Browse

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

ID PMID Title PublicationDate abstract
12730548 Natural killer cells in the synovial fluid of rheumatoid arthritis patients exhibit a CD56 2003 Jul BACKGROUND: Natural killer (NK) cells play an important role in several animal models of autoimmunity by modulating T-cell responses, but it is unclear whether human NK cells have similar functions. METHODS: We characterized the phenotype of NK cells in synovial fluid (SF) and peripheral blood (PB) of patients with rheumatoid arthritis (RA) and in healthy control subjects using flow cytometry and quantitative PCR. RESULTS: The proportions of NK cells in PB and SF of RA patients were not significantly different from those in healthy PB. However, the SF NK cell phenotype was strikingly different, with increased CD94 and CD56 densities and greatly reduced proportions of cells expressing CD158a/b. These cells also had reduced mRNAs coding for CD158a/b and low perforin levels compared with RA PB and healthy PB NK cells. CONCLUSIONS: We identified a novel phenotype of SF NK cells that is of potential significance in RA. Experiments are now under way to determine the function of these SF NK cells and their potential role in RA.
12233876 Androgen receptors in human synoviocytes and androgen regulation of interleukin 1beta (IL- 2002 Sep OBJECTIVE: To investigate the hypothesis that synoviocytes possess androgen receptors (AR) that could be modulated by the non-aromatizable androgen, dihydrotestosterone (DHT), resulting in altered levels of inflammatory cytokines. METHODS: Using molecular analyses of AR in combination with the multiprobe ribonuclease protection assay and ELISA, we investigated the presence of AR and the effect of DHT on interleukin 1beta (IL-1beta) induced expression of the IL-6 superfamily of cytokines in synoviocytes. RESULTS: Our studies corroborate the presence of AR in synoviocytes. DHT exerts a suppressive effect on IL-1beta induced IL-6, macrophage-colony stimulating factor (CSF), and granulocyte-CSF production by synoviocytes. This modulatory effect is exerted at both the transcriptional and translational level; 17beta-estradiol, at high concentrations, had a stimulatory effect. CONCLUSION: The identification of functional AR in synoviocytes and the modulatory effect of DHT on the inflammatory process in the joint suggest a direct link between hypoandrogenicity and rheumatoid arthritis (RA) disease status. Understanding the complex regulation of inflammatory cytokines by hormones may contribute to the development of new therapeutic targets for clinical intervention in RA.
12188477 Failure of hydroxyapatite-coated acetabular cups. Ten-year follow-up of 85 Landos Atoll ar 2002 Jul Between March 1990 and May 1991 we performed 85 primary total hip replacements in 74 patients using the Landos Atoll hydroxyapatite (HA)-coated cup and the Corail HA-coated stem. The patients were followed up for a mean of ten years. Of the 85 cups, 26 (31%) have already been revised and a further six are radiologically unstable and awaiting revision. Two femoral stems have been revised for infection without loosening. The retrieved acetabular cups were studied by SEM and image-processing techniques to quantify the amount of residual HA on the cup. This was correlated with the clinical variables and modes of failure. The residual HA (as a percentage of the surface) on the loose cups correlated negatively with the duration of implantation (r = -0.732, p < 0.001). Six cups were stable at revision and had more residual HA coating than those which were loose (p < 0.01). The rate of failure of the Landos Atoll HA-coated, smooth hemispherical cup with screw fixation is unacceptably high. Resorption of the HA coating is markedly increased in loose cups compared with stable cups. HA coating cannot substitute for stable mechanical fixation.
