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ID PMID Title PublicationDate abstract
14673959 Leflunomide use during the first 33 months after food and drug administration approval: ex 2003 Dec 15 OBJECTIVE: To describe leflunomide (LEF) use in a national cohort of 3,325 veterans. METHODS: Prescriptions for LEF and 9 disease-modifying antirheumatic drugs written between October 1998 and June 2001 at all Veterans Affairs (VA) medical centers were obtained from VA national databases. RESULTS: LEF was initiated with a loading dose of 100 mg daily for 3 days in 61% of patients, and 42% of patients discontinued LEF. LEF was more likely to be discontinued if a 3-day 100-mg loading dose was prescribed, patients were younger than 44 years or older than 75 years, or reported an annual family income <$60,000. Review of medical records of 291 discontinuers revealed that the most common reasons for discontinuation were inefficacy (30%), gastrointestinal symptoms (29%), medication noncompliance or lost to followup (14%), and elevated liver enzymes (5%). CONCLUSION: LEF is relatively safe in clinical practice. The VA's national databases provide an excellent, inexpensive resource for postmarketing evaluation of rheumatologic medications.
15270610 Sinusoidal dilatation and congestion in liver biopsy: is it always due to venous outflow i 2004 Aug CONTEXT: Impairment of venous outflow manifests as zone 3 sinusoidal dilatation and congestion (SDC) in liver biopsy. However, the finding of SDC is not specific for venous outflow impairment.Objectives.-To determine the specificity of SDC in liver biopsies for venous outflow impairment and to seek an explanation for SDC in patients without clinical or radiologic features of venous outflow impairment. DESIGN: Liver biopsies from 51 patients with sinusoidal dilatation were reviewed. Biopsies from transplant recipients, patients with cirrhosis, and patients with hepatic neoplasms (primary or metastatic) were not included. Clinical records were reviewed for laboratory tests and final clinicopathologic diagnosis. RESULTS: Thirty-four patients (66.7%) had confirmed venous outflow impairment. Of the 17 cases (33.3%) without clinical and/or radiologic evidence of venous outflow impairment, vascular causes were present in 5 cases (9.8%; nodular regenerative hyperplasia in 2 cases and portal vein thrombosis, congenital absence of the portal vein, and sickle cell anemia in 1 case each). Systemic inflammatory disorders were identified in 6 patients (11.8%). These included 2 cases of Castleman disease and 1 each of sarcoidosis, Crohn disease, rheumatoid arthritis, and Still disease. Three patients (5.9%) had tumors without direct involvement of the liver (1 case each of Hodgkin lymphoma, renal cell carcinoma, and pancreatic serous pseudopapillary tumor). In the remaining 3 patients, SDC was identified in wedge liver biopsies performed at the time of surgery, including gastric bypass surgery, cholecystectomy, and splenectomy. No other disease association was apparent in these cases. CONCLUSION: Sinusoidal dilatation and congestion in liver biopsy is associated with venous outflow impairment in two thirds of the cases. In the absence of clinical and/or radiological evidence of venous outflow, diagnostic considerations include other vascular conditions, such as portal vein insufficiency and nodular regenerative hyperplasia. Sinusoidal dilatation and congestion can also occur in the setting of systemic inflammatory diseases, granulomatous disorders, and neoplasms, as well as in wedge biopsies obtained during abdominal surgery.
14593899 [Cyclic citrullinated peptide antibodies (anti-CCP) together with some other parameters us 2003 Apr Rheumatoid arthritis (RA) is one of the most common rheumatic disease, which is primarily diagnosed by clinical history, physical examination, and laboratory tests, including a large number of biochemical and biologic markers. Recently, it has been shown that the amino acid citrulline, which is a unit of filaggrin, is a substantial component of the antigenic epitope, and enzyme immunoassays which use synthetic citrullinated peptide are highly effective tests for the detection of autoantibodies against cyclic citrullinated peptide (CCP), which are a new a highly specific marker for RA. The aim of this study was to investigate the presence of anti-CCP antibodies in RA suspected patients and to evaluate the combination of these autoantibodies with some other serologic markers such as IgM-rheumatoid factor (IgM-RF), C-reactive protein (CRP) and antinuclear antibodies (ANAs). For this purpose, the concentrations of RF and CRP were determined by quantitative immunonephelometry, titres of ANAs by indirect immunofluorescence, and presence of anti-CCP by a commercial semiquantitative microELISA method, in 88 patients with clinically suspected RA, as well as 42 sex- and age-matched healthy blood donors. As a result, the high levels of IgM-RF and CRP were found in 48 (54.5%) and 49 (55.7%) of the patients, respectively, while 47 (53.4%) and 25(28.4%) patients were found positive for ANAs and anti-CCP, respectively. Of 48 RF positive patients, 25 were also positive for anti-CCP, and the distribution rates of the markers in 25 anti-CCP positive patients were as follows; 100% for RF, 84% for CRP and 52% for ANA. The sensitivity of anti-CCP ELISA was 52.1% and specificity was 100%, when evaluated according to RF positivity as a main serologic marker of RA. In conclusion, anti-CCP antibody testing may be useful in the serologic diagnosis of RA patients, especially in combination with RF, however more detailed follow-up clinical studies on the large number of patients with established RA, would be needed for our country.
