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ID PMID Title PublicationDate abstract
26420684 Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc 2015 Sep 30 BACKGROUND: The identification of biomarkers that predict optimal and individual choices of treatment for patients with rheumatoid arthritis gains increasing attention. The purpose of this study was to investigate if the proto-oncogene survivin might aid in treatment decisions in early rheumatoid arthritis. METHODS: Serum survivin levels were measured in 302 patients who completed the Swedish pharmacotherapy (SWEFOT) trial at baseline, 3, 12, and 24 months. Survivin levels > 0.45 ng/mL were considered positive. Based on the survivin status, core set outcomes measuring disease activity, functional disability, as well as global health and pain were evaluated after methotrexate (MTX) monotherapy at 3 months, and at 12 and 24 months of follow-up. Treatment of non-responders was randomly intensified with either a combination of disease-modifying antirheumatic drugs (triple therapy: MTX, sulfasalazine, and hydroxychloroquine) or by adding antibodies against tumor necrosis factor (anti-TNF). RESULTS: Antirheumatic treatment resulted in an overall decrease of serum survivin levels. Survivin-positive patients at baseline who initially responded to MTX had a higher risk of disease re-activation (OR 3.21 (95% CI 1.12-9.24), P = 0.032) and failed to improve in their functional disability (P = 0.018) if having continued on MTX monotherapy compared to survivin-negative patients. Ever-smokers who were survivin-positive were less likely to respond to MTX than those who were survivin-negative (OR 1.91 (1.01-3.62), P = 0.045). In survivin-positive patients, triple therapy led to better improvements in disease activity than did MTX + anti-TNF. At 24 months, survivin-positive patients randomized to anti-TNF had a higher risk of active disease than those randomized to triple therapy (OR 3.15 (1.09-9.10), P = 0.037). DISCUSSION: We demonstrate for the first time that survivin is a valuable serologic marker that can distinguish drug-specific clinical responses in early rheumatoid arthritis through the pragmatic clinical setting of the care-based SWEFOT trial. Although treatment response cannot solely be attributable to survivin status, per protocol sensitivity analyses confirmed the superior effect of triple therapy on survivin-positive patients. CONCLUSIONS: Survivin-positive patients have poor outcomes if treated with MTX monotherapy. A decrease of survivin levels during treatment is associated with better clinical responses. For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy. TRIAL REGISTRATION: WHO database at the Karolinska University Hospital: CT20080004 ; ClinicalTrials.gov: NCT00764725, registered 1 October 2008.
27993829 Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combinati 2017 Jun OBJECTIVES: To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX. METHODS: In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response. RESULTS: Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100  or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported. CONCLUSIONS: Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated. TRIAL REGISTRATION NUMBER: NCT01888874.
25979151 Temperature-responsive polymeric nanospheres containing methotrexate and gold nanoparticle 2015 Sep 1 Inflammation plays a crucial role in rheumatoid arthritis progress. In the present work, a novel stealth polymeric nanospheres platform able to carry anti-inflammatory drugs and an imaging agent was developed. Incorporation of gold nanoparticles will allow photoacoustic imaging and near infra-red photothermal application. Through emulsion-diffusion evaporation technique methotrexate and gold nanoparticles were incorporated in the pegylated-poly(DL-lactic-co-glycolic acid) nanospheres. In vitro drug release assays revealed pH and temperature-dependence on gold nanoparticles. Blank nanospheres exhibited negligible in vitro cytotoxicity, while methotrexate-loaded nanospheres hampered monocytes and macrophages viability at a higher level than free methotrexate. Confocal fluorescent microscopy and flow cytometry revealed effective nanospheres internalization, and that their cellular uptake was energy dependent mediated by caveolae and clathrin-endocytosis mechanism. Finally, MTX-loaded multifunctional nanospheres containing gold lead to a significant reduction of IL-1β, IL-6 and TNF-α inflammatory cytokines produced by monocytes and macrophages upon in vitro inflammatory stimulation, suggesting a favorable anti-inflammatory activity. These results confirm that the multifunctional nanospheres represent a promising theranostic platform for RA diagnosis and intracellular treatment, by combining methotrexate and gold nanoparticles for a highly effective targeted chemo-photothermal therapy.
