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ID PMID Title PublicationDate abstract
17178563 Antigen-induced differential gene expression in lymphocytes and gene expression profile in 2006 Dec To explore early signature genes playing critical roles in the initial steps in an autoimmune murine model of rheumatoid arthritis (RA) (proteoglycan (PG)-induced arthritis; PGIA), we performed gene expression profiling of "arthritogenic" spleen cells stimulated with cartilage PG, and compared them to differentially expressed genes, identified in joints prior to the onset of arthritis, and then in the acute and chronic phases of the disease. A total of 280 genes were up-regulated and 226 genes were suppressed in in vitro PG-stimulated lymphocytes at a minimum of 2-fold expression change. Functional gene classification identified several major clusters of biological activity. Expression of immunoglobulin genes (66 transcripts) was downregulated by approximately 3.7-fold, whereas most of the other genes with immune/inflammation-associated functions such as interleukins (IL-1, -2, -4, -6, -10, -12, -16, -17), chemokine receptors and their ligands (Cxcl1, Ccl2, 7, 8, 9, 10, 22, Ccr2, Ccr5), and major components of the complement cascade were upregulated. Using adoptive disease transfer with stimulated lymphocytes into SCID mice, followed by gene expression profiling of SCID paws, indicated that 37 genes were differentially expressed in yet non-inflamed (pre-arthritic) paws; these genes were related mostly to chemokine, IFN-gamma and TNF-alpha signaling. However, the majority of differentially expressed immune response-related genes were silent in pre-arthritic joints, and only 12 genes were found differentially expressed both in antigen (PG)-stimulated lymphocytes and in the synovium prior to the onset of arthritis. Most of these "arthritis-initiation" genes belonged to chemokine mediated cell motility. Transcripts of chemokine receptor 5 (Ccr5), chemokine ligand 7 (Ccl7) and IFN-gamma-inducible proteins (Ifi47) and GTP-ase 1 were expressed at the highest levels in both antigen-stimulated lymphocytes and pre-inflamed synovium, which suggests a key role of these genes in both lymphocyte maturation and arthritis initiation.
17207383 Frequency of musculoskeletal conditions among patients referred to Italian tertiary rheuma 2006 Nov OBJECTIVE: To describe the occurrence of different rheumatic diseases and to examine the characteristics of patients referred to six Italian rheumatological units. To compare these data with those from other countries. METHODS: Six Italian rheumatological tertiary referral centers participated in the study. Diagnoses of in- and outpatients aged over 16 years were classified according to the International Classification of Diseases, ninth revision. RESULTS: Three thousand, five hundred and thirty-seven patients with mean age 56 +/- 14.8 years, of which 2604 (73.6%) were women, were studied. Inflammatory joint and spine diseases were diagnosed in 40.4%, connective tissue diseases in 14.4%, degenerative joint and spine diseases in 21.4%, soft tissue rheumatisms in 18.5%, and metabolic bone diseases in 5.3%. There was a significant difference among centers in the frequency of most diagnoses: non-academic centers cared for more patients with arthritis and connective tissue diseases and for less patients with degenerative diseases, soft tissue rheumatisms and metabolic bone diseases. Connective tissue diseases were constantly seen more often in Italian centers, whereas soft tissue rheumatisms were seen more often abroad. CONCLUSION: Our data emphasize the great variability of the diagnostic case-mix in different centers from the same country, an observation that raises some concerns of the results of descriptive multicenter studies. Studies on the breakdown of diagnoses made in rheumatological centers could be helpful to determine the burden of rheumatic diseases on the health system, and for the planning of health interventions by both the national rheumatological societies and health authorities.
17967265 [Vitamin D insufficiency--possible etiologic factor of autoimmune diseases]. 2007 Oct 22 The primary source of vitamin D in humans is sun exposure to the skin. The incidence of certain autoimmune diseases correlates positively with latitude. As vitamin D production increases with sun exposure, vitamin D insufficiency is hypothesised to influence the development of autoimmune diseases. In experimental animal and cellular studies in vitro 1.25-(OH)2-vitamin D reduces inflammation. This article discusses the role of vitamin D in inflammatory bowel disease, type 1 diabetes mellitus, multiple sclerosis, and rheumatoid arthritis.
