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ID PMID Title PublicationDate abstract
23545338 Histamine 4 receptor plays an important role in auto-antibody-induced arthritis. 2013 Jul Rheumatoid arthritis is a widespread autoimmune disease. In the murine K/B×N arthritis model, anti-GPI (anti-glucose 6-phosphate isomerase) antibodies lead to the formation of immune complexes. In the course of pathogenesis, these complexes activate the immune system and induce degranulation of mast cells, which are essential in this model of rheumatoid arthritis. A major mediator in mast cell granules is histamine, which is proven to be indispensable for joint inflammation in K/B×N mice. Histamine is known to bind to four different receptors (HR1-4), which have different expression profiles and exert a variety of different functions, including activation of the immune system. To analyze the contribution of the different histamine receptors, we employed histamine receptor antagonists (cetirizine, ranitidine, thioperamide and clozapine) blocking the receptors in C57BL/6 mice. Arthritis was induced via K/B×N serum injection. The results demonstrated that mice treated with all four histamine receptor antagonists simultaneously showed no arthritic symptoms, while positive control mice injected with K/B×N serum and vehicle suffered from severe symptoms. When antagonists specific for HR1-4 were applied individually, only the HR4 antagonist clozapine could protect mice from arthritis, reflecting its expression and functionality in the immune system.
24103582 A 5 item version of the Compliance Questionnaire for Rheumatology (CQR5) successfully iden 2013 Oct 8 BACKGROUND: Taking DMARDs as prescribed is an essential part of self-management for patients with Rheumatoid Arthritis. To date, the Compliance Questionnaire for Rheumatology (CQR) is the only self-report adherence measure created specifically for and validated in rheumatic diseases. However, the factor structure of the CQR has not been reported and it can be considered lengthy at 19 items. The aim of this study was to test the factor structure of the CQR and reduce the number of items whilst retaining robust explanation of non-adherence to DMARDs. Such a reduction would increase the clinical utility of the scale, to identify patients with sub-optimal adherence to DMARDs in the clinic as well as for research purposes. METHODS: An exploratory factor analysis was performed to reduce the number of items in the CQR and then a confirmatory factor analysis was run to establish the fit of a 5 item version (CQR5) to the data. A discriminant function analysis was performed to determine the optimal combination of questions to identify suboptimal adherence. RESULTS: The factor analyses identified a unidimensional 5 item model that explains 50.3% of the variance in adherence and has good internal consistency and fit to the data. Discriminant function analysis shows that the CQR5 can affectively detect 69% of low adherers to DMARDs using Fisher's weighted regression equation. CONCLUSION: A shortened version of the CQR increases the clinical utility by reducing the patient burden whilst maintaining a good level of reliability and validity for a short, self-administered, self-report questionnaire.
24191910 Differentiation between early rheumatoid arthritis patients and healthy persons by convent 2014 OBJECTIVES: To identify the magnetic resonance imaging (MRI) parameter that best differentiates healthy persons and patients with early rheumatoid arthritis (RA), and to investigated responsiveness to treatment of various MRI parameters. METHOD: Conventional MRI and dynamic contrast-enhanced (DCE)-MRI of the hand were performed once for 26 healthy persons, and before and after 6 and 12 months of disease-modifying anti-rheumatic drug (DMARD) treatment for 14 early RA patients, using a 1.0-T MRI unit. One-slice DCE-MRI was analysed using Dynamika version 4.2. The number of enhancing voxels (Nvoxel), the initial rate of enhancement (IRE), the maximum enhancement (ME), ME×Nvoxel, and IRE×Nvoxel were calculated for wrist and 2nd-5th metacarpophalangeal (MCP) joints. Conventional MR images were evaluated using the RA MRI scoring system (RAMRIS) synovitis score. RESULTS: Using DCE-MRI, enhancement was demonstrated in 61.5% of healthy persons and in 91.7% of RA patients at baseline, with a median Nvoxel of 3 and 362, respectively. At baseline, all parameters were higher for patients than for healthy persons (all p ≤ 0.003). Only one patient had a baseline RAMRIS synovitis score below the 95th percentile of the healthy persons. The corresponding number of patients was 3 for Nvoxel, ME×Nvoxel and IRE×Nvoxel, and 10 for IRE and ME. The RAMRIS synovitis score and IRE showed the highest responsiveness, with a standardized response mean (SRM) of -1.00 and -0.88, respectively. CONCLUSIONS: The RAMRIS synovitis scoring of conventional MRI, and to a lesser extent the one-slice DCE-MRI parameters of synovial volume, differentiated early RA patients and healthy persons. The decrease in RAMRIS synovitis score, Nvoxel, and IRE showed sensitivity to change during treatment.
