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ID PMID Title PublicationDate abstract
11857065 Rheumatoid arthritis association in Colombian population is restricted to HLA-DRB1*04 QRRA 2002 Feb In most ethnic groups genetic susceptibility to rheumatoid arthritis (RA) is associated with certain HLA-DRB1 alleles encoding a similar sequence motif called the 'shared epitope' (SE) spanning amino acid positions 70 to 74 in the third diversity region of the outermost domain of the HLA-DRB1 molecule. We examined the association of the SE and RA in 83 Colombian women with established RA and 90 healthy controls. The group HLA-DRB1*04 was associated with RA with respect to controls (47% vs 18%, respectively. OR: 4.1, 95%CI: 2.1-8.2, P < 0.001). HLA-DRB1 alleles carrying the SE QRRAA, but not those carrying QKRAA or RRRAA, were associated with disease (OR: 3.7, 95%CI: 1.73-7.83, P = 0.0009). This association was stronger among HLA-DRB1*04 carriers (OR: 23, 95%CI: 1.3-414, P = 0.002). In our population, the SE QRRAA expressed in DRB1*04 alleles appears critical in identifying women with increased susceptibility to RA.
12066969 Transient pulmonary infiltrates possibly induced by quinine sulfate. 2002 Jun Quinine sulfate, which has been available for many years, has not been implicated definitively in the development of pulmonary toxicity. A variety of adverse effects, however, have been reported with quinine administration. A 45-year-old woman with longstanding rheumatoid arthritis experienced wheezing, severe anxiety, breathlessness, cough, orthopnea, mild fever, chills, and pleuritic chest discomfort after taking a single dose of quinine for nocturnal leg cramps. Radiographic imaging demonstrated diffuse, bilateral pulmonary infiltrates suggestive of pulmonary edema. No cause other than acute quinine ingestion could be identified despite thorough cardiac and infectious disease evaluations. Clinicians should be aware of a possible association between quinine sulfate and pulmonary toxicity.
15252212 Antibody response to the human stress protein BiP in rheumatoid arthritis. 2004 Oct OBJECTIVES: The human stress protein BiP (immunoglobulin binding protein) has been implicated in the pathogenesis of rheumatoid arthritis (RA) since BiP was found to stimulate synovial T-cell proliferation and anti-BiP antibodies are present in the serum of RA patients. The aim of this study was the development of a rapid and reproducible enzyme-linked immunosorbent assay (ELISA) to determine the specificity and sensitivity of anti-BiP antibodies in RA. METHODS: An ELISA was developed that detected antibodies to BiP. The prevalence of anti-BiP antibodies was determined in sera from patients with early and established RA, sera antedating the onset of RA and sera from patients with other inflammatory and autoimmune diseases and healthy controls. RESULTS: We have confirmed the increased prevalence of antibodies to BiP in the sera of a large cohort of patients with established RA (specificity 71% and sensitivity 73%) and early RA (specificity 65% and sensitivity 66%). In pre-disease sera, median 2.5 yr (interquartile range 1.1-4.7) before symptoms of joint disease, the sensitivity for anti-BiP antibodies was 45% and the specificity was 65% for the development of RA. CONCLUSION: Antibodies to BiP are found in the sera of patients with RA and in sera antedating the onset of RA.
12871269 Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: n 2003 Jul In contrast to VEGF and its receptor VEGFR-2, PlGF and its receptor VEGFR-1 have been largely neglected and therefore their potential for therapy has not been previously explored. In this review, we describe the molecular properties of PlGF and VEGFR-1 and how this translates into an important role for PlGF in the angiogenic switch in pathological angiogenesis, by interacting with VEGFR-1 and synergizing with VEGF. PlGF was effective in the growth of new and stable vessels in cardiac and limb ischemia, through its action on different cell types (i.e. endothelial, smooth muscle and inflammatory cells and their precursors) that play a cardinal role in blood vessel formation. Accordingly, blocking its receptor VEGFR-1 with monoclonal antibodies (anti-VEGFR-1 mAb), expressed on al these cell types, successfully attenuated blood vessel formation during cancer, ischemic retinopathy and rheumatoid arthritis. In addition, while blocking this receptor was effective in reducing inflammatory disorders like atherosclerosis and rheumatoid arthritis, blocking the anti-angiogenic receptor VEGFR-2 was without effect. This indicates that in the latter diseases the beneficial effects of anti-VEGFR1 mAb were mainly due to its effect on inflammatory cells. Importantly, VEGFR-1 was also present on hematopoietic stem/progenitor cells, the precursors of inflammatory cells. Thus, these preclinical studies show proof-of-principle that PlGF and VEGFR-1 are promising therapeutic targets to treat angiogenesis and inflammation related disorders. Clinical trials will reveal whether this is also true for patients.
