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ID PMID Title PublicationDate abstract
24659153 [Recommendations for use of rituximab in patients with rheumatoid arthritis]. 2014 Mar Treatment with rituximab (RTX) has been approved since 2006 for patients with rheumatoid arthritis who previously failed to respond to tumor necrosis factor (TNF) inhibitor therapy or who experienced side effects. In these updated treatment recommendations new data relating to evaluation of the therapeutic response, retreatment, the role of predictive factors as well as safety data are incorporated and discussed.
24551036 Functional annotation of rheumatoid arthritis and osteoarthritis associated genes by integ 2014 BACKGROUND: Rheumatoid arthritis (RA) and osteoarthritis (OA) are two major types of joint diseases that share multiple common symptoms. However, their pathological mechanism remains largely unknown. The aim of our study is to identify RA and OA related-genes and gain an insight into the underlying genetic basis of these diseases. METHODS: We collected 11 whole genome-wide expression profiling datasets from RA and OA cohorts and performed a meta-analysis to comprehensively investigate their expression signatures. This method can avoid some pitfalls of single dataset analyses. RESULTS AND CONCLUSION: We found that several biological pathways (i.e., the immunity, inflammation and apoptosis related pathways) are commonly involved in the development of both RA and OA. Whereas several other pathways (i.e., vasopressin-related pathway, regulation of autophagy, endocytosis, calcium transport and endoplasmic reticulum stress related pathways) present significant difference between RA and OA. This study provides novel insights into the molecular mechanisms underlying this disease, thereby aiding the diagnosis and treatment of the disease.
23264071 Association of the CTLA-4 +49A/G polymorphism with rheumatoid arthritis in Chinese Han pop 2013 Mar Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is an important molecule in the regulation of T cells, so the CTLA-4 gene has been considered as a strong candidate associated with T cell-mediated autoimmune diseases such as rheumatoid arthritis (RA). CTLA-4 has many variants and polymorphic forms, among which the +49A/G polymorphism, causing a non-synonymous substitution, has been studied most. However, previous studies of the association between the +49A/G polymorphism of the CTLA-4 gene and RA have provided conflicting results. The aim of this study was to determine the potential relationship of the CTLA-4 +49A/G polymorphism and the risk of RA in Chinese Han population. TaqMan assay was used to genotype the +49A/G polymorphism in 1,489 RA patients and 1,200 healthy controls. Furthermore, a meta-analysis of all studies relating this polymorphism in Chinese population to the risk of RA was performed. The genotype and allele frequencies of the CTLA-4 +49A/G in patients with RA differed significantly from those of controls (P = 0.03 and P = 0.007, respectively). The meta-analysis also revealed that the CTLA-4 +49G allele was associated with an increased risk of RA in Chinese population. Our results suggested that the CTLA-4 gene might contribute to the pathogenesis of RA, and the +49A/G polymorphism of this gene was a risk factor associated with increased RA susceptibility in Chinese Han population.
24504805 Therapeutic effect of human amniotic membrane-derived cells on experimental arthritis and 2014 Feb OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Cells isolated from human amniotic membrane (HAMCs) were recently found to display immunosuppressive properties. The aim of this study was to characterize the effect of HAMCs on antigen-specific T cell responses in RA patients and to evaluate their therapeutic potential in a preclinical experimental model of RA. METHODS: We investigated the effects of HAMCs on collagen-reactive T cell proliferation and cytokine production, on the production of mediators of inflammation by synoviocytes, and on the generation of Treg cells in peripheral blood mononuclear cells and synovial membrane cells isolated from RA patients. Mice with collagen-induced arthritis (CIA) were treated with HAMCs after disease onset, and clinical scores and joint levels of mediators of inflammation were evaluated. We determined Th1/Th17-mediated autoreactive responses in the mice by measuring the proliferation and the cytokine profile of lymph node cells restimulated with collagen. RESULTS: Treatment with HAMCs suppressed synovial inflammatory responses and antigen-specific Th1/Th17 activation in cells isolated from RA patients. Moreover, HAMCs stimulated the generation of human CD4+CD25+FoxP3+ Treg cells with a capacity to suppress collagen-specific T cell responses. Systemic infusion of HAMCs significantly reduced the incidence and severity of CIA by down-regulating the 2 deleterious components of disease: Th1-driven autoimmunity and inflammation. In mice with CIA, HAMC treatment decreased the production of various inflammatory cytokines and chemokines in the joints, impaired antigen-specific Th1/Th17 cell expansion in the lymph nodes, and generated peripheral antigen-specific Treg cells. HAMCs also protected the mice from experimental sepsis, inflammatory bowel disease, and autoimmune encephalomyelitis. CONCLUSION: HAMCs have emerged as attractive candidates for a cell-based therapy for RA.
