Increased levels of autoantibodies against copper-oxidized low density lipoprotein, malondialdehyde-modified low density lipoprotein and cardiolipin in patients with rheumatoid arthritis

J. T. Cvetkovic, S. Wållberg-Jonsson1, E. Ahmed, S. Rantapää-Dahlqvist1 and A. K. Lefvert1,

Immunological Research Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm and
1 Department of Rheumatology, University Hospital, Umeå, Sweden


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objectives. To analyse the association of autoantibodies against cardiolipin (CL) and oxidized low density lipoproteins [copper-oxidized low density lipoprotein (oxLDL), malondialdehyde-modified LDL (MDA-LDL)] with rheumatoid arthritis (RA) and cardiovascular complications.

Methods. One hundred and twenty-one patients with RA were consecutively included. Autoantibodies were determined by ELISA. Healthy individuals from the same region were used as controls.

Results. Levels of IgG, IgM and IgA antibodies against MDA-LDL and CL, as well as IgG and IgA antibodies against oxLDL were increased in the patients (P<0.01). The prevalence of IgG, IgM and IgA antibodies against CL was higher than in the normal population (74, 82 and 14%, respectively). The prevalence of IgG and IgA antibodies against oxLDL was also significantly increased (35 and 25%, respectively) and so was the prevalence of IgG and IgM antibodies against MDA-LDL (17 and 26%, respectively) compared with controls. The levels of IgM and IgA antibodies against aCL and IgM against MDA-LDL were increased in patients with extra-articular manifestations. Patients who developed myocardial infarction had a higher prevalence of IgG antibodies against MDA-LDL (P=0.04). There were substantial correlations between the levels of antibodies against oxLDL, MDA-LDL and CL.

Conclusions. RA patients had increased levels and prevalence of autoantibodies against CL, oxLDL and MDA-LDL, with associations to severity of disease and cardiovascular complications.

KEY WORDS: Autoantibody, Rheumatoid arthritis, Cardiolipin, oxLDL, MDA-LDL, Cardiovascular disease.


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is a chronic inflammatory disease with a wide variety of disease manifestations. In many patients, the outcome of RA is complicated by cardiovascular diseases and this is the main cause of the increased mortality in this disorder [1, 2]. Autoantibodies against cardiolipin (CL) [36] and oxidatively modified low density lipoproteins [copper-oxidized LDL (oxLDL)] [5, 7], including malondialdehyde-modified LDL (MDA-LDL) [8], have been suggested to have a predictive value for cardiovascular diseases. These antibodies have been shown to partially recognize the same epitopes, and might thus represent overlapping specificities [9]. RA is also characterized by the presence of rheumatoid factors (RF) [10] and, in some patients, of antinuclear antibodies (ANA). However, the relationship between different types of autoantibodies and especially their relation to RA and cardiovascular disease, is unclear.

Autoantibodies against cardiolipin (aCL) have been associated with several other autoimmune diseases, like antiphospholipid syndrome (APS) [11] and systemic lupus erythematosus (SLE) [12]. aCL are considered risk factors for arterial and venous thrombotic events [13], cerebral infarction [14, 15], thrombocytopenia [16] and recurrent abortion [17].

A correlation between oxidative processes of lipids and atherosclerosis or myocardial infarction (MI) [3, 5, 18] has been supported by experiments in which endothelial cells, monocytes/macrophages and smooth muscle cells were incubated with LDL [19, 20], leading to the formation of oxLDL. The pathogenic function of oxLDL was proven in animal models and Ylä-Herttuala et al. [21, 22] showed that atherosclerotic lesions of rabbit and man contained oxLDL. Several groups have now reported that autoantibodies against oxLDL are elevated in different cardiovascular diseases [5, 8, 2326]. One possible pathogenic/atherogenic role of these autoantibodies could be increased formation of immune complexes by oxLDL and autoantibodies, leading to an acceleration of the formation of foam cells [27].

As a byproduct of the lipid peroxidation, malondialdehyde (MDA) is formed. This compound can bind to lysine residues of proteins and build up covalent links to proteins. Increased levels of autoantibodies against MDA-LDL are present in sera of patients with SLE, scleroderma and severe inflammatory vasculitis, e.g. periarteritis nodosa [28].

