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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
12176809 Transforming growth factor beta1 gene polymorphism in rheumatoid arthritis. 2002 Sep OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease and synovial cells, antigen presenting cells, lymphocytes, and their cytokines might be associated with the disease. Transforming growth factor beta1 (TGFbeta1) has been reported to have important roles in unresolved inflammation, immune suppression, fibrosing processes, and angiogenesis. TGFbeta1 is highly expressed in joints in RA and is considered to be a regulator of anti-inflammation in RA. Polymorphisms of TGFbeta1 have been reported to be associated with the production of TGFbeta1 protein, and to increase the risk of acquiring several diseases. It was speculated that these polymorphisms might also be involved in RA, and therefore the TGFbeta1 codon 10 T869C polymorphism in a series of patients and controls was investigated. METHOD: A total of 155 patients with RA and 110 healthy subjects were studied. DNA was extracted from peripheral leucocytes and TGFbeta1 codon 10 T869C polymorphism was determined by polymerase chain reaction restriction fragment polymorphism. RESULTS: A significantly higher proportion of patients with RA with the T allele (CT type or TT type) was found compared with the CC type (p=0.039). CONCLUSION: The T allele, previously reported to be linked with production of TGFbeta1, may be associated with an increased risk of RA.
15308531 Diagnostic characteristics of a gelatin based Waaler-Rose assay (Serodia-RA) for the detec 2004 Sep OBJECTIVE: To evaluate the diagnostic usefulness of a gelatin based Waaler Rose assay (Serodia-RA) for the detection of rheumatoid factor (RF) in rheumatoid arthritis (RA). METHODS: RF was measured by Serodia-RA and rate nephelometry in 90 patients with RA according to the revised ACR criteria and 102 patients with rheumatological diseases other than RA. Sensitivity, specificity, accuracy, likelihood ratios, and area under the curve using receiver operating characteristics (ROC) analysis were determined for both tests. Agreement between assays was assessed on 1657 consecutive samples. RESULTS: At equal specificity, Serodia-RA tended to be more sensitive than rate nephelometry (0.66 v 0.58; p = 0.04). ROC plots showed an area under the curve of 0.843 for Serodia-RA and 0.784 for nephelometry, providing further evidence that Serodia-RA was slightly better at differentiating between RA and non-RA arthropathy. Good agreement was found between both assays. CONCLUSION: Serodia-RA is slightly more accurate than rate nephelometry for the detection of RF in RA, and a combination of both assays only marginally improves the diagnostic usefulness of RF detection. Use of two tests for detection of RF is not recommended. One test for detection of RF together with a more specific test, such as antibodies to cyclic citrullinated peptide, is suggested.
15067740 [Effect of Triptolide on TNFalpha-induced activation of NF-kappaB and expression of COX-2 2004 Mar OBJECTIVE: To explore the effects of Triptolide (TP) on TNFalpha-induced cell proliferation and expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and their inducing products PGE2, NO in human rheumatoid arthritis synovial fibroblasts (RASF). METHODS: Fibroblasts (RASF) were obtained from synovial tissue of patients with RA and were cultured in vitro. RASF were stimulated with TNFalpha(20 microg/L) in the presence or absence of TP(0 - 100 microg/L) for 20 h. The RASF proliferation was determined by (3)H-TdR incorporation, and the productions of PGE2 and NO in culture supernatants of RASF were detected with competitive ELISA and enzyme reduction of nitrate. Expressions of COX-2 and iNOS mRNA in RASF were analyzed by semi-quantitative RT-PCR. Expressions of COX-2 and iNOS protein were estimated by Western-blot method and cellular enzyme immunoassay in synovial fibroblasts. NF-kappaB activity in whole-cell extract of RASF was also measured by an ELISA-based method. RESULTS: TP (>20 microg/L) down-regulated markedly TNFalpha-induced COX-2 and iNOS mRNA and protein expression, and their inducing products PGE2 and NO of synovial fibroblasts. This effect was positively correlated with TP concentrations. NF-kappaB activity in TNFalpha-stimulated synovial cells was suppressed profoundly by TP treatment (IC(50) approximately 35microg/L). The activity of NF-kappaB was correlated with the levels of COX-2 and iNOS expression in TNFalpha-stimulated RASF. No change was observed in proliferation of synovial cells after treatment of TP. CONCLUSION: TP could significantly down-regulate TNFalpha-induced COX-2, iNOS expression and production of PGE2, NO in human RASF, which is associated with the suppression of NF-kappaB activity.
