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Anti-hnRNP B1 (RA33) autoantibodies are associated with the clinical phenotype in Russian patients with rheumatoid arthritis and systemic sclerosis.

ABSTRACT: Heterogeneous nuclear ribonucleoproteins (hnRNPs) are potent autoantigenic targets in systemic autoimmune rheumatic diseases (SARD). Loss of tolerance to the RA33 complex consisting of hnRNP A2 and its alternatively spliced variants B1 and B2 has been the interest of rheumatologists. A novel ELISA for the detection of anti-hnRNP B1 autoantibodies has been developed to investigate the prevalence thereof in 397 patients with SARD, including patients with rheumatoid arthritis (RA), spondyloarthropathy (SPA), juvenile chronic arthritis, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjögren's syndrome (SS), in comparison to 174 controls. Anti-hnRNP B1 autoantibodies were significantly more prevalent in patients with SARD than controls (47/397, 11.8% versus 2/174, 1.1%; P<0.001). In particular, anti-hnRNP B1 were found more frequently in the disease cohorts than in the controls and were present in 24/165 (14.5%) patients with RA, 6/58 (10.3%) SPA, 11/65 (16.9%) SSc, and 4/50 (8.0%) SLE. In RA patients, anti-hnRNP B1 autoantibodies correlated significantly with C-reactive protein levels and erythrocyte sedimentation rate, while in patients with SSc it was associated with features of arterial wall stiffness and presence of hypertension. Anti-hnRNP B1 autoantibodies occur in SARD and seem to be correlated with distinct clinical characteristics in patients with RA and SSc.

SUBMITTER: Maslyanskiy A

PROVIDER: S-EPMC4027001 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Anti-hnRNP B1 (RA33) autoantibodies are associated with the clinical phenotype in Russian patients with rheumatoid arthritis and systemic sclerosis.

Maslyanskiy Aleksey A Lazareva Natalya N Olinek Polina P Schierack Peter P Hentschel Christian C Cuccato Juliane J Bogdanos Dimitrios P DP Lapin Sergey V SV Roggenbuck Dirk D

Journal of immunology research 20140504

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are potent autoantigenic targets in systemic autoimmune rheumatic diseases (SARD). Loss of tolerance to the RA33 complex consisting of hnRNP A2 and its alternatively spliced variants B1 and B2 has been the interest of rheumatologists. A novel ELISA for the detection of anti-hnRNP B1 autoantibodies has been developed to investigate the prevalence thereof in 397 patients with SARD, including patients with rheumatoid arthritis (RA), spondyloarthropa ...[more]

PMID: 24883333

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Project description:Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder affecting the joints. Many patients carry anti-citrullinated protein autoantibodies (ACPA). Overactivation of the complement system seems to be part of the pathogenesis of RA, and autoantibodies against the pathway initiators C1q and MBL, and the regulator of the complement alternative pathway, factor H (FH), were previously reported. Our aim was to analyze the presence and role of autoantibodies against complement proteins in a Hungarian RA cohort. To this end, serum samples of 97 ACPA-positive RA patients and 117 healthy controls were analyzed for autoantibodies against FH, factor B (FB), C3b, C3-convertase (C3bBbP), C1q, MBL and factor I. In this cohort, we did not detect any patient with FH autoantibodies but detected C1q autoantibodies in four patients, MBL autoantibodies in two patients and FB autoantibodies in five patients. Since the latter autoantibodies were previously reported in patients with kidney diseases but not in RA, we set out to further characterize such FB autoantibodies. The isotypes of the analyzed autoantibodies were IgG2, IgG3, IgGκ, IgGλ and their binding site was localized in the Bb part of FB. We detected in vivo formed FB-autoanti-FB complexes by Western blot. The effect of the autoantibodies on the formation, activity and FH-mediated decay of the C3 convertase in solid phase convertase assays was determined. In order to investigate the effect of the autoantibodies on complement functions, hemolysis assays and fluid phase complement activation assays were performed. The autoantibodies partially inhibited the complement-mediated hemolysis of rabbit red blood cells, inhibited the activity of the solid phase C3-convertase and C3 and C5b-9 deposition on complement activating surfaces. In summary, in ACPA-positive RA patients we identified FB autoantibodies. The characterized FB autoantibodies did not enhance complement activation, rather, they had inhibitory effect on complement. These results support the involvement of the complement system in the pathomechanism of RA and raise the possibility that protective autoantibodies may be generated in some patients against the alternative pathway C3 convertase. However, further analyses are needed to assess the exact role of such autoantibodies.

