DMARD-free remission as novel treatment target in rheumatoid arthritis: A systematic literature review of achievability and sustainability

OBJECTIVES: Although current treatment guidelines for rheumatoid arthritis (RA) suggest tapering disease-modifying anti-rheumatic drugs (DMARDs), it is unclear whether DMARD-free remission (DFR) is an achievable and sustainable outcome. Therefore, we systematically reviewed the literature to determine the prevalence and sustainability of DFR and evaluated potential predictors for DFR. METHODS: A systematic literature search was performed in March 2019 in multiple databases. All clinical trials and observational studies reporting on discontinuation of DMARDs in RA patients in remission were included. Our quality assessment included a general assessment and assessment of

Factors that influence biological survival in rheumatoid arthritis: results of a real-world academic cohort from the Netherlands

We aim to explore real-world biological survival stratified for discontinuation reason and determine its influenceability in rheumatoid arthritis (RA) patients. Data from the local pharmacy database and patient records of a university hospital in th

Extracellular matrix analysis of human renal arteries in both quiescent and active vascular state

In vascular tissue engineering strategies, the addition of vascular-specific extracellular matrix (ECM) components may better mimic the in vivo microenvironment and potentially enhance cell–matrix interactions and subsequent tissue growth. For this purpose, the exact composition of the human vascular ECM first needs to be fully characterized. Most research has focused on characterizing ECM components in mature vascular tissue; however, the developing fetal ECM matches the active environment required in vascular tissue engineering more closely. Consequently, we characterized the ECM protein composition of active (fetal) and quiescent (mature) renal arteries using a proteome analysis of decellularized tissue. The obtained human fetal renal artery ECM proteome dataset contains higher levels of 15 ECM proteins versus the mature renal artery ECM proteome, whereas 16 ECM proteins showed higher levels in the mature tissue compared to fetal. Elastic EC

Factors that influence biological survival in rheumatoid arthritis: results of a real-world academic cohort from the Netherlands

We aim to explore real-world biological survival stratified for discontinuation reason and determine its influenceability in rheumatoid arthritis (RA) patients. Data from the local pharmacy database and patient records of a university hospital in the Netherlands were used. RA patients who started a biological between 2000 and 2020 were included. Data on age, anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) status, presence of erosions, gender, body mass index, time to first biological, biological survival time, use of csDMARDs, and discontinuation reasons were collected. Of the included 318 patients, 12% started their first biological within 6 months after diagnosis. The median time to first biological was 3.6 years (95% CI, 1.0–7.2). The median survival of the first- and second-line biological was respectively 1.7 years (95% CI, 1.3–2.2) and 0.8 years (95% CI, 0.5–1.0) (p = 0.0001). Discontinuation reasons for the first-line biological were ineffectiveness (47%), adverse events (17%), remission (16%), pregnancy (30%), or patient preference (10%). Multivariable Cox regression analyses for discontinuation due to inefficacy or adverse events showed that concomitant use of csDMARDs (HR = 1.32, p < 0.001) positively while RF positivity negatively (HR = 0.82, p = 0.03) influenced biological survival. ACPA positivity was associated with the inability to discontinue biologicals after achieving remission (HR = 1.43, p = 0.023). Second-line TNF inhibitor survival was similar between patients with a primary and secondary non-response on the first-line TNF inhibitor (HR = 1.28, p = 0.34). Biological survival diminishes with the number of biologicals used. Biological survival is prolonged if patients use csDMARDs. RF was negatively associated with biological survival. ACPA was negatively associated with the inability to discontinue biologicals after achieving remission. Therefore, tailoring treatment based upon autoantibody status might be the first step towards personalized medicine in RA.Key Points• Prolonged biological survival is a surrogate for treatment effectiveness; however, an increasing amount of patients will taper treatment due to remission, and factors influencing biological survival based on separate reasons for discontinuation have not been explored.• We found that combining a biological DMARD with a conventional synthetic DMARD increases biological DMARD survival. Rheumatoid factor is negatively associated with biological survival. Anti-citrullinated protein antibody is negatively associated with the inability to discontinue the biological when remission was reached.• The first step towards personalized medicine might be tailoring of treatment based upon autoantibody status

Biological and Methotrexate Survival after Pregnancy in Patients With a Rheumatic Disease

Objective: Patients with a rheumatic disease who discontinue their disease-modifying anti-rheumatic drug (DMARD) due to pregnancy often wonder if treatment will be as effective after pregnancy. This study investigates the effect of a temporary discontinuation of DMARDs due to pregnancy on the effectiveness of the same DMARD postpartum in patients with a rheumatic disease. Methods: Pregnant, rheumatic patients were derived from the Preconceptional Counseling in Active Rheumatoid Arthritis (PreCARA) cohort. DMARD-survival after pregnancy, for biological and methotrexate (MTX) therapy, was analyzed and compared to controls with stable DMARD-treatment from a retrospective cohort. Results: In total, 234 patients were included, of whom 114 patients had stable biological or MTX treatment before their pregnancy. After pregnancy, 40 out of 56 (71%) patients restarted their biological, for MTX this was 49%. One year after restart, and censoring for a following pregnancy, 88.9% of patients were still using their biological, and 85% still used their MTX (p = 0.92). Compared to the matched controls the survival after pregnancy was significantly lower 1 year after restart for both biologicals (98.3%) and MTX (99.6%); p = 0.002 and p 85%). In addition, this difference was no longer observed after 3 years

