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ID PMID Title PublicationDate abstract
23245655 The usefulness of computer-aided joint space analysis in the assessment of rheumatoid arth 2013 Jul OBJECTIVE: Computer-aided joint space analysis (CAJSA) is a newly developed technique for the measurement of radiogeometrically detectable joint space widths of the metacarpal-phalangeal (JSD-MCP) and proximal-interphalangeal articulations (JSD-PIP). The aim of this study was to verify the sensitivity and specificity of these CAJSA measurements in the assessment of established RA. METHODS: Four hundred and fifty-eight participants (248 healthy subjects, 210 RA patients) underwent computerized semi-automated measurements of the JSD-MCP and JSD-PIP articulations (CAJSA, Radiogrammetry Kit, Version 1.3.6) based on digitally performed radiographs. The Sharp joint space narrowing score was also performed to determine RA-related joint space narrowing. RESULTS: The significant severity-dependent reduction for JSD-MCP was -44.0% and for JSD-PIP, -25.94% between Sharp scores 0 and 3. The sensitivity and specificity of JSD-MCP (total) was 88.1% versus 77.8%, respectively (AUC = 0.920; P < 0.001). Furthermore, JSD-PIP (total) revealed a lower sensitivity and specificity with 61.4% and 88.7% (AUC = 0.878; P < 0.001). CONCLUSION: The CAJSA method presented a reliable assessment of disease-related joint space narrowing in patients suffering from RA with excellent sensitivity and specificity. By providing quantitative data, other scoring methods could be significantly improved, and thereby the accuracy of the diagnosis and a better therapeutic evaluation could be achieved.
24840097 Association of transforming growth factor-β1 T869C, G915C, and C509T gene polymorphisms 2014 Dec The association of transforming growth factor-β1 (TGFβ1) is an important signaling pathway factor involving extracellular matrix regulation, and its gene polymorphisms with the risk of rheumatoid arthritis (RA) is currently still fiercely debated. Therefore, this meta-analysis was performed to determine if TGFβ1 T869C, G915C, and C509T gene polymorphisms correlate with the risk of developing RA. Association reports were identified from PubMed, Cochrane Library and CBM-disc (China Biological Medicine Database) on 1 May 2013, and eligible studies were recruited and synthesized to identifying patterns among study results. T869C TT genotype in the overall population was associated with increased RA risk (OR = 1.28, 95% CI: 1.02-1.60, p = 0.03). In the sub-group analysis, T869C TT genotype was shown to be a risk factor for RA, and T869C C allele or CC genotype a protective factor against RA disease in Asians, but these associations were not found in Caucasians. Furthermore, TGFβ1 C509T TT genotype was distinctly associated with RA susceptibility, but the T allele and CC genotype were not. TGFβ1 G915C gene polymorphism was not associated with RA susceptibility. In conclusion, the TT genotype of TGFβ1 T869C was associated with RA risk in the overall population and Asians. Furthermore, CC genotype or C allele was determined to be protective factors with respect to the RA risk in the overall population and Asians. Nonetheless, additional studies are required to firmly establish a correlation between the aforementioned polymorphisms and RA risk.
23637327 High-density lipoprotein profiling changes in patients with rheumatoid arthritis treated w 2013 Jun OBJECTIVE: We investigated changes in high-density lipoprotein (HDL) profiling in patients with rheumatoid arthritis who started treatment by taking tumor necrosis factor (TNF) inhibitors. The patients were stratified for European League Against Rheumatism (EULAR) response. METHODS: A group of 100 patients naive for TNF inhibitors at baseline were randomly selected from 204 adalimumab-treated and 203 etanercept-treated patients on the basis of their EULAR response. HDL profiling was measured using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. RESULTS: In EULAR good responders, mass charged markers representing serum amyloid A (SAA-1 and -2) decreased significantly after 4 months' therapy. There were no significant differences in HDL profiling in EULAR nonresponders. CONCLUSION: Effective suppression of inflammation with TNF inhibitors results in favorable changes in HDL composition.
