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ID PMID Title PublicationDate abstract
11764343 Long-term results using the anatomic medullary locking hip prosthesis. 2001 Dec Since the introduction of cementless total hip arthroplasty in the early 1980s, concern has shifted from component loosening toward polyethylene wear and osteolysis. The current review of 223 consecutive unselected Anatomic Medullary Locking femoral and acetabular components extends the followup on a series of patients previously reported on at 5 and 10 years. The purposes are to describe the reasons for revisions and to assess the onset and size of osteolytic lesions, with the hypothesis that osteolysis represents an important cause of loosening. The population included 204 patients (211 hips) with mean followup of 13.9 years (range, 2-18 years). Among them, 122 patients (129 hips) had a minimum 15-year followup. Minimum 2-year radiographs with a mean radiographic followup of 12.2 years (range, 2-18 years) were available for 204 hips (197 patients). Of the entire study group, 39 hips (38 patients) had 44 component revisions, increasing the number of revisions by 24 since this series was reported previously. Twenty-six patients (27 hips) had their first revision surgery more than 10 years after the primary surgery. The most common reason for revision of original components was wear or osteolysis occurring in 22 of the 39 hips (21 of 38 patients). The overall loosening rate was 3.4% (seven of 204) for femoral components and 5.4% (11 of 204) for acetabular components. Twenty-four percent of hips (48 of 204) had evidence of femoral or pelvic osteolytic lesions larger than 1.5 cm2. Femoral osteolysis was not associated with any case of femoral loosening, whereas seven of the 11 loose acetabular components were associated with pelvic lesions larger than 1.5 cm2.
10770182 Adrenocorticotropin, glucocorticoid, and androgen secretion in patients with new onset syn 2000 Apr To determine whether alterations in adrenocortical function occur early in the development of inflammatory joint disease, we examined patients with new onset synovitis (<1 yr) prior to treatment with corticosteroids or other disease-modifying antirheumatic drugs. Thirty-two patients with new onset synovitis, including 15 fitting criteria for rheumatoid arthritis (RA), taking no medications, were referred for study by local rheumatologists; 32 age- and sex-matched healthy individuals were recruited as controls. Patients and controls had blood drawn under identical conditions between 0900 and 1100 h. Plasma ACTH, cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate, free and total testosterone, erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor were measured. Compared with controls, patients had higher inflammatory indices (erythrocyte sedimentation rate, C-reactive protein) and lower basal morning levels of free testosterone (lower in males age > or =45 yr), but similar levels of ACTH, cortisol, DHEA, DHEA sulfate, and total testosterone. In addition, the positive correlations between ACTH-cortisol, ACTH-DHEA, and cortisol-DHEA, observed in the normal controls, were weakened or abolished in the patients (both total and RA subset). No positive relations between inflammatory indices and ACTH or cortisol were noted, yet an inverse correlation between these indices and DHEA and testosterone was observed. Moreover, a steeper age-associated decline in DHEA was observed in our cross-sectional sample of patients with new onset synovitis. We conclude that patients with synovitis (including those fitting criteria for RA) have adrenocortical hormone alterations within a year of disease onset. Paradoxically, these patients have no positive relation between indices of inflammation and ACTH or cortisol, but rather serum androgen levels are inversely correlated with these indices. In addition, the relations between ACTH, the classic stimulus of cortisol and adrenal androgens, and these hormones are weakened or abolished, whereas the negative relation between age and zona reticularis function is steeper than that of controls.
11765224 Expression of Fas-associated death domain-like interleukin-1beta-converting enzyme (FLICE) 2001 Nov Although chondrocyte apoptosis has been noted in arthritic joints, the mechanism is not clear. To investigate whether Fas-mediated apoptosis has a role in this process, the presence of Fas mRNA and expression of cell surface Fas protein in monolayer-cultured human articular chondrocytes was analyzed. Fas mRNA was found in all chondrocyte samples analyzed; moreover, the majority of cells in chondrocyte populations expressed cell-surface Fas (12-90%, average 49%). Nevertheless, treatment with an agonistic anti-Fas antibody did not induce significant apoptosis in these chondrocytes in vitro. However, it was also found that chondrocytes express Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (FLIP), a molecule which blocks Fas-mediated apoptosis. Correspondingly, activation of caspase-8 was minimal in these cultured chondrocytes. In conclusion, although human articular chondrocytes do express cell-surface Fas, this receptor did not fully mediate death-inducing signals in vitro. This resistance to Fas may be partly due to the constitutive expression of FLIP.