23729241 Association between fatigue and pain in rheumatoid arthritis: does pain precede fatigue or 2013 Jun OBJECTIVE: Fatigue and pain are important symptoms for patients with rheumatoid arthritis (RA), but their temporal association is unknown. Therefore, the objective of this study was to investigate the longitudinal relationship between fatigue and pain in patients with RA using time-lag models. METHODS: Consecutive RA outpatients (n = 228) were enrolled for this 1-year study. Fatigue was assessed monthly with the Checklist Individual Strength (CIS; range 8-56) and pain was assessed monthly with the bodily pain subscale (inverted, range 0-100) of the Short Form 36. The association between monthly changes in fatigue and pain was analyzed using longitudinal regression (mixed models), using the same months and with a 1-month time lag. RESULTS: A total of 198 patients were included in the analyses. At baseline, the mean ± SD pain score was 35.23 ± 19.82 and the mean ± SD CIS fatigue score was 31.0 ± 12.4. Severe fatigue at baseline (CIS score ≥35) was present in 42% of the patients. The mean ± SD patient-averaged CIS fatigue score over 1 year was 30.9 ± 6.0 and the mean ± SD patient-averaged pain score over 1 year was 36.4 ± 18.3. The longitudinal regression analysis showed a significant positive relationship between fatigue and pain during the same month (β = 2.04; 95% confidence interval 1.82, 2.27). The models using a time lag showed no significant association between changes in pain and changes in fatigue. CONCLUSION: In established RA, pain and fatigue show monthly fluctuations that are synchronous rather than showing a temporal relationship with a time lag; within this timeframe, the results do not indicate that one precedes the other.
20379839 Precore mutant hepatitis B virus-associated fulminant hepatitis during infliximab therapy 2013 Mar A 73-year-old female, who suffered from rheumatoid arthritis for 10 years, developed precore mutant hepatitis B virus-associated fulminant hepatitis after 1 year of infliximab therapy and subsequent methotrexate withdrawal. We emphasize the importance of preemptive antiviral therapy before starting infliximab administration and withdrawing immunosuppressive drugs.
23306098 Identification of novel markers in rheumatoid arthritis through integrated analysis of DNA 2013 Mar Autoimmune rheumatic diseases are complex disorders, whose etiopathology is attributed to a crosstalk between genetic predisposition and environmental factors. Both variants of autoimmune susceptibility genes and environment are involved in the generation of aberrant epigenetic profiles in a cell-specific manner, which ultimately result in dysregulation of expression. Furthermore, changes in miRNA expression profiles also cause gene dysregulation associated with aberrant phenotypes. In rheumatoid arthritis, several cell types are involved in the destruction of the joints, synovial fibroblasts being among the most important. In this study we performed DNA methylation and miRNA expression screening of a set of rheumatoid arthritis synovial fibroblasts and compared the results with those obtained from osteoarthritis patients with a normal phenotype. DNA methylation screening allowed us to identify changes in novel key target genes like IL6R, CAPN8 and DPP4, as well as several HOX genes. A significant proportion of genes undergoing DNA methylation changes were inversely correlated with expression. miRNA screening revealed the existence of subsets of miRNAs that underwent changes in expression. Integrated analysis highlighted sets of miRNAs that are controlled by DNA methylation, and genes that are regulated by DNA methylation and are targeted by miRNAs with a potential use as clinical markers. Our study enabled the identification of novel dysregulated targets in rheumatoid arthritis synovial fibroblasts and generated a new workflow for the integrated analysis of miRNA and epigenetic control.
