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ID PMID Title PublicationDate abstract
25678110 The RNA-binding protein HuR/ELAVL1 regulates IFN-β mRNA abundance and the type I IFN res 2015 May Secretion of type I interferon (IFN) is the first cellular reaction to invading pathogens. Despite the protective function of these cytokines, an excessive response to their action can contribute to serious pathologies, such as autoimmune diseases. Transcripts of most cytokines contain adenylate-uridylate (A/U)-rich elements (AREs) that make them highly unstable. RNA-binding proteins (RBPs) are mediators of the regulatory mechanisms that determine the fate of mRNAs containing AREs. Here, we applied an affinity proteomic approach and identified lethal, abnormal vision, drosophila-like 1 (ELAVL1)/Hu antigen R (HuR) as the predominant RBP of the IFN-β mRNA ARE. Reduced expression or chemical inhibition of HuR severely hampered the type I IFN response in various cell lines and fibroblast-like synoviocytes isolated from joints of rheumatoid arthritis patients. These results define a role for HuR as a potent modulator of the type I IFN response. Taken together, HuR could be used as therapeutic target for diseases where type I IFN production is exaggerated.
27783394 Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthriti 2017 Mar NKG2D (KLRK1) is a C-type lectin receptor present on natural killer (NK) cells, γδ, CD8(+) and CD4(+) T cells. Upon ligand binding, NKG2D mediates activatory and co-stimulatory signals to NK cells and activated CD4(+) T cells, respectively. Polymorphisms in NKG2D predispose to infectious diseases, cancer, transplantation and autoimmune disorders. We studied the influence of this NK receptor polymorphism on predisposition to and modification of the disease phenotype in patients with rheumatoid arthritis (RA). Eight different single nucleotide polymorphisms (SNP) in the NKG2 gene were genotyped in 236 patients with RA and 187 controls using Taqman 5' nuclease assays. NKG2D genotype/allele frequency did not differ between patients and controls. Subgroup analysis showed that the frequency of A allele of NKG2D9 and T allele of NKG2D10 was significantly higher in patients with deformities (a marker of severe disease) [11 versus 5%, Pc = 0·03, odds ratio (OR) = 2·44, 95% confidence interval (CI) = 1·09-5·98 and 10 versus 4%, Pc = 0·04, OR = 2·45, 95% CI = 1·05-6·39, respectively], while the frequency of alleles G of NKG2D9 and A of NKG2D10 was greater in patients without deformities (Pc = 0·03, OR = 0·41, 95% CI = 0·17-0·91 and Pc = 0·04, OR = 0·41, 95% CI = 0·16-0·96). Similar trends of association were observed with deforming phenotype of RA in female patients and deforming young onset RA subgroups. Haplotype analysis revealed that the frequency of haplotype G-C-A-G-A-T-C-C was higher in patients than in controls (12 versus 8%, P = 0·04, OR = 1·61, 95% CI = 1·01-2·55), suggesting that it may predispose to RA. Our study suggests that the NKG2D gene polymorphisms may modify the risk of development and severity of RA.
24356672 Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arth 2015 Apr OBJECTIVES: Non-steroidal anti-inflammatory drugs (NSAIDs) may cause kidney damage. This study assessed the impact of prolonged NSAID exposure on renal function in a large rheumatoid arthritis (RA) patient cohort. METHODS: Renal function was prospectively followed between 1996 and 2007 in 4101 RA patients with multilevel mixed models for longitudinal data over a mean period of 3.2 years. Among the 2739 'NSAID users' were 1290 patients treated with cyclooxygenase type 2 selective NSAIDs, while 1362 subjects were 'NSAID naive'. Primary outcome was the estimated glomerular filtration rate according to the Cockroft-Gault formula (eGFRCG), and secondary the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formula equations and serum creatinine concentrations. In sensitivity analyses, NSAID dosing effects were compared for patients with NSAID registration in ≤/>50%, ≤/>80% or ≤/>90% of assessments. FINDINGS: In patients with baseline eGFRCG >30 mL/min, eGFRCG evolved without significant differences over time between 'NSAID users' (mean change in eGFRCG -0.87 mL/min/year, 95% CI -1.15 to -0.59) and 'NSAID naive' (-0.67 mL/min/year, 95% CI -1.26 to -0.09, p=0.63). In a multivariate Cox regression analysis adjusted for significant confounders age, sex, body mass index, arterial hypertension, heart disease and for other insignificant factors, NSAIDs were an independent predictor for accelerated renal function decline only in patients with advanced baseline renal impairment (eGFRCG <30 mL/min). Analyses with secondary outcomes and sensitivity analyses confirmed these results. CONCLUSIONS: NSAIDs had no negative impact on renal function estimates but in patients with advanced renal impairment.