24307431 Tocilizumab monotherapy in a patient with rheumatoid arthritis and iatrogenic Kaposi sarco 2014 Feb Kaposi sarcoma (KS) is a human herpesvirus-8-associated lymphoangioproliferative neoplasm. Both human and viral interleukin-6 (IL-6) proteins seem to drive much of the clinical manifestations of KS, which provides a new target for intervention by using IL-6-neutralizing antibodies. We describe the clinical course of a patient in whom tocilizumab, a monoclonal anti-IL-6 receptor antibody approved for rheumatoid arthritis (RA) treatment, was effective not only in inducing RA remission but was also safe for KS.
24297384 Performance of the new 2012 EULAR/ACR classification criteria for polymyalgia rheumatica: 2014 Jun OBJECTIVE: To compare the performance of published classification/diagnostic criteria for polymyalgia rheumatica (PMR), including the new 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria, in a single-centre study. METHODS: We studied all consecutive patients with new-onset PMR seen in our centre over 6 years, whose diagnosis was confirmed during a prospective 12-month follow-up period. Subjects were classified by each of the seven different criteria. Sensitivity and specificity were compared. Control population consisted of all consecutive patients aged ≥50 years seen in a 4-year period in our early arthritis clinic who had a 12-month confirmation of a diagnosis of rheumatoid arthritis (RA) or other inflammatory articular diseases. RESULTS: Data were collected from 136 cases and 149 controls, including 94 patients with RA. The most sensitive criteria were the new 2012 EULAR/ACR classification criteria (92.6%). Adding ultrasound (US) specificity increased from 81.5% to 91.3% in total cases and from 79.7% to 89.9% in RA. Bird criteria had a sensitivity of 89.2% but the lowest specificity (40.2% in total cases and 72.5% in RA). Jones and Nobunaga criteria were the most specific criteria (96.7% and 97.8% in total cases and 98.6% and 99.5% in RA) but the less sensitive (63.1% and 58.2%) ones. Overall, discriminatory ability, as reflected by the area under the receiver operating characteristic curve, was better for the 2012 US EULAR/ACR criteria (0.920 in total cases and 0.910 in RA). CONCLUSIONS: The new EULAR/ACR criteria in new-onset PMR patients perform best in discriminating PMR from RA and other inflammatory articular diseases. Ultrasound further increases the specificity of the criteria.
25256232 Anticyclic citrullinated protein antibodies are implicated in the development of cardiovas 2014 Dec OBJECTIVE: Previous studies have suggested a relationship between anticyclic citrullinated protein (CCP) levels and development of cardiovascular disease in rheumatoid arthritis (RA). However, a limited number of studies have demonstrated an involvement of anti-CCPs in those processes. This study was aimed to define the specific role of these auto-antibodies in the pro-oxidative, inflammatory, and proatherogenic profile observed in leukocytes from RA patients. APPROACH AND RESULTS: Seventy-five RA patients and 31 healthy donors were enrolled. Carotid intima media thickness was evaluated as atherosclerosis marker. Several procoagulant and inflammatory factors, leukocyte activation, and oxidative stress markers were analyzed in plasma and leukocyte subsets. Anti-CCPs were purified from plasma of RA patients, and in vitro treatment of healthy leukocytes was conducted. High titers of anti-CCPs were associated to altered expression of prothrombotic and inflammatory markers, high oxidative stress, and pathological carotid intima media thickness in RA patients. Notably, gene expression analysis showed that lymphocytes were major players in altered inflammatory profile, monocytes were responsible for the protrombotic and atherogenic status, and neutrophils mainly displayed a pro-oxidative feature. In vitro treatment with purified anti-CCPs fully recapitulated that pathogenic profile, promoting the activation of leukocytes. CONCLUSIONS: Anti-CCPs are key players in the inflammatory and proatherogenic status of RA patients. The effects are specific of the immune cell targeted, promoting overexpression of thrombotic, inflammatory, and pro-oxidative markers in monocytes; pro-oxidative status in neutrophils; and proinflammatory profile in lymphocytes. Targeting these autoantibodies would be an excellent strategy to prevent the development of cardiovascular disease in RA.
