Arthritis Research & Therapy - Latest articles

Association of single-nucleotide polymorphisms in RHOB and TXNDC3 with knee osteoarthritis susceptibility: two case-control studies in East Asian populations and a meta-analysis

2008-05-10

IntroductionTwo contradictory results on the association of single-nucleotide polymorphisms (SNPs) in RHOB and TXNDC3 with knee osteoarthritis (OA) susceptibility have been reported in European Caucasians. To examine their association in East Asian populations and evaluate their global significance, two case-control studies were conducted using 955 Chinese and 750 Japanese subjects. Methods: We genotyped the previously-reported associated SNPs, rs585017 in RHOB and rs4720262 in TXNDC3 in patients who had primary symptomatic knee OA with radiographic confirmation and in matched controls, and analyzed their association. We further performed a meta-analysis for the studies together with the previous European studies using the DerSimonian-Laird procedure. Results: Significant association of RHOB with knee OA was observed in male Chinese (P=0.02). No significant associations were found for RHOB in any other comparisons, either in meta-analysis for East Asian study. The association of TXNDC3 was replicated in Chinese female (P=0.04) and in Japanese (P=0.03), although all these associations by themselves did not overcome the Bonferroni's correction. Significant association (P=0.02 for the allelic frequency) with non-significant heterogeneity was found in the East Asian replication study. No significant association was found in any comparisons in the meta-analysis for all studies. Conclusions: Our study suggested a replication of the association of TXNDC3 with knee OA susceptibility in the East Asian populations.

Discontinuation rates in clinical trials in musculoskeletal pain: meta-analysis from etoricoxib clinical trial reports

R Andrew Moore, Sheena Derry and Henry J McQuay — 2008-05-08

Background: Patient adherence to therapy in clinical practice is often low, and the difference between efficacy measured in clinical trials and effectiveness in clinical practice is probably a function of discontinuation of therapy because of lack of efficacy or because of unmanageable or intolerable adverse events. Discontinuation is frequently measured in clinical trials, but is not usually described in detail in published reports, often because of limitations in the size of publications. By contrast, company clinical trial reports have much more detail. Methods: We examined company clinical trial reports of trials involving etoricoxib in four musculoskeletal conditions, osteoarthritis, rheumatoid arthritis, chronic low back pain, and ankylosing spondylitis. Information was available on 18 randomised trials (10,143 patients) lasting 4-12 weeks (one four weeks, three six weeks, one eight weeks, seven 12 weeks), and three trials with a mean duration of about 80 weeks (34,695 patients). These clinical trial reports contained over 73,000 pages of information. Results: Over 12 weeks, lack of efficacy and adverse event discontinuations were comparable in osteoarthritis, rheumatoid arthritis, and back pain, with lack of efficacy discontinuation rates some three times higher than for adverse events. All cause and lack of efficacy discontinuations were lower with etoricoxib (all doses combined) and traditional non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) than placebo, though NSAIDs produced higher rates of clinical adverse event and gastrointestinal discontinuations than placebo. Etoricoxib had fewer discontinuations than NSAIDs for lack of efficacy, clinical adverse events, and laboratory and gastrointestinal adverse events, but with more discontinuations because of hypertension and oedema. Comparison with two similar meta-analyses of other Cox-2 selective inhibitors (over 80,000 patients in total) showed consistency between analyses. Conclusion: Examining discontinuation data from clinical trials, even where the numbers of patients is very large, does not necessarily predict what will happen in real world practice that assesses the effectiveness of therapy rather than efficacy in clinical trials. Data from these analyses seems to agree with reports from real world practice.

Metabolic syndrome in rheumatic diseases: epidemiology, pathophysiology, and clinical implications

Prodromos I Sidiropoulos, Stylianos A Karvounaris and Dimitrios T Boumpas — 2008-05-08

Subjects with metabolic syndrome, a constellation of cardiovascular risk factors of which central obesity and insulin resistance are the more characteristic, are at increased risk for developing diabetes mellitus and cardiovascular disease. In these subjects, abdominal adipose tissue is a source of inflammatory cytokines such as TNFa, known to promote insulin resistance. The presence of inflammatory cytokines together with the well documented increased risk for cardiovascular diseases in patients with inflammatory arthritides and systemic lupus erythematosus, has prompted studies to examine the prevalence of the metabolic syndrome in an effort to identify subjects at risk, in addition to that conferred by traditional cardiovascular risk factors. These studies have documented a high prevalence of metabolic syndrome which correlates with disease activity and markers of atherosclerosis. The correlation of inflammatory disease activity with metabolic syndrome, provide additional evidence for a link between inflammation and metabolic disturbances/vascular morbidity.

