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ID PMID Title PublicationDate abstract
17009233 In vitro and in vivo efficacy of a recombinant immunotoxin against folate receptor beta on 2006 Oct OBJECTIVE: To investigate the effects of the recombinant immunotoxin dsFv anti-FRbeta-PE38, which consists of the disulfide-stabilized Fv fragment (dsFv) of the anti-folate receptor beta (anti-FRbeta) antibody and the 38-kd portion of Pseudomonas exotoxin A (PE38), on the activation and proliferation of cells that function in inflammatory and degradative processes in rheumatoid arthritis (RA) synovial tissue. METHODS: The Ig VH-PE38 fusion protein and the Ig VL protein were produced in Escherichia coli, and then joined with a disulfide bond by engineering cysteine residues in the framework regions of these proteins. The effects of dsFv anti-FRbeta-PE38 on the activation and proliferation of cells in RA synovial tissue were investigated by immunohistochemistry; the numbers of cells expressing CD68, vascular cell adhesion molecule 1, angiopoietin 1, CD34, proliferating cell nuclear antigen, and interleukin-6 and the numbers of apoptotic cells were counted in RA synovial tissue engrafted into SCID mice treated or not treated with dsFv anti-FRbeta-PE38. The effects of dsFv anti-FRbeta-PE38 on the generation of osteoclasts from RA adherent synovial mononuclear cells in vitro was investigated by counting the number of resorption pits on dentin slices treated or not treated with dsFv anti-FRbeta-PE38. RESULTS: Administration of dsFv anti-FRbeta-PE38 reduced the numbers of macrophages, activated fibroblast-like cells, endothelial cells, and proliferating cells and increased the numbers of apoptotic cells in RA synovial tissue engrafted into SCID mice. In vitro, the generation of osteoclasts from RA adherent synovial mononuclear cells was largely suppressed by treatment with dsFv anti-FRbeta-PE38. CONCLUSION: Our findings show that dsFv anti-FRbeta-PE38 immunotoxin would be a promising tool for the treatment of RA synovitis, especially when administered intraarticularly.
17369316 Use of quantitative ultrasound scans of the calcaneus to diagnose osteoporosis in patients 2007 Mar BACKGROUND: Patients with rheumatoid arthritis are recognized as being at risk for osteoporosis as a result of the disease process as well as the medication used to treat it. This study was conducted to consider the use of calcaneal scanning with quantitative ultrasound-contact ultrasound bone analysis (CUBA)-to diagnose osteoporosis in patients with rheumatoid arthritis. METHODS: Forty-six patients (11 men and 35 women) with established rheumatoid arthritis underwent dual-energy x-ray absorptiometry (DEXA) of the nondominant wrist and CUBA of the nondominant heel. Sensitivity, specificity, and positive and negative predictive values were used to determine the correlation between osteoporosis as diagnosed by the CUBA heel scan compared with the DEXA wrist scan given that DEXA is widely seen as the gold standard for the diagnosis of osteoporosis. RESULTS: The CUBA heel scan revealed a sensitivity of 90% and a specificity of 44% for a diagnosis of osteoporosis compared with DEXA. The positive predictive value of the CUBA scan was 31%, and the negative predictive value was 94%. Therefore, if normal bone density is found using CUBA, there is 94% certainty this is correct. However, if osteoporosis is diagnosed using CUBA, there is only 31% certainty this is correct. In such instances a secondary scan using a different method (eg, DEXA) would be required. Future work should consider the effect of minor alterations to the equipment or scanning protocol, because this may improve diagnosis. CONCLUSIONS: The CUBA unit could be used as a primary screening device. Given the cost and accessibility issues associated with DEXA, quantitative ultrasound may have a role in screening for osteoporosis in the primary-care setting to determine the most appropriate routes of referral for patients requiring further investigations.
