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ID PMID Title PublicationDate abstract
28877868 Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid 2018 Jan OBJECTIVES: Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. METHODS: In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. RESULTS: 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). CONCLUSIONS: In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.
27688201 Do tumor necrosis factor inhibitors increase cancer risk in patients with chronic immune-m 2018 Jan Inhibition of tumor necrosis factor (TNF) activity has profoundly changed the management of several immune-mediated inflammatory diseases with great benefit for patients. The application of TNF inhibitors (TNFi), however, also brings a new concern, malignancy. We performed a systemic review to collect the studies reporting cancer incidences and risks in TNFi users regardless of indications. TNFi were most frequently used in treating patients with rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD). In RA patients without prior cancer history, the incidences of malignancies ranged from the lowest rate 0 per 1000 person-years in etanercept users regarding lymphoma to the highest rate 35.62 per 1000 person-years in adalimumab users on non-melanoma skin cancer (NMSC), while in those patients with prior cancer history, the recurrent incidences of malignancies ranged from the lowest rate 5.05 per 1000 person-years regarding melanoma to the highest rate 63.20 per 1000 person-years on basal cell carcinoma (BCC) in TNFi users. In IBD patients, incidences ranged from 0 per 1000 person-years in TNFi users on lymphoma to 34.0 per 1000 person-years in infliximab users on overall cancer. However, these incidence rates of overall cancer, lymphoma and melanoma were not higher in comparison with those patients who were not treated with TNFi. Compared to general population, incidences of lymphoma were elevated in RA patients and rates of NMSC were higher in patients with psoriasis, RA and IBD. In conclusion, cancer incidences vary across different studies, indications, cancer types and studies with different individual TNFi. Treatment with TNFi is not associated with increased malignant risks of overall cancer, lymphoma or melanoma. Results of NMSC risk were inconsistent among studies. A latest prospective registry study demonstrated a small increased risk of squamous cell cancer in RA patients treated with TNFi (one additional case for every 1600years of treatment experience). Further prospective studies are needed to verify whether TNFi users have higher NMSC risk than non-TNFi users.
30677809 Incidence rates of comorbidities among patients with psoriasis in the United States. 2018 Oct 15 Psoriasis is associated with a substantial burden of comorbidities; however, incidence rates (IRs) of these comorbidities following psoriasis diagnosis are not well characterized. Using administrative claims data from the Truven Health Analytics MarketScan Commercial and Medicare Supplemental Databases between January 1, 2002 and September 30, 2015, we compared the incidence of newly diagnosed comorbidities among patients with psoriasis versus demographically matched (birth year, gender, and geographic region) control patients without psoriasis in the United States. Comorbidities of interest were identified using ICD-9-CM codes. A total of 114,824 matched pairs of patients with psoriasis and control patients were included. IRs of all selected comorbidities were significantly higher among patients with psoriasis compared with controls (P<0.05). The most common newly diagnosed comorbidities in both groups were hyperlipidemia (psoriasis versus control, IR per 1,000 patient-years, 127.5 versus 102.8) and hypertension (94.3 versus 80.6). The greatest differences in IRs between patients with psoriasis and controls were observed for rheumatoid arthritis (9.7 versus 3.1; IR ratio [IRR], 3.15) and psoriatic arthritis (24.0 versus 0.2; IRR, 151.57). In this real-world study, patients with psoriasis were more likely to develop new selected comorbidities after diagnosis compared with demographically matched patients without psoriasis.
