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ID PMID Title PublicationDate abstract
12500262 Mast cells and angiogenesis. 2003 Jan 1 There is much evidence that angiogenesis is related to mast cells. Mast cells accumulate in many angiogenesis-dependent situations, including tumor growth, rheumatoid arthritis, ovulation, would healing, and tissue repair. Several mast cell mediators are angiogenic and regulate endothelial cell proliferation and function. Stem cell factor, vascular endothelial growth factor, epidermal growth factor, basic fibroblast growth factor, and platelet-derived growth factor induce chemotactic migration of mast cells to sites of neovascularization. Mast cell products such as tryptase also degrade connective tissue matrix to provide space for neovascular sprouts. Angiogenesis has been proposed as a target for anticancer therapy and for treatment of inflammatory disorders such as rheumatoid arthritis. Future studies on the cascade of angiogenic events, including mast cell-target cell interaction, and various intracellular signaling pathways are indicated to provide a new approach for the treatment of cancer and inflammatory disorders and for tissue repair.
14979936 Decreased response to IL-12 and IL-18 of peripheral blood cells in rheumatoid arthritis. 2004 Inflamed synovium of rheumatoid arthritis (RA) has been associated with a T helper (Th)1 cytokine profile but the blood situation remains to be clarified. We studied the differential IFN-gamma producing activity of peripheral blood mononuclear cells (PBMCs) from RA patients (RA-PBMCs) and from healthy controls (H-PBMCs) in response to IL-12 and IL-18. RA-PBMCs had a decreased IFN-gamma production in response to IL-12 and IL-18 when compared with H-PBMCs. RA-PBMCs activated with phytohemagglutinin and phorbol 12-myristate 13-acetate showed an increased sensitivity to IL-12 and IL-18, but still the RA-PBMC response was lower. IL-18 increased IL-12-stimulated IFN-gamma production from RA synovium cells obtained after collagenase digestion more effectively than that of RA- or H-PBMCs. A specific inhibitor of IL-18 bioactivity, IL-18-binding protein (IL-18BP), down-regulated IL-12-induced IFN-gamma production by RA- or H-PBMCs and had a remarkable effect on RA synovium cells. In conclusion, RA disease combines a polarized immune response with an active Th1 in inflamed joints and a reduced Th1 pattern in peripheral circulation.
11811933 Occupational exposures and autoimmune diseases. 2002 Feb Autoimmune diseases are pathologic conditions defined by abnormal autoimmune responses and characterized by immune system reactivity in the form of autoantibodies and T cell responses to self-structures. Here we review the limited but growing epidemiologic and experimental literature pertaining to the association between autoimmune diseases and occupational exposure to silica, solvents, pesticides, and ultraviolet radiation. The strongest associations (i.e., relative risks of 3.0 and higher) have been documented in investigations of silica dust and rheumatoid arthritis, lupus, scleroderma and glomerulonephritis. Weaker associations are seen, however, for solvent exposures (in scleroderma, undifferentiated connective tissue disease, and multiple sclerosis) and for farming or pesticide exposures (in rheumatoid arthritis). Experimental studies suggest two different effects of these exposures: an enhanced proinflammatory (TH1) response (e.g., TNF-alpha and IL-1 cytokine production with T cell activation), and increased apoptosis of lymphocytes leading to exposure to or modification of endogenous proteins and subsequent autoantibody formation. The former is a general mechanism that may be relevant across a spectrum of autoimmune diseases, whereas the latter may be a mechanism more specific to particular diseases (e.g., ultraviolet radiation, Ro autoantibodies, and lupus). Occupational exposures are important risk factors for some autoimmune diseases, but improved exposure assessment methods and better coordination between experimental/animal models and epidemiologic studies are needed to define these risks more precisely.
