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ID PMID Title PublicationDate abstract
19820822 Rheumatoid pneumoconiosis (Caplan's syndrome) with a classical presentation. 2009 Sep Although rare, rheumatoid pneumoconiosis, also known as Caplan's syndrome, can occur in workers exposed to silica, as well as in patients with silicosis, coal workers' pneumoconiosis or asbestosis. Prevalence is higher among patients with silicosis, despite the fact that it was originally described in coal workers with pneumoconiosis. The classical finding that defines this syndrome is that of rheumatoid nodules in the lungs, regardless of whether there are small rounded opacities suggestive of pneumoconiosis or large opacities consistent with massive pulmonary fibrosis, with or without clinical rheumatoid arthritis. We describe the case of a female patient with rheumatoid arthritis, diagnosed 34 years after 7 years of occupational exposure to silica at a porcelain plant. A chest X-ray showed circular opacities of 1-5 cm in diameter, bilaterally distributed at the periphery of the lungs. A CT-guided thoracic punch biopsy of one of those nodules revealed that it was rheumatoid nodule surrounded by a palisade of macrophages, which is typical of Caplan's syndrome. Aspects of diagnosis, classification and occurrence of this syndrome are discussed, emphasizing the importance of the occupational anamnesis of patients with rheumatoid arthritis and lung opacities on chest X-rays.
19790074 Soluble neuropilin-2, a nerve repellent receptor, is increased in rheumatoid arthritis syn 2009 Oct OBJECTIVE: In inflammatory lesions, sympathetic nerve fibers disappear soon after the start of inflammation. We identified sympathetic nerve repellents as possible causal agents in rheumatoid arthritis (RA). On nerve terminals, repellent factors bind to neuropilin-2 and its coreceptor. The aim of this study was to investigate the role of neuropilin-2 in the synovial tissue of patients with RA and patients with osteoarthritis (OA) and in experimental arthritis. METHODS: The density of neuropilin-2-positive fibers and cells positive for semaphorin 3F (a sympathetic repellent) was investigated using immunofluorescence staining. Enzyme-linked immunosorbent assay was used to detect soluble neuropilin-2 in body fluids from patients with RA and patients with OA. An axon outgrowth assay and a neuropilin-2 Fc fusion construct (neuropilin-2Fc) were used to investigate semaphorin 3F-induced sympathetic nerve repulsion. In an animal model of type II collagen-induced arthritis, soluble neuropilin-2Fc was studied in vivo. RESULTS: The synovial density of neuropilin-2-positive sympathetic nerve fibers was lower in RA than in OA, but the density of cells positive for semaphorin 3F was similar. In synovial fluid, the level of soluble neuropilin-2 was markedly higher in RA compared with OA. Mouse sympathetic ganglia served as an excellent model with which to study semaphorin 3F-induced nerve fiber repulsion. Neuropilin-2 and its coreceptor were present on sympathetic neurons, and semaphorin 3F bound to neuropilin-2Fc (binding constant 96 nmoles/liter). Semaphorin 3F dose-dependently increased sympathetic nerve fiber repulsion (at a 50% maximum response concentration of 160-210 nmoles/liter). In contrast to our expectations, soluble neuropilin-2Fc did not inhibit repulsion but increased the repellent effect of semaphorin 3F. In experimental arthritis, therapy with neuropilin-2Fc aggravated arthritis. CONCLUSION: Soluble neuropilin-2 has no antirepellent activity but aggravates sympathetic nerve fiber repulsion and arthritis. Increased shedding of neuropilin-2 is probably an unfavorable sign in RA.
