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ID PMID Title PublicationDate abstract
19126559 Comparative effectiveness of tumour necrosis factor alpha inhibitors in combination with e 2009 Dec OBJECTIVE: The objective of this study was to compare the effectiveness of a combination of tumour necrosis factor alpha (TNFalpha) inhibitors with either methotrexate or leflunomide in the treatment of patients with rheumatoid arthritis in a real-world setting. METHODS: Data from 1769 outpatients enrolled in the German biologics register RABBIT who were treated with one of the TNFalpha inhibitors adalimumab, etanercept, or infliximab in combination with either methotrexate (n = 1375) or leflunomide (n = 394) were included in the analysis. Clinical status including disease activity as well as treatment data were documented by the treating rheumatologist at baseline and at 3, 6, 12, 18, 24, 30 and 36 months of follow-up. RESULTS: Patients treated with a combination of biologics with leflunomide had significantly higher baseline disease activity than those treated with methotrexate. The highest disease activity was found for patients treated with the combination infliximab/leflunomide. After 36 months, the discontinuation rates were 46.3%, 51.3% and 61.5% for combinations of etanercept, adalimumab and infliximab with methotrexate and 53.4%, 63.1% and 67.1% for combinations with leflunomide, respectively. European League Against Rheumatism response rates after 24 months ranged from 74% to 81% for combinations with methotrexate and 72% to 81% for combinations with leflunomide. CONCLUSION: The current clinical practice is to use methotrexate as a first choice for the combination with TNFalpha antagonists. In a number of patients methotrexate has to be replaced by another disease-modifying antirheumatic drug. Our data support the view that leflunomide is a useful alternative if methotrexate is contraindicated.
19565500 Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases 2009 Jul OBJECTIVE: Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors. METHODS: Cases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single-nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61-0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05-1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02-1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01-1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA. CONCLUSION: We have demonstrated associations between JIA and variants in the TNFAIP3, STAT4, and C12orf30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors.
19273456 Clinical features and prognosis of adult-onset still's disease: 61 cases from China. 2009 May OBJECTIVE: To describe the onset, clinical features, prognostic factors, and treatment of adult-onset Still's disease (AOSD) in cases from China. METHODS: Sixty-one Chinese patients with AOSD were analyzed retrospectively. RESULTS: Common clinical features were fever (100.0%), rash (88.5%), and arthritis (82.0%). The laboratory findings were as follows: leukocytosis (83.6%), increased erythrocyte sedimentation rate (100.0%), elevated transaminase concentrations (23.0%), elevated ferritin levels (79.6%), negative antinuclear antibody (88.5%), and negative rheumatoid factor (88.5%). Of the 61 patients, 44.3% exhibited a monocyclic disease pattern, 29.5% experienced disease relapse at least once, 16.4% exhibited chronic articular course, and 9.8% died; most deaths were due to pulmonary infection and respiratory failure. Based on the disease course, we divided the 61 patients into 2 groups: those with favorable outcome (cyclic disease course, n = 45) and unfavorable outcome (chronic disease course or death, n = 16). We analyzed the prognostic factors for the 2 groups, and found that pleuritis, interstitial pneumonia, elevated ferritin levels, and failure of fever to subside after 3 days of prednisolone at 1 mg/kg/day were unfavorable prognostic factors for patients with AOSD. CONCLUSION: Patients with AOSD had complex symptoms with no specific laboratory findings. Our results indicate that AOSD is not a relatively benign disease, especially in cases that are refractory to high doses of prednisone.
20180383 [Anti-TNF: beneficial or hamful for the lung?]. 2009 Sep The Tumor Necrosis Factor is a pro-inflammatory cytokine which plays a key role in the pathogenesis of many diseases. Therefore, the anti Tumor necrosis factors have been used for treating many inflammatory pathologies such as rheumatoid arthritis or Crohn's disease with success. However, the use of these drugs has revealed during the formal years many side effects dominated by the tuberculosis. Lung cancer and asthma might be other side effects of the drugs. More recently they have been used for other pulmonary indications such as sarcoidosis. Their benefits for treating asthma is being studied. Therefore, a wise use of these drugs is mandatory to benefit from good effects and avoid hamful ones.