18584289 Co-occurrence of subchondral insufficiency fracture of the femoral head and contralateral 2008 We describe a 79-year-old woman with rheumatoid arthritis who suffered from subchondral insufficiency fracture of the femoral head (SIF) and contralateral femoral neck fracture. Radiographs obtained two months after the onset of thigh pain showed collapse of the right femoral head and contralateral femoral neck fracture. MRI revealed a subchondral serpiginous low-intensity band in the right femoral head on the T2-weighted image. This case report suggests that SIF should be considered in the differential diagnoses of rheumatic patients who suffer from thigh pain without antecedent trauma.
17338641 Effects of disease-modifying anti-rheumatic drugs (DMARDs) on the activities of rheumatoid 2007 Mar Rheumatoid arthritis is an inflammatory and disabling joint disease affecting 0.5-1.5% of the population. Although various anti-inflammatory (NSAIDs) and disease-modifying (DMARDs) drugs are in clinical use, their precise mechanisms of action are not always defined. In this report, we discuss the effects of widely used DMARDs such as gold derivatives and chloroquine on cathepsins K and S, which have been implicated as critical mediators of inflammation and joint erosion in rheumatoid arthritis. We demonstrate that clinically potent gold derivatives inhibit cathepsins K and S in in vitro and cell-based assays. An X-ray analysis of the gold thiomalate/cathepsin K complex reveals that the inhibitor is bound to the active-site cysteine residue of the protease. Chloroquine, a lysosomotropic agent of lower clinical potency than gold derivatives, inhibits neutral pH-labile cathepsins intracellularly, but does not affect the neutral pH-stable cathepsin S. The potent inhibition of cathepsins implicated in the pathogenesis of rheumatoid arthritis by gold derivatives may explain the therapeutic efficacy of these drugs.
17603697 [Recurrent new-onset uveitis in a patient with rheumatoid arthritis during anti-TNFalpha t 2007 Apr Inflammation involving the uveal tract of the eye, termed uveitis, is frequently associated with various rheumatic disease, including seronegative spondylarthropathies, juvenile rheumatoid arthritis, Crohn's disease and Behçet's disease. Scleritis and keratitis may be associated with rheumatoid arthritis and systemic vasculitides such as Wegener's granulomatosis. Immune-mediated uveitis can have a chronic relapsing course and produce numerous possible complications, many of which can result in permanent vision loss. Treatment typically includes topical or systemic corticosteroids with cycloplegic-mydriatic drugs and/or noncorticosteroid immunosuppressants, but often there is an insufficient clinical effectiveness. Anti-TNFalpha therapy is promising in the treatment of sight threatening uveitis, particularly in patients with Behçet's disease. However, there have been also reports of new-onset uveitis during treatment of joint disease with TNFalpha inhibitors. We describe a case of new-onset uveitis in a patient with rheumatoid arthritis during therapy with etanercept at first and infliximab at last. Although we cannot exclude uveitis as linked to rheumatoid arthritis, it is unlike that the uveitis arises when the joint disease is well controlled. The hypothetical paradoxical effect of anti-TNF is here discussed.
17408492 Contribution for new genetic markers of rheumatoid arthritis activity and severity: sequen 2007 The objective of this study was to assess whether clinical measures of rheumatoid arthritis activity and severity were influenced by tumor necrosis factor-alpha (TNF-alpha) promoter genotype/haplotype markers. Each patient's disease activity was assessed by the disease activity score using 28 joint counts (DAS28) and functional capacity by the Health Assessment Questionnaire (HAQ) score. Systemic manifestations, radiological damage evaluated by the Sharp/van der Heijde (SvdH) score, disease-modifying anti-rheumatic drug use, joint surgeries, and work disability were also assessed. The promoter region of the TNF-alpha gene, between nucleotides -1,318 and +49, was sequenced using an automated platform. Five hundred fifty-four patients were evaluated and genotyped for 10 single-nucleotide polymorphism (SNP) markers, but 5 of these markers were excluded due to failure to fall within Hardy-Weinberg equilibrium or to monomorphism. Patients with more than 10 years of disease duration (DD) presented significant associations between the -857 SNP and systemic manifestations, as well as joint surgeries. Associations were also found between the -308 SNP and work disability in patients with more than 2 years of DD and radiological damage in patients with less than 10 years of DD. A borderline effect was found between the -238 SNP and HAQ score and radiological damage in patients with 2 to 10 years of DD. An association was also found between haplotypes and the SvdH score for those with more than 10 years of DD. An association was found between some TNF-alpha promoter SNPs and systemic manifestations, radiological progression, HAQ score, work disability, and joint surgeries, particularly in some classes of DD and between haplotypes and radiological progression for those with more than 10 years of DD.