23470089 Retention of tocilizumab and anti-tumour necrosis factor drugs in the treatment of rheumat 2013 OBJECTIVES: The retention of the anti-rheumatic agent tocilizumab (TCZ) has not been well documented in patients with rheumatoid arthritis (RA). We conducted an observational study to compare the retention of TCZ and anti-tumour necrosis factor (TNF) drugs in the treatment of patients with RA. METHOD: We reviewed continuation rates and causes of discontinuation of biological agents (biologics) by assessing medical records of patients with RA who were administered biologics at our institute from September 1999 to April 2012, using the Osaka University Biologics for Rheumatic Diseases (BiRD) registry. RESULTS: A total of 401 patients were included. TCZ, infliximab (IFX), etanercept (ETN), and adalimumab (ADA) were administered to 97, 103, 143, and 58 patients, respectively. There were some differences between the baseline characteristics of the groups. The median duration (range) of TCZ, IFX, ETN, and ADA administration was 2.5 (0.1-12.6), 1.9 (0.0-7.7), 2.9 (0.0-11.3), and 1.3 (0.0-3.4) years, respectively. Continuation rates for TCZ and ETN were significantly higher than those for IFX and ADA. Multivariate analyses showed that discontinuation due to lack or loss of efficacy was significantly less common in the TCZ group than in the other groups. Discontinuation due to overall adverse events was not significantly different between treatment groups. CONCLUSION: TCZ and ETN show better retention than IFX or ADA in the treatment of RA.
24286269 Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conju 2013 Oct 30 INTRODUCTION: The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA). METHODS: Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post- and pre-vaccination antibody levels and a positive antibody response (posAR) was AR ≥ 2. RESULTS: In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%. CONCLUSION: In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment. TRIAL REGISTRATION: NCT00828997 and EudraCT EU 2007-006539-29.
25670363 Plasma kinetics of an LDL-like non-protein nanoemulsion and transfer of lipids to high-den 2015 Jan BACKGROUND: Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with cardiovascular risk, but with normal plasma lipids. OBJECTIVE: The aim was to investigate low-density lipoprotein (LDL) and high-density lipoprotein (HDL) metabolism in RA patients using radioactive nanoemulsions resembling an LDL lipid structure (LDE) as metabolic probes. METHODS: Thirty patients with RA, 16 in remission and 14 in high activity, and 30 healthy controls were studied. LDE labeled with (14)C-cholesteryl ester ((14)C-CE) and (3)H-unesterified cholesterol ((3)H-UC) was intravenously injected followed by 24-hour plasma sampling. Fractional clearance rates (FCR, h(-1)) were calculated by compartmental analysis. Lipid transfers to HDL were assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids; % lipids transferred to HDL were quantified after chemical precipitation. RESULTS: LDL cholesterol, triglycerides, unesterified cholesterol, and oxidized LDL were equal in RA and controls, and HDL cholesterol was even higher in RA. Compared with controls, apolipoprotein B was lower, apolipoprotein A1 was equal, and apolipoprotein E was higher in RA. Decay curves of LDE labels were faster in RA patients than in controls ((14)C-CE: 0.072 ± 0.066 and 0.038 ± 0.027, P = .0115; (3)H-UC: 0.066 ± 0.042 and 0.035 ± 0.039; P < .0044). FCRs were equal in 2 RA subgroups. Transfer of UC, triglycerides, and phospholipids to HDL was equal between RA and controls, but CE transfer was lower in RA. HDL size was smaller in RA patients than in controls (8.5 ± 0.5 nm; 9.2 ± 0.8 nm, P < .0001). CONCLUSION: RA patients were more efficient in removing atherogenic LDL from plasma, as indicated by higher CE and UC FCR, with in lower apolipoprotein B. This was unexpected because of the higher cardiovascular risk in RA.