15550531 Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune dis 2005 Jun OBJECTIVE: To assess the tolerance and efficacy of rituximab in patients with various autoimmune diseases seen in daily rheumatological practice. METHODS: 866 rheumatology and internal medicine practitioners were contacted by e-mail to obtain the files of patients treated with rituximab for systemic autoimmune diseases. Patients with lymphoma were analysed if the evolution of the autoimmune disease could be evaluated. RESULTS: In all, 43 of 49 cases could be analysed, including 14 with rheumatoid arthritis (RA), 13 with systemic lupus erythematosus (SLE), six with primary Sjogren's syndrome (pSS), five with systemic vasculitis, and five with other autoimmune diseases. Rituximab was prescribed for lymphoma in two patients with RA and two with pSS. In the 39 other cases, rituximab was given because of the refractory character of the autoimmune disease. The mean follow up period was 8.3 months (range 2 to 26). There were 11 adverse events in 10 patients and treatment had to be discontinued in six. Efficacy was observed in 30 patients (70%): RA 11, SLE 9, pSS 5, vasculitis 2, antisynthetase syndromes 2, sarcoidosis 1. The mean decrease in corticosteroid intake was 9.5 mg/d (range 0 to 50) in responders. Seven patients experienced relapse after mean 8.1 months (5 to 15). Three patients died because of refractory autoimmune disease. CONCLUSIONS: Despite absence of marketing authorisation, rituximab is used to treat various refractory autoimmune diseases in daily rheumatological practice. This study showed good tolerance and short term clinical efficacy, with marked corticosteroid reduction in patients with SLE, pSS, vasculitis, and polymyositis.
15014430 Linkage analysis of SLE susceptibility: confirmation of SLER1 at 5p15.3. 2004 May We detected a novel susceptibility gene, SLER1, for systemic lupus erythematosus (SLE) at 5p15.3.(1) This finding was based on a selected subgroup of SLE families, where two or more family members have had alleged rheumatoid arthritis (SLE-RA). The main objective of this study was to replicate the linkage at 5p15.3 based on an independent data set of 88 SLE-RA families. Heterogeneity in the genetic model led us to use a nonparametric allele-sharing method. Since our a priori hypothesis of linkage at 5p15.3 was fixed, we genotyped six markers at the linked region. Our new results replicate the initial linkage at 5p15.3 (Zlr=2.58, P<0.005, LOD=1.45). Moreover, evidence of linkage was sustained when analysis was restricted to the subset of SLE families who had 3 or more individuals with alleged RA (Zlr=3.32, P=0.008, LOD=2.40) The results of our previous findings, together with these new results, confirm the SLER1 linkage at 5p15.3. Our results also demonstrate the utility of clinically defined subgroup analysis for detecting susceptibility loci for complex genetic diseases, such as SLE.
