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ID PMID Title PublicationDate abstract
19264209 [What's new in internal medicine?]. 2008 Dec Brief virologic news included the discovery of the virophage, a unique parasite of the giant mimivirus and the association of HHV-8 infection with a peculiar form of African diabetes. Secondly, this news focused on risk factors for arterial or venous thrombosis and therapy for auto-immune disorders. Only oral estrogen therapy increases the risk of venous thromboembolism in postmenopausal women. Despite significant homocysteine lowering, vitamin supplementation with folic acid, vitamins B6 and B12 did not reduce total cardiovascular events among high-risk patients. Patients with venous thromboembolism have a substantially increased long-term risk of subsequent cardiovascular events while obesity, systemic arterial hypertension, and diabetes are common risk factors for arterial and venous thrombosis. The non fasting ApoB/ApoA1 ratio was superior to any of the cholesterol ratios for estimation of the risk of acute myocardial infection in all ethnic groups. Preventive anticoagulation of in-patients with risk of venous thromboembolism was inadequately prescribed in many hospitals of the world. Subcutaneous administration of methotrexate was more effective than the oral administration at the same dosage in patients suffering from active rheumatoid arthritis. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers. Anti-IL-5 and anti-IL-6 antibodies were effective for the treatment of respectively hypereosinophilic syndrome and rheumatoid arthritis. The efficacy of proteasome inhibitors and mesenchymal stems cells have been demonstrated in respectively two mouse strains with lupus-like disease and steroid-resistant severe acute graft-versus-host disease. These treatments may be useful for auto-immune disorders if their long term toxicity is acceptable. In conclusion, subcutaneous injections of physiological saline, used as placebo in two different trials, enhanced in vitro activation of immunocompetent cells in healthy individuals.
17205215 Distinct expression of mast cell tryptase and protease activated receptor-2 in synovia of 2007 Aug The objective of this study is to examine the differential expression of mast cell tryptase and its receptor, protease-activated receptor-2 (PAR-2), in the synovium and synovial fluid of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Biochemical and immunohistochemical analyses were performed to determine whether the trypsin-like protease in the synovium is identical to mast cell tryptase. The effects of mast cell tryptase on the proliferation of synovial fibroblast-like cells (SFCs) and the release of IL-8 thereof were evaluated by the [3H]-thymidine incorporation and ELISA, respectively. The trypsin-like protease in the synovium of RA patients was identical to human mast cell tryptase, which was composed of two subunits: 33 and 34 kDa. The 33- and 34-kDa proteins are different glycosylated forms of the 31-kDa protein, which was unglycosylated. Mast cell tryptase activity in RA synovial fluid was significantly higher than that in OA synovial fluid, while their activities and expression in the synovium were similar. Expression of PAR-2 mRNA in the synovium was higher in RA than in OA. Mast cell tryptase containing the unglycosylated 31-kDa subunit was the predominant form in synovial fluid. RA patients had higher amounts of this subunit in their synovial fluid than OA patients. Mast cell tryptase and PAR-2 activating peptide stimulated the proliferation of SFCs and release of IL-8 from these cells. Mast cell tryptase secretion into RA synovial fluid is higher than OA synovial fluid. Mast cell tryptase in synovial fluid stimulates the proliferation of SFCs and the release of pro-inflammatory cytokines via PAR-2, which may contribute to exacerbation of synovitis in RA.