25279663 Role of key TYMS polymorphisms on methotrexate therapeutic outcome in portuguese rheumatoi 2014 BACKGROUND: Therapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) can be modulated by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (TYMS). This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients. METHODS: Clinicopathological data from 233 Caucasian RA patients treated with MTX were collected, outcomes were defined and patients were genotyped for the following TYMS polymorphisms: 1) 28 base pairs (bp) variable number tandem repeat (rs34743033); 2) single nucleotide polymorphism C>G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches. RESULTS: Considering TYMS genotypes, 3R3R (p = 0.005, OR = 2.34), 3RC3RG (p = 0.016, OR = 3.52) and 6bp- carriers (p = 0.011, OR = 1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp- carriers (p = 0.016, OR = 2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp- alleles were associated with non-response to MTX. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes. CONCLUSION: Our study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences.
23407601 Clinical and functional evaluation of patients after total elbow arthroplasty. 2013 Feb 14 BACKGROUND: The operation of the total elbow arthroplasty (TEA) is recommended in case of advanced joint destruction. At present both in our country and abroad, the number of elbow arthroplasties performed per year is increasing. Surgical procedures are difficult, and postoperative complications may arise. The aim of this study is to evaluate the function of the elbow and the clinical status of patients after having undergone TEA. MATERIAL/METHODS: Our research is based on 18 patients who had undergone total elbow arthroplasty. The average patient age was 60. The follow-up time varied from 8-108 months. Postoperative assessment included the evaluation of the range of motion and grip strength using a dynamometer. Functional evaluation was carried out using Mayo Elbow Performance Score (MEPS), Disabilities of the Arm, Shoulder and Hand (DASH) and the SECEC Elbow Score (SES). We had also assessed the pain level (VAS), postoperative complications and patient satisfaction. The study included X-rays of the elbow for the evaluation of prosthesis integrity and possible signs of implant loosening. RESULTS: The increase of the range of motion was seen among all patients. The amplitude of flexion and extension increased by an average of 25.3° (p<0.02). The results of all questionnaires of functional assessment showed a significant improvement comparing to results before surgery: DASH - 82.6 (±24.6) vs. 116.7 (±24.2), SECEC - 39.3 (±8.5) vs. 27.9 (±9.2), MEPS - 65 (±23.3) vs. 35.8 (±16.9). The VAS pain decreased from 10.9 (±3) to 5.3 (±4). In the postoperative period, 4 patients experienced inflammation, 2 patients had a loosening of prosthesis, and 6 needed a revision of the prosthesis. 94.4% patients were satisfied with the treatment. CONCLUSIONS: Total elbow arthroplasty effectively improves the clinical status of the patient by reducing pain, increasing range of motion and improving many activities of daily life.
