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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27432356 | Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Sli | 2017 Mar | OBJECTIVES: Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year. METHODS: The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness (ClinicalTrial.gov identifier NCT01172639). RESULTS: 98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals. CONCLUSIONS: MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed. TRIAL REGISTRATION NUMBERS: EudraCT-number 2008-007225-39 and NCT01172639; Results. | |
27180974 | Pneumocystis jirovecii pneumonia developed in a patient with rheumatoid arthritis after 14 | 2018 Nov | A 66-year-old woman who had rheumatoid arthritis and underwent a long-term treatment with methotrexate and etanercept developed Pneumocystis jirovecii pneumonia (PCP) 3 months after iguratimod add-on. Although most rheumatologists might have the impression that iguratimod has less toxicity and immunosuppressive effect compared with methotrexate and biologic disease-modifying antirheumatic drugs, this case suggests that iguratimod may increase the risk of PCP, especially in combination with other drugs. | |
25737174 | Pattern of drugs use and association with anti-mutated citrullinated vimentin antibody in | 2015 Mar | OBJECTIVES: To demonstrate the pattern of disease-modifying antirheumatic drugs (DMARDs) use in Saudi and non-Saudi rheumatoid arthritis (RA) patients, and to evaluate the association of DMARDs use with anti-mutated citrullinated vimentin (anti-MCV) positivity and other factors. METHODS: Retrospectively, for a period of 7 years (2007-2014), we studied 205 RA patients, at King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia. All patients used DMARDs. Pattern of use for all 6 DMARDs was almost the same among Saudis and non-Saudis with no significant difference (p>0.05) for each DMARD; MTX was the most commonly used DMARD (71-76%). RESULTS: There was no association between anti-MCV positivity and different DMARDs use. Methotrexate was used 76 times as combination, scoring the highest in this respect. There was a significant correlation (p<0.05) between Plaquenil with Methotrexate and with Sulfasalazine; Leflunomide with anti-TNF and with Prednisolone; age with Methotrexate and with Plaquenil; anti-MCV positivity with Prednisolone. Saudi/non-Saudi status showed no correlation with all factors or drugs. There was no significant association between DMARDs and comorbidity. CONCLUSION: Similar to worldwide results, MTX was the most commonly used DMARD; with the addition of anti-TNF to increase the effect, and folic acid to minimize the side effects. In this cohort, the pattern of use for all DMARDs was similar among Saudis and non-Saudis; treatment depended neither on anti-MCV positivity nor on the presence of comorbid conditions. A study of the association of DMARDs with disease activity is recommended. | |
27894399 | Effect of iguratimod and methotrexate on RANKL and OPG expression in serum and IL-1β-indu | 2016 Oct 31 | The receptor activator of nuclear factor κB ligand (RANKL)/receptor activator of nuclear factor κB (RANK)/osteoprotegerin (OPG) system plays a key role in rheumatoid arthritis (RA)-associated bone erosion. The upregulation of the RANKL/OPG ratio promotes bone erosion. The objective of this study is to explore the effects of iguratimod, a small-molecule disease-modifying antirheumatic drug (DMARD), alone or in combination with methotrexate (MTX), on RANKL and OPG expression in RA. We performed an enzyme-linked immunosorbent assay (ELISA) to investigate the modulatory effects of iguratimod, MTX, or their combination on serum RANKL and OPG levels of patients with RA before and after treatment for 12 and 24 weeks. Furthermore, fibroblast-like synoviocytes (FLS) from patients with RA were interleukin (IL)-1β-stimulated and then treated with different concentrations of iguratimod, MTX, or both, and RANKL and OPG expressions were investigated by using ELISA, quantitative real-time polymerase chain reaction (qPCR) and western blot analysis. We found that RANKL levels and the RANKL/OPG ratio significantly decreased in both serum and IL-1β-induced RA FLS after treatment. Moreover, combination therapy with iguratimod and MTX showed an even stronger inhibition than each drug alone did. Our results suggest that iguratimod and MTX, especially in combination, efficaciously protected against bone erosion by suppressing the production of RANKL. | |
