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ID PMID Title PublicationDate abstract
31203399 Baseline adenosine receptor mRNA expression in blood as predictor of response to methotrex 2019 Aug Methotrexate (MTX) reduces inflammation by increasing extracellular adenosine levels in rheumatoid arthritis (RA) patients. Adenosine acts via G-protein coupled receptors; ADORA1, ADORA2a, ADORA2b and ADORA3. We studied if baseline expression of whole blood adenosine receptors can predict response to MTX. RA patients [American College of Rheumatology/European-League-Against-Rheumatism (EULAR) 2010 criteria], Disease modifying anti-rheumatic drug (DMARD) naïve with active disease [Disease Activity Score 28 (DAS28) > 3.2] were enrolled. Blood samples were collected at baseline (n = 100) and at 4 months after therapy (n = 50). Patients were treated with MTX monotherapy. Based on EULAR response, patients were categorized into three groups i.e. good, moderate and non-responders. Adenosine receptors gene expression (ADORA1, ADORA2a, ADORA2b and ADORA3) in whole-blood RNA was measured using real-time PCR. HPRT1 was used as housekeeping gene. Receptor expression at baseline was correlated with response to MTX. All values are expressed as median (interquartile range). Hundred patients [87% females; age 40 (18) years]; duration of disease 24 (24.75) months; DAS28 4.7 (1.25) were enrolled. Fifty-one were classified as good, 28 moderate and 21 as non-responders. No expression of ADORA1 and ADORA2b was detected. Significant difference was observed in the expression levels of ADORA3 between good vs non-responder (P = 0.03) and moderate vs non-responder (P = 0.002). On ROC curve analysis, ADORA3 with cut-off value of less than - 0.60 (ΔCt) predicted non-response to MTX treatment (AUC: 0.7, P = 0.006). ADORA3 mRNA levels in whole blood may serve as a biomarker of response to MTX.
31812161 Parallel comparison of fibroblast-like synoviocytes from the surgically removed hyperplast 2019 Dec 7 BACKGROUND: Fibroblast-like synoviocytes (FLS) are essential cellular components in inflammatory joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Despite the growing use of FLS isolated from OA and RA patients, a detailed functional and parallel comparison of FLS from these two types of arthritis has not been performed. METHODS: In the present study, FLS were isolated from surgically removed synovial tissues from twenty-two patients with OA and RA to evaluate their basic cellular functions. RESULTS: Pure populations of FLS were isolated by a sorting strategy based on stringent marker expression (CD45(-)CD31(-)CD146(-)CD235a(-)CD90(+)PDPN(+)). OA FLS and RA FLS at the same passage (P2-P4) exhibited uniform fibroblast morphology. OA FLS and RA FLS expressed a similar profile of cell surface antigens, including the fibroblast markers VCAM1 and ICAM1. RA FLS showed a more sensitive inflammatory status than OA FLS with regard to proliferation, migration, apoptosis, inflammatory gene expression and pro-inflammatory cytokine secretion. In addition, the responses of OA FLS and RA FLS to both the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and the anti-inflammatory drug methotrexate (MTX) were also evaluated here. CONCLUSION: The parallel comparison of OA FLS and RA FLS lays a foundation in preparation for when FLS are considered a potential therapeutic anti-inflammatory target for OA and RA.
31429794 Efficacy and safety of intravenous golimumab plus methotrexate in patients with rheumatoid 2019 Aug 20 OBJECTIVE: To evaluate the safety and efficacy of intravenous golimumab + methotrexate (MTX) in patients with active rheumatoid arthritis (RA) aged < 65 years and those ≥ 65 years who were enrolled in the GO-FURTHER study. METHODS: In the phase III, double-blind, randomized, placebo-controlled GO-FURTHER trial, patients with active RA were randomized to intravenous (IV) golimumab 2 mg/kg + MTX or placebo + MTX at weeks 0 and 4, then every 8 weeks thereafter (with crossover to golimumab at week 16 [early escape] or week 24 [per-protocol]). The final golimumab infusion was at week 100. Assessments included American College of Rheumatology (ACR) 20/50/70 response criteria. Efficacy and adverse events (AEs) were monitored through 2 years. Efficacy and AEs were summarized for patients aged < 65 years or ≥ 65 years; AEs were also summarized for patients < or ≥ 70 years and patients < or ≥ 75 years. RESULTS: In GO-FURTHER, 592 patients were randomized to receive placebo (n = 197) or golimumab (n = 395), 515 were aged < 65 years and 77 were ≥ 65 years. At week 24, ACR20 response rates were greater for golimumab + MTX patients compared with placebo + MTX for patients < 65 years (61.6% vs 31.3%, p < 0.001) and those ≥ 65 years (69.5% vs 33.3%; p < 0.01). Infections were the most common AE through week 112 (51.6% in patients < 65 years; 55.3% in patients ≥ 65 years); upper respiratory infections were the most common infection in patients < 65 years (13.2%) and those ≥ 65 years (11.8%). Serious AEs occurred in 17.7% in patients < 65 years and 25.0% of patients ≥ 65 years and included malignancies, pneumonia, fractures, acute pancreatitis, cellulitis, and bacterial arthritis. CONCLUSIONS: In GO-FURTHER, ACR response rates were similar between patients < 65 years and patients ≥ 65 years within each treatment group. AEs in elderly patients were similar to the known safety profile of IV golimumab. Immunosenescence is known to increase the risk of infections in the elderly. Elderly patients had a numerically higher incidence of serious infections. Six malignancies occurred in golimumab-treated patients, all in patients < 65 years. TRIAL REGISTRATION: clinicaltrials.gov: NCT00973479 . Registered September 9, 2009.