The aim of this study was to analyse the three isotypes of autoantibodies against CL, oxLDL and MDA-LDL in RA and to evaluate their relation to cardiovascular complications.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study groups
One hundred and twenty-one patients with rheumatoid arthritis (RA) [29], 33 men and 88 women, from northern Sweden were consecutively included at the Department of Rheumatology during 4 months of the study. All patients except nine had RF (according to Waaler-Rose), with titres ranging between 1/40 and 1/40 000. ANA were present in 37 of 116 tested patients. The demographic and clinical data at time of inclusion are summarized in Table 1Go. The accumulated inflammatory activity of the disease was estimated as described [30]. Cardiovascular and/or cerebrovascular events, defined as MI (n=12), stroke/transient ischaemic attacks (n=8) and deep vein thrombosis/pulmonary embolism (n=3) (as defined in Wållberg-Jonsson et al. [2]) occurred in 18 patients after the onset of RA. Fifty-five patients were current or ex-smokers. One hundred and six patients were or had been treated with disease-modifying anti-rheumatic drugs (DMARDs) including sulphasalazine, antimalarials, intramuscular or oral gold, penicillamine, methotrexate, cyclosporin, azathioprine, chlorambucil and cyclophosphamide (>=6 months with each drug).


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TABLE 1. Demographic and clinical data in 121 patients with RA at inclusion

 
As a control group, we used referents that were part of an extensive nested case-referent study (MONICA) organized in the same region, described in detail in published references [31, 32]. The mean age (±S.D.) of the referents at sampling was 55.0±7.6 yr and there were 142 men and 84 women.

This study was approved by the Research Ethics Committee of Umeå University.

Isolation and oxidative modifications of LDL
Serum lipoproteins were isolated by preparative ultracentrifugation [33]. Oxidative modifications of LDL were done by CuSO4 and malonaldehyde bis-dimethylacetal [27, 34].

Determination of antibodies against CL, oxLDL and MDA-LDL
Autoantibodies against CL, oxLDL and MDA-LDL were determined by ELISA as previously described [5, 27] with minor modifications. To obtain the highest possible specificity of the assay, the serum dilution for determination of IgG antibodies against CL was 1/100, for IgM antibodies 1/50 and for IgA antibodies 1/30. For assay of autoantibodies against oxLDL and MDA-LDL, plates were coated with antigens using 5 µg/ml, while serum dilutions for assay of all isotypes were 1/20. All samples were analysed at the same time, using the same batch of antigen. The intra-assay variation for antibodies against CL was 8–12%, for antibodies against MDA-LDL 8–11% and for antibodies against oxLDL 13%. The inter-assay variation for determination of all antibody species was <15%. Positive and negative controls were included on each plate. The plates were incubated until the OD of the positive control sample reached a predetermined value. The levels of antibodies were expressed as units of optical density. As a cut-off value, the mean + 2 S.D. of the OD values of control group was used.

Statistics
Student's unpaired t-test and the Mann–Whitney U-test were used to compare levels of autoantibodies found in patients and controls, and to compare levels in different subgroups of patients. The prevalence of autoantibodies was compared by chi-square test or Fisher's exact test. The non-parametric Spearman rank correlation test was used to determine the association between levels of antibodies, the different antibodies and between levels of antibodies and inflammation and disease activity. The significance level was set at P<0.05.


    Results
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Autoantibody levels in patients and referents are presented in Figs 1–3GoGoGo. Levels of IgG, IgM and IgA antibodies against MDA-LDL and CL were increased in patients (P<0.01). Also, IgG and IgA antibodies against oxLDL were increased (P<0.01). Table 2Go shows that the prevalence of all three isotypes of autoantibodies against CL was increased in patients, as well as IgG and IgA antibodies against oxLDL and IgG and IgM antibodies against MDA-LDL (P<0.01).



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FIG. 1. Box plots showing the levels of IgG, IgM and IgA autoantibodies against CL in RA patients and in referents. The levels are expressed as OD values. The lower, middle and upper horizontal lines represent 25th, 50th and 75th percentiles, while vertical lines extend from the 10th to the 90th percentile.

