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Hydroxychloroquine/chloroquine and the risk of acute kidney injury in COVID-19 patients: a systematic review and meta-analysis.
Liao, ZM, Zhang, ZM, Liu, Q
Renal failure. 2022;(1):415-425
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Abstract
OBJECTIVES Hydroxychloroquine/chloroquine has been widely used as part of the standard treatment for patients with coronavirus disease 2019 (COVID-19). We conducted a systematic review and meta-analysis to determine whether hydroxychloroquine/chloroquine increases the risk of acute kidney injury (AKI) in COVID-19 patients. METHODS PubMed and Embase were searched for related publications from inception to Dec 31, 2021, including randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) comparing the risk of AKI and/or increased creatinine in COVID-19 patients receiving hydroxychloroquine/chloroquine and other controls (active treatment and placebo). We conducted separate meta-analyses for RCTs and NRSIs based on fixed-effect model, with odds ratios (ORs) being considered as effect sizes. RESULTS We included 21 studies in the analysis, with 12 were RCTs. Based on the RCTs, compared to placebo, the OR was 1.19 (95% confidence interval [CI]: 0.86, 1.64; p = .30, n = 4, moderate quality) for AKI and 1.00 (95%CI: 0.64, 1.56; p = .99, n = 5, moderate quality) for increased creatinine for patients received hydroxychloroquine/chloroquine treatment; compared to active treatment, the odds was 1.28 (95%CI: 0.65, 2.53; p = .47, n = 2, low quality) for AKI and 0.64 (95%CI: 0.13, 3.20; p = .59, n = 1, low quality) for increased creatine. Evidence from NRSIs showed slightly increased odds of AKI, with low quality. CONCLUSION Based on current available studies which were graded as low to moderate quality, there is insufficient evidence to conclude that hydroxychloroquine/chloroquine use is associated with increased risk of AKI or raised creatinine. Abbreviations: AKI: acute kidney injury; COVID-19: Coronavirus Disease 2019; RCT: randomized controlled trials; NRSI non-randomized studies of interventions; OR: odds ratios; ROBIS-I: Risk Of Bias In Non-randomized Studies - of Interventions.
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Phytochemicals targeting JAK/STAT pathway in the treatment of rheumatoid arthritis: Is there a future?
Kour, G, Choudhary, R, Anjum, S, Bhagat, A, Bajaj, BK, Ahmed, Z
Biochemical pharmacology. 2022;:114929
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disorder and the treatment involves the use of traditional and biological disease modifying anti-rheumatic drugs (DMARDs). Recent studies have shown JAK/STAT signaling pathway as potential target for the treatment of RA. Novel JAK/STAT inhibitors viz tofacitinib and baricitinib have been recently approved by FDA for RA treatment and have attained substantial importance. However, the discernible risks of thromboembolism, gastrointestinal (GIT) perforations, hepatotoxicity and serious infections including tuberculosis, herpes zoster associated with their administration cannot be overlooked. Furthermore, these are highly expensive which limits their application for a broader use. These limitations provide the basis of exploring novel JAK/STAT inhibitors of natural origin with increased tolerability, safety and cost-effectiveness. In this review we confer an account of various natural compounds/phytochemicals that have proved to be beneficial in attenuating inflammation in RA via modulation of JAK/STAT signaling pathway. Some of these natural compounds including resveratrol have clearly indicated biochemical and clinically significant therapeutic effects in ameliorating RA both in vivo and in clinical settings. We further discuss the physicochemical challenges of poor solubility and absorption coupled with the use of natural JAK/STAT inhibitors. We thereafter discuss and summarize various drug delivery systems (DDS) to confront the physicochemical limitations of natural JAK/STAT inhibitors with the aim to enhance the therapeutic efficacy. Overall the review unveils the potential of natural JAK/STAT inhibitors as a cost-effective approach in ameliorating RA without incorporating the risks of adverse repercussions, thus setting the stage for clinical exploration of these compounds that may possibly complement the present RA therapy.
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Antirheumatic treatment is associated with reduced serum Syndecan-1 in Rheumatoid Arthritis.
