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ID PMID Title PublicationDate abstract
25504080 Pre-treatment whole blood gene expression is associated with 14-week response assessed by 2014 Approximately 30% of rheumatoid arthritis patients achieve inadequate response to anti-TNF biologics. Attempts to identify molecular biomarkers predicting response have met with mixed success. This may be attributable, in part, to the variable and subjective disease assessment endpoints with large placebo effects typically used to classify patient response. Sixty-one patients with active RA despite methotrexate treatment, and with MRI-documented synovitis, were randomized to receive infliximab or placebo. Blood was collected at baseline and genome-wide transcription in whole blood was measured using microarrays. The primary endpoint in this study was determined by measuring the transfer rate constant (Ktrans) of a gadolinium-based contrast agent from plasma to synovium using MRI. Secondary endpoints included repeated clinical assessments with DAS28(CRP), and assessments of osteitis and synovitis by the RAMRIS method. Infliximab showed greater decrease from baseline in DCE-MRI Ktrans of wrist and MCP at all visits compared with placebo (P<0.001). Statistical analysis was performed to identify genes associated with treatment-specific 14-week change in Ktrans. The 256 genes identified were used to derive a gene signature score by averaging their log expression within each patient. The resulting score correlated with improvement of Ktrans in infliximab-treated patients and with deterioration of Ktrans in placebo-treated subjects. Poor responders showed high expression of activated B-cell genes whereas good responders exhibited a gene expression pattern consistent with mobilization of neutrophils and monocytes and high levels of reticulated platelets. This gene signature was significantly associated with clinical response in two previously published whole blood gene expression studies using anti-TNF therapies. These data provide support for the hypothesis that anti-TNF inadequate responders comprise a distinct molecular subtype of RA characterized by differences in pre-treatment blood mRNA expression. They also highlight the importance of placebo controls and robust, objective endpoints in biomarker discovery. TRIAL REGISTRATION: ClinicalTrials.gov NCT01313520.
25675680 Predictors for low disease activity and remission in rheumatoid arthritis patients treated 2014 Nov BACKGROUND: Optimal outcome of treatment in rheumatoid arthritis (RA) is early clinical remission to delay joint damage. Therefore, severe RA patients with inadequate response to conventional disease modifying anti-rheumatic drugs (cDMARDs) need highpotency drug as biological DM4RDs (bDMARDs). In general, one-third of RA patient could not get into disease remission with cDMARDs, and half ofthem are still suffering from severe arthritis. However, high cost of this agent is the major barrier for patient engagement, and it is affordable to only 5-10% of patients. We need a good strategy to distribute bDMARDs to patients, especially in limited resource situation. OBJECTIVE: We explored the characteristics ofRA patients who were currently using biologic agents in Ramathibodi Hospital to determine the favorable treatment outcome. MATERIAL AND METHOD: The studied patients were RA patients classified according to ACR/EULAR 2010 criteria and using any biologic agents, between 2010 and2012. Demographic data and treatment outcome (low disease activity and remission) were retrievedfrom patient records. Univariate analysis and generalized estimating equation (GEE) were used to analyze predicting factors to control disease at one year. Kaplan-Meier and log rank test were used to analyze time to disease remission or low disease activity. RESULTS: Patients treated with bDMARDs in Ramathibodi Hospital demonstrated long disease duration (mean 130.7 months) and severe disease activity (mean DAS28 5.37). At 1-year after treatment, 19.4% and 12.9% ofpatients achieved low disease activity (low DAS) and disease remission, respectively. At 3-years after treatment, 88.9% and 45.2% of patients attained low DAS and remission. Patients who started bDMARDs after 2010 had significantly shorter time to control disease when compared to patients who started bDMARDs before 2010 (10 months vs. 34 months). Moreover, we observed that patient who started bDMARDs after 2010 using more cDMARDs (2.5 vs. 1.7, p = 0.02) and higher dose of methotrexate (10.7 vs. 6.5, p = 0.03). There were no association between disease control status and treatment (methotrexate, prednisolone, biologic agent) or disease duration. However the exposedstatus ofbiologic agent was associated with low DAS or remission at the first year of observation (p = 0.004 and 0.04, respectively). CONCLUSION: Chance to control rheumatoid arthritis in the level of remission or low disease activity is predicted by time of bDAMRDs exposure. This result is mainly influenced by dose ofmethotrexate and number of cDMARDs.