29730637 Comparative effectiveness of tocilizumab versus TNF inhibitors as monotherapy or in combin 2018 Sep OBJECTIVE: To compare the effectiveness of tocilizumab (TCZ) and tumour necrosis factor (TNF) inhibitors (TNFi) as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) after the use of at least one biologic DMARD (bDMARD). METHODS: We included patients with RA having used at least one bDMARD from 10 European registries. We compared drug retention using Kaplan-Meier and Cox models and Clinical Disease Activity Index (CDAI) change over time with mixed-effects models for longitudinal data. The proportions of CDAI remission and low disease activity (LDA) at 1 year were compared using LUNDEX correction. RESULTS: 771 patients on TCZ as monotherapy (TCZ mono), 1773 in combination therapy (TCZ combo), 1404 on TNFi as monotherapy (TNFi mono) and 4660 in combination therapy (TNFi combo) were retrieved. Crude median retention was higher for TCZ mono (2.31 years, 95% CI 2.07 to 2.61) and TCZ combo (1.98 years, 95% CI 1.83 to 2.11) than TNFi combo (1.37 years, 95% CI 1.30 to 1.45) and TNFi mono (1.31 years, 95% CI 1.18 to 1.47). In a country and year of treatment initiation-stratified, covariate-adjusted analysis, hazards of discontinuation were significantly lower among patients on TCZ mono or combo compared with patients on TNFi mono or combo, and TNFi combo compared with TNFi mono, but similar between TCZ mono and combo. Average adjusted CDAI change was similar between groups. CDAI remission and LDA rates were comparable between groups. CONCLUSION: With significantly longer drug retention and similar efficacy to TNFi combo, TCZ mono or combo are reasonable therapeutic options in patients with inadequate response to at least one bDMARD.
28841334 Eyelid Merkel cell carcinoma in a patient treated with golimumab. 2018 Feb PURPOSE: To describe a clinical case of biopsy-proven Merkel cell carcinoma of the eyelid following golimumab therapy for rheumatoid arthritis (RA). METHODS: Interventional case report. RESULTS: A 73-year-old woman with a history of chronic RA presented with a right upper eyelid mass. She had been treated with golimumab (tumor necrosis factor (TNF) inhibitors) injection therapy for the past 6 months. A biopsy showed findings suggestive of a Merkel cell carcinoma of the eyelid. CONCLUSIONS: Merkel cell carcinoma may be associated with anti-TNF treatment and should be included in the differential diagnosis of an eyelid tumor in patients treated with TNF inhibitors.
29419463 HLA-DRB1 Analysis Identified a Genetically Unique Subset within Rheumatoid Arthritis and D 2018 Apr OBJECTIVE: HLA-DRB1 is the most important locus associated with rheumatoid arthritis (RA) and anticitrullinated protein antibodies (ACPA). However, fluctuations of rheumatoid factor (RF) over the disease course have made it difficult to define fine subgroups according to consistent RF positivity for the analyses of genetic background and the levels of RF. METHODS: A total of 2873 patients with RA and 2008 healthy controls were recruited. We genotyped HLA-DRB1 alleles for the participants and collected consecutive data of RF in the case subjects. In addition to RF+ and RF- subsets, we classified the RF+ subjects into group 1 (constant RF+) and group 2 (seroconversion). We compared HLA-DRB1 alleles between the RA subsets and controls and performed linear regression analysis to identify HLA-DRB1 alleles associated with maximal RF levels. Omnibus tests were conducted to assess important amino acid positions. RESULTS: RF positivity was 88%, and 1372 and 970 RF+ subjects were classified into groups 1 and 2, respectively. RF+ and RF- showed similar genetic associations to ACPA+ and ACPA- RA, respectively. We found that shared epitope (SE) was more enriched in group 2 than 1, p = 2.0 × 10(-5), and that amino acid position 11 showed a significant association between 1 and 2, p = 2.7 × 10(-5). These associations were independent of ACPA positivity. SE showed a tendency to be negatively correlated with RF titer (p = 0.012). HLA-DRB1*09:01, which reduces ACPA titer, was not associated with RF levels (p = 0.70). CONCLUSION: The seroconversion group was shown to have distinct genetic characteristics. The genetic architecture of RF levels is different from that of ACPA.
