Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
22209316 TNFα: activator or inhibitor of regulatory T cells? 2012 Mar TNFα is a cytokine that is central to the pathogenesis of several autoimmune diseases. More specifically, the deleterious effects of TNFα in rheumatoid arthritis (RA) are well established. The proinflammatory influence of TNFα in RA is related both to direct effects mediated by the induction of other proinflammatory cytokines, metalloproteinases, and free radicals; and to modulation of the regulatory T cells (Tregs). Furthermore, the TNFα antagonists used to treat RA can induce the emergence of a distinctive Treg subpopulation. Nevertheless, a recent body of data suggests that TNFα may also exert anti-inflammatory effects, which may be mediated in part via Tregs. TNFα binds to the TNF receptor 2 expressed preferentially at the Treg surface, thereby activating and promoting the development of Tregs. Data from patients with RA and more recent evidence obtained in the absence of disease are consistent with a paradoxical effect of TNFα on Tregs. TNFα may have different effects on naturally occurring Tregs and induced Tregs.
22402142 Combination etanercept and methotrexate provides better disease control in very early (<=4 2012 Jun OBJECTIVE: The objective of this post hoc analysis was to test the benefits of treating very early rheumatoid arthritis (VERA; ≤4 months) using COMET trial data. Treatment response in VERA and early rheumatoid arthritis (ERA; >4 months to 2 years) with combination etanercept+methotrexate (ETN+MTX) or MTX monotherapy was compared. METHODS: Data assessed at week 52 for baseline disease duration effect included remission (disease activity score (DAS)28 <2.6, SDAI ≤3.3, Boolean), low disease activity (LDA; DAS28 <3.2), Boolean components of remission and radiographic non-progression. Subjects who discontinued because of lack of efficacy were included as non-responders. RESULTS: Higher proportions of VERA subjects achieved LDA (79%) and DAS28 remission (70%) than ERA (62%, 48%, respectively, p<0.05) with ETN+MTX. Such high responses with MTX monotherapy were not observed (VERA, LDA=47%, DAS28 remission=35%; ERA, 47% and 32% respectively, p>0.70 for each). Regardless of disease duration, no radiographic progression was seen in 80% of subjects with ETN+MTX. In contrast, a higher proportion of VERA subjects showed no radiographic progression compared with ERA subjects treated with MTX (73.9% vs 50%, p=0.01). CONCLUSIONS: Treatment of VERA with ETN+MTX provides qualitatively improved clinical outcomes not seen with MTX monotherapy, supporting the pivotal role of TNF inhibition in early disease.
22392632 Multifunctional T cell reactivity with native and glycosylated type II collagen in rheumat 2012 Aug OBJECTIVE: Type II collagen (CII) is a cartilage-specific protein to which a loss of immune tolerance may trigger autoimmune reactions and cause arthritis. The major T cell epitope on CII, amino acids 259-273, can be presented by several HLA-DRB1 04 alleles in its native or posttranslational glycosylated form. The present study was undertaken to functionally explore and compare CII-autoreactive T cells from blood and synovial fluid of patients with rheumatoid arthritis (RA). METHODS: Peripheral blood was obtained from HLA-DRB1 04-positive RA patients (n = 10) and control subjects (n = 10) and stimulated in vitro with several variants of the CII(259-273) epitope, i.e., unmodified, glycosylated on Lys-264, glycosylated on Lys-270, or glycosylated on both Lys-264 and Lys-270. Up-regulation of CD154 was used to identify responding T cells. These cells were further characterized by intracellular staining for interleukin-17 (IL-17), interferon-γ (IFNγ), and IL-2 by flow cytometry. Synovial T cells from RA patients were investigated in parallel. RESULTS: Multifunctional T cell responses toward all examined variants of the CII(259-273) peptide could be detected in RA patients and, to a lesser extent, also in healthy HLA-matched controls (P < 0.001). In RA patients, a comparison between blood- and joint-derived T cell function revealed a significant increase in levels of the proinflammatory cytokine IFNγ in synovial T cells (P = 0.027). Studies of longitudinally obtained samples showed that T cell responses were sustained over the course of disease, and even included epitope spreading. CONCLUSION: The identification of inflammatory T cell responses to both glycosylated and nonglycosylated variants of the major CII epitope in RA patients suggests that CII autoreactivity in RA may be more common than previously recognized.