20381217 [Non tuberculous anti-TNF associated opportunistic infections]. 2010 May Anti-TNFalpha agents have revolutionized the treatment of patients with rheumatoid arthritis, spondylarthropathies and Crohn's disease. However, their use is associated with an increased risk of infections. Pyogenic infections (involving the lungs, skin and urinary tract) and tuberculosis are the more commonly observed infectious complications in patients receiving anti-TNFalpha agents. However, opportunistic infections have been increasingly reported in anti-TNFalpha-treated patients, and include non tuberculous mycobacteria, fungi (Pneumocystis jiroveci, Candida sp, Aspergillus, Cryptococcus, Histoplasma), opportunistic bacterial (Nocardia), parasitic (Leishmania) and viral (e.g. Cytomegalovirus, human herpes virus 8 [HHV 8]) infections. These infectious complications usually occur within the first months of therapy and are important causes of morbidity and mortality in anti-TNFalpha-treated patients. It is recommended to rule out infections, especially latent or active tuberculosis, before the initiation of anti-TNFalpha therapy. However, it is necessary to follow-up closely these patients to detect the possible occurrence of opportunistic infections.
20808168 Evolving connective tissue disease influenced by splenectomy: beneath the sword of Dameshe 2010 Sep In years past, there was concern that splenectomy could lead to dissemination of occult systemic lupus erythematosus. Clinical studies subsequently effectively refuted that concept. However, there remains uncertainty regarding the role of the spleen in autoimmune diseases and the effect of splenectomy on their course. We present a case of a 56-year-old woman with autoimmune hepatitis and rheumatoid arthritis, without clinical or serologic features of lupus, who developed glomerulonephritis and antiphospholipid syndrome subsequent to an elective splenectomy. Literature review was performed to identify examples of the effect of splenectomy on other autoimmune diseases. Splenectomy has been linked with the development of new autoimmune phenomenon, alterations in the clinical course of patients with prior autoimmune disease, such as in our patient, and in a progressive redistribution of memory B cells that may influence autoimmune disease activity and may have been involved in the alteration in our patient's clinical course.
19736814 [Guidelines in RA treatment: concepts on safety and recommendations using anti-TNF-alpha i 2009 May Recommendations for the use of Disease-Modifying Antirheumatic Drugs (DMARD) with both conventional and biological agents in Rheumatoid Arthritis (RA) must be based on their safety profile, adverse effects, risks, and advantages. With the purpose of presenting the most updated information about the safety of tumor necrosis factor alpha (TNFalpha) antagonists, in this article we summarize the literature published during the last three years about this sort of biological agents in specific clinical situations, such as risk of developing infections, cancer, cardiovascular diseases, and autoimmunity; as well as their administration to patients who will undergo surgical procedures, pregnant and/or breast-feeding women, and patients who need immunizations. Likewise, in this analysis we offer specific recommendations, based on evidence, for the best anti-TNF-alfa management.
19305422 Sinomenine influences capacity for invasion and migration in activated human monocytic THP 2009 Apr AIM: The aim of this study was to investigate the mechanism of the effects of Sinomenine (SIN) on the invasion and migration ability of activated human monocytic THP-1 cells (A-THP-1). Sinomenine is a pure alkaloid extracted from the Chinese medical plant Sinomenium acutum. METHODS: Human monocytic THP-1 cells were induced to differentiate into macrophages with phorbol 12-myristate 13-acetate (PMA). Cells were treated with different concentrations of SIN. The invasion and migration ability of cells was tested by in vitro transwell assays. The levels of CD147 and MMPs were evaluated by flow cytometric analysis and zymographic analysis, respectively. The mRNA expression of CD147, MMP-2, and MMP-9 was measured by RT-PCR. RESULTS: The invasion and migration ability of A-THP-1 cells was significantly inhibited by SIN in a concentration-dependent fashion; at the same time, the levels of CD147, MMP-2, and MMP-9 were markedly down-regulated. This inhibitory effect was most notable at concentrations of 0.25 mmol/L and 1.00 mmol/L (P<0.01). CONCLUSION: A possible mechanism of the inhibitory effect of SIN on cell invasion and migration ability is repression of the expression of MMP-2 and MMP-9, which strongly correlates with the inhibition of CD147 activity.
