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ID PMID Title PublicationDate abstract
17968936 Microparticles stimulate the synthesis of prostaglandin E(2) via induction of cyclooxygena 2007 Nov OBJECTIVE: Microparticles are small vesicles that are released from activated or dying cells and that occur abundantly in the synovial fluid of patients with rheumatoid arthritis (RA). The goal of these studies was to elucidate the mechanisms by which microparticles activate synovial fibroblasts to express a proinflammatory phenotype. METHODS: Microparticles from monocytes and T cells were isolated by differential centrifugation. Synovial fibroblasts were cocultured with increasing numbers of microparticles. Gene expression was analyzed by real-time polymerase chain reaction and confirmed by Western blotting and enzyme immunoassay. Arachidonic acid labeled with tritium was used to study the transport of biologically active lipids by microparticles. The roles of NF-kappaB and activator protein 1 (AP-1) signaling were analyzed with electrophoretic mobility shift assay and transfection with small interfering RNA and IkappaB expression vectors. RESULTS: Microparticles strongly induced the synthesis of cyclooxygenase 2 (COX-2), microsomal prostaglandin E synthase 1 (mPGES-1), and prostaglandin E(2) (PGE(2)). In contrast, no up-regulation of COX-1, mPGES-2, cytosolic PGES, or phospholipase A(2) was observed. The induction of PGE(2) was blocked by selective inhibition of COX-2. Microparticles activated NF-kappaB, AP-1, p38, and JNK signaling in synovial fibroblasts. Inhibition of NF-kappaB, AP-1, and JNK signaling reduced the stimulatory effects. Arachidonic acid was transported from leukocytes to fibroblasts by microparticles. Arachidonic acid derived from microparticles was converted to PGE(2) by synovial fibroblasts. CONCLUSION: These results demonstrate that microparticles up-regulate the production of PGE(2) in synovial fibroblasts by inducing COX-2 and mPGES-1. These data provide evidence for a novel mechanism by which microparticles may contribute to inflammation and pain in RA.
16873097 Intracellular Th1/Th2 balance of pulmonary CD4(+) T cells in patients with active intersti 2006 The balance between CD4(+) T helper (Th1) lymphocytes producing interferon-gamma or Interleukin-4 (Th2) in the lungs may vary among diseases and during the progression of interstitial pneumonia (IP). Both idiopathic pulmonary fibrosis (IPF) and collagen vascular diseases (CVD) are associated with IP, but the clinical course and the response to treatment are different. Since Th1 or Th2 modulating drugs have been proven to alter the lymphocyte balance in vitro, it is important to elucidate the Th1/Th2 profile in patients with active IP. Bronchoalveolar lavage (BAL) was performed in patients who had IPF (n = 12) or CVD (n = 12) with IP, as well as in patients who had bronchoectasis and bronchopneumonia (n = 12). The CVD patients had rheumatoid arthritis (n = 6), Sjogren's syndrome (n = 2), dermatomyositis (n = 1), progressive systemic sclerosis (n = 2), and CREST syndrome (n = 1) as the underlying diseases. IP activity was evaluated by measuring serum KL-6, which is a clinically useful indicator for IP. The Th1/ Th2 balance and the CD4(+)/CD8(+) ratio were determined for lymphocytes obtained from BAL by flow cytometric analysis. In IPF patients, the CD4(+)/CD8(+) ratio was lower than in CVD patients. IPF patients showed Th2 dominance and CVD patients showed Th1 dominance when IP was active as evaluated by the serum KL-6 level. These data indicated that the Th1/Th2 balance of CD4(+) T cells in the BAL differs between active IPF and CVD, even though KL-6 is elevated in both diseases. Therefore, the Th1/Th2 profile should be investigated to determine the use of Th1/Th2 modulator therapy for active IP with elevation of KL-6.