21936606 Immunological reconstitution after autologous stem cell transplantation in patients with r 2012 Mar OBJECTIVE: High-dose chemotherapy followed by autologous haematopoietic stem cell transplantation (AHSCT) can be a salvage therapy for patients with severe, refractory systemic autoimmune diseases. The function of the newly rebuilt immune system is important, but little is known about immune reconstitution after AHSCT in autoimmune disorders. Our aim was to investigate the repopulation of different lymphocyte subsets in patients with systemic autoimmune diseases after AHSCT. METHODS: Twelve patients with severe refractory, autoimmune diseases were enrolled in the study: four with rheumatoid arthritis (RA), four with systemic sclerosis (SSc), three with systemic lupus erythematosus (SLE), and one with autoimmune overlap syndrome (myositis and RA). After stem-cell mobilization, CD34+ apheresis was carried out, followed by conditioning and AHSCT. After transplantation, peripheral lymphocyte subsets were regularly assessed by flow cytometry. RESULTS: The follow-up time was 24 months. The overall transplantation-related mortality (TRM) was 16.7% and the transplant-related toxicity was 33% 2 years after AHSCT. Regarding the immune reconstitution, CD56+ natural killer (NK) cells appeared in the earliest phase after transplantation, followed by CD8+ T cells. B cells and CD4+ T cells became normal within 150 days. The ratio of naive cells was low 30 days after AHSCT; however, naive B cells regenerated within 2 months whereas the repopulation of naive T cells took longer. After a short increase, the ratio of memory cells decreased 2 months after transplantation. Regulatory T (Treg) cells did not change significantly in the peritransplant period. Altogether approximately 5-6 months were required for the reconstitution of the peripheral immune network. CONCLUSIONS: AHSCT can be a salvage therapeutic modality in autoimmune patients who are refractory to other conventional therapies.
21670968 Abrogation of Treg function deteriorates rheumatoid arthritis. 2012 Feb An early prognostic indicator which warns of progressive joint destruction of rheumatoid arthritis (RA) was explored using a novel suspension-array technique in moderate (Steinbrocker stage I and II) and severe (Steinbrocker stage IV) RA patients. DNA microarray analysis of peripheral blood lymphocytes showed significant increase of interleukin (IL)-2 receptor α-chain (CD25) gene expression, a regulatory T cell (Treg) surface marker in severe RA patients. In contrast, suspension array, a comprehensive bead-based enzyme-linked immunosorbent assay (ELISA), revealed decreased production of IL-10 and increased production of interferon (IFN)-γ in sera in the incipient stage of the aggressive disease process. Both in moderate and in severe RA patients, the IFN-γ/IL-10 ratio indicated deterioration of the disease with universal validity. Fluorescence-activated cell sorting (FACS) and reverse-transcription polymerase chain reaction (RT-PCR) analysis showed extant CD4+CD25+ regulatory T cells in severe RA patients, however Foxp3, a regulatory T cell-specific transcription factor, gene expression was absent, while glucocorticoid-induced tumor necrosis factor (TNF) receptor family-related protein (GITR), which transmits a signal that abrogates regulatory T cell functions, was elevated. In the current study, we showed the validity of suspension-array analysis for enabling more complete understanding of RA, and showed that IFN-γ/IL-10 ratio can be a prognostic tool for early lesion and more aggressive RA.