PTPN22, PADI-4 and CTLA-4 genetic polymorphisms and risk of rheumatoid arthritis in two longitudinal cohort studies: evidence of gene-environment interactions with heavy cigarette smoking

2008-05-07

IntroductionPTPN22, PADI-4, and CTLA-4 have been associated with rheumatoid arthritis (RA) risk. We investigated whether polymorphisms in these genes were associated with RA among Caucasian women in two large prospective cohorts, adjusting for confounding factors and testing for interactions with smoking. Methods: We studied RA risk associated with PTPN22 (rs2476601), PADI-4 (rs2240340) and CTLA-4 (rs3087243), in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII). Participants in NHS were aged 30-55 years at entry in 1976; those in NHSII were 25-42 at entry in 1989. We confirmed incident RA cases through 2002 in NHS and 2003 in NHSII by questionnaire and medical record review. We excluded reports not confirmed as RA. In a nested case-control design involving participants with samples for genetic analyses (45% of NHS and 25% of NHSII), each incident RA case was matched to a participant without RA by year of birth, menopausal status and postmenopausal hormone use. Genotyping was performed using Taqman SNP allelic discrimination on the ABI 7900HT with published primers. HLA-shared epitope (HLA-SE) genotyping was performed at high resolution. We employed conditional logistic regression analyses, adjusting for smoking and reproductive factors. We tested for additive and multiplicative interactions between each genotype and smoking. Results: 437 incident RA cases were matched to healthy female controls. Mean age at RA diagnosis was 55 (10), 57% of RA cases were RF positive, and 31% had radiographic erosions at diagnosis. PTPN22 was associated with increased RA risk (pooled OR in multivariable dominant model: 1.46 [95% confidence interval (CI) 1.02, 2.08]). The risk was stronger for RF+ than for RF- RA. A significant multiplicative interaction between PTPN22 and smoking > 10 pack-years was observed (p = 0.04). CTLA-4 and PADI-4 genotypes were not associated with RA risk in the pooled results (pooled ORs in multivariable dominant models 1.27 [95%CI 0.88 to 1.84] for CTLA-4 and 1.04 [95%CI 0.77 to 1.40] for PADI-4). No gene-gene interaction was observed between PTPN22 and HLA-SE. Conclusions: After adjusting for smoking and reproductive factors, PTPN22 was associated with RA risk among Caucasian women in these cohorts. We found both additive and multiplicative interactions between PTPN22 and heavy cigarette smoking.

Anti-cyclic citrullinated peptide antibodies in primary Sjogren's syndrome may be associated with non-erosive synovitis

2008-05-07

Background: To investigate the prevalence of cyclic citrullinated peptide (anti-CCP) antibodies in patients with primary Sjogren's syndrome (pSS), and their correlations with clinical and laboratory data. Methods: We analysed the clinical and serological data of 155 consecutive patients with pSS; among these, 14 were excluded due to fulfillment of American College of Rheumatology classificative criteria for Rheumatoid Arthritis . So, 141 patients (27 males and 114 females; mean age 48 years, range 39-60) were clinically assessed for the presence of synovitis (objective swelling of one or more joints) and extra-glandular involvement. The anti-CCP antibodies were tested using a commercially available second-generation enzyme-linked immunosorbent assay (ELISA); IgM rheumatoid factor (RF) was determined by nephelometry. Results: Fourteen patients (9.9%) had moderate to high level anti-CCP levels, and 94 (66.7%) were positive for RF. Eighty-one (57.4%) showed extra-glandular involvement, and 44 (31.2%) had synovitis without any radiographic signs of erosion. There was a close correlation between the presence of anti-CCP and synovitis (p<0.001), but no association between anti-CCP and extra-glandular involvement (p=0.77). Multivariate analysis confirmed the association between anti-CCP and an increased prevalence of synovitis (prevalence odds ratio for positive vs negative anti-CCP status 7.611; 95% CI 1.475-74.870; P=0.010). Conclusions: Only a minority of pSS patients are anti-CCP positive, which seems to be closely associated with the prevalence of synovitis. Anti-CCP positivity in pSS patients may therefore be a predictor of future progress to RA, or an expression of the inflammatory process of synovial tissue.