12705062 [Cyclooxygenase 2 selective antirheumatic analgesics]. 2003 Because of Cyclooxygenase-2 selective non steroidal anti-inflammatory drugs (NSAIDs), the therapy of articular pain has become safer and more convenient. Currently, two highly Cyclooxygenase-2 selective drugs, celecoxib and rofecoxib, are available. Both are effective for patients with osteoarthritis (at daily dosages of 200 mg and 12.5 mg, respectively) and rheumatoid arthritis (RA) (at twice the above dosages). At higher daily dosages of 800 mg and 50 mg these substances still appear safe with regard to life-threatening gastrointestinal complications (perforation, obstruction, bleeding), if not given with concomitant aspirin. However, Cyclooxygenase-2 selective non steroidal anti-inflammatory drugs do not confer protection against platelet aggregation and aspirin must be given where required for cardiovascular prophylaxis. Most patients will then routinely need gastroprotective agents such as proton pump inhibitors or misoprostol; it is unclear whether coxibs confer any benefit under such circumstances. Although not a coxib, Meloxicam does not appear to cause serious gastrointestinal complications if the low daily dosage of 7.5 mg is sufficient for the control of less pronounced pain and thus not exceeded. The gastrointestinal safety of nimesulide can not be sufficiently evaluated based on the available clinical data.
12785554 Relocating rheumatology patients to a new infusion center at Duke: a case study. 2003 Apr This case study concerns relocating rheumatology patients at Duke University Medical Center to a new infusion center located in a physician based treatment setting. The case study follows the managerial decision-making process as it describes how the infusion center treatment site was chosen, how it was set up, how it functions, and what benefits to patient care it provides. A successful site-of-car relocation requires strong managers who are able to weigh objectively alternative courses of action. Moreover, the project champion must be able to distinguish key factors inside and outside the organization and chart the project's course accordingly.
15266426 Short-term low-dose corticosteroids vs placebo and nonsteroidal antiinflammatory drugs in 2004 BACKGROUND: The effect of low dose corticosteroids, equivalent to 15 mg prednisolone daily or less, in patients with rheumatoid arthritis has been questioned. We performed a systematic review of trials which compared corticosteroids with placebo or non-steroidal, anti-inflammatory drugs. OBJECTIVES: To determine whether short-term (i.e. as recorded within the first month of therapy), oral low-dose corticosteroids (corresponding to a maximum of 15 mg prednisolone daily) is superior to placebo and non-steroidal, anti-inflammatory drugs in patients with rheumatoid arthritis. SEARCH STRATEGY: PubMed, The Cochrane Central Register of Controlled Trials (CENTRAL ), reference lists were searched until February 2004. SELECTION CRITERIA: All randomised studies comparing an oral corticosteroid (not exceeding an equivalent of 15 mg prednisolone daily) with placebo or a non-steroidal, anti-inflammatory drug were eligible if they reported clinical outcomes within one month after start of therapy. For adverse effects, long-term trials and matched cohort studies were also selected. DATA COLLECTION AND ANALYSIS: Decisions on which trials to include were made independently by two observers based on the methods sections of the trials. Standardised mean difference (random effects model) was used for the statistical analyses. MAIN RESULTS: Ten studies, involving 320 patients, were included. Prednisolone had a marked effect over placebo on joint tenderness (standardised mean difference 1.30, 95% confidence interval 0.78 to 1.83), pain (1.75, 0.87 to 2.64) and grip strength (0.41, 0.13 to 0.69). Measured in the original units, the differences were 12 tender joints (6 to 18) and 22 mm Hg (5 to 40) for grip strength. Prednisolone also had a greater effect than non-steroidal, anti-inflammatory drugs on joint tenderness (0.63, 0.11 to 1.16) and pain (1.25, 0.26 to 2.24), whereas the difference in grip strength was not significant (0.31, -0.02 to 0.64). Measured in the original units, the differences were 9 tender joints (5 to 12) and 12 mm Hg (-6 to 31). The risk of adverse effects, also during moderate- and long-term use, seemed acceptable. REVIEWERS' CONCLUSIONS: Prednisolone in low doses (not exceeding 15 mg daily) may be used intermittently in patients with rheumatoid arthritis, particularly if the disease cannot be controlled by other means. Since prednisolone is highly effective, short-term placebo controlled trials studying the clinical effect of low-dose prednisolone or other oral corticosteroids are no longer necessary.
15208519 COX-2 inhibitors: a CLASS act or Just VIGORously promoted. 2004 Mar 23 Abstract Selective cyclo-oxygenase (COX)-2 inhibitors were developed with the hope of producing lesser gastrointestinal (GI) side effects as compared with the conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Soon after their introduction into the market, the sales of celecoxib and rofecoxib went up considerably. Most of this was attributed to the results of the Celecoxib Long-term Arthritis Safety Study (CLASS) and Vioxx Gastrointestinal Outcome Research (VIGOR) trials. However, several discrepancies were noted in the presentation of the actual trial results submitted to the US Food and Drug Administration (FDA) and those used for the purpose of publication in scientific journals. These issues were discussed subsequently by the way of scientific communications. Moreover, with increasing use of these agents, evidence of their adverse effects is coming to light. The present review aims at discussing the above issues, with emphasis on the results of the CLASS and VIGOR trials.