12208866 The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis. 2002 Sep Rheumatoid arthritis (RA) is a chronic inflammatory disorder leading to bone and cartilage destruction. A substantial body of evidence suggests that prostaglandin E2 (PGE2) contributes to the pathogenesis of RA, and nonsteroidal anti-inflammatory drugs, inhibitors of the synthesis of PGE2 and other prostanoids, continue to be used in the treatment of this disease. To begin to understand the mechanism by which prostaglandins modulate the pathophysiology of this disease, we examined mice lacking each of the four known PGE2 (EP) receptors after generation of collagen antibody-induced arthritis, an animal model of RA. Homozygous deletion of the EP1, EP2, or EP3 receptors did not affect the development of arthritis, whereas EP4 receptor-deficient mice showed decreased incidence and severity of disease. These animals also showed reduced inflammation as assessed by circulating IL-6 and serum amyloid A levels. Joint histopathology of EP4(-/-) animals revealed reduced bone destruction, proteoglycan loss, and type II collagen breakdown in cartilage compared with EP4(+/+) mice. Furthermore, liver and macrophages isolated from EP4(-/-) animals produced significantly less IL-1 beta and IL-6 than control samples. Thus, PGE2 contributes to disease progression at least in part by binding to the EP4 receptor. Antagonists of this receptor might therefore provide novel agents for the treatment of RA.
12858344 Expression of matrix metalloproteinase-9 (gelatinase B) in gouty arthritis and stimulation 2003 Jul 1 To investigate the relevance of gelatinase-B (matrix metalloproteinase 9, MMP-9) in gouty arthritis (GA), we tested the occurrence of MMP-9 in GA patients and cell culture system. Gelatinolytic activity in the synovial fluid (SF) of patients with different kinds of arthritis was assessed by gelatin zymography. A predominant 92-kDa MMP-9 gelatinolytic activity was evident in rheumatoid arthritis (RA) and GA samples, but no activity was observed in osteoarthritis (OA) samples. Among the 53 SF samples (9 RA, 24 GA, and 20 OA) analyzed for MMP-9 and tissue inhibitor of metalloproteinase (TIMP-1) antigen levels by ELISA, MMP-9 antigen levels were elevated tenfold in GA SF compared with OA SF. In addition, GA synovial tissue extracts revealed elevated levels of MMP-9 expression as compared to OA tissue extracts by Western blot and RT-PCR analysis. Immunohistochemical studies demonstrated that MMP-9 immunoreactivity was more intense in GA than in OA synovial tissues. Furthermore, macrophages activation by gouty crystals in vitro was examined. Crystals stimulated MMP-9 gene expression in macrophage cell line and such stimulation was suppressed by PD98059. These findings suggest that the abnormal production of MMP-9 by macrophages is a reflection of the pathological conditions in joints of patients with GA, and that the activation of MMP-9 in the joint is known to play an important role in joint disease.
12571842 Association of interleukin-18 expression with enhanced levels of both interleukin-1beta an 2003 Feb OBJECTIVE: To examine the expression patterns of interkeukin-18 (IL-18) in synovial biopsy tissue of patients with rheumatoid arthritis (RA), and to determine whether expression of this primary cytokine is related to the expression of other cytokines and adhesion molecules and related to the degree of joint inflammation. METHODS: Biopsy specimens of knee synovial tissue either without synovitis (n = 6) or with moderate or severe synovitis (n = 11 and n = 12, respectively) were obtained from 29 patients with active RA. Paraffin-embedded, snap-frozen sections were used for immunohistochemical detection of IL-18, tumor necrosis factor alpha (TNFalpha), IL-1beta, IL-12, and IL-17. Furthermore, adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin, and cell markers CD3, CD14, and CD68 were stained. RESULTS: IL-18 staining was detectable in 80% of the RA patients, in both the lining and sublining of the knee synovial tissue. IL-18 expression in the synovial tissue was strongly correlated with the expression of IL-1beta (in the sublining r = 0.72, in the lining r = 0.71; both P < 0.0001) and TNFalpha (in the sublining r = 0.59, P < 0.0007, and in the lining r = 0.68, P < 0.0001). In addition, IL-18 expression in the sublining correlated with macrophage infiltration (r = 0.64, P < 0.0007) and microscopic inflammation scores (r = 0.78, P < 0.0001), and with the acute-phase reaction as measured by the erythrocyte sedimentation rate (r = 0.61, P < 0.0004). Interestingly, RA synovial tissue that coexpressed IL-18 and IL-12 demonstrated enhanced levels of the Th1-associated cytokine IL-17. CONCLUSION: Our results show that expression of IL-18 is associated with that of IL-1beta and TNFalpha and with local inflammation in the synovial tissue of patients with RA. In addition, synovial IL-18 expression correlates with the acute-phase response. These data indicate that IL-18 is a primary proinflammatory cytokine in RA that drives the local production of IL-1beta and TNFalpha.
