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ID PMID Title PublicationDate abstract
18505368 B-cell infiltrates induce endosteal bone formation in inflammatory arthritis. 2008 Oct The objective of this study was to investigate the function of inflammatory bone marrow infiltrates found in vicinity to joints affected by inflammatory arthritis. These bone marrow infiltrates are rich in B cells and emerge at the interphase between bone marrow and synovial inflammatory tissue, where cortical bone has been broken. We deleted an essential molecule of B-cell development, Brutońs tyrosine kinase (Btk), in arthritic TNF-transgenic mice and studied its effect on bone marrow inflammation. Although antigen responses, immunoglobulin levels, and autoantibody production were diminished in Btk(-/-)hTNFtg mice, synovial inflammation developed normally. However, bone marrow infiltrates were significantly diminished in Btk(-/-)hTNFtg mice, which lead to impaired bone formation at endosteal sites underneath bone erosions and an increased invasion of synovial inflammatory cells into the bone marrow. Expression of bone morphogenic protein-7 was dramatically decreased in Btk(-/-)hTNFtg mice. These results do not only indicate that bone formation at endosteal regions next to bone marrow infiltrates is driven by B cells but also show that bone marrow aggregates in the vicinity of inflamed joint appear as an attempt to counter the invasion of inflammatory tissue into the bone marrow.
18683105 Golimumab, a fully human monoclonal antibody against TNFalpha. 2008 Aug Centocor Inc and licensees Schering-Plough Corp, Mitsubishi Tanabe Pharma Corp and Janssen Pharmaceutical KK are developing golimumab, a fully human mAb antibody against TNFalpha, for the potential treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and ulcerative colitis. Golimumab is currently in phase III clinical trials for RA, PsA and AS and preliminary data have shown an improvement in a number of physical functions, disease activity, productivity and quality-of-life measurements.
16670074 Atypical lymphoproliferation progressing into B-cell lymphoma in rheumatoid arthritis trea 2006 May A patient with rheumatoid arthritis (RA) developed an atypical lymphoproliferative disorder (LPD) after methotrexate and cyclosporine A, which regressed after suspension of both drugs. After subsequent treatment with rituximab, the LPD was still undetectable. Anti-tumor necrosis factor a therapy was used when the arthritis relapsed, but an aggressive B-cell non Hodgkin's lymphoma developed. Molecular analyses showed an oligoclonal B-cell expansion at the LPD step. A minor clone with significant sequence homology to B-cell lymphomas arising in Sjogren's syndrome and mixed cryoglobulinemia syndrome, given rise to the non-Hodgkin's lymphoma. Treatment of rheumatoid arthritis associated with lymphoproliferation represents a clinical challenge, and common pathogenetic pathways to lymphoma may occur in different autoimmune diseases.
19007422 Dynamic interactions between T cells and dendritic cells and their derived cytokines/chemo 2008 This review focuses on the contributions made by interactions between dendritic cells (DCs) and T cells, and by local production of cytokines and chemokines to the pathogenesis of rheumatoid arthritis (RA) synovitis. DCs are efficient professional antigen-presenting cells, which are critical for the development of innate and adaptative immune responses through interactions with T cells. Cytokines from DCs play a key role in the switch inside effector T-cell pathways. Chemokines are important mediators of the immune response because they regulate leucocyte recruitment to tissue, and they play a key role in inflammatory diseases by acting on T-cell and DC migration. Furthermore, the recently discovered T-helper-17 proinflammatory cytokines, present in syno-vium samples, are associated with the migration, differentiation and maturation of inflammatory cells, and they facilitate a network of interactions between all components of the immune response. An understanding of such interactions is essential because it is the key to therapeutic application.