18612925 Patients with rheumatoid arthritis report greater physical functional deterioration in low 2008 Jul OBJECTIVE: To examine the overall magnitude of change in self-reported physical function over a 10-year period in patients with rheumatoid arthritis (RA), and to compare changes in physical function between the lower and upper limbs. METHODS: Self-reported data on physical function were collected from the patients in the Oslo RA register (ORAR) through mail surveys between 1994 and 2004. The change in overall physical function was measured by the Short Form 36 (SF-36), the Modified Health Assessment Questionnaire (MHAQ), and the Arthritis Impact Measurement Scales (AIMS2). The MHAQ and AIMS2 were used to address activities related to lower and upper limb function. The magnitude of changes was expressed as crude and adjusted changes and standardized response means (SRMs). The analyses were adjusted for age, sex, duration of disease, and number of surgical procedures in the lower and upper limbs. RESULTS: A total of 414 patients [323 (78%) females, mean age 54.9 years and median disease duration 11.6 years] were included in these analyses. The overall physical function measured by AIMS2 physical and MHAQ deteriorated during 10 years. The magnitude of change in physical function was generally worse for activities related to lower limbs (SRM for adjusted changes 0.16-0.27) than upper limbs (SRM 0.06-0.08). During the 10-year follow-up period, 231 patients (56%) underwent orthopaedic surgery because of their RA. Findings were consistent after adjusting for surgical procedures. CONCLUSION: Patient-reported lower limb function deteriorated more than upper limb function over a 10-year period in patients with established RA.
17539763 Elbow arthritis. 2007 Patients with elbow arthritis typically present with complaints of pain and stiffness. Rheumatoid arthritis is the most common cause of elbow arthritis, followed by posttraumatic arthritis and primary osteoarthritis. Nonoperative management consisting of oral analgesics, intra-articular steroid injections, physical therapy, and splinting may provide symptomatic relief in the majority of patients. If these modalities fail, operative treatment is guided by the severity of disease as well as several patient-related factors such as age, activity level, and expectations. Total elbow arthroplasty can provide satisfactory results in the majority of patients with significant degeneration of the elbow. However, due to issues regarding prosthesis longevity, this procedure is generally avoided in young active patients. Other operative treatment options for such patients include arthroscopic or open synovectomy, debridement arthroplasty, and interpositional arthroplasty. As all of these operations may provide a satisfactory outcome for the appropriate patient, a thorough preoperative evaluation is essential in choosing the suitable surgical procedure for each individual patient.
16819694 Revision total knee arthroplasty with the total condylar III system: a comparative analysi 2006 Jun BACKGROUND: As revision total knee arthroplasty surgery is becoming more common, it is necessary to evaluate how individual revision prosthesis systems perform in degenerative and inflammatory arthritides. In this study, results of the use of the Total Condylar III (TC III) system in osteoarthritis (55 knees) were compared to results of its use in inflammatory arthritis (16). METHODS: Patients were followed radiographically for 5.9 (3.0-10.2) years and clinically for 3.0 (0.2-6.8) years, using re-revision as the endpoint. RESULTS: At 1 year after revision and at final follow-up, the total Knee Society knee score, function score and range of motion had improved (p < 0.001) with no differences between osteoarthritis and inflammatory arthritis. No knee had definite component loosening, although 23 knees had asymptomatic radiolucent lines. Complications comprised 4 infections, 1 patellar pain syndrome and 1 rupture of the patellar tendon. Using any re-revision of the prosthesis as the endpoint, 5-year survival was 95% and 8-year survival was 94%. INTERPRETATION: Concentration of demanding revision knee arthroplasties to a few hands led to good or excellent knee joint knee score results in four-fifths of the patients, and showed good outcome with the TCIII system. In spite of ligamentous laxity, propensity to develop infections, bone destruction and poor general health, patients with inflammatory arthritis had results similar to those with osteoarthritis.
