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ID PMID Title PublicationDate abstract
22130325 IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid art 2012 Apr The interleukin (IL)-17/IL-23 axis is an important pro-inflammatory pathway in rheumatoid arthritis (RA). IL-23 maintains CD4(+) T-helper 17 (Th(17)) cells, whereas IL-12 negates IL-17A production by promoting Th(1)-cell differentiation. We sought evidence for any effect of polymorphisms within the interleukin-23 receptor (IL-23R), IL-12 or IL-21 genes on serum cytokine concentrations in 81 patients with RA. Serum cytokines were measured using bead-based multiplex assays. Targeted cytokines were detected in up to 66% of samples. A subgroup of 48 patients had detectable serum IL-17A. Within this subgroup, patients, homozygous for the IL-23R rs11209026 major allele had significantly higher serum IL-17A concentrations compared with patients with the minor allele (394.51 ± 529.72 pg ml(-1) vs 176.11 ± 277.32 pg ml(-1); P = 0.017). There was no significant difference in any of the cytokine concentrations examined in patients positive for the minor allele vs homozygosity for the major allele of IL-12B rs3213337, IL-12Bpro rs17860508 and IL-21 rs6822844. Our results suggest the IL-23R Arg381Gln substitution may influence serum IL-17A concentrations. In patients with the 381Gln allele higher IL-23 concentrations may be needed to produce similar IL-17A concentrations to those in patients with the 381Arg allele. This suggests altered IL-23R function in patients with the minor allele and warrants further functional studies.
22827495 Fewer and older patients with rheumatoid arthritis need total knee replacement. 2012 Oct OBJECTIVES: Recent studies have suggested a decreased need for orthopaedic surgery in patients with rheumatoid arthritis (RA). We analysed trends in total knee replacement (TKR) in RA using TKR in osteoarthritis (OA) as a point of reference. METHODS: Data on TKRs from the Finnish Arthroplasty Register and population data from Statistics Finland were used to analyse the trends in TKRs among patients aged ≥ 40 years with primary osteoarthritis (OA) or RA in Finland for the period from 1980 to 2010. RESULTS: During 1980-2010, the overall incidence of TKRs increased 20-fold from 14.2 to 305.3 operations per 10(5) person-years. After peaking in 1992, the annual incidence of TKRs for RA decreased gradually from 19.6 to 10.8 per 10(5) [incidence rate ratio (IRR) 0.97, p < 0.001]. The decrease was more pronounced in women and the older (≥ 60 years) age group. The mean age at the time of TKR among patients with RA increased over time, converging with that of patients with OA. CONCLUSION: There is a clear decrease in the annual incidence of TKRs in RA, while among OA patients the incidence is increasing steadily. Furthermore, patients with RA seem to receive their TKRs at an older age. Both of these findings suggest improving long-term outcome in RA.
22092471 Periodontal disease, tooth loss and incident rheumatoid arthritis: results from the First 2011 Nov AIMS: Infection may be a rheumatoid arthritis (RA) risk factor. We examined whether signs of periodontal infection were associated with RA development in the First National Health and Nutrition Examination Survey and its epidemiological follow-up study. MATERIAL AND METHODS: In 1971-1974, 9702 men and women aged 25-74 were enrolled and surveyed longitudinally (1982, 1986, 1987, 1992). Periodontal infection was defined by baseline tooth loss or clinical evidence of periodontal disease. Baseline (n = 138) and incident (n = 433) RA cases were defined via self-report physician diagnosis, joint pain/swelling, ICD-9 codes (714.0-714.9), death certificates and/or RA hospitalization. RESULTS: Adjusted odds ratios (ORs) (95% CI) for prevalent RA in gingivitis and periodontitis (versus healthy) were 1.09 (0.57, 2.10) and 1.85 (0.95, 3.63); incident RA ORs were 1.32 (0.85, 2.06) and 1.00 (0.68, 1.48). The ORs for prevalent RA among participants missing 5-8, 9-14, 15-31 or 32 teeth (versus 0-4 teeth) were 1.74 (1.03, 2.95), 1.82 (0.81, 4.10), 1.45 (0.62, 3.41) and 1.30 (0.48, 3.53); ORs for incident RA were 1.12 (0.77, 1.64), 1.67 (1.12, 2.48), 1.40 (0.85, 2.33) and 1.22 (0.75, 2.00). Dose-responsiveness was enhanced among never smokers. The rate of death or loss-to-follow-up after 1982 was two- to fourfold higher among participants with periodontitis or missing ≥9 teeth (versus healthy participants). CONCLUSIONS: Although participants with periodontal disease or ≥5 missing teeth experienced higher odds of prevalent/incident RA, most ORs were non-statistically significant and lacked dose-responsiveness. Differential RA ascertainment bias complicated the interpretation of these data.