12911103 Differentiating simple versus complex processing speed: influence on new learning and memo 2003 Jun The current study was designed to examine how the construct of human information processing speed is conceptualized and measured, while also examining the influence of information processing speed on higher cognitive processes (i.e., learning). A mixed medical sample of 92 subjects participated in this study. Subjects underwent a broad-based neuropsychological evaluation, including measures of verbal and visuospatial new learning, spatial and verbal working memory, simple reaction time, choice reaction time, and information processing speed. Principal components factor analysis with varimax rotation resulted in a three-factor solution, comprised of: (1) simple speed/reaction time, (2) complex information processing and new learning, and (3) working memory. Notably, this factor solution identified 2 distinct forms of processing speed--simple and complex information processing speeds. In contrast to the abundance of literature grouping these two constructs together under one term (i.e., processing speed), these results indicate simple and complex speed to be distinct constructs assessed with different neuropsychological instruments. While the expected relationship between complex information processing capacities and working memory abilities was evident in this study, information processing speed also showed a significant relationship with new learning ability. The implications of this intriguing relationship are discussed.
11861721 Twenty-five-year survivorship of two thousand consecutive primary Charnley total hip repla 2002 Feb BACKGROUND: Charnley total hip arthroplasty has been demonstrated to provide good clinical results and a high rate of implant survivorship for twenty years and longer. Most long-term series are not large enough to stratify the many demographic factors that influence implant survivorship. The purpose of this study was to analyze the effects of demographic factors and diagnoses on the long-term survivorship of the acetabular and femoral components used in Charnley total hip arthroplasty. METHODS: Two thousand primary Charnley total hip arthroplasties (1689 patients) were performed at one institution from 1969 to 1971. Patients were contacted at five-year intervals after the arthroplasty. Twenty-five years after the surgery, 1228 patients had died and 461 patients were living. Hips that had not had a reoperation, revision or removal of a component for any reason, or revision or removal for aseptic loosening were considered to have survived. Survivorship data were calculated with use of the method of Kaplan and Meier. Patients were stratified by age, gender, and underlying diagnosis to determine the influence of these factors on implant survivorship. RESULTS: The twenty-five year rates of survivorship free of reoperation, free of revision or removal of the implant for any reason, and free of revision or removal for aseptic loosening were 77.5%, 80.9% and 86.5%, respectively. The twenty-five-year survivorship free of revision for aseptic loosening was poorer for each decade earlier in life at which the procedure was performed; this survivorship ranged from 68.7% for patients who were less than forty years of age to 100% for patients who were eighty years of age or older. Men had a twofold higher rate of revision for aseptic loosening than did women. CONCLUSIONS: Age, gender, and underlying diagnosis all affected the likelihood of long-term survivorship of the acetabular and femoral components used in Charnley total hip arthroplasty.