16519793 Ultrasonography of the metacarpophalangeal and proximal interphalangeal joints in rheumato 2006 Signs of inflammation and destruction in the finger joints are the principal features of rheumatoid arthritis (RA). There are few studies assessing the sensitivity and specificity of ultrasonography in detecting these signs. The objective of the present study was to investigate whether ultrasonography can provide information on signs of inflammation and destruction in RA finger joints that are not available with conventional radiography and clinical examination, and comparable to the information provided by magnetic resonance imaging (MRI). The second to fifth metacarpophalangeal and proximal interphalangeal joints of 40 RA patients and 20 control persons were assessed with ultrasonography, clinical examination, radiography and MRI. With MRI as the reference method, the sensitivity, specificity and accuracy of ultrasonography in detecting bone erosions in the finger joints were 0.59, 0.98 and 0.96, respectively; they were 0.42, 0.99 and 0.95 for radiography. The sensitivity, specificity and accuracy of ultrasonography, with signs of inflammation on T1-weighted MRI sequences as the reference method, were 0.70, 0.78 and 0.76, respectively; they were 0.40, 0.85 and 0.72 for the clinical examination. With MRI as the reference method, ultrasonography had higher sensitivity and accuracy in detecting signs of inflammation and destruction in RA finger joints than did clinical and radiographic examinations, without loss of specificity. This study shows that ultrasonography has the potential to improve assessment of patients with RA.
19035487 Modulation of molecular imprints in the antigen-experienced B cell repertoire by rituximab 2008 Dec OBJECTIVE: Transient B cell depletion by rituximab has recently gained more importance in the treatment of rheumatic disorders. Nevertheless, little is known about the reemerging B cells. We analyzed dynamic changes in the repopulating B cells, particularly the postswitch B cells, and studied the mutational patterns of Ig genes in antigen-experienced B cells. METHODS: Five patients with active rheumatoid arthritis (RA) were treated with rituximab. In 3 patients, B cell receptor (BCR) gene analysis was performed before treatment and during B cell recovery using genomic DNA. In 2 patients, B cell subsets were studied during the early recovery phase using single-cell technology. For comparison, immunophenotyping of B cell subsets was performed. RESULTS: Early B cell recovery was marked by a relatively expanded population of highly mutated B cells, which were correlated with B cells with a plasmablast phenotype on comparative immunophenotyping. Analysis of the mutational pattern in these cells revealed increased RGYW/WRCY (where R = A/G, Y = C/T, and W = A/T) hotspot targeting (44% before rituximab versus 59% after) and elevated ratios of replacement to silent mutations within the complementarity-determining regions in Ig genes (1.87 before rituximab versus 2.67 after; P < or = 0.0025). CONCLUSION: Our findings show that rituximab leads to qualitative changes in the imprints of highly mutated, antigen-experienced BCRs, representing the result of selection, whereas molecular processes such as Ig V rearrangements are not affected by this treatment.
16962143 Effect of anti-TNFalpha treatment on circulating endothelial progenitor cells (EPCs) in rh 2006 Nov 17 Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, which may be attenuated by anti-inflammatory treatment. Endothelial progenitor cells (EPCs) have the ability to differentiate into mature endothelium and have a potentially reparative role protecting against ischemia and atherosclerosis. OBJECTIVE: To investigate the effect of treatment with infliximab on the number and functional capacity of endothelial progenitor cells (EPCs) in patients with RA, as a possible mechanism for reducing cardiovascular morbidity in this disorder. PATIENTS: Active seropositive RA patients (N = 14) considered candidates for starting infliximab treatment, were recruited. Assessment, based on DAS-28, was performed before treatment and 14 days later. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by the colony-forming unit (CFU) method. Endothelial phenotyping of CFU was performed by immunofluorescence employing antibodies to Tie-2 VEGF-receptor 2, and CD31. EPC Functional properties were evaluated by fibronectin adherance. RESULTS: A significant 33.4% increase (p < 0.001) in EPC levels was observed after infliximab. A 60% increase was noted in the EPC differentiation scale, (p < 0.002) while a 37.6% increase was observed in mean EPC adhesion (p < 0.001). These changes were associated with a 17.5% decrease in the DAS-28 (p < 0.0001). A significant correlation was observed between the clinical response, reflected by changes in DAS-28 and the degree of increase in EPC CFUs. CONCLUSION: A single dose of infliximab improved the number and functional properties of EPCs, in parallel with an early clinical effect, suggesting a possible mechanism by which anti-inflammatory treatment may reduce cardiovascular risk in RA patients.