30148441 Tocilizumab modulates serum levels of adiponectin and chemerin in patients with rheumatoid 2019 Mar OBJECTIVES: Adipokines play an important role in the pathophysiology of rheumatoid arthritis (RA), provide a link between the disease and overweight, contributing to explain the enhanced cardiovascular (CV) risk and influence the response to disease-modifying anti-rheumatic drugs. The aim of this study was to determine the possible effects of intravenous (IV) tocilizumab (TCZ), an interleukin-6 receptor antagonist, on serum levels of leptin, adiponectin, resistin, visfatin, and chemerin. METHODS: Forty-four RA patients with active disease (DAS28-ESR ≥3.2) were treated with IV TCZ (8 mg/kg) once every 4 weeks for six months: 20 patients received TCZ as monotherapy and 24 in association with methotrexate (MTX). At baseline and monthly, before each infusion, body mass index, DAS28-ESR and Health Assessment Questionnaire (HAQ) were recorded. The laboratory parameters, including the adipokines serum levels were collected at baseline and after six months. RESULTS: At the end of the follow-up, ESR, CRP, DAS28-ESR and HAQ resulted significantly improved in patients received TCZ as monotherapy or combined with MTX. Lipid profile showed only a significant increase of total cholesterol. A significant reduction of chemerin and an increase of adiponectin were observed in the whole population and in the subgroups of the patients analysed (TCZ mono or combined therapy) without any significant correlations with clinical and biochemical parameters. No changes in the leptin and resistin levels were detected. CONCLUSIONS: TCZ is able to regulate serum levels of chemerin and adiponectin in RA patients, independently of the disease treatment response, which contributes to explain the CV safety of TCZ.
31287230 Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Ina 2019 Nov OBJECTIVE: To evaluate the efficacy, including capacity for inhibition of radiographic progression, and safety of upadacitinib, a JAK1-selective inhibitor, as compared to placebo or adalimumab in patients with rheumatoid arthritis (RA) who have experienced an inadequate response to methotrexate (MTX). METHODS: In total, 1,629 RA patients with an inadequate response to MTX were randomized (2:2:1) to receive upadacitinib (15 mg once daily), placebo, or adalimumab (40 mg every other week) while continuing to take a stable background dose of MTX. The primary end points were achievement of an American College of Rheumatology 20% (ACR20) improvement response and a Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) of <2.6 in the upadacitinib group compared to the placebo group at week 12; inhibition of radiographic progression was evaluated at week 26. The study was also designed and powered to test for the noninferiority and superiority of upadacitinib compared to adalimumab, as measured both clinically and functionally. RESULTS: At week 12, both primary end points were met in patients receiving upadacitinib compared to those receiving placebo (P ≤ 0.001). An ACR20 improvement response was achieved by 71% of patients in the upadacitinib group compared to 36% in the placebo group, and a DAS28-CRP score of <2.6 was observed in 29% of patients receiving upadacitinib compared to 6% of patients receiving placebo. Upadacitinib was superior to adalimumab based on the ACR50 response rate, achievement of a DAS28-CRP score of ≤3.2, change in pain severity score, and change in the Health Assessment Questionnaire disability index. At week 26, more patients receiving upadacitinib than those receiving placebo or adalimumab achieved low disease activity or remission (P ≤ 0.001). Radiographic progression was significantly inhibited in patients receiving upadacitinib and was observed in fewer upadacitinib-treated patients than placebo-treated patients (P ≤ 0.001). Up to week 26, adverse events (AEs), including serious infections, were comparable between the upadacitinib and adalimumab groups. The proportions of patients with serious AEs and AEs leading to discontinuation were highest in the adalimumab group; the proportions of patients with herpes zoster and those with creatine phosphokinase (CPK) elevations were highest in the upadacitinib group. Three malignancies, 5 major adverse cardiovascular events, and 4 deaths were reported among the groups, but none occurred in patients receiving upadacitinib. Six venous thromboembolic events were reported (1 in the placebo group, 2 in the upadacitinib group, and 3 in the adalimumab group). CONCLUSION: Upadacitinib was superior to placebo and adalimumab for improving signs, symptoms, and physical function in RA patients who were receiving background MTX. In addition, radiographic progression was significantly inhibited by upadacitinib as compared to placebo. The overall safety profile of upadacitinib was generally similar to that of adalimumab, except for higher rates of herpes zoster and CPK elevations in patients receiving upadacitinib.
