Genetic Biomarkers as Predictors of Response to Tocilizumab in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis
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SUBMITTER: Janahiraman S
PROVIDER: S-EPMC9323282 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects ~1% of the Caucasian population. Over the last decades, the availability of biological drugs targeting the proinflammatory cytokine tumour necrosis factor ?, anti-TNF drugs, has improved the treatment of patients with RA. However, one-third of the patients do not respond to the treatment. We wanted to evaluate the status of pharmacogenomics of anti-TNF treatment. We performed a PubMed literature search and all studies reporting original data on associations between genetic variants and anti-TNF treatment response in RA patients were included and results evaluated by meta-analysis. In total, 25 single nucleotide polymorphisms were found to be associated with anti-TNF treatment response in RA (19 from genome-wide association studies and 6 from the meta-analyses), and these map to genes involved in T cell function, NF?B and TNF signalling pathways (including CTCN5, TEC, PTPRC, FCGR2A, NFKBIB, FCGR2A, IRAK3). Explorative prediction analyses found that biomarkers for clinical treatment selection are not yet available.
| S-EPMC5637244 | biostudies-literature
Project description:Tocilizumab (TCZ), a humanized anti-interleukin-6 receptor monoclonal antibody, represents a new treatment strategy for patients with rheumatoid arthritis (RA) and is currently approved in the United States for RA patients who have failed to improve with at least one anti-tumor necrosis factor therapy.The goal of this study was to summarize the efficacy and safety profile of TCZ.A systematic literature review was conducted to identify English-language articles within PubMed and the Cochrane Library from January 1989 to August 2011 reporting results from Phase III TCZ double-blind, randomized controlled trials (RCTs), noncontrolled clinical trials, and open-label extensions with a duration ?6 months. Study outcomes had to include at least one of the following: American College of Rheumatology (ACR) 20, 50, or 70 response rates; tender/swollen joint count; Health Assessment Questionnaire-Disability Index; radiographic outcomes and drug persistence. Phase II RCTs were included only if they contained relevant information not available in Phase III RCTs. Relevant studies were selected to evaluate TCZ's pharmacokinetics and pharmacodynamics.Ten published clinical trials (7 Phase III, 3 Phase II) for TCZ were retrieved (7833 articles initially identified) from PubMed and 31 from the Cochrane library. Compared with methotrexate (MTX) monotherapy, TCZ 8 mg/kg IV monotherapy had higher rates of ACR20 (P < 0.001), ACR50 (P = 0.002), and ACR70 (P < 0.001) scores at week 24. TCZ 8 mg/kg IV plus oral MTX had a higher ACR20 response rate than oral MTX plus placebo in patients with RA who failed to respond to MTX or anti-tumor necrosis factor therapy (P < 0.001). Patients receiving TCZ 8 mg/kg had less radiographic progression on the Genant-modified Sharp score (85% had no progression) than the control group (67% had no progression) (P < 0.001). The rate of serious infections was 4.7 events/100 patient-years of exposure in the TCZ groups. A greater frequency of neutropenia, thrombocytopenia, hyperlipidemia, and transaminitis was observed with TCZ compared with placebo.The short-term efficacy and safety profile of TCZ is promising. Additional long-term safety data are needed to better characterize the risk-benefit profile of this agent.
| S-EPMC3805022 | biostudies-literature
Project description:IntroductionUnderstanding the durability of response to treatment and factors associated with failure to maintain response in a real-world setting can inform treatment decisions for patients with rheumatoid arthritis (RA). The aim of this study was to analyze durability of response to tocilizumab (TCZ) and factors associated with durability among US patients with RA in routine clinical practice.MethodsTCZ initiators in the Corrona RA Registry were included. Durability of response was defined as maintaining continuous TCZ treatment and either an improvement of at least minimum clinically important difference (MCID) in Clinical Disease Activity Index (CDAI) score or low disease activity (LDA). Secondary analyses included patients treated with intravenous (IV) TCZ and excluded those who discontinued TCZ without reporting reasons for discontinuation. Durability was calculated with Kaplan-Meier survival analysis. Cox proportional hazards modeling identified factors associated with durability.ResultsAmong 1789 TCZ initiators, 466, 272, and 162 were persistent (with or without durable response) with follow-up visits at 1, 2, and 3 years, respectively. Median MCID durability of response in CDAI was > 50% after 36 months overall, 26 months for TCZ-IV, and > 50% after 36 months for those with known reasons for discontinuation; longer durability was associated with increased duration of RA and higher baseline CDAI score and shorter durability with history of malignancy and history of diabetes. Median LDA durability of response was 13.0 months overall, for TCZ-IV, and for those with known reasons for discontinuation; shorter durability was associated with history of malignancy, history of diabetes, and higher baseline CDAI score.ConclusionsMedian durability of response to TCZ in RA was > 3 years when defined as maintenance of MCID in CDAI score and > 1 year with the more stringent criteria of maintenance of LDA.Trial registrationClinicalTrials.gov identifier, NCT01402661.