19153104 Autoantibody profiling in patients with very early rheumatoid arthritis: a follow-up study 2010 Jan OBJECTIVE: To investigate time courses of autoantibody profiles in patients with early arthritis. PATIENTS AND METHODS: A total of 200 patients with very early arthritis (<3 months duration), among them 102 patients with a final diagnosis of rheumatoid arthritis (RA) and 98 with other rheumatic diseases, were followed up for several years. First follow-up testing was performed in all patients (mean 5 months from baseline), and 82 patients with RA and 35 patients without RA were available for last follow-up testing (mean 32 months from baseline). IgM-rheumatoid factor (RF) was measured by nephelometry, IgA-RF, IgG-RF and anti-cyclic citrullinated peptide antibodies (ACPA) by ELISA, and anti-RA33 antibodies were determined by immunoblotting. RESULTS: At baseline, IgA-RF was detectable in 29% and IgG-RF in 14% of patients with RA while IgM-RF>50 IU/ml (RF50) was positive in 45% of the patients; specificities were 97%, 99% and 96%, respectively. However, the vast majority of patients positive for IgA-RF or IgG-RF were also positive for RF50 or ACPA. During follow-up, the prevalence of ACPA slightly increased while prevalence of all RF subtypes and anti-RA33 decreased. Remarkably, the number of patients positive for RF50 and/or ACPA remained constant, and these patients had a highly increased risk for developing erosive disease in contrast to patients solely positive for anti-RA33. CONCLUSIONS: Testing for RF subtypes did not provide additional diagnostic information. Patients positive for RF50 and/or ACPA had an unfavourable prognosis, irrespectively of changes in the antibody profile during follow-up, whereas anti-RA33 positivity was inversely associated with erosiveness at baseline and at later time points.
19962219 [Regulatory T cells and systemic autoimmune diseases: systemic lupus erythematosus, rheuma 2010 Feb Regulatory/suppressor T cells (Tregs) maintain immunologic homeostasis and prevent autoimmunity. They are the guardians of dominant tolerance. Recent research reveals quantitative and/or functional defect of Tregs in systemic autoimmune diseases. In this article, past and recent studies of Tregs in human systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and primary Sjögren's syndrome (pGSS) are reviewed. Most studies report that Tregs are decreased in peripheral blood of subjects with active SLE. A population of CD4+CD25-Foxp3+ is specifically described in SLE. Tregs functions are still discussed. Tregs counts in peripheral blood of RA patients vary across studies. Enrichment of synovial fluid in Tregs contrasts with inflammation. Tregs suppressive effects are altered in vivo in RA secondary to proinflammatory cytokines environment and resistance of effector T cells to Tregs. In pGSS, the conflicting place of Tregs in the balance prevention of autoimmunity/antitumor immunity is unspecified. Immunosuppressive treatments, like corticosteroids and anti-TNF, modulate Tregs cells population. There is increasing interest in the use of Tregs as a biological therapy to preserve and restore tolerance to self-antigen. However, difficulties to characterize these lymphocytes and controversies in the results of studies refrain their use in current clinical practice.
21187297 Tumour necrosis factor alpha-driven IL-32 expression in rheumatoid arthritis synovial tiss 2011 Apr OBJECTIVE: To investigate the interplay between IL-32 and tumour necrosis factor alpha (TNFα) during the chronic inflammation of rheumatoid arthritis (RA) and to assess whether anti-TNFα treatment of RA patients modulates synovial IL-32 expression. METHODS: Induction of IL-32γ by Pam3Cys, lipopolysaccharide, IL-1β or TNFα was investigated in human fibroblast-like synoviocytes (FLS). Stimulation of TNFα production by IL-32γ was studied by adenoviral overexpression of IL-32γ (AdIL-32γ) and lipopolysaccharide stimulation of THP1 cells. Silencing of endogenous IL-32 was employed to study cytokine regulation in FLS. AdIL-32γ followed by TNFα stimulation was performed in FLS to investigate cytokine induction. Immunohistochemistry was applied to study IL-32 expression in synovial biopsies from RA patients. RESULTS: TNFα potently induced IL-32γ expression in FLS. Increased TNFα, IL-1β, IL-6 and CXCL8 production was observed after IL-32γ overexpression and lipopolysaccharide stimulation of THP1 cells. TNFα stimulation of FLS after silencing IL-32γ resulted in diminished IL-6 and CXCL8 production, whereas IL-32γ overexpression resulted in enhanced IL-6 and CXCL8 levels. Remarkably, the mechanism through which IL-32γ overexpression induced TNFα, IL-1β and CXCL8 was by counteracting messenger RNA decay. Importantly, treatment of RA patients with anti-TNFα resulted in significant reduction of IL-32 protein in synovial tissue. CONCLUSIONS: TNFα is a potent inducer of endogenous IL-32 expression and IL-32 itself contributes to prolonged TNFα production, thus inducing an important auto-inflammatory loop. Treatment of RA patients with anti-TNFα antibodies diminished IL-32 expression in synovial tissue. The potent anti-inflammatory effect of TNFα blockade in RA patients may be partly due to the reduction of synovial IL-32 expression.