24092417 Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated 2015 Jan OBJECTIVE: To report the long-term safety data of certolizumab pegol (CZP) in rheumatoid arthritis (RA) accumulated as of 30 November 2011. DESIGN: Data from 10 completed randomised controlled trials (RCT) of CZP in RA and several open-label extensions (OLE) were pooled across all doses. Reported adverse events (AE) occurred between the first dose and 84 days after the last dose. All deaths, serious infectious events (SIE) and malignancies were reviewed by external experts, classified according to predefined rules, and validated by an external steering committee. Incidence rates (IR) and event rates (ER) per 100 patient-years (PY) are presented. RESULTS: 4049 RA patients who received CZP were included in the safety pooling; total exposure 9277 PY, mean exposure 2.1 years (range 0.04-7.6). SIE, most frequently pneumonia (IR 0.73/100 PY), were the most common serious AE, occurring more frequently in CZP compared to placebo-treated patients in RCT (IR 5.61/100 PY vs 1.35/100 PY, odds ratio (OR) 4.35, 95% CI 0.65 to 29.30). SIE rates were lower in the CZP-treated population including OLE (ER 4.33/100 PY). 44 patients developed tuberculosis (IR 0.47/100 PY), 39 from high endemic regions. 58 deaths occurred in CZP-exposed patients (IR 0.63/100 PY) and 70 developed malignancies excluding non-melanoma skin cancer (IR 0.76/100 PY), including five lymphomas (IR 0.05/100 PY). CONCLUSIONS: No new or unexpected safety signals associated with CZP emerged in this updated long-term safety analysis. While SIE rates were higher for CZP than for placebo in RCT, the rate decreased with continued exposure to CZP. These rates are consistent with data previously reported for CZP and other tumour necrosis factor inhibitors.
24297383 Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in 2015 Feb OBJECTIVE: To investigate if erythrocyte-methotrexate-polyglutamate (MTX-PG) concentrations in patients with rheumatoid arthritis (RA) are associated with disease activity or adverse events. METHODS: We used a longitudinal study design with two cohorts. The derivation cohort included 102 and the validation cohort included 285 patients with RA on MTX. We measured erythrocyte-MTX-PG with 1-5 glutamate residues at 3 months, 6 months and 9 months after MTX start with a liquid chromatography (LC)-mass spectrometry (MS)/MS assay. Outcomes were disease activity score in 28 joints (DAS28) and adverse events. Longitudinal associations of MTX-PG concentrations after 3 months, 6 months and 9 months with DAS28 were tested with a linear mixed model adjusted for age, gender, baseline DAS28, MTX dose and comedication. RESULTS: In the derivation cohort, mean DAS28 decreased from 4.26 (SE=0.14) at baseline to 2.72 (SE=0.13) after 9 months. Thirty per cent of patients in the derivation cohort experienced more than three adverse events after 3 months, which decreased to 18% after 9 months. In the validation cohort, DAS28 and adverse events were comparable with the derivation cohort. In the derivation cohort, MTX-PG1 (ß=-0.005), MTX-PG2 (ß=-0.022), MTX-PG3 (β=-0.007) and total MTX-PG (ß=-0.004) were associated (p<0.05) with lower DAS28 over 9 months. In the validation cohort, MTX-PG2 (ß=-0.015), MTX-PG3 (ß=-0.010), MTX-PG4 (ß=-0.008) and total MTX-PG (ß=-0.003) were associated with lower DAS28 over 9 months. None of the MTX-PGs was associated with adverse events. CONCLUSIONS: In this first longitudinal study, we showed that an increase in erythrocyte-MTX-PG concentration was associated with a decreased DAS28 over 9 months in two cohorts, and is therefore a potential tool for therapeutic drug monitoring of MTX in RA.