17041377 Are monoclonal gammopathies in rheumatoid arthritis predictive for lymphoproliferative dis 2002 Oct There is limited evidence for the association of specific malignancies with rheumatoid arthritis (RA). Monoclonal gammopathies can occur in RA. Their predictive value for the development of a lymphoproliferative disorder remains unclear and disputed. We reviewed charts of 214 RA patients all of whom had at least one serum protein electrophoresis. We performed a retrospective study of 12 patients with RA and an M spike. We further characterized the M spike by serum immunofixation and bone marrow studies. The median age at which the M spike was identified was 69 years. IgG was the predominant gammopathy in 50% of patients, with no difference in the amount of kappa (kappa) and lambda (lambda) chains. One patient was diagnosed with multiple myeloma, one with an undefined primary lymphoproliferative disorder, one with T-cell leukemia, five with myelodysplastic syndrome, and four with monoclonal gammopathy of undetermined significance at most recent evaluation. Of our patients, 42% had a myelodysplastic syndrome, which has not been previously reported, and, in contrast to previous reports, no lymphomas were identified. The follow-up evaluation of patients with myelodysplastic syndrome and monoclonal gammopathy of undetermined significance is important because they may progress to an overt neoplasia.
15580149 Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: overview of r 2004 The past decade has brought forth a series of novel biologic agents targeting tumor necrosis factor (TNF) for the treatment of Crohn's disease. The introduction of infliximab has paved the way for additional anti-TNF strategies that have the potential to build on that drug's efficacy and safety profile. However, the anti-TNF strategies might not have identical efficacy and safety profiles and might differ in dosing compared with therapy for rheumatoid arthritis. Most recently, adalimumab has been approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis and is undergoing evaluation in Crohn's disease, with promising initial results. This review discusses the results of controlled clinical trials of anti-TNF agents for Crohn's disease.
17041461 Influence of leflunomide on renal handling of urate and phosphate in patients with rheumat 2003 Aug Reduction of serum urate and phosphate levels has been observed in patients receiving leflunomide therapy, but the mechanism for such changes has not been evaluated. Thirty-eight patients with rheumatoid arthritis who began leflunomide were studied. Serum urate, creatinine, and phosphate, and 24-hour uric acid, creatinine, and phosphate were measured before, during, and in some instances after leflunomide treatment. Clearances of urate and creatinine, fractional excretion of urate, and tubular reabsorption of phosphate were calculated. Undissociated urinary uric acid was estimated with a nomogram. Twelve patients gave consent to withdraw leflunomide treatment of a 2-week period and underwent a third study. Decreases in serum urate and phosphate levels were observed, with parallel increases in clearances of urate and in fractional excretion of urate, and a reduction in tubular reabsorption of phosphate. Clearances of creatinine and undissociated urinary uric acid remained unchanged. Two weeks after withdrawing the drug, a partial return toward baseline values was observed, but residual changes were apparent. No case of clinical gout was observed. Leflunomide enhances urate and phosphate loss, an effect that partially persisted after 2-week withdrawal. The long-term effect of mild phosphate wasting warrants further investigation. The urate-lowering effect of leflunomide may be useful in monitoring compliance in leflunomide therapy.
17041440 Differentiating the new rheumatoid arthritis biologic therapies. 2003 Apr Current understanding of the mechanisms behind the pathogenesis of rheumatoid arthritis (RA) has led to the development of therapies involving biologic agents that target specific mediators of the disease process. Although the biologic agents used to treat RA share the ability to alter the cytokine cascade, they differ in ways that are clinically important. For example, they vary with regard to how they block cytokine activity (ie, as receptors, as receptor blockers, or as anticytokine antibodies) and the particular cytokine they target (eg, tumor necrosis factor [TNF] versus interleukin-1). Biologic therapies for RA also differ in mode of administration. Several are administered subcutaneously, whereas others are given intravenously. They also have molecular dissimilarities that result in differences in pharmacokinetics (ie, long versus medium half-life) and that may influence their safety profiles.Some biologic agents, such as the TNF inhibitors etanercept and infliximab, have been rigorously examined for long-term safety and efficacy, whereas other agents, like the TNF inhibitor adalimumab, have not. Differences between the various biologic agents may relate to the usefulness of each individual drug as a long-term treatment in RA. For example, the need for physician visits may impact the practicality of drugs that are administered intravenously. Also, physicians should be aware that use of cytokine inhibitors increases the risk of infection. The prevalence of tuberculosis during therapy with infliximab exceeds the background rate in patients with RA. Accordingly, physicians should be familiar with the updated warnings in the package inserts that accompany these drugs.