26846283 | Methotrexate and Rheumatoid Arthritis: Current Evidence Regarding Subcutaneous Versus Oral | 2016 Mar | Methotrexate (MTX) is still considered the drug of choice in rheumatoid arthritis (RA) management. Comparing subcutaneous (MTX SC) and oral (MTX OR) routes of administration is important to optimize the everyday therapeutic strategy in the real-life setting. This review summarizes scientific evidence currently available on this topic. As shown by pharmacokinetic studies, at the same dose level, bioavailability of MTX SC is significantly higher and less variable than that of MTX OR. This difference is even more pronounced for medium-to-high dosages (i.e., >15 mg/week). With regard to clinical response (Disease Activity Score-28, American College of Rheumatology Criteria), randomized, double-blind studies and retrospective or longitudinal analyses in real-life settings showed that MTX SC is more effective than MTX OR. This is true both in MTX-naive patients with early RA, and in patients who switch from MTX OR to MTX SC due to previous treatment failure, lack of efficacy and/or adverse events. Finally, MTX SC has a better tolerability profile than MTX OR, with fewer gastroenterological side effects. Delaying the use of more expensive biological therapies by switching from MTX OR to MTX SC in non-responders might provide cost savings, with relevant implications in the management of patients with RA. FUNDING: Alfa Wassermann. | |
25145773 | Exogenous IL-2 controls the balance in Th1, Th17, and Treg cell distribution in patients w | 2015 Apr | Interleukin-2 (IL-2) has been suggested to control Treg/Th17 balance. Recently, we reported a relationship of rheumatoid arthritis (RA) activity/progression with irreversible systemic Treg and Th1 defects including serum IL-2 shortage. Herein, we explore the role of in vitro stimulation with rIL-2 in the observed immune alterations reversal. Patients with stable or progressive RA were assigned to methotrexate (MTX) group or to TNF-alpha inhibitors (iTNF) group, respectively. Flow cytometric analyses were performed before and after 6 months of treatment. Circulating Th1, Th17, and Treg cells were determined before and after 72-h culture with anti-CD3 + rIL-2. Before therapy, 72-h stimulation restored recently observed phenotypic Th cell alterations, except for the enriched Th17 subset normalized as late as after therapy in all patients. Under 6-month therapy, anti-CD3 stimulation changed the Th cell distribution only in progressive RA; despite Th1 enrichment, it revealed Treg population defects, which were completely reversed by exogenous IL-2 added to the stimulating culture. Our paper shows that in aggressive RA patients exhibiting serum IL-2 shortage despite iTNF therapy, exogenous rIL-2 is capable of promoting Treg differentiation affected by chronic activation, thus supporting its use in the combined strategy of biologic treatment of the progressive form of RA. | |
25592233 | The number of circulating monocytes as biomarkers of the clinical response to methotrexate | 2015 Jan 16 | BACKGROUND: The aim of this work was to analyze the number and distribution of circulating monocytes, and of their CD14(+high)CD16(-), CD14(+high)CD16(+) and CD14(+low)CD16(+) subset cells, in treatment-naive patients with rheumatoid arthritis (RA), and to determine their value in predicting the clinical response to methotrexate (MTX) treatment. METHODS: This prospective work investigated the number of circulating monocytes, and the numbers of CD14(+high)CD16(-), CD14(+high)CD16(+) and CD14(+low)CD16(+) subset cells, in 52 untreated patients with RA before MTX treatment, and at 3 and 6Â months into treatment, using flow cytometry. RESULTS: The absolute number of circulating monocytes, and the numbers of CD14(+high)CD16(-), CD14(+high)CD16(+) and CD14(+low)CD16(+) subset cells, were significantly higher in MTX non-responders than in responders and healthy controls before starting and throughout treatment. Responders showed normal numbers of monocytes, and of their subset cells, over the study period. The pre-treatment absolute number of circulating monocytes, and the numbers of CD14(+high)CD16(-) and CD14(+high)CD16(+) subset cells, were found to be predictive of the clinical response to MTX, with a sensitivity and specificity of >70% and >88%, respectively. CONCLUSIONS: Treatment-naive patients with RA showed an anomalous distribution of circulating monocyte subsets, and an anomalous number of cells in each subset. A higher pre-treatment number of circulating monocytes, and higher numbers of CD14(+high)CD16(-) and CD14(+high)CD16(+) subset cells, predict a reduced clinical response to MTX in untreated patients with RA. | |
