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ID PMID Title PublicationDate abstract
18466472 Constructing gene association networks for rheumatoid arthritis using the backward genotyp 2007 BACKGROUND: Rheumatoid arthritis (RA, MIM 180300) is a common and complex inflammatory disorder. The North American Rheumatoid Arthritis Consortium (NARAC) data, as part of the Genetic Analysis Workshop 15 data, consists of both genome scan and candidate gene studies on RA patients. RESULTS: We applied the backward genotype-trait association (BGTA) algorithm to capture marginal and gene x gene interaction effects of multiple susceptibility loci on RA disease status. A two-stage screening approach was used for the genome scan, whereas a comprehensive study of all possible subsets was conducted for the candidate genes. For the genome scan, we constructed an association network among 39 genetic loci that demonstrated strong signals, 19 of which have been reported in the RA literature. For the candidate genes, we found strong signals for PTPN22 and SUMO4. Based on significant association evidence, we built an association network among the loci of PTPN22, PADI4, DLG5, SLC22A4, SUMO4, and CARD15. To control for false positives, we used permutation tests to constrain the family-wise type I error rate to 1%. CONCLUSION: Using the BGTA algorithm, we identified genetic loci and candidate genes that were associated with RA susceptibility and association networks among them. For the first time, we report possible interactions between single-nucleotide polymorphisms/genes, which may be useful for biological interpretation.
18466469 Genome-wide analysis of single-locus and epistasis single-nucleotide polymorphism effects 2007 The goal of this study was to identify single-locus and epistasis effects of SNP markers on anti-cyclic citrullinated peptide (anti-CCP) that is associated with rheumatoid arthritis, using the North American Rheumatoid Arthritis Consortium data. A square root transformation of the phenotypic values of anti-CCP with sex, smoking status, and a selected subset of 20 single-nucleotide polymorphism (SNP) markers in the model achieved residual normality (p > 0.05). Three single-locus effects of two SNPs were significant (p < 10-4). The epistasis analysis tested five effects of each pair of SNPs, the two-locus interaction, additive x additive, additive x dominance, dominance x additive, and dominance x dominance effects. A total of ten epistasis effects of eight pairs of SNPs on 11 autosomes and the X chromosome had significant epistasis effects (p < 10-7). Three of these epistasis effects reached significance levels of p < 10-8, p < 10-9, and p < 10-10, respectively. Two potential SNP epistasis networks were identified. The results indicate that the genetic factors underlying anti-CCP may include single-gene action and gene interactions and that the gene-interaction mechanism underlying anti-CCP could be a complex mechanism involving pairwise epistasis effects and multiple SNPs.
18766126 Refractory vertebral sarcoidosis responding to infliximab. 2008 Aug Treatment of refractory sarcoidosis may be challenging for clinicians. Despite treatment with conventional therapy, sarcoidosis may be progressive and debilitating. Previous studies have implicated a role for tumor necrosis factor-alpha in granuloma formation as seen in sarcoidosis. Tumor necrosis factor-alpha inhibitors are currently approved to treat rheumatoid arthritis, Crohn disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis. There have been recent case-reports supporting treatment of refractory and multisystem sarcoidosis with such agents. We report a case of sarcoidosis, involving the lung and vertebrae, which was refractory to conventional therapy. Our patient's clinical symptoms and radiologic lesions of vertebral sarcoid dramatically improved after treatment with infliximab.
18466554 Analyses of single marker and pairwise effects of candidate loci for rheumatoid arthritis 2007 Using parametric and nonparametric techniques, our study investigated the presence of single locus and pairwise effects between 20 markers of the Genetic Analysis Workshop 15 (GAW15) North American Rheumatoid Arthritis Consortium (NARAC) candidate gene data set (Problem 2), analyzing 463 independent patients and 855 controls. Specifically, our work examined the correspondence between logistic regression (LR) analysis of single-locus and pairwise interaction effects, and random forest (RF) single and joint importance measures. For this comparison, we selected small but stable RFs (500 trees), which showed strong correlations (r~0.98) between their importance measures and those by RFs grown on 5000 trees. Both RF importance measures captured most of the LR single-locus and pairwise interaction effects, while joint importance measures also corresponded to full LR models containing main and interaction effects. We furthermore showed that RF measures were particularly sensitive to data imputation. The most consistent pairwise effect on rheumatoid arthritis was found between two markers within MAP3K7IP2/SUMO4 on 6q25.1, although LR and RFs assigned different significance levels.Within a hypothetical two-stage design, pairwise LR analysis of all markers with significant RF single importance would have reduced the number of possible combinations in our small data set by 61%, whereas joint importance measures would have been less efficient for marker pair reduction. This suggests that RF single importance measures, which are able to detect a wide range of interaction effects and are computationally very efficient, might be exploited as pre-screening tool for larger association studies. Follow-up analysis, such as by LR, is required since RFs do not indicate high-risk genotype combinations.
