Browse

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

ID PMID Title PublicationDate abstract
12110128 VEGF and imaging of vessels in rheumatoid arthritis. 2002 Angiogenesis is a prominent feature of rheumatoid synovitis. Formation of new blood vessels permits a supply of nutrients and oxygen to the augmented inflammatory cell mass and so contributes to perpetuation of joint disease. Vascular endothelial growth factor (VEGF) is a potent endothelial cell-specific growth factor that is upregulated by proinflammatory cytokines and by hypoxia. Serum VEGF concentrations are elevated in rheumatoid arthritis (RA) and correlate with disease activity. Furthermore, serum VEGF measured at first presentation in RA is highly significantly correlated with radiographic progression of disease over the subsequent year. Power Doppler ultrasonography is a sensitive method for demonstrating the presence of blood flow in small vessels and there is a very close relation between the presence or absence of vascular flow signal on power Doppler imaging and the rate of early synovial enhancement on dynamic gadolinium-enhanced magnetic resonance imaging (MRI) of joints with RA. Images obtained by both dynamic enhanced MRI and power Doppler ultrasonography correlate with vascularity of synovial tissue as assessed histologically. In early RA, there is a striking association between joint erosions assessed on high-resolution ultrasonography and vascular signal in power Doppler mode. Collectively, these findings implicate vascular pannus in the erosive phase of disease and strongly suggest that proangiogenic molecules such as VEGF are targets for novel therapies in RA. Animal model data supports this concept. It seems likely that serological and imaging measures of vascularity in RA will become useful tools in the assessment of disease activity and response to therapy.
12463657 Lateral femoral sliding osteotomy lateral release in total knee arthroplasty for a fixed v 2002 Nov We treated 13 patients who had a fixed valgus deformity of the knee with a semiconstrained total knee arthroplasty combined with advancement of the lateral collateral ligament by means of a lateral femoral condylar sliding osteotomy. At follow-up of between one and 6.5 years all patients were assessed using the Knee Society score. The mean knee score improved from 32 to 88 and the functional score from 45 to 73. The mean tibiofemoral angle was corrected from 191 degrees to 180 degrees. There was no postoperative tibiofemoral or patellar instability and, in most knees, distal transposition of the lateral femoral condyle achieved satisfactory stable alignment.
14722200 Acquired resistance of human T cells to sulfasalazine: stability of the resistant phenotyp 2004 Feb BACKGROUND: A recent study from our laboratory showed that induction of the multidrug resistance related drug efflux pump ABCG2 contributed to acquired resistance of human T cells to the disease modifying antirheumatic drug (DMARD) sulfasalazine (SSZ). OBJECTIVES: To investigate the duration of SSZ resistance and ABCG2 expression after withdrawal of SSZ and rechallenging with SSZ, and to assess the impact of SSZ resistance on responsiveness to other DMARDs. METHODS: Human CEM cells (T cell origin) with acquired resistance to SSZ (CEM/SSZ) were characterised for (a) SSZ sensitivity and ABCG2 expression during withdrawal and rechallenge of SSZ, and (b) antiproliferative efficacy of other DMARDs. RESULTS: ABCG2 protein expression was stable for at least 4 weeks when CEM/SSZ cells were grown in the absence of SSZ, but gradually declined, along with SSZ resistance levels, to non-detectable levels after withdrawal of SSZ for 6 months. Rechallenging with SSZ led to a rapid (<2.5 weeks) resumption of SSZ resistance and ABCG2 expression as in the original CEM/SSZ cells. CEM/SSZ cells displayed diminished sensitivity to the DMARDs leflunomide (5.1-fold) and methotrexate (1.8-fold), were moderately more sensitive (1.6-2.0 fold) to cyclosporin A and chloroquine, and markedly more sensitive (13-fold) to the glucocorticoid dexamethasone as compared with parental CEM cells. CONCLUSION: The drug efflux pump ABCG2 has a major role in conferring resistance to SSZ. The collateral sensitivity of SSZ resistant cells for some other (non-related) DMARDs may provide a further rationale for sequential mono- or combination therapies with distinct DMARDs upon decreased efficacy of SSZ.
15642152 Interleukin-18: a therapeutic target in rheumatoid arthritis? 2005 Interleukin 18 (IL-18), a member of the IL-1 superfamily of cytokines has been demonstrated to be an important mediator of both innate and adaptive immune responses. Several reports have implicated its role in the pathogenesis of rheumatoid arthritis (RA). Although biologic therapy is firmly established in the treatment of a number of inflammatory diseases including RA, partial and non-responder patients constitute residual unmet clinical need. The aim of this article is to briefly review the biology of, and experimental approaches to IL-18 neutralisation, together with speculation as to the relative merits of IL-18 as an alternative to existing targets.