20635831 Formulary review of 2 new biologic agents: tocilizumab for rheumatoid arthritis and usteki 2010 Jul BACKGROUND: Two autoimmune biologics were recently approved by the FDA: ustekinumab in September 2009 for the treatment of moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy and tocilizumab in January 2010 for adult patients with moderate to severe rheumatoid arthritis (RA) who have not responded adequately to 1 or more tumor necrosis factor (TNF) antagonist therapies. Both agents use new mechanisms of action and add to the growing group of autoimmune biologics. OBJECTIVE: To critically review the phase 3 trials for ustekinumab and tocilizumab and provide managed care considerations in the context of the 9 other biologic agents on the market in the United States that are used to treat moderate to severe RA or psoriasis. METHODS: A MEDLINE review was performed for articles published and available through January 2010 using keywords "ustekinumab" and "tocilizumab" with an emphasis on phase 3 trials. The literature search was limited to articles in English, clinical trials, randomized controlled trials, and research conducted in humans. Search results for ustekinumab included 8 articles of which 4 were excluded for not being psoriasis or psoriatic arthritis trials. Search results for tocilizumab included 16 articles of which 8 were excluded for not being RA trials or using biomarkers as primary endpoints. Additional information was obtained from the FDA website. RESULTS: Three phase 3 trials are available for ustekinumab. Ustekinumab demonstrated superior efficacy to placebo in 2 trials for the treatment of psoriasis. In a 12-week trial, ustekinumab 45 milligrams (mg) and 90 mg demonstrated significantly higher rates of 75% improvement in the psoriasis area and severity index (PASI 75) (67.5% and 73.8%, respectively) compared with etanercept (56.8%) in the first phase 3 comparative psoriasis trial between autoimmune biologics (P < 0.05 for both comparisons). In a phase 3 trial of RA patients who had failed prior TNF antagonist therapy, a 20% improvement in signs or symptoms according to the American College of Rheumatology criteria (ACR 20) at week 24 was achieved by significantly more study participants in the tocilizumab 8 mg per kilogram (kg) (50.0%) and 4 mg per kg (30.4%) groups than the placebo group (10.1%, P < 0.001 for both tocilizumab groups compared with placebo). Safety data for ustekinumab are limited to use for less than 2 years, and the prescribing information contains warnings regarding infection and malignancy. Tocilizumab is associated with neutropenia, thrombocytopenia, and elevations in lipids and liver function tests. Tocilizumab has unique adverse events when compared with other autoimmune biologics and requires laboratory testing and careful monitoring. CONCLUSIONS: Ustekinumab and tocilizumab are new additions to the treatment of autoinflammatory disease. The majority of safety data for both agents are from trials lasting 3 to 6 months. Published long-term safety data for tocilizumab are limited to less than 143 patients treated longer than 5 years, and safety data for ustekinumab are scant beyond 2 years of use; therefore, clinicians should exercise caution prior to widespread adoption. The comparative efficacy and safety trial of etanercept and ustekinumab brings important clinical information to decision makers. Tocilizumab is indicated after failure or intolerance to a TNF antagonist and has unique safety concerns. Managed care plans will consider the experience and long-term data of these agents along with efficacy data and cost when establishing management programs such as prior authorization or step therapy.
