Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
17163236 Methotrexate and hepatic toxicity in rheumatoid arthritis and psoriatic arthritis. 2006 BACKGROUND: We set out in this study to demonstrate the adverse effect profile of methotrexate when used in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in a district general hospital population, and to investigate the effect of alcohol consumption in these patients. METHODS: A prospective evaluation of 550 RA patients and 69 PsA patients was undertaken, controlling for confounding factors. Systematically randomised patients were further analysed regarding alcohol consumption. A transaminase level of three times the upper limit of normal on two or more occasions was taken to indicate hepatic injury. RESULTS: Gastrointestinal disturbance was the predominant adverse effect in RA patients (9.8%); hepatic disturbance was the most frequent in PsA patients (14.5%). Both groups had hepatic enzyme elevation; PsA patients were at significantly greater risk of elevated transaminases than RA patients (14.5% vs 7.5%, respectively, chi2 = 4.017). Alcohol consumption did not correlate with hepatic injury (mean 5.15 vs 6.6 alcohol units/week consumed by RA and PsA patients, respectively). CONCLUSION: Our data show methotrexate-treated PsA patients have a higher incidence of hepatotoxicity compared with methotrexate-treated patients with RA. It is proposed that psoriatic patients may be inherently more susceptible to methotrexate hepatotoxicity than are rheumatoid patients.
17032244 Interleukin-21 induces T-cell activation and proinflammatory cytokine secretion in rheumat 2006 Nov Interleukin (IL)-21 is a CD4+ T-cell-derived cytokine, which is involved in innate and adaptive immune response. In this study, we analysed IL-21 receptor (IL-21R) expression in peripheral blood and synovial fluid mononuclear cells, and investigated the role of IL-21 in the induction of proinflammatory cytokine production by peripheral blood T cells (PB-T) and synovial fluid T cells (SF-T) from patients with rheumatoid arthritis (RA). Immunohistochemical staining demonstrated that IL-21R-positive cells were significantly increased in inflamed synovial tissues of RA patients compared with osteoarthritis (OA) and healthy controls. Flow cytometric analysis confirmed that IL-21R was mainly expressed in freshly isolated CD4, CD8, B and NK cells from peripheral blood and synovial fluid, but decreased gradually in T cells 24 h after anti-CD3 stimulation. PB- and SF-T cells from RA patients were more responsive to IL-21 when compared with controls. Importantly, isolated PB- or SF-T cells from RA patients, when stimulated with IL-21 and anti-CD3 MoAb, secreted markedly higher levels of TNF-alpha and IFN-gamma than controls. These data indicate that IL-21R is overexpressed in the inflamed synovial membrane and in peripheral blood or synovial fluid leukocytes of RA patients, and that IL-21 enhances local T-cell activation, proliferation and proinflammatory cytokine secretion. Thus, blockade of IL-21R signalling pathway may have a therapeutic potential in acute RA patients.
17602995 Role of central sensitization in symptoms beyond muscle pain, and the evaluation of a pati 2007 Jun Patients with widespread pain or fibromyalgia syndrome have many symptoms besides musculoskeletal pain: e.g. fatigue, sleep difficulties, a swollen feeling in tissues, paresthesia, cognitive dysfunction, dizziness, and symptoms of overlapping conditions such as irritable bowel syndrome, headaches and restless legs syndrome. There is evidence for central sensitization in these conditions, but further studies are needed. Anxiety, stress and depression are also present in 30-45% of patients. Other factors that may contribute to symptoms include endocrine dysfunction, psychosocial distress, trauma, and disrupted sleep. Evaluation of a patient presenting with widespread pain includes history and physical examination to diagnose both fibromyalgia and associated or concomitant conditions. Fibromyalgia should be diagnosed by its own characteristic features. Some patients with otherwise typical symptoms of fibromyalgia may have as few as four to six tender points in clinical practice. Patients with rheumatoid arthritis and systemic lupus erythematosus should be evaluated for fibromyalgia, since 20-30% of them have associated fibromyalgia, requiring a different treatment approach.