27418051 Drug survival of adalimumab in patients with rheumatoid arthritis over 10 years in the re 2016 Nov The purpose of the study was to estimate the clinical profile of naïve biological patients with rheumatoid arthritis (RA) starting adalimumab through 3-year calendar periods and their clinical outcomes such as drug survival and global clinical disease control (GCDC). RA patients starting adalimumab as first biological drug between 2003 and 2012 were subdivided in 3-year calendar periods. Survival on therapy was estimated using the Kaplan-Meier analysis. One and 2-year clinical response was assessed by calculating percentage of patients attaining GCDC (28-joint Disease Activity Score (DAS28) ≤ 2.6 + Health Assessment Questionnaire (HAQ) ≤ 0.5), low disease activity (DAS28 ≤ 3.2), remission (DAS28 ≤ 2.6) and good European League Against Rheumatism (EULAR) response. Multivariate regression models were used to assess baseline predictors of drug discontinuation or achievement of clinical remission. We recruited 1695 RA patients. Overall drug persistence at 3 years was 40.6 %, while the global rate of nonswitching patients was 54.7 %. Compared to 2003-2005, initiators in more recent years had a significantly lower 3-year crude drug retention rate (log rank, p < 0.0001) and a significantly higher rate of switching to alternative biologics (log rank, p < 0.0001). No difference in adverse events or effectiveness rate among the calendar periods was found. A substantial proportion of patients (up to 27 %) achieved GCDC at 2 years, regardless of the calendar period. In real-life setting, RA patients starting adalimumab in more recent years had a higher rate of drug discontinuation not related to ineffectiveness or side effects but to switching, probably due to a wider availability of biologics. A meaningful proportion of patients attained GCDC without any difference across calendar periods.
27049384 Triptolide Modulates TREM-1 Signal Pathway to Inhibit the Inflammatory Response in Rheumat 2016 Apr 2 Triptolide (TP), an active component isolated from Tripterygiumwilfordii Hook F, has therapeutic potential against rheumatoid arthritis (RA). However, the underlying molecular mechanism has not been fully elucidated. The aim of this study is to investigate the mechanisms of TP acting on RA by combining bioinformatics analysis with experiment validation. The human protein targets of TP and the human genes of RA were found in the PubChem database and NCBI, respectively. These two dataset were then imported into Ingenuity Pathway Analysis (IPA) software online, and then the molecular network of TP on RA could be set up and analyzed. After that, both in vitro and in vivo experiments were done to further verify the prediction. The results indicated that the main canonical signal pathways of TP protein targets networks were mainly centered on cytokine and cellular immune signaling, and triggering receptors expressed on myeloid cells (TREM)-1 signaling was searched to be the top one shared signaling pathway and involved in the cytokine and cellular immune signaling. Further in vitro experiments indicated that TP not only remarkably lowered the levels of TREM-1 and DNAX-associated protein (DAP)12, but also significantly suppressed the activation of janus activating kinase (JAK)2 and signal transducers and activators of transcription (STAT)3. The expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in lipopolysaccharides (LPS)-stimulated U937 cells also decreased after treatment with TP. Furthermore, TREM-1 knockdown was able to interfere with the inhibition effects of TP on these cytokines production. In vivo experiments showed that TP not only significantly inhibited the TREM-1 mRNA and DAP12 mRNA expression, and activation of JAK2 and STAT3 in ankle of rats with collagen-induced arthritis (CIA), but also remarkably decreased production of TNF-α, IL-1β and IL-6 in serum and joint. These findings demonstrated that TP could modulate the TREM1 signal pathway to inhibit the inflammatory response in RA.