10546597 Total knee replacement in patients older than 85 years. 1999 Oct Between 1987 and 1995, 62 unilateral total knee replacements performed in patients older than 85 years (mean age, 87 years) were followed up for a minimum of 2 years (range, 2-11 years, mean, 5.4 years). This group represented 3.8% of all the total knee replacements performed during the same time. The majority of the patients were women with osteoarthritis. There was a 70% preoperative cardiac disease comorbidity. Overall, confusion after surgery was greater in this older group than in the patients younger than 85 years of age, however, confusion was lower in the group of patients who had epidural anesthesia as compared with those patients who had surgery under general anesthesia. The mean knee score at followup was 89 points and the mean pain score was 43 points (of 50 points). The mean flexion was 114 degrees. Seventy-five percent of these elderly patients still required the use of a cane for walking outdoors compared with 18% of the patients who were younger than 85 years. More than 855 of the older patients could travel independently to socialize and shop after surgery. Seventy-six percent of the patients were living independently or in senior retirement housing after surgery. Only two of the patients required living accommodations in a nursing home. One third of the patients still could drive their own car after surgery. Quality of life improvement was markedly increased in this elderly group of patients. The results of this study indicate that total knee replacement still is a valuable procedure even for this elderly group, and most of these patients returned to a more functional lifestyle.
9525978 Synovium as a source of increased amino-terminal parathyroid hormone-related protein expre 1998 Apr 1 Proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin 1 (IL-1), mediate the joint destruction that characterizes rheumatoid arthritis (RA). Previous studies have shown that parathyroid hormone-related protein (PTHrP) is a member of the cascade of proinflammatory cytokines induced in parenchymal organs during lethal endotoxemia. To test the hypothesis that NH2-terminal PTHrP, a potent bone resorbing agent, could also be a member of the synovial cascade of tissue-destructive cytokines whose expression is induced in RA, PTHrP expression was examined in synovium and synoviocytes obtained from patients with RA and osteoarthritis (OA). PTHrP production, as determined by measurement of immunoreactive PTHrP(1-86) in tissue explant supernatants, was increased 10-fold in RA versus OA synovial tissue. Synovial lining cells and fibroblast-like cells within the pannus expressed both PTHrP and the PTH/PTHrP receptor, findings that were confirmed by in vitro studies of cultured synoviocytes. TNF-alpha and IL-1beta stimulated PTHrP expression in synoviocytes, while dexamethasone and interferon-gamma, agents with some therapeutic efficacy in the treatment of RA, inhibited PTHrP release. Treatment of synoviocytes with PTHrP(1-34) stimulated IL-6 secretion. These results suggest that proinflammatory cytokine-stimulated production of NH2-terminal PTHrP by synovial tissue directly invading cartilage and bone in RA may mediate joint destruction through direct effects on cartilage or bone, or, indirectly, via the induction of mediators of bone resorption in the tumor-like synovium.
11700999 Hashimoto's encephalopathy: documentation of mesial temporal seizure origin by ictal EEG. 2001 Sep Hashimoto's encephalopathy is a chronic relapsing and remitting encephalopathy associated with antithyroid antibodies. Seizures are a frequent manifestation, but are not well characterized in the literature with respect to their onset. We describe a 48-year-old patient with recurrent encephalopathy and seizures, and elevated antithyroid antibodies. One seizure was documented with video-EEG monitoring using scalp and sphenoidal electrodes. The ictal discharge originated in the left mesial-basal temporal region. MRI showed an increased T2 signal in the white matter of the centrum semiovale, but no temporal pathology. Symptoms resolved after treatment with prednisone and azathioprine. Hashimoto's encephalopathy should be considered in patients with unexplained encephalopathy and seizures, including those originating in the temporal lobe.
9278178 Are immunoconjugates useful for therapy with autoimmune diseases? 1997 Feb Immunoconjugates or immunotoxins (ITs) are targeting molecules which consist of a monoclonal antibody together with a toxin--thereby they can selectively kill target cells in a highly efficient manner. The use of ITs as a drug targeting approach is one of the most attractive research fields for tumor therapy; however, the study of ITs for the treatment of autoimmune diseases has been given little attention until recently. It has been shown that ITs could help alleviate the symptoms of myasthenia gravis and rheumatoid arthritis in animal models. In the last 3 yr ITs have been used in clinical trials (phase I and phase II) for the treatment of various autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, insulin-dependent diabetes mellitus and psoriasis. This article reviews the main progress on the application of ITs for the therapies of autoimmune diseases. The preliminary results suggest the future may hold some promise, but side effects, in addition to there being no convincing efficacy, remain unresolved.