20444266 Association of IL4R single-nucleotide polymorphisms with rheumatoid nodules in African Ame 2010 INTRODUCTION: To determine whether IL4R single-nucleotide polymorphisms (SNPs) rs1805010 (I50V) and rs1801275 (Q551R), which have been associated with disease severity in rheumatoid arthritis (RA) patients of European ancestry, relate to the presence of rheumatoid nodules and radiographic erosions in African Americans. METHODS: Two IL4R SNPs, rs1805010 and rs1801275, were genotyped in 749 patients from the Consortium for Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) registries. End points were rheumatoid nodules defined as present either by physical examination or by chest radiography and radiographic erosions (radiographs of hands/wrists and feet were scored using the modified Sharp/van der Heijde system). Statistical analyses were performed by using logistic regression modeling adjusted for confounding factors. RESULTS: Of the 749 patients with RA, 156 (20.8%) had rheumatoid nodules, with a mean age of 47.0 years, 84.6% female gender, and median disease duration of 1.9 years. Of the 461 patients with available radiographic data, 185 (40.1%) had erosions (score>0); their mean age was 46.7 years; 83.3% were women; and median disease duration was 1.5 years. Patients positive for HLA-DRB1 shared epitope (SE) and autoantibodies (rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP)) had a higher risk of developing rheumatoid nodules in the presence of the AA and AG alleles of rs1801275 (odds ratio (OR)adj=8.08 (95% confidence interval (CI): 1.60-40.89), P=0.01 and ORadj=2.97 (95% CI, 1.08 to 8.17), P=0.04, respectively). Likewise, patients positive for the HLA-DRB1 SE and RF alone had a higher risk of developing rheumatoid nodules in presence of the AA and AG alleles of rs1801275 (ORadj=8.45 (95% CI, 1.57 to 45.44), P=0.01, and ORadj=3.57 (95% CI, 1.18 to 10.76), P=0.02, respectively) and in the presence of AA allele of rs1805010 (ORadj=4.52 (95% CI, 1.20 to 17.03), P=0.03). No significant association was found between IL4R and radiographic erosions or disease susceptibility, although our statistical power was limited by relatively small numbers of cases and controls. CONCLUSIONS: We found that IL4R SNPs, rs1801275 and rs1805010, are associated with rheumatoid nodules in autoantibody-positive African-American RA patients with at least one HLA-DRB1 allele encoding the SE. These findings highlight the need for analysis of genetic factors associated with clinical RA phenotypes in different racial/ethnic populations.
20924627 Serum cysteine proteases and their inhibitors in rheumatoid arthritis: relation to disease 2011 May This study aims to investigate the serum levels of cysteine proteases cathepsins B and H and their inhibitors stefin A, stefin B, and cystatin C, as well as traditional inflammatory markers such as C-reactive protein in patients with rheumatoid arthritis and to correlate these markers with scores of disease activity and radiographic progression. Seventy-two patients with rheumatoid arthritis were included from two previously described cohorts of patients with chronic polyarthritis. At inclusion, disease activity was assessed by a 28-joint count, patient global assessment, and serum C-reactive protein. Erosive status of hands and wrists was expressed by the Larsen score and recorded at inclusion and after 1 year. Serum levels of cathepsin B, cathepsin H, stefin A, stefin B, and cystatin C were determined by enzyme-linked immunosorbent assay. Neither cathepsin B nor cathepsin H serum levels were associated with disease activity, presence or progression of erosive disease. Number of swollen joints correlated with serum levels of stefin A and B and correlated negatively with cystatin C serum levels. Erosive disease was associated with high serum levels of C-reactive protein and stefin A and low serum levels of cystatin C. Progression of radiographic destruction was associated with high serum levels of C-reactive protein, stefin A and B, whereas serum levels of cystatin C were not associated with radiographic progression. The findings in this study support further investigation in the regulation of the activity of cathepsins and their inhibitors in erosive rheumatoid arthritis.
20601593 Abatacept limits breach of self-tolerance in a murine model of arthritis via effects on th 2010 Aug 1 Abatacept modulates CD28-mediated T cell costimulation and is efficacious in the treatment of rheumatoid arthritis (RA). Its mechanism of action has not been fully elucidated but will likely reveal critical pathologic pathways in RA. We show that abatacept substantially modulated Ag-specific T and B cell responses in vivo. Ag-specific T cell proliferation was reduced, and the acquisition of an activated phenotype, characterized by upregulation of CD69, OX40, ICOS, and programmed death-1 and downregulation of CD62L, was suppressed. Furthermore, abatacept suppressed the production of inflammatory cytokines, such as IFN-gamma and IL-17. These effects were associated with a failure of Ag-specific T cells to acquire the CXCR5(+)ICOS(+) T follicular helper cell phenotype. This, in turn, led to a failure of these cells to enter B cell follicles, resulting in reduced specific Ab responses, despite normal B cell clonal expansion. To test the pathologic significance of this, we used a novel model of RA associated with breach of self-tolerance to self-Ag and demonstrated that abatacept prevented the emergence of self-reactivity. Thus, CD28-dependent signaling is required for optimal T follicular helper cell maturation and expansion, and its inhibition prevents loss of self-tolerance in a model of articular pathology. Thus, we provide a novel mode of action for abatacept with profound implications for its potential usefulness in early inflammatory arthropathies associated with autoantibody expression.