15026265 Cysteine proteases as disease markers. 2004 Apr This review comprises issues concerning cysteine cathepsins (CCs): human peptidases belonging to papain family (C1) of clan CA of cysteine proteases: cathepsins B, L, H, S, K, F, V, X, W, O and C. The involvement of these enzymes in physiological and pathological processes is described, especially with respect to their application as diagnostic and prognostic markers. They participate in precursor protein activation (including proenzymes and prohormones), MHC-II-mediated antigen presentation, bone remodeling, keratinocytes differentiation, hair follicle cycle, reproduction and apoptosis. Cysteine cathepsins upregulation has been demonstrated in many human tumors, including breast, lung, brain, gastrointestinal, head and neck cancer, and melanoma. Besides cancer diseases, they have been implied to participate in inflammatory diseases, such as inflammatory myopathies, rheumatoid arthritis, and periodontitis. Also, certain hereditary disorders are connected with mutations in CCs genes, what is observed in pycnodysostosis resulted from catK gene mutation and Papillon-Lefevre and Haim-Munk syndrome caused by catC gene defect. The potential application of cysteine cathepsins in diagnosis and/or prognosis is discussed in cancer diseases (breast, lung, head and neck, ovarian, gastrointestinal cancers, melanoma), as well as other disorders (periodontitis, rheumatoid arthritis, osteoarthritis).
17041478 Are isolated antinucleolar antibodies a marker of scleroderma? 2003 Oct This study was designed to determine the prevalence and positive predictive value of isolated antinucleolar antibody (ANA) in scleroderma patients. We identified 73 rheumatology clinic patients with isolated ANAs. ANA titers greater than 1:160 were considered positive. The overall prevalence of isolated ANAs was 2.9%. The prevalence of isolated ANAs in scleroderma, systemic lupus erythematosus (SLE), and rheumatoid arthritis were 20.3%, 2.68%, and 3.3%, respectively. Scleroderma and SLE were present in 12 patients (16.4%) each. Other rheumatologic disorders identified in these patients were RA (12.3%), undifferentiated connective tissue disease (8.2%), mixed connective tissue disease (4.1%), vasculitis (6.8%), fibromyalgia (8.2%), osteoarthritis (5.4%), crystal-related arthropathy (6.8%), seronegative arthritis (2.7%), sarcoidosis (4.1%), and others (8.2%). There were no statistically significant differences in the median ANA titers in scleroderma versus systemic lupus (P = 0.16) or undifferentiated connective tissue disease (P = 0.18). The median titers were higher in scleroderma in comparison with rheumatoid arthritis (P = 0.01), osteoarthritis (P = 0.007), fibromyalgia (P = 0.001), and crystal-related arthropathy (P = 0.009). Isolated ANAs have poor sensitivity (20.3%) and the positive predictive value for this test is only 16.4% for scleroderma.
15059280 The synovial proteome: analysis of fibroblast-like synoviocytes. 2004 The present studies were initiated to determine the protein expression patterns of fibroblast-like synovial (FLS) cells derived from the synovia of rheumatoid arthritis patients. The cellular proteins were separated by two-dimensional polyacrylamide gel electrophoresis and the in-gel digested proteins were analyzed by matrix-assisted laser desorption ionization mass spectrometry. A total of 368 spots were examined and 254 identifications were made. The studies identified a number of proteins that have been implicated in the normal or pathological FLS function (e.g. uridine diphosphoglucose dehydrogenase, galectin 1 and galectin 3) or that have been characterized as potential autoantigens in rheumatoid arthritis (e.g. BiP, colligin, HC gp-39). A novel uncharacterized protein product of chromosome 19 open reading frame 10 was also detected as an apparently major component of FLS cells. These results demonstrate the utility of high-content proteomic approaches in the analysis of FLS composition.