26899313 | Examining Time to Initiation of Biologic Disease-modifying Antirheumatic Drugs and Medicat | 2016 Mar | PURPOSE: Little is known about the transition from nonbiologic disease-modifying antirheumatic drugs (DMARDs) to biologic DMARDs or about individual nonbiologic DMARD use patterns among patients with rheumatoid arthritis (RA). This study examined time to initiation of biologic DMARDs and nonbiologic DMARD medication adherence and persistence among Texas Medicaid recipients with RA taking nonbiologic DMARDs. METHODS: In this retrospective study (July 1, 2003-December 31, 2010) of the Texas Medicaid database, patients were aged 18 to 62 years at index, were diagnosed with RA (International Classification of Diseases, Ninth Revision, Clinical Modification, code 714.xx), had no claims for nonbiologic or biologic DMARDs in the preindex period, and had a minimum of 2 prescription claims for the same nonbiologic DMARD in the postindex period. Kaplan-Meier survival analysis and log-rank tests were used to compare time to initiation of biologic DMARDs according to nonbiologic DMARD type and therapy. Adherence and persistence were examined according to nonbiologic type and therapy by using ANOVA models and χ(2), Duncan, and t tests. FINDINGS: On average, patients were 47.9 (± 10.4) years of age, mostly female (89.1%) and Hispanic (55.2%). Methotrexate (MTX) and leflunomide (LEF) users took the shortest time to initiate biologic DMARDs (207 [190] days and 188 [205] days, respectively). LEF users had the highest mean adherence of 37.5% (27.5%), which was similar to MTX users (35.7% [26.9%]), whereas dual-therapy users had the lowest mean adherence at 17.1% (14.4%). Sulfasalazine users (108 [121] days) had the lowest persistence, whereas LEF (227 [231] days) and MTX (211 [222] days) users had the longest persistence. Nonbiologic DMARD monotherapy users were more adherent than dual-therapy users (32.6% [25.8%] vs 17.1% [14.4%]). IMPLICATIONS: These results should be interpreted in light of some study limitations, such as using proportion of days covered as a proxy for adherence, not having clinical data to control for RA severity, and lack of generalizability to all US populations. Given the study findings, both clinicians and other decision makers may want to investigate the potential driving factors of initiation of biologic DMARDs to provide effective RA management and consider patient education programs to enhance medication adherence and persistence to RA medications. | |
24746914 | Recommendations for the use of methotrexate in rheumatoid arthritis: up and down scaling o | 2015 Jan | OBJECTIVES: To describe the optimal therapeutic strategy for use of methotrexate in RA patients over the initial dose, route of administration, dose increase and decrease, patient monitoring, and use of folic/folinic acid. MATERIAL AND METHOD: Eleven clinical experts proposed some questions to be solved. A systematic literature search was conducted. The contents were selected in a work session and subsequently validated via email to establish the level of agreement. RESULTS: The initial dose of methotrexate should not be <10mg/week, preferably orally, but considering the parenteral route as an alternative due to compliance, non effectiveness of treatment or gastrointestinal side effects, polypharmacy, obesity (if required doses are >20mg/week), patient preference, very active disease or to avoid administration errors. Changing to a parenteral administration is proposed when the oral route is not effective enough, gastrointestinal toxicity appears, there is non-compliance or due to cost-effectiveness reasons before using more expensive drugs. On the contrary, due to patient preferences, intolerance to injections, dose reduction <7.5mg/week, non effectiveness of the route, poor compliance or gastrointestinal side effects. There should be a rapid dose escalation if inadequate responses occurr up to 15-20 or even 25mg/week in about 8 weeks, with increments of 2.5-5mg. The reduction will be carried out according to the dose the patient had, with decreases of 2.5-5mg every 3-6 months. Patient monitoring should be performed every 1-1.5 months until stability and then every 1-3 months. CONCLUSIONS: This document pretends to solve some common clinical questions and facilitate decision-making in RA patients treated with methotrexate. | |