25399339 Factors influencing ultrasonographic remission in patients with rheumatoid arthritis. 2015 Mar The aim of this study was to define the ultrasonographic factors that indicate clinical remission in patients with RA. We enrolled a cohort of patients with RA in whom the disease had been in remission for at least 6 months. Musculoskeletal ultrasound (US) examination was used to evaluate the status of active synovitis, power Doppler (PD) signalling, and synovitis in the bilateral metacarpophalangeal; proximal interphalangeal; and radiocarpal, ulnocarpal, and intercarpal, compartments of the wrist. A total of 64 RA patients with a mean disease duration of 79.97 months were studied. Of all patients, 36% had ultrasonographic synovitis and 29% an increased PD signal from at least one joint. Delay in diagnosis was highly correlated with synovitis and PD synovitis (r = 0.55, p = 0.000; and r = 0.51, p = 0.001, respectively). A weak negative correlation was evident between synovitis, PD synovitis, tenosynovitis, PD tenosynovitis, and duration of clinical remission (respectively, r = -0.426, p = 0.000; r = -0.333, p = 0.007; r = -0.243, p = 0.050; and r = -0.247, p = 0.049). Upon multivariate logistic regression analysis, the duration of clinical remission and delay in diagnosis were the factors that most influenced ultrasonographic remission (OR 3.46, p = 0.046; OR 3.27, p = 0.016, respectively). Synovial inflammation may persist in RA patients exhibiting clinical remission. We found that US detected subclinical synovitis. The most important factors preventing ultrasonographic remission were a short duration of clinical remission and delay in diagnosis.
24384061 Generation of monoclonal antibodies against peptidylarginine deiminase 2 (PAD2) and develo 2014 Mar The enzyme peptidylarginine deiminase 2 (PAD2) has been associated with inflammatory diseases, such as rheumatoid arthritis and neurodegenerative diseases including multiple sclerosis. To investigate the association of various diseases with extracellular PAD2, we raised monoclonal antibodies (mAbs) against rabbit PAD2 and evaluated their cross-reactivity with human PAD2 by indirect enzyme-linked immunosorbent assay (ELISA), western blotting and immunohistological staining of inflamed synovial tissue. Moreover, we established a sandwich ELISA detecting human PAD2, based on two different monoclonal antibodies, mAbs DN2 and DN6. The assay had a lower detection limit of 200pg/mL in serum and plasma samples, and showed dilution linearity and recovery ranging from 95 to 106%. The mAbs and the ELISA showed isotype specificity for PAD2. Circulating PAD2 was found in 8/28 (29%) serum samples from healthy donors. In conclusion, several of our mAbs proved useful in western blotting and immunohistochemistry, and the ELISA described here reliably measures PAD2 levels in blood. This allows investigation of PAD2 as a possible biomarker and further investigation of PAD2's involvement in various inflammatory diseases.
23179259 Immunoglobulin subtypes predict therapy response to the biologics in patients with rheumat 2013 Jun To analyze the effectiveness of rituximab (RTX) versus alternative TNF antagonists (aTNFs) on rheumatoid arthritis (RA) disease activity in different subgroups of patients and relation with extraarticular manifestations of RA and to assess that RF-subsets have potential as predictors of clinical response to RTX. Patients with RA (n = 40, M/F: 3/37) who received aTNFs at least 6 months with good response (group I; n = 20) or discontinued at least one aTNFs because of the ineffectiveness and subsequently received RTX at least one course (group II; n = 20) were retrospectively evaluated. IgM-, IgA-, IgG-rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) levels were measured by ELISA technique. Extraarticular manifestations and radiological scores were also recorded. The mean (SD) age was 51.7 ± 6.5 years in group I and 52.1 ± 6.1 years in group II patients (p > 0.05). The median disease durations were higher in group II than group I [8.0 (2-30) vs. 13 (3-35) years, respectively, p = 0.04]. Presence of RF [13(61.9 %) vs. 20(100 %) p = 0.001] and extraarticular involvement [5(25 %) vs. 13(65 %) p = 0.01] were higher in group II patients. When Ig-RF subgroups analyzed, all subgroup (IgA, IgM, IgG) levels were higher in group II (p = 0.001, p = 0.05, p = 0.001). IgA-RF levels were significantly high in patients with extraarticular involvement (p = 0.04). Association between high RF levels and having extraarticular manifestations in RA patients may largely be attributed to the IgA isotype.
