Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
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| 25572282 | Population-based study of QT interval prolongation in patients with rheumatoid arthritis. | 2015 Jan | OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular morbidity and mortality. Heart rate corrected QT interval (QTc) (which is obtained from a 12-lead electrocardiogram (ECG) and reflects ventricular repolarisation duration) is a strong predictor of cardiovascular mortality. Our primary purpose is to determine the impact of QTc prolongation on mortality in RA patients. METHODS: A population-based inception cohort of patients with RA fulfilling the 1987 ACR criteria in 1988-2007 was identified, with an age- and sex-matched comparison cohort and followed until death, migration or until the end of 2008. Data were collected on ECG variables, medications known to prolong QT interval, electrolytes, cardiovascular risk factors and disease status and RA disease characteristics. Cox proportional hazards models were used to examine QTc prolongation as predictor of mortality. RESULTS: QTc prolongation prior to RA incidence/index date was similar in RA (15%) and non-RA (18%) subjects. During follow-up, the cumulative incidence of QTc prolongation was higher among RA (48% at 20 years after RA incidence) than non-RA (38% at 20 years after index date; p=0.004). Idiopathic QTc prolongation (excluding prolongations explained by ECG changes, medications, etc.) was marginally associated with all-cause mortality (HR: 1.28; 95% CI: 0.91-1.81, p=0.16), but was not associated with cardiovascular mortality (HR: 1.10; 95% CI:0.43-2.86, p=0.83) in RA. CONCLUSIONS: RA patients have a significantly elevated risk of developing QTc prolongation. However, idiopathic prolonged QTc was only marginally associated with all-cause mortality in RA patients. The clinical implications of these findings in RA require further study. | |
| 25853899 | The paradox of high availability and low recognition of soluble HLA-G by LILRB1 receptor i | 2015 | HLA-G is a regulatory molecule involved in immunologic tolerance. Growing evidence indicates that HLA-G plays a role in the regulation of inflammatory processes and autoimmune diseases. This study aimed at a systematic evaluation of soluble HLA-G (sHLA-G) in plasma of rheumatoid arthritis (RA) patients with long-lasting chronic inflammation. RA patients (n=68) and healthy controls (n=26) had their plasmatic sHLA-G measured by ELISA whereas the binding capability of sHLA-G to its cognate LILRB1 receptor was measured by a Luminex-based assay. All subjects were PCR-genotyped for HLA-G 14 bp polymorphism (rs66554220). Significantly higher sHLA-G levels were observed in patients (p<0.001), however no significant differences were observed in LILRB1 binding capacity between RA patients and controls. Remarkably, the proportion of patients presenting specific binding of sHLA-G to LILRB1 was significantly decreased as compared to controls (56% vs. 81%, p=0.027). Patients without rheumatoid factor (RF-) were significantly overrepresented in the group of patients positive for LILRB1 binding as compared to patients without LILRB1 binding (31% vs 10%, p=0.033). Furthermore, methotrexate treated patients (n=58) revealed significantly lower LILRB1 binding to sHLA-G molecules than non-treated patients (medians: 12.2 vs. 67.7 units/ml, p=0.031). Unlike in controls, no significant differences in sHLA-G levels were observed among patients grouped by 14 pb genotype. Thus, in a substantial number of late RA patients, the circulating sHLA-G molecules are impaired regarding LILRB1 recognition, meaning that although increased levels are observed; these molecules are not qualified to exert their protective functions against inflammation. Our findings offer new insights into the immunopathology of RA patients with long-lasting anti-RA-treatment and highlight the importance to also measure the binding capability of sHLA-G to LILRB1. | |