17491318 [Two cases of respiratory infection complicating treatment with infliximab]. 2007 Apr Infliximab, an anti-TNF-alpha agent, is highly effective against rheumatoid arthritis and Crohn's disease. However, respiratory infection can occur as a complication. We report two cases complicated by respiratory infection following administration of infliximab. The first case, a 67-year-old woman with rheumatoid arthritis, developed pneumocystis pneumonia after three courses of infliximab therapy. The second case, a 31-year-old man with Crohn's disease, developed pulmonary tuberculosis after four courses of infliximab therapy. Respiratory complications associated with anti-TNF therapy include infectious diseases such as pneumocystis pneumonia, tuberculosis, and bacterial pneumonia. They often lead a fulminant course, and early diagnosis is essential. The final report of a survey of the initial 5000 cases with rheumatoid arthritis treated with infliximab in Japan was released in April 2006; pulmonary infectious complications included 22 cases of pneumocystis pneumonia, 14 cases of tuberculosis, and 108 cases of bacterial pneumonia. The growing use of anti-TNF therapy might lead to increasing pulmonary complications. Accumulation of similar cases is expected to elucidate the mechanism of the complications and methods for effective prophylaxis.
16585962 Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune 2006 Apr Antibodies against citrullinated proteins are specific and predictive markers for rheumatoid arthritis although the pathologic relevance of these antibodies remains unclear. To investigate the significance of these autoantibodies, collagen-induced arthritis (CIA) in mice was used to establish an animal model of antibody reactivity to citrullinated proteins. DBA/1J mice were immunized with bovine type II collagen (CII) at days 0 and 21, and serum was collected every 7 days for analysis. Antibodies against both CII and cyclic citrullinated peptide, one such citrullinated antigen, appeared early after immunization, before joint swelling was observed. Further, these antibodies demonstrated specific binding to citrullinated filaggrin in rat esophagus by indirect immunofluorescence and citrullinated fibrinogen by Western blot. To evaluate the role of immune responses to citrullinated proteins in CIA, mice were tolerized with a citrulline-containing peptide, followed by antigen challenge with CII. Tolerized mice demonstrated significantly reduced disease severity and incidence compared with controls. We also identified novel murine monoclonal antibodies specific to citrullinated fibrinogen that enhanced arthritis when coadministered with a submaximal dose of anti-CII antibodies and bound targets within the inflamed synovium of mice with CIA. These results demonstrate that antibodies against citrullinated proteins are centrally involved in the pathogenesis of autoimmune arthritis.
