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ID PMID Title PublicationDate abstract
11605312 [Treatment of rheumatoid arthritis by inhibition of tumor necrosis factor with infliximab 2001 Sep 29 The current pharmacotherapy of rheumatoid arthritis (RA) consists of non-steroidal anti inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) such as sulphasalazine, leflunomide and methotrexate. DMARDs can be given as monotherapy or in combination. However, not all patients show an adequate response due to toxicity or lack of efficacy. From animal studies and clinical studies in patients with RA, we know that tumour necrosis factor (TNF) is directly involved in the pathogenesis of RA. Two forms of TNF inhibition therapy have been extensively investigated in RA: anti-TNF monoclonal antibodies (infliximab) and TNF receptor-Fc fusion protein (etanercept). Both types of TNF inhibition induce a rapid improvement in multiple clinical measures of disease activity and patient functional status. Furthermore, a beneficial effect was demonstrated on radiographic progression of joint damage. Etanercept and the combination infliximab-methotrexate are generally well tolerated.
11155592 [Eosinophilic meningoencephalitis in a case of rheumatoid arthritis]. 1998 Dec A 56-year-old man was admitted to our hospital due to gradually developing consciousness disturbance. He had an 11-year history of sero-negative rheumatoid arthritis (Stage III) maintained by daily administration of 10 mg of prednisolone and 300 mg of actarit. On admission, he showed meningeal irritation and a marked increase in eosinophils in his cerebrospinal fulid (CSF) (457/microliter), while eosinophils in his peripheral blood were not increased (0/microliter). Shortly after admission he fell into a coma. Upon measurement in the coma state, his peripheral blood eosinophil count was found to be increased (max: 1742/microliter). Parasitic infection, Angiostrongylus cantonensis in particular, was excluded both by repeated microscopic examination of CSF and by immunological approaches for CSF and serum. Serum examinations showed broad cross-reaction between various parasitic antigens and positive myeloperoxdase-antineutrophil cytoplasmic antibody (18 EU/ml). Three pulses of methylprednisolone (500 mg/day) followed by conventional prednisolone therapy (60 mg/day) was effective for alleviating the signs and symptoms of eosinophilic meningoencephalitis. In this patient, it was considered that the cerebrospinal angiitis resulting in eosinophilic meningoencephalitis had been elicited by immunological abnormalities.
10405927 Isolation of an IgG monoclonal anti-dnaJ antibody from an immunoglobulin combinatorial lib 1999 Jul OBJECTIVE: Previously, we showed that rheumatoid arthritis (RA) had both antibodies and T cells specific for the QKRAA-encompassing Escherichia coli dnaJ protein. These findings suggest that the bacteria induced anti-dnaJ responses may cross react with the human homolog of bacterial dnaJ in the joint, resulting in tissue damage. METHODS: We used the combinatorial library technique to isolate and characterize an IgG monoclonal anti-dnaJ antibody (designated CG1) from the blood of a patient with RA. RESULTS: Sequence analysis of CG1 revealed that its heavy and light chain V regions were respectively most homologous to the 3d279d VH4 and the O18 Vk1 genes. Interestingly, 3d279d is frequently expressed by B cells stimulated with staphylococcal enterotoxin; and O18 is the main gene employed by the Vk1 IgG antibodies against Haemophilus influenzae. CONCLUSION: The combinatorial immunoglobulin library method represents an interesting model of how to approach the isolation and characterization of antibody-like reagents in the elucidation of autoantigens in RA.
