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ID PMID Title PublicationDate abstract
15248210 Sulfasalazine is a potent inhibitor of the reduced folate carrier: implications for combin 2004 Jul OBJECTIVE: To investigate whether interactions of sulfasalazine (SSZ) with reduced folate carrier (RFC), the dominant cell membrane transporter for natural folates and methotrexate (MTX), may limit the efficacy of combination therapy with MTX and SSZ in patients with rheumatoid arthritis. METHODS: Human RFC-(over)expressing CEM cells of T cell origin were used to analyze the effect of SSZ on the RFC-mediated cellular uptake of radiolabeled MTX and the natural folate leucovorin. Moreover, both cells with and those without acquired resistance to SSZ were used to assess the antiproliferative effects of MTX in combination with SSZ. RESULTS: Transport kinetic analyses revealed that SSZ was a potent noncompetitive inhibitor of RFC-mediated cellular uptake of MTX and leucovorin, with mean +/- SD K(i) (50% inhibitory concentration) values of 36 +/- 6 microM and 74 +/- 7 microM, respectively. Consistent with the inhibitory interaction of SSZ with RFC, a marked loss of MTX efficacy was observed when MTX was coadministered with SSZ: up to 3.5-fold for CEM cells in the presence of 0.25 mM of SSZ, and >400-fold for SSZ-resistant cells in the presence of 2.5 mM of SSZ. Importantly, along with diminished efficacy of MTX, evidence for cellular folate depletion was obtained by the demonstration of an SSZ dose-dependent decrease in leucovorin accumulation. CONCLUSION: At clinically relevant plasma concentrations, interactions of SSZ with RFC provide a biochemical rationale for 2 important clinical observations: 1) the onset of (sub)clinical folate deficiency during SSZ treatment, and 2) the lack of additivity/synergism of the combination of SSZ and MTX when these disease-modifying antirheumatic drugs are administered simultaneously. Thus, when considering use of these drugs in combination therapies, the present results provide a rationale both for the use of folate supplementation and for spacing administration of these drugs over time.
12945803 Expression and activities of matrix metalloproteinases under oscillatory shear in IL-1-sti 2003 Matrix metalloproteinases (MMPs) are known to play a critical role in tissue disintegration, and an elevated level of MMPs is observed in synovium and synovial fluid of joints with rheumatoid arthritis. During joint movement, synovial tissue receives various mechanical stimuli, but effects of mechanical challenges on regulation of MMPs in rheumatic synovium are poorly understood. Focusing on cellular responses to oscillatory fluid shear in human synovial cells, we determined the expression of MMP-1 and MMP-13 by polymerase chain reaction and immunoblotting as well as proteolytic activities of total MMPs by a fibril degradation assay and zymography. The results revealed that approximately 0.5 dyn/cm2 oscillatory shear at 1 Hz not only reduced an mRNA level and a protein level of MMP-1 and MMP-13, but it also decreased collagenase and gelatinase activities of total MMPs. Furthermore, the induction of the MMP expression and activities by interleukin-1 was suppressed by the oscillatory shear. Interestingly, the oscillatory shear upregulated the mRNA expression of TIMP-1 and TIMP-2. Our results support a potential role of oscillatory shear in regulating expression and activities of MMPs in the presence and the absence of proinflammatory cytokine.
12594231 Matrix metalloproteinase production by COOH-terminal heparin-binding fibronectin fragment 2003 Feb Fibronectin with IIICS region is present in rheumatoid synovium, and fibronectin fragments are increased in rheumatoid joints. We investigated the ability of COOH-terminal heparin-binding fibronectin fragment (COOH-HBFN-f) containing IIICS to induce matrix metalloproteinase (MMP) production and the role of mitogen-activated protein kinase (MAPK) pathway and CS-1 sequence that can bind alpha4beta1 integrin in MMP induction by COOH-HBFN-f in rheumatoid synovial fibroblasts (RSF). When RSF in monolayer culture were incubated with COOH-HBFN-f, COOH-HBFN-f stimulated the production of MMP-1, MMP-3, and MMP-13 by RSF in association with activation of extracellular signal-regulated kinase, p38 MAPK, and c-Jun NH(2)-terminal kinase. Immunoprecipitation of cell lysates demonstrated the presence of alpha4 integrin in cultured RSF. Similar to COOH-HBFN-f, treatment with CS-1 synthetic peptide derived from IIICS resulted in increased MMP production and activation of the kinases, although the MMP levels were low. Preincubation of RSF with anti-alpha4 integrin antibody resulted in partial suppression of the COOH-HBFN-f-stimulated MMP production. Inhibition studies using protein kinase inhibitors (PD98059 and SB203580) showed that those MAPK pathways contributed to MMP up-regulation by COOH-HBFN-f and CS-1. Thus, the present results have clearly shown that COOH-HBFN-f and CS-1 stimulate MMP production in association with activation of MAPK pathways in RSF. Integrin alpha4beta1 may be partially involved in the MMP induction by COOH-HBFN-f.