26724937 Utilization of Subcutaneous Methotrexate in Rheumatoid Arthritis Patients After Failure or 2016 Jan INTRODUCTION: Low-dose weekly methotrexate (MTX) is the mainstay in the therapy of rheumatoid arthritis (RA). It can be given via oral, intramuscular or subcutaneous (SC) route. This study sought to determine the real-world pattern of treatment with SC MTX in Portuguese adult patients with active RA. METHODS: Utilization of Metoject(®) in Rheumatoid Arthritis (UMAR) was a non-interventional, cohort multicenter study with retrospective data collection. Eligible patients had active RA, at least 18 years of age, and started SC MTX treatment in 2009 or 2010 after failure or intolerance to oral MTX. Data were collected from patient's clinical records. Both non-parametric and parametric survival methods were used to obtain a detailed understanding of SC MTX treatment duration. RESULT: Fifty patients were included, of which only 9 discontinued SC MTX during the study follow-up period. The probability of discontinuation after 1, 2, and 3 years of treatment of SC MTX treatment is expected to be 6.10%, 8.50%, and 23.20%, respectively. The extrapolated median duration of SC MTX using an exponential model was 106.4 months/8.87 years. Mean dose of SC MTX was 18.36 mg. The reasons for treatment discontinuation were occurrence of adverse events in six patients and lack of efficacy in three. CONCLUSION: The long treatment duration of SC MTX highlights its excellent tolerability compared to oral MTX, especially concerning the frequent adverse gastrointestinal events of MTX. Furthermore, long MTX treatment duration provides the opportunity to postpone or even avoid expensive therapies with biologics. The results obtained from the UMAR study provide important information for the utilization and public financing of SC MTX in Portugal.
26473625 Patient-Reported Outcomes From a Two-Year Head-to-Head Comparison of Subcutaneous Abatacep 2016 Jul OBJECTIVE: To report 2-year patient-reported outcomes (PROs) from the head-to-head Abatacept versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate (MTX) (AMPLE) trial. METHODS: AMPLE was a phase IIIb, randomized, investigator-blinded trial. Biologic-naive patients with rheumatoid arthritis (RA) and an inadequate response to MTX were randomized to subcutaneous (SC) abatacept (125 mg/week) or adalimumab (40 mg every 2 weeks) with background MTX. PROs (pain, fatigue, ability to perform work, and ability to perform daily activities) were compared up to year 2 for patients in each treatment group, as well as those who achieved low disease activity at both years 1 and 2 (responders) and those who did not (nonresponders). RESULTS: A total of 646 patients were randomized and treated with SC abatacept (n = 318) or adalimumab (n = 328). Baseline characteristics were balanced between the 2 treatment arms. Comparable improvements in PROs were observed in the abatacept and adalimumab groups over 2 years, with both groups achieving clinically meaningful improvements in PROs from baseline. At year 2, fatigue improved by 23.4 mm and 21.5 mm on a 100-mm visual analog scale with abatacept and adalimumab, respectively. Clinical responders achieved greater improvements in PROs than nonresponders. CONCLUSION: In biologic-naive patients with active RA, despite prior MTX, treatment with SC abatacept or adalimumab with background MTX resulted in comparable improvements in PROs, which were highly correlated with physician-reported clinical response end points.
