The Pathogenesis of Rheumatoid Arthritis

McInnes, Iain B.; Schett, Georg

doi:10.1056/nejmra1004965

Cited by 4,470 publications

(3,745 citation statements)

References 97 publications

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“…An increased prevalence of traditional risk factors, such as diabetes mellitus, hypertension, obesity, smoking, and physical inactivity, may explain, in part, this excess cardiovascular risk in RA 8, 11. However, innate as well as adaptive immune mechanisms shared by RA and cardiovascular disease, namely atherosclerosis, have emerged as potential contributors to the heightened cardiovascular risk observed in these patients 43, 44…”

Section: Discussionmentioning

confidence: 99%

Incident Heart Failure in Patients With Rheumatoid Arthritis: A Nationwide Cohort Study

Khalid

Egeberg

Ahlehoff

et al. 2018

JAHA

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BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease associated with a wide range of comorbidities, including cardiovascular disease, but its association with heart failure (HF) is not fully clear. We investigated the risk of incident HF in a nationwide cohort of patients with RA.Methods and ResultsThe study comprised the entire Danish population aged ≥18 years followed from January 1, 2008 until first hospitalization for HF, emigration, December 31, 2012, or death. Information on comorbidity, medication, and socioeconomic status was identified by individual‐level linkage of administrative registers. Patients with a rheumatologist diagnosis of RA between 1978 and 2008 were included. The primary study outcome was incident HF defined as first hospital admission for HF. Incidence rates of HF per 1000 person‐years were calculated and incidence rate ratios adjusted for age, sex, calendar year, comorbidity, medications, socioeconomic status, smoking, and alcohol consumption were estimated. A total of 4 305 225 subjects with no history of HF were eligible for analysis at the study start. Of these subjects, 24 343 developed RA and 50 623 were hospitalized for HF. Overall incidence rates of incident HF were 2.43 and 6.64 for the reference population (n=49 879) and patients with RA (n=744), respectively. Correspondingly, the fully adjusted incidence rate ratio for incident HF was increased in patients with RA with incidence rate ratio 1.30 (95% confidence interval, 1.17–1.45).ConclusionsIn this cohort study, RA was associated with an increased hospitalization for HF. These findings add significantly to the existing evidence of RA as a clinically relevant risk factor for HF.

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Section: Discussionmentioning

confidence: 99%

Incident Heart Failure in Patients With Rheumatoid Arthritis: A Nationwide Cohort Study

Khalid

Egeberg

Ahlehoff

et al. 2018

JAHA

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“…Furthermore, this expansion of ACPA response has been correlated closely with an elevation of specific inflammatory cytokines such as tumour necrosis factor (TNF)-α and interferon (IFN)-γ that precedes the appearance of arthritis [37]. Thus, the breakdown of peripheral immune tolerance is centred probably in the preclinical phase of the disease, when citrullination is taking place and citrullinated autoantigens are being presented and recognized by the immune system, eliciting an autoimmune response [38]. Various contributors could interfere with these processes and therefore affect the diversity of ACPA specificity, including genetic features [39,40] and environmental factors [41].…”

Section: Discussionmentioning

confidence: 99%

Fine specificity of anti-citrullinated peptide antibodies discloses a heterogeneous antibody population in rheumatoid arthritis

Goules

Tzioufas

2013

Clinical and Experimental Immunology

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SummaryAnti-citrullinated peptide antibodies (ACPA) are highly specific for rheumatoid arthritis (RA). However, the predominant B cell epitopes have not yet been defined. The aim of this study was to examine the reactivity of ACPA against different peptides derived from citrullinated proteins and to investigate whether or not these antibodies constitute a homogeneous population. For this purpose, sera from patients with RA (n = 141), systemic lupus erythematosus (SLE) (n = 60), Sjögren's syndrome (SS) (n = 54) and healthy controls (n = 100) were tested for their reactivity against six citrullinated peptides derived from peptidyl arginine deiminase (PAD), vimentin (vim), alpha-enolase (enol), fibrin, type II collagen (col-II) and filaggrin, respectively. A non-citrullinated control peptide derived from PAD was used as control (ctrlPAD 621-40 ). Antibody reactivity against each individual peptide was evaluated by enzyme-linked immunosorbent assay (ELISA). Specificity and cross-reactivity of ACPA were tested by using two prototype sera with homologous and cross-inhibition assays. Specificity of ACPA from two prototype sera was confirmed by purification of anti-peptide antibodies and homologous-inhibition experiments. We found that sera from patients with RA reacted diversely with the six citrullinated peptides. More specifically, PAD 211-30 displayed 29·08% sensitivity, vim 60-75 29·08%, enol 5-21 37·59%, fibrin 617-31 31·21%, col-II 358-75 29·97% and filaggrin 306-24 28·37%, while control ctrlPAD 621-40 showed no reactivity. All reactive peptides were found to be highly specific for RA. A notable cross-reaction (>70%) was found mainly between filaggrin and the majority of anti-citrullinated peptide antibodies. We concluded that ACPA in RA constitute a heterogeneous population with limited cross-reactivity and without a predominant epitope.

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“…Although the cause of RA remains elusive, it has been demonstrated that in genetically predisposed subjects carrying the (Human Leukocyte Antigen) HLAeDRB1*04 cluster, environmental factors such as the oral and gut microbiota may lead to the abnormal activation of the innate and adaptive immunity, which involve cellular and humoral immune responses [4]. This activation leads to the formation of autoantibodies [rheumatoid factors (RF) and antibodies against citrullinated peptides/proteins (ACPA)] and invasion of T cells and B cells into the synovium [4] (Fig. 1).…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

The role of the gastrointestinal tract in the pathogenesis of rheumatic diseases

Ciccia

Ferrante

Guggino

et al. 2016

Best Practice & Research Clinical Rheumatology

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a b s t r a c tDysregulation of the intestinal epithelial barrier in genetically susceptible individuals may lead to both intestinal and extraintestinal autoimmune disorders. There is emerging literature on the role of microbiota changes in the pathogenesis of systemic rheumatic diseases such as rheumatoid arthritis, spondyloarthropathies, and connective tissue diseases. Although the role of the gastrointestinal tract in the pathogenesis of spondyloartropathies is well defined and many studies underline the importance of gastrointestinal inflammation in modulating local and systemic inflammation, the data are inconclusive regarding the effect of dysbiosis on rheumatoid arthritis and connective tissue diseases. This review aims to summarize current data on the role of the gastrointestinal involvement and intestinal microbiota in the pathogenesis of systemic rheumatic disease.

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The Pathogenesis of Rheumatoid Arthritis

Cited by 4,470 publications

References 97 publications

Incident Heart Failure in Patients With Rheumatoid Arthritis: A Nationwide Cohort Study

Incident Heart Failure in Patients With Rheumatoid Arthritis: A Nationwide Cohort Study

Fine specificity of anti-citrullinated peptide antibodies discloses a heterogeneous antibody population in rheumatoid arthritis

The role of the gastrointestinal tract in the pathogenesis of rheumatic diseases

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