29887576 [Quality characteristics and nonclinical/clinical profiles of Etanercept BS SC [MA]]. 2018 Etanercept is a dimeric genetic recombinant glycoprotein consisting of Fc domain of human Immunoglobulin G1 and the extracellular domain of human tumor necrosis factor (TNF) receptor type II. Etanercept exerts therapeutic effects on inflammatory diseases such as rheumatoid arthritis and juvenile idiopathic arthritis by neutralizing biological activities of TNFα/Lymphotoxin (LT) α. Mochida Pharmaceutical and LG Chem have developed syringe, pen, and vial products of Etanercept BS (biosimilar) as the first biosimilar of Enbrel in Japan. The active ingredient of those products "Etanercept biosimilar 1" has the identical primary structure to that of Enbrel. The development of the Etanercept BS, including evaluations of quality attributes, nonclinical and clinical studies was performed in accordance with "Policies on Assurance of Quality, Safety and Efficacy of Biosimilars". The quality attributes of Etanercept BS were similar to those of Enbrel, and the binding affinities to TNFα/LTα, TNFα neutralizing activity, nonclinical pharmacokinetics and toxicological profiles of Etanercept BS were comparable to Enbrel. Additionally, the pharmacokinetic profile and efficacy of Etanercept BS were equivalent to those of Enbrel and there was no clinically significant difference in safety profiles between them in Phase I and Phase III clinical studies. The marketing approval application of the Etanercept BS with the same indications as Enbrel filed by Mochida Pharmaceutical was approved in January 2018 and the products will be launched by Ayumi Pharmaceutical in the near future. The Etanercept BS, which is as highly effective as Enbrel is expected to make beneficial therapies more easily accessible to patients.
30426396 Risks of hepatocellular carcinoma and cirrhosis-associated complications in patients with 2018 Nov BACKGROUND/PURPOSE: Although rheumatoid arthritis (RA) has been linked to several important malignancies, data for the risks of hepatocellular carcinoma (HCC) in patients with RA are scarce. We aimed to examine the risk of HCC and cirrhosis-associated complications and the use of biologics in a national representative RA sample in Taiwan. METHODS: All study subjects aged ≥ 18 years in the Taiwan National Health Insurance program between January 1, 2000, and December 31, 2009 were enrolled. We matched RA and non-RA subjects by propensity scores in a 1:1 ratio. Our primary outcome was a diagnosis of HCC and cirrhosis-associated complications during a 10-year follow-up period. The risk of outcomes was represented as a hazard ratio (HR) calculated in Cox proportional hazard regression models. RESULTS: 24,245 RA and 24,245 non-RA subjects were included in the primary outcome analysis. Mean overall person-years (PY) of follow-up were 116,608 PY for the RA cohort, and 234,280 PY for the non-RA cohort. The overall incidence of HCC and cirrhosis-associated complications was lower in the RA cohort than in the non-RA cohort (0.66% vs. 1.41% HCC events and 1.45% vs. 1.95% cirrhosis-associated complications events during 10-year follow-up). The HRs adjusted for age, sex, the frequency of medical visits, and CCI were 0.57 (0.46-0.71) for HCC and 0.67 (0.59-0.76) for HCC and cirrhosis-associated complications. Although immunomodulatory agents may alter the risk of malignancy, use of biologics did not increase HCC risk in RA patients. CONCLUSIONS: RA is associated with a reduced risk of developing HCC and cirrhosis-associated complications. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02880306.
30402512 Reduced Activity of HDAC3 and Increased Acetylation of Histones H3 in Peripheral Blood Mon 2018 Aberrant histone acetylation and deacetylation are increasingly thought to play important roles in the pathogenesis of rheumatoid arthritis (RA). However, limited data from studies about the activity of histone deacetylases (HDACs) and histone acetyltransferase (HAT) in RA are controversial. Those conflicting results may be caused by sample size, medication, and age- and sex-matched controls. The aim of this study is to investigate the expression and activity of class I HDACs (1-3.8) and their effects on histone acetylation in peripheral blood mononuclear cells (PBMCs) from RA patients. The expression of class I HDACs in PBMCs from RA patients was decreased in both mRNA and protein levels in comparison with HCs. The nuclear HAT activities were dramatically increased. Further, we found HDAC3 activity to be the most significantly reduced in overall reduction of HDACs in the RA group. The extent of total histone H3, but not H4, acetylation in PBMCs from RA patients was increased compared to that in healthy controls (HCs) (p < 0.01). In RA PBMCs, the activity and expression of class I HDACs are decreased, which is accompanied with enhanced HAT activity. An altered balance between HDAC and HAT activity was found in RA PBMCs.
