Cross-reactive rheumatoid factors in rheumatoid arthritis with extra-articular disease.

Rheumatoid factors (RF) have been shown to have considerable heterogeneity and bind with IgG as well as with a variety of substances such as nuclear histone, non-histone nuclear protein, nitrophenyl groups or ssDNA. We describe evidence that polyclonal RF cross-reactive with ssDNA (CRRF) are widely distributed in a variety of rheumatic diseases, and that their serum level is significantly higher in rheumatoid arthritis (RA) with extra-articular disease. Although the mechanism of the cross-reactivity is not clear, the presence of CRRF could be a serological feature of a clinical subset of RA. The high prevalence rate of CRRF in RA with extra-articular disease also suggests its pathogenetic role in the extra-articular manifestation of this disease.     

HLA antigen associations with extra-articular rheumatoid arthritis

Seventy-seven patients with rheumatoid arthritis were investigated to examine the frequency of HLA antigens and their relationship to clinical and serological manifestations of extra-articular disease. The phenotype frequencies of DR4, DRw53, Bw62 and Cw3 were significantly increased, compared to normal controls, and there were negative associations with DR2 and DR7. The HLA antigen in strongest association with rheumatoid arthritis was DR4 (73.6%) and the relationship with DRw53 appeared to be secondary. The frequency of DR4 rose to 92% in seropositive patients with extra-articular disease manifestations whose serum contained immune complexes. A high frequency of DR4 was also seen in male patients (86%), reaching 100% in the small group of seropositive male patients with immune complexes. It is suggested that extra-articular disease represents a manifestation of severe classical rheumatoid arthritis and is not an 'overlap' syndrome. We propose that the HLA haplotype Cw3-Bw62-Dw4-DR4-DRw53 makes a greater genetic contribution to disease susceptibility in both extra-articular and male rheumatoid arthritis patients than in other subsets of RA.     

Allergic manifestations in patients with rheumatoid arthritis

A functional dichotomy between Th1- and Th2-type immune responses has been suggested. This study was performed to investigate whether rheumatoid arthritis (RA), a disease with indications of Th1-deviated immune activation, is inversly related to atopic conditions which are Th2-mediated. Two hundred and sixty-three adult cases of RA, fulfilling the American Rheumatism Association (ARA) 1987 Revised Classification Criteria for RA, were identified in 1995 and compared with 541 randomly selected population referents. The presence of atopic manifestations was established through a postal questionnaire and by demonstrating circulating IgE antibodies to common allergens. RA was inversely associated with certain manifestations of rhinitis, which were regarded as the most reliable indicators of atopic disease in the present study. However, no negative association was seen between RA and asthma and eczema, respectively. The main results give some support for an inverse relationship between RA and rhinitis. The prevalence of circulating IgE antibodies was however similar in cases and controls, suggesting that the T-cell commitment mainly occurs in the affected organs.     

Extra-articular manifestations of rheumatoid arthritis: An update

Rheumatoid arthritis (RA) is an immune-mediated disease involving chronic low-grade inflammation that may progressively lead to joint destruction, deformity, disability and even death. Despite its predominant osteoarticular and periarticular manifestations, RA is a systemic disease often associated with cutaneous and organ-specific extra-articular manifestations (EAM). Despite the fact that EAM have been studied in numerous RA cohorts, there is no uniformity in their definition or classification. This paper reviews current knowledge about EAM in terms of frequency, clinical aspects and current therapeutic approaches. In an initial attempt at a classification, we separated EAM from RA co-morbidities and from general, constitutional manifestations of systemic inflammation. Moreover, we distinguished EAM into cutaneous and visceral forms, both severe and not severe. In aggregated data from 12 large RA cohorts, patients with EAM, especially the severe forms, were found to have greater co-morbidity and mortality than patients without EAM. Understanding the complexity of EAM and their management remains a challenge for clinicians, especially since the effectiveness of drug therapy on EAM has not been systematically evaluated in randomized clinical trials.     