12133271 Tetracycline-inducible interleukin-10 gene transfer mediated by an adeno-associated virus: 2002 Jul 1 The adeno-associated viruses (AAV) offer new perspectives for cytokine gene transfer in rheumatoid arthritis (RA) because they are nonpathogenic and allow long-term transgene expression in vivo. Moreover, the use of a tetracycline-inducible promoter allows regulation of therapeutic gene expression. This study assessed the potential long-term gene regulation of a recombinant AAV vector expressing viral interleukin-10 (vIL-10) in human rheumatoid synovium and the therapeutic efficiency in a mouse model of RA. We constructed a recombinant AAV vector in which the transcription of vIL-10 cDNA is controlled by the TetON system. Transduction of human primary RA synovial cells with AAV-tetON-vIL10 conferred in vitro controlled vIL-10 expression. After intramuscular injection, both incidence and severity of collagen-induced arthritis were significantly reduced at macroscopic, radiological, and histological levels in the group of DBA1 mice treated with AAV-TetON-vIL10 vector plus doxycycline after immunization and boosting compared to control groups. When coinjecting two separate AAV vectors, one encoding the inducible vIL-10 and the other the transcriptional activator, a 10 times excess of the transactivator vector dose allowed efficient control of vIL-10 secretion by doxycycline administration or withdrawal, over an 8-week period. Our results supported, for the first time, the utility of AAV-tetON-vIL10 as a therapeutic tool for gene therapy in RA.
16518244 Radiocarpal fusion. 2003 Jun Limited wrist fusion is a common and often effective method of treatment for many painful wrist conditions. When post-traumatic, inflammatory and noninflammatory arthritis affects only the articular surfaces of the proximal carpal joint, a limited radiocarpal fusion can be considered. Specific indications are painful arthritis following distal radial fractures, rheumatoid arthritis with ulnar shift of the carpus, scapholunate instability with radioscaphoid arthritis, and stage IV Kienbock's disease. It is necessary for the midcarpal joint surfaces to be essentially normal. Either a radioscapholunate or radiolunate fusion can be performed, depending on the underlying condition. Up to 70 degrees of wrist flexion-extension can be obtained after a radioscapholunate fusion. Keys to a successful postoperative result are proper alignment of the scaphoid and lunate, use of bone graft or bone graft substitute and careful positioning of internal fixation devices. Evidence of radiographic union is usually seen by eight weeks. Nonunion rates are quoted to be from 10 to 20%.
13130486 A highly selective inhibitor of I kappa B kinase, BMS-345541, blocks both joint inflammati 2003 Sep OBJECTIVE: The transcription of several cytokines, cell adhesion molecules, and enzymes involved in the inflammatory and destructive mechanisms of rheumatoid arthritis is dependent on nuclear factor kappa B (NF-kappa B). Because I kappa B kinase (IKK) is critical in transducing the signal-inducible activation of NF-kappa B, we examined whether the highly selective and orally bioavailable IKK inhibitor BMS-345541 is efficacious against collagen-induced arthritis (CIA) in mice. METHODS: Arthritis in DBA/1LacJ male mice was induced by subcutaneous immunization with bovine type II collagen on day 0 and day 21. BMS-345541 was administered perorally daily, either prophylactically (before disease onset) or therapeutically (after disease onset). Clinical assessment of the incidence and severity of disease was conducted throughout the study, and histologic evaluation was performed at the time of study termination (day 42). RESULTS: When administered prophylactically, BMS-345541 (in a dose range of 10-100 mg/kg) was effective, in a dose-dependent manner, in reducing the incidence of disease and inhibiting clinical signs of disease. Histologic evaluation of the joints showed that both inflammation and joint destruction were blocked by the IKK inhibitor. Message levels of interleukin-1 beta in the joints were also dose-dependently inhibited in the mice that received BMS-345541. Dose-dependent efficacy in terms of both disease severity and histologic end points was observed with the therapeutic dosing regimen of BMS-345541, with use of the 100-mg/kg dose resulting in resolution of disease. CONCLUSION: IKK plays a key role in CIA in mice, and inhibitors of this enzyme represent a promising target for the development of novel agents to treat rheumatoid arthritis and other inflammatory diseases. BMS-345541 represents the first example of an inhibitor of IKK that has antiinflammatory activity in vivo.
