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

ID PMID Title PublicationDate abstract
14760791 Effect of repeated infliximab therapy on serum matrix metalloproteinases and tissue inhibi 2004 Feb OBJECTIVE: Matrix metalloproteinases (MMP) are involved in the articular tissue destruction processes in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of multiple infusions of infliximab, a chimeric anti-tumor necrosis factor-a (anti-TNF-a) antibody, on concentrations of serum MMP and tissue inhibitors of metalloproteinases (TIMP) in patients with active RA. METHODS: Patients with RA were scheduled to receive 9 infusions of infliximab (3 mg/kg) at Weeks 0, 2, 6, and every 8 weeks thereafter. The therapy was combined with methotrexate (MTX) (7.5-20 mg/week). Serum concentrations of interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), gelatinase B (MMP-9), TIMP-1, and TIMP-2 were measured by ELISA prior to infusion at Weeks 0, 2, 6, 14, 38, and 62. RESULTS: The initial infusion of infliximab downregulated serum levels of MMP-1 (p < 0.001), MMP-3 (p < 0.001), MMP-9 (p < 0.001), TIMP-1 (p < 0.01), and TIMP-2 (p < 0.05). The second drug administration caused even more remarkable reduction of measured MMP (p < 0.001 in all cases) but not of TIMP levels. These changes were accompanied by decreased ratios of measured MMP to TIMP. Further infliximab therapy also significantly suppressed serum MMP levels, but was less effective. Before the first infliximab infusion serum concentrations of MMP and TIMP correlated with markers of RA activity such as the Disease Activity Score and C-reactive protein levels. After further drug administrations such associations, although less significant, were also noted. CONCLUSION: Anti-TNF-a antibody therapy combined with MTX resulted in rapid clinical improvement and reduced serum MMP concentrations in patients with RA. Further infusions of infliximab maintained the decrease of MMP, although to a lesser extent than the first and second doses.
14575258 Complete arcuate foramen precluding C1 lateral mass screw fixation in a patient with rheum 2003 Case report of a complete arcuate foramen in a human atlas vertebra inhibiting the placement of lateral mass screw instrumentation at C1. Our objective is to report the presentation of the case, the operative considerations, and the management for this anatomic variation. The groove for the vertebral artery on the posterolateral surface of the atlas (C1) varies in size and depth from a slight impression to a clear sulcus. With anomalous ossification the sulcus can be bridged which results in a posterolateral tunnel within the posterior arch of the atlas. With increasing rates of screw fixation instrumentation that include the atlas, it is of paramount importance to know the location and course of the vertebral artery in relation to the planned route of instrumentation. The patient underwent a posterolateral fusion from C1 to C4 using autogenous iliac crest bone graft. Internal fixation from C2 to C4 was obtained using lateral mass screw instrumentation. After the vertebral artery was identified passing through the posterior arch of C1, sublaminar wires were utilized for fixation from C1 to C2. The patient responded well to surgical intervention without complications. Abnormal vertebral artery coursing through a posterolateral tunnel in the posterior arch of C1 has been described and its incidence has a range from 1.14% to 18%. When this variant is present, lateral mass screw fixation at C1 may be contra-indicated. We recommend close scrutiny of preoperative radiographs to avoid the possibility of endangering the vertebral artery when this situation exists.
12848989 Accelerated atherogenesis in autoimmune rheumatic diseases. 2002 Dec The observation that systemic inflammatory rheumatic diseases such as rheumatoid arthritis (RA) are associated with a significantly increased rate of cardiovascular disease, which often occurs at a younger age than in the normal population, is particularly important given the increasing interest in the role of inflammation in atherogenesis in the general population. This review examines the accumulating evidence for accelerated atherogenesis of RA and updates the hypothesis that vasculitis plays a major role in this. Endothelial dysfunction (ECD), widely regarded as initial lesion in atherogenesis, has been shown to occur commonly in primary vasculitis. This ECD is a diffuse event, demonstrable in more than one vascular bed. It is not simply due to scarring in the vessel wall, related to the focal inflammation of the underlying vasculitis, since it may be reversed by suppression of the immune inflammation. However, the mechanisms for this ECD differ from that of the primary vasculitis. Preliminary evidence suggests that inflammatory mediators such as CRP, TNF, or sphingolipids may be involved. The diffuse ECD of vasculitis may have important consequences for both the progression of the primary disease and for cardiovascular events. A model for the role of vasculitis-induced ECD in the accelerated atherogenesis of rheumatic diseases is presented. These concepts are discussed together with the messages they suggest for 'idiopathic' atherosclerosis in the general population.