27166512 In vivo microvascular and macrovascular endothelial function is not associated with circul 2016 Jul OBJECTIVES: To examine associations between asymmetric (ADMA), symmetric dimethylarginine (SDMA) and ADMA:SDMA ratio with assessments of endothelial function and coronary artery perfusion in RA patients. METHODS: ADMA and SDMA levels were measured in 197 RA individuals [144 (77.4%) females, median age: 66 years (quartiles: 59-73)]. Patients underwent assessments of microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-dependent and endothelium-independent function and vascular morphology (pulse wave analysis, carotid intima-media thickness (cIMT), and carotid plaque). Coronary perfusion was assessed by subendocardial viability ratio (SEVR). RESULTS: SEVR correlated with SDMA (r = 0.172, p = 0.026) and ADMA:SDMA (r = -0.160, p = 0.041) in univariable analysis, but not in multivariable analysis accounting for confounding factors. Neither ADMA:SDMA ratio nor SDMA were significantly correlated with microvascular or macrovascular endothelial function, or with arterial stiffness and cIMT. Within subgroup of patients (n = 26) with high inflammatory markers, a post-hoc analysis showed that SDMA and the ADMA:SDMA ratio were significantly associated with endothelium-dependent microvascular function in univariable analysis, with Pearson's r correlation coefficients of -0.440 (p = 0.031) and 0.511 (p = 0.011), respectively. Similar finding were established between ADMA:SDMA ratio and arterial stiffness in univariable analysis, with Pearson's r of 0.493, (p = 0.024). CONCLUSION: Dimethylarginines were not found to be significantly associated with several assessments of vascular function and morphology in patients with RA, however, post-hoc analysis indicates that there may be associations in patients with raised inflammatory markers. Our results suggest that dysregulated NO metabolism may not be the sole mechanism for the development of preclinical atherosclerosis in RA.
24389293 Performance of four current risk algorithms in predicting cardiovascular events in patient 2015 Apr OBJECTIVE: This study was undertaken to assess the predictive ability of 4 established cardiovascular (CV) risk models for the 10-year risk of fatal and non-fatal CV diseases in European patients with rheumatoid arthritis. METHODS: Prospectively collected data from the Nijmegen early rheumatoid arthritis (RA) inception cohort was used. Discriminatory ability for CV risk prediction was estimated by the area under the receiver operating characteristic curve. Calibration was assessed by comparing the observed versus expected number of events using Hosmer-Lemeshov tests and calibration plots. Sensitivity and specificity were calculated for the cut-off values of 10% and 20% predicted risk. RESULTS: Areas under the receiver operating characteristic curve were 0.78-0.80, indicating moderate to good discrimination between patients with and without a CV event. The CV risk models Systematic Coronary Risk Evaluation (SCORE), Framingham risk score (FRS) and Reynolds risk score (RRS) primarily underestimated CV risk at low and middle observed risk levels, and mostly overestimated CV risk at higher observed risk levels. The QRisk II primarily overestimated observed CV risk. For the 10% and 20% cut-off values used as indicators for CV preventive treatment, sensitivity ranged from 68-87% and 40-65%, respectively and specificity ranged from 55-76% and 77-88%, respectively. Depending on the model, up to 32% of observed CV events occurred in patients with RA who were classified as low risk (<10%) for CV disease. CONCLUSIONS: Established risk models generally underestimate (Systematic Coronary Risk Evaluation score, Framingham Risk Score, Reynolds risk score) or overestimate (QRisk II) CV risk in patients with RA.
25269524 Performance of self-reported measures for periodontitis in rheumatoid arthritis and osteoa 2015 Jan BACKGROUND: This study evaluates the performance of self-report against the reference standard of clinically defined periodontitis in patients with rheumatoid arthritis (RA) and osteoarthritis (OA) after accounting for factors associated with periodontitis. METHODS: Six self-report periodontitis questions were evaluated in patients with RA and OA. Questions were validated against a reference standard of severe and moderate-to-severe periodontitis based on full-mouth examination. Multivariable logistic regression was used to evaluate the performance of: 1) self-report alone; 2) age, sex, education, and smoking status; and 3) a combination of the above. Model performance was assessed using the c-statistic. Convergent validity of self-reported "bone loss/deep pockets" and "loose teeth" was assessed; associations of self-report with RA disease characteristics were explored. RESULTS: Self-report performed similarly in RA and OA, with individual question specificity for periodontitis ≥ 68% and sensitivity from 9.8% to 45%. Question-only models yielded c-statistics of 0.66 to 0.72, whereas risk factor-only models yielded c-statistics of 0.74 to 0.79. The highest-performing models incorporated both self-report questions and periodontitis risk factors, with c-statistics ≥ 0.79. Greater radiographic alveolar bone loss was observed among participants reporting "bone loss/deep pockets" (P < 0.001) and "loose teeth" (P < 0.001). Among patients with RA, "loose teeth," but not other self-report items, was associated with rheumatoid factor positivity (P = 0.047) and higher disease activity (P < 0.001). CONCLUSIONS: Patient self-report, when combined with other risk factors, performs well in identifying periodontitis among patients with RA and OA. Self-report questions related to alveolar bone loss exhibit excellent convergent validity in these patient subsets.
