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ID PMID Title PublicationDate abstract
23877487 Cost per responder of TNF-α therapies in Germany. 2013 Dec Tumor necrosis factor α (TNF-α) inhibitors ranked highest in German pharmaceutical expenditure in 2011. Their most important application is the treatment of rheumatoid arthritis (RA). Our objective is to analyze cost per responder of TNF-α inhibitors for RA from the German Statutory Health Insurance funds' perspective. We aim to conduct the analysis based on randomized comparative effectiveness studies of the relevant treatments for the German setting. For inclusion of effectiveness studies, we require results in terms of response rates as defined by European League Against Rheumatism (EULAR) or American College of Rheumatology (ACR) criteria. We identify conventional triple therapy as the relevant comparator. We calculate cost per responder based on German direct medical costs. Direct clinical comparisons could be identified for both etanercept and infliximab compared to triple therapy. For infliximab, cost per responder was 216,392 euros for ACR50 and 432,784 euros for ACR70 responses. For etanercept, cost per ACR70 responder was 321,527 euros. Cost was lower for response defined by EULAR criteria, but data was only available for infliximab. Cost per responder is overestimated by 40% due to inclusion of taxes and mandatory rebates in German drugs' list prices. Our analysis shows specific requirements for cost-effectiveness analysis in Germany. Cost per responder for TNF-α treatment in the German setting is more than double the cost estimated in a similar analysis for the USA, which measured against placebo. The difference in results shows the critical role of the correct comparator for a specific setting.
23509798 Targeting the immunogenetic diseases with the appropriate HLA molecular typing: critical a 2013 We compared the immunogenetic data from 2666 patients affected by HLA-related autoimmune diseases with those from 4389 ethnically matched controls (3157 cord blood donors CBD, 1232 adult bone marrow donors BMD), to verify the appropriateness of HLA typing requests received in the past decade. The frequency of HLA-B∗27 phenotype was 10.50% in 724 ankylosing spondylitis, 16.80% in 125 uveitis (3.41% BMD, 4.24% CBD, P < 0.0001); HLA-B∗51 allele was 15.57% in 212 Behçet's disease (12.91% BMD, 9.88% CBD, P < 0.0001); the HLA-DRB1-rheumatoid arthritis (RA) shared epitope was 13.72% in 554 RA (10.85% BMD, 13.48% CBD, P = 0.016); the carriers of almost one of HLA-DQB1 susceptibility alleles were 84.91% in 795 celiac disease (CD) and 59.37% in 256 insulin-dependent diabetes mellitus (IDDM) (46.06% in 875 CBD, 42.75% in 662 BMD P < 0.0001). Overall, our results show that the HLA marker frequencies were higher in patients than controls, but lower than expected from the literature data (excluding CD and IDDM) and demonstrate that, in complex immunogenetic conditions, a substantial number of genetic analyses are redundant and inappropriate, burdening to the public health costs. For this reason, we suggest the Italian Scientific Society of Immunogenetics to establish guidelines to improve the appropriateness of typing requests.
23786438 High frequencies of activated B cells and T follicular helper cells are correlated with di 2013 Nov This study aimed to examine the frequency of different subsets of circulating B and T follicular helper (Tfh) cells in patients with new-onset rheumatoid arthritis (RA) and following standard therapies. Twenty-five RA patients and 15 healthy controls (HC) were recruited for characterizing the frequency of CD27⁺, immunoglobulin (Ig)D⁺, CD86⁺, CD95⁺, Toll-like receptor (TLR)-9⁺ B cells and inducible T cell co-stimulator (ICOS) and programmed death 1 (PD-1)-positive Tfh cells and the level of serum interleukin (IL)-21. The potential correlation between the frequency of different subsets of B and Tfh cells and the values of clinical measures in RA patients was analysed. In comparison with HC, significantly higher percentages of circulating IgD⁺ CD27⁻ CD19⁺ naive B, CD86⁺ CD19⁺ and CD95⁺ CD19⁺ activated B, CD3⁺ CD4⁺ CXCR5⁺, CD3⁺ CD4⁺ CXCR5⁺ ICOS⁺, CD3⁺ CD4⁺ CXCR5⁺ PD-1⁺ and CD3⁺ CD4⁺ CXCR5⁺ ICOS⁺ PD-1⁺ Tfh cells but lower IgD⁺ CD27⁺ CD19⁺ preswitch memory B cells were detected, accompanied by significantly higher levels of serum IL-21 in the RA patients. Furthermore, the percentages of CD95⁺ B cells were correlated positively with the frequency of PD-1⁺ Tfh cells, but negatively with ICOS⁺ Tfh cells. The percentages of CD86⁺ B cells and ICOS⁺ Tfh cells were correlated positively with the values of disease activity score 28 (DAS28). Following the drug therapies for 1 month, the percentages of CD86⁺ B and PD-1⁺ Tfh cells were reduced significantly in the drug-responding patients. Our data suggest that activated B and Tfh cells may contribute to the pathogenesis of RA and the frequency of activated B and Tfh cells may be used as biomarkers for evaluating the therapeutic responses of individual patients with RA.