15302335 Stem cell transplantation for autoimmune disorders. Preclinical experiments. 2004 Jun The clinical use of autologous stem cell transplants for the treatment of refractory severe autoimmune diseases was preceded by convincing proof of its underlying principle in animal models. The various categories of experimental autoimmune disease in laboratory rodents are briefly described here, and the rationale that was used in the selection of suitable experimental autoimmune diseases for translational research is explained. The two models that provided the bulk of the data needed for designing the initial clinical treatment protocols were adjuvant arthritis (AA) and experimental allergic encephalomyelitis (EAE), which were both induced in Buffalo rats. In this strain, AA is manifested as a chronic, progressive, systemic polyarthritis and EAE as a chronic, remitting/relapsing form of encephalomyelitis resembling multiple sclerosis. Both diseases can be cured with autologous stem cell transplantation provided that adequate conditioning is given and that the disease has not yet progressed to the stage of 'scarring'. It is basically the inflammatory stages that respond well to this therapy. The success of treatment depends on how completely the autoantigen-specific activated T-lymphocytes and memory cells are eradicated. Because of a lack of information on the nature of the autoantigens involved in human disease and on the size of those cell populations in the animal models as well as in humans, this aspect of translation is difficult. The experiments have, however, provided important guidelines. High-dose conditioning regimens yield better results than low-dose conditioning, certain conditioning agents perform better than others, and care should be taken not to reintroduce too many T-cells with the autologous graft. The clinical results obtained so far indicate a high predictive power of these two animal models, which are therefore recommended strongly for additional preclinical studies.
12173297 Tumor necrosis factor-alpha blockade: a novel therapy for rheumatic disease. 2002 Jun Overproduction of tumor necrosis factor-alpha (TNF) plays a key role in the pathogenesis of rheumatoid arthritis (RA) and other chronic inflammatory diseases. In RA, excessive production of TNF-alpha can drive synovial inflammation and proliferation as well as degradation of articular cartilage and bone. The importance of TNF-alpha in these mechanisms is supported by the results of clinical trials. In these studies, treatment with etanercept and infliximab, two recently approved TNF-alpha inhibitors, has been shown to significantly decrease the signs and symptoms of joint inflammation and slow the progression of radiological joint damage. Although TNF-alpha inhibitors have had acceptable toxicity in clinical trials, commercial use of these agents has produced growing concerns about the potential risk for opportunistic infections, most notably the reactivation of latent tuberculosis. The TNF-alpha inhibitors stand as a powerful example of the therapeutic potential of a targeted biological agent. Longer-term clinical experience with these cytokine antagonists will illuminate their optimal use in RA and other rheumatic diseases.
12777638 Evaluation of technetium-99m-ciprofloxacin (Infecton) for detecting sites of inflammation 2003 Oct OBJECTIVE: To study the frequency of technetium-99m-positive ciprofloxacin scans (Infecton scintigraphy) thought to be specific for bacterial DNA in patients with arthritis and to assess the clinical relevance of positive scans. METHODS: Four groups of adults with arthritis were studied. Group 1: 53 patients with inflammatory arthritis, 36 with spondylarthropathy (SpA) and 17 with rheumatoid arthritis (RA); group 2: five patients with crystal arthropathy; group 3: those patients with osteoarthritis (OA) of the knee, wrist or spine; and group 4: 28 patients who had no arthritis but were being investigated for renal infection. Patients were injected with 10 mCi 99Tcm-ciprofloxacin with isotope uptake analysis at 4 h. Clinically swollen joints were assessed by a rheumatologist and the positive scans assessed by a physician in nuclear medicine. RESULTS: Increased Infecton uptake was noted in inflamed joints independent of the pathology. It was seen in 10 of 17 patients with SpA, 12 of 17 with RA, all five with crystal arthropathy, eight with knee OA, two with wrist OA, none with spinal OA and none in uninflamed joints. A close correlation between clinically swollen joints and articular Infecton uptake was noted (P = 0.0003), with the uptake being in the distribution of the synovial perimeter. Additional uptake was noted in the abdomen (n = 9) and pulmonary region (n = 2) of SpA patients. CONCLUSION: The Infecton scan is not specific for infection but may be a reliable procedure for identifying the presence and distribution of the inflammation within joints. It has the potential for monitoring the response of inflamed joints to treatment.