17055648 Daily fatigue in women with osteoarthritis, rheumatoid arthritis, and fibromyalgia. 2007 Mar We examined between and within-person variability, affective correlates, and diagnostic differences in daily fatigue in women with rheumatoid arthritis (RA), osteoarthritis (OA), and fibromyalgia syndrome (FMS). Two hundred and fifty-five female patients recruited from the community served as participants for this project. The patients had a physician-confirmed diagnosis of RA (n=89), OA (n=76), or FMS (n=90). Individuals completed an initial questionnaire and up to 32 daily diaries assessing illness symptoms and psychosocial variables (i.e., fatigue, pain, sleep problems, depression, and affect). The primary outcome for the current project was variability in fatigue. We examined affective, pain, and sleep correlates of fatigue, and tested whether these relations varied by diagnosis. Results indicated that FMS patients had higher overall levels of and greater daily variability in fatigue compared with the other pain groups. For all patients, fatigue correlated highly with lower positive affect (PA). Moreover, day-to-day increases in fatigue were associated with decreases in PA, particularly among FMS patients, and with increases in negative affect (NA). Daily pain was associated with increased fatigue in all groups, although OA patients showed less pain reactivity than either FMS or RA patients. These findings indicate that fatigue is a common feature of rheumatologic conditions. Nonetheless, there are important differences between RA, OA, and FM patients in both the everyday manifestations and the biopsychosocial correlates of fatigue.
18329283 The topical application of nerve growth factor as a pharmacological tool for human corneal 2008 Apr AIM: The nerve growth factor is a soluble protein produced by and acting upon a number of different cells located in the nervous, endocrine and immune systems. Recent studies have shown that nerve growth factor (NGF) exerts a critical role on epithelial cells and fibroblasts under normal and pathological conditions. In this review, we present data prospecting the clinical potentiality of NGF in cutaneous and ocular "non-healing" chronic ulcers. DATA SYNTHESIS: A consistent number of in vitro and in vivo studies carried out on animal models and in humans indicated that fibroblasts and epithelial cells are receptive to the action of NGF and that NGF promotes skin and cornea ulcer healing. These observations lead to the hypothesis that NGF can be a potential useful pharmacological agent for clinical investigations. CONCLUSION: The available clinical evidences suggest that the topical application of NGF promotes healing action without side effects on corneal and cutaneous tissues damaged by chemical, physical and surgical insults and autoimmune disorders.
19004045 Construct validity and reliability of the disability of arm, shoulder and hand questionnai 2008 Dec OBJECTIVE: The Disability of Arm, Shoulder and Hand (DASH) questionnaire is a tool for measuring physical function and symptoms of the upper extremity. Although widely used, it is not validated for rheumatoid arthritis (RA). In this study the DASH was validated for this patient group. METHODS: In total, 102 patients participated in this study. For the validation, the questionnaires of the DASH, the Health Assessment Questionnaire (HAQ), the Medical Outcomes Study Short Form-36 (SF-36), and the Arthritis Impact Measurement Scale (AIMS2) were used. Patients were examined clinically before completing the questionnaires. Pain was scored by each patient using a visual analog scale (VAS). The Disease Activity Score (DAS28) was obtained and grip strength was measured. Reliability was tested by a second DASH questionnaire after 2 days. Validity was tested using a Pearson correlation analysis for the relevant domains of the questionnaires and for the clinical aspects. RESULTS: The reliability of the DASH was excellent (intraclass correlation coefficient 0.97). Internal consistency was strong (Cronbach's alpha 0.97). Validity was proven with excellent results for Pearson correlation with the relevant domains of the questionnaires: HAQ, r = 0.88; SF-36, r = 0.70; and AIMS2, r = 0.85. The clinical scores had a relatively low correlation with the DASH (DAS28, r = 0.42; and grip strength, r = 0.41-0.48), except for the VAS (r = 0.60-0.65). CONCLUSION: The DASH is a reliable and valid questionnaire in patients with RA. It can be used as a measurement tool of physical disability of the upper extremity.