30656399 [Cardiovascular comorbidities in rheumatoid arthritis]. 2019 Apr Approximately 80% of patients with rheumatoid arthritis (RA) suffer from comorbidities including more than 50% from cardiovascular (CV) diseases. Inflammatory activity is the main factor connecting RA with atherosclerosis, coronary heart disease, stroke, thromboembolic events and heart failure. Altogether these affect RA patients twice as frequently as the general population and CV events are the major cause of death in RA. Besides inflammatory activity, which can be reduced or eliminated by optimal treatment and controlling the RA activity, traditional CV risk factors also contribute to the total CV risk. These risk factors, such as hypertension, diabetes and hyperlipidemia can also be found more frequently in RA patients but often remain undetected and untreated for a long time. Reducing this deficit means improvement of the life expectancy for RA patients, which has been demonstrated in studies by treatment of hyperlipoproteinemia. Among the drugs used for RA treatment non-steroidal antirheumatic drugs and glucocorticoids increase the CV risk if used in the long term. Hydroxychloroquine, methotrexate and biologics on the other hand are able to dramatically reduce the risk. Elevated CV risks of inflammatory rheumatic diseases are widely unknown in primary care. Therefore, the rheumatologist should be responsible for assessment of risk factors but in real life motivation to do so is relatively low. Some studies could demonstrate that using nursing-based standardized assessment is an excellent opportunity to reduce these deficits. Depending on the individual risk reassessment should take place every 1-5 years.
31092411 Medications associated with fracture risk in patients with rheumatoid arthritis. 2019 Aug OBJECTIVE: To examine the fracture risk with use of disease-modifying antirheumatic drugs (DMARDs), statins, proton pump inhibitors (PPIs), opioids, non-opioid analgesics and psychotropic medications in a US-wide observational rheumatoid arthritis (RA) cohort. METHODS: Patients with RA without prior fracture from 2001 through 2017 in FORWARD, a longitudinal observational registry, were assessed for osteoporosis-related site fractures (vertebra, hip, forearm and humerus). DMARD exposure was assessed in four mutually exclusive groups: (1) methotrexate monotherapy-reference, (2) tumour necrosis factor-α inhibitors (TNFi), (3) non-TNFi biologics and (4) others. Non-DMARDs and glucocorticoids were classified as current/ever use and based on treatment duration. Fracture Risk Assessment Tool (FRAX) scores estimating for 10-year major osteoporotic fractures were calculated. Cox proportional hazard models stratified by FRAX were used to adjust for confounders. RESULTS: During median (IQR) 3.0 (1.5-6.0) years of follow-up in 11 412 patients, 914 fractures were observed. The adjusted models showed a significant fracture risk increase with use of any dose glucocorticoids ≥3 months (HR (95% CI) for <7.5 mg/day 1.26 (1.07 to 1.48) and for ≥7.5 mg/day 1.57 (1.27 to 1.94)), opioids (for weak: 1.37 (1.18 to 1.59); strong: 1.53 (1.24 to 1.88)) and selective serotonin reuptake inhibitors (SSRIs) (1.37 (1.15 to 1.63)). Fracture risk with opioids increased within 1 month of use (1.66 (1.36 to 2.04)) and with SSRIs >3 months of use (1.25 (1.01 to 1.55)). Statins (0.77 (0.62 to 0.96)) and TNFi (0.72 (0.54 to 0.97)) were associated with reduction in vertebral fracture risk only. PPIs and other psychotropic medications were not associated with increased fracture risk. CONCLUSION: Use of opioids, SSRIs and glucocorticoids were associated with increased risk of any fracture in patients with RA, whereas statins and TNFi were associated with decreased vertebral fractures.