18466531 Case-control association analysis of rheumatoid arthritis with candidate genes using relat 2007 We performed a case-control association analysis of rheumatoid arthritis (RA) for several candidate genes using the North American Rheumatoid Arthritis Consortium (NARAC) data provided in Genetic Analysis Workshop 15. We conducted the case-control association analysis using all related cases and unrelated controls and compared the results with those from the analysis of samples using only one randomly selected case from each family and all unrelated controls. For both analyses we used a weighted composite likelihood ratio test based on single-nucleotide polymorphism (SNP) markers or haplotypes accounting for the correlation among samples within a family. Several SNPs, including R620W in the candidate gene PTPN22, showed an association with RA status, which confirmed previously reported results. Several other SNPs in the candidate genes, such as CTLA4, HAVCR1, and SUMO4, also had rather small p-values (<0.05), suggesting the associations between them and RA. Our results showed that the p-values obtained from the analysis including all related cases were generally smaller than those obtained from the analysis including only one randomly selected case per family. These results, together with the results, based on simulated data, showed that higher power could be achieved using all related cases.
18466461 Meta-genetic association of rheumatoid arthritis and PTPN22 using PedGenie 2.1. 2007 PedGenie beta version 2.1 is a unique, flexible, and easily implemented analysis software tool that is enhanced significantly by incorporation of meta-statistics to allow valid combined analysis of multiple studies, including mixtures of family-based and independent resources, in the detection of genetic association with common disease. Genetic Analysis Workshop 15 Problem 2 data, provided by the North American Rheumatoid Arthritis Consortium, were used to demonstrate PedGenie 2.1 meta-association testing of variants in the PTPN22 gene and rheumatoid arthritis across multiple resources containing both family-based and independent individuals. Our findings are generally consistent with previous reports for a panel of 14 single-nucleotide polymorphism (SNP) markers, including functional coding SNP R620W, in which the minor allele conferred a significant two-fold increased risk. More power to detect associations was achieved in certain analyses by using extra family-based samples, rather than restricting analyses to single cases randomly selected from each pedigree.
18466457 Rheumatoid arthritis, item response theory, Blom transformation, and mixed models. 2007 We studied rheumatoid arthritis (RA) in the North American Rheumatoid Arthritis Consortium (NARAC) data (1499 subjects; 757 families). Identical methods were applied for studying RA in the Genetic Analysis Workshop 15 (GAW15) simulated data (with a prior knowledge of the simulation answers). Fifty replications of GAW15 simulated data had 3497 +/- 20 subjects in 1500 nuclear families. Two new statistical methods were applied to transform the original phenotypes on these data, the item response theory (IRT) to create a latent variable from nine classifying predictors and a Blom transformation of the anti-CCP (anti-cyclic citrinullated protein) variable. We performed linear mixed-effects (LME) models to study the additive associations of 404 Illumina-genotyped single-nucleotide polymorphisms (SNPs) on the NARAC data, and of 17,820 SNPs of the GAW15 simulated data. In the GAW15 simulated data, the association with anti-CCP Blom transformation showed a 100% sensitivity for SNP1 located in the major histocompatibility complex gene. In contrast, the association of SNP1 with the IRT latent variable showed only 24% sensitivity. From the simulated data, we conclude that the Blom transformation of the anti-CCP variable produced more reliable results than the latent variable from the qualitative combination of a group of RA risk factors. In the NARAC data, the significant RA-SNPs associations found with both phenotype-transformation methods provided a trend that may point toward dynein and energy control genes. Finer genotyping in the NARAC data would grant more exact evidence for the contributions of chromosome 6 to RA.
