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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
10219558 Aortic regurgitation in rheumatoid arthritis necessitating aortic valve replacement. 1999 Feb Four cases of patients with aortic incompetence secondary to rheumatoid arthritis are presented. All survived aortic surgery (two having bioprosthetic aortic valve replacement and two a homograft aortic root replacement). A review of the pathophysiology and pathology of this rare cause of aortic regurgitation is presented. A rationale for the choice of aortic valve prosthesis is discussed.
9489808 Invasion of human cartilage by cultured multicellular spheroids of rheumatoid synovial cel 1998 Feb OBJECTIVE: A new 3-dimensional cell culture system was established to examine the invasion of rheumatoid synovial cells into cartilage. METHODS: Synovial cells from 20 patients with rheumatoid arthritis (RA) and 15 patients with osteoarthritis (OA) were co-cultured as multicellular spheroids with cartilage fragments. RESULTS: After 4 weeks the rheumatoid spheroids eroded the cartilage. The destruction of cartilage was supported by a high expression level of cathepsin D and matrix metalloproteinases. In contrast, the OA tissue showed attachment to the cartilage only. CONCLUSION: Our results indicate that spheroid/cartilage co-cultures seem to be a suitable in vitro model for the study of destructive cellular mechanisms that occur in RA.
11411959 The new antirheumatic drug KE-298 suppresses monocyte chemoattractant protein (MCP)-1 and 2001 May We analyzed the effects of the new antirheumatic drug KE-298 on monocyte chemoattractant protein (MCP)-1 and regulated on activation normal T-cell expressed and secreted (RANTES) production in rats with adjuvant-induced arthritis and in interleukin (IL)-1beta-stimulated rheumatoid arthritis (RA) synoviocytes. In rats with adjuvant-induced arthritis, the enhanced production of MCP-1 and RANTES and the development of arthritis were suppressed by oral treatment with 100 mg/kg per day of KE-298 for 18 days. Furthermore, KE-298 (10-100 microg/ml) suppressed MCP-1 and RANTES production by IL-1beta-stimulated RA synoviocytes through inhibition of NF-kappaB and AP-1 activation. These results suggest that the inhibitory effect of KE-298 on MCP-1 and RANTES production might partly explain its efficacy in rats with adjuvant-induced arthritis and in patients with RA.
9034980 HLA-DR restrictive supertypes dominate promiscuous T cell recognition: association of mult 1997 Feb The association of individual autoimmune diseases with multiple HLA molecules has remained an enigma. That T cells can recognize the same peptide presented by several different HLA-DR alleles (i.e., promiscuous recognition) has been well documented. To explain this, we propose the "DR restrictive supertype pattern (DR RSP)" hypothesis. We focus on the known amino acid polymorphisms at positions beta 70, beta 71, and beta 74 located within pocket 4 of the DR molecule and their potential influence on promiscuous T cell recognition. We have shown that HLA-DR alleles may be grouped, on the basis of their polymorphisms at these positions, into at least 6 sets of DR alleles, 4 of which share, respectively, one of the RSP: A (Q/RR/KA), D (DE/R[K]A/L), E (Q/RRE), or R (QKR/Q) and 2 of which share the restrictive patterns Q (DRQ) or a (QAA). Most of the RSP have been shown to be associated with promiscuous T cell recognition of antigenic peptides. We also provide a rationale on how different DR alleles, exhibiting a particular RSP, might be capable of binding an antigenic peptide and presenting it, in a promiscuous fashion, to peptide-specific T cells. By identifying these RSP represented by DR alleles that have been clinically associated with certain autoimmune disease, we also extend the DR RSP hypothesis to account for the association of certain autoimmune diseases with multiple HLA-DR alleles.
