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Inflammation-independent defective early B cell tolerance checkpoints in rheumatoid arthritis.

ABSTRACT: Rheumatoid arthritis (RA) patients who have never received treatment for RA have been found to have defective early B cell tolerance checkpoints, resulting in impaired removal of developing autoreactive B cells. However, it is unclear whether these defects in B cell tolerance checkpoints are a primary aspect of the disease or are the result of ongoing inflammatory processes in these patients. The aim of this study was to assess the impact of standard immunosuppressive treatments, methotrexate and anti-tumor necrosis factor ? (anti-TNF?) agents, on early B cell tolerance checkpoints in RA patients.Blood samples were obtained from RA patients before and after treatment with methotrexate and/or anti-TNF? agents. B cells were tested pre- and posttherapy for reactivity of recombinant antibodies cloned from single B cells, which allowed us to determine the evolution of the frequency of autoreactive clones in the mature naive B cell compartment in RA patients before and after treatment. B cells from healthy donors were used as controls.Posttreatment frequencies of autoreactive mature naive B cells were elevated in the blood of RA patients. Nevertheless, the frequencies after treatment remained similar to those observed in the same patients before treatment.Despite the achievement of clinical improvement in RA patients following treatment with methotrexate and/or anti-TNF? agents, these therapies did not correct the accumulation of peripheral autoreactive mature naive B cells in these patients, suggesting that inflammation is not responsible for the defective early B cell tolerance checkpoints in RA.

SUBMITTER: Menard L

PROVIDER: S-EPMC3699182 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Inflammation-independent defective early B cell tolerance checkpoints in rheumatoid arthritis.

Menard Laurence L Samuels Jonathan J Ng Yen-Shing YS Meffre Eric E

Arthritis and rheumatism 20110501 5

<h4>Objective</h4>Rheumatoid arthritis (RA) patients who have never received treatment for RA have been found to have defective early B cell tolerance checkpoints, resulting in impaired removal of developing autoreactive B cells. However, it is unclear whether these defects in B cell tolerance checkpoints are a primary aspect of the disease or are the result of ongoing inflammatory processes in these patients. The aim of this study was to assess the impact of standard immunosuppressive treatment ...[more]

PMID: 21538313

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Project description:BackgroundPrevious studies have linked rheumatoid arthritis (RA) risk and disease activity with vitamin D-deficiency (low serum 25-hydroxyvitamin D (25OHD)), but a causal role for vitamin D in RA is still unclear, with conflicting results from many previous studies, partly due to heterogeneity in study design and patient populations. In this study we aimed to (1) analyse serum 25OHD in early inflammatory arthritis, (2) compare 25OHD with disease activity and fatigue in early RA and (3) determine whether low 25OHD is associated with progression to RA.MethodsAn analysis of 790 patients recruited to the Birmingham Early Inflammatory Arthritis Cohort and followed longitudinally to determine clinical outcomes. The following were recorded at baseline: demographic data, duration of symptoms, duration of early morning stiffness (EMS), tender and swollen joint counts, Visual Analogue Scale (VAS) pain/fatigue/EMS, PHQ-9, HAQ and FACIT-Fatigue scores, DAS28-ESR, DAS28-CRP, CRP, ESR, anti-CCP antibody status, rheumatoid factor status, and serum 25OHD (ng/ml). Diagnosis was recorded at 0 and 12 months onwards as either RA, Undifferentiated Inflammatory Arthritis (UIA; synovitis not meeting other classification/diagnostic criteria), Clinically Suspect Arthralgia (CSA; arthralgia of an inflammatory type without synovitis), or Other.ResultsBaseline demographic data were similar between all groups, with median symptom duration of 16.8-34.0 days. Baseline 25OHD was not significantly different between groups [median, interquartile range (IQR): RA 46.7, 30.0-73.3; UIA 51.4, 30.0-72.3; CSA 47.7, 30.3-73.0; Other 39.9, 28.6-62.2]. In RA (n = 335), there were no significant differences between 25OHD and measures of disease activity or fatigue. No association between 25OHD and progression from UIA or CSA to RA was observed.ConclusionsThere was no clear association between serum 25OHD and baseline diagnosis, RA disease activity, or progression from UIA or CSA to RA. Future studies of other vitamin D metabolites may better define the complex role of vitamin D in RA.

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Inflammation-independent defective early B cell tolerance checkpoints in rheumatoid arthritis.

Publications

Inflammation-independent defective early B cell tolerance checkpoints in rheumatoid arthritis.

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