25147922 Genome-wide DNA methylation profiling in rheumatoid arthritis identifies disease-associate 2014 Sep Changes to the DNA methylome have been described in patients with rheumatoid arthritis (RA). In previous work, we reported genome-wide methylation differences in T-lymphocyte and B-lymphocyte populations from healthy individuals. Now, using HumanMethylation450 BeadChips to interrogate genome-wide DNA methylation, we have determined disease-associated methylation changes in blood-derived T- and B-lymphocyte populations from 12 female patients with seropositive established RA, relative to 12 matched healthy individuals. Array data were analyzed using NIMBL software and bisulfite pyrosequencing was used to validate array candidates. Genome-wide DNA methylation, determined by analysis of LINE-1 sequences, revealed higher methylation in B-lymphocytes compared with T-lymphocytes (P ≤ 0.01), which is consistent with our findings in healthy individuals. Moreover, loci-specific methylation differences that distinguished T-lymphocytes from B-lymphocytes in healthy individuals were also apparent in RA patients. However, disease-associated methylation differences were also identified in RA. In these cases, we identified 509 and 252 CpGs in RA-derived T- and B-lymphocytes, respectively, that showed significant changes in methylation compared with their cognate healthy counterparts. Moreover, this included a restricted set of 32 CpGs in T-lymphocytes and 20 CpGs in B-lymphocytes (representing 15 and 10 genes, respectively, and including two, MGMT and CCS, that were common to both cell types) that displayed more substantial changes in methylation. These changes, apparent as hyper- or hypo-methylation, were independently confirmed by pyrosequencing analysis. Validation by pyrosequencing also revealed additional sites in some candidate genes that also displayed altered methylation in RA. In this first study of genome-wide DNA methylation in individual T- and B-lymphocyte populations in RA patients, we report disease-associated methylation changes that are distinct to each cell type and which support a role for discrete epigenetic regulation in this disease.
24382277 The role of bromocriptine in the treatment of patients with active rheumatoid arthritis. 2013 Dec AIM: We decided to determine the effectiveness of oral bromocriptine in patients with active rheumatoid arthritis (RA) who are in methotrexate (MTX) therapy. METHODS: Patients receiving stable doses of MTX were randomized to one of two groups and received 3 months of double-blind bromocriptine (5 mg/day) or matching placebo. The moderate and major outcome measures were the proportion of patients with > 0.6 and > 1.2 improvement in RA based on the Disease Activity Score 28 (DAS28) at 3 months. Safety measures included adverse events and laboratory assessments. RESULTS: On a background treatment of MTX, the percentage of patients with moderate and major DAS28 responses at 3 months in the bromocriptine group (73.8%/59.5%) was not significantly different from placebo (63.1%/31.6%). Side effects were typically mild and included mild nausea and sleep disturbance; we did not have any adverse events resulting in discontinuation of the study drug. CONCLUSION: In patients with active RA receiving stable doses of MTX, bromocriptine showed non-significant improvement in efficiency outcomes compared to placebo.
24394350 Of mice and men: how animal models advance our understanding of T-cell function in RA. 2014 Mar The involvement of autoreactive T cells in the pathogenesis of rheumatoid arthritis (RA) as well as in autoimmune animal models of arthritis has been well established; however, unanswered questions, such as the role of joint-homing T cells, remain. Animal models of arthritis are superb experimental tools in demonstrating how T cells trigger joint inflammation, and thus can help to further our knowledge of disease mechanisms and potential therapies. In this Review, we discuss the similarities and differences in T-cell subsets and functions between RA and mouse arthritis models. For example, various T-cell subsets are involved in both human and mouse arthritis, but differences might exist in the cytokine regulation and plasticity of these cells. With regard to joint-homing T cells, an abundance of synovial T cells is present in humans compared with mice. On the other hand, local expansion of type 17 T-helper (TH17) cells is observed in some animal models, but not in RA. Finally, whereas T-cell depletion therapy essentially failed in RA, antibody targeting of T cells can work, at least preventatively, in most arthritis models. Clearly, additional human and animal studies are needed to fill the gap in our understanding of the specific contribution of T-cell subsets to arthritis in mice and men.