15681763 Constraints on the efficacy of mucosal tolerance in treatment of human and animal arthriti 2004 Dec Mucosal administration of an autoantigen has been shown to be a powerful way of inducing tolerance in both animal and human arthritis clinical trials. Bovine or chicken type II collagen has been administered orally to rheumatoid arthritis patients, resulting in some, although in many cases rather limited, clinical improvement. Animal studies have revealed that the mechanisms that underlie induction of mucosal tolerance include clonal deletion, suppression of the proinflammatory Th1 cells, and the induction of regulatory T cells. These cells, defined as a persistently CD25-expressing subset of CD4(+) cells, are frequently anergic, may produce anti-inflammatory cytokines such as IL-10 and TGF-beta, and are likely to be agents of bystander suppression. A key feature that may affect the induction of these cells and other suppressive mechanisms is the dose of antigen administered. The results from human clinical trials suggest a daily dose of significantly less than 1 mg is optimal. Similarly data from collagen-induced arthritis studies reveal an optimal dose above and below which there is little or no immune suppression. Indeed, the incorrect dose can prime the immune response and aggravate disease. The timing and frequency of administration is also vital to the level of immune tolerance induced and the control of the pathological process. This and other findings derived from animal studies are discussed here in relation to the results from human clinical trials.
11899752 Treating rheumatoid arthritis with new disease modifying drugs. 2002 Rheumatoid arthritis (RA) is a serious illness that can only be controlled by the appropriate use of disease modifying anti-rheumatic drugs (DMARDs). In spite of the successful use of such substances, and of methotrexate in particular, a large number of patients still experience disease progression. Leflunomide and the two anti-TNF agents, infliximab and etanercept, were therefore warmly greeted as very welcome additions to the rheumatologist's armamentarium. These successful newcomers, their strengths and problems are the focus of the present review.
14969053 Number of active joints, not diagnosis, is the primary determinant of function and perform 2003 Sep OBJECTIVE: A substudy within a larger study of patients with inflammatory arthritis of less than one year, to analyze baseline measures or joint counts, laboratory values, patient questionnaires and ARA diagnostic criteria for rheumatoid arthritis, as predictors of one year performance and functional status. METHODS: 229 patients with synovitis of less than one year were enrolled and evaluated at baseline and one year. Measures included the number of swollen or tender joints [active joint counts]; biological indices of inflammation [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)]; and patient questionnaire measures of pain [Wisconsin Brief Pain Inventory], fatigue [multi-dimensional assessment of fatigue], depression [Center for Epidemiologic Studies--Depression Scale], sleep [Sleep Quality Index], performance [Human Activity Profile], and function [Sickness Impact Profile ambulation subscale and Health Assessment Questionnaire]. Correlations between these measures were evaluated using the Spearman rank order correlation. Patients were classified according to whether they met ARA criteria for RA, had high (> 7) or low (< or = 7) numbers of affected joints; and high, intermediate, or low levels of performance; and were compared using the Kruskal-Wallis test. RESULTS: At baseline, an active joint count of > 7 versus < or = 7 was associated significantly with higher age, rheumatoid factor positivity, a diagnosis of rheumatoid arthritis versus spondyloarthropathy or undifferentiated arthritis, and receiving a disease modifying antirheumatic drug (DMARD), but not with sex, race, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), or receiving prednisone. Furthermore, high baseline active joint counts were associated significantly with patient questionnaire scores for maximum activity, fatigue and depression, but differences were not significant for sleep, ambulation and pain scores. A comparison of patients who met or did not meet criteria for RA indicated significant differences only according to the fatigue scores, but none of the other questionnaire measures. Correlations of baseline measures with one-year performance were highest for the baseline active joint count compared to laboratory and questionnaire variables. The maximum activity score at one year was predicted significantly by the baseline maximum activity score, active joint count, and age, but not by laboratory tests or whether the patient met criteria for RA. CONCLUSION: The active joint count predicts subsequent performance and function for patients with recent onset, inflammatory synovitis more effectively than whether patients met ARA criteria for RA.