31012257 Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term fol 2019 Jul AIM: To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT. METHODS: All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5× over the upper limit of normal (ULN) were identified by multiple regression analysis. RESULTS: The study comprised 213 RA patients starting MTX. During a mean follow-up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5× ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2-20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non-alcoholic fatty liver disease. No patient developed hepatic failure. CONCLUSION: Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre-treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.
31624331 Predictive genetic biomarkers for the efficacy of methotrexate in rheumatoid arthritis: a 2020 Apr Multiple pharmacogenetic studies investigated the effectiveness of methotrexate. However, due to the use of nonvalidated outcomes, lack of validation or conflicting results it remains unclear if genetic markers can help to predict response to MTX treatment. Therefore, a systematic review was performed. PubMed was searched for articles reporting potential pharmacogenetic biomarkers associated (p < 0.05) with MTX efficacy using the validated endpoints DAS(28), EULAR, or ACR response criteria. The PICO method was used for study selection, and PRISMA guidelines to prepare the report. Thirty-five studies met the inclusion criteria, providing 39 potential genetic biomarkers in 19 genes. After Bonferroni correction, six genetic biomarkers were associated with the efficacy of MTX: ATIC rs7563206; SLC19A1 rs1051266; DHFR rs836788; TYMS rs2244500, rs2847153, and rs3786362 in at least one study. Only SLC19A1 rs1051266 was replicated in an independent cohort and promising for predicting methotrexate efficacy.
31072400 Differential synovial tissue biomarkers among psoriatic arthritis and rheumatoid factor/an 2019 May 9 BACKGROUND: Differential diagnosis among psoriatic arthritis (PsA) and seronegative rheumatoid arthritis (Ab(neg) RA) can be challenging particularly in the clinical setting of peripheral phenotype and autoantibodies seronegativity. The aim of the study was to identify synovial tissue (ST) biomarkers differentially expressed in PsA and Ab(neg) RA and test their predictive value of therapeutic response. METHODS: Thirty-four PsA patients [12 DMARD naive and 22 non-responder to methotrexate (MTX-IR)] with peripheral joint involvement and 55 Ab(neg) RA (27 DMARD naive and 28 MTX-IR) underwent US-guided ST biopsy and immunohistochemistry (IHC) for CD68(+), CD3(+), CD20(+), CD21(+), CD117(+), and CD138(+) cells. After study entry, each DMARD-naive patient started MTX therapy and was followed in an outpatient setting for at least 6 months to define the achievement of Minimal Disease Activity (PsA) and DAS remission (Ab(neg) RA) status respectively. Each IR-MTX patient was treated according to EULAR recommendations. RESULTS: At study entry, IHC analysis revealed that PsA patients had comparable levels of lining and sublining CD68(+) and sublining CD21(+), CD20(+), and CD3(+) cells than Ab(neg) RA, despite the therapeutic regimen. Moreover, regardless of the therapeutic scheme, PsA patients showed higher IHC score of CD117(+) cells (p = 0.0004 and p = 0.0005 for naive and MTX-IR patients respectively) compared to Ab(neg) RA patients. Conversely, Ab(neg) RA patients showed higher IHC score of CD138(+) cells, irrespective to the therapeutic scheme (p = 0.04 and p = 0.002 for naive and MTX-IR patients respectively). Analyzing the response rate to the therapeutic scheme, naive PsA patients reaching MDA status at 6 months follow-up, showed, at the study entry, lower IHC score of CD3(+) cells compared to PsA patients not reaching this outcome (p = 0.02); conversely, naive Ab(neg) RA patients reaching DAS remission status at 6 months follow-up, showed, at the study entry, lower IHC score of sublining CD68(+) cells compared to Ab(neg) RA patients not reaching this outcome (p < 0.001). CONCLUSIONS: CD117(+) and CD138(+) cells are differentially distributed among PsA and Ab(neg) RA. Histological analysis of ST may help to solve the clinical overlap between the two diseases and provides prognostic data about the therapy success.