29928978 Dual-functional lipid polymeric hybrid pH-responsive nanoparticles decorated with cell pen 2018 Sep Methotrexate (MTX), as a disease modifying antirheumatic drug (DMARD), was first line drug to treat rheumatoid arthritis. However, the severe side effect during long term and high dosage usage limit its application. The aim of this study was to develop dual-functional lipid polymeric hybrid pH-responsive nanoparticles to deliver MTX to inflamed joints selectively. The designed MTX loaded stearic acid-octa-arginine and folic acid decorated poly lactic-co-glycolic acid (PLGA) -PK3-based lipid polymeric hybrid nanoparticles (Sta-R8-FA-PPLPNs/MTX) were composed of PK3, Folate-PEG-PLGA, egg PC, and Sta-R8. The nanoparticles exhibited smooth spherical morphology and particle size of 100-150 nm. The in vitro release study indicated that MTX was released faster in phosphate buffered solution (PBS) of pH 5.0 than that in PBS of pH 7.4 from Sta-R8-FA-PPLPNs/MTX. The cellular uptake study revealed that Sta-R8-FA-PPLPNs/MTX were internalized through folate receptor mediated endocytosis into activated macrophages. Therapeutic effects on adjuvant-induced arthritis (AIA) rats further confirm that Sta-R8-FA-PPLPNs/MTX could be promising against rheumatoid arthritis.
29513929 Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells: A Novel Exp 2018 Aug OBJECTIVE: To develop a new chronic rheumatoid arthritis model that is driven by the innate immune system. METHODS: Injection of a cocktail of 4 monoclonal antibodies against type II collagen, followed on days 5 and 60 by intraperitoneal injections of mannan (from Saccharomyces cerevisiae), was used to induce development of chronic arthritis in B10.Q mice. The role of the innate immune system as compared to the adaptive immune system in this arthritis model was investigated using genetically modified mouse strains. RESULTS: A new model of chronic relapsing arthritis was characterized in B10.Q mice, in which a persistently active, chronic disease was found. This relapsing disease was driven by macrophages lacking the ability to mount a reactive oxygen species response against pathogens, and was associated with the classical/alternative pathway, but not the lectin pathway, of complement activation. The disease was independent of Fcγ receptor type III, and also independent of the activity of adaptive immune cells (B and T cells), indicating that the innate immune system, involving complement activation, could be the sole driver of chronicity. CONCLUSION: Chronic active arthritis can be driven innately by macrophages without the involvement of T and B cells in the adaptive immune system.
30353269 Factors associated with long-term retention of treatment with golimumab in a real-world se 2019 Mar The retention rate of a biological drug (percentage of patients remaining on treatment over time) provides an index of a drug's overall effectiveness. The golimumab retention rate as first-line biological therapy was high in clinical trial extensions lasting 5 years. Real-world studies also indicate good retention rates but have been of shorter duration. The probability of retention with golimumab treatment was assessed, as any line of anti-tumor necrosis factor-alpha therapy, for up to 5 years in patients with rheumatoid arthritis (RA), axial spondyloarthritis (SpA) or psoriatic arthritis (PsA), associated factors were analyzed. A retrospective database analysis of the Spanish registry of patients with rheumatic disorders receiving biological drugs (BIOBADASER) was performed. Among 353 patients, 29.8% had RA, 41.6% SpA and 28.6% PsA. Golimumab was the first biological drug in 40.1% of patients, second in 30.1% and third/later in 29.8%. The overall probability of retention of golimumab at years 1, 2, 3, 4 and 5 was 85.9% (95% confidence interval 81.4-89.5%), 73.7% (67.1-79.1%), 68.5% (60.5-75.1%), 60.6% (50.2-69.5%) and 57.1% (44.9-67.5%), respectively. Retention was similar across indications (p = 0.070) but was greater when golimumab was used as the first biological agent compared with later therapy lines (p < 0.001). Factors associated with higher retention of golimumab treatment (Cox regression) were use as a first-line biological and concomitant methotrexate treatment; corticosteroid need was associated with lower retention. The long-term probability of golimumab retention was high in this real-world study of patients with rheumatic diseases, especially when used as the first biological drug.