12115175 Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthri 2002 Jun OBJECTIVE: A dose-response relationship for hydroxychloroquine (HCQ), in terms of the proportion of patients achieving the Paulus 20% criteria for improvement, had previously been observed in patients with rheumatoid arthritis (RA) receiving a 6-week loading regimen of 400, 800, or 1,200 mg HCQ daily. This present retrospective analysis was performed to investigate possible relationships between the blood HCQ and HCQ-metabolite concentrations and measures of efficacy and toxicity. In addition, we sought to ascertain whether further investigation of HCQ/HCQ-metabolite levels might lead to testing of one of these substances as a new antirheumatic drug. METHODS: Patients with active RA (n = 212) began a 6-week, double-blind trial comparing 3 different doses of HCQ at 400, 800, or 1,200 mg/day, followed by 18 weeks of open-label HCQ treatment at 400 mg/day. Patients were repeatedly evaluated for treatment efficacy and toxicity. Blood samples were available from 123 patients for analysis of HCQ, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ) levels using high-performance liquid chromatography. Achievement of the modified Paulus 20% improvement criteria for response in RA was used as the primary efficacy parameter. Spontaneously reported adverse events were categorized and analyzed as toxicity outcome variables. The relationship between response (efficacy and toxicity) and drug levels was evaluated using logistic regression analysis. RESULTS: The subset of patients with blood concentration data was equivalent to the larger study population in all demographic and outcome characteristics. The mean HCQ, DHCQ, and DCQ elimination half-lives were 123, 161, and 180 hours, respectively. There was a positive correlation between the Paulus 20% improvement criteria response and blood DHCQ concentrations during weeks 1-6 (P < 0.001). A potential relationship between ocular adverse events and BDCQ levels was found (P = 0.036). Logistic regression analysis of adverse events data showed that adverse gastrointestinal events were associated with higher HCQ levels (P = 0.001-0.021) during weeks 1, 2, and 3. CONCLUSION: There is a weak, but predictable, relationship between blood DHCQ concentrations and efficacy of treatment with HCQ. In addition, there is an association between gastrointestinal adverse events and elevated blood HCQ concentrations. Further investigation of these relationships is warranted to see if DHCQ may be introduced as a new antirheumatic drug.
12594102 Tartrate resistant acid phosphatase (TRAP) positive cells in rheumatoid synovium may induc 2003 Mar OBJECTIVE: To examine the role of tartrate resistant acid phosphatase (TRAP) positive mononuclear and multinucleated cells in the destruction of articular cartilage in patients with rheumatoid arthritis (RA). METHODS: The presence of TRAP positive cells in the synovial tissue of patients with RA was examined by enzyme histochemistry and immunohistochemistry. Expression of mRNAs for matrix metalloproteinases (MMPs) was assessed by the reverse transcriptase-polymerase chain reaction (RT-PCR) and northern blot analysis. Production of MMPs by mononuclear and multinucleated TRAP positive cells was examined by immunocytochemistry, enzyme linked immunosorbent assay (ELISA) of conditioned medium, and immunohistochemistry of human RA synovial tissue. In addition, a cartilage degradation assay was performed by incubation of (35)S prelabelled cartilage discs with TRAP positive cells. RESULTS: TRAP positive mononuclear cells and multinucleated cells were found in proliferating synovial tissue adjacent to the bone-cartilage interface in patients with RA. Expression of MMP-2 (gelatinase A), MMP-9 (gelatinase B), MMP-12 (macrophage metalloelastase), and MMP-14 (MT1-MMP) mRNA was detected in TRAP positive mononuclear and multinucleated cells by both RT-PCR and northern blot analysis. Immunocytochemistry for these MMPs showed that MMP-2 and MMP-9 were produced by both TRAP positive mononuclear and multinucleated cells, whereas MMP-12 and MMP-14 were produced by TRAP positive multinucleated cells. MMP-2 and MMP-9 were detected in the conditioned medium of TRAP positive mononuclear cells. TRAP positive mononuclear cells also induced the release of (35)S from prelabelled cartilage discs. CONCLUSION: This study suggests that TRAP positive mononuclear and multinucleated cells located in the synovium at the cartilage-synovial interface produce MMP-2 and MMP-9, and may have an important role in articular cartilage destruction in patients with RA.