25664505 Genetic polymorphisms in metabolic pathways of leflunomide in the treatment of rheumatoid 2015 May Leflunomide (LEF) is a disease-modifying anti-rheumatic drug used for treating rheumatoid arthritis (RA). More than 50% of patients are withdrawn from LEF treatment within one year, mainly due to AEs. Importantly, it is not possible to predict which patients will respond to LEF therapy nor if adverse outcome occurs. Pharmacogenetic studies indicate an impact of single nucleotid polymorphisms (SNPs) on the variability in LEF serum levels with potential relevance to effectiveness and tolerability in individual RA patients. In vitro studies have demonstrated that cytochromes P450 (CYPs), mainly CYP1A2, CYP2C19, and CYP3A4, are involved in LEF metabolite activation. It was shown that CYP1A2*1F allele may be associated with LEF toxicity in patients with RA. In case of dihydroorotate dehydrogenase (DHODH) gene SNP (rs3213422, 19C>A), it was shown that C allele may be associated with LEF toxicity and therapeutic effect. Finally, oestrogen receptor genes SNPs in females may be associated with LEF therapy efficacy. In summary, the results of the current studies suggest a possible diagnostic value of genotyping for patients with RA as biomarkers of LEF therapy efficacy or conversely as indicators of serious side effects. In the future, it will be necessary to corroborate these results in studies with larger numbers of patients and longer follow-up. Moreover, it would be appropriate to focus on CYP2C19, ATP5A1 and PKD1L3 genes.
26448682 Differences of IL-1β Receptors Expression by Immunocompetent Cells Subsets in Rheumatoid 2015 IL-1β is involved in the induction and maintenance of chronic inflammation in rheumatoid arthritis (RA). Its activity is regulated and induced by soluble and membrane-bound receptors, respectively. The effectiveness of the cytokine depends not only on the percentage of receptor-positive cells in an immunocompetent subset but also on the density of receptor expression. The objective of this study was to investigate the expression of IL-1β membrane-bound receptors (IL-1R1 and IL-1R2) in terms of the percentage of receptor-positive cells and the number of receptors per cell in different subsets of immune cells in RA patients before and after a course of basic (excluding anticytokine) therapy and in healthy individuals. The resulting data indicate differences in the expression of IL-1β receptors among T cells, B cells, and monocytes in healthy volunteers and in rheumatoid arthritis patients. The importance of determining both the relative percentage of cells expressing receptors to immunomodulatory cytokines and the number of membrane-bound receptors per cell is highlighted by evidence of unidirectional or multidirectional changing of these parameters according to cell subset and health status.
25512476 Switching from intravenous to subcutaneous formulation of abatacept: a single-center Itali 2015 Feb OBJECTIVE: Subcutaneous (SC) abatacept (ABA) is comparable to intravenous (IV) formulation in terms of efficacy and safety profile. Our work analyzed the switch to SC formulation from IV administration in patients with rheumatoid arthritis. METHODS: Fifty-one patients treated with SC ABA were included. Clinical data were obtained from clinical charts. RESULTS: Fourteen patients relapsed and needed to return to the IV administration. Neither clinical and laboratory features nor the previous therapies were identified as risk factors for SC formulation inefficacy. Disease activity decreased after the return to IV infusions. CONCLUSION: SC ABA showed a risk of relapse in 27% of cases. The reinsertion of the IV administration quickly reinstated disease control.