22605859 Visceral leishmaniasis in immunosuppressed Caucasian patient. 2012 May 8 A 64-year-old man was admitted with fever, weight loss, fatigue and night sweats. He was known to have rheumatoid arthritis and had been taking methotrexate for 1 year. He had worked in Saudi Arabia until 1994 and had been living in Spain for 6 months every year. Clinical examination showed an enlarged spleen. Routine investigations showed pancytopaenia. Serial blood cultures were negative. CT scan confirmed splenomegaly and was otherwise unremarkable. Bone marrow biopsy revealed Leishmania amastigote consistent with a diagnosis of visceral leishmaniasis. After discussing with the hospital for tropical diseases (HTD), he was started on liposomal amphotericin B. Following two infusions of amphotericin B, he started improving as his fever, night sweats and weakness had settled. He was then discharged and followed up in HTD clinic 4 weeks later where he was found to be consistently improving.
21516373 Standard treatment in daily clinical practice for early rheumatoid arthritis improved dise 2011 Dec We aimed to clarify the degree of improvement in disease control following early treatment of rheumatoid arthritis (RA) in daily clinical practice in 2006 compared to that in 2001. Using a large observational Japanese RA cohort (IORRA), we analyzed changes in clinical parameters, including disease activity assessed by the disease activity score 28 (DAS28) and physical disability assessed by the Japanese version of the Health Assessment Questionnaire (J-HAQ), which occurred within 2 years of cohort inception. All patients had enrolled in the IORRA cohort within 1 year of RA onset, in either 2001 (2001-cohort) or 2006 (2006-cohort). For both cohorts, changes in clinical features over 2 years were compared by Fisher's exact test or the Wilcoxon test. The 2001-cohort included 71 patients and the 2006-cohort included 56 patients. Over the 2-year period for each cohort, DAS28 significantly decreased from 3.9 to 3.5 in the 2001-cohort (p < 0.001) and from 4.1 to 3.1 in the 2006-cohort (p < 0.0001), and J-HAQ significantly decreased from 0.62 to 0.49 (p < 0.02) in the 2001-cohort and from 0.71 to 0.41 (p < 0.001) in the 2006-cohort. Greater improvement in disease activity over 2 years occurred in the 2006-cohort than in the 2001-cohort (p < 0.05). Better disease control was obtained following changes in RA treatment strategy that occurred in Japan between 2001 and 2006.
21362769 Autosome-wide copy number variation association analysis for rheumatoid arthritis using th 2011 May OBJECTIVE: Rheumatoid arthritis (RA) is a complex autoimmune rheumatic disease that is strongly influenced by genetic factors. Numerous genes are convincingly associated with RA, including genes in tumor necrosis factor signaling (TNF) and the nuclear factor-κB pathway. To date, except for genes within the HLA region, no data exist regarding potential copy number variations (CNV) involving RA-associated genes. We set out to identify genes affected by CNV that are associated with RA at a genome-wide level. METHODS: Data from the Wellcome Trust Case Control Consortium (WTCCC) were used in our analyses. The initial WTCCC cohort genotyped 3004 controls and 1999 RA cases using the GeneChip 500k Mapping Array Set. We performed a comparative intensity analysis using the PennCNV algorithm, which uses a hidden Markov model to detect CNV. A total of 2271 controls and 1572 RA samples passed quality control criteria and were included for association analysis. Association analysis was performed in 2 phases: (1) to identify CNV that are < 1 Mb with a population frequency < 5%; and (2) to identify large CNV that are > 1 Mb. Fishers' exact test was performed to quantify significance of the CNV. RESULTS: We observed that the genome-wide CNV burden is 2-fold higher in patients with RA compared with controls. We identified 11 rare copy number variable regions with < 5% frequency that had an association with RA that reached a p < 1 × 10(-4). These include TNFAIP3 and TNIP1, which has been implicated in association studies for RA, systemic lupus erythematosus, and psoriasis. We identified CNV involving IRF1, which functions as a transcription activator of genes induced by interferons; ALOX5AP and LCP2, involved in inflammatory mediation; B2M, an MHC-class I associated gene; and PRKCH, a gene involved in T cell signaling pathways. A 57 kb deletion with 1% frequency in RA cases at 7p21.3 was also observed. Six of these loci overlap with CNV catalogued in the Database of Genomic Variants. CONCLUSION: This is the first study to identify non-HLA RA-associated CNV using genome-wide analyses. Validation and functional significance of these deletions/duplications in RA and other autoimmune diseases need to be further investigated.