15339135 [Osteoporosis]. 2002 Mar It is well known that people, especially white people, are getting osteoporosis more often than previously thought. Until now, no direct causative factor has been determined, but genetic factors are very likely to be involved. Usually, affected individuals are initially asymptomatic while the disease process is going on, and they come to the attention of the medical profession only late when their bones are fractured as a result of a simple trauma. Also it is vital to let people know that heavy sports, at times, can be harmful.
14621575 [Measures for tuberculosis in compromised hosts--mainly on chemoprophylaxis]. 2003 Oct As for the measures for tuberculosis in Japan, BCG inoculation and chemoprophylaxis have been done with emphasis placed on children and young people. Since, however, about 90% are older than 30 years and more than 50% are older than 60 years among the new TB patients, measures, particularly chemoprophylaxis aiming at the middle-old aged people are needed in the future. We discuss the method to select cases for chemoprophylaxis as to the cases of diabetes, collagen diseases and lung cancer administered corticosteroid preparations as well as the cases of Crohn's disease and rheumatoid arthritis administered anti-TNF-alpha among compromised hosts. In diabetics, chemoprophylaxis is necessary for those who show healing of TB despite there being no history of TB treatment. Where a corticosteroid preparation, more than 10 mg in terms of prednisolone is administered over a long period of time for collagen disease and lung cancer, chemoprophylaxis is necessary for those who show healing of TB despite there being no history of TB treatment and those who are suspected of having TB infection by a tuberculin test. In the cases of Crohn's disease and rheumatoid arthritis administered anti-TNF-alpha, chemoprophylaxis is necessary for those who show healing of TB despite those who are suspected of having TB infection by a tuberculin test. The administration period of INH as chemoprophylaxis should preferably be set at 9 months instead of 6 months hitherto used.
12175101 D-penicillamine cooperates with copper sulfate to enhance the surface expression of functi 2002 Jul OBJECTIVE: D-penicillamine (DP) has been shown to cooperate with copper ion to inhibit cell growth in a variety of cell types. To determine whether this inhibitory action is involved in Fas-mediated apoptosis, we examined the effect of DP and copper sulfate on the expression and function of Fas antigen in rheumatoid synovial fibroblasts (RSFs). METHODS: The expression of Fas antigen on the cell surface was determined by flow cytometric analysis. Western blot analysis was performed to examine the protein expressions of Fas and Fas-ligand In addition, the amounts of apoptotic cells were determined by 4', 6-diamidino-2'-phenylindol dihydrochloride (DAPI) and propidium iodide (PI) staining. RESULTS: Although DP and copper sulfate alone did not affect the surface expression of Fas antigen on RSFs, both in combination augmented the Fas expression in dose- and time-dependent manners. The enhanced expression of Fas antigen on their surface was also observed in interleukin-1alpha (IL-1alpha) and/or tumor necrosis factor a (TNFalpha) stimulated RSFs. On the other hand, the combination of DP and copper sulfate did not increase the amounts of cellular Fas protein, as determined by Western blot analysis. To determine whether the induced Fas antigen is functional, we examined the effect of DP and copper sulfate on Fas-mediated apoptosis, using an agonistic anti-Fas antibody. The treatment of this antibody induced the apoptosis in untreated RSFs, as determined by DAPI staining. The combination of DP and copper sulfate further enhanced the Fas-mediated apoptosis. The enhanced apoptosis and cell surface expression of Fas was completely prevented by catalase, indicating that hydrogen peroxide may be involved in these effects of DP and copper sulfate. The protein expression of Fas-ligand, a natural ligand for Fas antigen, in RSFs. was expressed in untreated RSFs. However, the protein levels were not modulated by DP and copper sulfate. CONCLUSIONS: Our data demonstrated that DP cooperated with copper sulfate to enhance the cells surface expression of functional Fas antigen in RSFs. In addition, Fas-ligand was expressed in the RSFs. These findings suggested that DP might regress rheumatoid synovial hyperplasia via Fas-mediated apoptosis.