14584021 Etanercept for the treatment of rheumatoid arthritis. 2003 BACKGROUND: Etanercept is a soluble tumour necrosis factor alpha-receptor DMARD for the treatment of rheumatoid arthritis (RA). OBJECTIVES: To assess the efficacy and safety of etanercept for the treatment of RA. SEARCH STRATEGY: Five electronic databases were searched from 1966 to February 2003 with no language restriction. SELECTION CRITERIA: All randomized controlled trials (minimum 6 month duration) comparing three possible combinations 1) etanercept (10 mg or 25 mg twice weekly) with methotrexate (MTX) to MTX alone 2) etanercept to MTX, or 3) etanercept to placebo were eligible. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed the methodological quality of the trails. The American College of Rheumatology (ACR) core set of disease activity measures for RA clinical trials, radiographic, withdrawals and toxicity outcomes were analyzed. MAIN RESULTS: Three trials were included in this review. Two trials compared an experimental group who were started on etanercept compared to a control group; both groups had the same ongoing background therapy of nonsteroidals in both trials plus in one trial one group was on stable methotrexate. In these two trials the ACR 20, ACR 50 and ACR 70 response rates at 6 months were statistically significantly and clinically important with etanercept 25 mg subcutaneous injections (SC) twice weekly. Sixty-four percent of people receiving etanercept ache vied an ACR 20 response compared to 15% of controls and the number needed to treat (NNT) with etanercept is 2 people. Thirty-nine percent of those receiving etanercept achieved an ACR 50 response compared to 4% of taking control treatment and the NNT is three. Fifteen percent of people taking etanercept achieved an ACR 70 compared to 1% of controls with a NNT of 7 people. In the third trial of starting etanercept compared to starting methotrexate the number of participants who achieved an ACR 20, 50 or response at 6 and 12 months were not statistically significant for either etanercept dose. Etanercept treatment showed a statistically significantly and clinically important affect on joint damage as measured by the Sharp erosion score. Among participants who received etanercept 72% had no increase in their erosion score compared to 60% of participants in the methotrexate group. Withdrawal and toxicity results were acceptable. REVIEWER'S CONCLUSIONS: Etanercept 25 mg SC twice weekly was more efficacious than control treatment for ACR 20, 50 and 70 at 6 months, and over 12 months it slowed joint damage.
12822010 [Combination therapy in rheumatoid arthritis]. 2003 May 29 BACKGROUND: During the last decade patients with active rheumatoid arthritis have been offered early and aggressive drug therapy in order to decrease the damaging effect of inflammation on cartilage and bone. Combination of two or more disease-modifying antirheumatic drugs has been used more frequently to achieve better efficacy than with monotherapy without increasing drug side effects. MATERIALS AND METHODS: We have studied available rheumatological literature to find the best documented drug combinations. RESULTS: The combination of methotrexate, sulfasalazine and hydroxychloroquine seems to be a well documented alternative, and so is the combination of methotrexate and cyclosporine. Modern biologic drugs like etanercept, infliximab and anakinra work best in combination with methotrexate. INTERPRETATION: The combination of two or more disease-modifying antirheumatic drugs can be a good alternative to monotherapy in the treatment of patients with active rheumatoid arthritis, either when monotherapy has failed or unacceptable side effects have occurred, or as a first choice in patients who need very early and aggressive therapy. Combination therapy should only be initiated by a rheumatologist, after informed consent. A safe clinical and chemical monitoring must be organized in cooperation with the patient and the primary physician.
11892706 Upper gastrointestinal tolerability of celecoxib compared with diclofenac in the treatment 2002 Jan OBJECTIVE: To compare the upper gastrointestinal (UGI) tolerability of celecoxib (a cyclooxygenase-2 specific inhibitor) and diclofenac using data from three randomised, double-blind clinical trials in osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: Patients in two OA studies received either celecoxib 100 mg BID (n = 545), diclofenac 50 mg BID or TID (n = 540), or placebo (n = 200) for 6 weeks. In the RA study, patients received celecoxib 200 mg BID (n = 326) or diclofenac 75 mg BID (n = 329) for 24 weeks. The cumulative incidence of abdominal pain, dyspepsia, nausea or any of these events (UGI tolerability composite endpoint) after the first 6 weeks was estimated using time-to-event analysis. RESULTS: In the pooled OA trials, the cumulative incidence of the composite endpoint was significantly higher with diclofenac (17.6%; 95% CI: 14.4-20.9%) than celecoxib (11.1%; 95% CI: 8.4-13.8%; p = 0.002) and comparable with placebo (13.3%; 95% CI: 8.1-18.4%; p = 0.157). In the PA trial, the cumulative incidence of the UGI tolerability composite endpoint was also significantly higher with diclofenac (20.7%; 95% CI: 16.3-25.1%) than celecoxib (15.9%; 95% CI: 11.9-20.0%; p = 0.013). Celecoxib was also better tolerated than diclofenac in this trial in terms of the cumulative incidences of abdominal pain (p = 0.031) and dyspepsia (p = 0.062). The results of the UGI tolerability composite endpoint analysis were confirmed using the Cox proportional hazards model to controlfor other predictors of UGI adverse events. CONCLUSION: The UGI tolerability of therapeutic dosages of celecoxib was significantly better than diclofenac in patients with RA or OA.
