Extra-articular Rheumatoid Arthritis Research Articles

Role of blood cholesterol transport system disturbances in atherosclerosis development in rheumatoid arthritis

Objective. To study role of inflammation and disturbances of blood cholesterol transport system in atherosclerotic damage development in rheumatoid arthritis (RA). Material and methods. 84 RA pts with mean age 48 years and mean disease duration 87 months were included. Control group consisted of 15 humans of comparable age and sex without rheumatic diseases. Carotid sonographic scanning was performed to reveal vascular atherosclerotic damage. Cholesterol (CL), triglycerides (TG) and high-density lipoprotein cholesterol (HDLC) serum levels were evaluated with colorimetric and photometric methods, CRP, apoAl and LP(a) levels were assessed by immunonephelometric method. Results. Dyslipidemia (DLP) frequency analysis showed differences only for LP(a). Increase of LP(a) and TG concentrations in RA was more frequent than in control. CL and HDLC levels did not differ. Intima-media complex (IMC) thickness in RA and control was the same. Atherosclerotic plaques (AP) in RA were more frequent. RA pts showed negative correlation between IMC thickness and HDLC, as well as between HDLC values, apoAl and CRP. LP(a) level correlated with DAS4. There was no association between concentrations of CL, TG, HDLC, low-density lipoprotein cholesterol (LDLC), apo В and Al, LP(a) and extra-articular RA features and glucocorticoid administration. In pts with high LP(a) level AP were more frequent, activity of RA, apo B, LDLC levels were higher than in pts with normal level of this LP. LP(a) values in pts with AP were higher than in pts without AP (p<0,05). Conclusion. Chronic inflammation in RA plays an important role in disturbances in blood cholesterol transport system. LP(a) level increase is a risk factor of atherosclerotic vascular damage.

Extra-articular manifestations and complications of rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disease that can involve other tissues and organs as well as synovial joints. This chapter reviews the clinical aspects of extra-articular RA, from the early descriptions in rheumatology texts to reports from more recent cross-sectional and inception cohort studies. There is no agreed classification for these manifestations and, because criteria and definitions vary so much, this report includes not only the classic extra-articular features but also the non-articular complications of RA, for example normochromic normocytic anaemia and chronic leg ulcers, and the important disease-associated comorbidities, including non-Hodgkin's lymphoma, ischaemic heart disease and osteoporosis. Incidence and frequency figures for extra-articular RA vary according to study design. Nodules are the most common extra-articular feature, and are present in up to 30%; many of the other classic features occur in 1% or less in normal clinic settings. Sjögren's syndrome, anaemia of chronic disease and pulmonary manifestations are relatively common - in 6-10% - are frequently present in early disease and are all related to worse outcomes measures of rheumatoid disease, in particular functional impairment and mortality. Currently, there are no reliable predictors for these features in early RA, although they are associated with men, smokers, more severe joint disease, worse function, high levels of inflammatory markers, and the presence of rheumatoid factor (RF), antinuclear antibodies (ANA) and the RA HLA-related shared epitope. Many of these manifestations are related to the more active and severe RA, so early and more aggressive RA drug therapies are being employed and, although evidence from randomised studies is not available, this approach would seem appropriate in view of the adverse effect of extra-articular manifestations on RA outcomes. Unfortunately, specific therapies for extra-articular manifestations of RA are largely disappointing or unavailable, except for steroids and cyclophosphamide for vasculitis. The place for biological therapies is still not clear. Pulmonary fibrosis in RA has a poor prognosis whether treated with large doses of steroids, cytotoxic or disease modifying drugs like cyclosporine, or biologics. In summary, extra-articular features and non-articular complications of RA are common and are generally related to worse disease. They need to be recognised early and managed promptly.

