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ID PMID Title PublicationDate abstract
11840438 Comparative assessment of leflunomide and methotrexate for the treatment of rheumatoid art 2002 Feb OBJECTIVE: Ethical constraints on the conduct of placebo-controlled trials evaluating new therapies for serious chronic diseases, such as rheumatoid arthritis (RA), indicate the need for discerning methods to assess treatment effect in active-controlled clinical trials. Dynamic gadolinium-enhanced magnetic resonance imaging (DEMRI) is a sensitive technique for the detection of synovial inflammation in RA. Therefore, this investigation was undertaken to evaluate DEMRI as an efficacy assessment tool for differentiating treatment effect in a randomized, active-controlled trial comparing leflunomide and methotrexate. METHODS: Patients with active RA (n = 39) were randomized in a 2-center, prospective, double-blind clinical trial to receive either leflunomide (n = 18) or methotrexate (n = 21) therapy for 4 months. DEMRI scans were obtained at baseline and at 4 months, and the initial rate of enhancement (IRE) and the maximal signal intensity (SI) enhancement (ME) were calculated from the SI curves. Clinical improvement was assessed by conventional outcome measures. RESULTS: Thirty-four patients (17 treated with leflunomide and 17 with methotrexate) had usable baseline and end point DEMRI scans. Leflunomide treatment was associated with a significantly greater improvement in IRE compared with methotrexate treatment (P < 0.05). Average values of ME indicated reduction of inflammation with both leflunomide and methotrexate. The improvement in clinical signs and symptoms, as measured by traditional assessments, was comparable for both active treatments. CONCLUSION: Results of this study validate the sensitivity of DEMRI in detecting inflammatory changes in active RA in response to treatment. Improvement in synovial inflammation as measured by IRE was significantly better with leflunomide than with methotrexate over 4 months of therapy.
14513118 [Idiopathic hypereosinophilic syndrome associated with rheumatoid arthritis. A case report 2003 The idiopathic hypereosinophilic sindrome (HES) is a disease characterized by persistent blood eosinophilia (> 1500 eosinophils/mm3 > 6 months) -in absence of other ethiologies for eosinophilia (parasitic, allergic, immunological or malignant diseases)- associated with multiple organ involvement (heart, lung, central nervous system, skin, bone marrow, gastrointestinal tract). Reports on rheumatologic manifestations in patients with HES are very rare. In the case we report a typical rheumatoid arthritis developed in a 58-year-old woman with HES treated with glucocorticoids. Because of the marked glucocorticoids side effects shown by the patient (cushingoid habitus, hyperglycemia), we stopped this treatment and replaced it at first by methotrexate and later by cyclosporin, both of them associated with sulfasalazine. These drugs revealed very efficacious both on articular pathology and on the clinical and laboratory manifestations of HES. These data suggest that common pathogenetic mechanisms are likely acting in rheumatoid arthritis and idiopathic hypereosinophilic syndrome.
15370720 Pulmonary hypertension in rheumatoid arthritis. 2004 Using Doppler echocardiography (DE), we measured pulmonary arterial systolic pressure (PASP) in rheumatoid arthritis (RA) patients without coexisting cardiopulmonary diseases. Accepting the normal upper limit of PASP as 30 mmHg, we found elevated PASP in 11 out of 40 (27.5%) RA patients, values being mostly 30-40 mmHg, indicating mild pulmonary hypertension (PHT). Although estimation of PASP by DE is not as reliable as cardiac catheterisation, it is possible that mild elevations in PASP may contribute to the high incidence of cardiovascular events not explained by traditional cardiac risk factors in patients with RA. Long-term follow-up will be obviously necessary to ascertain the impact of mild PHT on the prognosis and mortality rate of RA patients.