22333689 Diagnostic value of antibodies to modified citrullinated vimentin in early rheumatoid arth 2012 Apr The aim of this study was to evaluate the usefulness of antibodies to modified citrullinated vimentin (anti-MCV) for diagnosing early rheumatoid arthritis (RA) and to examine the correlations between anti-MCV and clinical parameters as well as radiographic and ultrasound data. Our results suggest that anti-MCV has a sensitivity and specificity of 53.3 and 83.3%, respectively, and a positive prognostic value of 96% in patients with early RA. Anti-MCV antibodies were observed in 48.5% of rheumatoid factor (RF)-negative RA patients in data from a latex test and in 35.7% of patients with negative results for immunoglobulin (Ig)-M-RF. The positive result for both anti-MCV and IgM-RF has a sensitivity of 42.2% and a specificity of 100%. No significant correlation was observed between anti-MCV and disease activity score using 28 joint counts, radiographic RA stage, number of erosions on ultrasonography of joints, and quality-of-life scores at disease onset. The Spearman correlation was significant in early RA patients with positive results of anti-MCV between the titers of this marker and arthritis duration, level of erythrocyte sedimentation rate, and IgM-RF. The best diagnostic strategy in early RA may be to assay both anti-MCV and IgM-RF. Thus, a question arises regarding the possible inclusion of anti-MCV in future revisions of the classification criteria of RA.
21751641 Post-chikungunya chronic arthritis--our experience with DMARDs over two year follow up. 2011 Feb AIM: 1) To study clinical features and laboratory findings in patients of post chikungunya chronic arthritis (PCCA). 2) To study effectivity of disease modifying antirheumatic drugs (DMARDs) in treatment of post-chikungunya chronic arthritis. MATERIALS AND METHODS: Sixteen Chikungunya IgM positive patients having arthritis lasting more than 3 months in spite of NSAIDs and Hydroxychloroquine therapy were selected. Their clinical, laboratory and radiological features were noted. Disease activity was assessed by clinical parameters and Disease Activity Score System (DAS 28). Functional status was assessed by HAQ Questionnaire on follow-up visits over next 2 years. Effectivity of treatment with Sulfasalazine and Methotrexate was assessed. RESULTS: Chronic inflammatory polyarthritis does occur following chikungunya infection. It involves large and small joints of hands and feet and is erosive and deforming. It is rheumatoid factor negative. AntiCCP antibody was positive in majority. Synovial biopsy revealed nongranulomatous chronic synovitis with infiltration with lymphocytes and plasma cells. It was negative for chikungunya RNA. Treatment with Sulfasalazine with and without methotrexate produced good response in 71.4 % and 12.5% respectively. CONCLUSIONS: Chronic inflammatory, erosive and rarely deforming polyarthritis does occur after acute chikungunya infection in some (5.6%). It is seronegative and AntiCCP positive in majority. DMARDs like sulfasalazine and methotrexate are required and effective in treatment of PCCA.
21974844 Free fatty acids are associated with insulin resistance but not coronary artery atheroscle 2011 Dec BACKGROUND: Free fatty acids (FFAs) affect insulin signaling and are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines such as interleukin-6 (IL-6) increase lipolysis and thus levels of FFAs. We hypothesized that increased IL-6 concentrations are associated with increased FFAs resulting in insulin resistance and atherosclerosis in rheumatoid arthritis (RA). METHODS: Clinical variables, serum FFAs and inflammatory cytokines, homeostasis model assessment for insulin resistance (HOMA-IR), and coronary artery calcium were measured in 166 patients with RA and 92 controls. We compared serum FFAs in RA and controls using Wilcoxon rank sum tests and further tested for multivariable association by adjusting for age, race, sex and BMI. Among patients with RA, we assessed the relationship between serum FFAs and inflammatory cytokines, HOMA-IR, and coronary artery calcium scores using Spearman correlation and multivariable regression analyses. RESULTS: Serum FFAs did not differ significantly in patients with RA and controls (0.56mmol/L [0.38-0.75] and 0.56mmol/L [0.45-0.70] respectively, p=0.75). Presence of metabolic syndrome was associated with significantly increased serum FFAs in both RA and controls (p=0.035 and p=0.025). In multivariable regression analysis that adjusted for age, race, sex and BMI, serum FFAs were associated with HOMA-IR (p=0.011), CRP (p=0.01), triglycerides (p=0.005) and Framingham risk score (p=0.048) in RA, but not with IL-6 (p=0.48) or coronary artery calcium score (p=0.62). CONCLUSIONS: Serum FFAs do not differ significantly in patients with RA and controls. FFAs may contribute to insulin resistance, but are not associated with IL-6 and coronary atherosclerosis in RA.