18625616 Evaluating guidelines on continuation of anti-tumour necrosis factor treatment after 3 mon 2009 Jun OBJECTIVE: To study the adherence of rheumatologists to the Dutch guidelines for anti-tumour necrosis factor alpha (TNF-alpha) treatment. The secondary objective was to evaluate alternatives to the present guidelines with regard to the percentage of responders and costs. METHODS: The response (>1.2 DAS28 decrease) in patients who started on anti-TNF-alpha treatment for the first time was evaluated at 3 and 6 months after initiation. How many patients continued or discontinued their initial anti-TNF-alpha treatment was evaluated. Possible alternative guidelines were evaluated by means of a decision tree, with regard to the expected percentage of successfully (responders) and unsuccessfully treated patients and expected costs. RESULTS: At 3 months 56% (N = 306) and 44% (N = 233) of all 539 evaluable patients were classified as responders or non-responders, respectively. Despite the guidelines, most (81%) (N = 189) of the non-responders continued treatment. 37% of the non-responders who continued anti-TNF-alpha treatment were eventually classified as responders at 6 months. Decision analytical modelling showed that with equal expected costs all alternative strategies would result in more responders than according to theoretical full adherence with the guidelines. "Continuation in case of partial response" had the best trade-off between successfully treated patients (64%) and unsuccessfully treated patients (17%). CONCLUSION: There was suboptimal adherence to the Dutch guidelines for treatment with anti-TNF-alpha for rheumatoid arthritis patients. This seemed to be justified by the fact that a delayed response up to 6 months was shown. If treatment is continued despite a non-response at 3 months, this is only recommended in patients with at least a partial response (at least 0.6 DAS28 improvement).
20722020 Relationship between the type I interferon signature and the response to rituximab in rheu 2010 Dec OBJECTIVE: To analyze the relationship between the type I interferon (IFN) signature and clinical response to rituximab in rheumatoid arthritis (RA) patients. METHODS: Twenty RA patients were treated with rituximab (cohort 1). Clinical response was defined as a decrease in the Disease Activity Score evaluated in 28 joints (DAS28) and as a response according to the European League Against Rheumatism (EULAR) criteria at week 12 and week 24. The presence of an IFN signature was analyzed in peripheral blood mononuclear cells by measuring the expression levels of 3 IFN response genes by quantitative polymerase chain reaction analysis. After comparison with the findings in healthy controls, patients were classified as having an IFN high or an IFN low signature. The data were confirmed in a second independent cohort (n = 31). Serum IFNα bioactivity was analyzed using a reporter assay. RESULTS: In cohort 1, there was a better clinical response to rituximab in the IFN low signature group. Consistent with these findings, patients with an IFN low signature had a significantly greater reduction in the DAS28 and more often achieved a EULAR response at weeks 12 and 24 as compared with the patients with an IFN high signature in cohort 2 versus cohort 1. The pooled data showed a significantly stronger decrease in the DAS28 in IFN low signature patients at weeks 12 and 24 as compared with the IFN high signature group and a more frequent EULAR response at week 12. Accordingly, serum IFNα bioactivity at baseline was inversely associated with the clinical response, although this result did not reach statistical significance. CONCLUSION: The type I IFN signature negatively predicts the clinical response to rituximab treatment in patients with RA. This finding supports the notion that IFN signaling plays a role in the immunopathology of RA.
20692487 Surgical technique in cadaveric donors for partial hand allotransplant in patients with rh 2010 Jul For patients with severe hand deformities due to rheumatoid arthritis, we propose an allotransplantation of an osteomyotendinose structure (OMTS), preserving the recipient's skin and sensory nerves. Our objective was to develop the surgical technique in a 10 cadavers, five as donors and five as recipients. The donor's hand was 10% to 15% smaller than the recipient's. Dissections were performed by two surgical teams under magnification. In the donor, the OMTS was procured at the distal third of the forearm, maintaining the integrity of the arterial system, with its concomitant veins and motor branches of the median and ulnar nerves, leaving the skin envelope. In the recipient, the OMTS was removed, taking care to preserve the cutaneous cover with the digital arteries in continuity with the superficial palmar arch and radial and ulnar arteries. Also, the digital nerves were maintained in the skin flap, in continuity with the median and ulnar nerves. Their motor branches were divided after emergence from the main nerves. The superficial dorsal veins and radial nerve were kept adhered to the cutaneous cover. Then, the donor OMTS was placed within the recipient cutaneous flap; all the anatomic structures were repaired. The average surgical time was 780 minutes. Methylene blue was present in the digital arteries. There were no difficulties in the anatomic repair. The surgical technique is quite laborious, especially the dissection of the recipient interdigital spaces. Due to the requirement for arterial system integrity, the cutaneous flap must be viable. Also, the allotransplanted OMTS has all necessary conditions to obtain good tissue perfusion for subsequent function. Procurement without skin permits a greater opportunity to find donors, and greater social and personal acceptance by the recipient.