18264741 Joint gap changes with patellar tendon strain and patellar position during TKA. 2008 Apr Balancing of the joint gap in extension and flexion is a prerequisite for success of a total knee arthroplasty. The joint gap is influenced by patellar position. We therefore hypothesized the state of the knee extensor mechanism (including the patellar tendon) would influence the joint gap. In 20 knees undergoing posterior-stabilized type total knee arthroplasties, we measured the joint gap and the patellar tendon strain from 0 degrees to 135 degrees flexion with the femoral component in position. When the patella was reduced, the joint gap was decreased at 90 degrees and 135 degrees (by 1.9 mm and 5.5 mm, respectively) compared with the gap with the patella everted. The patellar tendon strain increased with knee flexion. Patellar tendon strain at 90 degrees flexion correlated with the joint gap difference with the patella in everted and reduced positions. This suggests that in addition to the collateral ligaments, the knee extensor mechanism may have an influence on the joint gap. Therefore, accounting for extensor mechanism tightness may be important in achieving the optimal joint gap balance during total knee arthroplasty. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
17907228 Safety and efficacy of Ganoderma lucidum (lingzhi) and San Miao San supplementation in pat 2007 Oct 15 OBJECTIVE: To examine the efficacy of popular Chinese herbs used in a traditional Chinese medicine (TCM) combination of Ganoderma lucidum and San Miao San (SMS), with purported diverse health benefits including antioxidant properties in rheumatoid arthritis (RA). METHODS: We randomly assigned 32 patients with active RA, despite disease-modifying antirheumatic drugs, to TCM and 33 to placebo in addition to their current medications for 24 weeks. The TCM group received G lucidum (4 gm) and SMS (2.4 gm) daily. The primary outcome was the number of patients achieving American College of Rheumatology (ACR) 20% response and secondary outcomes included changes in the ACR components, plasma levels, and ex vivo-induced cytokines and chemokines and oxidative stress markers. RESULTS: Eighty-nine percent completed the 24-week study. Fifteen percent in the TCM group compared with 9.1% in the placebo group achieved ACR20 (P > 0.05). Pain score and patient's global score improved significantly only in the TCM group. The percentage, absolute counts, and CD4+/CD8+/natural killer/B lymphocytes ratio were unchanged between groups. CD3, CD4, and CD8 lymphocyte counts and markers of inflammation including plasma interleukin-18 (IL-18), interferon-gamma (IFNgamma)-inducible protein 10, monocyte chemoattractant protein 1, monokine induced by IFNgamma, and RANTES were unchanged. However, in an ex vivo experiment, the percentage change of IL-18 was significantly lower in the TCM group. Thirteen patients reported 22 episodes (14 in placebo group and 8 in TCM group) of mild adverse effects. CONCLUSION: G lucidum and San Miao San may have analgesic effects for patients with active RA, and were generally safe and well tolerated. However, no significant antioxidant, antiinflammatory, or immunomodulating effects could be demonstrated.