Molecular discrimination of responders and non-responders to anti-TNF-alpha therapy in rheumatoid arthritis by etanercept

2008-05-02

IntroductionAbout thirty percent of rheumatoid arthritis (RA) patients fail to respond adequately to TNFa blocking therapy. There is a medical and socioeconomic need to identify molecular markers for an early prediction of responders and non-responders. Methods: Hereto, RNA was extracted from PBMC of 19 RA patients before first application of the TNFa blocker etanercept as well as after 72. Clinical response was assessed over 3 months using the 28 joint count Disease Activity Score (DAS28) and X-rays. Supervised learning methods were applied to Affymetrix Human Genome U133 microarray data analysis to determine highly selective discriminatory gene pairs or triplets with prognostic relevance for the clinical outcome evinced by a decline of DAS28 by 1.2. Results: Early down-regulation of expression levels secondary to TNFa neutralization was associated with good clinical responses as shown by a decline in overall disease activity 3 months after start of treatment. Informative gene sets include genes (e.g. NFKBIA, CCL4, IL8, IL1B, TNFAIP3, PDE4B, PPP1R15A and ADM) involved in different pathways and cellular processes such as TNFa signalling via NFkB, NFkB independent signalling via cAMP, and the regulation of cellular and oxidative stress response. Pairs and triplets within these genes were found to have a high prognostic value reflected by prediction accuracies of over 89% for 7 selected gene pairs and 95% for 10 specific gene triplets. Conclusions: Our data underline that early gene expression profiling is instrumental in identifying candidate biomarkers to predict therapeutic outcomes of anti-TNFa treatment regimes.

Early atherosclerosis in systemic sclerosis and its relation to disease or traditional risk factors

2008-04-25

IntroductionSeveral systemic autoimmune diseases are associated with an increased prevalence of atherosclerosis which could not be explained by traditional risk factors alone. In systemic sclerosis (SSc) microvascular abnormalities are well recognized. Previous studies have suggested an increased prevalence of macrovascular disease as well. We compared patients with SSc to healthy controls for signs of early atherosclerosis by measuring intima-media thickness (IMT) of the common carotid artery in relation to traditional risk factors and markers of endothelial activation. Methods: 49 patients with SSc, in which 92% had limited cutaneous SSc, and 32 healthy controls were studied. Common carotid IMT was measured by using B-mode ultrasound. Traditional risk factors for cardiovascular disease were assessed and serum markers for endothelial activation measured. Results: In patients with SSc the mean IMT (median, interquartile ranges; 0.69 mm (0.62-0.79)) was not significantly increased compared to healthy controls (0.68 mm (0.56-0.75, p=0.067). Also, after correction for the confounders age, high density lipoprotein (HDL)-cholesterol and low density lipoprotein (LDL)-cholesterol (p=0.328), or using a different model taking into account the confounders age, HDL-cholesterol and history of macrovascular disease (p=0.474), no difference in IMT was present between SSc patients and healthy controls. Plaques were found in 3 patients and not in healthy controls (p=0.274). In patients no correlations were found between maximum IMT, disease related variables and markers of endothelial activation. Endothelial activation markers were not increased in SSc patients compared to controls. Conclusions: SSc is not associated with an increased prevalence of early signs of atherosclerosis.

Mechanisms of oral tolerance revisited

Jun Wang and Rene EM Toes — 2008-04-25

Oral tolerance induction is thought to depend on special antigen presenting cells in the gut. A new report in the previous issue of Arthritis Research & Therapy supports this idea by demonstrating that indoleamine 2,3-dioxygenase-expressing dendritic cells in Peyer's patches from orally tolerized mice suppress T-cell responses via the generation of CD4+CD25+ regulatory T cells. This finding provides novel input into the mechanisms of oral tolerance that could further facilitate its use for the treatment of autoimmunity and chronic inflammatory reactions.