17393394 Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor 2007 Apr OBJECTIVE: To evaluate the risk of serious bacterial infections associated with tumor necrosis factor alpha (TNFalpha) antagonists among rheumatoid arthritis (RA) patients. METHODS: A retrospective cohort study of US RA patients enrolled in a large health care organization identified patients who received either TNFalpha antagonists or methotrexate (MTX). Administrative data were used to identify hospitalizations with possible bacterial infections; corresponding medical records were abstracted and reviewed by infectious disease specialists for evidence of definite infections. Proportional hazards models evaluated time-dependent infection risks associated with TNFalpha antagonists. RESULTS: Hospital medical records with claims-identified suspected bacterial infections were abstracted (n=187) among RA patients who received TNFalpha antagonists (n=2,393; observation time 3,894 person-years) or MTX (n=2,933; 4,846 person-years). Over a median followup time of 17 months, the rate of hospitalization with a confirmed bacterial infection was 2.7% among the patients treated with TNFalpha antagonists compared with 2.0% among the patients treated with MTX only. The multivariable-adjusted hazard ratio (HR) of infection among the patients who received TNFalpha antagonists was 1.9 (95% confidence interval [95% CI] 1.3-2.8) compared with patients who received MTX only. The incidence of infections was highest within 6 months after initiating TNFalpha antagonist therapy (2.9 versus 1.4 infections per 100 person-years; multivariable-adjusted HR 4.2, 95% CI 2.0-8.8). CONCLUSION: The multivariable-adjusted risk of hospitalization with a physician-confirmed definite bacterial infection was approximately 2-fold higher overall and 4-fold higher in the first 6 months among patients receiving TNFalpha antagonists versus those receiving MTX alone. RA patients were at increased risk of serious infections, irrespective of the method used to define an infectious outcome. Patients and physicians should vigilantly monitor for signs of infection when using TNFalpha antagonists, particularly shortly after treatment initiation.
18939390 Using biochemical markers of bone turnover in clinical practice. 2008 Oct Biochemical markers of bone turnover provide clinically useful evidence of the normal and pathologic processes that reflect bone cell activity in the skeleton. Understanding the behavior of markers of bone formation and bone resorption should aid in managing patients with a variety of skeletal disorders.
16385499 Association between protein tyrosine phosphatase 22 variant R620W in conjunction with the 2006 Jan OBJECTIVE: To analyze the genetic impact of allelic variants of the protein tyrosine phosphatase N22 (PTPN22) and HLA-DRB1 alleles on IgG autoantibody formation directed toward an immunodominant conformational epitope (C1(III); amino acid residues 359-369) of type II collagen (CII) in early rheumatoid arthritis (RA). METHODS: Sera obtained at study inclusion from an inception cohort of RA patients (n = 221; mean symptom duration 6 months) were analyzed for circulating anti-C1(III) IgG autoantibodies. An enzyme-linked immunosorbent assay based on solid-phase-coupled synthetic triple-helical collagen peptides was used to quantify humoral autoimmune responses. HLA-DRB1 genotypes were determined by allele-specific polymerase chain reaction amplification of genomic DNA and sequence-specific hybridization. PTPN22*620W genotyping was performed using an allelic discrimination TaqMan assay. RESULTS: Anti-C1(III) IgG autoantibody titers were significantly elevated in patients with early RA as compared with those in healthy controls (n = 70). The increased titers were more pronounced in RA patients harboring alleles of the RA-associated HLA-DRB1 shared epitope (SE) consensus sequence than in those lacking the SE. In addition, the PTPN22*620W variant was strongly associated with a vigorous humoral autoimmune response to the cartilage-specific CII determinant C1(III). CONCLUSION: Allelic variants encoding the binding pocket for peptide presentation (SE) to T cells and a functional domain of a negative regulator of T cell receptor signaling (PTPN22*620W), respectively, synergize in early RA to break self tolerance toward C1(III), an evolutionarily conserved cartilage determinant that is also frequently targeted in arthritogenic humoral autoimmunity in mice.
17412304 Safety and efficacy of vaccination against streptococcus pneumonia in patients with rheuma 2007 Apr Vaccination against streptococcus pneumonia is currently recommended for patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Safety and efficacy issues of vaccination in patients suffering from rheumatic diseases are still unresolved. This review summarizes the studies performed on the safety and immunogenicity of pneumococcal vaccination in patients with RA and SLE, with special emphasis on the effect of immunosuppressive drugs on the efficacy of the vaccine. Several trials have shown that the vaccine does not induce clinical exacerbation of RA and that it does induce an adequate humoral response, albeit one lower than that in healthy controls.
16426246 Promoter polymorphism rs3087456 in the MHC class II transactivator gene is not associated 2006 Feb We analysed whether the single nucleotide polymorphism (SNP) rs3087456 in the promoter of the MHC class II transactivator (MHC2TA) gene is associated with manifestation of rheumatoid arthritis, multiple sclerosis, narcolepsy and Wegener granulomatosis. The recently reported association in a northern population of the MHC2TA variation with these autoimmune diseases is not evident in the German population.