17911480 Impact of treatment with infliximab on serum cytokine profile of patients with rheumatoid 2007 Sep This article analyzes the serum cytokine profile of a nonrandomized group of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who are destined to be treated with infliximab following failure after failure of different disease-modifiying antirheumatic drugs (DMARDs). Serial serum samples were collected from 11 patients with refractory RA, three with PsA and one with undifferentiated spondyloarthropathy. All were treated with the antitumor necrosis factor (TNF)alpha agent, infliximab, after failing to sustain a clinical remission with conventional DMARDs. Blood samples were obtained at different phases of their therapy. Serum levels of tumor necrosis factor (TNF)alpha, interferon (IFN)gamma, interleukin (IL)-1beta, IL-6, sIL-2R, IL-10, and IL-1 receptor antagonist (IL-1RA) were determined by commercial ELISA kits. Interestingly, only eight of the 11 patients with RA had elevated TNFalpha serum levels (at least once in their serial measurements). Only one was unresponsive to therapy and despite anti-TNFalpha therapy her serum TNFalpha levels remained extremely high. Two RA patients who responded to infliximab had normal TNFalpha serum levels prior to and following infliximab administration. One RA patient improved after infliximab therapy despite unrelenting high serum levels of TNFalpha, IL-6, and sIL-2R. Patients with active PsA who responded to infliximab therapy had sustained high serum TNFalpha levels. In an unselected population of RA and PsA patients, we noticed diverse patterns of serum cytokine profiles. These results imply that the cytokine profiles of RA and PsA are diverse and their pathogenesis is heterogeneous.
17530710 The role of vascular cell adhesion molecule 1/ very late activation antigen 4 in endotheli 2007 Jun OBJECTIVE: Marrow-derived endothelial progenitor cells (EPCs) are important in the neovascularization that occurs in diverse conditions such as cardiovascular disorders, inflammatory diseases, and neoplasms. In rheumatoid arthritis (RA), synovial neovascularization propels disease by nourishing the inflamed and hyperproliferative synovium. This study was undertaken to investigate the hypothesis that EPCs selectively home to inflamed joint tissue and may perpetuate synovial neovascularization. METHODS: In a collagen-induced arthritis (CIA) model, neovascularization and EPC accumulation in mouse ankle synovium was measured. In an antibody-induced arthritis model, EPC recruitment to inflamed synovium was evaluated. In a chimeric SCID mouse/human synovial tissue (ST) model, mice were engrafted subcutaneously with human ST, and EPC homing to grafts was assessed 2 days later. EPC adhesion to RA fibroblasts and RA ST was evaluated in vitro. RESULTS: In mice with CIA, cells bearing EPC markers were significantly increased in peripheral blood and accumulated in inflamed synovial pannus. EPCs were 4-fold more numerous in inflamed synovium from mice with anti-type II collagen antibody-induced arthritis versus controls. In SCID mice, EPC homing to RA ST was 3-fold greater than to normal synovium. Antibody neutralization of vascular cell adhesion molecule 1 (VCAM-1) and its ligand component alpha4 integrin potently inhibited EPC adhesion to RA fibroblasts and RA ST cryosections. CONCLUSION: These data demonstrate the selective recruitment of EPCs to inflamed joint tissue. The VCAM-1/very late activation antigen 4 adhesive system critically mediates EPC adhesion to cultured RA fibroblasts and to RA ST cryosections. These findings provide evidence of a possible role of EPCs in the synovial neovascularization that is critical to RA pathogenesis.
17276570 Anti-inflammatory and lysosomal stability actions of Cleome gynandra L. studied in adjuvan 2007 Jun The present study was aimed to assess the anti-arthritic nature of Cleome gynandra L. (Cat's whiskers) against Freund's complete adjuvant induced arthritis in rats. The ethanolic extract of C. gynandra was administered orally at a dose of 150 mg/kg body weight for 30 days to the experimental rats after the induction of adjuvant arthritis. The anti-inflammatory activity of C. gynandra leaves was assessed by paw volume measurement, and its capacity to stabilize lysosomal enzyme activities in the plasma and liver of control and experimental rats. The activity of pathophysiological enzymes such as AST, ALT, ALP, cathepsin-D, beta-glucuronidase, N-acetyl-beta-glucosaminidase LDH and the levels of glycoproteins were also estimated in plasma and liver. The increased levels of both lysosomal enzymes and protein-bound carbohydrates in arthritic rats were significantly suppressed to near normal level by the administration of C. gynandra extract. Further, the significantly elevated plasma levels of TNF-alpha found in arthritic rats were found to be significantly restored back to near normal levels by the extract in experimental animals. The membrane stabilizing activity of the extract was further evidenced by histological observations made on the limb tissue. Recently, we have reported the presence of many biologically active phyto chemicals such as triterpenes, tannins, anthroquinones, flavonoids, saponins, steroids, resins, lectins, glycosides, sugars, phenolic compounds, and alkaloids in the extract of C. gynandra and these compounds might be responsible for the anti-arthritic properties observed in the present study. The possible mechanism of action of the C. gynandra extract may be through its stabilizing action on lysosomal membranes and there by preventing the spread of inflammation.
