Strong combined gene–environment effects in anti–cyclic citrullinated peptide–positive rheumatoid arthritis: A nationwide case–control study in Denmark

Pedersen, Merete; Jacobsen, Søren; Garred, Peter; Madsen, Hans O.; Klarlund, Mette; Svejgaard, A.; Pedersen, Bo Vest; Wohlfahrt, Jan; Frisch, Mørten

doi:10.1002/art.22597

Cited by 181 publications

(128 citation statements)

References 29 publications

(33 reference statements)

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“…In contrast, the antigens that stimulate the ACPA response in healthy individuals and are responsible for the initial loss of immune tolerance are currently not known. Based on observations made in several populations, it has been hypothesized that the association between smoking and ACPAs may be attributable to increased expression of citrullinated antigens in the lungs of smokers (32)(33)(34). Alternatively, it has been proposed that the oral pathogen Porphyromonas gingivalis, which is capable of citrullinating endogenous antigens, may be involved in the initial breaking of immune tolerance (35).…”

Section: Discussionmentioning

confidence: 99%

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

Ioan‐Facsinay¹,

Willemze²,

Robinson³

et al. 2008

Arthritis & Rheumatism

166

144

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Objective. Anti-citrullinated protein antibodies (ACPAs) display high association with rheumatoid arthritis (RA) and are implicated in its pathogenesis. The presence of ACPAs is known to precede the onset of RA. In order to identify the features that could confer its pathogenicity, we extensively characterized this antibody response in a unique North American native population of patients with RA and their unaffected relatives.Methods. The levels of IgA, IgM, and IgG ACPAs, as well as IgM and IgA rheumatoid factor (RF), were measured in serum samples obtained from 81 patients with RA and 195 of their unaffected relatives. The isotype distribution, the fine specificity of the ACPA response, and its association with RF were compared in health and disease.Results. ACPA positivity was observed in 19% of the healthy relatives and ϳ91% of the patients with RA. ACPA isotype usage was strikingly lower in unaffected relatives than in patients with RA (1-2 versus 5-6 isotypes). Fine specificity studies showed that reactivity to citrullinated fibrinogen and vimentin was present in sera from patients with RA, while it was virtually absent in their unaffected relatives. Finally, the ACPA and RF responses were associated in patients with RA but were discordant in their healthy relatives. Extended analyses revealed that the presence of ACPAs was associated with RA irrespective of RF status, while the association of RF with disease relied on its interaction with ACPAs.Conclusion. The fine specificity and isotype usage of the ACPA response are qualitatively different in health and disease. Epitope spreading and expansion of the isotype repertoire might be necessary for development of RA, and this could be facilitated by the presence of RF antibodies.Autoantibodies are characteristic of a large number of autoimmune diseases. Determining the pathogenicity of autoantibodies by showing their capacity to transfer disease, however, is complicated by ethical and practical difficulties. Therefore, only a small minority of autoantibodies, such as antiplatelet antibodies in idiopathic thrombocytopenia purpura or the antidesmoglein antibodies in pemphigus vulgaris, were convincingly shown to mediate a pathogenetic effect through placental transfer (1) or transfer into experimental animals (2), respectively.

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Section: Discussionmentioning

confidence: 99%

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

Ioan‐Facsinay¹,

Willemze²,

Robinson³

et al. 2008

Arthritis & Rheumatism

166

144

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“…[6][7][8] Although RF and ACPA are strongly associated with each other, HLA-DRB1 SE has a much stronger association with ACPA than with RF. [9][10][11][12] Most studies show no RA susceptibility effect of HLA-DRB1 SE independent of ACPA, 10,[13][14][15] but recently an effect on ACPA-negative RA has been described. 16,17 Furthermore, there may be a hierarchy of risk among HLA-DRB1 SE alleles.…”

Section: Introductionmentioning

confidence: 99%

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

et al. 2011

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Previously-proposed rheumatoid arthritis (RA) HLA-DRB1 susceptibility and protective models were compared, based on amino acids at positions 67-74 and autoantibody combinations. 3 657 RA patients and 1 357 controls were studied using logistic regression, with secondary stratification by anti-citrullinated peptide antibodies(ACPA) and rheumatoid factor(RF). Susceptibility models were based on previously defined HLA-DRB1 shared epitope(SE) subgroups. 70 DERAA 74 , D 70 and I 67 protective models were compared, adjusting for HLA-DRB1 SE. A hierarchy of risk was observed within the HLA-DRB1 SE, particularly for ACPA-positive and RF-positive RA: HLA-DRB1*0401B*04044*0101B*1001 (*04044*0101: P ¼ 0.0003). HLA-DRB1*0401/*0404 compound heterozygosity conferred a risk similar to *0401 homozygosity (P ¼ 0.70). Protective effects of D 70 and I 67 were similar. Predictions of the D 70 model fitted the data better than those of the I 67 model. The protective effect of D 70 showed a gene-dose effect (OR 0.82, 95% CI 0.73-0.92, P ¼ 5.8 Â 10 À4 ), but was only seen in RA patients positive for RF or ACPA. HLA-DRB1 SE alleles were also associated with ACPA-negative, RF-positive RA (OR 1.42 (1.15-1.76), P ¼ 0.0012).In conclusion, HLA-DRB1 SE alleles show heterogeneity in RA susceptibility; their major effect appears to be mediated by ACPA positivity, but a significant association of HLA-DRB1 SE with RF-positive, ACPA-negative RA was also observed. D 70 specifically protected against antibody-positive RA.

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“…Silica exposure may theoretically be linked to other environmental exposures that may themselves be related to the increased possibility of developing CTD. For example, smoking in conjunction with silica exposure has been reported to be a risk factor for the development of radiographic changes of silicosis [42] and smoking has been reported to be a risk factor for the development of CTD, particularly rheumatoid arthritis (RA) [43]. Smoking has been identified to interact with certain susceptibility genes in the host to trigger a cascade of immuno-inflammatory events leading to anti-CCP positive RA.…”

Section: Pneumoconiosis (Silicosis)mentioning

confidence: 99%

Scleroderma Lung Disease – Other Lung Complications in Systemic Sclerosis

Almeida¹

2012

Rheumatology

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Scleroderma or systemic sclerosis (SSc) is a clinically heterogeneous, multi-system autoimmune disorder characterized by endothelial dysfunction, dysregulation of fibroblasts resulting in excessive production of collagen and profound abnormalities of the immune system. Pulmonary involvement is common and occurs in all SSc subsets, including limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis and SSC sine scleroderma. Aside from the common complications of pulmonary vasculopathy and interstitial lung disease (ILD], other less frequent pulmonary complications have been reported in SSc. The emphasis of this review will be on other lung complications in systemic sclerosis.

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Strong combined gene–environment effects in anti–cyclic citrullinated peptide–positive rheumatoid arthritis: A nationwide case–control study in Denmark

Cited by 181 publications

References 29 publications

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

Scleroderma Lung Disease – Other Lung Complications in Systemic Sclerosis

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