16869000 Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies 2006 Aug OBJECTIVE: Transient B cell depletion with the monoclonal anti-CD20 antibody rituximab has resulted in favorable clinical responses in patients with rheumatoid arthritis (RA). However, little is known about the regeneration profile of different peripheral B cell subpopulations. The aim of this study was to delineate the regeneration profile of different B cell subsets in the peripheral blood after selective anti-CD20-mediated B cell depletion. METHODS: Seventeen patients with RA refractory to standard therapy were treated with rituximab. Patients 1-6 received 4 weekly infusions of rituximab at a dose of 375 mg/m2, and patients 7-17 received 2 infusions of rituximab (1,000 mg), 2 weeks apart. Four-color staining was performed at several time points, using CD38, IgD, and CD27 in addition to other cell surface markers. In one patient, the mutational status of the immunoglobulin receptor was examined. RESULTS: The analysis revealed a distinct pattern of B cell regeneration. The first wave of repopulating B cells were immature B cells (CD38high,IgD+,CD10+,CD24high), the immunoglobulin receptors of which were not yet somatically mutated. In parallel, a recirculation of plasma cells was observed. Later, the number of naive B cells increased, and these cells predominated in the peripheral blood B cell pool. CD27+ memory B cells showed a slow and delayed repopulation, and the level of these cells stayed significantly reduced (<50%) compared with baseline values, for more than 2 years. CONCLUSION: Our findings provide evidence for a characteristic regeneration pattern of B cell subpopulations, with long-lasting modulation of B cell subset composition, after selective anti-CD20-mediated B cell depletion.
16859515 Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four oth 2006 We studied the diagnostic performance of the anti-human citrullinated fibrinogen antibody (AhFibA) ELISA for rheumatoid arthritis (RA) in a consecutive cohort (population 1) and evaluated the agreement between the AhFibA ELISA and four other assays for anti-citrullinated protein/peptide antibodies (ACPAs) as well as rheumatoid factor in patients with longstanding RA (population 2). Population 1 consisted of 1024 patients with rheumatic symptoms; serum samples from these patients were sent to our laboratory for ACPA testing within the context of a diagnostic investigation for RA. Ninety-two of these patients were classified as having RA according to the American College of Rheumatology criteria and 463 were classified as non-RA patients. Population 2 consisted of 180 patients with longstanding RA and was used to assess agreement and correlations between five ACPA assays: anti-cyclic citrullinated peptide (CCP)1 and anti-CCP2 antibodies were detected using a commercially available ELISA, AhFibA using ELISA, and anti-PepA and anti-PepB antibodies using line immunoassay. Applying previously proposed cut-offs for AhFibA, we obtained a sensitivity of 60.9% and a specificity of 98.7% in population 1. Receiver operating characteristic curve analysis could not detect a significant difference in diagnostic performance between the AhFibA ELISA and anti-CCP2 assay. Performing a hierarchical nearest neighborhood cluster analysis of the five different ACPA assays in population 2, we identified two clusters: a cluster of anti-pepA, anti-pepB and anti-CCP1, and a cluster of AhFibA and anti-CCP2. In conclusion, we found that AhFibA and anti-CCP2 antibodies had similar diagnostic performance. However, disagreement between ACPA tests may occur.
18591771 Treatment with SI000413, a new herbal formula, ameliorates murine collagen-induced arthrit 2008 Jul We tested the effects of SI000413, a new formula, consisting of Pyrolae herba and Trachelospermi caulis, on type II collagen-induced arthritis (CIA). CIA was induced in DBA/1J mice by immunization with bovine type II collagen (CII) on days 1 and 21. SI000413 was orally administered 3 times per week throughout the experiment and indomethacin was served as a positive control. Clinical scores, the count of arthritic legs, levels of interleukin 6 (IL-6) and anti-CII antibody, and lymphocyte subsets in blood were examined. SI000413 suppressed CIA development in a dose dependent manner and reduced the incidence of arthritic legs in mice. Histological analysis showed administration of SI000413 reduced inflammatory signs and cartilage destruction. Serum levels of IL-6 and anti-CII antibody were significantly decreased in SI000413-treated mice and the percentages of CD4 T cell, CD8 T cell and B cell in blood were restored to normal levels. In conclusion, we demonstrate that SI000413 ameliorates CIA both clinically and histologically and inhibits the production of anti-CII antibody and pro-inflammatory cytokine in the CIA mouse. These findings suggest that SI000413 is a potential new therapeutic herbal formula for the treatment of RA.
