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ID PMID Title PublicationDate abstract
10782805 Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with r 2000 Apr OBJECTIVE: To evaluate the safety and efficacy of single and multiple doses of a chimeric anti-TNF-alpha monoclonal antibody (infliximab) in patients with rheumatoid arthritis (RA) who had active disease despite therapy with methotrexate (MTX). METHODS: Twenty-eight patients with active RA despite receiving therapy with 10 mg/week of MTX were randomized to receive a single, blinded infusion of either placebo or 5, 10, or 20 mg/kg infliximab. Twenty-three patients who completed the blinded study entered an open, multiple dose extension study in which they received up to 3 additional infusions of 10 mg/kg infliximab at Weeks 12, 20, and 28. Safety, efficacy, and pharmacokinetics were evaluated during the blinded and open trial. RESULTS: There were no serious infusion related reactions. In the blinded phase, 17 (81.0%) of 21 patients receiving infliximab achieved an American College of Rheumatology (ACR) 20% response at some point during the 12 weeks of followup compared to one (14.3%) of 7 patients receiving placebo (p = 0.003). Clinical improvement was evident by the first week and was sustained through Week 12. For the 19 patients who received infliximab during the blinded part of the trial and continued into the open label trial, 53% maintained an ACR 20% response with multiple infusions of 10 mg/kg infliximab through Week 40. Three patients withdrew from the trial during the open continuation phase because of adverse events: cellulitis, infusion related dizziness and headache, and vasculitic rash. Infliximab in doses of 5 to 20 mg/kg had a mean terminal half-life ranging from 9 to 12 days and was detectable in sera from most patients 8 to 12 weeks after dosing. CONCLUSION: Infliximab is generally well tolerated during 40 weeks of therapy. A single infusion of 5 to 20 mg/kg infliximab significantly decreases the signs and symptoms of RA compared to placebo in patients with active disease receiving MTX. Multiple doses of infliximab produce sustained clinical benefit for up to 40 weeks.
9259420 The B cell repertoire of patients with rheumatoid arthritis. II. Increased frequencies of 1997 Aug OBJECTIVE: A qualitative and quantitative analysis of the functional, antigen-specific B cell receptor repertoire of patients with rheumatoid arthritis (RA) in synovial and peripheral compartments. METHODS: B cells were activated to grow and differentiate at high efficiency in vitro under limiting-dilution conditions. Isotype and specificity of the secreted Ig were tested by enzyme-linked immunosorbent assay. RESULTS: In contrast to peripheral B cells, most synovial B cells had already switched to IgG/IgA in vivo. The frequencies of B cells specifically recognizing foreign antigens were decreased within the synovial population, whereas the frequencies of B cells specific for type II collagen, mycobacterial heat-shock protein 60 (hsp60), or IgG Fc fragments were significantly increased, revealing a negative correlation in terms of frequencies. CONCLUSION: B cells specific for human type II collagen, hsp60, and IgG Fc fragments are produced and/or expanded locally within the affected joints of RA patients. Thus, the specific immune system is definitely involved in the local inflammatory and destructive processes.
9797550 Prediction of postpartum onset of rheumatoid arthritis. 1998 Aug OBJECTIVE: To investigate the prediction of the postpartum onset of rheumatoid arthritis (RA). METHODS: Two thousand five hundred and forty seven healthy pregnant subjects were examined prospectively and the relation between serum rheumatoid factors (RF) and postpartum onset of RA was observed. Rheumatoid factors were measured in early pregnancy by the antihuman IgG latex agglutination test (Latex test) and antirabbit IgG haemagglutination test (RAHA test). RESULTS: Latex test and RAHA test were positive in 26 (1.0%) and 64 (2.5%) pregnant subjects, respectively. Four hundred and ten subjects of 2547 pregnant women could be followed up for one year after delivery. None of 401 subjects without RF, or with only one RF on either Latex test or RAHA test, developed RA after delivery. Two (22.2%) of nine subjects with both RFs developed RA at one and three months postpartum, respectively. Transient arthralgia was found within 12 months postpartum in three of nine (33.3%) subjects with both RFs and this prevalence was significantly higher than that in RF negative subjects (8.1%). CONCLUSION: Postpartum onset of RA was found in at least 2 of 2547 healthy subjects (0.08%) and onset was predicted by positive test for rheumatoid factors.