17086384 Ten years of clinical experience with adult onset Still's disease: is the outcome improvin 2007 Jul This study aims to report on the clinical and laboratory picture and the disease course and outcome in patients having adult onset Still's disease (AOSD), to briefly review existing literature on the subject, and to compare our findings with those previously reported. Results are reported for 28 patients with AOSD satisfying the preliminary criteria of Yamaguchi et al. seen in a teaching hospital over the last 10 years. A high percent of the patients with AOSD were women. The mean (+SD) age at disease onset was 27.8 (+8.4) years. We found fever in 100%, rash in 85%, arthritis in 64%, lymphadenopathy in 60%, splenomegaly in 57%, hepatomegaly in 35%, pleural effusion in 17.9%, and pericardial effusion in 3.6% of our patients. Leukocytosis was present in 96% of the patients, a normochromic, normocytic anemia in 54%, and an elevated erythrocyte sedimentation rate (ESR) in all. Serum ferritin levels were raised in 89% of the patients. The mean follow-up of the patients was 3.72 + 2.46 years. The mean delay in diagnosis was 7.32 + 18.0 months. The mean time to enter remission was 9.7 months. Self-limited, intermittent, and chronic disease course was seen in 14.3, 57.1, and 28.6% of patients, respectively. The outcome was good in about 89% of patients, and mortality was nil. No particular clinical or laboratory variable was found to predict the subsequent disease course and outcome in our patients. On comparing our data with important previous series, we found a higher percentage of women and of patients presenting in the age group 16-35 years, a lower frequency of arthritis and pericardial effusion, and some other notable differences. Importantly, the disease course was benign, probably as an outcome of heightened awareness and less diagnostic delay than in the past, allowing for early, aggressive, and appropriate treatment. It is concluded that AOSD is now a relatively benign disease if diagnosed early and treated appropriately.
17611347 Celiac disease: association with adult-onset Still's disease: apropos of a clinical case. 2007 Jul Adult-onset Still's disease (AOSD) is a rheumatic disorder of unknown etiology characterized by a triad of fever, polyarthritis and evanescent rash. We present a case report of a 28-year-old female who presented with complaints of fever, joint pains, rash, weakness for the past 4 years and diarrhea for the past 2 years. On investigation the patient was diagnosed to be a case of AOSD. Duodenal biopsy report was suggestive of celiac disease with a positive IgA tissue transglutaminase and anti-endomysial antibody. The patient was started on weekly methotrexate and gluten-free diet and her symptoms gradually improved. The patient remains in our follow-up and is doing well.
17417107 Utility of lip biopsy in the diagnosis and treatment of Sjogren's syndrome. 2007 Jun OBJECTIVE: Sjogren's syndrome (SS) is an autoimmune disease involving primarily the salivary and lacrimal glands ("sicca" symptoms) with extraglandular features including joint and nervous system involvement. In patients with a questionable diagnosis of SS but severe extraglandular symptoms, a lip biopsy is often performed to firmly establish the diagnosis of SS. This study was undertaken to identify areas of uncertainty regarding the accuracy of biopsy interpretation and the diagnostic benefits of the procedure. STUDY DESIGN: : Retrospective review of clinical and pathologic data. METHODS: Clinical data from 47 patients referred to the otolaryngology-head and neck surgery service for lip biopsy were reviewed. Archival pathologic specimens were scored using the currently accepted grading system. RESULTS: The grading system was incorrectly applied during initial interpretation of 45% (n = 21) of specimens. This resulted in five (10%) pathologic misdiagnoses and 16 (34%) nondiagnoses. On re-interpreting the specimens with consistent application of the grading system, 62% (n = 29) of the biopsies were definitely positive, and 36% (n = 17) were negative. Neither positive serology nor the presence of sicca symptoms predicted a positive biopsy (likelihood ratio = 0.95 and 0.96, respectively). Lip biopsy guided treatment in at least 65% (n = 31) of patients but was ignored in the presence of other clinical findings in 17% (n = 8) of patients. CONCLUSIONS: Consistent application of the grading system is essential in avoiding incorrect diagnosis and aiding clinical decisions. However, not all patients undergoing lip biopsy will derive diagnostic benefit from the procedure. In this series, clinical symptoms and serology did not predict positive lip biopsy.
19410128 Sjogren's syndrome masquerading as nasopharyngeal carcinoma. 2009 May OBJECTIVE: The aim of the study was to describe a case of nasopharyngeal involvement by Sjogren's syndrome masquerading as nasopharyngeal carcinoma. METHODS: A description of clinical and radiologic features of facial pain, nasopharyngeal bulge, middle ear effusion, restriction of palatal movement, and infiltrating nasopharyngeal mass on imaging was given. Histologic evaluation, response to treatment with steroids and hydrochloroquine, and long-term follow-up, however, subsequently indicated the mass to be secondary to Sjogren's syndrome. CONCLUSION: A previously undescribed manifestation of Sjogren's syndrome is described.