12913927 Toward a definition and method of assessment of treatment failure and treatment effectiven 2003 Aug OBJECTIVE: Time to treatment discontinuation (TTD) is an accepted method of assessing treatment effectiveness in the community, but is susceptible to channeling bias and secular and cohort effects. In addition, TTD does not consider the addition of new disease modifying antirheumatic drugs (DMARD) to insufficiently effective therapies. We expand the definition of treatment failure to include discontinuation or addition of a second DMARD (1) to examine leflunomide (LEF) versus methotrexate (MTX) effectiveness in clinical practice; (2) to obtain an estimate of overall clinical effectiveness; and (3) to identify factors associated with treatment successes and failure. In addition, (4) we test the feasibility of performing a clinical trial using a longitudinal data bank. METHODS: Using the National Data Bank for Rheumatic Diseases longitudinal data bank, 1431 patients with rheumatoid arthritis (RA) who began taking LEF or MTX as part of their routine medical care were followed from 1998 through 2001. None of the 1431 patients had received either treatment previously. Patients were assessed at 6 month intervals for periods up to 36 months by mailed questionnaires concerning DMARD therapy and demographic and RA severity factors. Kaplan-Meier survivor functions and Cox regression analyses were used to assess treatment failure, defined as time to discontinuation or to the addition of a second DMARD. RESULTS: For 756 patients taking LEF, the failure rate was 55.5 per 100 patient-years, and the median time to failure was 15 (95% CI 13, 17) months. For 675 patients taking MTX the failure rate was 57.3 per 100 patient-years, and the median failure time was 14 (95% CI 12, 18) months. These differences were not statistically significant. The overall rate of discontinuation was 68.7% of the failure rate. Discontinuation was predicted by adverse effects [hazard ratio 1.76 (95% CI 1.51, 2.04)] and by clinical status prior to starting DMARD, and these results were not affected by specific DMARD treatment. Discontinuation was more common with LEF, and addition of a second DMARD was more common with MTX. More than 77% of treatment failures, defined by use of additional therapy, resulted in starting anti-tumor necrosis factor treatment rather than a conventional DMARD. CONCLUSION: In an observational clinical trial using a contemporary longitudinal data bank, with time to treatment failure as the outcome, LEF and MTX had equal effectiveness as measured by time to treatment failure. Treatment failure rates were substantially greater than noted historically. Given the availability of many efficacious additional treatment options, this increase in failure rate appears to reflect a greater propensity to discontinue and/or add therapy.
15271770 When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to contin 2005 Jan OBJECTIVE: To evaluate the efficacy and safety of adding sulfasalazine to leflunomide treatment compared with switching to sulfasalazine alone in patients with RA with an inadequate response to leflunomide monotherapy. METHODS: Patients with active RA ((DAS28) >3.2) who were enrolled in the first open label phase of the RELIEF study received leflunomide for 24 weeks. Inadequate responders then entered the double blind phase and received a further 24 weeks' treatment with leflunomide (20 mg once daily) plus sulfasalazine (final dose 2 g once daily), or placebo plus sulfasalazine (dose as above). The primary efficacy variable was the DAS28 response rate, and secondary efficacy outcomes were ACR 20%, 50%, and 70% response rates. Adverse events, including standard laboratory tests, were recorded. RESULTS: 106 inadequate responders entered the double blind phase; 56 received leflunomide plus sulfasalazine, and 50 placebo plus sulfasalazine. In the intention to treat population, more patients receiving leflunomide plus sulfasalazine (25/56 (45%)) achieved a DAS28 response than those receiving placebo plus sulfasalazine (17/50 (34%)) (p = 0.179). In week 24 completers, more patients receiving leflunomide plus sulfasalazine (17/56 (30%)) were DAS28 responders than those receiving placebo plus sulfasalazine (10/50 (20%)) (p = 0.081). Comparable numbers in each group were ACR 20% responders; the ACR 50% response rate was significantly higher in the leflunomide plus sulfasalazine group (8.9%) than in the placebo plus sulfasalazine group (0%) (p = 0.038). The safety profiles of both groups were comparable. CONCLUSION: Patient numbers are small and firm conclusions cannot be reached, but a non-significant benefit is indicated for combining leflunomide with sulfasalazine compared with switching to sulfasalazine alone in patients inadequately responding to leflunomide.
12505892 Characteristics of telephone survey respondents according to willingness to participate. 2003 Jan 1 When conducting epidemiologic case-control studies, some investigators include only controls who can be interviewed within a certain time after contact and/or do not recontact potential participants who initially refuse, whereas others expend considerable effort to recruit reluctant respondents. This additional effort is only worthwhile if it results in a sample that is more representative of the target population. In this study, the authors used data collected from in-person interviews of 5,616 female controls to compare characteristics of willing, accessible respondents with those of their less accessible or less willing counterparts to determine whether or not the two groups differed with respect to lifestyle, socioeconomic status, health history, and demographic characteristics. Late responders were younger, were more likely to be non-White, were less likely to have attended college, and were more likely to be current smokers than early responders. Initial refusers were similar to late responders with respect to education and race. Initial refusers were also older, were less likely to be currently married, were less likely to have a managerial occupation, had fewer lifetime sexual partners, and were more likely to have a history of diabetes than early responders. These findings suggest that additional effort expended in recruiting reluctant respondents may often result in more accurate estimates of population characteristics that are of interest in epidemiologic research.