9608316 Disease-modifying antirheumatic drugs. 1998 May Disease-modifying antirheumatic drug (DMARD) therapy is now clearly accepted as the primary treatment for rheumatoid arthritis, with an increasing emphasis on use of combination therapy. Data on combination therapy have highlighted the difficulties in performing these studies and the large number of patients required to produce meaningful results. Combination studies have focused on use of rapidly decreasing high-dose steroids as a part of the combination and emphasize the importance of using patients with early rheumatoid arthritis. Even with relatively aggressive use of DMARDs, the majority of patients develop erosions. Adverse reactions to DMARDs continue to concern clinicians, although evaluation of the frequency of these events has led to a reappraisal of previously accepted monitoring strategies in some cases. For example, it may not be cost-effective to subject patients on antimalarials to regular review by an ophthalmologist because of the low frequency of serious eye defects. Studies have also identified risk factors for the development of pulmonary toxicity in association with methotrexate. That DMARDs are effective in treating rheumatoid arthritis is beyond question-just how effective they are and what combinations of DMARDs will show improved efficacy will provide data for the next annual review.
10424492 Salivary proteins in rheumatoid arthritis and Sjögren's syndrome: one-dimensional and two 1999 Jun Parotid saliva from patients with rheumatoid arthritis and Sjögren's syndrome contains elevated levels of multiple anionic proteins of pI approximately 3.75-4.75 and Mr approximately 32,000. Further studies on these components involving narrow range pH 3.5-5.0 immobilized pH gradients (IPGs) and two-dimensional (2D) electrophoresis with narrow- or broad-range IPGs in the first dimension have confirmed their association with these disorders. Immunoblotting showed that these proteins include multiple forms of tissue kallikrein. Treatment with neuraminidase results in removal of these anionic substances from the pH 3.75-4.75 region of gels, thereby indicating that heterogeneity arises from differences in sialation of the carbohydrate residues. The results of treatment with endo-beta-N-acetylglucosaminidase (Endo F) or peptide N-glycosidase (PNGase F) and comparison of the results with studies on human urinary kallikrein suggest that proteins other than kallikrein may also comigrate in the anionic region of gels and that deglycosylation of kallikrien is incomplete in the experimental conditions used, probably because of inadequate denaturation. The paper also reviews the limitations of current criteria used in the investigation of salivary gland function associated with connective tissue disorders and the diagnosis of these. It assesses the potential of electrophoresis in forming the basis of new diagnostic techniques and furthering the understanding of the nature of these diseases. The findings presented in this paper could make a key contribution to this.
11419149 MRI of the arthritic small joints: comparison of extremity MRI (0.2 T) vs high-field MRI ( 2001 The aim of this study was to compare the diagnostic capabilities of extremity MRI (E-MRI) with high-field MRI in arthritic small joints, and to evaluate the patients' acceptance and perceptions of the two MR systems. One hundred three patients (group 1 = 28 patients with RA < 3 years, group 2 = 25 patients with reactive and psoriatic arthritis and mixed connective tissue disease, group 3 = 25 patients with rheumatoid arthritis (RA) more than 3 years and group 4 = 25 patients with arthralgia) underwent dedicated E-MRI and high-field MRI of the wrist and finger joints. Coronal short tau inversion recovery and transversal 3D T1-weighted images before and after gadodiamide (Gd) were performed in both cases to outline the volume of the synovial membrane (Vsm) and to evaluate joints with enhancement, effusion, bone edema, and erosions. Investigators blinded to the clinical findings evaluated the images. Patients' compliance and acceptance of E-MRI and high-field MRI were evaluated. The median Vsm obtained on E-MRI did not differ significantly from that obtained on high-field MRI. Vsm = 1 ml (E-MRI) and 1.1 ml (high-field MRI) before Gd and Vsm = 0.1 ml (E-MRI) and 0 ml (high-field MRI) after Gd (Wilcoxon test, p > 0.05). The difference in agreement was 8% for joint enhancement, 2% for joint effusion, 3% for bone edema, and 4% for bone erosions. Of the patients, 64% preferred E-MRI due to more comfortable positioning and less claustrophobia and noise. Extremity MRI of the small arthritic joints is comparable to high-field MRI and more readily accepted than high-field MRI by this patient group.