19329235 Mobile bearing knee kinematics change over time. A fluoroscopic study in rheumatoid arthri 2009 Jun BACKGROUND: In a previous fluoroscopy study the motion of a mobile bearing total knee prosthesis was evaluated. That study showed that the axial rotation of the insert was limited. Three possible explanations are given for the limited rotation: low conformity between the femoral component and insert, the fixed anterior position of the insert-tibia pivot point leading to impingement and fibrous tissue formation. While the effect of the conformity on the axial rotation will not change over time, the effect of impingement and fibrous tissue is likely to increase, and thereby further decreasing the axial rotation. METHODS: In order to accurately assess changes in axial rotation over time in a mobile bearing total knee prosthesis rheumatoid arthritis patient group, patients were evaluated 8 months and 3 years postoperatively using fluoroscopy. FINDINGS: In comparison with the 8 months evaluation, the rotation of the femoral component (range: -10.8 degrees to 2.8 degrees) and the insert (range: -5.9 degrees to 1.4 degrees) were further limited at 3 years (respectively, -5.9 degrees to 4.9 degrees and -2.8 degrees to 5.4 degrees). Patterns of axial rotation for the femoral component and insert varied considerably between the trials within patients while at the 8 months evaluation no significant difference within patients was observed. INTERPRETATION: This study shows the importance of re-evaluating knee kinematics over time. The axial rotation of both the femoral component as the insert decreased over time, indicating a kinematic change caused by intrinsic factors. The decline in rotation of the insert could be explained by increased impingement and the formation of fibrous tissue.
19363023 Arthritis development in patients with arthralgia is strongly associated with anti-citrull 2010 Mar BACKGROUND: Anti-citrullinated protein antibodies (ACPA) are associated with increased risk for rheumatoid arthritis. OBJECTIVE: To investigate the effect of the presence and levels of ACPA on arthritis development in patients with arthralgia. METHODS: Patients with arthralgia positive for ACPA or IgM rheumatoid factor (IgM-RF) were tested for the shared epitope (SE) and were prospectively followed up for at least 12 months. Absence of clinical arthritis at inclusion and arthritis development during follow-up were independently confirmed by two investigators. Cox regression hazard analyses were used to calculate hazard ratios (HRs) for arthritis development. RESULTS: 147 patients with arthralgia were included (50 ACPA positive, 52 IgM-RF positive and 45 positive for both antibodies). After a median follow-up of 28 months (interquartile range (IQR) 19-39), 29 patients developed arthritis in a median of 4 (IQR 3-6) joints and 26 (90%) of these were ACPA positive. The presence of ACPA (HR = 6.0; 95% confidence interval (95% CI) 1.8 to 19.8; p = 0.004), but not of IgM-RF (HR = 1.4, 95% CI 0.6 to 3.1) nor the SE (HR = 1.5, 95% CI 0.7 to 3.0), was associated with arthritis development. Within the group of ACPA-positive patients, the risk for arthritis was enhanced by the presence of IgM-RF (HR = 3.0; 95% CI 1.4 to 6.9; p = 0.01) and high ACPA levels (HR = 1.7; 95% CI 1.1 to 2.5; p = 0.008), but not the SE (HR = 1.0; 95% CI 0.5 to 2.1; p = 1.0). CONCLUSION: In patients with arthralgia the presence of ACPA (but not of IgM-RF or SE) predicts arthritis development. The risk in ACPA-positive patients may be further increased by the concomitant presence of IgM-RF or high levels of ACPA.