20177421 In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase 2011 Feb The clinical development of a candidate p38 kinase inhibitor was terminated because of its unexpectedly rapid clearance in human subjects. Its short half-life and metabolic profile in human beings were vastly different from that in rats, dogs, and monkeys characterized during routine pre-clinical studies. Mice generated the predominant drug (4-hydroxylated) metabolite produced in human beings, which was not found in other species. The data from a murine in vitro drug biotransformation assay that used liver extracts from 14 inbred mouse strains were analyzed by haplotype-based computational genetic analysis. This led to the identification of aldehyde oxidase-1 (AOX1) as the enzyme responsible for the rapid metabolism of this drug. Specific enzyme inhibitors and expressed recombinant enzymes were used to confirm that AOX catalyzed the formation of the 4-hydroxylated drug metabolite in mouse and man. Genetic variation within Aox1 regulated the level of hepatic Aox1 mRNA, AOX1 protein, and enzyme activity among the inbred strains. Thus, computational murine pharmacogenetic analysis can facilitate the identification and characterization of drug metabolism pathways that are differentially utilized by humans and other species.
19898481 Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk 2009 Dec To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls. We used Gene Relationships Across Implicated Loci (GRAIL), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 x 10(-6) replication, P = 1 x 10(-9) overall), CD28 (rs1980422, P = 5 x 10(-6) replication, P = 1 x 10(-9) overall) and PRDM1 (rs548234, P = 1 x 10(-5) replication, P = 2 x 10(-8) overall). An additional four were replicated (P < 0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 x 10(-7) overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 x 10(-7) overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 x 10(-6) overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 x 10(-5) overall). Many of these loci are also associated to other immunologic diseases.
21111629 Lymphotoxin α stimulates proliferation and pro-inflammatory cytokine secretion of rheumat 2011 Feb OBJECTIVE: TNFα plays a crucial role in rheumatoid arthritis (RA) by stimulating fibroblast-like synoviocytes (FLS). Lymphotoxin α (LTα) is a pro-inflammatory cytokine with significant homology to TNFα. We compared the effects of both cytokines on cultured RA FLS. METHODS: Receptor expression on RA FLS was analyzed by FACS. Cells were stimulated with LTα or TNFα and proliferation was measured by [3H]thymidine incorporation and secretion of inflammatory cytokines and metalloproteinase 3 by ELISA. Activation of MAP kinases and Akt was analyzed by Western blotting. Nuclear translocation of NFκB was visualized by immunofluorescence. RESULTS: 60-80% and 30-50% of the RA FLS tested expressed TNF receptors I and II, respectively, and 70-75% expressed HVEM. LTα induced RA FLS proliferation at the same level of TNFα, which was blocked by etanercept. Both LTα and TNFα induced activation of MAP kinases ERK1/2 and p38 as well as Akt. 95-98% of FLS showed nuclear translocation of NFκB after stimulation with either cytokines. LTα and TNFα were potent to induce secretion of IL-6, IL-8 and metalloproteinase 3 in FLS. CONCLUSION: LTα is as effective as TNFα in stimulating RA FLS. Blocking both cytokines might allow a better control of inflammation and synovial proliferation in RA.
19015145 Suppression of tumour necrosis factor production from mononuclear cells by a novel synthet 2009 Jan OBJECTIVES: To evaluate the clinical efficacy of a novel synthetic peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, CLX-090717, in several in vitro cell culture systems and murine CIA, an experimental model of RA. METHODS: Peripheral blood monocytes purified by elutriation, and rheumatoid synovial cells isolated from clinical tissue were cultured with CLX-090717 and TNF-alpha release was measured. Molecular mechanism of action was analysed by western blotting and electrophoretic mobility shift assay. Thioglycollate-elicited murine peritoneal macrophages were cultured with CLX-090717 and lipopolysaccharide (LPS)-induced TNF-alpha release was assayed. Therapeutic studies were done in mice with established arthritis by evaluating clinical parameters and histology. In addition, type II collagen response of lymphocytes from mice with CIA was examined. RESULTS: CLX-090717 significantly inhibited spontaneous TNF-alpha release by RA synovial membrane cells, as well as LPS-induced TNF-alpha release from human and murine monocytic cells. Inhibition of TNF-alpha in monocytes was mediated partially through a nuclear factor-kappaB (NF-kappaB)-dependent pathway, as judged by sustained levels of IkappaBalpha in cytosolic extracts and a reduced level of LPS-induced NF-kappaB activity in nuclear extracts. CLX-090717 reduced clinical signs of arthritis and damage to joint architecture when administered therapeutically to arthritic mice. Mechanisms of action in CIA involved the reduction in proliferation of arthritic lymphocytes to antigen in vitro as well as reduced TNF-alpha release. CONCLUSIONS: Our data suggest that the synthetic compound CLX-090717 has potential as a small molecular weight anti-inflammatory therapeutic for chronic inflammatory conditions.