| 26342738 | Effects of Coenzyme Q10 Supplementation on Inflammatory Cytokines (TNF-α, IL-6) and Oxida | 2015 Oct | BACKGROUNDS AND AIMS: Overproduction of proinflammatory cytokines is a main trait of rheumatoid arthritis. Coenzyme Q10 (CoQ10), an endogenous antioxidant, has shown anti-inflammatory effects in some diseases. In this study we aimed to assess the effects of CoQ10 supplementation on cytokines generation and oxidative stress in rheumatoid arthritis. METHODS: In this double-blind, randomized controlled clinical trial, 44 patients with rheumatoid arthritis were recruited. Twenty two patients received 100 mg/day capsules of CoQ10 and 22 patients took placebo for 2 months. At the beginning and the end of the intervention, 7 mL of fasting blood was taken from patients to measure malondialdehyde (MDA), total antioxidant capacity (TAC), interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α). RESULTS: At the end of the study, serum MDA significantly decreased in supplemented group (mean difference = -1.47 nmol/mL; 95% confidence interval (CI), -2.52 to -0.43; p = 0.008). CoQ10 also suppressed overexpression of TNF-α (difference in median was +1.1 in placebo vs. +0.03 in CoQ10 group; p = 0.033). There was no significant difference in TAC and IL-6 levels between groups. CONCLUSIONS: This study showed beneficial effects of CoQ10 supplementation on inflammatory cytokines and oxidative stress in rheumatoid arthritis patients. | |
| 26604133 | Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4+ T cells. | 2016 Jan 15 | Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)γ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNγ expression in the rs874040(CC) memory CD4(+) T cells compared with their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA. | |
| 27898717 | Gene-Based Genome-Wide Association Analysis in European and Asian Populations Identified N | 2016 | OBJECTIVE: Rheumatoid arthritis (RA) is a complex autoimmune disease. Using a gene-based association research strategy, the present study aims to detect unknown susceptibility to RA and to address the ethnic differences in genetic susceptibility to RA between European and Asian populations. METHODS: Gene-based association analyses were performed with KGG 2.5 by using publicly available large RA datasets (14,361 RA cases and 43,923 controls of European subjects, 4,873 RA cases and 17,642 controls of Asian Subjects). For the newly identified RA-associated genes, gene set enrichment analyses and protein-protein interactions analyses were carried out with DAVID and STRING version 10.0, respectively. Differential expression verification was conducted using 4 GEO datasets. The expression levels of three selected 'highly verified' genes were measured by ELISA among our in-house RA cases and controls. RESULTS: A total of 221 RA-associated genes were newly identified by gene-based association study, including 71'overlapped', 76 'European-specific' and 74 'Asian-specific' genes. Among them, 105 genes had significant differential expressions between RA patients and health controls at least in one dataset, especially for 20 genes including 11 'overlapped' (ABCF1, FLOT1, HLA-F, IER3, TUBB, ZKSCAN4, BTN3A3, HSP90AB1, CUTA, BRD2, HLA-DMA), 5 'European-specific' (PHTF1, RPS18, BAK1, TNFRSF14, SUOX) and 4 'Asian-specific' (RNASET2, HFE, BTN2A2, MAPK13) genes whose differential expressions were significant at least in three datasets. The protein expressions of two selected genes FLOT1 (P value = 1.70E-02) and HLA-DMA (P value = 4.70E-02) in plasma were significantly different in our in-house samples. CONCLUSION: Our study identified 221 novel RA-associated genes and especially highlighted the importance of 20 candidate genes on RA. The results addressed ethnic genetic background differences for RA susceptibility between European and Asian populations and detected a long list of overlapped or ethnic specific RA genes. The study not only greatly increases our understanding of genetic susceptibility to RA, but also provides important insights into the ethno-genetic homogeneity and heterogeneity of RA in both ethnicities. | |
