Current and Emerging DMARDs for the Treatment of Rheumatoid Arthritis.
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ABSTRACT:
SUBMITTER: Mysler E
PROVIDER: S-EPMC8179789 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rheumatoid arthritis (RA) is a common systemic autoimmune disease whose fibro-inflammatory manifestations may affect a number of tissues and organs, including the lungs. In fact, interstitial lung disease (ILD) is a leading cause of mortality among patients with RA. RA-related interstitial lung disease (RA-ILD) most often presents in an injury pattern called usual interstitial pneumonia (UIP), which portends a relatively worse prognosis than other less commonly occurring patterns of RA-ILD, like non-specific interstitial pneumonia (NSIP). Biomarkers from serum or bronchoalveolar lavage fluid could aid in the identification of patients at risk for RA-ILD, the detection of patients most likely to develop the UIP pattern of RA-ILD, and the prediction of disease behaviour over time. Notably, the use of highly sensitive serologic biomarkers, including rheumatoid factor (RF) and antibodies targeting cyclic citrullinated peptides, while somewhat specific for RA joint disease, have only limited utility as biomarkers for RA-ILD. Candidate biomarkers for RA-ILD include these and other autoantibodies as well as certain genes and molecules that hold promise as biomarkers in other forms of ILD. In this manuscript, we summarize the state of knowledge on biomarkers for the development and progression of RA-ILD.
| S-EPMC6800546 | biostudies-literature
Project description:ObjectivesTo evaluate the 1-year cost-effectiveness between three different initial treatment strategies in autoantibody-negative RA patients, according to 2010 criteria.MethodsFor this analysis we selected all RA patients within the intermediate probability stratum of the treatment in the Rotterdam Early Arthritis Cohort (tREACH) trial. The tREACH had a treat-to-target approach, aiming for low DAS <2.4, and treatment adjustments could occur every 3 months. Initial treatment strategies consisted of MTX 25 mg/week (initial MTX, iMTX), iHCQ 400 mg/day or an oral glucocorticoids tapering scheme without DMARDs (iGCs). Data on quality-adjusted life-years, measured with the European Quality of Life 5-Dimensions 3 Levels (EQ-5D-3L), healthcare and productivity costs were used.ResultsAverage quality-adjusted life-years (s.d.), for iMTX, iHCQ and iGCs were respectively 0.71 (0.14), 0.73 (0.14) and 0.71 (0.15). The average total costs (s.d.) for iMTX, iHCQ and iGCs were, respectively, €10 832 (14.763), €11 208 (12.801) and €10 502 (11.973). Healthcare costs were mainly determined by biological costs, which were significantly lower in the iHCQ group compared with iGCs (P < 0.05). However, costs due to presenteeism were the highest in the iHCQ group (55%) followed by iMTX (27%) and iGCs (18%). The incremental cost-effectiveness ratios did not differ between treatment strategies. At a willingness-to-pay level of €50 000, the Dutch threshold for reimbursement of medical care, iHCQ had the highest probability (38.7%) of being cost-effective, followed by iGCs (31.1%) and iMTX (30.2%).ConclusioniHCQ had the lowest healthcare and highest productivity costs, resulting in a non-significant incremental cost-effectiveness ratio. However, iHCQ had the highest chance of being cost-effective at the Dutch willingness-to-pay threshold for healthcare reimbursement. Therefore, we believe that iHCQ is a good alternative to iMTX in autoantibody-negative RA patients, but validation is needed.Clinical trial registration numberISRCTN26791028.
| S-EPMC8645278 | biostudies-literature
Project description:Rheumatoid arthritis (RA), one of the most common immune system diseases, mainly affects middle-aged and elderly individuals and has a serious impact on the quality of life of patients. Pain and disability caused by RA are significant symptoms negatively affecting patients, and they are especially seen when inappropriate treatment is administered. Effective therapeutic strategies have evolved over the past few decades, with many new disease-modifying antirheumatic drugs (DMARDs) being used in the clinic. Owing to the breakthrough in the treatment of RA, the symptoms of patients who could not be treated effectively in the past few years have been relieved. However, some patients complain about symptoms that have not been reported, implying that there are still some limitations in the RA treatment and evaluation system. In recent years, biomarkers, an effective means of diagnosing and evaluating the condition of patients with RA, have gradually been used in clinical practice to evaluate the therapeutic effect of RA, which is constantly being improved for accurate application of treatment in patients with RA. In this article, we summarize a series of biomarkers that may be helpful in evaluating the therapeutic effect and improving the efficiency of clinical treatment for RA. These efforts may also encourage researchers to devote more time and resources to the study and application of biomarkers, resulting in a new evaluation system that will reduce the inappropriate use of DMARDs, as well as patients' physical pain and financial burden.