12730543 Predominant cellular immune response to the cartilage autoantigenic G1 aggrecan in ankylos 2003 Jul OBJECTIVES: Based on their HLA association, both ankylosing spondylitis (AS) and rheumatoid arthritis (RA) seem to be T-cell-driven diseases in which the autoantigens remain to be defined. One possible autoantigen is the G1 domain of aggrecan, the major cartilage proteoglycan. In BALB/c mice immunized with this protein, spondylitis and erosive polyarthritis have been reported. Immune reactivity to the G1 has been described in patients with RA and AS in an earlier study. Using novel and more sensitive techniques and relevant controls we sought to define the role of G1 as an autoantigen more precisely and to extend the specific analyses to the peptide level. METHODS: Peripheral blood (PB) mononuclear cells (MNC) from 47 AS patients, 22 RA patients and 20 healthy normal controls were exposed in vitro for 6 h to the cartilage-derived autoantigens G1, human cartilage (HC) gp-39 and collagen II. Synovial fluid (SF) MNC from seven AS and four RA patients were similarly analysed. Furthermore, PB MNC of 15 AS and 10 RA patients were examined with overlapping 18-mer peptides covering the whole G1 protein to identify the immunodominant epitopes. T cells were stained by monoclonal antibodies directed against the surface markers CD4, CD69 and against the intracellular cytokines interferon-gamma (IFN gamma), tumour necrosis factor-alpha (TNF alpha), interleukin 4 (IL-4) and IL-10. The percentage of reactive T cells was quantified by flow cytometry. RESULTS: After antigen-specific stimulation with the G1 protein, the CD4+ T cells of 30 AS patients (61.7%) and of 12 RA patients (54.5%) secreted significant amounts of IFN gamma and TNF alpha, while, in contrast, only 10% of the normal controls showed a response (P < 0.05). The synovial CD4+ T cells of five AS (71.5%) and of all four RA patients showed antigen-specific responses to the G1. In contrast, stimulation with HC gp-39 and collagen II showed no significant IFN gamma and TNF alpha secretion of MNC in all groups. Several G1-derived T-cell epitopes were identified as immunodominant in PB MNC of AS and RA patients and were partly overlapping. CONCLUSIONS: These data show that a cellular immune response to G1 is present in most AS and RA patients. G1-immunodominant epitopes were identified. The relevance of this finding for the pathogenesis of AS and RA remains to be established.
15313154 Alternative immunoassay for tartrate-resistant acid phosphatase isoform 5b using the fluor 2004 Sep OBJECTIVE: Our purpose was to develop a specific immunoassay for tartrate-resistant acid phosphatase (TRACP) 5b using naphthol ASBI phosphate (N-ASBI-P) as a selective substrate for isoform 5b and heparin as a selective inhibitor of isoform 5a. METHODS: Serum TRACP 5a and 5b and recombinant TRACP 5a were used to optimize and standardize the immunoassay for specificity, linearity, analytical recovery, sensitivity and reproducibility. Serum N-telopeptide cross-links (NTX) and bone alkaline phosphatase (bone ALP) were also measured. The clinical sensitivity and specificity were assessed in healthy control subjects and patients with osteoarthritis (OA), rheumatoid arthritis (RA) and endstage renal disease (ESRD). RESULTS: TRACP 5b specificity was achieved at pH 6.3 with 2.5 mmol/l substrate and 25 U/ml heparin. Isoform 5b specificity was increased over our original immunoassay using 4-nitrophenyl phosphate (4-NPP) without heparin. The alternative immunoassay was linear with 110% analytical recovery and no serum matrix effects. The average intra-assay error was 10.65%; the average inter-assay error was 10.11% for values of 1-3 U/l and 6.5% for values of 7-11 U/l. Mean serum TRACP 5b in OA and RA were not significantly different from control using either immunoassay. Mean serum TRACP 5b was significantly increased in ESRD with both immunoassays. Serum TRACP 5b levels correlated significantly with NTX and bone ALP in the disease groups, but not always in the control group. CONCLUSION: This alternative immunoassay for TRACP 5b activity is highly specific. It should have applications in evaluating patients with bone disease and will improve our understanding of the biological significance of TRACP 5b expression in health and disease.