Airway obstruction in rheumatoid arthritis: CT manifestations, correlated with pulmonary function testing

In the present study, the signs of airflow obstruction on inspiratory and expiratory CT scans in 45 patients with rheumatoid arthritis were investigated. Radiologic findings were evaluated and correlated with the clinical data, which included rheumatoid factors and pulmonary function tests results. A lung biopsy was performed in five patients. The pattern of CT findings was as follows: infiltrative (n=15), obstructive (n=12), mixed (infiltrative and obstructive; n=10), other complicating diseases (n=7), and normal (n=1). The rheumatologic factor between patients with bronchial wall thickenings and patients without thickenings was significantly different (p=0.009). The forced expiratory flow rate between 25% and 75% of the vital capacity (FEF(25-75%)) was significantly more reduced in patients with interlobular septal thickenings than in patients without these thickenings. The patients with mosaic attenuation had significantly lower mean values of FEF(25-75% ) (p=0.001) and a lower peak expiratory flow (p=0.003) than patients without mosaic attenuation. On expiratory scans, the mean air-trapping score was 21%. These air-trapping scores were found to be well correlated with FEV1/FVC (r=0.230, p=0.0452), and FEF25-75% (r=-0.63, p= 0.05). It is widely known that a relatively higher percentage of mosaic attenuation with air-trapping and a good correlation between these and functional values contribute to the detection of early airway obstruction in patients with rheumatoid arthritis, and even in patients with infiltrative lung disease only.     

Spotlight on etanercept in rheumatoid arthritis,psoriatic arthritis and juvenile rheumatoid arthritis

Etanercept (Enbrel) is a subcutaneously administered biological response modifier that binds and inactivates tumour necrosis factor-alpha, a proinflammatory cytokine. In patients with early active rheumatoid arthritis, etanercept 25mg twice weekly was associated with a more rapid improvement in disease activity and a significantly greater cumulative response than methotrexate over 12 months of treatment in a randomised, double-blind trial. In addition, etanercept recipients showed a slower rate of radiographic progression and a more rapid improvement in quality of life than methotrexate recipients. The efficacy of etanercept was maintained at 3 years' follow-up. Etanercept was also significantly better than placebo at reducing disease activity in patients who had an inadequate response to previous treatment with disease-modifying antirheumatic drugs (DMARDs) in several well controlled trials. At study end (after 3 or 6 months' treatment), the percentage of patients achieving an American College of Rheumatology 20% (ACR20) response with etanercept (25mg or 16 mg/m(2) twice weekly) was 59-75% as monotherapy and 71% in combination with methotrexate; corresponding placebo response rates were 11-14% and 27%, respectively. Response has been maintained in patients who continued treatment for up to 5 years. In patients with psoriatic arthritis, etanercept 25mg twice weekly significantly reduced disease activity and improved skin lesions in two double-blind, placebo-controlled, 12- to 24-week trials. In the 24-week study, ACR20 response rates (50 vs 13%), psoriatic arthritis response rates (70 vs 23%) and the median improvement in skin lesions (33 vs 0%) were significantly greater in etanercept than in placebo recipients. In patients with polyarticular-course juvenile rheumatoid arthritis, etanercept resulted in improvements in all measures of disease activity and was significantly more effective than placebo at reducing disease flare. Eighty percent of patients receiving etanercept achieved a > or =30% reduction in disease activity over 7 months of treatment, and this was maintained for up to 2 years in a trial extension. Etanercept was generally well tolerated in children and adults in clinical trials; the most commonly occurring adverse effects included injection site reactions, infection, headache, rhinitis and dizziness. In conclusion, etanercept has emerged as an important new treatment option in inflammatory arthritis. Etanercept provides rapid and sustained improvements in disease activity in patients with early and DMARD-refractory rheumatoid arthritis and has been shown to inhibit radiographic progression in those with early disease. Well controlled studies have also demonstrated the efficacy of etanercept in patients with psoriatic arthritis or polyarticular-course juvenile rheumatoid arthritis.     

