Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved.
To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate ...(MTX)-based treatment strategy for tight control in early RA increases its effectiveness.
A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II Computer Assisted Management in Early Rheumatoid Arthritis trial-II). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169)
7 hospitals in the Netherlands.
236 patients with early RA (duration <1 year).
Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission.
The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment.
Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group.
A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible.
Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes.
Catharijne Foundation.
We sought to identify immunoglobin G autoantibodies predictive of early treatment response to methotrexate, the recommended first-line therapy for patients with newly diagnosed rheumatoid arthritis, ...and to the interleukin-6 receptor inhibitor biologic tocilizumab, initiated as the first disease-modifying anti-rheumatic drug.
In baseline sera of a subset of patients with newly diagnosed rheumatoid arthritis in the U-Act-Early study, selected based on specific responder/non-responder criteria using the Disease Activity Score assessing 28 joints (DAS28) within the first 20 weeks, we measured immunoglobin G antibody reactivity against 463 protein antigens and performed supervised cluster analysis to identify predictive autoantibodies for treatment response. The analysis subset comprised 56 patients in the methotrexate arm (22 responders, 34 non-responders) and 50 patients in the tocilizumab arm (34 responders, 16 non-responders). For comparison, these analyses were also performed in 50 age- and gender-matched healthy controls.
Increased reactivity in responders versus non-responders was found in the methotrexate arm against two antigens-DOT1-like histone lysine methyltransferase (p = 0.009) and tropomyosin (p = 0.003)-and in the tocilizumab arm against one antigen-neuro-oncological ventral antigen 2 (p = 0.039). Decreased reactivity was detected against two antigens in the methotrexate arm-G1 to S phase transition 2 (p = 0.023) and the zinc finger protein ZPR1 (p = 0.021). Reactivity against the identified antigens was not statistically significant in either treatment arm for patients with rheumatoid factor-positive versus-negative or anti-cyclic citrullinated test-positive versus test-negative rheumatoid arthritis (p ≥ 0.06).
Comprehensive profiling of baseline sera revealed several novel immunoglobin G autoantibodies associated with early treatment response to methotrexate and to tocilizumab in disease-modifying anti-rheumatic drug-naive patients with rheumatoid arthritis. These findings could eventually yield clinically relevant predictive markers, if corroborated in different patient cohorts, and may facilitate future benefit in personalised healthcare.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Previous studies in patients with rheumatoid arthritis (RA) have shown that switching to tocilizumab (TCZ) monotherapy (TCZ
) or combination therapy (TCZ
) with conventional synthetic ...disease-modifying anti-rheumatic drugs (csDMARDs) is efficacious in reducing disease activity in patients with inadequate response to csDMARDs. However, hitherto there is no consensus on whether TCZ
is as effective as TCZ
. The objective of this study was therefore to evaluate the efficacy and safety of TCZ
versus add-on TCZ
and both TCZ therapies versus continuing the current csDMARD therapy, by performing a systematic review and meta-analyses.
The MEDLINE, EMBASE and CENTRAL databases were searched until February 2016 for relevant randomized controlled trials (RCTs). We performed meta-analyses of Disease Activity Score in 28 joints (DAS28 < 2.6), American College of Rheumatology (ACR) 20/50/70 responses, adverse events (AEs) and serious AEs (SAEs) to compare the three different strategies, whereas a random-effect model was used for pooling relative risks (RR) and 95 % confidence intervals (CI). In addition, sensitivity analyses were performed for evaluating differences in study duration.
In total, 13 RCTs were included in the meta-analysis, involving 6679 patients. When comparing both TCZ strategies, a marginally greater proportion of patients achieving DAS28 < 2.6 (RR 1.21; 95 % CI 1.09, 1.36) and ACR50 response (RR 1.14; 95 % CI 1.03, 1.26) was found in favor of the TCZ
strategy. However, the risk of SAEs was also significantly higher using this strategy (RR 1.40; 95 % CI 1.03, 1.92, p = 0.03). Pooled effect estimates showed statistical superiority of switching to either TCZ strategy compared to continuing csDMARD therapy.
In the management of active RA, almost similar efficacy can be expected in patients unable to tolerate csDMARDs, who switch to TCZ
compared to inadequate responders switching to add-on TCZ
. Although TCZ
is marginally superior to TCZ
in achieving DAS28 < 2.6 and ACR50 response, this is at the cost of an increased risk of SAEs.
To evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted ...management in early rheumatoid arthritis (CAMERA) study.
Twenty biomarkers were measured in the CAMERA cohort, in which patients were treated with either intensive or conventional methotrexate-based treatment strategies. The MBDA score was calculated using the concentrations of 12 biomarkers (SAA, IL-6, TNF-RI, VEGF-A, MMP-1, YKL-40, MMP-3, EGF, VCAM-1, leptin, resistin and CRP) according to a previously trained algorithm. The performance of the scores was evaluated relative to clinical disease activity assessments. Change in MBDA score over time was assessed by paired Wilcoxon rank sum test. Logistic regression was used to evaluate the ability of disease activity measures to predict radiographic progression.