24591094 Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: 2014 Jun OBJECTIVE: The aim of this prospective multicenter study was to identify biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with rheumatoid arthritis (RA). METHODS: We recruited patients with RA who were treated with tocilizumab for the first time, and determined therapeutic responses at 6 months. In the training cohort (n = 40), gene expression in peripheral blood mononuclear cells (PBMCs) at baseline was analyzed using genome-wide DNA microarray, with 41,000 probes derived from 19,416 genes. In the validation cohort (n = 20), expression levels of the candidate genes in PBMCs at baseline were determined using real-time quantitative polymerase chain reaction (qPCR) analysis. RESULTS: We identified 68 DNA microarray probes that showed significant differences in signal intensity between nonresponders and responders in the training cohort. Nineteen putative genes were selected, and a significant correlation between the DNA microarray signal intensity and the qPCR relative expression was confirmed in 15 genes. In the validation cohort, a significant difference in relative expression between nonresponders and responders was reproduced for 3 type I interferon response genes (IFI6, MX2, and OASL) and MT1G. Receiver operating characteristic curve analysis of models incorporating these genes showed that the maximum area under the curve was 0.947 in predicting a moderate or good response to tocilizumab in the validation cohort. CONCLUSION: Using genome-wide DNA microarray analyses, we identified candidate biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with RA. These findings suggest that type I interferon signaling and metallothioneins are involved in the pathophysiology of RA.
25011482 Interferon regulatory factor 5 genetic variants are associated with cardiovascular disease 2014 Jul 10 INTRODUCTION: Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased cardiovascular (CV) disease risk. Interferon regulatory factor 5 (IRF5) is a regulator of type I interferon induction. Recently, researchers have described an association between multiple single-nucleotide polymorphisms of the IRF5 gene and some rheumatic disorders. In this study, we aimed to evaluate whether three different haplotype blocks within the IRF5 locus which have been shown to alter the protein function are involved in the risk of CV events occurring in Spanish RA patients. METHODS: Three IRF5 polymorphisms (rs2004640, rs2070197 and rs10954213) representative of each haplotype group were genotyped by performing TaqMan assays using a 7900HT Fast Real-Time PCR System with tissue from a total of 2,137 Spanish patients diagnosed with RA. Among them, 390 (18.2%) had experienced CV events. The relationship of IRF5 genotypes and haplotypes to CV events was tested using Cox regression. RESULTS: Male sex, age at RA diagnosis and most traditional risk factors (hypertension, dyslipidemia and smoking habit) were associated with increased risk for CV events in the RA population. Interestingly, a protective effect of both IRF5 rs2004640 GG and IRF5 rs10954213 GG genotypes against the risk for CV events after adjusting the results for sex, age at RA diagnosis and traditional CV disease risk factors was observed (hazard ratio (HR) = 0.6, 95% confidence interval (CI) = 0.38 to 0.92, P = 0.02; and HR = 0.58, 95% CI = 0.36 to 0.95, P = 0.03, respectively). Moreover, we detected a protective effect of the GTG haplotype against the risk for CV events after adjusting the results for potential confounding factors (HR = 0.72, 95% CI = 0.56 to 0.93, P = 0.012). CONCLUSIONS: Our results reveal that IRF5 gene variants are associated with risk of CV events in patients with RA.
24334642 Health literacy predicts discrepancies between traditional written patient assessments and 2014 Feb OBJECTIVE: Patient assessments of disease activity (PtGA) and general health (GH) measured by visual analog scale (VAS) are widely used in rheumatoid arthritis (RA) clinical practice and research. These require comprehension of the question's wording and translation of disease activity onto a written VAS, which is problematic for patients with limited health literacy (HL) or difficulty completing forms. This study's objective was to validate verbally administered versions of patient assessments and identify factors that might explain discrepancies between verbal and written measures. METHODS: We enrolled patients with RA at the Denver Health rheumatology clinic (n = 300). Subjects were randomized to complete the traditional written PtGA and GH and one of the verbal assessments. Subjects provided a verbal numeric response after reading the question, having the question read to them in person, or hearing the question over the phone. Spearman and Lin correlations comparing written and verbal assessments were determined. Multivariate logistic regression was performed to explain any discrepancies. RESULTS: The instruments administered verbally in-person showed good, but not excellent, correlation with traditional written VAS forms (Spearman coefficients 0.59 to 0.70; p < 0.001 for all correlations). Twenty-three percent of subjects were unable to complete 1 of the written VAS assessments without assistance. HL predicted missing written data and discrepancies between verbal and written assessments (p < 0.05 for all correlations). CONCLUSION: Providers should use verbal versions of PtGA and GH with caution while caring for patients unable to complete traditional written version. Limited HL is widely prevalent and a barrier to obtaining patient-oriented data.