18798391 [Prevalence and cervical human papilloma virus associated factors in patients with rheumat 2008 Jan BACKGROUND: Nevertheless its association with cervicouterine cancer, there is no information about cervical human papillomavirus infection prevalence in patients with rheumatoid arthritis. OBJECTIVE: To evaluate human papillomavirus infection prevalence through molecular biology tests, and to analyze this infection related factors in patients with rheumatoid arthritis. MATERIAL AND METHOD: Analytic, transversal study to 250 patients: 61 women with rheumatoid arthritis selected from a rheumatologic external consult of a second level hospital, and 189 healthy women, with cervical cytology, of a first level hospital. They were polled to find infection risk factors. They were exfoliated to get cervix cells to extract its DNA and detect human papillomavirus (chain reaction of polymerase with specific consensus markers), and identification of restriction enzyme in high and low risks viruses. Prevalence was calculated, and adjusted factors analysis was performed through logistic regression with odds ratio and confidence intervals of 95%. RESULTS: Prevalence of papillomavirus infection in patients with rheumatoid arthritis was 30%, and in control group was 24%, with an odds ratio of 0.8 (CI 95% 0.42-1.6, p = 0.5). Ninety-four percent of the most frequent viral types in women with rheumatoid arthritis were high risk (mainly types 16, 58, and 18). Factors associated with higher human papillomavirus adjusted to rheumatoid arthritis were: more than one sexual partner (OR = 5.8 CI 95% 1.1-31.1, p = 0.04), more than one sexual intercourse weekly (OR = 6.7, CI 95% 0.9-51.6, p = 0.06), circumcised sexual partner (OR = 9.0, CI 95% 1.2-64.4, p = 0.02). Patients and controls had same values of marital status. Seventy-four percent of controls worked, compared to 44% of women with rheumatoid arthritis (p < 0.01). CONCLUSION: One out of three women with rheumatoid arthritis has human papillomavirus infection and 94% has the high-risk viral type. Infection associated factors mainly includes sexual partner ones; due to high risk of cervical dysplasia, it is necessary the early detection of the infection and surveillance.
18277630 [Rituximab (MabThera)--a new biological medicine in rheumatoid arthritis therapy]. 2007 Nov Rheumatoid arthritis (RA) is a serious, chronic, inflammatory disorder that damages the joints. The chronic destructive process causes pain to patients with RA and leads to the development of permanent disability. At present, great emphasis is placed on timely and effective therapy for RA, which is able to halt or slow the development of the disorder. At present we do not have any means of curing RA, the main objective for treatment is to induce remission of the disorder and prevent structural damage to the joints and the development of permanent disability. The relatively frequent failure of disease modifying medications (DMARDs) lead to efforts to find new resources for the treatment of RA. So called biological medicines were recently introduced into therapeutic use. These were mainly TNFalpha blockers. Experience has shown that approximately a third of patients with RA do not respond even to treatment with such medicines. Rituximab (MabThera), a monoclonal antibody against CD20 positive B-lymphocytes, is a new biological medicine approved for RA therapy. It represents a new hope for patients with active RA, for whom earlier therapy with TNFa blockers has failed.
17417994 Adaptation and validation of a telephone questionnaire--Serbian version for case detection 2007 Jan OBJECTIVE: To adapt and validate a telephone questionnaire for case detection of rheumatoid arthritis (RA) and spondyloarthropathies (SpA) in the Serbian population. METHODS: A questionnaire, developed by the French Society of Rheumatology and successfully tested in France, was adapted to the Serbian language using a cross-cultural adaptation process. It was validated in 150 patients: 50 with RA, 50 with SpA and 50 with degenerative rheumatic disorders. They were recruited from Institute of Rheumatology in Belgrade, hospital registry, years 2001 and 2002. The questionnaire validity was assessed in reference to clinical diagnosis and ACR 1987 and ESSG 1991 classification criteria. A logistic regression model was used for RA-control and SpA-control comparison to identify the set of items that best discriminates these groups. RESULTS: Cross-cultural adaptation of the Questionnaire was successfully achieved, verifying its equivalence with the original (semantic, idiomatic, experiential, conceptual). According to the logistic regression, two items selected for RA provided 92.1% agreement when using either clinical diagnosis or ACR classification criteria as a standard. SpA-control comparison included five items providing 96.8% agreement with clinical diagnosis and four items providing 94.1% agreement with ESSG criteria. Results of the present study are similar to those found in the French study. CONCLUSION: Validation results of the telephone questionnaire, translated and adapted to the Serbian language, confirm that it can be used as a detection tool for RA and SpA cases in the population of Serbia, whose diagnoses would have to be further confirmed.