22192852 Correlation of antinuclear antibody and anti-double-stranded DNA antibody with clinical re 2011 INTRODUCTION: The induction of antinuclear antibodies (ANAs) or anti-double-stranded (ds) -DNA antibodies (Abs) after infliximab (IFX) therapy in rheumatoid arthritis (RA) is a well-known phenomenon, but the correlation of such Abs with the clinical response to IFX has not yet been determined. The aims of this retrospective observational study were to examine the prevalence of positive ANA and anti-ds-DNA Abs before and after IFX therapy in patients with RA and to investigate whether an increased titer of such Abs is associated with the clinical efficacy of IFX. METHODS: One hundred eleven RA patients who had received IFX were studied. ANA (indirect immunofluorescence with HEp-2 cells) and anti-ds-DNA Abs (Farr assay) results were examined before and after IFX therapy. RESULTS: The overall clinical response assessed by EULAR response criteria was as follows: good response in 55%, including remission in 38%; moderate response in 18%; and no response (NOR) in 27%. The positivity of ANA (≥ 1:160) and anti-ds-DNA Abs significantly increased from 25% to 40% (P = 0.03) and from 3% to 26% (P < 0.001) after IFX, respectively. EULAR response differed significantly according to the ANA titer before IFX (P = 0.001), and the efficacy of IFX became worse as the ANA titer before starting IFX increased. Furthermore, the differences in the clinical response of the ANA titer before IFX ≤ 1:80 and ≥ 1:160 were significant (good, moderate, and no response were 66%, 9%, and 25% in ≤ 1:80 group versus 26%, 33%, 41% in ≥ 1:160 group, respectively; P < 0.001). In 13 patients whose ANA had increased after IFX, 10 showed NOR, only one showed a good response, and none reached remission. These clinical responses were significantly different from ANA no-change patients. In 21 patients with positive anti-ds-DNA Abs after IFX, 16 showed NOR, only two showed a good response, and none reached remission. CONCLUSIONS: The present study suggests that the ANA titer before starting IFX predicts the clinical response to IFX. The increased titers of ANA or anti-ds-DNA Abs after IFX may be useful markers of NOR.
21340497 Lower extremity ulcers in rheumatoid arthritis: features and response to immunosuppression 2011 Jun Lower extremity ulcers are a recognized complication of rheumatoid arthritis (RA). Their prevalence has not been assessed since the advent of more aggressive disease modifying antirheumatic therapies. The purpose of this study was to establish the period prevalence of lower extremity ulcers in a modern-day unselected cohort of patients with RA, and to report the features associated with ulcer development and response to therapy. Between June 2007 and June 2010, 366 RA patients were evaluated at the Georgetown Division of Rheumatology. Data were collected and analyzed retrospectively on demographics, antibody and prothrombotic profile, comorbidities, disease activity, and outcomes. The period prevalence of ulcers in this cohort of 366 patients with RA followed over 3 years was 4.37%. Patients with ulcers were predominantly female (81.25%) and more commonly African American (56.2%). The mean disease duration at ulcer development was 25.9 years. All patients with ulcers had erosive disease and 63% were seropositive. Only five patients (31.25%) healed over a mean follow-up of 22.8 months. However, in this small sample, treatment with anti-tumor necrosis factor-α (anti-TNFα) therapy was associated with significantly higher likelihood of healing (p = 0.039). In this modern-day cohort of patients with RA, we found a prevalence of lower extremity ulcers of 4.37% over 3 years. Only 31.25% of patients healed after a mean 22.8 months of follow-up. However, treatment with a biologic agent was associated with a significant increased likelihood of healing (RR 3.27, 95% CI 0.59-18.29, p = 0.039).