15374610 Inhibitory effects of the Gentiana macrophylla (Gentianaceae) extract on rheumatoid arthri 2004 Nov Acute treatment of rheumatoid rats with an extract from the roots of Gentiana macrophylla (Gentianaceae) produced a significant inhibitory effect on rheumatoid arthritis (RA). When rats were administered the Gentiana macrophylla extract orally at a daily dose of 100 mg/kg body weight, the prostaglandin E(2) (PGE(2)) levels in the inflammatory tissues, sole thickness, and ankle circumferences of feet were significantly decreased. The anti-inflammatory activity observed in Gentiana macrophylla is comparable to that observed in prednisone. These observations suggest that Gentiana macrophylla displays considerable potency in anti-inflammatory action and could be used as an anti-inflammatory agent in the control of inflammation of rheumatoid arthritis.
11994689 [Combination therapy for rheumatoid arthritis]. 2002 Feb What can be expected from combination therapy? What is the goal of combination therapy? What criteria allow drug selection? Is combination therapy regularly used for controlling rheumatoid arthritis? What combination therapies have been assessed with clinical trials? What is the contribution of prolonged combination therapy? Conclusion
12707576 Immunoglobulin for rheumatic diseases in the twenty-first century: take it or leave it? 2003 May There is no simple answer to the question: intravenous immunoglobulin-take it or leave it? A thorough review of the current data on mechanisms of action, efficacy, and safety of intravenous immunoglobulins in rheumatic diseases demonstrates that the answer depends on the disease and the patients involved.
12794787 Bacterial components in the synovial tissue of patients with advanced rheumatoid arthritis 2003 Jun 15 OBJECTIVE: To study the presence of bacterial components in the synovial tissue (ST) of patients with advanced rheumatoid arthritis (RA). METHODS: ST was collected during joint surgery from 41 RA patients. Tissue from 39 patients with osteoarthritis (OA), 4 patients with undifferentiated inflammatory arthritis (UA), and 3 cases of accidental deaths served as controls. The pan-bacterial polymerase chain reaction (PCR) with primers for the 23S ribosomal RNA (rRNA) and 16S rRNA genes was used to detect bacterial DNA. In addition, synovial fluid (SF) samples from patients with chlamydial reactive arthritis (ReA) were also examined by the same method. The positive controls, bacterial DNA or ST spiked with different living bacteria, were analyzed alongside clinical samples. Most of the ST samples were also analyzed by gas chromatography-mass spectrometry (GC-MS) for determining the presence of bacteria-derived muramic acid. Strict precautions were followed in the clinics and the laboratory to prevent contamination. RESULTS: In GC-MS analysis, muramic acid was observed in the ST from 4 of 35 RA patients and from 2 of 14 OA patients, but not in ST from 2 patients with UA and 3 cadavers. Bacterial DNA was not detected by either one of the PCR primers used in ST from 42 patients with RA and 39 patients with OA. However, 5 of 15 SF samples from ReA patients were PCR positive. The sensitivity of GC-MS to detect muramic acid was 2 pg/injected amount (227 pg muramic acid/mg ST), and that of the pan-bacterial PCR was 2-20 bacteria colony forming units/reaction. CONCLUSION: These results indicate that a bacterial component, muramic acid, is detectable by GC-MS in ST from a few patients with advanced RA or OA. However, no bacterial DNA was detectable by PCR.
12106500 B lymphocytopenia in rheumatoid arthritis is associated with the DRB1 shared epitope and i 2002 The influence of HLA DRB1 alleles on B-cell homeostasis was analyzed in 164 patients with rheumatoid arthritis (RA). The percentages of CD19+ B lymphocytes determined in the peripheral circulation of 94 retrospectively recruited RA patients followed a bimodal distribution. Two frequency peaks (B-cell(low) patients and B-cell(high) patients) were separated by the population median of a B-cell frequency of 8.5% of all lymphocytes. Human leucocyte antigen genotyping revealed that the B-cell(low) patients were more frequently positive for the RA-associated HLA DRB1 shared epitope (SE) than were B-cell(high) patients. Accordingly, SE-positive patients had lower CD19 percentages in the rank-sum analysis when compared with SE-negative patients, and were markedly B lymphocytopenic when compared with a healthy control group. To confirm the differential frequencies of CD19+ B cells, absolute numbers in peripheral blood were determined prospectively in a cohort of 70 RA patients with recent onset disease. SE-positive patients were found to have lower absolute numbers of circulating CD19+ B cells. B-cell counts below the mean of the study population were associated with higher acute phase response and with increased levels of rheumatoid factor IgA. No correlation between absolute numbers of circulating B cells and radiographic progression of joint destruction was seen. The influence of immunogenetic parameters on B-cell homeostasis in RA reported here has not been described previously. The clinical relevance of B lymphocytopenia in SE-positive RA will be further investigated in longitudinal studies.