16690762 Are rheumatologists' treatment decisions influenced by patients' age? 2006 Dec OBJECTIVES: The objective of this study was to determine whether physicians' treatment preferences are influenced by patients' age. METHODS: We mailed a survey to a random sample of rheumatologists practicing in the US. The survey included a scenario describing a hypothetical patient with rheumatoid arthritis (RA) on hydroxychloroquine, sulfasalazine and low-dose prednisolone, who presents with active disease during a follow-up appointment. The scenario was formulated in two versions that were identical except for the age of the patient. After reading the scenario, respondents were asked to rate (on a 10 cm numerical rating scale) their recommendations for each of the three options: (i) increasing the dose of prednisolone, (ii) adding a new disease-modifying anti-rheumatic drug (DMARD) and (iii) switching DMARDs. Rheumatologists who rated either adding a new DMARD or switching DMARDs higher than increasing the dose of prednisolone were classified as 'preferring aggressive treatment with DMARDs', while the others were classified as 'NOT preferring aggressive treatment with DMARDs'. RESULTS: A total of 480 rheumatologists were mailed a questionnaire; 204 responded, giving a response rate of 42.5%. Overall 163 (80%) respondents were classified as preferring aggressive treatment with DMARDs. Rheumatologists responding to this survey were more likely to prefer aggressive DMARD treatment for the young RA patient vs the older RA patient (87 vs 71%, P= 0.007). CONCLUSIONS: Our findings suggest that rheumatologists' treatment recommendations may be influenced by age. Future educational efforts should increase physician awareness of this possible bias in order to ensure equal service delivery across ages.
17763449 Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by ac 2007 Sep OBJECTIVE: To investigate the in vitro effect of activated protein C (APC), a natural anticoagulant and novel antiinflammatory agent, on the regulation of the gelatinases matrix metalloproteinase 2 (MMP-2) and MMP-9. METHODS: Synovial fibroblasts and peripheral blood monocytes isolated from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) and Mono Mac6 cells were used in this study. After treatment, cells and culture supernatants were collected for zymography, enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction, and Western blot analysis. RESULTS: Fibroblasts and monocytes from RA patients produced substantially more MMP-9 than did those from OA patients; however, there was no difference in MMP-2 production. The addition of recombinant APC markedly reduced MMP-9 at the gene and protein levels. In contrast, APC up-regulated and activated MMP-2. Using a blocking antibody to the endothelial protein C receptor (EPCR), we showed that the inhibition of MMP-9 by APC was EPCR-dependent. Furthermore, APC directly suppressed the production of tumor necrosis factor (TNF) and the activation of NF-kappaB and MAP kinase p38, and inhibitors of NF-kappaB or p38 reduced the production of MMP-9, suggesting that APC inhibits MMP-9 by blocking TNF, NF-kappaB, and p38. Thus, APC acts on MMP-9 by binding to EPCRs on the cell surface and, subsequently, inhibiting the intracellular activation of the proinflammatory signaling molecules NF-kappaB and p38. CONCLUSION: APC appears to be the first physiologic agent to inhibit the production of proinflammatory MMP-9, yet increase antiinflammatory MMP-2 activity. Our results provide the initial evidence that APC may be beneficial in the prevention of inflammation and joint destruction in RA.
