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ID PMID Title PublicationDate abstract
19473562 Genetic polymorphisms of glutathione S-transferases and disease activity of rheumatoid art 2009 Mar OBJECTIVES: Glutathione S-transferases (GST); GST-mu1 (GSTM1), GST-pi1 (GSTP1) and GST-theta1 (GSTT1) have peroxidase activity towards cytotoxic metabolites produced in inflammatory reactions, the main feature of rheumatoid arthritis (RA). Genetic polymorphisms in GSTM1, GSTP1 and GSTT1 modify the enzyme conjugation capacity and may be associated with the activity of RA. METHODS: A genotyping approach was used to analyze GSTM1-0, GSTT1-0 and GSTP1 Ile105Val and Ala114Val polymorphisms in 213 RA patients. Disease activity was assessed by the disease activity score of 28 joint counts (DAS28) twice for each patient and mean DAS28 values were calculated. RESULTS: The patients with GSTT1-0 genotype had a higher risk for developing high activity RA than the patients with GSTT1 genes present (p=0.028, OR=2.761, 95% CI=1.114-6.843). An interaction between the GSTT1 polymorphism and smoking was observed. In the group of smokers, the carriers of a homozygous deletion GSTT1 had an 8.5-fold higher risk for developing high disease activity than the patients with the GSTT1-1 genotype (p=0.004, OR=8.640, 95% CI=1.995-37.426). GSTM1 and GSTP1 polymorphisms were not associated with the disease activity. CONCLUSION: Our results suggest that the presence of the GSTT1-0 genotype contributed to higher disease activity in RA patients. The risk for developing highly active RA was the highest in smokers with the GSTT1-0 genotype.
20109438 Lipoteichoic acid enhances IL-6 production in human synovial fibroblasts via TLR2 receptor 2010 Jun 1 Patients with rheumatoid arthritis (RA) are at increased risk of developing infections and appear to be particularly susceptible to septic arthritis. Lipoteichoic acid (LTA), a cell wall component of Gram-positive bacteria is an amphiphilic, negatively charged glycolipid. However, the effects of LTA on human synovial fibroblasts are largely unknown. We investigated the signaling pathway involved in IL-6 production stimulated by LTA in rheumatoid arthritis synovial fibroblasts (RASF). LTA caused concentration- and time-dependent increases in IL-6 production. LTA-mediated IL-6 production was attenuated by Toll-like receptor 2 (TLR2) monoclonal antibody or siRNA. Pretreatment with PKCdelta inhibitor (rottlerin), c-Src inhibitor (PP2), AP-1 inhibitor (tanshinone IIA) and NF-kappaB inhibitor (PDTC and TPCK) also inhibited the potentiating action of LTA. However, focal adhesion kinase (FAK) mutant and siRNA did not affect LTA-mediated IL-6 production. Stimulation of cells with LTA increased the PKCdelta and c-Src phosphorylation and kinase activity. LTA increased the accumulation of p-c-Jun and p-p65 in the nucleus, as well as AP-1 and NF-kappaB luciferase activity. LTA-mediated increase of AP-1 and NF-kappaB luciferase activity was inhibited by rottlerin and PP2 or TLR2 and PKCdelta siRNA or c-Src mutant. Our results suggest that LTA-increased IL-6 production in human synovial fibroblasts via the TLR2 receptor, PKCdelta, c-Src, AP-1 and NF-kappaB signaling pathways.