12415565 CD157, the Janus of CD38 but with a unique personality. 2002 Dec CD157 is a pleiotropic ectoenzyme which belongs to the CD38 family and to the growing number of leukocyte surface molecules known to act independently as both receptors and enzymes. A 45-kDa surface structure with a GPI anchor, the CD157 molecule displays two distinct domains in its extracellular component. The first is implicated in the enzymic activities of the molecule and the second features adhesion/signalling properties. CD157 shares several characteristics with CD38, including a similar amino acid sequence and enzymic functions. Both molecules are involved in the metabolism of NAD(+), and the CD157 gene is synthenic on 4p15 with CD38, with which it also shares a unique genomic organization. Their conservation in phylogeny is striking evidence for their relevance in the life and death cycle of the cell.
12658905 [Cortisone therapy today]. 2003 Jan 31 Five decades of experimental and clinical experience have changed corticoid therapy thoroughly. Corticoides have two modes of action. The first is a genomic effect through which anti-inflammatory proteins are formed which inhibit pro-inflammatory cytokines. This effect is initiated even by small doses, but is of late onset. The use of high doses initiates non-genomic effects through alterations of the cell membrane; these effects are found early after initiation of treatment. The risk of adverse corticoid effects are extremely rare when modern application forms and therapy regimens are used: Very high doses for a short time in case of acute states of illness, very low doses in long-term therapy of chronic illnesses, and the use of topical substances wherever this is possible. As for the dose regimen, one should start with an initial dose which suffices to treat the acute state, and subsequently reduce the dosage after the first positive results are obtained. In long-term therapy a daily dose of 5 mg prednisolone should not be exceeded; usually even lower doses are sufficient. These very low doses can only be reached by reducing in steps of one half to one milligram over very long periods of time. During long-term therapy osteoporosis prophylaxis is mandatory. Due to these new therapeutic concepts treatment of rheumatoid arthritis with corticoids is experiencing a revival. Low-dose corticoid therapy is of lower risk than nonsteroidal antirheumatic treatment and slows down disease progression, i.e. joint destruction is significantly inhibited. Corticoids have also undergone a new development in the treatment of asthma. Previously used only in acute systemic therapy, they have now been established in basic therapy, i.e. long term therapy using special topic applications.
15485092 Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. 2004 Sex hormones seem to play an important role as modulators of the autoimmune disease onset/perpetuation. Generally, steroid hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immunosuppressors. Synovial fluid levels (SF) of proinflammatory estrogens relative to androgens are significantly elevated in both male and female rheumatoid arthritis (RA) patients, as compared to controls, which is most probably due to increase of local enzymatic aromatase activity. Serum levels of estrogens have been found altered in RA patients, particularly estradiol in man. Thus, available steroid prehormones are rapidly converted to proinflammatory estrogens in the synovial tissue in the presence of inflammatory cytokines (i.e., TNFalpha, IL-1, IL-6). The increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by the hydroxylated forms, in particular, 16alpha-hydroxyestrone, showing a mitogenic tumor growth stimulating role. Altered serum hydroxylated estrogens have been found also in serum of systemic lupus erythematosus (SLE) patients. As a matter of fact, our recent studies indicate that 17-beta estradiol (E2) clearly enhanced the expression of markers of cell growth and proliferation, whereas testosterone (T) induced an increase of markers indicating DNA damage and apoptosis. In particular, our data further shows that the enhancing role of estrogens on immune/inflammatory response is exerted by activating the NFkB complex pathway. In conclusion, locally increased estrogens (i.e., synovial tissue in RA or skin in SLE) might exert activating effects on cell proliferation, including macrophages and fibroblasts, suggesting new roles for estrogens in autoimmunity.