31264830 Injectable Click-Crosslinked Hyaluronic Acid Depot To Prolong Therapeutic Activity in Arti 2019 Jul 17 The aim of this study was to design a click-crosslinked hyaluronic acid (HA) (Cx-HA) depot via a click crosslinking reaction between tetrazine-modified HA and trans-cyclooctene-modified HA for direct intra-articular injection into joints affected by rheumatoid arthritis (RA). The Cx-HA depot had significantly more hydrogel-like features and a longer in vivo residence time than the HA depot. Methotrexate (MTX)-loaded Cx-HA (MTX-Cx-HA)-easily prepared as an injectable formulation-quickly formed an MTX-Cx-HA depot that persisted at the injection site for an extended period. In vivo MTX biodistribution in MTX-Cx-HA depots showed that a high concentration of MTX persisted at the intra-articular injection site for an extended period, with little distribution of MTX to normal tissues. In contrast, direct intra-articular injection of MTX alone or MTX-HA resulted in rapid clearance from the injection site. After intra-articular injection of MTX-Cx-HA into rats with RA, we noted the most significant RA reversal, measured by an articular index score, increased cartilage thickness, extensive generation of chondrocytes and glycosaminoglycan deposits, extensive new bone formation in the RA region, and suppression of tumor necrosis factor-α or interleukin-6 expression. Therefore, MTX-Cx-HA injected intra-articularly persists at the joint site in therapeutic MTX concentrations for an extended period, thus increasing the duration of RA treatment, resulting in an improved relief of RA.
31892533 Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patie 2020 Mar OBJECTIVES: Anti-citrullinated protein antibodies (ACPAs) form immune complexes with citrullinated proteins binding toll-like receptor (TLR) 4, which has been proposed as a mediator of rheumatoid arthritis (RA). NI-0101 is a first-in-class humanised monoclonal antibody blocking TLR4, as confirmed by inhibition of in vivo lipopolysaccharide-induced cytokine release in healthy volunteers. This study was design to confirm preclinical investigations supporting a biomarker-driven approach for treatment of patients with RA who present positive for these immune complexes. METHODS: Placebo-controlled, double-blind, randomised (2:1) trial of the tolerability and efficacy of NI-0101 (5 mg/kg, every 2 weeks for 12 weeks) versus placebo in ACPA-positive RA patients with inadequate response to methotrexate. Efficacy measures included Disease Activity Score (28-joint count) with C reactive protein (DAS28-CRP), European League Against Rheumatism (EULAR) good and moderate responses, and American College of Rheumatology (ACR) 20, ACR50 and ACR70 responses. Subgroup analyses defined on biomarkers were conducted. Pharmacokinetics, pharmacodynamics and safety were reported. RESULTS: 90 patients were randomised (NI-0101 (61) and placebo (29)); 86 completed the study. No significant between-group difference was observed for any of the efficacy endpoints. Subgroup analyses using baseline parameters as covariants did not reveal any population responding to NI-0101. Treatment-emergent adverse events occurred in 51.7% of patients who received placebo versus 52.5% for NI-0101. CONCLUSIONS: We demonstrate for the first time that in RA, a human immune-mediated inflammatory disease, blocking the TLR4 pathway alone does not improve disease parameters. Successful targeting of innate immune pathways in RA may require broader and/or earlier inhibitory approaches.
31405169 The Abnormal CD4+T Lymphocyte Subset Distribution and Vbeta Repertoire in New-onset Rheuma 2019 Aug 10 Patients with long-term, treated, rheumatoid arthritis (RA) show abnormalities in their circulating CD4+ T-lymphocytes, but whether this occurs in recently diagnosed naïve patients to disease-modifying drugs (DMARDs) is under discussion. These patients show heterogeneous clinical response to methotrexate (MTX) treatment. We have examined the count of circulating CD4+ T-lymphocytes, and their naïve (T(N)), central memory (T(CM)), effector memory (T(EM)) and effector (T(E)) subsets, CD28 expression and Vβ TCR repertoire distribution by polychromatic flow cytometry in a population of 68 DMARD-naïve recently diagnosed RA patients, before and after 3 and 6 months of MTX treatment. At pre-treatment baseline, patients showed an expansion of the counts of CD4+ T(N), T(EM), T(E) and T(CM) lymphocyte subsets, and of total CD4+CD28- cells and of the T(E) subset with a different pattern of numbers in MTX responder and non-responders. The expansion of CD4+T(EM) lymphocytes showed a predictive value of MTX non-response(.) MTX treatment was associated to different modifications in the counts of the CD4+ subsets and of the Vβ TCR repertoire family distribution and in the level of CD28 expression in responders and non-responders. In conclusion, the disturbance of CD4+ lymphocytes is already found in DMARD-naïve RA patients with different patterns of alterations in MTX responders and non-responders.