19533570 [Proximal interphalangeal joint silicone arthroplasty--comparison of Swanson and NeuFlex i 2009 Jun Proximal interphalangeal joint arthroplasty with a silicone implant has proven to be successful in cases of degenerative, post-traumatic or rheumatic arthritis. The recent changing of the implant's design by introducing a 30-degree preflexion has replaced the common Swanson implant in some centres. Nevertheless, directly comparing follow-up studies between the two implant forms are still lacking as well as the use of a standard evaluation score for proximal interphalangeal joint arthroplasties. Between 1990 and 2007 a series of 67 proximal interphalangeal joint arthroplasties with a silicone device has been carried out in 54 patients. Among these a retrospective clinical and radiological investigation could be performed on 43 patients with 53 joints at 6-144, in the mean 34 months, after operation. 39 cases of degenerative, 12 cases of post-traumatic, 1 case of rheumatic arthritis and 1 post-traumatic arthrodesis were treated with 20 Swanson implants and 33 NeuFlex implants. In 41 joints a mediolateral approach taking care of the extensor tendon's integrity was used, in 12 joints the extensor tendon was dissected longitudinally using a dorsal approach. At the time of investigation 5 implants had already been removed due to infection, implant fracture and painful extensive osteophytes. Comparing the remaining prostheses, 18 Swanson implants and 30 NeuFlex implants, the latter showed a better average total range of motion, improving from 42.5 degrees preoperatively to 56 degrees postoperatively, in contrast to the Swanson implants with a deterioration from 50.8 degrees preoperatively to 47.2 degrees postoperatively. However, they were inferior to the classic Swanson implant as the joint's circumference was more enlarged by 1.8 mm in the mean and a greater finger length shortening of average 2.5 mm as well as a higher rate of stress pain and instability (15%) were evident. While the NeuFlex implants led to a better subjective satisfaction, the Swanson implants gained better objective results using a new evaluation score (11% very good, 50% good, 28% satisfactory, 11% bad) than the NeuFlex implants (50% good, 40% satisfactory, 10% bad). Remarkably the NeuFlex devices showed an extremely high rate of early implant fractures after 8-31 months, in the mean 18 months, postoperatively, which was not seen with any of the Swanson implants--in spite of an average duration of 59.4 months.
20415779 IL-23 in the pathogenesis of rheumatoid arthritis. 2010 Mar Interleukin-23 (IL-23) is a heterodimeric cytokine belonging to the IL-6/IL-12 family that plays a key role in several of autoimmune and inflammatory disorders. This family contains the 34 type I cytokine receptor chains and 27 ligands, which share structural and functional similarities, but on the other hand they display distinct roles in shaping Th cells responses. IL-12 family cytokines have not only proinflammatory effects but they also promote inflammatory responses. IL-23 is composed of the p40 subunit in common with IL-12, and with a unique p19 subunit. IL-23 binding to an IL-23 receptor expressed on dendritic cells, macrophages and monocytes triggers the activation of Jak2 and Tyk2, which in turn phosphorylates STAT1, STAT3, STAT4 and STAT5 as well as induce formation of STAT3-STAT4 heterodimers. IL-23 is one of the essential factors required for the survival and/or expansion of Th17 cells, which produce IL-17, IL-17F, IL-6 and TNF-alpha. Th17 cells stimulated by the IL-23 promote osteoclastogenesis through production of IL-17, which induce receptor activator of NF-kappa B ligand on mesenchymal cells. The IL-23-IL-17 axis includes Th17 cells and plays a key role in the development of autoimmune arthritis.
18853156 Reinfusion of unwashed salvaged blood after total knee arthroplasty in patients with rheum 2009 Dec Autotransfusion with unwashed salvaged blood (USB) is effective for avoiding allogeneic blood transfusion (ABT) in patients undergoing total knee arthroplasty (TKA). We performed a retrospective study to determine the percentage of patients receiving ABT and the volume of postoperative blood drainage after introduction of autotransfusion with USB for patients with rheumatoid arthritis (RA) undergoing TKA. In 100 patients without autotransfusion (group 1) and 100 patients receiving autotransfusion of USB (group 2), we compared the number of patients who required ABT, as well as the postoperative drainage volume, ABT volume, and autotransfusion volume. In group 1, 83% of the patients received ABT, while only 47% received ABT in group 2, and there was a significant decrease (p < 0.001). However, the postoperative drainage volume was significantly increased in group 2 (p < 0.001).
20835636 The SF-6D Brazil questionnaire: generation models and applications in health economics. 2010 Jul OBJECTIVE: Compare the preference measures derived from the SF-36, based on the two Brazilian versions of the Short Form 6 Dimensions questionnaire-Brazil (SF-6D Brazil). METHODS: Observational and transversal study. The following quality of life assessment instruments were applied: HAQ, SF-36, EQ-5D and SF-6D (1998 and 2002 versions). Descriptive statistics and correlation coefficients were used for data analysis. RESULTS: The study assessed 200 patients suffering from rheumatoid arthritis, with a mean age of 49.22 years, mean time with the disease of 11.16 years and mean HAQ score of 1.02. Preferences measured by the two versions of the SF-6D and by the EQ-5D showed significant correlations with one another, and Pearson coefficients ranged from 0.59 to 0.88 (p<0.01). CONCLUSION: The most current version of the SF-6D, based on the 2002 model, was found to be valid when compared to the version initially validated to Brazil and is a questionnaire alternative to assess preferences in economic analyses carried out in health care.
