Rheumatoid arthritis and enteric bacteria

Abstract

Factors in the etiopathogenesis of rheumatoid arthritis (RA) include the genetic back-ground, environmental factors and perpetuation of the inflammatory process. This review focuses on enteric bacteria as initiating or perpetuating factors in the etiopathogenesis of RA. Based on the hypothesis that entrobacterial antigens that originated from intestinal flora induce rheumatoid inflammation in the joints, animal models of arthritis due to Enterobacteriaceae, studies on humoral and cellular responses to entrobacterial antigens in RA, etiology of RA involving both genetic and environmental factors, pathogenesis of rheumatoid inflammation accompanied by joint destruction, and clinical trials with basic therapeutic considerations are reviewed. The results of immunological studies on RA suggest that some patients with RA are sensitized to antigens common among Enterobacteriaceae (bacterial outer membrane proteins of 35 and 38 kDa). A bacterial outer membrane protein of 38 kDa was identified as OmpC having amino acid homology (NYGVV) with HLA-DR4. This OmpC peptide elicited peripheral blood T cell proliferative responses in patients with RA. The presentation of this enterobacterial peptide by the RA-associated DR motif to CD4⁺ T cells could lead to initiation of disease. We now consider that in some patients, RA may be based on autoimmunity from molecular mimicry by entrobacterial antigens of HLA-DR4.     

Rheumatoid arthritis and proteus: a possible aetiological association

Summary The presence of specific anti-Proteus antibodies in active, rheumatoid arthritis (RA) patients, has been demonstrated by four different techniques: indirect bacterial agglutination, ELISA, Western blotting and immunofluorescence. Furthermore, anti-HLA-DR4 tissue typing sera have been shown to bind to Proteus microorganisms, thereby suggesting some molecular similarity or cross-reactivity between bacteria and HLA antigens. The concept is proposed that Proteus-reactive arthritis occurs during active phases of RA and tissue damage is mediated through immunological activity involving HLA antigens.     

Rheumatoid arthritis is linked to oral bacteria: etiological association

Abstract

The purpose of this review is to evaluate the association between rheumatoid arthritis (RA) and periodontopathic bacteria. Clinical studies of RA and periodontal disease have provided evidence for a significant association between the two disorders. Patients with long-standing active RA have a substantially increased frequency of periodontal disease compared with that among healthy subjects. High levels of oral anaerobic bacterial antibodies have been found in the serum and synovial fluid of RA patients. Porphyromonas gingivalis, Tannerella forsythensis, and Prevotella intermedia have been identified in RA synovial fluid. Ornidazole, levofloxacin, and clarithromycin are used in the treatment of infections caused by anaerobic bacteria. These antibiotics have been shown to be effective against RA. The evidence in this review indicates that oral bacteria directly associate with etiopathogenesis of RA.     

类风湿关节炎患者抗环瓜氨酸抗体、HLA—DR4基因与其临床特征的关系

目的 探讨抗环胍氨酸（CCP）抗体、人类白细胞抗原HLA-DR4基因与进展性类风湿关节炎（RA）临床特征的关系.方法 记录73例类风湿关节患者的临床资料和实验室检查结果,并采用细胞毒法检测全部病例的HLA-DR4基因携带情况,比较HLA-DR4阳性组与阴性组的临床表现、实验室指标、X线表现及关节功能分级.结果 HLA-DR4阳性者27例,基因频率为37%.HLA-DR4阳性组关节肿胀指数、疼痛指数较高,晨僵持续时间较长,关节功能分级为Ⅲ～Ⅳ级的比例较高,出现骨质破坏比例也较高,抗CCP抗体、类风湿因子、血沉、C反应蛋白值均高于阴性组.结论 HLA-DR4和抗CCP抗体阳性的RA患者与HLA-DR4阴性组的RA患者比较炎症活动严重,且进展较快,应积极治疗.     

Lymphatic obstruction in Rheumatoid arthritis

Summary We describe four patients with rheumatoid arthritis and unilateral upper limb oedema. In all cases, qualitative lymphoscintigraphy showed lymphatic obstruction in the affected limb.     

Rheumatoid leptomeningitis: rare complication of rheumatoid arthritis

Rheumatoid leptomeningitis is a rare complication of rheumatoid arthritis (RA). We describe a woman with rheumatoid leptomeningitis presenting with acute-onset behavioral changes and consciousness disturbance in the early stage of RA. On fluid-attenuated inversion recovery images or diffusion-weighted images, high-signal-intensity lesions in the subarachnoid spaces of the right frontal lobe were observed. Biopsies of brain tissues and the dura mater located in the right frontal lobe were obtained. On the basis of the findings of histopathological analysis, a diagnosis of necrotizing granulomas involving the leptomeninges consistent with rheumatoid leptomeningitis was made. An early diagnosis of rheumatoid leptomeningitis and immediate initiation of treatment may prevent neurological sequelae.     