| S-EPMC8995470 | biostudies-literature
Project description:Novel treatments in development for rheumatoid arthritis target 3 broad areas: cytokines, cells, and signaling pathways. Therapies from each domain share common advantages (for example previously demonstrated efficacy, potential long-term immunomodulation, and oral administration respectively) that have stimulated research in each area but also common obstacles to their development. In this review recent progress in each area will be discussed alongside the factors that have impeded their path to clinical use.
| S-EPMC4896612 | biostudies-literature
Project description:BackgroundCurrent guidelines suggest reduction of DMARDs can be considered in RA patients in remission. Objectives were (1) to estimate the relative importance of patient characteristics rheumatologists consider in their decision to de-escalate (2) to assess whether heterogeneity exists among rheumatologists with respect to de-escalation and (3) to identify the preferred de-escalation strategy.MethodsA discrete choice experiment (DCE) was conducted. All rheumatologists and trainees in The Netherlands were invited to participate. A conditional logit model was estimated to assess overall preference for de-escalation and its determinants. Heterogeneity was estimated by latent class analysis.ResultsThe DCE questionnaire was completed by 156 doctors. This questionnaire was constructed using the results of semi-structured interviews with 12 rheumatologists that identified five patient characteristics relevant for de-escalation: number of swollen joints (SJC), presence of DAS remission/low disease activity (LDA), patient history, duration of remission/LDA and patient willingness to de-escalate DMARDs. Overall SJC and patient history were most important. Latent class analysis revealed five subgroups of doctors, showing differences regarding willingness to de-escalate and relative importance of patient characteristics. De-escalation of the TNF inhibitor rather than methotrexate first was the most preferred strategy.ConclusionsRheumatologists are not uniform in their decision on whom to de-escalate. Differences emerged in which characteristics they traded off resulting in five subgroups: those that taper (1) always, (2) in absence of swollen joints, (3) in absence of swollen joints and presence of favorable patient history, (4) in DAS remission and favorable patient history, and (5) taking into account all factors.
| S-EPMC5405491 | biostudies-literature
Project description:ObjectivesOur goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab.MethodsSynovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3+, CD20+, and CD68+ cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR.ResultsGene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders.ConclusionWe provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.
| S-EPMC8435834 | biostudies-literature
Project description:ObjectiveThis observational cohort study investigated the impact of biological (b) disease-modifying antirheumatic drugs (DMARDs) on the outcomes of serious infections (SIs) in patients with rheumatoid arthritis.MethodsWe investigated outcomes of SIs observed in 947 patients enrolled in the German biologics register RABBIT(Rheumatoid arthritis: observation of biologic therapy). Outcomes were (1) recovery without complication, (2) sepsis following SI (?30?days), and (3) death after SI without known sepsis (?90?days). We applied a multinomial generalised estimating equation model for longitudinal data to evaluate the risks of sepsis and death simultaneously.ResultsSepsis within 30?days after SI was reported in 135 out of 947 patients, 85 of these had a fatal outcome. Fifty-three patients died within 90?days after SI without known sepsis. The adjusted risk of developing sepsis increased with age and was higher in patients with chronic renal disease. Compared with conventional synthetic (cs)DMARDs, the risk was significantly lower when patients were exposed to bDMARDs at the time of SI (OR: 0.56, 95% CI 0.38 to 0.81). Risk factors of fatal SI were higher age, use of glucocorticoids at higher doses and heart failure. Patients treated with bDMARDs and those with better physical function had a significantly lower mortality risk.ConclusionsThese results suggest a beneficial effect of bDMARDs on the risk of sepsis after SI and the risk of a fatal outcome. Successful immunosuppression may prevent an unregulated host response to SI, that is, the escalation to sepsis. Further investigation is needed to validate these results.
