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ID PMID Title PublicationDate abstract
27099776 Effectiveness of four dynamic treatment strategies in patients with anticitrullinated prot 2016 OBJECTIVE: To determine the most effective treatment strategy among anticitrullinated protein antibodies (ACPA)-negative patients with early rheumatoid arthritis. METHODS: In the BeSt study, 184 ACPA-negative patients were randomised to: (1) sequential monotherapy, (2) step-up therapy, (3) initial combination including prednisone, (4) initial combination including infliximab. Treatment was targeted at the disease activity score (DAS) ≤2.4. Early response and 10-year outcomes were compared between the four strategy-arms in ACPA-negative patients. RESULTS: ACPA-negative patients achieved more short-term functional improvement from initial combination therapy than when on monotherapy (at month 3, mean Health Assessment Questionnaire (HAQ) 0.71 vs 0.98, p=0.006; at month 6, 0.59 vs 0.87, p=0.004). Functional ability over time was comparable between the strategy-arms (p=0.551) with a mean HAQ of 0.6 at year 10 (p=0.580 for comparison across the strategy-arms). 10-year radiographic progression was negligible (median 0.5) and comparable between the 4 strategy-arms (p=0.082). At year 10, remission was achieved by 11/40 (28%), 9/45 (20%), 17/56 (30%) and 17/43 patients (40%) in strategy-arms 1-4, respectively (p=0.434). Over time, similar remission percentages were achieved in all strategy-arms (p=0.815). 18%, 16%, 20% and 21% in strategy-arms 1 to 4 (p=0.742) were in drug-free remission at year 10, with a median duration of 60 months across the arms. CONCLUSIONS: Initial combination therapy with methotrexate, sulfasalazine and prednisone, or methotrexate and infliximab, is the most effective treatment strategy for ACPA-negative patients, resulting in earlier functional improvement than when on initial methotrexate monotherapy. After 10 years of targeted treatment, in all strategy-arms favourable clinical outcomes were achieved and radiographic progression was limited. TRIAL REGISTRATION NUMBER: NTR262, NTR265.
26925252 Adalimumab discontinuation in patients with early rheumatoid arthritis who were initially 2016 OBJECTIVES: To evaluate the impact of discontinuation of adalimumab (ADA) for 1 year in Japanese patients with early rheumatoid arthritis (RA). METHODS: This 52-week postmarketing study, HOPEFUL-2, enrolled patients who had completed HOPEFUL-1 for early RA, in which patients received either ADA + methotrexate (MTX) or MTX alone in a 26-week randomised phase, followed by ADA+MTX in a 26-week open-label phase. RESULTS: A total of 220 patients (ADA discontinuation: 114 patients vs ADA continuation: 106 patients) were enrolled in this study. The proportion of patients with sustained low disease activity (LDA) in the ADA discontinuation group was significantly lower than that in the continuation group (80% (64/80 patients) vs 97% (71/73 patients); p=0.001); however, most patients sustained LDA in both groups. In patients with 28-joint disease activity score (DAS28)-C reactive protein ≤2.0 at week 52, the proportion of patients who achieved sustained LDA at week 104 was 93%, suggesting that DAS28 remission may be a predictor to indicate biological-free disease control in patients with early RA. The incidence of adverse events (AE) was significantly lower in the ADA discontinuation group than in the continuation group (34.2% (39/114 patients) vs 48.1% (51/106 patients); p=0.04), most notably for infection (14.9% vs 27.4%, p=0.031). CONCLUSIONS: Although ADA discontinuation was associated with an increase in disease activity, a large proportion of patients maintained LDA with MTX monotherapy after ADA discontinuation. Since ADA discontinuation was associated with a lower AE incidence, physicians should weigh the risks and benefits of ADA discontinuation. TRIAL REGISTRATION NUMBER: NCT01163292.