11502616 Performance of two ELISAs for antifilaggrin autoantibodies, using either affinity purified 2001 Sep OBJECTIVE: To develop a standardisable enzyme linked immunosorbent assay (ELISA), using human filaggrin, for detection of antifilaggrin autoantibodies in rheumatoid arthritis (RA). To compare the diagnostic performance of the ELISA with those of reference tests: "antikeratin antibodies" ("AKA"), and antibodies to human epidermis filaggrin detected by immunoblotting (AhFA-IB). METHODS: Two ELISAs were developed using either affinity purified neutral-acidic human epidermis filaggrin (AhFA-ELISA-pur) or a recombinant human filaggrin deiminated in vitro (AhFA-ELISA-rec) as immunosorbent. Antifilaggrin autoantibodies were assayed in 714 serum samples from patients with well characterised rheumatic diseases, including 241 RA and 473 other rheumatic diseases, using the two ELISAs. "AKA" and AhFA-IB tests were carried out in the same series of patients. The diagnostic performance of the four tests was compared and their relationships analysed. RESULTS: The titres of "AKA", AhFA-IB, and the AhFA-ELISAs correlated strongly with each other. The diagnostic sensitivity of the AhFA-ELISA-rec, which was better than that of AhFA-ELISA-pur, was 0.52 for a specificity of 0.95. This performance was similar to those of "AKA" or AhFA-IB. However, combining AhFA-ELISA-rec with AhFA-IB led to a diagnostic sensitivity of 0.55 for a specificity of 0.99. CONCLUSION: A simple and easily standardisable ELISA for detection of antifilaggrin autoantibodies was developed and validated on a large series of patients using a citrullinated recombinant human filaggrin. The diagnostic performance of the test was similar to that of the "AKA" and AhFA-IB. Nevertheless, combining the AhFA-ELISA-rec with one of the other tests clearly enhanced the performance.
10403932 Peripheral blood mononuclear cells from patients with rheumatoid arthritis spontaneously s 1999 Jul This study was designed to investigate VEGF production from peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA) compared with healthy controls and to identify the predominant cellular source in PBMC isolated from RA patients. The regulation of PBMC VEGF production by cytokines and synovial fluid (SF) was studied. PBMC were isolated from RA patients and healthy controls and stimulated with lipopolysaccharide (LPS), IL-1beta, IL-4, IL-6, IL-8, IL-10, TNF-alpha and transforming growth factor-beta (TGF-beta) isoforms for varying time points up to 72 h at 37 degrees C/5% CO2. The effect of SF on VEGF secretion by PBMC was also studied. Supernatant VEGF levels were measured using a flt-1 receptor capture ELISA. RA patients had significantly higher spontaneous production of VEGF compared with controls, and monocytes were identified as the predominant cellular source. RA PBMC VEGF production was up-regulated by TGF-beta isoforms and TNF-alpha and down-regulated by IL-4 and IL-10, with no effect observed with IL-1beta, IL-6 and IL-8. Antibody blocking experiments confirmed that TNF-alpha and not TGF-beta isoforms in SF increased VEGF secretion by RA PBMC. These results emphasize the importance of monocytes as a source of VEGF in the pathophysiology of RA. Several cytokines known to be present in SF can modulate the level of VEGF secretion, but the predominant effect of SF in VEGF up-regulation is shown to be dependent on TNF-alpha.
9489810 Nondepleting humanized anti-CD4 monoclonal antibody in patients with refractory rheumatoid 1998 Feb OBJECTIVE: To investigate the safety, tolerability, pharmacokinetics, and immunologic activity of single intravenous infusions (0.2-10 mg/kg) of Orthoclone OKTcdr4a, a nondepleting humanized anti-CD4 monoclonal antibody (Mab) in patients with rheumatoid arthritis. METHODS: Eighteen patients were treated with a single intravenous dose of Mab. Three patients each received 0.2, 0.5, 1.0, 2.0, 5.0, or 10.0 mg/kg of OKTcdr4a. RESULTS: No patient had a significant change in CD4+ T cells in peripheral blood after treatment. No human antimurine antibodies were detected. At > or = 1.0 mg/kg dose level, CD4 receptor saturation was > or = 95% 24 h after infusion. At 5.0 mg/kg, CD4 receptor occupancy was a mean of 88% at 6 days after infusion. At 10 mg/kg, CD4 receptor occupancy was still a mean of 79% 2 weeks after infusion. No significant infusion related adverse events occurred. Two subjects had headaches at the time of drug administration. Two subjects were hospitalized for infections (pneumonia, Day 45; cellulitis, Day 14), which resolved with antibiotic therapy. CONCLUSION: OKTcdr4a was well tolerated at the doses used and saturation of CD4 receptors in peripheral blood could be routinely obtained for over one week with a single infusion of Mab.