30074624 Erythema elevatum diutinum: a case report and review of literature. 2019 Apr Erythema elevatum diutinum (EED) is a rare cutaneous leukocytoclastic vasculitis thought to be related to increased levels of circulating antibodies. It has been shown to be associated with HIV infection, tuberculosis, as well as various autoimmune diseases. A retrospective review of all cases of EED indexed in PubMed between 1990 and 2014 was performed. Inclusion criteria for articles was availability of full text in English and a biopsy-confirmed diagnosis of EED. All other articles were excluded. Cases were stratified by age and anatomic location of the lesions. Treatment response was coded as "complete," "partial," and "none." A total of 133 cases of EED with 381 lesions detailed in case reports and case series were included. Twenty-one cases were associated with HIV. Of 47 patients with reported paraproteinemias, IgA paraproteinemia was found in 57.45%, IgG paraproteinemia in 29.8%, IgM paraproteinemia in 10.6%, and IgD paraproteinemia in 2.1% of cases. Of 40 (30.1%) patients with reported comorbid autoimmune disease, rheumatoid arthritis was associated with 10 cases. Cancer was found to be associated with 9.77% of cases. Seventy-five patients were treated with dapsone, with 36 (48%) achieving complete treatment response, 24 (32%) achieving partial response, and seven (9.3%) achieving no response. Keeping the clinical associations of EED in mind, especially malignancy, is critical in management of the disease. More structured studies need to take place in order to fully define the mechanisms and strength of these associations.
29621160 Therapeutic Potential and Recent Advances of Curcumin in the Treatment of Aging-Associated 2018 Apr 5 Curcumin, a low molecular weight, lipophilic, major yellow natural polyphenolic, and the most well-known plant-derived compound, is extracted from the rhizomes of the turmeric (Curcuma longa) plant. Curcumin has been demonstrated as an effective therapeutic agent in traditional medicine for the treatment and prevention of different diseases. It has also shown a wide range of biological and pharmacological effects in drug delivery, and has actively been used for the treatment of aging-associated diseases, including cardiovascular diseases, atherosclerosis, neurodegenerative diseases, cancer, rheumatoid arthritis, ocular diseases, osteoporosis, diabetes, hypertension, chronic kidney diseases, chronic inflammation and infection. The functional application and therapeutic potential of curcumin in the treatment of aging-associated diseases is well documented in the literature. This review article focuses mainly on the potential role of plant-derived natural compounds such as curcumin, their mechanism of action and recent advances in the treatment of aging-associated diseases. Moreover, the review briefly recaps on the recent progress made in the preparation of nanocurcumins and their therapeutic potential in clinical research for the treatment of aging-associated diseases.
29142040 Use of Disease-modifying Antirheumatic Drugs for Inflammatory Arthritis in US Veterans: Ef 2018 Mar OBJECTIVE: To evaluate the effect of access to and distance from rheumatology care on the use of disease-modifying antirheumatic drugs (DMARD) in US veterans with inflammatory arthritis (IA). METHODS: Provider encounters and DMARD dispensations for IA (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) were evaluated in national Veterans Affairs (VA) datasets between January 1, 2015, and December 31, 2015. RESULTS: Among 12,589 veterans with IA, 23.5% saw a rheumatology provider. In the general IA population, 25.3% and 13.6% of veterans were exposed to a synthetic DMARD (sDMARD) and biologic DMARD (bDMARD), respectively. DMARD exposure was 2.6- to 3.4-fold higher in the subpopulation using rheumatology providers, compared to the general IA population. The distance between veterans' homes and the closest VA rheumatology site was < 40 miles (Near) for 55.9%, 40-99 miles (Intermediate) for 31.7%, and ≥ 100 miles (Far) for 12.4%. Veterans in the Intermediate and Far groups were less likely to see a rheumatology provider than veterans in the Near group (RR = 0.72 and RR = 0.49, respectively). Exposure to bDMARD was 34% less frequent in the Far group than the Near group. In the subpopulation who used rheumatology care, the bDMARD exposure discrepancy did not persist between distance groups. CONCLUSION: Use of rheumatology care and DMARD was low for veterans with IA. DMARD exposure was strongly associated with rheumatology care use. Veterans in the general IA population living far from rheumatology sites accessed rheumatology care and bDMARD less frequently than veterans living close to rheumatology sites.