27481900 | Effectiveness of Tumor Necrosis Factor Inhibitors in Combination with Various csDMARD in t | 2016 Oct | OBJECTIVE: To analyze and compare the effectiveness and drug survival in patients with rheumatoid arthritis, as measured by 28-joint Disease Activity Score (DAS28) and Health Assessment Questionnaire-Disability Index (HAQ-DI), of tumor necrosis factor inhibitor (TNFi) monotherapy, TNFi + leflunomide (LEF), TNFi + sulfasalazine (SSZ), TNFi + other conventional synthetic disease-modifying antirheumatic drugs (csDMARD), and TNFi + methotrexate (MTX) therapy, in daily practice. METHODS: Data were collected from the DREAM registry. Patients beginning their first TNFi treatment were included in the study: TNFi monotherapy (n = 320), TNFi + SSZ (n = 103), TNFi + LEF (n = 80), TNFi + other csDMARD (n = 99), TNFi + MTX alone (n = 919), TNFi + MTX + other csDMARD (n = 412). Treatment effectiveness was analyzed using DAS28 and HAQ-DI with linear mixed models and the TNFi drug survival was analyzed using Kaplan-Meier curves and Cox regression. All analyses have been corrected for confounders. RESULTS: The patients who received TNFi + MTX had significantly better DAS28 and HAQ-DI values over time (both p < 0.001) and longer TNFi drug survival than TNFi monotherapy (p < 0.001). TNFi + SSZ and TNFi + other csDMARD had significantly better DAS28 values over time (p = 0.001) and longer drug survival (p = 0.001) versus TNFi monotherapy. TNFi + LEF was not significantly better compared to monotherapy. Adding other csDMARD to the TNFi + MTX combination provided no added value. CONCLUSION: Preferably, TNFi should be prescribed together with MTX. If this is not possible, we advise the use of other csDMARD. | |
26879353 | The Longterm Effect of Early Intensive Treatment of Seniors with Rheumatoid Arthritis: A C | 2016 May | OBJECTIVE: Disease-modifying antirheumatic drugs (DMARD) have the greatest effect when initiated early. We evaluated the influence of early exposure to DMARD on time to joint replacement surgery among patients with incident rheumatoid arthritis (RA). METHOD: Using a common protocol, we undertook 2 independent population-based cohort studies of patients with incident RA aged 66 years or older in Ontario (ON) and Quebec (QC) covering the period 2000-2013. We used Cox proportional hazards regression with time-dependent variables measuring duration of drug use in the first year, separately for methotrexate (MTX) and other DMARD, adjusting for baseline demographics, clinical factors, and other potentially confounding drug exposures. Our outcome measure was any joint replacement derived from standardized procedure codes. Adjusted HR and 95% CI were estimated. RESULTS: Among 20,918 ON and 6754 QC patients with RA followed for a median of 4.5 years, 2201 and 494 patients underwent joint replacement surgery for crude event rates of 2.0 and 1.4 per 100 person-years, respectively. Greater cumulative exposure to MTX (HR 0.97, 95% CI 0.95-0.98) and other DMARD (HR 0.98, 95% CI 0.97-0.99) in the first year after diagnosis was associated with longer times to joint replacement in ON, corresponding to a 2-3% decrease in the hazard of surgery with each additional month of early use. Similar results were observed in QC. CONCLUSION: Greater duration of exposure to DMARD soon after RA diagnosis was associated with delays to joint replacement surgery in both provinces. Early intensive treatment of RA may ultimately reduce demand for joint replacement surgery. | |
26379787 | Identification of 7 Proteins in Sera of RA Patients with Potential to Predict ETA/MTX Trea | 2015 | OBJECTIVE: The recent growth of innovating biologics has opened fascinating avenues for the management of patients. In rheumatoid arthritis, many biologics are currently available, the choice of which being mostly determined empirically. Importantly, a given biologic may not be active in a fraction of patients and may even provoke side effects. Here, we conducted a comparative proteomics study in attempt to identify a predictive theranostic signature of non-response in patients with rheumatoid arthritis treated by etanercept/methotrexate combination. METHODS: A serum sample was collected prior to treatment exposure from a cohort of 22 patients with active RA. A proteomic "label free" approach was then designed to quantitate protein biomarkers using mass spectrometry. To verify these results, a relative quantification followed by an absolute quantification of interesting protein candidates were performed on a second cohort. The criterion of judgment was the response to etanercept/methotrexate combination according to the EULAR criteria assessed at 6 months of treatment. RESULTS: These investigations led to the identification of a set of 12 biomarkers with capacity to predict treatment response. A targeted quantitative analysis allowed to confirm the potential of 7 proteins from the latter combination on a new cohort of 16 patients. Two highly discriminating proteins, PROS and CO7, were further evaluated by ELISA on this second cohort. By combining the concentration threshold of each protein associated to a right classification (responders vs non-responders), the sensitivity and specificity reached 88.9 % and 100 %, respectively. CONCLUSION: Prior to methotrexate/etanercept treatment, abundance of several sera proteins, notably PROS and CO7, were associated to response status of RA patients 6 month after treatment initiation. | |