9662482 Role of T-cells in the development of arthritis. 1998 Jul 1. Arthritis can be induced in rodents by priming T-cells to respond to a foreign antigen and then challenging with antigen intra-articularly. This may be a model of the situation in human reactive arthritis in which T-cell responses are induced by antigens from organisms which trigger reactive arthritis (e.g. Chlamydia trachomatis) and antigen finds its way to the joint, most probably within macrophages. Priming by previous exposure to antigens similar to those of the triggering organism could also play a part in pathogenesis. Genetic factors determining the nature and control of the immune response affect the severity and duration of the arthritis. 2. T-cell-dependent arthritis can be induced in rodents by immunization with an antigen known to be expressed in the joint (e.g. Type II collagen). Whether this is an important mechanism in human arthritis is still unclear, even though diseases such as rheumatoid arthritis are conventionally thought of as 'autoimmune'. No convincing candidate autoantigen has yet been identified in rheumatoid arthritis, and recent experiments in transgenic mice indicate that arthritis can be induced by an autoimmune T-cell response which does not target an antigen confined to the joint. 3. Adjuvant arthritis is a classical T-cell-dependent animal model of human arthritis; recently arthritis has been described as a rare complication in patients receiving adjuvant (intra-vesical live BCG organisms) for bladder cancer. Increasing attention is being paid to the role of adjuvants as 'danger signals', which allow the immune system to determine whether an antigenic challenge poses a threat. Inappropriate attachment of danger signals to self antigens may result in T-cell-mediated immune responses, which could play a part in the pathogenesis of arthritis. 4. Animal studies indicate that autoimmune/inflammatory diseases can be produced by imbalances within T-cell populations, and that certain T-cells also have the capacity to regulate inflammatory responses. Among the latter are T-cells specific for conserved epitopes within heat shock protein 60. The extent to which T-cells of this kind operate in human disease has yet to be determined.
11481825 [Atelectasis of the right lower lobe in association with bronchiolitis obliterans organizi 2001 Apr A 58-year-old woman with underlying rheumatoid arthritis was admitted to the hospital because of a dry cough and the presence of an abnormal shadow in the right lower lung field. Consolidation and volume loss in the right lower lobe with air bronchogram were recognized on a chest tomogram. Bronchofiberscopic examination disclosed neither stenosis nor tumors in the large bronchi. Organizing pneumonia was recognized pathologically in transbronchial lung biopsy (TBLB) specimens. The volume of the right lower lobe decreased rapidly, and new infiltration shadows appeared in the right upper and middle lobes. Another bronchofiberscope examination revealed organizing pneumonia, and macrophage infiltrations were seen in the alveoli on histopathological examination of the TBLB specimens. The diagnosis of RA-associated BOOP was made on the basis of agreement of the expansion of the shadows on chest radiographs, the RA symptoms and the RA factor. The patient was treated with prednisolone, and the clinical course was satisfactory, with no recurrence. This case was of interest because BOOP inducing lobar cicatricial atelectasis is very rare.
9799335 An extended HLA-DQ-DR haplotype rather than DRB1 alone contributes to RA predisposition. 1998 Nov In the present study, we tested our hypothesis on the role of a DQ-DR haplotype in rheumatoid arthritis (RA) predisposition. Using two groups of patients and controls, one from The Netherlands and one from Switzerland, we found that DQA1*0301-homozygous and DQA1*0301//DQA1*0101/04-heterozygous individuals are highly predisposed to RA in both populations, while DQA1*0101/04-homozygous are not. The DQA1*0301-DRB1*0403/06/07 and DQA1*0301-DRB1*0901 haplotypes are not associated with RA by themselves but strongly increase the risk of developing disease in DQA1*0301- and DQA1*0101/04-heterozygous. DRB1 alleles carrying the motif DERAA in their third hypervariable region, i.e., *0103, *0402, *1102, *1103, *1301, and *1302, provide a long-lasting protection against RA in DQA1*0101/04- but not in DQA1*0301-positive individuals. These data show that considering both DQ and DR gives a better distinction between patients and controls than the shared epitope hypothesis.