12525391 Effects of treatment with etanercept (Enbrel, TNRF:Fc) on rheumatoid arthritis evaluated b 2003 Feb OBJECTIVE: to estimate and visualise the efficacy of treatment with etanercept (Enbrel) in patients with rheumatoid arthritis (RA) using colour Doppler and spectral Doppler ultrasonography to determine the possible changes in synovial perfusion during a one year observation period. METHODS: Eleven patients from the European multicentre trial of the efficacy and safety of etanercept were included in this study when transferred into the open label, long term safety, and efficacy study. Before a scheduled dosage increase to 50 mg/week they were examined clinically, serologically, and by ultrasonography using the colour Doppler pixels and the spectral Doppler resistance index (RI) as indicators of inflammation. The patients were re-examined at two weeks and at one year follow up RESULTS: The clinical activity decreased significantly from baseline to week 2, but no significant changes were seen from baseline to one year. The number of coloured pixels in each region of interest decreased from baseline to week 2 with a median reduction of 60% (p=0.005). This effect on the perfusion in the synovium could not be found after one year of treatment. During the initial treatment we detected an increase in synovial RI by spectral Doppler. The median increase in peripheral resistance from baseline to week 2 as estimated by the mean RI was 22.6% (p=0.005). The increase in peripheral resistance was maintained to some extent after one year (mean RI increased by 18.8% p=0.074). CONCLUSION: Ultrasonography seems to be a promising tool for the detection of treatment response using spectral Doppler and pixel estimation.
14719219 Inflammatory arthritis secondary to metastatic gastric cancer. 2003 Dec Metastatic spread of malignancy to the joints is rare and only a few cases of solid tumors have been reported. We describe a patient with inflammatory arthritis of the knee and ankle secondary to metastatic gastric adenocarcinoma to the joints and bone diagnosed by synovianalysis. Arthritis secondary to metastatic cancer is a poor prognostic sign. The diagnosis is based on a strong clinical suspicion, magnetic resonance imaging, and joint fluid cytology or synovial biopsy.
15210141 B-Lymphocytes in plaque and adventitia of coronary arteries in two patients with rheumatoi 2004 Jul OBJECTIVES: To describe the subtypes of lymphocytes in coronary arteries of two patients with rheumatoid arthritis (RA) and coronary artery disease (CAD). MATERIALS AND METHODS: The Mayo Clinic database was searched for patients with RA and CAD who underwent an autopsy in 2001. Medical records were reviewed, and coronary arteries were examined microscopically. The percentage of B- and T-lymphocytes was determined using histomorphometry on representative sections stained with CD20 and CD3 antibodies, respectively. RESULTS: Two men were diagnosed with RA at ages 52 and 70 years and died at ages 60 and 82 years. One sustained an acute myocardial infarction 2 years prior to the diagnosis of RA and had stable CAD until an arrhythmic death. The other developed congestive heart failure secondary to ischemic heart disease 5 years after RA was diagnosed. Both patients had severe three-vessel CAD with both stable fibrocalcific plaques and acute lesions. B- and T-lymphocytes were identified in the plaque and adventitia of all coronary arteries. The mean percentage of B-lymphocytes was 37% to 52% in the plaque and 78% to 85% in the adventitia, while that of T-lymphocytes was 38% to 51% and 28%, for plaque and adventitia, respectively. CONCLUSIONS: In typical CAD, lymphocytic infiltrates are almost exclusively T-cells. In contrast, the two patients with RA and CAD showed prominent infiltrates of B-lymphocytes within plaques and adventitia. Thus, the leukocytic response in atherosclerotic plaques may be altered in patients with autoimmune disorders. This warrants further study.
11925907 [Difference in the management of rheumatoid arthritis (RA) by internists and orthopedists: 2002 Feb OBJECTIVE AND METHODS: One of the reasons of the wide variation in the management of RA in Japan might be due to the different behaviors between internists and orthopedists. To investigate this possibility, a survey was done at the 44th annual meeting of Japan Rheumatism Association in 2000. RESULTS: Four hundred and ninety clinicians responded to our survey, including 212 internists and 252 orthopedists, respectively. In the management of RA, there was a wide difference between two groups. In particular, although both agreed that an appropriate communication between internists and orthopedists is necessary, half of the orthopedists answered that they don't refer their patients to internists. There was a wide variation in their ways of evaluations and prescribing behaviors. In particular, the use of DMARDs, both as monotherapy and combination, was significantly different between two groups. CONCLUSIONS: There was a great difference in the management of RA by internists and orthopedists. These results might be associated with the outcome of RA patients in Japan. Dissemination of information concerning the management of RA, such as guidelines, as well as the establishment of a better health care system is necessary.