14722198 Hepatic manifestations of autoimmune rheumatic diseases. 2004 Feb Hepatic manifestations in autoimmune disease include chronic active hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and nodular regenerative hyperplasia. These diseases are rare and may occur concomitantly or serially. Clinicians must be aware of the possibility of liver disease so that it can be treated as soon as possible.
12772498 Development of novel decoy oligonucleotides: advantages of circular dumb-bell decoy. 2003 Apr The inhibition of specific transcription regulatory proteins is a novel approach to regulate gene expression. The transcriptional activities of DNA binding proteins can be inhibited by the use of double-stranded oligonucleotides (ODNs) that compete for binding to their specific target sequences in promoters and enhancers. Transfection of this cis-element double-stranded ODN, referred to as decoy ODN, has been reported to be a powerful tool that provides a new class of anti-gene strategies to gene therapy and permits examination of specific gene regulation. We have demonstrated the usefulness of this decoy ODN strategy in animal models of restenosis, myocardial infarction, glomerulonephritis and rheumatoid arthritis. However, one of the major limitations of decoy ODN technology is the rapid degradation of phosphodiester ODNs by intracellular nucleases. To date, several different types of double-stranded decoy ODNs have been developed to overcome this issue. Circular dumb-bell (CD) double-stranded decoy ODNs that were developed to resolve this issue have attracted a high level of interest. In this review, the applications of decoy ODN strategy and the advantages of modified CD double-stranded decoy ODNs will be discussed.
14576988 Proteus mirabilis and rheumatoid arthritis: no association with the disease. 2003 Oct Proteus mirabilis (PM) is implicated in different studies in the pathogenesis of rheumatoid arthritis (RA) because of the structural homogeneity of its haemolysin B precursor with EQRRAA sequences in DRB 1 haplotype. The aim of the study was to compare the levels of antibodies specific to PM in the sera of patients with RA and healthy controls in our population. Serum samples from 78 consecutive RA patients and 75 healthy controls were analysed for the presence of IgG isotype and total immunoglobulins (IgG + IgA + IgM) against PM using enzyme-linked immunosorbent assay (ELISA) with two kinds of antigen preparations, whole bacteria and SDS-lysed bacterial extract. There was no significant increase in the concentrations of anti- Proteus antibodies (APA) in patients with RA compared to healthy controls in our population, when SDS-lysed bacterial extract or whole bacteria were used as antigen. The APA levels did not correlate with serum CRP levels. We conclude that P. mirabilis has no pathological or aggravating role in RA.
12659832 Prevalence of HSP47 antigen and autoantibodies to HSP47 in the sera of patients with mixed 2003 Apr 4 The 47-kDa heat shock protein (HSP47) is an endoplasmic reticulum molecular chaperone that assists in the maturation of collagen molecules and whose expression is known to be upregulated in lesions of fibrotic diseases. We examined the levels of HSP47 protein and autoantibodies to HSP47 in the sera of patients with rheumatic autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, and mixed connective tissue disease (MCTD) by enzyme-linked immunosorbent assay and immunoblot analysis. Patients with idiopathic pulmonary fibrosis (IPF) were assessed as an example of non-autoimmune fibrotic disease. HSP47 antigen and autoantibody levels are significantly elevated in the sera of the rheumatic autoimmune disease patients, but not in the sera of the IPF patients. The sera of the MCTD patients showed particularly high levels of HSP47 antigen relative to healthy controls (1.99+/-0.22 vs 0.41+/-0.07 ng/ml). Autoantibodies to HSP47 were also in high levels in the sera of MCTD patients. These results suggest that simultaneous occurrence of systemic inflammation and upregulation of HSP47 caused leakage of HSP47 from fibrotic lesions into the peripheral blood, and the leaked antigen induced high titer of autoantibodies to HSP47. The high levels of HSP47 antigen and autoantibody may be useful blood markers of MCTD.