17469140 Identification of distinct gene expression profiles in the synovium of patients with syste 2007 May OBJECTIVE: Synovitis is a common feature of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), but the pattern of joint involvement differs in each disease. This study was undertaken to investigate the global gene expression profiles in synovial biopsy tissue from the swollen knees of untreated SLE patients (n = 6), RA patients (n = 7), and osteoarthritis (OA) patients (n = 6). METHODS: Synovial biopsy samples were obtained from the affected knees of patients in the 3 groups by needle arthroscopy. Half of the material was used for extraction of total RNA, amplification of complementary RNA, and high-density oligonucleotide spotted hybridization arrays. On the remaining tissue samples, real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical experiments were performed to confirm the microarray data. RESULTS: SLE synovial biopsy tissue displayed a significant down-regulation of genes involved in extracellular matrix (ECM) homeostasis and a significant up-regulation of interferon-inducible (IFI) genes. Real-time RT-PCR experiments confirmed the up-regulation of selected IFI genes (IFI27, IFI44, and IFI44L) in the SLE synovial tissue. Immunohistochemical analyses showed that 3 molecules involved in ECM regulation, chondroitin sulfate proteoglycan 2, latent transforming growth factor beta binding protein 2, and fibroblast activation protein alpha, were significantly down-regulated in SLE synovium. In contrast, immunostaining for IFI27, Toll-like receptor 4, and STAT-1 resulted in higher quantitative scores in SLE synovial tissue, which could be attributed to the fact that the RA samples had a large population of inflammatory cell infiltrates that were negative for these markers. CONCLUSION: Arthritis in SLE has a very distinct molecular signature as compared with that in OA and RA, characterized by up-regulation of IFI genes and down-regulation of genes involved in ECM homeostasis.
16960243 Medical therapy: where are we now? 2006 Sep 15 PURPOSE: This article reviews the mechanisms of action, safety, and efficacy of the nonbiologic, or traditional, disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. It also addresses various aspects of rheumatoid arthritis (RA) clinical trials that warrant careful interpretation, including response criteria, outcomes measurements, study designs, and results of combination therapy trials. SUMMARY: The considerable progress in the treatment of RA over the past 20 years is due in large part to a better understanding of how to use DMARDs optimally and the introduction of biologic agents. In addition to their ability to suppress inflammation, and thereby reduce symptoms of pain and stiffness, these drugs also have the potential to alter the course of RA by slowing disease progression and reducing joint damage. CONCLUSION: Studies have demonstrated that early treatment of RA and rapid suppression of inflammation are extremely important as they provide long-term benefits and improve the overall prognosis for patients with the disease.
19006759 Effectiveness of splinting for the treatment of trigger finger. 2008 Oct The purpose of this study was to evaluate the efficacy of custom thermoplastic splinting designed to limit metacarpalphalangeal (MCP) joint flexion for trigger finger as a first treatment option. This study was a single group, prepost design with 28 participants fit with a low-profile custom thermoplastic MCP blocking (ring) splint. The pre- and post outcome measures included: stages of stenosing tenosynovitis (SST), grip strength, Numeric Pain Rating Scale (NPRS), the number of triggering events in ten active fists, and participant perceived improvement in symptoms. These measures were taken at the time of initial assessment before splint fabrication and after six weeks of continuous splint wear. Participants were given an educational handout on trigger finger and exercises to complete independently. After the use of a splint, there were statistically significant improvements in the SST, NPRS, the number of triggering events in ten active fists, and in the participant perceived improvement in symptoms. Grip strength did not significantly change. This study demonstrated a benefit from the use of a custom thermoplastic splint for an isolated incidence of trigger finger based on chosen outcome measures.
16830885 Necrotizing fasciitis in rheumatic diseases. 2006 Necrotizing fasciitis is an uncommon but life-threatening complication in immunocompromised hosts. We reported four patients with rheumatic diseases complicated by necrotizing fasciitis and reviewed 14 others from literature search. Most patients were on corticosteroid treatment. Septic shock, disseminated intravascular coagulopathy and acute renal deterioration were common giving rise to an overall mortality rate of 27.8%. Septic arthritis may also complicate the condition. Statistical analysis on the series showed the lack of major surgical debridement as the only risk factor associated with increased mortality (RR 7.5, 95% CI 2.1-27.3, P = 0.01). Timely debridement of necrotic tissue is important for reducing mortality.