17277125 Suppression of the effector phase of inflammatory arthritis by double-stranded RNA is medi 2007 Feb 15 Innate immune receptors that recognize nucleic acids, such as TLRs and RNA helicases, are potent activators of innate immunity that have been implicated in the induction and exacerbation of autoimmunity and inflammatory arthritis. Polyriboinosine-polyribocytidylic acid sodium salt (poly(IC)) is a mimic of dsRNA and viral infection that activates TLR3 and the RNA helicases retinoic acid-induced gene-1 and melanoma differentiation-associated gene-5, and strongly induces type I IFN production. We analyzed the effects of systemic delivery of poly(IC) on the inflammatory effector phase of arthritis using the collagen Ab-induced and KRN TCR-transgenic mouse serum-induced models of immune complex-mediated experimental arthritis. Surprisingly, poly(IC) suppressed arthritis, and suppression was dependent on type I IFNs that inhibited synovial cell proliferation and inflammatory cytokine production. Administration of exogenous type I IFNs was sufficient to suppress arthritis. These results suggest a regulatory role for innate immune receptors for dsRNA in modulating inflammatory arthritis and provide additional support for an anti-inflammatory function of type I IFNs in arthritis that directly contrasts with a pathogenic role in promoting autoimmunity in systemic lupus.
17127411 Aberrant Gi protein coupled receptor-mediated cell survival signaling in rheumatoid arthri 2007 Jan 1 Sphingosine 1-phosphate (S1P) is a pleiotropic bioactive lipid that transmits potent signals through a family of G protein coupled receptors with resultant anti-apoptotic and pro-angiogenic effects. We have recently reported that lymphoblastoid B cell lines (LCLs) from rheumatoid arthritis (RA) patients are resistant to Fas-mediated cell death due to over-production of S1P, secondary to over-activity of sphingosine kinase-1 (SphK1). Here we investigated the signaling events that S1P triggers in those cells. Our results show that RA-derived LCLs display increased constitutive enzymatic activity of phosphatidylinositol 3-kinase (PI3K). Incubation of LCLs with a PI3K inhibitor wortmannin reversed PI3K over-activity and the resistance to Fas-mediated cell death. Incubation of RA LCLs with nanomolar concentration of S1P triggered exaggerated activation of both SphK and PI3K in RA LCLs compared to control cells. PI3K was mapped upstream of SphK, since wortmannin could block SphK activation by S1P. S1P signaling effect could be blocked by the Gi/G0 protein inhibitor, pertussis toxin and by an inhibitor of S1P-receptor interaction, suramin. S1P receptor expression levels did not appear to be the cause of disparate S1P-triggered signaling, since LCLs from RA patients and their healthy twin controls did not show statistically significant differences in the expression levels of the five known S1P receptors, as determined by quantitative real time reverse transcription-polymerase chain reaction analyses. Thus, we conclude that Fas death signaling aberration in RA LCLs is caused by extracellular S1P, which triggers PI3K-dependent SphK over-activity through a Gi protein-coupled receptor-mediated signaling cascade.
