Applying science in practice: the optimization of biological therapy in rheumatoid arthritis.
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ABSTRACT:
SUBMITTER: Ramiro S
PROVIDER: S-EPMC3046505 | biostudies-other | 2010
REPOSITORIES: biostudies-other
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Applying science in practice: the optimization of biological therapy in rheumatoid arthritis.
Ramiro Sofia S Machado Pedro P Singh Jasvinder A JA Landewé Robert B RB da Silva José António P JA
Arthritis research & therapy 20101104 6
Most authorities recommend starting biological agents upon failure of at least one disease-modifying agent in patients with rheumatoid arthritis. However, owing to the absence of head-to-head studies, there is little guidance about which biological to select. Still, the practicing clinician has to decide. This review explores the application of published evidence to practice, discussing the goals of treatment, the (in) ability to predict individual responses to therapy, and the potential value o ...[more]
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Project description:BackgroundReducing the dose of biological therapy (BT) when patients with immune-mediated arthritis achieve a sustained therapeutic goal may help to decrease costs for national health services and reduce the risk of serious infection. However, there is little information about whether such a decision can be applied universally. Therefore, the objective of this study was to develop appropriateness criteria for reducing the dose of BT in patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), and peripheral spondyloarthritis (pSpA).MethodsThe RAND/UCLA appropriateness method was coordinated by experts in the methodology. Five rheumatologists with clinical research experience in RA and/or SpA selected and precisely defined the variables considered relevant when deciding to reduce the dose of BT in the 3 diseases, in order to define patient profiles. Ten rheumatologists with experience in prescribing BT anonymously rated each profile on a scale of 1 (completely inappropriate) to 9 (completely appropriate) after revising a summary of the evidence obtained from 4 systematic literature reviews carried out specifically for this project.FindingsA total of 2,304 different profiles were obtained for RA, 768 for axSpA, and 3,072 for pSpA. Only 327 (14.2%) patient profiles in RA, 80 (10.4%) in axSpA, and 154 (5%) in pSpA were considered appropriate for reducing the dose of BT. By contrast, 749 (32.5%) patient profiles in RA, 270 (35.3%) in axSpA, and 1,243 (40.5%) in pSpA were considered inappropriate. The remaining profiles were considered uncertain.InterpretationAppropriateness criteria for reducing the dose of BT were developed in 3 inflammatory conditions. These criteria can help clinicians treating these disorders to optimize the BT dose. However, further research is needed, since more than 50% of the profiles were considered uncertain and the real prevalence of each profile in daily clinical practice remains unknown.
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Project description:Pharmacogenomics of Rheumatoid Arthritis Therapy
| PRJNA294477 | ENA
Project description:BackgroundBiological therapies have improved the clinical course and quality of life of rheumatoid arthritis (RA) patients. Despite the availability and effectiveness of these treatments, some patients experience multiple failures to biologic disease-modifying antirheumatic drugs (bDMARDs), constituting a particular challenge to clinicians.ObjectivesThis study aims to determine the percentage of rheumatoid arthritis (RA) patients who fail to respond to subsequent bDMARDs, describe their characteristics, and identify specific baseline and early features during the first bDMARD as possible predictors of consecutive multiple bDMARD failure.MethodsThis is a longitudinal study involving RA patients from the prospective biological cohort drawn from the La Paz University Hospital RA Registry (RA-Paz), starting a bDMARD during the years 2000 to 2019. Patients who presented insufficient response (due to primary or secondary inefficacy) to at least three bDMARDs or two bDMARDs with different mechanism of action were considered multi-refractory (MR-patients). Patients who achieved low disease activity or remission (by DAS-28) with the first bDMARD and maintained this over a follow-up period of at least 5 years were considered non-refractory (NR-patients).ResultsA total of 41 out of 402 (10%) patients were MR-patients and 71 (18%) NR-patients. In the multivariate analysis, the presence of erosions, younger age, higher baseline DAS-28 and mostly achieving delta-DAS < 1.2 after 6 months of the first bDMARD (OR 11.12; 95% CI 3.34-26.82) were independently associated with being MR-patients to bDMARDs.ConclusionsIn our cohort, 10% of patients with RA were observed to have multi-refractoriness to bDMARDs. This study supports the contention that younger patients with erosive disease and especially the early absence of clinical response to the first bDMARDs are predictors of multi-refractoriness to consecutive biologics. Hence, patients with these characteristics should be monitored more closely and may benefit from personalized treatments.