26819752 A multicentre, randomised, controlled, open-label pilot study on the feasibility of discon 2016 OBJECTIVES: Treatment with tumour necrosis factor (TNF) blockers, once started as therapy for rheumatoid arthritis (RA), is usually continued indefinitely. The aim of this trial was to assess the possibility of discontinuing treatment with adalimumab (ADA) while maintaining remission in patients with RA with established disease in stable remission on combination therapy with ADA and methotrexate (MTX). METHODS: In a randomised, controlled, open-label pilot study of patients with RA in stable remission treated with ADA+MTX, patients were randomised in a 1:1 ratio to continue with ADA plus MTX (arm AM) or MTX monotherapy (arm M) for 52 weeks. Flare was defined as Disease Activity Score (DAS28) ≥2.6 or a change in DAS28 (ΔDAS28) of >1.2 from baseline at any time. Patients in arm M with a flare restarted ADA. The primary end point was the proportion of patients in remission at week 28. RESULTS: 31 patients were enrolled in the study and randomised to arm AM (n=16) or arm M (n=15). At 28 weeks, 15/16 patients (94%) and 5/15 patients (33%) in arms AM and M, respectively, were in remission (p=0.001). During the first 28 weeks, 50% (8/16) in the AM arm and 80% (12/15) in the M arm had a flare (p=0.08). The number of patients in the AM and M arms with ≥1 ΔDAS28 >1.2 during the first 28 weeks was 1/16 (6%) and 8/15 (53%), respectively (p=0.005). CONCLUSIONS: In this study, remission was rarely maintained in patients with long-standing disease who discontinued ADA. Discontinuation may be feasible in only a minority of patients with established RA in stable clinical remission. TRIAL REGISTRATION NUMBER: NCT00808509.
26535138 Longer durations of antitumour necrosis factor treatment are associated with reduced risk 2015 OBJECTIVE: To assess the effects of treatment with antitumour necrosis factor (TNF) agents, methotrexate, or other non-biological disease-modifying antirheumatic drugs (DMARDs) on cardiovascular event risks among patients with rheumatoid arthritis (RA). METHODS: We conducted a retrospective study using data from the MarketScan claims database. Patients with RA with ≥1 prescription for an index drug were included. Each patient's use of an index drug was calculated cumulatively as a time-varying exposure. The incidence of cardiovascular events among patients with RA was determined. Associations between drug exposures and occurrence of cardiovascular events were assessed with Cox proportional hazards models. RESULTS: Of 113 677 patients identified, 35.8%, 41.1% and 23.1% received anti-TNF agents, methotrexate and other DMARDs, respectively. Patients were treated for an average of 7.6 months; 2138 patients (1.9%) had a cardiovascular event following their index prescription. Each additional 6 months of anti-TNF therapy use versus non-use reduced the risk (HR; 95% CI) for any cardiovascular event by 12% (0.88; 0.81 to 0.95, p=0.002). Anti-TNF therapy was associated with a 13% and 12% reduction in cardiovascular events in patients aged ≥50 years (0.87; 0.80 to 0.95, p=0.002) and in those without prior methotrexate use (0.88; 0.78 to 0.99, p=0.04), respectively. Cumulative use of 1, 2 or 3 years of anti-TNF therapy versus non-use is expected to reduce cardiovascular event risks by 21%, 38% and 51%, respectively. CONCLUSIONS: Anti-TNF therapy was associated with a significantly lower risk of cardiovascular events among patients with RA, older patients with RA and patients without prior exposure to methotrexate.