10606375 Development of a questionnaire to investigate patient compliance with antirheumatic drug t 1999 Dec OBJECTIVE: To develop a rheumatology oriented questionnaire that measures compliance to drug regimen and identifies factors that contribute to suboptimal compliance in patients with rheumatoid arthritis (RA), polymyalgia rheumatica (PMR), and gout. METHODS: Thirty-two patients (16 RA, 8 PMR, 8 gout) participated in semistandardized home interviews about their attitude toward their antirheumatic medication, actual drug intake, and reasons for not taking medication. A focus group interview with 7 patients (3 RA, 2 PMR, 2 gout) was held. Following an advertisement in the rheumatology patient organization magazine (>8000 patients) 14 patients (9 RA, 5 PMR) telephoned and explained their reasons for noncompliance. All interviews were recorded on tape, transcribed, and independently reviewed by 2 investigators. Thirty-one statements were selected. After a field test, the phrasing of some items was revised. The questionnaire was then sent by mail to 117 consecutive outpatients (58 RA, 30 PMR, 29 gout). RESULTS: Twelve items were excluded because of low or high corrected item-total correlation or skew distribution of the answers. Internal consistency of the remaining 19 items was intermediate (0.71). Discriminant analyses with an overall patient self-report compliance measure showed a sensitivity of 98%, a specificity of 67%, and a Cohen's kappa of 0.71. Stepwise discriminant analyses revealed that 3 items classified 84% of all cases correctly with a sensitivity of 99%, specificity 80%, and kappa 0.78. CONCLUSION: The 19 item measure was well accepted. It is useful to detect possible barriers for optimal compliance and to predict patient compliance to drug regimen.
10361248 Elevated serum levels of soluble membrane cofactor protein (CD46, MCP) in patients with sy 1999 Jun Membrane cofactor protein (MCP, CD46) is a cell surface complement regulatory protein which acts as a cofactor for the factor I-mediated cleavage of the activated complement components C3b/C4b. To evaluate the clinical usefulness of serum soluble CD46 as a marker of disease activity in patients with SLE, serum levels of sCD46 were measured by ELISA, using two MoAbs (M160 and M177), each of which recognized two different epitopes on CD46 molecule in SLE, other autoimmune diseases and healthy controls. Serum sCD46 levels in active SLE patients (30.5 +/- 14.1 ng/ml) were significantly higher than those of inactive SLE (5.8 +/- 7.1 ng/ml; P = 0.0003), rheumatoid arthritis (14.9 +/- 11.6 ng/ml; P = 0.0218), primary Sjögren's syndrome (12.3 +/- 11.6 ng/ml; P = 0.0039) and normal controls (7.3 +/- 3.6 ng/ml; P = 0.0005). The elevated serum sCD46 levels in active SLE patients significantly decreased from 30.5 +/- 14.1 ng/ml to 8.0 +/- 6.3 ng/ml after effective corticosteroid and immunosuppressant therapy (P = 0.018). Additionally, we found a significant negative association between increasing concentration of sCD46 and decreasing levels of CH50 in SLE (r = -0.598, P = 0.0009). These results suggest that sCD46 reflects in vivo activation of complement system and provides an additional useful serum parameter of active SLE.
9399601 Mycophenolate mofetil. 1997 Nov Mycophenolate mofetil is the morpholinoethylester prodrug of mycophenolic acid, an agent that inhibits the proliferation of B and T lymphocytes through noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, a key enzyme in the de novo synthetic pathway of guanine nucleotides. Currently, mycophenolate mofetil is approved for the prevention of acute renal allograft rejection when given in combination with cyclosporine and steroids. Several studies also demonstrated that the agent is effective in the treatment of refractory rejection in renal, heart, and liver transplant recipients, and may have efficacy in the treatment of chronic rejection as well.