20673155 Perioperative management of tumor necrosis factor antagonists in patients with psoriasis a 2011 Apr Tumor necrosis factor alpha (TNF-α) plays an important role in host defense and possibly wound healing. It is also linked to the pathophysiology of many inflammatory diseases, including psoriasis. The TNF antagonists are a class of agents that have proven effective in treating psoriasis and psoriatic arthritis, yet the immunosuppressive effects of these agents raise concern over their use perioperatively. Currently, there is no consensus as to when TNF antagonists should be discontinued prior to surgery. Furthermore, data on the topic are limited to inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). This paper reviews the literature on post-surgical outcomes in patients with RA and IBD receiving anti-TNF therapy. Although most studies reveal no statistically significant increased risk of post-surgical complications in these patients, the retrospective design and small sample size of these studies limits interpretation. Furthermore, when applying these data to psoriasis and psoriatic arthritis, physicians must also consider disease severity, individual comorbidities, and the pharmacokinetics of the different TNF antagonists. Additional studies are needed in psoriasis and psoriatic arthritis in order to develop truly evidence-based dermatologic guidelines for perioperative management of the TNF antagonists.
18625628 Responsiveness of the International Classification of Functioning, Disability and Health ( 2009 Jun BACKGROUND: The comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for rheumatoid arthritis (RA) is a selection of 96 categories from the ICF, representing relevant aspects in the functioning of patients with RA. OBJECTIVES: To study the responsiveness of the ICF Core Set for RA in rheumatological practice. METHODS: A total of 46 patients with RA (72% women, mean (SD) age 53.6 (12.6) years, disease duration 6.3 (8.0) years) were interviewed at baseline and again after 6 months treatment with a disease-modifying antirheumatic drug (DMARD), applying the ICF Core Set for RA with qualifiers for problems on a modified three-point scale (no problem, mild/moderate, severe/complete). Patient-reported outcomes included Modified Health Assessment Questionnaire (MHAQ) and Short-Form 36 (SF-36) health survey, and disease activity was calculated. Responsiveness was measured as change in qualifiers in ICF categories, and was also compared with change in patient-reported outcomes. RESULTS: After 6 months of DMARD treatment, improvement by at least one qualifier was seen in 20% of patients (averaged across all ICF categories), 71% experienced no change and 9% experienced worsening symptoms. Findings were similar across the different aspects of functioning. Mainly moderate effect sizes were seen for 6-month changes in the ICF Core Set for RA, especially in patients with improved health status, with similar effect size for disease activity. The components in the ICF Core Set for RA were only weakly associated with patient-reported outcomes and disease activity. CONCLUSIONS: The ICF Core Set for RA demonstrated moderate responsiveness in this real-life setting of patients where minor changes occurred during treatment with DMARDs.
21355418 Determination of oxidant stress in plasma of rheumatoid arthritis and primary osteoarthrit 2010 Dec Determination of oxidant stress in plasma of rheumatoid arthritis (RA) and primary osteoarthritis (POA) patients is important in understanding the pathogenesis of these diseases. In this study, we examined the relationship between oxidant stress and inflammation by measuring protein carbonyl content, thiol levels and plasma protein fractions as the oxidation markers and erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) tests as inflammation markers. Protein carbonyls content was higher in RA and POA patients, as compared to controls (p<0.0001), while the plasma thiol levels in both groups of patients were significantly lower than controls (p<0.0001). Increased levels of proteins under 40 kDa molecular mass were detected in the RA and POA patients compared to that of controls (p<0.0001) both in HPLC and SDS-PAGE analysis. Total protein concentration in plasma of RA patients was higher than the controls (p<0.001), while in POA patients was lower than that of controls (p<0.001). ESR and CRP levels were higher in both the patient groups than the normal group (p<0.001). These results suggested that alterations in the oxidant stress markers could be the cause of inflammation in these diseases. Thus, while working for RA/POA treatment strategies, consideration of the relationship between oxidant stress and inflammation would be worth evaluating.