24289731 Usability testing of ANSWER: a web-based methotrexate decision aid for patients with rheum 2013 Dec 1 BACKGROUND: Decision aids are evidence-based tools designed to inform people of the potential benefit and harm of treatment options, clarify their preferences and provide a shared decision-making structure for discussion at a clinic visit. For patients with rheumatoid arthritis (RA) who are considering methotrexate, we have developed a web-based patient decision aid called the ANSWER (Animated, Self-serve, Web-based Research Tool). This study aimed to: 1) assess the usability of the ANSWER prototype; 2) identify strengths and limitations of the ANSWER from the patient's perspective. METHODS: The ANSWER prototype consisted of: 1) six animated patient stories and narrated information on the evidence of methotrexate for RA; 2) interactive questionnaires to clarify patients' treatment preferences. Eligible participants for the usability test were patients with RA who had been prescribed methotrexate. They were asked to verbalize their thoughts (i.e., think aloud) while using the ANSWER, and to complete the System Usability Scale (SUS) to assess overall usability (range = 0-100; higher = more user friendly). Participants were audiotaped and observed, and field notes were taken. The testing continued until no new modifiable issues were found. We used descriptive statistics to summarize participant characteristics and the SUS scores. Content analysis was used to identified usability issues and navigation problems. RESULTS: 15 patients participated in the usability testing. The majority were aged 50 or over and were university/college graduates (n = 8, 53.4%). On average they took 56 minutes (SD = 34.8) to complete the tool. The mean SUS score was 81.2 (SD = 13.5). Content analysis of audiotapes and field notes revealed four categories of modifiable usability issues: 1) information delivery (i.e., clarity of the information and presentation style); 2) navigation control (i.e., difficulties in recognizing and using the navigation control buttons); 3) layout (i.e., position of the videos, text, diagrams and navigation buttons); 4) aesthetic (i.e., the colour, look and feel of the online tool). CONCLUSIONS: Although the SUS score indicated high usability before and after major modification, findings from the think-aloud sessions illustrated areas that required further refinement. Our results highlight the importance of formative evaluation in usability testing.
23560463 Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, 2013 Jul OBJECTIVES: Patients with rheumatoid arthritis (RA) may develop lymphoproliferative disorders (RA-LPD). Immunosuppressive states due to methotrexate (MTX) and Epstein-Barr virus (EBV) reactivation have been regarded as causes. Sometimes spontaneous regression occurs after withdrawal of MTX. The objective of this study was to identify factors predictive of relapse and survival in patients with RA-LPD, and spontaneous regression in patients with RA-LPD treated with MTX (MTX-LPD). METHODS: We evaluated the clinicopathological features, clinical characteristics, and treatment outcomes in 102 cases of RA-LPD. In addition, EBV infection and clonality of immunoglobulin heavy chain gene (IGH) were analyzed by in situ hybridization and polymerase chain reaction, respectively. RESULTS: The 102 cases included patients with diffuse large B-cell lymphoma (DLBCL; n = 53), Hodgkin lymphoma (n = 9), polymorphic B-cell LPD (n = 20), reactive lymphadenitis (n = 11), peripheral T-cell lymphoma (PTCL; n = 4), composite lymphoma (n = 2), and follicular lymphoma (n = 3). EBV was detected in 60% (56/93) of patients. Spontaneous regression occurred in 59% (28/47) of patients in whom MTX was withdrawn. Regression was associated with EBV positivity (P = 0.007) and non-DLBCL (P = 0.006), but not with MTX amount and other clinical features. Monoclonal bands of IGH were observed in 31 of 74 cases. In patients with DLBCL, poor disease-free survival (P = 0.05) was associated with clonality of IGH. In all patients, factors predictive of shorter survival were age (>70 yr) and histological type of DLBCL. CONCLUSIONS: Histology, EBV positivity, and monoclonality of IGH are useful for predicting clinical outcomes in patients with RA-LPD.