18765972 [Complete atrioventricular block in a patient with rheumatoid arthritis]. 2008 Jun Atrioventricular (AV) block is rare in patients with rheumatoid arthritis (RA), but it is usually of complete type. A 55-year-old woman had complaints of fatigue, dizziness, and light-headedness, all of a week history. She had been receiving treatment for RA for about six years, and had been on methylprednisolone 5 mg/day for a year. On physical examination, her heart rate was 32 bpm, blood pressure was 160/80 mmHg. She had a grade 1-2/6 apical systolic ejection murmur. The electrocardiogram showed complete AV block. Transthoracic echocardiography showed grade I mitral regurgitation. No rheumatoid nodule was noted on transesophageal echocardiography. Coronary arteries appeared normal on coronary angiography. A temporary pacemaker was implanted in the coronary care unit, after which complete AV block improved to a second-degree Mobitz type II block. Her heart rate was 45 bpm. As no further improvement was observed in the AV block during a 10-day monitoring, she underwent DDD-R permanent pacemaker implantation.
18046766 Gene by environment interactions. 2007 This paper summarizes the contributions of group 8 to the Genetic Analysis Workshop 15. Group 8 focused on ways to address the possibility that genetic and environmental effects on phenotype may not be independent, but instead may interact in ways that could play important roles in determining phenotype. Among the eight contributors to this group, all three data sets (expression data, rheumatoid arthritis data, and simulated data) were analyzed. Contributions to this section fell into the two broad categories of refining the data (e.g. stratifying or weighting based on a covariate value) and explicitly modeling the interactions. The contributions also illustrate that there are at least two possible goals for such studies. One goal is simply to identify factors contributing to phenotype in the presence of interactions that might mask the signal to univariate methods. A related but distinct goal is to characterize an interaction (e.g. to determine if the interaction is significant).
16981801 Review of eight pharmacoeconomic studies of the value of biologic DMARDs (adalimumab, etan 2006 Sep BACKGROUND: Treatment options for the management of rheumatoid arthritis (RA) have expanded from the traditional disease-modifying antirheumatic drugs (DMARDs) to include the biologic DMARDs that inhibit tumor necrosis factoralpha (TNF-a). OBJECTIVE: To assess the medical literature for studies of the economic value of biologic DMARDs, specifically the 3 TNF-a inhibitors (adalimumab, etanercept, and infliximab) used for the management of RA, compared with the traditional DMARDs such as sulfasalazine, antimalarials, penicillamine, gold, methotrexate, azathioprine, leflunomide, and cyclophosphamide. METHODS: A comprehensive search of the MEDLINE and HealthSTAR databases was conducted to identify cost-efficacy, cost-effectiveness, or cost-utility studies published in the English language (from 1966 through November 2004). The search terms and/or MeSH (medical subject headings) titles were cost-benefit analysis, rheumatoid arthritis, antirheumatic agents, antineoplastic and immunosuppressive agents. Studies were critically reviewed and quality was assessed using the Quality of Health Economic Studies instrument. Most studies evaluated the use of biologics among RA patients resistant to DMARDs. Studies were assessed with regard to comparators evaluated, measures of efficacy, perspectives, model duration, treatment duration, and discount rate. RESULTS: From 180 titles identified, 155 were excluded for the following reasons: 89 because they did not consider the drugs of interest, 15 because the population was not RA, 19 because of having the wrong drugs and population, 22 because they were review articles, and 10 because they were general articles. Twentyfive abstracts were accepted for further review. Of these, 13 abstracts were subsequently selected for full-text review. One of the authors identified a study not indexed in MEDLINE. Ultimately, 2 cost-effectiveness and 6 cost-utility studies were selected for this critical review. One study over 6 months reported that triple therapy with DMARDs (methotrexate-hydroxychloroquine-sulfasalazine) was cost effective for methotrexate-resistant patients, which is consistent with American College of Rheumatology (ACR) guidelines that support the use of triple therapy prior to biologics. The incremental cost-effectiveness ratio (ICER) was $1,500 per patient to achieve an ACR20 response for this triple therapy compared with no second-line agent. Overall, biologic therapies cost considerably more than traditional DMARDs but produced more quality-adjusted life-years (QALYs). Despite differences in design and assumptions, published economic models consistently reported ICERs <50,000 dollars per QALY gained for biologics compared with traditional DMARDs, although ICERs of >100,000 dollars were reported from sensitivity analyses. CONCLUSIONS: Clinical guidelines currently recommend the use of biologics as step therapy after failure of traditional DMARDs. Reported ICERs comparing biologics with traditional DMARDs are within a range that is comparable with other accepted medical interventions. The worth of the additional expenditure will ultimately be judged by formulary and policy decision makers because no maximum cost has been defined. Models can be used to inform decision makers, but they must be interpreted and applied carefully. More research is also needed to differentiate the relative economic value of the various biologic agents by therapeutic indication.