22270346 Discontinuation of adalimumab treatment in rheumatoid arthritis patients after achieving l 2012 Nov OBJECTIVE: We implemented a retrospective study to explore discontinuation of therapy with adalimumab (ADA) without exacerbation in rheumatoid arthritis (RA) patients who had achieved low disease activity (LDA) with the biological agent. METHODS: We enrolled 46 RA patients who had completed open extension of a double-blind, placebo-controlled trial of ADA monotherapy in Japan and who had LDA (DAS28-CRP <2.7) at the last administration of ADA in the extension trials; this date was defined as week 0 in the present study. Treatment of RA was at the discretion of the attending physician after week 0. The primary endpoint of this study was the percentage of patients who maintained discontinuation of biological agents and LDA for 52 weeks. RESULTS: Twenty-four of the enrolled patients continued ADA while the rest discontinued ADA after the administration of the drug at week 0. Fourteen of the 22 patients did not restart biological agents, and 4 (18.2%) of these maintained LDA through week 52. All 4 of these patients had received ADA monotherapy before week 0. CONCLUSION: Some RA patients who have achieved LDA with ADA monotherapy can discontinue the biologic without incurring increased disease activity. A prospective randomized study is required to confirm the results of our study.
21912880 Promoting physical activity in patients with rheumatoid arthritis: rheumatologists' and he 2011 Dec Despite the proven health benefits, patients with rheumatoid arthritis (RA) are found to be less physically active than their healthy peers. The aim of this study was to examine to what extent and how physical activity, defined as any bodily movement resulting in energy expenditure, is currently promoted by health care providers in patients with RA and how they perceive their competencies and educational needs. For this cross-sectional study, Dutch rheumatologists, rheumatology clinical nurse specialists, and expert physical therapists were sent a postal survey including four domains: attitudes towards physical activity in RA, advices given to patients with RA, and perceived competencies and educational needs. A total of 126 rheumatologists (50%), 132 clinical nurse specialists (56%), and 112 physical therapists (53%) returned the questionnaire. More than 90% agreed that physical activity is an important health goal for RA patients and regularly advised their patients to engage in physical activity. Public health recommendations for moderate-intensity physical activity were found attainable in RA patients by 66%, 74%, and 65% and were by used by 19%, 41%, and 49% of them, respectively. On average, respondents rated their competency to promote physical activity as low to medium, and 54%, 85%, and 72% of the respondents expressed a need for additional education regarding this topic. Rheumatologists, nurses, and physical therapists considered regular physical activity to be an important health goal for RA patients. The majority of them commonly gave advice on physical activity but felt not sufficiently competent and indicated a need for additional education.
22552437 PADI4 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. 2013 Jan The objective of the study was to investigate the association between peptidylarginine deiminase 4 (PADI4) polymorphism and susceptibility to rheumatoid arthritis (RA). An electronic searching strategy was employed to collect relevant studies on the association between PADI4 polymorphism and susceptibility to RA. The odds ratio (OR) with the 95 % confidence interval (95 % CI) was used to evaluate the RA risk presented by PADI4 polymorphism. Fixed or random effects models were selected based on heterogeneity. Publication bias was assessed using funnel plots, Begg's test, and Egger's test. A total of 27 studies from 21 articles were included. Six gene loci (padi4_94, 104, 92, 90, 89, and 100) were chosen for the meta-analysis. The pooled ORs (95 % CI) for allele 2 versus 1 were 1.08 (1.05-1.12), 1.17 (1.12-1.23), 1.26 (1.18-1.36), 1.17 (1.10-1.24), 1.30 (1.17-1.44), and 1.25 (1.11-1.40), respectively. All six SNPs were significantly associated with RA in Asian populations. Three SNPs (PADI4_104, 90, 89) showed significant associations, while the other three SNPs (PADI4_94, 92, 100) exhibited no associations in the European population. A dose-response relationship between allele 2 of PADI4 and the risk of RA was also identified. In conclusion, this meta-analysis suggests that PADI4 polymorphisms represent a significant risk factor for RA, especially in Asians.