12235232 PPA250 [3-(2,4-difluorophenyl)-6-[2-[4-(1H-imidazol-1-ylmethyl) phenoxy]ethoxy]-2-phenylpy 2002 Oct Nitric oxide (NO) plays an important role in various physiological processes. Excessive NO production is closely related to inflammatory and autoimmune diseases such as septic shock and rheumatoid arthritis. Suppression of excess NO formation in participating cells may be helpful in improving disease status. In this study, we examined the effects of a newly synthesized imidazole derivative, 3-(2,4-difluorophenyl)-6-[2-[4-(1H-imidazol-1-ylmethyl) phenoxy]ethoxy]-2-phenylpyridine (PPA250), on NO production in vitro and in vivo, as well as on the dimerization of inducible nitric-oxide synthase (iNOS). PPA250 at concentrations of 25 nM and higher inhibited NO production in activated mouse macrophage-like RAW264.7 cells. The IC(50) was approximately 82 nM. Western blot analysis revealed that PPA250 prevents dimerization of iNOS but has no effect on transcription and translation. In addition, oral administration of PPA250 (10 mg/kg and higher) reduced the NO concentration in serum from mice in which sepsis was induced by bacterial lipopolysaccharide. Since the inhibitory activity was observed not only in vitro but also in vivo, we examined the therapeutic potential of PPA250 in two animal models of arthritis, collagen-induced arthritis in mice and adjuvant arthritis in rats. PPA250 suppressed the development of a destructive polyarthritis in both models after the appearance of clinical signs. These results indicate that inhibitors of iNOS homodimerization, including PPA250, could be useful therapeutic agents for inflammatory and autoimmune diseases, such as rheumatoid arthritis, in which NO is involved.
15022456 [Study on a new antarthritic injection--O-carboxymethyl chitosan]. 2004 Feb A type of water-soluble carboxymethyl chitosan (O--CMC), with 76% degree of substitution determined by conductivity method, was prepared by using chloroacetic acid to react with C6-OH of chitosan. The solubility of O--CMC was characterized also. Animal experiment in rabbits showed that O--CMC could lubricate arthron, inhibit proliferation of fibroblast cells on rabbits' knee joints, benefit the process of repairing pathologic articular cartilage, and produce good therapeutic effect on rheumatoid arthritis.
12856142 Detecting abnormal regional cerebral blood flow in patients with primary Sjögren's syndro 2003 Jul Technetium-99m ethyl cysteinate dimer (Tc-99m ECD) brain single photon emission computed tomography (SPECT) was used to detect abnormal regional cerebral blood flow (rCBF) in 32 female patients with primary Sjögren's syndrome (PSS) showing definite neuropsychiatric symptoms/signs and normal brain magnetic resonance imaging (MRI) findings. It demonstrated hypoperfusion brain lesions in 18 (56.3%) of the patients, most frequently in the parietal lobes, and appears to be a sensitive tool for this clinical application.
11965177 [Acute rhombencephalitis with fever and bilateral hearing loss secondary to Gougerot-Sjög 2002 Feb The usual polymorphic central nervous system involvement observed in primary Sjögren's syndrome is classified as monofocal, multifocal or diffuse involvement. We present a case of acute rhombencephalitis associated with hearing loss that could correspond to an intermediate form between diffuse and monofocal involvement. The acute onset with fever and not clinical sign of xerostomia or xerophthalmia suggest the possibility of vascular-like or infectious-like forms. We emphasize the importance of obtaining a minor salivary gland biopsy for diagnosis of Sjögren's syndrome and suggest that Sjögren's syndrome could be frequently misdiagnosed.