15088287 Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration 2004 Apr OBJECTIVE: To determine the bioavailability of higher oral doses of methotrexate (MTX) in adult patients with rheumatoid arthritis (RA). METHODS: A pharmacokinetic analysis was performed in 15 patients with RA taking a stable dose of MTX (> or = 25 mg weekly). Separated by 2 weeks, a pharmacokinetic analysis was performed in each patient after oral and subcutaneous administration of the same dose of MTX. MTX serum concentrations were measured by a fluorescence polarization immunoassay. Pharmacokinetic analysis was performed with an iterative 2-stage Bayesian population procedure, obtaining population and individual pharmacokinetic parameters. RESULTS: The median MTX dose was 30 mg weekly (range 25-40 mg). A 2-compartment model best described the serum MTX concentration versus time curves. The mean bioavailability after oral MTX was 0.64 (range 0.21-0.96) compared to subcutaneous administration. There was a statistically significant difference in the bioavailability of the 2 administration regimens. CONCLUSION: Bioavailability of a higher oral dose of MTX in adult patients with RA is highly variable, and on average two-thirds that of the subcutaneous administration. To improve efficacy of MTX at dosages of 25 mg weekly or more, a change to parenteral administration should be considered.
12509632 Non-inherited maternal HLA alleles are associated with rheumatoid arthritis. 2003 Jan BACKGROUND: Rheumatoid arthritis (RA) is strongly associated with a series of HLA-DRB1 alleles that encode a conserved sequence of amino acids ((70)Q/R K/R R A A(74)) in the DRbeta1 chain, known as the shared epitope (SE). However 30% of patients are negative for DRB1*04 and 15% are SE-negative. Exposure to these alleles as non-inherited maternal antigens (NIMA) might explain this discrepancy. We undertook a family study to investigate the role of NIMA in RA. METHODS: One hundred families, including the RA proband and both parents, were recruited. HLA-DRB1 genotyping was performed using an allele-specific polymerase chain reaction by standard methods. The frequencies of NIMA and non-inherited paternal antigens (NIPA) were compared using contingency tables and a two-tailed P test. We then reviewed four previously published studies of NIMA in RA and conducted an analysis of the combined data RESULTS: We identified 36 families in which the proband was DRB1*04-negative and 13 in which the proband lacked the SE. There was an excess of DRB1*04 and SE NIMA (P=0.05) compared with NIPA. Combined analysis with previous studies showed that 53/231 mothers (23%) versus 25/205 fathers (12%) had a non-inherited DRB1*04 (P=0.003) and 30/99 mothers versus 18/101 fathers had a non-inherited SE allele (P=0.03). CONCLUSION: A role for HLA NIMA in RA is suggested by these results.
12110137 Cytokine regulation in RA synovial tissue: role of T cell/macrophage contact-dependent int 2002 Several groups have documented the expression of cytokines in rheumatoid arthritis synovial tissue over the past 15 years or so. These studies have indicated that most cytokines examined are expressed at the mRNA levels at least, and many other cytokines are found in abundance as proteins. Our attention has recently focused on the mechanisms that induce and regulate tumour necrosis factor and IL-10. Other workers and ourselves have found that cell-cell contact is an important signal for the induction of cytokines, and our work has demonstrated that tumour necrosis factor and IL-10 production in rheumatoid arthritis synovial joint cells cultures is dependent on T cell/macrophage interaction. In this chapter, we review recent advances in this area and also highlight areas where new therapeutic intervention opportunities arise.