 


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FIG. 2. Box plots showing the levels of IgG, IgM and IgA autoantibodies against oxLDL in RA patients and in referents. The levels are expressed as OD values. The lower, middle and upper horizontal lines represent 25th, 50th and 75th percentiles, while vertical lines extend from the 10th to the 90th percentile.

 


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FIG. 3. Box plots showing the levels of IgG, IgM and IgA autoantibodies against MDA-LDL in RA patients and in referents. The levels are expressed as OD values. The lower, middle and upper horizontal lines represent 25th, 50th and 75th percentiles, while vertical lines extend from the 10th to the 90th percentile.

 

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TABLE 2. Prevalence of autoantibodies in RA patients and healthy individuals

 
The levels of IgM and IgA antibodies against CL and of IgM antibodies against MDA-LDL were increased in patients with extra-articular manifestations compared with patients with no such complications (Table 3Go). When comparing the 15 patients with extra-articular manifestations of the disease except for rheumatoid nodules (e.g. vasculitic ulcers/neuropathy, pericarditis, pleuritis or scleritis) with other patients, there was no difference between the groups (data not shown). Patients with ANA had higher levels of IgG (P<0.05) and IgM antibodies against MDA-LDL (P<0.01) and of IgM antibodies against CL (P<0.01).


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TABLE 3. Levels of autoantibodies against oxLDL, MDA-LDL and CL in RA patients with and without extra-articular manifestation

 
Levels of autoantibodies in subgroups of patients with a cardiovascular or cerebrovascular event, such as MI, stroke/transient ischaemic attacks and deep vein thrombosis/pulmonary embolism, as well as patients with hypertension, were compared with the levels in the rest of the patient group. There were no differences in the levels of autoantibodies against CL, oxLDL or MDA-LDL between patients with these complications and those without. The patients with MI had a significantly higher prevalence of IgG antibodies against MDA-LDL (P=0.04) compared with patients without MI. There were significant relations between certain of these autoantibody species. Correlations between IgG, IgM and IgA antibodies against oxLDL and MDA-LDL were present (r=0.38, P<0.0001; r=0.71, P<0.0001; r=0.54, P<0.0001, respectively). There were also significant correlations between IgM and IgA antibodies against oxLDL and CL (r=0.59, P<0.0001; r=0.31, P=0.0005, respectively). Also, IgG, IgM and IgA antibodies against MDA-LDL and CL showed strong relations (r=0.34, P=0.0001; r=0.69, P<0.0001; r=0.31, P=0.0004, respectively). There were no relations between the levels of RF and antibodies against aCL, oxLDL or MDA-LDL and no correlation between these autoantibodies and accumulated disease activity. There was no influence of actual or previous DMARD therapy on the antibody levels. Patients treated with corticosteroids had higher levels of IgM antibodies against MDA-LDL (P=0.03) and CL (P=0.04). These patients also had an increased prevalence of IgM antibodies against MDA-LDL (32.8%) compared with untreated patients (15.8%) (P=0.04). There was no difference in the prevalence of aCL antibodies between patients treated with corticosteroids and other patients (data not shown).


    Discussion
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 Abstract
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 Methods
 Results
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Patients with RA had increased levels and prevalence of all three isotypes of aCL autoantibodies compared with healthy controls. Moreover, patients with extra-articular disease had increased IgM and IgA antibodies against CL compared with RA patients without these manifestations.

The high mortality of RA patients has been the subject of several investigations [1]. Epidemiological investigations of autoimmune diseases have linked inflammation to cardiovascular events [2]. Cellular and humoral components of the immune system are involved in the pathogenesis of both RA and atherosclerosis. The significance of autoantibodies in RA has not been settled as of yet. Autoantibodies in serum of RA patients include RF and ANA, but also antiphospholipid antibodies, like aCL.

aCL antibodies have been suggested to be predictive markers for MI [3, 5] and for arterial and venous thrombosis [13, 35]. A recent prospective study, which included hyperlipidaemic patients, showed that aCL antibodies are independent risk factors for atherosclerotic vascular diseases [6]. aCL antibodies occur in both RA and SLE. The antibodies are commonly present in SLE [35], while reports in patients with RA are inconsistent [3638]. Jacobs et al. [36] reported that aCL antibodies, especially of IgM class, were present in RA patients, but there was no association of these autoantibodies to clinical or laboratory measurements of disease activity. In another study, autoantibodies against CL were present in 16% of RA and SLE patients [37]. There was no association of aCL to clinical manifestations. Vittecoqet et al. [38] registered low concentrations of aCL antibodies in only 7% of patients with mild RA and there was no relationship to RF or clinical manifestations.