17879543 [Effect of chinese herbs in enhancing prednisone for treatment of refractory rheumatoid ar 2007 Aug OBJECTIVE: To investigate the Chinese herbal medicine in enhancing effect of prednisone for treatment of refractory rheumatoid arthritis (RA). METHODS: One hundred and twenty patients with refraetory RA were assigned to two groups, the treated group was orally administered with Qingbi Tablet, a patent Chinese herbal preparation formulated based on the clearing heat and removing toxic substances principle, and the control group was treated with intramuscular injection of amethopterin (MTX), oral intake of voltaren 75 mg and hydroxychloroquine 0.2 g once a day. Besides prednisone was given to all patients orally, the initiating dosage used in the treated group was lesser than that in the control group. The clinical index, dosage and adverse reaction of prednisone were recorded every 2 weeks. RESULTS: The curative effect evaluated by American College of Rheumatology (ACR) standard showed no statistical difference between the two groups (P > 0.05). Either clinical or laboratory indexes were improved significantly in both groups (P < 0.05), but the improvement in resting pain, patient's self-evaluation and doctor's evaluation in the treated group were better than those in the control group, showing statistical difference (P < 0.05). The 20-week total amount of prednisone used in the treated group was less than that in the control group (32,935 mg vs. 51,170 mg), while the dosage of prednisone used in various observation time points between the two groups was also significantly different respectively (P < 0.05), the former was less than the latter. CONCLUSION: Chinese herbal medicine can enhance the effect of prednisone in patients of refractory RA and alleviate the adverse reactions of prednisone.
18690936 Adverse dermatological reactions in rheumatoid arthritis patients treated with etanercept, 2006 Aug Etanercept is an anti-TNF drug with marked efficacy in inflammatory arthritis. This review addresses dermatological side effects that have been encountered in our 85 patients on the drug for rheumatoid arthritis, and reviews other reported cutaneous adverse events. Injection site reactions are common and usually self-limiting. We and others have encountered patients with recall site reactions where the four rotated injection sites simultaneously develop a hypersensitivity reaction. In all cases, the rash has responded to antihistamines and the etanercept was thereby continued. Other injection site reactions include discoid lupus and cutaneous vasculitis that respond to cessation of treatment and appropriate therapy. Skin reactions more distant from the injection site are also reviewed, with erythema nodosum, widespread lupus rashes, infections and skin tumours summarised. A patient who developed a purpuric rash at the site of last injection with a drug induced worsening of thrombocytopaenia is described. Although the therapeutic advantages of etanercept outweigh the side effects, clinicians need to be aware of the adverse reactions of these drugs with their increasing use.
17200409 Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rh 2007 Jan 22 The induction of regulatory T (T reg) cells holds considerable potential as a treatment for autoimmune diseases. We have previously shown that CD4+CD25hi T reg cells isolated from patients with active rheumatoid arthritis (RA) have a defect in their ability to suppress proinflammatory cytokine production by CD4+CD25- [corrected] T cells. This defect, however, was overcome after anti-tumor necrosis factor (TNF)-alpha antibody (infliximab) therapy. Here, we demonstrate that infliximab therapy gives rise to a CD4+CD25hiFoxP3+ T reg cell population, which mediates suppression via transforming growth factor (TGF)-beta and interleukin 10, and lacks CD62L expression, thereby distinguishing this T reg cell subset from natural T reg cells present in healthy individuals and patients with active RA. In vitro, infliximab induced the differentiation of CD62L- T reg cells from CD4+CD25- T cells isolated from active RA patients, a process dependent on TGF-beta. In spite of the potent suppressor capacity displayed by this CD62L- T reg cell population, the natural CD62L+ T reg cells remained defective in infliximab-treated patients. These results suggest that anti-TNF-alpha therapy in RA patients generates a newly differentiated population of T reg cells, which compensates for the defective natural T reg cells. Therefore, manipulation of a proinflammatory environment could represent a therapeutic strategy for the induction of T reg cells and the restoration of tolerance.
17265016 [Primary headaches and the influence of inflammatory diseases of the CNS and their respect 2007 Oct Headaches are a well known symptom in systemic or local inflammatory diseases such as pneumonia or meningitis. These headaches may mimic primary headaches and are thought to be generated by inflammatory mediators acting directly on nociceptors or indirectly - via facilitation of neurons. Apart from prostaglandin and nitric oxide also cytokines (TNF-alpha or interleukin-6) may play a role. In primary headaches such as migraine inflammatory mechanisms also have been acclaimed to contribute to pain generation. The recently observed increase of migraine attacks under immunmodulatory therapy in multiple sclerosis has focussed attention on primary headaches in states of altered immunity, for instance in autoimmune disorders like lupus erythematosus, rheumatoid arthritis, or in patients treated with immunosuppressants. This article describes the standard of knowledge and tries to shed light on possible mechanisms of pain generation in the respective conditions.