15024101 Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheu 2004 Mar 23 Modulation of epitope-specific immune responses would represent a major addition to available therapeutic options for many autoimmune diseases. The objective of this work was to induce immune deviation by mucosal peptide-specific immunotherapy in rheumatoid arthritis (RA) patients, and to dissect the related immunological mechanisms by using a technology for the detection of low-affinity class II-restricted peptide-specific T cells. A group of patients with early RA was treated for 6 months orally with dnaJP1, a peptide that induces proinflammatory T cell responses in naive RA patients. Immunological analysis at initial, intermediate and end treatment points showed an intriguing change from proinflammatory to regulatory T cell function. In fact, dnaJP1-induced T cell production of IL-4 and IL-10 increased significantly when initial and end treatment points were compared, whereas dnaJP1-induced T cell proliferation and production of IL-2, IFN-gamma, and tumor necrosis factor-alpha decreased significantly. The total number of dnaJP1-specific cells did not change over time, whereas expression of foxP3 by CD4+CD25(bright) cells increased, suggesting that the treatment affected regulatory T cell function. Thus, rather than clonal deletion, the observed change in immune reactivity to dnaJP1 was the outcome of treatment-induced emergence of T cells with a different functional phenotype. This study contributes to our knowledge of mechanisms and tools needed for antigen-specific immune modulation in humans, thus laying the foundation for exploitation of this approach for therapeutic purposes.
12661795 Leflunomide. 2003 Mar Leflunomide (Arava) was approved for the treatment of rheumatoid arthritis by the regulatory authorities in the US and Europe in 1998. This approval was based on three pivotal randomised clinical trials conducted in the US and Europe. This report will focus on the use of leflunomide in rheumatoid arthritis based on the data from these trials as well information on the efficacy and safety learned from post release clinical experience.
15080263 Multidrug resistance proteins in rheumatoid arthritis, role in disease-modifying antirheum 2003 Drug resistance is generally accepted as an important cause of treatment failure for patients with neoplastic or infectious diseases. Molecular mechanisms underlying drug resistance include the action of drug efflux pumps belonging to the super-family of ATP binding cassette (ABC) proteins, which mediate the cellular extrusion of a large variety of therapeutic drugs, a phenotype that is referred to as multidrug resistance (MDR). Unlike neoplastic and infectious diseases, chronic inflammatory diseases have received little attention. The potential role of ABC transporters in determining the efficacy of anti-rheumatic drugs, notably disease modifying anti-rheumatic drugs (DMARDs), in patients with rheumatoid arthritis is unclear. Based on knowledge from the field of oncology and immunology, this review concentrates on the pharmacological role of MDR proteins in the (clinical) efficacy of several DMARDs, as well as the physiological role of MDR proteins in transporting signalling molecules important in inflammatory processes.
14558083 Differential expression of HLA class II genes associated with disease susceptibility and p 2003 Oct OBJECTIVE: Rheumatoid arthritis (RA)-associated HLA class II genes are assumed to promote susceptibility to and/or progression of the disease. Among the various modes of action proposed so far is the effect of the differential expression of HLA class II genes in different types of antigen-presenting cells on the Th1/Th2 balance. The aim of this study was to investigate the differential expression of genes encoded within the RA-associated HLA-DR4 superhaplotype and within the neutral DR7 and DR9 superhaplotypes. METHODS: The promoters encoded within these 3 haplotypes were first analyzed for sequence polymorphisms. To test for functional consequences, we assumed that the binding of nuclear factors to the promoter elements was correlated with the transcription activity, and we used surface plasmon resonance technology. To that end, oligonucleotides representing the polymorphic regulatory sequences and nuclear extracts from a monocyte cell line and a B cell line were used. RESULTS: While the promoters of the highly polymorphic HLA-DRB1*04, *07, and *09 alleles showed comparable binding of nuclear factors, differential binding was observed for the 2 promoters that drive the relatively nonpolymorphic DRB4 alleles in linkage disequilibrium with DRB1. Interestingly, analysis of RA patients positive for DR4, DR7, and DR9 revealed the segregation of radiographic progression with the stronger of the 2 DRB4 promoters, independent of the DRB1 allele. Moreover, DRB1*04 alleles in RA patients showed a reduced association with the DRB4 splice variant, completely preventing DRB4 expression. CONCLUSION: Our findings represent the first evidence of a correlation between the differential expression of HLA class II genes and both the susceptibility and the progression of RA.