15248209 Dissection of class III major histocompatibility complex haplotypes associated with rheuma 2004 Jul OBJECTIVE: We have previously identified a single-nucleotide polymorphism (SNP) haplotype involving the lymphotoxin alpha (LTA) and tumor necrosis factor (TNF) loci (termed haplotype LTA-TNF2) on chromosome 6 that shows differential association with rheumatoid arthritis (RA) on HLA-DRB1*0404 and *0401 haplotypes, suggesting the presence of additional non-HLA-DRB1 RA susceptibility genes on these haplotypes. To refine this association, we performed a case-control association study using both SNPs and microsatellite markers in haplotypes matched either for HLA-DRB1*0404 or for HLA-DRB1*0401. METHODS: Fourteen SNPs lying between HLA-DRB1 and LTA were genotyped in 87 DRB1*04-positive families. High-density microsatellite typing was performed using 24 markers spanning 2,500 kb centered around the TNF gene in 305 DRB1*0401 or *0404 cases and 400 DRB1*0401 or *0404 controls. Single-marker, 2-marker, and 3-marker minihaplotypes were constructed and their frequencies compared between the DRB1*0401 and DRB1*0404 matched case and control haplotypes. RESULTS: Marked preservation of major histocompatibility complex haplotypes was seen, with chromosomes carrying LTA-TNF2 and either DRB1*0401 or DRB1*0404 both carrying an identical SNP haplotype across the 1-Mb region between TNF and HLA-DRB1. Using microsatellite markers, we observed two 3-marker minihaplotypes that were significantly overrepresented in the DRB1*0404 case haplotypes (P = 0.00024 and P = 0.00097). CONCLUSION: The presence of a single extended SNP haplotype between LTA-TNF2 and both DRB1*0401 and DRB1*0404 is evidence against this region harboring the genetic effects in linkage disequilibrium with LTA-TNF2. Two RA-associated haplotypes on the background of DRB1*0404 were identified in a 126-kb region surrounding and centromeric to the TNF locus.
12942798 [New drugs and treatment strategies for rheumatoid arthritis]. 2003 Sep The management of rheumatoid arthritis (RA) has changed considerably during the past 15 years. Current strategies emphasize the need for early diagnosis and therapeutic intervention based on the use of disease modifying antirheumatic drugs (DMARDs). More than a dozen drugs or drug classes of DMARDs are currently in common use in RA. After a long hiatus, drug development for RA resumed a few years ago with the introduction of Leflunomide and the biologic agents. Unlike the older DMARDs (apart from the cytotoxics) the newer drugs were designed with strict reference to RA pathophysiology and the intended action of these agents is highly likely the explanation for the observed efficacy. Proinflammatory cytokines, such as interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF), play an important role in maintaining the chronicity of RA and mediating tissue damage. TNF antagonists have rapidly emerged as a valuable class of antirheumatic agents. Etanercept, a dimerized version of the soluble TNF receptor II, and infliximab, a chimeric anti-TNF monoclonal antibody, are currently approved in our country for the treatment of refractory RA in the frame of ANTARES Project. Other two biologic agents, adalimumab, a fully humanized anti-TNF monoclonal antibody, and anakinra, a recombinant human IL-1 receptor antagonist, will be also soon available. It is recommended to initiate pharmacological treatment with an effective DMARD early in the course of the disease. Biological therapies have the potential to revolutionize the treatment of RA; however the use of TNF blocking agents as the first DMARD for the treatment of RA should, at present, be limited, because these compounds are expensive and one needs to include cost considerations along with those of efficacy, effectiveness and long-term safety.
15762257 Increased risk of dislocation after primary total hip arthroplasty in inflammatory arthrit 2004 Dec BACKGROUND: It is unclear whether patients with inflammatory arthritis have a higher risk of dislocation after hip replacement. PATIENTS AND MATERIAL: We carried out a prospective study assessing the incidence of dislocation within 2 years after surgery for patients diagnosed with inflammatory arthritis (IA) and osteoarthrosis (OA). One single type of prosthesis was implanted using a lateral approach. Both diagnostic groups were compared by univariate analysis with respect to dislocation, sex, age, diagnosis, prior hip surgery, experience of the surgeon and malposition of the acetabular component. In a multivariate logistic regression approach, the difference in dislocation incidence was assessed after adjusting for the effect of the potential confounders given above. Between 1996 and 1999, 410 THA were performed: 70 in IA and 340 in OA. After 2 years no patients were lost to follow-up, but 12 patients had died, and 5 revisions were carried out for reasons other than dislocation. RESULTS: The dislocation rate in patients with IA was higher than in patients with OA: 10% (7 hips) in the IA group and 3% (10 hips) in the OA group (p = 0.006). No significant differences were found among the risk factors for dislocation between the two groups. Multivariate logistic regression analysis showed that IA is an independent risk factor for dislocation (odds ratio (OR) 3.7, 95% CI 1.3-11), together with malposition of the cup in more than 55 degrees abduction (OR 7.7, CI 2.3-26) and increased anteversion (OR 7.6, CI 1.4-42.4). INTERPRETATION: Our findings clearly suggest that inflammatory arthritis has to be considered as an independent risk factor for dislocation after primary THA.