12528106 Screening for atherosclerosis in patients with rheumatoid arthritis: comparison of two in 2003 Jan OBJECTIVE: Inflammation appears to play a central role in atherosclerosis, and endothelial damage mediated by systemic inflammation may contribute to the increased cardiovascular mortality in rheumatoid arthritis (RA). Brachial artery flow-mediated dilatation (FMD) and pulse wave analysis (PWA) are measures of vascular function. The aim of this study was to determine if FMD and PWA are abnormal in patients with RA. METHODS: Twenty-five RA patients and 25 matched healthy controls were studied. All were free of traditional cardiovascular risk factors. FMD was measured in all subjects. PWA was performed in 18 RA patients and 18 controls, with results expressed as large and small artery compliance (C1 and C2). Modified Sharp scores were calculated in 13 RA patients. RESULTS: Results (mean +/- SD) in RA patients and controls, respectively, were as follows: FMD 107.6 +/- 4.6% versus 108.5 +/- 4.1% (P = 0.49), C1 14.8 +/- 2.8 ml/mm Hg x 10 versus 17.9 +/- 3.1 ml/mm Hg x 10 (P = 0.0033), C2 4.5 +/- 2.3 ml/mm Hg x 100 versus 7.7 +/- 3.7 ml/mm Hg x 100 (P = 0.0039). There was an inverse correlation between C2 and modified Sharp scores in the RA patients (Spearman's rho -0.69, P = 0.0085). CONCLUSION: FMD was normal in these RA patients, whereas arterial compliance was markedly reduced. PWA appears to be a more sensitive measure of vascular dysfunction than FMD in RA and may be the preferred surrogate marker of vascular dysfunction in longitudinal studies of RA patients. The inverse correlation between C2 and the modified Sharp score, a measure that reflects disease activity over time, supports the notion that chronic inflammation plays a role in RA-associated atherosclerosis.
12005365 Effect of heparinoid on the production of tissue inhibitor of metalloproteinases (TIMP)-3 2002 May Heparinoid is one of the major contents of Mobilat widely used as an antirheumatic drug. To clarify the precise mechanisms of the antirheumatic effect of heparinoid, we investigated its effects on the production of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) from rheumatoid synovial fibroblasts stimulated (or not) with interleukin-1 alpha (IL-1alpha) at 100 units mL(-1). The expression of TIMP-3 mRNA was also investigated in a similar manner. The production of both MMPs and TIMPs and the expression of TIMP-3 mRNA were investigated by western-blot analysis and northern-blot hybridization, respectively. Under the stimulation of IL-1alpha, heparinoid increased the production of TIMP-3 in a concentration-dependent manner, but not TIMP-1, TIMP-2, MMP-1 or MMP-3. Heparinoid did not affect the expression of TIMP-3 mRNA that was increased by the stimulation of IL-1alpha. These findings suggest that the anti-rheumatoid effect of heparinoid may be due to increased production of TIMP-3. This increase in TIMP-3 may help redress the imbalance between the amounts of MMPs and TIMPs as observed in the joint tissues of rheumatoid arthritis and osteoarthritis patients.
15224227 [Unusual complication of silicon synovitis in the rheumatoid wrist]. 2004 Jun Silicone synovitis is an important clinical entity recognized in rheumatoid patients after arthroplasties with silicone implants. It is a foreign body reaction to particulate material (silicone elastomer) characterized clinically by the re-occurrence of pain, stiffness and swelling at the site of arthroplasty after initial relief of symptoms. Whereas silicone synovitis is a rare complication in metacarpophalangeal implants, it is an important one in the wrist implant. Long-term follow-up studies have revealed that the rates of fracture and subsidence are high and that the implants deteriorate with time necessitating operative revisions in up to 50% of cases. Indications should therefore be restricted to a painful wrist in the elderly, very low demand patient with insufficient bone stock to permit total wrist arthroplasty with a metal-on-plastic design. Severe preoperative deformity and the need for use of ambulatory aids may further limit the indication. The unusual case of direct perforation of silicone particles from the wrist into the tendon sheath of the M. flexor pollicis longus inducing a tumor-like synovitis and a secondary carpal tunnel syndrome is presented. The importance of silicone synovitis and the indication at present for implantation of a silicone wrist spacer in the rheumatoid patient are discussed.