26001074 | Drug-loaded gold/iron/gold plasmonic nanoparticles for magnetic targeted chemo-phototherma | 2015 Aug | We have developed methotrexate (MTX)-loaded poly(lactic-co-glycolic acid, PLGA) gold (Au)/iron (Fe)/gold (Au) half-shell nanoparticles conjugated with arginine-glycine-aspartic acid (RGD), which can be applied for magnetic targeted chemo-photothermal treatment, and in vivo multimodal imaging of rheumatoid arthritis (RA). Upon near-infrared (NIR) irradiation, local heat is generated at the inflammation region due to the NIR resonance of Au half-shells and MTX release from PLGA nanoparticles is accelerated. The Fe half-shell layer embedded between the Au half-shell layers enables in vivo T2-magnetic resonance (MR) imaging in addition to NIR absorbance imaging. Furthermore, the delivery of the nanoparticles to the inflammation region in collagen-induced arthritic (CIA) mice, and their retention can be enhanced under external magnetic field. When combined with consecutive NIR irradiation and external magnetic field application, these nanoparticles provide enhanced therapeutic effects with an MTX dosages of only 0.05% dosage compared to free MTX therapy for the treatment of RA. | |
26474779 | Optimizing Methotrexate Treatment in Rheumatoid Arthritis: The Case for Subcutaneous Metho | 2015 Nov | Methotrexate is the most common disease-modifying antirheumatic drug (DMARD) used in the treatment of rheumatoid arthritis (RA). Current evidence supports its efficacy in the treatment of RA, resulting in improved short-term disease control and long-term outcomes in terms of radiographic progression. Oral methotrexate has traditionally been used first-line due to various reasons, including ease of administration, low cost and easy availability. A methotrexate dose of >15 mg/week is generally required for disease control but oral methotrexate may be only partially effective or poorly tolerated in some patients. The rationale for using subcutaneous (SC) methotrexate is based on its improved bioavailability at higher doses and better tolerability in some patients who have side effects when receiving oral methotrexate. Current guidance advocates 'treating to target', with the aim of inducing remission in RA patients. In some patients, this can be achieved using methotrexate alone or in combination with other traditional DMARDs. Patients who have not responded to two DMARDs, including methotrexate, are eligible for biological therapy as per current National Institute for Health and Care Excellence (NICE) guidance in the UK. Biological treatments are expensive and using SC methotrexate can improve disease control in RA patients, thus potentially avoiding or delaying the requirement for future biological treatment. | |
25991396 | Concomitant methotrexate and tacrolimus augment the clinical response to abatacept in pati | 2015 Oct | This observational retrospective study examined whether abatacept efficacy could be augmented with concomitant methotrexate (MTX) or tacrolimus (TAC) in patients with rheumatoid arthritis (RA) who experienced failure with prior biological disease-modifying antirheumatic drugs (DMARDs) and in whom favorable therapeutic efficacy is difficult to achieve. All patients with a prior biological DMARD history who were treated with abatacept for 52 weeks and registered in a Japanese multicentre registry were included. Clinical efficacy and safety of abatacept according to the concomitant drug used, i.e., none (ABT-mono), MTX (ABT-MTX), and TAC (ABT-TAC), were compared. A greater mean percent change of DAS28-ESR was observed in the ABT-TAC group compared with the ABT-mono group at weeks 12 (-20.5 vs. -5.4 %, p = 0.035) and 24 (-25.0 vs. -11.0 %, p = 0.036). ABT-MTX and ABT-TAC groups had a significantly higher proportion of patients who achieved low disease activity (LDA) within 52 weeks compared with the respective baselines, while no significant change was observed in the ABT-mono group. A higher proportion of patients in the ABT-TAC group achieved EULAR moderate response compared with the ABT-mono group at week 52 (66.7 vs. 35.0 %, p = 0.025). Multivariate logistic regression analysis revealed that concomitant TAC use was independently associated with the achievement of LDA and EULAR response at 52 weeks, while concomitant MTX use was not. Concomitant TAC use may offer a suitable option for RA patients treated with abatacept after prior biological DMARD failure, likely because both abatacept and TAC affect T cell activation. | |