9464528 Heterogeneous RF structures between and within healthy individuals are not related to HLA 1997 Aug To study variations in Rheumatoid Factor (RF) autoantibodies between and within healthy individuals, we have produced and analysed the variable heavy chain (VH) regions of 18 new monoclonal IgM RFs from the peripheral blood of two healthy subjects before and after immunization with tetanus toxoid (TT). The majority of these RFs used germline genes of the VH3 family, but RFs of the VH1, VH2 and VH7 families were also found. No RF of the VH4 RF is found. Fourteen different VH germline (GL) genes encoded the RFs, suggesting an extraordinary heterogeneity in structure. Consequently, changes in RF V region structures following immunization were difficult to identify. There were, however, structural differences between RFs from the two donors. RFs from one donor (IP) used more lambda light chains than RFs from the other donor and previously described RFs. In addition, 50% of the RFs from donor IP were encoded by GL genes frequently found to encode RFs from patients with Rheumatoid Arthritis (RA) but not described in RFs from other healthy subjects. The predominant use of VH3 RFs in the two healthy donors contrasts with the over-expression and expansion of VH1 RFs in one previously described healthy immunized donor. There are thus large individual differences in RF structures, which might be related to the immunological status, environment or genetic background of the donors. However, since these three donors are all HLA DRB1*0401, it is unlikely that this HLA type, associated with seropositive RA, accounts for the individual differences.
11227381 [The role of angiogenesis in rheumatoid arthritis]. 2000 The paper presents recent data on the angiogenesis and the angiogenic and angiostatic mediators in rheumatoid arthritis.
11826749 [IV: Small group workshop for developing future measures and projects. Evidence-based ther 2001 Dec Secondary osteoporosis is a common, late complication of inflammatory rheumatic diseases. Despite its great socio-economic implications for the individual, there is still a lack of appreciation of this problem. This may result in an inadequate or insufficient prophylaxis and therapy. The participants of this discussion group, therefore, approve of further investigations in this field to gather new relevant data, e.g., for our core documentation on rheumatic diseases. Of special importance is the registration of long-term patients obtaining documented, individual long-term therapy (e.g., cortisone). As well as epidemiologic and clinical research projects, it is imperative to do basic research into the pathogenesis of secondary osteoporosis and find new therapeutic approaches for curing rheumatic disease.
10925283 Frequent contribution of T cell clonotypes with public TCR features to the chronic respons 2000 Aug 15 In an attempt to provide a global picture of the TCR repertoire diversity of a chronic T cell response against a common Ag, we performed an extensive TCR analysis of cells reactive against a dominant HLA-A2-restricted EBV epitope (hereafter referred to as GLC/A2), obtained after sorting PBL or synovial fluid lymphocytes from EBV-seropositive individuals using MHC/peptide multimers. Although TCR beta-chain diversity of GLC/A2+ T cells was extensive and varied greatly from one donor to another, we identified in most cell lines several recurrent Vbeta subsets (Vbeta2, Vbeta4, and Vbeta16 positive) with highly conserved TCRbeta complementarity-determining region 3 (CDR3) length and junctional motifs, which represented from 11 to 98% (mean, 50%) of GLC/A2-reactive cells. While TCR beta-chains expressed by these subsets showed limited CDR1, CDR2, and CDR3 homology among themselves, their TCR alpha-chains comprised the same TCRAV region, thus suggesting hierarchical contribution of TCR alpha-chain vs TCR beta-chain CDR to recognition of this particular MHC/peptide complex. The common occurrence of T cell clonotypes with public TCR features within GLC/A2-specific T cells allowed their direct detection within unsorted PBL using ad hoc clonotypic primers. These results, which suggest an unexpectedly high contribution of public clonotypes to the TCR repertoire against a dominant epitope, have several implications for the follow-up and modulation of T cell-mediated immunity.
