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ID PMID Title PublicationDate abstract
16242974 Induction of MMP-13 expression by soluble human glucocorticoid-induced tumor necrosis fact 2006 Feb OBJECTIVE: We tested the hypothesis that human glucocorticoid-induced tumor necrosis factor receptor (hGITR/TR11) expressed on the surface of activated CD4(+) T cells is responsible for up-regulating the production of matrix metalloproteinase (MMP)-13 by fibroblast-like synoviocytes (FLSs). METHODS: The level of MMP-13 was measured by Western blot and reverse transcriptase polymerase chain reaction (RT-PCR). Expressions of hGITR ligand (hGITRL) on the surface of FLSs and hGITR on the surface of human CD4(+) T cells were analyzed by flow cytometry and RT-PCR. Neutralizing antibodies (Abs) were used to block hGITRL and hGITR on the surface of FLSs and human CD4(+) T cells, respectively. Human CD4(+) T cells were cocultured with FLSs to facilitate interaction between hGITR on CD4(+) T cells and hGITRL on FLSs. RESULTS: Soluble hGITR (shGITR) stimulated FLSs to produce MMP-13, and blockade of hGITRL reduced this effect. Direct contact between activated CD4(+) T and FLSs also induced the production of MMP-13, and neutralization of hGITR on activated CD4(+) T cells during coculture decreased the amount of MMP-13 produced by FLSs. CONCLUSION: shGITR stimulated FLSs to produce MMP-13 via a signal through hGITRL. Direct contact between activated CD4(+) T cells and FLSs facilitated hGITR-hGITRL interaction, and resulted in inducing MMP-13. This effect may increase tissue destruction in chronic inflammation such as rheumatoid arthritis (RA).
17141011 Sexual dimorphism in degenerative disorders of the spine. 2006 Oct Sexual dimorphism is evident during formation, growth, and development of the spine. Pregnancy alters spine physiology and is a risk factor for back pain. The processes of aging and spinal degeneration adversely affect men and women slightly differently. Although degenerative changes are observed at similar rates in both sexes, women seem to be more susceptible to degenerative changes leading to instability and malalignment, structural deterioration, such a stenosis or disc degeneration. Surgical satisfaction is greater in men, which has been attributed to poorer preoperative function secondary to more advanced disease at time of surgery and lower patient expectations for clinical improvement, both observed in women.
16409818 [Prevalence of antiepithelial cell antibody in systemic vasculitis and identification of t 2005 Dec 7 OBJECTIVE: To investigate the prevalence of antiepithelial cell antibody (AECA) in systemic vasculitis (SV) and the target antigen thereof. METHOD: Sera of 113 patients with SV of different kinds, 46 patients with Behcet's disease, 23 patients with Takayasu arteritis, 19 patients with Wegener's granulomatosis, 8 patients with polyarteritis nodosa, 7 patients with microscopic polyangiitis, and 10 patients with Churg-Strauss syndrome were collected to detect the protein expression of AECA by Western blotting, with the protein of the endothelial cells of the line EA. hy926 line as substrate. Two-dimensional electrophoresis combined with immunoblotting, liquid chromatography-electrospray ionization mass spectrography was used to detect the target antigens related to vasculitis. Sera of 57 patients with systemic lupus erythematosus (SLE), 25 patients with rheumatoid arthritis (RA), and 20 healthy persons were collected as controls. RESULTS: The AECA-positive rate of the SV patients was 69.0%, not significantly different from that of the SLE patients (66.7%), but significantly higher than those of the RA patients (6.7%, P < 0.01) and healthy persons (0, P < 0.01). The AECA from the SV patients reacted with the endothelial cell (EC) antigens with the molecular size of 26 to 125 kDa, and the AECA from the SLE patients reacted with the EC antigens with the molecular size of 15 to 97 kDa. The EC antigens with the molecular size of 47 kDa was commonly found in the sera of the AECA-positive SV patients and SLE patients, however, was not found in the RA, and polymyositis-dermatomyositis patients. The EC protein reacted by 47 kDa protein was identified by proteomic techniques as alpha-enolase. CONCLUSION: A group of heterogeneous antibodies, AECA can be found frequently in patients with SV and SLA. AECA reacts against a common EC antigen, alpha-enolase.