18625033 Polymorphisms in the selenoprotein S gene: lack of association with autoimmune inflammator 2008 Jul 14 BACKGROUND: Selenoprotein S (SelS) protects the functional integrity of the endoplasmic reticulum against the deleterious effects of metabolic stress. SEPS1/SelS polymorphisms have been involved in the increased release of pro-inflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 in macrophages. We aimed at investigating the role of the SEPS1 variants previously associated with higher plasma levels of these cytokines and of the SEPS1 haplotypes in the susceptibility to develop immune-mediated diseases characterized by an inflammatory component. RESULTS: Six polymorphisms distributed through the SEPS1 gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171) were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study. CONCLUSION: Lack of association of SEPS1 polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.
18267980 Association between beta2 adrenergic receptor polymorphisms and rheumatoid arthritis in co 2008 Dec OBJECTIVE: In the present work, the frequency of inherited polymorphisms of the beta2 adrenergic receptor (beta2AR) gene and their association with rheumatoid arthritis (RA) as well as human leukocyte antigen (HLA)-DRB1 alleles was examined. METHODS: An allele-specific polymerase chain reaction was used to determine the common variants of the beta2AR at positions 16, 27 and 164 in patients with RA (n=310) and ethnically matched healthy controls (n=305) from Germany. HLA-DRB1 genotyping was performed by oligonucleotide hybridisation of enzymatically amplified DNA allowing low-resolution HLA-DRB1 genotyping comprising specificities DRB1*01 to DRB1*17. RESULTS: Arginine (Arg) at codon 16 was present in 278 patients with RA (89.7%) compared to 202 controls (66.2%; odds ratio (OR) 4.43, 95% CI 2.81 to 7.02, p<0.001). Homozygosity for Arg16 was found in 107 patients with RA (34.5%) compared to 14 controls (4.6%; OR 10.9, CI 5.9 to 20.5, p<0.001). Stratifying patients for their HLA-DR status revealed that homozygosity for Arg16 exhibited the greatest risk for RA in combination with HLA-DRB1*04 (OR 17.1, 95% CI 1.71 to 414.4, p=0.004). Interestingly, patients with the Arg16 allele have a younger mean (SD) age at disease onset compared to patients without Arg16 (46.1 (2.0) vs 53.1 (2.7) respectively, p<0.05). Furthermore, 93.3% patients with homozygosity for Arg16 were positive for anti-cyclic citrullinated peptide (CCP) antibodies vs 75% patients with homozygosity for Gly16 (p<0.05). CONCLUSION: There was a highly significant distortion between patients with RA and controls in the distribution of beta2AR polymorphisms at codon 16, contributing (together with the HLA-DR alleles) to the genetic background of RA.
17728331 The safety and efficacy of adding etanercept to methotrexate or methotrexate to etanercept 2008 Feb OBJECTIVE: To determine if adding etanercept (ETN) to methotrexate (MTX) or MTX to ETN for 52 weeks in rheumatoid arthritis (RA) patients with moderate disease activity provides higher efficacy. METHODS: All patients (n = 227) received open-label ETN 25 mg subcutaneously twice-weekly and MTX orally up to 20 mg weekly for 52 weeks and had completed a 3-year study in which patients received MTX, ETN or combination therapy. Endpoints were based on Disease Activity Score (DAS) and European League Against Rheumatism (EULAR) responses. RESULTS: Patients previously receiving combination therapy (Combination group; n = 96) had a lower disease activity at baseline. The mean DAS for those previously receiving MTX (ETN-added group; n = 55) and previously receiving ETN (MTX-added group; n = 76) were in the moderate disease activity range at baseline; Combination patients had a low disease activity. The greatest increase in DAS remission rates from baseline to week 52 was in the ETN-added group (23.6% to 41.8%, p<0.01), although Combination (37.6% to 50.0%, p<0.01) and MTX-added (26.7% to 36.8%, p = NS) also demonstrated improvements. DAS low disease activity and EULAR responses showed similar results. No new safety issues were identified. CONCLUSION: RA patients who were partial responders to long-term MTX or etanercept monotherapy obtained a higher efficacy with combination therapy. Responses achieved by patients with combination therapy after 3 years in the previous study were sustained or improved during the fourth year of treatment. This trial supports the higher therapeutic effect of combination treatment with etanercept and MTX in RA patients with moderate disease activity despite monotherapy with one of the two agents.