9336418 Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associate 1997 Oct OBJECTIVE: To describe the clinical, laboratory, radiologic, and histopathologic features of methotrexate (MTX)-induced lung injury in a combined cohort of selected patients with rheumatoid arthritis (RA) and all cases reported in the English-language literature. METHODS: Retrospective combined cohort review and abstraction from the medical literature. Case reports were obtained from 6 centers that had 4 or more cases of potential MTX lung injury per site. RA patients who were seen between 1981 and 1993 and who satisfied predetermined criteria for the presence of MTX lung injury were identified. RESULTS: Twenty-seven patients satisfied the criteria for definite MTX lung injury, and 2 for probable MTX lung injury. Predominant clinical features of MTX lung injury included shortness of breath in 27 patients (93.1%), which was present for 23.5 +/- 22.3 days (mean +/- SD), cough in 24 (82.8%), present for 26.9 +/- 28.5 days, and fever in 20 (69.0%), present for 10.4 +/- 12.8 days. Five patients (17.2%) died, compared with 12 of 68 (17.6%) reported in the medical literature. Four of the 6 patients who were re-treated with MTX after an initial pulmonary event developed recurrent lung toxicity, resulting in 2 deaths, compared with a recurrence rate of 3 of 6 in the literature. CONCLUSION: MTX lung injury is most often a subacute process, in which symptoms are commonly present for several weeks before diagnosis. Approximately 50% of the cases are diagnosed within 32 weeks from initiation of MTX treatment. A patient who recovers from MTX lung injury should not be re-treated. Earlier recognition and drug withdrawal may avoid the serious and sometimes fatal outcome that has been observed in this and other studies.
10426274 An HLA-DRB1*0402 derived peptide (HV3 65-79) prevents collagen-induced arthritis in HLA-DQ 1999 Jul On the basis of our studies with HLA class II transgenic mice, we had proposed that complementation of HLA-DQ and HLA-DR alleles may determine both disease susceptibility and severity in rheumatoid arthritis (RA). According to our model, certain HLA-DQ alleles, such as HLA-DQ8, predispose individuals to RA, while a self-peptide derived from the third hypervariable region (HV3 65-79) of HLA-DR alleles, such as DRB 1*0402, can protect from disease if presented by the DQ molecule. To test this hypothesis, we examined the immunomodulatory effects of the DRB1*0402 derived peptide (HV3 65-79) on collagen-induced arthritis (CIA) in HLA-DQ8 mice. Co-immunization of the DRB 1*0402 peptide significantly reduced the severity of arthritis (mean score = 1.5+/-0.6 vs 5.2+/-1.4 in controls), whereas multiple doses of the peptide reduced the incidence of disease (3.5% vs 35-60% in controls). Subsequent analysis revealed that the DRB1*0402 peptide mediated protection may be due to the generation of a subset of regulatory cells, which down-regulate collagen-specific pro-inflammatory responses. These results provide additional insights towards understanding the role of MHC class II molecules in RA predisposition.
10655922 Neither nociceptin nor its receptor are present in human synovial fluid or tissue. 1999 Sep Our aim was to identify the nociceptin receptor and its endogenous ligand, nociceptin, in human peripheral tissue. Synovial tissue was obtained from 11 patients (ASA I-III, 66-84 yr) undergoing elective total knee replacement. Synovial fluid was obtained from another 10 patients (ASA I-III, 57-81 yr). Fluid was mixed with trifluoroacetic acid and the tissue with isopentone before freezing at -70 degrees C. Nociceptin receptor identification was performed using a [3H]nociceptin binding assay and nociceptin detection by radioimmunoassay. There was no specific [3H]nociceptin binding to knee synovial tissue and radioimmunoassay did not detect nociceptin. Neither the nociceptin receptor nor nociceptin was found in human synovial tissue or fluid.
10468412 T cells: pathogenic cells and therapeutic targets in rheumatoid arthritis. 1999 Aug OBJECTIVES: To provide: 1) a brief review of current thought on the role of T cells in the pathogenesis of rheumatoid arthritis (RA); and 2) To provide an overview of RA therapies directed against T cells. METHODS: The following papers in relevant American and European medical journals were reviewed. Those related to: the role of T cells in the pathogenesis of RA; to biological therapy directed against cell surface markers specific to T cell populations implicated in RA; and to treatment of RA with cyclosporin A and leflunomide, pharmacological agents known to interfere with the T cell response to antigens. RESULTS: Although a variety of cell types are now recognized as contributors to the progressive joint destruction that is a hallmark of RA, T cell activation is still thought to be a central event in the initiation and progression of this disease. As a result, various therapeutic options directed against T cells have been developed. These include biological agents directed against specific populations of activated T cells and pharmacological agents that have specific T cell-modulatory actions. CONCLUSIONS: Use of T cell-directed biological therapies for RA has been disappointing, as a result of both lack of efficacy and serious toxicity. Treatment of RA with pharmacological agents that interfere with antigen-driven T cell proliferation has been more successful.