Antiperinuclear factor – clinical, serological and genetic correlates in Israeli patients with rheumatoid arthritis

The possible association between the presence of antiperinuclear factor (APF) and clinical and genetic parameters was investigated in 54 Israeli patients with rheumatoid arthritis (RA). Rheumatoid factor (RF) was detected in the sera of 43 patients (80%) and APF was positive in 33 (61%). No significant statistical differences were found in the presence of HLA-DR4 and/or DR1 between APF-positive and -negative patients. Furthermore, neither the Ritchie articular index nor the patient's functional class correlated with the presence of APF. The results of our study suggested that although Israeli patients have a different genetic background, the presence and behaviour of APF is similar to that of other Caucasian populations. Received: 14 April 1997 / Accepted: 25 August 1997     

Rheumatoid arthritis: diagnosis and management

Accurate diagnosis of rheumatoid arthritis may be difficult early in its course and demands high clinical suspicion, astute examination, and appropriate investigations. Early use of disease-modifying antirheumatic drugs and biologics has improved outcomes but requires close monitoring of disease course and adverse events.     

Rheumatoid arthritis quality measures and radiographic progression

Objective

Documentation of quality measures (QMs) in rheumatoid arthritis (RA) is used as a surrogate for measure of quality of care, but the association of this documentation with radiographic outcomes is uncertain. We examined documentation of RA QMs, for disease activity and functional status and the association with radiographic outcomes.

Methods

Data were analyzed for 438 RA patients in a longitudinal cohort with complete data on van der Heijde-modified Total Sharp Score (TSS). All rheumatologist (N = 18) notes in the electronic medical record during a 24-month period were reviewed for RA QMs. Any mention of disease activity categorized as low, moderate, or high was considered documentation of the QM for disease activity. Functional status QM documentation included any mention of the impact of RA on function. Change in TSS was quantified with progression defined as ≥1 unit per year. We compared percent of visits with an RA QM documented and mean change in TSS.

Results

The mean age in the cohort was 56.9 years, disease duration was 10.8 years, baseline DAS28 score was 3.8 (±1.6), 67.7% were seropositive, and 33.9% used a biologic DMARD. Radiographic progression was observed in 28.5%. Disease activity was documented for 29.0% of patient visits and functional status in 74.7%; neither had any significant relationship to mean TSS change (both P > 0.10).

Conclusion

The documentation of RA QMs was infrequent and not associated with radiographic outcomes over 24 months.     

Rheumatoid arthritis: Evolving recognition of a common disease

Rheumatoid arthritis (RA) is a highly prevalent autoimmune disease and the most common form of autoimmune inflammatory arthritis. Studies of RA pathogenesis have contributed significantly to understanding the basis for complex immune-mediated disease, identified key steps in the development of autoimmune activation and joint damage in RA, and led to the development of targeted therapies that opened up the era biologic therapy. Current studies are linking differences in gene expression to abnormalities in cellular function that will help optimize therapy for individual patients and advance the goal of personalized medicine. Our evolving understanding and current important issues in RA are highlighted.     

Rheumatoid arthritis associated with osteopetrosis

Abstract

Osteopetrosis is an inherited disorder characterized by reduced bone resorption. We here report a rare case of osteopetrosis associated with rheumatoid arthritis. The patient was diagnosed as autosomal dominant osteopetrosis type II in his youth and developed rheumatoid arthritis at 42 years of age. In spite of the severe inflammation and rapid progression of cartilage destruction, the progression of bone erosion was slow in this patient.     

中国汉族类风湿关节炎患者HLA-DR4基因与抗环瓜氨酸肽抗体的相关性研究

目的：探讨中国汉族类风湿关节炎（RA）患者中抗环瓜氨酸肽抗体（ACCP）与人类白细胞抗原（HLA）-DR4基因的相关性。方法：入选RA104例、正常对照122名。ACCP检测采用酶联免疫吸附法（ELISA）,类风湿因子检测采用散色比浊法,HLA-DR4基因采用序列特异性引物-聚合酶链方法（PCR-SSP）检测。结果：RA患者中HLA-DR4基因携带率为34.6%,主要亚型为HLA-DRB1＊0405,正常对照组为17.2%,差异有统计学意义（P=0.01）。RA患者的共同表位（SE）携带率为30.9%,与国内相关研究结果（33.2%,36.8%）相似,但明显低于国外相关研究（78.5%,65.4%,85%,67%）,差异有统计学意义（P〈0.01）。RA患者中ACCP阳性率为76.5%,与国内外报道相符,正常对照组为0,两者差异有统计学意义。SE（＋）患者的ACCP阳性率为84%,SE（-）患者的ACCP阳性率73.2%,两者差异无统计学意义。RA患者中ACCP的滴度与X线分期相关（r=0.233,P〈0.05）。结论：我国汉族RA患者中ACCP与HLA-DR4或SE无明显的相关性。ACCP可能与关节破坏的严重程度相关。     