22568326 [Rheumatoid forefoot reconstruction with first metatarsophalangeal fusion and arthroplasty 2012 Apr OBJECTIVE: To evaluate the surgical treatment and effectiveness of rheumatoid forefoot reconstruction with arthrodesis of the first metatarsophalangeal joint and arthroplasty of lesser metatarsal heads. METHODS: Between January 2007 and August 2009, 7 patients with rheumatoid forefoot were treated by reconstruction with arthrodesis of the first metatarsophalangeal joint and arthroplasty of lesser metatarsal heads. They were all females with an average age of 62 years (range, 56-71 years) and with an average disease duration of 16 years (range, 5-30 years). All patients manifested hallux valgus, hammer toe or mallet toe of 2-5 toes, 5 feet complicated by subluxation of the second metatarsophalangeal joint. The improved American Orthopaedic Foot & Ankle Society (AOFAS) score was 36.9 +/- 6.4. The hallux valgus angle was (46 +/- 5) degrees, and the intermetarsal angle was (12 +/- 2) degrees by measuring the load bearing X-ray films preoperatively. RESULTS: All incisions healed by first intention after operation. The X-ray films showed bone fusion of the first metatarsophalangeal joint at 3-4 months after operation. Seven patients were followed up 2.9 years on average (range, 2-4 years), gait was improved and pain was relieved. The hallux valgus angle decreased to (17 +/- 4) degrees and the intermetarsal angle was (11 +/- 2) degrees at 3 months postoperatively, showing significant differences when compared with preoperative values (P < 0.05). The improved AOFAS score was 85.3 +/- 5.1 at 2 years postoperatively, showing significant difference when compared with preoperative score (t = 4.501, P = 0.001). One patient had recurrent metatarsalgia at 4 years after operation. CONCLUSION: Arthrodesis of the first metatarsophalangeal joint and arthroplasty of lesser metatarsal heads for rheumatoid forefoot reconstruction can correct hallux valgus, remodel the bearing surface of the forefoot, and relieve pain, so it can be considered as a procedure that provides improvement in the clinical outcome.
23173679 Chronic inflammation and low-dose glucocorticoid effects on glucose metabolism in premenop 2013 Chronic systemic inflammation is associated with increased cardiovascular mortality in patients with rheumatoid arthritis (RA). The aim of our study was to investigate association of glucose metabolism and inflammatory markers in a group of patients with rheumatoid arthritis free of other metabolic risk factors. Twenty-two premenopausal RA females (11 patients on low-dose GC (<8.5 mg/day of prednisone or equivalent), 11 patients without glucocorticoid therapy) and 15 age- and BMI-matched healthy females underwent the oral glucose tolerance test. The insulin sensitivity indices according Matsuda (ISI(MAT)) and Cederholm (ISI(CED)) as well as HOMA2 %S were calculated. Cytokines, lipid profile, non-esterified fatty acids (NEFA) and plasminogen activator inhibitor-1 (PAI-1) were measured in baseline blood samples. Despite elevated interleukin IL-6 and TNF alpha, glucose, insulin and C-peptide responses to oral glucose load as well as ISI(MAT), ISI(CED), PAI-1 and NEFA were comparable in both RA groups and healthy controls. HOMA2 %S correlated with disease activity. In conclusions, low-dose glucocorticoid treatment does not lead to glucose metabolism impairment in RA patients without other metabolic risk factors. Increased cardiovascular mortality and morbidity is probably due to a direct effect of systemic inflammation on myocardium and/or blood vessels.