24103404 Breast cancer in systemic sclerosis: results of a cross-linkage of an Italian Rheumatologi 2014 Feb OBJECTIVE: Increased frequency of few types of cancer in systemic sclerosis (SSc) has been reported in the literature; in particular, breast carcinoma has been proposed as one of the most frequent malignancy in SSc patients, even though data are not univocal. The aim of the present study was to retrospectively evaluate the prevalence of breast cancer in our SSc series, compared with sex-/age-matched general population of the same geographical area, and the possible correlations with SSc features, including X-ray exposure for clinical investigations. A review of the world literature about this topic was also done. METHODS: Clinical records of 318 consecutive SSc patients, 31 M and 287 F, age 51.5±14.5 SD years, disease duration 10±6.5 SD years, referred to our Rheumatology Unit between January 2002 and December 2012 were evaluated. RESULTS: Twelve (3.8%) cases of breast cancer were recorded, including 11/287 females (3.8%) and 1/31 (3.2%) male patients. Considering the subgroup of 202 SSc patients resident in the Province of Modena compared with data of the local Tumor Registry, the incidence of breast cancer observed in our SSc series is significantly higher than expected (SIR 2.1; 95% interval of confidence: 1.13-3.90; p<0.01). On the whole, the comparison between SSc patients with cancer and those without did not show any significant differences with regard to SSc clinical features, including the X-ray exposure. Of note is the relatively shorter disease duration at the time of breast cancer detection (median 2.5years, range 1-21; disease duration of mean 10±6.5 SD years in the entire cohort). The review of the literature revealed that the observed incidence of breast cancer in our case series is comparable to the few studies reporting the highest percentages of this malignancy. CONCLUSIONS: A significant increase of breast cancer incidence compared to sex-age-matched general population from the same geographic area was observed. Moreover, a close temporal relationship between SSc and breast cancer onset was found, independently from clinical, serological, and instrumental features of SSc. The possible pathogenetic link between this systemic autoimmune disease and complicating breast cancer, as well as the results of previous studies, are discussed.
23221326 Changes in bone mineral density during long-term treatment with adalimumab in patients wit 2013 Mar OBJECTIVE: To investigate the effect of long-term adalimumab treatment on BMD of the lumbar spine, total hip and hands in patients with RA. METHODS: In 184 established RA patients treated with adalimumab for at least 1 year, BMD measurements of the total hip and lumbar spine were performed using dual-energy X-ray absorptiometry. Metacarpal cortex BMD was measured using digital X-ray radiogrammetry. RESULTS: After 1 year of treatment, BMD of the hip and lumbar spine remained stable, while BMD of the hands decreased significantly by -1.41% (P < 0.0001). After a mean follow-up of 4.0 (s.d. 1.0) years, mean BMD change per year was -0.58% and 0.07% for the hip and lumbar spine, respectively (overall P-value of hip was <0.0001 and spine was 0.67). Predictors for BMD loss of the hip were anti-CCP positivity, non-use of bisphosphonates at baseline and BMI. In European League Against Rheumatism (EULAR) non-responders at 52 weeks, BMD change of the hip and spine was -1.25% and 1.08%, respectively, for moderate responders -0.61% and -1.87%, respectively, and in EULAR good responders, BMD remained stable: -0.02% and 0.06%, respectively. BMD of the hands decreased in non-, moderate and good responders (-2.85%, -1.47% and -1.26%, respectively). CONCLUSION: In patients with severe, established RA, loss of BMD in the spine was arrested over 4 years of adalimumab treatment, whereas BMD of the hands and hip continued to decrease after 1 and 4 years, respectively. The changes in BMD are related to disease activity, underlining the importance of monitoring disease activity.