The MBDA score had a significant correlation with the disease activity score based on 28 joints-C reactive protein (DAS28-CRP) (r=0.72; p<0.001) and an area under the receiver operating characteristic curve for distinguishing remission/low from moderate/high disease activity of 0.86 (p<0.001) using a DAS28-CRP cut-off of 2.7. In multivariate analysis the MBDA score, but not CRP, was an independent predictor of disease activity measures. Additionally, mean (SD) MBDA score decreased from 53 (18) at baseline to 39 (16) at 6 months in response to study therapy (p<0.0001). Neither MBDA score nor clinical variables were predictive of radiographic progression.
This multi-biomarker test performed well in the assessment of disease activity in RA patients in the CAMERA study. Upon further validation, this test could be used to complement currently available disease activity measures and improve patient care and outcomes.
To determine the optimal methotrexate dose in individual patients and to explore whether this optimal dose and the level of disease activity at that dose could be predicted.
Data from CAMERA II trial ...comparing MTX and MTX with 10 mg of prednisone both in a tight control treatment strategy in early RA was used. For each patient a curve for disease activity over time was fitted and the MTX dose after which further step-up did not result in relevant improvement in disease activity anymore was determined the 'lowest optimally effective MTX dose (LOED)'. The association of demographic and clinical characteristics at baseline with this LOED and with the level of disease activity reached at LOED was studied.
In 204 (100 MTX and 104 MTX with prednisone) out of 236 patients LOED could be defined. 10 mg/wk was the most prevalent LOED in patients treated with MTX and prednisone and 10 mg/wk, 20 mg/wk and 30 mg/wk in the MTX strategy. Although the specific LOED could not reliably be predicted, higher baseline disease activity, height and lower weight were associated with higher LOEDs (i.e at least 15 mg/wk). A score was presented to decide on a starting dose of 10 mg/wk or (at least) 15 mg/wk. The level of disease activity at LOED could not be reliably predicted.
A starting dose of 10 mg/wk might be a good choice for most patients and is frequently already the optimal dose. However, a subgroup of patient can be determined who would require higher MTX doses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glucocorticoids are widely used anti-inflammatory and immunosuppressive drugs for rheumatoid arthritis (RA). The disease-modifying potential of low to medium doses of glucocorticoids has been ...reconfirmed in the past decade, and co-administration of DMARDs and glucocorticoids has become standard in many treatment protocols, especially those for early disease stages but also for long-standing RA. The glucocorticoid regimens used range from continuous low doses to intermittent high doses. Studies of the rationale for and clinical use of glucocorticoids as co-therapy with DMARDs in RA have shown that this approach has a place in modern (tight control) treatment strategies, and that glucocorticoid co-therapy has disease-modifying effects during the first 2 years of treatment in patients with early RA. Furthermore, medium and high doses of glucocorticoids are useful for bridging the interval between initiation of DMARDs and onset of their therapeutic effect. Intra-articular glucocorticoids give good local control and have been used in tight control strategies. New glucocorticoid compounds are becoming available for clinical use that might have an enhanced risk:benefit ratio. Better monitoring of glucocorticoid use will also improve this ratio, and help to allay both patient and rheumatologist concerns about treatment-related adverse effects.
Methotrexate is endorsed to be used as first-line treatment in rheumatoid arthritis (RA). However, a large proportion of patients need additional treatment with a biological disease-modifying ...anti-rheumatic drug (DMARD) to adequately suppress their disease activity. A better understanding of genotypes could help to distinguish between patients with different pathogenic mechanisms. The aim of this study was therefore to identify networks of genes within DMARD-naive early RA patients associated with achieving sustained drug-free remission (sDFR) after initiating tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy.
Samples were used from 60 patients from the U-Act-Early study who received tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy, and who achieved sDFR (≥3 months in drug-free remission until the end of the study, n = 37) after therapy was tapered and subsequently stopped, or who were not able to discontinue the therapy as controls (n = 23). Whole blood samples were collected and ribonucleic acid (RNA) was isolated from positive cluster of differentiation 4 (CD4
) and CD14
cells and analysed using high-throughput sequencing. Weighted gene co-expression network analyses were performed to identify clusters (i.e. modules) of differently expressed genes associated with achieving sDFR and which were subsequently used for pathway analyses.
Network analyses within CD4
cells identified two significant modules in the tocilizumab plus methotrexate arm and four modules in the tocilizumab and methotrexate arms, respectively (p ≤ 0.039). Important pathways in the module best correlating with achieving sDFR were in the tocilizumab plus methotrexate arm related to processes involved with transcription and translation; in the tocilizumab arm, pathways were related to migration of white blood cells and G-protein coupled receptors, and in the methotrexate arm pathways were involved with the response to a bacterial or biotic (i.e. biological material)-related stimulus. No relevant networks could be identified in the sequenced CD14
cells.