16385500 A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis su 2006 Jan OBJECTIVE: Anticitrullinating autoantibodies are specific markers for rheumatoid arthritis (RA). A functional haplotype of 4 exonic single-nucleotide polymorphisms (SNPs) in a citrullinating enzyme, peptidylarginine deiminase 4 (PADI4), was shown to be associated with susceptibility to RA in a Japanese population and was shown to increase the stability of PADI4 messenger RNA. However, the association was not confirmed in 4 subsequent studies involving Caucasian RA patients living in the UK, a French Caucasian population, and a Spanish population. The aim of the current study was to investigate the association of SNPs in the PADI4 gene with RA in a Korean population. METHODS: Four exonic SNPs of the PADI4 gene (padi4_89, padi4_90, padi4_92, and padi4_104) were genotyped in 545 unrelated patients with RA and 392 controls, using the MassArray SNP genotyping system. Allelic, genotypic, and haplotypic associations of the SNPs with RA susceptibility were examined using the chi-square test and multivariate logistic regression analyses. RESULTS: Increased RA susceptibility was significantly associated with the minor alleles of padi4_89 (P = 2.3 x 10(-5)), padi4_90 (P = 2.3 x 10(-5)), padi4_92 (P = 2.1 x 10(-5)), and padi4_104 (P = 1.1 x 10(-3)) and the haplotype carrying the 4 minor alleles (P = 1.0 x 10(-4)). Genotypes carrying the minor alleles and HLA-DRB1 shared epitope (SE) alleles (P = 9.4 x 10(-21)) were also associated with increased RA susceptibility. The genotypic associations were sustained among individuals who did not carry any SE alleles, except in the case of padi4_104. Individuals carrying the risk SNPs and/or SE alleles were more susceptible to RA than were individuals carrying neither risk SNPs nor SE alleles. CONCLUSION: The PADI4 SNPs and haplotypes are associated with RA susceptibility in Koreans. Thus, the association of PADI4 with RA may depend on genetic heterogeneity between Asians and Europeans.
17427142 Oxygen, nitric oxide and articular cartilage. 2007 Apr 11 Molecular oxygen is required for the production of nitric oxide (NO), a pro-inflammatory mediator that is associated with osteoarthritis and rheumatoid arthritis. To date there has been little consideration of the role of oxygen tension in the regulation of nitric oxide production associated with arthritis. Oxygen tension may be particularly relevant to articular cartilage since it is avascular and therefore exists at a reduced oxygen tension. The superficial zone exists at approximately 6% O2, while the deep zone exists at less than 1% O2. Furthermore, oxygen tension can alter matrix synthesis, and the material properties of articular cartilage in vitro. The increase in nitric oxide associated with arthritis can be caused by pro-inflammatory cytokines and mechanical stress. Oxygen tension significantly alters endogenous NO production in articular cartilage, as well as the stimulation of NO in response to both mechanical loading and pro-inflammatory cytokines. Mechanical loading and pro-inflammatory cytokines also increase the production of prostaglandin E2 (PGE2). There is a complex interaction between NO and PGE2, and oxygen tension can alter this interaction. These findings suggest that the relatively low levels of oxygen within the joint may have significant influences on the metabolic activity, and inflammatory response of cartilage as compared to ambient levels. A better understanding of the role of oxygen in the production of inflammatory mediators in response to mechanical loading, or pro-inflammatory cytokines, may aid in the development of strategies for therapeutic intervention in arthritis.
17673937 Genetic regulation of T regulatory, CD4, and CD8 cell numbers by the arthritis severity lo 2007 May T cells have a central role in the pathogenesis of autoimmune arthritis, and several abnormalities in T cell homeostasis have been described in rheumatoid arthritis (RA). We hypothesized that T cell phenotypes, including frequencies of different subsets of T regulatory (Treg) cells and in vitro functional responses could be genetically determined. Furthermore, we considered that the genetic contribution would be accounted for by one of the arthritis regulatory quantitative trait loci (QTL), thus providing novel clues to gene mode of action. T cells were isolated from thymus, peripheral blood, and spleen from DA (arthritis-susceptible) and ACI and F344 (arthritis-resistant) strains and from F344.DA(Cia1), DA.F344(Cia5a), and DA.F344(Cia5d) rats congenic for arthritis QTL. T cell subpopulations differed significantly between DA, F344, and ACI. DA rats had an increased frequency of CD4(+) cells, and a reduction in CD8(+) and CD4(+)CD45RC(|o) Treg cells, compared with F344. The differences in CD4/CD8 and CD4(+)CD45RC(|o) Treg cells were accounted for by Cia5a. DA rats also had a reduced frequency of CD8(+)CD45RC(|o) CD25(+) Treg cells compared with F344, and that difference was explained by Cia5d. DA rats also had a significantly lower frequency of CD4(+)CD25(+) and CD8(+)CD25(+) thymocytes, and of peripheral blood CD8(+)CD45RC(|o) Treg cells, compared with F344 rats, and that difference was accounted for by the MHC. This is the first identification of arthritis severity QTL regulating numbers of CD4(+)CD45RC(|o) (Cia5a) and CD8(+)CD45RC(|o) CD25(+) (Cia5d) Treg cells. The MHC effect on CD8(+) Treg cells and CD25(+) thymocytes raises a novel potential explanation for its association with arthritis.