26331989 Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is assoc 2016 Jan AIM: Leflunomide, via its active metabolite teriflunomide, is used in rheumatoid arthritis (RA) treatment, yet approximately 20 to 40% of patients cease due to toxicity. The aim was to develop a time-to-event model describing leflunomide cessation due to toxicity within a clinical cohort and to investigate potential predictors of cessation such as total and free teriflunomide exposure and pharmacogenetic influences. METHODS: This study included individuals enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2000 and 2013 who received leflunomide. A time-to-event model in nonmem was used to describe the time until leflunomide cessation and the influence of teriflunomide exposure and pharmacogenetic variants. Random censoring of individuals was simultaneously described. The clinical relevance of significant covariates was visualized via simulation. RESULTS: Data from 105 patients were analyzed, with 34 ceasing due to toxicity. The baseline dropout hazard and baseline random censoring hazard were best described by step functions changing over discrete time intervals. No statistically significant associations with teriflunomide exposure metrics were identified. Of the screened covariates, carriers of the C allele of CYP1A2 rs762551 had a 2.29 fold increase in cessation hazard compared with non-carriers (95% CI 2.24, 2.34, P = 0.016). CONCLUSIONS: A time-to-event model described the time between leflunomide initiation and cessation due to side effects. The C allele of CYP1A2 rs762551 was linked to increased leflunomide toxicity, while no association with teriflunomide exposure was identified. Future research should continue to investigate exposure-toxicity relationships, as well as potentially toxic metabolites.
27698106 Heterogeneity of Cortical Breaks in Hand Joints of Patients with Rheumatoid Arthritis and 2016 Oct OBJECTIVE: Conventional radiographs (CR) of the hands are the gold standard for imaging bone erosions. The presence of bone erosions, reflected by the presence of cortical breaks, is a poor prognostic factor in patients with rheumatoid arthritis (RA). The availability of high-resolution peripheral quantitative computed tomography (HR-pQCT) enables detailed investigation of cortical breaks in rheumatic diseases. The aim of this image review is to show HR-pQCT images of the spectrum of cortical breaks with and without underlying trabecular bone changes in metacarpophalangeal (MCP) joints of healthy controls (HC) and patients with RA, with corresponding images on CR and magnetic resonance imaging (MRI). METHODS: Second and third MCP joints of 41 patients (of which 10 were early RA with ≤ 2 years and 24 longstanding RA with ≥ 10 years of disease duration) and 38 HC were imaged by CR, MRI, and HR-pQCT (XtremeCT1, Scanco Medical AG). Representative images of the spectrum of cortical breaks were selected. RESULTS: Cortical breaks were found in early and longstanding RA, but also in HC. They were heterogeneous in size, location, and number per joint, with a variety of surrounding cortical and underlying trabecular bone characteristics. CONCLUSION: Using HR-pQCT images of MCP joints, heterogeneous cortical breaks with and without surrounding trabecular bone changes were found, not only in RA but also in HC. The underlying mechanisms and significance of this spectrum of cortical breaks as found with high 3-D resolution needs further investigation.
26264946 Obstructive eosinophilic gastroenteritis in a patient with rheumatoid arthritis. 2015 Aug 11 Eosinophilic gastroenteritis (EG) is a rare disease characterised by abnormal eosinophilic infiltration of the gastrointestinal tract. We describe a case of EG presenting as an intestinal obstruction in a patient with rheumatoid arthritis (RA). A 54-year-old man with RA presented to the emergency department with abdominal pain and vomiting. On examination, his abdomen was distended and tender. Laboratory data showed leucocytosis with raised inflammatory markers and without eosinophilia. CT revealed dilated small bowel loops, with a couple of loops forming a mass and abscess formation. Emergency laparotomy was performed with segmental resection of the ileum and side-to-side anastomosis. Histology confirmed the diagnosis of EG. The patient recovered well and was asymptomatic at the time of writing this report.
27107057 Stress fracture of the proximal fibula after total knee arthroplasty. 2016 Apr 22 We report a rare case of proximal fibular fatigue fracture developing 14 years after total knee arthroplasty in a known case of rheumatoid arthritis. A valgus deformity of the knee can put abnormal stress on the upper fibula leading to its failure. We believe that, as the fibula acts as an important lateral strut, its disruption due to a fracture led to rapid progress of the valgus deformity of the knee in this patient.