23743624 Do impaired memory, cognitive dysfunction and distress play a role in methotrexate-related 2013 Oct We evaluated the roles of sociocultural status, distress and cognitive functions in rheumatoid arthritis (RA) patients who developed methotrexate (MTX)-related neutropenia. The data of 37 RA patients with MTX-related neutropenia who were being followed up at 3 centers were evaluated. The control group included 74 RA patients. The clinical features, biochemical tests and treatment modalities of the patients were obtained from hospital files. The mini-mental state examination (MMSE) test and the Hospital Anxiety and Depression Scale (HADS) were administered for all RA patients with neutropenia as well as the control group. The frequencies of male patients, illiterate patients, patients living alone, patients with serious visual impairment, those with low income, and patients with high creatinine were significantly higher among RA patients with MTX-related neutropenia than in controls (p values <0.05). The RA patients with MTX-related neutropenia had significantly lower MMSE scores, and significantly higher HADS-A and HADS-D scores than controls (p values <0.05). In addition, the proportion of patients with probable dementia was significantly higher in RA patients with MTX-related neutropenia than in controls (p < 0.001). Twenty-six of the 37 patients (70.3 %) developed neutropenia with daily dosing. Patients who used MTX daily were more likely to be living alone than those using weekly dosing (p = 0.011). Multivariate analysis showed that having probable dementia on the MMSE test (OR 52.6), low income level (OR 56.8) and age (OR 1.12) were independent risk factors for the development of MTX-related neutropenia. The presence of probable dementia on MMSE, low socioeconomical status and older age are associated with serious toxicity in RA patients using MTX. Measures should be taken to prevent wrong MTX dosing by the patients. Compliance and patient education is of major importance, in particular, in the patients presented in this study.
23983001 Barriers to optimal disease control for rheumatoid arthritis patients with moderate and hi 2014 Feb OBJECTIVE: To evaluate barriers that prevent rheumatoid arthritis (RA) patients from achieving Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) scores within the current recommended levels for low disease activity (LDA) or clinical remission (DAS28-ESR score <3.2). METHODS: Using an electronic medical record program, clinical data for RA patients treated in Optimising Patient Outcomes in Australian Rheumatology clinics, with a recorded DAS28-ESR score, were collected at one point in time. The data included demographics, medications, disease measures, and the rheumatologist's opinion of the main barriers preventing improvement to the recommended DAS28 score. RESULTS: Of the 4,037 patients with a recorded DAS28-ESR score, 304 patients (7.5%) had high disease activity (HDA) and 1,211 patients (30%) had moderate disease activity (MDA). For 584 HDA or MDA patients, the barriers to disease control (BTCs) were recorded by the rheumatologist when there was no adjustment to disease-modifying antirheumatic drug (DMARD) therapy. The recorded BTCs were irreversible joint damage (19.7%), patient-driven preference (14.7%), noninflammatory musculoskeletal pain (9.2%), insufficient time to assess the effect of recently initiated DMARDs (9.2%), safety concerns (7.5%), comorbidities (6.5%), resistant disease (6.3%), and other less common reasons. These patients received DMARDs (97.4%), including biologic agents (34.1%), methotrexate (74.8%), and oral corticosteroids (41.8%). CONCLUSION: This study identified clinical situations in which rheumatologists elected to continue RA patients with MDA or HDA on DMARD therapy without adjustment to achieve clinical remission or an LDA target of a DAS28-ESR score <3.2.