15468366 Comparing the AUSCAN Osteoarthritis Hand Index, Michigan Hand Outcomes Questionnaire, and 2004 Oct OBJECTIVE: The Australian Canadian Osteoarthritis Hand Index (AUSCAN), Michigan Hand Outcomes Questionnaire (MHQ), and the Sequential Occupational Dexterity Assessment (SODA) are assessments of hand function. Investigation of psychometric properties, administration, acceptability, and content of an assessment add strength to the findings of research and treatment. We evaluated the validity and reliability of the AUSCAN, MHQ, and the SODA for assessing disability in patients with rheumatoid arthritis (RA). METHODS: Sixty-two patients with RA completed the AUSCAN (visual analog scale version), the MHQ, and the SODA. Seventeen patients repeated the assessments within one week. RESULTS: The assessments recorded high variability within the sample of 62 patients with RA. The AUSCAN and MHQ provided patient and context-specific information, while the SODA provided more impairment information that could be readily compared between patients. Seventeen patients were tested twice within 5 days, showing good reliability of all assessments. Unlike the MHQ, AUSCAN and SODA do not provide information about individual hands or hand dominance. The physical function scales of the AUSCAN and the SODA were related (r = 0.81), and the AUSCAN and MHQ pain scales were related (r = 0.68). CONCLUSION: Clinicians and researchers should decide whether impairment, ability, or handicap outcome is the goal of assessment, and whether bilateral function or the function of one hand is of interest before choosing a hand assessment. The AUSCAN and MHQ are valid and reliable for assessment of hand disability in patients with RA, and they allow the patients to answer questions about their home environment. The SODA is also valid and reliable for assessing disability in a clinical situation that cannot be generalized to the home.
12450578 SSR125329A, a high affinity sigma receptor ligand with potent anti-inflammatory properties 2002 Dec 5 SSR125329A ([(Z)-3-(4-Adamantan-2-yl-3,5-dichloro-phenyl)-allyl]-cyclohexyl-ethyl-amine) is a new ligand exhibiting high affinity for sigma(1) and sigma(2) receptors and for the human Delta8-Delta7-sterol isomerase. Here we show that this molecule has potent immunoregulatory properties both in vitro and in vivo. SSR125329A inhibited staphylococcal enterotoxin B-induced mouse splenocyte proliferation in vitro, whereas in vivo it enhanced lipopolysaccharide-induced systemic release of interleukin-10 while simultaneously inhibiting tumor necrosis factor-alpha (TNF-alpha) synthesis. It also prevented graft-versus-host disease in B6D2F1 mice and protected Mrl/lpr mice against the development of its spontaneous rheumatoid-like syndrome. There is high interplay of pro- and anti-inflammatory cytokines in inflammatory processes, particularly in human rheumatoid arthritis. The results of this study provide substantial evidence that sigma receptor ligands may represent a new effective approach for rheumatoid arthritis treatment.
15474390 Assessing damage in individual joints in rheumatoid arthritis: a new method based on the L 2004 Sep OBJECTIVES: To evaluate observer agreement using the Larsen system (LS) and a Modified Larsen system (ML) when assessing individual joints of the hands and wrists in rheumatoid arthritis, and to compare the two systems. To determine the minimally important difference (MID) for the ML. METHODS: Thirty radiographs of hands and wrists from 10 patients who presented with RA were graded by two blinded observers, using the LS and then the ML. Patients were followed for a mean of 7.2 years (range: 4-10 years). Inter- and intra-observer agreement were calculated using the kappa statistic with linear incremental weights. Inter-observer agreement was also computed for the summed score, using an intraclass correlation coefficient. Inter-observer error was estimated by calculating the mean and standard deviation of the grading differences between the two observers. Prevalence of damage was calculated as a ratio of damage: no damage and expressed as a percentage. Pairs of radiographs were comparatively graded using a seven-point Likert scale. RESULTS: The kappa statistic for inter-observer agreement was 0.38 (marginal reproducibility) for the LS and 0.52 (good reproducibility) for the ML (P = 0.004). Using a difference of one grade as perfect agreement, it was 0.56 (good reproducibility) for the LS and 0.87 (excellent reproducibility) for the ML (P = 0.001). Intra-observer agreement was high in both systems. The distribution of ML-grade differences varied according to the level of the Likert scale: for "a little bit worse", representing the smallest amount of detectable damage progression, the distribution differences peaked around two grades. This value represented a MID 87% of the time. CONCLUSIONS: The LS lacks precision for individual joints. The ML, it is proposed, has more detailed definitions of grades, and is more reliable. When pairs of radiographs were compared, a two-grade difference on the ML was the MID.