17967830 B lymphocyte stimulator expression in patients with rheumatoid arthritis treated with tumo 2008 Aug OBJECTIVE: To assess the effects of tumour necrosis factor (TNF) antagonist therapy on B lymphocyte stimulator (BLyS) expression in patients with rheumatoid arthritis (RA). METHODS: Blood from 38 patients with RA from a single centre was collected prior to and following initiation of TNF antagonist therapy. Plasma BLyS protein levels, blood leukocyte BLyS mRNA levels and disease activity were longitudinally monitored. Twelve patients with RA who either refused or were felt not to be candidates for TNF antagonist therapy and five normal healthy volunteers served as TNF antagonist-naïve controls. RESULTS: Baseline plasma BLyS protein levels, but not blood leukocyte BLyS mRNA levels, were elevated in patients with RA. Plasma BLyS protein levels declined following initiation of TNF antagonist therapy in good responders (GR) to TNF antagonist therapy but not in poor responders (PR). By contrast, the erythrocyte sedimentation rate (ESR) declined in response to TNF antagonist therapy in GR and PR. TNF antagonist therapy did not promote change in blood leukocyte BLyS mRNA levels in either GR or PR, suggesting that the TNF antagonist-associated changes in circulating BLyS protein levels reflected changes in local BLyS production in the affected joints rather than changes in systemic BLyS production. BLyS expression did not change over time in either the normal or RA control groups. CONCLUSIONS: A good clinical response to TNF antagonist therapy in patients with RA is associated with a decline in plasma BLyS protein levels. Increased BLyS expression in affected joints may contribute to ongoing disease activity, and reduction of such expression may help promote a favourable clinical response to TNF antagonist therapy.
17564779 Nonsteroidal anti-inflammatory drug use does not affect short-term endoscopic and histolog 2007 We evaluated the effects of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) on endoscopic and histological findings in patients with rheumatoid arthritis (RA) before and after the eradication of Helicobacter pylori infection. Helicobacter pylori (H. pylori) eradication using lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 mg twice daily for 1 week was conducted in 44 patients (mean age: 56.5 years) with RA. Using the updated Sydney system, endoscopic and histological findings of the greater curvature of the antrum, the greater curvature of the upper corpus, and the lesser curvature of the lower corpus were compared before and after eradication, for a mean follow-up period of 3.5 months. Overall, H. pylori eradication was successful in 32 patients (72.7%). Of these 32 patients, 23 were NSAID users. In the successful eradication group, (1) there was no significant change on endoscopic findings, including gastric erythema and erosion in all three regions irrespective of NSAIDs use; (2) of 17 active ulcers before eradication in NSAIDs users, all healed except for one duodenal ulcer that persisted, where one patient newly developed a gastric ulcer, one developed erosive duodenitis, and two developed reflux esophagitis, all in NSAID users; (3) neutrophil infiltration and chronic inflammation were significantly improved in all three regions after H. pylori eradication irrespective of use of NSAIDs, while atrophic change and intestinal metaplasia did not change. In the eradication failure group; (1) there was no significant change on endoscopic and histological findings in the three regions; (2) two of three ulcers present before eradication on NSAID users persisted even after eradication, and no new cases of gastric ulcer or erosive duodenitis occurred. In conclusion, over a mean follow-up period of 3.5 months, use of NSAIDs in Japanese patients with RA did not impair the healing process of gastric and duodenal ulcers nor did it affect the endoscopic and histological improvements associated with H. pylori eradication.