25073613 Presence of comorbidity affects both treatment strategies and outcomes in disease activity 2015 Mar To clarify the impact of comorbidities on treatment strategies and outcomes in patients with rheumatoid arthritis (RA) using a large observational RA cohort, the presence of comorbidities was assessed using the Charlson Comorbidity Index (CCI). Changes in medication, disease activity by Disease Activity Score-28 joint count (DAS28) over 6 months, disability assessed by the Japanese version of the Health Assessment Questionnaire (J-HAQ), and quality of life by EuroQOL-5-Dimensions (EQ-5D) over 1 year in patients with high disease activity (DAS28 > 5.1) at baseline were assessed according to age-adjusted CCI (CCI(A)) and categorized into four groups (CCI(A) 0, 1-2, 3-4, and ≥5). Among 5,317 patients, 975 patients (18.3%) had at least one comorbidity listed by CCI. DAS28, J-HAQ, and EQ-5D increased in severity with increased CCI(A) levels. Among patients with high disease activity (n = 267), treatment with methotrexate and/or biologics and improved DAS28 scores, shown by attenuated intensity, were associated with increased CCI(A) levels. J-HAQ improved from 1.29 ± 0.31 to 0.87 ± 0.37 in 1 year in the CCI(A) 0 group. The adjusted difference (standard error) in J-HAQ at 1 year in CCI(A) 1-2, 3-4, and ≥5 groups was worse than J-HAQ in the CCI(A) 0 group by 0.32 (0.09, p < 0.001), 0.45 (0.10, p < 0.001), and 0.45 (0.15, p < 0.01), respectively. The magnitude of improvement of EQ-5D was significantly attenuated with increasing CCI(A) levels. Thus, patients with comorbidities may not experience the same degree of benefit from recent RA treatments compared with patients without comorbidities in daily practice.
25355728 MRI assessment of suppression of structural damage in patients with rheumatoid arthritis r 2016 Jan OBJECTIVE: To evaluate changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in a Phase 3 study of patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) who were naive to biological therapy. METHODS: Patients were randomised to receive two infusions of placebo (n=63), rituximab 500 mg (n=62), or rituximab 1000 mg (n=60) intravenously on days 1 and 15. MRI scans and radiographs of the most inflamed hand and wrist were acquired at baseline, weeks 12 (MRI only), 24 and 52. The primary end point was the change in MRI erosion score from baseline at week 24. RESULTS: Patients treated with rituximab demonstrated significantly less progression in the mean MRI erosion score compared with those treated with placebo at weeks 24 (0.47, 0.18 and 1.60, respectively, p=0.003 and p=0.001 for the two rituximab doses vs placebo) and 52 (-0.30, 0.11 and 3.02, respectively; p<0.001 and p<0.001). Cartilage loss at 52 weeks was significantly reduced in the rituximab group compared with the placebo group. Other secondary end points of synovitis and osteitis improved significantly with rituximab compared with placebo as early as 12 weeks and improved further at weeks 24 and 52. CONCLUSIONS: This study demonstrated that rituximab significantly reduced erosion and cartilage loss at week 24 and week 52 in MTX-inadequate responder patients with active RA, suggesting that MRI is a valuable tool for assessing inflammatory and structural damage in patients with established RA receiving rituximab. TRIAL REGISTRATION NUMBER: NCT00578305.
25078871 Atacicept as an investigated therapy for rheumatoid arthritis. 2014 Sep INTRODUCTION: Rheumatoid arthritis (RA) is a chronic, painful and debilitating autoimmune disease. Although the outcome for patients with RA has improved markedly in the past decades, adequate disease control cannot be achieved in a substantial proportion of patients. Since RA is a syndrome with different biological subsets, new drugs with a novel mechanism of action may represent a valuable addition to the current armamentarium. AREAS COVERED: This review focuses on the pharmacodynamics and pharmacokinetics of atacicept . Furthermore, the article both summarises and comments on the drug's efficacy and safety profile in RA patients. EXPERT OPINION: Atacicept is designed to neutralise B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand, two cytokines involving B-cell function and survival. Two recent Phase II studies have demonstrated that atacicept was not effective in RA patients with an inadequate response to methotrexate or TNF antagonists. However, atacicept displayed significant biological activity, including reduction of Ig and rheumatoid factor levels. Adverse events were slightly more frequent among patients treated with atacicept compared with placebo. In contrast to patients with systemic lupus erythematosus, RA patients receiving atacicept did not show an increased susceptibility to infections. In view of its important impact on immunoglobulin-secreting cells, this drug might be a rational therapy for hematological diseases.
