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16761535 Placental umbilical cord whole blood transfusion to combat anemia in the background of adv 2006 Rheumatoid arthritis is the commonest form of inflammatory arthritis and affects about 1-3% of the population in the West and even more in the developing world due to the compounded factors of late detection and inadequate treatment in the overall background of poverty, deprivation, and improper macro and micronutrients in the diet in a sizeable segment of the population. Nearly 90% of patients with aggressive disease will become clinically disabled within 20 years. Furthermore, in patients with severe disease or extra-articular symptoms, mortality is equal to that for patients with triple artery coronary artery disease or Stage IV Hodgkin's lymphoma. Anemia is a very common comorbidity of rheumatoid arthritis. Anemia in rheumatoid arthritis is caused by various factors, for instance, cytokine impact of the advanced arthritic process on the host, or lack of proper nutrition and essential micronutrients in the diet, or coexistent helminthiasis, and/or impact of antiarthritic drugs on the host system, i.e., high steroid induced gastritis or ulcerations in gastric mucosa or subclinical or clinical hepatitis due to methotrexate or salazopyrin effects on bone marrow, only to name a few. Other pre-existing or compounding gastrointestinal problems, which alter the available iron stores or cause bone marrow dysfunction, may also help in adding to an anemic condition. If the anemia is 8 g/dl or less, blood transfusion or erythropoietin injection with adequate hematinic reserve is effective in normal situations, but is not that effective in anemia with a chronic disease background like rheumatoid arthritis. Cord blood, because of its rich mix of fetal and adult hemoglobin, high platelet and white blood cell (WBC) counts, and a plasma filled with cytokine and growth factors, as well as its hypo antigenic nature and altered metabolic profile, has all the potential of a real and safe alternative to adult blood transfusion. Seventy-eight units (42 ml -136 ml mean 80.6 ml +/- 3.6 ml SD, median 82.4 ml, mean packed cell volume 48.2 +/- 2.1 SD, mean percent hemoglobin concentration 16.4 g/dl +/- 1.5 g/dl SD) of placental umbilical cord whole blood was transfused (from 1 April 1999 to April 2005) after lower uterine cesarean section (LUCS) from consenting mothers to 28 informed consenting patients with advanced rheumatoid arthritis who had plasma hemoglobin of 8 g/dl or less. After collection, the blood was immediately transfused following the standard adult blood transfusion protocol. Each case was passed through the institutional ethical committee. The patients received two to six units of freshly collected placental umbilical cord blood without encountering any clinical, immunological or non-immunological reactions. Three days after completion of the transfusion of placental umbilical cord blood, the peripheral blood hematopoietic stem cell (CD34) estimation revealed a rise from the pretransfusion base level (.09%), varying from 2.03 to 23%, which returned to base level in most of the cases at the three-month CD34 re-estimation, without provoking any clinical graft vs host reaction in any of the patients.
17804842 STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. 2007 Sep 6 BACKGROUND: Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q. METHODS: We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus. RESULTS: A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81x10(-7); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87x10(-9); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis. CONCLUSIONS: A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.
16907988 Serum, urinary, and salivary nitric oxide in rheumatoid arthritis: complexities of interpr 2006 Nitric oxide (NO) may play important roles in rheumatoid arthritis (RA). RA is an inflammatory disease involving joints and other systems including salivary glands. To assess NO production in RA patients, we compared levels of serum, urine, and salivary nitrite and nitrate (NOx) in patients with RA and normal subjects, and we examined the relationships of these measures to disease activity. Serum, urine, and NOx levels as well as renal creatinine, NOx clearance and fractional excretion rates were compared in 25 RA patients and 20 age- and gender-matched healthy controls. Subjects were hospitalized for 3 days and placed on a NOx restricted diet. NOx was assayed using nitrate reductase and the Griess reagent. RA activity was assessed using standard clinical and laboratory measures. While consuming a restricted diet for 3 days to eliminate the effects of oral intake of NOx, 24 hour urinary NOx excretion decreased in both RA patients and healthy controls. Urine NOx levels at all time points were not significantly different between RA patients and normal subjects. Serum NOx levels also decreased during the 3 days of NOx restriction, but RA patients had higher serum NOx levels at all time points compared with the control group. Likewise, serum NOx/creatinine ratios were higher in RA patients than in controls. Although basal salivary flow rate and tear flow were lower in RA patients, salivary NOx levels did not differ between normal and RA subjects. While renal creatinine clearance was not different between the two groups, we found that RA patients had lower renal NOx clearance and lower renal NOx fractional excretion. After correction of p values for multiple comparisons, there were no significant relationships for the RA group between measures of disease activity and the urinary NOx, serum NOx, or urinary NOx clearance. Despite interest in the use of NO as a marker of disease activity, alterations in renal NOx clearance and fractional excretion in RA make it difficult to assess in vivo NO production even with strict dietary restriction of NOx intake.