28541464 Quality and Usability of Arthritic Pain Self-Management Apps for Older Adults: A Systemati 2018 Mar 1 OBJECTIVE: To appraise the quality and usability of currently available pain applications that could be used by community-dwelling older adults to self-manage their arthritic pain. METHODS: A systematic review. Searches were conducted in App Store and Google Play to identify pain self-management apps relevant to arthritic pain management. English language pain management apps providing pain assessment and documentation function and pain management education were considered for inclusion. A quality evaluation audit tool based on the Stanford Arthritis Self-Management Program was developed a priori to evaluate app content quality. The usability of included apps was assessed using an established usability evaluation tool. RESULTS: Out of the 373 apps that were identified, four met the inclusion criteria. The included apps all included a pain assessment and documentation function and instructions on medication use, communication with health professionals, cognitive behavioral therapy-based pain management, and physical exercise. Management of mood, depression, anxiety, and sleep were featured in most apps (N = 3). Three-quarters (N = 3) of the apps fell below the acceptable moderate usability score (≥3), while one app obtained a moderate score (3.2). CONCLUSIONS: Few of the currently available pain apps offer a comprehensive pain self-management approach incorporating evidence-based strategies in accordance with the Stanford Arthritis Self-Management Program. The moderate-level usability across the included apps indicates a need to consider the usability needs of the older population in future pain self-management app development endeavors.
30183595 Efficacy and safety of certolizumab pegol in combination with methotrexate in methotrexate 2019 Mar OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) in Chinese patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: This 24-week, phase 3, double-blind, placebo-controlled study was conducted in 30 centres across China. A total of 430 patients were randomised 3:1 to receive CZP 200 mg every 2 weeks (loading dose: 400 mg CZP at Weeks 0, 2 and 4) plus MTX or placebo (PBO) plus MTX. The primary endpoint was ACR20 response at Week 24, for which the superiority of CZP+MTX over PBO+MTX was evaluated. Additional parameters for clinical efficacy, health outcomes, immunogenicity and safety were assessed. RESULTS: At Week 24, 54.8% of CZP+MTX patients and 23.9% of PBO+MTX patients achieved ACR20 (odds ratio: 3.9, p<0.001). CZP+MTX patients also achieved greater improvements in HAQ-DI, higher ACR50/70 responses and higher DAS28(ESR) remission rate at Week 24. Rapid onset of response to CZP+MTX was observed as early as Week 1 for most of the clinical, functional and patient-reported outcomes. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment arms. Serious TEAEs were reported by 6.3% of CZP+MTX patients and 2.7% of PBO+MTX patients. No new safety signals were observed. CONCLUSIONS: CZP in combination with MTX showed an acceptable safety profile, a rapid onset of response and sustained effects in reducing the signs and symptoms of RA and improving physical function in Chinese patients with RA and an inadequate response to MTX.