22802011 Association of hepatitis B with antirheumatic drugs: a case-control study. 2013 Jul BACKGROUND: Though concern of hepatitis B virus (HBV) reactivation by antirheumatic agents has limited therapeutic opportunities in HBV-infected rheumatoid arthritis (RA) patients, the relative risks (RR) among such agents have not been clarified. OBJECTIVE: We compared the reporting of antirheumatic-agent-associated hepatitis B. PATIENTS: We assessed 92 hepatitis B cases and 98,069 controls from a population of 98,161 RA patients registered into the US Food and Drug Administration's (FDA's) adverse event database between 2004 and 2010. MEASUREMENTS: A reporting odds ratio (ROR), a signal suggesting a risk for hepatitis B among antirheumatic agents, was measured. RESULTS: Treatment with corticosteroids [ROR 2.3 (95% confidence interval 1.3-4.0)], methotrexate [4.9 (3.9-6.0)], rituximab [7.2 (5.3-9.9)], tacrolimus [4.2 (1.5-11.9)], or reporting from Japan [2.2 (1.1-4.2)] were associated with higher signal, whereas adalimumab had a lower ROR [0.2 (0.1-0.4)]. LIMITATIONS: There are known limitations of spontaneous reporting, such as underreporting, the Weber effect, reporting bias, indication bias, and limited clinical information such as HBV status. CONCLUSIONS: Adalimumab's low reporting rate is most likely be due to notoriety. However, the possibility that adalimumab might suppress reactivation of HBV cannot be denied. Until the possibility is clarified in well-designed clinical studies, physicians should use adalimumab cautiously in patients with HBV.
24928345 Adalimumab decreases aortic stiffness independently of its effect in disease activity in p 2015 Feb Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality attributed to traditional cardiovascular risk factors and/or the chronic systemic inflammation. We investigated the effect of a TNF antagonist (adalimumab-ADA) on aortic stiffness in RA patients. We studied 18 RA patients with active disease despite therapy with disease modifying antirheumatic drugs (DMARDs), treated with ADA (alone or in combination with DMARDs) for 12 weeks. Disease activity markers as well as aortic stiffness indices (carotid-femoral pulse wave velocity-PWV, augmentation index-AIx), were measured at baseline and at the end of treatment. Eighteen RA patients treated with methotrexate (MTX) were included as controls. Patients were categorized as responders (decrease of Disease Activity Score-DAS28 > 1.2) or nonresponders. There was a statistically significant decrease in PWV (from 8.18 ± 2.03 to 7.01 ± 1.78 m/s, p = 0.00006) and DAS28 (from 6.65 ± 1.22 to 4.69 ± 1.46, p = 0.00007) in RA patients treated with ADA. The decrease in PWV was observed both in responders (n = 12) and nonresponders (n = 6). Multivariate analysis showed that the decrease of PWV was independent of changes in disease activity or other parameters. There was no significant change in PWV in patients treated with MTX (from 8.87 ± 1.91 to 8.41 ± 2.17, p = 0.29). No significant change in AIx or traditional cardiovascular risk factors was observed. Treatment with ADA significantly reduced aortic stiffness in RA patients regardless of their response to therapy. These findings imply a direct protective effect of ADA in vascular wall in RA patients.