25560583 | Myelosuppressive and hepatotoxic potential of leflunomide and methotrexate combination in | 2015 Feb | BACKGROUND: Safety of the combination of leflunomide and methotrexate was examined in several studies with inconclusive results. The present study was designed to compare the efficacy and safety of the combination of leflunomide and methotrexate in adjuvant-induced arthritis (AIA) in rats focusing on immunosuppressive and hepatotoxic effects. METHODS: Eighty four rats were divided into seven groups. Group 1: Sham control, group 2: the vehicle control, group 3: methotrexate group, group 4-5: leflunomide (5 and 10mg/kg/day) groups, group 6-7: combination 1 and 2 [methotrexate+leflunomide (5 and 10mg/kg/day)] groups, respectively. RESULTS: The current results indicated that combination therapies improved the ankle circumference and clinical scores compared to monotherapies; histopathological examination confirmed these findings. The myelosuppressive effect of leflunomide (10mg/kg/day) was comparable to that produced by methotrexate as indicated by the complete blood count and bone marrow cellularity; however their combination resulted in greater toxicity. Furthermore, methotrexate greatly affected the splenic histopathology compared to leflunomide and the combination therapy produced a greater effect compared to leflunomide not methotrexate. Differently, assessment of the hepatotoxic potential of the two drugs highlighted that leflunomide induced a dose-dependent increase in the fibrosis score which was higher in their magnitude than that induced by methotrexate. Leflunomide (10mg/kg/day) and combination 2 groups showed the greatest degree of liver fibrosis. CONCLUSIONS: In rats with AIA, current drug combinations provided higher therapeutic benefit compared to monotherapies, however, greater toxicities were observed. Therefore, continuous monitoring of hematologic parameters and liver function will be recommended in clinical settings. | |
25707477 | Efficacy and Safety of Anti-Interleukin-20 Monoclonal Antibody in Patients With Rheumatoid | 2015 Jun | OBJECTIVE: Interleukin-20 (IL-20) is implicated in the pathogenesis of rheumatoid arthritis (RA). The efficacy, safety, and tolerability of NNC0109-0012, a selective anti-IL-20 recombinant human monoclonal antibody (mAb), were assessed in patients with active RA who had an inadequate response to methotrexate therapy. METHODS: Sixty-seven patients with RA were enrolled and randomized (2:1) to receive NNC0109-0012 (3 mg/kg per week, subcutaneously) or placebo in a phase IIa, double-blind, 12-week trial with a 13-week followup. The primary end point was change in the Disease Activity Score in 28 joints based on C-reactive protein level (DAS28-CRP) from baseline to week 12. RESULTS: In patients treated with NNC0109-0012, the primary end point, improvement in the DAS28-CRP at week 12, was achieved (estimated difference -0.88; P = 0.02), with significant improvement starting at week 1. A greater response was observed in seropositive patients (estimated difference -1.66; P < 0.001), which was sustained through 13 weeks of followup, whereas no improvement was noted in patients with seronegative RA. A significant proportion of patients with seropositive RA receiving NNC0109-0012, compared to those receiving placebo, achieved treatment responses according to the American College of Rheumatology 20% (ACR20) (59% versus 21%), ACR50 (48% versus 14%), and ACR70 (35% versus 0%) levels of improvement, and showed greater improvements in the Health Assessment Questionnaire disability index (P = 0.047). The most frequent adverse events reported with NNC0109-0012 were injection site reactions and infections (e.g., herpes, nasopharyngitis, respiratory, and urinary). No serious infections or discontinuations associated with NNC0109-0012 were observed. CONCLUSION: In this phase IIa trial, treatment with NNC0109-0012 (anti-IL-20 mAb) was effective in patients with seropositive RA as early as week 1, with further improvements to week 12. No safety or tolerability concerns were identified with weekly NNC0109-0012 administration. | |
27217051 | Clinical-pharmacogenetic predictive models for MTX discontinuation due to adverse events i | 2017 Oct | We describe a novel approach to investigate and evaluate combined effect of a large number of clinical and pharmacogenetic factors on treatment outcome. We have used this approach to investigate predictors of methotrexate (MTX)-induced adverse events (AEs) leading to treatment discontinuation in rheumatoid arthritis (RA) patients. In total, 333 RA patients were genotyped for 34 polymorphisms in MTX transporters, folate and adenosine pathways. The effect of clinical and pharmacogenetic factors was assessed with penalized regression in the cause-specific Cox proportional hazards model. The predictive capacity was evaluated with the area under time-dependent receiver operating characteristic curve where cross-validation was applied. SLC19A1, ABCG2, ADORA3 and TYMS were associated with discontinuation because of AEs in clinical-pharmacogenetic model. Cross-validation showed that both clinical-pharmacogenetic model and nongenetic model had worthless predictive ability for MTX discontinuation because of AEs. These models could be further improved, either with additional polymorphisms or with epigenetic predictors. | |