Cardiovascular risk factors and intima-media complex thickness in women of childbearing age with rheumatoid arthritis

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CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

T cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28-null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells. Seventy-two patients with RA (ages 35-84 years) and 53 healthy persons (32 young controls ages 19-34 years, 21 older controls ages 39-86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long-term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA-associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays. Chronic stimulation of CD28(+) T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56(+),CD28-null T cells than in patients with disease confined to the joints or in healthy controls. CD56(+),CD28-null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56(+) T cells had skewed T cell receptor (TCR) alpha/beta-chain usage and restricted TCR third complementarity-determining region spectra. Histologic studies showed that CD56(+) T cells were components of cellular infiltrates in RA-associated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels. Chronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR-independent and TCR-dependent activation pathways. We propose that accumulation of CD56(+) T cells in RA contributes to maladaptive immune responses and that CD56(+) T cells are potential targets for therapy.

Severe extra-articular rheumatoid arthritis is associated with noncardiac vascular disease

Severe extra-articular rheumatoid arthritis is associated with noncardiac vascular disease

The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis

Published data were reviewed to evaluate the occurrence of antiphospholipid antibodies (aPL) in rheumatoid arthritis (RA) patients and to investigate their clinical relevance in this population. The mean prevalence was calculated at 28% and the median was 22%. Few studies have found a relationship between aPL antibodies and thrombosis, particularly in combination with other risk factors. Conflicting results have been reported on the association of anticardiolipin (aCL) antibody positivity and neurologic symptoms, Reynaud's phenomenon, disease activity, radiographic erosions, extra-articular RA manifestations, rheumatoid factor, and atherosclerosis. Some studies, however, suggest that there is a correlation present between those antibodies and C-reactive protein levels, rheumatoid nodules, and antinuclear antibodies. TNF-alpha blocking agents may cause an induction of aCL antibodies, but it seems like they do not cause any clinical features related to the antiphospholipid syndrome. Higher 17beta-estradiol levels were observed in aCL antibody-positive RA patients than in aCL antibody-negative patients and especially in premenopausal women, which may predispose to a more efficient immune response.

Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extraarticular disease manifestations

To investigate the incidence of noncardiac vascular disease in patients with rheumatoid arthritis (RA) and its relationship to systemic extraarticular disease in a community-based cohort. A retrospective medical record review of 609 patients with incident RA diagnosed during 1955-1994 was carried out in Olmsted County, Minnesota. Patients were followed up from 1955 to 2000 (median followup 11.8 years). Incident noncardiac vascular disease and severe extraarticular RA manifestations (including pericarditis, pleuritis, and vasculitis) were recorded according to predefined criteria, and incidence rates were estimated. Using Cox proportional hazards models, the risk (hazard ratio [HR]) of developing vascular events was assessed in patients with and without severe extraarticular RA. Cerebrovascular and peripheral arterial events occurred in 139 patients (22.8%). The 30-year cumulative incidence rates of peripheral arterial events, cerebrovascular events, and venous thromboembolic events were estimated to be 19.6%, 21.6%, and 7.2%, respectively. The presence of severe extraarticular RA manifestations was found to be associated with all subgroups of noncardiac vascular disease except cerebrovascular disease alone (HR 2.3, 95% confidence interval [95% CI] 1.2-4.3 for peripheral arterial events; HR 3.7, 95% CI 1.3-10.3 for venous thromboembolic events; HR 1.5, 95% CI 0.7-3.2 for cerebrovascular events) after adjusting for age, sex, body mass index, smoking, and rheumatoid factor status. This is the first study to assess the incidence of noncardiac vascular disease in RA. Severe extraarticular RA was associated with all forms of noncardiac vascular disease except cerebrovascular disease alone. Similar to cardiac disease, the excess risk of noncardiac vascular disease in RA is likely to be related, in part, to the systemic inflammation associated with the extraarticular manifestations of RA.

HLA-DRB1 genes and extraarticular rheumatoid arthritis

The factors that trigger the development of extraarticular features of rheumatoid arthritis (RA) are still unknown. HLA-DR alleles such as HLA-DR4 and HLA-DR1 are associated with the risk to develop RA. A large scale study from Sweden and the Mayo Clinic suggests that HLA-DR4, but not HLA-DR1, is associated with the risk to develop extraarticular RA.