9421605 Double armed reinsertion suture (DARS) of the profundus flexor tendon with immediate activ 1997 Between 1982 and 1994, the authors performed 63 flexor digitorum profundus tendon reinsertions according to the "lost-suture" DARS method (double armed reinsertion suture). This technique consists of 2 Bunnell sutures fixed to the lateral and anterior parts of the cut surface of the tendon. Nylon suture material is passed through a transverse hole made in the base of the distal phalanx. Active flexion without resistance is commenced postoperatively. A similar limit to extension is only applied in the case of an associated lesion if the neurovascular pedicle. Forty tendons were reviewed for this study (patients between the ages of 7 and 75 years, 35 males for 5 females). The lesion involved the thumb in 13 cases and long fingers in 27 cases. According to the authors' criteria, the results were scored as excellent 20% (8 cases); good 70% (28 cases); poor 10% (10 cases). The "lost-suture" DARS technique is a simple method which allows immediate active mobilization of the finger and appears to guarantee satisfactory functional results with no risk of tendon rupture.
9552765 Leukocytoclastic vasculitis induced by low-dose methotrexate: in vitro evidence for an imm 1998 Jan The rare occurrence of methotrexate (MTX)-induced vasculitis has been associated mainly with high or intermediate MTX doses. We report herein a case of cutaneous leukocytoclastic vasculitis (LCV) following treatment with low-dose oral MTX (7.5 mg/week) for rheumatoid arthritis. The histological findings of a cutaneous lesion were consistent with drug-induced vasculitis. The clinical and histological findings, including the temporal relationship between MTX intake and the onset of vasculitis, and the results of withdrawal and rechallenge tests, suggest a causal relationship, and indicate a drug-induced LCV due to MTX. The role of MTX in the induction of the vasculitis was further supported by a positive mast cell degranulation (MCD) test.
10852254 In vitro and in vivo inhibition of activation induced T cell apoptosis by bucillamine. 2000 Jun OBJECTIVE: To investigate the mechanism of autoimmune phenomena, occasionally seen in patients with rheumatoid arthritis treated with bucillamine (BUC) and D-penicillamine (D-Pen), by evaluating their effects on apoptosis of T cells induced by T cell receptor activation or dexamethasone. METHODS: In vitro apoptosis was induced in a T cell hybridoma (SSP3.7) and a B cell line (WEHI 231) by activation of respective receptors or dexamethasone, in the presence or absence of BUC or D-Pen. In vivo apoptosis was induced in BALB/c mice by staphylococcal enterotoxin B (SEB), with or without BUC or D-Pen, and thymocytes were examined for it by FACS. RESULTS: Stimulation with anti-CD3 and dexamethasone induced apoptosis in 72% and 71% of SSP3.7 cells, respectively. However, only 16% of SSP3.7 cells became apoptotic by anti-CD3 when BUC was added to the culture media. By contrast, 80% of SSP3.7 cells became apoptotic when stimulated by dexamethasone, even in the presence of BUC. BUC did not affect apoptosis of WEHI 231 cells induced by anti-IgM. Although SA981 (a metabolite of BUC) inhibited apoptosis of SSP3.7 cells induced by anti-CD3, D-Pen did not. BUC, SA981, or D-Pen did not significantly influence the level of interleukin 2 secretion stimulated by anti-CD3. In contrast, both BUC and D-Pen inhibited apoptosis of Vbeta8+ thymocytes induced in vivo by SEB superantigen. Neither BUC nor D-Pen significantly changed the number of CD4+CD8+ thymocytes in BALB/c mice injected with dexamethasone. CONCLUSION: BUC decreased, while D-Pen did not, the apoptosis of T cells stimulated by anti-CD3 in vitro, although they both inhibited the deletion of immature thymocytes reactive with SEB in vivo. This may explain autoimmune phenomena sometimes seen during the treatment of rheumatic patients with these drugs.
11766957 The use of outcome measures in physical medicine and rehabilitation within Europe. 2001 Nov The aim of the study was to survey the use of outcome measures in rehabilitation within Europe. It was envisaged that this would provide the basis for further studies on the cross-cultural validity of outcome measures. A postal questionnaire was distributed in November 1998 to 866 units providing rehabilitation. In total, 418 questionnaires were returned, corresponding to a response rate of 48%. These 418 centres treated an estimated 113,000 patients annually, undertaking 360,000 assessments. The survey focused on nine diagnostic groups: hip and knee replacement, low back pain, lower limb amputees, multiple sclerosis, neuromuscular disorders, rheumatoid arthritis, spinal cord lesions, stroke and traumatic brain injury. It identified a relatively small number of dominant outcome assessments for each diagnostic group and some variation in the preference for measures across regions. A large number of measures, however, are being used in one or a small number of locations and with relatively few patients. For rehabilitation of orthopaedic patients the majority of assessments undertaken are at the impairment level. For patients with neurological disorders the emphasis is mostly upon measures of disability.
