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ID PMID Title PublicationDate abstract
11235048 Successful use of cyclooxygenase-2 inhibitor in a patient with aspirin-induced asthma. 2001 Feb We describe the case of an aspirin-sensitive asthma patient with a history of anaphylactic reactions to nonsteroidal anti-inflammatory drugs. The patient was subsequently diagnosed with rheumatoid arthritis and treated with a cyclooxygenase (COX)-2 inhibitor without an adverse response. Current prescribing information warns to avoid using COX-2 inhibitors in aspirin-sensitive asthma patients. New evidence suggests that aspirin sensitivity may be linked to the COX-1 pathway, and COX-2 inhibitors, as a result of their selectivity, may be beneficial in patients with aspirin-induced asthma.
11109614 [Approaches to prediction of gastropathy development risk due to non-steroidal antiinflamm 2000 AIM: Examination of gastric secretion in rheumatoid arthritis (RA) patients and its response to sodium diclophenak and indomethacine. MATERIALS AND METHODS: 46 RA patients entered the study. All of them have been long on nonsteroid antiinflammatory drugs (NAID). Two groups of patients were analysed: group 1--free of NAID gastropathy, group 2--with NAID gastropathy. pH was followed by Gastroscan system. RESULTS: The analysis of 24-h pH-grams in both groups when NAID were not taken showed that in NAID gastropathy acid-forming gastric function is not affected while the alkalizing function markedly declines. Indomethacine is more aggressive to upper gastrointestinal tract mucosa than sodium diclophenak. CONCLUSION: Dynamic intragastric pH-metry can prognosticate the risk of NAID gastropathy.
9249146 Glycosylation of alpha1-acid glycoprotein in inflammatory disease: analysis by high-pH ani 1997 Jun High-pH anion-exchange chromatography with pulsed amperometric detection is a highly sensitive technique that can be used for detecting changes in sialylation and fucosylation, as well as different branching patterns of N-linked oligosaccharides in glycoproteins. We examined the N-glycans of alpha1-acid glycoprotein obtained from twelve patients with various inflammatory conditions with this technique, as well as traditional concanavalin A crossed affinity immunoelectrophoresis. We found the chromatographic profiles of N-glycans in all patients with rheumatoid arthritis to be very similar, but significantly different from normal controls. N-glycans from patients with ulcerative colitis also showed specific alterations in their chromatographic profiles. However, some heterogeneity was found between these patients, perhaps reflecting changes in glycosylation secondary to certain states of the disease, or to medical treatment. We conclude that this technique is useful for detailed mapping of glycosylation changes in alpha1-acid glycoprotein in clinical samples, and that it may be used to further increase our knowledge about glycosylation changes in response to inflammatory disease.
10895048 Treatment of juvenile rheumatoid arthritis with growth hormone. 2000 Severe growth retardation and profoundly altered body composition are observed in children with juvenile chronic arthritis receiving glucocorticoids. This study assessed the effects of growth hormone (GH) on height velocity, body composition and bone density. Fourteen patients were treated with GH (1.4 U/kg/week) for 1 year and then studied for a 2nd year off GH. The treatment increased insulin-like growth factor 1 and insulin-like growth factor binding protein 3 plasma levels. All patients showed an increase in height velocity. Lean body mass increased by 12%. After the cessation of GH therapy, height velocity fell to pretreatment values, and weight and fat mass increased markedly. Bone formation and resorption markers significantly increased during treatment and returned to pretreatment values after discontinuation of GH treatment. These results suggest that GH may partially counteract the adverse effects of glucocorticoids on growth and metabolism in patients with chronic inflammatory disease.