31140226 ADORA2A Polymorphisms Influence Methotrexate Adverse Events in Rheumatoid Arthritis. 2019 May BACKGROUND: Methotrexate is the most frequently administered first-line treatment for rheumatoid arthritis (RA). The disease-modifying effects of methotrexate are mainly associated with enhanced release of free adenosine. The downstream anti-inflammatory effects of adenosine are mediated via its binding to adenosine receptor 2A (ADORA2A) and 3 (ADORA3). Many clinically important single nucleotide polymorphisms (SNPs) were reported in ADORA2A and ADORA3 genes. OBJECTIVES: To investigate whether tagging ADORA2A and ADORA3 polymorphisms influences methotrexate treatment in RA. METHODS: In total, 212 RA patients treated with methotrexate were genotyped for tagging ADORA2A (rs2298383, rs8141793, rs2236624, rs5751876, rs35320474, and rs17004921) and ADORA3 SNPs (rs2298191, rs1544223, rs78594984, rs35511654, rs2229155, rs3393, and rs3394). RESULTS: RA patients who carried ADORA3 rs35511654 G allele showed a tendency toward better response to methotrexate treatment (P = 0.054). Carriers of ADORA2A polymorphic allele rs2298383 (P = 0.011), rs2236624 (P = 0.027), rs5751876 (P = 0.018), and rs35320474 (P = 0.026) were less likely to experience methotrexate induced adverse events. All associations remained significant after adjustment for clinical factors. The effects of these polymorphisms were also significant in haplotype analyses. CONCLUSIONS: Polymorphisms in the ADORA2A gene may influence methotrexate treatment response and may be considered as a potential biomarker for methotrexate treatment in rheumatoid arthritis.
31843461 Auxiliary in vitro and in vivo biological evaluation of hydrogen peroxide sensitive prodru 2020 Jan 15 Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes severe joints damage and other extra-articular alterations. Despite the efficacy of low-dose methotrexate (LD-MTX) in RA treatment, adverse effects are the predominant reasons for discontinuation of therapy. As a therapeutic targeting strategy, the presence of increased concentrations of reactive oxygen species (ROS) in the inflammatory environment can serve as the stimulus for prodrug activation in site-selective drug delivery systems. Our group has previously reported novel ROS sensitive prodrugs (1-3) of MTX and aminopterin (AMT) for site-selective delivery to inflammatory tissue associated with RA, with the aim of reducing side effects in RA therapy. Herein, we investigate the effect and toxicity of the same prodrugs in a rat CIA (collagen-induced arthritis) model of RA. We find that prodrug 1, an arylboronic acid ROS-sensitive MTX-prodrug, displays similar in vivo efficacy as MTX at an equimolar dose, while avoiding adverse effects known to restrict MTX treatment. To further characterize prodrug 1 and its ROS mediated activation, we synthesized compound 4, a negative control lacking the boronic acid moiety. We then investigated the effect of molecules on cell proliferation and cytotoxicity in the presence of the ROS scavenger pyruvate, as well as their stability in buffer and cell media, demonstrating a direct correlation between ROS concentration and the prodrug activity. Moreover, the in vitro ADME properties were investigated, including permeability, rat plasma and microsomal stability.
30569216 Inhibition of periarticular bone loss is associated with clinical remission and ACR70-Resp 2019 Apr The aim of this study, based on a post hoc analysis of the data set used in the RAPID 1 trial, focuses on the associations between metacarpal bone mineral density, as estimated by digital X-ray radiogrammetry (DXR), and clinical remission as well as ACR70-Response in rheumatoid arthritis (RA) patients treated with certolizumab pegol (CZP). The trial evaluates a total of 345 RA patients treated with methotrexate versus CZP 200 mg versus CZP 400 mg. All patients underwent X-rays of the hand at baseline and week 52 as well as computerized calculations of bone mineral density (BMD) by DXR. Clinical remission was defined as DAS28 < 2.6. ACR70-Response was also evaluated. The radiological assessment of disease progression was estimated using the modified total Sharp Score. The mean difference for DAS28 was observed for patients treated with CZP 400 mg (median: - 3.53, minimum: - 6.77; maximum: + 0.48) and CZP 200 mg (median: - 3.13, minimum: - 6.37; maximum: - 0.52) compared to the methotrexate group (median - 2.41, minimum: - 4.76; maximum: + 0.31). The DXR-BMD showed a minor bone loss for the treatment groups undergoing therapy with CZP 200 mg (median: - 0.009 g/cm(2), minimum: - 0.059 g/cm(2); maximum: + 0.095 g/cm(2)) and CZP 400 mg (median: - 0.008 g/cm(2), minimum: - 0.064 g/cm(2); maximum: + 0.080 g/cm(2)). The methotrexate group presented an advanced periarticular metacarpal bone loss as measured by DXR-BMD (median: - 0.024 g/cm(2), minimum: - 0.102 g/cm(2); maximum: + 0.057 g/cm(2)). In the case of clinical remission and ACR70-Response, no significant change of the DXR-BMD was observed for both CZP groups. The study highlights that patients treated with CZP show a less accentuated periarticular bone loss as estimated by DXR in comparison to patients with methotrexate plus placebo. In addition, patients with clinical remission and ACR70-Response revealed no periarticular demineralisation.