16859524 A novel approach to measure the contribution of matrix metalloproteinase in the overall ne 2006 Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibitors have been successful in clinical trials of arthritis. One of the central problems associated with this failure may be our inability to monitor the local activity of proteases in the joints since the integrity of the extracellular matrix results from an equilibrium between noncovalent, 1:1 stoichiometric binding of protease inhibitors to the catalytic site of the activated forms of the enzymes. In the present work, we have measured by flow cytometry the net proteolytic activity in synovial fluids (SF) collected from 95 patients with osteoarthritis and various forms of inflammatory arthritis, including rheumatoid arthritis, spondyloarthropathies, and chronic juvenile arthritis. We found that SF of patients with inflammatory arthritis had significantly higher levels of proteolytic activity than those of osteoarthritis patients. Moreover, the overall activity in inflammatory arthritis patients correlated positively with the number of infiltrated leukocytes and the serum level of C-reactive protein. No such correlations were found in osteoarthritis patients. Members of the MMP family contributed significantly to the proteolytic activity found in SF. Small-molecular-weight MMP inhibitors were indeed effective for inhibiting proteolytic activity in SF, but their effectiveness varied greatly among patients. Interestingly, the contribution of MMPs decreased in patients with very high proteolytic activity, and this was due both to a molar excess of tissue inhibitor of MMP-1 and to an increased contribution of other proteolytic enzymes. These results emphasize the diversity of the MMPs involved in arthritis and, from a clinical perspective, suggest an interesting alternative for testing the potential of new protease inhibitors for the treatment of arthritis.
16149125 Sample-size calculations for studies with correlated ordinal outcomes. 2005 Oct 15 Correlated ordinal response data often arise in public health studies. Sample-size (power) calculations are a crucial step in designing such studies to ensure an adequate sample to detect a significant effect. Here we extend Rochon's method of sample-size estimation with a repeated binary response to the ordinal case. The proposed sample-size calculations are based on an analysis with generalized estimating equations (GEE) and inference with the Wald test. Simulation results demonstrate the merit of the proposed power calculations. Analysis of an arthritis clinical trial is used for illustration.
16169244 Do NK cells regulate human autoimmunity? 2005 Oct 21 Natural killer cells have been shown to regulate autoimmune responses under experimental conditions in animals. However, a similar role for human NK cells has not been investigated, although NK cells constitute a significant fraction of the infiltrating cells in a range of autoimmune diseases. This review investigates the evidence, both theoretical and experimental, for the involvement of these cells in human immunopathology.
16947773 Function of interleukin-20 as a proinflammatory molecule in rheumatoid and experimental ar 2006 Sep OBJECTIVE: The pathogenesis of rheumatoid arthritis (RA) reflects an ongoing imbalance between proinflammatory and antiinflammatory cytokines. Interleukin-20 (IL-20) has proinflammatory properties for keratinocytes. In this study, we sought to determine whether IL-20 is involved in RA. METHODS: We analyzed IL-20 levels in synovial fluid from RA patients. IL-20 and its receptors were detected in RA synovial fibroblasts (RASFs), using immunohistochemical staining. The effect of IL-20 on endothelial cells, neutrophils, and RASFs was investigated using MTT and migration assays. The expression of IL-20 and its receptors in healthy rats and in rats with collagen-induced arthritis (CIA) was also analyzed. Soluble IL-20 receptor type I (sIL-20RI) or sIL-20RII was administered to rats with CIA by intramuscular electroporation, and the severity of arthritis was monitored. RESULTS: RA patients expressed significantly higher levels of synovial fluid IL-20 than did the rheumatic disease controls. IL-20 and its receptors were expressed in the synovial membranes and RASFs. IL-20 induced RASFs to secrete monocyte chemoattractant protein 1, IL-6, and IL-8, and it promoted neutrophil chemotaxis, RASF migration, and endothelial cell proliferation. Both IL-20 and IL-20RI were up-regulated in the rat CIA model. In vivo, electroporated sIL-20RI plasmid DNA decreased the severity of arthritis in the rats with CIA. CONCLUSION: IL-20 was up-regulated in the synovial fluid of RA patients and acted as a chemokine that attracted the migration of neutrophils and RASFs in vitro. The rat CIA model demonstrated that IL-20 was involved in the pathogenesis of arthritis, because sIL-20RI significantly reduced arthritis in rats with CIA. Thus, IL-20 may modulate the incidence and severity of arthritis and play important roles at local sites of inflammation.