14585913 Drug utilization review of celecoxib in Ontario. 2003 Nov Cyclooxygenase (COX)-2-specific inhibitors were developed to circumvent the gastrointestinal toxicity of non-specific non-steroidal anti-inflammatory drugs while maintaining efficacy. However, the higher acquisition cost of COX-2-specific inhibitors has resulted in the implementation of a programme for cost containment in the Ontario public drug program. This programme consists of limited use (LU) criteria that need to be met for drug reimbursement of patients with osteoarthritis (OA) or rheumatoid arthritis (RA). Determining the proportion of patients eligible for reimbursement for celecoxib according to the LU criteria (based on prior treatment failure and the presence or history of serious ulcer-related gastrointestinal complications) can provide an indication of the extent of adherence to suggested guidelines. Using a patient-based survey and an analysis of the Ontario Drug Benefit Program database, the proportion of patients prescribed celecoxib who met rigorous or pragmatic definitions of the LU criteria was determined. The extent of coprescription of gastroprotective agents among patients taking celecoxib was also determined. Using the pragmatic definition, the majority of patients in the patient-based survey (53% for OA and 81% for RA) met the LU criteria. Similarly, in the database analysis, the majority of patients (76% for OA and 78% for RA) met the LU criteria. These data suggest that physician prescribing of celecoxib is consistent with the LU criteria. Concomitant prescription of gastroprotective agents in patients taking celecoxib was approximately 40%. It is recommended that further investigations be performed to determine the long-term impact of LU criteria on clinical and economic outcomes, since these criteria may also serve to restrict use in patients who may benefit from taking COX-2-specific inhibitors.
12563671 Expression of lactoferrin on neutrophil granulocytes from synovial fluid and peripheral bl 2003 Feb OBJECTIVE: To analyze lactoferrin expression on synovial fluid (SF) and peripheral blood neutrophils of patients with rheumatoid arthritis (RA) and to compare it with the lactoferrin expression on neutrophils from patients with osteoarthritis (OA). METHODS: Paired samples of peripheral blood and SF were obtained from 14 patients with RA and 9 patients with OA. Lactoferrin expression was evaluated on cell surfaces by cytofluorimetric analysis utilizing both polyclonal antibodies and the monoclonal anti-lactoferrin antibody AGM 2.29. Data are presented as mean fluorescence intensity. RESULTS: In patients with RA, the expression of membrane lactoferrin was significantly increased on SF neutrophils in comparison with those in peripheral blood. This increase was found using both polyclonal antibodies and AGM 2.29 (p = 0.0001, p = 0.0017, respectively). In patients with OA, the difference was not significant. In addition, lactoferrin expression on SF neutrophils of patients with RA was significantly increased compared with that found on SF neutrophils of patients with OA (polyclonal antibodies, p = 0.0015; AGM 2.29, p = 0.005). In patients with RA, no correlation was found between lactoferrin expression and disease activity. CONCLUSION: Our results provide evidence for an activation of neutrophil granulocytes at site of inflammation in RA and indicate that lactoferrin surface expression represents a reliable neutrophil activation marker.
12150262 Dentition status and temporomandibular joint disorders in patients with rheumatoid arthrit 2002 Jul We compared dentition status and temporomandibular joint (TMJ) disorders in 142 women with rheumatoid arthritis (RA, ages, 40 to 69 years) and 143 women of similar age without RA. The RA group had significantly fewer remaining teeth than the non-RA group. Number of decayed, missing, and filled (DMF) teeth, number of edentulous subjects, and number of subjects with complete and removable partial dentures were significantly higher in the RA group. Among RA subjects, 1.4% had unprovoked TMJ pain, 4.9% had pain on mouth opening, and 14.8% noted difficulty with opening. In the RA group, TMJ tenderness was elicited in 9.2%, clicking in 12.7%, and crepitus in 35.9%, representing a significant excess occurrence of crepitus. The prevalence of TMJ disorders was 67.6% in the RA group and 32.9% in the non-RA group; degenerative joint disorders were particularly frequent. TMJ disorders correlated with Steinbrocker stage and the duration of RA.
12823852 Serum cartilage oligomeric matrix protein (COMP) decreases in rheumatoid arthritis patient 2003 Changes in serum cartilage oligomeric matrix protein (COMP) were studied during a 6-month period from initiation of treatment of rheumatoid arthritis patients with either infliximab or etanercept, to elucidate whether the favourable results of tissue protection reported in clinical trials are corroborated by changing levels of circulating COMP. Rheumatoid arthritis patients commencing treatment with infliximab (N = 32) or etanercept (N = 17) were monitored in accordance with a structured protocol. Only patients who were not receiving glucocorticoids or who were on a stable dose of oral prednisolone (<10 mg daily) were included. Serum COMP was measured by a sandwich immunoassay based on two monoclonal antibodies against human COMP in samples obtained at treatment initiation and at 3 and 6 months. Serum COMP decreased at 3 months in both infliximab- and etanercept-treated patients (P < 0.001 and <0.005, respectively) and remained low at 6 months. There was no significant correlation between changes in or concentrations of serum COMP and serum C-reactive protein at any time point. A decrease in serum COMP was seen both in ACR20 responders (patients meeting the American College of Rheumatology criteria for 20% improvement) and in nonresponders. The pattern of changes of serum COMP, a marker for cartilage turnover, in these patient groups supports the interpretation that infliximab and etanercept have a joint protective effect. Serum COMP has potential as a useful marker for evaluating tissue effects of novel treatment modalities in rheumatoid arthritis.