22915618 Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimm 2013 Jun OBJECTIVE: We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with systemic inflammation in a prospective cohort of first-degree relatives (FDRs) of RA probands, a population without RA but at increased risk for its future development. METHODS: We studied 44 autoantibody positive FDRs, of whom 29 were rheumatoid factor (RF) positive, 25 were positive for the high risk autoantibody profile (HRP), that is, positive for anti-cyclic citrullinated peptide and/or for at least two RF IgM, IgG or IgA isotypes, and nine FDRs who were positive for both; and 62 FDRs who were never autoantibody positive. Twenty-five cytokines/chemokines were measured using a bead-based assay in serum. As a comprehensive measure of inflammation, we calculated a Cytokine Score by summing all cytokine/chemokine levels, weighted by their regression coefficients for RA-autoantibody association. We compared C-reactive protein, individual cytokines/chemokines and Cytokine Score to the outcomes: positivity for RF and for the HRP using logistic regression. RESULTS: Adjusting for age, sex, ethnicity and ever smoking, the Cytokine Score and levels of IL-6 and IL-9 were associated with both RF and HRP. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon (IFN)-γ were associated with HRP only. Associations between the Cytokine Score and RF and HRP positivity were replicated in an independent military personnel cohort. CONCLUSIONS: In first-degree relatives of patients with RA, RA-related autoimmunity is associated with inflammation, as evidenced by associations with multiple cytokines and chemokines.
24488390 Retention rates of infliximab and tocilizumab during a 3-year period in a Brazilian hospit 2013 Dec OBJECTIVE: To compare the efficacy and the period of use of tocilizumab and infliximab during treatment of rheumatoid arthritis patients. METHODS: The period of use of two biologics with different mechanisms of action were compared in treatment of rheumatoid arthritis patients. RES ULTS: Both medications showed efficacy, but the period of use with no loss of efficacy was longer in patients receiving tocilizumab when compared to infliximab. CONCLUSION: Tocilizumab maintains a period of use significantly longer as compared with infliximab in patients with rheumatoid arthritis treated at a single organization.
24020899 Peroxisome proliferator-activated receptor γ agonist effect on rheumatoid arthritis: a ra 2013 INTRODUCTION: Rheumatoid arthritis (RA), a chronic inflammatory disease, is associated with insulin resistance. Experimental evidence indicates that the relationship between insulin resistance and inflammation is bidirectional: Inflammation promotes insulin resistance, and insulin resistance promotes inflammation. Therefore, we examined the hypothesis that pioglitazone, a thiazolidinedione peroxisome proliferator-activated receptor γ agonist, would decrease inflammation and disease activity and improve insulin resistance in patients with RA. METHODS: In a single-center, randomized, double-blind, placebo-controlled crossover study patients with RA (N = 34) receiving stable therapy were randomized to also receive either pioglitazone 45 mg daily (n = 17) or matching placebo (n = 17) for eight weeks. This was followed by a four-week washout period and alternative treatment for eight weeks. Outcomes included change in Disease Activity Score in 28 joints (DAS28) score, individual components of the DAS28 score and homeostatic model assessment for insulin resistance (HOMA). Intention-to-treat analysis and linear mixed-effects models were used. RESULTS: Patients had a mean (± SD) age of 51 (± 14.2) years, 82.4% were female and baseline DAS28 high-sensitivity C-reactive protein (DAS28-CRP) was 4.58 (± 1.1) units. Addition of pioglitazone was associated with a 9.3% reduction (95% confidence interval (CI) = 0.17% to 17.6%) in DAS28-CRP (P = 0.046), but no significant change in DAS28 erythrocyte sedimentation rate (DAS28-ESR) (P = 0.92). There was a 10.7 mm (95% CI = 0.4 to 20.9 mm) improvement in patient-reported global health (P = 0.042), a 48.6% decrease (95% CI = 27.6% to 63.5%) in CRP (P < 0.001) and a 26.4% decrease (95% CI = 3.7% to 43.8%) in insulin resistance as measured by HOMA (P = 0.025), but no significant reduction in swollen or tender joint count or in ESR (all P > 0.05). Lower-extremity edema was more common during pioglitazone treatment (16%) than placebo (0%). CONCLUSION: Addition of pioglitazone to RA therapy improves insulin resistance and modestly reduces RA disease activity measured by DAS28-CRP and two of its components, including patient-reported global health and CRP, but not DAS28-ESR or ESR. TRIAL REGISTRATION: NCT00763139.