15993360 Bone morphogenetic protein signaling in joint homeostasis and disease. 2005 Jun Despite advances in therapies that target inflammation and tissue destruction in chronic arthritis, stimulation of tissue repair and restoration of joint function, the ultimate goal of treatment, is far from achieved. We introduce a new paradigm that may help to improve our understanding and management of chronic arthritis. The presence or absence of tissue responses distinguishes destructive arthritis, steady-state arthritis and remodeling arthritis. Increasing evidence suggests that reactivation of embryonic molecular pathways is an important mechanism to stimulate postnatal tissue repair. Bone Morphogenetic Proteins (BMPs) have critical roles in skeletal development and joint morphogenesis, but also in postnatal joint homeostasis and joint tissue remodeling. Therefore, modulation of BMP signaling may be an attractive therapeutic target in chronic arthritis to restore homeostasis and function of synovial joints.
17134787 The impact of cost sharing of prescription drug expenditures on health care utilization by 2007 Aug PURPOSE: To estimate healthcare demand elasticity and evaluate the impact of deductible/co-payment policy changes for prescription drugs on the use of drugs and physician visits among seniors with rheumatoid arthritis (RA) in British Columbia (BC), Canada. METHODS: According to the BC drug insurance program, prior to 2002, seniors co-paid the dispensing fee of each prescription to an annual maximum of CAN$ 200 (plan A). Starting in 2002, this plan was split into plan A and plan A1 (Premium Assistance) such that the co-payment amount equaled a maximum of CAN$ 25 and CAN$ 10 per prescription to an annual maximum of CAN$ 275 and CAN$ 200, respectively. Because of the endogeneity of the beneficiary price in the presence of a non-linear price schedule resulting from the cost-sharing policy, we implemented the method of instrumental variables to estimate price elasticities. The instrument was based on the price an individual would face under the new cost-sharing policy if their consumption remained at the pre-policy level. RESULTS: A total of 8017 patients were included. The estimated own-price elasticity of demand for prescription drugs and the cross-price elasticity of demand for physician visits were found to be negative and positive, respectively. The implications of our findings were that when cost sharing for prescription drugs increased, the demand for prescription drugs decreased and the demand for physician visits increased. CONCLUSIONS: In a predominantly publicly funded health care system, the selective introduction of market driven cost containment concepts such as patient cost-sharing might have the unintended impact of increasing overall health utilization for seniors with RA.
16981287 Hypertrophic pachymeningitis in rheumatoid arthritis after adalimumab administration. 2006 Nov Tumor necrosis factor-a (TNF-a) inhibition, used in the treatment of rheumatoid arthritis (RA), is associated with central nervous system (CNS) events including new onset and/or exacerbations of pre-existing demyelinating neurological diseases. We describe a patient with refractory RA where adalimumab, a fully humanized IgG1 monoclonal antibody against TNF-a, may have contributed to the development of meningoencephalitis, with brain biopsy suggestive of hypertrophic pachymeningitis, a rare complication of this disease. The patient had recurrence of neurological symptoms upon repeated administration of adalimumab, and resolution of symptoms after withdrawal.