9300723 Increased expression of signaling lymphocytic activation molecule in patients with rheumat 1997 Sep 15 In the present study the expression and function of signaling lymphocytic activation molecule (SLAM) in lymphocytes from patients with rheumatoid arthritis (RA) were investigated. The expression levels of SLAM were significantly up-regulated on synovial fluid and synovial tissue T cells from patients with RA compared with peripheral blood T cells from the same patients or from healthy volunteers. In addition, the expression of SLAM on peripheral blood B cells from patients with RA was elevated compared with that in healthy volunteers. SLAM+ T cells in synovial fluid coexpressed CD45RO and demonstrated decreased expression of CD27, indicative of a primed phenotype. In addition, the activation state of SLAM+ T cells was enhanced, as judged by increased expression of CD25, CD28, CD69, and CD95 on these cells. Interestingly, SLAM expression on activated CD4+ and CD8+ T cells from both patients and healthy individuals could be down-regulated by IL-10, which has been previously shown to function as an anti-inflammatory molecule in rheumatoid synovium. Furthermore, anti-SLAM mAbs increased the production of IL-10, IFN-gamma, and TNF-alpha by in vitro activated synovial fluid mononuclear cells, supporting the idea that signaling through SLAM may play a role in the regulation of synovial inflammation in patients with RA. Given the fact that SLAM was recently shown to be a high affinity self ligand, our data suggest that synovial T cells may stimulate their own cytokine production through homophilic SLAM-SLAM interactions.
11485128 Upper gastroduodenal ulceration in arthritis patients treated with celecoxib. 2001 Jul OBJECTIVE: To evaluate the comparative incidence of endoscopic gastroduodenal ulcers in patients with rheumatoid arthritis or osteoarthritis treated with celecoxib. DESIGN: Quantitative systematic review of randomized controlled trials. SUBJECTS: Patients (n = 4632) with rheumatoid arthritis or osteoarthritis reported in five trials. MAIN OUTCOME MEASURES: Rate ratios, rate differences, and the number needed to harm were calculated for the incidence of endoscopically documented gastroduodenal ulcers. RESULTS: Pooled rate ratios (RRs) relative to placebo for endoscopic ulcers at 12 weeks were 1.96 (95% CI 0.85 to 4.55) for celecoxib 100 mg twice daily and 2.35 (95% CI 1.02 to 5.38) for celecoxib 200 mg twice daily. There was no significant difference in gastroduodenal ulcers at 12 weeks between celecoxib 200 mg twice daily and celecoxib 100 mg twice daily; the corresponding pooled RR was 1.21 (95% CI 0.62 to 2.38). In contrast, celecoxib 200 mg twice daily was associated with a significantly lower rate of gastroduodenal ulcers than was naproxen 500 mg twice daily at 12 weeks (RR 0.24; 95% CI 0.17 to 0.33). On average, for every seven patients treated with naproxen, one more had an endoscopic ulcer than if they were treated with celecoxib. Celecoxib 200 mg twice daily also had a significantly lower risk of endoscopic ulcers than did either modified-release diclofenac 75 mg twice daily at 24 weeks (RR 0.24; 95% CI 0.11 to 0.52) or ibuprofen 800 mg three times daily at 12 weeks (RR 0.30; 95% CI 0.20 to 0.46). CONCLUSIONS: Endoscopic studies have shown that celecoxib, at a wide range of doses, is associated with a lower incidence of gastroduodenal ulcers than are diclofenac, ibuprofen, or naproxen. The incidence rates of gastroduodenal ulcers associated with celecoxib were similar, although not equivalent, to placebo. Head-to-head comparisons suggest that, at the wide range of doses studied (100-800 mg/d), there are no dose-related increases in endoscopic gastroduodenal ulcers with celecoxib. The results of longer term comparative trials of celecoxib based on clinical outcomes are needed to determine celecoxib's ultimate risk-benefit profile.
11451131 Twenty-year evaluation of meniscal bearing and rotating platform knee replacements. 2001 Jul Clinical results of the initial cemented and cementless series of 373 New Jersey Low Contact Stress total knee replacements in 282 patients surviving at least 10 years were analyzed using a strict knee scoring scale. The study showed excellent, good, fair, or poor results in 68.1%, 29.8%, 2.1%, or 0% of primary posterior cruciate-retaining meniscal bearing knee replacements, 46.7%, 53.3%, 0%, or 0% results in primary cemented rotating platform knee replacements, and 68.1%, 29.8%, 2.1%, or 0% results in primary cementless rotating platform knee replacements, respectively. Radiographic evaluation at minimum 10-year followup showed stable fixation of all components, no gross migration but significant osteolysis requiring bearing exchange and bone grafting in three cementless rotating platform knee replacements (1.8%) in three patients who underwent previous surgeries at an average of 10.2 years from the index surgery. Survivorship of the patients who underwent primary cementless posterior cruciate-retaining meniscal bearing knee replacements with an end point of revision for any mechanical reason was 97.4% at 10 years and 83% at 16 years; using an end point of a poor clinical knee score the survivorship was 98.9% at 10 years and at 16 years. Survivorship of the patients who underwent primary cemented rotating platform knee replacements with end points of revision for any mechanical reason or a poor clinical knee score was 97.7% at 10 years and at 20 years. Survivorship of the patients who underwent cementless rotating platform knee replacements with end points of revision for any mechanical reason or a poor clinical knee score was 98.3% at 10 years and at 18 years.