23106832 Risk of venous thrombosis in patients with major illnesses: results from the MEGA study. 2013 Jan BACKGROUND: The risk of venous thrombosis associated with major illnesses is not well known, and neither is the risk associated with the combined effect of immobilization and thrombophilia. The aim of this study was to assess the effect on the development of venous thrombosis of several major illnesses in combination with immobilization, body mass index, and thrombophilia, to identify high-risk groups that may provide a basis for personalized prevention. METHODS: This study included 4311 consecutive patients with a first episode of venous thrombosis, and 5768 controls from a case-control study (MEGA study). We calculated odds ratios (ORs) for venous thrombosis for patients with a self-reported history of major illnesses. RESULTS: Venous thrombosis risk was increased for all investigated major illnesses: liver disease, OR 1.7 (95% confidence interval [CI]1.0-2.9); kidney disease, OR 3.7 (95% CI 2.3-5.9); rheumatoid arthritis, OR 1.5 (95% CI 1.2-1.9); multiple sclerosis, OR 2.4 (95% CI 1.3-4.3); heart failure, OR 1.7 (95% CI 1.2-2.3); hemorrhagic stroke, OR 4.9 (95% CI 2.4-9.9); arterial thrombosis, OR 1.5 (95% CI 1.2-1.8); and the presence of any of the above major illnesses, OR 1.7 (95% CI 1.5-1.9). Combinations of major illnesses with immobilization and increased factor VIII (OR 79.9; 95% CI 33.2-192.2), increased FIX (OR 35.3; 95% CI 14.2-87.8), increased von Willebrand factor (OR 88.0; 95% CI 33.9-228.3), FV Leiden (OR 84.2; 95% CI 19.5-363.6), and blood group non-O (OR 53.1; 95% CI 30.9-91.4) were associated with increased venous thrombosis risks. CONCLUSIONS: All of the major illnesses reported here were associated with an increased risk of venous thrombosis. These risks were most pronounced at the time of immobilization or in the presence of thrombophilia.
24346772 Sialic acid level reflects the disturbances of glycosylation and acute-phase reaction in r 2014 Mar In the rheumatic diseases, the changes in the carbohydrate part of serum glycoproteins occur and these abnormalities can be monitored by serum level of total and free sialic acid. The aim of this study was to evaluate the total and free sialic acid level as a marker of inflammation activity (TSA) and the changes in glycosylation of blood glycoproteins (FSA) in rheumatoid arthritis (RA), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Studies were carried out in 50 patients with RA, 24 with SLE and 32 with SSc. TSA concentration was measured with an enzymatic, colorimetric method and FSA with a thiobarbituric method. The serum levels of TSA in RA and SLE patients were significantly increased compared to controls and in RA patients were higher than that in SSc patients. The mean serum level of FSA in RA patients was significantly higher, but in SSc patients significantly lower than that in the controls, and in RA patients was significantly higher than in SLE and in SSc patients. All acute-phase proteins were changed: Positive acute-phase proteins were elevated, and the negative protein was decreased. The positive acute-phase proteins positively correlated with the levels of TSA and FSA in RA and SSc patients. In SLE patients, TSA positively correlated with haptoglobin and α1-antitrypsin. In RA patients, there was the positive correlation of TSA and FSA with DAS 28. The changes in the serum levels of TSA and FSA in the course of rheumatic diseases could reflect the abnormalities in glycosylation/sialylation patterns of glycoproteins induced by acute-phase response.
24060261 Factors associated with disability in a sample of adults with arthritis. 2013 Oct BACKGROUND: Arthritis is the most common cause of disability among US adults. Few studies have comprehensively examined factors associated with disability in this population. OBJECTIVE: To investigate the relationship between a number of disease and non-disease related factors and disability in sample of adults with self-reported doctor-diagnosed arthritis. METHODS: Participants (n = 396) taking part in a randomized controlled trial of arthritis self-management completed a comprehensive survey assessing a number of demographic, arthritis-specific, health-related, behavioral, and psychological variables at baseline. Disability, as measured by the Health Assessment Questionnaire (HAQ), was also measured. Hierarchical regression models examined the independent associations between blocks of variables and disability. RESULTS: Demographic variables (R(2) = 0.13), arthritis-specific demographics (i.e., type, medication use; ΔR(2) = 0.16), physical health-related variables (ΔR(2) = 0.06), arthritis-specific symptoms (ΔR(2) = 0.12), health behaviors (ΔR(2) = 0.00), and psychological variables (ΔR(2) = 0.03) explained 50% of the variance in disability score (R(2) = 0.50). With the exception of health behaviors, the addition of each block of variables significantly improved the model, explaining additional variance in HAQ scores (p < 0.0001). In the final model, older age, less than a high school education, rheumatoid arthritis, greater arthritis duration, taking steroids, taking narcotics, greater pain, greater stiffness, greater depressive symptoms, and lower arthritis self-efficacy were associated with greater disability whereas male gender, fibromyalgia, and excellent/very good health were associated with less disability. CONCLUSIONS: A number of disease and non-disease related variables were associated with disability. These findings suggest that disability in adults with arthritis may be a complicated phenomenon; such complexity may make decreasing disability in this population challenging.