16956437 Hematologic manifestations of primary Sjögren's syndrome. 2006 Jul Sjögren's syndrome (SS) is a chronic autoimmune disorder, primarily characterized by the mononuclear cell infiltration of exocrine glands exiting in parenchymal damage and secretory impairment. The spectrum of the disease extends from an autoimmune exocrinopathy to a systemic process with extraglandular manifestations. SS is defined as primary (pSS) when isolated, or secondary when associated with another autoimmune disease. Patients with pSS may present hematologic abnormalities, such as anemia, hemocytopenias, monoclonal gammopathies and lymphoprolipherative disorders, predominantly non-Hodgkin's lymphoma of B-cell origin. The increased prevalence of B-cell malignancies suggests that SS may be a boundary disease between autoimmunity and lymphoproliferation. In this paper, the hematologic manifestations of pSS are reviewed.
17164948 Abrupt temperature change triggers arthralgia in patients with juvenile rheumatoid arthrit 2006 Dec BACKGROUND AND PURPOSE: Juvenile rheumatoid arthritis (JRA) is the most common form of arthritis in children and affects both quality of life and school attendance. Weather and temperature conditions are believed to affect joint pains; however, very few studies have investigated this issue. This study examined the association between joint pain in JRA patients and weather conditions. METHODS: The daily pain ratings of 52 patients previously diagnosed with JRA were recorded on visual analog scales over 4 months beginning January 1, 2004. These ratings were then compared with weather data to evaluate possible correlation between these two factors. RESULTS: Twenty nine patients kept daily records during the first 2 months. There was no positive correlation between weather parameters (such as temperature, humidity, and barometric pressure) and pain ratings. Interestingly, the pain rating significantly increased the day after the advent of a cold wave (sign test, p<0.01; Wilcoxon signed ranks test, p=0.001). The number of patients who experienced joint swelling was not related to weather conditions. Twenty one participants continued maintaining the diaries during the next 2 months. The patients reported higher pain levels in the first 2 months during the cold wave period than in the next 2 months when the cold wave period had ended (p<0.001). CONCLUSION: A dramatic weather change such as a sudden cold wave might influence the experience of joint pain.
20476973 Use of prognostic markers in early rheumatoid arthritis to identify patients at risk of de 2006 Nov As the benefits of early aggressive treatment of rheumatoid arthritis have become clear, and with the availability of newer (and more expensive) therapies, we need to be able to identify which patients are most at risk of destructive disease and poorer outcomes, and therefore, pinpoint which patients are most likely to benefit from intensive intervention at an early stage. A need for reliable prognostic markers is paramount in identifying these patients. Anticyclic citrullinated peptide antibody and serum inflammatory markers can precede the onset of disease by months and aid in both diagnosis and prognosis. Newer imaging modalities are now available and add to information gained from conventional radiography. This article reviews laboratory markers and imaging currently used in recognizing those patients at risk of nonreversible, destructive disease.
25983886 Clinical and histological features of lupus nephritis induced by anti-TNFα therapy. 2008 Aug It is known that anti-TNFα therapy has opened a new era in treatment of rheumatoid arthritis, and it is emerging as a new successful treatment in the current rheumatologic practice. Besides, there is evidence that this therapy is an important cause of iatrogenic autoimmune disease. Several studies reported the possible onset of lupus syndrome that can be resolved with withdrawal of anti-TNFα drugs. Our report describes the first lupus nephritis case developing in a rapidly progressive renal failure that required haemodialysis treatment in a patient affected with rheumatoid arthritis, treated with anti-TNFα therapy. So, we confirm the importance of a careful clinic and immunologic evaluation before starting anti-TNFα therapy.
21794327 [Antimalarials: an update in rheumatic diseases]. 2006 Jul Antimalarials are long-standing drugs that have been used since the nineteenth century for the treatment of skin rashes and lesions in lupus and rheumatoid arthritis. In recent decades, their use in these disorders has been consolidated, and new mechanisms of action have been incorporated, broadening the therapeutic perspectives of these drugs. Antimalarials are the treatment of choice in mild and moderate manifestations of systemic lupus erythematosus and are established as part of combined therapy in rheumatoid arthritis. They have been shown to have beneficial effects on atherosclerosis, as well as a possible role in the early treatment of antiphospholipid syndrome. Lastly, they have been shown to have a potential use in other rheumatic diseases such as Sjögren's Syndrome and palindromic rheumatism. This review aims to provide an update on the use of these drugs in rheumatology and to discuss their toxicity profile.