18512774 Synovial lymphoid neogenesis does not define a specific clinical rheumatoid arthritis phen 2008 Jun OBJECTIVE: To investigate the relationship between lymphoid neogenesis in the synovium of patients with rheumatoid arthritis (RA) and characteristics of inflammation and disease severity. METHODS: Arthroscopic synovial biopsy was performed in 103 patients with active RA (Disease Activity Score 28-joint assessment >or=3.2) who had not received treatment with biologic agents. Sections were stained and assessed by digital image analysis. Lymphocyte aggregates were counted and graded for size (1-3). Synovial lymphoid neogenesis was defined as the presence of grade 2 or 3 aggregates and subclassified based on the presence of follicular dendritic cells (FDCs). RESULTS: Lymphoid neogenesis was present in 31% of the RA synovial tissues, whereas an additional 25% contained only grade 1 aggregates. FDCs were present in 28% of the samples with lymphoid neogenesis, corresponding to 8% of the total RA cohort. Histologically, synovia with lymphoid neogenesis showed increased infiltration by T and B lymphocytes, plasma cells, and macrophages, and increased expression of tumor necrosis factor alpha and lymphotoxin beta compared with samples without lymphoid neogenesis. Patients with lymphoid neogenesis also had higher C-reactive protein levels, erythrocyte sedimentation rates, and leukocyte and thrombocyte counts, but exhibited no increase in the severity of clinical signs and symptoms. Of importance, there was no relationship between the presence of lymphoid neogenesis and IgM rheumatoid factor or anti-citrullinated protein antibodies. The presence of lymphocyte aggregates with FDCs did not define a specific clinical phenotype compared with lymphocyte aggregates without FDCs. CONCLUSION: These findings indicate that synovial lymphoid neogenesis is associated with more severe synovial and systemic inflammation, but this is not confined to a specific clinical subset of RA.
18684978 Delineating the role of the HLA-DR4 "shared epitope" in susceptibility versus resistance t 2008 Aug 15 In humans, HLA-DR alleles sharing amino acids at the third hypervariable region with DRB1*0401(shared epitope) are associated with a predisposition to rheumatoid arthritis, whereas DRB1*0402 is not associated with such a predisposition. Both DRB1*0402 and DRB1*0401 occur in linkage with DQ8 (DQB1*0302). We have previously shown that transgenic (Tg) mice expressing HLA-DRB1*0401 develop collagen-induced arthritis. To delineate the role of "shared epitope" and gene complementation between DR and DQ in arthritis, we generated DRB1*0402, DRB1*0401.DQ8, and DRB1*0402.DQ8 Tg mice lacking endogenous class II molecules, AE(o). DRB1*0402 mice are resistant to develop arthritis. In double-Tg mice, the DRB1*0401 gene contributes to the development of collagen-induced arthritis, whereas DRB1*0402 prevents the disease. Humoral response to type II collagen is not defective in resistant mice, although cellular response to type II collagen is lower in *0402 mice compared with *0401 mice. *0402 mice have lower numbers of T cells in thymus compared with *0401 mice, suggesting that the protective effect could be due to deletion of autoreactive T cells. Additionally, DRB1*0402 mice have a higher number of regulatory T cells and show increased activation-induced cell death, which might contribute toward protection. In DRB1*0401.DQ8 mice, activated CD4(+) T cells express class II genes and can present DR4- and DQ8-restricted peptides in vitro, suggesting a role of class II(+) CD4 T cells locally in the joints. The data suggest that polymorphism in DRB1 genes determines predisposition to develop arthritis by shaping the T cell repertoire in thymus and activating autoreactive or regulatory T cells.