| S-EPMC7991054 | biostudies-literature
Project description:Purpose: Rheumatoid arthritis (RA) is a pervasive inflammatory autoimmune disease that seriously impairs human health and requires more effective non-pharmacologic treatment approaches. This study aims to systematically review and evaluate the efficacy of yoga for patients with RA. Methods: Medline (through PubMed), Cochrane Library, EMBASE (through SCOPUS), and Web of Science database were screened through for articles published until 20 July 2020. Randomized controlled trials (RCTs) of yoga in patients with RA were included. Outcomes measures were pain, physical function, disease activity, inflammatory cytokines, and grip strength. For each outcome, standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated. Result: Ten trials including 840 patients with RA aged 30-70 years were identified, with 86% female participants. Meta-analysis revealed a statistically significant overall effect in favor of yoga for physical function (HAQ-DI) (5 RCTs; SMD = -0.32, 95% CI -0.58 to -0.05, I 2 = 15%, P = 0.02), disease activity (DAS-28) (4 RCTs; SMD = -0.38, 95% CI -0.71 to -0.06, I 2 = 41%, P = 0.02) and grip strength (2 RCTs; SMD = 1.30, 95% CI 0.47-2.13, I 2 = 63%, P = 0.002). No effects were found for pain, tender joints, swollen joints count or inflammatory cytokines (i.e., CRP, ESR, IL-6, and TNF-α). Summary: The findings of this meta-analysis indicate that yoga may be beneficial for improving physical function, disease activity, and grip strength in patients with RA. However, the balance of evidence showed that yoga had no significant effect in improving pain, tender joints, swollen joints count, and inflammatory cytokines in patients suffering from RA. Considering methodological limitations, small sample size, and low-quality, we draw a very cautious conclusion in the results of the estimate of the effect. High-quality and large-scale RCTs are urgently needed in the future, and the real result may be substantially different.
| S-EPMC7732597 | biostudies-literature
Project description:BACKGROUND Infliximab shows good efficacy in treating refractory rheumatoid arthritis (RA). However, many patients responded poorly and related studies were inconsistent in predictive biomarkers. This study aimed to identify circulating biomarkers for predicting infliximab response in RA. MATERIAL AND METHODS Public databases of Gene Expression Omnibus (GEO) and ArrayExpress were searched for related microarray datasets, focused on the response to infliximab in RA. All peripheral blood samples were collected before infliximab treatment and gene expression profiles were measured using microarray. Differential genes associated with infliximab efficacy were analyzed. The genes recognized by half of the datasets were regarded as candidate biomarkers and validated by prospective datasets. RESULTS Eight microarray datasets were identified with 374 blood samples of RA patients, among which 191 (51.1%) were diagnosed as non-responders in the subsequent infliximab treatment. Five genes (FKBP1A, FGF12, ANO1, LRRC31, and AKR1D1) were associated with the efficacy and recognized by half of the datasets. The 5-gene model showed a good predictive power in random- and prospective-designed studies, with AUC (area under receiver operating characteristic [ROC] curve)=0.963 and 1.000, and it was also applicable at the early phase of treatment (at week 2) for predicting the response at week 14 (AUC=1.000). In the placebo group, the model failed to predict the response (AUC=0.697), indicating the model's specificity in infliximab treatment. CONCLUSIONS The model of FKBP1A, FGF12, ANO1, LRRC31, and AKR1D1 in peripheral blood is useful for efficiently predicting the response to infliximab treatment in rheumatoid arthritis.