14586628 High migration rate of two types of threaded acetabular cups. 2004 Jan INTRODUCTION: Survivorship analysis was performed on 479 Link V-type threaded cups and on 110 modified V-type Bad Bramstedt cups (a modification of the Link V-type cup since 1993 with a smaller primary coil) to evaluate the effect of the modifications. MATERIALS AND METHODS: Indication for hip arthroplasty with a Link V-type cup was an inflammatory arthritis in 310 patients, osteoarthritis in 138 patients and dysplastic hip joints in 31 patients. The average follow-up was 8.6+/-3.2 (range 3.0-15.2) years. The 110 modified V-type Bad Bramstedt cups had a mean follow-up period of 4.5+/-0.7 (range 3.0-5.9) years, including 49 with inflammatory arthritis, 49 with osteoarthritis and 12 with dysplastic hip joints. To evaluate the migration rate and radiolucent lines, radiographical examination according to the method of Nunn et al. and Delee and Charnley was performed on 264 Link V-type cups with a mean follow-up period of 8.2+/-2.7 years and 59 modified V-type Bad Bramstedt cups with a mean follow-up period of 4.6+/-0.7 years. Relevant parameters influencing cup migration were analysed. RESULTS: The cumulative survival rate of the former Link V-type acetabular cup was 94.5% after 5 years, 88.1% after 10 years and 70.2% after 15 years. The Bad Bramstedt cup showed a 5-year survivorship rate of 97.9%. Migration of more than 3 mm or tilting of the cup greater than 5 degrees was found in 73% of the former type and in 39% of the modified cup. Radiolucent lines greater than 2 mm and detectable in two zones appeared in 6.4% of the former Link V-type and in 1.7% of the Bad Bramstedt cup design. Among the influencing factors analysed, length of follow-up and primary cup positioning showed a significant correlation to cup migration. CONCLUSION: The modification of the Link V-type cup showed no satisfactory improvement in cup migration. Therefore, both threaded cups were abandoned in favour of cementless press-fit cups.
15248206 Diagnostic value of magnetic resonance imaging of the forefeet in early rheumatoid arthrit 2004 Jul OBJECTIVE: To investigate the diagnostic role of magnetic resonance imaging (MRI) of the forefeet in patients with early rheumatoid arthritis (RA) in whom findings on MR images of the hands are normal and conventional radiographs of the hands and feet do not show erosions. METHODS: The study group comprised 25 patients with early RA (disease duration of <12 months) in whom erosions were not demonstrated on conventional radiographs of the hands and feet. These patients underwent MRI of the clinically dominant hand to detect signs of arthritis. If results of MRI of the hand were normal according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA-MRI scoring system (RAMRIS), MRI of the dominant forefoot was performed. The MRI protocol comprised coronal and sagittal T1-weighted spin-echo (before and after administration of contrast medium), coronal fat-suppressed short tau inversion recovery sequences, coronal and sagittal T2-weighted turbo spin-echo sequences, and axial fat-suppressed T1-weighted spin-echo sequences after administration of contrast medium. MRI of the forefeet was analyzed on the basis of a modified RAMRIS. RESULTS: MRI revealed pathologic findings in the hands of 15 of 25 patients (edema in 9 patients, synovitis in 12, erosions in 6, defects in 3). In 10 patients with a mean disease duration of 9.4 weeks, hand MRI scans were normal according to RAMRIS. Four of these 10 patients had tenosynovitis of the finger flexor tendons (there was no OMERACT criterion for tenosynovitis). RAMRIS analysis of the corresponding MRI scans of the forefeet of these patients revealed signs of edema in 7 patients, synovitis in all 10 patients (at the third metatarsophalangeal [MTP] joint in 7, at the fourth MTP joint in 6, at the first MTP joint in 4, and at the fifth MTP joint in 2 patients), tenosynovitis of the foot flexor tendons in 2 patients, erosions at the second and third MTP joints in 1 patient, and a single defect at the first MTP joint in 1 patient. CONCLUSION: RAMRIS analysis of MRI scans of the forefeet detected synovitis and bone edema in patients with early RA in whom MRI of the finger joints was normal. MRI of the forefeet contributes an additional tool aimed at earlier and more accurate diagnosis and thus might allow an earlier decision to start appropriate medication in patients with early RA.