Deyab, G, Reine, TM, Vuong, TT, Jenssen, T, Hjeltnes, G, Agewall, S, Mikkelsen, K, Førre, Ø, Fagerland, MW, Kolset, SO, et al
PloS one. 2021;(7):e0253247
Abstract
The endothelial glycocalyx (EG) is essential for proper function of the endothelium and for vascular integrity, but its role in premature atherogenesis in rheumatoid arthritis (RA) has not been studied yet. EG impairment can play a role in pathogenesis of vascular disease, and one of its characteristics is shedding of syndecan-1 from endothelial cells. Syndecan-1 shedding is mediated by matrix metalloproteinase-9 (MMP-9) and counteracted by tissue inhibitor of metalloproteinases (TIMP)-1. Cardiovascular disease risk in RA is reversible by disease modifying antirheumatic drugs (DMARDs), but the exact modes of action are still unclear. Therefore, we examined effects of DMARDs on syndecan-1, MMP-9 and TIMP-1 in RA patients, and searched for associations between these parameters and inflammatory activity. From the observational PSARA study, we examined 39 patients starting with methotrexate (MTX) monotherapy (in MTX naïve patients, n = 19) or tumor necrosis factor inhibitors (TNFi) in combination with MTX (in MTX non-responders, n = 20) due to active RA. Serum syndecan-1, MMP-9 and TIMP-1 were measured at baseline and after six weeks of treatment. Serum syndecan-1 (p = 0.008) and TIMP-1 (p<0.001) levels decreased after six weeks of anti-rheumatic treatment. Levels of MMP-9 also decreased, but the difference was not statistically significant. The improvement in syndecan-1 levels were independent of changes in inflammatory activity. There was no significant difference in changes in syndecan-1 levels from baseline to 6 weeks between the MTX and TNFi groups, however the change was significant within the MTX group. Six weeks of antirheumatic treatment was associated with reduction in serum levels of syndecan-1, which might reflect reduced syndecan-1 shedding from EG. Thus, it is possible that EG-preserving properties of DMARDs might contribute to their cardioprotective effects. These effects may be at least partly independent of their anti-inflammatory actions. Our findings do not support the notion that syndecan-1 shedding in RA is mediated mainly by increased MMP-9 or decreased TIMP-9 serum concentration.
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Exposure-response modeling of peficitinib efficacy in patients with rheumatoid arthritis.
Toyoshima, J, Kaibara, A, Shibata, M, Kaneko, Y, Izutsu, H, Nishimura, T
Pharmacology research & perspectives. 2021;(3):e00744
Abstract
The aim was to analyze the relationship between peficitinib exposure and efficacy response according to American College of Rheumatology (ACR) 20 criteria and 28-joint disease activity score based on C-reactive protein (DAS28-CRP) in rheumatoid arthritis (RA) patients, and to identify relevant covariates by developing exposure-response models. The analysis incorporated results from three multicenter, placebo-controlled, double-blind studies. As an exposure parameter, individual post hoc pharmacokinetic (PK) parameters were obtained from a previously constructed population PK model. Longitudinal ACR20 response rate and individual longitudinal DAS28-CRP measurements were modeled by a non-linear mixed effect model. Influential covariates were explored, and their effects on efficacy were quantitatively assessed and compared. The exposure-response models of effect of peficitinib on duration-dependent increase in ACR20 response rate and decrease in DAS28-CRP were adequately described by a continuous time Markov model and an indirect response model, respectively, with a sigmoidal Emax saturable of drug exposure in RA patients. The significant covariates were DAS28-CRP and total bilirubin at baseline for the ACR20 response model, and CRP at baseline and concomitant methotrexate treatment for the DAS28-CRP model. The covariate effects were highly consistent between the two models. Our exposure-response models of peficitinib in RA patients satisfactorily described duration-dependent improvements in ACR20 response rates and DAS28-CRP measurements, and provided consistent covariate effects. Only the ACR20 model incorporated a patient's subjective high expectations just after the start of the treatment. Therefore, due to their similarities and differences, both models may have relevant applications in the development of RA treatment. CLINICAL TRIAL REGISTRATION NCT01649999 (RAJ1), NCT02308163 (RAJ3), NCT02305849 (RAJ4).
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Similar lipid level changes in early rheumatoid arthritis patients following 1-year treat-to-target strategy with adalimumab plus methotrexate versus placebo plus methotrexate: secondary analyses from the randomised controlled OPERA trial.