19225717 Expression of interleukin-18, IL-18BP, and IL-18R in serum, synovial fluid, and synovial t 2009 Sep Rheumatoid arthritis (RA) is a chronic immunological disease, the invasive monocytes/macrophages and lymphocytes present in synovial cells and synovial tissue produce many cytokines and inflammatory mediators by paracrine signaling and plays a role in the pathological progress in RA patients. Interleukin-18 (IL-18) is a representative proinflammatory factor and displays multiple biological functions. This study was designed to investigate the expression of IL-18 and its receptor (IL-18R) and IL-18 binding protein (IL-18BP) in serum, synovial fluid, and synovial tissue of patients with RA, and to identify the pathological role of IL-18 in RA. Serum, synovial fluid, and synovial tissue were obtained from RA patients. Samples from patients with osteoarthritis and healthy people were obtained as controls. Levels of IL-18, IL-18BP, and PGE2 in serum and synovial fluid were measured by enzyme-linked immunosorbent assay. The biological activity of IL-18 in serum and synovial fluid was detected on the basis of IFN-gamma secretion from IL-18-responding human myelomonocytic KG-1 cells. NO in serum and synovial fluid was detected by Griess reaction. Expression of IL-18, IL-18BP, IL-18R, iNOS, and COX-2 mRNA and protein in synovial tissues was determined by quantitative reverse transcriptase polymerase chain reaction and Western blot. This study shows the expression levels of IL-18, IL-18R, iNOS, COX-2, and the biological activity of IL-18 in both serum and synovial fluid and tissue of patients with RA were significantly increased compared with the corresponding samples from the two control groups. In addition, expression of IL-18BP in patients with RA was decreased compared with samples from the two control groups. In conclusion, the overexpression of IL-18 and IL-18R may play an important role in the pathogenesis of RA.
18984608 Contemporary patterns of care and disease activity outcome in early rheumatoid arthritis: 2009 Jan OBJECTIVES: To report from the Early Rheumatoid Arthritis Network (ERAN), time from symptom onset to start of therapy, treatment choices and disease outcome in early RA. METHODS: Patients with newly diagnosed RA were prospectively enrolled from 19 centres in the UK and Eire. Standardized information was collected on case report forms at first presentation, 3-6 months, 1 yr and annually thereafter. The choice and intensity of drug treatment was left to the discretion of individual centres. RESULTS: A total of 808 patients were recruited between 2002 and 2007, with a mean follow-up of 16 (0-60) months. Of them, 62% fulfilled four or more ACR criteria for RA at first visit. The median time from onset of symptoms to referral to secondary care was 4 months [interquartile range (IQR) 2-9, n = 655] and to start of first DMARD 8 months (IQR 4-13, n = 638). DMARDs were prescribed in 97% of the patients, initially as monotherapy in 91%, and as combination therapy in 9%. The second DMARD (n = 220) was a switch to another as monotherapy in 52% and step-up to combination therapy in 48%. The proportions with a 28-joint disease activity score >5.1 at baseline and 3 yrs were 46 and 19%, >3.2 were 84 and 54% and <2.6 were 6 and 33%, respectively. CONCLUSIONS: Patients presenting with RA in ERAN do not receive DMARDs promptly, largely due to delays in referral to secondary care. Contemporary treatment practice is to start with DMARD monotherapy, and to use combination DMARDs as second-line therapy in approximately half of them. Over 3 yrs the proportion of patients continuing to have active disease remains high.