12228155 Power Doppler sonography in the assessment of synovial tissue of the knee joint in rheumat 2002 Oct OBJECTIVE: To investigate the intra-articular vascularisation of the synovial pannus in the knee of patients with rheumatoid arthritis (RA) with power Doppler ultrasonography (PDS) and an echo contrast agent and correlate the area under the time-intensity curves with the clinical findings and laboratory measures of disease activity. METHOD: Forty two patients with RA (31 women, 11 men) with history and signs of knee arthritis, classified according to a modified index of synovitis activity (active, moderately active, and inactive), were studied. Clinical and functional assessment (number of swollen joints, intensity of pain, general health-visual analogue scale, disability index-Health Assessment Questionnaire, Ritchie articular index) and a laboratory evaluation were made on all patients. Disease activity was evaluated using the disease activity score (DAS) and the chronic arthritis systemic index (CASI) for each patient. All patients were examined with conventional ultrasonography and PDS before injection of intravenous ultrasound contrast agent (Levovist). The quantitative estimation of the vascularisation of the synovial membrane was performed with time-intensity curves and calculation of the area under the curves. RESULTS: The mean (SD) value of the area underlying time-intensity curves was 216.2 (33.4) in patients with active synovitis, 186.8 (25.8) in patients with moderately active synovitis, and 169.6 (20.6) in those with inactive synovitis. The mean value of the areas differed significantly between the patients with active and those with inactive synovitis (p<0.01). The mean value of the area under the curve of the entire group was weakly correlated with the number of swollen joints (p=0.038), but a strong correlation was found with composite indexes of disease activity such as the DAS (p=0.006) and CASI (p=0.01). No correlation was found with age, disease duration, and other laboratory and clinical variables. CONCLUSION: PDS may be a valuable tool to detect fractional vascular volume and to assist clinicians in distinguishing between inflammatory and non-inflammatory pannus. The transit of microbubbles of ultrasound contrast across a tissue can be used to estimate haemodynamic alterations and may have a role in assessing synovial activity and the therapeutic response to treatment of synovitis of the knee joint.
12843855 [Lichenoid drug reaction to leflunomide]. 2003 Apr INTRODUCTION: Leflunomide (Arava) is an immunomodulator, recently introduced for systemic treatment of rheumatoid arthritis. We report the first case of lichenoid drug reaction due to this drug. CASE REPORT: A sixty-four year-old woman received leflunomide for rheumatoid arthritis. Two months after initiation of treatment, pruritus and lichenoid papules appeared on her hands and subsequently on her arms and her trunk, with a few bullous lesions. A skin biopsy was evocative for the diagnosis of drug induced lichenoid eruption. The treatment was stopped, and a wash out with colestyramine and topical corticotherapy resulted in dramatic improvement. No relapse was observed. Two months later, patch-tests with leflunomide diluted to 30 p. 100 in white petrolatum were negative. DISCUSSION: Side effects of leflunomide are frequent, generally benign for the cutaneous features. In our case, the delay, clinical and histological aspect and improvement on withdrawal of the drug emphasize the imputability of leflunomide. Few cases have been reported with others immunomodulators.