23874006 Methotrexate in rheumatoid arthritis: a quarter century of development. 2013 Methotrexate (MTX) is now the most popular drug worldwide for the treatment of rheumatoid arthritis. Low-dose, weekly MTX (10 to 25 mg/wk) used as either monotherapy or in combination with other drugs has a superior efficacy profile as defined in placebo-controlled trials and comparable efficacy to other drugs including anti-TNF therapy. At 1 year, one third of patients on MTX have no radiographic progression and even greater effects are seen when combined with targeted biological therapies. MTX is well tolerated; gastrointestinal toxicity is the most common toxicity with rarely bone marrow, lung, or liver toxicity. MTX therapy has been a major advance in the treatment of rheumatoid arthritis and is now the cornerstone of therapy.
25535886 Circadian rhythms of cellular immunity in rheumatoid arthritis: a hypothesis-generating st 2015 Jan OBJECTIVES: The circadian rhythm of clinical symptoms in rheumatoid arthritis (RA) has been primarily attributed to circadian variations in humoral factors and hormones. In this study, we investigated circadian rhythms of cellular immunity in RA (CiRA study). METHODS: Peripheral blood of female postmenopausal patients with active RA (DAS 28 ≥ 4.2) (n=5) and female postmenopausal non-RA controls (n=5) was collected every 2 hours for 24 hours and analysed by flow cytometry, cytokine multiplex suspension array and quantitative RT-PCR of clock gene expression in isolated CD14+ monocytes. Endogenous circadian rhythms of macrophages were investigated by BMAL1-luciferase bioluminescence. Significance of circadian rhythms was tested by Cosinor analysis. RESULTS: We found (i) circadian rhythms in the relative frequency of peripheral blood cell populations that were present in postmenopausal non-RA controls but absent in patients with active RA, (ii) circadian rhythms that were absent in non-RA controls but present in patients with RA and (iii) circadian rhythms that were present in both groups but with differences in peak phase or amplitude or amplitude/magnitude. The circadian rhythm in expression of the clock genes PER2 and PER3 in CD14+ monocytes was lost in patients with RA. The amplitude of BMAL1-luciferase bioluminescence tended to be lower in patients with RA than in non-RA controls. CONCLUSIONS: We conclude that (i) in RA some immune cell populations lose their normal circadian rhythms whereas others establish new 'inflammatory' circadian rhythms and (ii) these findings provide a good basis for further identifying pathophysiological aspects of RA chronobiology with potential therapeutic implications.
23432328 Rigid occipitocervical fixation: indications, outcomes, and complications in the modern er 2013 Apr OBJECT: Over the past 40 years, various methods and instrumentation types have been developed for occipitocervical fixation (OCF) in the management of occipitocervical instability. This study reports indications, outcomes, and complications with rigid OCF using screw-rod and screw-plate instrumentation, which has comparatively less long-term data. METHODS: A prospectively maintained database identified 100 consecutive patients who underwent rigid OCF in a single unit over a period of 13 years. Patient demographics, clinical indications, pre- and postoperative radiographic findings, neck disability indices (NDIs), myelopathy disability indices (MDIs), visual analog scale (VAS) scores, and Ranawat scores were recorded. Complications including instrumentation failure were also documented. RESULTS: Underlying etiologies included rheumatoid arthritis (RA; 41%), tumor (16%), trauma (15%), congenital etiologies (14%), metabolic (6%) and inflammatory (6%) conditions, and infection (2%). The pre- and postoperative MDI and VAS scores for neck pain showed significant improvements in the RA group (MDI 64.5% vs 42.5%, p = 0.02; mean VAS 7.5 of 10 vs 3.7 of 10, p < 0.001). Improvements in MDI and NDI outcome measures were also seen in the trauma and tumor categories. Overall, there were 4 cases of instrumentation failure; all included broken rods in the stress riser region of occipitocervical rod curvature, and 1 patient also had occipital plate screw pullout. Other complications included 5 wound infections requiring wound washout, 1 vertebral artery injury (no clinical sequelae), and 1 perioperative death due to myocardial infarction. CONCLUSIONS: Rigid OCF is a safe and effective method of managing occipitocervical instability due to a variety of causes. Outcome measures are favorable, and patients with chronically debilitating diseases such as RA may benefit in terms of improvements in neurological deficit and neck pain. The complication profile is comparable to that reported in other series of OCF in the literature, as well as to the previously used semirigid type of rod/sublaminar wire fixation.