17694257 Power Doppler and spectral Doppler measurements of knee-joint synovitis in rheumatoid arth 2007 Power Doppler and spectral Doppler ultrasonography were used to scan 127 knee joints of 72 patients with rheumatoid arthritis (RA). Synovial effusion thickness and synovial proliferation (pannus) thickness, as well as the flow signal diameter, were measured on ultrasonogram prints of the power Doppler using digital calipers. In addition, color-flow signal grades on power Doppler and the resistance index (RI) values on spectral Doppler were evaluated. The values of these five variables were compared among 58 joints with superficial pattern flow signals and 69 joints with deep pattern flow signals. Compared with the joints with deep pattern signals, the joints with superficial pattern signals had significantly higher mean values of effusion thickness (P < 0.0001) and flow signal grades (P < 0.0001), and significantly lower mean RI (P < 0.0001). On the other hand, the joints with deep pattern signals had a significantly higher value of signal diameter (P = 0.0125) and had a trend to higher value of pannus thickness (P = 0.079) as well. Significant correlations were observed between effusion thickness and signal grades (P < 0.0001); effusion thickness and RI (P < 0.0001); signal diameter and pannus thickness (P = 0.0102); signal diameter and RI (P < 0.0001); and signal grades and RI (P < 0.0001). The ultrasonographic measurements of synovitis in RA patients provide valuable information on synovial inflammation.
17235652 Spontaneous multiple insufficiency fractures after pelvic abscess and sepsis in a rheumato 2007 Nov We report the unique occurrence and treatment of spontaneous multiple insufficiency fractures after sepsis in a patient with rheumatoid arthritis (RA). The patient was a 53-year-old woman with a 13-year history of RA. Her disease activity was not influenced by a disease-modifying antirheumatic drug (DMARD) regimen that included bucillamine, D-penicillamine, gold, sulfasalazine, and methotrexate. Due to an increased disease activity, her DMARD treatment regimen was changed to leflunomide. She had also undergone corticosteroid therapy with prednisolone ranging from 10 to 15 mg daily over the previous 8 years. She first presented with a wound infection at the surgical site of resection arthroplasty on her left foot, which had caused hematogenous dissemination that led to pelvic abscess and sepsis. For the next 2 years, she experienced multiple insufficiency fractures in parts of the ilium, sacral body, sacral ala, three thoraco-lumbar vertebral bodies (T12, L1, and L2), and subcapital femoral neck without low energy trauma. Postmenopausal osteoporosis, pelvic abscess, sepsis, decreasing daily activity, high RA disease activity, and high-load corticosteroid therapy were considered to be the causes of these fractures. Nonspecific symptoms such as low back pain and fever delayed diagnosis, which may have led to secondary fractures. Although her course after treatment was satisfactory during the study period, we recommend taking repetitive radiographs to detect insufficiency fracture for RA patients with continuing pain and reducing the corticosteroid dose to prevent infection and fracture.