9596550 Prevention of gastrointestinal complications associated with nonsteroidal antiinflammatory 1998 May Nonsteroidal antiinflammatory drugs (NSAID), although used frequently for the treatment of arthritis and musculoskeletal disorders, may produce deleterious effects related to the gastrointestinal (GI) tract, including dyspeptic symptoms, erosions, ulcers, and serious GI complications (i.e., bleeding, perforation, and gastric outlet obstruction). Endoscopic studies with the synthetic prostaglandin E1 analog misoprostol, various acid-reducing agents (e.g., H2 receptor antagonists and proton pump inhibitors), and surface-active drugs such as sucralfate, have been shown to prevent NSAID induced gastric and/or duodenal ulcers. The Misoprostol Ulcer Complication Outcomes Safety Assessment (MUCOSA) trial was a 6 month, randomized, double blind, placebo controlled study to investigate whether concurrent administration of misoprostol would significantly reduce the occurrence of serious upper GI complications in patients with rheumatoid arthritis (RA) who were receiving NSAID. Results showed that overall complications were reduced by 40% (p = 0.049) among patients receiving misoprostol (25 patients with definite serious GI events among 4404 patients treated) compared with those receiving placebo (42 out of 4439 patients). Thus, cotherapy with misoprostol resulted in a statistically significant reduction in the incidence of serious NSAID induced upper GI complications compared with placebo in patients with RA.
10853166 Deep venous thrombosis after total hip or total knee arthroplasty in patients in Japan. 2000 Jun A single center, prospective, epidemiologic study was conducted to estimate the incidence of deep venous thrombosis detected by venography in patients in Japan undergoing total hip arthroplasty or total knee arthroplasty without prophylactic anticoagulant therapy. Venograms of 164 patients who had total hip arthroplasty and 138 patients who had total knee arthroplasty were evaluated. The incidences of deep venous thrombosis were 22.6% in patients who had total hip arthroplasty and 48.6% in those who had total knee arthroplasty. The incidences of proximal deep venous thrombosis were 9.8% in patients who had total hip arthroplasty and 14.5% in those who had total knee arthroplasty. Statistical analysis revealed that the type of operation influenced the development of deep venous thrombosis. Patients who had total knee arthroplasty were 3.2 times more likely to have deep venous thrombosis develop than were patients who had total hip arthroplasty. Body mass index and age were identified as statistically significant risk factors.
11190043 Topical cyclosporin stimulates neovascularization in resolving sterile rheumatoid central 2000 OBJECTIVE: To report the successful use of topical cyclosporin for treatment of central sterile corneal ulcers associated with rheumatoid disease. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS/INTERVENTION: Five patients (7 eyes) with collagen vascular disorders presented with central, sterile corneal ulcers. An extensive medical evaluation did not reveal active underlying rheumatoid disease in any patient. Inadequate clinical response with use of topical steroids and lubricants led to corneal perforations requiring multiple tectonic procedures. Systemic immunosuppressive therapy either could not be initiated owing to a systemic contraindication or was discontinued owing to intolerance and side effects. The patients were ultimately treated with topical cyclosporin. RESULTS: Six of the 7 eyes responded favorably. An intense limbal vascularization began within 48 hours of treatment. The neovascularization progressed centrally with the simultaneous arresting of epithelial and stromal ulceration. Over a 2-week period, re-epithelization occurred with vascularization proceeding throughout the cornea. After several months, the corneal vessels attenuated, and all signs of inflammation subsided. Intrastromal bleeding with corneal blood staining occurred in 1 patient; this resolved over several months. No recurrences of corneal ulceration occurred in a mean follow-up period of 28 months (range, 7 to 60 months). None of the 5 patients have had a reactivation of their rheumatoid disease in the follow-up period. CONCLUSION: The clinical response in these patients contrasts with previous animal studies demonstrating an anti-angiogenic property of cyclosporin. We report that an immediate intense neovascularization is the first sign of a favorable clinical response. Treatment with topical cyclosporin alone may be considered in patients with sterile corneal ulcers associated with rheumatoid disease in the absence of systemic activation.
