Bone marrow edema is the most specific finding for rheumatoid arthritis (RA) on noncontrast magnetic resonance imaging of the hands and wrists: a comparison of patients with RA and healthy controls.

OBJECTIVE: To evaluate the sensitivity and specificity of magnetic resonance imaging (MRI) in detecting erosions, bone edema, and synovitis in the metacarpophalangeal and wrist joints for rheumatoid arthritis (RA). METHODS: MRI scans of bilateral hands and wrists of 40 healthy subjects and 40 RA patients were performed using 0.2 T extremity-MRI and read blindly using a modified RA MRI (RAMRIS) system (no contrast injection, imaging in 1 plane only). To determine interreader reliability, images of 10 randomly selected subjects were read independently by a musculoskeletal radiologist. RESULTS: A total of 3360 bones were evaluated. Patients with RA had significantly more erosions as well as higher scores for bone edema and synovitis than healthy subjects. Age had a significant effect on the number of erosions in both groups. However, when disease duration was factored in, age became insignificant in RA patients. Erosion number correlated with positive rheumatoid factor and higher C-reactive protein values. The intraclass correlation coefficient between the 2 readers was 0.76 for individual joints and 0.88 for total scores. When having a single erosion was used as a positive test for RA, the sensitivity of this test was 90%, but the specificity was only 35%. Presence of bone edema provided 65% sensitivity and 82.5% specificity. Eliminating the lunate from scoring for bone edema increased the specificity to 87.5% while decreasing the sensitivity to 62.5%. CONCLUSION: While MRI is a highly sensitive tool for identifying and tracking the progression of erosions, erosions detected by MRI with measures commonly used in a rheumatologist's office (no contrast, imaging in 1 plane) provide low specificity for RA. Bone marrow edema is the most specific MRI lesion for RA in this setting.

Assessment of a sixteen-week training program on strength, pain, and function in rheumatoid arthritis patients.

OBJECTIVE: To assess the effects of a 16-week progressive, individualized, high-intensity strength training program on muscle strength, pain, and function in patients with rheumatoid arthritis (RA). METHODS: Twenty-four RA patients (men, n = 5; women, n = 19) receiving infliximab participated in a randomized controlled trial. The strength training (ST) group (n = 16) participated in a supervised program 3 times per week, and the control (C) group (n = 8) continued with standard of care as overseen by their rheumatologist. Assessments were completed at baseline and at weeks 8 and 16. Strength was measured by 3 repetition maximum (3RM), isometric hand dynamometer, and isokinetic dynamometer. A 100-mm visual analogue scale was used to assess pain. Functional performance was derived from a timed 50-foot walk and the Health Assessment Questionnaire Disability Index. RESULTS: The mean percent increase in strength (3RM) for the ST group from baseline to week 16 was 46.1% +/- 31.6% (P < 0.01) (mean of all three 3RM exercises: hammer curl, leg press, and incline dumbbell press), with mean gains in strength up to 4 times that of baseline values reported in all strength training exercises (upper and lower body) performed during exercise sessions. On average, right-hand grip strength increased by 2.9 +/- 4.0 kg in the ST group, in comparison with a loss of 1.2 +/- 3.0 kg in the C group over 16 weeks. The ST group had a 53% reduction in pain, in comparison with almost no change in the C group. The ST group had a significant improvement in 50-foot walk time, with a mean reduction of -1.2 +/- 1.6 seconds, in comparison with the C group (mean increase of 0.8 +/- 1.0 seconds; P = 0.01) over the 16 weeks. There was a clinically important difference (predefined as mean change +/-0.25) in the Health Assessment Questionnaire Disability Index in the ST group (-0.4 +/- 0.4) but not in the C group (-0.1 +/- 0.4). CONCLUSION: High-intensity strength training in RA patients with varying levels of disease activity and joint damage had a large, significant effect on strength, and led to improvements in pain and function, with additive patient benefits beyond the effect of their infliximab use.

Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.

BACKGROUND: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. METHODS: We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. RESULTS: The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. CONCLUSIONS: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).

Severity of joint pain and Kellgren-Lawrence grade at baseline are better predictors of joint space narrowing than bone scintigraphy in obese women with knee osteoarthritis.