Mašić, D, Stengaard-Pedersen, K, Løgstrup, BB, Hørslev-Petersen, K, Hetland, ML, Junker, P, Østergaard, M, Ammitzbøll, C, Möller, S, Christensen, R, et al
Rheumatology international. 2021;(3):543-549
Abstract
To compare changes in low-density lipoprotein cholesterol and other lipids in patients with rheumatoid arthritis (RA) randomised to a 1-year treat-to-target strategy with either adalimumab plus methotrexate or placebo plus methotrexate. Prespecified secondary analyses from the OPERA trial, where 180 early and treatment-naïve RA patients received methotrexate 20 mg once weekly in combination with either placebo or subcutaneous adalimumab 40 mg every other week. Serum lipid levels were measured at baseline and after 1 year. Changes in lipid levels were analysed using mixed linear models based on the intention-to-treat (ITT) population. Overall, 174 patients were included in the ITT population (adalimumab plus methotrexate n = 86; placebo plus methotrexate n = 88). Differences between changes in lipid levels were low-density lipoprotein cholesterol 0.18 mmol/l [95% CI - 0.05 to 0.42], total cholesterol 0.27 mmol/l [- 0.002 to 0.54], high-density lipoprotein cholesterol 0.05 mmol/l [- 0.06 to 0.15], triglycerides 0.11 mmol/l [- 0.08 to 0.29], very-low-density lipoprotein cholesterol 0.03 mmol/l [- 0.05 to 0.12], and non-high-density lipoprotein cholesterol 0.22 mmol/l [- 0.02 to 0.46]. In early RA patients treated to tight control of inflammation over a period of 1 year with either adalimumab plus methotrexate or placebo plus methotrexate, changes in lipid levels were similar. Trial registration number: NCT00660647.
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The Role of TNF-α and Anti-TNF-α Agents during Preconception, Pregnancy, and Breastfeeding.
Romanowska-Próchnicka, K, Felis-Giemza, A, Olesińska, M, Wojdasiewicz, P, Paradowska-Gorycka, A, Szukiewicz, D
International journal of molecular sciences. 2021;(6)
Abstract
Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.
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COVID-19 and the burning issue of drug interaction: never forget the ECG.
Sciaccaluga, C, Cameli, M, Menci, D, Mandoli, GE, Sisti, N, Cameli, P, Franchi, F, Mondillo, S, Valente, S
Postgraduate medical journal. 2021;(1145):180-184
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Abstract
The coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), has been rapidly escalating, becoming a relevant threat to global health. Being a recent virus outbreak, there are still no available therapeutic regimens that have been approved in large randomised trials and so patients are currently being treated with multiple drugs. This raises concerns regarding drug interaction and their implication in arrhythmic burden. In fact, two of the actually used drugs against SARS-CoV2, such as chloroquine and the combination lopinavir/ritonavir, might determine a QT (the time from the start of the Q wave to the end of the T wave) interval prolongation and they show several interactions with antiarrhythmic drugs and antipsychotic medications, making them prone to an increased risk of developing arrhythmias. This brief review focuses the attention on the most relevant drug interactions involving the currently used COVID-19 medications and their possible association with cardiac rhythm disorders, taking into account also pre-existing condition and precipitating factors that might additionally increase this risk. Furthermore, based on the available evidence and based on the knowledge of drug interaction, we propose a quick and simple algorithm that might help both cardiologists and non-cardiologists in the management of the arrhythmic risk before and during the treatment with the specific drugs used against SARS-CoV2.
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A Review on Rheumatoid Arthritis Interventions and Current Developments.
Khanna, N, Kumar, A, Pawar, SV
Current drug targets. 2021;(4):463-483
Abstract
Rheumatoid arthritis is a chronic autoimmune disorder characterized by inflammation, swelling, and joint destruction primarily affecting the peripheral joints. In recent years, RA has become an alarming concern affecting more than 1.5% of the population worldwide. The majority of the drugs in clinical trials for rheumatoid arthritis are immunomodulatory. The development of novel drugs for RA is impending and scientists are exploring new strategies through various innovative approaches for RA drug development. Treat-to-target and window of opportunity hypothesis are the new approaches that are used to treat, improve outcomes, and prevent long-term use of ineffective therapy, respectively. Novel therapeutic agents (e.g. GM-CSF inhibitors, Matrix metalloproteinase inhibitors) and delivery systems (e.g., Liposomes, Superparamagnetic iron oxide nano particles (SPIONs)) are under investigation for more target based therapy with reduced side effects and toxicity. The new drug discovery and repositioning of previously FDA-approved drugs are also being considered for chronic inflammatory disorder. The review encompasses a vast array of information, including genetics, etiology, clinical symptoms, current treatment, and newer therapeutics approaches, focused on the development of RA interventions. The introduction of the bioinformatics-based approach in RA has also been significantly discussed in the review. This review provides a general understanding of the challenges and uncertainties in the treatment of RA and summarizes the evolving scenario as well as innovative approaches taken into consideration for drug development in rheumatoid arthritis.