17721785 [Laboratory diagnosis of rheumatic diseases. Part 3: arthritides caused by infection]. 2007 Sep This third part of this series of articles on laboratory diagnostics of rheumatic diseases considers the rheumatic diseases caused by infection by microorganisms, or reactive arthritides. The basis for laboratory diagnostics of infection-reactive arthritides is the investigation of anti-infection antibodies. In some situations, DNA amplification methods may be helpful. Bacterially infected joints should be immediately examined by arthrocentesis and microscopic examination and laboratory culture of the synovial fluid.
18292521 Interactions of T cells with fibroblast-like synoviocytes: role of the B7 family costimula 2008 Mar 1 Fibroblast-like synoviocytes (FLS) and T cells can activate each other in vitro, and in vivo interactions between these cells may be important in rheumatoid arthritis (RA), yet FLS lack significant expression of CD28 ligands. We sought to identify molecules homologous to CD28 ligands that are strongly expressed by FLS, and documented strong B7-H3 expression on FLS and by fibroblasts of other tissues, which was unaffected by a variety of cytokines. Western blot analysis of FLS lysates showed predominant expression of the larger, four Ig-like domain isoform of B7-H3. Immunohistological sections of RA synovial tissue showed strong staining for B7-H3 on FLS. Cells expressing B7-H3 were distinct from but in close proximity to cells that expressed CD45, CD20, and CD3. Confocal microscopy of FLS and T cell cocultures showed localization of B7-H3 in the region of the T cell-FLS contact point, but distinct from the localization of T cell CD11a/CD18 (LFA-1) and FLS CD54 (ICAM-1). Reduction of B7-H3 expression on FLS by RNA interference affected interactions of FLS with resting T cells or cytokine-activated T cells. Resting T cells showed increased production of TNF-alpha, IFN-gamma, and IL-2, whereas cytokine-activated T cells showed reduced cytokine production relative to control. However, cytokine production by T cells activated through their TCR was not notably altered by knock down of B7-H3. These observations suggest that B7-H3 may be important for the interactions between FLS and T cells in RA, as well as other diseases, and the outcome of such interactions depends on the activation state of the T cell.
17675524 Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid 2007 Aug 15 Rheumatoid arthritis (RA) is characterized by premature immune aging with accumulation of degenerate T cells deficient for CD28. Gene expression profiling of CD4(+)CD28(-) and CD4(+)CD28(+) T cells to discover disease-promoting activities of CD28(-) T cells identified expression of CD70 as a most striking difference. Hence, CD70 was significantly more expressed in CD4 T cells from RA patients compared with age-matched controls (p < 0.006). The underlying mechanism was a failure to repress CD70 expression after activation-dependent induction. This defect in RA was not related to differential promoter demethylation. CD70 on bystander CD4(+)CD28(-) T cells functioned by lowering the threshold for T cell activation; admixture of CD4(+)CD28(-) T cells augmented TCR-induced responses of autologous naive CD4(+)CD28(+) T cells, particularly of low-avidity T cells. The data support a model in which CD70 expressed on T cells causes degeneracy in T cell responses and undermines tolerance mechanisms that normally control T cell autoreactivity.