25943002 Comparative Efficacy of Novel DMARDs as Monotherapy and in Combination with Methotrexate i 2015 May BACKGROUND: Given the availability of a number of alternative biologic treatment options and other novel disease-modifying antirheumatic drugs (DMARDs) for the treatment of patients with rheumatoid arthritis (RA), clinicians are faced with an increasingly challenging choice regarding optimal treatment. Biologics are usually combined with traditional DMARDs, primarily methotrexate (MTX), but some biologics and tofacitinib (together referred to in this article as novel DMARDs) have been shown to be efficacious as monotherapy as well. In real-world practice, approximately one-third of RA patients receiving biologics are on monotherapy, primarily because of intolerance of, or noncompliance with, MTX. Limited data, however, are available analyzing the effectiveness of monotherapy compared with combination therapy across novel DMARDs. OBJECTIVE: To compare American College of Rheumatology (ACR) responses to approved novel DMARDs used as monotherapy or as combination therapy with methotrexate (MTX) at 24 weeks in RA patients who have shown inadequate response to conventional DMARDs (DMARD-IR).  METHODS: Through a systematic review of the literature, we identified randomized controlled trials that assessed approved novel DMARDs used as monotherapy or as combination therapy with MTX in DMARD-IR RA patients. Twenty-eight RCTs were identified that evaluated abatacept, anakinra, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, tocilizumab, or tofacitinib. ACR responses at 24 weeks were extracted and combined by means of Bayesian network meta-analyses.  RESULTS: With the exception of anakinra plus MTX, which was less efficacious, most novel DMARDs, when used in combination with MTX, demonstrated comparable ACR responses. When novel DMARDs were used as monotherapies, greater ACR20/50/70 responses were observed with tocilizumab than with anti-tumor necrosis factor agents (aTNF) or tofacitinib. Furthermore, ACR20/50/70 responses with tocilizumab plus MTX were similar to those with tocilizumab monotherapy (odds ratio [OR] for the indirect comparison = 1.08, 95% credible interval [CrI] = 0.40-2.84; OR = 1.24, CrI = 0.44-3.61; OR = 0.95, CrI = 0.33-2.72, respectively), whereas greater responses were observed with aTNF plus MTX than with aTNF monotherapy (OR = 2.41, CrI = 0.51-11.61; OR = 2.85, CrI = 0.51-17.67; OR = 1.28, CrI = 0.21-8.42, respectively). Relative efficacy estimates for the indirect comparison of tofacitinib plus MTX with tofacitinib monotherapy were very uncertain. CONCLUSIONS: Results suggest that in combination with MTX most of the available novel DMARDs have similar levels of efficacy in DMARD-IR patients. As monotherapy, however, tocilizumab displayed higher ACR responses than aTNF or tofacitinib. ACR responses with tocilizumab plus MTX were similar to those with tocilizumab as monotherapy, whereas aTNF in combination with MTX demonstrated greater ACR responses than aTNF as monotherapy.
27053094 Frequency of methotrexate intolerance in rheumatoid arthritis patients using methotrexate 2016 May The objective of the study was to determine the frequency of methotrexate intolerance in rheumatoid arthritis (RA) patients by applying the methotrexate intolerance severity score (MISS) questionnaire and to see the effect of dose and concomitant use of other disease-modifying antirheumatic drugs (DMARDS) on methotrexate (MTX) intolerance. For the descriptive study, non-probability sampling was carried out in the Female Rheumatology Department of Fauji Foundation Hospital (FFH), Rawalpindi, Pakistan. One hundred and fifty diagnosed cases of RA using oral MTX were selected. The MISS questionnaire embodies five elements: abdominal pain, nausea, vomiting, fatigue and behavioural symptoms. The amplitude of each element was ranked from 0 to 3 being no complaint (0 points), mild (1 point), moderate (2 points) and severe (3 points). A cut-off score of 6 and above ascertained intolerance by the physicians. A total of 33.3 % of the subjects exhibited MTX intolerance according to the MISS questionnaire. Out of which, the most recurring symptom of all was behavioural with a value of 44 % whereas vomiting was least noticeable with a figure of 11 %. About 6.6 % of the women with intolerance were consuming DMARDs in conjunction with MTX. Those using the highest weekly dose of MTX (20 mg) had supreme intolerance with prevalence in 46.2 % of the patients. The frequency of intolerance decreased with a decrease in weekly dose to a minimum of 20 % with 7.5 mg of MTX. MTX intolerance has moderate prevalence in RA patients and if left undetected, the compliance to use of MTX as a first-line therapy will decrease. Methotrexate intolerance is directly proportional to the dose of MTX taken. Also, there is no upstroke seen in intolerance with the use of other disease-modifying agents.