| S-EPMC5404751 | biostudies-literature
Project description:IntroductionPsoriatic arthritis (PsA) is a chronic inflammatory disease that frequently develops in patients with psoriasis (PsO) but can also occur spontaneously. As a result, PsA diagnosis and treatment is commonly delayed, or even missed outright due to the manifold of clinical presentations that patients often experience. This inevitably results in progressive articular damage to axial and peripheral joints and entheses. As such, patients with PsA frequently experience reduced expectancy and quality of life due to disability. More recently, research has aimed to improve PsA diagnosis and prognosis by identifying novel disease biomarkers.MethodsHere, we conducted a systematic review of the published literature on candidate biomarkers for PsA diagnosis and prognosis in MEDLINE(Pubmed), EMBase and the Cochrane library with the goal to identify clinically applicable PsA biomarkers. Meta-analyses were performed when a diagnostic bone and cartilage turnover biomarker was reported in 2 or moredifferent cohorts of PsA and control.ResultsWe identified 1444 publications and 124 studies met eligibility criteria. We highlighted bone and cartilage turnover biomarkers, genetic markers, and autoantibodies used for diagnostic purposes of PsA, as well as acute phase reactant markers and bone and cartilage turnover biomarkers for activity or prognostic severity purposes. Serum cartilage oligometrix metalloproteinase levels were significantly increased in the PsA sera compared to Healthy Control (HC) with a standardized mean difference (SMD) of 2.305 (95%CI 0.795-3.816, p=0.003) and compared to osteoarthritis (OA) with a SMD of 0.783 (95%CI 0.015-1.551, p=0.046). The pooled serum MMP-3 levels were significantly higher in PsA patients than in PsO patients with a SMD of 0.419 (95%CI 0.119-0.719; p=0.006), but no significant difference was highlighted when PsA were compared to HC. While we did not identify any new genetic biomarkers that would be useful in the diagnosis of PsA, recent data with autoantibodies appear to be promising in diagnosis, but no replication studies have been published.ConclusionIn summary, no specific diagnostic biomarkers for PsA were identified and further studies are needed to assess the performance of potential biomarkers that can distinguish PsA from OA and other chronic inflammatory diseases.
| S-EPMC9749424 | biostudies-literature
Project description:Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi.
| S-EPMC5937760 | biostudies-literature
Project description:Genetics of autoimmune diseases represent a growing domain with surpassing biomarker results with rapid progress. The exact cause of Rheumatoid Arthritis (RA) is unknown, but it is thought to have both a genetic and an environmental bases. Genetic biomarkers are capable of changing the supervision of RA by allowing not only the detection of susceptible individuals, but also early diagnosis, evaluation of disease severity, selection of therapy, and monitoring of response to therapy. This review is concerned with not only the genetic biomarkers of RA but also the methods of identifying them. Many of the identified genetic biomarkers of RA were identified in populations of European and Asian ancestries. The study of additional human populations may yield novel results. Most of the researchers in the field of identifying RA biomarkers use single nucleotide polymorphism (SNP) approaches to express the significance of their results. Although, haplotype block methods are expected to play a complementary role in the future of that field.
| S-EPMC4703421 | biostudies-literature
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:Toxoplasmosis is a cosmopolitan infection caused by an intracellular obligatory protozoan, Toxoplasma gondii. Infection to this parasite in immunocompetent patients is usually asymptomatic, but today it is believed that the infection can be a risk factor for a variety of diseases, including rheumatoid arthritis (RA). RA is an autoimmune disease and the most common type of inflammatory arthritis that is a major cause of disability. The aim of this systematic review and meta-analysis was to address the association between RA and toxoplasmosis in light of the available research.Based on the keywords, a systematic search of eight databases was conducted to retrieve the relevant English-language articles. Then, the studies were screened based on the inclusion and exclusion criteria. The random effect model was used to calculate the odds ratio (OR) using forest plot with 95% confidence interval (CI).Overall, 4168 Individual, extracted from 9 articles were included for systematic review evaluation, with 1369 RA patients (46% positive toxoplasmosis) and 2799 individuals as controls (21% positive toxoplasmosis). Then, eight articles (10 datasets) were used for meta-analysis (1244 rheumatoid arthritis patients and 2799 controls). By random effect model, the combined OR was 3.30 (95% CI: 2.05 to 5.30) with P < 0.0001.Although toxoplasmosis could be considered as a potential risk factor for rheumatoid arthritis, more and better quality studies are needed to determine the effect of T. gondii infection on induction or exacerbation of RA. Our study was registered at the International Prospective Register of Systematic Reviews (PROSPERO; code: CRD42017069384).
| S-EPMC6003687 | biostudies-literature