26535135 Estimating the monetary value of the annual productivity gained in patients with early rhe 2015 OBJECTIVE: To measure and value the impact of combined etanercept (ETN) and methotrexate (MTX) therapy on work productivity in patients with early rheumatoid arthritis (RA) over 52 weeks. METHODS: MTX- and biological-naïve patients with RA (symptom onset ≤12 months; Disease Activity Score based on a 28-joint count (DAS28) >3.2) received open-label ETN50/MTX for 52 weeks. The Valuation of Lost Productivity (VOLP) questionnaire, measuring paid and unpaid work productivity impacts, was completed approximately every 13 weeks. Bootstrapping methods were used to test changes in VOLP outcomes over time. One-year productivity impacts were compared between responders (DAS28 ≤3.2) at week 13 and non-responders using zero-inflated models for time loss and two-part models for total costs of lost productivity. RESULTS: 196 patients were employed at baseline and had ≥1 follow-up with VOLP. Compared with baseline, at week 52, patients gained 33.4 h per 3 months in paid work and 4.2 h per week in unpaid work. Total monetary productivity gains were €1322 per 3 months. Over the 1-year period, responders gained paid (231 h) and unpaid work loss (122 h) compared with non-responders, which amounted to a gain of €3670 for responders. CONCLUSIONS: This is the first clinical trial to measure and value the impact of biological treatment on all the labour input components that affect overall productivity. Combination therapy with ETN50/MTX was associated with a significant productivity gain for patients with early RA who were still observed at week 52. Over the 1-year treatment period, responders at week 13 suffered significantly less productivity loss than non-responders suggesting this gain was related to treatment response. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number NCT00913458.
26150616 A case of neurosarcoidosis secondary to treatment of etanercept and review of the literatu 2015 Jul 6 There are only three cases in the literature that describe development of neurosarcoidosis in a patient who is on tumour necrosis factor α inhibitors. We describe a case of a 33-year-old woman with a history of juvenile rheumatoid arthritis and refractory uveitis (with previous treatment trials of adalimumab, infliximab, mycophenolate, methotrexate) who had been stable for 2 years on etanercept. She was diagnosed with biopsy-proven systemic sarcoidosis with meningeal and parenchymal neurosarcoidosis. She was switched to infliximab and methotrexate, with clinical and imaging improvements. This is a case that demonstrates the difficulty of choosing tumour necrosis factor α (TNF-α) inhibitors when treating patients with multiple clinical autoimmune entities. It is also a case where a change in the mechanism of TNF-α inhibition pathway can still be used to treat refractory sarcoidoisis and rheumatoid arthritis. It is still unclear what the exact difference between the TNF-α blockers and their neurological complications is, and who the patients at risk of developing neurological complications are.
27747509 Early Prognostic Factors Associated with the Efficacy of Infliximab Treatment for Patients 2016 Jun INTRODUCTION: Early prognostic factors for the clinical response in patients with rheumatoid arthritis (RA) after 1 year of treatment with infliximab (IFX) as part of routine clinical practice were investigated. METHODS: Thirty-five patients with RA with an inadequate response to methotrexate were enrolled and administered IFX (3-9 mg/kg, every 4-8 weeks). Serum trough levels of IFX and levels of 9 cytokines were measured at baseline and at 3, 6 months, and 1 year. Associations between these parameters and clinical indicators were statistically analyzed. RESULTS: Serum trough levels of IFX and serum levels of interleukin (IL)-6 in the early phase of IFX treatment were investigated. Patients with low serum IL-6 achieved a higher clinical response as evaluated by the European League Against Rheumatism response criteria. Notably, the serum levels of IL-6 and IL-10 at baseline exhibited a significant positive correlation with disease activity at 1 year. Low serum levels of IL-6 and IL-10 at baseline were associated with low Disease Activity Score 28 erythrocyte sedimentation rate (DAS28-ESR). Cut-off values of IL-6 (5.45 pg/mL) and IL-10 and (1.68 pg/mL) enabled discrimination of DAS28-ESR remission from non-remission with high sensitivity and moderate specificity. CONCLUSION: Following the initiation of IFX treatment, early disease activity and remission were associated with serum levels of IL-6. Serum levels of IL-6 and IL-10 at baseline predict the efficacy after 1 year of treatment with IFX. Patients with high serum levels of IL-6 and IL-10 at baseline before IFX treatment might require more intensive therapy to achieve higher rates of clinical remission at 1 year. FUNDING: Eisai Co., Ltd.