24880103 Peripheral and synovial mechanisms of humoral autoimmunity in rheumatoid arthritis. 2014 Aug One of the hallmarks of rheumatoid arthritis (RA) is the development of humoral autoimmunity resulting in circulating autoantibodies. The clinical efficacy of B cell-depleting biologic treatments highlighted a key role for autoreactive B cell activation in the pathogenesis of RA. In this review, we discuss the key mechanisms leading to breach of B cell self-tolerance in the peripheral compartment. We also highlight the contribution of synovial ectopic lymphoid structures (ELS) in the development of functional niches of autoreactive B cells promoting humoral autoimmunity in the inflamed RA joints over and above secondary lymphoid organs (SLO).
25222824 Self-efficacy for exercise, more than disease-related factors, is associated with objectiv 2015 OBJECTIVES: Until recently, reports of physical activity in rheumatoid arthritis (RA) were limited to self-report methods and/or leisure-time physical activity. Our objectives were to assess, determine correlates of, and compare to well-matched controls both exercise and sedentary time in a typical clinical cohort of RA. METHOD: Persons with established RA (seropositive or radiographic erosions; n = 41) without diabetes or cardiovascular disease underwent assessments of traditional and disease-specific correlates of physical activity and 7 days of triaxial accelerometry. Twenty-seven age, gender, and body mass index (BMI)-matched controls were assessed. RESULTS: For persons with RA, objectively measured median (25th-75th percentile) exercise time was 3 (1-11) min/day; only 10% (n = 4) of participants exercised for ≥ 30 min/day. Time spent in sedentary activities was 92% (89-95%). Exercise time was not related to pain but was inversely related to disease activity (r = -0.3, p < 0.05) and disability (r = -0.3, p < 0.05) and positively related to self-efficacy for endurance activity (r = 0.4, p < 0.05). Sedentary activity was related only to self-efficacy for endurance activity (r = -0.4, p < 0.05). When compared to matched controls, persons with RA exhibited poorer self-efficacy for physical activity but similar amounts of exercise and sedentary time. CONCLUSIONS: For persons with RA and without diabetes or cardiovascular disease, time spent in exercise was well below established guidelines and activity patterns were predominantly sedentary. For optimal care in RA, in addition to promoting exercise, clinicians should consider assessing sedentary behaviour and self-efficacy for exercise. Future interventions might determine whether increased self-efficacy can increase physical activity in RA.
24782181 Thymic stromal lymphopoietin, a novel proinflammatory mediator in rheumatoid arthritis tha 2014 May OBJECTIVE: To determine the levels of thymic stromal lymphopoietin (TSLP) and the numbers of TSLP receptor (TSLPR)-expressing CD1c+ (blood dendritic cell antigen 1-positive) myeloid dendritic cells (MDCs) in the joints as compared with the peripheral blood (PB) of patients with rheumatoid arthritis (RA), as well as to determine the capacity of TSLP to induce MDC-dependent T cell activation. METHODS: TSLP levels were measured in synovial fluid (SF) samples from patients with RA and those with osteoarthritis (OA). MDC numbers in PB and SF samples from RA patients and TSLPR expression on these cells were assessed by fluorescence-activated cell sorter analysis. PB and SF MDCs from RA patients were stimulated with TSLP, and cytokine production was measured by multiplex immunoassay. TSLP-primed MDCs were cocultured with autologous CD4+ T cells in the absence of additional stimuli, and subsequently, cell proliferation and cytokine production were measured. RESULTS: TSLP levels were significantly increased in SF samples from RA versus OA patients. The numbers of TSLPR-expressing MDCs in the SF of RA patients were significantly increased as compared to those in the PB, and SF MDCs displayed increased levels of TSLPR. TSLP selectively stimulated the production of thymus and activation-regulated chemokine and macrophage inflammatory protein 1α by CD1c+ MDCs. TSLP-primed MDCs from PB and SF potently stimulated the proliferation of autologous CD4+ T cells as compared to unstimulated MDCs. Enhanced proliferation was associated with increased production of interferon-γ, interleukin-17 (IL-17), and IL-4. CONCLUSION: These data support an inflammatory mechanism by which increased intraarticular TSLP in RA potently activates TSLPR-expressing CD1c+ MDCs in the joints to secrete chemokines, causing chemotaxis and subsequent activation of CD4+ T cells. In addition to the demonstrated inflammatory potential of TSLP in experimental arthritis, this suggests that TSLP and TSLPR-expressing MDCs could both play a pivotal role in the immunopathology of RA.