24798350 Good response to infliximab in rheumatoid arthritis following failure of interleukin-1 rec 2016 Apr AIM: To evaluate the efficacy of tumor necrosis factor inhibitor infliximab in patients with rheumatoid arthritis (RA) who were disease-resistant to recombinant human interleukin-1 receptor antagonist (IL-1Ra). METHODS: A total of 104 patients with active RA despite methotrexate (MTX) treatment were enrolled in the open trial. Among them, 27 IL-1Ra nonresponders 'Switchers' and 51 biologic-naive patients 'Naivers' received an infusion of 3 mg/kg infliximab at weeks 0, 2, 6 and 14, combined with concurrent MTX therapy, while the other 26 patients who had never received any biologics 'Controls' continued MTX monotherapy. Clinical outcomes and safety were assessed at weeks 0, 2 and every 4 weeks thereafter for 18 weeks with the American College of Rheumatology (ACR) core set criteria, the Disease Activity Score in 28 joints, and records of adverse events (AEs) and abnormal laboratory findings. RESULTS: At week 18, an ACR20 response was achieved in 56% of Switchers and 61% of Naivers, compared with 23% of Controls (P = 0.0013 and 0.0126, respectively). Compared with Controls, both Switchers and Naivers achieved a significant improvement in tender-joint count, swollen-joint count, patient's assessment of pain, patient's and physician's global assessment of disease activity, erythrocyte sedimentation rate and C-reactive protein. Switchers even achieved a greater benefit from health assessment questionnaire (HAQ) scores than Naivers. Infliximab was well tolerated, with a similar incidence of AEs across all study groups. CONCLUSION: Switching from IL-1Ra to infliximab is effective in improving disease activity and maintaining joint function.
23176063 Impact of a multi-biomarker disease activity test on rheumatoid arthritis treatment decisi 2013 Jan OBJECTIVE: To assess how use of a multi-biomarker disease activity (MBDA) blood test for rheumatoid arthritis (RA) affects treatment decisions made by health care providers (HCPs) in clinical practice. RESEARCH DESIGN AND METHODS: At routine office visits, 101 patients with RA were assessed by their HCPs (N = 6), and they provided blood samples for MBDA testing. HCPs completed surveys before and after viewing the MBDA test result, recording dosage and frequency for all planned RA medications and physician global assessment of disease activity. Frequency and types of change in treatment plan that resulted from viewing the MBDA test result were determined. MAIN OUTCOME MEASURE: Percentage of cases in which the HCP changed the planned treatment after viewing the MBDA test result. RESULTS: Prior to HCP review of the MBDA test, disease modifying anti-rheumatic drug (DMARD) use by the 101 patients included methotrexate in 62% of patients; hydroxychloroquine 29%; TNF inhibitor 42%; non-TNF inhibitor biologic agent 19%; and other drugs at lower frequencies. Review of MBDA test results changed HCP treatment decisions in 38 cases (38%), of which 18 involved starting, discontinuing or switching a biologic or non-biologic DMARD. Other changes involved drug dosage, frequency or route of administration. The total frequency of use of the major classes of drug therapy changed by <5%. Treatment plans changed 63% of the time when the MBDA test result was perceived as being not consistent or somewhat consistent with the HCP assessment of disease activity. STUDY LIMITATIONS: Limited sample size; lack of control group; no longitudinal follow-up. CONCLUSIONS: The addition of the MBDA test to clinical assessment led to meaningful changes in the treatment plans of 38% of RA patients being cared for by HCPs in office practice. Even though treatment was potentially improved, the overall quantity of drug use was minimally affected.
24399184 Systematic review of 2008-2012 literature and update of recommendations for the use of met 2013 Dec 18 The objective of this review is to update the recommendations of the 2010 Italian Consensus on the use of methotrexate (MTX) in rheumatoid arthritis (RA) and other rheumatic diseases. The literature published between 2008 and 2012 was systematically reviewed and updated recommendations on MTX use in rheumatic diseases, particularly RA, were formulated. These recommendations were approved by a panel of expert Italian Rheumatologists. A total of 10,238 references were identified, among which 70 studies were selected for critical evaluation. Sufficient evidence had accumulated to warrant changes to several of the recommendations in the new version. A new recommendation for patients with RA who are in MTX-induced clinical remission was also proposed and approved by the panel. Updated recommendations for the use of MTX in patients with RA or other rheumatologic disease are proposed.