19626391 Impact of trough serum level on radiographic and clinical response to infliximab plus meth 2009 This study is a prospective, randomized, double-blind study to compare the efficacy and safety of 10 mg/kg infliximab with those of 3 mg/kg infliximab treatment in methotrexate-refractory rheumatoid arthritis patients. After the patients received 3 mg/kg infliximab infusion at weeks 0, 2, and 6, they were randomly assigned to be administered 3, 6 or 10 mg/kg infliximab every 8 weeks from week 14 to 46. Mean American College of Rheumatology improvement (ACR-N) at week 54, the primary endpoint, was 51.3% and 58.3% for the 3 mg/kg and 10 mg/kg groups, respectively, with a statistically significant difference. Treatment with 10 mg/kg was found to be remarkably beneficial in patients who had not responded to three infusions with 3 mg/kg at week 10. The median changes in the modified Sharp score were 0.0 in the two groups. There were no significant differences in the incidences of adverse events between the groups. In patients who achieved better clinical response or greater inhibition of progression of joint damage, trough serum infliximab level was significantly higher than in patients who did not. The magnitudes of both efficacies were correlated with the trough serum infliximab level (ClinicalTrials.gov number: NCT00691028).
20646367 The role of anti-cyclic citrullinated peptide antibody in periodontal disease. 2010 Apr The anti-Cyclic Citrullinated Peptide Antibodies (anti-CCP) are produced locally in the inflamed synovium of Rheumatoid arthritis (RA) patients, suggesting that citrullinated proteins are located in the inflamed synovium. In scientific literature were find periodontal bacterial DNA in serum and synovial fluid of RA with PD patients. RA and adult periodontitis share common pathogenetic mechanisms and immunologic and pathological findings RA. One oral pathogen strongly implicated in the pathogenesis of periodontal disease (PD), Porphyromonas. gingivalis, possesses a unique microbial enzyme, peptidylarginine deiminase (PAD), the human equivalent of which has been identified as a susceptibility factor for RA. Under this point of view, we speculate about the presence of anti-CCP antibodies in sera of PD with RA patients. We conducted this study to evaluate and compare the diagnostic and predictive utility of anti-CCP antibodies in patients with PD and patients with PD and RA. Anti-CCP antibody was not found in 21 sera (U/ml<10), included RA controls, while only 1 patient with chronic PD and probing depth of 7,1 mm was identified positive for anti-CCP (22.2 U/ml). Our data do not support a role for anti-CCP in diagnoses of periodontal disease.
19882908 [A case of etanercept-induced pneumonitis]. 2009 Oct A 64-year-old man was admitted to our hospital because of fever and dyspnea with marked hypoxemia and diffuse ground-glass opacities in bilateral lung fields revealed by a chest CT scan. He had used etanercept therapy for his rheumatoid arthritis. His PaO2/FiO2 had decreased to 130.4 Torr. On bronchoalveolar lavage, lymphocytes were elevated to 54.4% and bacteria culture was negative. We diagnosed drug-induced pneumonitis caused by etanercept, clinically and started high dose corticosteroid therapy. Despite his severe hypoxemia, the corticosteroid therapy and use of non-invasive positive pressure ventilation improved his condition. Interstitial lung disease induced by etanercept is rare, and a severe case requiring mechanical ventilation has never been reported. Because of the critical condition it can cause, it is suggested that evaluation of interstitial pneumonia is crucial.
20679476 Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases. 2010 Dec BACKGROUND: Interleukin 18 (IL-18) is a novel mediator of angiogenesis in rheumatoid arthritis (RA). OBJECTIVE: To examine the role of IL-18 in RA angiogenesis and the signalling mechanisms involved. METHODS: Human dermal microvascular endothelial cell (HMVEC) chemotaxis, capillary morphogenesis assays and Matrigel plug angiogenesis assays were performed in vivo using IL-18 with or without signalling inhibitors. A novel model of angiogenesis was devised using dye-tagged HMVECs to study their homing into RA and normal (NL) synovial tissues (STs) engrafted in severe combined immunodeficient (SCID) mice. RESULTS: IL-18-mediated angiogenesis depended on Src and Jnk, as the inhibitors of Src and Jnk blocked IL-18-induced HMVEC chemotaxis, tube formation and angiogenesis in Matrigel plugs. However, inhibitors of Janus kinase 2, p38, MEK, phosphatidylinositol-3-kinase and neutralising antibodies to vascular endothelial growth factor or stromal derived factor-1α did not alter IL-18-induced HMVEC migration. These results were confirmed with Jnk or Src sense or antisense oligodeoxynucleotides. Moreover, IL-18 induced phosphorylation of Src and Jnk in HMVECs. As proof of principle, IL-18 null mice had a significantly decreased angiogenesis compared with wild-type mice in Matrigel plug angiogenesis assays in vivo. IL-18 markedly enhanced mature HMVEC homing to human RA ST compared with NL ST in SCID mice, confirming the role of IL-18-induced angiogenesis in RA ST in vivo. CONCLUSION: Targeting IL-18 or its signalling intermediates may prove to be a potentially novel therapeutic strategy for angiogenesis-dependent diseases, such as RA.