OBJECTIVE: To compare the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a baseline late-phase bone scan and assessments of the radiographic and symptomatic severity of knee osteoarthritis (OA) at baseline as predictors of loss of articular cartilage thickness, as reflected in joint space narrowing (JSN) in the medial tibiofemoral compartment. METHODS: Subjects (174 obese women, 45-64 yrs of age, with unilateral knee OA) were a subset of a larger cohort who participated in a placebo controlled trial of a disease modifying OA drug. Uptake of technetium medronate (99mTc-MDP) in anteroposterior (AP) and lateral views of a late-phase bone scan was measured at baseline in a region of interest drawn around the medial tibia, and was adjusted for (i.e., expressed as a ratio to) uptake in a reference segment of the tibial shaft, which served as an internal standard. Each subject underwent a fluoroscopically standardized radiographic examination of the knees (semiflexed AP view) and a pain assessment with the WOMAC OA Index at baseline, 16 months, and 30 months. RESULTS: Controlling for baseline joint space width and treatment group, multiple linear regression models showed that the adjusted 99mTc-MDP uptake at baseline was a significant predictor of joint space narrowing (JSN) in the index knee at 16 months (b = 0.180, p = 0.015) and 30 months (b = 0.221, p = 0.049). In the contralateral knee, uptake was only a marginally significant predictor of JSN at 30 months (b = 0.246, p = 0.083). Uptake in the upper and middle tertiles of the distribution predicted subjects who would exhibit JSN >/= 0.50 mm within 16 months with 65% sensitivity (PPV 23%) and 36% specificity (NPV 77%). In contrast, a prediction rule based solely on the presence of Kellgren-Lawrence grade 3 OA severity and greater than median WOMAC Pain score identified progressors with 65% sensitivity (PPV 48%) and 79% specificity (NPV 88%). CONCLUSION: Although the level of adjusted 99mTc-MDP uptake was significantly associated with JSN in knees with established radiographic OA, baseline bone scintigraphy is inferior to the radiographic severity of OA and knee pain (alone or in combination) as a predictor of loss of articular cartilage in subjects with knee OA.

Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment. METHODS: In this placebo-controlled trial, obese women (n = 431) ages 45-64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals. RESULTS: Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean +/- SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 +/- 0.42 mm versus 0.24 +/- 0.54 mm); after 30 months, it was 33% less (0.30 +/- 0.60 mm versus 0.45 +/- 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a > or = 20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a > or = 20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase. CONCLUSION: Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee.

The benefit/risk profile of TNF-blocking agents: findings of a consensus panel.

OBJECTIVE: To review the benefits and risks associated with the use of the tumor necrosis factor (TNF)-blockers in various indications (eg, rheumatoid arthritis [RA], Crohn's disease [CD], psoriasis). METHODS: The members of the consensus panel were selected based on their expertise. Centocor, Inc provided an educational grant to the Center for Health Care Education to facilitate the consensus panel. Peer-reviewed articles discussing clinical studies and clinical experiences with TNF-blockers form the basis of this review. Emerging data that have not been peer-reviewed are also included. RESULTS: The TNF-blockers infliximab, etanercept, and adalimumab are all approved for treatment of RA. All 3 are effective, and there are currently no published data from head-to-head clinical trials to support using 1 agent over another. Preliminary data from small, retrospective studies indicate that switching among agents to overcome inadequate efficacy or poor tolerability is beneficial in some patients. The only TNF-blocker currently approved for the induction and maintenance of remission in CD is infliximab. Preliminary data indicate that etanercept and infliximab are effective in treating psoriasis. Some risks associated with TNF-blockers have become apparent, including congestive heart failure, demyelinating diseases, and systemic lupus erythematosus, but in most cases can be identified and managed. Several of these risks (eg, lymphoma and serious infections) are associated with either the condition per se or the concomitant medication use. Simple screening procedures help manage the risk of tuberculosis infection; however, it is recommended that physicians and patients be alert to the development of any new infection so that appropriate treatment may be initiated promptly. Rare infusion reactions, particularly with infliximab, may also be effectively managed. CONCLUSION: TNF-blockers are effective and may be safely used for short- and long-term management of RA or CD. TNF-blockers also show efficacy in other emerging indications.