18375541 Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not 2009 Jan OBJECTIVE: To determine whether rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, or carriage of shared epitope (SE) and PTPN22 genetic susceptibility variants predict response to therapy in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) agents. METHODS: UK-wide multicentre collaborations were established to recruit a large cohort of patients treated with anti-TNF drugs for RA. Serum RF, anti-CCP antibody and SE status were determined using commercially available kits. PTPN22 R620W genotyping was performed by Sequenom MassArray. Linear regression analyses were performed to investigate the role of these four factors in predicting response to treatment by 6 months, defined as the absolute change in 28-joint Disease Activity Score (DAS28). RESULTS: Of the 642 patients analysed, 46% received infliximab, 43% etanercept and 11% adalimumab. In all, 89% and 82% of patients were RF and anti-CCP positive, respectively. Patients that were RF negative had a 0.48 (95% CI 0.08 to 0.87) greater mean improvement in DAS28 compared to patients that were RF positive. A better response was also seen among patients that were anti-CCP negative. No association was demonstrated between drug response and SE or PTPN22 620W carriage. CONCLUSION: The presence of RF or anti-CCP antibodies was associated with a reduced response to anti-TNF drugs. However, these antibodies only account for a small proportion of the variance in treatment response. It is likely that genetic factors will contribute to treatment response, but these do not include the well established RA susceptibility loci, SE and PTPN22.
18348715 Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprot 2008 INTRODUCTION: The purpose of this study was to investigate the effects of vegan diet in patients with rheumatoid arthritis (RA) on blood lipids oxidized low-density lipoprotein (oxLDL) and natural atheroprotective antibodies against phosphorylcholine (anti-PCs). METHODS: Sixty-six patients with active RA were randomly assigned to either a vegan diet free of gluten (38 patients) or a well-balanced non-vegan diet (28 patients) for 1 year. Thirty patients in the vegan group completed more than 3 months on the diet regimen. Blood lipids were analyzed by routine methods, and oxLDL and anti-PCs were analyzed by enzyme-linked immunosorbent assay. Data and serum samples were obtained at baseline and after 3 and 12 months. RESULTS: Mean ages were 50.0 years for the vegan group and 50.8 years for controls. Gluten-free vegan diet induced lower body mass index (BMI) and low-density lipoprotein (LDL) and higher anti-PC IgM than control diet (p < 0.005). In the vegan group, BMI, LDL, and cholesterol decreased after both 3 and 12 months (p < 0.01) and oxLDL after 3 months (p = 0.021) and trendwise after 12 months (p = 0.090). Triglycerides and high-density lipoprotein did not change. IgA anti-PC levels increased after 3 months (p = 0.027) and IgM anti-PC levels increased trendwise after 12 months (p = 0.057). There was no difference in IgG anti-PC levels. In the control diet group, IgM anti-PC levels decreased both after 3 and 12 months (p < 0.01). When separating vegan patients into clinical responders and non-responders at 12 months, the effects on oxLDL and anti-PC IgA were seen only in responders (p < 0.05). CONCLUSION: A gluten-free vegan diet in RA induces changes that are potentially atheroprotective and anti-inflammatory, including decreased LDL and oxLDL levels and raised anti-PC IgM and IgA levels.