23379548 Carbohydrate-deficient transferrin depends on disease activity in rheumatoid arthritis and 2013 OBJECTIVES: Changes in the glycosylation of plasma proteins have been linked to the aetiology of the rheumatic diseases. The aim of this study was to determine and compare the levels of carbohydrate-deficient transferrin (CDT) in patients with rheumatoid arthritis (RA), systemic sclerosis (SSc), and systemic lupus erythematosus (SLE). METHOD: Studies were carried out in 29 female patients with RA, 27 with SSc, and 17 with SLE. CDT was assayed by the N Latex CDT immunonephelometric assay. RESULTS: The levels of %CDT in the sera of RA, SLE, and SSc patients were significantly higher than in controls while the absolute concentrations of CDT were unchanged. %CDT, CDT, and transferrin do not differ significantly between patients with rheumatic diseases. In RA and SSc patients, a positive correlation was observed between %CDT and C-reactive protein (CRP), as well as a positive correlation in RA patients between %CDT and 28-joint Disease Activity Score (DAS28). CONCLUSIONS: The changes in the serum %CDT concentration in patients with RA and SSc correlated with disease activity markers.
24782182 AT-rich-interactive domain-containing protein 5A functions as a negative regulator of reti 2014 May OBJECTIVE: The proinflammatory cytokines tumor necrosis factor α and interleukin-6 (IL-6) and the Th17 cell cytokine IL-17A are implicated in the pathogenesis of rheumatoid arthritis (RA), and the blockade of these cytokines by biologic agents provides clinical benefits for RA patients. We undertook this study to clarify the mechanisms underlying the efficacy of IL-6 blockade in RA and to find a novel target for treatment of RA. METHODS: We examined gene expression profiles of CD4+ T cells by DNA microarray analysis before and after treatment with an anti-IL-6 receptor antibody, tocilizumab (TCZ), in RA patients who exhibited good clinical responses to the treatment. Using murine CD4+ T cells, we then examined the roles of a newly identified molecule whose expression was significantly reduced in CD4+ T cells by TCZ therapy. We also examined the effect of the forced expression of the molecule on retinoic acid receptor-related orphan nuclear receptor γt (RORγt)-induced IL-17A production in CD4+ T cells and on RORγt-induced IL-17A promoter activation. RESULTS: We identified AT-rich-interactive domain- containing protein 5A (ARID-5A) as a new molecule down-regulated by IL-6 blockade in the form of TCZ therapy. IL-6 induced the expression of ARID-5A in CD4+ T cells during Th17 cell differentiation by a STAT-3-dependent mechanism, whereas IL-6-induced ARID-5A expression was not affected by the absence of RORγt, a lineage-specifying transcription factor of Th17 cells. Furthermore, ARID-5A physically associated with RORγt through its N-terminal region and inhibited RORγt-induced Th17 cell differentiation. CONCLUSION: ARID-5A is a lineage-specific attenuator of Th17 cell differentiation and may be involved in the pathogenesis of RA.
23686494 CD40 mediates downregulation of CD32B on specific memory B cell populations in rheumatoid 2013 Jun 15 Altered B cell function is important in the pathogenesis of rheumatoid arthritis (RA). In this report, we show that patients with active RA have an increased frequency of CD32B low/neg cells in the CD27(+)IgD(-) memory B cell subset and that these changes are associated with phenotypic and functional B cell activation. Studies using PBMCs from healthy donors revealed that downregulation of CD32B on B cells is mediated by CD40-CD40L interactions and is potentiated by IL-4 and inhibited by both IL-10 and IL-21. These findings appear physiologically relevant because CD4 T cell expression of CD40L correlated with the frequency of CD32B low/neg cells in the CD27(+)IgD(-) memory B subset in patients with RA. Our data support a model in which high levels of CD40L, present on circulating T cells in patients with RA, causes B cell activation and CD32B downregulation, resulting in secondary protection of memory B cells from CD32B-mediated cell death.