23888363 Cardiovascular risk in the rheumatic disease patient undergoing orthopedic surgery. 2013 Sep A hallmark of the rheumatic diseases, including systemic lupus erythematosis, spondyloarthritis, and rheumatoid arthritis, has been sustained inflammation, which typically targets the joint and may lead to joint destruction. Inflammation also plays a role in atherosclerotic cardiovascular disease, which is highly prevalent in patients with rheumatic diseases. Total joint arthroplasty, considered an intermediate cardiac risk procedure by the American College of Cardiology, maintains an important role in the management of rheumatic disease patients who progress to end-stage joints. The purpose of this article is to discuss the role of inflammation in cardiovascular disease, the prevalence of cardiovascular disease in patients with systemic rheumatic diseases, and the role of cardiovascular risk assessment when these patients undergo total joint arthroplasty.
24965753 Barcode-enabled sequencing of plasmablast antibody repertoires in rheumatoid arthritis. 2014 Oct OBJECTIVE: A hallmark of rheumatoid arthritis (RA) is the production of autoantibodies, including anti-citrullinated protein antibodies (ACPAs). Nevertheless, the specific targets of these autoantibodies remain incompletely defined. During an immune response, B cells specific for the inciting antigen(s) are activated and differentiate into plasmablasts, which are released into the blood. We undertook this study to sequence the plasmablast antibody repertoire to define the targets of the active immune response in RA. METHODS: We developed a novel DNA barcoding method to sequence the cognate heavy- and light-chain pairs of antibodies expressed by individual blood plasmablasts in RA. The method uses a universal 5' adapter that enables full-length sequencing of the antibodies' variable regions and recombinant expression of the paired antibody chains. The sequence data sets were bioinformatically analyzed to generate phylogenetic trees that identify clonal families of antibodies sharing heavy- and light-chain VJ sequences. Representative antibodies were expressed, and their binding properties were characterized using anti-cyclic citrullinated peptide 2 (anti-CCP-2) enzyme-linked immunosorbent assay (ELISA) and antigen microarrays. RESULTS: We used our sequencing method to generate phylogenetic trees representing the antibody repertoires of peripheral blood plasmablasts from 4 individuals with anti-CCP+ RA, and recombinantly expressed 14 antibodies that were either "singleton" antibodies or representative of clonal antibody families. Anti-CCP-2 ELISA identified 4 ACPAs, and antigen microarray analysis identified ACPAs that differentially targeted epitopes on α-enolase, citrullinated fibrinogen, and citrullinated histone H2B. CONCLUSION: Our data provide evidence that autoantibodies targeting α-enolase, citrullinated fibrinogen, and citrullinated histone H2B are produced by the ongoing activated B cell response in, and thus may contribute to the pathogenesis of, RA.
24957665 HLA-G gene polymorphisms associated with susceptibility to rheumatoid arthritis disease an 2014 Sep We analyzed the possible association between human leukocyte antigen-G (HLA-G) genetic variants, supposed to regulate HLA-G expression, and the susceptibility to develop rheumatoid arthritis (RA) as well as its clinical manifestations. The 5'upstream regulatory region (5'URR) and 3'untranslated region (3'UTR) regions of the HLA-G gene were screened in 127 RA patients and 128 controls: 10 5'URR and 3 3'UTR HLA-G polymorphisms as well as two haplotypes were associated with risk for RA development, while a polymorphism in the 5'URR showed an association with the degree of disease activity. These findings, although the number of cases analyzed is limited and the P-values are modest, indicate a possible association between HLA-G gene polymorphisms and susceptibility to develop RA disease and its severity.