16543723 The active form of leflunomide, HMR1726, facilitates TNF-alpha and IL-17 induced MMP-1 and 2006 BACKGROUND/AIMS: To elucidate the influence and mode of action of HMR1726 (the active metabolite of leflunomide) on TNF-alpha and IL-17 activated metalloproteinases expression in synoviocytes. METHODS: Synovial fibroblasts from RA and OA patients were stimulated with both cytokines and altered gene expression in the presence or absence of leflunomide was detected by microarray analyses and quantitative RT-PCR. Protein expression was detected by western blotting and commercial ELISAs. RESULTS: Microarray analyses revealed that the addition of HMR1726 (50 microM) to TNF-alpha and IL-17- stimulated synoviocytes induced gene expression of metallo-proteinases, especially MMP-1 and -3 in comparison to activated synoviocytes in the absence of leflunomide. To confirm these data, we examined the influence of different concentrations of HMR1726 in synoviocytes from further 5 OA and 7 RA patients by quantitative PCR. HMR1726 gradually induced MMP-1 and MMP-3 gene expression in a dose-dosedependent manner. Similar results were observed on protein levels. Examination of signal transduction pathways participating in the regulation of leflunomideinduced MMPs expression showed that the mechanism underlying activation of MMP-1 is in part p38- and activation of MMP-3 was MEK1/2- dependent. CONCLUSION: Leflunomide was not able to abolish expression of metallo-proteinases in synoviocytes activated with TNF-a and IL-17.
16332240 Cytokine profiles in peripheral blood and whole blood cell cultures associated with aggres 2005 Dec BACKGROUND: Cytokines play a key role in the pathogenesis of inflammatory diseases. An obvious question is whether patients with aggressive periodontitis, juvenile idiopathic arthritis, or rheumatoid arthritis share blood cytokine profiles distinguishing them from individuals free of disease. METHODS: The study population consisted of Danish white adults, <35 years of age, diagnosed with localized aggressive periodontitis (LAgP; N = 18), generalized aggressive periodontitis (GAgP; N = 27), juvenile idiopathic arthritis (JIA; N = 10), or rheumatoid arthritis (RA; N = 23) and healthy individuals with no systemic or oral diseases (control [CTRL]; N = 25). Enzyme-linked immunosorbent assays were used to determine the levels of interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-10, tumor necrosis factor (TNF)-alpha, and lymphotoxin (LT)-alpha in peripheral blood (plasma) and unstimulated and stimulated whole blood cell cultures from the same blood collection. Autoantibodies (aAb) to IL-1alpha and IL-6 were quantitated by radioimmunoassay. RESULTS: Similar patterns of slightly higher IL-10 levels in plasma were found for GAgP and RA patients and in unstimulated cultures for GAgP, RA, and JIA patients. Interestingly, unstimulated cultures also demonstrated similar patterns of higher TNF-alpha levels for these three groups of patients. Similar group patterns of periodontitis patients (LAgP and GAgP) included increased IL-1Ra levels in stimulated cultures, which also showed similar group patterns of arthritis patients (JIA and RA) with respect to higher IL-1alpha and lower LT-alpha levels. Low titers of aAb to IL-1alpha and IL-6 were found in almost all individuals. CONCLUSION: Patients with aggressive periodontitis and types of arthritis presented with similar components of blood cytokine profiles distinguishing them from individuals free of disease.
17160529 Unusual cause of painful shoulder in an elderly woman with rheumatoid arthritis. 2007 Sep The painful shoulder is a very common condition encountered in the rheumatology clinic with rotator cuff disorders, glenohumeral disorders, acromioclavicular joint disease and referred neck pain being the most common causes. Other rare causes have to be considered in the presence of "red flag" indicators. We describe a case of a patient with mild rheumatoid arthritis and a past medical history of stage 2C epithelial ovarian carcinoma who presented to the rheumatology clinic with a painful shoulder and who was initially diagnosed with rotator cuff tendinopathy. When seen 3 months later she was found to have a 15 x 10-cm firm, non-tender soft tissue mass over the right scapula and X-rays showed a large lytic mass destroying much of the upper border of the scapula, suggestive of metastasis. Bone metastases in patients with ovarian carcinoma are very rare; they occur in about 2% of cases and are invariably predictors of poor prognosis. To our knowledge, this is the first case of ovarian cancer metastasised to the scapula. We suggest that rheumatologists should be aware of the differential diagnosis of painful shoulder and look for "red flag" indicators in patients with known rheumatic conditions.