23078630 Interleukin-29 modulates proinflammatory cytokine production in synovial inflammation of r 2012 Oct 19 INTRODUCTION: The immunoregulatory function of interleukin (IL)-29 has recently been recognized. However, little is known about the involvement of IL-29 in the pathogenesis of rheumatoid arthritis (RA). This study aimed to examine the expression profiles of IL-29 in blood, synovial fluid (SF) and synovium in RA patients and investigate the effect of IL-29 on cytokines production in RA synovial fibroblasts. METHODS: The transcript levels of IL-29 and its specific receptor IL-28Rα in peripheral blood mononuclear cells (PBMC) and synovium were determined by real-time reverse transcription-polymerase chain reaction (real-time PCR). The concentrations of IL-29 in serum and synovial fluid (SF) were quantified by enzyme-linked immunoassay (ELISA), and the correlation of serum IL-29 levels with disease activity in RA patients was investigated. Furthermore, the expression of IL-29 in RA synovium was examined by immunohistochemistry and double immunofluorescence analysis. Finally, the expression of IL-6, IL-8, IL-10, IL-17 and matrix metalloproteinase-3 (MMP-3) in synovial fibroblasts upon IL-29 stimulation was determined by real-time PCR. RESULTS: IL-29 and IL-28Rα mRNA expression in PBMC was significantly increased in patients with RA compared with healthy controls (HC). The serum levels of circulating IL-29 were higher in RA than those in HC. Increased IL-29 levels were detected in RA SF when compared with osteoarthritis (OA) SF. However, serum IL-29 levels showed no significant correlation with RA disease activity. IL-29 was mostly expressed in the lining region of RA synovium. Moreover, IL-29 was expressed predominately in synovial macrophages and fibroblasts. RA synovial fibroblasts exposed to IL-29 specifically upregulated IL-6, -8 and MMP-3 but downregulated IL-10. CONCLUSIONS: The findings in the present study indicate, for the first time, that IL-29 is dysregulated in patients with RA, which may contribute to the RA pathogenesis via inducing the production of proinflammatory cytokines, chemokines or matrix metalloproteinases in synovial fibroblasts.
23117243 Response to glucocorticoids at 2 weeks predicts the effectiveness of DMARD induction thera 2013 Oct OBJECTIVE: To investigate if a glucocorticoid (GC) response at 2 weeks, defined by EULAR response criteria, can predict active disease (Disease Activity Score (DAS)>2.4) at 3 months. METHODS: For this study, data of the Treatment in the Rotterdam Early Arthritis Cohort study (tREACH), an ongoing clinical trial that evaluates different induction therapies in early rheumatoid arthritis, were used. We selected patients who had a high probability of progressing to persistent arthritis (>70% based on the prediction model of Visser). All patients within the high-probability stratum, who had a baseline DAS>2.2 and a DAS assessment at 2 weeks after randomisation, were included (n=120). Besides GC response at 2 weeks, we investigated which other factors were associated with active disease (DAS>2.4) after 3 months of disease-modifying antirheumatic drug (DMARD) treatment. All variables with a p≤0.25 were assessed in our logistic regression model with backward selection. Variables were eliminated until all remaining variables had a significant association (p<0.05). RESULTS: Patients who did not respond to GC bridging therapy at 2 weeks had an overall OR of having active disease at 3 months of 10.29 (95% CI 3.34 to 31.64; p<0.001) in comparison with responders. The corrected OR was 14.00 (95% CI 3.31 to 59.21; p<0.001). Our final model predicting response at 3 months included the following variables: gender, GC response, induction therapy arms and baseline DAS, which had an explained variance of 39%. CONCLUSIONS: GC response at 2 weeks is a useful tool for recognising those patients who will probably have active disease (DAS>2.4) after 3 months of DMARD treatment.