21709014 Proliferation of the synovial lining cell layer in suggested metal hypersensitivity. 2011 Jul Synovial tissues in joints with prostheses display characteristic morphological changes in cases with aseptic failure, particularly macrophage infiltration. Since proliferation of the synovial lining cell layer represents a feature characteristic of autoimmune joint diseases, the possibility of morphological changes of the synovial lining cell layer in periprosthetic tissues was investigated. Synovial biopsies from five groups of morphologically well-defined lesions (osteoarthritis, rheumatoid arthritis, aseptic loosened metal-on-polyethylene and metal-on-metal arthroplasty and suggested metal hypersensitivity) were compared using a conventional staining method and immunohistochemistry. The synovial lining cell layer was substantially enlarged in both rheumatoid arthritis and cases suggestive of metal hypersensitivity. Macrophage infiltrates were apparent in rheumatoid arthritis and all specimens from retrieved hip arthroplasties. Although both synovial and subsynovial macrophages were positive for CD163 (indicating synovial M2 macrophages), the remaining fibroblast-like synoviocytes and scattered stromal fibroblasts showed a positive reaction with the D2-40 antibody (indicating fibroblast-like synoviocytes). Furthermore, in contrast to CD163-positive macrophages, the enlarged D2-40-positive fibroblast-like synoviocytes displayed cytoplasmatic tubular projections. Proliferation of the periprosthetic synovial lining cell layer occurred in cases with unexplained groin pain following metal-on-metal hip resurfacing arthroplasty, suggestive of hypersensitivity. Despite some important study limitations, the present observation adds to the evidence that metal hypersensitivity shares characteristic morphological features with autoimmune diseases of the joints.
21240618 In rheumatoid arthritis patients treated with tocilizumab, the rate of clinical disease ac 2011 Aug We aimed to evaluate the efficacy of tocilizumab in patients with rheumatoid arthritis (RA), using the clinical disease activity index (CDAI), and to determine the baseline variables associated with CDAI remission. Fifty-eight patients with active RA were enrolled. We tried to evaluate whether baseline variables were associated with CDAI remission at 24 weeks. Twenty-two of the 58 patients (37.9%) had received tumor necrosis factor (TNF) inhibitors. The continuation rate of tocilizumab at 24 weeks was 87.9%. The seropositivity rates of IgM-rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies at baseline were both 91.4%. The rate of CDAI remission at 24 weeks was 20.7%. We selected baseline variables including age, gender, duration of disease, concomitant use of glucocorticoids, concomitant use of methotrexate (MTX), previous anti-TNF therapy, titer of anti-CCP antibodies (high or low toward median), titer of IgM-RF (high or low toward median), and CDAI, and found that a high titer of IgM-RF was the only variable to be associated with CDAI remission, according to univariate and logistic regression analyses. This is a new finding, and may be specific to tocilizumab as compared with previous observations in anti-TNF therapy.
22298073 [Biomarker of bone destruction]. 2012 Feb Patients with rheumatoid arthritis (RA) often have progression of bone destruction owing to chronic inflammation. Treatment for bone destruction is still insufficient in these patients although goal of treatment has become remission since biologics have been used widely. It is shown that collagen cross-linked C-peptide (CTX- I ) and tartrate-resistant acid phosphatase (TRACP) have correlated with bone destruction in patients with RA, in addition, evidence of new biomarker such as hepatocyte growth factor and macrophage inhibitory factor have been accumulated recently. These biomarkers may help evaluation of bone quality clinically.
22399309 Cardiovascular risk in rheumatic patients: the link between inflammation and atherothrombo 2012 Jul In addition to a high prevalence of the metabolic syndrome and a significant under-diagnosis of vascular risk factors (VRFs), the effect of chronic inflammation also represents the cornerstone of the raised cardiovascular (CV) risk in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Moreover, the finding that among current anti-inflammatory treatments, the use of tumor necrosis factor (TNF)-α blockers is associated with optimal rheumatologic and CV outcomes further supports the impact of inflammation on the CV risk. However, up-to-date treatment guidelines suggest that TNF-α blockers should be used only after the failure of traditional disease-modifying antirheumatic drugs (DMARDs). Early predictors of the therapeutic efficacy of traditional DMARDs are needed to identify candidates for TNF-α blocker treatment. Furthermore, whether the CV risk should be taken into account while choosing antirheumatic treatments is an emerging issue to be addressed. Common educational programs for specialists and general practitioners and appropriate CV prevention programs, taking into consideration traditional VRFs as well as the inflammatory status, should be planned to prevent ischemic events and to achieve optimal inflammation control in rheumatic patients.