13130151 Glucocorticoids inhibit induced and non-induced mRNA accumulation of genes encoding hyalur 2004 Feb OBJECTIVE: Glucocorticoids are still a mainstay in the treatment of rheumatoid arthritis (RA). Unfettered hyaluronan release is a hallmark of RA. The discovery of three genes encoding hyaluronan synthase (HAS) led us to investigate the effect of hydrocortisone and dexamethasone on the activation of these genes at the molecular level and, at least in part, the mode of action of these drugs. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to monitor levels of HAS1, HAS2, and HAS3 mRNAs in cultured fibroblast-like synoviocytes (FS) and in leucocytes isolated from synovial fluid of RA patients. Western blot experiments were used to investigate the effect of hydrocortisone on transforming growth factor beta (TGF-beta)-induced activation of the p38 mitogen-activated protein kinase (MAPK) pathway. RESULTS: Hydrocortisone and dexamethasone suppressed HAS2 and HAS3 mRNAs accumulation concentration-dependently. Contrary to HAS2 and HAS3, HAS1 in FS was not constitutively activated. When cells were stimulated with TGF-beta, a potent activator of HAS1 mRNA transcription, treating them with hydrocortisone suppressed induced activation of HAS1 in a concentration- and time-dependent manner. Similar suppressive effects of hydrocortisone were observed when leucocytes isolated from synovial fluid of inflamed joints were used instead of cultured FS. Furthermore, western blot experiments confirmed that hydrocortisone blocked TGF-beta-induced phosphorylation of p38 MAPK, a kinase essential for TGF-beta-induced HAS activation. CONCLUSION: Our data demonstrate that glucocorticoids suppress all genes encoding hyaluronan. We speculate that inhibition of HAS genes might account for the beneficial effect of glucocorticoid treatment, and also for the detrimental effects of long-term use.
11908555 A randomized, placebo controlled trial of an antisense oligodeoxynucleotide to intercellul 2002 Mar OBJECTIVE: To determine the safety of an antisense oligodeoxynucleotide to intercellular adhesion molecule-1 (ICAM-1) (ISIS 2302), administered in an intensive 4 week regimen with dose escalation; and to provide preliminary evidence for efficacy in rheumatoid arthritis (RA). METHODS: Patients with active RA were enrolled in a 6 month, double blind, placebo controlled, dual center, dose escalation (0.5, 1, and 2 mg/kg) study. Subjects received a total of 13 intravenous ISIS 2302 infusions, given on alternate days for 2 weeks and then 3 times a week for another 2 weeks. Doses of corticosteroids (< or = 10 mg/day) and disease modifying antirheumatic drugs (stable > or = 3 months) remained constant throughout the study. The primary efficacy endpoint was the Day 26 Paulus index, with secondary evaluations at Months 2-6. RESULTS: A total of 43 patients were enrolled with 11, 10, 3, and 19 patients receiving placebo or 0.5, 1, or 2 mg/kg of ISIS 2302, respectively. There were no differences between groups after randomization and the mean baseline swollen joint count was 22.5. Pharmacokinetic studies revealed a T(1/2) of 63 min and first-order kinetics with slight dose dependency, suggesting a saturable clearance process, although no accumulation was noted with repeat dosing. The Paulus 20% responses at Day 26 were 20%, 0%, and 5% for patients treated with ISIS 2302 (0.5, 1, 2 mg/kg, respectively) and 36% with placebo. For Months 2-6, the average intent-to-treat Paulus 20% responses were 21.2% for ISIS 2302 and 12.6% for placebo. Only ISIS 2302 treated subjects (19%) achieved Paulus 50% responses. ISIS 2302 was well tolerated. An expected and transient mean activated partial thromboplastin time increase of roughly 7 s was observed at the highest dose (2 mg/kg), as were small and clinically insignificant increases in serum C3a levels. T/B cell immunophenotyping, recall antigen skin testing, and serum immunoglobulin levels revealed no significant immunosuppressive effects. CONCLUSION: This study shows that 13 ISIS 2302 infusions over 4 weeks are well tolerated in patients with active RA. Although significant efficacy was not evident at the primary endpoint (1 month), the study lacked sufficient power to draw any formal conclusions. We tested a 4-fold drug concentration range, which led to a lower area under the curve range than was therapeutic in a subsequent Crohn's disease trial. Any further evaluation of this well tolerated ICAM-1 antisense agent should therefore be conducted at higher dosing.