27871200 Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis. 2017 Jan Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by focal pathologic bone resorption due to excessive activity of osteoclasts (OC). Receptor activator of nuclear factor kappa B ligand (RANKL) is essential for the proliferation, differentiation, and survival of OC. Denosumab (DMab) is a humanized monoclonal antibody that binds to RANKL with high affinity and blocks its subsequent association with its receptor RANK on the surface of OC precursors. Area covered: The authors review the molecular and cellular mechanisms underlying therapeutic applications of DMab, provide recent highlights on pharmacology, efficacy and safety of DMab, and discuss the potential of DMab as a novel therapeutic option for the treatment of rheumatoid arthritis. Expert opinion: Clinical results suggest that DMab is efficient both in systemic and articular bone loss in RA with limited side effects. Diminished bone erosion activity was also noted in RA patients on corticosteroids and bisphosphonates. Combination of DMab with an anti-TNF agent was not associated with increased infection rates. Collectively, these data indicate that DMab, in combination with methotrexate and possibly other conventional synthetic Disease Modifying Anti-Rheumatic Drugs (csDMARDs), is an effective, safe and cost-effective option for the treatment of RA.
27118040 Identifying factors associated with concordance with the American College of Rheumatology 2016 Apr 26 BACKGROUND: Factors associated with care concordant with the American College of Rheumatology (ACR) recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) are unknown. METHODS: We identified a national cohort of biologic-naive patients with RA with visits between December 2008 and February 2013. Treatment acceleration (initiation or dose escalation of biologic and nonbiologic DMARDs) in response to moderate to high disease activity (using the Clinical Disease Activity Index) was assessed. The population was divided into two subcohorts: (1) methotrexate (MTX)-only users and (2) multiple nonbiologic DMARD users. In both subcohorts, we compared the characteristics of patients who received care consistent with the ACR recommendations (e.g., prescriptions for treatment acceleration) and their providers with the characteristics of those who did not at the conclusion of one visit and over two visits, using logistic regression and adjusting for clustering of patients by rheumatologist. RESULTS: Our study included 741 MTX monotherapy and 995 multiple nonbiologic DMARD users cared for by 139 providers. Only 36.2 % of MTX monotherapy users and 39.6 % of multiple nonbiologic DMARD users received care consistent with the recommendations after one visit, which increased over two visits to 78.3 % and 76.2 %, respectively (25-30 % achieved low disease activity by the second visit without DMARD acceleration). Increasing time since the ACR publication on RA treatment recommendations was not associated with improved adherence. CONCLUSIONS: Allowing two encounters for treatment acceleration was associated with an increase in care concordant with the recommendations; however, time since publication was not.
27018050 Methotrexate-associated orbital lymphoproliferative disorder in a patient with rheumatoid 2016 May PURPOSE: Lymphoproliferative disorders (LPDs) can develop in patients treated with methotrexate (MTX) and usually respond well to MTX withdrawal. Mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare type of MTX-LPD. The development of MTX-LPD in the orbit has not been previously described. We here report a case of orbital MALT lymphoma that disappeared after MTX withdrawal in a patient treated with MTX for rheumatoid arthritis. CASE: A 78-year-old woman who complained of swelling of the left upper eyelid had been treated with MTX for >8 years for rheumatoid arthritis. Slit-lamp examination revealed a temporal subconjunctival mass, salmon pink in color, in the left eye. Fundus photographs also suggested the presence of a temporal tumor in the left orbit. [(18)F]Fluorodeoxyglucose positron emission tomography-computed tomography revealed highly integrated lesions in the left inferotemporal orbit and a left external iliac lymph node, a left obturator lymph node, and an inguinal lymph node. Pathologic analysis of a tumor biopsy specimen showed small- and medium-sized lymphocytes positive for CD20, MIB-1, and bcl-2 and negative for CD10, CD3, bcl-1, IgG4, and EBV-ISH. On the basis of these findings, we diagnosed the tumor as MTX-induced MALT lymphoma. The subconjunctival and orbital masses disappeared gradually over 10 months after MTX withdrawal and did not recur within 2 years. CONCLUSION: This case of orbital MTX-LPD suggests that the possibility of MTX-LPD should be considered even for ocular tumors in patients treated with MTX.