23098925 Linking systemic angiogenic factors (VEGF, angiogenin, TIMP-2) and Doppler ultrasound to a 2013 May OBJECTIVE: To evaluate an association between synovial Doppler flow and serum levels of vascular endothelial growth factor (VEGF), angiogenin and TIMP-2 in patients with rheumatoid arthritis during anti-inflammatory treatment with glucocorticoids and TNF-α inhibitors. METHODS: Inflamed wrists of 15 patients with rheumatoid arthritis (RA) were examined by two independent ultrasound investigators prior to and at days 3, 7, 14 and 42 after the initiation of treatment with glucocorticoids in therapy-naïve patients or after the beginning of a therapy with a TNF-α inhibitor in patients with DMARD failure. Quantitative three-dimensional power Doppler ultrasonographic assessment of synovial vascularization was compared at each visit with serum levels of VEGF, angiogenin and TIMP-2. RESULTS: In the glucocorticoid group, synovial Doppler signals decreased significantly at day 3 (-44%; P=0.003) in comparison to a delayed decrease in the TNF-α inhibitor group after 6 weeks (-46%; P=0.001). A significant reduction of serum VEGF levels could be determined with a delay of 1 week after the decrease of Doppler activity but no correlation was found between both parameters (rho: P=0.7; r=-0.03). Angiogenin concentrations decreased in the TNF group and increased in the GC group. Levels of TIMP-2 did not change significantly in both groups. CONCLUSION: The decrease of serum VEGF levels under treatment with glucocorticoids or TNF-α inhibitors followed the reduction of the intra-articular synovial Doppler flow. This result supports the idea that the reduction of synovial perfusion due to anti-inflammatory treatment is not regulated by systemic VEGF, but that the inflamed joints are the source for circulating VEGF.
23950185 Five-year favorable outcome of patients with early rheumatoid arthritis in the 2000s: data 2013 Oct OBJECTIVE: To report the 5-year outcome of a large prospective cohort of patients with very early rheumatoid arthritis (RA), and to identify factors predictive of outcome. METHODS: Patients were recruited if they had early arthritis of < 6 months' duration, had a high probability of developing RA, and had never been prescribed disease-modifying antirheumatic drugs (DMARD) or steroids. Logistic regression analysis was used to determine factors that predict outcome. RESULTS: We included 813 patients from December 2002 to April 2005. Age was 48.1 ± 12.6 years, delay before referral 103.1 ± 52.4 days, 28-joint Disease Activity Score (DAS28) 5.1 ± 1.3, Health Assessment Questionnaire (HAQ) 1.0 ± 0.7; 45.8% and 38.7% had rheumatoid factor or antibodies to cyclic citrullinated peptide (anti-CCP), respectively; 22% had hand or foot erosions; 78.5% fulfilled the American College of Rheumatology/European League Against Rheumatism criteria for RA at baseline and 93.8% during followup. At 5 years, 573 patients were evaluated. The outcome was mild for most patients: disease activity (median DAS28 = 2.5) and HAQ disability (median 0.3) were well controlled over time; 50.6% achieved DAS28 remission and 64.7% low disease activity. Radiographic progression was low (2.9 Sharp unit/year) and only a few patients required joint surgery. Nevertheless, some patients developed new comorbidities. During the 5 years, 82.7% of patients had received at least 1 DMARD (methotrexate, 65.9%), 18.3% a biological DMARD, and about 60% prednisone at least once. Anti-CCP was the best predictor of remaining in the cohort for 5 years, of prescription of synthetic or biologic DMARD, and of radiographic progression. CONCLUSION: The 5-year outcome of an early RA cohort in the 2000s was described. Anti-CCP was a robust predictor of outcome. The generally good 5-year outcome could be related to early referral and early effective treatment, key processes in the management of early RA in daily practice.
23983153 Association of genetic variants in the IL4 and IL4R genes with the severity of joint damag 2013 Dec OBJECTIVE: The progression of joint destruction in rheumatoid arthritis (RA) is determined by genetic factors. Changes in IL4 and IL4R genes have been associated with RA severity, but this finding has not been replicated. This study was undertaken to investigate the association between IL4- and IL4R-tagging single-nucleotide polymorphisms (SNPs) and the progression rate of joint damage in RA in a multicohort candidate gene study. METHODS: IL4- and IL4R-tagging SNPs (n = 8 and 39, respectively) were genotyped in 600 RA patients for whom 2,846 sets of radiographs of the hands and feet were obtained during 7 years of followup. Subsequently, SNPs significantly associated with the progression of joint damage were genotyped and studied in relation to 3,415 radiographs of 1,953 RA patients; these included data sets from Groningen (The Netherlands), Lund (Sweden), Sheffield (UK), the North American Rheumatoid Arthritis Consortium (US), Wichita (US), and the National Data Bank (US). The relative increase in progression rate per year in the presence of a genotype was determined in each cohort. An inverse variance weighting meta-analysis was performed on the 6 data sets that together formed the replication phase. RESULTS: In the discovery phase, none of the IL4 SNPs and 7 of the IL4R SNPs were significantly associated with the joint damage progression rate. In the replication phase, 2 SNPs in the IL4R gene were significantly associated with the joint damage progression rate (rs1805011 [P = 0.02] and rs1119132 [P = 0.001]). CONCLUSION: Genetic variants in IL4R were identified, and their association with the progression rate of joint damage in RA was independently replicated.