9012754 Pathogenesis of rheumatoid arthritis. 1997 Jan Chronicity and destructive potential are characteristic features of the inflammatory response in the synovial membrane typical for RA. The dominant paradigm has proposed that an exogenous antigen, likely an infectious organism, targets the synovia and elicits a chronic immune response. Support for this disease model has come from describing the cellular components of the inflammatory lesions, which are composed of macrophages, T cells, and B cells. The observation that HLA molecules function by specifically binding antigenic peptides and presenting them to T cells has boosted the concept of an antigen-driven response. The last decade in RA research has been dominated by a shift from premolecular to molecular techniques. A major effort has been made to determine which cytokines and inflammatory mediators are produced at the site of disease. Tissue residing and infiltrating cells secrete proinflammatory cytokines in situ, which likely have a critical role in amplifying and maintaining the inflammation. We are beginning to understand that migration of inflammatory cells into the tissue is an important component of disease, specifically because adhesion molecules not only facilitate tissue infiltration, but also affect cell activation and cell-cell and cell-matrix interactions. The paradigm that RA is an antigen-driven and thus T cell-mediated disease has brought attempts to use T cell-depleting reagents as therapeutics. Although T cells could be eliminated in the peripheral blood, overall therapeutic benefits have been minimal and accompanied by major side effects. The lack of therapeutic efficacy has been demonstrated to be combined with the persistence and the selective proliferation of T cells in the joint, reemphasizing the role of tissue-infiltrating T cells in the disease. Studies of the composition of the T cell infiltrate have demonstrated heterogeneity, indicating that disease-relevant T cells are probably low in frequency. A new perspective on the role of T cells in RA has been opened by studies establishing that RA patients select a unique repertoire of T cells in the thymus and that clonal expansion of CD4 T cells is a frequent event in RA patients. Pathology of T cell function might be much more systemic than suspected so far. RFs remain the major autoantibodies in RA patients. In the last 10 years, it has become clear that they are not exclusively built under pathologic conditions but that RF-expressing B cells are an important element of normal immune responses. All immunoglobulin isotypes are represented among RF molecules. Some of them have accumulated somatic mutations, suggesting the influence of antigen recognition and T cell help. T cell control of RF production may explain the observation that RF positivity is an HLA-dependent phenomenon. Major progress in understanding pathologic events leading to RA can be expected by abandoning single hit models, which are too simplified and underestimate the complexity of the disease. In particular, taking into account that nonimmune tissues and mechanisms might be equally important in pathogenesis will open new avenues of conceptual approaches. Cross-fertilization will likely come from genetic studies aimed at detecting underlying genetic risk factors in common genetic disease. Emerging data indicate that several genetic risk determinants, each of which is nonpathologic if occurring alone, can add up to confer disease risk. One of these genetic elements in RA has been mapped to the HLA region. A sequence polymorphism in the HLA-DR B1 gene appears to be a strong genetic risk factor in several ethnic groups. Correlation of clinical presentation of RA and the inheritance of the RA risk gene suggests that the gene product is not necessary in disease initiation but functions by modulating disease pattern and severity. The next decade in RA research will be dedicated toward unraveling how genetic determinants can introduce pathology (e.g., how HLA genes can function as progre
10567673 Various extrahepatic manifestations caused by hepatitis C virus infection. 1999 Dec It has been reported that hepatitis C virus (HCV) causes not only liver disease but also disorders of other organs and tissues. Previously, many HCV-related extrahepatic manifestations have been reported. In this study, we report 2 patients in whom tongue cancer was detected during the treatment of HCV-related liver disease. In one patient, tongue cancer was detected during the treatment of HCV-related liver cirrhosis, and articular rheumatism developed thereafter. The duration of HCV-related liver disease was 10 years. In the other patient, tongue cancer was detected during the treatment of HCV-related hepatocellular carcinoma. This patient had a past history of thyroid disease. The duration of HCV-related liver disease was 6 years. In these patients, the possibility that several conditions incidentally and concurrently developed cannot be denied. However, the conditions described above may be regarded as HCV-related extra-hepatic manifestations. In patients with HCV infection, it is important to examine conditions in organs other than the liver. Careful follow-up is needed.