19269957 A novel paradigm for dendritic cells as effectors of cartilage destruction. 2009 May OBJECTIVE: Dendritic cells (DCs) are enriched in RA synovium and have been implicated in the pathogenesis of RA primarily through their ability to present autoantigen and activate T cells. However, whether DCs play an effector role in cartilage destruction is unknown. The aim of this study was to investigate whether DCs can induce collagen release from cartilage and the mechanism involved. METHODS: Human monocyte-derived DCs (mDCs) were activated with CD40 ligand (CD40L) to mimic DC-T-cell interaction, and supernatants were incubated with cartilage explants. Hydroxyproline was assessed as a measure of collagen release and collagenolytic activity was measured by a bioassay using tritiated collagen. TNF-alpha in DC supernatants was measured by specific ELISA. RESULTS: Supernatants from CD40L-activated mDCs, but not unstimulated mDCs, strongly induced the destruction of cartilage collagen. mDC supernatants did not contain collagenases but did induce collagenolytic activity in cartilage explants. Neutralization of TNF-alpha in mDC supernatants completely abolished collagenolysis. CONCLUSIONS: This study shows that mDCs, upon CD40-ligation, induce cartilage collagen degradation through an indirect mechanism via the production of TNF-alpha. Our data suggest a potential important role for mDC-derived TNF-alpha in RA, which is in line with the previously reported observations that DCs are a major source of TNF-alpha in early autoimmune lesions and that anti-TNF-alpha therapeutics effectively suppress joint damage in RA patients. We propose that DCs can act as effectors in cartilage destruction, adding a new aspect to the functional role of DCs in RA pathogenesis.
19174012 [Preparation of human antibodies to TNF-alpha using ribosome display technology]. 2009 Feb AIM: To prepare distinct human McAbs to TNF-alpha with high neutralizing potency using ribosome display technology. METHODS: The immunoglobulin heavy and light chain variable (VH, VL) genes were prepared from the peripheral blood lymphocytes in three arthritis patients by PCR. The genes encoding VH/K fragments were prepared by randomly combining VH and VL genes by SOE PCR. TNF-alpha binding fragments were selected over three cycles of ribosome display and the selected VH/Ks genes were cloned into pET22b(+)/BL21(DE3), from which soluble VH/K fragments were prepared. The expressed products of selected clones were analyzed by ELISA. Then the positive clones were characterized. RESULTS: A human VH/K gene library with 6.7x10(12) numbers used for ribosome display was constructed. Among the 180 selected clones, two clones TRB21 and TRB409 exhibiting the highest ELISA signals were isolated. The analysis of the sequence of TRB21 and TRB409 showed that they were new human immunoglobulin V genes to TNF-alpha and they recognize TNF-alpha specifically and antagonize the cytolytic effect of TNF-alpha on 1929 cell. CONCLUSION: The selected VH/Ks to TNF-alpha will be useful for constructing engineering antibodies with high affinity against arthritis. Ribosome display is a rapid means of generating fully human antibody fragments in vitro.
20715466 [Multiple nodular pulmonary amyloidosis complicated with Sjögren syndrome]. 2010 Aug A 67-year-old woman, who had been treated for Sjögren syndrome and rheumatoid arthritis for 10 years, was consulted for examination of multiple nodular pulmonary nodules. She has been pointed out multiple pulmonary nodules on chest computed tomography (CT) for 7 years, of which the number and the size gradually increased. When visuting our hospital, approximately 20 nodules up to 10 mm in size were noted. Thoracoscopic resection of the nodule was performed and histological diagnosis was amyloid, which was negative for A- and P- component and positive for transthyretin. Neither amyloid deposition in other organs nor abnormal protein in serum and urine was detected. The diagnosis of localized nodular pulmonary amyloidosis was established. As far as our knowledge, this is the 1st report of transthyretin amyloidosis with Sjögren syndrome.