27252893 Malignancy rates in patients with rheumatoid arthritis treated with tocilizumab. 2016 OBJECTIVE: To analyse malignancy rates in patients with rheumatoid arthritis (RA) treated with tocilizumab. METHODS: Patients who received tocilizumab or placebo+methotrexate/disease-modifying antirheumatic drugs in the double-blind phases of 5-phase three trials or who received at least 1 dose of tocilizumab in the long-term extension studies were analysed up to the 2 May 2012 cut-off date. Malignancies were monitored throughout the studies, analysed and adjudicated as malignant by medical review. Risk was compared with that in the general population using standardised incidence ratios (SIRs) based on data from the Surveillance Epidemiology and End Results SEER (US general population) and GLOBOCAN (non-US general population) databases. RESULTS: In total, 4009 patients in the tocilizumab all-exposure population were included. Mean treatment duration was 4.0 years (mean 5.1 (range 0.0-6.8); total observation time was 16 120.1 patient-years (PY). The adjudicated malignancy rate (95% CI) was 1.26/100 PY (1.09 to 1.44) and remained constant over time. The SIR (95% CI) for all malignancies combined, excluding non-melanoma skin cancer, was 1.36 (1.01 to 1.80) for US and 1.81 (1.44 to 2.23) for non-US populations, driven primarily by higher rates in lung and bronchus (US/non-US) malignancies and prostate cancer and non-Hodgkin lymphoma (non-US), in contrast to those for the general populations; these higher rates are in line with those expected in patients with RA or in the geographic regions studied. CONCLUSIONS: Malignancy rates remained stable with long-term tocilizumab treatment, and malignancy types and rates were consistent with those expected in patients with RA.
26622326 Treatment of rheumatoid arthritis-associated interstitial lung disease: a perspective revi 2015 Dec Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting 0.5-1% of the worldwide population. Whilst predominantly causing chronic pain and inflammation in synovial joints, it is also associated with significant extra-articular manifestations in a large proportion of patients. Among the various pulmonary manifestations, interstitial lung disease (ILD), a progressive fibrotic disease of the lung parenchyma, is the commonest and most important, contributing significantly to increased morbidity and mortality. The most frequent patterns of RA-associated ILD (RA-ILD) are usual interstitial pneumonia and nonspecific interstitial pneumonia. New insights during the past several years have highlighted the epidemiological impact of RA-ILD and have begun to identify factors contributing to its pathogenesis. Risk factors include smoking, male sex, human leukocyte antigen haplotype, rheumatoid factor and anticyclic citrullinated protein antibodies (ACPAs). Combined with clinical information, chest examination and pulmonary function testing, high-resolution computed tomography of the chest forms the basis of investigation and allows assessment of subtype and disease extent. The management of RA-ILD is a challenge. Several therapeutic agents have been suggested in the literature but as yet no large randomized controlled trials have been undertaken to guide clinical management. Therapy is further complicated by commonly prescribed drugs of proven articular benefit such as methotrexate, leflunomide (LEF) and anti-tumour necrosis factor α agents having been implicated in both ex novo occurrence and acceleration of existing ILD. Agents that offer promise include immunomodulators such as mycophenolate and rituximab as well as newly studied antifibrotic agents. In this review, we discuss the current literature to evaluate recommendations for the management of RA-ILD and discuss key gaps in our knowledge of this important disease.
27230134 Anti-arthritic activity of 11-O-(4'-O-methyl galloyl)-bergenin and Crassula capitella extr 2016 Jun OBJECTIVES: Isolation and identification of phytochemicals of Crassula capitella (Thunberg), evaluation of the anti-arthritic potential of the extract and the major isolated compound; 11-O-(4'-O-methyl galloyl)-bergenin and underlying their mechanism on rat model of rheumatoid arthritis (RA). METHODS: Different fractions were subjected to column chromatography giving fourteen compound identified by mass and NMR spectroscopic techniques. RA was induced by intraplantar injection of complete Freund's adjuvant into the right hind paw of rats. Influence of tested samples in comparable to methotrexate on paw oedema, body weight gain, serum diagnostic markers, cartilage and bone degeneration enzymes, pro-inflammatory mediators and oxidative stress biomarkers in arthritic rats. KEY FINDINGS: Fourteen phenolic compounds were isolated and identified for the first time from C. capitella. The major compound identified as 11-O-(4'-O-methyl galloyl)-bergenin. Treatment of arthritic rats with extract or 11-O-(4'-O-methyl galloyl)-bergenin with the tested doses can reduce the progression and severity of RA. CONCLUSION: Crassula capitella is a new natural and abundant source for 11-O-(4'-O-methyl galloyl)-bergenin for resolving chronic inflammatory diseases as RA through antioxidant, anti-inflammatory and membrane stabilizing mechanism.