| 26209790 | Cardiorespiratory fitness levels and their association with cardiovascular profile in pati | 2015 Dec | OBJECTIVE: The aim of this study was to investigate the association of different physical fitness levels [assessed by the maximal oxygen uptake (VO2max) test] with cardiovascular disease (CVD) risk factors in patients with RA. METHODS: A total of 150 RA patients were assessed for cardiorespiratory fitness with a VO2max test and, based on this, were split in three groups using the 33rd (18.1 ml/kg/min) and 66th (22.4 ml/kg/min) centiles. Classical and novel CVD risk factors [blood pressure, body fat, insulin resistance, cholesterol, triglycerides, high-density lipoprotein (HDL), physical activity, CRP, fibrinogen and white cell count], 10-year CVD risk, disease activity (DAS28) and severity (HAQ) were assessed in all cases. RESULTS: Mean VO2max for all RA patients was 20.9 (s.d. 5.7) ml/kg/min. The 10-year CVD risk (P = 0.003), systolic blood pressure (P = 0.039), HDL (P = 0.017), insulin resistance and body fat (both at P < 0.001), CRP (P = 0.005), white blood cell count (P = 0.015) and fibrinogen (P < 0.001) were significantly different between the VO2max tertiles favouring the group with the higher VO2max levels. In multivariate analyses of variance, VO2max was significantly associated with body fat (P < 0.001), HDL (P = 0.007), insulin resistance (P < 0.003) and 10-year CVD risk (P < 0.001), even after adjustment for DAS28, HAQ and physical activity. CONCLUSION: VO2max levels are alarmingly low in RA patients. Higher levels of VO2max are associated with a better cardiovascular profile in this population. Future studies need to focus on developing effective behavioural interventions to improve cardiorespiratory fitness in RA. | |
| 24759686 | Subjective numeracy and preference to stay with the status quo. | 2015 Jan | BACKGROUND: Preference for the status quo, or clinical inertia, is a barrier to implementing treat-to-target protocols in patients with chronic diseases such as rheumatoid arthritis (RA). The objectives of this study were to examine the influence of subjective numeracy on RA-patient preference for the status quo and to determine whether age modifies this relationship. METHODS: RA patients participated in a single face-to-face interview. Numeracy was measured using the Subjective Numeracy Scale. Treatment preference was measured using Adaptive Conjoint Analysis. RESULTS: Of 205 eligible subjects, 156 agreed to participate. Higher subjective numeracy was associated with lower preference for the status quo in a regression model including race, employment, and use of biologics (adjusted odds ratio [95% confidence interval] = 0.71 [0.52-0.95], P = 0.02). Higher subjective numeracy was protective against status quo preferences among subjects younger than 65 years (adjusted odds ratio [95% confidence interval] = 0.64 (0.43-0.94), P = 0.02) but not among older subjects. CONCLUSIONS: Subjective numeracy is independently associated with younger, but not older, RA patients' preferences for the status quo. Our results add to the literature demonstrating age and numeracy differences in treatment preferences and medical decision-making processes. | |
| 26873159 | Association of anti-Ro/SSA antibody with response to biologics in patients with rheumatoid | 2016 Nov | OBJECTIVE: To compare the effectiveness of three different biologics in anti-Ro/SSA antibody-positive and antibody-negative patients with rheumatoid arthritis (RA). METHODS: The study subjects were 110 biologics naïve patients with RA who started treatment with biologics and examined for anti-Ro/SSA antibody between December 2003 and March 2014. For patients treated with intravenous infliximab (IFX), tocilizumab (TCZ), or abatacept (ABT), we compared the clinical characteristics and changes in composite disease activity index, such as DAS28, SDAI, and CDAI, for 12 months in anti-Ro/SSA antibody-positive and antibody-negative patients. RESULTS: We examined 59 patients (nine were positive and 50 were negative for anti-Ro/SSA antibody) treated with IFX, 27 patients (5 positive and 22 negative) treated with TCZ, and 24 patients (13 positive and 11 negative) treated with ABT. For patients treated with IFX, parameters of disease activity did not change significantly from baseline in anti-Ro/SSA antibody-positive patients, whereas they improved in antibody-negative patients. On the other hand, treatment with TCZ and ABT significantly decreased disease activity, relative to baseline, in both anti-Ro/SSA antibody-positive and antibody-negative patients. Anti-Ro/SSA antibody-positive patients treated with IFX showed higher frequency of HACA and seroconversion of ANA, and lower serum TGF-β levels. CONCLUSIONS: Positivity to anti-Ro/SSA in RA seems to confer resistance to IFX via production of HACA and ANA, and low serum TGF-β levels, but not to TCZ and ABT. | |