26991245 Effect of Drug Therapy on Net Cholesterol Efflux Capacity of High-Density Lipoprotein-Enri 2016 Sep OBJECTIVE: Patients with rheumatoid arthritis (RA) have an increased risk of coronary heart disease (CHD). Some RA therapies may modify this risk, but the underlying mechanisms are unclear. The cholesterol efflux capacity of high-density lipoprotein (HDL) is associated with a reduced CHD risk in non-RA populations; however, inflammation may impair the function of HDL. The aim of this study was to evaluate whether reduced inflammation resulting from treatment with methotrexate (MTX), adalimumab (ADA), or tocilizumab (TCZ) would increase the net cholesterol efflux capacity of HDL in patients with RA. METHODS: A longitudinal multicenter study repository (Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository) provided clinical information for and serum samples from 70 patients with RA before and 6 months after starting treatment with a new drug (MTX [n = 23], ADA [n = 22], or TCZ [n = 25]). Disease activity was measured using the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR). The net cholesterol efflux capacity was measured in paired serum samples using THP-1 macrophages, and total cellular cholesterol was measured by fluorometric assay. RESULTS: The DAS28-ESR decreased with all treatments (P < 0.001). Net cholesterol efflux capacity was not significantly changed after 6 months of new RA therapy (mean ± SD 36.9 ± 17.3% units at baseline versus 38.0% ± 16.9% units at 6 months [P = 0.58]). However, change in net cholesterol efflux capacity was associated with change in the DAS28-ESR (ρ = -0.25, P = 0.04). In a post hoc analysis of patients with impaired net cholesterol efflux capacity at baseline, treatment with TCZ resulted in significant improvement in net cholesterol efflux capacity (21.9 ± 14.7% units at baseline versus 31.3% ± 12.8% units at 6 months [P < 0.02]), but this was not observed with MTX or ADA. CONCLUSION: Net cholesterol efflux capacity of HDL cholesterol did not change significantly after 6 months of new RA therapy, except in patients with impaired baseline cholesterol efflux capacity who were receiving TCZ. Change in disease activity was associated with change in the net cholesterol efflux capacity.
30641006 [Efficacy of Hebi Formula Combined Methotrexate on Early Rheumatoid Arthritis Patients wit 2016 Oct Objective To observe the efficacy of Hebi Formula (HF) combined Methotrexate (MTX) on early rheumatoid arthritis (RA) patients with disharmony of Gan and Pi syndrome (DGPS) and its effects on matrix metalloproteinase-3 (MMP-3) activator of nuclear factor-KB/receptor activator of nu- clear factor-KB/osteoprotegerin (RANK/RANKL/OPG). Methods Totally 72 early RA patients with DGPS were assigned to the treatment group and the control group according to random digit table, 36 in each group. Patients in the control group took MTX, while those in the treatment group additionally took HF. MTX dose was increased from 7. 5 mg to 12. 5 mg gradually, once per week, and the course of treatment was 24 weeks. Efficacy for Chinese medicine (CM) syndromes, ACR20 improvement rate, laboratory re- lated indices [ rheumatoid factor ( RF ) , erythrocyte sedimentation rate ( ESR ) , C-reactive protein (CRP) , anti-cyclic citrullinated peptide antibody (CCP)], serum levels of MMP-3, OPG, RANKL, and adverse reactions were observed. Results The standard arriving rate of ACR20 was 82. 86% (2935) in the treatment group, higher than that in the control group [51. 52% (173) ;P <0. 05). The effective rate of CM syndrome was 85. 7% (30f35) in the treatment group, higher than that in the control group [63. 6% (21/33) ;P <0. 05). Compared with before treatment in the same group, levels of RF,ESR,CRP,MMP-3, and RANKL decreased, the OPG level increased in the two groups after treatment (P <0. 05, P <0. 01). Compared with the control group, levels of RF, ESR, CRP, and RANKL all decreased with statistical difference (P <0. 01 , P <0. 05). Liver dysfunction occurred in 1 case of the treatment group. Leucopenia occurred in 1 case and liver dysfunction occurred in 2 cases of the control group. Conclusion HF com- bined MTX could improve symptoms of early RA patients with DGPS, and regulate bone destruction in- duced by RANK/RANKL/OPG systems.