9782754 [Combination therapy of rheumatoid arthritis]. 1998 Sep 28 The prevalence of rheumatoid arthritis (RA) is about 0.5-1%. The disease course is variable, but RA causes substantial morbidity and mortality. The effect of conventional therapy for RA, i.e. nonsteroidal antiinflammatory drugs (NSAID), glucocorticosteroids and Slow Acting Anti-Rheumatic Drugs (SAARD) including methotrexate, gold salts, anti-malarials, d-penicillamine and salazopyrine, is often suboptimal. Since the aim of treatment is a complete remission, combination therapy, i.e. treatment with two or more SAARDs, may be feasible since an additive/synergistic effect may be obtained. In this paper the literature about the effectiveness and toxicity of combination therapy is reviewed. Only a few randomized, clinically controlled trials have been published. None of them have documented that gold salts, d-penicillamine and azathioprine in combination with other SAARDs are better than monotherapy. However, recent trials have indicated that methotrexate in combination with salazopyrine and hydroxychloroquine or in combination with cyclosporine may cause a better therapeutic effect than methotrexate alone, without additional toxicity. Long term studies of the effect of combination therapy are not yet available.
10782808 Epstein-Barr virus infection in peripheral blood mononuclear cells, synovial fluid cells, 2000 Apr OBJECTIVE: Different infectious agents have been proposed to be involved in the pathogenesis of rheumatoid arthritis (RA). We investigated the role of latent Epstein-Barr virus (EBV) infection in patients with RA. METHODS: Sera of 55 patients with RA and 60 age and sex matched healthy controls were examined for antibodies against EBV encoded antigens (EBNA-1, VCA, and EA) by ELISA. The presence of viral DNA was analyzed by polymerase chain amplification of DNA isolated from peripheral blood mononuclear cells (PBMC) of these samples and from cells of synovial fluid (SF) specimens. Paraffin sections of synovial membranes from 25 patients were subjected to in situ hybridization analysis for the EBV encoded small RNA EBER1 and EBER2. RESULTS: Two-fold increased values of IgG antibodies against EBNA-1 were found in patients with RA in comparison to healthy controls (p = 0.029). No statistically significant difference could be observed for antibody levels against EBV-VCA. Fourteen (24.1%) of 55 patients with RA had serological evidence of reactivated EBV infection in comparison to none of the control group (p = 0.028). In PBMC, EBV DNA was detected in a significantly higher proportion in the patient group (50.9 vs. 30%; p = 0.02). In addition, SF cells harbored the viral DNA in 30% of RA cases compared to 16.6% of control cases (p = 0.02). However, EBER1/2 transcripts could only be found within synovial membranes of 2 (8%) of 25 patients with RA. CONCLUSION: These findings support the hypothesis that EBV infection may be involved in the pathogenesis of RA. Further studies may define the precise pathogenetic mechanisms of viral infection for the development of inflammatory arthritis.
9100607 Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis 1997 Apr Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and this cytokine is also a potent stimulus of the hypothalamic-pituitary-adrenal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, cortisol, and IL-6 and their interactions in patients with early untreated RA, we recruited and studied five newly diagnosed, untreated RA patients early in the course of their disease and five age-, gender-, and race-matched control subjects. We collected serial blood samples over 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 every hour. The 24-h collection was followed by administration of ovine CRH (oCRH) and post-oCRH serial blood samples over 2 h. We analyzed the 24-h overall levels of these hormones and their circadian variations and performed time-lagged cross-correlation analyses among them. The untreated RA patients had 24 h time-integrated plasma ACTH, plasma cortisol levels, and urinary free cortisol excretion that were not significantly different from control subjects, in spite of their disease activity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCRH were similar in RA patients and controls. IL-6 levels were significantly increased in the RA patients compared with control subjects during the early morning hours (P < 0.05). There was pronounced circadian variation of plasma Il-6 levels. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with elevated levels of IL-6 before the elevations of ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. The data presented here suggest that although endogenous IL-6 may stimulate secretion of ACTH and cortisol, overall activity of the hypothalamic-pituitary-adrenal axis remains normal and apparently is insufficient to inhibit ongoing inflammation in early untreated RA patients.