| 25889979 | The interface between cholinergic pathways and the immune system and its relevance to arth | 2015 Mar 31 | The nervous and immune systems are likely to be interacting in arthritis, with the possible involvement of both neural and non-neural cholinergic transmission. Centrally acting muscarinic agonists, electrical stimulation of the vagus and treatment with nicotinic receptor agonists can all act systemically to reduce inflammation, although the responsible pathways are incompletely understood. While this 'cholinergic anti-inflammatory pathway' is widely viewed as a significant pathophysiological mechanism controlling inflammation, the evidence supporting this view is critically reviewed and considered inconclusive; an alternative pathway via sympathetic nerves is implicated. This review also discusses how cholinergic pathways, both neural and non-neural, may impact on inflammation and specifically arthritis. Nicotinic agonists have been reported to reduce the incidence and severity of murine arthritis, albeit an observation we could not confirm, and clinical studies in rheumatoid arthritis have been proposed and/or are underway. While the therapeutic potential of nicotinic agonists and vagal stimulation is clear, we suggest that the 'cholinergic anti-inflammatory pathway' should not be uncritically embraced as a significant factor in the pathogenesis of rheumatoid arthritis. | |
| 25815310 | Lack of association between JAK3 gene polymorphisms and cardiovascular disease in Spanish | 2015 | Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. JAK/STAT signalling pathway is involved in autoimmune diseases and in the atherosclerotic process. JAK3 is a highly promising target for immunomodulatory drugs and polymorphisms in JAK3 gene have been associated with CV events in incident dialysis patients. Therefore, the aim of this study was to assess the potential role of JAK3 polymorphisms in the development of CV disease in patients with RA. 2136 Spanish RA patients were genotyped for the rs3212780 and rs3212752 JAK3 gene polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 539 of these patients by carotid ultrasonography (US). No statistically significant differences were found when each polymorphism was assessed according to carotid intima-media thickness values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV events after adjusting for potential confounders. In conclusion, our results do not confirm association between JAK3 polymorphisms and CV disease in RA. | |
| 25644583 | Characteristic features of tacrolimus-induced lung disease in rheumatoid arthritis patient | 2016 Feb | This paper aims to study the background and clinical characteristics of tacrolimus (TAC)-induced lung disease. A case of a rheumatoid arthritis (RA) patient who developed TAC-induced interstitial lung disease (TAC-ILD) is reported. The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) website was searched for cases of TAC-ILD and its prevalence among all cases of TAC-related adverse events. As for cases of TAC-ILD, its underlying disease, preexisting lung diseases, and fatal outcome were also searched. Literature review of TAC-ILD cases was added. A 65-year-old female RA patient with preexisting bronchiectasis developed near-fatal TAC-ILD. Amelioration of RA, ground-glass opacities in the upper, anterior, and central lung fields, and decrease in peripheral blood lymphocyte count were the major findings in this patient. A search of the PMDA website revealed the following: the prevalence of TAC-ILD was 3 % of all cases of TAC-related adverse events, 56 out of 85 RA cases (66 %), and one out of 15 other cases had a preexisting lung disease; the prevalences of fatal outcome in RA and other cases were 24 and 38 %, respectively. A few cases in the literature had preexisting ILD and developed diffuse alveolar damage. In our case, preexisting bronchiectasis, arthritis remission, newly developed ground-glass opacities (GGOs) in the upper, anterior, and central lung fields, and decrease in peripheral blood lymphocyte count were the major findings. From the search of the PMDA website, about one fourth of the cases with TAC-related lung injury had a fatal outcome, and among RA patients, two thirds had preexisting lung diseases. | |