12632416 Bacterial peptidoglycans but not CpG oligodeoxynucleotides activate synovial fibroblasts b 2003 Mar OBJECTIVE: To test the hypothesis that bacterial products acting as adjuvants, such as CpG oligodeoxynucleotides (ODNs) and peptidoglycans (PGs), are able to activate synoviocytes, and to determine the involvement of Toll-like receptors (TLRs) in this activation process. METHODS: Cultured synovial fibroblasts obtained from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) were stimulated with CpG ODNs or PGs. The expression of various integrins was determined by fluorescence-activated cell sorting. TLR and matrix metalloproteinase (MMP) messenger RNA (mRNA) was measured by real-time polymerase chain reaction. Additionally, levels of interleukin-6 (IL-6) and IL-8 in the culture supernatants were assessed by enzyme-linked immunosorbent assay. Blocking experiments were performed by adding anti-TLR-2 and anti-TLR-4 monoclonal antibodies to cultures stimulated with bacterial PGs. RESULTS: Incubation of synovial fibroblasts with CpG ODNs resulted in neither up-regulation of the expression of integrins on the cell surface, up-regulation of MMP mRNA expression, nor IL-6 and IL-8 production. However, incubation of RA synovial fibroblasts as well as OA synovial fibroblasts with staphylococcal PGs led to an up-regulation of CD54 (ICAM-1) surface expression and to increased expression of MMP-1, MMP-3, and MMP-13 mRNA. Furthermore, production of the proinflammatory cytokines IL-6 and IL-8 was increased by treatment with PGs. We demonstrated that cultured synovial fibroblasts express low levels of TLR-2 and TLR-9 mRNA. TLR-2 was up-regulated after stimulation with PGs, whereas TLR-9 mRNA remained at baseline levels after stimulation with CpG ODNs. Anti-TLR-2 monoclonal antibodies significantly inhibited production of IL-6 and IL-8 induced by stimulation with PGs. CONCLUSION: We demonstrate that bacterial PGs activate synovial fibroblasts, at least partially via TLR-2, to express integrins, MMPs, and proinflammatory cytokines. Inhibition of TLR signaling pathways might therefore have a beneficial effect on both joint inflammation and joint destruction.
14652683 Effect of hypoxia on monocyte chemotactic protein-1 (MCP-1) gene expression induced by Int 2003 Nov OBJECTIVE: Rheumatoid arthritis (RA) synovial membrane is characterized by leucocyte infiltration and secretion of chemotactic and proinflammatory factors. Since hypoxia is an important pathogenic factor in inflamed synovium, we examined the effects of hypoxia on monocyte chemotactic protein-1 (MCP-1) expression in human rheumatoid arthritis synovial fibroblasts (RASF) under IL-1beta-stimulated and -unstimulated conditions. METHODS: Synovial fibroblasts were isolated from RA, osteoarthritis (OA) and healthy knee joints and subjected to hypoxia or/and IL-1beta treatment. MCP-1 expression and protein secretion were measured by real-time PCR and ELISA, respectively. RESULTS: Hypoxia reduces MCP-1 expression and protein secretion in RASF. The same response to hypoxia was found in OA and healthy SF cultures. Treatment with actinomycin D showed that hypoxic down-regulation of MCP-1 expression was due to a decrease in transcription, since the half-life of MCP-1 mRNA was unchanged. A cycloheximide study demonstrated that de novo protein synthesis was not required for the hypoxic effect. The decrease in MCP-1 expression by hypoxia was mimicked by cobalt chloride in unstimulated RASF with no effect on IL-1beta-activated MCP-1, suggesting differences in the signaling mechanisms. The analysis of IkappaB degradation and NF-kappaB translocation revealed that hypoxia did not affect IL-1beta activation of NF-kappaB. CONCLUSION: Hypoxia regulates MCP-1 expression under both basal and cytokine-stimulated conditions, suggesting that reduced oxygen supply is an important factor that mediates chemotaxis of monocytes to the area of inflammation.