12226061 Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis 2002 Sep Treatment options for patients with pulmonary fibrosis associated with rheumatoid disease are limited. We report a case of a 71-year-old man with a 3-year history of seropositive rheumatoid arthritis (RA) referred to the pulmonary clinic because of progressive pulmonary symptoms associated with radiographic fibrosis that was progressive in spite of corticosteroid treatment. In an attempt to control his articular symptoms and alter the course of his pulmonary fibrosis, treatment with IV infusion of the tumor necrosis factor (TNF)-alpha inhibitor infliximab was initiated. Following 1 year of therapy with this agent, the patient reported sustained improvement in dyspnea, cough, and exercise tolerance, in addition to improvement in joint symptoms. Stabilization of pulmonary function was indicated by repeat pulmonary function test findings. This report suggests that inhibition of TNF-alpha may be of significant benefit to patients with fibrosing lung conditions in the setting of RA.
12428235 Stratification of pedigrees multiplex for systemic lupus erythematosus and for self-report 2002 Nov OBJECTIVE: Arthritis is a common manifestation in systemic lupus erythematosus (SLE), appearing in approximately 85% of patients. Often, the polyarthritis at presentation of SLE cannot be distinguished from rheumatoid arthritis (RA) by physical examination or history. Indeed, physicians initially tell many SLE patients that they have RA (one source of "self-reported RA"), only to have SLE established later. In addition, RA aggregates in families with an SLE proband. We predicted that pedigrees multiplex for both SLE and for self-reported RA would better isolate particular genetic effects. If this proved to be true, we would then use the increased genetic homogeneity to more easily reveal genetic linkage. METHODS: From a collection of 160 pedigrees multiplex for SLE, we selected 36 pedigrees that also contained >or=2 members with self-reported RA (19 pedigrees were African American, 14 were European American, and 3 were of other ethnic origin). Data from a genome scan of 307 microsatellite markers were evaluated for SLE linkage by contemporary genetic epidemiologic techniques. RESULTS: The most significant evidence of linkage to SLE was obtained at 5p15.3 in the European American pedigrees by both parametric (logarithm of odds [LOD] score 6.2, P = 9.3 x 10(-8)) and nonparametric (LOD score 6.9, P = 1.7 x 10(-8)) methods. The best-fitting model for this putative SLE gene in this region was a recessive gene with a population frequency of 5% and with 50% penetrance in females and 15% penetrance in males at virtually 100% homogeneity. CONCLUSION: For a genetically complex disease phenotype, an unusually powerful linkage has been found with SLE at 5p15.3 in European American pedigrees multiplex for SLE and for self-reported RA. This result predicts the presence of a gene at the top of chromosome 5 in this subset of patients that is important for the pathogenesis of SLE.
15088291 Identification of wrist and metacarpophalangeal joint erosions using a portable magnetic r 2004 Apr OBJECTIVE: To compare magnetic resonance (MR) images obtained using a portable MR system to radiographs for identifying bone erosions in the wrists and metacarpophalangeal (MCP) joints of patients with inflammatory arthropathy. METHODS: MR imaging and radiographs were performed in wrists (n = 227) and 2nd and 3rd MCP (n = 188) of 132 patients with inflammatory arthritis to identify erosions. MR imaging was performed using a portable MR system. Findings per body location and per patient were calculated and compared. Additionally, intraobserver and interobserver reliabilities were calculated. RESULTS: MR imaging identified bony erosions in 125 (95%) patients and in 315 (78%) body locations. By comparison, radiographs identified erosions in 78 (59%; p < 0.05) patients and in 156 (39%; p < 0.05) body locations. Intraobserver reliability (K = 0.564) and interobserver reliability (K = 0.429) exhibited moderate agreement, with reader agreement in 80% of the joints scored. CONCLUSION: There was superior sensitivity to bone damage using the portable MR system compared to radiographs of the wrists and MCP joints, suggesting that this scanner is extremely promising for assessment of inflammatory arthritis.