18585759 Effect of tumor necrosis factor alpha inhibition on bone density and turnover markers in p 2009 Oct OBJECTIVES: Anti-tumor necrosis factor-alpha (TNFalpha) therapy has proven efficacious in improving both disease activity and focal bone erosions in patients with rheumatoid arthritis (RA) and spondyloarthopathies. We review the current literature reporting on the effect of anti-TNFalpha on bone density as measured by dual energy radiograph absorptiometry at the lumbar spine and hip, as well as markers of bone turnover and resorption, in patients using anti-TNFalpha for rheumatic disease indications. METHODS: A PubMed search, as well as manual search of related articles and references of articles retrieved, was performed to identify all studies pertaining to the effect of anti-TNFalpha therapy on bone mineral density (BMD) and bone turnover markers. RESULTS: In RA, 4 studies (238 patients) showed a stabilization or increase of BMD at the spine (up to 2.8%) or hip (up to 13.1%), with only 1 negative study in 48 patients (decline of 3.2% at the spine and 2.7% at the hip). In spondyloarthopathies, 3 studies (75 patients) all demonstrated an increase in BMD at the lumbar spine (3.2-3.6%) and at the hip (1.8-2.2%). Changes in markers of bone formation and bone resorption were heterogeneous but in general represented a modest increase in formation and decline in resorption. CONCLUSIONS: In general, anti-TNFalpha therapy has a beneficial effect on bone density and bone turnover markers. Retrieved studies were heterogeneous with regards to patients studied, underlying risks for osteoporosis, and supplemental therapy, which may limit the findings of the true effect of anti-TNFalpha therapy on bone.
16800070 [Intra- and postoperative fractures of the femur in total knee arthroplasty: risk factors 2006 Apr PURPOSE OF THE STUDY: We reviewed fractures of the distal femur occurring during or after total knee arthroplasty in order to identify risk factors. MATERIAL AND METHODS: Twelve intraoperative fractures occurred between 1990 and 2000 among 617 total knee arthroplasties performed during this period. The circumstances of these fractures were noted in comparison with other prosthetic implants. Twenty other fractures of the distal femur occurred in 20 patients who had had a total knee arthroplasty during the same time period. Mean patient age at surgery was 72 years (range 69-77). In addition to demographic data, we noted risk factors: bone demineralization related to general condition, rheumatoid arthritis or corticosteroid therapy, trochlear notch prior to the trochlear cut, bone resorption under the femoral implant, repeated knee surgery, abnormal stress on the distal femur due to hip disease, periprosthetic osteolysis without loosening related to polyethylene debris or metallosis, loosening, type of prosthesis, loss of bone stock because of the femoral implant, life of prosthesis. RESULTS: Intraoperative fractures usually occurred in specific circumstances: use of a posterior stabilized prosthesis, probably with insufficient preparation and position of the stabilization element, probably excessive impaction in osteoporotic bone (rheumatoid arthritis), difficult exposure (arthroplasty after prior osteotomy), fracture starting from the separator passing over the posterior aspect of the tibia and reaching the intercondylar notch. Independently of these intercondylar fractures, supracondylar or diaphyseal fractures were essentially observed for revision prostheses using a femoral stem. Postoperative fractures were observed in patients who had prior surgery of the distal femur (revision of femoral osteotomy, fracture of the distal femur, arthrodesis), in patients with significant loss of bone stock (posterior stabilized prosthesis), or poor bone quality (rheumatoid arthritis), and in elderly patients with neurological impairment and frequent falls. The trochlear notch did not appear to be sufficient to be the only cause of fracture but was nevertheless an element frequently associated with other risk factors. DISCUSSION AND CONCLUSION: This study shows that fracture of the distal femur occurs in certain preferential circumstances. Considering these elements, a certain number of preventive measures can be discussed for technical modifications or choice of implants.