12649398 Elevated levels of synovial fluid antibodies reactive with the small proteoglycans biglyca 2003 Apr OBJECTIVES: To determine whether patients with rheumatoid arthritis (RA) express humoral immunity to the small proteoglycans biglycan and decorin and to compare the response to that of patients suffering from other joint diseases. METHODS: Serum and synovial fluid IgG and IgM antibody levels were determined by enzyme-linked immunosorbent assay. Antibodies to biglycan and decorin as well as to other known and extensively investigated cartilage matrix components such as type II collagen, aggrecan and fibronectin were investigated. Patients suffering from RA, osteoarthritis (OA), psoriatic arthritis and other seronegative spondylarthropathies were included in the study. Correlation between antibody levels and clinical/laboratory parameters was determined. RESULTS: Patients with RA expressed an increased humoral immunity to biglycan, while patients with seronegative spondylarthropathies displayed elevated decorin-specific synovial antibody levels compared with OA patients. CONCLUSION: These results indicate a significantly higher immunity to small proteoglycans in RA and seronegative spondylarthropathies than in OA suggesting a possible involvement in the pathogenesis of inflammatory rheumatic diseases.
15270001 [Etoricoxib (Arcoxia)]. 2004 May Etoricoxib (Arcoxia) is a novel non steroidal anti-inflammatory drug (NSAID) that selectively inhibits the inducible form of cyclo-oxygenase (COX), COX-2. Etoricoxib has a higher COX-1/COX-2 selectivity ratio than the other COX-2-selective NSAIDs as rofecoxib, valdecoxib or celecoxib. Tablets of 60, 90 and 120 mg are available. The recommended dosage of etoricoxib is 60 mg/day for osteoarthritis, 90 mg/day for rheumatoid arthritis and 120 mg/day for acute gouty arthritis. Etoricoxib's efficacy has been widely studied in comparative studies, showing the same efficacy as non-COX-2 selective NSAID, with fewer gastro-intestinal adverse effects.
12407546 Morbidity and quality of life in adult patients with a congenital abdominal wall defect: a 2002 Nov BACKGROUND: In children with congenital abdominal wall defects (CAWD), surgical treatment of the abdominal defect and the associated anomalies cause considerable morbidity in the first years of life. Afterward, most of the CAWD patients with correctable anomalies develop as other children. The morbidity and quality of life (QoL) of CAWD patients who have reached their adulthood is less well known and the subject of this study. METHODS: A 3-part questionnaire was sent to 75 former patients with CAWD, aged 17 years or more. The first part included questions about health, symptoms, and education; the second part consisted of 3 tests of psychosocial functioning; and the third part was a SF-36 questionnaire measuring the QoL. RESULTS: Of the 75 patients, 57 (76%) answered: (25 males, 32 females); omphalocele (n = 16) gastroschisis (n = 11); median age, 27 (range, 17 to 48) years. With the exception of rheumatoid arthritis (in 7% of patients), the prevalence of acquired diseases in CAWD patients was comparable with that of the general population; 50 of 57 (88%) considered their health good. The most frequent causes of morbidity were disorders in the abdominal scar in 21 (37%) patients, and functional gastrointestinal disorders in 29 (51%) of patients. Low self-esteem was found in 12% of patients, but the QoL and educational level of CAWD patients were not different from that of the general population. CONCLUSIONS: In CAWD patients the morbidity from acquired disorders is similar to morbidity in the general population. Disorders with the abdominal scar and various functional gastrointestinal disorders are common, but they rarely cause serious problems. The majority of CAWD patients have a quality of life not different from the general population.