10074579 POEMS syndrome, steroid-dependent diabetes mellitus, erythema elevatum diutinum, and rheum 1998 Apr POEMS syndrome is a rare synopsis of different multisystemic disorders (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammapathy, and skin lesions) associated with plasma cell dyscrasia. We herein report the atypical case of a 44-year-old white man presenting with glomerulopathy, POEMS syndrome, and erythema elevatum diutinum with a few-year history of non-insulin-dependent diabetes mellitus (NIDDM) and seronegative rheumatoid arthritis (RA) as early manifestations of IgAlambda multiple myeloma. The prescription of 1 mg/kg/day prednisone improved the patient's features dramatically. Skin lesions improved by the association of glucocorticoids and plasma exchange, recurred when plasmapheresis ceased, and remitted when plasma exchange was reintroduced. NIDDM requiring insulinotherapy recurred when corticoids were discontinued and remitted when prednisone was reintroduced. However, prednisone and plasmapheresis had no effect on polyneuropathy, M-paraprotein, and plasma cell dyscrasia in our patient, who developed indolent multiple myeloma a few years later. We thus concluded that POEMS syndrome, steroid-dependent diabetes mellitus, rheumatoid arthritis, RA, and skin vasculitis in our patient were triggered by plasma cell dyscrasia.
9572681 Elevated nerve growth factor levels in the synovial fluid of patients with inflammatory jo 1998 Jun A novel pH shock extraction procedure was used to measure nerve growth factor (NGF) levels in both normal and inflamed synovial fluids using a sensitive and specific two-site enzyme linked immunosorbant assay. To date no data is available on NGF levels in normal synovial fluids. Synovial fluids were taken from 5 normal volunteers, 12 patients with rheumatoid arthritis and 10 patients with other inflammatory arthropathies. The mean +/- SEM NGF concentration in normal synovial fluids was 95 +/- 33.2 pg/ml (range 39.1-143.1 pg/ml), whereas the mean NGF concentration in the synovial fluids taken from patients with rheumatoid arthritis was 532.5 +/- 123.8 pg/ml (range 152-1686 pg/ml). The mean NGF concentration in patients with other inflammatory arthropathies was also raised (430.6 +/- 90 pg/ml; range 89-1071 pg/ml). The NGF concentrations were significantly higher in the synovial fluids from both inflamed groups (ANOVA p < 0.05) compared to normals. Raised levels of NGF in synovial fluid may contribute directly to joint inflammation via activation of inflammatory cells.
9225882 Thoracic myelopathy due to intraspinal rheumatoid nodules. 1997 A fifty-six-year-old woman with classical rheumatoid arthritis had subacute onset of paraparesis due to thoracic epidural rheumatoid nodules. Although plain radiograms and computed tomograms of the thoracic spine were negative except for old compression fractures, magnetic resonance imaging revealed thoracic spinal cord compression due to masses at multiple levels. There was a steady recovery after excision surgery.
11511755 Systemic lupus erythematosus and rheumatoid arthritis patients differ from healthy control 2001 Aug OBJECTIVE: To study whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) differ from healthy individuals in their immune responses to acute psychological stress. METHODS: The phenotype and function of peripheral blood lymphocytes were analysed before and after stress exposure in patients and healthy subjects. RESULTS: Natural killer (NK) cell numbers increased transiently in all groups under stress. NK activity, however, increased in healthy controls only. We observed a stress-induced increase in interleukin (IL)-4-producing (IL-4(+)) cells in SLE patients only, whereas interferon (IFN) gamma(+) cell numbers increased due to stress in all three groups. An analysis of supernatants from phytohaemagglutinin (PHA) cultures revealed increased IFN gamma and IL-10 levels in healthy subjects but not in SLE or RA patients after stress exposure. CONCLUSIONS: These data demonstrate that RA and SLE patients differ in their immune response to stress from healthy controls. Changes in cytokine patterns might be responsible for stress-induced exacerbation of disease activity in RA and SLE patients.