15170904 Leflunomide: a manageable safety profile. 2004 Jun The safety profile of leflunomide in the treatment of rheumatoid arthritis has been well documented in clinical trials, postmarketing surveillance, and epidemiological studies. Both postmarketing surveillance and epidemiological study results are consistent with the safety profile of leflunomide reported in clinical trials, and no increased risk was observed with leflunomide, compared with other disease modifying antirheumatic drugs; these studies have allowed a more precise representation of the incidence of adverse events occurring with leflunomide under normal conditions of care. The most common leflunomide-associated adverse events include diarrhea, elevated liver enzymes, alopecia, and rash. Ninety-five percent of the Expert Panel considered the adverse events associated with leflunomide to be manageable. If an adverse event required treatment to be stopped, many of the experts would consider subsequently restarting leflunomide. For minor adverse events, it was suggested that the physician might also consider using cholestyramine or charcoal to determine if the side effect is dose-related and, if it was, reduce the leflunomide dose accordingly. In addition to informing patients about the likelihood of side effects, it is important to emphasize that their incidence appears to diminish with continued treatment. It is also important to adequately support patients who are experiencing side effects and involve them in their disease management, for example, by offering the choice of reducing the leflunomide dose and/or having symptomatic treatment. Other patient management recommendations in this review reflect the views of the majority of participants as expressed in the meeting.
15526004 Genetic risk factors for infection in patients with early rheumatoid arthritis. 2004 Dec We analyzed clinical and genetic factors contributing to infections in 457 subjects with early rheumatoid arthritis (RA) enrolled in a prospective, 1-year clinical trial of methotrexate and the TNF inhibitor etanercept. Subjects were genotyped for the following single nucleotide polymorphisms (SNPs): (TNF -308, -238, and + 488); lymphotoxin-alpha (LTA) (LTA + 249, + 365, and + 720); and Fc gamma receptors FCGR2A 131 H/R; FCGR3A 176 F/V; and FCGR3B NA 1/2 and genotypes were correlated with infections. At least one URI was noted in 52% of subjects (99/191) with the NA2/NA2 genotype of the neutrophil-specific FCGR3B gene, compared to 42% (77/181) of those with the NA1/NA2 genotype and 39% (23/59) of those with the NA1/NA1 genotype (P = 0.038). Urinary tract infection (UTI) was associated with the TNF -238 A (odds ratio(OR) 2.56, 95% confidence interval (CI) 1.05-6.25) and LTA +365 C (OR 1.73, 95% CI 1.07-2.79) alleles, and marginally with the FCGR3A F allele (OR 1.72, 95% CI 0.99-3.00). There was a striking linear correlation between UTI and the number of risk alleles defined by these three SNPs (P < 0.001), suggesting an additive effect on susceptibility. These findings have important implications for the role of genetics in susceptibility to bacterial and viral infections.
15133697 Surface replacement of the humeral head in rheumatoid arthritis. 2004 Jul INTRODUCTION: The concept of a newly developed cup arthroplasty (Durom Cup) involves the replacement of the destroyed joint surface of the humeral head with minimal bone resection. In cases of additional massive cuff tear, the cup can be placed in a more valgic position to articulate with the glenoid and the acromion. The aim of this prospective study was to evaluate the results of this surface replacement as a hemiarthroplasty in rheumatoid arthritis. MATERIAL AND METHODS: Forty-five Durom Cups in 39 patients (30 women, 9 men) with rheumatoid arthritis were evaluated preoperatively and every 3 months postoperatively. Their average age was 62.7+/-12.3 years and the average follow-up 45.1+/-11.6 months with a minimum of 36 months. Concerning the cuff, 15 shoulders had an intact cuff (group A), 18 shoulders a partial tearing or a repaired rotator cuff (group B), and 12 shoulders a massive cuff tear (group C). The Constant Score was used, and the cups were examined radiologically. RESULTS: In group A rheumatic shoulders, the Constant Score increased from 21.5+/-9.6 points preoperatively to 66.1+/-9.8 points at 36 months postoperatively; in shoulders of group B, from 19.6+/-9.7 points preoperatively to 64.9+/-9.6 points at 36 months postoperatively; and in shoulders of group C, from 17.5+/-8.7 points to 56.9+/-9.8 points at the latest follow-up examination. All shoulders were pain-free at the latest examination. No complications, component loosening or changes of cup position were observed. CONCLUSION: The results of the Durom Cup are encouraging. In shoulders with additional massive cuff tear, the limited goal criteria were always achieved. Therefore, cup arthroplasty is a good alternative to other kinds of shoulder endoprostheses in rheumatic shoulders with and without massive cuff tear.