29532531 Defective glucose and lipid metabolism in rheumatoid arthritis is determined by chronic in 2018 Jul BACKGROUND: Rheumatoid arthritis (RA) patients are at increased risk of insulin resistance (IR); however, the specific mechanisms mediating this association are currently unknown. OBJECTIVE: To investigate whether the inflammatory activity associated with RA accounts for the observed defective glucose metabolism and lipid metabolism in these patients. METHODS: We followed two main strategies: (i) extensive metabolic profiling of a RA cohort of 100 patients and 50 healthy control subjects and (ii) mechanistic studies carried out in both a collagen-induced arthritis mouse model and 3T3-L1 adipocytes treated with conditioned serum from RA patients. RESULTS: Following the exclusion of obese and diabetic subjects, data from RA patients demonstrated a strong link between the degree of systemic inflammation and the development of IR. These results were strengthened by the observation that induction of arthritis in mice resulted in a global inflammatory state characterized by defective carbohydrate and lipid metabolism in different tissues. Adipose tissue was most susceptible to the RA-induced metabolic alterations. These metabolic effects were confirmed in adipocytes treated with serum from RA patients. CONCLUSIONS: Our results show that the metabolic disturbances associated with RA depend on the degree of inflammation and identify inflammation of adipose tissue as the initial target leading to IR and the associated molecular disorders of carbohydrate and lipid homeostasis. Thus, we anticipate that therapeutic strategies based on tighter control of inflammation and flares could provide promising approaches to normalize and/or prevent metabolic alterations associated with RA.
30398879 Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Ant 2018 Dec 3 The prostaglandin E(2) receptor, EP2, plays an important role in physiology and in a variety of pathological conditions. Studies indicate that EP2 is pro-inflammatory in chronic peripheral and central nervous system disease and cancer models. Thus, targeting the EP2 receptor with small molecules could be a therapeutic strategy for treating inflammatory diseases and cancer. We recently reported a novel class of competitive antagonists of the EP2 receptor. However, earlier leads displayed low selectivity against the DP1 prostanoid receptor, moderate plasma half-life, and low aqueous solubility, which renders them suboptimal for testing in animal models of disease. We now report a novel compound TG8-69, which has suitable drug-like properties. We present synthesis, lead-optimization studies, pharmacological characterization, and anti-inflammatory properties of this compound that support its use in chronic peripheral inflammatory diseases, including rheumatoid arthritis, endometriosis, and cancer, in which EP2 appears to play a pathogenic role.
29490676 Pharmacological characterisation of CR6086, a potent prostaglandin E(2) receptor 4 antagon 2018 Mar 1 BACKGROUND: Prostaglandin E(2) (PGE(2)) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD). METHODS: CR6086 affinity and pharmacodynamics were studied in EP4-expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively. In immune cells, IL-6 and vascular endothelial growth factor (VEGF) expression were analysed by RT-PCR, and IL-23 and IL-17 release were measured by enzyme-linked immunosorbent assay (ELISA). In collagen-induced arthritis (CIA) models, rats or mice were immunised with bovine collagen type II. Drugs were administered orally (etanercept and methotrexate intraperitoneally) starting at disease onset. Arthritis progression was evaluated by oedema, clinical score and histopathology. Anti-collagen II immunoglobulin G antibodies were measured by ELISA. RESULTS: CR6086 showed selectivity and high affinity for the human EP4 receptor (K(i) = 16.6 nM) and functioned as a pure antagonist (half-maximal inhibitory concentration, 22 nM) on PGE(2)-stimulated cAMP production. In models of human immune cells in culture, CR6086 reduced key cytokine players of RA (IL-6 and VEGF expression in macrophages, IL-23 release from dendritic cells, IL-17 release from Th17 cells). In the CIA model of RA in rats and mice, CR6086 significantly improved all features of arthritis: severity, histology, inflammation and pain. In rats, CR6086 was better than the selective cyclooxygenase-2 inhibitor rofecoxib and at least as effective as the Janus kinase inhibitor tofacitinib. In mice, CR6086 and the biologic DMARD etanercept were highly effective, whereas the non-steroidal anti-inflammatory drug naproxen was ineffective. Importantly, in a study of CR6086/methotrexate, combined treatment greatly improved the effect of a fully immunosuppressive dose of methotrexate. CONCLUSIONS: CR6086 is a novel, potent EP4 antagonist showing favourable immunomodulatory properties, striking DMARD effects in rodents, and anti-inflammatory activity targeted to immune-mediated inflammatory diseases and distinct from the general effects of cyclooxygenase inhibitors. These results support the clinical development of CR6086, both as a stand-alone DMARD and as a combination therapy with methotrexate. The proof-of-concept trial in patients with RA is ongoing.