12411093 [Retrospective study of adverse events in patients with rheumatoid arthritis treated with 2002 Jun OBJECTIVE: To evaluate rates on the adverse side effect and discontinuation of second-line drugs frequently used in the treatment of rheumatoid arthritis (RA). METHOD: Eight hundred and sixty-four RA patients were studied in a retrospective program. RESULTS: Upper abdominal discomfort was most commonly seen when using second-line drugs. Rash was often associated with D-penicillamine (20.6%) and Sinomenium therapy (13.7%). Methotrexate (MTX) was uniquely characterized by substantial upper GI toxicity (32.2%) and Tripterygium wilfordii Hook. f. (TWH) (14.4%) by menstrual abnormality. Sulfasalazine users reported adverse events including upper abdominal trouble (39.0%), nausea (7.3%) and anorexia (7.3%) while the risk of GI malaise was greater. Patients taking hydroxychloroquine complained of blurred vision (19.6%) but no one went blind. Toxic side effects seemed to be the most common reasons for stoppages, and the patients taking MTX had the lowest discontinuation rate. Combination of D-penicillamine and Methotrexate did not increase the incidence of adverse events. CONCLUSIONS: Knowledge on these different patterns of toxicity provided choices in the selection of second line agents for particular RA patients. However, long-term monitor are required when drugs are being used.
12483719 Induction of apoptosis in rheumatoid synovial fibroblasts by celecoxib, but not by other s 2002 Dec OBJECTIVE: Selective cyclooxygenase 2 (COX-2) inhibitors are now being used as antiinflammatory agents that cause fewer gastrointestinal complications, compared with other antiinflammatory drugs, in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether selective COX-2 inhibitors could induce apoptosis of RA synovial fibroblasts (RASFs). METHODS: RASFs were exposed to selective COX-2 inhibitors, i.e., celecoxib, etodolac, meloxicam, nimesulide, N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methanesulfonamide, and rofecoxib, under various conditions. Cell proliferation and cell viability were assessed by incorporation of 5-bromo-2'-deoxyuridine and by the 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, respectively. Apoptosis was detected by identifying DNA fragmentation. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) was measured by the luciferase reporter gene assay with a PPAR response element-driven luciferase reporter plasmid and a PPARgamma expression plasmid. RESULTS: Celecoxib strongly inhibited the proliferation of RASFs, whereas other selective COX-2 inhibitors had little or no effect. In addition, celecoxib reduced the viability of RASFs by induction of apoptosis, in a concentration-dependent manner. This action was abolished by addition of caspase inhibitors. Interleukin-1beta had a weak enhancing effect on celecoxib-induced apoptosis in RASFs. In contrast, other selective COX-2 inhibitors at concentrations up to 100 microM did not induce apoptosis of RASFs. Indomethacin, a nonselective COX inhibitor, activated PPARgamma transcription, while celecoxib did not. CONCLUSION: Celecoxib suppressed the proliferation of RASFs by COX-2-independent and PPARgamma-independent induction of apoptosis. Although the mechanism involved remains unclear, celecoxib may have not only antiinflammatory activity, but also a disease-modifying effect on rheumatoid synovial proliferation.
11896393 Dynamic visualization of a joint-specific autoimmune response through positron emission to 2002 Apr In the K/BxN mouse model of rheumatoid arthritis, the transfer of autoantibodies specific for glucose-6-phosphate isomerase (GPI) into naïve mice rapidly induces joint-specific inflammation similar to that seen in human rheumatoid arthritis. The ubiquitous expression of GPI and the systemic circulation of anti-GPI immunoglobulin G (IgG) seem incongruous with the tissue specificity of this disease. By using PET (positron emission tomography), we show here that purified anti-GPI IgG localizes specifically to distal joints in the front and rear limbs within minutes of intravenous injection, reaches saturation by 20 min and remains localized for at least 24 h. In contrast, control IgG does not localize to joints or cause inflammation. The rapid kinetics of anti-GPI IgG joint localization supports a model in which autoantibodies bind directly to pre-existing extracellular GPI in normal healthy mouse joints.