11036833 Large macrophage colony-forming cells identical to high proliferative potential colony-for 2000 Oct OBJECTIVE: To examine peripheral blood (PB) of patients with various collagen vascular diseases (CVD) for the presence of colony-forming cells (CFC) that form large macrophage colonies (> 2.5 mm in diameter, > 10,000 cells). METHODS: Peripheral blood mononuclear cells were obtained from 92 patients with various active CVD and 20 healthy controls, and assayed for in vitro colony formation. There were 14 patients with systemic lupus erythematosus (SLE), 30 with rheumatoid arthritis (RA), 17 with systemic sclerosis (SSc), 20 with polymyositis (PM)/dermatomyositis (DM) (11 PM, 9 DM) and 11 with systemic vasculitis. RESULTS: Large macrophage CFC were detected in PB of 7% of patients with SLE (1/14), 17% with RA (5/30), 47% with SSc (8/17), 30% with PM/DM (6/20) [9% PM (1/11) and 56% DM (5/9)], 0% of those with systemic vasculitis (0/11) and 0% of the healthy subjects (0/20). There was a significant difference between the occurrence of CFC in patients with PM versus patients with DM (p < 0.05). The occurrence of CFC in patients with SSc or DM was significantly higher than that in patients with other CVD including SLE, RA, PM, and systemic vasculitis (p < 0.05). CONCLUSION: Based on the size of the colonies they formed, the CFC corresponded to high proliferative potential colony-forming cells, a subset of primitive hematopoietic cells. Our findings among patients with CVD indicate that these primitive hematopoietic progenitor cells, which are believed to constitute a noncirculating population in healthy individuals, are found most frequently in PB of patients with SSc and DM. It is likely that primitive hematopoietic cells are frequently mobilized into the peripheral circulation during the pathogenesis of SSc and DM.
11053069 Characterisation of autoantibodies to neutrophil granule constituents among patients with 2000 Nov OBJECTIVE: To study the frequency and distribution of antineutrophil cytoplasmic autoantibodies (ANCA) among patients with reactive arthritis (ReA), rheumatoid arthritis (RA), and ulcerative colitis (UC) using different immunological methods. METHODS: Fifty serum samples from patients with reactive arthritis (26 with acute disease and 24 with chronic disease-that is disease of more than one year) were analysed for ANCA with indirect immunofluorescence, enzyme linked immunosorbent assay (ELISA) with six different neutrophil granule proteins as antigens, and immunoblotting on whole neutrophil extract and extracts of azurophil and specific granules. Thirty serum samples from patients with RA and UC served as controls in ELISA and indirect immunofluorescence. RESULTS: Sixteen per cent of patients with ReA were positive in immunofluorescence compared with 30% of patients with RA, and 70% of patients with UC. Thirty two per cent of patients with ReA were positive in ELISA. Antibodies directed against lactoferrin occurred in 20%, antibodies against bactericidal permeability increasing protein (BPI), elastase, cathepsin G, myeloperoxidase, and proteinase 3 were found in 8%, 2%, 2%, 8%, and 6%, respectively. Overall, 50% of RA sera and 53% of UC sera were positive in one or more ELISA assays, the corresponding figures for antibodies against individual antigens were for RA 7%, 3%, 0%, 13%, 47%, 17% and for UC 13%, 20%, 0%, 23%, 10%, and 17%. In immunoblotting, bands corresponding to lactoferrin and BPI were recognised in 44% and 22% of ReA sera. CONCLUSION: Antibodies against neutrophil granule antigens are often found in patients with ReA, primarily among those with chronic disease. The different methods detect various subsets of antibodies, with immunoblotting being the most and immunofluorescence the least sensitive.