12635940 Clonal analysis of B cells in the synovial membrane of patients with rheumatoid arthritis. 2003 OBJECTIVE: To investigate the clonal characteristics of B cells in the synovial membranes of rheumatoid arthritis (RA) patients. METHODS: The clonality of B cells at separate sites of the synovial membrane and other tissues from RA patients were investigated by a reverse transcriptase-polymerase chain reaction with a VH framework 3 consensus primer and a subsequent single-strand conformation polymorphism analysis. RESULTS: Several dominant bands were observed in all synovial membrane samples and some of the dominants bands were common among the 2 or 3 separate regions of each synovial sample. The persistent existence of clonal B cells was observed in metachronous synovial fluid samples. CONCLUSION: Infiltrating B cells are oligoclonal and antigen-driven mechanisms may play a role in the generation of clonal B cells in RA synovium. The stable presence of B cell clones in synovial fluid suggests the involvement of these clones in the perpetuation of the chronic inflammation in RA.
12607796 Molecular aspects of glucocorticoid hormone action in rheumatoid arthritis. 2002 Dec Glucocorticoids (GC) are the most powerful anti-inflammatory drugs used in the treatment of autoimmune diseases such as rheumatoid arthritis. In addition, endogenous GC are involved in numerous physiological processes. Most of their effects are mediated by the glucocorticoid receptor (GR) via activation or repression of gene expression. Whereas activation requires DNA binding of the receptor, repression is mediated by protein-protein interactions with other transcription factors. In particular, most immunosuppressive and anti-inflammatory effects are exerted by an interaction of GR with the activating protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB) families of transcription factors without DNA binding. Cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1) activate the hypothalamus pituitary adrenal (HPA) axis, whereas GC inhibit IL-1 and TNF-alpha forming a cytokine-HPA axis feedback circuit. The high effectiveness of cytokine-antagonists blocking TNF-alpha or IL-1 in RA and the understanding of the precise molecular mechanisms of GC function will enhance our understanding of autoimmune diseases, such as RA, and could suggest new beneficial therapeutic approaches with fewer side-effects.
12066275 Fixation of the NexGen HA-TCP-coated cementless, screwless total knee arthroplasty: compar 2002 Jun We performed a 12-month prospective study on 59 patients (92 knees) who underwent NexGen (Zimmer Inc, Warsaw, IN) cruciate-retaining total knee arthroplasty. In the control group, uncoated components were fixed using screws, whereas the hydroxyapatite-tricalcium phosphate (HA-TCP) group underwent screwless fixation of coated components. At 12 months postoperatively, there was a radiographic clear zone around the femoral and tibial components of 56.5% and 32.6% of the knees in the control group. The HA-TCP group showed a clear zone at the medial aspect of the tibial component in only 1 knee. These results suggested that HA-TCP-coated articular components show good initial fixation without using screws. The NexGen coated knee arthroplasty may be useful for solving the problems of cementless fixation.
12114312 Prolactin/cortisol ratio in rheumatoid arthritis. 2002 Jun Prolactin (PRL) and glucocorticoids are hormones involved in the regulation of the immune system. Rheumatoid arthritis (RA) is an inflammatory condition that presents a diurnal rhythm of disease activity. PRL/cortisol ratio, and IL-1beta and TNF-alpha levels were determined in patients with RA and in control subjects at 0600, 1000, 1400, 1800, 2200, and 0200 hours. In patients with RA we observed higher PRL/cortisol ratio at 0200 hours, whereas IL-1beta and TNF-alpha reached their highest serum levels at 0200 and 0600 hours. In patients with RA we observed an imbalance in favor of proinflammatory hormones as opposed to levels of antiinflammatory hormones during nocturnal hours together with increased levels of IL-1beta and TNF-alpha of the diurnal rhythm of disease activity.