22938792 Baseline comorbidities in patients with rheumatoid arthritis who have been prescribed biol 2013 Jan AIM: To determine whether rheumatoid arthritis (RA) patients who have been prescribed biological agents exhibit a different comorbidity burden than RA patients who take disease-modifying antirheumatic drugs (DMARDs) alone, and to understand the association between comorbidity and other variables, as well as the association between comorbidity and multimorbidity. METHODS: This observational case-control study included 114 RA patients treated with biological agents and a control group comprising 163 sex- and age-matched RA patients treated with DMARDs only. Current and previous data regarding the patients' disease activity, comorbidities, and treatments were collected. The data were analysed using bivariate and multivariate regression models. RESULTS: The patients who were prescribed biological agents exhibited poorer disease control, received more DMARDs and steroids, and underwent more total joint arthroplasties compared with the patients in the control group. However, the risk factors for cardiovascular disease and the comorbidity frequency were similar between cases and controls. The most prevalent comorbidities were hypertension, obesity, and respiratory, thyroid, and upper gastrointestinal disorders. The incidence of cardiovascular disease was low, and only 29% of the patients exhibited multimorbidities. A bivariate association of age, late diagnosis, joint replacements and a high score on the health assessment questionnaire score (HAQ) with comorbidity was observed. There were also correlations between the Charlson index and age, joint reconstructive surgery, disease activity (DAS28), and HAQ score. However, when binary logarithmic regression models were applied, only patient age remained significantly associated with comorbidity and multimorbidity [hazard ratio, 1.08; 95% confidence interval, 1.05-1.12; p<0.0005]. CONCLUSION: RA patients taking biological drugs have a comorbidity burden equivalent to those treated with DMARDs alone. Age is the main predictive factor of comorbidity in these patients.
21824583 Radiologic evaluation of the neck: a review of radiography, ultrasonography, computed tomo 2011 Aug The patient with neck pain may pose a diagnostic dilemma for the treating physician. As with other areas of medicine, imaging is guided by the history and physical examination. The steady advance of 3-dimensional, functional, and nuclear medicine studies make it increasingly important that the ordering physician be aware of the potential benefits and disadvantages of imaging options. This article reviews the current literature on imaging for the patient with neck pain, illustrates several imaging abnormalities, and discusses the workup of commonly seen patient populations.
21883133 Using penalised logistic regression to fine map HLA variants for rheumatoid arthritis. 2011 Nov Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA) genomic region, most notably with a group of HLA-DRB1 alleles termed the shared epitope (SE). There is also substantial evidence of other risk loci in the HLA region, but refinement has been hampered by extensive linkage disequilibrium (LD). Using genotype imputation, we analysed 6575 RA cases and controls with genotypes at 6180 HLA SNPs; about half the subjects had four-digit DRB1 genotypes. Single-SNP tests revealed hundreds of strong associations across the HLA region, even after adjusting for DRB1. We implemented penalised logistic regression in a multi-SNP association analysis using the double-exponential (DE) penalty term on the regression coefficients and the normal-exponential-gamma (NEG). The penalised approaches identified sparse sets of SNPs that could collectively explain most of the association with RA over the whole HLA region. The HLA-DPB1 SNP rs3117225, was consistently identified in our analyses and was confirmed by results from the North American Rheumatoid Arthritis Consortium study (NARAC). We conclude that SNP selection using penalised regression shows a substantial benefit over single-SNP analyses in identifying risk loci in regions of high LD, and the flexibility of the NEG conveys additional advantages.