12509612 Cost-effectiveness of low dose corticosteroids versus non-steroidal anti-inflammatory drug 2003 Jan OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) are used in nearly every patient with rheumatoid arthritis (RA) as part of a comprehensive management programme, but their use can be associated with side-effects. Low dose corticosteroid (<10 mg/day prednisone) in the treatment of RA is controversial. Although it is effective and possibly disease modifying, concerns exist about potential adverse events. We assessed costs and health effects of corticosteroids compared with NSAIDs and cyclo-oxgenase-2 (COX-2) inhibitors. METHODS: Markov (state transition) models were used to simulate a cohort of RA patients taking disease-modifying antirheumatic drugs and either corticosteroids or NSAIDs. The regimens were assumed to be equally effective for the control of RA. Data on incidence, costs and consequences of adverse events from corticosteroids and from NSAIDs were taken from the literature. Costs were measured in 1999 US dollars; health effects expressed as quality-adjusted life years (QALYs). Sensitivity analyses were performed including best-case scenarios (0.5x adverse event rate) and worst-case scenarios (1.5x adverse event rate). RESULTS: In the base-case analysis corticosteroids were superior to NSAIDs. The sensitivity analyses of adverse event rate, using best-case and worst-case scenarios, and age showed that the results were sensitive to each combination of adverse event rate and age. In contrast, the sensitivity analyses of costs and utilities were robust. Using misoprostol or omeprazole prophylaxis with NSAIDs would make corticosteroids cost-effective. Compared with NSAIDs with COX-2 specific inhibition, corticosteroids were still cost-effective. CONCLUSION: Corticosteroids are more cost-effective than NSAIDs and COX-2 inhibitors in the long-term treatment of RA.
11822409 Evidence that rheumatoid arthritis synovial T cells are similar to cytokine-activated T ce 2002 Jan OBJECTIVE: To investigate the mechanism that leads to the spontaneous production of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) synovial tissue. METHODS: Normal blood monocytes were cocultured either with fixed activated T cells generated from normal blood or RA synovial T cells purified from synovium. TNFalpha production was measured in supernatants from these cocultures following blockade of the transcription factor nuclear factor kappaB (NF-kappaB) using adenoviral transfer of the inhibitor of NF-kappaB kinase alpha into the responding monocytes, or blockade of phosphatidylinositol 3-kinase (PI 3-kinase) using the inhibitory drugs wortmannin or LY294002. TNFalpha production was measured by enzyme-linked immunosorbent assay. RESULTS: TNFalpha production in synovial tissue from patients with RA but not osteoarthritis was found to be T cell dependent. The RA synovial joint T cells resembled normal T cells that had been activated for 8 days using a cocktail of cytokines. These T cells, designated Tck (cytokine-activated T cells), and RA synovial T cells both induced TNFalpha production in resting monocytes in a cell-contact-dependent manner, which was abrogated by blockage of the transcription factor NF-kappaB but augmented if PI 3-kinase was inhibited. Normal blood T cells activated conventionally via the T cell receptor with crosslinked anti-CD3 antibody resulted in TNFalpha production from monocytes; this was unaffected by NF-kappaB blockade, but was inhibited in the presence of PI 3-kinase-blocking drugs. CONCLUSION: These data provide strong evidence for the importance of T cells in inducing TNFalpha in chronic inflammatory rheumatoid tissue, and give insight into the mechanism whereby these T cells are activated in vivo. Furthermore, they indicate that production of TNFalpha in pathologic tissue is regulated differently from physiologic antigen-dependent TNFalpha production, which raises the possibility that selective inhibitors of TNFalpha in disease may be developed.
12905491 Defects in the regulation of B cell apoptosis are required for the production of citrullin 2003 Aug OBJECTIVE: Protein deimination, a process to modify arginine residues to citrulline by the addition of a neutral oxygen group, is associated with apoptosis. The presence of autoantibodies recognizing citrullinated peptides is highly specific to rheumatoid arthritis (RA) and is therefore a useful marker for the early diagnosis of RA. In this study, we explored whether anti-cyclic citrullinated peptide (anti-CCP) autoantibodies are produced in several experimental models of autoimmune diseases in mice. METHODS: The levels of anti-CCP autoantibodies were analyzed by enzyme-linked immunosorbent assay in several lupus-prone strains of mice, in animals with type II collagen (CII)-induced arthritis, and after induction of neonatal tolerance to alloantigens. RESULTS: We observed the production of these autoantibodies in 2 different lupus-prone mice, MRL-lpr/lpr and (NZW x B6)F(1)-hbcl-2 transgenic mice, characterized by the presence of abnormalities in the regulation of B cell apoptosis. Other genetic defects, determining autoimmune susceptibility, present in MRL and NZW mice were additionally required for anti-CCP autoantibody production. The induction of autoantibodies in normal BALB/c mice injected at birth with semiallogeneic spleen cells from (BALB/c x B6)F(1)-hbcl-2 transgenic mice suggested that these additional autoimmune defects may be related, at least in part, to the establishment of abnormal interactions between T cells and B cells. In addition, anti-CCP autoantibodies were not produced in the course of CII-induced arthritis, an experimental model of RA in mice. CONCLUSION: Our study provides evidence for the association between defects in the regulatory cell death machinery of B lymphocytes and the production of certain autoantibody specificities.