15187208 Leflunomide-associated pancytopenia with or without methotrexate. 2004 Jul OBJECTIVE: To report 18 cases of pancytopenia associated with leflunomide use in Australia, 5 of which were treated at Princess Alexandra Hospital, Brisbane. case summaries: Leflunomide was used in the treatment of rheumatoid arthritis in 17 of 18 patients; the other patient was diagnosed with systemic lupus erythematosus. Median age was 65.5 years (range 18-79), and 15 of the patients were female. Fourteen patients were on combined treatment with methotrexate. Pancytopenia was typically severe, requiring hospital admission, withdrawal of the immunosuppressant(s), intensive supportive therapy, and treatment of neutropenic sepsis. Five patients died, 4 of whom were receiving concomitant methotrexate. Time to onset of pancytopenia ranged from 11 days to 4 years (median 4 mo). In one case in which the patient had been stable while receiving leflunomide, methotrexate, and hydroxychloroquine for 4 years, fatal pancytopenia was triggered by acute renal failure secondary to dehydration and use of nonsteroidal antiinflammatory drugs. The Naranjo probability scale suggested a probable causal association in 5 cases and possible association in the remainder. DISCUSSION: Leflunomide, indicated for treatment of active rheumatoid arthritis, inhibits pyrimidine synthesis in lymphocytes and other rapidly dividing cells and may rarely be associated with life-threatening pancytopenia. Combination therapy with methotrexate may increase the risk. Time to onset is variable, and clinicians should remain vigilant, particularly when there is a change in the patient's baseline health status. CONCLUSIONS: The risk of pancytopenia during leflunomide therapy appears to be increased when the drug is combined with methotrexate and in older patients. Onset may be delayed, and ongoing monitoring of blood counts is essential.
14532145 Survival during treatment with tumour necrosis factor blocking agents in rheumatoid arthri 2003 Nov Tumour necrosis factor (TNF) blocking agents are an important advance in the clinical treatment of rheumatoid arthritis (RA). They were introduced into clinical practice while limited safety information was available. This means that intensive monitoring is needed early in the life cycle of these new drugs. Setting up large cohort studies to monitor efficacy, safety, and tolerability in long term use of these so-called biological agents will provide information about the consequences of using TNF blocking agents in chronic rheumatic disease like RA. Currently, a Dutch multicentre registry on biological agents in RA is being set up. This study aimed at investigating the efficacy and toxicity of TNF blocking agents in patients with RA at one participating academic centre by a drug survival analysis. Since 1997 230 patients with RA at the centre have been treated with TNF blocking agents for the first time (94 with adalimumab, 120 with infliximab, and 16 with etanercept). No differences in drug survival between the three TNF blocking agents were found despite the diversity in selection and patient numbers. Adverse events which occurred, leading to discontinuation, were similar to those from previous reports.
15361377 Better efficacy of methotrexate given by intramuscular injection than orally in patients w 2004 Oct OBJECTIVE: To compare the clinical efficacy of methotrexate and tolerance to the drug in patients with rheumatoid arthritis who were switched from intramuscular to oral administration because of a shortage of the intramuscular preparation. METHODS: 143 patients were switched from intramuscular to oral methotrexate. Of these, 47 were switched back to the intramuscular form. A multiple choice questionnaire was sent by mail to evaluate clinical and biological criteria of efficacy and tolerance. RESULTS: When methotrexate was first switched from intramuscular to oral administration, increased disease activity, exacerbation of morning pain and hand stiffness, duration of morning stiffness, increased joint pain, and increased joint swelling were observed. There was a greater frequency of gastrointestinal symptoms, but without a significant increase in liver abnormalities. When intramuscular methotrexate became available again, 47 of the 143 patients were switched back and were followed for at least three months. On average, disease manifestations were improved and side effects reduced by the switch. CONCLUSIONS: Methotrexate given intramuscularly had improved clinical efficacy with fewer side effects than given orally. Intramuscular methotrexate administration should be considered when rheumatoid arthritis remains active in spite of high dose oral methotrexate.