16142689 Investigation of protein oxidation and lipid peroxidation in patients with rheumatoid arth 2006 Jul We aimed to determine the importance of neutrophil activation and the source of oxidative stress in the pathogenesis of rheumatoid arthritis (RA) by quantification of advanced oxidation protein products (AOPP) and total thiol levels as markers of oxidative protein damage, malondialdehyde (MDA) levels as a marker of lipid peroxidation and myeloperoxidase (MPO) activity as a marker of neutrophil activation in patients with RA. Fifty-seven rheumatoid arthritis patients were included in the study and sub-grouped according to disease activity (active, n = 31; inactive, n = 26) and compared with healthy controls (n = 25). Serum MPO activity, AOPP, MDA, and thiol levels were measured by an enzymic spectrophotometric method. Serum MPO activity (p < 0.001), AOPP (p < 0.001), MDA (p < 0.001) and levels of thiol (p < 0.002), were higher in the patient group than the controls. Active and inactive RA groups were compared with the control group and there were significant differences between each parameter. MPO activity, AOPP, MDA and thiol levels were significantly higher in both active and inactive RA patients than the controls. On the other hand, when a comparison was made between active and the inactive stage, a statistically significant difference was present only in MDA (p < 0.05) and AOPP levels (p < 0.05). There was also a significant positive correlation between all parameters. These data strongly suggest that neutrophils, which constitute the most important source of chlorinated oxidants due to their high MPO content, may be involved in serum AOPP formation and therefore the production of a novel class of pro-inflammatory mediators of oxidative stress in RA patients and that protein oxidation could play an important role in the pathogenesis of RA as does lipid peroxidation.
17629820 [Multiple sclerosis and other autoimmune diseases]. 2007 May Autoimmune diseases are caused by a defect of the human immune system characterised by an inability to recognize their own antigens and by a pathological response against these antigens. Although the aetiology of these diseases is unknown, there is a number of cellular and molecular mechanisms which can underlie these reactions. Complex interactions between genetic, infectious and/or environmental factors probably contribute to the presence of these diseases. Autoimmune diseases affect 3-8% of the general population; women account for 78-85% of all patients with autoimmune diseases. Although most of those diseases are systemic, some of them primarily affect a single organ or structure. Rarely, a few autoimmune diseases coexist in one person, which can suggest similar pathogenetic mechanisms. In this article we present a review of the literature on coexistence of multiple sclerosis and other autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, chronic active hepatitis, type 1 diabetes mellitus, uveitis, pemphigus, psoriasis, Crohn's disease, inflammatory bowel disease, anaemia and autoimmune thyroiditis.
16944082 [Insufficiency fractures in rheumatology. Case report and overview]. 2006 Sep Stress fractures occur as insufficiency fractures, with a prevalence of 0.8% in patients with rheumatological illness. The main sites of insufficiency fractures are the pelvis and sacrum, parts of the tibia and fibula that are close to the joints, and the calcaneus and hip. Since the painful symptoms overlap with the clinical picture of the painful joint diseases and because of the low sensitivity of conventional diagnostic X-ray, insufficiency fractures are not diagnosed directly or their diagnosis is delayed. The high sensitivity of computer tomography, skeletal scintigraphy and nuclear magnetic resonance imaging should be exploited in the diagnosis of insufficiency fractures. The case report presented describes insufficiency fractures of the distal right tibia and fibula in an elderly female patient with rheumatoid arthritis being treated with long-term glucocorticoids. In addition to advanced age, female gender, immobility and rheumatoid arthritis requiring long-term cortisone, there are further risk factors for insufficiency fractures: fluoride treatment over many years in the past, hypovitaminosis D3, renal failure. The DXA bone density values of the neck of the femur and the lumbar vertebrae do not show any osteoporosis, and the calcium concentration in the serum is low; phosphate is raised and parathormone is normal; osteocalcin, beta crosslaps and alkaline phosphatase are raised. Bone biopsy specimens taken from the iliac crest and the proximal femur and investigated for the purpose of differential diagnosis revealed renal osteopathy with secondary hyperparathyroidism and osteomalacia. In elderly patients with kidney failure, the possibility of renal osteopathy must be considered as the possible cause of reduced bone quality with a raised risk of insufficiency fractures, even when the parathormone levels are normal. In view of the frequency of osteopathies in rheumatological patients, osteology is of enormous significance in rheumatology.