11302874 Impaired catecholaminergic signalling of B lymphocytes in patients with chronic rheumatic 2001 May OBJECTIVE: To investigate further the influence of the autonomic nervous system on chronic rheumatic diseases. METHODS: The density and affinity of beta2 adrenergic receptors (beta2R) on CD19+ lymphocytes in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), as well as intracellular cAMP levels in patients with RA and SLE, were determined. Human peripheral blood mononuclear cells were separated from venous blood of patients and healthy controls by Ficoll-Hypaque density centrifugation. CD19+ lymphocytes were purified by magnetic cell sorting, and beta2R were determined by a radioligand binding assay with [125I]iodocyanopindolol. Intracellular cAMP levels and beta2R agonist induced cell death were measured by a radioimmunoassay and flow cytometry using annexin-V binding, respectively. Systemic disease activity of the patients was evaluated using multifactorial scoring systems. RESULTS: The density of beta2R on peripheral CD19+ lymphocytes was significantly decreased in patients with RA, SLE, and SSc compared with healthy controls. In patients with RA and SSc beta2R density was negatively correlated with systemic disease activity. Furthermore, although basal intracellular cAMP levels were raised in patients with RA and SLE, the increase of cAMP upon stimulation of beta2R was significantly reduced in these patients compared with control subjects. Preliminary data suggest that beta2R agonist induced cell death is diminished in patients with RA exhibiting decreased beta2R densities. CONCLUSIONS: The results of this study show a reduction of beta2R densities on B lymphocytes mirrored by an impaired intracellular cAMP generation in patients with chronic rheumatic diseases, indicating a decreased influence of the autonomic nervous system on B cells in these conditions.
9624164 Identification and characterization of small molecule functional antagonists of the CCR1 c 1998 Jun 19 The CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and RANTES (regulated on activation normal T cell expressed) have been implicated in rheumatoid arthritis and multiple sclerosis. Since their effects are mediated through the CCR1 chemokine receptor, we set up a small molecule CCR1 antagonist program to search for inhibitors. Through high capacity screening we discovered a number of 4-hydroxypiperidine compounds with CCR1 antagonist activity and report their synthesis and in vitro pharmacology here. Scatchard analysis of the competition binding data revealed that the compounds had Ki values ranging from 40 to 4000 nM. The pharmacological profile of the most potent member of this series, compound 1 (2-2-diphenyl-5-(4-chlorophenyl)piperidin-lyl)valeronitri te), was further evaluated. Compound 1 showed concentration-dependent inhibition of MIP-1alpha-induced extracellular acidification and Ca2+ mobilization demonstrating functional antagonism. When given alone, the compound did not elicit any responses, indicating the absence of intrinsic agonist activity. Compound 1 inhibited MIP-1alpha- and RANTES-induced migration in peripheral blood mononuclear cells in a dose-responsive manner. Selectivity testing against a panel of seven transmembrane domain receptors indicated that compound 1 is inactive on a number of receptors at concentrations up to 10 microM. This is the first description of CCR1 receptor antagonists that may be useful in the treatment of chronic inflammatory diseases involving MIP-1alpha, RANTES, and CCR1.
11159476 Tear film MMP accumulation and corneal disease. 2001 Feb BACKGROUND/AIMS: Matrix metalloproteinases (MMPs) accumulate in the tears of patients with active peripheral ulcerative keratitis (PUK) but it is unknown whether these enzymes have a central role in disease progression. The aims of the present investigation were to determine the source of these enzymes and to ascertain whether their accumulation in tears is a phenomenon specific to PUK or a general feature of other anterior segment diseases. METHODS: The experimental samples were obtained from the culture media of conjunctival and corneal epithelial cells, from fractionated blood plasma and leucocytes of healthy subjects and patients with rheumatoid arthritis, and from the tears of healthy subjects and patients with a variety of anterior segment diseases. The MMPs of all samples were visualised by zymography and tear samples were assayed using nitrophenol acetate and an MMP-9 susceptible quenched fluorescent peptide as substrate. RESULTS: The major MMPs that accumulate in the tears of patients with rheumatoid arthritis with active ocular disease are MMP-9 and a species of M(r) 116,000. By comparing the zymographic activity profiles of the gelatinases present in the samples obtained, it was deduced that the main source of these MMPs was granulocytes. Their accumulation in tears was not unique to patients with PUK; detectable amounts of the enzymes also occurred in the tears of patients with keratoconus with associated atopic disease, patients undergoing treatment for herpetic eye disease, and patients with systemic and non-systemic dry eye disease. CONCLUSION: The MMPs that accumulate in tears are mainly derived from granulocytes. This may be effected by autoimmune diseases that involve ocular tissue or by ocular diseases that induce an inflammatory response.