16691185 Cia27 is a novel non-MHC arthritis severity locus on rat chromosome 10 syntenic to the rhe 2006 Jul Cia27 on rat chromosome 10 is a collagen-induced arthritis (CIA) severity quantitative trait locus originally identified in a study of (DA x ACI) F2. As an initial step towards the positional cloning of the Cia27 gene, a 17 cM (21 Mb) interval from the DA strain (arthritis-susceptible) containing the two-logarithm of odds support interval comprising Cia27 was introgressed into the ACI (arthritis-resistant) background through genotype-guided congenic breeding. ACI.DA(Cia27) congenics developed a significantly more severe form of arthritis (CIA), with a 5.9-fold increase in median arthritis severity index, a parameter known to correlate with synovial inflammation, and cartilage and bone erosions, compared with ACI (P< or =0.001). The arthritis severity enhancing effect could be detected from day 21 onwards. Rats heterozygous at the congenic interval developed a disease similar to ACI rats, suggesting that DA alleles operate in a recessive manner. Levels of autoantibodies anti-rat type II collagen did not correlate with arthritis severity. Synovial tissue mRNA levels of interleukin-1beta (IL-1beta) were significantly increased in ACI.DA(Cia27) congenics compared with ACI. These results demonstrate that Cia27 harbors a novel arthritis severity regulatory gene. The identification of this gene should facilitate the identification of the rheumatoid arthritis gene mapped to the human syntenic region on chromosome 17q22-q25.
16977463 Cathepsin G: the significance in rheumatoid arthritis as a monocyte chemoattractant. 2007 Feb Human cathepsin G (EC 3.4.21.20) has been reported to have the in vitro chemotactic activity for human monocytes. In this study, we examined the role of cathepsin G in monocyte involvement in joint inflammation of rheumatoid arthritis (RA) as a monocyte chemoattractant. Eighteen patients with RA and four patients with osteoarthritis (OA) were used in this study. Thiobenzylester substrate, Succ-Phe-Leu-Phe-S-Bzl, was used to measure the activity of cathepsin G in synovial fluids. Monocyte migration induced by cathepsin G and synovial fluids was assessed by a 48-well microchemotaxis chamber technique. Immunohistochemical staining was performed to determine the cellular origin of cathepsin G in RA synovial tissue. A very low activity of cathepsin G was detected in synovial fluids from patients with OA. On the other hand, significantly increased activity of cathepsin G was detected in patients with RA when compared with the value of OA patients. A considerable monocyte chemotactic activity was detected in the synovial fluid of RA patients, and the activity was partially decreased by the treatment with inhibitors for cathepsin G, alpha1-antichymotrypsin and phenylmethylsulfonyl fluoride. The activity of cathepsin G was significantly correlated with the neutrophil counts in synovial fluids and the concentration of interleukin-6. Immunohistochemical studies showed that cathepsin G was strongly expressed by synovial lining cells, and weakly expressed by macrophages and neutrophils in synovial tissues. This study indicates that the monocyte chemotactic activity of cathepsin G may have a role in the pathogenesis of RA synovial inflammation.
16762149 Influenza virus haemagglutinin-derived peptides inhibit T-cell activation induced by HLA-D 2006 Mar OBJECTIVE: To investigate whether influenza virus haemagglutinin (HA)-derived altered peptide ligands (APLs) could abrogate T-cell responses to wild type HA308-317 or type II collagen (CII) 263-272 peptides and explore the potential inhibitory effects of the altered HA308-317 peptides on T-cell activation in rheumatoid arthritis (RA). METHODS: Altered HA308-317 peptides containing substitutions of T-cell receptor (TCR)-contact residues were synthesized. Peripheral blood mononuclear cells (PBMC) were obtained from 27 HLA-DR4/1-positive RA patients. Impact of the altered HA308-317 peptides on T-cell responses and the inhibitory effects on T-cell activation were determined by using PBMC from RA. RESULTS: The results showed that the altered HA308-317 peptides could bind to HLA-DR4/1 on cell surface and had no effects on T-cell proliferation and CD25 expression. Moreover, all the altered HA308-317 peptides inhibited T-cell proliferative responses to wild type HA308-317 or CII263-272. In addition, Th1 type cytokine profile was found when PBMC were cultured with wild type HA308-317 or CII263-272, but not the altered HA 308-317 peptides. CONCLUSIONS: It is suggested that altered HA308-317 peptides bind to the RA-associated HLA-DR4/1 with no stimulating effects on T cells and might be potentially important in inhibition of T-cell activation in RA.