16849507 Expression of CD44 and L-selectin in the innate immune system is required for severe joint 2006 Aug 1 Proteoglycan (PG)-induced arthritis, a murine model of rheumatoid arthritis, is characterized by autoimmunity against mouse cartilage PG and chronic joint inflammation. L-selectin (CD62L) and CD44 are major adhesion molecules on leukocytes that regulate their homing to lymph nodes and entry into inflamed tissues. In the present study, we studied the requirement for CD44 and CD62L expression for mediating lymphocyte homing, thus permitting the development of autoimmunity vs mediating the entry of leukocytes into the joints, thus allowing inflammation in PG-induced arthritis. We immunized wild-type, CD44 knockout (KO), CD62L KO, and double (CD44/CD62L) KO BALB/c mice with PG and monitored the effects of gene deficiencies on PG-specific immunity, arthritis severity, leukocyte trafficking, and the ability of lymphocytes to adoptively transfer disease to syngeneic SCID mice. Single and double KO mice demonstrated reduced PG-specific spleen cell proliferation, but the production of Th cytokines and autoantibodies was comparable in KO and wild-type mice. KO leukocytes had reduced ability to adhere tightly to the synovial endothelium in arthritic joints. This diminished leukocyte adhesion correlated with the magnitude of granulocyte (neutrophil) influx and the severity of inflammation, which were both reduced in the joints of KO mice. However, transfer of spleen cells from mildly arthritic KO donors to SCID hosts resulted in development of severe arthritis. Our results indicate that CD44 and CD62L expression in the cells of the innate immune system (granulocytes) is important for their efficient influx into the joints and also suggest that granulocytes play a crucial role in arthritis progression.
17612900 Carbonic anhydrase III: a new target for autoantibodies in autoimmune diseases. 2007 Jul The objective of this study was to identify new autoantibodies that could be useful for the diagnosis of rheumatoid arthritis (RA) using immunoblotting on synovial membrane proteins which represent the best source of candidate RA autoantigens. A new target protein with a molecular weight of 26 kDa was found to be recognized by autoantibodies in RA sera and was identified using MALDI-TOF mass spectrometry and second-dimension electrophoresis as carbonic anhydrase III (CAIII). Three similar protein spots at 26 kDa were recognized by both human sera and monoclonal antibody (mAb) directed against CAIII on immunoblotting using the human recombinant CAIII. Interestingly, CAIII expression within the synovial membrane was not observed in non-RA patients and was differentially expressed among RA patients. The sensitivity of these new autoantibodies for RA, using an immunoenzymatic technique, was 17%. Specificity was high when comparing non-autoimmune diseases (100%), while it was found to be weak (67%) when comparing some other autoimmune diseases, and particularly systemic lupus erythematosus (SLE). In conclusion, this study demonstrates that these new autoantibodies against CAIII are not restricted to RA. However the expression of CAIII in the synovial membrane of RA warrants further investigation of the pathophysiological relevance of this finding.