23784528 Selective blockade of tumor necrosis factor receptor I inhibits proinflammatory cytokine a 2013 Sep OBJECTIVE: To determine whether selective blockade of tumor necrosis factor receptor I (TNFRI) affects spontaneous proinflammatory cytokine and chemokine production in ex vivo-cultured human rheumatoid arthritis synovial membrane mononuclear cells (MNCs) and to compare this response to that of TNF ligand blockade using etanercept. METHODS: A bispecific, single variable-domain antibody (anti-TNFRI moiety plus an albumin binding moiety [TNFRI-AlbudAb]) was used to selectively block TNFRI. Inhibition of TNFα-mediated responses in cell lines expressing TNFRI/II confirmed TNFRI-AlbudAb potency, human rhabdomyosarcoma cell line KYM-1D4 cytotoxicity, and human umbilical vein endothelial cell (HUVEC) vascular cell adhesion molecule 1 (VCAM-1) upregulation. Eighteen RA synovial membrane MNC suspensions were cultured for 2 days or 5 days, either alone or in the presence of TNFRI-AlbudAb, control-AlbudAb, or etanercept. Proinflammatory cytokines and chemokines in culture supernatants were measured by enzyme-linked immunosorbent assays. A mixed-effects statistical analysis model was used to assess the extent of TNFRI selective blockade, where the results were expressed as the percentage change with 95% confidence intervals (95% CIs). RESULTS: TNFRI-AlbudAb inhibited TNFα-induced KYM-1D4 cell cytotoxicity (50% inhibition concentration [IC50 ] 4 nM) and HUVEC VCAM-1 up-regulation (IC50 12 nM) in a dose-dependent manner. In ex vivo-cultured RA synovial membrane MNCs, selective blockade of TNFRI inhibited the production of proinflammatory cytokines and chemokines to levels similar to those obtained with TNF ligand blockade, without inducing cellular toxicity. Changes in cytokine levels were as follows: -23.5% (95% CI -12.4, -33.2 [P = 0.004]) for granulocyte-macrophage colony-stimulating factor, -33.4% (95% CI -20.6, -44.2 [P ≤ 0.0001]) for interleukin-10 (IL-10), -17.6% (95% CI 3.2, -34.2 [P = 0.0880]) for IL-1β, and -19.0% (95% CI -3.4, -32.1 [P = 0.0207]) for IL-6. Changes in chemokine levels were as follows: -34.2% (-14.4, -49.4 [P = 0.0030]) for IL-8, -56.6% (-30.7, -72.9 [P = 0.0011]) for RANTES, and -24.9% (2, -44.8 [P = 0.0656]) for monocyte chemotactic protein 1. CONCLUSION: In ex vivo-cultured RA synovial membrane MNCs, although a limited role of TNFRII cannot be ruled out, TNFRI signaling was found to be the dominant pathway leading to proinflammatory cytokine and chemokine production. Thus, selective blockade of TNFRI could potentially be therapeutically beneficial over TNF ligand blockade by retaining the beneficial TNFRII signaling.
23731934 How to interpret plain radiographs in clinical practice. 2013 Apr In this article I will consider the basic principles of requesting, acquiring, interpreting and reporting plain radiographs of joints, including assessment of the distribution of joint abnormalities, and specific pathological changes that may occur in bone, cartilage and soft tissues. I will then move on to a more specific discussion of the major arthropathies and the role of radiographs in the diagnosis and assessment in each condition as well as reviewing the combined abnormalities that may be visible on radiographs and how these relate to underlying pathological processes.