16260763 Crystal structures of T cell receptor (beta) chains related to rheumatoid arthritis. 2005 Dec The crystal structures of the Vbeta17+ beta chains of two human T cell receptors (TCRs), originally derived from the synovial fluid (SF4) and tissue (C5-1) of a patient with rheumatoid arthritis (RA), have been determined in native (SF4) and mutant (C5-1(F104-->Y/C187-->S)) forms, respectively. These TCR beta chains form homo-dimers in solution and in crystals. Structural comparison reveals that the main-chain conformations in the CDR regions of the C5-1 and SF4 Vbeta17 closely resemble those of a Vbeta17 JM22 in a bound form; however, the CDR3 region shows different conformations among these three Vbeta17 structures. At the side-chain level, conformational differences were observed at the CDR2 regions between our two ligand-free forms and the bound JM22 form. Other significant differences were observed at the Vbeta regions 8-12, 40-44, and 82-88 between C5-1/SF4 and JM22 Vbeta17, implying that there is considerable variability in the structures of very similar beta chains. Structural alignments also reveal a considerable variation in the Vbeta-Cbeta associations, and this may affect ligand recognition. The crystal structures also provide insights into the structure basis of T cell recognition of Mycoplasma arthritidis mitogen (MAM), a superantigen that may be implicated in the development of human RA. Structural comparisons of the Vbeta domains of known TCR structures indicate that there are significant similarities among Vbeta regions that are MAM-reactive, whereas there appear to be significant structural differences among those Vbeta regions that lack MAM-reactivity. It further reveals that CDR2 and framework region (FR) 3 are likely to account for the binding of TCR to MAM.
17101049 T-cell contact-dependent regulation of CC and CXC chemokine production in monocytes throug 2006 We and others have reported that rheumatoid arthritis (RA) synovial T cells can activate human monocytes/macrophages in a contact-dependent manner to induce the expression of inflammatory cytokines, including tumour necrosis factor alpha (TNFalpha). In the present study we demonstrate that RA synovial T cells without further activation can also induce monocyte CC and CXC chemokine production in a contact-dependent manner. The transcription factor NFkappaB is differentially involved in this process as CXC chemokines but not CC chemokines are inhibited after overexpression of IkappaBalpha, the natural inhibitor of NFkappaB. This effector function of RA synovial T cells is also shared by T cells activated with a cytokine cocktail containing IL-2, IL-6 and TNFalpha, but not T cells activated by anti-CD3 cross-linking that mimics TCR engagement. This study demonstrates for the first time that RA synovial T cells as well as cytokine-activated T cells are able to induce monocyte chemokine production in a contact-dependent manner and through NFkappaB-dependent and NFkappaB-independent mechanisms, in a process influenced by the phosphatidyl-inositol-3-kinase pathway. Moreover, this study provides further evidence that cytokine-activated T cells share aspects of their effector function with RA synovial T cells and that their targeting in the clinic has therapeutic potential.
17142384 Arthritis of the large joints - in particular, the knee - at first presentation is predict 2007 May OBJECTIVE: To investigate the predictive value of the distribution of inflamed joints at first presentation for the severity of the disease course in rheumatoid arthritis (RA). METHODS: Of the 1009 consecutive patients included in the Leiden Early Arthritis Clinic (Leiden, The Netherlands), 285 patients fulfilled the American College of Rheumatology criteria for RA within 1 year of follow-up. Of these, 28 patients achieved remission. Radiographs of hands and feet were scored according to the Sharp-van der Heijde method, and the 28 patients with the most destructive disease were selected. The distribution of inflamed joints of the patients with the extreme disease courses was compared. The association between the distribution of inflamed joints and the level of destruction of the joints of hands and feet in the whole group of patients with RA was assessed using regression analysis. RESULTS: Comparison of patients with extreme disease courses using univariate and logistic regression analyses showed that arthritis of the large joints - in particular, the knee - was associated with severe RA. In the whole group of patients with RA, the total number of swollen joints and the presence of knee arthritis were associated independently with the level of destruction of the small joints. Patients with RA with knee arthritis had higher C reactive protein (CRP) levels than patients without knee arthritis, and investigating the distribution of inflamed joints together with other variables yielded the number of swollen joints, CRP, presence of anti-cyclic citrullinated peptide antibodies and symptom duration as predictors for severity of RA. CONCLUSION: Arthritis of large joints - in particular, the knee - at first presentation is associated with a destructive course of RA.