26330155 Assessment of global DNA methylation in peripheral blood cell subpopulations of early rheu 2015 Aug 29 INTRODUCTION: DNA methylation is an epigenetic mechanism regulating gene expression that has been insufficiently studied in the blood of rheumatoid arthritis (RA) patients, as only T cells and total peripheral blood mononuclear cells (PBMCs) from patients with established RA have been studied and with conflicting results. METHOD: Five major blood cell subpopulations: T, B and NK cells, monocytes, and polymorphonuclear leukocytes, were isolated from 19 early RA patients and 17 healthy controls. Patient samples were taken before and 1 month after the start of treatment with methotrexate (MTX). Analysis included DNA methylation with high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring (HPLC-ESI-MS/MS-SRM) and expression levels of seven methylation-specific enzymes by quantitative polymerase chain reaction (qPCR). RESULTS: Disease-modifying anti-rheumatic drug (DMARD)-naïve early RA patients showed global DNA hypomethylation in T cells and monocytes, together with a lower expression of DNA methyltrasnferase 1 (DNMT1), the maintenance DNA methyltransferase, which was also decreased in B cells. Furthermore, significantly increased expression of ten-eleven translocation1 (TET1), TET2 and TET3, enzymes involved in demethylation, was found in monocytes and of TET2 in T cells. There was also modest decreased expression of DNMT3A in B cells and of growth arrest and DNA-damage-inducible protein 45A (GADD45A) in T and B cells. Treatment with MTX reverted hypomethylation in T cells and monocytes, which were no longer different from controls, and increased global methylation in B cells. In addition, DNMT1 and DNMT3A showed a trend to reversion of their decreased expression. CONCLUSIONS: Our results confirm global DNA hypomethylation in patients with RA with specificity for some blood cell subpopulations and their reversal with methotrexate treatment. These changes are accompanied by parallel changes in the levels of enzymes involved in methylation, suggesting the possibility of regulation at this level.
25022442 Efficacy and safety of golimumab as add-on therapy to disease-modifying antirheumatic drug 2015 May OBJECTIVES: To assess the efficacy and safety of golimumab in the 140 patients included in Spain as the first part of the GO-MORE trial, a multinational study involving patients with active rheumatoid arthritis (RA) despite treatment with different disease-modifying antirheumatic drugs (DMARDs). PATIENTS AND METHODS: The patients received subcutaneous golimumab 50mg once a month during 6 months. The primary endpoint was the percentage of individuals with a good or moderate EULAR DAS28-ESR response after 6 months of treatment. RESULTS: A total of 140 patients were included. Of these, 76.4% had very active disease (DAS28-ESR>5.1). 76.4% were taking methotrexate, 40.0% other DMARDs in monotherapy or combined, and 65.0% received corticosteroids. After 6 months, 82.9% of the patients showed a good or moderate EULAR response, 41.4% had low disease activity, and 30.7% were in remission. The percentage of responders one month after the first dose was 69.3%. The efficacy was similar in patients treated with methotrexate or other DMARDs, with different methotrexate doses, with or without corticosteroids, or in subjects who had failed one or more DMARDs. The response to golimumab was observed from the first dose. Golimumab was well tolerated and its safety profile was consistent with the findings of previous studies. Serious adverse events were reported in 11 patients (7.9%). CONCLUSION: The addition of subcutaneous golimumab 50 mg once a month to different DMARDs in patients with active RA yielded a moderate or good response after 6 months in 82.9% of the cases. The response was observed early, from the start of the second month, after a single dose of golimumab.