18095785 Health-related quality of life--an introduction. 2007 Dec Chronic diseases often have a relapsing and remitting course with substantial impact on function and quality of life. Rheumatoid arthritis (RA) is considered a chronic, inflammatory autoimmune disorder that causes disabling and painful inflammation in the joints that can lead to detrimental effects on health-related quality of life (HRQOL). This article provides an overview of HRQOL and a comprehensive description of the attributes of different instruments to measure it. A wide variety of instruments have been created to measure HRQOL using 2 approaches: health status and health utility. Commonly used generic health status instruments in RA are the Medical Outcomes Study 36-Item Short Form (SF-36) and the Health Assessment Questionnaire Disability Index. Health utility measures are divided into 2 categories, direct and indirect. The most common direct health utility measures are the standard gamble, time to trade-off, and rating scale, while the most commonly used indirect measures are EuroQOL, SF-6D, and the Health Utility Index. Different applications of the instruments are analyzed in this article, including their utility to estimate burden of disease, as end points in clinical trials, and to monitor outcomes in clinical practice, as well as their uses in public policy and in individual decision making.
17456529 Contribution of anti-cyclic citrullinated peptide antibody and rheumatoid factor to the di 2007 Sep OBJECTIVE: To investigate the prevalence of antibodies to cyclic citrullinated peptide (anti-CCP) and rheumatoid factor in patients with hereditary haemochromatosis (HHC) and to evaluate their diagnostic reliability in distinguishing HHC-associated arthropathy from rheumatoid arthritis. METHODS: Anti-CCP antibodies and rheumatoid factor levels were determined by ELISA in sera from 87 patients with HHC homozygous for the C282Y mutation of the HFE gene, 31 patients with rheumatoid arthritis and 162 healthy controls. RESULTS: Of the 87 patients with HHC, 32 (36.8%) had joint involvement. Anti-CCP antibodies were detected in only 1 patient (1.1%) with HHC, who had no joint disease, and in (1.2%) healthy controls. In total, 18 (58.1%) patients with rheumatoid arthritis displayed anti-CCP reactivity (p<0.001). Rheumatoid factor was detected in 10 (11.5%) patients with HHC compared with 7 (4.3%) healthy control subjects (p = 0.03) and 21 of 31 (65.6%) patients with rheumatoid arthritis. CONCLUSIONS: Testing for anti-CCP antibodies discriminates HHC arthropathy from rheumatoid arthritis, as these patients were consistently anti-CCP negative. Thus, HHC arthropathy should be considered in the differential diagnosis of CCP-negative arthritis.
17328055 Elevated plasma asymmetric dimethyl-L-arginine levels are linked to endothelial progenitor 2007 Mar OBJECTIVE: Similarities between rheumatoid arthritis (RA) and atherosclerosis include endothelial dysfunction (an antecedent of plaque formation) and depletion of circulating bone marrow-derived endothelial progenitor cells. This study was undertaken to test the hypothesis that endothelial progenitor cell depletion and subclinical atherosclerosis in RA may be related to accumulation of an endogenous inhibitor of nitric oxide (NO) synthesis, asymmetric dimethyl-L-arginine. METHODS: We studied 30 patients with active RA and 20 age- and sex-matched healthy controls. Exclusion criteria were clinically evident atherosclerosis, traditional risk factors, hyperhomocysteinemia, and renal dysfunction. The blood endothelial progenitor cell count was assayed by flow cytometry and expressed as a percentage of lymphocytes. Plasma L-arginine, asymmetric dimethyl-L-arginine, and symmetric dimethyl-L-arginine were measured with liquid chromatography-mass spectrometry. Mean carotid intima-media thickness (IMT) was assessed by B-mode ultrasound. RESULTS: In RA patients, we found elevated levels of asymmetric dimethyl-L-arginine (mean +/- SD 0.49 +/- 0.07 micromoles/liter versus 0.40 +/- 0.07 micromoles/liter in controls; P < 0.001), a depressed endothelial progenitor cell count (0.039 +/- 0.025% versus 0.063 +/- 0.035%; P < 0.05), and increased IMT (0.65 +/- 0.13 mm versus 0.55 +/- 0.10 mm; P < 0.01), with no differences in levels of L-arginine or symmetric dimethyl-L-arginine. The endothelial progenitor cell count was inversely correlated with the level of asymmetric dimethyl-L-arginine. IMT was positively related to the ratio of asymmetric dimethyl-L-arginine to L-arginine and negatively related to the endothelial progenitor cell count, in univariate and multivariate analyses. CONCLUSION: Plasma asymmetric dimethyl-L-arginine levels are elevated in RA patients free of cardiovascular disease or risk factors. Asymmetric dimethyl-L-arginine accumulation may contribute to endothelial progenitor cell depletion via depressed NO-dependent endothelial progenitor cell mobilization and/or survival, with consequent impairment of endothelial progenitor cell-mediated endothelial repair, which can promote atherogenesis in RA.