| 26164150 | A European chart review study on early rheumatoid arthritis treatment patterns, clinical o | 2015 Nov | This retrospective medical chart review aimed to provide a current, real-world overview of biologic usage in patients with rheumatoid arthritis (RA) in Germany, Spain, and the UK, and estimate clinical and healthcare utilization outcomes associated with early versus late treatment. Adults (≥18 years) with a confirmed RA diagnosis between January 2008 and December 2010, who received biologic treatment for ≥3 months and had ≥12 months of follow-up were included. Early treatment was receipt of biologic agent ≤1 year after RA diagnosis. Outcomes included 28-joint disease activity score (DAS28) reduction of ≥1.2 from biologic start and remission (DAS28 < 2.6). Time to outcome was evaluated using Kaplan-Meier curves and log-rank tests. Of 328 patients enrolled (Germany [n = 111], Spain [n = 106], UK [n = 111]), 58.2 % received early biologic (Germany: 55.0 %, UK: 55.9 %, Spain: 64.2 %; p = 0.321). First-line biologics were more frequent in Spain (26.4 %) and Germany (19.8 %) versus the UK (7.2 %; p < 0.001). Late-treated patients were hospitalized more often than early-treated patients (10.5 vs 2.9 % [p = 0.006] for 9.0 vs 5.4 mean inpatient days [p = 0.408]). DAS28 was 5.1 at biologic initiation (n = 310); 73.5 % of patients had a DAS28 decrease of ≥1.2 and 44.5 % achieved remission. More patients had DAS28 decrease of ≥1.2 (79.2 vs 65.9 %; p = 0.009) and remission (51.1 vs 35.6 %; p = 0.007) with early versus late treatment, with a significant difference in Kaplan-Meier curves when indexing on time since diagnosis (p < 0.001) and biologic start (p = 0.024). In RA patients receiving biologic therapy, over half received biologic therapy early. Early initiation was associated with improved clinical outcomes and reduced hospitalization rates versus late treatment. | |
| 26385602 | Association of complement factor B allotypes and serum biomarkers in rheumatoid arthritis | 2015 Dec | The aim of the study was to investigate the allotypic variability of complement factor B (BF) in patients and relatives with rheumatoid arthritis (RA) and its association with serological biomarkers and clinical features of the disease. BF allotypes were determined by high-voltage agarose gel electrophoresis in serum samples of 180 patients with RA, 198 relatives and 98 controls from Southern Brazil. Anticyclic citrullinated peptide (anti-CCP), antimutated citrullinated vimentin (anti-MCV) and IgA-rheumatoid factor (RF) were determined by ELISA and IgM-RF by latex agglutination in all samples. No significant differences were found in the allotypic variants of BF between patients with RA, relatives and controls, nor associations with gender and age of RA onset. BF*S07 allotype was significantly associated with extra-articular manifestations (EAMs; Secondary Sjögren Syndrome, pneumonitis, rheumatoid nodules) in patients with RA (P = 0.02; OR = 6.62). Patients with phenotype BF F had lower positivity for anti-MCV biomarker (P = 0.02; OR = 0.22) and those with allotype BF*S had higher prevalence of this autoantibody (P = 0.02; OR = 3.77). An increased frequency of RF-IgA was detected in relatives of patients with RA with BF FS07 phenotype (P = 0.02; OR = 7.78). Complement BF variability did not influence the development of RA in the studied patients, but BF variants may act as markers of disease prognosis, such as development of EAMs, corroborating with the role of the alternative pathway in the pathogenesis of RA. | |