17557891 Rheumatoid arthritis is associated with a high prevalence of hypothyroidism that amplifies 2008 Feb OBJECTIVE: Rheumatoid arthritis (RA) patients have an increased risk of developing cardiovascular diseases (CVD). Other autoimmune diseases such as hypothyroidism are also associated with an enhanced risk for CVD. Our objective was to determine first, the prevalence of hypothyroid disorders in RA patients, and second, the risk of CVD in RA patients with hypothyroid abnormalities. SUBJECTS: were RA patients who participated in an ongoing prospective cohort study of cardiovascular mortality and morbidity (n = 358) in which hypothyroid abnormalities were assessed. CVD was defined as a verified medical history of coronary, cerebral or peripheral arterial disease. RESULTS: Clinical hypothyroidism was observed in 16 of 236 female RA patients (6.8%), which is significantly higher than in the general population of The Netherlands. Subclinical hypothyroidism was detected in 6 out of 236 RA women (2.5%). In female RA patients, CVD was present in 6 out of 16 (37.5%) of all hypothyroid women. The odds ratio for CVD comparing female hypothyroid RA patients with female euthyroid RA patients was 4.1 (95% CI 1.2-14.3) after adjustment for sex, age, diabetes, smoking (ever), hypertension and statin use. CONCLUSIONS: Clinical hypothyroidism was observed three times more often in female RA patients than females in the general population. In female RA patients, clinical hypothyroidism was associated with a fourfold higher risk of CVD in comparison with euthyroid female RA patients independently of the traditional risk factors.
18533773 Association among rheumatoid arthritis, oral hygiene, and periodontitis. 2008 Jun BACKGROUND: A limited number of studies suggest a higher prevalence of periodontal disease among individuals with rheumatoid arthritis (RA); however, results have been inconsistent. Further, it is unclear to what extent poor oral hygiene among patients with RA may account for this association. METHODS: The association between RA and periodontitis was examined in 57 subjects with RA and 52 healthy controls, matched by age and gender. Oral examination included plaque index (PI), gingival index (GI), probing depth (PD), and clinical attachment loss (CAL). Potential risk factors for periodontal disease, such as smoking, education, alcohol consumption, and body mass index (BMI), as well as chronic diseases associated with RA and periodontal disease were assessed through questionnaires. RESULTS: In a stepwise logistic regression, including RA status, age, gender, education, smoking, alcohol consumption, and BMI, only RA status and age remained significant predictors of periodontal disease. Subjects with RA had a significant 8.05-fold increased odds (95% confidence interval: 2.93 to 22.09) of periodontitis compared to controls. The strength of the association was attenuated but remained statistically significant after further adjustment for PI, GI, or both. PI alone accounted for 12.4%, GI alone accounted for 11.1%, and PI and GI combined accounted for 13.4% of the association between RA and periodontitis. CONCLUSIONS: Subjects with RA have significantly increased periodontal attachment loss compared to controls. Oral hygiene may only partially account for this association.
18667700 IL-33 exacerbates antigen-induced arthritis by activating mast cells. 2008 Aug 5 IL-33, a cytokine of the IL-1 family, is closely associated with type II T cell responses. Here, we report an unexpected proinflammatory role of IL-33 in inflammatory arthritis. IL-33 was expressed in synovial fibroblasts from patients with rheumatoid arthritis (RA). Expression was markedly elevated in vitro by inflammatory cytokines. Mice lacking ST2, the IL-33 receptor alpha-chain, developed attenuated collagen-induced arthritis (CIA) and reduced ex vivo collagen-specific induction of proinflammatory cytokines (IL-17, TNFalpha, and IFNgamma), and antibody production. Conversely, treatment of wild-type (WT) but not ST2(-/-) mice with IL-33 exacerbated CIA and elevated production of both proinflammatory cytokines and anti-collagen antibodies. Mast cells expressed high levels of ST2 and responded directly to IL-33 to produce a spectrum of inflammatory cytokines and chemokines in vitro. In vivo, IL-33 treatment exacerbated CIA in ST2(-/-) mice engrafted with mast cells from WT but not from ST2(-/-) mice. Disease exacerbation was accompanied by elevated expression levels of proinflammatory cytokines. Our results demonstrate that IL-33 is a critical proinflammatory cytokine for inflammatory joint disease that integrates fibroblast activation with downstream immune activation mainly via an IL-33-driven, mast-cell-dependent pathway. Thus, this IL-1 superfamily member represents a therapeutic target for RA.