11548909 A clinical and economic review of disease-modifying antirheumatic drugs. 2001 Rheumatoid arthritis is one of the most common chronic systemic inflammatory diseases, affecting approximately 1% of the adult population. Disease-modifying antirheumatic drugs (DMARDs) have been the mainstay of treatment for rheumatoid arthritis when combined with physical therapy and aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory drugs. Recently, a number of new biological therapies have been introduced for the treatment of this condition and will have a major impact on the future management of this disabling disease. In this review, we summarise data on the efficacy and tolerability of the currently available DMARDs, including gold compounds, antimalarials, penicillamine, cytotoxic drugs (azathioprine and cyclophosphamide), sulfasalazine, methotrexate, leflunomide, cyclosporin, anti-tumour necrosis factor agents, combination therapy and apheresis. A literature review and quality assessment of economic evaluations of DMARDs is presented, illustrating that there has been a paucity of economic evaluations on these agents and showing the variable quality of those studies that are available. The manuscript also addresses the pharmacoeconomic implications of the new agents for rheumatoid arthritis; the need for formal long term economic evaluations in order to determine the cost effectiveness of these costly, but highly effective, new treatments is emphasised.
9440142 Anti-Ro (SSA) antibodies in rheumatoid arthritis patients with gold-induced side effects. 1997 The purpose of our study was to investigate the significance of the presence of anti-Ro antibodies found by us in an earlier study of rheumatoid arthritis (RA) patients with gold-induced side effects. Sera of 29 anti-Ro (SSA) positive RA patients who had gold-induced side effects were studied. All sera were examined by Western blot using recombinant antigens, encoding the Ro 60 kD and the La proteins. HLA typing was done in all patients. Thirteen patients reacted only with the Ro 52 kD antigen and all had severe skin eruptions caused by gold therapy. Another ten patients who reacted only with the Ro 60 kD antigen had other side effects to gold (six had proteinuria and four leucopenia). Six patients who reacted to all three antigens (Ro 52 kD, Ro 60 kD and La) had secondary Sjögren's syndrome. No significant statistical differences were noted in the incidence of HLA-DR3 between the subgroups of patients. Our data indicated that antibodies to the Ro 52 kD antigen are associated with skin eruptions in RA patients treated with gold.
11203736 Plasma and serum serotonin levels and their relationship to orofacial pain and anxiety in 2000 Winter AIMS: Serum serotonin levels (S-5-HT) have been reported to be reduced in patients with fibromyalgia and to show a negative correlation with pain. We hypothesized that one mechanism behind this could be that platelets are activated to release 5-HT into the plasma compartment (P-5-HT), which then binds to nociceptors. The aims of this study were therefore to investigate the relation between P-5-HT and S-5-HT and their relationship versus orofacial pain and anxiety in fibromyalgia. METHODS: Twelve patients with fibromyalgia, 12 patients with rheumatoid arthritis, and 12 healthy individuals participated in the study. Pain measures used were pain intensity assessed with a visual analog scale, pain drawings, and influence of pain on daily living activities (ADL). The Spielberger State and Trait Anxiety Inventory (STAI) scale was used for self-rating of anxiety levels. The participants were examined clinically, and the pressure pain threshold (PPT) over the masseter muscle was assessed. Finally, venous blood was collected for analysis of P-5-HT and S-5-HT. RESULTS: The ratio between P-5-HT and S-5-HT was calculated to determine the relative plasma fraction of serotonin (RPS). Patients with fibromyalgia showed significantly lower S-5-HT than did patients with rheumatoid arthritis. They also showed significantly higher STAI scores and tender point index of orofacial muscles and significantly lower PPT than the healthy individuals. High RPS was associated with high ADL and STAI scores. CONCLUSION: This study indicates that a high level of plasma serotonin in relation to serum level is associated with pain discomfort and increased anxiety in fibromyalgia.