11845012 Epidemiology of psoriatic arthritis. 2002 Mar Research into psoriatic arthritis continues to be hampered by the lack of a validated case-definition. There may be progress toward consensus with a new data-derived diagnostic classification criteria set recently reported and a current international project aiming to firmly validate criteria. Statistical techniques such as latent class analysis may permit a comparison of the accuracy of competing criteria sets, in the absence of a gold standard for diagnosis. Genetic studies are inconclusive, but ethnic differences in disease expression suggest a definite genetic role. Recent community-based research suggests an incidence rate of about 6/100,000 per annum, and a prevalence of about 1/1000. Clinic-based disease may be associated with increased mortality, whereas community based disease is not. The development of internationally accepted criteria for the diagnosis of psoriatic arthritis will be a major impetus towards research into this complex disease.
11999339 Monoclonal autoantibodies from patients with autoimmune diseases: specificity, affinity an 2002 Mar Serum autoantibodies produce typical immunofluorescence staining patterns on HEp-2 cells, which are frequently used for diagnostic purposes. These include antibodies recognizing cytoskeletal and nuclear epitopes. The detailed analysis of human monoclonal antibodies (MAbs) should help to understand which antigens or autoantigens were involved in the generation of these immune responses. Here, three MAbs are described staining HEp-2 cells in a characteristic pattern. They were derived from peripheral blood B cells of two patients with rheumatic diseases (rheumatoid arthritis and relapsing polychondritis). Their binding reactivities were characterized in detail in several assay systems and their affinities measured. Although the antibodies differed in their fine specificity and crossreactivity, all three MAbs (2 IgM, 1 IgA) bound to purified cytoskeletal antigens (desmin) and, in addition, to cartilage antigens (human collagen type II, proteoglycans). The binding to HEp-2 cells could be inhibited specifically with soluble antigens as shown by intracellular flow cytometry. The affinities for both groups of antigens were relatively high (examples: K(D) (desmin) = 0.1 x 10(-7) M; K(D) (collagen) = 3.5 x 10(-7) M). Two of the MAbs also bound to heat-shock protein 60 (HSP60) derived from Mycobacterium tuberculosis. The results prove that antibodies and B cells with reactivity to both intracellular cytoskeletal and nuclear antigens and exogenous antigens (e. g. HSP60) exist in patients with rheumatic diseases. Similar to an animal model such human B cells may be induced by the exogenous antigen (HSP60) and crossreact with local auto-antigens related to the disease (cartilage). In this way they might contribute to pathogenic processes. Due to their additional crossreactivity with intracellular cytoskeletal and nuclear antigens, these antibodies simultaneously can be detected in the HEp-2 immunofluorescence assay.
12793199 The role of HLA-DRB1*04 alleles and their association with HLA-DQB genes in genetic suscep 2003 We investigated the HLA-DRB, and DQB polymorphism and haplotypes in RA subjects of Hungarian origin by PCR typing using sequence-specific primers. Molecular subtyping of HLA-DRB1*04 alleles in RA patients showed strongest association with highest relative risk with DRB1*0404. A significantly decreased frequency of DRB1*0403 was observed in patients compared to controls. A significant number of patients carried DR4 haplotypes on DQB1*0302 (54%) relative to DQB1*0301 which was present on 36% of the haplotypes. When compared to controls, the frequency was higher in the latter allele only. Few unique DRB-DQB haplotypes were observed in Hungarian RA patients. In spite of the fact, that the Hungarian population has been isolated linguistically over centuries, a considerable racial admixture has occurred following immigration and invasions, thus the present study confirms in Hungarian patients with RA, previous findings for RA and HLA in European countries.
12598827 Recommendations for the prevention and management of tuberculosis in patients taking infli 2002 Nov An unusually large number of cases of tuberculosis, often with miliary or widespread dissemination, has been reported in patients taking infliximab for rheumatoid arthritis or Crohn's disease. Recommendations have been issued in France regarding the definition of high-risk patients, the screening methods to be used in these patients, and possible prophylactic treatments. The present update is also intended to help physicians manage tuberculosis occurring before or during infliximab therapy.