11035417 Determination of autoantibodies to annexin XI in systemic autoimmune diseases. 2000 Annexin XI, a calcyclin-associated protein, has been shown to be identical to a 56,000 Da antigen recognized by antibodies found in sera from patients suffering from systemic autoimmune diseases. In this work hexahistidine-tagged recombinant annexin XI (His6- rAnn XI) was used as antigen in ELISA experiments for determination of autoantibodies to annexin XI in sera of patients with systemic rheumatic autoimmune diseases. Immunoblotting with HeLa cell extract and with His6-rAnn XI as antigen was used for confirmation of positive ELISA results. We found eleven anti-annexin XI positive sera (3.9%) out of 282 sera from patients with systemic rheumatic diseases. The highest number of annexin XI positive sera were found in primary antiphospholipid syndrome (3/17), and in subacute lupus erythematosus (1/6), while lower frequencies of positive sera were found in patients with systemic sclerosis (5/137), rheumatoid arthritis (1/21), and systemic lupus erythematosus (1/58). Sera from healthy donors and patients with chronic infections were negative, except for one Salmonella typhimurium antibody positive serum. Autoantibodies to annexin XI were found to relate to thrombosis, but not to other clinical or laboratory features. A relation between antibodies to annexins and thrombosis has so far only been known for annexin V.
9704636 Important immunoregulatory role of interleukin-11 in the inflammatory process in rheumatoi 1998 Aug OBJECTIVE: To investigate the possible immunoregulatory role of interleukin-11 (IL-11) in rheumatoid arthritis (RA). METHODS: IL-11 protein was assayed in RA tissue, and the effect of exogenous IL-11 on neutralization of endogenous IL-11 was investigated with respect to tumor necrosis factor alpha (TNFalpha), matrix metalloproteinase (MMP), and tissue inhibitor of metalloproteinases (TIMP) production. RESULTS: IL-11 was found in RA synovial membranes, synovial fluids, and blood sera. Blockade of endogenous IL-11 resulted in a 2-fold increase in TNFalpha levels, which increased to 22-fold if endogenous IL-10 was also blocked. Addition of exogenous IL-11 inhibited spontaneous TNFalpha production in RA synovium only in the presence of soluble IL-11 receptor. However, exogenous IL-11 directly inhibited spontaneous MMP-1 and MMP-3 production, and up-regulated TIMP-1 in RA synovial tissue. CONCLUSION: IL-11 has important endogenous immunoregulatory effects in RA synovium, which suggests that exogenous IL-11 may have therapeutic activity in RA.
9196444 Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compar 1997 Apr Recently, a new player in the cytokine network has been described that is produced by monocytes and can be detected in the rheumatoid synovium: interleukin-15 (IL-15). Since this cytokine may play a role in the accumulation and activation of T-cells, B-cells, and natural killer (NK) cells characteristic of synovial tissue (ST) from patients with rheumatoid arthritis (RA), the expression of IL-15 was studied in ST from RA patients in comparison with ST from patients with reactive arthritis (ReA) and osteoarthritis (OA) and the phenotype of IL-15-positive cells was determined. IL-15 expression was investigated by immunohistochemical analysis of ST from ten patients with RA, ten patients with Yersinia enterocolitica-induced ReA, and nine patients with OA. The immunohistological findings were quantified and the results obtained in the different patient groups were compared. To determine the phenotype of IL-15-expressing cells, double-labelling immunofluorescence was performed. The expression of IL-15 was significantly higher in ST from patients with RA than in ST from patients with ReA or OA. In double-label experiments, co-expression was observed with markers for macrophages, T-cells, and NK cells. The composition of the cellular infiltrate in the synovium of patients with RA might be partly explained by the specific increase in expression of IL-15 in rheumatoid ST. It can be speculated that IL-15 production by inflammatory cells other than macrophages may occur in the rheumatoid synovium.