26792343 Higher expression of TNFα-induced genes in the synovium of patients with early rheumatoid 2016 Jan 20 BACKGROUND: IL6-related T cell activation and TNFα-dependent cell proliferation are major targets of therapy in the RA synovium. We investigated whether expression of these pathways in RA synovial biopsies is associated with disease activity and response to therapy. METHOD: Correlation and gene set enrichment studies were performed using gene expression profiles from RA synovial biopsies. Immunostaining experiments of GADD45B and PDE4D were performed on independent additional sets of early untreated RA samples, obtained in two different centers by needle-arthroscopy or US-guided biopsies. RESULTS: In 65 RA synovial biopsies, transcripts correlating with disease activity were strongly enriched in TNFα-induced genes. Out of the individual variables used in disease-activity scores, tender joint count, swollen joint count and physician's global assessment, but not CRP or patient's global assessment displayed a similar correlation with the expression of TNFα-dependent genes. In addition, TNFα-induced genes were also significantly enriched in transcripts over-expressed in synovial biopsy samples obtained from poor-responders to methotrexate or tocilizumab, prior to initiation of therapy. GADD45B (induced by TNFα in monocytes) and PDE4D (induced by TNFα in FLS) immunostaining was significantly higher in overall poor-responders to therapy in 46 independent baseline samples obtained from early untreated RA patients prior to initiation of therapy. GADD45B (but not PDE4D) immunostaining was significantly higher in the sub-group of patients with poor-response to methotrexate therapy, and this was confirmed in another population of methotrexate-treated patients. CONCLUSION: Higher expression of TNFα-induced transcripts in early RA synovitis is associated with higher disease activity, and predicts poor response to first-line therapy. That over-expression of TNFα-induced genes predicts poor-response to therapy regardless of the drug administered, indicates that this molecular signature is associated with disease severity, rather than with specific pathways of escape to therapy.
26097194 Etanercept-Methotrexate Combination Therapy Initiators Have Greater Adherence and Persiste 2015 Dec OBJECTIVE: To estimate adherence and persistence with etanercept plus methotrexate (ETN-MTX) combination therapy and MTX, hydroxychloroquine, and sulfasalazine triple therapy at 1 year following treatment initiation in adults with rheumatoid arthritis (RA). METHODS: This retrospective analysis used data from the Truven Health MarketScan Commercial and Medicare Supplemental databases from January 2009 to July 2013. Adherence was defined as having percentage of days covered >80% for all drugs within each regimen. Persistence was defined as no treatment gap >45 days for any drug and no addition or switching to other disease-modifying antirheumatic drugs. Multiple logistic regression models were employed in the analyses to control for potential confounders. RESULTS: A total of 3,724 ETN-MTX patients and 818 triple therapy patients were eligible. At 1 year, 27.9% who were taking ETN-MTX and 18.2% using triple therapy were adherent to all agents in their regimen (P < 0.0001), and 29.4% who were taking ETN-MTX and 23.2% using triple therapy were persistent (P < 0.001). After adjusting for confounders, ETN-MTX patients had significantly greater odds of being adherent (odds ratio [OR] 1.79, 95% confidence interval [95% CI] 1.47-2.17) and persistent (OR 1.45, 95% CI 1.20-1.72) compared with patients using triple therapy. CONCLUSION: Patients with RA initiating treatment with ETN-MTX combination therapy demonstrated greater adherence and persistence at 1 year than patients initiating triple therapy.
27470609 Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control 2016 Nov INTRODUCTION: It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-α, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-α, the relationship between AD and RA remains unknown. OBJECTIVE: To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients. METHODS: We performed a nested case-control study of more than 8.5 million commercially insured adults (aged ≥18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease. RESULTS: AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04-2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32-2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06-2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22-0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23-0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08-0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08-0.89; p = 0.02) was associated with a decreased risk of AD in RA patients. CONCLUSION: There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD.
