormalities on the CR or PFTs, a high-resolution chest computed tomography scan (HRCT) was performed. We included 40 patients (30 women). Altered PFTs were detected in 18 (45%) of these patients. These cases had a diffusion lung transfer capacity of carbon monoxide (DLCO) of <80% of predicted, without a significant reduction in the forced vital capacity. The HRCT detected abnormalities in 11 of the 18 patients. Diffuse bronchiectasis was the main finding. An inverse correlation between the anti-citrullinated peptide antibody (ACPA) levels and DLCO was found. Asymptomatic lung disease is present in up to 45% of early RA patients and can be determined by PFTs and ACPA levels.

Circulating anti-citrullinated peptide antibodies, cytokines and genotype as biomarkers of response to disease-modifying antirheumatic drug therapy in early rheumatoid arthritis.

BackgroundTo measure circulating anti-citrullinated peptide antibodies (ACPA) and cytokines pre- and 6 months post-therapy as a strategy to predict and optimize responses to traditional disease-modifying antirheumatic drugs (DMARDs) in early RA, which is an unmet need in developing countries.Patients and methodsA cohort of 140 predominantly (88.5 %) black female South African patients with early RA was treated with synthetic DMARDs, mostly methotrexate (MTX) alone, or in combination with low-dose oral corticosteroids (CS). Circulating ACPA and a panel of circulating cytokines/chemokines/growth factors were measured at baseline and after 6 months of therapy in relation to disease activity and Shared Epitope (SE).ResultsFollowing 6 months of therapy, the median simplified disease activity index (SDAI) declined from a baseline of 41.4 to 16.0 (p = 0.0001) for the entire cohort, which was paralleled by significant falls in median serum ACPA levels (516.6 vs. 255.7 units/ml, p = <0.0001) and several of the circulating cytokines (IL-4, IL-7, IL-8, G-CSF, VEGF; p < 0.0010 – p < 0.0001) which were most evident in the subgroup of patients treated with a combination of MTX and CS. Although biomarker concentrations decreased most notably in the low-disease activity group post-therapy, no significant correlations between these biomarkers and disease activity were observed, Baseline ACPA levels, but not SDAI or cytokines, were significantly higher in the subgroup of risk allele-positive patients (561.1 vs. 331.9 units/ml, p < 0.05), while no associations with ACPA and a smoking history were evident.ConclusionsThe use of DMARDs in RA is associated with significant decreases in ACPA and cytokines which did not correlate with changes in SDAI, precluding the utility of serial measurement of these biomarkers to monitor early responses to therapy, but may have prognostic value.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-015-0587-1) contains supplementary material, which is available to authorized users.

A PREDICTIVE MODEL FOR SIMPLIFIED DISEASE ACTIVITY INDEX (SDAI) REMISSION IN RHEUMATOID ARTHRITIS

Objectives. To identify predictors for Simplified Disease Activity Index (SDAI) remission in patients with established rheumatoid arthritis (RA) under 12 months of anti-TNF therapy combined with synthetic disease modyfing antirheumatic drugs (sDMARD). Methods. We performed a prospective observational study in 90 RA patients with a high active disease refractory to sDMARDs, starting anti-TNFs. Patients were assessed every 3 months based on a well-defined protocol, including individual parameters (clinical, inflammatory) and composite tools (simplified disease activity index SDAI, functional index HAQ-DI); total and IgA-isotype rheumatoid factor (RF) as well as anti-citrullinated peptide antibodies (ACPAs) were measured at baseline, 6 and 12 months. Therapeutic response was evaluated according to EULAR criteria. The primary endpoint was SDAI remission (≤ 3.3) at 12 months of treatment. Univariate and multivariate logistic regression analysis (Forward LR method) were used to assess the manner and intensity in which several parameters (demographics, disease-related, labs and medication) power SDAI remission. Results. SDAI remission was reported in 39.7% cases. We identified nine relevant predictors for SDAI remission at 12 months of therapy by univariate analysis, including: age ≤ 50 years, disease onset ≤ 5 years, RA stages I and II, functional capacity stages I and II, HAQ-DI ≤ 2, concomitent sDMARD, baseline CRP ≤ 20 mg/l, IgA-RF ≤ 20 IU/ml and ACPAs ≤ 40 IU/ml. A mathematical model was further generated, based only on six out of nine parameters: age, disease stage, functional capacity, concomitent sDMARDs, CRP and ACPA. This model expresses a solid approximation for the analysed casess (the Hosmer-Lemeshow test λ² = 0.931, p = 0.920 ≥ 0.05, Cox and Snell R2 0.399). Finally, three significant factors were recognized (age under 50, disease stages I and II, ACPA levels ≤ 40 IU/ml), predicting SDAI remission with an overall constant precision of 83.3%. However, no significant impact on SDAI remission prediction was reported when adding other parameters to the above mentioned model. Conclusion. SDAI remission can be predicted in established RA patients using three major predictors, including age ≤ 50 years, disease stages I and II and baseline ACPA levels ≤ 40 IU/ml.