30861334 Efficacy and safety of add-on tacrolimus versus leflunomide in rheumatoid arthritis patien 2019 Jun AIM: To investigate the efficacy and safety of tacrolimus (TAC) versus leflunomide (LEF) when combined with methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHOD: This was a 24-week multi-center, double-blind, randomized, non-inferiority study targeting RA patients with moderate to severe Disease Activity Score of 28 joints (DAS28 > 3.2) who showed inadequate response to MTX. Patients were randomized into TAC or LEF (add-on to MTX) groups. Initial daily doses of TAC and LEF were 1.5 and 10 mg, respectively, for 4 weeks and then doubled until the end of the study. The primary endpoint was DAS28 comparison at 24 weeks. RESULTS: Eighty-seven patients were screened in 10 centers and 75 patients were randomized into two groups. Baseline demographics were comparable between TAC + MTX and LEF + MTX groups. The TAC + MTX group was non-inferior to the LEF + MTX group in terms of DAS28 at 24 weeks (mean difference of DAS28: -0.1812, 95% confidence interval: -0.8073, 0.4450). There was a greater number of adverse events in the LEF + MTX group (66 in LEF + MTX and 49 in TAC + MTX). Six patients presented with transaminitis in the LEF + MTX group compared with two patients in the TAC + MTX group. CONCLUSION: The efficacy of TAC combined with MTX was non-inferior to LEF + MTX. It had a reasonable safety profile in RA patients with moderate to severe disease activity (http://cris.nih.go.kr; KCT0000781).
30192070 Mobile Phone Text Messages and Effect on Treatment Adherence in Patients Taking Methotrexa 2019 Oct OBJECTIVE: To assess the impact of weekly text messages on adherence in patients taking methotrexate (MTX) for rheumatoid arthritis (RA). METHODS: This prospective, randomized pilot, single-site study included patients with RA stabilized using MTX alone or combined with biologics. Participants were randomized to 3 interventions: a standard consultation (controls), a 15-minute pharmacist-led counseling session, or the receipt of text message reminders. The change over time in the Compliance Questionnaire Rheumatology (CQR-19) score between baseline and 6 months was defined as the primary outcome for adherence. Multivariable analyses and final adherence (as a composite outcome of the CQR-19 score, the Girerd score, and the medication possession ratio) were probed in sensitivity tests. Rheumatologic scales, inflammation, and patient satisfaction were also analyzed. RESULTS: A total of 96 patients (mean ± SD Disease Activity Score in 28 joints 2.42 ± 1.03) were monitored. The change over time in the CQR-19 score was significantly higher in the text message group (mean ± SD 3.32 ± 5.66; P = 0.02) than in the control group (mean ± SD 0.22 ± 6.56) and the pharmacist-led counseling group (mean ± SD -0.14 ± 7.56). Multivariable logistic regression showed that text messages remained associated with an increase in the CQR-19 score, independently of the baseline CQR-19 score (odds ratio 3.63 [95% confidence interval 1.26-10.49]; P = 0.017). In the text message group, the increase in the CQR-19 score was correlated with the Health Assessment Questionnaire score (r = -0.405, P = 0.021), and patient satisfaction was significantly higher (P < 0.01) than in the control group. CONCLUSION: Our results showed evidence of a positive impact of text messages on adherence to MTX treatment for RA. The clinical benefit and the ideal target patient remain to be determined.