20662063 No evidence of association between anti-tumor necrosis factor treatment and mortality in p 2010 Nov OBJECTIVE: To study the association between anti-tumor necrosis factor (anti-TNF) therapy and mortality in a national cohort of patients with rheumatoid arthritis. METHODS: We prospectively followed up 12,672 patients who were beginning anti-TNF therapy and 3,522 biologic-naive patients receiving disease-modifying antirheumatic drugs (DMARDs) until either July 31, 2008, or death, whichever occurred first. Notification of death and cause of death was received from the UK National Death Register. Mortality was compared using Cox proportional hazards models. Inverse probability of treatment weighting was used to adjust for the confounding effects of baseline differences between groups, including age, sex, disease severity, disability, and comorbidity. Missing baseline data were accounted for using multiple imputation. RESULTS: When compared with the DMARD cohort, the anti-TNF cohort was younger (median age 57 years versus 61 years), had greater disease activity (median Disease Activity Score in 28 joints 6.6 versus 5.1), and had greater disability (median Health Assessment Questionnaire score 2.1 versus 1.6). Patients in the DMARD cohort were more likely to have a history of myocardial infarction (4.8% versus 3.1%) and chronic obstructive pulmonary disease (8.1% versus 4.8%) but were less likely to have had depression (16.5% versus 18.9%). There were 9,445 and 50,803 person-years of followup in the DMARD and anti-TNF cohorts, respectively, during which time 204 DMARD-treated and 856 anti-TNF-treated patients died. The weighted mortality hazard ratios in the anti-TNF cohort were as follows: all-cause 0.86 (95% confidence interval [95% CI] 0.64-1.16), circulatory disease 0.73 (95% CI 0.44-1.23), neoplasm 0.65 (95% CI 0.39-1.09), and respiratory disease 0.81 (95% CI 0.36-1.83). CONCLUSION: Our results indicate that, compared with standard DMARD therapy, treatment with anti-TNF therapies was not associated with an increase in mortality.
21199468 Diagnostic value of anti-modified citrullinated vimentin in rheumatoid arthritis. 2010 Oct BACKGROUND: Rheumatoid factors (RF) are currently used in the diagnosis of rheumatoid arthritis (RA). Several other autoantibodies found in RA are directed to epitopes in citrullinated proteins such as anti-cyclic citrullinated and recently anti-modified citrullinated vimentin (MCV). OBJECTIVE: In this study we determined the sensitivity and specificity of anti-MCV in comparison with anti-cyclic citrullinated peptide (CCP) antibodies and RF in RA patients and in a control group using the American College of Rheumatology (ACR) criteria as the gold standard. MATERIALS AND METHODS: A cross sectional study was conducted from January to December 2008 on 100 patients with RA and 153 patients with arthritis or arthralgia but not fulfilling ACR criteria for RA. Serum from each subject was tested for anti-MCV, anti-CCP antibodies and immunoglobulin G (IgG) RF by enzyme-linked immunosorbent assay. Sensitivity and specificity of the tests were evaluated using the ACR criteria as the gold standard. RESULTS: The sensitivity of RF was 85% with 74.5% specificity. For anti-CCP antibodies the sensitivity was 71% and the specificity was 94.8%. The sensitivity of anti-MCV antibodies was 80% with 59.5% specificity. The area under the curve for RF was 0.759, for anti-CCP antibodies was 0.866 and for anti-MCV antibodies was 0.681, while for at least one positive test it was 0.691. CONCLUSION: Anti-CCP antibodies have higher diagnostic specificity and positive predictive value than RF and anti-MCV antibodies. RF has the highest sensitivity when compared to anti-CCP and anti-MCV antibodies. Thus anti-MCV antibody is not a better marker when compared to RF or anti-MCV antibody in the diagnosis of RA patients.
21062340 Mechanism of alveolar bone loss in a collagen-induced arthritis model in mice. 2011 Feb OBJECTIVE: the aim of this study was to understand the cellular/molecular mechanisms of periodontal breakdown in a collagen-induced arthritis (CIA) model in mice to enhance the understanding of rheumatoid arthritis (RA)-associated alveolar bone loss in humans. MATERIALS AND METHODS: all analyses were performed on paired samples from CIA and control group mice. Mandibles were retrieved for micro-computed tomography (micro-CT), histomorphometric analysis, and isolation of alveolar bone cells (ABCs). In vitro osteoclastogenic/osteogenic/adipogenic potentials of ABCs were evaluated and the mRNA expression of downstream effector genes was assessed. Bone formation of ABCs was assessed using an ectopic transplantation model. RESULTS: histomorphometric and micro-CT data showed that alveolar bone loss was significantly increased in the CIA group (p<0.05). Osteoclastogenesis was significantly increased in the CIA group in vivo (p<0.05), with upregulated mRNA expressions of osteoclastogenesis-associated genes. Osteoblasts appeared to undergo increased apoptosis, and the bone-forming activity of ABCs concomitantly decreased with in vitro osteogenic differentiation and in vivo ectopic transplantation (p<0.05). Also, adipogenesis-associated mRNA expression was highly expressed in the CIA group, resulting in significantly enhanced adipocyte differentiation in vitro (p<0.05). CONCLUSIONS: these data demonstrate that increased osteoclastic activity, decreased bone-forming activity and enhanced adipogenesis promote alveolar bone loss in a CIA model in mice, and they suggest that these mechanisms could account for the same outcome in human RA.