Dysregulated Fc receptor function in active rheumatoid arthritis

Given the critical role of Fc gamma receptors (FcγR) as primary targets for autoantibody-mediated effects an important issue is how the FcγR pathway is affected in autoimmune disorders. Here we investigated the FcγR function in monocytes from rheumatoid arthritis (RA) patients in relation to immunoglobulin levels and disease activity. Peripheral blood was obtained from 30 RA patients with clinical acute joint synovitis (active RA), 28 RA patients with no clinical signs of acute joint synovitis (non-active RA) and 34 healthy controls. Prior the functional studies the monocytes were characterized of their FcγRI (CD64), II (CD32), IIb (CD32b) and III (CD16) expression as well as their cell surface bound IgG. The monocytic FcγR function was assessed by binding of human IgG1 and IgG3 immune complexes (IC) and TNF secretion in vitro. IgG anti-citrullinated peptide antibodies (ACPA) were analyzed in the plasma. We found that monocytes from active RA patients had increased levels of FcγRI, II and cell surface IgG concurrently with impaired FcγR function. This was evident by reduced IgG1-IC binding and decreased TNF secretion in response to IgG3-IC. In contrast, monocytes from non-active RA patients displayed a normal FcγR function and had increased FcγRIIb expression together with elevated FcγRI, II and cell surface IgG. The ACPA levels did not differ in active and non-active RA patients but correlated with the monocytic FcγRIII expression in the patients.In conclusion, active RA patients display a dysregulated FcγR function that may represent a novel phenotypic and likely pathogenetic marker for active RA. A disease and FcγR function controlling effect is suggested by the increased inhibitory FcγRIIb in non-active RA.

Serological status: a predictor of response to intensive therapy in rheumatoid arthritis

BackgroundRheumatoid arthritis is the most common chronic inflammatory disease in the UK. Serological status such as rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA) positivity predict poor outcomes. Early intensive treatment regimens targeting remission reduce disease activity, structural damage, and long-term disability. However, we do not know whether all patients with active disease should have such intensive treatment regimens. Can serological status be used to predict the need for intensive therapy? MethodsWe analysed samples from a published randomised controlled trial which compared four treatment regimens in patients with early active rheumatoid arthritis (disease duration <2 years): methotrexate monotherapy, double therapy (methotrexate plus either ciclosporin or prednisolone), and triple therapy (methotrexate plus ciclosporin plus prednisolone). The trial randomised 467 patients (68% female, median age 54 years [IQR 46–63]). Disease activity was assessed with the disease activity score of 28 joints (DAS28). Remission was defined as DAS28 less than 2·6 at 24 months. RF isotypes (IgM and IgA) and ACPA levels were measured with commercial ELISA kits. Statistical analysis used Pearson's chi-squared test. Findings402 (86%) patients were positive for IgM RF, 346 (74%) for IgA RF, and 346 (74%) for ACPA. 98 (21%) patients achieved remission at 24 months. In RF IgM negative cases (n=65) the proportion of patients achieving remission at 24 months was similar in all treatment groups (25%, 22%, and 30% for monotherapy, double therapy, and triple therapy, respectively). In RF IgM positive cases, significantly fewer patients achieved remission with monotherapy (13/65, 17%) and double therapy (24/157, 15%) than with triple therapy (27/80, 34%) (p=0·001). There were similar, consistent findings with IgA RF and ACPA, with significantly more seropositive patients achieving remission with triple therapy than with monotherapy. InterpretationContemporary treatment of rheumatoid arthritis emphasises the use of intensive therapy to achieve remission. However, we have shown that not all patients require such an aggressive approach to therapy. Given the heterogeneity of the diease, treatment should be personalised to the individual, which would minimise costs of treatment as well as potentially toxic side-effects. Our study shows that only seropositive patients with rheumatoid arthritis should be given more intensive therapies. FundingNational Institute for Health Research.

Baseline anti-citrullinated peptide antibody (ACPA) titers and serum interleukin-6 (IL-6) levels possibly predict progression of bone destruction in early stages of rheumatoid arthritis (ERA)

A prospective study was made to seek for a convenient biomarker to predict progression of bone destruction (PBD) in early stages of rheumatoid arthritis (ERA). All participated patients had definite RA and their radiographic stages were mild less than stage II of the Steinbrocker classification, naïve for treatment of any DMARDs or corticosteroids. After the entry, they were treated according to the 2002 ACR management guideline for RA. The candidate biomarkers (RF-IgM, RF-IgG, CARF, ACPA, CRP, ESR, NTx, MMP-3, IL-6 and osteopontin) were measured at the entry. PBD was assessed radiographically by interval changes in the modified Sharp scores (ΔSHS) for 24 months. The associations between ΔSHS and baseline biomarkers were assessed statistically by multivariate regression analyses. Both the baseline ACPA and IL-6 levels correlated with PBD, suggesting that they could predict PBD in ERA.