18473869 The blockade of IL-6 signaling in rational drug design. 2008 After three decades from the development of the hybridoma technology, a monoclonal antibody-based therapy targeting the inflammatory cytokine has been established as an ultimate treatment for chronic inflammatory diseases. Interleukine-6 (IL-6) is one of the inflammatory cytokines playing a pivotal role in these conditions, and strategies targeting IL-6 signal show promise in the treatment of chronic inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, and Crohn's disease. Although many groups have been exploring the approach to block the IL-6 signal, tocilizumab, a humanized monoclonal antibody of the IL-6 receptor, has been the most intensively studied agent for clinical use. Clinical trials regarding chronic inflammatory diseases described above have demonstrated efficacy of tocilizumab, however, this treatment has limitations in terms of economic costs and ease of administration, and further advances are necessary to expand the concept of IL-6-specific therapeutics. In this review, we discuss targeting IL-6 in a rational drug design and present the various strategies to achieve this.
18723565 Sustained changes in lipid profile and macrophage migration inhibitory factor levels after 2009 Aug BACKGROUND: Macrophage migration inhibitory factor (MIF) has recently emerged as an important cytokine possibly linking rheumatoid arthritis (RA) and atherogenesis. Because atherogenesis is accelerated in RA this study was conducted to investigate whether anti-tumour necrosis factor (TNF) therapy could lead to sustained downregulation of systemic MIF levels and improvement in lipid profiles. METHODS: Fifty RA patients with active disease (disease activity score in 28 joints (DAS28) >or=3.2), who started adalimumab therapy at 40 mg every other week, were included. At baseline, weeks 16 and 52 serum levels of MIF and lipids were assessed. In addition, the DAS28 and serum C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) were determined. RESULTS: After 16 weeks of adalimumab therapy, both DAS28 and MIF levels were significantly decreased (p<0.001 and p = 0.020, respectively). This was sustained up to week 52 (p<0.001 and p = 0.012, respectively). CRP levels and ESR were significantly reduced after 16 and 52 weeks of adalimumab therapy (p<0.001). High-density lipoprotein cholesterol levels increased at week 16 (p<0.001), but returned to baseline at week 52. Apolipoprotein (apo) A-I levels increased at week 16 (p<0.001) and remained stable (p = 0.005). This resulted in an improved apo B/A-I ratio. CONCLUSIONS: The results underline the sustained downregulation of MIF as a potential new mechanism by which anti-TNF therapy might reduce vascular inflammation, and as such perhaps cardiovascular morbidity in RA patients. This hypothesis is supported by an improved apo B/A-I ratio as well as reduced CRP levels in these patients.