15040007 CXCL12 chemokine up-regulates bone resorption and MMP-9 release by human osteoclasts: CXCL 2004 May Chemokines are involved in a number of inflammatory pathologies and some of them show a pivotal role in the modulation of osteoclast development. Therefore, we evaluated the role of CXCL12 chemokine on osteoclast differentiation and function and we analyzed its expression on synovial and bone tissue biopsies from rheumatoid arthritis (RA) patients. Osteoclasts were obtained by 7 days in vitro differentiation with RANKL and M-CSF of CD11b positive cells in the presence or absence of CXCL12. The total number of osteoclast was analyzed by Tartrate-resistant acid phosphatase (TRAP)-staining and bone-resorbing activity was assessed by pit assay. MMP-9 and TIMP-1 release was evaluated by ELISA assay. CXCL12 expression on biopsies from RA patients was analyzed by immunohistochemistry. Osteoclasts obtained in the presence of CXCL12 at 10 nM concentration displayed a highly significant increase in bone-resorbing activity as measured by pit resorption assay, while the total number of mature osteoclasts was not affected. The increased resorption is associated with overexpression of MMP-9. Immunostaining for CXCL12 on synovial and bone tissue biopsies from both rheumatoid arthritis (RA) and osteoarthritis (OA) samples revealed a strong increase in the expression levels under inflammatory conditions. CXCL12 chemokine showed a clear activating role on mature osteoclast by inducing bone-resorbing activity and specific MMP-9 enzymatic release. Moreover, since bone and synovial biopsies from RA patients showed an elevated CXCL12 expression, these findings may provide useful tools for achieving a full elucidation of the complex network that regulates osteoclast function in course of inflammatory diseases.
12934467 [A search for genes of predisposition to rheumatoid arthritis]. 2003 Rheumatoid arthritis belongs to the group of autoimmune multifactor diseases with an essential involvement of genetic components in its genesis. The HLA DRB1* polymorphism was studied in 68 RA patients and in their 75 healthy relatives. 135 blood donors, who were tested at the Institute for Immunology of the Ministry of Health, Russian Federation, Moscow, were in the control group. The carrier-state of the HLA DRB1* 04 gene contributes to a higher probability of RA onset by 8.5 times, while the presence, in genotype, of genes HLADRB1* 02, 05, 06 reduces the risk of RA by 2.1, 2.3 and 7.2 times, respectively. Allele *0401 is encountered reliably more often in RA patients versus healthy controls. Within a sample of patients with familial RA, 43.9% turned out to be the carriers with various combinations of two alleles of genes coding the conservative amine acids of sequences QKRAA or QRRAA, which were named "shared epitope" (SE), versus 5.1% among the controls. The presence of homozygous "SE genotypes" among the RA patients contributed to a higher risk of morbidity by 5.8 times, while the carrier state of haplotypes with "duel SE positivity" enhanced the risk of morbidity by 17.8 times mainly due to the 01/0401 halotype. The RA linkage with two intragenic DNA markers, i.e. with the polymorphous micro-satellite replication of gene TCRA (CA)n and with the point-type changeability (localized in the coding area of the second variable region of V2 TCRD gene), was analyzed. The maximal possible value of the lod-point for (CA)n, i.e. replication of TCRA gene, was equal to +1.30 in males under the condition of zero recombination frequency, and to 16% of frequency recombination in females. The maximal possible value of the lod-point for the point-type changeability of gene TCRD was equal to +0.70 in males under the conditions of zero frequency recombination and to 40% of frequency recombination in females. The maximal lod-point value amounting to +1.20 in males and females in an identical frequency recombination of 5% was found on the basis of a three-point analysis of the linkage between RA and two intragenic markers from gene clusters coding the alpha- and beta-chains of T-cellular receptors. Therefore, our familial data are indicative of the opportunity of localizing the gene predisposed to RA is at a distance of 5 cM, in the direction of the telomere, from the locus of the examined (CA)n, i.e. replication of gene TCRA.