24106048 Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotyp 2015 Jan OBJECTIVE: To determine whether anticitrullinated protein antibodies (ACPA) exhibit specific changes in Fc glycosylation prior to the onset of arthritis. METHODS: Serum samples of patients with ACPA-positive arthralgia (n=183) were collected at baseline and at various time points of follow-up. 105 patients developed arthritis after a median of 12 months (IQR 6-24) and were classified as having either rheumatoid arthritis (RA, n=48) or undifferentiated arthritis (UA, n=57) based on the 1987 American College of Rheumatology (ACR) criteria. ACPA and total serum IgG were isolated by affinity purification and cleaved by trypsin. ACPA-IgG1 Fc-glycopeptides were subsequently analysed by nano-liquid chromatography mass spectrometry and compared to those of total IgG1. RESULTS: At baseline, ACPA-IgG1 and total IgG1 from arthralgia patients displayed similar Fc glycosylation patterns. By contrast, at the onset of arthritis, ACPA exhibited a decrease in galactose residues in RA patients, but not in UA patients. This decrease occurred around 3 months prior to diagnosis and was paralleled by an increase in systemic inflammation (erythrocyte sedimentation rate). Galactosylation of total IgG1 was also decreased in RA, but this did not precede the onset of arthritis. Interestingly, we additionally noted a higher degree of ACPA-IgG1 Fc core fucosylation at baseline as compared with total IgG1, which further increased prior to diagnosis. CONCLUSIONS: ACPA display significant changes in Fc galactosylation and fucosylation prior to the onset of RA. These changes towards a more pro-inflammatory phenotype could be involved in driving the disease process.
25726631 Rheumatoid arthritis and ischemic strokes in a young woman. Are these conditions interrela 2014 Oct Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which is associated with an increased risk of cardio and cerebrovascular pathology. A 48-year old Caucasian female was admitted for diffuse arthralgias. She was diagnosed eight years before with seropositive RA and she received Methotrexate, Prednisone and anti-inflammatory drugs. A week after the admission the patient presented sudden onset of left hemiplegia. Cerebral CT scan was suggestive for acute infarction in the right middle cerebral artery area and an old sequelar infarction in the left posterior artery area. Laboratory tests revealed: erythrocyte sedimentation rate of 40 mm/hour, fibrinogen 656 mg/dL, C-reactive protein of 20 mg/dL, rheumatoid factor 66.83 U/mL, anti CCP3 IgG 213.54 U/mL, ANA 128.126 U/mL. Also, she had high LDL-cholesterol serum concentration (190 mg/dL). The ECG revealed sinus rhythm, QRS axis-45 degrees, antero-lateral ischemia. Ultrasound examination of cervico-cerebral arteries emphasized occlusion of the left internal carotid artery, large atheromas in both carotid and vertebral arteries. A treatment with anti-aggregant and statin was started, and the former treatment for RA was continued with a raised Prednisone dose. The outcome was favorable, the patient's motor deficit improved (3/5 BMRC at the upper limb and 4/5 at the inferior limb) and she was able to walk with a cane support. She also presented an alleviation in the laboratory test status. Ischemic stroke is a possible complication of RA, presenting as principal risk factor precocious atherosclerosis. A better control of inflammation by new anti-rheumatic treatments will protect the RA patients of deleterious effects of ischemic stroke.