12535238 Drug-related problems and quality of life in arthritis and low back pain sufferers. 2003 Jan OBJECTIVE: The objective of this study was to determine the relationship between drug-related problems (DRPs) and health-related quality-of-life (HRQoL) in ambulatory, community-dwelling patients with musculoskeletal disorders. METHODS: A 12-month, prospective, observational study was conducted in 12 independent community pharmacies in eastern Iowa. Ambulatory patients with self-reported diagnoses of osteoarthritis, rheumatoid arthritis, or low back pain were invited to participate. During quarterly visits to the pharmacy, patients used touch-screen computers to fill out the Short Form-36 (SF-36) general health survey. Using the results of these point-of-service health status assessments, community pharmacists interviewed patients to assess for DRPs. To examine the influences of different DRP characteristics on HRQoL and controlling for potential confounders, both univariate and multivariate analyses were performed using the change in physical component summary (PCS) score and mental component summary (MCS) score of the SF-36 from baseline to 12 months as the dependent variables. In each regression, the independent variables were those significant variables from the univariate analyses, as well as the types of DRPs and their outcomes. RESULTS: A total of 461 patients were enrolled in the study. Through 12 months, 926 cumulative DRPs were identified. Overall regression models were significant for the PCS and MCS scores, respectively. Two types of DRPs showed significant negative associations with change in PCS: wrong drug and needs additional drug therapy. One type of DRP showed significant negative association with change in MCS: needs additional drug therapy. Resolution or improvement in DRPs showed a significant positive correlation with change in MCS but not PCS. CONCLUSIONS: Two DRPs, needs additional drug therapy and wrong drug, are associated with reduced self-reported physical health in arthritis and low back pain, while the DRP needs additional drug therapy is also associated with reduced self-reported mental health. Resolution of DRPs is associated with improvement in mental health in this cohort.
12420264 Analysis of temporomandibular joint synovial fluid using Fourier transform/infrared spectr 2002 Nov PURPOSE: In recent years infrared spectroscopy has been increasingly used for the analytical determination of biologic fluids and tissues. With the help of this method it was possible to investigate the various types of arthritis affecting the knee joint, among others. The aim of our study was to show that infrared spectroscopy can also be used as a method to analyze the synovial fluid of the temporomandibular joint to differentiate between inflammatory and noninflammatory disorders. MATERIALS AND METHODS: Using Fourier transform/infrared spectroscopy analysis, comparable absorption spectra with characteristic signals in the corresponding range of wavelength were shown and used to prove pathologic alterations in the synovial fluid. Samples of 22 patients with arthritis of the temporomandibular joint and 12 patients with noninflammatory internal derangement were investigated and compared with each other. RESULTS: Our measurements presented a distinct intensity difference between the absorption spectra of patients who had arthritis and those without signs of an inflammatory change but with an internal derangement as control specimens. Due to the small number of undiluted samples it was not possible to follow up with a multivariant analysis, necessary for a differential diagnostic evaluation between the individual types of arthritis. CONCLUSIONS: A certain differentiation between arthritic and noninflamed temporomandibular joints can be noted with infrared spectroscopy of the synovial fluid. This represents a valuable option for minimally invasive diagnostic proof of inflammation in cases of joint disorders.
15390088 Influence of rheumatoid arthritis in the enantioselective disposition of fenoprofen. 2004 Nov To investigate the influence of rheumatoid arthritis on the stereoselective disposition of fenoprofen administered as a racemic mixture, eight patients with rheumatoid arthritis receiving calcium rac-fenoprofen (200 mg/8 h) and 7 healthy volunteers given single oral dose (600 mg) were investigated. Serial blood samples and urine were collected from zero to 24 h after fenoprofen (FEN) administration. The following differences were observed between the (+)-(S) and (-)-(R)-FEN in the patients with rheumatoid arthritis (means 95% CI, Wilcoxon test, P < 0.05): C(max) 14.1 (12.5-15.8) versus 3.6 (2.5-4.7) microg/ml; AUC(ss) (0-8) 80.5 (67.3-93.7) versus 12.1 (8.8-15.4) microg.h/ml; Cl(T)/f 1.3 (1.0-1.5) versus 9.1 (6.5-11.8) l/h; and t(1/2) 3.1 (2.3-3.9) versus 1.2 (0.8-1.6) h. The Cl(T)/f of (-)-(R)-FEN was reduced in patients with rheumatoid arthritis when compared to healthy volunteers: 9.1 (6.5-11.8) versus 17.4 (13.9-20.9) l/h; P < 0.05 Mann-Whitney test. The administration of rac-FEN as a single dose to healthy volunteers or multiple doses to patients with rheumatoid arthritis resulted in lower Cl(T)/f for the (+)-(S)-FEN. The lower Cl(T)/f of (-)-(R)-FEN observed for patients with rheumatoid arthritis is consistent with lower clearance by inversion, although other metabolic pathways, drug interactions, and bioavailability of the individual enantiomers may also contribute to the difference.