19035474 Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhib 2008 Dec OBJECTIVE: To evaluate the ability of SNX-7081, a novel small molecule inhibitor of Hsp90, to block components of inflammation, including cytokine production, protein kinase activity, and angiogenic signaling. A close analog was evaluated in preclinical in vivo models of rheumatoid arthritis (RA). METHODS: SNX-7081 binding to Hsp90 was characterized in Jurkat cells and RA synovial fibroblasts (RASFs). Inhibition of NF-kappaB nuclear translocation was evaluated in cellular systems, using lipopolysaccharide (LPS), tumor necrosis factor alpha, or interleukin-1beta stimulation. Suppression of cytokine production in THP-1 cells, human umbilical vein endothelial cells, and RASFs was studied. Disruption of MAPK signaling cascades by SNX-7081 following growth factor stimulation was assessed. SNX-7081 was tested in 2 relevant angiogenesis assays: platelet-derived growth factor activation of fibroblasts and LPS-induced nitric oxide (NO) release in J774 macrophages. A close analog, SNX-4414, was evaluated in rat collagen-induced arthritis and adjuvant-induced arthritis, following oral treatment. RESULTS: SNX-7081 showed strong binding affinity to Hsp90 and expected induction of Hsp70. NF-kappaB nuclear translocation was blocked by SNX-7081 at nanomolar concentrations, and cytokine production was potently inhibited. Growth factor activation of ERK and JNK signaling was significantly reduced by SNX-7081. NO production was also sharply inhibited. In animal models, SNX-4414 fully inhibited paw swelling and improved body weight. Scores for inflammation, pannus formation, cartilage damage, and bone resorption returned to normal. CONCLUSION: The present results demonstrate that a small molecule Hsp90 inhibitor can impact inflammatory disease processes. The strong in vivo efficacy observed with SNX-4414 provides preclinical validation for consideration of Hsp90 inhibitors in the treatment of RA.
18652199 [State-of-the-art biological therapy of rheumatoid arthritis]. 2008 State-of-the-art state of biological therapy of rheumatoid arthritis is analyzed. Its pathogenetic reasons are represented. Main direction of this therapy, such as blocking of tumor necrosis factor alpha and interleukin-1, inhibition of interaction between T-lymphocytes and antigen representing cells, elimination of B-cells, are considered. Special attention is devoted to new perspective methods of biological treatment, among which the special interest has first applied in RAMS Institute of Rheumatology method of interferon-gamma neutralization. Combination of anti-inflammatory, immune depressive and significant destructive actions leads to significant curative effect of biological therapy, exceeding results of the use of classic basic drugs including methotrexate. The achievement of clinical remission of rheumatoid arthritis first became the real aim of its treatment, and methods of biological therapy in contrast to former "disease-modifying" remedies could be considered as real "disease-controlling" drugs. Biological therapy revolutionized modern rheumatology and in the nearest years would demonstrated new fundamental accesses.
19022409 Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients. 2009 Jan The objective was to estimate the incidence of serious infections in the patients treated with anti-TNFalpha agents for rheumatoid arthritis (RA) recorded in the Lombardy Rheumatology Network (LORHEN) registry. The study inclusion criteria were met by 1064 of the 1114 patients with long-standing RA, 519 treated with infliximab, 303 with adalimumab, and 242 with etanercept; their mean age was 55.8 years and the mean duration of RA 9.4 years. Seventy-three patients (6.9%) experienced a total of 74 serious infections, an incidence rate for all treatment courses of 35.9 per 1000 patient-years (95% confidence interval [95% CI] 27.66-44.13). Most were lower respiratory tract (34.2%) or skin and soft tissue infections (20.5%). Of the 1064 patients, the 790 treated with anti-TNFalpha after March 2002 underwent screening tests for LTBI; five patients developed active tuberculosis. Three patients died of septic shock. The type of anti-TNFalpha agent did not seem to affect the incidence or site of the infections. Both univariate and multivariate analyses identified age at the start of anti-TNFalpha treatment (p=0.008), baseline erythrocyte sedimentation rate ([ESR] p=0.014), and the concomitant use of corticosteroids (p=0.029) as significant predictors of infections. There was no statistically significant difference in risk between the anti-TNFalpha agents.