Subject retention and adherence in a randomized placebo-controlled trial of a disease-modifying osteoarthritis drug.

OBJECTIVE: To describe the methods by which remarkable levels of subject retention and adherence were achieved in a 30-month multicenter randomized placebo-controlled trial (RCT) of a disease-modifying osteoarthritis drug (DMOAD). METHODS: Subjects were obese 45-64-year-old women with unilateral knee osteoarthritis. Before randomization, each volunteer completed a 4-week "faintness-of-heart" (FOH) test, during which she was required to demonstrate reliable appointment keeping and > or =80% adherence to the dosing regimen. Subjects who passed the FOH test were randomized to treatment with doxycycline or placebo for 30 months. The double-blind phase entailed 15 bimonthly followup visits; intervisit adherence data were downloaded from the dosing monitor and used to estimate therapeutic coverage and to identify correctable patterns of nonadherence. Subjects received token incentives and a small cash payment at each followup visit. Measures to prevent or treat side effects of doxycycline were dispensed free of charge. Study coordinators monitored safety and reinforced participation through between-visit telephone calls. RESULTS: Of 463 eligible volunteers, 32 (7%) failed the FOH test and were excluded from the double-blind phase. Among the 431 subjects randomized to treatment groups, 307 (71%) completed the 30-month RCT and 124 discontinued the study drug prematurely. Nearly half of the dropouts returned for their 16- and 30-month radiographs, resulting in loss to followup of 14.8% of randomized subjects. The 2 treatment groups did not differ significantly with respect to rates of discontinuation or retention. Therapeutic coverage over 30 months was very high in both groups. CONCLUSION: The rate of discontinuation in this 30-month RCT (29%) was lower than that of any DMOAD trial of > or =2 years duration published to date. The proportion of subjects for whom 30-month radiographs were available (85%) and adherence to the dosing regimen (mean >80%) also were remarkably high.

Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus.

OBJECTIVE: To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms. METHODS: Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (/=6 weeks prior to enrollment and remain unchanged during protocol treatment. Responders were patients who experienced no clinical deterioration and had improvement or stabilization over the duration of the study in 2 disease activity measures (the SLE Disease Activity Index [SLEDAI] and the Systemic Lupus Activity Measure) and 2 quality of life measures (patient's global assessment and the Krupp Fatigue Severity Scale). RESULTS: A total of 381 women with SLE were enrolled. Among patients with clinically active disease at baseline (SLEDAI score >2), 86 of 147 in the prasterone group (58.5%) demonstrated improvement or stabilization without clinical deterioration, as compared with 65 of 146 in the placebo group (44.5%) (P = 0.017). Acne and hirsutism were reported in 33% and 16%, respectively, of the prasterone group and in 14% and 2%, respectively, of the placebo group (P < 0.05 for both comparisons). However, most cases of acne and hirsutism were mild and did not require withdrawal from therapy. Myalgias and oral stomatitis were reported less frequently in the prasterone group (22% and 15%, respectively) than in the placebo group (36% and 23%, respectively) (P < 0.05 for both comparisons). Serum levels of high-density lipoprotein cholesterol, triglycerides, and C3 complement significantly decreased, while levels of testosterone and, to a lesser extent, estradiol increased in the prasterone group. CONCLUSION: In adult women with active SLE, administration of prasterone at a dosage of 200 mg/day improved or stabilized signs and symptoms of disease and was generally well tolerated.

Increased activation-induced cell death in peripheral lymphocytes of rheumatoid arthritis patients: the mechanism of action.

Recently, we have described a soluble survival signal for activated lymphocytes from CD14(+) cells. As a result of the importance of T lymphocytes in the pathogenesis of rheumatoid arthritis (RA), we speculate a possible role for CD14(+) cells in supporting the outgrowth of autoreactive lymphocytes in RA. To address this issue further, supernatants from activated CD14(+) cells (CD14 cocktails) in both normal controls and RA patients were collected. The relative strength of the CD14 cocktails from normal controls and RA patients was compared. The data showed that depletion of CD14(+) cells resulted in a much higher increase of activation-induced cell death (AICD) and a decrease of lymphocyte proliferation in the peripheral blood mononuclear cells of RA patients compared to normal controls. Interestingly, CD14 cocktails from RA patients provide much stronger protection against AICD compared to those from normal controls. The observed soluble survival signal from CD14(+) cells is a general phenomenon because CD14 cocktails prevent both phytohaemagglutinin A-p- and anti-CD3-induced AICD. Furthermore, supernatants collected from human dendritic cell cultures also prevent activated lymphocytes from undergoing AICD. The data implicate an important role of the CD14(+) cell and its secreted form of survival signal in the pathogenesis of RA.

Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists.

OBJECTIVE: To describe a group of patients who were treated with tumor necrosis factor alpha (TNF alpha) antagonists and who developed coccidioidomycosis, and to test the hypothesis that patients with inflammatory arthritis receiving TNF alpha antagonist therapy are at higher risk for developing symptomatic coccidioidomycosis. METHODS: Cases of coccidioidomycosis were identified and reviewed from among patients receiving TNF alpha antagonist therapy from May 1998 through February 2003 in 5 practices within the areas endemic for coccidioidomycosis (Arizona, California, and Nevada). In addition, the relative risk of developing symptomatic coccidioidomycosis was calculated in patients with inflammatory arthritis who were receiving treatment with infliximab, in comparison with patients with inflammatory arthritis who were not receiving infliximab, from January 2000 to February 2003 in a single medical center. RESULTS: Thirteen cases of documented coccidioidomycosis were associated with TNF alpha antagonist therapy. Twelve cases were associated with the use of infliximab and 1 case with etanercept. Among the cohort of patients from a single medical center, 7 of the 247 patients receiving infliximab and 4 of the 738 patients receiving other therapies developed symptomatic coccidioidomycosis (relative risk 5.23, 95% confidence interval 1.54-17.71; P < 0.01). CONCLUSION: Patients with inflammatory arthritis who are undergoing treatment with infliximab appear to be at higher risk for developing symptomatic coccidioidomycosis as compared with those not receiving infliximab.

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: a double-blind trial.

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA). METHODS: This was a 6-month, phase III, double-blind, multicenter study. Patients with active RA who had discontinued all disease-modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg. RESULTS: A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3-mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD-intolerant patients had better ACR response rates than did DMARD-resistant patients. Although serum creatinine levels increased by >/=40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in approximately 90% of patients. CONCLUSION: Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3-mg dose of tacrolimus resulted in generally better ACR response rates.

Characterizing a soluble survival signal for activated lymphocytes from CD14+ cells.

T-cell activation requires at least two signals: antigen and a costimulatory signal. As antigen-presenting cells play an important role in this area, the role of CD14+ cells in T-cell activation, proliferation and activation-induced cell death (AICD) was investigated. Using phytohaemagglutinin (PHA) activation, it was found that CD14+ cell depletion resulted in significantly greater AICD, decreased lymphocyte growth and up-regulated interleukin-2 (IL-2) secretion. However, T-cell activation was delayed according to the expression of CD69 and CD25. Dynabeads conjugated with anti-CD14 monoclonal antibody (mAb) bound CD14+ cells and induced secretion of IL-1beta, tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and IL-6, but not IL-2, IL-12 or IL-15. Supernatants were collected from Dynabeads-activated CD14+ cell cultures and designated as 'CD14 cocktails'. Addition of CD14 cocktails to CD14+ cell-depleted mononuclear cell cultures reversed the increased AICD, decreased lymphocyte growth and increased IL-2 secretion. Depletion of IL-1beta and TNF-alpha in the CD14 cocktails by panning followed by blocking with the corresponding mAbs had no effect on the active AICD protection. TGF-beta was determined not to be the active factor owing to the presence of >1.0 ng of TGF-beta in the media for culturing both CD14+ and CD14- peripheral blood mononuclear cells (PBMC). The CD14 cocktails did not contain IL-12 and IL-15. Depletion of IL-6 with panning followed by blocking residual IL-6 with anti-IL-6 mAb significantly reduced the protective effect of the CD14 cocktails. Human recombinant IL-6 also partially reversed the effects of CD14+ cell depletion on AICD, lymphocyte growth and IL-2 secretion. The data suggest that IL-6 is one of the active factors in the survival signal from CD14+ cells.