12921510 Infliximab treatment of rheumatoid arthritis and Crohn's disease. 2003 Sep OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, and pharmacoeconomic impact of infliximab in the treatment of Crohn's disease (CD) and rheumatoid arthritis (RA). DATA SOURCES: MEDLINE and Pre-MEDLINE (1966-June 2002) and manufacturer prescribing literature were employed to find English-language articles on infliximab. Additional studies and abstracts were identified from the bibliographies of reviewed literature and conference proceedings. STUDY SELECTION/DATA EXTRACTION: All articles identified from data sources were evaluated, and all information deemed relevant was included in this review. Information regarding basic pharmacology was collected from studies in animals. Pharmacokinetic data were collected from human trials. Safety data were extracted from clinical trials and postmarketing surveillance. Priority was given to randomized, double-blind, placebo-controlled studies for the assessment of efficacy. All available economic evaluations were included. DATA SYNTHESIS: Infliximab is a new monoclonal antibody that appears to work by a unique mechanism: inhibiting the action of tumor necrosis factor-alpha (TNF-alpha). Infliximab is administered by intravenous infusion. In clinical trials in CD, infliximab significantly decreased the CD activity index compared with placebo in treatment-resistant disease and significantly reduced the number of draining fistulas in fistulizing disease. In RA, when infliximab was added to methotrexate (MTX), it resulted in a significant improvement in most disease outcome measures when compared with MTX plus placebo. Few major adverse effects were reported in the clinical trials; however, serious adverse events, including malignancy and demyelination, have been reported in postmarketing surveillance. Also, increased susceptibility to infections (including tuberculosis) has been reported. CONCLUSIONS: Infliximab is an effective new agent for the treatment of CD and RA. Its apparent unique mechanism of action makes infliximab an important addition to therapy. Caution should be exercised when considering infliximab for individuals who have chronic or recurrent infections, mild congestive heart failure (New York Heart Association [NYHA] class I/II), nervous system disorders, or live or have lived in an area endemic for histoplasmosis. Infliximab is contraindicated for patients with a clinically important, active infection, moderate to severe congestive heart failure (NYHA class III/IV), or an allergy to mouse proteins or any of the ingredients in infliximab. Further long-term efficacy, safety, and economic data on infliximab are required. Also, for the treatment of RA, the burden of administering infliximab (as a 2-hour supervised infusion) has to be considered when choosing among anti-TNF-alpha medication (as the other 2 approved agents, etanercept and adalimumab, can be self-administered by subcutaneous injection).
12517948 IL-6 and matrix metalloproteinase-1 are regulated by the cyclin-dependent kinase inhibitor 2003 Jan 15 During the pathogenesis of rheumatoid arthritis (RA), the synovial fibroblasts increase in number and produce proinflammatory cytokines and matrix metalloproteinases (MMPs) that function to promote inflammation and joint destruction. Recent investigations have suggested that cell cycle activity and inflammation may be linked. However, little is known about the mechanisms responsible for the coordinate regulation of proliferation and the expression of proinflammatory molecules in RA synovial fibroblasts. Here, we demonstrate a 50 +/- 10% decrease in the expression of p21, a cell cycle inhibitor, in the synovial fibroblast population from RA compared with osteoarthritis (OA) synovial tissue. Moreover, p21 positivity in the synovial fibroblasts inversely correlates with medium synovial lining thickness (r = -0.76; p < 0.02). The expression of p21 is also reduced in isolated RA synovial fibroblasts compared with OA synovial fibroblasts. Adenovirus-mediated delivery of p21 (Ad-p21) arrests both RA and OA synovial fibroblasts in the G(0)/G(1) phase of the cell cycle without inducing cytotoxicity. However, the spontaneous production of IL-6 and MMP-1 is suppressed only in the Ad-p21-infected RA synovial fibroblasts, indicating a novel role for p21 in RA. Analyses of p21-deficient mouse synovial fibroblasts reveal a 100-fold increase in IL-6 protein and enhance IL-6 and MMP-3 mRNA. Restoration of p21, but not overexpression of Rb, which also induces G(0)/G(1) cell cycle arrest, decreases IL-6 synthesis in p21-null synovial fibroblasts. Furthermore, in RA synovial fibroblasts the ectopic expression of p21 reduces activation of the AP-1 transcription factor. Additionally, p21-null synovial fibroblasts display enhanced activation of AP-1 compared with wild-type synovial fibroblasts. These data suggest that alterations in p21 expression may activate AP-1 leading to enhanced proinflammatory cytokine and MMP production and development of autoimmune disease.