9183027 Reported symptoms from the masticatory system and general well-being in rheumatoid arthrit 1997 May Eighty-one patients with rheumatoid arthritis (RA) and 41 patients with temporomandibular disorders (TMD) were evaluated with questionnaires regarding subjective symptoms from the masticatory system. The general well-being was assessed using the Mood Adjective Check List (MACL) and the Body Symptom Scale (BSS). Patients with rheumatoid arthritis in general had less symptoms from the masticatory system than TMD patients. The RA patients reported that their symptoms were related to acute phases of the general disease, while the TMD patients reported that mental stress, anxiety, bruxism and chewing aggravated their symptoms. The RA patients had more general physical discomfort than TMD patients according to the BSS. The RA patients rated their mental well-being (MACL) close to normal, except that they were less active than TMD patients. The TMD patients, on the other hand, showed higher values for mental tension. In conclusion, many patients with RA will develop TMD symptoms but there is a great variation in time relationship between the onset of RA and involvement of the masticatory system.
11409111 Serum cytokines in different histological variants of rheumatoid arthritis. 2001 Jun OBJECTIVE: Rheumatoid arthritis (RA) is characterized by an invasive and tissue destructive infiltrate of lymphocytes, macrophages, and synoviocytes formed in the joints. Its etiopathogenesis and the role of the particular morphological components of synovitis remain unclear. There is evidence that its histological heterogeneity is correlated with synovium cytokine transcription. We investigated whether the serum cytokine profile is associated with the morphological appearance of the disease. METHODS: Tissue and serum samples were collected from 25 patients with clinically active RA and 25 with osteoarthritis (OA) as a control group. After histological analysis RA synovial biopsies were divided into 2 distinct types; 16 samples were characterized by diffuse lymphocyte infiltrates with no additional microanatomical organization. Lymphocytic aggregates with germinal center-like structures were found in 9 specimens. Serum concentrations of interferon-gamma (IFN-gamma), interleukin 12 (IL-12, p70 heterodimer), tumor necrosis factor-alpha (TNF-alpha), and IL-15 were measured by ELISA. RESULTS: Low concentrations of IFN-gamma (p < 0.01) and IL-12 (NS) were found in RA patients' serum compared with OA controls. RA patients with follicular synovitis had lower serum concentration of IFN-gamma (p < 0.05) and IL-12 (p < 0.05) than patients with diffuse infiltrates. High concentration of TNF-alpha and IL-15 characterized RA patient serum in comparison with controls (respectively, p < 0.001 and p < 0.01). In the serum of RA patients with follicular synovitis TNF-alpha was a dominant cytokine (p < 0.01) compared to patients with diffuse disease. At TNF-alpha level > or = 44 pg/ml, 5 (56%) of 9 patients with follicular RA had such elevated values vs one of 16 diffuse patients (< 10%; p < 0.02). Only serum concentrations of TNF-alpha could effectively differentiate between patients with OA and subgroups of RA. Analysis of clinical data suggested that activity of rheumatoid disease in patients with follicular synovitis was more severe than in those with diffuse infiltrates. CONCLUSION: The association between distinct histological appearance of rheumatoid synovitis and serum cytokine profile and diverse clinical activity of disease seems to confirm its heterogeneity.