21683716 Signal transducer and activator of transcription 4 gene polymorphisms associated with rheu 2011 Aug 1 AIMS: Signal transducer and activator of transcription 4 (STAT4) gene encode a transcriptional factor that transmits signals induced by several key cytokines which play important roles in the development of autoimmune diseases. Recently, several single nucleotide polymorphisms (SNPs) in STAT4 gene have been reported to be significantly associated with Rheumatoid arthritis (RA) in different ethnic populations. We undertook this study to investigate whether the association of STAT4 genetic polymorphisms with RA is present in Northwestern Chinese Han population. MAIN METHODS: A case-control association study in individuals with RA (n=208) and healthy controls (n=312) was conducted. Four SNPs (rs7574865, rs8179673, rs10181656, rs11889341) in STAT4 gene were genotyped by using polymerase chain reaction followed by denaturing high-performance liquid chromatography (PCR-DHPLC) and DNA sequencing. KEY FINDINGS: The genotype and allele distributions of four polymorphisms were significantly different in individuals with RA compared to controls, with SNP rs7574865 T allele and T/T genotype showing the most significant association with susceptibility to RA (uncorrected P=1×10(-4), OR=1.645, 95% CI=1.272-2.129; uncorrected P=4.8×10(-5), OR=3.111, 95% CI=1.777-5.447, respectively). Stratification studies showed that STAT4 gene polymorphisms were significantly associated with anti-cyclic citrullinated peptide (anti-CCP) positive subgroup in Northwestern Chinese Han population. SIGNIFICANCE: These findings strongly suggest that STAT4 genetic polymorphisms are associated with RA in Northwestern Chinese Han population, and support the hypothesis of STAT4 gene polymorphisms increasing the risk for RA across major populations.
21496252 Mannan Binding Lectin (MBL) genotypes coding for high MBL serum levels are associated with 2011 Apr 15 INTRODUCTION: Previous studies have provided inconsistent results on whether variants in the MBL2 gene, coding for the complement-activating mannan-binding lectin (MBL) protein, associate with rheumatoid arthritis (RA). We re-evaluated this in context of the main environmental and genetic risk factors (smoking, HLA-DRB1 'shared epitope' (SE), PTPN22*620W), which predispose to rheumatoid factor (RF) and/or anti-citrullinated-protein antibody (ACPA)-positive RA. METHODS: In this population-based EIRA study, rheumatoid factor (RF), ACPA, smoking, SE and PTPN22*620W status was determined in incident RA cases and matched controls. MBL-high (n = 1330) and MBL-low (n = 1257) genotypes predicting MBL levels were constructed from four promoter and exon-1 polymorphisms in the MBL2 gene. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated by logistic regression. In extended families (n = 316), previously reported data were re-analyzed, considering RF and smoking. RESULTS: MBL-high genotypes tended to be associated with RF-negative (OR = 1.20, 95% CI 0.96-1.51) but not RF-positive (OR = 1.00, 95% CI 0.83-1.20) RA. Results divided by ACPA status did not differ. When stratified for smoking, MBL-high genotype was strongly associated with RF-negative RA in never smokers (OR = 1.82, 95% CI 1.24-2.69) but not in ever smokers (OR = 0.96, 95% CI 0.73-1.30). In never smokers, the association was observed in both the RF-negative/ACPA-negative (OR = 1.67, 95% CI 1.10-2.55) and RF-negative/ACPA-positive subgroups (OR = 3.07, 95% CI 1.37-6.89), and remained on an SE/PTPN22*620W negative background. In the extended families, the reported association between high MBL and RA was in fact confined to never smokers. CONCLUSIONS: High MBL may predispose to RF-negative RA but only in individuals who have never smoked. This illustrates the importance of phenotypic subgrouping in genetic studies.