11352232 Potential role of HOXD9 in synoviocyte proliferation. 2001 May OBJECTIVE: To investigate the role of HOXD9 in the proliferation activity of cultured synoviocytes as well as the mechanisms that regulate HOXD9 transcription. METHODS: Synoviocytes from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were transfected with HOXD9 complementary DNA to establish stable transformants that overexpressed HOXD9. HOXD9 expression was detected by Western blotting with anti-HOXD9 antibody. The growth properties of the transformants were investigated by proliferation and colony formation assays. The expression of basic fibroblast growth factor (bFGF), tumor necrosis factor alpha (TNFalpha), interleukin-1beta, c-Fos, and c-Myc was examined by Western blotting. Transcriptional regulation of HOXD9 was examined by transient cotransfection. RESULTS: HOXD9 protein was highly expressed in RA synoviocytes, but there was no expression in OA synoviocytes. HOXD9 transfection induced stable HOXD9 protein expression in synoviocytes and showed an increased proliferation rate under both normal and serum-starved conditions, as well as an enhanced capacity to proliferate anchorage independently to form colonies in soft agar cultures, compared with control transfectants. Higher levels of bFGF and c-Fos were detected in HOXD9 transformants than in controls. Transient cotransfection assays of NIH3T3 fibroblasts and synoviocytes showed that HOXD9 activated the luciferase reporter construct containing the highly conserved region (HCR), an autoregulatory element of HOXD9 promoter. This activation was significantly increased by bFGF, suppressed by TNFalpha, and unchanged by transforming growth factor beta in synoviocytes. Human T lymphotropic virus type I tax also activated the luciferase reporter construct containing the HCR and had a synergistic effect with HOXD9 on HCR promoter activation. CONCLUSION: Our data suggest that HOXD9 plays a potential role in synovial proliferation. In addition, they suggest that the involvement of HOXD9 in the regulation of cellular growth might be mediated, at least in part, by up-regulation of growth-related factors such as bFGF and c-Fos and/or might result from increased transcription activity by its regulators.
11247878 Type I collagen degradation does not diminish with RA disease duration. 2001 Apr OBJECTIVE: To assess the relation between type I collagen degradation and the duration of rheumatoid arthritis (RA). METHODS: The serum concentrations of cross linked carboxyterminal telopeptide of type I collagen (ICTP) measured earlier in a community based series (90 patients) and a hospital based series (59 patients) were re-evaluated with reference to the duration of RA. RESULTS: The serum ICTP showed a positive correlation with the duration of the disease in the hospital based series (r(s)=0.40, p<0.01) but not in the community based one (r(s)=0.18, p=0.10). CONCLUSIONS: Type I collagen degradation predominantly reflecting pathological bone destruction does not seem to diminish in longlasting RA.
9676756 Bayesian calculation of methotrexate clearance after low dose intramuscular administration 1998 Jul OBJECTIVE: To determine a pharmacokinetic procedure (Bayesian method) for estimation of methotrexate (MTX) clearance, using only 2 blood samples, in outpatients with rheumatoid arthritis treated with low dose intramuscular (i.m.) MTX. METHODS: Population pharmacokinetic parameters were obtained by the weighted least squares (WLSQ) method in plasma samples from 14 patients with rheumatoid arthritis (RA). In each patient, 11 samples were measured by fluorescence polarization immunoassay, at Time 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, and 24 h after i.m. administration. These measures were validated by pharmacokinetic studies in 20 other patients with RA. Individual total body clearance of MTX was calculated using only 2 plasma samples (at 0.5 and 2 h after i.m. injection) by the Bayesian method using the population pharmacokinetic parameters. The clearance measures obtained by the Bayesian method were compared with those obtained by the WLSQ method. RESULTS: The pharmacokinetic variables (clearance, half-life, area under the curve) of 14 patients were determined, as well as the covariance and the mean values necessary to apply the Bayesian method. No significant difference was found between clearance values obtained by the Bayesian method compared to the WLSQ method, confirming the validity of the Bayesian values. CONCLUSION: The present population pharmacokinetic parameters allowed the determination of individual clearance of MTX with only 2 plasma samples (0.5 and 2 h after administration) in patients treated with low dose im MTX. Individual clearance is used to modulate MTX administration in patients presenting adverse reactions in spite of good clinical response. Individual determination of MTX pharmacokinetics in patients at risk for adverse MTX reactions could be useful for adjustment of the drug regimen.