HLA-DR1 and DRw6 association in DR4-negative rheumatoid arthritis patients

Summary This study of 110 seropositive rheumatoid arthritis (RA) patients confirms the significant association of susceptibility to RA with HLA-DR4 specificity (P<0.001). The DR1 frequency is elevated in the entire seropositive patient group, reaching marginal significance (P<0.025). The DR4-negative patients, however, have a much higher prevalence of DR1 (P<0.001). Surprisingly, the DRw6 specificity is significantly increased in the remaining DR4- and DR1-negative patients (P<0.01). These results demonstrate that RA is not associated with a single HLA-specificity, but to various degrees with DR4, DR1, and DRw6. These findings, and particularly the newly recognized association with DRw6, support the hypothesis that functionally equivalent shared epitopes or conformations on otherwise distinct MHC molecules may confer risk for developing RA.     

Rheumatoid factors in psoriatic arthropathy and in Waaler-Rose negative rheumatoid arthritis

Summary Serum levels of IgG, IgA and IgM rheumatoid factor (IgG RF, IgA RF and IgM RF) were determined by means of the diffusion-in-gel enzyme-linked immunosorbent assay (DIG-ELISA) in 42 Waaler-Rose negative patients with psoriatic arthropathy (PsA) type 1 (arthritis with involvement of distal interphalangeal joints) and type 3 (polyarthritis of rheumatoid type) according to the criteria of Moll and Wright as well as in 53 patients with Waaler-Rose negative rheumatoid arthritis (RA). Elevated levels of RF were found in 22% of patients with PsA type 3 and 45% of patients with Waaler-Rose negative RA. In contrast, none of the patients with PsA type 1 had detectable amounts of RF. It is suggested that the presence of IgG, IgA or IgM RF in patients having psoriasis in conjunction with inflammatory polyarthritis indicates the RA nature of the joint disease and should be considered as exclusion criterion for the diagnosis of PsA.     

Rheumatoid arthritis induced by alpha-interferon therapy

Interferon (IFN) therapy has been used for the treatment of common diseases such as hepatitis C, myeloproliferative disorders, autoimmune diseases and various types of cancer. Given the biological properties of interferon, it is not surprising that there are a larger number of side effects due to its use. Although rheumatoid arthritis (RA) is one of the most common autoimmune diseases found in clinical practice, it does not seem to be frequently related to IFN therapy. We report a 40-year-old female patient who, after high doses of IFN-α therapy for malignant melanoma, developed symmetrical polyarthritis, with pain and oedema in small and large joints, associated with prolonged morning stiffness. She had positive rheumatoid factor and DR4 HLA phenotype. She was treated with deflazacort (6 mg/day), chloroquine and NSAIDs, with a partial response. In conclusion, although the development of RA after IFN therapy is a rare event, IFN may work as a ‘trigger’ for such complication, leading to deregulation in the immune cascade in a person genetically predisposed. Received: 20 October 2000 / Accepted: 31 January 2001     

Rheumatoid arthritis in greece

Summary A high frequency of anti-Ro (SSA) circulating antibodies and lack of HLA-DR₄ association described recently in Greek rheumatoid arthritis (RA) patients, prompted us to study their clinical and laboratory picture and compare it with that described in the literature. One hundred and ninety seven patients with definite or classical RA were divided into three groups A, B, and C with age at disease onset below 39, between 40 and 59, and above 60 years respectively. Disease duration below 5 and above 5 years resulted in further division of each group into subgroups 1 and 2. With few exceptions, there were no significant differences between the groups in terms of maximal articular index, lymphadenopathy, splenomegaly, hepatomegaly, frequency of rheumatoid nodules and lowest hematocrit, highest erythrocyte sedimentation rate, and C-reactive protein values. The presence of rheumatoid factor, antinuclear antibodies, cryoglobulins, and elevated levels of globulins, C₃ and C₄ in patients' sera were not significantly different among the groups. A statistically significant radiologic deterioration was observed with disease duration, common in all groups. Diffuse interstitial lung disease was the most common pulmonary abnormality noted. There were no differences between the groups. Penicillamine toxicity was independent of age and disease duration. This study suggests that the clinical picture of RA in Greece is similar to that in other populations and that there are no significant differences in general among its age groups.     