24097830 Effects of Ureaplasma urealyticum lipid-associated membrane proteins on rheumatoid arthrit 2013 Oct OBJECTIVES: As an infectious agent might play a role in rheumatoid arthritis (RA) development, this study investigated effects of Ureaplasma urealyticum lipid-associated membrane proteins (UuLAMPs) on RA synovial fibroblast (RASF) proliferation, and tumour necrosis factor (TNF)-α and interleukin (IL)-1β production by THP-1 macrophages. Possible immunogenic proteins in UuLAMPs were identified. METHODS: RASFs were cultured from synovial tissue from donors with RA. Serum samples from donors with/without RA and with/without U. urealyticum infection were used for immunogenicity analyses. THP-1 macrophages served as a model for synovial macrophages. TNF-α and IL-1β mRNA levels were assessed using reverse transcription-polymerase chain reaction; protein levels were estimated using enzyme-linked immunosorbent assay. UuLAMPs underwent separation and Western blot analyses. RESULTS: UuLAMPs (0.025-0.4 µg/ml) stimulated RASF proliferation in a dose- and time-dependent manner, and increased TNF-α and IL-1β levels in THP-1 macrophages. Several immunogenic UuLAMPs were identified, but antibodies to a 25 kDa protein were only found in RA patients with U. urealyticum infection. CONCLUSIONS: UuLAMPs might induce RASF proliferation and proinflammatory cytokine secretion in synovium from RA patients. A 25 kDa U. urealyticum protein might act as a cross-reactive antigen.
25102962 Mycobacterial diseases developed during anti-tumour necrosis factor-α therapy. 2014 Nov Nontuberculous mycobacterial (NTM) disease and tuberculosis (TB) develop during anti-tumour necrosis factor (TNF)-α therapy. We compared clinical characteristics and outcomes between the two diseases. A total of 1165 patients were screened for TB and treated with TNF-α antagonists from July 2004 to July 2013 for the following conditions: inflammatory bowel disease (n = 422), rheumatoid arthritis (n = 320), and ankylosing spondylitis (n = 389). TB and NTM disease were diagnosed at baseline screening in four and three patients, respectively, and developed during anti-TNF-α therapy in 19 and six patients, respectively. The incidence rate of TB and NTM disease was 747.7 per 100 000 and 238.2 per 100 000 person-years, respectively. Patients with NTM disease were older, with a greater proportion of females. All cases of NTM disease involved the lung, with rheumatoid arthritis (83.3%) being the most frequent underlying disease. The most common radiological feature was consolidation in NTM disease, and honeycombing was present in two rheumatoid arthritis patients with NTM disease. The most common pathogen was Mycobacterium intracellulare (n = 3) followed by Mycobacterium avium (n = 2). Both the NTM and TB group showed favourable outcomes. The clinical characteristics differed between NTM disease and TB that developed on anti-TNF-α agents, but clinical outcomes were favourable in both diseases.
25109449 Clock gene expression in different synovial cells of patients with rheumatoid arthritis an 2014 Sep Patients with rheumatoid arthritis (RA) show modulated circadian rhythms of inflammatory cytokines and cortisol, which may be associated with a modified expression of clock genes. The expression of major clock genes was previously studied in synovial tissues and fibroblasts of patients with RA and osteoarthritis (OA). We therefore especially aimed to examine the localization of clock genes at the cellular level in synovial tissue. Furthermore we were interested in studying the expression of the D site of albumin promoter (albumin D-box) binding protein (DBP) at the immunohistochemical level in human samples. Methods used include the in situ expression of the clock genes Brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal 1), Circadian Locomotor Output Cycles Kaput (Clock), Period 1 and 2 (Per 1 and Per 2), and DBP was examined by immunohistochemistry in synovial tissues of patients with RA or OA. Additionally, expression profiles of different clock genes were determined over 24h by real time PCR in synovial fibroblasts (SFs) after a 2h serum shock or TNF-α. Results show that all clock genes investigated were found to be expressed both in RA and OA synovial tissues. Double staining against cell specific markers revealed that clock proteins were especially seen in macrophages, SFs and B-lymphocytes. Cell counting showed that clock proteins were found in approximately 5-20% of cells. Additionally, preliminary cell culture experiments showed that TNF-α treatment resulted in differential 24h expression profiles between RA and OA samples and also compared to the results obtained from the serum shock experiments. From our study we conclude that the major clock genes, including DBP, are expressed in samples from RA and OA patients, especially in macrophages and synovial fibroblasts, but also in B-lymphocytes. Preliminary experiments suggest that TNF-α seems to be able to modify clock gene expression in synovial fibroblasts.