Within networks of co-expressed genes, several pathways were found related to achieving sDFR after initiating therapy with tocilizumab, methotrexate, or the combination. Between the three strategy arms, we identified different networks of predisposing genes which indicates that specific gene expression profiles, depending on the treatment strategy chosen, are associated with a higher chance of achieving sDFR.
Clinicaltrials.gov, NCT01034137 . Registered on 16 December 2009.
Abstract Objective Disturbances in emotional functioning may contribute to psychological and physical symptoms in patients with fibromyalgia. This study examined emotions and emotion-regulation ...strategies in women with fibromyalgia and in controls, and how these variables relate to symptoms of fibromyalgia. Methods We compared 403 women with fibromyalgia to 196 control women using self-report questionnaires. Results Negative emotions and the use of emotional-avoidance strategies were elevated, and positive emotions were reduced, in fibromyalgia patients; the alexithymia scale “difficulty identifying feelings” showed a large deviation from normal. Emotional-approach measures were not deviant. In the fibromyalgia sample, emotional-avoidance strategies were highly correlated with more mental distress and were modestly correlated with more pain and fatigue, while emotional-approach strategies were only minimally related to better functioning. We tested two interaction models. The intense experiencing of emotions was related to more pain only in patients who lack the ability to process or describe emotions. Although fibromyalgia patients showed deficits in the experiencing of positive affect, positive affect did not buffer the association between pain and negative affect. Conclusion This study demonstrates increased negative emotions and decreased positive emotions, as well as increased emotional-avoidance strategies, in women with fibromyalgia. Research should test whether interventions that reduce emotional avoidance lead to health improvements in women with fibromyalgia.
We previously identified, in newly diagnosed rheumatoid arthritis (RA) patients, networks of co-expressed genes and proteomic biomarkers associated with achieving sustained drug-free remission (sDFR) ...after treatment with tocilizumab- or methotrexate-based strategies. The aim of this study was to identify, within the same patients, metabolic pathways important for achieving sDFR and to subsequently study the complex interactions between different components of the biological system and how these interactions might affect the therapeutic response in early RA.
Serum samples were analyzed of 60 patients who participated in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) and initiated treatment with methotrexate, tocilizumab, or the combination and who were thereafter able to achieve sDFR (n = 37); as controls, patients were selected who never achieved a drug-free status (n = 23). Metabolomic measurements were performed using mass spectrometry on oxidative stress, amine, and oxylipin platforms covering various compounds. Partial least square discriminant analyses (PLSDA) were performed to identify, per strategy arm, relevant metabolites of which the biological pathways were studied. In addition, integrative analyses were performed correlating the previously identified transcripts and proteins with the relevant metabolites.
In the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy, respectively, 19, 13, and 12 relevant metabolites were found, which were subsequently used for pathway analyses. The most significant pathway in the tocilizumab plus methotrexate strategy was "histidine metabolism" (p < 0.001); in the tocilizumab strategy it was "arachidonic acid metabolism" (p = 0.018); and in the methotrexate strategy it was "arginine and proline metabolism" (p = 0.022). These pathways have treatment-specific drug interactions with metabolites affecting either the signaling of interleukin-6, which is inhibited by tocilizumab, or affecting protein synthesis from amino acids, which is inhibited by methotrexate.
In early RA patients treated-to-target with a tocilizumab- or methotrexate-based strategy, several metabolites were found to be associated with achieving sDFR. In line with our previous observations, by analyzing relevant transcripts and proteins within the same patients, the metabolic profiles were found to be different between the strategy arms. Our metabolic analysis further supports the hypothesis that achieving sDFR is not only dependent on predisposing biomarkers, but also on the specific treatment that has been initiated.
ClinicalTrials.gov, NCT01034137 . Registered on January 2010.
To determine the psychological impact of the COVID-19 pandemic on people with and without an inflammatory rheumatic disease and establish whether psychological flexibility buffers this impact.
From ...online surveys in the general Dutch population in 2018 and during the peak of the COVID-19 pandemic in 2020, we analysed data of people with (index group, n = 239) and without (control group, n = 1821) an inflammatory rheumatic disease. Worry, stress, mental well-being (SF-36) and psychological flexibility levels were subjected to covariate-adjusted analyses of variance or linear regression analyses.
During the peak of the COVID-19 pandemic in 2020, as compared with the control group, the index group was more worried about getting infected with the virus (partial η2=0.098; medium effect) and more stressed (partial η2= 0.040; small effect). However, as compared with data acquired in 2018, the level of mental well-being during the COVID-19 pandemic peak was not lower in both groups. Levels of psychological flexibility did not moderate associations of group or year with mental well-being.
Although patients with an inflammatory rheumatic disease were more worried and stressed during the peak of the COVID-19 pandemic, their level of mental well-being was not reduced, which may have prevented us from finding a buffering effect of psychological flexibility. Overall, our results suggest that the psychological impact of the COVID-19 pandemic in patients with inflammatory rheumatic disease is modest, which could imply that common education and health care will do for most patients.
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