19127111 [Diagnostic utility of AxSYM anti-cyclic Citrullinated peptide antibody assay]. 2008 Dec BACKGROUND: The presence of rheumatoid factor (RF) is one of the classification criteria of the American College of Rheumatology (ACR) for rheumatoid arthritis (RA), but it has a limitation of low specificity. We compared the diagnostic utility of anti-cyclic citrullinated peptide (CCP) antibodies analyzed by an automated immunoassay system with that measured by a 96 well plate ELISA method. METHODS: The RF and anti-CCP antibodies were determined in 172 serum samples: 52 RA patients, 73 disease controls (systemic lupus, Sjogren's syndrome, palindromic rheumatism), and 47 healthy controls. Anti-CCP antibodies were measured by DIASTAT 96 well plate ELISA method (Axis-Shield Diagnostics, UK) and AxSYM automated microparticle enzyme immunoassay system (Abbott Laboratories, USA). RF was assayed by latex immunoturbidimetry (Toshiba 200 FR, Japan). The diagnostic performances of these tests were compared using a ROC curve analysis, and linearity and precision analysis of AxSYM anti-CCP was carried out. RESULTS: The sensitivities of RF, DIASTAT anti-CCP, and AxSYM anti-CCP were 78.8%, 84.6%, and 82.7%, respectively and the specificities were 72.5%, 88.3%, and 88.3%, respectively. On ROC curve analysis, the area under the curve was 0.924 for AxSYM anti-CCP, 0.886 for DIASTAT anti-CCP, and 0.847 for RF. AxSYM anti-CCP showed a good linearity, and within-run and total-run precision. CONCLUSIONS: Diagnostic performance of automated AxSYM anti-CCP assay was comparable to that of DIASTAT 96 well plate ELISA method. AxSYM anti-CCP assay has an advantage of random access capability and will be useful in laboratories with low sample number and/or with a need of rapid turnaround time.
18365836 Review: Immune cells and mediators of inflammatory arthritis. 2008 Apr Cytokine expression in the inflamed synovial membrane of patients with rheumatoid arthritis and other forms of chronic inflammatory arthritis and other forms of chronic inflammatory arthritis leads to formation of osteoclasts. These cells are primarily involved in the resorption of mineralized cartilage and bone and thus participate in joint damage in the course of chronic arthritides. Osteoclastogenesis in the synovial membrane is driven by cytokines such as RANKL, MCSF but also classical proinflammatory mediators such as TNF, IL-1 and IL-6. Inhibition of osteoclast formation has proven as an effective approach to inhibit structural damage in experimental arthritis and preliminary data suggest that such approaches are also effective in human RA.
18331529 Association of the HLA-G 14-bp insertion/deletion polymorphism with juvenile idiopathic ar 2008 May We tested the possible association of the 14-bp polymorphism of the HLA-G gene in the course of two inflammatory diseases, rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Patients and controls were genotyped for the 14-bp polymorphism by polymerase chain reaction with specific primers for the exon 8 of the human leukocyte antigen (HLA)-G gene and the amplified fragment was visualized in a 6% polyacrylamide gel. A total of 106 JIA patients, 265 RA patients, 356 healthy adults and 85 healthy children were genotyped for the 14-bp polymorphism. Female JIA patients presented a higher frequency of the -14 bp allele when compared with female healthy children (0.743 and 0.500, corrected P=0.003), which reflected in the JIA group as a whole. This increased frequency of the -14-bp allele was observed in all JIA subtypes. In RA patients, no differences in allelic and genotypic frequencies were observed between patients and controls. No correlations were observed among genotype and disease severity or clinical manifestations. Our data suggest that the HLA-G -14 bp allele is probably a risk factor for JIA, mainly in females. Considering the differences observed in relation to gender, we suggest that hormonal differences can interfere with the development of JIA. Considering the RA patients, our data agree with results from the literature and highlight the differences in the etiology of RA and JIA.
18221890 Investigation into the neural correlates of emotional augmentation of clinical pain. 2008 Apr 1 Although depressive mood is an important psychological determinate of chronic pain, the neural circuitry that mediates its influence on the pain experience is largely unknown. We used functional magnetic resonance imaging (FMRI) to investigate the neurophysiological interactions between depressive symptoms and disease-relevant pain in rheumatoid arthritis (RA) patients. RA is associated with chronic joint pain and swelling, but peripheral joint pathology often does not fully explain the amount of pain a patient experiences. We investigated the neural circuitry that relates joint pain and depressive symptoms and contrasted this with experimental heat pain. We hypothesized that (1) depressive symptoms influence the cerebral processing of provoked joint pain in RA, and (2) the interaction of depressive symptoms with pain processing contributes to the pain RA patients experience on a daily basis. Twenty patients underwent whole brain FMRI during which disease-relevant joint pain was provoked. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). The tender-to-swollen joint ratio (T/S) was assessed as one component of the patients' clinical pain. BDI scores correlated significantly with T/S and medial prefrontal cortex (MPFC) activation during provoked joint pain. The association between BDI scores and T/S was partly mediated by the MPFC activation. Furthermore, the MPFC activation co-varied significantly with the FMRI signal in limbic areas and in areas that process self-relevant information. These results suggest that the MPFC may play an important role in mediating the relationship between depressive symptoms and clinical pain severity in RA, possibly by engaging brain areas important for affective and self-relevant processing.