11360737 [Liver and renal tolerance to paracetamol: 3 g or 4 g per day?]. 2001 Apr 21 OBJECTIVES: To compare the hepatic and renal safety profiles of two daily dosage regimens of paracetamol (acetaminophen) (3 g versus 4 g) in patients with painful chronic rheumatoid diseases. METHODS: Medical files of outpatients in the United Kingdom were investigated using an automated database. Two acetaminophen groups (3 g and 4 g) were compared with regard to demographic variables, treatments, associated diseases and occurrence of hepatorenal adverse events. Variables collected from the files for selected patients were also analyzed using the decision tree method to identify the specific variables best explaining the occurrence of hepatorenal adverse events. RESULTS: A total of 1.5 million medical files were investigated. Of the 7781 patients identified with paracetamol prescriptions for chronic rheumatoid disorders, 1868 (24%) were treated with 3 g/day and 5913 (76%) with 4 g/day. The mean overall duration of paracetamol exposure was 277 and 201 days respectively. No difference between the two acetaminophen groups was found with the numbers of patients with hepatorenal adverse events potentially related to acetaminophen intake (0.86%: group 3 g versus 0.68% group 4 g). Using the decision tree method, daily dosage of paracetamol (3 g or 4 g) was never identified as a discriminating variable capable of explaining the occurrence of hepatorenal adverse events. CONCLUSION: When risk factors are taken into account, such as concomitant chronic diseases, both daily dosages of paracetamol (3 g and 4 g) have a comparable hepatorenal safety profiles in rheumatology, even in elderly patients.
10090160 Trends in the use of disease modifying antirheumatic medications in rheumatoid arthritis, 1999 Mar OBJECTIVE: Current treatment of rheumatoid arthritis (RA) emphasizes the early and consistent use of disease modifying antirheumatic drugs (DMARD). We studied how often these medications were used to treat patients with RA, and whether use of these medications has increased over time. METHODS: We used the National Ambulatory Medical Care Surveys to determine national probability estimates of the use of DMARD [hydroxychloroquine, intramuscular gold, auranofin, methotrexate (MTX), sulfasalazine, azathioprine, D-penicillamine, and cyclosporine] by patients with RA. The National Ambulatory Medical Care Surveys record information about treatments provided in outpatient settings by a nationally representative cross sectional sample of physicians. Estimates of the use of DMARD were based on the treatments reported on 502 visits by patients with RA in 1980-81, 339 visits by patients with RA in 1985, 386 visits by patients with RA in 1989-91, and 383 visits by patients with RA in 1993-95. RESULTS: DMARD were used in 30.3% of visits in 1980-81, 36.3% of visits in 1985, 24.9% of visits in 1989-91, and 43.6% of visits in 1993-95 (p for trend < 0.0001). Increased use of MTX accounted for most of the increased prevalence of DMARD use; MTX was used in 27.3% of visits in 1993-95. Use of DMARD increased in 1993-95 in all age, sex, and racial subgroups, and among visits reported by rheumatologists, but did not increase over time among visits reported by physicians other than rheumatologists. CONCLUSION: Use of DMARD in RA has increased in the recent past, but DMARD are currently used by fewer than 44% of patients with RA. Use of DMARD has not increased over time among patients of physicians other than rheumatologists.