12608021 [Human endogenous retroviruses and disease?]. 2003 Feb 3 Endogenous retroviruses represent sequences descended from ancient virus infections integrated in the host genome. They participate in processes, such as speciation, recombination, ontogenesis, and regulation of tissue specificity and gene expression. It has been suggested in recent years that human endogenous retroviruses may play a role in certain types of cancer and autoimmune diseases. Human endogenous retroviruses represent both putative susceptibility genes and putative pathogenic viruses in diseases like systemic lupus erythematosus, Sjögren's disease, rheumatoid arthritis, and possibly type 1 diabetes. Multiple sclerosis is specifically associated with expression of human endogenous retroviruses as virions. It is not yet known if the human endogenous retroviruses also represent causal factors, but several pathogenic mechanisms are possible.
11801687 In vivo imaging of NF-kappa B activity. 2002 Feb 1 A wide range of human disorders involves inappropriate regulation of NF-kappaB, including cancers and numerous inflammatory conditions. Toward our goal to define mechanisms through which NF-kappaB leads to the development of disease, we have developed transgenic mice that express luciferase under the control of NF-kappaB, enabling real-time in vivo imaging of NF-kappaB activity in intact animals. We show that in the absence of extrinsic stimulation, strong luminescence is evident in lymph nodes in the neck region, thymus, and Peyer's patches. Treating mice with TNF-alpha, IL-1alpha, or LPS increased the luminescence in a tissue-specific manner, with the strongest activity observed in skin, lungs, spleen, Peyer's patches, and the wall of the small intestine. Liver, kidney, heart, muscle, and adipose tissue displayed less intense activities. Also, exposure of skin to a low dose of UV radiation increased luminescence in the exposed areas. Furthermore, induction of chronic inflammation resembling rheumatoid arthritis produced strong NF-kappaB activity in the affected joints, as revealed by in vivo imaging. Thus, we have developed a versatile model for monitoring NF-kappaB activation in vivo.
12784382 Most patients receiving routine care for rheumatoid arthritis in 2001 did not meet inclusi 2003 Jun OBJECTIVE: To determine the proportion of 2 cohorts of patients with rheumatoid arthritis (RA) in Nashville, Tennessee, who met 4 common criteria for inclusion in clinical trials: > or = 6 swollen joints, > or = 6 tender joints, erythrocyte sedimentation rate > or = 28 mm/h, and/or morning stiffness > or = 45 min. METHODS: Two cohorts of patients with RA, all of whom had met American Rheumatism Association (ARA) [now American College of Rheumatology (ACR)] criteria for RA at some time, were studied. Cohort L (late) included 146 consecutive patients whose mean disease duration was 14.0 years and who had been under care at a weekly academic rheumatology clinic for a mean of 6.2 years when seen in 1998-2001. Cohort E (early) included 232 patients of 5 private practice rheumatologists whose symptoms began in 1998 or later and whose mean disease duration was 1.8 years when seen in 2001. Patients were reviewed for the 4 inclusion criteria as well as 6 ARA remission criteria. RESULTS: In Cohort L, on a 28 joint count, 42.5% of patients had > or = 6 swollen joints, 25.3% had > or = 6 tender joints, 19.9% had both > or = 6 swollen and > or = 6 tender joints, 25.0% had ESR > or = 28, and 45.9% had morning stiffness > or = 45 min. In Cohort E, on a 42 joint count, 63.4% of patients had > or = 6 swollen joints, 50.4% had > or = 6 tender joints, 38.8% had both > or = 6 swollen and > or = 6 tender joints, 49.3% had ESR > or = 28, and 50.9% had morning stiffness > or = 45 min. Overall, 15.3% of Cohort L and 34.1% of Cohort E patients had > or = 6 swollen and tender joints, as well as an ESR > or = 28 or morning stiffness > or = 45 min. Only 4.1% of Cohort L and no patient in Cohort E met ARA criteria for remission. CONCLUSION: The majority of patients seen in routine care in these 2 cohorts did not meet criteria for inclusion in most contemporary RA clinical trials, including clinical trials sponsored by pharmaceutical companies to introduce new drugs or biological agents. Few of these patients met ARA criteria for remission. Controlled trial data are not available concerning results of treatment with new biological agents or disease modifying antirheumatic drugs in a large proportion, if not a majority, of patients with RA at this time.