18347524 Diffuse alveolar hemorrhage after leflunomide therapy in a patient with rheumatoid arthrit 2008 Feb We report the case of a young man, affected by rheumatoid arthritis who developed a rapid-onset short-of-breath, hemoptysis, and severe weakness, about 2 weeks after the administration of leflunomide. Chest radiography showed central bilateral opacities and pleural effusion as confirmed by the high-resolution computed tomography that demonstrated diffuse ground-glass and interlobular septal thickening as well. On admission at the Emergency Department, a microhematuria and a severe anemia were also documented. On the basis of the clinico-radiologic presentation, a pulmonary hemorrhage was likely to occur; so to clarify the origin of this process, a complete serologic examination was performed but all the antibodies were negative. Finally a renal biopsy was performed and it showed a pauci-immunologic glomerulonephritis and the bronchioloalveolar lavage confirmed the diffuse alveolar hemorrhage. In conclusion, the diagnosis of leflunomide-pulmonary-renal syndrome was rendered. The treatment with leflunomide was suspended; the conditions of the patient gradually improved and he became completely asymptomatic 1 week later.
17541168 Dihydrotestosterone inhibits tumor necrosis factor alpha induced interleukin-1alpha mRNA e 2007 Jun Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects multiple synovial joints. Proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)alpha play important roles as principle inflammatory and destructive components of the disease. RA is known to be associated with significant gender differences in its prevalence and clinical features. We found that a potent androgen, 5alpha-dihydrotestosterone (DHT) inhibits IL-1alpha mRNA expression induced by TNFalpha and the DHT effect was inhibited by an androgen receptor antagonist, hydroxyflutamide (OHF). DHT inhibited the NF-kappaB activation induced by TNFalpha in a manner dependent on the androgen receptor (AR). These results suggest that DHT inhibits the TNFalpha-induced IL-1alpha mRNA expression by inhibiting NF-kappaB activation, and contributes to the gender differences of the disease.
17599732 Increased macrophage activation mediated through toll-like receptors in rheumatoid arthrit 2007 Jul OBJECTIVE: Macrophages are the major source of inflammation mediators that are important in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to analyze macrophages obtained from the joints of RA patients in order to characterize the expression of Toll-like receptor 2 (TLR-2) and TLR-4 and the responses to TLR ligation. METHODS: Cells were isolated from the synovial fluid (SF) of RA patients or patients with other forms of inflammatory arthritis. Cell surface TLR-2 and TLR-4 expression and intracellular tumor necrosis factor alpha (TNFalpha) and interleukin-8 (IL-8) expression by CD14+ macrophages were determined by flow cytometry. Peptidoglycan (PG) and lipopolysaccharide (LPS) were used as ligands for TLR-2 and TLR-4, respectively. RESULTS: The expression of TLR-2 and TLR-4 was increased on CD14+ macrophages from the joints of RA patients compared with that on control in vitro-differentiated macrophages or control peripheral blood monocytes. Neither TLR-2 expression nor TLR-4 expression differed between RA and other forms of inflammatory arthritis. However, PG- and LPS-induced TNFalpha expression and IL-8 expression were greater with RA SF macrophages than with those obtained from the joints of patients with other forms of inflammatory arthritis or with control macrophages. PG-induced TNFalpha expression and IL-8 expression were highly correlated with TLR-2 expression in normal macrophages, but not with that in macrophages obtained from joints of RA patients or patients with other forms of inflammatory arthritis. CONCLUSION: TLR-2 and TLR-4 ligation resulted in increased activation of RA synovial macrophages compared with those from patients with other forms of inflammatory arthritis or compared with control macrophages. Factors other than the level of TLR-2 and TLR-4 expression contributed to the increased activation of RA SF macrophages. These observations support the notion of a potential role for activation through TLR-2 and TLR-4 in the inflammation and joint destruction of RA.