14707104 Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like r 2004 Jan 15 To analyze the role of Toll-like receptors (TLR) in the pathogenesis of rheumatoid arthritis, we have assessed the effects of stimulation of cultured synovial fibroblasts by the TLR-2 ligand bacterial peptidoglycan. By using high density oligonucleotide microarray analysis we identified 74 genes that were up-regulated >2.5-fold. Fourteen CC and CXC chemokine genes were among the genes with the highest up-regulation. Quantitative real-time PCR analysis confirmed up-regulation of granulocyte chemotactic protein (GCP)-2, RANTES, monocyte chemoattractant protein (MCP)-2, IL-8, growth-related oncogene-2, and to a lesser extent, macrophage-inflammatory protein 1alpha, MCP-1, EXODUS, and CXCL-16. GCP-2, RANTES, and MCP-2 were detected in culture supernatants of synovial fibroblasts stimulated with peptidoglycan. Chemokine secretion induced by stimulation of rheumatoid arthritis synovial fibroblasts via TLR-2 was functionally relevant as demonstrated by chemotaxis assays. GCP-2 and MCP-2 expression, which have not been reported previously in rheumatoid arthritis, was demonstrated in synovial tissue sections of patients diagnosed with rheumatoid arthritis but not in those with osteoarthritis. Correspondingly, synovial fluid levels were significantly higher in patients diagnosed with rheumatoid arthritis as compared with osteoarthritis. Thus, we present evidence for an induction of chemokine secretion by activation of synovial fibroblasts via TLR-2, possibly contributing to the formation of inflammatory infiltrates characteristically found in rheumatoid arthritis joints.
15246021 Thrombogenicity of TNF alpha in rheumatoid arthritis defined through biological probes: TN 2004 Jun Rheumatoid arthritis is a disease at high cardiovascular risk. It has recently been shown that RA patients with more than 10 years disease duration present a risk of myocardial infarction more than three times higher than osteoarthritis controls. The major determinant is thought to be the chronic inflammatory process, driven by some key cytokines among which TNF alpha is thought to play the leading role in the majority of the patients. TNFalpha, therefore, once blocked by specific inhibitors like TNF alpha blockers (Infliximab, Etanercept) should profoundly decrease the cardiovascular risk. However, TNF blockers induce the appearance of autoimmunity though in a small minority of the patients. This autoimmunity is thought to be due to the poor clearance of apoptotic bodies once the systemic inflammation (CRP, SAP) is controlled by the specific blockers, and to the lack of control of some B cell populations producing autoantibodies to specific autoantigens. Among the autoantibodies arising during TNF blockade, anticardiolipin appear to be the most crucial with respect to the cardiovascular risk. The appearance of anticardiolipins at clinically significant levels appears to be driven by two possible mechanisms, one due to common infections of the urinary or upper airways tract during blockade of soluble TNF alpha, the other due to the escape of some autoreactive B cells during blockade of soluble and membranous TNF alpha. Since both autoantibodies related to infections as well as the high levels unrelated to infections, can be well controlled by appropriate therapies, clinicians should pay attention to the biological phenomenon before it becomes a clinical problem.
12591910 Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by to 2003 Feb 17 Inflammatory arthritis is associated with the release of a network of key cytokines. In T cell receptor transgenic K/BxN mice interleukin (IL)-1 plays a key role in joint swelling and destruction, as suggested by the ability of anti-IL-1receptor (IL-1R) antibody treatment to delay the onset and slow the progression of this disease. This mechanism is dependent on the signaling pathway intermediary myeloid differentiation factor 88 (MyD88), such that neither IL-1R nor MyD88-deficient mice developed visually detectable synovitis after transfer of arthritogenic sera. The Toll-like receptors (TLRs) share the same signaling pathway through MyD88 as the IL-1R. The administration of a TLR-4 ligand, lipopolysaccharide, concomitant with arthritogenic serum in IL-1 receptor-deficient mice resulted in acute paw swelling, but not in MyD88-deficient mice. Also, serum transferred arthritis was not sustained in TLR-4 mutant mice compared with controls. These results suggest that innate immune functions via TLR-4 might perpetuate inflammatory mechanisms and bypass the need for IL-1 in chronic joint inflammation.