27921185 | Hand bone loss in early rheumatoid arthritis during a methotrexate-based treat-to-target s | 2017 Apr | This study aims to investigate 1-year hand bone loss (HBL(1-year)) in early rheumatoid arthritis (RA) patients treated with a methotrexate (MTX) and intra-articular triamcinolone treat-to-target strategy +/- adalimumab and to determine if HBL(6months) is associated with radiographic progression after 2 years. In a clinical trial (OPERA) of 180 treatment-naive early RA patients, bone mineral density (BMD) was estimated from hand radiographs with digital X-ray radiogrammetry (DXR) at baseline, after 6 (n = 90) and 12 months (n = 70) of follow-up. Baseline and 2-year radiographs were scored according to the Sharp/van der Heijde method. Baseline characteristics and HBL(6months) (0-6 months changes in DXR-BMD) were investigated as predictors of structural damage by univariate linear (∆ total Sharp/van der Heijde score (TSS) as dependent variable) and logistic (+/-radiographic progression (∆TSS >0) as dependent variable) regression analyses. Variables with p < 0.10 were included in multivariable models. In 70 patients with available HBL(1-year) data, HBL(1-year) was median (interquartile range (IQR)) -1.9 (-3.3; -0.26 mg/cm(2)) in the MTX + placebo group and -1.8 (-3.6; 0.06) mg/cm(2) in the MTX + adalimumab group, p = 0.98, Wilcoxon signed-rank. Increased HBL (compared to general population reference values) was found in 26/37 and 23/33 patients in the MTX + placebo and MTX + adalimumab groups, chi-squared = 0.99. In 90 patients with HBL(6months) data and 2-year radiographic data, HBL(6months) was independently associated with ∆TSS after 2 years (β = -0.086 (95% confidence interval = -0.15; -0.025) TSS unit/mg/cm(2) increase, p = 0.006) but not with presence of radiographic progression (∆TSS >0) (OR 0.96 (0.92-1.0), p = 0.10). In early RA patients treated with a methotrexate-based treat-to-target strategy, the majority of patients had increased HBL(1-year), irrespective of adalimumab; HBL(6months) was independently associated with ∆TSS after 2 years. | |
25604080 | Methotrexate Restores Regulatory T Cell Function Through Demethylation of the FoxP3 Upstre | 2015 May | OBJECTIVE: We have previously shown, in a cohort of untreated rheumatoid arthritis (RA) patients, that the suppressive function of Treg cells is defective. However, other studies in cohorts of patients with established RA have shown that Treg cell function is normal. We hypothesized that treatment may restore Treg cell function and lead to reduced disease activity. The aim of this study was to investigate whether treatment with methotrexate (MTX) can result in epigenetic changes that lead to restoration of the Treg cell suppressive function in RA. METHODS: Peripheral blood samples from RA patients were assessed using (3) H-thymidine incorporation to measure Treg cell suppression of T cell proliferation, and by enzyme-linked immunosorbent assay to determine Treg cell suppression of interferon-γ production. CTLA-4 and FoxP3 expression was measured by flow cytometry and quantitative polymerase chain reaction (qPCR) in Treg cells from healthy individuals and RA patients. CD4+ T cells isolated from healthy individuals were cultured with interleukin-2 (IL-2), IL-6, and tumor necrosis factor α in the presence or absence of MTX, and FoxP3 expression was determined using qPCR and flow cytometry. Methylation of the FOXP3 upstream enhancer was analyzed by bisulfite sequencing PCR. RESULTS: Defective Treg cell function was observed only in RA patients who had not been treated with MTX, whereas Treg cells from MTX-exposed RA patients had restored suppressive function. This restored suppression was associated with increased expression of FoxP3 and CTLA-4 in Treg cells. Bisulfite sequencing PCR of Treg cells cultured in MTX revealed a significant reduction in methylation of the FOXP3 upstream enhancer. CONCLUSION: This study identifies a novel mechanism of action of MTX, in which treatment of RA patients with MTX restores defective Treg cell function through demethylation of the FOXP3 locus, leading to a subsequent increase in FoxP3 and CTLA-4 expression. |