27110385 Reductions in disease activity in the AMPLE trial: clinical response by baseline disease d 2016 OBJECTIVES: To evaluate clinical response by baseline disease duration using 2-year data from the AMPLE trial. METHODS: Patients were randomised to subcutaneous abatacept 125 mg weekly or adalimumab 40 mg bi-weekly, with background methotrexate. As part of a post hoc analysis, the achievement of validated definitions of remission (Clinical Disease Activity Index (CDAI) ≤2.8, Simplified Disease Activity Index (SDAI) ≤3.3, Routine Assessment of Patient Index Data 3 (RAPID3) ≤3.0, Boolean score ≤1), low disease activity (CDAI <10, SDAI <11, RAPID3 ≤6.0), Health Assessment Questionnaire-Disability Index response and American College of Rheumatology responses were evaluated by baseline disease duration (≤6 vs >6 months). Disease Activity Score 28 (C-reactive protein) <2.6 or ≤3.2 and radiographic non-progression in patients achieving remission were also evaluated. RESULTS: A total of 646 patients were randomised and treated (abatacept, n=318; adalimumab, n=328). In both treatment groups, comparable responses were achieved in patients with early rheumatoid arthritis (≤6 months) and in those with later disease (>6 months) across multiple clinical measures. CONCLUSIONS: Abatacept or adalimumab with background methotrexate were associated with similar onset and sustainability of response over 2 years. Patients treated early or later in the disease course achieved comparable clinical responses. TRIAL REGISTRATION NUMBER: NCT00929864, Post-results.
27721905 Combination therapy with biologic agents in rheumatic diseases: current and future prospec 2016 Oct Strategies in rheumatoid arthritis (RA) based on 'treat to target' aim to control disease activity, minimize structural damage, and promote longer life. Several disease-modifying antirheumatic drugs (DMARDs) have been shown to be effective including biological DMARDs (bDMARDs). Treatment guidelines and recommendations for RA have also been published. According to those guidelines, conventional synthetic DMARDs (csDMARDs), as monotherapy or combination therapy, should be used in DMARD-naïve patients, irrespective of the addition of glucocorticoids (GCs). Combination therapies with bDMARDs are also essential for conducting treatment strategies for RA, because in every recommendation or guideline for the management of RA, combination therapies of csDMARDs with bDMARDs are recommended for RA patients with moderate or high disease activity after failure of csDMARD treatment. bDMARDs are more efficacious if used concomitantly with methotrexate (MTX) than with MTX monotherapy or bDMARD monotherapy. Thus, retention has been reported to be longer when combined with MTX. The superior efficacy of combination therapy compared with MTX monotherapy or bDMARD monotherapy could be because: (1) it could help to minimize MTX toxicity by reducing the dose of MTX, thus retention rate of the same therapeutic regimen would become high; (2) anti-bDMARD antibodies are observed at lower concentrations when using MTX concomitantly, so less clearance of bDMARDs via less formation of bDMARD and an anti-bDMARD immune complex; (3) of the additive effects of MTX to bDMARD, especially the combination of tumor necrosis factor inhibitors (TNFis) with MTX. Hence, evidence suggests that combination therapy with bDMARDs is more efficacious than monotherapy using a csDMARD or bDMARD, and that MTX is the best drug for this purpose (if MTX is not contraindicated). Finding the most effective drug regimen at the lowest cost will be the aim of RA treatment in the future.
27589009 The underlying inflammatory chronic disease influences infliximab pharmacokinetics. 2016 Oct Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a one-compartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.