20505629 Ultrasonographic study of the painful shoulder in patients with rheumatoid arthritis and p 2010 Jan OBJECTIVE: to compare ultrasound (US) changes of the painful shoulder between patients with rheumatoid arthritis (RA) and patients with degenerative shoulder disease (DSD). PATIENTS AND METHODS: Patients with painful shoulder (n=178) were divided according to clinical diagnosis made by rheumatologist: Group1-77 patients with RA, Group2-101 patients with DSD. US changes were evaluated by linear transducer 7.5 MHz for: long head biceps tendon-LHB, supraspinatus tendon-SSP, infraspinatus tendon-ISP, subscapularis tendon-SSC, subacromial/subdeltoid bursa-SA/SD-B, glenohumeral joint effusion-JE, bone cartilage-BC and humeral erosions-HE. The ultrasound examiner was blinded for clinical findings, diagnosis and patient identification. RESULTS: Frequent pathological changes were found in: SSP tendon (84.4% RA and 71.7% DSD), LHB tendon (81,8% RA and 69,3% DSD), ISP tendon (58.4% RA and 56.4% DSD) and SSC tendon (49,4% RA and 46,5% DSD) (p=0.045 p=0.058 p=0.951 and p=0.710 respectively). Evaluating changes separately, statistical differences were noted in: LHB tenosynovitis, SSP tendon rupture (three times more in RA patients), ISP tendon rupture (five times more in RA patients), as well as in glenohumeral JE, BC reduction and HE (p=0,019 p=0.001 p=0.005 p=0.000 p=0.003 and p=0.007, respectively). LHB tendon pathology (tendinopathy, subluxatio and rupture), SSC tendinopathy, global SSP and ISP tendinopathy as well as bursitis of SA/SD did not show statistical difference between the patient groups. Using logistic regression model, the following set of items: glenohumeral JE, BC reduction and HE has shown to be distinctive between RA and DSD group. CONCLUSION: Ultrasound detected different frequencies of LHB tenosynovitis, SSP and ISP tendon ruptures, glenohumeral JE, BC reduction and HE in RA and DSD patients comparisons. Combination of glenohumeral joint effusion, bone cartilage reduction and humeral erosions was able to identify patients with RA in a population of patients with painful shoulder disease with a moderately high degree of confidence.
20966752 Rheumatic diseases and pregnancy. 2010 Dec PURPOSE OF REVIEW: This review discusses how inflammatory rheumatic diseases [rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE)] of the mother can influence the course of pregnancy and the development of the fetus. Antirheumatic drug therapy of the mother and strategies to prevent fetal complications namely in SLE must be considered with care. RECENT FINDINGS: The current literature is presented discussing hypotheses about the immunologic mechanisms leading to amelioration or exacerbation of the rheumatic symptoms in rheumatoid arthritis and ankylosing spondylitis during pregnancy. In SLE, several recent studies have been published concerning fetal complications in the antiphospholipid syndrome and in Ro/SSA-positive and La/SSB-positive mothers and how to diagnose, treat, or prevent these. SUMMARY: Today, women with inflammatory rheumatic diseases are normally fertile and can be encouraged to become pregnant, when there is a stable and quiescent phase of the disease. This is in particular important for patients with SLE, although pregnancy outcome in SLE has improved over the last decades. Pregnancy in SLE is still a high-risk period during the disease course with the highest risk in women with active lupus nephritis. In contrast, women with rheumatoid arthritis develop amelioration of the rheumatic symptoms during the course of pregnancy in most cases; female ankylosing spondylitis patients are likely to show unaltered or aggravated symptoms of back pain and impaired function.