18336869 Carotid intima-media thickness predicts the development of cardiovascular events in patien 2009 Apr OBJECTIVE: To establish whether carotid intima-media wall thickness (IMT) may be a good predictor for the development of cardiovascular (CV) events in patients with rheumatoid arthritis (RA). METHODS: A series of 47 RA patients who at the time of recruitment did not have traditional CV risk factors or CV disease were assessed by carotid ultrasonography. Carotid IMT and carotid plaques were measured in the right common carotid artery. Then, a prospective assessment of the CV outcome was performed over a 5-year period. Logistic regression models and receiver operating characteristic curves were performed to evaluate the ability of different variables to predict CV events. RESULTS: Carotid IMT was greater in RA patients who over the extended follow-up experienced CV events (1.01 +/- 0.16 mm) compared with the remaining RA patients who did not have CV complications (0.74 +/- 0.12 mm) (P < 0.001). Also, carotid IMT categorized in quartiles was strongly associated with CV events. In this regard, none of the patients with carotid IMT less than 0.77 mm had CV events. However, 6 of the 10 patients with carotid IMT greater than 0.91 mm experienced CV events (P value for the trend <0.001). Carotid IMT yielded a high predictive power for the development of CV events over the 5-year follow-up period. The area under the receiver operating characteristic curve was 0.93 for a model that only included carotid IMT and 0.90 for carotid plaque. CONCLUSIONS: The results from the present study support the use of carotid ultrasonography as a predictor of CV events in RA.
18022200 7'-(3',4'-dihydroxyphenyl)-N-[(4-methoxyphenyl)ethyl]propenamide (Z23), an effective compo 2007 Dec 14 Fissistigma oldhamii (Hemsl.) Merr [F. oldhamii], a traditional Chinese herb medicine, is widely used for treating rheumatoid arthritis (RA) in China. Following bioactivity-guided isolation, a representative immunosuppressive compound with low cytotoxicity, 7'-(3',4'-dihydroxyphenyl)-N-[(4-methoxyphenyl)ethyl]propenamide (Z23), was been identified in this herb medicine. We investigated the immunosuppressive effects of Z23 on T cells in vitro and in vivo. The results showed that Z23 in a dose-dependent manner significantly inhibited the proliferation of splenocytes induced by concanavalin A (ConA) and by the mixed lymphocyte culture reaction (MLR), with half inhibitive concentration (IC(50)) values of 6.22 microM and 0.78 microM, respectively. Z23 also dose-dependently inhibited the proliferation and type 1 cytokine (IFN-gamma and IL-2) production of primary T cells stimulated by anti-CD3/CD28 mAbs, but did not affect IL-12 production by mouse peritoneal macrophages (pMphi) stimulated with LPS plus IFN-gamma in vitro. Administration of Z23 (6.25 mg/kg, 12.5 mg/kg, 25 mg/kg, i.p.) dose-dependently suppressed 2,4-dinitrofluorobenzene (DNFB)-induced delayed-type hypersensitivity (DTH) reactions. Furthermore, administration of Z23 (25 mg/kg, i.p.) significantly reduced the incidence and severity of type II bovine collagen (CII)-induced arthritis (CIA), which was associated with the inhibition of CII-specific T cell proliferation and type 1 cytokine (IFN-gamma and IL-2) production. In this study, we report that a representative immunosuppressive compound from F. oldhamii, Z23, effectively inhibits murine immune responses in vitro and in vivo, and that the immunosuppressive effects of Z23 might be attributed to suppression of T cell activation and function and Th1 type cytokine production.