Severe rheumatoid valvular heart disease

Rheumatoid arthritis (RA) is a systemic inflammatory disease in which extra-articular involvement is not uncommon. Cardiac compromise may be frequent, although most often, it is clinically silent. Herein, two cases of RA-related endocarditis, one of which required valve replacement, are described. Etanercept was useful in controlling the articular and extra-articular RA compromise in both cases.

The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis

The objective of this study was to examine HLA-DRB1 and HLA-DQB1 genotypes in patients with severe extra-articular rheumatoid arthritis (ExRA) and to compare them with the genotypes of rheumatoid arthritis (RA) patients without extra-articular manifestations. Patients with severe ExRA were recruited from a large research database of patients with RA, from two cohorts of prevalent RA cases, and from a regional multicenter early RA cohort. Cases with ExRA manifestations (n = 159) were classified according to predefined criteria. Controls (n = 178) with RA but no ExRA were selected from the same sources. Cases and controls were matched for duration of RA and for clinical center. PCR based HLA-DRB1 and HLA-DQB1 genotyping was performed using the Biotest SSP kit, with additional sequencing in order to distinguish DRB1*04 subtypes. Associations between alleles and disease phenotypes were tested using multiple simulations of random distributions of alleles. There was no difference in global distribution of HLA-DRB1 and HLA-DQB1 alleles between patients with ExRA and controls. DRB1*0401 (P = 0.003) and 0401/0401 homozygosity (P = 0.002) were more frequent in Felty's syndrome than in controls. The presence of two HLA-DRB1*04 alleles encoding the shared epitope (SE) was associated with ExRA (overall odds ratio 1.79, 95% confidence interval 1.04–3.08) and with rheumatoid vasculitis (odds ratio 2.44, 95% confidence interval 1.22–4.89). In this large sample of patients with ExRA, Felty's syndrome was the only manifestation that was clearly associated with HLA-DRB1*0401. Other ExRA manifestations were not associated with individual alleles but with DRB1*04 SE double dose genotypes. This confirms that SE genes contribute to RA disease severity and ExRA. Other genetic and environmental factors may have a more specific impact on individual ExRA manifestations.

Management of extra-articular disease manifestations in rheumatoid arthritis.

To discuss the rationale for various treatment strategies in rheumatoid arthritis with extra-articular manifestations, and to review advances in understanding the impact of extra-articular rheumatoid arthritis and its management. Recent epidemiologic studies of extra-articular rheumatoid arthritis manifestations have emphasized their major role as predictors of premature mortality in patients with rheumatoid arthritis, and provide a rationale for aggressive ant-rheumatic treatment of extra-articular rheumatoid arthritis. Previous uncontrolled or nonrandomized studies favor the use of cyclophosphamide in patients with systemic rheumatoid vasculitis, and methotrexate in the case of other manifestations of extra-articular rheumatoid arthritis. Recent case reports indicate that patients with rheumatoid lung disease may respond to cyclosporine or tumor necrosis factor inhibitors, and that tumor necrosis factor blocking therapy also may be successful in cases of treatment-resistant vasculitis. By contrast, it has been suggested that tumor necrosis factor inhibitors may induce some manifestations of extra-articular rheumatoid arthritis. Data indicating a high risk of serious infections and cardiovascular disease in patients with extra-articular rheumatoid arthritis underline the importance of carefully monitoring such patients. Extra-articular rheumatoid arthritis is a serious condition, and rheumatoid arthritis patients with extra-articular manifestations should be aggressively treated and monitored. Advances in the understanding of the pathogenesis of rheumatoid arthritis and developments of new, more specific drugs may be of particular benefit to patients with extra-articular disease.

Increased endothelial expression of HLA-DQ and interleukin 1alpha in extra-articular rheumatoid arthritis. Results from immunohistochemical studies of skeletal muscle.