9855215 Carnitine and antioxidants levels in patients with rheumatoid arthritis. 1998 Rheumatoid arthritis (RA) is a heterogeneous disorder with a spectrum of clinical severity ranging from mild arthritis to a crippling joint disease with involvement of internal organs. Carnitine is essential for muscle energy production and is required for the transport of long chain fatty acids and the acyl coenzyme A derivatives across the inner mitochondrial membrane. The levels of malondialdehyde (MDA), an index of lipid peroxidation, and the antioxidants copper-zinc superoxide dismutase (CuZnSOD), glutathione (GSH), ceruloplasmin (CP), catalase (CAT), and carnitine were assessed in 42 patients with RA and 24 control subjects. While plasma carnitine and erythrocyte CuZnSOD levels were significantly lower in the patients with RA compared with the control group (p<0.01 and p<0.001, respectively), the CAT level was not different from controls (p>0.05). Plasma MDA, CP, and erythrocyte GSH levels were significantly higher than in the control group (p<0.001, p<0.001 and p<0.01, respectively). MDA levels showed a positive correlation with CP and GSH levels (r=0.716, p<0.001 and r=0.492, p<0.01, respectively). However, MDA, GSH, and CP demonstrated a negative correlation with carnitine (r=-0.719, p<0.001; r=-0.559, p<0.01, and r=-0.635, p<0.001, respectively) in the patient group but not in controls. There was also a significant positive correlation between CP and GSH levels (r=0.561, p<0.01). However, neither CuZnSOD nor CAT levels demonstrated correlation withcarnitine, MDA, GSH, or CP levels. It was interesting that CAT activity was not altered and CuZnSOD activity decreased when compared with the control group. These results suggest that while CP, MDA and GSH levels increased, carnitine and CuZnSOD levels decreased, but CAT activity was unchanged.
9212766 Azathioprine-induced lymphoma manifesting as fulminant hepatic failure. 1997 Jul Azathioprine and rheumatoid arthritis are known to be associated with an increased risk of the development of non-Hodgkin's lymphoma; however, the manifestation of fulminant hepatic failure is extremely uncommon in patients with non-Hodgkin's lymphoma. In this article, we describe a patient with rheumatoid arthritis who was taking azathioprine, in whom fulminant hepatic failure occurred because of massive lymphomatous infiltration of the liver.
9216455 Serum concentrations of free ubiquitin and multiubiquitin chains. 1997 Jul Ubiquitin, which can conjugate with cellular proteins, is classified into two forms: free ubiquitin and multiubiquitin chains. The latter is active as a signal for degradation of the targeted proteins. We found both forms in human serum and, using two immunoassays, quantitated them in sera from healthy subjects and patients with some diseases. Because of putative leakage of erythrocyte ubiquitin, hemolytic serum and serum obtained after long incubation (> 1-2 h) of blood at room temperature were excluded. Serum concentrations of multiubiquitin chains and free ubiquitin were substantially higher in rheumatoid arthritis and hemodialysis patients, respectively, than healthy subjects. Additionally, in acute viral hepatitis, serum multiubiquitin chain concentrations were increased in the acute phase, decreased in the recovery phase, and correlated with alanine and aspartate aminotransferase activities (r = 0.676 and 0.610, P < 0.0001 and < 0.001, respectively). Therefore, serum ubiquitin may have prognostic value.
10943860 Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene 2000 Aug OBJECTIVE: Joint destruction in rheumatoid arthritis (RA) is a result of degradation and invasion of the articular cartilage by the pannus tissue. The present study was undertaken to examine the role of the plasminogen activation system in cartilage degradation and invasion by synovial fibroblasts and investigate a novel gene therapeutic approach using a cell surface-targeted plasmin inhibitor (ATF.BPTI). METHODS: Adenoviral vectors were used for gene transfer. The effects of ATF.BPTI gene transfer on RA synovial fibroblast-dependent cartilage degradation were studied in vitro, and cartilage invasion was studied in vivo in the SCID mouse coimplantation model. RESULTS: The results indicate that cartilage matrix degradation by rheumatoid synovial fibroblasts is plasmin mediated and depends on urokinase-type plasminogen activator for activation. Targeting plasmin inhibition to the cell surface of the fibroblasts by gene transfer of a cell surface-binding plasmin inhibitor resulted in a significant reduction of cartilage matrix degradation in vitro and of cartilage invasion in vivo. Compared with uninfected rheumatoid synovial fibroblasts, the mean +/-SEM cartilage degradation in vitro was reduced to 87.9+/-0.9% after LacZ gene transfer versus a reduction to 24.0+/-1.6% after ATF.BPTI gene transfer (P<0.0001). The mean +/- SEM in vivo cartilage invasion score was 3.1+/-0.4 in the control-transduced fibroblasts and 1.8+/-0.4 in the ATF.BPTI-transduced fibroblasts (P<0.05). CONCLUSION: These results indicate a role of the plasminogen activation system in synovial fibroblast-dependent cartilage degradation and invasion in RA, and demonstrate an effective way to inhibit this by gene transfer of a cell surface-targeted plasmin inhibitor.