The action of fibroblast growth factor-2 on the intervertebral disc

2008-04-24

Background: Fibroblast growth factor-2 (FGF2) is a growth factor that is immediately released after cartilage injury and plays a pivotal role in cartilage homeostasis. In human adult articular cartilage, FGF2 mediates anti-anabolic and potentially catabolic effects via the suppression of proteoglycan (PG) production along with the upregulation of matrix-degrading enzyme activity. The aim of the present study was to determine the biological effects of FGF2 in spine disc cells and to elucidate the complex biochemical pathways utilized by FGF2 in bovine intervertebral disc (IVD) cells in an attempt to further understand the pathophysiologic processes involved in disc degeneration. Methods: We studied the effect of FGF2 on IVD tissue homeostasis by assessing MMP-13 expression (potent matrix-degrading enzyme), PG accumulation, and PG synthesis in the bovine spine IVD, as well as evaluating whether FGF2 counteracts known anabolic factors such as BMP7. In order to understand the molecular mechanisms by which FGF2 antagonizes BMP7 activity, we also investigated the signaling pathways utilized by FGF2 in bovine disc tissue. Results: The primary receptor expressed in bovine NP cartilage is FGFR1 and this receptor is upregulated in degenerative human IVD tissue compared to normal IVD tissue. Stimulation of bovine NP cells cultured in monolayer with FGF2 augmented the production of MMP-13 at the transcriptional and translational level in a dose-dependent manner. Stimulation of bovine NP cells cultured in alginate beads for 21 days with FGF2 resulted in a dose-dependent decrease in PG accumulation due at least in part to the inhibition of PG synthesis. Further studies demonstrate that FGF2 (10 ng/ml) antagonizes BMP7-mediated acceleration of PG production in bovine NP cells via the upregulation of noggin, an inhibitor of the TGFbeta/BMP signaling pathway. Chemical inhibitor studies showed that FGF2 utilizes the MAPK and NFkappaB pathways to upregulate noggin, serving as one potential mechanism for its anti-anabolic effects. Conclusion: FGF2 is anti-anabolic in bovine spine disc cells, revealing the potential of FGF2 antagonists as unique biologic treatments for both prevention and reversal of IVD degeneration.

Prolonged, granulocyte-macrophage-colony stimulating factor dependent, neutrophil survival following rheumatoid synovial fibroblast activation by IL-17 and TNF-alpha

2008-04-23

IntroductionA surprising feature of the inflammatory infiltrate in rheumatoid arthritis is the accumulation of neutrophils within synovial fluid and at the pannus cartilage boundary. Recent findings suggest that a distinct subset of IL-17-secreting T-Helper cells (TH17) plays a key role in connecting the adaptive and innate arms of the immune response and in regulating neutrophil homeostasis. We therefore tested the hypothesis that synovial fibroblasts bridge the biological responses that connect TH17 cells to neutrophils by producing neutrophil survival factors following their activation with IL-17. Methods: IL-17 expressing cells in the rheumatoid synovium and peripheral blood and synovial fluid IL-17 expressing cells were examined by confocal microscopy and flow cytometry respectively. Peripheral blood neutrophils were co-cultured with either rheumatoid synovial fibroblasts (RASF), or conditioned medium from RASF that had been pre-exposed to rhIL-17, TNF-alpha or a combination of the two cytokines. Neutrophils were harvested and stained with the vital mitochondrial dye DiOC6 before being enumerated by flow cytometry. Results: TH17 expressing CD4+ cells were found to accumulate within rheumatoid synovial tissue and in RA synovial fluid. RASF treated with IL-17 and TNF-alpha(RASFIL17/TNF) effectively doubled the functional lifespan of neutrophils in co-culture. This was entirely due to soluble factors secreted from the fibroblasts. Specific depletion of GM-CSF from RASFIL17/TNF conditioned medium demonstrated that this cytokine accounted for approximately half of the neutrophil survival activity. Inhibition of phosphatidylinositol-3-kinase (PI3K) and NF-kB pathways showed a requirement for both signalling pathways in RASFIL-17/TNF mediated neutrophil rescue. Conclusions: We conclude that the increased number of neutrophils with an extended life span found in the rheumatoid synovial microenvironment is partly accounted for by IL-17 and TNF-alpha activation of synovial fibroblasts. TH17 expressing T cells within the rheumatoid synovium are likely to contribute significantly to this effect.