24156537 Drug safety evaluation of certolizumab pegol. 2014 Feb INTRODUCTION: The introduction of antibodies directed against tumor necrosis factor (anti-TNF) has dramatically changed our concept of treating both patients with Crohn's disease (CD) and patients with rheumatoid arthritis (RA). Subcutaneous injections with certolizumab pegol (CZP) have been shown efficacious for both CD and RA. In this review, the authors focus on the safety of CZP among other anti-TNF agents. AREAS COVERED: A literature search till June 2013 was performed to identify all trials studying CZP in patients with CD and RA. In addition, abstracts of major congresses were assessed. The authors first focused on the mechanism of action of CZP, and evaluated the efficacy of this drug in both CD and RA. Next, they explored the available safety data on CZP, including infection and malignancy risk, injection site reactions, the development of antibodies against CZP, as well as its use during pregnancy. EXPERT OPINION: Based on the provided literature, CZP seems to have a similar safety profile to other anti-TNF agents. However, in young females considering pregnancy, CZP may be advocated over other anti-TNF agents as it does not actively cross the placenta.
23287362 Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey. 2013 May OBJECTIVE: To determine the pattern of demyelinating disorders (DDs) occurring during anti-TNF-α therapy. METHODS: Between June 2005 and April 2008, 1800 French rheumatologists and internists were contacted to report cases of DDs occurring in patients treated with anti-TNF-α. RESULTS: After a median of 10.2 (1.5-39.9) months of treatment, 33 patients developed DDs: 22 had CNS and 11 peripheral nervous system (PNS) involvement. Underlying diseases were RA (n = 16), AS (n = 11), PsA (n = 4), JIA (n = 1) and PM (n = 1). Anti-TNF-α was infliximab (n = 15), etanercept (n = 12) or adalimumab (n = 6). CNS involvement was encephalic lesions (n = 16), transverse myelitis (n = 8) or retrobulbar optic neuritis (n = 5). Cerebrospinal fluid (CSF) analysis in 16 patients and MRI in 20 patients were abnormal. All patients discontinued anti-TNF-α. Fifteen patients required steroids. Twenty patients initially improved. Five patients developed multiple sclerosis. PNS involvement was chronic (n = 9) or acute inflammatory demyelinating polyneuropathy (n = 2). CSF analysis revealed an increased protein level in nine patients. Nerve conduction studies confirmed DD in all these patients. Anti-TNF-α was discontinued in 10 patients and 8 received i.v. immunoglobulins. Two patients relapsed after introduction of another anti-TNF-α. Overall, a causal relationship between anti-TNF-α and DD was considered as probable in 31 patients and definite in 2 who had positive rechallenge. CONCLUSION: Causal relationship between anti-TNF-α and induction of DD remains unclear, but in some cases the chronology of clinical events is suggestive. Nevertheless, DD might persist despite treatment discontinuation, suggesting that anti-TNF-α could trigger the demyelinating process, which further evolves independently.
25561237 Cytokine-modulating strategies and newer cytokine targets for arthritis therapy. 2014 Dec 31 Cytokines are the key mediators of inflammation in the course of autoimmune arthritis and other immune-mediated diseases. Uncontrolled production of the pro-inflammatory cytokines such as interferon-γ (IFN-γ), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-17 can promote autoimmune pathology, whereas anti-inflammatory cytokines including IL-4, IL-10, and IL-27 can help control inflammation and tissue damage. The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis (RA). For example, the neutralization of TNFα, either by engineered anti-cytokine antibodies or by soluble cytokine receptors as decoys, has proven successful in the treatment of RA. The activity of pro-inflammatory cytokines can also be downregulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling. Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity. Unexpectedly, under certain conditions, TNFα, IFN-γ, and few other cytokines can display anti-inflammatory activities. Increasing awareness of this phenomenon might help develop appropriate regimens to harness or avoid this effect. Furthermore, the relatively newer cytokines such as IL-32, IL-34 and IL-35 are being investigated for their potential role in the pathogenesis and treatment of arthritis.