12554061 Peripheral-type benzodiazepine receptors in human mononuclear cells of patients affected b 2003 Feb OBJECTIVES: The objective of this study was to evaluate the kinetic parameters at equilibrium of peripheral benzodiazepine receptors (PBR) in human mononuclear cells from patients affected by osteoarthritis (OA), rheumatoid arthritis (RA) and psoriasic arthritis (PA). DESIGN AND METHODS: Mononuclear cells were obtained from 10 patients with OA, 10 patients with RA and 10 patients with PA. Evaluation of kinetic parameters of PBR was performed using [(3)H]PK 11195, a specific radioligand for this receptor, and compared with 10 healthy controls. RESULTS: The results show a statistically significant decrease (37.5%, as an absolute percentage) in the maximal number of binding sites (B(max)) of patients with OA, compared with healthy controls; however, the values of the dissociation constant (K(d)) at equilibrium do not show any statistically significant variations. CONCLUSIONS: These data further confirm the presence of peripheral biochemical alterations in OA. As peripheral benzodiazepine receptors appear to be involved in the immune function, and in the protection of hematopoietic cells against oxygen radical damage, the observed decrease in B(max) might be related to cellular protection.
15115504 Disseminated cutaneous infection with Mycobacterium chelonae in a patient with steroid-dep 2004 May Mycobacterium chelonae is a rapidly growing atypical mycobacterium that is a normal commensal of water and soil. We report a case of a 61-year-old man with seronegative rheumatoid arthritis and fibrosing alveolitis on long-term prednisolone who presented with a number of tender, red, subcutaneous nodules on his upper arms and a pustule on his left cheek. Histopathologic examination revealed dense neutrophilic collections within the deep dermis and subcutaneous fat with abscess formation. Long filamentous organisms were seen within these collections and were subsequently identified by special stains and PCR as Mycobacterium chelonae. Treatment was not possible as the patient developed bacteria bronchopneumonia before identification of the organism and he subsequently died. Post-mortem revealed no extra-cutaneous evidence of mycobacterium infection.
15059275 IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via 2004 Recent studies of the pathogenesis of rheumatoid arthritis (RA) have revealed that both synovial fibroblasts and T cells participate in the perpetuation of joint inflammation as dynamic partners in a mutual activation feedback, via secretion of cytokines and chemokines that stimulate each other. In this study, we investigated the role of IL-17, a major Th1 cytokine produced by activated T cells, in the activation of RA synovial fibroblasts. Transcripts of IL-17R (IL-17 receptor) and IL-17RB (IL-17 receptor B) were present in fibroblast-like synoviocytes (FLS) of RA patients. IL-17R responded with increased expression upon in vitro stimulation with IL-17, while the level of IL-17RB did not change. IL-17 enhanced the production of IL-6 and IL-8 in FLS, as previously shown, but did not affect the synthesis of IL-15. IL-17 appears to be a stronger inducer of IL-6 and IL-8 than IL-15, and even exerted activation comparable to that of IL-1beta in RA FLS. IL-17-mediated induction of IL-6 and IL-8 was transduced via activation of phosphatidylinositol 3-kinase/Akt and NF-kappaB, while CD40 ligation and p38 MAPK (mitogen-activated protein kinase) are not likely to partake in the process. Together these results suggest that IL-17 is capable of more than accessory roles in the activation of RA FLS and provide grounds for targeting IL-17-associated pathways in therapeutic modulation of arthritis inflammation.