17341304 Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils 2007 Functional links between bone remodeling and the immune system in chronic inflammatory arthritis are mediated, in part, by the ligand of receptor activator of nuclear factor-kappa-B (RANK-L). Because neutrophils play a crucial role in chronic inflammation, the goal of this study was to determine whether proteins of the RANK/RANK-L pathway are expressed by synovial fluid (SF) neutrophils from patients with rheumatoid arthritis (RA) and to characterize this pathway in normal human blood neutrophils. The expression of RANK-L, osteoprotegerin (OPG), RANK, and tumor necrosis factor receptor-associated factor 6 (TRAF6) was determined by polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and cytofluorometry. RANK signaling was analyzed by the degradation of inhibitor of kappaB-alpha (I-kappaB-alpha). SF neutrophils from patients with RA express and release OPG and express the membrane-associated forms of RANK-L and RANK. In contrast, normal blood neutrophils express only the membrane-associated form of RANK-L. They do not express the mRNAs encoding OPG and RANK. SF neutrophils from RA patients and normal blood neutrophils release no soluble RANK-L. They express the mRNA for TRAF6. The expression of OPG and RANK by normal human blood neutrophils, however, can be induced by interleukin-4 + tumor necrosis factor-alpha and by SFs from patients with RA. In contrast, SFs from patients with osteoarthritis do not induce the expression of OPG and RANK. Moreover, the addition of RANK-L to normal blood neutrophils pretreated by SF from patients with RA decreased I-kappaB-alpha, indicating that RANK signaling by neutrophils stimulated with SF is associated with nuclear factor-kappa-B activation. In summary, RANK-L is expressed by inflammatory and normal neutrophils, unlike OPG and RANK, which are expressed only by neutrophils exposed to an inflammatory environment. Taken together, these results suggest that neutrophils may contribute to bone remodeling at inflammatory sites where they are present in significantly large numbers.
18264550 Humeral resurfacing arthroplasty: rationale, indications, technique, and results. 2007 Dec Humeral head resurfacing arthroplasty has evolved into a reliable method of shoulder arthroplasty designed to restore the natural anatomy of an arthritic or damaged articular humeral surface. Recent implant changes have improved the ability of the surface replacement implants to recreate the humeral head surface and the initial implant fixation. Instrument changes have improved the ability to place the implant in the anatomical position that recreates an individual's humeral articular surface posterior offset, neck-shaft angle, and version. These implant and instrument changes have led to a more refined surgical technique that avoids the complications associated with use of stemmed implants. Minimal bone resection occurs in shoulder resurfacing arthroplasty--the result being bone stock preservation, which is important in active or young patients with shoulder arthritis. Cementless surface replacements have been shown to provide results comparable to those of stemmed implants similar in diagnosis and follow-up. In this article, I outline the current rationale for resurfacing arthroplasty implants and the indications for their use. I also present the surgical technique and review the results of proximal humeral resurfacing arthroplasty.
18474096 Characteristics of T-cell large granular lymphocyte proliferations associated with neutrop 2008 INTRODUCTION: The purpose of this study was to analyze the data of patients with T-cell large granular lymphocyte (T-LGL) lymphocytosis associated with inflammatory arthropathy or with no arthritis symptoms. METHODS: Clinical, serological as well as histopathological, immunohistochemical, and flow cytometric evaluations of blood/bone marrow of 21 patients with T-LGL lymphocytosis were performed. The bone marrow samples were also investigated for T-cell receptor (TCR) and immunoglobulin (IG) gene rearrangements by polymerase chain reaction with heteroduplex analysis. RESULTS: Neutropenia was observed in 21 patients, splenomegaly in 10, autoimmune diseases such as rheumatoid arthritis (RA) in 9, unclassified arthritis resembling RA in 2, and autoimmune thyroiditis in 5 patients. T-LGL leukemia was recognized in 19 cases. Features of Felty syndrome were observed in all RA patients, representing a spectrum of T-LGL proliferations from reactive polyclonal through transitional between reactive and monoclonal to T-LGL leukemia. Bone marrow trephines from T-LGL leukemia patients showed interstitial clusters and intrasinusoidal linear infiltrations of CD3+/CD8+/CD57+/granzyme B+ lymphocytes, reactive lymphoid nodules, and decreased or normal granulocyte precursor count with left-shifted maturation. In three-color flow cytometry (FCM), T-LGL leukemia cells demonstrated CD2, CD3, and CD8 expression as well as a combination of CD16, CD56, or CD57. Abnormalities of other T-cell antigen expressions (especially CD5, CD7, and CD43) were also detected. In patients with polyclonal T-LGL lymphocytosis, T cells were dispersed in the bone marrow and the expression of pan-T-cell antigens in FCM was normal. Molecular studies revealed TCRB and TCRG gene rearrangements in 13 patients and TCRB, TCRG, and TCRD in 4 patients. The most frequently rearranged regions of variable genes were Vbeta-Jbeta1, Jbeta2 and Vgamma If Vgamma10-Jgamma. Moreover, in 4 patients, additional rearrangements of IG kappa and lambda variable genes of B cells were also observed. CONCLUSION: RA and neutropenia patients represented a continuous spectrum of T-LGL proliferations, although monoclonal expansions were most frequently observed. The histopathological pattern and immunophenotype of bone marrow infiltration as well as molecular characteristics were similar in T-LGL leukemia patients with and without arthritis.