23334213 Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo d 2014 Feb OBJECTIVE: To assess long-term disease outcome of undifferentiated arthritis (UA) after initial treatment with methotrexate (MTX) or placebo. METHODS: 110 patients with UA were randomised to receive MTX (n=55) or placebo (n=55) for 1 year. After 5 years the outcomes for diagnosis (rheumatoid arthritis, 1987 criteria (RA (1987)), UA or UA in remission) and radiographic progression were compared between treatment arms and anti-citrullinated protein antibody (ACPA)-positive and -negative patients. Outcomes were recalculated for patients who, with hindsight, might have been classified at baseline as having RA according to the 2010 criteria (RA (2010)). RESULTS: 25 patients in the MTX group and 29 in the placebo group progressed to RA (1987) (p=0.45). MTX delayed progression from UA to RA (1987) but only in ACPA-positive patients. Drug-free remission was achieved in 35 patients, 20 of whom were initially treated with MTX, and 32 were ACPA-negative. ACPA-positive patients had more radiographic progression, regardless of treatment. Forty-three patients (39%) could be reclassified as having had RA (2010) at baseline, 6/24 (25%) of whom achieved remission after placebo treatment. CONCLUSIONS: After 5 years there is no lasting benefit of a 1 year initial course of MTX for patients with undifferentiated arthritis, compared with initial placebo. Progression to classifiable RA was not suppressed, drug-free remission not induced and the progression of radiological damage was similar in both groups. Reclassification at baseline with the 2010 criteria showed that 25% of patients with RA (2010) achieved spontaneous drug-free remission.
22562973 Clinical, functional and radiographic consequences of achieving stable low disease activit 2013 Jan OBJECTIVE: To assess the efficacy and safety of adalimumab plus methotrexate (ADA+MTX) compared with methotrexate monotherapy in achieving stable low disease activity (LDA; disease activity score (DAS28(CRP)) <3.2 at weeks 22 and 26) and clinical, radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis (RA). METHODS: 1032 patients with active RA were randomly assigned 1:1 to ADA+MTX or placebo plus methotrexate (PBO+MTX) for 26 weeks. Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP) <3.2 at weeks 22 and 26. Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission. RESULTS: Among patients completing 6 months, 44% (207/466) ADA+MTX versus 24% (112/460) PBO+MTX patients achieved stable LDA at weeks 22 and 26 (p<0.001). Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses, more clinical remissions, greater mean reductions in DAS28(CRP), no radiographic progression, and normal functional status at week 26 (p<0.001 for all). The only factor predicting stable LDA was disease activity at week 12. Patients achieving ACR/EULAR remission, particularly in the PBO+MTX group, had some advantage in radiographic outcomes compared with patients who only achieved LDA (but not remission). The overall frequency of adverse events was comparable between groups. There were more serious infections and deaths in the ADA+MTX group, with a possible age effect. CONCLUSIONS: Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical, radiographic and functional outcomes in patients with early active RA. Before initiating treatment with adalimumab, individual patient evaluation of the benefit/risk ratio should be carefully considered.
22986992 Patients' access to biologics in rheumatoid arthritis: a comparison between Portugal and o 2013 Dec BACKGROUND: Despite the widespread availability of biologics across Europe, rheumatoid arthritis (RA) patients' access to these drugs differs significantly among countries. OBJECTIVES: To compare the proportion of RA patients treated with biologics across Europe and investigate the factors that most influence it, with focus on the Portuguese case, reportedly with low access rates to biologics. METHODS: The biologics' market was characterized for 15 selected European countries. Variables potentially influencing patients' access to biologics (PAB) in RA were also collected, including demographic, disease, economic, funding and biologics' market-related data. A multivariable regression model identified the factors that best explain PAB. Based on these determinants, a cluster analysis was performed to group the countries with most similar behaviour regarding PAB allowing the evaluation of Portugal's relative position among these countries. RESULTS: The regression model (R(2) = 0.953) indicated that PAB in selected countries is explained mostly by its gross domestic product (GDP) per capita, the usage of methotrexate (MTX) and the biologics' distribution channel. Current MTX usage in Portugal shows similarity with practice from UK, France, Germany or Spain 5 years before, explaining why PAB in Portugal stood at 7% in 2010, 12 percentage points below the average of selected countries. CONCLUSIONS: Variations in RA PAB were found across selected countries with Portugal showing the lowest proportion. GDP per capita, biologics distribution channel and consumption of MTX appear to be the best explanatory factors for these fluctuations in European countries.