12120905 Methotrexate twice weekly vs once weekly in rheumatoid arthritis: a pilot double-blind, co 2002 May Methotrexate (MTX) is the most commonly used disease-modifying antirheumatoid drug used in patients with rheumatoid arthritis. It is usually given on a weekly schedule, but as the half-life of its active compound, the polyglutamate MTX, is 3 days, we did a pilot study to see if MTX twice weekly is superior to MTX once weekly. Eighty patients with rheumatoid arthritis (RA) fulfilling the American College of Rheumatology (ACR) criteria were enrolled into a double-blind, controlled trial of 16-week duration. Patients achieving ACR scores of 20 and 50 were determined at 8 and 16 weeks. In addition, the incidence of hepatotoxicity was also studied. Of the 80 patients, 66 completed 8 weeks of study, whereas 53 completed 16 weeks of study. Most withdrawals were because of inefficacy. At 8 weeks, ACR 20 response (24/34 in once weekly and 22/32 in twice weekly) and ACR 50 response (16/34 in once weekly and 16/32 in twice weekly) in both groups were similar. Even at 16 weeks, there was no significant difference in ACR 20 and ACR 50 responses. Intent-to-treat analysis also yielded similar results. Five patients in each group had a mild reversible rise in transaminases. Our study suggests that MTX twice weekly has no advantage over once weekly regarding efficacy, and thus the currently used once weekly regimen is good enough till alternate dosing schedules are evaluated in a large multicentric trial.
15194591 Methotrexate (MTX) and albumin coupled with MTX (MTX-HSA) suppress synovial fibroblast inv 2004 Jul OBJECTIVE: To investigate the effect of methotrexate (MTX) and albumin coupled with methotrexate (MTX-HSA) on cartilage invasion and induction of perichondrocytic degradation by rheumatoid arthritis synovial fibroblasts (RA SF) in vivo. METHODS: Human cartilage and RA SF were co-transplanted in three groups of severe combined immunodeficient mice (SCID), which received 1 mg/kg free MTX (n = 9), 1 mg/kg MTX-HSA (n = 6), or 0.9% NaCl (n = 5), respectively, intraperitoneally twice a week. After 4 weeks' treatment, the mice were killed and the implants analysed histologically. RESULTS: The control group had a mean (SEM) score for cartilage invasion of RA SF of 2.0 (0.26) and for perichondrocytic cartilage degradation of 1.5 (0.34). In contrast, mice which received MTX showed a significantly reduced invasion (0.78 (0.14), p<0.01) and a reduction in perichondrocytic cartilage degradation scores (0.69 (0.2), p<0.05) in comparison with the control group. Mice treated with MTX-HSA also had significantly reduced scores for RA SF invasion into the cartilage (0.92 (0.41), p<0.05) and for cartilage degradation (0.83 (0.44), p<0.05) compared with controls. The effects of MTX and MTX-HSA were not significantly different between these two groups. CONCLUSION: Treatment with MTX or MTX-HSA significantly ameliorates cartilage destruction in the SCID mouse model for human RA.
12594850 Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the ta 2003 Jan In the homeostasis of the immune system regulatory cells play a major role. Removal of one group of regulatory cells, the CD25(+)CD4(+) T cells, leads to autoimmune manifestations in experimental animal models, and reintroduction of this population prevents disease. This study addresses the role of such regulatory T cells in humans with an autoimmune disease, where we demonstrate the presence of CD25(bright)CD4(+) T cells in the target organ of patients with active rheumatoid arthritis. The patients displayed an enrichment of CD25(bright)CD4(+) T cells in synovial fluid as compared to peripheral blood. These cells are functional regulatory cells, as they were able to suppress in vitro proliferation of autologous T cells, both from synovial and peripheral blood origin. Although the frequency of CD25(bright)CD4(+) T cells varied between patients, it was found to be constant over time in any one joint during each relapse. Numbers were also comparable in two inflamed knee joints of one and the same patient, emphasizing the symmetry of the disease. In summary, it is striking that in addition to all activated, potentially pathological T cells the synovial fluid from RA patients also contains CD25-expressing CD4(+) T cells with a regulatory capacity.
15288364 Rheumatoid arthritis increases the risk of coronary heart disease via vascular endothelial 2004 Patients with rheumatoid arthritis (RA) have an increased prevalence of coronary heart disease and a high cardiovascular mortality rate. The causes of increased coronary heart disease in RA patients are poorly understood. Conventional cardiovascular risk factors, such as inactivity, overweight or dyslipidemia may play a role, but they do not seem to be wholly responsible for the increased cardiovascular risk. RA is associated with a high incidence of inflammation and vascular endothelial injuries. Endothelial dysfunction is one of the key steps in the pathogenesis of atherosclerosis in non-RA patients. Therefore, we hypothesized that inflammation-induced vascular endothelial injuries may be responsible for the increased risk of coronary heart disease and high rates of cardiovascular mortality in patients with RA.