24671668 Sulforaphane inhibits IL-1β-induced proliferation of rheumatoid arthritis synovial fibrob 2014 Oct This study was performed to define the effects of sulforaphane on interleukin-1β (IL-1β)-induced proliferation of rheumatoid arthritis synovial fibroblasts (RASFs), the expression of matrix metalloproteinases (MMPs) and cyclooxygenase (COX), and the production of prostaglandin E2 (PGE2) by RASFs. The proliferation of RASFs was evaluated with CCK-8 reagent in the presence of IL-1β with/without sulforaphane. The expression of MMPs, tissue inhibitor of metalloproteinase-1, COXs, intracellular mitogen-activated protein kinase signalings, including p-ERK, p-p38, p-JNK, and nuclear factor-kappaB (NF-kB), and the production of PGE2 were examined by Western blotting or semi-quantitative RT-PCR and ELISA. Sulforaphane inhibits unstimulated and IL-1β-induced proliferation of RASFs; the expression of MMP-1, MMP-3, and COX-2 mRNA and protein; and the PGE2 production induced by IL-1β. Sulforaphane also inhibits the phosphorylation of ERK-1/2, p-38, and JNK and activation of NF-kB by IL-1β. These results indicate that sulforaphane inhibits the proliferation of synovial fibroblasts, the expression of MMPs and COX-2, and the production of PGE2, which are involved in synovitis and destruction of RA, and suggest that sulforaphane might be a new therapeutic agent for RA.
24641160 Medication adherence and persistence in the treatment of rheumatoid arthritis with adalimu 2014 May OBJECTIVE: The aim of this study was to evaluate medication adherence and persistence of patients treated with Etanercept and Adalimumab for Rheumatoid Arthritis, also giving economic evaluations on therapy costs for Received Daily Dose (RDD). MATERIALS AND METHODS: This retrospective study took into account 6 years from January 1, 2007 to December 31, 2012. Medication adherence was quantified utilizing the ratio between RDD and Prescribed Daily Dose (PDD). Persistence has been reckoned taking into account the actual days of therapy comparing posology with supplied dose. The persistence has been graphed according to Kaplan-Meier method. The cost per RDD was reckoned starting from the expense incurred by Pescara General Hospital. RESULTS: Medication adherence gave results in values between 0.88-0.97 for Etanercept and 0.83-0.90 for Adalimumab. The value of persistence was 100% for Etanercept and 90% for Adalimumab for the first year, and 70% for Etanercept and 80% for Adalimumab for the second year. In the 3rd year the persistence for Etanercept was 50% while for Adalimumab it was 60%. In the fourth year the persistence for Etanercept was 21% while for Adalimumab it was 27%. The statistical analysis was conducted using the Log rank test. The average cost per RDD was €32.97 for Etanercept and for Adalimumab it was €32.00 as an average of 6 years. CONCLUSION: The medication adherence was good for both Etanercept and Adalimumab. The rate of persistence decreased strictly in the fourth year of treatment. This data suggests the need for continuous monitoring of patients in treatment with TNF blockers.