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Project description:BackgroundDespite advances in the treatment of rheumatoid arthritis (RA) and the wide range of therapies available, there is a percentage of patients whose treatment presents a challenge for clinicians due to lack of response to multiple biologic and target-specific disease-modifying antirheumatic drugs (b/tsDMARDs).ObjectiveTo develop and validate an algorithm to predict multiple failure to biological therapy in patients with RA.DesignObservational retrospective study involving subjects from a cohort of patients with RA receiving b/tsDMARDs.MethodsBased on the number of prior failures to b/tsDMARDs, patients were classified as either multi-refractory (MR) or non-refractory (NR). Patient characteristics were considered in the statistical analysis to design the predictive model, selecting those variables with a predictive capability. A decision algorithm known as 'classification and regression tree' (CART) was developed to create a prediction model of multi-drug resistance. Performance of the prediction algorithm was evaluated in an external independent cohort using area under the curve (AUC).ResultsA total of 136 patients were included: 51 MR and 85 NR. The CART model was able to predict multiple failures to b/tsDMARDs using disease activity score-28 (DAS-28) values at 6 months after the start time of the initial b/tsDMARD, as well as DAS-28 improvement in the first 6 months and baseline DAS-28. The CART model showed a capability to correctly classify 94.1% NR and 87.5% MR patients with a sensitivity = 0.88, a specificity = 0.94, and an AUC = 0.89 (95% CI: 0.74-1.00). In the external validation cohort, 35 MR and 47 NR patients were included. The AUC value for the CART model in this cohort was 0.82 (95% CI: 0.73-0.9).ConclusionOur model correctly classified NR and MR patients based on simple measurements available in routine clinical practice, which provides the possibility to characterize and individualize patient treatments during early stages.
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Project description:Over 70 different genetic variants with a significant association with rheumatoid arthritis (RA) have been discovered. Anti-citrullination protein antibodies (ACPA)-positive RA variants are more well-defined than their ACPA-negative counterparts. The human leukocyte antigen, HLA-DRB1 locus remains the prime suspect in anti-citrullination protein antibodies (ACPA)-positive RA. Different HLA-DRB1 alleles are linked to RA susceptibility across different ethnicities. With evolving techniques, like genome-wide association studies (GWAS) and single nucleotide polymorphism (SNP) arrays, more non-HLA susceptibility loci have been identified for both types of RA. However, the functional significance of only a handful of these variants is known. Their roles include increasing susceptibility to RA or in determining the speed at which the disease progresses. Additionally, a couple of variations are associated with protection from RA. Defining such clear-cut biological functions can aid in the clinical diagnosis and treatment of RA. Recent research has focused on the implication of microRNAs, with miR-146a widely studied. In addition to disease susceptibility, genetic variations that influence the efficacy and toxicity of anti-RA agents have also been identified. Polymorphisms in the MTHFR gene influence the effectiveness of methotrexate, the first line of therapy in RA. Larger studies are, however, needed to identify potential biomarkers for early disease identification and monitoring disease progression.
| S-EPMC4926434 | biostudies-literature
Project description:Background: The treatment of rheumatoid arthritis (RA), a chronic systemic inflammatory autoimmune disease, is based on disease-modifying anti-rheumatic drugs (DMARDs). Typically, it starts with conventional synthetic DMARDs (csDMARDs), and depending on the patient's response to the treatment and the adverse events experienced, biological DMARDs (bDMARDs) are initiated. bDMARDs are more specific to inflammatory factors than csDMARDs and more efficient in inducing remission and low disease activity. Thus, this study aimed to assess the effectiveness of biological therapy in patients with rheumatoid arthritis in administrative health databases. Methods: PubMed, Embase, Lilacs, Ovid, Scopus, and Web of Science databases were searched from inception to 21 October 2021, to identify observational studies that evaluated the effectiveness of biological therapy in patients with rheumatoid arthritis using administrative databases and real-world data. The methodological quality was assessed by the methodological index for non-randomized studies (MINORS). A fixed or random-effects model estimated risk ratios with 95% confidence intervals. The analysis was divided into four groups: tumor necrosis factor inhibitors (TNFi) versus non-TNFi; TNFi versus TNFi (adalimumab, etanercept, and golimumab versus infliximab); bDMARDs versus Janus kinase inhibitors (JAKi); and bDMARDs monotherapy versus combination therapy (bDMARDs and MTX). Results: Twenty-one records were eligible for inclusion in this systematic review and meta-analysis; seven population-based cohorts, eight prospective, and six retrospective cohort studies. Overall, 182,098 rheumatoid arthritis patients were evaluated. In the meta-analysis, lower effectiveness was observed among TNFi users than in non-TNFi (RR: 0.88; 95% CI: 0.81-0.95; p < 0.01; I2 = 94.0%) and bDMARDs than in JAKi (RR: 0.86; 95% CI: 0.79-0.94; p < 0.01; I2 = 93.0%). Higher effectiveness among adalimumab, etanercept, and golimumab than in infliximab (RR: 1.19; 95% CI: 1.05-1.36; p < 0.01; I2 = 96.0%) was found. No significant differences in the effectiveness of bDMARD monotherapy compared to combination therapy (RR: 0.83; 95% CI: 0.68-1.00; p < 0.01; I2 = 81.0%) was observed. E-value analysis indicated that the estimates were not robust against unmeasured confounding. Conclusion: According to the available real-world data, our results suggest that biological therapy effectively treats patients with rheumatoid arthritis, indicating higher effectiveness with non-TNFi and JAKi than with TNFi. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID#CRD42020190838, identifier CRD42020190838.