17645497 Auranofin blocks interleukin-6 signalling by inhibiting phosphorylation of JAK1 and STAT3. 2007 Dec Auranofin (AF) is a sulphur-containing gold compound. Because of its anti-inflammatory and immunosuppressive activities, AF has been widely used for the therapeutic treatment of rheumatoid arthritis. However, little is known about its mechanism of action. To elucidate the molecular mechanism underlying the anti-inflammatory effect of AF, we studied the effects of AF on cellular responses to interleukin-6 (IL-6). In HepG2 human hepatoma cells, AF markedly inhibited IL-6-induced phosphorylation of janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) and STAT3 translocation into the nucleus. Consistent with this, AF diminished IL-6-induced production of the acute-phase proteins, haptoglobin, fibrinogen, C3 complement and alpha(1)-acid glycoprotein, and gene expression of vascular endothelial growth factor, all of whose transcriptional activities are regulated by STAT3. The inhibitory activity of AF on STAT3 phosphorylation was also demonstrated in primary cells, i.e. fibroblast-like synoviocytes from rheumatoid arthritis patients, human umbilical vein endothelial cells and rat astrocytes. Auranofin-mediated inhibition of STAT3 phosphorylation was recovered by pretreatment with antioxidants containing thiol groups. These findings suggest that the anti-inflammatory action of AF is associated with a blockade of JAK1/STAT3 signalling. Thiol-group-reactive proteins may be involved in AF-induced suppression of JAK1/STAT3 phosphorylation.
18414459 Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheum 2008 Jun The success of agents that inhibit tumor necrosis factor (TNF), such as infliximab, adalimumab and etanercept, has led to a desire for orally available small molecules that have a better safety profile and are less costly to produce than current agents. One target for anti-TNF therapy that is currently under investigation is TNF-converting enzyme, which promotes the release of soluble TNF from its membrane-bound precursor. Inhibitors of this enzyme with drug-like properties have been made and tested in the clinic. These inhibitors include TMI-005 and BMS-561392, both of which have entered into phase II clinical trials. This article summarizes preclinical and clinical findings regarding the use of inhibitors of TNF-converting enzyme for the treatment of rheumatoid arthritis.
17855452 Functional characterization of NF-kappaB inhibitor-like protein 1 (NFkappaBIL1), a candida 2007 Dec 15 Several studies have implicated the NF-kappaB inhibitor-like protein 1 (NFkBIL1) gene located in the class III region of the major histocompatibility complex (MHC) as a possible susceptibility locus for rheumatoid arthritis (RA). Based on limited homology, it has been suggested to be a member of the inhibitor of NF-kappaB (IkappaB) family of proteins, but a role in mRNA processing has also been proposed. We have investigated the expression of NFkBIL1 in RA synovial tissue and characterized its function. Real-time PCR showed the two NFkBIL1 mRNA splice variants are expressed in a tissue-specific manner. Dual immunofluorescent staining of human RA synovium with polyclonal anti-NFkBIL1 antibodies and anti-CD68, anti-CD3 or anti-factor VIII showed that NFkBIL1 was expressed in the rheumatoid synovial lining and sub-lining layers and co-localized in CD68+ and CD3+, but not Factor VIII+ cells. Confocal microscopy of cultured synovial fibroblasts revealed expression in speckled nuclear and homogenous cytoplasmic distributions, suggesting shuttling between the cytoplasmic and nuclear compartments. Functional tests showed that NFkBIL1 isoforms were incapable of associating with NF-kappaB and did not inhibit it, thus disproving the hypothesis that NFkBIL1 functions as an IkappaB. Affinity purification of endogenous NFkBIL1 proteins and co-immunoprecipitation experiments showed that NFkBIL1 can associate with mRNA and with three protein partners, identified by mass spectrometry as leukophysin, translation elongation factor 1 alpha and CTP synthase I. These data support a potential role for NFkBL1 in the pathogenesis of RA and indicates that it may be involved in mRNA processing or the regulation of translation.