9778228 Reduced thiopurine methyltransferase activity and development of side effects of azathiopr 1998 Oct OBJECTIVE: To investigate thiopurine enzyme activities for their possible value in predicting the development of azathioprine (AZA)-related toxicity in patients with rheumatoid arthritis (RA). METHODS: Patients with longstanding RA (n = 33) were enrolled in a study of treatment with AZA. Before the initiation of AZA treatment and at months 1 and 6 of treatment, we measured activities of the purine key enzymes hypoxanthine guanine phosphoribosyltransferase, 5'-nucleotidase, purine nucleoside phosphorylase, and thiopurine methyltransferase (TPMT). Controls included patients with early RA (n = 24) and healthy volunteers (n = 42). RESULTS: Fourteen of the 33 patients rapidly developed severe side effects, most frequently gastrointestinal (GI) intolerance. Compared with the other groups, the group with adverse effects had significantly lower TPMT activities (P = 0.004). Seven of 8 patients with reduced ("intermediate") baseline TPMT levels developed toxicity, resulting in a significant relationship (P = 0.005) between toxicity and "intermediate" TPMT activity. Compared with "high" activity, baseline intermediate TPMT activity gave a relative risk of 3.1 (95% confidence interval 1.6-6.2) for the development of severe toxicity with AZA treatment. CONCLUSION: In RA patients, inherited intermediate TPMT activity seems predictive for the development of severe side effects of AZA. Clinicians should consider measuring TPMT prior to treatment initiation to improve the safety of AZA use. We hypothesize that GI intolerance may also be related to a thiopurine metabolic imbalance.
11579716 Homocysteine and antiphospholipid antibodies in rheumatoid arthritis patients: relationshi 2001 Sep OBJECTIVE: To investigate the possible relationships between plasma homocysteine levels and thrombotic events in a select population of rheumatoid arthritis (RA) patients with or without antiphospholipid (aPL) antibody positivity. METHODS: 168 female RA patients attending the Extra-articular Involvement RA Clinic of University of Genova and 72 female subjects matched for age and vascular diseases as controls were included in the study. 30 of the RA patients showed aPL antibody positivity and 138 aPL antibody negativity on the basis of the concomitant presence or absence of high concentrations of anticardiolipin (aCL) antibodies or the presence of lupus anticoagulant (LA). All subjects were evaluated for plasma homocysteine concentrations and for the occurrence of thrombotic events. RESULTS: Twenty-five RA patients and 5 controls reported a history of thrombotic events. Eleven and 5 of RA patients were found to have been previously affected by venous or arterial thrombosis, respectively. Plasma levels of homocysteine in aPL antibody positive patients with thrombosis were found to be significantly higher than in aPL antibody positive RA patients without thrombosis (p < 0.001). When RA patients with thromboses were analyzed, a significant increase of plasma homocysteine levels was found in aPL antibody-positive RA patients versus aPL antibody-negative RA patients (p < 0.04) and versus related controls (p < 0.003). CONCLUSIONS: The association observed between aPL antibody positivity and high levels of plasma homocysteine in RA patients may represent a possible risk factor for thrombotic events. Therefore, it is suggested that hyperhomocysteinemia might be involved in the vascular-related mortality observed in RA patients with a history of thrombosis.
9117176 N-acetyl-beta-D-glucosaminidase urinary excretion as an early indicator of kidney dysfunct 1997 Jan The N-acetyl-beta-D-glucosaminidase (NAG) activities and albumin levels in the urine of 32 patients with active rheumatoid arthritis treated with low-dose pulse methotrexate (MTX) have been investigated. An increase in NAG urinary excretion was more frequent than the incidence of micro- or macroalbuminuria on entry, and during treatment with MTX. There was also a significant decrease in NAG levels observed at week 24. Parameters such as patient's age, time from onset, previous and current treatment did not allow us to predict the degree of NAG enzymuria. We conclude that MTX does not cause marked damage to renal proximal tubules; on the contrary, the observed significant decrease of urinary NAG on week 24 could be interpreted as a beneficial effect of MTX on kidney function. Early detection of high NAG enzymuria and elevated albumin levels in urine before the initiation of MTX therapy could be helpful in predicting possible MTX toxicity probably related to impaired renal clearance of MTX. Patients withdrawn from the study for non-renal-related adverse events also had an unusually large increase in urine NAG activity and urine albumin levels.
10225403 Polyarticular septic arthritis caused by non-encapsulated haemophilus influenzae biotype I 1998 Haemophilus influenzae causes less than 1% of all septic arthritis cases in adults. Most often serotype b is responsible. Here we describe a rare case of non-encapsulated H. influenzae-induced polyarticular septic arthritis in a rheumatic patient with no other infectious focus.