15084857 Efficacy and retention rate of two types of silicone punctal plugs in patients with and wi 2004 Apr OBJECTIVE: To compare the efficacy, retention rates, and complications of two types of silicone lacrimal punctal plugs in patients with or without Sjögren syndrome. METHODS: We studied 36 patients with keratoconjunctivitis sicca (KCS) including 17 cases with Sjögren syndrome (SS) and 19 without SS. The fluorescein and rose bengal staining scores and the Schirmer values with and without nasal stimulation were evaluated before and after insertion of the Eagle Plugs and the punctal plugs (FCI Punctal Plugs). The retention rates and complications of these plugs were also investigated. RESULTS: The staining scores were significantly improved after the insertion of the plugs, but the Schirmer values did not increase significantly in either SS or non-SS patients. A spontaneous loss of the plugs was observed in 29% of all plugs within 1 month after insertion. The Eagle Plugs were lost more frequently, and plugs in the upper punctum were lost more often for the Eagle Plugs. There was one case of granulomatous proliferation and two cases of punctal infection with the FCI Punctal Plugs. CONCLUSIONS: Both types of punctal plugs led to an improvement of the fluorescein and rose bengal staining scores in eyes with KCS. The difference in the retention rate and complications between the two types of plugs was probably caused by the differences in the material and the design of the plugs. Close monitoring is necessary to check for loss of plugs and to prevent complications.
15082115 Sjögren's syndrome: a condition with features of chronic graft-versus-host disease: does 2004 Primary and Secondary Sjögren's syndrome are disease complexes characterized by periductal inflammatory cell infiltration of the salivary and lacrimal glands and manifest as dry mouth and dry eyes. Secondary Sjögren's syndrome may be associated with a connective tissue disorder. Additional extraglandular features in Sjögren's syndrome include a generalized inflammatory exocrinopathy that might be associated with abnormalities of both humoral and cellular mediated immunity. Similar inflammatory changes and extraglandular features, including an altered immune response, have been reported in patients developing graft-versus-host disease after bone-marrow transplantation and in patients with primary biliary cirrhosis. The periductal nature of the inflammatory response involving minor salivary and other glands raises the possibility of altered duct cell adhesion or permeability in playing a role in the aetiopathogenesis of Sjögren's syndrome. The paper pulls together evidence that could be interpreted in this light. Evidence for bacterial or viral factor(s) altering the antigenicity of the histocompartibility (HC) complex on ductal cells in Sjögren's syndrome patients is also described. A hypothesis is proposed for Sjögren's syndrome in which the principal feature is an alteration in salivary gland duct cell adhesion or permeability. A re-evaluation of current knowledge of these two conditions from a clinical and experimental context are interpreted in this light.
12176800 Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sj 2002 Sep OBJECTIVE: Technetium-99m ethyl cysteinate dimer (99mTc ECD) single photon emission computed tomography (SPECT) of the brain was used to detect abnormal regional cerebral blood flow (rCBF) in patients with primary Sjögren's syndrome (pSS) and normal findings on brain magnetic resonance imaging (MRI). METHODS: (99m)Tc ECD brain SPECT was performed to detect brain lesions showing hypoperfusion in 32 female patients with pSS and definite neuropsychiatric symptoms or signs. Seventeen female patients with pSS without neuropsychiatric symptoms and signs were included as a control group for comparison. All of the 49 patients with pSS had normal findings on brain MRI. RESULTS: 99mTc ECD brain SPECT showed brain regions with hypoperfusion in 18 (56.3%) of the 32 patients, and parietal lobes were the most common areas with such lesions. By contrast, 99mTc ECD brain SPECT showed brain regions with hypoperfusion in only three (17.6%) of the 17 patients with pSS without neuropsychiatric symptoms or signs. CONCLUSION: This study suggests that 99mTc ECD SPECT is a sensitive tool for detecting regions of hypoperfusion in the brains of patients with pSS and neuropsychiatric symptoms or signs and normal findings on brain MRI. However, a review of the literature showed that the (99m)Tc ECD SPECT findings in patients with pSS were non-specific.