20074669 CEL-2000: A therapeutic vaccine for rheumatoid arthritis arrests disease development and a 2010 Apr The mouse model of collagen induced arthritis (CIA) effectively mimics human disease and thus is useful for testing and development of rheumatoid arthritis (RA) therapies. We developed a Ligand Epitope Antigen Presentation System (LEAPS) peptide hetero-conjugate vaccine containing an epitope of human collagen type II (CEL-2000) that acted as a therapeutic vaccine in the collagen induced arthritis (CIA) mouse model. LEAPS technology converts a small peptide containing a disease specific epitope into an immunogen by attaching it to an immune or T cell binding peptide (I/TCBL). For CEL-2000, a peptide from human collagen type II (254-273) is attached to the I/TCBL peptide from human beta2 microglobulin (J). Treatment with CEL-2000 limited disease (CIA) progression, as demonstrated by reduced Arthritic Index (AI) score, and footpad swelling. Efficacy was confirmed by histopathological microscopic examination of tissues at the end of the study. CEL-2000 limited disease progression as well or better than the etanercept (Enbrel) therapeutic control with significantly better histopathological results than the etanercept treated mice. Most interestingly, CEL-2000 therapy modulated serum cytokine levels with an increase in IL-12p70 and IL-10, which are not seen with etanercept therapy, and reduced IL-17 and TNF-alpha, also seen with etanercept, among other cytokines studied. CEL-2000 was safe and well tolerated for the mice that received 5 injections given every 2weeks in a 90day study supporting its potential usage for long term therapy. These studies demonstrate that fewer treatments with CEL-2000 provide therapy at least as effective as etanercept by specifically modulating the disease producing autoimmune response.
20033813 Perioperative management of immunosuppression in rheumatic diseases--what to do? 2010 Jun To stop or not to stop immunosuppressive therapy in the perioperative setting puts the clinician to a challenge. The risk of potential wound infection with possible septic or even lethal consequences needs to be weighted against exacerbation of the rheumatic disease. However, exacerbation of autoimmune inflammatory activity needs to be treated with increasing immunosuppressive medication, thus leading to enhanced risk of local and systemic infection as well. Unfortunately, up to now there is no data from randomized, double-blind controlled clinical trials available on how to steer immunosuppressive therapy in the perioperative setting, making evidence-based recommendations difficult. Neither is there good evidence, if the risk of infectious complications under immunosuppressive therapy differs according to the type and localization of surgery performed. Finally, immunosuppressive co-medication, like glucocorticoid dosage, is not adequately addressed in the available studies, making interpretation of these studies even more problematic. Therefore, a decision has to be made on an individual basis. We discuss the available data on DMARD and biologics therapy in the perioperative setting and describe our own perioperative management with different DMARDs and biologics.
19744146 IL7RA polymorphisms and chronic inflammatory arthropathies. 2009 Nov The C allele of a single nucleotide polymorphism (SNP), rs6897932, located in the interleukin-7 receptor alpha chain (IL7RA) was recently found to be associated with multiple sclerosis and Type I diabetes. We analysed 13 SNPs in the IL7RA gene in a combined cohort of patients with chronic inflammatory arthropathies (rheumatoid arthritis and juvenile idiopathic arthritis; 368 patients and 532 unaffected subjects). No significant associations with disease were found with the exception of the non-synonymous SNP rs6897932. This SNP showed modest enrichment of the TT genotype in arthritic patients compared with controls [P = 0.02; OR 1.72 (95% CI 1.08-2.75)]. Our data are suggestive for a role of rs6897932 in predisposition to chronic inflammatory arthropathies.