9255115 Measurement of the quality of life in rheumatic disorders using the EuroQol. 1997 Jul The EuroQol is a validated quality of life (QOL) scale that has been used in population and clinical studies, and has been reported in patients with rheumatoid arthritis (RA). It is short, simple to complete, and might be suitable for surveys of rheumatic disease patients. The properties of this instrument were investigated in a postal survey of 1372 rheumatic disease patients, including 537 with RA, 319 with osteoarthritis (OA) and 516 with fibromyalgia. In addition, simultaneous measurements of functional disability, pain, psychological status, global severity and demographic characteristics were made. EuroQol scores (0.57) were significantly lower than VAS health state scores (0.67) and arthritis-related global severity scores (0.62). QOL was similar in RA and OA, but lower in fibromyalgia, across all instruments. The distribution of EuroQol scores had many gaps and was not continuous. EuroQol did not reflect VAS QOL scores at EuroQol levels below 0.5, and the mean score difference between the instruments below that level was 0.43. Many patients with low EuroQol scores (including some with health states that were 'worse than death') had high VAS scores. These differences appear to have arisen because disability, pain and depression questions ask about mild or moderate problems, but not both, thereby forcing scale compression in the mid ranges. In addition, the 'severe' value is so extremely abnormal that few patients endorse it. Finally, penalty scores are applied to those with at least one maximally abnormal score. The scoring properties and distributional aspects of the EuroQol indicate substantial problems in its use in rheumatic disease patients.
9389222 Clinical trials in rheumatoid arthritis: methodological suggestions for assessing radiogra 1997 Oct OBJECTIVES: The three x ray assessors of the GRISAR study (blinded to treatment) gave consensual erosion and damage scores to the baseline and 12 month radiographs of 284 rheumatoid arthritis (RA) patients using three different methods: single readings (blinded as to patient and chronological sequence of the x rays), paired readings (blinded as to sequence), and chronologically ordered paired readings. The aim was to evaluate which of these reading procedures is the most appropriate for clinical trials. METHODS: The progression of the scores obtained using each procedure was compared by means of descriptive statistics, principal components analysis, and intra-patient correlation coefficients of pairs of methods. Bootstrap estimates of the variance of the difference in the means of two equally sized random samples were calculated to evaluate the power of the statistical analysis performed to assess the possible treatment effect for both paired and chronological reading methods. RESULTS: (a) The standard deviations of the paired and chronological readings were similar, but that of the single readings was higher. (b) The knowledge that two x rays were of the same patient accounted for a sizeable proportion of the between method variability. (c) Agreement was satisfactory between the paired and chronological methods for both scores but, between them and the single readings, it was modest for erosions and poor for damage. (d) The bootstrap estimate of the variance of the difference was smaller for the paired than the chronological method, possibly giving it greater power to test treatment effect. CONCLUSIONS: These results suggested that paired readings were the most suitable for evaluating the progression of joint damage in the GRISAR study.
9676385 Sialic acid, transketolase and Na+, K+, ATPase in patients with rheumatoid arthritis. 1998 May We studied transketolase activity of red blood cell hemolysates, and Na+, K+, ATPase activity and sialic acid concentration in red blood cell membranes from 52 patients with rheumatoid arthritis and 24 control subjects. Decreased red blood cell membrane Na+, K+, ATPase activity and sialic acid concentration and decreased transketolase in red blood cell hemolysates were observed in rheumatoid arthritis patients compared with control subjects (p < 0.001). Erythrocyte sedimentation rate and C-reactive protein values were increased in rheumatoid arthritis patients compared with control subjects (p < 0.0001). Significant correlations between sialic acid and Na+, K+, ATPase (r = 0.65, p < 0.001) and between sialic acid and transketolase (r = 0.58, p < 0.001) were observed. Erythrocyte sedimentation rate and C-reactive protein levels did not correlate with Na+, K+, ATPase activity or with sialic acid or transketolase in rheumatoid arthritis patients. These data show that decreases in Na+, K+, ATPase, and transketolase activities and sialic acid concentration are present in rheumatoid arthritis patients, and that the decrease in Na+, K+, ATPase and transketolase activities in rheumatoid arthritis might be due to decreased sialic acid.