16277695 Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid art 2005 Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis (RA), but little is understood about their citrullinated target antigens. We have detected a candidate citrullinated protein by immunoblotting lysates of monocytic and granulocytic HL-60 cells treated with peptidylarginine deiminase. In an initial screen of serum samples from four patients with RA and one control, a protein of molecular mass 47 kDa from monocytic HL-60s reacted with sera from the patients, but not with the serum from the control. Only the citrullinated form of the protein was recognised. The antigen was identified by tandem mass spectrometry as alpha-enolase, and the positions of nine citrulline residues in the sequence were determined. Serum samples from 52 patients with RA and 40 healthy controls were tested for presence of antibodies against citrullinated and non-citrullinated alpha-enolase by immunoblotting of the purified antigens. Twenty-four sera from patients with RA (46%) reacted with citrullinated alpha-enolase, of which seven (13%) also recognised the non-citrullinated protein. Six samples from the controls (15%) reacted with both forms. Alpha-enolase was detected in the RA joint, where it co-localised with citrullinated proteins. The presence of antibody together with expression of antigen within the joint implicates citrullinated alpha-enolase as a candidate autoantigen that could drive the chronic inflammatory response in RA.
15876361 Inflammation and atherosclerosis in rheumatoid arthritis. 2005 May 6 Rheumatoid arthritis (RA) associates with increased cardiovascular mortality. This appears to be predominantly due to ischaemic causes, such as myocardial infarction and congestive heart failure. The higher prevalence of cardiac ischaemia in RA is thought to be due to the accelerated development of atherosclerosis. There are two main reasons for this, which might be inter-related: the systemic inflammatory load, characteristic of RA; and the accumulation in RA of classical risk factors for coronary heart disease, which is reminiscent of the metabolic syndrome. We describe and discuss in the context of RA the involvement of local and systemic inflammatory processes in the development and rupture of atherosclerotic plaques, as well as the role of individual risk factors for coronary heart disease. We also present the challenges facing the clinical and scientific communities addressing this problem, which is receiving increasing attention.
16199007 Suppressive effects of QFGJS, a preparation from an anti-arthritic herbal formula, on rat 2005 Nov 18 To analyze the anti-arthritic effects of QFGJS (a pharmaceutical preparation from herbs) on rheumatoid arthritis, adjuvant-induced arthritis (AIA) was established in male SD rats, and two administration protocols, i.e., oral treatment with different doses of QFGJS on the day of arthritis induction or on the day when visible clinical signs of arthritis occurred, were initiated and continued until day 30. Treatments with QFGJS using both administration protocols significantly suppressed the incidence and severity of arthritis in a dose-dependent manner, showing dramatic reduction of paw swelling and ESR throughout the disease progression of AIA. Radiological and histopathological examinations showed markedly decreased tissue and bone destruction of ankle joints in the QFGJS-treated rats. The serum levels of TNF-alpha, IL-1beta, and IL-6 were significantly decreased in the QFGJS-treated rats. QFGJS demonstrates pronounced anti-arthritic effects on AIA, indicating that this herbal preparation would be a potent candidate as a novel botanical drug for further investigation.
17141021 Sex differences in autoimmune disease. 2006 Oct Many, but not all, autoimmune diseases primarily affect women. In humans, severity of illness does not differ between men and women. Men and women respond similarly to infection and vaccination, which suggests that the intrinsic differences in immune response between the sexes do not account for differences in disease frequency. In autoimmune-like illnesses caused by recognized environmental agents, sex discrepancy is usually explained by differences in exposure. Endogenous hormones are not a likely explanation for sex discrepancy; hormones could have an effect if the effect is a threshold rather than quantitative. X and Y chromosomal differences have not been studied in depth. Other possibilities to explain sex discrepancy include chronobiologic difference and various other biologies, such and pregnancy and menstruation, in which men differ from women.