19265168 IL-17 induces monocyte migration in rheumatoid arthritis. 2009 Mar 15 Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which is in part mediated by the migration of monocytes from blood to RA synovial tissue, where they differentiate into macrophages and secrete inflammatory cytokines and chemokines. The T cell cytokine IL-17 is expressed in the RA synovial tissue and synovial fluid. To better understand the mechanism by which IL-17 might promote inflammation, its role in monocyte trafficking was examined. In vivo, IL-17 mediates monocyte migration into sponges implanted into SCID mice. In vitro, IL-17 was chemotactic, not chemokinetic, for monocytes at the concentrations detected in the RA synovial fluid. Further, IL-17-induced monocyte migration was mediated by ligation to IL-17RA and RC expressed on monocytes and was mediated through p38MAPK signaling. Finally, neutralization of IL-17 in RA synovial fluid or its receptors on monocytes significantly reduced monocyte migration mediated by RA synovial fluid. These observations suggest that IL-17 may be important in recruiting monocytes into the joints of patients with RA, supporting IL-17 as a therapeutic target in RA.
19854715 Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti 2010 Mar BACKGROUND: The risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) is thought to be increased following anti-tumour necrosis factor (anti-TNF) therapy, with a proposed differential risk between the anti-TNF drugs etanercept (ETA), infliximab (INF) and adalimumab (ADA). OBJECTIVE: To compare directly the risk between drugs, to explore time to event, site of infection and the role of ethnicity. METHODS: Data from the British Society for Rheumatology Biologics Register (BSRBR), a national prospective observational study, were used to compare TB rates in 10 712 anti-TNF treated patients (3913 ETA, 3295 INF, 3504 ADA) and 3232 patients with active RA treated with traditional disease-modifying antirheumatic drugs. RESULTS: To April 2008, 40 cases of TB were reported, all in the anti-TNF cohort. The rate of TB was higher for the monoclonal antibodies ADA (144 events/100,000 person-years) and INF (136/100,000 person-years) than for ETA (39/100,000 person-years). After adjustment, the incidence rate ratio compared with ETA-treated patients was 3.1 (95% CI 1.0 to 9.5) for INF and 4.2 (1.4 to 12.4) for ADA. The median time to event was lowest for INF (5.5 months) compared with ETA (13.4 months) and ADA (18.5 months). 13/40 cases occurred after stopping treatment. 25/40 (62%) cases were extrapulmonary, of which 11 were disseminated. Patients of non-white ethnicity had a sixfold increased risk of TB compared with white patients treated with anti-TNF therapy. CONCLUSION: The rate of TB in patients with RA treated with anti-TNF therapy was three- to fourfold higher in patients receiving INF and ADA than in those receiving ETA.
18647855 Evidence for association of an interleukin 23 receptor variant independent of the R381Q va 2009 Aug OBJECTIVE: The rare allele of a non-synonymous interleukin 23 receptor (IL23R) single nucleotide polymorphism (SNP) rs11209026 (p.Arg381Gln) confers strong protection against Crohn disease (CD) and psoriasis. Other IL23R variants also exhibit association with CD, genetically independent of rs11209026. In rheumatoid arthritis (RA), IL23 is an important determinant of the production of IL17A, a cytokine of consequence in inflammation and bone destruction. While there is no previous support for strong association of IL23R with RA, the possibility of a weaker role for IL23R variants in the aetiology of RA cannot be eliminated. METHODS: A New Zealand RA cohort was tested for association with six IL23R SNPs and the resulting data combined with a reanalysis of the Wellcome Trust Case Control Consortium data and a previously published Spanish data set. The combined data set totals over 3000 Caucasian cases and 3800 controls, which has sufficient power to detect a risk of as low as odds ratio (OR) = 1.2. RESULTS: Our data emphasise the lack of association of rs11209026 with RA (OR 1.01, 95% confidence interval (CI) 0.88 to 1.16, p = 0.86). However there was some evidence for association of rs1343151 with RA (OR 1.14, 95% CI 1.06 to 1.22, p = <0.001). CONCLUSIONS: While requiring further replication, these data further support a role for the IL17A/IL23 pathway in RA. Understanding how different variants of IL23R associate, at varying levels of strength, with contrasting groups of immune-mediated diseases (CD, psoriasis, ankylosing spondylitis, RA) will enhance knowledge on the aetiology of these diseases.