27721903 Combination leflunomide and methotrexate in refractory rheumatoid arthritis: a biologic sp 2016 Oct BACKGROUND: In resource-constrained settings where biologic agents are not widely available, there are limited therapeutic options for patients with rheumatoid arthritis (RA) refractory to other synthetic disease modifying antirheumatic (DMARD) therapies. The aim of this study is to evaluate the effectiveness and safety of leflunomide (LEF) with methotrexate (MTX) in refractory RA. METHODS: A retrospective record review of adult RA patients treated with LEF/MTX. Demographic details, adverse reactions, and the 3-variable 28 joint disease activity score (DAS28-3) were recorded at initiation of LEF/MTX therapy, and after 4 and 12 months of treatment. RESULTS: Of 194 patients, most were middle-aged seropositive Black African females, with established disease [mean (standard deviation, SD) disease duration 9.4 (8.2) years] and time on previous DMARDs of 7.0 (5.5) years. Before adding LEF, the mean (SD) dose of MTX was 21.7 (3.5) mg/week, and 87.6% of patients used low dose oral corticosteroids. A good or moderate EULAR response was achieved by 44% and 42% of patients, and the retention rate was 71%. Major infections were seen in 6 patients: comprising 2 deaths, 3 cases of leucopaenia and septicaemia and 1 case of tuberculosis. Hepatotoxicity (n = 3), intolerable gastrointestinal symptoms (n = 3), and hypertension (n = 17) were the most common problems. Predictors of remission or low disease activity at 12 months was a baseline DAS28-3 ⩽ 5.5 [odds ratio (OR) = 2.7; 95% confidence interval (CI) 1.1-5.6; p = 0.01]. CONCLUSIONS: LEF/MTX was effective in the majority of patients in this cohort of mainly Black African women who failed other combination synthetic DMARDs, particularly in those with moderate disease activity at the time of addition of LEF. Infections and hypertension were important complications. In a setting where biologic DMARDs are not readily accessible, the combination of LEF/MTX is a cost-effective approach.
27006728 Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rhe 2016 BACKGROUND: Although long-term data are available from biologic studies in North American/European populations with rheumatoid arthritis (RA), long-term findings in Latin American RA populations are limited. OBJECTIVE: To examine long-term safety/efficacy of etanercept, methotrexate, and/or other disease-modifying anti-rheumatic drugs (DMARDs) in Latin American patients with moderate-to-severe active RA. METHODS: In the first phase of this open-label study, patients were randomized to etanercept 50 mg weekly plus methotrexate or conventional DMARD (hydroxychloroquine or sulfasalazine) plus methotrexate for 24 weeks. At the start of the second phase (week 24), investigators selected a treatment regimen that included any combination/dosage of etanercept, methotrexate, hydroxychloroquine, or sulfasalazine based on previous treatment response, preference, and local product labeling, and was continued for the 104-week extension. RESULTS: In the extension, in the group previously randomized to etanercept-plus-methotrexate therapy, etanercept was continued in 259/260 patients; methotrexate continued in 260/260; and hydroxychloroquine and sulfasalazine added in 8/260 and 3/260, respectively. In the group previously randomized to conventional DMARD-plus-methotrexate therapy, conventional DMARD was discontinued in 86/126 and etanercept added in 105/126. Among etanercept-exposed patients (total exposure, 798.1 patient-year [PY]), rates of adverse events, serious adverse events, and serious infections per PY were 1.7, 0.07, and 0.02 events per PY. In both groups, after treatment modification was permitted, clinical response rates and improvements in clinical/patient-reported outcomes from baseline were sustained to week 128. CONCLUSION: After investigators were permitted to modify treatment, etanercept was part of the treatment regimen in 95% of patients. Continuation or addition of etanercept in the 2-year extension resulted in a consistently good risk:benefit profile. TRIAL REGISTRATION: Open-Label Study Comparing Etanercept to Conventional Disease Modifying Antirheumatic Drug (DMARD) Therapy; ClinicalTrials.gov, number NCT00848354; https://clinicaltrials.gov/ct2/show/NCT00848354.