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AHR-dependent genes and response to MTX therapy in rheumatoid arthritis patients.
Wajda, A, Walczuk, E, Stypińska, B, Lach, J, Yermakovich, D, Sivitskaya, L, Romanowska-Próchnicka, K, Wysocki, T, Jarończyk, M, Paradowska-Gorycka, A
The pharmacogenomics journal. 2021;(5):608-621
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Abstract
Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis. Nevertheless, MTX resistance is quite a common issue in clinical practice. There are some premises that aryl hydrocarbon receptor (AhR) gene battery may take part in MTX metabolism. In the present retrospective study, we analyzed genes expression of AHR genes battery associated with MTX metabolism in whole blood of RA patients with good and poor response to MTX treatment. Additionally, sequencing, genotyping and bioinformatics analysis of AHR repressor gene (AHRR) c.565C > G (rs2292596) and c.1933G > C (rs34453673) have been performed. Theoretically, both changes may have an impact on H3K36me3 and H3K27me3. Evolutionary analysis revealed that rs2292596 may be possibly damaging. Allele G in rs2292596 and DAS28 seems to be associated with a higher risk of poor response to MTX treatment in RA. RA patients with poor response to MTX treatment revealed upregulated AhR and SLC19A1 mRNA level. Treatment with IL-6 inhibitor may be helpful to overcome the low-dose MTX resistance. Analysis of gene expression revealed possible another cause of poor response to MTX treatment which is different from that observed in the case of acute lymphoblastic leukemia.
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Comprehensive exploratory autoantibody profiling in patients with early rheumatoid arthritis treated with methotrexate or tocilizumab.
Teitsma, XM, Devenport, J, Jacobs, JWG, Pethö-Schramm, A, Borm, MEA, Budde, P, Bijlsma, JWJ, Lafeber, FPJG
PloS one. 2020;(12):e0241189
Abstract
BACKGROUND We sought to identify immunoglobin G autoantibodies predictive of early treatment response to methotrexate, the recommended first-line therapy for patients with newly diagnosed rheumatoid arthritis, and to the interleukin-6 receptor inhibitor biologic tocilizumab, initiated as the first disease-modifying anti-rheumatic drug. MATERIALS AND METHODS In baseline sera of a subset of patients with newly diagnosed rheumatoid arthritis in the U-Act-Early study, selected based on specific responder/non-responder criteria using the Disease Activity Score assessing 28 joints (DAS28) within the first 20 weeks, we measured immunoglobin G antibody reactivity against 463 protein antigens and performed supervised cluster analysis to identify predictive autoantibodies for treatment response. The analysis subset comprised 56 patients in the methotrexate arm (22 responders, 34 non-responders) and 50 patients in the tocilizumab arm (34 responders, 16 non-responders). For comparison, these analyses were also performed in 50 age- and gender-matched healthy controls. RESULTS Increased reactivity in responders versus non-responders was found in the methotrexate arm against two antigens-DOT1-like histone lysine methyltransferase (p = 0.009) and tropomyosin (p = 0.003)-and in the tocilizumab arm against one antigen-neuro-oncological ventral antigen 2 (p = 0.039). Decreased reactivity was detected against two antigens in the methotrexate arm-G1 to S phase transition 2 (p = 0.023) and the zinc finger protein ZPR1 (p = 0.021). Reactivity against the identified antigens was not statistically significant in either treatment arm for patients with rheumatoid factor-positive versus-negative or anti-cyclic citrullinated test-positive versus test-negative rheumatoid arthritis (p ≥ 0.06). CONCLUSIONS Comprehensive profiling of baseline sera revealed several novel immunoglobin G autoantibodies associated with early treatment response to methotrexate and to tocilizumab in disease-modifying anti-rheumatic drug-naive patients with rheumatoid arthritis. These findings could eventually yield clinically relevant predictive markers, if corroborated in different patient cohorts, and may facilitate future benefit in personalised healthcare.