Circulating chromogranin A reveals extra-articular involvement in patients with rheumatoid arthritis and curbs TNF-alpha-elicited endothelial activation

TNF-alpha plays an important role in the natural history of rheumatoid arthritis (RA), a systemic disease characterized by endothelial activation and synovial involvement with bone erosions. Neuroendocrine signals contribute as well to RA, but their role is poorly understood. We measured in 104 RA patients and in an equal number of sex- and age-matched, healthy controls the blood levels of chromogranin A (CgA), a candidate marker linking the neuroendocrine system to TNF-alpha-mediated vascular inflammation. CgA levels were significantly higher in patients with RA and remained stable over time. High levels of CgA were significantly associated with severe extra-articular manifestations, namely pulmonary fibrosis, rheumatoid vasculitis, serositis, and peripheral neuropathy. RA sera curbed the response of human microvascular endothelial cells to TNF-alpha, as assessed by the expression of ICAM-1, the release of MCP-1/CCL2, and the export of nuclear high-mobility group box 1; the effect abated in the presence of anti-CgA antibodies. The efficacy of the blockade was significantly correlated with the CgA concentration in the serum. The recombinant aminoterminal portion of CgA, corresponding to residues 1-78, had similar inhibitory effects on endothelial cells challenged with TNF-alpha. Our results suggest that enhanced levels of CgA identify patients with extra-articular involvement and reveal a negative feedback loop that limits the activation of endothelial cells in RA.     

Conjugal prevalence of rheumatoid arthritis, rheumatoid factor and other autoantibodies in rheumatoid arthritis

The prevalence of rheumatoid arthritis, rheumatoid factor, antinuclear autoantibodies, thyroglobulin and thyroid `microsomal'' autoantibodies and gastric parietal cell autoantibodies has been studied in 327 husbands and 181 wives of 508 probands with seropositive `definite'' or `classical'' rheumatoid arthritis as defined by the American Rheumatism Association diagnostic criteria. Two husbands and three wives had definite rheumatoid arthritis: this prevalence is no higher than one might expect. A higher prevalence of all five autoantibodies was found in husbands compared with age matched controls, but only in respect of antinuclear autoantibodies and thyroglobulin autoantibody were the differences statistically significant. In the wives only rheumatoid factor showed a significantly higher prevalence as compared with controls. The presence of autoantibodies in husbands and wives showed no relationship to the duration of marital contact nor to the presence of the autoantibodies in the probands. The prevalence of autoantibodies in spouses of probands who developed their arthritis after marriage showed no difference when compared with that in probands who developed their arthritis before marriage.     

Skin manifestations and serum IgE levels in levamisole-treated rheumatoid arthritis patients.

Skin manifestations may occur as adverse effects of immunostimulant therapy with Levamisole. They are generally regarded as drug-induced hypersensitivity reactions. Our observations revealed that, in Levamisole-treated rheumatoid arthritis patients, urticaria was accompanied by an elevation of serum IgE, but other types of skin reactions were not. Moreover, elevation of IgE occurred without any skin reactions in some cases. It is suggested that Levamisole - stimulating T lymphocytes - may also stimulate IgE-mediated atopic responses.     

Metabolic alterations in the synoviocytes in chronically inflamed knee joints in immune arthritis in the rabbit: comparison with rheumatoid arthritis

The metabolism of the synovial lining cells of the normal and chronically inflamed joints of rabbits, in the Dumonde and Glynn model of rheumatoid arthritis, has been examined by quantitative cytochemistry. Significant alterations in metabolic activity were found in the synovial lining cells of the chronically inflamed joints. These alterations in metabolic activity closely resemble the pattern of metabolic changes found in human synovial lining cells in rheumatoid arthritis.     