Analysis of the HLA-DR gene frequencies in Japanese cases of juveniles rheumatoid arthritis and rheumatoid arthritis by oligonucleotide DNA typing

Summary HLA-DR gene frequencies in 59 Japanese children with juvenile rheumatoid arthritis (JRA) and 62 Japanese adults with rheumatoid arthritis (RA) were analyzed by oligonucleotide DNA typing. As in other studies, the frequency of DRB1*0405 in RA patients was significantly higher than in the Japanese controls. In a comparison of non-calssified JRA patients with Japanese controls, no significant differences were observed in the frequency of DR types. However, when the JRA patients were classified into four clinical types, i.e., a rheumatoid factor-positive [RF(+)] polyarticular type, a rheumatoid factor-negative [RF(-)] polyarticular type, a pauciarticular type, and a systemic onset type, DRB1*0405 was found to be significantly higher in the RF(+) polyarticular JRA patients than in the controls (P>0.05). Thus, the RF(+) polyarticular type of JRA had the same HLA association as RA. This result is consistent with the fact that both RF(+) polyarticular JRA and RA cases have a similar clinical course.     

Rheumatoid arthritis,periodontal disease and coronary artery disease

Rheumatoid arthritis (RA), periodontal disease (PD), and coronary artery disease (CAD) are common chronic inflammatory diseases. RA is associated with accelerated vascular risk resulting in an increased prevalence of CAD with attendant early mortality and excess morbidity. RA and PD have a common pathobiology. Accordingly, the aim of this study was to evaluate the association between RA, PD, and CAD and the influence of systemic inflammatory factors. A total of 100 active RA patients of which 50 had established CAD and 50 had no CAD were assessed for PD. All subjects underwent a clinical, cardiac, dental, laboratory, and radiological evaluation. Blood samples were obtained, and the level of high sensitivity C-reactive protein (hs-CRP), total white blood counts (WBC), erythrocyte sedimentation rate (ESR), fibrinogen and tumor necrosis factor (TNF) alpha, total cholesterol (TC), and high density lipoprotein (HDL) were assayed. The findings of this study demonstrated an association between RA, PD, and CAD. The RA patients with CAD had significantly more PD than RA patients without CAD. The inflammatory markers, hsCRP, ESR, WBC, fibrinogen, and TNF-α, were raised in all patients but were significantly higher in RA patients with CAD who also had PD. HDL levels were lower in RA patients with CAD when compared to RA patients without CAD. Evidence from this study shows an association between RA, PD, CAD, and systemic levels of the inflammatory mediators. The implication is that inflammation may be the central link between the chronic inflammatory, autoimmune disorders, and atherosclerosis. An erratum to this article can be found at     

HLA-DR antigens in rheumatoid arthritis

Summary In a Swiss multicenter study, a significant increase of HLA-DR4 was found in patients with rheumatoid arthritis when compared with normal controls (P<0.01). This increase was limited to patients with rheumatoid factors; it was strongest in patients with high titers. Similarly, the frequency of HLA-DR4 was higher in patients with larger amounts of circulating immune complexes when compared with patients with low amounts. No correlation with the presence of antinuclear antibodies was found. HLA-DR1 was more frequent in patients with rheumatoid arthritis than in controls (N.S.). This was due to an increase of HLA-DR1 in patients without rheumatoid factors (P<0.05), low amounts of circulating immune complexes (N.S.) and without antinuclear antibodies (P<0.05). Participants: T. L. Vischer (coordination and correspondence), Division of Rheumatology, Hôpital Cantonal, CH-1211 Genève 4;M. Jeannet and V. von Fliedner (HLA-antigen determinations), Transplantation Immunology Unit, Division of Immunology; A. Cruchaud (antinuclear antibodies), Division of Immunology; A. Micheli (rheumatoid factors), Division of Rheumatology; N. Carpentier and P.H. Lambert (C1q-binding tests), WHO Immunology Research and Training Laboratory; all from the Department of Medicine, University of Geneva. P. Vuagnat (statistics), Department of Mathematics, University of Geneva Centers: Basel: U. Steiger (Medizinische Universitätsklinik); Bern: N. Gerber (Universitäts-Rheumaklinik); Fribourg: I. Radi (Hôpital Cantonal); Genève: T. L. Vischer (Hôpital Cantonal); La Chaux-de-Fonds: H. Ott (Service de Physiatrie, Hôpital de la Chaux-de-Fonds); Lausanne: T. Bitter and J. C. Gerster (Service de Physiatrie, CHUV);Leukerbad: N. Fellmann (Rheumaklinik); Valens: B. Stojan (Klinik Valens); Winterthur: H. Hunziker (Kantonsspital); Zürich: M. Baumgartner (Klinik Wilhelm Schulthess), D. Gross and M. Lamoth (Triemlispital), K. Fehr and M. Felder (Universitäts-Rheumaklinik); Zurzach: W. Kunz (Rheumaklinik)