Human monoclonal natural autoantibodies against the T-cell receptor inhibit interleukin-2 production in murine T cells.

Natural autoantibodies (NAAbs) specific for the T-cell receptor (TCR) are present in all human sera, but individuals with rheumatoid arthritis (RA) generally produce higher titres of immunoglobulin M (IgM) isotype autoantibodies (AAbs) against Vbeta TCR epitopes. To investigate possible correlations between the specificity of such AAbs and their role in immunomodulation, we generated seven B-cell hetero-hybridomas, secreting monoclonal IgM NAAbs, from the synovial tissue and peripheral blood of patients with RA. Here we report three anti-TCR monoclonal autoantibodies (mAAbs)--OR2, OR5 and Syn 2H-11--with the ability to bind subsets of murine T cells, including the ovalbumin-specific DO-11.10 clone. These antibodies did not induce apoptosis in vitro, but prevented interleukin-2 (IL-2) production by antigen-specific T cells. These findings suggest an immunomodulatory function for NAAbs to TCR V-region epitopes and serve as the foundation for testing human anti-TCR mAAbs in animal models with the eventual goal of using them as therapeutic agents in human disease.

Specificity mapping of human anti-T cell receptor monoclonal natural antibodies: defining the properties of epitope recognition promiscuity.

The classical concept of antibody binding is defined as an exclusive and high-affinity interaction with one epitope. The emerging reality about antibody combing sites, however, is that some can bind unrelated determinants. The studies presented here define this quality as epitope recognition promiscuity by analyzing the capacity of monoclonal human autoantibodies to bind sets of overlapping peptides duplicating the complete structures of T cell receptor (TCR) alpha and beta chains and immunoglobulin lambda chain. We assessed the binding of these monoclonal antibodies (mAbs) to a set of homologous peptides corresponding to the CDR1 segments of human Vbeta gene products, a major epitope used in the selection of the antibodies. We present data on the binding characteristics of four human mAbs selected for the ability to bind TCR epitopes. These mAbs are IgM molecules with VH and VL sequences in germline configuration, but have diverse VH CDR3 regions. These studies aim to characterize the property of epitope promiscuity and show that the relationship between the binding site and its epitope is a complex interaction and unpredictable from antigen sequence alone. Our results support the conclusion that epitope recognition promiscuity is a genuine feature of antibody and TCR recognition.

An in vitro Model for Studying Mechanisms Underlying Synoviocyte-Mediated Cartilage Invasion in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of joints involving the pathological development of an invasive and destructive pannus tissue which contributes to the loss of cartilage and bone. To further analyze the process of cartilage degradation and invasion, we have developed an in vitro model composed of cartilage matrix and synoviocytes (isolated from RA pannus tissue, as well as normal synovial membrane). The matrix is derived from pig articular cartilage and contains collagen type II and proteoglycans and is similar in composition to human cartilage. Data generated from this model reveal that synoviocytes isolated from RA pannus tissue invaded cartilage matrix in a manner which directly correlated with the severity of the disease. Analysis of mechanisms associated with the invasive process demonstrate that highly invasive RA synoviocytes maintain a round morphology during attachment and spreading on cartilage matrix, compared with their normal counterparts. Furthermore, the level of secretion of matrix metalloproteinase (MMP) activity was shown to correlate with the RA phenotype, which could be modulated with a novel MMP inhibitor. Normal synoviocytes could be "converted" to an RA phenotype by specific inflammatory cytokines, such that invasion of cartilage matrix was augmented by culturing these cells in the presence of 5 U/ml IL-1b or 18 U/ml TGFb. Invasion was inhibited by 150 U/ml TNFa, and unaffected by 100 ng/ml PDGF. In addition, synovial fluid from RA patients induced invasion of normal synoviocytes, in a concentration dependent manner, from 150% to 460%; however, synovial fluid from another inflammatory arthritidy (Crohn's) did not augment invasion to the same degree. Moreover, this "conversion effect" appears to be specific for synoviocytes, since similar effects could not be achieved with human skin fibroblasts. This in vitro model of synoviocyte-mediated cartilage invasion allows for further molecular characterization of the invasive properties of the synoviocyte which contribute to RA.