19037063 Obesity and arthritis. 2008 Dec Obesity affects over 20% of the UK's adult population and its prevalence is rising. Obesity can lead to a variety of musculoskeletal problems and is independently associated with locomotor disability and joint pain. Obesity increases the risk of radiographic knee osteoarthritis (OA), but has a lesser effect on disease progression. The association with hip and hand OA is weaker, but implies that excess adipose tissue produces humoral factors, altering articular cartilage metabolism. It has been postulated that the leptin system could be a link between metabolic abnormalities in obesity and increased risk of OA. Although obesity was initially thought to increase the risk of rheumatoid arthritis (RA), further studies showed, that heavier patients with RA have less radiological disease progression and possibly better survival. On the other hand, obesity is strongly associated with hypeuricaemia and gouty arthritis. High body weight correlates independently with metabolic syndrome and may contribute to increased cardiovascular morbidity in patients with gout. Weight reduction should be an important part of treatment for OA and gout. Because obesity at a young age correlates with the development of OA and gout in later life, preventive public health strategies aimed at lowering the incidence of obesity are of most importance.
16960928 Sleep disturbance in patients with rheumatoid arthritis: evaluation by medical outcomes st 2006 Oct OBJECTIVE: Except for some polysomnography studies, there have been no large quantitative studies of sleep disturbance (SD) in rheumatoid arthritis (RA). SD has taken on new importance with the observation that etanercept and infliximab reduce daytime sleepiness, and patient groups indicate that sleep is an important issue. METHODS: We evaluated 8676 patients with RA and a comparison group of 1364 subjects with non-fibromyalgia, noninflammatory disorders (NID) using the Medical Outcome Study (MOS) sleep questionnaire, including 2 MOS sleep problem indexes (SPI-I, SPI-II) and the MOS SD scale. In addition, patients completed a visual analog scale (VAS) sleep disturbance scale (SDS). RESULTS: The scales had similar mean values: SPI-I 35.4 (19.4), SPI-II 36.0 (19.1), SDS 35.0 (24.7), and VAS sleep 36.1 (29.7), and the values for the MOS scales exceeded population norms by 25% (VAS by 42%). In multivariable analyses SD was primarily determined by pain and mood. Patients receiving anti-tumor necrosis factor (TNF) did not have less abnormal sleep scores. SD was comparable in RA and NID. The VAS scale was more strongly associated with RA clinical variables than the MOS scales; however, the distributional characteristics of the scales differed, with the VAS scales capturing more extreme values. The standard error of the measurement (SEM), which is related to minimal (important) change, was SPI-I 9.0, SPI-II 7.3, SDS 9.6, and VAS sleep 10.4. CONCLUSION: SD is increased in RA, and 25% to 42% of SD can be attributed to RA. SD is linked to pain, mood, and disease activity. SD is slightly greater in women and is less with increasing age. All scales appear to be valid in RA, with minimal differences in SEM.
16871413 Tumor necrosis factor receptor 2 M196R polymorphism in rheumatoid arthritis and osteoarthr 2006 Nov We investigate the clinical association of tumor necrosis factor receptor 2 (TNFR2) M196R polymorphism with rheumatoid arthritis (RA) and knee osteoarthritis (OA). Acute phase reactants, lipid profile, sTNFR2 levels, disease activity-disability indexes, and TNFR2 M196R polymorphism were analyzed in 50 RA, 50 knee OA patients, and 120 healthy subjects (HS). The M/M genotype frequency was 0.74 (RA), 0.80 (OA), and 0.64 (HS). The M/R genotype frequency was RA (0.26), OA (0.20), and HS (0.29). The R/R genotype was observed only in HS (0.07). The M allele was associated with OA (P = 0.0137, OR = 2.43). Total cholesterol, triglyceride levels, apolipoprotein A-I and B showed significant differences (P < 0.05). The highest sTNFR2 levels were observed in RA and OA (P = 0.001), however M/M and M/R carriers do not correlate with sTNFR2 production. Our findings suggest an association of the M allele with knee OA. In addition, high sTNFR2 levels in RA and OA were found.