15166329 Rheumatoid arthritis-related lung diseases: CT findings. 2004 Jul PURPOSE: To evaluate computed tomographic (CT) findings of rheumatoid arthritis-related lung disease and categorize findings according to pathologic features. MATERIALS AND METHODS: CT scans obtained in 63 patients (27 men, 36 women; mean age, 61.7 years +/- 11.2 [SD]; range, 28-81 years) with rheumatoid arthritis were assessed. Mean duration of disease was 7.6 years +/- 9.2. Lung parenchymal abnormalities that included airspace consolidation, ground-glass opacity (GGO), reticulation, honeycombing, nodules, bronchiectasis, and air trapping were assessed retrospectively by two chest radiologists. Final decision was reached with consensus of these radiologists and a third radiologist. Patients were classified according to the predominant CT pattern. One of the chest radiologists and a pulmonary pathologist compared CT findings with pathologic findings in 17 patients. Interobserver agreement between the first two radiologists was assessed. Correlation between CT finding extent score and pulmonary function test results was estimated with Spearman rank correlation coefficient. RESULTS: GGO (57 [90%] patients) and reticulation (62 [98%] patients) were the most common CT features. Four major CT patterns were identified: usual interstitial pneumonia (n = 26), nonspecific interstitial pneumonia (n = 19), bronchiolitis (n = 11), and organizing pneumonia (n = 5). Usual interstitial pneumonia and nonspecific interstitial pneumonia CT patterns overlapped; GGO was more extensive in patients with nonspecific interstitial pneumonia CT pattern (P =.028). In 17 patients who underwent biopsy, CT findings reflected pathologic findings. Exceptions were two patients classified with usual interstitial pneumonia at CT but with nonspecific interstitial pneumonia at pathologic analysis; one patient, with nonspecific interstitial pneumonia at CT but desquamative interstitial pneumonia at pathologic analysis; and one patient, with lymphoid interstitial pneumonia at CT but nonspecific interstitial pneumonia at pathologic analysis. CONCLUSION: Rheumatoid arthritis is associated with four CT patterns: usual interstitial pneumonia, nonspecific interstitial pneumonia, bronchiolitis, and organizing pneumonia. The most common CT features of rheumatoid arthritis-related lung disease were GGO and reticulation.
12428227 Migration of CX3CR1-positive T cells producing type 1 cytokines and cytotoxic molecules in 2002 Nov OBJECTIVE: Rheumatoid arthritis (RA) is characterized by chronic inflammation of multiple joints. Large numbers of T cells, which produce type 1 cytokines, infiltrate into RA synovium. Chemokines and chemokine receptors are considered to contribute to the T cell infiltration. In this study, we examined the role of CX3CL1/fractalkine and its receptor CX3C chemokine receptor 1 (CX3CR1) in the T cell migration into RA synovium. METHODS: Using flow cytometry, immunohistochemistry, and reverse transcription-polymerase chain reaction, we analyzed CX3CR1 expression by peripheral blood and synovial T cells, and CX3CL1 expression in synovium from patients with RA. Cytokine and cytotoxic molecule expression by CX3CR1-positive T cells was analyzed by flow cytometry. RESULTS: CX3CR1 expression by peripheral CD4+ and CD8+ T cells was up-regulated in RA patients. The peripheral CD4+ and CD8+ T cells expressing CX3CR1 predominantly produced interferon-gamma and tumor necrosis factor alpha, and expressed cytotoxic molecules such as granzyme A and perforin. Furthermore, CX3CR1+,CD3+ T cells infiltrated into RA synovium. CX3CL1, the unique ligand of CX3CR1, was expressed by endothelial cells and synoviocytes in RA synovium, but not in osteoarthritis synovium. CONCLUSION: Our findings suggest that the interactions of CX3CL1 and CX3CR1 might contribute to the accumulation of CX3CR1+ T cells expressing type 1 cytokines and possessing cytotoxic granules in RA synovium.