24423328 Exploring the role of vitamin D in type 1 diabetes, rheumatoid arthritis, and Alzheimer di 2014 Mar CONTEXT AND OBJECTIVE: A comprehensive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to quantify 10 forms of vitamin D in sera from healthy adults and patients suffering from rheumatoid arthritis (RA), type 1 diabetes (T1-D), and Alzheimer disease (AD). DESIGN: The rapid assay, validated according to US Food and Drug Administration guidelines with Chromsystems and DEQAS samples, was applied to 36 nonhealthy sera samples (41.7% male, age range of 14-95, mean = 54.00 ± 21.98 years), consisting of individuals with RA, T1-D, and AD (n = 12 each) and was compared to samples from 32 healthy individuals (50% male, age range of 19-90, mean = 58.83 ± 22.93 years). RESULTS: The key findings are (1) the 23R,25-dihydroxyvitamin D3 form was quantified for the first time (healthy = 0.427 ± 0.633 nmol/L; combined disease = 0.395 ± 0.483 nmol/L), (2) the 3-epi-25-hydroxyvitamin D3 metabolite was found in all groups with significantly higher concentration in the diseased samples [healthy = 6.093 ± 6.711 nmol/L; combined disease = 22.433 ± 13.535 nmol/L, t(52.5) = -6.411; P < .001], (3) a significant difference was found for the active form (1α-25-dihydroxyvitamin D3) between health (0.027 ± 0.035 nmol/L) and disease (0.433 ± 0.870 nmol/L) [t(35.1) = -2.797, P = 0.008], and (4) there was no significant correlation between the total circulating and total active forms in either the disease or healthy group (r = -0.180 and -0.274, respectively, with no difference between the correlation coefficients, z = -0.389, P = .697). Receiver operating characteristic curve analysis showed good sensitivity and specificity for using the 3-epi-25-hydroxyvitamin D concentration to predict disease status (area under the curve = 0.880, P < .001). Discriminant function analysis using concentrations of 23R,25-dihydroxyvitamin D3, 25-hydroxyvitamin D2, and 3-epi-25-hydroxyvitamin D classified 94.4% (91.7% in cross-validation) of the cases correctly. CONCLUSIONS: This study reveals significant differences between health and disease with epimers having the potential to relate to disease. The potential implications of the information gleaned from measuring all forms warrant application of more comprehensive assays for future clinical studies investigating the link between vitamin D and health.
24204938 A mouse model of adoptive immunotherapeutic targeting of autoimmune arthritis using allo-t 2013 OBJECTIVE: Tolerogenic dendritic cells (tDCs) are immunosuppressive cells with potent tolerogenic ability and are promising immunotherapeutic tools for treating rheumatoid arthritis (RA). However, it is currently unknown whether allogeneic tDCs (allo-tDCs) induce tolerance in RA, and whether the numbers of adoptively transferred allo-tDCs, or the requirement for pulsing with relevant auto-antigens are important. METHODS: tDCs were derived from bone marrow precursors of C57BL/B6 mice, which were induced in vitro by GM-CSF, IL-10 and TGF-β1. Collagen-induced arthritis (CIA) was modeled in D1 mice by immunization with type II collagen (CII) to test the therapeutic ability of allo-tDCs against CIA. Clinical and histopathologic scores, arthritic incidence, cytokine and anti-CII antibody secretion, and CD4(+)Th subsets were analyzed. RESULTS: tDCs were characterized in vitro by a stable immature phonotype and a potent immunosuppressive ability. Following adoptive transfer of low doses (5×10(5)) of CII-loaded allo-tDCs, a remarkable anti-arthritic activity, improved clinical scores and histological end-points were found. Serological levels of inflammatory cytokines and anti-CII antibodies were also significantly lower in CIA mice treated with CII-pulsed allo-tDCs as compared with allo-tDCs. Moreover, treatment with allo-tDCs altered the proportion of Treg/Th17 cells. CONCLUSION: These findings suggested that allo-tDCs, especially following antigen loading, reduced the severity of CIA in a dose-dependent manner. The dampening of CIA was associated with modulated cytokine secretion, Treg/Th17 polarization and inhibition of anti-CII secretion. This study highlights the potential therapeutic utility of allo-tDCs in autoimmune arthritis and should facilitate the future design of allo-tDC immunotherapeutic strategies against RA.
23899748 Aldosterone glucuronidation inhibition as a potential mechanism for arterial dysfunction a 2013 Sep OBJECTIVES: Adverse cardiovascular (CV) effects of non-steroidal anti-inflammatory drugs (NSAIDs) are largely independent of their cyclooxygenase (COX) enzyme selectivity, but could be a consequence of aldosterone 18ß-glucuronidation inhibition (AGI), which varies between NSAIDS. This study assesses the chronic effects of celecoxib (selective COX-2 inhibitor) versus diclofenac (non-selective NSAID) therapy on arterial dysfunction in patients with rheumatoid arthritis (RA). METHODS: AGI was assessed in vitro using human kidney cortical microsomes. Arterial function was measured clinically as the extent (augmentation index, AIX%) and timing (reflected wave transit time, RWTT, msec) of arterial wave reflection using radial applanation pulse wave analysis (SphygmoCor PWA device) in 39 RA patients without overt CV disease aged 40-65. A higher AIX% (and lower RWTT) indicates arterial dysfunction. Clinical assessment on a single occasion included a fasting blood sample, patient questionnaire and medical record review. Multivariable analysis was used to adjust for sex, mean blood pressure, arthritis duration, cumulative ESR-years and current DMARD therapy. RESULTS: The inhibition constant (Ki) for celecoxib was lower than that of diclofenac (Ki, 3.5 vs. 8.4 μM). Chronic celecoxib use was associated with a higher AIX% (34.8 vs. 32.3) and lower RWTT (130.1 vs. 132.7 msec) compared with diclofenac. Adjusted mean differences were AIX% 4.7 (95%CI 0.6 to 8.9; p=0.03) and RWTT -3.6 (95%CI -10.0 to 2.7; p=0.26). CONCLUSIONS: Celecoxib has a greater potency for AGI than diclofenac and its use is associated with a significantly higher AIX%. Our findings support AGI as a plausible mechanism for the CV toxicity of NSAIDs.