11196673 New polymorphisms of human CD80 and CD86: lack of association with rheumatoid arthritis an 2000 Oct The crucial role of costimulatory molecules, CD28, CTLA-4, CD80 and CD86, for T cell activation and inhibition has been established. In the previous study, we reported the results of a polymorphism screening of human CTLA-4 gene. In this study, we screened for polymorphisms of human CD28, CD80 and CD86 genes, and detected that polymorphisms were tested for the association with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Variations were identified in the coding regions of CD80 (452G/A, 614C/G and 864A/G) and CD86 (1057A/G), while no variation was observed in the coding region of CD28. The variations at CD80 position 452 and CD86 position 1057 were present in a substantial proportion of the Japanese population, and were considered to be single nucleotide polymorphisms within the coding sequence (cSNPs). CD80 864 (G-->A) leads to the amino acid substitution N186D, and CD86 1057 (A-->G) results in A304T substitution. Furthermore, in the analysis of CD80 5'-flanking region, six SNPs, -454C/A, -387T/C, -232G/A, -79G/C, -7T/C and /A, and one insertion, -558ins (CATGA), were identified. The combination of these variations was found to constitute four promoter alleles of CD80. None of the observed variations was significantly associated with RA or SLE. Further studies will be of particular interest to examine the functional difference of the promoter alleles for the transcriptional activity of CD80, as well as the evolutionary pathway of the four alleles.
9547903 Endothelin-1 production by human synoviocytes. 1998 Mar Immunoreactive (ir)-endothelin (ET)-1 concentrations in serum samples and synovial fluids from patients with rheumatoid arthritis were higher than concentrations in sera obtained from healthy volunteers. No significant difference in ir-ET-1 concentrations in synovial fluid was observed between rheumatoid arthritis patients and osteoarthritis patients. Cultured fluids of synovial cells collected from synovial tissues and leucocytes from synovial fluids of rheumatoid arthritis patients were studied to determine the origin of ir-ET-1 in synovial fluids. Ir-ET-1 was detected in the cultured fluids of synovial macrophage-like type A cells, but not in those of fibroblast-like type B cells from the synovial tissues or leucocytes from the synovial fluids. Longitudinal studies showed that the ir-ET-1 concentration in the cultured fluid reached a peak around 24 h after starting the culture. ET-1 secreted from macrophage-like synoviocytes may be involved in the pathogenesis of inflammatory arthritis.
11302864 Incidence of clinically manifest ulcers and their complications in patients with rheumatoi 2001 May BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are often prescribed in patients with rheumatoid arthritis (RA). Because of its frequency and severity, NSAID gastropathy is the most important side effect. The clinical spectrum of NSAID gastropathy includes gastrointestinal complaints, ulcers and their complications. To reduce NSAID gastropathy, rheumatologists in greater Amsterdam decided in January 1997 that prophylactic agents should be prescribed for patients with RA at high risk for NSAID gastropathy, defined as age 60 or older or a history of gastrointestinal (GI) ulcers, or both. OBJECTIVE: To determine the incidence of clinically manifest ulcers and their complications in patients with RA at high risk for NSAID gastropathy during a period in which prophylaxis was recommended. Published reports show that the incidence of clinically manifest ulcers and their complications varies from 1.3% to 5%. PATIENTS AND METHODS: Within one year, three questionnaires were sent to all outpatients with RA of our clinic (n=2680). The patients were asked if they had had a gastroscopy and/or complication of an ulcer in the preceding months. When a GI event (ulcer or complication) had occurred an analysis was carried out to determine whether the event was possibly related to a compliance failure or a policy failure-for example, no prophylaxis prescribed when it was recommended. RESULTS: The response rate for the three questionnaires was 88%, 76%, and 77%, respectively. All three questionnaires were returned by 1856 patients; NSAIDs were used in 1246 (67%) of them. Of the NSAID users 731 (59%) were in the high risk group. Clinically manifest ulcers occurred in seven high risk NSAID users (four gastric ulcers, two duodenal ulcers, and in one patient both types of ulcer). Complications of ulcers were diagnosed in eight (other) patients: seven (upper) GI bleedings and one perforation. Thus the incidence during one year of clinically manifest ulcers in the high risk group was 1.0% and of complications of ulcers 1.1%, together 2.1%. In the group of 15 patients with GI events, only one patient had not taken the adequately prescribed gastroprotective drugs (compliance failure). Misguidedly, gastroprotective drugs were not prescribed in seven patients (policy failure), but in the remaining seven patients gastroprotective drugs were adequately prescribed and used. CONCLUSION: The incidence of clinically manifest ulcers and of complications of ulcers in patients with RA at high risk for NSAID gastropathy is relatively low, and might be related to our strategy to prescribe prophylactic agents in these patients.