| 27882832 | Geographic Variation in the Quality and Cost of Care for Patients with Rheumatoid Arthriti | 2016 Dec | BACKGROUND: There is considerable push to improve value in health care by simultaneously increasing quality while lowering or containing costs. However, for diseases that are best treated with comparatively expensive treatments, such as rheumatoid arthritis (RA), there could be tension between these aims. In this study, we measured geographic variation in quality, access, and cost for patients with RA, a disease with effective but costly specialty treatments. OBJECTIVE: To assess the geographic differences in the quality, access, and cost of care for patients with RA. METHODS: Using large claims databases covering the period between 2008 and 2014, we measured quality of care metrics by metropolitan statistical areas (MSAs) for patients with RA. Quality measures included use of disease-modifying antirheumatic drugs (DMARDs) and tuberculosis (TB) screening before initiating biologic DMARD therapy. Access to care measures included measured detection and the share of patients with RA who visited a rheumatologist. Regression models were used to control for differences in patient demographics and health status across MSAs. RESULTS: For the 501,376 patients diagnosed with RA, in the average MSA 64.1% of RA patients received a DMARD, and 29.6% of RA patients initiating a biologic DMARD appropriately received a TB screening. Only 17% (73/430) of MSAs comprised the top 2 Medicare Advantage star ratings for DMARD use. Measured detection was 0.59% (IQR = 0.47%-0.71%; CV = 0.355) on average, and 57.6% (IQR = 48%-69%; CV = 0.341) of RA patients visited a rheumatologist. MSAs with the highest DMARD use spent $26,724 (in 2015 U.S. dollars) annually treating patients with RA, $5,428 more (P < 0.001) than low DMARD-use MSAs, largely because of higher pharmacy cost ($5,090 vs. $7,610, P < 0.001). However, MSAs with higher DMARD use had lower RA-related inpatient cost ($1,890 vs. $2,342, P = 0.024). CONCLUSIONS: There were significant geographic variations in the quality of care received by patients with RA, although quality was poor in most areas. Fewer than 1 in 5 MSAs could be considered high quality based on patient DMARD use. Access to specialist care may be an issue, since just over half of patients with RA visited a rheumatologist annually. Efforts to incentivize better quality of care holds promise in terms of unlocking value for patients, but for some diseases, this approach may result in higher costs. DISCLOSURES: The research reported in this manuscript was supported by AbbVie through consulting fees paid to Precision Health Economics (PHE). AbbVie and PHE collaborated to develop the study design and protocol. AbbVie and PHE participated in the interpretation of data, review, and approval of the manuscript. Shafrin and Shim are employed by PHE. Ganguli and Sanchez Gonzalez are employed by AbbVie. Seabury reports consulting fees from PHE. The results from this study were presented in poster form at the Academy of Managed Care Pharmacy's 2015 Annual Meeting and Expo; April 7-10, 2015; San Diego, California, and at the Academy of Managed Care Pharmacy's 2016 Annual Meeting and Expo; April 19-22, 2016; San Francisco, California. Study concept and design were contributed primarily by Shafrin, along with Ganguli and Seabury. Shafrin and Shim took the lead in data collection, and data interpretation was performed by Ganguli, Sanchez Gonzalez, Seabury, and Shafrin. The manuscript was written primarily by Shafrin, along with Shim and Seabury, and revised primarily by Ganguli, along with Sanchez Gonzalez and Seabury. | |
| 27041172 | Recurrent Stenosis of the Ileum Caused by Rheumatoid Vasculitis. | 2016 | A 65-year-old man with a 20-year history of rheumatoid arthritis was transferred to our hospital due to a second episode of intestinal obstruction, a fever, and joint pain within the previous 6 months. He had an extremely high rheumatoid factor level and decreased complement levels. Abdominal computed tomography, a small bowel series, and small intestinal endoscopy revealed severe ileal stenosis. Resection of the stenotic lesion was performed, and a histopathological examination revealed vasculitis. Rheumatoid vasculitis was diagnosed, and the patient began treatment with prednisolone and methotrexate, which improved his condition. Rheumatoid vasculitis is a rare, but possible cause of recurrent bowel obstruction. | |