12755552 Case reports of heart failure after therapy with a tumor necrosis factor antagonist. 2003 May 20 BACKGROUND: Etanercept and infliximab are U.S. Food and Drug Administration-approved tumor necrosis factor (TNF) antagonists. OBJECTIVE: To describe adverse event reports of heart failure after TNF antagonist therapy. DESIGN: Case series. SETTING: The U.S. Food and Drug Administration's MedWatch program. PATIENTS: 47 patients who developed new or worsening heart failure during TNF antagonist therapy. MEASUREMENTS: Clinical and laboratory reports. RESULTS: After TNF antagonist therapy, 38 patients developed new-onset heart failure and 9 patients experienced heart failure exacerbation. Of the 38 patients with new-onset heart failure, 19 (50%) had no identifiable risk factors. Ten patients younger than 50 years of age developed new-onset heart failure after receiving TNF antagonists. After TNF antagonist therapy was discontinued and heart failure therapy was started in these 10 patients, 3 had complete resolution of heart failure, 6 improved, and 1 died. CONCLUSION: In a fraction of patients, TNF antagonists might induce new-onset heart failure or exacerbate existing disease.
15189743 Leflunomide in the treatment of rheumatoid arthritis. 2004 Apr BACKGROUND: Current drug therapies for rheumatoid arthritis (RA), including nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs, help control inflammation but can cause significant toxicity. Drugs are needed that are able to suppress inflammation and modify the underlying immune response with improved tolerability. Leflunomide is an agent that affects the inflammatory process, particularly in RA. OBJECTIVE: This paper reviews the pharmacology of leflunomide, its approved use in RA, and the results of major clinical trials, including adverse events. METHODS: Relevant trials were identified through a search of the English-language literature indexed on EMBASE, MEDLINE, Current Contents, and the Cochrane Controlled Trials Register from January 1980 to November 2003. Search terms were limited to leflunomide. RESULTS: In 3 large Phase III clinical trials (US301, MN301, and MN302), leflunomide had equivalent clinical efficacy and tolerability to methotrexate and sulfasalazine and superior efficacy and tolerability compared with placebo. In US301 (N = 482), the ACR (American College of Rheumatology) 20 response rate (proportion of patients with > or =20% improvement from baseline in tender and swollen joint counts, patient's assessment of pain, patient's and physician's global assessment of disease activity, physical function, and acute-phase reactant value) at 1 year was similar with leflunomide and methotrexate and significantly greater with both active treatments than with placebo (52%, 46%, and 26%, respectively; both, P < 0.001). The efficacy of leflunomide was seen early (after 4 weeks of treatment) and was sustained throughout the study. There was less radiographic damage in both active-treatment groups compared with placebo (leflunomide, P < or = 0.001; methotrexate, P = 0.02). In MN301 (N = 358), the ACR20 response rate at 6 months was similar with leflunomide and sulfasalazine and significantly greater with both active treatments compared with placebo (55%, 56%, and 29%, respectively; both, P < 0.001). Radiographic progression was also similar with leflunomide and sulfasalazine, both of which were significantly superior to placebo (Larsen score, 0.42, 0.41, and 1.4; both, P < 0.001). An extension of this study revealed maintenance of efficacy at 12 and 24 months. In MN302 (intent-to-treat population, N = 999), 50.5% of patients in the leflunomide group were ACR20 responders at the end of 1 year, compared with 64.8% in the methotrexate group (P < 0.001 vs leflunomide). After 2 years, ACR20 response rates were similar with leflunomide and methotrexate (64.3% and 71.7%). The overall safety profile of leflunomide appears promising, although monitoring for elevations in liver enzymes and bone marrow suppression is recommended. The most common drug-related adverse events associated with leflunomide in these clinical trials were diarrhea, abnormalities in liver enzymes, rash, and hypertension.