Neutrophil apoptosis in rheumatoid arthritis is regulated by local oxygen tensions within joints

Neutrophils are normally short-lived cells and die by apoptosis, but when recruited into tissues, their apoptosis is delayed, and they survive for much longer time periods. In inflammatory diseases, such as rheumatoid arthritis (RA), this delayed apoptosis may lead to increased tissue damage and a failure of the inflammation to resolve. However, there are conflicting reports in the literature as to whether neutrophil apoptosis is delayed or accelerated in rheumatoid joints. In this report, we show that neutrophils isolated from the synovial fluid (SF) of patients with RA show accelerated rates of apoptosis when incubated ex vivo and that SF, despite containing a variety of antiapoptotic cytokines, is proapoptotic. Paradoxically, levels of the key neutrophil survival protein Mcl-1 are elevated in freshly isolated SF neutrophils compared with matched peripheral blood samples from the same patients, indicating that delayed neutrophil apoptosis has been signaled in vivo as the cells enter the joints. However, when SF was added to neutrophils and incubated under hypoxia (1% O(2)), conditions known to exist in vivo within joints, the SF was antiapoptotic. These data reveal that the rheumatoid synovial joint contains a complex mixture of pro- and antiapoptotic factors and that the low, local oxygen tensions that exist within these joints can exert profound effects on neutrophil survival. These experiments also highlight the importance of performing in vitro experiments under laboratory conditions that closely mimic those that occur in vivo; otherwise, misleading conclusions may be drawn.     

Metabolic alterations in the synoviocytes in chronically inflamed knee joints in immune arthritis in the rabbit: comparison with rheumatoid arthritis.

The metabolism of the synovial lining cells of the normal and chronically inflamed joints of rabbits, in the Dumonde and Glynn model of rheumatoid arthritis, has been examined by quantitative cytochemistry. Significant alterations in metabolic activity were found in the synovial lining cells of the chronically inflamed joints. These alterations in metabolic activity closely resemble the pattern of metabolic changes found in human synovial lining cells in rheumatoid arthritis.     

Histamine releasing factor (HRF) in pannus of joints affected by rheumatoid arthritis

Inflammation Research -     

The complement fixing ability of putative circulating immune complexes in rheumatoid arthritis and its relationship to extra-articular disease.

The hypothesis that the pathogenicity of putative circulating immune complexes (CIC) in rheumatoid arthritis (RA) is related to their ability to fix complement was investigated. Three assays for CIC were employed; (a) the 125I C1q binding assay (C1q BA), (b) the C1q solid phase assay (C1q SP) and (c) the Raji cell assay (RCA). Evidence for hypercatabolism of complement was obtained by using a highly sensitive quantitative assay for C3d (a breakdown product of C3) by rocket immunoelectrophoresis. One hundred and fifty-two patients with classical or definite RA were studied; 54 had clinical evidence of extra-articular disease including vasculitis, nodules, scleritis, neuropathy and lung disease; 98 patients had clinical evidence of joint disease alone. Plasma levels of C3d were significantly elevated in the RA group as a whole 16.7 +/- 4.4 mg/l (mean +/- 1 s.d.) compared with 13.1 +/- 3.25 mg/l in a group of 55 normal controls (P less than 0.01). Elevated levels of C3d were found in 26% of all patients but occurred significantly more often in the extra-articular disease group (P less than 0.05). Fifty-four percent of patients had at least one positive assay for CIC although no individual assay was positive in more than 36% of the group as a whole. The prevalence of positive CIC was significantly greater in those patients with extra-articular disease than in those with joint disease alone (P less than 0.005). Of the total of 82 patients with putative CIC, 30 (37%) had a raised C3d level. The coincident finding of positive tests for CIC and an elevated C3d level was very significantly correlated with the presence of extra-articular disease (chi 2 = 12.7 P = 10(-3)). Whilst putative CIC are frequent in RA (54%) these findings in contrast to previous work, suggest that the majority are not associated with abnormal complement activation and may account for the relative infrequency of clinically detectable active extra-articular disease.     