| 26243076 | Cost-effectiveness of Tofacitinib in the Treatment of Moderate to Severe Rheumatoid Arthri | 2015 Aug | PURPOSE: This study evaluated the cost-effectiveness of introducing tofacitinib, an oral Janus kinase inhibitor, to the treatment of Korean patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs. METHODS: In this cost-utility analysis model, patients transitioned through treatment sequences based on Korean guidelines for RA patients with inadequate response to conventional disease-modifying antirheumatic drugs. Lifetime health-related quality of life and costs were evaluated. Characteristics of the model cohort were based on those reported by the Oral Rheumatoid Arthritis phase 3 triaL (ORAL) Standard randomized Controlled trial of tofacitinib or adalimumab versus placebo. Efficacy was assessed using American College of Rheumatology response rates, converted to the changes in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, based on tofacitinib clinical trials data. Published clinical trial data on discontinuation rates of the indicated drugs were incorporated in the model. The HAQ-DI scores were mapped onto utility values to calculate outcomes in terms of quality-adjusted life-years (QALYs); HAQ-DI-to-utility (EuroQoL 5D) mapping was based on data from 5 tofacitinib clinical trials. Costs were analyzed from a societal perspective, with values expressed in 2013 Korean won (KRW). Cost-effectiveness is presented in terms of incremental cost-effectiveness ratios (ICERs). One-way sensitivity analyses were performed to assess the robustness of the model. FINDINGS: First-line tofacitinib used before the standard of care (base-case analysis) increased both treatment costs and QALYs gained versus the standard-of-care treatment sequence, resulting in an ICER of KRW 13,228,910 per QALY. Tofacitinib also increased costs and QALYs gained when incorporated as a second-, third-, or fourth-line therapy. The inclusion of first-line tofacitinib increased the duration of active immunomodulatory therapy from 9.4 to 13.2 years. Tofacitinib-associated increases in costs were attributable to the increased lifetime drug costs. In sensitivity analyses, variations in input parameters and assumptions yielded ICERs in the range of KRW 6,995,719 per QALY to KRW 37,450,109 per QALY. IMPLICATIONS: From a societal perspective, the inclusion of tofacitinib as a treatment strategy for moderate to severe RA is cost-effective; this conclusion was considered robust based on multiple sensitivity analyses. The study was limited by the lack of clinical data on follow-up therapy after tofacitinib administration and a lack of long-term data on discontinuation of drug use. | |
| 25760301 | Rheumatoid arthritis: an evolutionary force in biologics. | 2015 | The advent of biologic therapy has transformed the outcomes of patients with Rheumatoid Arthritis (RA), but has also highlighted important issues for their development. Early attempts at T-cell driven therapies gave mixed results with difficulties extrapolating from non-human models to first in man trials. There is currently one T-cell modulating therapy - abatacept - licenced for use in RA. Cytokine inhibition has proven to be more fruitful with a number of anti-TNF and IL6 agents either licenced for use in RA or in development. The B-cell depleting therapy rituximab has also shown good efficacy as a chemotherapy agent repurposed for RA treatment. Overall the biologics show good efficacy in RA and have been shown to retard progression of radiographic joint damage. However, this benefit comes with a burden of increased infection risk and a financial cost significantly higher than conventional disease modifying therapies. As a result current UK licencing holds the biologics in reserve following failure of a conventional therapy and the presence of moderate to severely active disease. The long term use of the biologics in RA has highlighted the risk of immunogenicity, with significant proportions of patients developing anti-drug antibodies and losing therapeutic effect. The side effect profile and cost also raise the question around duration of therapy and trials of drug tapering following disease remission are now taking place with several biologic agents. Our inability to stratify patients to the most appropriate biologic drug (stratified or precision medicine) has also catalysed a large and critically important research agenda. Beyond identifying new biologic targets, the development of biosimilar agents will likely drive the future shape of the RA biologics market as lower cost alternatives are developed, thereby improving access to these therapies. | |