19900478 IL-23 induces receptor activator of NF-kappaB ligand expression in fibroblast-like synovio 2010 Jan 4 Interleukin (IL)-23 stimulates T lymphocytes to produce inflammatory molecules, which can cause inflammatory arthritis. This study was undertaken to explore the role of IL-23 in stimulating the expression of the receptor activator of the nuclear factor kappa B (NF-kappaB) ligand (RANKL) and osteoclastogenic activity in human fibroblast-like synoviocytes (FLS). These cells were separated from the synovium of patients with rheumatoid arthritis (RA-FLS) and osteoarthritis (OA-FLS) and stimulated with IL-23. RANKL expression was measured by real-time polymerase chain reaction (PCR) amplification and immunostaining. Osteoclast precursor cells were cocultured with IL-23-stimulated RA-FLS and OA-FLS and subsequently stained for tartrate-resistant acid phosphatase (TRAP) activity. IL-23 upregulated RANKL expression in RA-FLS. The expression of RANKL mRNA and protein was blocked completely by inhibitors of NF-kappaB (parthenolide) or of the JAK II-STAT3 pathway (AG490), showing that the RANKL expression pathway is mediated by NF-kappaB and STAT3. TRAP-positive osteoclastogenesis was enhanced in IL-23-stimulated FLS. RA-FLS were more responsive to IL-23 in terms of their RANKL expression than OA-FLS or normal FLS. Thus, IL-23 appears to induce joint inflammation and bone destruction by stimulating RANKL expression in RA-FLS. These interactions between IL-23 and FLS indicate possible new therapeutic approaches for treating bone destruction in patients with inflammatory diseases.
20091647 Vitamin D for the treatment of chronic painful conditions in adults. 2010 Jan 20 BACKGROUND: Vitamin D is produced in the skin after sun-light exposure and can also be obtained through food. Vitamin D deficiency has recently been linked with a range of diseases including chronic pain. Observational and circumstantial evidence suggests that there may be a role for vitamin D deficiency in the aetiology of chronic pain conditions. OBJECTIVES: To assess the efficacy and adverse events of vitamin D supplementation in chronic painful conditions. SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to September 2009. This was supplemented by searching the reference lists of retrieved articles, textbooks and reviews. SELECTION CRITERIA: Studies were included if they were randomised double blind trials of vitamin D supplementation compared with placebo or with active comparators for the treatment of chronic pain conditions in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies for inclusion, assessed methodological quality, and extracted data. Pooled analysis was not undertaken due to paucity and heterogeneity of data. MAIN RESULTS: Four studies, with a total of 294 participants, were included. The studies were heterogeneous with regard to study quality, the chronic painful conditions that were investigated, and the outcome measures reported. Only one study reported a beneficial effect, the others found no benefit of vitamin D over placebo in treating chronic pain. AUTHORS' CONCLUSIONS: The evidence base for the use of vitamin D for chronic pain in adults is poor at present. This is due to low quality and insufficient randomised controlled trials in this area of research.