22466401 Does searching for antineutrophil cytoplasmic antibodies help with the diagnosis of Adult- 2013 Mar Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. It is a seronegative disease with multisystemic manifestations. One of the important laboratory findings in AOSD is negative results for rheumatoid factor and antinuclear antibody. Because there is no specific, pathognomonic test for AOSD, diagnosis is based on a set of clinical and laboratory criteria and exclusion of other diseases like infections, malignancies, and vasculitis. It is obvious that antineutrophil cytoplasmic antibodies (ANCAs) are specific for vasculitis; however, few studies detected some types of these antibodies in rheumatoid arthritis, juvenile chronic arthritis, and still's disease. The aim of this study was to investigate whether or not ANCAs exist in sera of patients with AOSD. Forty-one AOSD patients were enrolled in this prospective study; patients were diagnosed according to Yamaguchi criteria and exclusion of other diseases by at least 6-months follow-up. Sera from all patients were tested for p-ANCA and c-ANCA by indirect immunofluorescence assay. Confirmatory antigenic testing for proteinase 3 (PR3) and myeloperoxidase (MPO) ANCA subtypes then were performed on positive sera. Only one patient with AOSD in this study showed low titer of MPO-ANCA in her sera. In a 1-year follow-up, ANCA did not predict vasculitis in this patient. This study suggested that patients with AOSD are mostly seronegative for ANCAs too. Positive ANCA appears to be an epiphenomenon and has not any association with vasculitis in AOSD.
23661492 Periarticular and generalised bone loss in patients with early rheumatoid arthritis: influ 2014 Jun OBJECTIVES: The aims of this study were to investigate the influence of alendronate and intra-articular betamethasone treatment on bone mineral density (BMD) changes in hand, lumbar spine and femoral neck during 1 year of a treat-to-target study (Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA)). PATIENTS AND METHODS: A hundred and sixty patients with early, active rheumatoid arthritis (RA) received methotrexate, intra-articular betamethasone and ciclosporin /placebo-ciclosporin. Patients with Z-score ≤0 also started alendronate 10 mg/day. BMD of the hand (digital x-ray radiogrammetry (DXR-BMDhand)), BMD of lumbar spine and femoral neck (dual x-ray absorptiometry (DXA-BMDlumbar spine and DXA-BMDfemoral neck)) and x-rays of hands, wrists and forefeet (modified Sharp-van der Heijde score) were measured at baseline and 1 year, with complete data available in 107 patients. RESULTS: The change in BMD in hand, lumbar spine and femoral neck was negatively associated with the dose of intra-articular betamethasone (p<0.01 for all), but the bone loss in hand was modest and in the axial skeleton comparable with that of healthy individuals. Alendronate did not influence changes in DXR-BMDhand, which averaged -2.8%, whereas significant changes were observed in DXA-BMDlumbar spine and DXA-BMDfemoral neck in alendronate-treated patients (1.8% and 0.8%) compared with untreated patients (-1.8% and -2.2%) (p<0.01 and 0.02). Alendronate did not affect the radiographic progression (alendronate-treated patients: 0 (range 0-19), non-alendronate: 0 (0-18)). CONCLUSIONS: In early active RA, intra-articular betamethasone injections added to disease-modifying antirheumatic drug (DMARD) treatment led to minimal loss of hip and lumbar BMD, and the loss could be prevented by treatment with alendronate. Alendronate treatment did not affect radiographic progression.