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Project description:Rheumatoid arthritis (RA) is a common autoimmune disease characterized by persistent inflammation of joints resulting in progressive destruction of cartilage and bone. Recently, biological agents that suppress the activities of proinflammatory cytokines have shown efficacy as antirheumatic drugs, but require frequent administration, and often result in systemic immune suppression. Thus, gene transfer approaches are being developed as an alternative approach for targeted, more efficient, and sustained delivery of inhibitors of inflammatory cytokines as well as other therapeutic agents. Several gene therapy approaches have been established in preclinical animal models. In these models, autoantigen-specific T cells have been demonstrated to be ideal gene delivery vehicles for the local delivery of "immunoregulatory molecules" because these cells have tissue-specific homing and retention properties. Indeed, bioluminescence studies in an animal model of inflammatory arthritis revealed that these cells accumulated in and remained in inflamed joints. Transfer of genetically modified dendritic cells (DCs) may also have interesting effects. We conclude that modifying antigen-specific T cells or autologous DCs by retroviral transduction for local expression of regulatory proteins is a promising therapeutic strategy for the treatment of RA.
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Project description:We compared whole CD4+ and CD8+ T cells from frozen PBMC samples that were collected before and after treatment initiation of each patient with rheumatoid arthritis. Lists consisting of 858 and 950 differentially expressed genes were created from CD4 and CD8, respectively, and these were used for enrichment analysis. As a result, we found that certain pathways were downregulated after TCZ treatment in both CD4+ and CD8+ T cells, including mechanistic target of rapamycin complex 1 (mTORC1) signaling, the IL-2 pathway, and IFN-related genes.
2019-06-06 | GSE113156 | GEO
Project description:The term "immuno-autonomics" has been coined to describe an emerging field evaluating the interaction between stress, autonomic nervous system (ANS), and inflammation. The field remains largely unknown among practicing rheumatologists. Our objective was to evaluate the perspectives of rheumatologists regarding the role of stress in the activity and management of rheumatoid arthritis (RA). A 31-item survey was conducted with 231 rheumatologists. Rheumatologists were asked to assess the role of stress in rheumatoid arthritis (RA) disease activity and were provided with information regarding immuno-autonomics. They were asked to consider how immuno-autonomics resonated with their patient management needs. The majority of rheumatologists are eager to better understand non-response, believe that stress biology and ANS dysfunction interfere with disease activity, and embrace the theory that measurement of ANS via next-generation HRV may be able to evaluate autonomic dysfunction and the biology of stress. Rheumatologists are open to the idea that quantitative measurement of ANS function using next-generation HRV can be a helpful tool to RA practice. The majority agree that ANS state influences RA disease control and that quantitative measures of ANS state are helpful to RA practice. Rheumatologists also agree that patients with poor ANS function may be at risk for not responding adequately to conventional, biologic, or targeted synthetic DMARDs. Almost all would use an in-office test to quantitatively measure ANS using next-generation HRV. This study shows that rheumatologists are open to embracing evaluation of ANS function as a possible tool in the management and treatment of RA.
| S-EPMC9349152 | biostudies-literature
Project description:OBJECTIVES:To determine whether patients with early rheumatoid arthritis (ERA) have cardiovascular disease (CVD) that is modifiable with disease-modifying antirheumatic drug (DMARD) therapy, comparing first-line etanercept (ETN) + methotrexate (MTX) with MTX strategy. METHODS:Patients from a phase IV ERA trial randomised to ETN+MTX or MTX strategy±month 6 escalation to ETN+MTX, and with no CVD and maximum one traditional risk factor underwent cardiovascular magnetic resonance (CMR) at baseline, years 1 and 2. Thirty matched controls underwent CMR. Primary outcome measure was aortic distensibility (AD) between controls and ERA, and baseline to year 1 AD change in ERA. Secondary analyses between and within ERA groups performed. Additional outcome measures included left ventricular (LV) mass and myocardial extracellular volume (ECV). RESULTS:Eighty-one patients recruited. In ERA versus controls, respectively, baseline (geometric mean, 95% CI) AD was significantly lower (3.0×10-3 mm Hg-1 (2.7-3.3) vs 4.4×10-3 mm Hg-1 (3.7-5.2), p<0.001); LV mass significantly lower (78.2 g (74.0-82.7), n=81 vs 92.9 g (84.8-101.7), n=30, p<0.01); and ECV increased (27.1% (26.4-27.9), n=78 vs 24.9% (23.8-26.1), n=30, p<0.01). Across all patients, AD improved significantly from baseline to year 1 (3.0×10-3 mm Hg-1 (2.7-3.4) to 3.6×10-3 mm Hg-1 (3.1-4.1), respectively, p<0.01), maintained at year 2. The improvement in AD did not differ between the two treatment arms and disease activity state (Disease Activity Score with 28 joint count)-erythrocyte sedimentation rate-defined responders versus non-responders. CONCLUSION:We report the first evidence of vascular and myocardial abnormalities in an ERA randomised controlled trial cohort and show improvement with DMARD therapy. The type of DMARD (first-line tumour necrosis factor-inhibitors or MTX) and clinical response to therapy did not affect CVD markers. TRIAL REGISTRATION NUMBER:ISRCTN: ISRCTN89222125; ClinicalTrials.gov: NCT01295151.
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