21324169 Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients 2011 Feb 16 INTRODUCTION: The long-term treatment of rheumatoid arthritis (RA) most often involves a sequence of different therapies. The response to therapy, disease progression and detailed knowledge of the role of different therapies along treatment pathways are key aspects to help physicians identify the best treatment strategy. Thus, understanding the effectiveness of different therapeutic sequences is of particular importance in the evaluation of long-term RA treatment strategies. The objective of this study was to systematically review and quantitatively evaluate the relationship between the clinical response to biologic treatments and the number of previous treatments with tumor necrosis factor α (TNF-α) inhibitors. METHODS: A systematic search was undertaken to identify published, peer-reviewed articles that reported clinical outcomes of biologic treatment among RA patients with an inadequate response to TNF-α inhibitors. Data were systematically abstracted. Efficacy rates were estimated for groups of patients who differed in the number of prior TNF-α inhibitors used. End points included American College of Rheumatology (ACR)-, European League Against Rheumatism (EULAR)- and Disease Activity Score 28 (DAS28)-based response criteria. RESULTS: The literature search identified 41 publications, of which 28 reported biologic treatment outcomes for RA patients with prior exposure to TNF-α inhibitors. Seven publications reported outcomes obtained in randomized clinical trials, while the remaining consisted of observational studies. The likelihood of responding to a subsequent biologic treatment decreased as the number of previous treatments with TNF-α inhibitors increased for six of the seven response criteria examined. CONCLUSIONS: For patients with prior exposure to TNF-α inhibitors, the likelihood of response to subsequent treatment with biologic agents declines with the increasing number of previous treatments with TNF-α inhibitors.
21937757 A plasmablast biomarker for nonresponse to antibody therapy to CD20 in rheumatoid arthriti 2011 Sep 21 An important goal for personalized health care is the identification of biomarkers that predict the likelihood of treatment responses. Here, we tested the hypothesis that quantitative mRNA assays for B lineage cells in blood could serve as baseline predictors of therapeutic response to B cell depletion therapy in subjects with rheumatoid arthritis (RA). In samples from the REFLEX trial of rituximab in inadequate responders to antibodies to tumor necrosis factor-α, a 25% subgroup of treated subjects with elevated baseline mRNA levels of IgJ, a marker for antibody-secreting plasmablasts, showed reduced clinical response rates. There were no significant efficacy differences in the placebo arm subjects stratified by this marker. Prospective testing of the IgJ biomarker in the DANCER and SERENE rituximab clinical trial cohorts and the SCRIPT ocrelizumab cohort confirmed the utility of this marker to predict nonresponse to anti-CD20 therapy. A combination mRNA biomarker, IgJhiFCRL5lo, showed improved test performance over IgJhi alone. This study demonstrates that baseline blood levels of molecular markers for late-stage B lineage plasmablasts identify a ~20% subgroup of active RA subjects who are unlikely to gain substantial clinical benefit from anti-CD20 B cell depletion therapy.
22683409 Blockade of IL-6 and TNF-α inhibited oxLDL-induced production of MCP-1 via scavenger rece 2012 Aug 15 In chronic inflammatory diseases, cardiovascular disease risk is increased and is the main cause of increased mortality. Oxidized LDL (oxLDL) and scavenger receptors participate in atherogenesis. Using human arterial endothelial cells (HAECs), we evaluated the effect of IL-6 and TNF-α on the expression of scavenger receptors. IL-6 induced expression of SR-A mRNA and TNF-α induced both SR-A and LOX-1 mRNA. Both did induce either CD36 or CD68. To assess the function of scavenger receptors, MCP-1 production by oxLDL from cytokine-pretreated HAEC was examined. In accordance with scavenger receptor expression, oxLDL-induced MCP-1 production was increased in IL-6- or TNF-α-pretreatment. Serum from rheumatoid arthritis patients but not from healthy subjects increased mRNA expressions of SR-A, LOX-1 and CD36 in HAEC. SR-A expression was inhibited by both anti-IL-6 receptor antibody (α-IL-6R Ab) and TNF-α receptor (p75)-Fc (TNFR-Fc) and LOX-1 expression was inhibited by TNFR-Fc. CD36 expression was affected by neither. Serum from rheumatoid arthritis patients augmented oxLDL-induced MCP-1 production. Both α-IL-6R Ab and TNFR-Fc partially inhibited this MCP-1 production. In conclusion, our results strongly support that blocking therapy of IL-6 and TNF-α might be beneficial to reduce atherosclerosis risk in chronic inflammatory diseases.