23025688 Validation of a multiplex chip-based assay for the detection of autoantibodies against cit 2012 Oct 1 INTRODUCTION: Autoantibodies directed against citrullinated proteins/peptides (ACPAs) are highly specific and predictive for the development of rheumatoid arthritis (RA). Different subgroups of RA patients, which have different prognoses and may require different treatments, are characterized by different autoantibody profiles. The objective of this study was to develop a microarray for the detection of multiple RA-associated autoantibodies, initially focusing on responses against citrullinated epitopes on candidate autoantigens in RA. METHODS: The microarray is based on Phadia's ImmunoCAP ISAC system, with which reactivity to more than 100 antigens can be analyzed simultaneously, by using minute serum volumes (< 10 μl). Twelve citrullinated peptides, and the corresponding native arginine-containing control peptides, were immobilized in an arrayed fashion onto a chemically modified glass slide, allowing a three-dimensional layer with high binding capacity. The assay was optimized concerning serum dilution and glass surface, whereas each individual antigen was optimized concerning coupling chemistry, antigen concentration, and selection of spotting buffer. The performance of each peptide in the ImmunoCAP ISAC system was compared with the performance in enzyme-linked immunosorbent assays (ELISAs). Serum from 927 RA patients and 461 healthy controls from a matched case-control study were applied onto reaction sites on glass slides, followed by fluorescent-labeled anti-human immunoglobulin G (IgG) antibody. Fluorescence intensities were detected with a laser scanner, and the results analyzed by using image-analysis software. RESULTS: Strong correlations between the ImmunoCAP ISAC system and ELISA results were found for individual citrullinated peptides (Spearman ρ typically between 0.75 and 0.90). Reactivity of RA sera with the peptides was seen mainly in the anticyclic citrullinated peptide 2 (CCP2)-positive subset, but some additional reactivity with single citrullinated peptides was seen in the anti-CCP2-negative subset. Adjusting for reactivity against arginine-containing control peptides did not uniformly change the diagnostic performance for antibodies against the individual citrullinated peptides. CONCLUSIONS: The multiplexed array, for detection of autoantibodies against multiple citrullinated epitopes on candidate RA autoantigens, will be of benefit in studies of RA pathogenesis, diagnosis, and potentially as a guide to individualized treatment.
21586439 The comparative risk of serious infections among rheumatoid arthritis patients starting or 2011 Aug BACKGROUND: It is unclear whether anti-tumour necrosis factor alpha and biological agents with different mechanisms of action have similar safety. This study evaluated the incidence of hospitalised infections among rheumatoid arthritis (RA) patients starting or switching various biological agents. METHODS: Using a database from a large US healthcare organisation from January 2005 to August 2009, the authors identified enrollees with RA and their treatment episodes entailing the new use of a biological agent, stratified by no biological use in the previous year ('biological-free') or switching from a different biological agent ('switchers'). Outcomes were hospitalised infections identified using previously validated algorithms. Proportional hazards models estimated the hazard ratio of hospitalised infections, comparing each biological agent with infliximab. RESULTS: Among 7847 biological treatment episodes, 63% were for biological-free patients and 37% for switchers. There were 364 hospitalised infections. Rates of hospitalised infection among biological-free patients and switchers were 4.6 and 7.0 per 100 person-years, respectively (p<0.0001). After multivariable adjustment controlling for biological-free/switcher status and other infection-related factors and compared with infliximab, users of abatacept (HR 0.68, 95% CI 0.48 to 0.96), adalimumab (HR 0.52, 0.39 to 0.71), etanercept (HR 0.64, 0.49 to 0.84) and rituximab (HR 0.81, 0.55 to 1.20) had lower rates of hospitalised infection. Patient risk factors contributed more to the risk of infection than did the risk associated with specific biological therapies. CONCLUSION: The rate of hospitalised infections among RA patients was highest for infliximab. Most of the variability in patients' risk of infection was driven by factors other than biological agent exposure.