27335660 Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in 2016 OBJECTIVE: To describe changes in immune parameters observed during long-term methotrexate (MTX) therapy in patients with active rheumatoid arthritis (RA) and explore correlations with simultaneously measured MTX pharmacokinetic (PKC) parameters. DESIGN: Prospective, open-label, long-term mechanism of action study. SETTING: University clinic. METHODS: MTX was initiated at a single weekly oral dose of 7.5 mg and dose adjusted for efficacy and toxicity for the duration of the study. Standard measures of disease activity were performed at baseline and every 6-36 months. Serum cytokine measurements in blood together with lymphocyte surface immunophenotypes and stimulated peripheral blood mononuclear cell (PBMC) cytokine production were assessed at each clinical evaluation. RESULTS: Cytokine concentrations exhibited multiple significant correlations with disease activity measures over time. The strongest correlations observed were for interleukin (IL)-6 (r=0.45, p<0.0001 for swollen joints and r=0.32, p=0.002 for tender joints) and IL-8 (r=0.25, p=0.01 for swollen joints). Significant decreases from baseline were observed in serum IL-1B, IL-6 and IL-8 concentrations. The most significant changes were observed for IL-6 (p<0.001). Significant increases from baseline were observed in IL-2 release from PBMCs ex vivo (p<0.01). In parallel, multiple statistically significant correlations were observed between MTX PKC measures and immune parameters. The change in swollen joint count correlated inversely with the change in area under the curve (AUC) for MTX (r=-0.63, p=0.007). CONCLUSIONS: MTX therapy of patients with RA is accompanied by a variety of changes in serum cytokine expression, which in turn correlate strongly with clinical disease activity and MTX pharmacokinetics (PKCs). These data strongly support the notion that MTX mediates profound and functionally relevant effects on the immunological hierarchy in the RA lesion.
26958364 Association of a multibiomarker disease activity score at multiple time-points with radiog 2016 OBJECTIVES: In rheumatoid arthritis (RA), predictive biomarkers for subsequent radiographic progression (RP) could improve therapeutic choices for individual patients. We previously showed that the multibiomarker disease activity (MBDA) score in patients with newly diagnosed RA identified patients at risk for RP. We evaluated the MBDA score at multiple time-points as a predictor of RP during 2 years of follow-up. METHODS: A subset of patients with RA (N=220) from the Swedish Farmacotherapy (SWEFOT) trial were analysed for MBDA score, disease activity score of 28 joints (DAS28), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) at baseline (BL), month 3 and year 1, for predicting RP based on modified Sharp/van der Heijde scores at BL, year 1 and year 2. RESULTS: Patients with persistently low MBDA (<30) scores or those with a decrease from moderate (30-44) to low MBDA scores, did not develop RP during 2 years of follow-up. The highest risk for RP during 2 years of follow-up (42%) was observed among patients with persistently high (>44) MBDA scores. Among methotrexate non-responders with a high MBDA score at BL or month 3, significantly more of those who received triple therapy had RP at year 2 compared with those who received antitumour necrosis factor therapy. CONCLUSIONS: Measuring the MBDA score both before and during treatment in RA was useful for the assessment of individual patient risk for RP during 2 years of follow-up. In comparison with low CRP, ESR or DAS28, a low MBDA score at any time-point was associated with numerically lower proportions of RP. TRIAL REGISTRATION NUMBER: NCT00764725.