17763341 Pharmacokinetic modeling of dynamic contrast-enhanced MRI of the hand and wrist in rheumat 2007 Sep Dynamic contrast-enhanced MRI (DCE-MRI) of the hand and wrist was performed in 11 patients with rheumatoid arthritis twice before and once 2 weeks after treatment with anti-tumor necrosis factor (TNF)-alpha therapy. A rapid, T1-weighted 3D spoiled gradient echo (SPGR) sequence was used for the dynamic imaging. T1 estimation was performed using similar images obtained at different flip angles. The relative radiofrequency field was estimated from the known T1 of the periarticular fatty marrow. The arterial input function (AIF) was measured at each examination, and normalized to the expected plasma concentration to reduce partial volume effects. Synovial enhancement was modeled to yield values for Ktrans, ve, and vp. Ktrans and ve showed good reproducibility. There was a significant decrease of about 20% in Ktrans after 2 weeks of treatment. This study demonstrates the potential of DCE-MRI and pharmacokinetic modeling to study early changes in inflammatory activity in rheumatoid arthritis following treatment.
18050238 Circulating levels of tumor necrosis factor receptors are highly predictive of mortality i 2007 Dec OBJECTIVE: To investigate whether circulating levels of soluble tumor necrosis factor receptors (sTNFR) are predictive of mortality in rheumatoid arthritis (RA). METHODS: Levels of sTNFRI and sTNFRII at study entry were quantified using enzyme-linked immunosorbent assays in sera from 401 white patients with RA followed up for 13 years. Patients were tracked via the National Health Service Central Register, and the relationship between sTNFR levels and mortality was analyzed using a Cox proportional hazards regression model. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: At the end of the followup period, 132 (32.9%) of 401 patients had died. Of these, 64 (48.5%) died of cardiovascular disease (CVD). Significant associations between all-cause mortality and baseline levels of sTNFRI and sTNFRII were identified in men (HR 1.7 [95% CI 1.2-2.4] and HR 1.18 [95% CI 1.05-1.32], respectively) and women (HR 1.33 [95% CI 0.99-1.8] and HR 1.14 [95% CI 1.02-1.28], respectively). Analysis including levels of both sTNFRI and sTNFRII indicated that the sTNFRII level was the best overall predictor of mortality. Multivariate analysis also revealed that the sTNFRII level was a predictor of all-cause and CVD mortality independently of age, sex, disease duration, C-reactive protein level, erythrocyte sedimentation rate, rheumatoid factor, nodular disease, modified Health Assessment Questionnaire score, taking CVD drugs, and smoking. CONCLUSION: Our data indicate that serum levels of sTNFR are powerful predictors of mortality in RA. Elevated levels are particularly associated with mortality due to CVD and may be useful for identifying patients at increased risk of premature death.