15014199 Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience. 2004 Aug OBJECTIVE: To evaluate the long-term safety of tacrolimus 3 mg/day in patients with rheumatoid arthritis (RA). METHODS: Patients with active RA who had discontinued all DMARDs for at least 2 weeks and had at least five tender/painful joints and three swollen joints, and required DMARD treatment in the opinion of the investigator, were enrolled into this open-label long-term safety trial. In addition, patients who had completed at least 3 months of treatment with tacrolimus 2 mg/day, tacrolimus 3 mg/day or placebo in a Phase III double-blind efficacy trial were allowed to roll over into this study. This latter group of patients did not have to fulfil any joint count requirements prior to entry into the long-term safety study, provided that no more than 14 days had elapsed between the end of their participation in the double-blind study and screening for the long-term safety study. All patients enrolled received tacrolimus 3 mg/day in addition to their current regimen of NSAIDs and corticosteroids. RESULTS: 896 patients received at least one dose of tacrolimus 3 mg. The median duration of treatment was 359 days. 145 patients (16.2%) withdrew from the study for adverse events possibly or probably related to tacrolimus, 33 patients (3.7%) withdrew from the study for adverse events unrelated to tacrolimus and 112 (12.5%) withdrew for lack of efficacy. No adverse event with an incidence >0.7% appeared for the first time after the first 3 months of treatment with 3 mg tacrolimus. 529 patients (59%) experienced an adverse event that was possibly or probably related to tacrolimus; the most common were diarrhoea (14.6%), nausea (10.3%), tremor (9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%), increased creatinine (6.8%) and hypertension (5.4%). Twenty-four patients (2.7%) experienced serious adverse events possibly or probably related to study drug; the most common were pneumonia (0.6%), hyperglycaemia (0.3%), gastroenteritis (0.2%), pancreatitis (0.2%) and diabetes mellitus (0.2%). The mean creatinine level increased from 67+/-19 micromol/l (0.76+/-0.22 mg/dl) at baseline to 75+/-26 micromol/l (0.85+/-0.30 mg/dl) (P<0.0001) at end of treatment. 351 (40.3%) of the 872 patients for whom creatinine levels were available at both baseline and during treatment had > or =30% increase from baseline in serum creatinine during the study, either related or unrelated to tacrolimus, with 73 patients (8.4%) having creatinine levels exceeding the normal range. At end of treatment, 177 patients (20.3%) had a > or =30% increase from baseline in creatinine. Serum creatinine remained within the normal range throughout the trial in approximately 90% of patients. At the end of treatment, the ACR20, ACR50 and ACR70 response rates were 38.4%, 18.6% and 9.0% respectively. Over 26% of patients had at least a 70% improvement in both swollen and painful/tender joints. CONCLUSION: This study demonstrates that tacrolimus was safe and well-tolerated and provided clinical benefit over a period of at least 12 months.
12009332 Reduction of cytokine-induced expression and activity of MMP-1 and MMP-13 by mechanical st 2002 Apr Excessive mechanical load induces harmful outcomes for joint diseases, such as osteoarthritis and rheumatoid arthritis, but physical stimuli at appropriate intensity are essential for growth and maintenance of bone and articular cartilage. Using a fibroblast-like synoviocyte cell line derived from a patient with rheumatoid arthritis, we examined the effects of gentle cyclic strain, focusing on the expression and activity of matrix metalloproteinase-1 (MMP-1) and MMP-13. Synovial cells were cultured on a collagen-coated agar block and exposed to 2% cyclic strain at 6 rev./min for 1 h. Expression of MMP-1 and MMP-13 was assayed using semi-quantitative and real-time PCR, as well as immunoblotting. Their activity was measured using spectrofluorometry and zymography. The results showed that the cyclic strain reduced the mRNA and protein levels of MMP-1 and MMP-13, and that both collagenase and gelatinase activity was decreased under the strain. The reduction in MMP activity by the cyclic strain was not achieved by the transcriptional inhibitor, actinomycin D. In the presence of proinflammatory cytokines, such as IL-1 beta and TNF-alpha, the strain reduced the cytokine-induced expression and activities of MMPs. Interestingly, the strain elevated the mRNA level of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. These results support a potential role of mechanical strain in down-regulating the cytokine-mediated proteolytic processes in synoviocytes.