17289161 Toll-like receptor 2 and 4 combination engagement upregulate IL-15 synergistically in huma 2007 Mar 15 Toll-like receptors (TLRs) are pattern-recognition receptors that connect innate and adaptive immunity. Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector functions in inflammatory synovitis of rheumatoid arthritis (RA). The aim of this study was to clarify whether stimulation of TLR2 and TLR4 by their specific ligands induces the production of IL-15 in fibroblast-like synoviocytes (FLS) from RA patients. FLS were isolated from RA synovial tissues and stimulated with the TLR2 ligand bacterial peptidoglycan (PGN) and the TLR4 ligand lipopolysaccharide (LPS). IL-15 in the culture supernatants was measured by ELISA, and mRNA levels were assessed by RT-PCR and real time PCR. The expression of TLR2, TLR4, and IL-15 in the RA synovium was quantified by immunohistochemistry and compared with values obtained in osteoarthritis synovium. IL-15 production increased in culture supernatants of RA FLS stimulated with PGN or PGN plus LPS, and this was upregulated at the transcriptional level. In contrast, LPS did not increase the level of IL-15 although it augmented the stimulatory effect of PGN on IL-15 production. Inhibition of nuclear factor (NF)-kappaB with a specific inhibitor abrogated the stimulatory effect of PGN or PGN plus LPS on IL-15. Neutralization of TLR2 with a blocking monoclonal antibody significantly reduced IL-15 production (P<0.05), reflecting the functional relevance of TLR2 activation in the induction of IL-15 production. These data suggest that TLR2 activation in RA FLS by microbial constituents is involved in the induction of IL-15 and that TLR2 promotes inflammation through NF-kappaB. TLR4 augmented the stimulatory effect of TLR2 on IL-15, possibly contributing to the maintenance of synovitis in patients with RA.
17719471 Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and 2007 Aug 28 OBJECTIVES: The aim of this study was to investigate the effect of simvastatin and ezetimibe on inflammation, disease activity, endothelial dysfunction, and arterial stiffness in a cohort of rheumatoid arthritis (RA) patients. BACKGROUND: Rheumatoid arthritis is a chronic inflammatory condition associated with increased cardiovascular risk. Statins reduce inflammation and disease activity in RA patients, but whether this is due to pleiotropism or cholesterol lowering per se is unclear. METHODS: Twenty patients received 20 mg simvastatin or 10 mg ezetimibe each for 6 weeks in a randomized double-blind crossover study. Disease activity, blood pressure, aortic pulse wave velocity (PWV), brachial artery flow-mediated dilation (FMD), and serum inflammatory markers were measured before and after each treatment. RESULTS: Both ezetimibe and simvastatin significantly reduced total cholesterol (-0.62 +/- 0.55 mmol/l and -1.28 +/- 0.49 mmol/l, respectively; p < 0.001), low-density lipoprotein cholesterol (-0.55 +/- 0.55 mmol/l and -1.28 +/- 0.49 mmol/l; p < 0.0001), and C-reactive protein (-5.35 +/- 9.25 mg/l and -5.05 +/- 6.30 mg/l; p < 0.001). Concomitantly, Disease Activity Score (-0.55 +/- 1.01 and -0.67 +/- 0.91; p = 0.002), aortic PWV (-0.69 +/- 1.15 m/s and -0.71 +/- 0.71 m/s; p = 0.001), and FMD (1.37 +/- 1.17% and 2.51 +/- 2.13%; p = 0.001) were significantly improved by both drugs. CONCLUSIONS: This study demonstrates that both ezetimibe and simvastatin reduce disease activity and inflammatory markers to a similar extent in patients with RA. Therapy is also associated with a concomitant reduction in aortic PWV and improvement in endothelial function. This suggests that cholesterol lowering per se has anti-inflammatory effects and improves vascular function in RA.