To investigate markers of endothelial activation in muscle biopsies from rheumatoid arthritis (RA) patients with and without extra-articular manifestations (ExRA). Nine consecutive ExRA patients were compared with nine RA controls without ExRA, matched for age, sex and duration of RA. Muscle biopsies were obtained from the lateral vastus or anterior tibial muscle. Macrophage and lymphocyte CD markers, HLA molecules, cytokines and adhesion molecules were investigated using immunohistochemistry, and stainings were evaluated using computer image analysis and conventional microscopy. Serum concentrations of soluble adhesion molecules, tumour necrosis factor alpha (TNF-alpha) and rheumatoid factor (RF) were determined using immunoassays. The number of HLA-DQ-positive capillaries (P=0.039) and the expression of interleukin 1alpha (IL-1alpha) in endothelial cells (mean pairwise difference 0.26%; 95% confidence interval 0-0.52) were increased in ExRA patients compared with non-ExRA controls. There were no signs of inflammatory cell infiltrates or fibre degeneration. Serum levels of TNF-alpha, the soluble form of intercellular adhesion molecule 1, the soluble form of vascular cell adhesion molecule 1 and IgM RF were increased in the ExRA group. The increased expression of HLA-DQ and IL-1alpha may indicate systemic endothelial activation in extra-articular RA, which could be of importance for cardiovascular comorbidity and mortality in such patients.

Association of MHC and rheumatoid arthritis:HLA polymorphisms in phenotypic variants of rheumatoid arthritis

Genes in the human leukocyte antigen (HLA) region remain the most powerful disease risk genes in rheumatoid arthritis (RA). Several allelic variants of HLA-DRB1 genes have been associated with RA, supporting a role for T-cell receptor-HLA-antigen interactions in the pathologic process. Disease-associated HLA-DRB1 alleles are similar but not identical and certain allelic variants are preferentially enriched in patient populations with defined clinical characteristics. Also, a gene dosing effect of HLA-DRB1 alleles has been suggested by the accumulation of patients with two RA-associated alleles, especially in patient subsets with a severe disease course. Therefore, polymorphisms in HLA genes are being explored as tools to dissect the clinical heterogeneity of the rheumatoid syndrome. Besides HLA polymorphisms, other risk genes will be helpful in defining genotypic profiles correlating with disease phenotypes. One such phenotype is the type of synovial lesion generated by the patient. HLA genes in conjunction with other genetic determinants may predispose patients to a certain pathway of synovial inflammation. Also, patients may or may not develop extraarticular manifestations, which are critical in determining morbidity and mortality. HLA genes, complemented by other RA risk genes, are likely involved in shaping the T-cell repertoire, including the emergence of an unusual T-cell population characterized by the potential of vascular injury, such as seen in extraarticular RA.

Anticardiolipin antibodies, free protein S levels and thrombosis: a survey in a selected population of rheumatoid arthritis patients.

To investigate plasma levels of natural anticoagulant proteins such as protein S, protein C and antithrombin III in a selected population of patients with rheumatoid arthritis (RA) with and without anticardiolipin antibody (aCL) positivity, and to evaluate the possible relationships with an increased risk of thrombotic events in RA. A total of 184 female RA patients attending our Extra-Articular Involvement RA Clinic were evaluated for aCL levels, total and free protein S, protein C and antithrombin III concentrations, and for the occurrence of thrombotic events. Patients were grouped as aCL positive (n = 35) and aCL negative (n = 149). Higher rates of venous and/or arterial thromboses were diagnosed in patients with RA compared to controls (P = 0.01). In particular, lower free protein S levels were found in aCL-positive patients with RA compared to both aCL-negative patients and controls (P = 0.001). Functional assays for protein C, antithrombin III as well as total protein S levels were found to be in the normal range in all patients and controls. The association observed between aCL positivity and decreased levels of free protein S in RA patients may represent one of the risk factors for thrombotic events.