Project description:BackgroundGiven that autoantibodies to peptidylarginine deiminase 4 (PAD4) are associated with erosive disease in established rheumatoid arthritis (RA), this study was conducted to compare the clinical and prognostic use of anti-PAD4 antibodies in patients with early and established RA.MethodsSera from patients with early (duration <2 years; n = 422) or established (duration ≥2 years; n = 359) RA from two randomized clinical trials of tofacitinib ± methotrexate compared with adalimumab + MTX or MTX alone were evaluated for the presence of anti-PAD4 and anti-PAD3/4 antibodies at baseline and posttreatment time points. Summary statistics were calculated for demographic, clinical, and serological characteristics, and generalized estimating equations were used to model clinical outcomes by disease duration according to anti-PAD4 status.ResultsAnti-PAD4 antibodies were present in 22% and 40% of patients with early and established RA, respectively, stable following treatment, and associated with baseline joint damage only in established RA. In early RA, baseline anti-PAD4 antibodies were associated with a greater improvement in disease activity score 28-joint count using C-reactive protein levels after treatment compared with individuals with negative anti-PAD4 (P = 0.049). Tofacitinib ± MTX was more broadly efficacious than MTX alone at improving clinical outcomes in early and established RA, irrespective of anti-PAD4 status (P < 0.05 for all), whereas adalimumab + MTX exhibited differential benefits in achieving disease activity score remission in early RA (P = 0.036) and American College of Rheumatology 20 responses in established RA (P = 0.002).ConclusionDifferences in prevalence, clinical associations, and treatment-response outcomes according to anti-PAD4 antibody status in early and established RA suggests the existence of a therapeutic window to prevent the accumulation of irreversible joint damage in early patients with RA with anti-PAD4 antibodies.

Project description:IntroductionWe investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with abnormalities on pulmonary function tests (PFTs).MethodsWe studied RA serostatus and PFT abnormalities within a RA registry. RA serostatus was assessed by research assays for cyclic citrullinated peptide (CCP) and rheumatoid factor (RF). Outcomes were abnormalities on clinically indicated PFTs, including restriction, obstruction, and diffusion abnormality. Logistic regression was used to obtain ORs and 95% CIs for the PFT abnormalities by RA serologic phenotypes independent of lifestyle and RA characteristics.ResultsAmong 1272 analyzed subjects, mean age was 56.3 years (SD 14.1), 82.2% were female, and 69.5% were seropositive. There were 100 subjects with abnormal PFTs. Compared with seronegativity, seropositivity was associated with increased odds of any PFT abnormality (multivariable OR 2.29, 95% CI 1.30-4.03). When analyzing type of PFT abnormality, seropositivity was also associated with restriction, obstruction, and diffusion abnormalities; multivariable ORs were 2.48 (95% CI 1.26-4.87), 3.12 (95% CI 1.28-7.61), and 2.30 (95% CI 1.09-4.83), respectively. When analyzing by CCP and RF status, the associations were stronger for RF+ than for CCP+ (any PFT abnormality OR 1.99, 95% CI 1.21-3.27 for RF+ vs. RF-; OR 1.67, 95% CI 1.03-2.69 for CCP+ vs. CCP-) with a dose effect of higher RF titer increasing odds for each PFT abnormality (p for trend < 0.05).ConclusionsSeropositive RA patients had two-fold increased risk for abnormalities on PFTs performed for clinical indications compared with seronegative RA. Patients with seropositive RA, particularly those with high-titer RF positivity, may be more likely to have obstructive and restrictive abnormalities, independent of smoking.Key points• Due to the known excess pulmonary morbidity/mortality in RA, we studied the relationship of rheumatoid arthritis (RA)-related autoantibodies with pulmonary function test (PFT) abnormalities using a large RA registry.• We evaluated whether presence and levels of cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) were associated with restriction, obstruction, and diffusion abnormalities on PFTs among 1272 subjects with RA.• Seropositivity was associated with two-fold increased risk for any PFT abnormality, independent of confounders including smoking. Higher titers of RF conferred greatest risk for all PFT outcomes: obstruction, restriction, and diffusion abnormality.• These results provide evidence that patients with RA should be closely monitored for pulmonary involvement, particularly those with high-titer RF seropositivity.

Dataset Information

Anti-hnRNP B1 (RA33) autoantibodies are associated with the clinical phenotype in Russian patients with rheumatoid arthritis and systemic sclerosis.

Publications

Anti-hnRNP B1 (RA33) autoantibodies are associated with the clinical phenotype in Russian patients with rheumatoid arthritis and systemic sclerosis.

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