17929076 Anti-nucleosome antibodies as prediction factor of development of autoantibodies during th 2008 Jan Anti-nucleosome antibodies have a role in the diagnosis and follow-up of systemic lupus erythematosus (SLE) and have a possible correlation with SLE activity and with kidney and hematological involvement. The aim of our study was to detect in 91 patients with rheumatoid arthritis (RA) the positivity of anti-nucleosome antibodies during therapy with three different TNFalpha blocking agents and to underline the possible correlation with the development of antinuclear autoantibodies (ANA) and anti-dsDNA autoantibodies. We detected anti-nucleosome antibodies, ANA, and anti-dsDNA during therapy with three different TNFalpha blocking agents at T-0 and after 12 and 24 weeks of treatment, respectively. Anti-nucleosome antibodies (IgG class) were analyzed by ELISA technique (Orgentec Diagnostika GmbH, Mainz, Germany), ANA both by indirect immunofluorescence (IIF) technique on Hep-2 (Scimedx, USA) and by ELISA (Autoimmune EIA ANA screening test Bio-Rad Laboratories, CA, USA), and anti-dsDNA (IgG and IgM classes) by ELISA (Kallestad, Bio-Rad Laboratories, CA, USA) and confirmed by IIF on Crithidia luciliae (ImmunoConcepts N.A., Sacramento, CA, USA). We observed 19 patients on infliximab treatment at 3 mg/kg every 8 weeks, 43 patients on etanercept treatment at 25 mg twice a week, and 29 patients on adalimumab treatment at 40 mg every other week. At baseline, we observed positivity as follow: in the group of patients treated with infliximab-anti-nucleosome 1/19 (5.26%), ANA 3/19 (15.7%), anti-dsDNA 1/19 (5.26%); in the group treated with etanercept--anti-nucleosome 2/43 (4.65%), ANA 1/43 (2.43%), anti-dsDNA 0/43; and in the group treated with adalimumab--anti-nucleosome 2/29 (6.89%), ANA 1/29 (3.44%), anti-dsDNA 0/29. The results at 12 weeks for the three autoantibodies were: for infliximab--3/19 (15.7%), 10/19 (52.6%), 2/19 (10.5%); for etanercept--3/43 (6.9%), 10/43 (23.2%), 1/43 (2.32%); and for adalimumab--3/29 (10.3%), 4/29 (13.7%), 1/29 (3.4%). At 24 weeks, the results were for infliximab 6/19 (31.5%), 12/19 (63.1%), 2/19 (10.5%); for etanercept 11/43 (25.5%), 22/43 (51.1%), 2/43 (4.65%); and for adalimumab 4/29 (13.7%), 13/29 (44.8%), 1/29 (3.4%). We observed a concordance anti-nucleosome/ANA antibodies of 85.5% (p < 0.001). Our data showed a concordance between anti-nucleosome antibodies and ANA positivity in patients with RA during therapy with TNFalpha blocking agents. The induction of autoantibodies positivity is different for each TNFalpha blocking agent.
18433499 Prolonged, granulocyte-macrophage colony-stimulating factor-dependent, neutrophil survival 2008 INTRODUCTION: A surprising feature of the inflammatory infiltrate in rheumatoid arthritis is the accumulation of neutrophils within synovial fluid and at the pannus cartilage boundary. Recent findings suggest that a distinct subset of IL-17-secreting T-helper cells (TH17 cells) plays a key role in connecting the adaptive and innate arms of the immune response and in regulating neutrophil homeostasis. We therefore tested the hypothesis that synovial fibroblasts bridge the biological responses that connect TH17 cells to neutrophils by producing neutrophil survival factors following their activation with IL-17. METHODS: IL-17-expressing cells in the rheumatoid synovium, and IL-17-expressing cells in the peripheral blood, and synovial fluid were examined by confocal microscopy and flow cytometry, respectively. Peripheral blood neutrophils were cocultured either with rheumatoid arthritis synovial fibroblasts (RASF) or with conditioned medium from RASF that had been pre-exposed to recombinant human IL-17, TNFalpha or a combination of the two cytokines. Neutrophils were harvested and stained with the vital mitochondrial dye 3,3'-dihexyloxacarbocyanine iodide before being enumerated by flow cytometry. RESULTS: TH17-expressing CD4+ cells were found to accumulate within rheumatoid synovial tissue and in rheumatoid arthritis synovial fluid. RASF treated with IL-17 and TNFalpha (RASFIL-17/TNF) effectively doubled the functional lifespan of neutrophils in coculture. This was entirely due to soluble factors secreted from the fibroblasts. Specific depletion of granulocyte-macrophage colony-stimulating factor from RASFIL-17/TNF-conditioned medium demonstrated that this cytokine accounted for approximately one-half of the neutrophil survival activity. Inhibition of phosphatidylinositol-3-kinase and NF-kappaB pathways showed a requirement for both signalling pathways in RASFIL-17/TNF-mediated neutrophil rescue. CONCLUSION: The increased number of neutrophils with an extended lifespan found in the rheumatoid synovial microenvironment is partly accounted for by IL-17 and TNFalpha activation of synovial fibroblasts. TH17-expressing T cells within the rheumatoid synovium are likely to contribute significantly to this effect.