Functional subsets of CD4 T cells in rheumatoid synovitis.

To identify the functional properties of CD4+ CD28- T cells, which accumulate and clonally expand in patients with rheumatoid arthritis (RA). The gene expression of molecules involved in T cell effector functions was compared in CD4+ CD28- and CD4+ CD28+ T cell clones. The expression of differentially up-regulated genes was confirmed by flow cytometry of T cells and by 2-color immunohistochemistry of rheumatoid synovial tissue. Cytotoxicity of CD4+ CD28- T cells was tested by anti-CD3 redirected lysis of Fc receptor-positive target cells. CD4+ CD28- T cell clones lacked messenger RNA for the CD40 ligand (CD40L) but transcribed the perforin gene. Perforin was also found in freshly isolated CD4+ CD28- peripheral blood lymphocytes from RA patients. CD4+ CD28-, but not CD4+ CD28+, T cell clones lysed Fc receptor-bearing target cells. CD4+ perforin-positive T cells were present in the synovial tissue, where their frequency correlated with the expansion of the CD4+ CD28- compartment in the periphery. Among tissue-infiltrating CD4+ T cells, only the CD40L-negative subset expressed perforin transcripts. Clonally expanded CD4+ CD28- T cells are functionally specialized for killing, while they lack the ability to provide B cell help. Tissue-infiltrating CD4+ T cells can be subdivided phenotypically and functionally into at least 2 distinct subsets based on their expression of perforin and CD40L. Because the expansion of CD4+ CD28- T cells is associated with extraarticular RA, T cell-mediated cytotoxicity may be particularly important in these most severe complications of RA.

Functional subsets of CD4 T cells in rheumatoid synovitis

Objective To identify the functional properties of CD4+ CD28− T cells, which accumulate and clonally expand in patients with rheumatoid arthritis (RA). Methods The gene expression of molecules involved in T cell effector functions was compared in CD4+ CD28− and CD4+ CD28+ T cell clones. The expression of differentially up-regulated genes was confirmed by flow cytometry of T cells and by 2-color immunohistochemistry of rheumatoid synovial tissue. Cytotoxicity of CD4+ CD28− T cells was tested by anti-CD3 redirected lysis of Fc receptor-positive target cells. Results CD4+ CD28− T cell clones lacked messenger RNA for the CD40 ligand (CD40L) but transcribed the perforin gene. Perforin was also found in freshly isolated CD4+ CD28− peripheral blood lymphocytes from RA patients. CD4+ CD28−, but not CD4+ CD28+, T cell clones lysed Fc receptor-bearing target cells. CD4+ perforin-positive T cells were present in the synovial tissue, where their frequency correlated with the expansion of the CD4+ CD28− compartment in the periphery. Among tissue-infiltrating CD4+ T cells, only the CD40L-negative subset expressed perforin transcripts. Conclusion Clonally expanded CD4+ CD28− T cells are functionally specialized for killing, while they lack the ability to provide B cell help. Tissue-infiltrating CD4+ T cells can be subdivided phenotypically and functionally into at least 2 distinct subsets based on their expression of perforin and CD40L. Because the expansion of CD4+ CD28− T cells is associated with extraarticular RA, T cell-mediated cytotoxicity may be particularly important in these most severe complications of RA.