22986971 [Risk of infection through use of selective immunomodulating drugs for rheumatoid arthriti 2012 Sep 4 BACKGROUND: New drugs for rheumatoid arthritis (RA) have resulted in an improvement in patients' functioning and morbidity, but are linked with increased risk of infections. Traditional immunosuppressant drugs are often used in combination with anti-tumour necrosis factor-alpha (TNF-α) inhibitors or anti-CD20 (rituximab). METHOD: The review is based on a search in PubMed and on the authors' own experience of treating infections in patients who receive immunosuppressant treatment. RESULTS: Traditional immunomodulating treatment results in an increased risk of infection. The disease RA in itself increases the risk of infections. There is evidence of an increased incidence of infections with both extracellular bacteria and intracellular microorganisms such as mycobacteria, including Mycobacterium tuberculosis, and viruses in patients who are treated with TNF-α inhibitors. Patients who are about to start taking TNF-α inhibitors must therefore undergo a tuberculosis-risk assessment. Rituximab may increase the incidence of infection, but long-term observations are limited. Combination therapy involving different drugs that selectively modulate immune response is normally contraindicated because of the increased risk of infection. INTERPRETATION: The benefit of TNF-α inhibitors and rituximab treatment for RA must be weighed up against the increased risk of infections. Symptoms, findings and laboratory test results pertaining to serious infections may be influenced by immunomodulation therapy and thereby make clinical assessment difficult.
22267731 PRELP protein inhibits the formation of the complement membrane attack complex. 2012 Mar 9 PRELP is a 58-kDa proteoglycan found in a variety of extracellular matrices, including cartilage and at several basement membranes. In rheumatoid arthritis (RA), the cartilage tissue is destroyed and fragmented molecules, including PRELP, are released into the synovial fluid where they may interact with components of the complement system. In a previous study, PRELP was found to interact with the complement inhibitor C4b-binding protein, which was suggested to locally down-regulate complement activation in joints during RA. Here we show that PRELP directly inhibits all pathways of complement by binding C9 and thereby prevents the formation of the membrane attack complex (MAC). PRELP does not interfere with the interaction between C9 and already formed C5b-8, but inhibits C9 polymerization thereby preventing formation of the lytic pore. The alternative pathway is moreover inhibited already at the level of C3-convertase formation due to an interaction between PRELP and C3. This suggests that PRELP may down-regulate complement attack at basement membranes and on damaged cartilage and therefore limit pathological complement activation in inflammatory disease such as RA. The net outcome of PRELP-mediated complement inhibition will highly depend on the local concentration of other complement modulating molecules as well as on the local concentration of available complement proteins.
21679443 Abnormal networks of immune response-related molecules in bone marrow cells from patients 2011 Jun 16 INTRODUCTION: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis that progresses to destruction of cartilage and bone. Bone marrow (BM) cells have been shown to contribute to this pathogenesis. In this study, we compared differentially expressed molecules in BM cells from RA and osteoarthritis (OA) patients and analyzed abnormal regulatory networks to identify the role of BM cells in RA. METHODS: Gene expression profiles (GEPs) in BM-derived mononuclear cells from 9 RA and 10 OA patients were obtained by DNA microarray. Up- and down-regulated genes were identified by comparing the GEPs from the two patient groups. Bioinformatics was performed by Expression Analysis Systemic Explorer (EASE) 2.0 based on gene ontology, followed by network pathway analysis with Ingenuity Pathways Analysis (IPA) 7.5. RESULTS: The BM mononuclear cells showed 764 up-regulated and 1,910 down-regulated genes in RA patients relative to the OA group. EASE revealed that the gene category response to external stimulus, which included the gene category immune response, was overrepresented by the up-regulated genes. So too were the gene categories signal transduction and phosphate metabolism. Down-regulated genes were dominantly classified in three gene categories: cell proliferation, which included mitotic cell cycle, DNA replication and chromosome cycle, and DNA metabolism. Most genes in these categories overlapped with each other. IPA analysis showed that the up-regulated genes in immune response were highly relevant to the antigen presentation pathway and to interferon signaling. The major histocompatibility complex (MHC) class I molecules, human leukocyte antigen (HLA)-E, HLA-F, and HLA-G, tapasin (TAP) and TAP binding protein, both of which are involved in peptide antigen binding and presentation via MHC class I molecules, are depicted in the immune response molecule networks. Interferon gamma and interleukin 8 were overexpressed and found to play central roles in these networks. CONCLUSIONS: Abnormal regulatory networks in the immune response and cell cycle categories were identified in BM mononuclear cells from RA patients, indicating that the BM is pathologically involved in RA.