18383357 Increased cortisol relative to adrenocorticotropic hormone predicts improvement during ant 2008 Apr OBJECTIVE: Some patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) improve rapidly from anti-tumor necrosis factor (anti-TNF) therapy. No sensitive markers are available that might predict outcome of anti-TNF therapy. We undertook this study to investigate the predictive value of hypothalamic-pituitary-adrenal (HPA) axis hormones for clinical improvement during anti-TNF therapy. METHODS: An observational study in 23 RA patients was followed by a validation study in 38 RA patients. The patients receiving anti-TNF antibodies had no glucocorticoid treatment, and we measured baseline serum levels of adrenocorticotropic hormone (ACTH) and cortisol. Improvement during anti-TNF antibody treatment was judged by the Disease Activity Score in 28 joints (DAS28), and serum levels of cortisol were measured at followup. RESULTS: The observational study demonstrated that improvement in the DAS28 correlated negatively with baseline serum levels of cortisol (R=-0.520, P=0.011) and the cortisol:ACTH ratio (R=-0.700, P=0.0002). In the longitudinal part of the study at followup, those patients with good improvement and initially low serum levels of cortisol demonstrated an increase of serum cortisol, in contrast to patients with little or no improvement. Findings in the observational study were supported by those in the validation study in a group of RA patients with less inflammation (correlation of improvement in the DAS28 with cortisol:ACTH ratio: R=-0.320, P=0.025). CONCLUSION: This is the first study in a human chronic inflammatory disease to demonstrate that inflammation-induced TNF interferes with HPA axis integrity, which is linked to the disease outcome. These findings position the HPA axis centrally in the vicious circle of perpetuation of chronic inflammation.
17597527 A 1-year case-control study in patients with rheumatoid arthritis indicates prevention of 2007 The goal of the present study was to record changes in bone mineral density (BMD) and markers of bone turnover in patients with rheumatoid arthritis (RA) who were treated with methotrexate combined (or not combined) with infliximab. Included were 90 patients with RA who required anti-TNF-alpha therapy with infliximab because of persistent active disease despite treatment with methotrexate. The historical control group included 99 patients with RA who were treated with methotrexate at a time when anti-TNF-alpha treatment was not yet available. Lumbar and femoral neck BMD was measured using dual energy X-ray absorptiometry at baseline and 1 year later. Osteocalcin, C-terminal cross-linked telopeptide of type I collagen, parathyroid hormone and 25-hydroxycholecalciferol were measured in plasma at baseline and 1 year later. At 1 year BMD had decreased in the control group at spine (P < 0.01) and femoral neck (P < 0.001). In contrast, BMD at spine and femoral neck did not change after 1 year of infliximab treatment. At the same time point, no change in bone remodelling markers was observed. No association was observed between clinical response and changes in BMD, indicating that even those who did not respond clinically did not lose bone over a 1-year period. These data confirm the BMD decrease observed in RA patients treated with methotrexate alone. This bone loss was prevented by infliximab therapy. Importantly, this beneficial effect was also observed in apparent nonresponders.