12510357 [Usefulness of serum matrix metalloproteinase-3(MMP-3) level in the diagnosis of rheumatoi 2002 Dec Matrix metalloproteinase-3 is abundantly expressed in active rheumatoid synovium, and serum level of MMP-3 is a useful marker not only for the diagnosis of rheumatoid arthritis but also for the evaluation of prognosis in the joint destruction. It should be noted, however, that serum MMP-3 may be increased in other inflammatory arthritis, thus its specificity for the diagnosis of early RA may not be high enough. Recent reports indicated that methotrexate or anti-TNF alpha therapy effectively suppressed the serum MMP-3 level during the course of the treatment, whereas corticosteroid didn't. Thus, suppression of serum MMP-3 could explain the discrepancy in the inhibition of bony destruction in RA patients by the therapeutic strategy.
12407135 Linezolid penetration into osteo-articular tissues. 2002 Nov Penetration of linezolid into osteo-articular tissue and fluid was studied in 10 patients undergoing primary total knee replacement. Linezolid 600 mg 12 hourly was given orally over the 48 h before operation and intravenously 1 h before induction of anaesthesia. Mean concentrations of linezolid at 90 min after the final dose, in serum, synovial fluid, synovium, muscle and cancellous bone, assayed by HPLC, were at least twice the MIC(90) for staphylococci and streptococci. The concentrations obtained indicate good penetration of this antibiotic and support its use in the management of multidrug-resistant Gram-positive bone, joint and deep-seated soft-tissue infections.
12610799 Allele and antigen-specific treatment of rheumatoid arthritis: a double blind, placebo con 2003 Mar OBJECTIVE: Human cartilage glycoprotein 39 (HC gp-39) appears to be a relevant autoantigen in patients with rheumatoid arthritis (RA). Administration of major histocompatibility complex (MHC) Class II complexed antigens without requisite costimulatory signals can induce immunologic tolerance. We evaluated the safety, pharmacokinetics, and preliminary efficacy of AG4263 in patients with RA. AG4263 is a soluble complex of native HLA-DR4 (beta*0401) complexed to Org 36601, a 13-mer peptide derived from HC gp-39 (also referred to as CDP263). METHODS: Thirty-one HLA-DRB1*0401 positive patients with persistent RA disease activity despite concurrent methotrexate were randomized to 7 infusions of AG4263 (n = 24) or placebo (n = 7) over 6 weeks. The initial dose of 0.5 micro g/kg was escalated in subsequent cohorts to a maximum of 150 micro g/kg. Safety analyses included recording of adverse events and measurement of CD4/CD8 counts, reactivity to recall antigens, and development of antibodies to HLA-DR4. Efficacy was assessed using the Paulus 20 criteria. RESULTS: Treatment was well tolerated, with injection site reaction the most common adverse event. There was no loss of reactivity to recall antigens, change in cell counts, or antibodies to HLA-DR. The mean half-life of AG4263 was 12.5 h. Some evidence of clinical response was seen; responses were more common among patients receiving the highest doses of AG4263 and among those with baseline T cell reactivity to CDP263. CONCLUSION: AG4263 was safe, well tolerated, and without evidence of generalized immune suppression. Along with the observed trend toward clinical efficacy, the results suggest that this therapeutic approach warrants further investigation in patients with RA.
12810924 Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled s 2003 Dec OBJECTIVE: To determine whether patients with early rheumatoid arthritis (RA) treated with cyclosporin A (CsA) and methotrexate (MTX) in combination for 12 months show a lower rate of radiographic deterioration than those treated with MTX alone. METHODS: In this controlled and randomized single-blind trial, 61 consecutive patients with untreated RA of less than 2 yr duration were treated with either CsA + MTX combination therapy (n = 30) or MTX alone (n = 31). The primary end-point was radiographic progression after 12 months, measured using the damage score (DS) of the Sharp and van der Heijde method. RESULTS: Although there was a significant difference between the mean baseline and 12-month DS in both treatment groups (MTX/CsA, 1.93 +/- 0.90; MTX, 7.47 +/- 2.03), it was significantly less in the combination arm (P = 0.018). Of the 30 evaluable CsA + MTX patients, 16 (53%) were ACR20 responders, 15 (50%) ACR50 and 14 (47%) ACR70; the corresponding figures in the MTX arm were 19 (61%), 13 (44%) and 6 (19%). Toxicity was acceptable in both groups. CONCLUSIONS: In patients with early RA, CsA + MTX combination therapy led to a significantly lower rate of 12-month radiographic progression, was effective on inflammatory articular symptoms, and was well tolerated.