Primary juxtaarticular soft tissue lymphoma arising in the vicinity of inflamed joints in patients with rheumatoid arthritis

AIMS: Primary soft tissue lymphoma is uncommon and little is known regarding its aetiology and pathogenesis. In a review of 37 soft tissue lymphomas we uncovered three cases associated with rheumatoid arthritis which we report herein. METHODS AND RESULTS: The clinical records and pathology of the cases are described together with the results of in situ hybridization studies with oligonucleotide probes to Epstein-Barr virus (EBV) encoded RNA (EBER). All three patients were females with a long-standing history of rheumatoid arthritis ranging from 9 to 17 years. Each presented with a soft tissue mass in the vicinity of a joint affected by rheumatoid disease. All had received prior treatment with nonsteroidal anti-inflammatory drugs and one also received gold, penicillamine and intra-articular steroids to affected joints. None had received methotrexate. Histologically, the juxtaarticular soft tissue masses were all B-cell lymphomas. None were associated with EBV as determined by in situ hybridization. CONCLUSIONS: These cases document an association between rheumatoid arthritis and soft tissue lymphoma of B-cell type, arising in the vicinity of an affected joint. Chronic local immune stimulation may have played a significant role in the genesis of these lymphomas, unlike the frequently reversible and EBV-positive lymphomas that occur in rheumatoid patients on immunosuppressive therapy.     

超微血管成像技术在类风湿性关节炎患者手腕关节中的应用价值

目的比较超微血管成像技术(SMI)和能量多普勒(PDUS)在评估类风湿性关节炎(RA)患者急性期和临床缓解期手腕关节滑膜内血管增生的应用价值。方法选择经临床诊断RA患者80例,其中男性25例,女性55例;年龄43~78岁,平均年龄55.5岁;急性期35例,临床缓解期45例。急性期患者中男性10例,女性25例;年龄43~76岁,平均年龄55.3岁。临床缓解期患者中男性15例,女性30例;年龄45~78岁,平均年龄55.6岁。同时采用PDUS和SMI两种超声成像方法检测手腕关节增厚滑膜内的血管增生显示率、血流分级和检查时长,评估血流分级与28个关节的疾病活动度评分(DAS28)的相关性。结果无论是急性期还是临床缓解期患者,SMI较PDUS血流信号显示率(急性期,88.46%vs53.85%;临床缓解期,86.49%vs 54.04%)和血流分级(急性期,3级50.00%vs 11.54%;临床缓解期,3级59.46%vs10.81%)明显增加,检查时长缩短(急性期,4.4 min±0.8 min vs 8.2 min±1.3 min;临床缓解期,4.6 min±0.7 min vs8.5 min±1.4 min)(P <0.05)。经Spearman检验发现,SMI显示血流信号分级与DAS28有较好的一致性(R=0.768、0.723,P=0.011、0.015)。对SMI显示血流信号患者进行强化干预后,血管显示率和血流信号分级均明显减少,DAS28也明显下降(P <0.05)。结论 SMI和PDUS是显示RA手腕关节滑膜内血管增生的重要方法,SMI较PDUS能够更加准确、方便显示血流信号,定量评估血流分级,与炎症活动度有较好的一致性,对指导临床制定正确的干预策略提供重要参考依据。     

Selective accumulation of CCR5+ T lymphocytes into inflamed joints of rheumatoid arthritis

Chemokines and their receptors play critical roles in the selectiverecruitment of various subsets of leukocytes. Recent studieshave indicated that some chemokine receptors are differentiallyexpressed on T_h1 and T_h2 cells. However, available data concerningthe presence of T cells with a T_h1 or a T_h2 character and theexpression of chemokine receptors on infiltrating T cells inthe rheumatic joint are still limited. In this study, we investigatedthe expression of CC chemokine receptor 4 (CCR4) and CCR5, whichhave been shown to be preferentially expressed on T_h2 and T_h1respectively on T cells from rheumatoid arthritis (RA) patients.Although both CCR5⁺ and CCR4⁺ CD4⁺ T cell populations were observedin peripheral blood mononuclear cells from healthy controlsand osteoarthritis patients, these cell populations were decreasedin patients with active RA. In contrast, the vast majority ofsynovial fluid (SF) T cells from active RA patients expressedCCR5 but not CCR4. CCR5 ligands, MIP-1 and RANTES, were foundin RA SF at high levels. CCR5⁺ CD4⁺ T cells from SF mononuclearcells of RA patients produced IFN- but not IL-4 in responseto anti-CD3 stimulation in vitro. These results indicated thatdifferential expression of chemokine receptors plays a criticalrole for selective recruitment of pro-inflammatory T cells intothe joints of RA.