The molecular basis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an inflammatory disease targeting the synovial membrane and extra-articular tissues. The most feared consequences are significant levels of pain, functional disability, and rheumatoid organ involvement. Molecular investigations of RA have markedly changed the understanding of the pathogenesis although the etiology remains unresolved. Despite the failure of intense efforts to confirm the presence of an infectious micro-organism in rheumatoid synovium, the concept that RA is infectious in origin has continued to be attractive. Theories on the autoimmune nature of RA have benefited from the enormous progress made in understanding the cellular and molecular components of normal immune responses. However, convincing experimental evidence of a joint-specific endogenous antigen in the synovial lesions is still lacking. The viewpoint that RA represents the sequelae of systemic lymphoproliferation has recently been supported by the finding of autoreactive T cells with atypical growth and differentiation behavior. Significant cross-fertilization for the understanding of RA can be expected by studies elucidating cell cycle control and the role of proto-oncogenes. The realization that RA is a genetic disease has had and will have a major impact on investigating pathological events. As in other common genetic disorders, multiple genetic determinants contribute to the risk of an individual developing chronic inflammatory rheumatoid synovitis. Individual genetic elements are seldom mutated or abnormal, but a risk threshold is reached by their accumulation and combination. Genes encoded in the HLA region are recognized as RA risk genes. Recent studies have emphasized that a gene dosing effect for RA-associated HLA alleles is functional, and that HLA polymorphisms act as progression factors rather than as initiation factors in the disease process. These data have challenged the traditional paradigm that disease-associated HLA molecules function solely through their capability to select, bind, and present an arthritogenic antigen. Current efforts focus on identifying the spectrum and nature of genes associated with various RA phenotypes. The future will likely see a broadening of biological systems involved in the pathogenesis of RA with anomalies other than immunoresponsiveness contributing to mechanisms driving articular and extra-articular RA.

Urine- and serum beta 2-microglobulin in patients with rheumatoid arthritis: a study of 101 patients without signs of kidney disease.

Serum levels and 24-hour urinary excretion of beta 2-Microglobulin (beta 2-M) was investigated in a group of 101 patients with rheumatoid arthritis (RA), without any other signs of renal disease in past or present, and in a comparable control group. Elevated 24-hour urinary beta 2-M excretion, due to renal proximal tubules dysfunction, was observed in 19% of the patients and not in the control group. There was a significant correlation with clinical signs of extra-articular RA. It is postulated that the observed increase may be an early symptom of renal involvement in RA. Elevated serum beta 2 levels, corrected for glomerular filtration rate, were observed in 44% of the RA patients and only in 3% of the control group and correlated with clinical signs of a more severe RA, as well as with increased 24-hour urinary beta 2-M excretion.

Complement (C3) metabolism in rheumatoid arthritis in relation to the disease course.

Metabolic turnover studies of the third component of complement, C3, were performed in 23 patients with rheumatoid arthritis (RA) to get a direct insight in the dynamics of complement synthesis and catabolism. Results of these turnover studies were related to the serum level of the total amount of C3 as well as to that of the activation product C3d. A hypercatabolism of C3 was observed in 12 of the 23 patients studied. Six of these 12 patients showed signs of extra-articular RA; only one patient with extra-articular manifestations had a normal catabolism of C3. Decreased serum levels of C3 were not found in any of the patients with a hypercatabolism of C3, indicating that the accelerated turnover was compensated by an increased synthesis. In RA patients levels of the activation product C3d could not correlate with the turnover of C3. However, in selected RA patients without signs of nodules or extra-articular manifestations, they could. Thus, our results indicate that serum levels of C3 and C3d do not reflect C3 metabolism in RA patients. Furthermore, the existence of extra-articular manifestations is accompanied by a more pronounced activation of the complement system.

Demonstration of an unidentified 48 kD polypeptide in circulating immune complexes in rheumatoid arthritis.

Circulating immune complexes (CIC) were isolated from 25 patients with rheumatoid arthritis (RA) by anti-C1q affinity chromatography. The components were detected by silver stained sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) gels and identified by the Western blot. The CIC were composed of 20 different polypeptides, including albumin, immunoglobulin, complement, and acute phase reactants. Two components (molecular weight 48 kD and 45 kD respectively) remained unidentified. The 48 kD polypeptide was found in CIC from six out of 14 patients (43%) with extra-articular RA, but from none of eight patients with vasculitic complications of other connective tissue diseases. All immunoreactants were more frequently found in the patients with extra-articular features of RA. Although these results emphasise that most CIC in RA are composed of endogenous proteins, the 48 kD polypeptide is a candidate for an extrinsic antigen in RA.