17763407 The performance of anti-cyclic citrullinated peptide antibodies in predicting the severity 2007 Sep OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies are a stronger predictor of the severity of rheumatoid arthritis than is rheumatoid factor (RF). Their role in predicting outcome in unselected patients with new-onset inflammatory polyarthritis (IP) has not been examined. The aims of this study were to examine the role of baseline RF and anti-CCP antibodies in determining the likelihood of patients having erosions at presentation or in predicting future radiologic damage, and to determine whether anti-CCP antibodies or RF is sufficiently robust to be clinically useful in guiding treatment decisions in early IP. METHODS: Patients were recruited from the Norfolk Arthritis Register. Logistic regression models were fitted to test the ability of anti-CCP antibodies and RF to predict erosions. Further models were investigated to examine the role of anti-CCP antibodies in patients stratified by RF status. RESULTS: The presence of anti-CCP antibodies at baseline was strongly associated with both prevalent erosions (odds ratio [OR] 2.53 [95% confidence interval (95% CI) 1.48-4.30]) and developing erosions at 5 years (OR 10.2 [95% CI 6.2-16.9]). These ORs were higher than those for RF (OR 1.63 [95% CI 0.94-2.82] and OR 3.4 [95% CI 2.2-5.2], respectively). The likelihood ratio (LR) for the prediction of prevalent erosions and erosions at 5 years was highest in the RF-subgroup (LR 2.2 and 5.8, respectively). However, 27% of anti-CCP-patients had developed erosions by 5 years. CONCLUSION: Despite their strong association with the presence, development, and extent of erosions, anti-CCP antibodies alone are not a sufficiently accurate measure upon which to base clinical treatment decisions. Knowledge of anti-CCP antibody status is most informative in RF-negative patients.
16424181 Therapeutic vaccination of active arthritis with a glycosylated collagen type II peptide i 2006 Feb 1 In both collagen-induced arthritis (CIA) and rheumatoid arthritis, T cells recognize a galactosylated peptide from type II collagen (CII). In this study, we demonstrate that the CII259-273 peptide, galactosylated at lysine 264, in complex with Aq molecules prevented development of CIA in mice and ameliorated chronic relapsing disease. In contrast, nonglycosylated CII259-273/Aq complexes had no such effect. CIA dependent on other MHC class II molecules (Ar/Er) was also down-regulated, indicating a bystander vaccination effect. T cells could transfer the amelioration of CIA, showing that the protection is an active process. Thus, a complex between MHC class II molecules and a posttranslationally modified peptide offers a new possibility for treatment of chronically active autoimmune inflammation such as rheumatoid arthritis.
17763447 Circulating C3 is necessary and sufficient for induction of autoantibody-mediated arthriti 2007 Sep OBJECTIVE: For the inflammation characteristic of rheumatoid arthritis, the relative contribution of mediators produced locally in the synovium versus those circulating systemically is unknown. Complement factor C3 is made in rheumatoid synovium and has been proposed to be a crucial driver of inflammation. The aim of this study was to test, in a mouse model of rheumatoid arthritis, whether C3 synthesized within the synovium is important in promoting inflammation. METHODS: Radiation bone marrow chimeras between normal and C3(-/-) mice were constructed in order to generate animals that expressed or lacked expression of C3 only in hematopoietic cells. Parabiotic mice were made by surgically linking C3(-/-) mice to irradiated wild-type mice to obtain animals having C3 only in the circulation. Arthritis was induced by injection of serum from arthritic K/BxN mice. RESULTS: In bone marrow chimeras, synthesis of C3 by radioresistant cells was necessary and sufficient to confer susceptibility to serum-transferred arthritis. Parabionts having C3 only in the circulation remained sensitive to arthritis induction, and the cartilage of these arthritic mice contained deposits of C3. CONCLUSION: In a mouse model in which the alternative pathway of complement activation is critical to the induction of arthritis by autoantibodies, circulating C3 was necessary and sufficient for arthritis induction.
16601542 Anakinra therapy in a child with systemic-onset juvenile rheumatoid arthritis after human 2006 Apr A 3-year-old patient with biopsy-proven herpesvirus 6 (HHV-6) encephalitis developed a clinical condition consistent with systemic-onset juvenile idiopathic rheumatoid arthritis (SoJIA) and responsive to synthetic interleukin-1 (IL-1) receptor therapy. This suggested both a temporal relationship between HHV-6 infection and the development of SoJIA and the likely involvement of IL-1 in his disease. This case adds to the current experience of IL-1 receptor antagonist therapy in SoJIA. In addition, it suggests that future prospective studies in new-onset SoJIA should include an evaluation for HHV-6 infection.