25240765 Increased plasma IL-17F levels in rheumatoid arthritis patients are responsive to methotre 2015 Feb The aims of this study are to compare plasma levels of IL17A, A/F, and F biomarkers in RA patients versus controls, and to determine responsiveness to methotrexate (MTX), anti-TNFs, and abatacept. We selected plasma samples from RA cohorts consisting of a cross-sectional RA cohort (N = 78) not receiving DMARDs at the time of sampling, as well as from longitudinal drug start cohorts (N = 71 patients) with pre/post samples including anti-TNF, abatacept, and MTX-treated patients. We assayed IL-17A, IL-17F, and IL17-A/F using a highly sensitive immunoassay system. Plasma levels of IL-17A, IL-17A/F, and IL-17F were all significantly increased in RA versus controls. The difference was largest in IL-17F, with median IL-17F levels in RA patients being approximately 18-fold higher than controls (81 pg/mL in RA vs. 4.4 pg/mL in controls, p < 0.001). Among the forms of IL-17, only IL-17F was decreased after therapy in the MTX cohort (p = 0.006), abatacept cohort (p < 0.001), and anti-TNF cohorts (p = 0.02), whereas IL-17A and IL-17A/F were not significantly decreased for any of the three drug cohorts. Synovial fluid analysis demonstrated higher IL-17F levels in RA (p = 0.016) than healthy controls. These results suggest a specific role for IL-17F in human RA pathogenesis and as a therapeutic target.
25149278 Combined effects of infliximab and methotrexate on rheumatoid arthritis osteoblastic cell 2015 Aug The goal of this study is to investigate the in vitro effects of two disease-modifying anti-rheumatic drugs, largely used in the treatment of rheumatoid arthritis (RA), [infliximab (IFX) and methotrexate (MTX)], in RA primary osteoblast cell cultures. MTX inhibited proliferation and metabolic activity in RA osteoblasts was able to increase apoptosis. Conversely, IFX increased the proliferation, osteocalcin production and the alkaline phosphatase activity. Interestingly, IFX appeared to antagonise the negative effect exerted by MTX. Both drugs significantly reduced the IL-6 production in osteoblasts when used alone, and the combination of the two agents resulted in a significant additional reduction of IL-6 synthesis, with an apparent additive effect. The present study suggests that MTX exerts negative direct effects on bone metabolism in RA patients, but the combined treatment with anti-TNF-α can be beneficial for the interaction of MTX with bone cells.
27383049 Safety profile of repeated rituximab cycles in unselected rheumatoid arthritis patients: a 2016 Sep OBJECTIVES: To evaluate the long-term safety of rituximab (RTX) in rheumatoid arthritis (RA) patients in daily clinical practice. METHODS: This was a multicentre (17 Greek Rheumatology sites), prospective, long-term, pharmacovigilance study of patients with moderate to severe RA and an inadequate response or intolerance to ≥1 anti-tumour necrosis factor (TNF) agents. Adverse events (AEs) were recorded and collected prospectively every 2-6 months. RESULTS: 234 patients (mean age: 59±12.5, 79.5% women, mean DAS28: 5.35±1.32) were included and followed for 27.7 months (median). The overall AEs, serious AE (SAEs) and serious infection (SIEs) rate were 48.36, 6.68 and 2.53/100 patient-years, respectively. Three cases of hepatitis B virus (HBV) reactivation were recorded (two in chronic and one in past HBV infection). Withdrawals due to AEs (5.6%) occurred more frequently during the first cycles of RTX therapy while repeated RTX cycles were not associated with an increased risk of AEs. There were 3 deaths with an incidence rate of 0.69/100 patient-years. Age ≥65 years was associated with a higher incidence rate ratio of AEs and SAEs as compared to <65 years (1.53, p=0.002 and 2.88, p=0.005, respectively). Drug retention rate during 434.28 patient-years of follow-up was 57.3%. Factors associated with drug discontinuation by multivariate analysis included age, baseline swollen joint count and no use of concomitant methotrexate therapy. CONCLUSIONS: Long-term RTX therapy in a real-life RA cohort, did not reveal any new safety issues. Advanced age was associated with increased risk of AEs and premature drug discontinuation.