17479856 [Autoimmunological and allergic disorders with Hashimoto and Graves disease]. 2006 Graves disease and Hashimoto disease are due to inappropriate activation of immunological system and production of the antibodies against thyroid gland. The aim of the study was to estimate potential risk of other autoagressive and allergic disease in patients with Hashimoto or Graves disease. 255 patients with Graves disease (216 females and 39 males) and 69 patients (63 females and 6 males) mean age 53.6 +/- 13.7 years were examined. The control group consists of 200 patients (175 females and 25 males) mean age 61.98 +/- 14.35 years with nodular goitre. There were 74 cases (i.e. 22.8%) of coexisting autoimmunological or allergic disorder among the patients with autoimmunological thyroid disorders (36 patients with Graves disease and 38 patients with Hashimoto disease). There were 20 cases of type 1 diabetes mellitus, 13 cases of bronchial asthma, 16 cases of Addison' disease, 4 cases of rheumatoid arthritis, 1 case of scleroderma, 4 cases of systemic lupus erythematosus, 2 cases of colitis ulcerosa, 2 cases of myasthenia gravis, 6 cases of Addison-Biermer disease, 3 cases of primary biliary cirrhosis and 3 cases of rhinitis allergica. There were 3 cases (1.5%) of additional auto-immunological or allergic disorder among the control subjects--1 case of type 1 diabetes mellitus and 2 cases of bronchial asthma. Because of the higher risk of coexisting auto-immnunologi-cal or allergic disorder, patients with autoimmunological thyroid disorders should be closely controlled.
18662305 Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients. 2008 Sep Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint disease that primarily affects the small joints of the hands and feet. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to proliferation of synoviocytes and destruction of cartilage and bone. In RA synovial tissue, the infiltrating cells such as macrophages, T cells, B cells and dendritic cells play important role in the pathogenesis of RA. Migration of leukocytes into the synovium is a regulated multi-step process, involving interactions between leukocytes and endothelial cells, cellular adhesion molecules, as well as chemokines and chemokine receptors. Chemokines are small, chemoattractant cytokines which play key roles in the accumulation of inflammatory cells at the site of inflammation. It is known that synovial tissue and synovial fluid from RA patients contain increased concentrations of several chemokines, such as monocyte chemoattractant protein-4 (MCP-4)/CCL13, pulmonary and activation-regulated chemokine (PARC)/CCL18, monokine induced by interferon-gamma (Mig)/CXCL9, stromal cell-derived factor 1 (SDF-1)/CXCL12, monocyte chemotactic protein 1 (MCP-1)/CCL2, macrophage inflammatory protein 1alpha (MIP-1alpha)/CCL3, and Fractalkine/CXC3CL1. Therefore, chemokines and chemokine-receptors are considered to be important molecules in RA pathology.
