Dataset Information

The Role of Shared Epitope in Rheumatoid Arthritis Prognosis in Relation to Anti-Citrullinated Protein Antibody Positivity.

ABSTRACT:

Introduction

Shared epitope (SE) is present in high proportions of anti-citrullinated protein antibody (ACPA) + patients with rheumatoid arthritis (RA) and is associated with poor prognosis. We assessed the role of SE in RA prognosis, in relation to ACPA positivity.

Methods

Patients enrolled in the Brigham and Women's RA Sequential Study were included. Changes from baseline in disease activity (Disease Activity Score in 28 joints using C-reactive protein [DAS28 (CRP)], Clinical Disease Activity Index [CDAI], Simplified Disease Activity Index [SDAI]) to 1 year were assessed. Baseline characteristics were compared by SE and ACPA status (±; chi-squared, Kruskal-Wallis). Association between number of SE alleles and ACPA status (logistic regression models), relationships between baseline characteristics and changes in disease activity (adjusted linear regression model), and effect of ACPA on the association between SE and changes in disease activity (mediation analysis) were studied.

Results

Nine hundred twenty-six patients were included. SE + versus SE - patients had significantly longer disease duration and higher disease activity scores and were more likely to have erosive disease, have higher comorbidity burden, and be RF + (all p < 0.05). Among patients with one or two SE alleles (vs. 0), odds of being ACPA + were 1.97 (p = 0.0003) and 3.82 (p < 0.0001), respectively. SE + versus SE - patients had worse disease activity scores as indicated by mean increases in DAS28 (CRP) of 0.22, CDAI of 2.07, and SDAI of 2.43 over 1 year (all p < 0.05). Direct effect of SE + accounted for 76.4-80.1% of total effect in disease activity increases.

Conclusions

SE is strongly associated with ACPA positivity and higher disease activity in patients with RA. SE was associated with greater increases in disease activity over 1 year, which was partially mediated by the presence of ACPA.

Trial registration

ClinicalTrials.gov identifier: NCT01793103; registration date: February 15, 2013, retrospectively registered.

SUBMITTER: Zhuo J

PROVIDER: S-EPMC8964857 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

The Role of Shared Epitope in Rheumatoid Arthritis Prognosis in Relation to Anti-Citrullinated Protein Antibody Positivity.

Zhuo Joe J Xia Qian Q Sharma Niyati N Gao Sheng S Lama Sonie S Cui Jing J Feathers Vivi V Shadick Nancy N Weinblatt Michael E ME

Rheumatology and therapy 20220216 2

<h4>Introduction</h4>Shared epitope (SE) is present in high proportions of anti-citrullinated protein antibody (ACPA) + patients with rheumatoid arthritis (RA) and is associated with poor prognosis. We assessed the role of SE in RA prognosis, in relation to ACPA positivity.<h4>Methods</h4>Patients enrolled in the Brigham and Women's RA Sequential Study were included. Changes from baseline in disease activity (Disease Activity Score in 28 joints using C-reactive protein [DAS28 (CRP)], Clinical Di ...[more]

PMID: 35174462

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Project description:OBJECTIVE:Because of its association with joint destruction, anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) is considered to be more severe than ACPA-negative RA. Clinically relevant joint destruction is now infrequent thanks to adequate disease suppression. According to patients, important outcomes are pain, fatigue, and independence. We evaluated whether ACPA-positive RA patients diagnosed during or after 2000 have more severe self-reported limitations and impairments, including restrictions at work, than ACPA-negative RA patients. METHODS:A total of 492 ACPA-positive and 450 ACPA-negative RA patients who fulfilled the 2010 criteria and were included in the Leiden Early Arthritis Clinic cohort during or after 2000 were compared for self-reported pain, fatigue, disease activity, general well-being (measured by numerical rating scales), physical function (measured by the Health Assessment Questionnaire), and work restrictions, including absenteeism at baseline and during the 4-year followup. Linear mixed models were used. RESULTS:At disease presentation, ACPA-negative patients had more severe pain, fatigue, self-reported disease activity scores, and functional disability (P < 0.05), although absolute differences were small. During followup, ACPA-negative patients remained somewhat more fatigued (P = 0.002), whereas other patient-reported impairments and limitations were similar. Thirty-eight percent of ACPA-negative and 48% of ACPA-positive patients reported absenteeism (P = 0.30), with median 4 days missed in both groups in the last 3 months. Also, restrictions at work among employed patients and restrictions with household work were not statistically different at baseline and during followup. CONCLUSION:In current rheumatology practice, ACPA-positive RA is not more severe than ACPA-negative RA in terms of patients' relevant outcomes, including physical functioning and restrictions at work. This implies that efforts to further improve the disease course should be proportional to both disease subsets.

Project description:ObjectiveAnti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are commonly present in rheumatoid arthritis (RA) without a clear rationale for their coexistence. Moreover, autoantibodies develop against proteins with different posttranslational modifications and native proteins without obvious unifying characteristics of the antigens. We undertook this study to broadly evaluate autoantibody binding in seronegative and seropositive RA to identify novel features of reactivity.MethodsAn array was created using a total of 172,828 native peptides, citrulline-containing peptides, and homocitrulline-containing peptides derived primarily from proteins citrullinated in the rheumatoid joint. IgG and IgM binding to peptides were compared between cyclic citrullinated peptide (CCP)-positive RF+, CCP+RF-, CCP-RF+, and CCP-RF- serum from RA patients (n = 48) and controls (n = 12). IgG-bound and endogenously citrullinated peptides were analyzed for amino acid patterns and predictors of intrinsic disorder, i.e., unstable 3-dimensional structure. Binding to IgG-derived peptides was specifically evaluated. Enzyme-linked immunosorbent assay confirmed key results.ResultsBroadly, CCP+RF+ patients had high citrulline-specific IgG binding to array peptides and CCP+RF- and CCP-RF+ patients had modest citrulline-specific IgG binding (median Z scores 3.02, 1.42, and 0.75, respectively; P < 0.0001). All RA groups had low homocitrulline-specific binding. CCP+RF+ patients had moderate IgG binding to native peptides (median Z score 2.38; P < 0.0001). The highest IgG binding was to citrulline-containing peptides, irrespective of protein identity, especially if citrulline was adjacent to glycine or serine, motifs also seen in endogenous citrullination in the rheumatoid joint. Highly bound peptides had multiple features predictive of disorder. IgG from CCP+RF+ patients targeted citrulline-containing IgG-derived peptides.ConclusionDisordered antigens, which are frequently citrullinated, and common epitopes for ACPAs and RF are potentially unifying features for RA autoantibodies.

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Dataset Information

The Role of Shared Epitope in Rheumatoid Arthritis Prognosis in Relation to Anti-Citrullinated Protein Antibody Positivity.

Introduction

Methods

Results

Conclusions

Trial registration

Publications

The Role of Shared Epitope in Rheumatoid Arthritis Prognosis in Relation to Anti-Citrullinated Protein Antibody Positivity.

Similar Datasets

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