27159840 LBH Gene Transcription Regulation by the Interplay of an Enhancer Risk Allele and DNA Meth 2016 Nov OBJECTIVE: To identify nonobvious therapeutic targets for rheumatoid arthritis (RA), we performed an integrative analysis incorporating multiple "omics" data and the Encyclopedia of DNA Elements (ENCODE) database for potential regulatory regions. This analysis identified the limb bud and heart development (LBH) gene, which has risk alleles associated with RA/celiac disease and lupus, and can regulate cell proliferation in RA. We identified a novel LBH transcription enhancer with an RA risk allele (rs906868 G [Ref]/T) 6 kb upstream of the LBH gene with a differentially methylated locus. The confluence of 3 regulatory elements, rs906868, an RA differentially methylated locus, and a putative enhancer, led us to investigate their effects on LBH regulation in fibroblast-like synoviocytes (FLS). METHODS: We cloned the 1.4-kb putative enhancer with either the rs906868 Ref allele or single-nucleotide polymorphism (SNP) variant into reporter constructs. The constructs were methylated in vitro and transfected into cultured FLS by nucleofection. RESULTS: We found that both variants increased transcription, thereby confirming the region's enhancer function. Unexpectedly, the transcriptional activity of the Ref risk allele was significantly lower than that of the SNP variant and is consistent with low LBH levels as a risk factor for aggressive FLS behavior. Using RA FLS lines with a homozygous Ref or SNP allele, we confirmed that homozygous Ref lines expressed lower LBH messenger RNA levels than did the SNP lines. Methylation significantly reduced enhancer activity for both alleles, indicating that enhancer function is dependent on its methylation status. CONCLUSION: This study shows how the interplay between genetics and epigenetics can affect expression of LBH in RA.
26338663 Suppression of inflammatory disease activity in rheumatoid arthritis is associated with im 2016 Feb OBJECTIVE: To investigate the effect of suppressing inflammation on retinal microvascular health in patients with RA. METHODS: Two groups of patients with RA were recruited and studied concurrently. Group A included patients with moderate to high disease activity [28-joint DAS with CRP (DAS28-CRP) >3.2] requiring treatment escalation, while group B had stable low disease activity (DAS28-CRP ≤3.2) not requiring treatment escalation. Retinal photography was performed at baseline and weeks 6 and 24 in group A and at baseline and week 12 in group B. RESULTS: Group A included 26 patients with a mean age of 50.7 years (s.d. 3.5) and a mean disease duration of 7.1 years (s.d. 8.0). Disease activity significantly improved during follow-up and was accompanied by a significant reduction in retinal venular calibre at week 6 [mean difference (MD) -7.9 μm (95% CI -13.3, -2.5)] and at week 24 [MD -6.8 μm (95% CI -12.2, -1.4)]. No significant change in retinal arteriolar calibre was identified at week 6 [MD -0.6 μm (95% CI -4.5, 3.28)] or week 24 [MD 0.7 μm (95% CI -3.1, 4.5)]. Group B included 27 patients with a mean age of 54.6 years (s.d. 1.8) and a mean disease duration of 14.5 years (s.d. 10.9). Disease activity and therapy remained unchanged during follow-up and no significant changes in retinal venular [MD 1.81 μm (95% CI -2.32, 5.95)] or arteriolar [MD 0.54 μm (95% CI -2.77, 3.86)] calibre were observed. CONCLUSION: We demonstrated that suppression of inflammation in RA is associated with a reduction of retinal venular calibre, suggesting that therapies targeting inflammation could improve vascular health in RA.
27523007 MYC/BCL2 Double-hit Lymphoma in a Patient with Rheumatoid Arthritis Associated with Methot 2016 Several reports have suggested an increased risk of malignant lymphoma in patients with rheumatoid arthritis treated with methotrexate (MTX). We herein describe the case of a 71-year-old woman with rheumatoid arthritis who developed MYC/BCL2 double-hit lymphoma associated with MTX therapy. She developed a fever and lymphadenopathies over a 2-week period and had elevated levels of soluble IL-2 receptor. Inguinal lymph node and bone marrow biopsies showed diffuse large B cell lymphoma. Fluorescent in situ hybridization revealed MYC and BCL2 gene rearrangements in her lymphoma cells. Accordingly, a diagnosis of MYC/BCL2 double-hit lymphoma was made. This is the first reported case of a double-hit lymphoma associated with MTX therapy.