23363614 Characterisation of fibroblast-like synoviocytes from a murine model of joint inflammation 2013 Jan 29 INTRODUCTION: Fibroblast-like synoviocytes (FLS) play a central role in defining the stromal environment in inflammatory joint diseases. Despite a growing use of FLS isolated from murine inflammatory models, a detailed characterisation of these cells has not been performed. METHODS: In this study, FLS were isolated from inflamed joints of mice expressing both the T cell receptor transgene KRN and the MHC class II molecule Ag7 (K/BxN mice) and their purity in culture determined by immunofluorescence and real-time reverse transcription polymerase chain reaction (real-time RT-PCR). Basal expression of proinflammatory genes was determined by real-time RT-PCR. Secreted interleukin 6 (IL-6) was measured by enzyme-linked immunosorbent assay (ELISA), and its regulation by tumor necrosis factor-alpha (TNF-α and corticosterone (the major glucocorticoid in rodents) measured relative to other mesenchymal cell populations. RESULTS: Purity of FLS culture was identified by positive expression of fibronectin, prolyl 4-hydroxylase, cluster of differentiation 90.2 (CD90.2) and 248 (CD248) in greater than 98% of the population. Cultured FLS were able to migrate and invade through matrigel, a process enhanced in the presence of TNF-α. FLS isolated from K/BxN mice possessed significantly greater basal expression of the inflammatory markers IL-6, chemokine ligand 2 (CCL-2) and vascular cell adhesion molecule 1 (VCAM-1) when compared to FLS isolated from non-inflamed tissue (IL-6, 3.6 fold; CCL-2, 11.2 fold; VCAM-1, 9 fold; P<0.05). This elevated expression was abrogated in the presence of corticosterone at 100 nmol/l. TNF-α significantly increased expression of all inflammatory markers to a much greater degree in K/BxN FLS relative to other mesenchymal cell lines (K/BxN; IL-6, 40.8 fold; CCL-2, 1343.2 fold; VCAM-1, 17.8 fold; ICAM-1, 13.8 fold; P<0.05), with secreted IL-6 mirroring these results (K/BxN; con, 169±29.7 versus TNF-α, 923±378.8 pg/ml/1×10⁵ cells; P<0.05). Dose response experiments confirmed effective concentrations between 10 and 100 nmol/l for corticosterone and 1 and 10 ng/ml for TNF-α, whilst inflammatory gene expression in FLS was shown to be stable between passages four and seven. CONCLUSIONS: This study has established a well characterised set of key inflammatory genes for in vitro FLS culture, isolated from K/BxN mice and non-inflamed wild-type controls. Their response to both pro- and anti-inflammatory signalling has been assessed and shown to strongly resemble that which is seen in human FLS culture. Additionally, this study provides guidelines for the effective characterisation, duration and treatment of murine FLS culture.
23328939 IL-17/Th17 mediated synovial inflammation is IL-22 independent. 2013 Oct BACKGROUND: Interleukin (IL)-17A and Th17 cells are critically involved in T cell-mediated synovial inflammation. Besides IL-17A, Th17 cells produce IL-22. Recently, Th22 cells were discovered, which produce IL-22 in the absence of IL-17. However, it remains unclear whether IL-22 and Th22 cells contribute to T cell-mediated synovial inflammation. Therefore, we examined the potential of IL-22 and Th22 cells to induce synovial inflammation and whether IL-22 is required for T cell-mediated experimental arthritis. METHODS: Peripheral and synovial Th17 and Th22 cells were identified and sorted from patients with rheumatoid arthritis (RA). Co-culture experiments of these primary T cell populations with RA synovial fibroblasts (RASF) were performed. The in vivo IL-22 contribution to synovial inflammation was investigated by inducing T cell-mediated arthritis in IL-22 deficient mice and wild-type mice. RESULTS: Peripheral Th17 and Th22 cell populations were increased in patients with RA and present in RA synovial fluid. In T cell-RASF co-cultures, IL-22 in the presence of IL-17A had limited effects on IL-6, IL-8, matrix metalloproteinase-1 (MMP-1) and MMP-3 production. Furthermore, primary peripheral blood and synovial Th17 cells were more potent in the induction of these factors by RASF compared with Th22 cells. In line with this, similar synovial inflammation and disease severity was found between IL-22 deficient and wild-type mice in T cell-mediated experimental arthritis. CONCLUSIONS: These findings show that IL-17A/Th17 cell-mediated synovial inflammation is independent of IL-22 and Th22 cells. This implies that targeting IL-17A/Th17 cells, rather than IL-22/Th22 cells, should be the focus for treatment of T cell-mediated synovial inflammation.