24460872 Kinase inhibitors: the next generation of therapies in the treatment of rheumatoid arthrit 2014 May Rheumatoid arthritis (RA) can be the source of significant pain and functional limitation. The past 20 years have seen a transition in treatment goals away from mere pain management toward disease modification through the suppression of autoimmunity. Disease-modifying anti-rheumatic drugs, such as methotrexate and biologic agents, impair disease progression and joint destruction. However, despite these achievements, a substantial subset of RA patients does not respond to or cannot tolerate current treatments for RA. Scientific insight into the cellular pathways of inflammation has revealed new therapeutic targets for the treatment of autoimmune diseases like RA. Attention has focused on pathways mediated by Janus kinase (JAK), mitogen-activated protein kinase (MAPK), and spleen tyrosine kinase (Syk). This review article summarizes the evidence supporting the use of various kinase inhibitors, including the newly approved JAK inhibitor tofacitinib, in the treatment of RA.
25515751 Modulation of toll-like receptor 4. Insights from x-ray crystallography and molecular mode 2014 Toll-like receptors (TLRs) are a family of proteins with a key role in the innate immune system. They are specialized in the recognition of molecular patterns present in microbial components, through mechanisms not yet unraveled at atomic level. Improvement in the understanding of the molecular mechanisms that drive TLR signaling is of paramount importance to grasp key aspects of immunity, potentially leading to the design of new molecules able to modulate their functions. Toll-like receptor 4 (TLR4), along with its accessory protein myeloid differentiation factor 2 (MD-2), builds a heterodimeric complex that specifically recognizes lipopolysaccharides (LPS), which are present on the cell wall of gramnegative bacteria, activating the immune response. Some TLR4 modulators are undergoing preclinical and clinical evaluation for the treatment of sepsis, inflammatory diseases, cancer, and rheumatoid arthritis. Reported X-ray crystal structures together with molecular modeling studies, not reviewed before in the literature, have recently contributed to the elucidation of key interactions at atomic level of the binding between the TLR4/MD-2 system and different TLR4/MD-2 ligands. The purpose of this review is to summarize these reported studies which may account for the SAR rationalization of natural/ synthetic agonist/antagonist TLR4 binders and may also guide further design of novel TLR4 modulators.
25179377 Association between butyrylcholinesterase activity and phenotypes, paraoxonase192 rs662 ge 2015 Jan OBJECTIVES: Evidences indicate that oxidative stress and inflammation are important processes in the development of destructive synovial tissue in rheumatoid arthritis (RA). The two major bioscavenger enzymes that are associated with inflammation and oxidative stress are human-butyrylcholinesterase (BuChE) and paraoxonase-1 (PON-1). Thus, the objective of this study was to determine the relation of BuChE phenotypes and PON-1 Q192R polymorphism with inflammatory markers such as anti-cytroline circulated peptide (CCP)-antibodies, CRP, neopterin, DAS28-CRP in RA patients. DESIGN AND METHODS: In this study, we examined association of BuChE-phenotypes and activity, PON192rs662 (Q192R) polymorphism and its arylesterase activity (ARE) with systemic-inflammatory-markers and oxidative stress. The present case-control study consisted of 419-RA patients and 398 gender-age-matched unrelated healthy controls from west population of Iran. PON192rs662 polymorphism was detected by real-time-PCR. BuChE phenotype, TAC level, serum BuChE and ARE activities were determined spectrophotometrically. Anti-CCP-antibody and CRP were measured by ELISA and neopterin level was detected by HPLC. We used the EULAR activity criteria to measure DAS28-CRP. RESULTS: We found that PON-1-Q192R was associated with severity of RA [remission-to-low and moderate-to-high in dominant Q/Q+Q/R vs. R/R: OR=2.27, p<0.001; codominant Q/Q vs. R/R: OR=1.65, p<0.001 and Q/R vs. R/R: OR=2.12, p=0.003; recessive Q/Q vs. R/R+Q/R: OR=1.79, p=0.032; and allele Q vs. R: OR=1.68, p<0.001] and presence of anti-CCP-antibody (codominant model Q/Q vs. R/R: OR=1.28, p=0.042). The carriers of Q/Q genotype PON-1-Q192R and BuChE non-UU-phenotype had higher ARE activity, serum levels of neopterin, anti-CCP antibody titer and number of tender-joint and lower activity of BuChE and serum level of TAC than that of R/R genotype and BuChE-UU-phenotype. CONCLUSIONS: The current findings demonstrate for the first time that there is a link between systemic inflammatory markers, oxidative stress, the PON192rs662-Q allele and BuChE-non-UU-phenotype and their corresponding enzymatic activity which may be considered as a risk factor for the severity of RA for a population in Iran.