| 25713985 | Progress in biosimilar monoclonal antibody development: the infliximab biosimilar CT-P13 i | 2015 | Biosimilars are biologic medical products whose active drug substance is made by a living organism or derived from it. The term is used to describe a subsequent version of an innovator biopharmaceutical product aiming at approval following patent expiry on the reference product. Biosimilars of monoclonal need to demonstrate similar but not identical quality of nonclinical and clinical attributes. Not all data of the originator product need to be recapitulated, as large numbers of patient-years of exposure data are already available. Thus, biosimilar development is largely based on the safety profiles of the originator product. The evaluation of biosimilarity includes immunogenicity attributed risks. CT-P13 (Remsimaâ„¢/Inflectraâ„¢, Celltrion/Hospira), a biosimilar of the innovator drug infliximab (INF), was the first approved complex biosimilar monoclonal antibody in the EU, within the framework of WHO, EMA and US FDA biosimilar guidelines. CT-P13 has shown analytical and nonclinical features highly similar to INF including pharmacokinetics, efficacy, safety and immunogenicity profiles in ankylosing spondylitis and rheumatoid arthritis. The objective of this article is to highlight the recent biosimilar development and to review the results from the studies PLANETRA and PLANETAS, which have supported the approval of CT-P13 for several indications. | |
| 25773155 | Evidence of different mediators of central inflammation in dysfunctional and inflammatory | 2015 Mar 15 | The purpose of this study was to relate central inflammation to autonomic activity (heart rate variability (HRV)) in patients with rheumatoid arthritis (RA) and fibromyalgia (FM). RA patients had reduced parasympathetic activity and FM patients had increased sympathetic activity compared to healthy controls. Comparisons between RA and FM showed higher cerebrospinal fluid (CSF) interleukin (IL)-1β inversely correlated to parasympathetic activity in RA. The FM patients had higher concentrations of CSF IL-8, IL-1Ra, IL-4 and IL-10, but none of these cytokines correlated with HRV. In conclusion, we found different profiles of central cytokines, i.e., elevated IL-1β in inflammatory pain (RA) and elevated IL-8 in dysfunctional pain (FM). | |
| 27749223 | Necessity of TNF-alpha inhibitor discontinuation in rheumatoid arthritis is predicted by s | 2017 Mar | OBJECTIVES: Despite the success of TNF-alpha inhibitor (TNFi) treatment in rheumatoid arthritis (RA), a substantial number of patients necessitate discontinuation. Prediction thereof would be clinically relevant and guide the decision whether to start TNFi treatment. METHODS: Data were used from the observational BiOCURA cohort, in which patients initiating biological treatment were enrolled and followed up for one year. In the model development cohort (n=192), a model predicting TNFi discontinuation was built using Cox-regression with backward selection (p<0.05). The parameters of the model were tested again in a model refinement cohort (n=60), for significance (p<0.05) and consistency of effect. In addition, we performed a systematic review to put our study results into perspective. RESULTS: Of the 252 patients who initiated TNFi treatment, 103 (41%) had to discontinue treatment. Discontinuation was predicted at baseline by female gender, current smoking, high visual analogue scale of general health, and higher number of previously used biological disease-modifying anti-rheumatic drugs (bDMARDs). At refinement, smoking status and number of previously used bDMARDs remained with re-estimated hazard ratios (HRs) in the total cohort of 1.74 (95%-CI 1.15-2.63, p<0.01) and 1.40 (95%-CI 1.1-1.68, p<0.01), respectively. Using these two predictors, we developed a simple score predicting discontinuation (PPV=72.3%). From literature, predictors were pack years of smoking, number of previously used bDMARDs, lack of any concomitant DMARD therapy and in particular lack of concomitant methotrexate (MTX). CONCLUSIONS: TNFi discontinuation is predicted by current smoking and number of previously used bDMARDs, as well as by pack years of smoking and lack of any concomitant DMARD/MTX therapy. |