10338479 Cross-reactivity between the rheumatoid arthritis-associated motif EQKRAA and structurally 1999 Jun Cross-reactivity or molecular mimicry may be one of the underlying mechanisms involved in the etiopathogenesis of rheumatoid arthritis (RA). Antiserum against the RA susceptibility sequence EQKRAA was shown to bind to a similar peptide ESRRAL present in the hemolysin of the gram-negative bacterium Proteus mirabilis, and an anti-ESRRAL serum reacted with EQKRAA. There was no reactivity with either anti-EQKRAA or anti-ESRRAL to a peptide containing the EDERAA sequence which is present in HLA-DRB1*0402, an allele not associated with RA. Furthermore, the EQKRAA and ESRRAL antisera bound to a mouse fibroblast transfectant cell line (Dap.3) expressing HLA-DRB1*0401 but not to DRB1*0402. However, peptide sequences structurally related to the RA susceptibility motif LEIEKDFTTYGEE (P. mirabilis urease), VEIRAEGNRFTY (collagen type II) and DELSPETSPYVKE (collagen type XI) did not bind significantly to cell lines expressing HLA-DRB1*0401 or HLA-DRB1*0402 compared to the control peptide YASGASGASGAS. It is suggested here that molecular mimicry between HLA alleles associated with RA and P. mirabilis may be relevant in the etiopathogenesis of the disease.
9280606 [Clinical application of interleukin-6 receptor antibody]. 1997 Apr Interleukin-6 (IL-6) is a pleiotropic cytokine which shows multiple biological functions. Pathological significance of IL-6 has been elucidated in various diseases including multiple myeloma, Castleman's disease, and rheumatoid arthritis. Thus the blockade of IL-6 signal transduction may be therapeutically effective for these diseases. For this purpose, humanized anti-IL-6 receptor antibody was prepared, and its therapeutic efficacy has been examined. Immediately after administration of humanized anti-IL-y receptor antibody to the patients with multiple myeloma, fever and systemic edema disappeared followed by the stability of M-protein which had been rapidly increased before the treatment. Humaniged anti-IL-6 receptor antibody also improved not only the chronic inflammatory symptoms but also laboratory findings such a hemoglobin, C-reactive protein, erythrocyte sedimentation rate observed both in Castleman's disease and in rheumatoid arthritis. The data suggest that the blockade of IL-6 signal transduction can be a new therapeutic approach based on the pathological significance of IL-6 in these diseases.
10074894 Increased plasma levels of homocysteine and other thiol compounds in rheumatoid arthritis 1999 Feb OBJECTIVES: Since moderate hyperhomocysteinemia is an independent risk factor for vascular disease and physiological thiol compounds mediate Cu2+- and Fe3+-dependent low-density lipoprotein (LDL) oxidation, we have studied the total plasma concentrations of thiol compounds including methionine as precursor of homocysteine in rheumatoid arthritis patients, in which the high mortality found is associated with cardiovascular disease. DESIGN AND METHODS: Thirty-eight women with rheumatoid arthritis and 25 age-matched control women were studied. Plasma was used to measure thiol compounds and amino acids by HPLC. RESULTS: Rheumatoid arthritis patients showed significantly higher levels than healthy controls of total plasma homocysteine (17.3 +/- 7.8 vs. 7.6 +/- 1.9; p <0.001), cysteine (293 +/- 61 vs. 201 +/- 45; p < 0.001), cysteinglycine (32.7 +/- 8.3 vs. 22.3 +/- 4.7; p < 0.001) and methionine (25 +/- 9 vs. 18 +/- 3; p < 0.01), whereas total glutathione levels were not increased (4.7 +/- 2.0 vs. 4.1 +/- 1.6). CONCLUSIONS: The increased levels of thiol compounds found in rheumatoid. arthritis patients may be implicated in the increased incidence of cardiovascular disease found in these patients by means of the toxic effect of homocysteine on endothelium and the increased susceptibility of LDL to oxidation by increased plasma amounts of thiol compounds such as cysteine.