23332236 Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and me 2013 Mar 16 BACKGROUND: Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis. Although moderately active rheumatoid arthritis is common, treatment effects in moderate disease have not been well studied. Additionally, optimum use of biologics needs further investigation, including the use of induction, maintenance, and withdrawal treatment strategies. The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease. METHODS: In a randomised controlled trial, patients aged between 18 and 70 years with moderately active rheumatoid arthritis (disease activity score in 28 joints [DAS28] >3.2 and ≤5.1) despite treatment with methotrexate were enrolled at 80 centres in Europe, Latin America, Asia, and Australia between March 6, 2008, and Sept 9, 2009. To be eligible, patients had to have been receiving 15-25 mg of methotrexate every week for at least 8 weeks. In an open-label period of 36 weeks, all patients were given 50 mg etanercept plus methotrexate every week. To be eligible for a subsequent double-blind period of 52 weeks, participants had to have achieved sustained low disease activity. These patients were randomly assigned (1:1:1) by an interactive voice-response system to one of three treatment groups: 50 mg etanercept plus methotrexate, 25 mg etanercept plus methotrexate, or placebo plus methotrexate. Patients were stratified in blocks of three by DAS28 response (low disease activity or remission) at week 36. Patients, investigators, data analysts, and study staff were all masked to treatment allocation. The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period. A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity. Modified intention-to-treat populations were used for analyses. This trial is registered with ClinicalTrials.gov, number NCT00565409. FINDINGS: 604 (72.4%) of 834 enrolled patients were eligible for the double-blind period, of whom 202 were assigned to 50 mg etanercept plus methotrexate, 202 to 25 mg etanercept plus methotrexate, and 200 to placebo plus methotrexate. At week 88, 166 (82.6%) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity, compared with 84 (42.6%) of 197 who had received placebo (mean difference 40.8%, 95% CI 32.5-49.1%; p<0.0001). Additionally, 159 (79.1%) of 201 patients given 25 mg etanercept had low disease activity at week 88 (mean difference from placebo 35.9%, 27.0-44.8%; p<0.0001). INTERPRETATION: Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept. FUNDING: Pfizer.
23044791 Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthri 2013 Feb OBJECTIVE: While medications used to treat rheumatoid arthritis (RA) may affect survival in RA, few studies take into account the propensity for medication use, which may reflect selection bias in treatment allocation in survival models. We undertook this study to examine the relationship between methotrexate (MTX) use and mortality in RA, after controlling for individual propensity scores for MTX use. METHODS: We studied 5,626 RA patients prospectively for 25 years to determine the risk of death associated with MTX use, modeled in time-varying Cox regression models. We used the random forest method to generate individual propensity scores for MTX use at study entry and during followup in a time-varying manner; these scores were included in the multivariate model. We also investigated whether selective discontinuation of MTX immediately prior to death altered the risk of mortality, and we examined the association of duration of MTX use with survival. RESULTS: During followup, 666 patients (12%) died. MTX use was associated with reduced risk of death (adjusted hazard ratio 0.30 [95% confidence interval 0.09-1.03]). Selective MTX cessation immediately before death did not account for the protective association of MTX use with mortality. Only MTX use for >1 year was associated with lower risks of mortality, but associations were not stronger with longer durations of use. CONCLUSION: MTX use was associated with a 70% reduction in mortality in RA.
24684409 Pulmonary and retroperitoneal lesions induced by methotrexate-associated lymphoproliferati 2016 A 78-year-old man had fatigue and appetite loss for 5 months. He had been receiving low-dose methotrexate for rheumatoid arthritis. Computed tomography revealed multiple pulmonary infiltrations and muddiness of the fatty tissue surrounding the right kidney, ureter wall thickening, and hydroureter/nephrosis, which were suspected retroperitoneal fibrosis. Lung biopsy revealed polymorphic/lymphoplasmacytic lymphoproliferative disorder. Methotrexate withdrawal resulted in spontaneous regression. Therefore, retroperitoneal lesion may account for the diagnosis as having retroperitoneal lymphoproliferative disorder, not retroperitoneal fibrosis.