The impact of a disease flare during tapering of DMARDs on the lives of rheumatoid arthritis patients

Objectives: To determine the impact of a disease flare on patient reported outcome measures (PROMs) in rheumatoid arthritis (RA) patients, who are tapering treatment. Methods: Data were used from the TARA trial; a multicenter, randomized controlled trial in which RA patients, with a well-controlled disease (DAS≤2.4 and SJC≤1) for at least 6 months, gradually tapered their DMARDs. PROMs of patients with a flare (DAS>2.4 and/or SJC>1) were compared every three months before and after a flare with their own norm values. Linear Mixed Models were used to investigate whether a disease flare influenced functional ability (HAQ-DI), fatigue (BRAF-MDQ), quality of life (EQ-5D and SF36), anxiety and depression (HADS), morning stiffness, general health (GH) and worker productivity, and if so, the duration was determined. For unemployment and sick leave we used descriptive statistics. Results: A flare negatively influenced GH, morning stiffness, HAQ-DI, EQ-5D, BRAF-MDQ, and the SF36 physical component scale and this effect lasted >3 months. Except for the HAQ-DI, effect sizes exceeded the minimum clinically important differences (MCIDs). For the physical outcomes effects lasted >6 months. Worker productivity was not significantly affected by a flare. Conclusion: A disease flare influenced patients’ lives, the largest effect was seen in the physical outcomes, and lasted 6 months. Although on a group level effect sizes for the separate PROMs were not always significant or larger than specific MCIDs, a disease flare can still be of great importance for individual patients

The complex mural cell : Pericyte function in health and disease

Pericytes are perivascular cells that can be distinguished from vascular smooth muscle cells by their specific morphology and expression of distinct molecular markers. Found in the microvascular beds distributed throughout the body, they are well known for their regulation of a healthy vasculature. In this review, we examine the mechanism of pericyte support to vasomotion, and the known pathways that regulate pericyte response in angiogenesis and neovascular stabilization. We will also discuss the role of pericytes in vascular basement membrane and endothelial barrier function regulation. In contrast, recent findings have indicated that pericyte dysfunction, characterized by changes in pericyte contractility or pericyte loss of microvascular coverage, plays an important role in onset and progression of vascular-related and fibrogenic diseases. From a therapeutic point of view, pericytes have recently been identified as a putative pool of endogenous mesenchymal stem cells that could be activated in response to tissue injury to contribute to the regenerative process on multiple levels. Wewill discuss the mechanisms viawhich pericytes are involved in disease onset and development in a number of pathophysiological conditions, as well as present the evidence that supports a role for multipotent pericytes in tissue regeneration. The emerging field of pericyte research will not only contribute to the identification of new drug targets in pericyte dysfunction associated diseases, but may also boost the use of this cell type in future cell-based regenerative strategies

Gradual tapering TNF inhibitors versus conventional synthetic DMARDs after achieving controlled disease in patients with rheumatoid arthritis: first-year results of the randomised controlled TARA study

OBJECTIVES: The aim of this study is to evaluate the effectiveness of two tapering strategies after achieving controlled disease in patients with rheumatoid arthritis (RA), during 1 year of follow-up. METHODS: In this multicentre single-blinded (research nurses) randomised controlled trial, patients with RA were included who achieved controlled disease, defined as a Disease Activity Score (DAS) ≤ 2.4 and a Swollen Joint Count (SJC) ≤ 1, treated with both a conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and a TNF inhibitor. Eligible patients were randomised into gradual tapering csDMARDs or TNF inhibitors. Medication was tapered if the RA was still under control, by cutting the dosage into half, a quarter and thereafter it was stopped. Primary outcome was proportion of patients with a disease flare, defined as DAS > 2.4 and/or SJC > 1. Secondary outcomes were DAS, European Quality of Life-5 Dimensions (EQ5D) and functional ability (Health Assessment Questionnaire Disability Index [HAQ-DI]) after 1 year and over time. RESULTS: A total of 189 patients were randomly assigned to tapering csDMARDs (n = 94) or tapering anti-TNF (n = 95). The cumulative flare rates in the csDMARD and anti-TNF tapering group were, respectively, 33 % (95% CI,24% to 43 %) and 43 % (95% CI, 33% to 53 % (p = 0.17). Mean DAS, HAQ-DI and EQ-5D did not differ between tapering groups after 1 year and over time. CONCLUSION: Up to 9 months, flare rates of tapering csDMARDs or TNF inhibitors were similar. After 1 year, a non-significant difference was found of 10 % favouring csDMARD tapering. Tapering TNF inhibitors was, therefore, not superior to tapering csDMARDs. From a societal perspective, it would be sensible to taper the TNF inhibitor first, because of possible cost reductions and less long-term side effects. TRIAL REGISTRATION NUMBER: NTR2754