10370156 Analysis of synovial fluid components of hydrarthrosis in long-term hemodialysis patients. 1999 The synovial fluid components in long-term hemodialysis patients (HD; 43 knees in 43 patients) were investigated and compared with those in patients with osteoarthritis (OA; 21 knees in 21 patients) and rheumatoid arthritis (RA; 26 knees in 26 patients). The average ages in the three groups were, respectively, 60.7 years (range, 34-79 years), 63.2 years (range, 48-88 years), and 59.7 years (range, 37-76 years). The duration of hemodialysis in the HD group averaged 14.0 years (range, 4-24 years). The concentrations of hyaluronic acid, protein, and isomers of chondroitin sulfate (chondroitin 6-sulfate [C6S] and chondroitin 4-sulfate [C4S]) in the synovial fluid, and its viscosity were measured. Differences in each of the parameters were investigated according to disease clinical stage, roentgenological grade, and periods of dialysis in the HD group. The viscosity of the synovial fluid and the concentration of hyaluronic acid in HD patients were similar to those in OA patients; however, the C6S/C4S ratio in the synovial fluid of HD patients was similar to that in RA patients. The latter finding suggests that synovitis may be present in the hydrarthrosis of HD patients. The cause of this synovitis in HD patients remains to be elucidated.
11053085 The role of national agencies in the managed introduction of new drugs for arthritis. 2000 Nov The role of the various agencies involved in the managed introduction of new drugs in the United Kingdom is discussed, particularly with regard to the work of the National Institute for Clinical Excellence (NICE). The process by which the National Health Service in the UK identifies key new drug technologies of major clinical, financial and service significance is discussed. This includes the decision making process for selection of products for appraisal by NICE. The appraisal procedure and the impact of NICE guidance for the NHS will, it is hoped, encourage quality in clinical practice. All healthcare systems face budgetary constraints and the introduction of new technologies bring particular challenges. The launch of the new biological agents for the treatment of rheumatoid arthritis, into a speciality where previously relatively inexpensive agents were prescribed, raises questions concerning managed introduction and reimbursement.
9571680 Posterior atlantoaxial fixation: the Magerl screw technique. 1998 Apr Atlantoaxial transarticular fixation is a proven stabilization technique used to augment conventional sublaminar fusion. Along with its superior biomechanical profile comes the inherent risk of neurovascular injury and potential compromised fixation during its application. This article presents a detailed systematic guide to this procedure including preoperative evaluation, positioning, and the more subtle aspects of the surgical technique. A new instrumentation design that has enhanced the ease and accuracy of screw placement with less operative frustration and potential morbidity of previous systems also is presented.
9926962 Non-Hodgkin's lymphoma as an unexpected diagnosis in a shoulder arthroplasty. 1999 Jan Shoulder arthroplasty (SA) is commonly performed in patients with rheumatoid arthritis (RA) who have been treated with long-term immunosuppressive medication. RA is associated with an increased risk of neoplasms of the immune system. A case of non-Hodgkin's lymphoma as an unexpected diagnosis after the routine pathologic examination of the soft tissues after SA was detected in a 54-year-old woman with long-standing RA and prolonged immunosuppressive therapy. Although this case does not support the cost-effectiveness of routine specimen evaluation during SA, we suggest that histological analysis of the surgical tissues is appropriate and should be performed in all patients who have been treated with prolonged immunosuppressive medication, especially RA patients as well as patients who have suspicious surgical findings.
11244034 Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? 2001 Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNF alpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNF alpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNF alpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNF alpha antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activity of TNF alpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNF alpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNF alpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.