31549885 Association of HLA-G 3'UTR Polymorphisms with Soluble HLA-G Levels and Disease Activity in 2020 Feb Background: Human leukocyte antigen (HLA)-G antigens are inducible non-classical major histocompatibility complex class Ib molecules which play an important role in the regulation of inflammatory processes and immunomodulation in autoimmune diseases. There are controversial reports on the impact of HLA-G gene polymorphisms on rheumatoid arthritis (RA). This study aimed at examining the impact of 14 base pair (bp) ins/del (rs66554220) and +3142G>C (rs1063320) polymorphisms and correlating these with soluble HLA-G (sHLA-G) levels to understand the susceptibility to RA in our sample cohort.Methods: Genomic DNA from 140 RA patients and 125 healthy controls was isolated using the salting out method. The genotyping of two polymorphisms of HLA-G (+3142G>C and 14 bp ins/del) was done by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and PCR method, respectively. Levels of sHLA-G were estimated by ELISA and disease activity was calculated by disease activity score (DAS28-ESR).Results: The HLA-G +3142G>C polymorphism was found to be associated with a decreased risk of RA as attributed to recessive inheritance tested model results (OR = 0.4, 95%C.I. = 0.2-0.9, p = .0313*, GG + GC versus CC). Our finding did not support an association between HLA-G 14 bp ins/del variant and risk/protection of RA. The sHLA-G levels were significantly lower in +3142GG and +3142GC RA patients as compared to healthy controls.Conclusion: HLA-G +3142G>C gene polymorphism might decrease the risk of occurrence of RA in our sample cohort as +3142CC genotype is associated with increased sHLA-G levels.Abbreviations: HLA-G: human leukocyte antigen-G; RA: rheumatoid arthritis; MHC: major histocompatibility complex; UTR: untranslated region; URR: upstream regulatory region; SLE: systemic lupus erythematous; PCR-RFLP: polymerase chain reaction restriction fragment length polymorphism; sHLA-G: soluble HLA-G; bp: base pair; ACR/EULAR: American College of Rheumatology/European League against Rheumatism; RF: rheumatoid factor; Anti-CCP: anti-cyclic citrullinated peptide; DAS28-ESR: Disease Activity Score 28- Erythrocyte Sedimentation Rate; TJC: tender joint count; SJC: swollen joint count; ESR: erythrocyte sedimentation rate; PGA: patient global assessment; HTN: hypertension; DM: diabetes mellitus; TB: tuberculosis; IEC: Institute Ethics Committee; ELISA: enzyme linked immunosorbent assay; ROC: receiver operating characteristics; AUC: area under curve; SNP: single nucleotide polymorphism; MTX: methotrexate; DMARDs: disease modifying anti-rheumatic drugs; Treg: regulatory T cells; IL: interleukinUnits: soluble HLA-G: Units/mL {U/mL}.
29464523 Methotrexate preferentially affects Tc1 and Tc17 subset of CD8 T lymphocytes. 2019 Jan Rheumatoid arthritis is considered a T-lymphocyte-mediated disease. However, studies have focussed on CD4 T-lymphocytes, ignoring CD8 T-lymphocytes despite the latter being found abundantly in the synovium. Specifically, there is little data of the effect of methotrexate, the gold-standard DMARD, on various CD8 cytokine T-lymphocyte subsets and conflicting data on CD4 subsets. In this prospective study, patients with active rheumatoid arthritis, who were 18 to 65 years of age, were treated with methotrexate (up to 25 mg per week) for 24 weeks. At baseline and 24 weeks, frequencies of CD8(+)IFNγ(+), CD8(+)IL17(+), CD8(+)IL4(+), corresponding CD4 subsets and plasma levels of IFNγ, IL-12, IL-10, IL-4 and IL-17 were determined by flow cytometry. These are summarised as median (IQR = interquartile range, 25th-75th percentile) and paired data compared using Wilcoxon signed rank test. This study included 67 patients (F/M = 4:1) with rheumatoid arthritis, 57 (85%) being RF positive and 20 receiving prednisolone at baseline. Mean (± SD) dose of methotrexate at 24 weeks was 22.9 ± 3.0 mg per week. On treatment with methotrexate, there was a significant (p = 0.04) decline in CD8(+)IFNγ(+) cells from 37.2 (IQR 19.4-60.2) to 22.7% (IQR 8.5-49.7) and a marginal increase in CD8(+)IL17(+) cells from 0.3 (IQR 0.1-0.6) to 0.4 (IQR 0.2-1.2), p = 0.006. There was no significant change in the other subsets. There was also a significant decline in circulating levels of IL-12, IL-10 and IL-17 and marginal increase in IL-4. On evaluating by response, non-responders but not responders had a significant increase in CD8(+)IL17(+) (p = 0.01). There is a significant decline of CD8(+)IFNγ(+) T cells and marginal increase in CD8(+)IL17(+) T cells after methotrexate. Change in Tc1 subset may be mediated through reduction in IL-12 levels.