28348775 Progressive multifocal leukoencephalopathy and black fungus in a patient with rheumatoid a 2016 Aug INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating brain infection caused by JC polyomavirus (JCV), primarily seen in patients with severely compromised cellular immunity. Clinical presentation varies depending on the affected white matter. PML prognosis is variable and effective treatments are lacking. CASE PRESENTATION: A 75-year-old Chinese woman with type 2 diabetes mellitus, chronic kidney disease and rheumatoid arthritis, treated with low-dose methotrexate and prednisolone for 2.5 years, developed a Pleurostomophora richardsiae infection of her left arm. After 6 months of treating this rare black fungus infection with voriconazole, surgery and immunosuppression discontinuation, she presented with progressive afebrile encephalopathy with right-sided hemiparesis. There were no signs of inflammation or metabolic abnormalities. Brain magnetic resonance imaging revealed diffuse frontal white matter lesions and a cerebrospinal fluid PCR confirmed PML due to JC virus. Severe lymphopenia was never present, and at PML diagnosis, CD4 and CD8 T-cell counts were 454 mm(-3) and 277 mm(-3). CD8 T-cells were able to respond to JCV VP1 peptide stimulation with TNFα secretion. Peripheral B-cell count was only 8 mm(-3). Mirtazapine and Maraviroc were started, but unfortunately, she rapidly deteriorated and died 5 weeks after PML diagnosis. CONCLUSION: Although peripheral lymphocyte counts were never low and CD4 T-cell count was close to normal, the persistent black fungus infection was a hallmark of severely compromised cellular immunity. The unexpected extremely low absolute B-cell count might suggest a protective role for B-cells. The paradoxical, clinical PML onset months after immunosuppressive discontinuation suggests that it was only discovered in the context of an immune reconstitution inflammatory syndrome.
27651929 Induction maintenance with tumour necrosis factor-inhibitor combination therapy with disco 2016 OBJECTIVE: To determine whether an induction-maintenance strategy of combined therapy (methotrexate (MTX)+tumour necrosis factor (TNF) inhibitor (TNFi)) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy, since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn. METHODS: We performed a meta-analysis of trials using the initial combination of MTX+TNFi in conventional synthetic disease-modifying antirheumatic drug-naïve patients with early rheumatoid arthritis (RA). A systematic literature search was performed for induction-maintenance randomised controlled trials (RCTs) where initial combination therapy was compared with MTX monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved low disease activity (LDA; Disease Activity Score (DAS)28<3.2) and/or remission (DAS28<2.6) at 12-76 weeks of follow-up. A random-effects model was used to pool the risk ratio (RR) for LDA and remission and heterogeneity was explored by subgroup analyses. RESULTS: We identified 6 published RCTs, 4 of them where MTX+adalimumab was given as initial therapy and where adalimumab was withdrawn in a subset of patients after LDA/remission had been achieved. 2 additional trials used MTX+infliximab as combination therapy. The pooled RRs for achieving LDA and clinical remission at follow-up after withdrawal of TNFi were 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively. There was significant heterogeneity between trials due to different treatment strategies, which was a limitation to this study. CONCLUSIONS: Initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNFi.
26535151 Tapering and discontinuation of methotrexate in patients with RA treated with TNF inhibito 2015 OBJECTIVES: To study the number of patients that taper or discontinue concomitant methotrexate (MTX) in daily practice in patients with rheumatoid arthritis (RA) treated with tumour necrosis factor inhibitor (TNFi) and to analyse the effects of that adaption on disease activity and drug survival. METHODS: Data were collected from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Patients who started their first TNFi were included in the study. Treatment effectiveness after MTX tapering or discontinuation was analysed using Disease Activity Score of 28 joints (DAS28). Drug survival of the TNFi was analysed using the Cox proportional hazard model with a time-dependent covariate. RESULTS: In 458 patients (34%), MTX was tapered, 126 patients (10%) discontinued MTX and 747 patients (56%) continued MTX at the same dose. On average, DAS28 improved after tapering MTX (-0.40, -0.45) and after stopping MTX (-0.28, -0.12) at 6 and 12 months. In the taper group, 21% of the patients relapsed (DAS28 increase >0.6), and in the discontinuation group this was 21% and 24% at 6 and 12 months, respectively. Patients who taper and discontinue MTX have a similar DAS28 score over time as patients who continue MTX. Moreover, there was no influence of tapering or discontinuation of MTX on long-term drug survival of TNFi. CONCLUSIONS: In daily practice, tapering or discontinuation of concomitant MTX in patients with RA treated with TNFi frequently occurs and it does not seem to influence the average DAS28 over time or the long-term TNFi drug survival. It appears that in daily clinical practice the correct patients are selected to taper or discontinue MTX.