18311751 The clinimetric properties of the World Health Organization Disability Assessment Schedule 2008 Mar 15 OBJECTIVE: To assess the clinimetric properties of a new health-related quality of life (HRQOL) instrument, the World Health Organization Disability Assessment Schedule II (WHODAS II), in patients with early inflammatory arthritis. METHODS: Internal consistency as well as criterion, construct, and discriminative validity of the WHODAS II were assessed in 172 patients with early inflammatory arthritis who completed the WHODAS II, the Medical Outcomes Study Short Form 36 (SF-36), and other measures of disease severity, functioning, pain, depression, and resource use. Test-retest reliability of the WHODAS II was assessed by having a subset of 20 patients complete the WHODAS II a second time, 1 week after the first assessment. RESULTS: The WHODAS II had high internal consistency (Cronbach's alpha = 0.96 for patients working or in school and 0.93 for patients not working or in school). Test-retest intraclass correlation coefficients of the WHODAS II total score and subscales ranged from 0.82-0.96. The WHODAS II total score was strongly correlated with the SF-36 physical component score (Kendall's tau-b 0.51, P < 0.001) and moderately correlated with the SF-36 mental component score (tau-b 0.43, P < 0.001). WHODAS II correlations with disease outcomes ranged from Kendall's tau-b 0.15-0.55. The WHODAS II significantly differentiated between every aspect of disease severity assessed with the exception of measures of health resource use. CONCLUSION: The WHODAS II is a valid and reliable measure of HRQOL in cross-sectional studies of patients with early inflammatory arthritis. Research is still required to investigate potential item redundancy and determine its usefulness in longitudinal studies.
17660216 Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refra 2008 Mar OBJECTIVE: P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, causes drug resistance by exclusion of intracellular drugs. Here, we elucidate the clinical relevance of P-gp expression on lymphocytes to drug resistance in patients with rheumatoid arthritis (RA). METHODS: P-gp expression on lymphocytes from 20 normal volunteers and 100 RA patients was analysed by flow cytometry. Drug exclusion analysis of lymphocytes was conducted by radioisotope-labelled dexamethasone. RESULTS: P-gp was overexpressed on RA lymphocytes compared with normal lymphocytes. P-gp expression levels were higher in partial responders with a Disease Activity Score (DAS) 28-3 of >5.1 despite taking at least two disease-modifying antirheumatic drugs (DMARDs) or one DMARD and corticosteroids for at least 2 years. P-gp expression levels correlated with DAS28-3. Intracellular dexamethasone levels (IDLs) in RA lymphocytes decreased according to P-gp expression. Tacrolimus, a P-gp inhibitor, restored IDLs in RA lymphocytes. P-gp overexpression in patients with highly active RA was suppressed by methotrexate but enhanced by corticosteroids. Furthermore, infliximab (3 mg/kg) resulted in improvement of RA disease activity, reduction of P-gp and recovery of IDLs. CONCLUSIONS: P-gp overexpression on lymphocytes might cause efflux of corticosteroids and DMARDs, P-gp substrates, from lymphocytes, resulting in drug resistance in patients with highly active RA. P-gp inhibition/reduction could overcome such drug resistance. Measurement of P-gp expression on lymphocytes could be a potentially useful marker for assessing drug resistance in RA, and may be suitable for selecting infliximab or DMARDs including tacrolimus for RA treatment.
18301866 Topoisomerase inhibitors as anti-arthritic agents. 2008 Mar INTRODUCTION: The pathophysiology of rheumatoid arthritis (RA) includes inflammation, synoviocyte proliferation, angiogenesis, and matrix metalloproteinase-driven degradation processes. The objective of this study was to investigate a variety of structurally unrelated anticancer topoisomerase inhibiting agents as inhibitors of aspects of these disease processes involved in RA. METHOD: The topoisomerase I inhibitors camptothecin and beta-laperchone and the topoisomerase II inhibitors, etoposide, doxorubicin, plumbagin and menadione were used in this study. Crystal induced neutrophil activation was measured by luminol dependent chemiluminescence. Synoviocyte proliferation was measured by an MTT assay using HIG 82 rabbit synoviocytes in cell culture. Angiogenesis was measured using the chorioallantoic membrane of the chick embryo. Chondrocyte (culture primary cells) expression of the matrix metalloproteinases collagenase and stromelysin was measured by Northern Blot analysis. RESULTS: All agents inhibited synoviocyte proliferation to some degree. Camptothecin had no effect on neutrophil activation but inhibited all other processes at low (nanomolar) concentrations. Plumbagin and menadione inhibited neutrophil activation, collagenases expression and angiogenesis. The other agents had little effect on neutrophil activation (except beta-laperchone) but inhibited angiogenesis and collagenase expression to a lesser degree than camptothecin. CONCLUSION: These studies support the explorative use of topoisomerase I (particularly camptothecin) and II inhibitors as potential agents for use against RA.