The prevalence of aCL antibodies in our study is thus higher than previously reported. Our control material is well defined and represents a true population-based selection. We have used the same control material in two earlier studies on autoantibodies as predictive factors for stroke [31, 32]. In these studies, the numbers of women and men in the patient and control groups were the same and there were only marginal differences in the prevalence and concentration of antibodies against CL between persons who developed stroke and those who remained healthy. Regarding antibodies against oxidatively modified LDL, there were no differences at all between those who remained healthy and those who developed stroke. Thus, the high prevalence and concentration of autoantibodies in RA found in this study should not depend on the selection of the control material and therefore should represent a true difference. The population from the northern part of Sweden is genetically different from the rest of the Swedish population, and this might also be of importance for the high prevalence and levels of autoantibodies found in our study.

There are few reports about the presence of autoantibodies to oxidatively modified LDL in RA patients [39]. Studies have shown oxLDL present in the synovium of RA patients [40, 41] and its involvement in joint destruction. Autoantibodies against oxLDL are present in cardiovascular diseases, and increased levels have been related to carotid atherosclerosis [42], peripheral vascular diseases [43] and MI [5, 7]. There was an association of IgG antibodies against MDA-LDL in patients with MI. Our earlier studies have shown a strong predictive effect of these antibodies for future MI [5]. The higher prevalence of IgM antibodies against MDA-LDL in patients treated with corticosteroids might indicate a more severe disease with an ongoing immune response. These reports are the first of their kind, showing that these antibodies might be related to disease activity and to cardiovascular complications. There were substantial correlations between the concentration of antibodies against CL and against oxidatively modified LDL. This phenomenon could be caused by common epitopes present on the different autoantigens [9], or by cross-reactions to the antibody level [44]. Thus, at the moment it is not clear which of these antibody species has the most important effects on the vessel wall.

Rheumatoid nodules are constituted of a ring of macrophages, surrounding necrotic tissue. These formations are initiated and chronically activated by extravascular immune complexes. Receptor FcgRIIIa expressed on macrophages binds immune complexes, which leads to secretion of TNFa and an inflammatory response [45]. High levels of autoantibodies might lead to formation of circulating immune complexes and activation of complements. In particular, antibodies against CL seem to have a rather strong tendency to immune complex formation [46, 47]. The effect of immune complexes on the vascular endothelium is activation of endothelial cells and upregulation of their adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) [48]. These molecules function as anchors for monocytes/macrophages and T cells. Infiltration of monocytes/macrophages and T cells in the vessel wall might be considered as the common event for both atherosclerosis and the inflammatory reaction initiated by immune complexes. This inflammation further leads to damage of surrounding bone tissue by the action of metalloproteinases, which are induced by the pro-inflammatory cytokines IL-1ß, TNF{alpha} and IL-6. Rajavashisth et al. [49] showed that pro-inflammatory cytokines and/or oxLDL increase endothelial cell expression of membrane type 1-metalloproteinase (MT1-MMP). Thus, there are many similarities in the pathogenesis of inflammatory vessel disease and atherosclerosis.

To summarize, we found increased levels and prevalence of autoantibodies against CL, oxLDL and MDA-LDL in RA patients, and also associations with the severe form of RA and with cardiovascular complications. To analyse these antibodies in RA might possibly be used to predict the severity of disease as well as cardiovascular complications. The functional correlations between the autoantibodies and disease remain to be elucidated.


    Acknowledgments
 
This study was supported by grants from the Swedish Medical Research Council (05646), the Swedish Heart–Lung Foundation, the King Gustaf Vth 80-years Foundation, the Serafimerlasarettet Foundation and the Swedish Rheumatism Association.


    Notes
 
Correspondence to: A. K. Lefvert, Immunological Research Unit, CMM L8:03, Karolinska Hospital, 171 76 Stockholm, Sweden. Back


    References
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 Introduction
 Methods
 Results
 Discussion
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Submitted 21 February 2001; Accepted 13 March 2002





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