20194453 Similarities and differences between primary and secondary Sjögren's syndrome. 2010 Apr OBJECTIVE: To define the clinical, serological, and histopathological characteristics of primary (pSS) and secondary Sjögren's syndrome (SS). METHODS: Fifty subjects with pSS and 300 with connective tissue diseases (CTD; systemic lupus erythematosus 100, rheumatoid arthritis 100, scleroderma 100) were selected randomly from our patient registry. Selected patients were assessed for fulfillment of the American-European Consensus Group criteria for SS using a 3-phase approach: screening (European questionnaire, Schirmer-I test, wafer test), confirmatory (fluorescein staining test, nonstimulated whole salivary flow, anti-Ro/La antibodies), and lip biopsy (H&E and immunohistochemical staining for anti-CD20 and anti-CD45RO scored by morphometry). RESULTS: All patients with pSS and 65 with CTD met criteria for SS. Oral symptoms (pSS = 92% and secondary SS = 84%; p = 0.02), parotid enlargement (pSS 56%, secondary SS 9.2%; p < 0.001), and higher prevalence (pSS 82%, secondary SS 41%; p < 0.001) and titers of anti-Ro/La antibodies were more common in pSS. Extraglandular manifestations were similar in both groups, except for Raynaud's phenomenon, which was more common in those with secondary SS (pSS 16% vs secondary SS 41%; p = 0.001). These results remained after 3 different sensitivity analyses. The prevalence of focal infiltration was also similar in both SS varieties; however, a higher B:T cell ratio and higher expression of CD20 cells (2922 vs 607.5 positive cells; p < 0.001) were observed in pSS. CONCLUSION: A higher frequency of oral symptoms and parotid enlargement and stronger B cell activity (autoantibody production and lymphocyte infiltration) were observed in pSS. Whether these results reflect a true difference between the 2 disease entities or derive from underlying variables remains uncertain.
19417005 Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q 2009 Jul 15 The most consistent finding derived from the WTCCC GWAS for rheumatoid arthritis (RA) was association to a SNP at 6q23. We performed a fine-mapping of the region in order to search the 6q23 region for additional disease variants. 3962 RA patients and 3531 healthy controls were included in the study. We found 18 SNPs associated with RA. The SNP showing the strongest association was rs6920220 [P = 2.6 x 10(-6), OR (95% CI) 1.22 (1.13-1.33)]. The next most strongly associated SNP was rs13207033 [P = 0.0001, OR (95% CI) 0.86 (0.8-0.93)] which was perfectly correlated with rs10499194, a SNP previously associated with RA in a US/European series. Additionally, we found a number of new potential RA markers, including rs5029937, located in the intron 2 of TNFAIP3. Of the 18 associated SNPs, three polymorphisms, rs6920220, rs13207033 and rs5029937, remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of rs6920220 and rs5029937 together with the absence of the protective allele of rs13207033 was strongly associated with RA when compared with carriage of none [OR of 1.86 (95% CI) (1.51-2.29)]. This equates to an effect size of 1.50 (95% CI 1.21-1.85) compared with controls and is higher than that obtained for any SNP individually. This is the first study to show that the confirmed loci from the GWA studies, that confer only a modest effect size, could harbour a significantly greater effect once the effect of additional risk variants are accounted for.
19205787 Prevalence of abnormal ankle brachial index in patients with primary Sjogren's syndrome. 2009 May Chronic inflammatory autoimmune conditions like rheumatoid arthritis and systemic lupus erythematosus are associated with an increased risk of accelerated atherosclerosis (ATS). Very limited data are available about the incidence of ATS in patients with primary Sjogren's syndrome (PSS). Ankle brachial index (ABI) is a recognized method of detecting subclinical atherosclerosis. The objective of this study was to compare the prevalence of abnormal ABI in patients with PSS and in controls without PSS. Twenty-five PSS patients were compared with an age-, ethnicity-, and sex-matched control group. Traditional risk factors such as smoking, high blood pressure, blood sugar, lipids, and family history of atherosclerosis were assessed in both groups. Baseline clinical and laboratory features of PSS patients were recorded. ABI was measured in both groups. ABI less than 1.0 is considered abnormal. Fifty individuals (25 in each group) were studied. PSS patients and controls did not differ significantly in age, sex, and ethnicity. The prevalence of traditional cardiovascular risk factors was the same in both groups. Five out of 25 PSS patients (20%) had an ABI < 1.0 compared to one of 25 (4%) in the control group [P = 0.189 (odds ratio (OR) = 6.000 and 95% confidence interval (CI) 0.6464 to 55.692)]. Eight out of 25 PSS patients (32%) had disease duration of more than 10 years. This group of patients had a higher prevalence of low ABI compared to the individuals with lesser disease duration [P = 0.02 (OR = 16, 95% CI 1.38 to 185)]. PSS patients had a higher prevalence of low ABI, although this did not reach statistical significance. The subgroup of PSS patients with a longer duration of disease had a significantly lower ABI. This study was underpowered and a larger study is required to confirm the findings of this pilot study.