| S-EPMC5013078 | biostudies-literature
Project description:The aim of the review is to highlight the current knowledge about established and new biologicals and to summarise recent advances by focusing on comparative efficacy, safety and possible discontinuation of treatment in patients with rheumatoid arthritis (RA). Up to now, comparative analyses showed only minor differences with respect to efficacy and safety among the established biologicals. Studies confirmed the excellent drug retention rate as well as efficacy and safety of approved biologicals including their use in monotherapy. Tapering and in some instances discontinuation of biologicals is possible in disease remission. In case of relapse, patients usually show full response after reintroduction of the same compound. The development of biologicals continues fast with several new biologicals targeting different or established cytokines or cellular subsets of the immune system. With several new biologicals in the pipeline and different formulations for established compounds, treatment options for RA will become even more versatile and sophisticated. Although we get closer to the aim of decreasing the proportion of refractory patients, many questions have to be addressed in the near future regarding emerging biosimilars and biologicals with new modes of action.
| S-EPMC4613149 | biostudies-other
Project description:Purpose: We analyzed RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-naïve RA patients and healthy subjects. Our goal was to evaluate the transcriptional profiles of ST2825-treated PBMC to identify its therapeutic potential. Methods: We analyzed bulk RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-naïve RA patients after stimulation with LPS and IL-1β, PBMC were treated with the MyD88 chemical inhibitor, ST2825. Collection of RNA was performed after 24 h of treatment and samples were sequenced to determine transcriptional changes and regulated processes in treated PBMC. Results: paired-end reads were mapped to the hg19 human genome assembly. RNA levels were normalized using DESeq. We identified 796 differentially expressed (DE) genes by 2-fold change (p<0.05) between RA patients and healthy subjects. Our analysis revealed 631 DE genes between DMARDs-naïve RA patients before and after ST2825 treatment. We identified 471 DE genes between LPS-stimulated RA PBMC and LPS-stimulated RA PBMC treated with ST2825. Conclusion: Our study provides comprehensive evidence supporting the potential application of the MyD88 inhibitor, ST2825, as a modulator of gene expression signtaures involved in pathogenic processes in PBMC from DMARDs-naïve RA patients. Our indepth analysis of RNA-seq data will serve as a valuable resource containing the inflammatory gene expression signatures by MyD88.
2021-11-30 | GSE189136 | GEO
Project description:BackgroundTreatment with disease-modifying anti-rheumatic drugs (DMARDs) has raised concerns about the risk of malignancies in rheumatoid arthritis (RA) patients. However, the association between biologic DMARDs (bDMARDs) and malignancy in previous reports remains controversial. Therefore we aimed to estimate the incidence of malignancy in early RA patients and to evaluate the relative risk of malignancy with use of bDMARDs.MethodsA retrospective cohort of incident RA patients was established using the Korean National Claims Database. Among a total of 14,081 RA patients identified, 1684 patients with a history of malignancy were excluded. We calculated the incidence rate of overall and individual malignancies. The standardized incidence ratio (SIR) of malignancies in bDMARD users was compared to that in nonusers. Multivariable logistic regression analysis was used to evaluate the impact of bDMARDs on the development of malignancies in early RA patients.ResultsA total of 12,397 early RA patients without a history of malignancy were enrolled. During 41,599 person-years (PY) of follow-up, 725 malignancies developed in 561 patients (174.3/10,000 PY) and 21 hematologic malignancies developed (5.0/10,000 PY). Patients treated with bDMARDs had a significantly lower incidence of overall malignancy compared to those not treated with bDMARDs (SIR 0.45 (95% CI 0.28-0.70)). However, this relationship was not significant with regard to hematologic malignancies (SIR 2.65 (95% CI 0.55-7.76)). On multivariable analysis, bDMARD use was a protective factor against the development of overall malignancy (odds ratio 0.42 (95% CI 0.25-0.73)). However, bDMARD use had no significant protective effect against the development of hematologic malignancies (odds ratio 1.69 (95% CI 0.38-7.59)).ConclusionsIn early RA patients, bDMARD use decreases the overall risk of developing malignancies; however, it does not affect the risk of developing hematologic malignancies.
| S-EPMC5732524 | biostudies-literature