24354889 Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis. 2014 Jul AIMS: Infliximab, an anti-tumour necrosis factor-α monoclonal antibody, is indicated in rheumatoid arthritis (RA). Our objective was to evaluate the influence of the sources of infliximab pharmacokinetic variability in RA. METHODS: Eighty-four patients treated with infliximab for RA were included in a prospective noncomparative study. They were analysed between two consecutive infliximab infusions. Infliximab concentrations were measured before the infusion, 2 h, 1 and 4 weeks after the infusion and immediately before the next infusion. Infliximab concentrations were described using a two-compartment population pharmacokinetic model. RESULTS: The mean (interindividual standard deviation) estimated central volume of distribution was 2.3 l (36%) and systemic clearance was 0.019 l h(-1) (37%). The central volume of distribution increased with bodyweight; it was doubled between 50 and 90 kg. Systemic clearance increased with pre-infusion C-reactive protein concentration by 20%, varying from 3 to 14 mg l(-) 1, and was decreased by 30% when methotrexate was coadministered. CONCLUSIONS: The influence of methotrexate and inflammation on infliximab clearance suggests that individual adjustment of infliximab doses according to disease activity may be useful in RA.
24721419 Effects of a biologic agent in a patient with rheumatoid arthritis after treatment for met 2014 Apr 11 BACKGROUND: Several studies have suggested an increased risk of malignant tumor in patients with rheumatoid arthritis. It has been also reported that rheumatoid arthritis patients have a high incidence of lymphoma compared with the general population, and that patients receiving methotrexate, which is the anchor drug for rheumatoid arthritis treatment, can develop lymphoproliferative disease. Nevertheless, management of rheumatoid arthritis after treatment for methotrexate-associated lymphoma has not been fully investigated. We here report a patient with rheumatoid arthritis who developed malignant lymphoma associated with methotrexate therapy. Moreover, we describe the use of a biologic agent for a rheumatoid arthritis patient after treatment for lymphoma associated with methotrexate. CASE PRESENTATION: A 60-year-old Japanese man with a 20-year history of rheumatoid arthritis was admitted to our hospital with a left inguinal tumor. Open biopsy was performed and a biopsy specimen revealed diffuse large B-cell lymphoma. As our patient had received methotrexate for 4 years, we diagnosed the lymphoproliferative disease as being methotrexate-related. This lymphoma was not associated with Epstein- Barr virus by Epstein-Barr virus-encoded ribonucleic acid in-situ hybridization, but this patient was an Epstein-Barr virus carrier, regarding serological testing. The lymphoma went into complete remission after 6 courses of rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/prednisolone therapy. Two years later, however, rheumatoid arthritis activity gradually increased and was not controlled with salazosulfapyridine. Etanercept was administered in view of its possible effect on B-cells, and this reduced the level of disease activity without recurrence of lymphoma. CONCLUSION: The management of rheumatoid arthritis after treatment for methotrexate-associated lymphoma has not been fully investigated yet. Etanercept appeared to be safe because of its B-cell effect, but further observation is necessary to make a firm conclusion. Further accumulation of cases is needed to clarify which biologics are safe and effective for treatment of methotrexate-associated B-cell lymphoma.