Mechanisms underlying DMARD inefficacy in difficult-to-treat rheumatoid arthritis: a narrative review with systematic literature search

Roodenrijs, Nadia M T; Welsing, Paco; Roon, Joël van; Schoneveld, J. Leonard M.; Goes, Marlies C van der; Nagy, György; Townsend, Michael J.; Laar, Jacob M van

doi:10.1093/rheumatology/keac114

Cited by 30 publications

(21 citation statements)

References 154 publications

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“…signs suggestive of presently active/progressive disease and management being perceived as problematic by the rheumatologist and/or patient). Although several studies have described D2T RA–related factors in RA patients (18)(32)(33) with long-standing disease, the effect of different variables on this outcome has not been studied in the early stages of disease, and comparisons between them would not be accurate.…”

Section: Discussionmentioning

confidence: 99%

Difficult-to-treat rheumatoid arthritis (D2T RA): clinical issues at early stages of disease

León

Madrid

Lopez-Viejo

et al. 2022

Preprint

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Objectives. Most studies on difficult-to-treat rheumatoid arthritis (D2T RA) have focused on established RA. Here, we analyze whether disease activity in the early stages of RA could influence progression to a D2T RA under real-life conditions. Other clinical and treatment-related factors were also analyzed. Methods. A longitudinal multicenter study of RA patients was conducted from 2009 to 2018. Patients were followed up until January 2021. D2T RA was defined based on EULAR criteria (treatment failure, signs suggestive of currently active/progressive disease, and management being perceived as problematic by the rheumatologist and/or patient). The main outcome was disease activity in the early stages. The covariates were sociodemographic, clinical, and treatment-related factors. We ran a multivariable logistic regression analysis to investigate risk factors associated with progression to D2T RA. Weighting techniques were also applied to balance data. Results. The study population comprised 631 patients and 35 developed D2T RA. At the time of diagnosis, the D2T RA group were younger, with a higher disability, DAS28 score, tender joint count and pain scores. In our final model, DAS28 was not statistically significantly associated with D2T RA. No differences were found between groups for therapy. Disability was independently associated with D2T RA (OR: 1.50; p=0.02). Conclusions. In this cohort of patients newly diagnosed with RA, our results do not allow us to prove the influence of active disease according to DAS28. However, we did find that patients with elevated initial disability scores are more likely to develop D2T RA regardless of other factors.

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Section: Discussionmentioning

confidence: 99%

Difficult-to-treat rheumatoid arthritis (D2T RA): clinical issues at early stages of disease

León

Madrid

Lopez-Viejo

et al. 2022

Preprint

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“…The disease most commonly begins in middle age, in the midst of working life, with significant social and economic impact, 92 despite currently available drug treatments. 93–96…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

Marshall

Bailey

Cassotta³

et al. 2023

Altern Lab Anim

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The failure rate for the translation of drugs from animal testing to human treatments remains at over 92%, where it has been for the past few decades. The majority of these failures are due to unexpected toxicity — that is, safety issues revealed in human trials that were not apparent in animal tests — or lack of efficacy. However, the use of more innovative tools, such as organs-on-chips, in the preclinical pipeline for drug testing, has revealed that these tools are more able to predict unexpected safety events prior to clinical trials and so can be used for this, as well as for efficacy testing. Here, we review several disease areas, and consider how the use of animal models has failed to offer effective new treatments. We also make some suggestions as to how the more human-relevant new approach methodologies might be applied to address this.

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“…Although the past decade has undoubtedly constituted a great revolution in treatment strategies for RA, some patients do no reach low disease activity or become non-responders, and most of the treatments cause long-term adverse side effects [ 28 , 29 ]. In this scenario, dietary bioactive compounds that exhibit anti-oxidant and anti-inflammatory properties have been proposed as potential candidates for the development of new therapeutic interventions [ 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis

2022

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Control of excessive mitochondrial oxidative stress could provide new targets for both preventive and therapeutic interventions in the treatment of chronic inflammation or any pathology that develops under an inflammatory scenario, such as rheumatoid arthritis (RA). Increasing evidence has demonstrated the role of mitochondrial alterations in autoimmune diseases mainly due to the interplay between metabolism and innate immunity, but also in the modulation of inflammatory response of resident cells, such as synoviocytes. Thus, mitochondrial dysfunction derived from several danger signals could activate tricarboxylic acid (TCA) disruption, thereby favoring a vicious cycle of oxidative/mitochondrial stress. Mitochondrial dysfunction can act through modulating innate immunity via redox-sensitive inflammatory pathways or direct activation of the inflammasome. Besides, mitochondria also have a central role in regulating cell death, which is deeply altered in RA. Additionally, multiple evidence suggests that pathological processes in RA can be shaped by epigenetic mechanisms and that in turn, mitochondria are involved in epigenetic regulation. Finally, we will discuss about the involvement of some dietary components in the onset and progression of RA.

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Mechanisms underlying DMARD inefficacy in difficult-to-treat rheumatoid arthritis: a narrative review with systematic literature search

Cited by 30 publications

References 154 publications

Difficult-to-treat rheumatoid arthritis (D2T RA): clinical issues at early stages of disease

Difficult-to-treat rheumatoid arthritis (D2T RA): clinical issues at early stages of disease

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis

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