15259675 Total modular wrist prosthesis: a new design. 2004 The common modes of failure of total wrist arthroplasty have been fracturing, loosening, pain on pronation and supination, and muscle soft-tissue imbalance. To overcome some of these problems a total modular wrist prosthesis has been designed for use both as a primary prosthesis and for revision surgery. An uncemented and cemented radial component, secure fixation in three metacarpal bones, and an unconstrained and constrained version account for the modularity, including optional treatment of the distal radioulnar joint. We present the design of the prosthesis including the preliminary clinical and radiographic results after a mean follow-up of 20 months in 32 patients of whom four have had earlier implants revised.
12707583 New developments in imaging in rheumatoid arthritis. 2003 May Despite the advances made in medical imaging over the past 3 decades and the central role that magnetic resonance imaging and other sophisticated technologies now play in routine clinical practice, patients with rheumatoid arthritis have benefited relatively little from these advances thus far. Over the past few years, however, evidence has accumulated to show that magnetic resonance imaging and ultrasonography can identify joint damage in patients with rheumatoid arthritis earlier and more sensitively than other techniques can, and that these techniques can directly visualize and monitor changes in synovium and bone that precede actual bone erosion. Much of this development is being driven by the pharmaceutical and biotechnology industries as they search for novel therapies to combat this disease. Accordingly, the imaging tools that ultimately will be used to direct patients to specific therapies and then to monitor treatment effectiveness and safety are currently being refined and validated in rigorous multicenter and multinational clinical trials aimed at gaining regulatory approval of these new therapies. As these therapies become available for clinical use, we can anticipate increased demand for expertise and experience in evaluating disease progression and treatment response, and to the emergence of magnetic resonance imaging systems specifically adapted for this application. The following discussion reviews the current status of this development, and notable advances that have been reported in the literature in the past year.
12649403 Prospective analysis of the impact of HLA-DR and -DQ on joint destruction in recent-onset 2003 Apr OBJECTIVE: To evaluate the differential impact of HLA-DR and -DQ on the progression of erosive disease in the clinical course of early rheumatoid arthritis (RA). METHODS: HLA genotyping for HLA-DR and -DQ was carried out in a prospective study of 87 patients with early RA. The progression of erosive disease was assessed by radiological scores over a period of 2 yr in all patients and over 4 yr in 77 patients. The impact of HLA markers was evaluated by univariate comparisons and by multiple logistic regression analyses. RESULTS: Patients expressing the RA-associated shared epitope (SE) on a DRB1*01-positive or, most prominently, on a DRB1*04-positive allele had higher Larsen scores at all time-points analysed when compared with SE-negative patients. A similar impact on radiological progression was seen for the RA-predisposing DQ3, but not for DQ5 heterodimers. In the presence or absence of the DRB1 SE, no additional effects could be discerned for RA-associated DQ molecules. The presence of a DERAA-positive DRB1 allele was associated with a slower pace of joint destruction. While gene dosage effects were seen for SE compound homozygosity, no effect for DQ3 homozygosity could be discerned. CONCLUSION: Although a significant influence of HLA-DQ3 heterodimers on the progression of erosive joint destruction was seen, the analysis of the HLA-DQ locus did not add additional information over the study of HLA-DR including the determination of the SE and the DERAA motif in order to predict the development of severe progressive joint destruction.
12630291 Kinases as targets: prospects for chronic therapy. 2002 Sep Several inhibitors of protein kinases have been launched or have reached late stages of clinical trials for the treatment of acute conditions such as cancer. Development was slow, mainly because of the associated toxicity, attributed to the poor selectivity of these compounds. Protein kinase inhibitors mainly bind at the active site of the enzyme, in competition with ATP, and whether such inhibitors could ever be used for the long-term treatment of chronic conditions, such as rheumatoid arthritis, is still questionable. This review concentrates on three enzymes, well established as potential drug targets for the treatment of chronic inflammatory conditions, and considers progress made in developing potent and selective inhibitors that could progress through clinical trials and eventually be launched on the market.