19015207 Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis 2009 Jun BACKGROUND: Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor. OBJECTIVE: To evaluate the efficacy and safety of certolizumab pegol versus placebo, plus methotrexate (MTX), in patients with active rheumatoid arthritis (RA). METHODS: An international, multicentre, phase 3, randomised, double-blind, placebo-controlled study in active adult-onset RA. Patients (n = 619) were randomised 2:2:1 to subcutaneous certolizumab pegol (liquid formulation) 400 mg at weeks 0, 2 and 4 followed by 200 mg or 400 mg plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks. The primary end point was ACR20 response at week 24. Secondary end points included ACR50 and ACR70 responses, change from baseline in modified Total Sharp Score, ACR core set variables and physical function. RESULTS: Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p< or =0.001); rates were 57.3%, 57.6% and 8.7%, respectively. Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at week 24 were 0.2 and -0.4, respectively, versus 1.2 for placebo (rank analysis p< or =0.01). Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo; mean changes from baseline in HAQ-DI at week 24 were -0.50 and -0.50, respectively, versus -0.14 for placebo (p< or =0.001). Most adverse events were mild or moderate, with low incidence of withdrawals due to adverse events. Five patients developed tuberculosis. CONCLUSION: Certolizumab pegol plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression. TRIAL REGISTRATION NUMBER: NCT00175877.
17207381 Synovial inflammation in active rheumatoid arthritis and psoriatic arthritis facilitates t 2006 Nov OBJECTIVE: To investigate the presence of oral bacterial DNAs in serum and synovial fluid (SF) of patients with active rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: Serum and SF samples from 16 RA patients, 14 PsA patients, and 9 osteoarthritis (controls) patients were extracted for oral bacterial DNA. This was used in a checkerboard DNA-DNA-hybridization set up, to identify 40 different bacteria. RESULTS: Mean number +/- standard deviation (SD) of oral bacterial species in sera were 6.2 (3.2) in the RA group (p = 0.004) and 5.4 (2.7) in the PsA group (p = 0.009) compared to 2.1 (1.7) in the controls. Periodontitis associated species Porphyromonas gingivalis and Prevotella nigrescens were exclusively detected in RA and PsA. Mean number (+/- SD) of oral bacterial species in SF were 14.0 (6.8) in the RA (p = 0.001) and 19.4 (7.1) in the PsA group (p < 0.001) compared to 4.0 (1.7) in controls. P. gingivalis, Tannerella forsythensis and Prevotella intermedia were exclusively identified in RA and PsA SF. Higher means of DNAs were found in RA SF compared to RA serum (p < 0.001), and in PsA SF compared to PsA serum (p < 0.001). Higher concentrations of bacterial DNAs were found in RA and PsA compared to controls. CONCLUSION: Higher variety and concentrations of oral bacterial DNAs were found in SF compared to serum of RA and PsA patients. These findings indicate that synovial inflammation in RA and PsA may favor trapping of oral bacterial DNAs, suggesting a perpetuating effect of oral pathogens in joint disease.
18516710 Inhibitory effect of triptolide on interleukin-18 and its receptor in rheumatoid arthritis 2008 Jun OBJECTIVE: To determine the effects of triptolide (TP) on the expression of interleukin-18 (IL-18) and its receptor in phorbol 12-myristate 13-acetate (PMA)-stimulated rheumatoid arthritis synovial fibroblasts (RASF). MATERIALS AND METHODS: RASF were obtained from the synovial tissue of patients with RA. RASF were pretreated with TP (0~100 ng/ml) for 2 h before stimulation with PMA (50 ng/ml). The bioactivity of IL-18 in the supernatant was detected based on IFN-gamma secretion from IL-18-responding human myelomonocytic KG-1 cells. IL-18 level was analyzed by ELISA. In situ expression of IL-18Ralpha was determined by immunofluorescence assay. To estimate the protein and mRNA expression of IL-18 and IL-18Ralpha in RASF, western blot and quantitative RT-PCR were performed. Nuclear factor-kappaB (NF-kappaB) activity in the whole-cell extract of treated RASF was also measured using an ELISA-based method. RESULTS: TP effectively inhibited the bioactivity of IL-18 in PMA-stimulated RASF. The expression of IL-18 and IL-18R at protein and gene levels was reduced by TP. NF-kappaB activity in PMA-stimulated RASF was profoundly suppressed by TP. These effects showed a high correlation with TP concentration (0~100 ng/ml). CONCLUSION: TP effectively inhibited the expression of IL-18 and its receptor in PMA-stimulated RASF. These results suggest a mechanism of TP in RA therapy.