18203328 Short-term course of chronic hepatitis B and C under treatment with etanercept associated 2008 Mar OBJECTIVE: To evaluate the short-term course of chronic hepatitis B and C under treatment with etanercept (ETN) associated with different disease modifying antirheumatic drugs (DMARD). METHODS: Patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) receiving anti-tumor necrosis factor-a (TNF-a) were retrospectively reviewed for the presence of hepatitis B or C serology, liver function tests, liver biopsy findings, and the relevant outcomes in terms of viral load. RESULTS: We identified 5 relevant cases receiving ETN, 3 RA patients with chronic hepatitis C, another RA patient with dual infection by B and C, and one AS patient with hepatitis B. Four patients met the American College of Rheumatology criteria for RA. The patient with AS fulfilled the modified New York diagnostic criteria for AS. In Case 1, ETN was started after having discontinued a-interferon and ribavirin due to viral clearance of hepatitis C. These patients had not received prophylactic antiviral therapy while being treated with ETN. Viral replication increased in 2 patients to an insignificant level, remained negative in 2, and decreased in the remaining one. No significant rise in patients' liver transaminases could be determined during followup. CONCLUSION: We observed reactivation of hepatitis C virus infection in 2 of 4 patients while they were receiving ETN with DMARD without antiviral prophylaxis.
17391739 Response-driven combination therapy with conventional disease-modifying antirheumatic drug 2007 Oct OBJECTIVES: To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA), with dose adjustments determined by response, in a clinic setting over 3 years. METHODS: Disease-modifying antirheumatic drug (DMARD)-naive patients with RA of median duration of 12 weeks (n = 61) attending an early arthritis clinic were treated with methotrexate, sulfasalazine, hydroxychloroquine, and fish oil. Dosage adjustments and additions of further DMARDs were contingent on response to therapy and tolerance. Outcome measures for efficacy were Disease Activity Score (DAS28), clinical remission, and modified Sharp radiographic score and for safety, adverse events, and DMARD withdrawal. RESULTS: At baseline, subjects had at least moderately active disease (mean +/- SD DAS28 was 5.3 +/- 1.1), impaired function as measured by the modified Health Assessment Questionnaire (mHAQ) (0.9 +/- 0.5), and 37% had bone erosions. By 3 months, 29% were in remission; this increased to 54% at 3 years. The greatest fall in DAS28 and improvement in mHAQ scores occurred in the first 12 months. Erosions were detected in 62% at 3 years. The mean dose of parenteral glucocorticoid was equivalent to 0.1 mg/d of prednisolone. After 3 years, 48% remained on triple therapy; fish oil was consumed by 75% of patients, and 21% used nonsteroidal anti-inflammatory drugs. Gastrointestinal intolerance was the most frequent unwanted event (leading to DMARD withdrawal in 17 patients). Sulfasalazine was most frequently withdrawn (30%). CONCLUSION: This implementation study demonstrates the feasibility, safety, and efficacy of combination therapy with inexpensive DMARDs, fish oil, and minimal glucocorticoid use, in routine clinical practice using predefined rules for dosage adjustment.
16362367 A hypothesis for the origin and pathogenesis of rheumatoid diseases. 2006 May It is well established that a correlation exists between rheumatoid arthritis (RA) and microbial damage. Material analyses have suggested that bacteria may be causative agents. This study was undertaken to further characterize the microbial agent responsible for pathogenesis of RA. In order to investigate whether substances in moist building materials can affect human cartilage, extracts from moist building materials were analysed for microbial components. Exposure of chondrocyte cultures to extracts in vitro showed that they were damaging the cultures. A direct correlation between strength of damage and concentration of MMP3 demonstrated that the effect was dose-dependent. High quantities of LPS were detected in the extracts. Experiments after deactivation with Polymyxin B showed that LPS are the causative agents. The present study leads to the hypothesis that LPS may bind to procollagen, as they bind to scavenger receptors. This procollagen endotoxin complex may block tropocollagen synthesis.