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How does methotrexate work?
Alqarni, AM, Zeidler, MP
Biochemical Society transactions. 2020;(2):559-567
Abstract
Developed over 70 years ago as an anti-folate chemotherapy agent, methotrexate (MTX) is a WHO 'essential medicine' that is now widely employed as a first-line treatment in auto-immune, inflammatory diseases such as rheumatoid arthritis (RA), psoriasis and Crone's disease. When used for these diseases patients typically take a once weekly low-dose of MTX - a therapy which provides effective inflammatory control to tens of millions of people worldwide. While undoubtedly effective, our understanding of the anti-inflammatory mechanism-of-action of low-dose MTX is incomplete. In particular, the long-held dogma that this disease-modifying anti-rheumatic drug (DMARD) acts via the folate pathway does not appear to hold up to scrutiny. Recently, MTX has been identified as an inhibitor of JAK/STAT pathway activity, a suggestion supported by many independent threads of evidence. Intriguingly, the JAK/STAT pathway is central to both the inflammatory and immune systems and is a pathway already targeted by other RA treatments. We suggest that the DMARD activity of MTX is likely to be largely mediated by its inhibition of JAK/STAT pathway signalling while many of its side effects are likely associated with the folate pathway. This insight into the mechanism-of-action of MTX opens the possibility for repurposing this low cost, safe and effective drug for the treatment of other JAK/STAT pathway-associated diseases.
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Updated pharmacological management of rheumatoid arthritis for women before, during, and after pregnancy, reflecting recent guidelines.
Murray, KE, Moore, L, O'Brien, C, Clohessy, A, Brophy, C, Minnock, P, FitzGerald, O, Molloy, ES, Mongey, AB, Higgins, S, et al
Irish journal of medical science. 2019;(1):169-172
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can cause significant disability, morbidity, mortality, and impaired fertility. It commonly affects women of childbearing age. Managing rheumatoid arthritis (RA) in the perinatal period poses challenges. There is concern about the teratogenic effects of many traditional disease-modifying anti-rheumatic drugs (DMARDs) and an ever-growing list of new therapeutic options with limited data in pregnancy and breastfeeding. AIMS We aimed to create a standardized approach to pharmacological management of RA patients seen in our newly established Rheumatology and Reproductive Health Service. METHODS We reviewed relevant publications on the use of anti-rheumatic drugs in pregnancy. These include recent guidelines from The British Society for Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) and the European League Against Rheumatism (EULAR). RESULTS After considering relevant publications, we developed a Saint Vincent's University Hospital/National Maternity Hospital consensus protocol for evidence-based medication in pregnancy in RA. CONCLUSIONS RA tends to improve during pregnancy and flare postpartum. Several anti-rheumatic medication options during pregnancy and breastfeeding are now available including anti-tumor necrosis factor (anti-TNF) agents. Good disease control at all stages of reproduction is important to ensure best outcome for both mother and baby.
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Remodeling of the HDL proteome with treatment response to abatacept or adalimumab in the AMPLE trial of patients with rheumatoid arthritis.
Charles-Schoeman, C, Gugiu, GB, Ge, H, Shahbazian, A, Lee, YY, Wang, X, Furst, DE, Ranganath, VK, Maldonado, M, Lee, T, et al
Atherosclerosis. 2018;:107-114
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Abstract
BACKGROUND AND AIMS To evaluate changes in the high-density lipoprotein (HDL) proteome and HDL function in active rheumatoid arthritis (RA) patients initiating therapy with abatacept or adalimumab in the Abatacept Versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) study. METHODS Ultra high-pressure liquid chromatography (UHPLC) coupled with ion mobility mass spectrometry (LC-IM-MS) was used to analyze proteins associated with immunoaffinity-captured HDL from plasma of 30 patients with RA randomized to either abatacept (n = 15) or adalimumab (n = 15) therapy. Paraoxonase 1 (PON1) activity, HDL anti-oxidant capacity, cholesterol profiles, and homocysteine levels were also measured at baseline and following treatment. Repeated-measures analyses were performed using mixed-effect linear models to model the within-subject covariance over time. RESULTS In models controlling for age, sex and treatment group, improvement in inflammation measured by decreases in CRP was associated with improvement in HDL function and changes in several HDL-associated proteins including significant decreases in lipopolysaccharide-binding protein, serum amyloid A-I (SAA-I) and inter-alpha-trypsin inhibitor heavy chain H4 (p values < 0.05). Improvement in disease activity was also associated with changes in multiple HDL-associated proteins. Adalimumab was associated with higher PON1 activity, HDL-associated serotransferrin, and HDL-associated immunoglobulin J chain, and lower HDL-associated SAA-I over time compared with abatacept. CONCLUSIONS Improvement in inflammation associated with treatment of RA, using either abatacept or adalimumab in the AMPLE study, was associated with improvement in HDL function and significant alterations in the HDL proteome, including proteins involved in the immune response, proteinase inhibition, and lipid metabolism.
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Vitamin D and immunomodulation in early rheumatoid arthritis: A randomized double-blind placebo-controlled study.
Buondonno, I, Rovera, G, Sassi, F, Rigoni, MM, Lomater, C, Parisi, S, Pellerito, R, Isaia, GC, D'Amelio, P
PloS one. 2017;(6):e0178463
Abstract
The aim of this study was to evaluate differences in T helper cell sub-types and osteoclast (OCs) precursors in peripheral blood between patients affected by early rheumatoid arthritis (eRA) and healthy controls. The effect of administration of cholecalcipherol on clinical and laboratory parameters was subsequently evaluated, by a parallel, randomized double blind, placebo controlled trial. Thirty nine eRA patients and 31 age-matched controls were enrolled and compared for levels of 25OH vitamin D, T helper cell sub-types, OCs precursors including both classical and non-classical and pro-inflammatory cytokines at baseline. Eligible patients were female ≥18 years of age with a diagnosis of RA, as defined by the American College of Rheumatology 2010 criteria for <6 months prior to inclusion in the study. Patients with auto-immune or inflammatory diseases other than RA were excluded. Patients treated with glucocorticoids (GCs), disease modifying activity drugs and biologic agents within the past 6 months were also excluded. In the second phase of the study, eRA patients were randomly assigned to standard treatment with methotrexate (MTX) and GCs with (21) or without (18) cholecalcipherol (300,000 IU) and followed for 3 months; the randomization was done by computer generated tables to allocate treatments. Three patients didn't come back to the follow up visit for personal reasons. None of the patients experienced adverse events. The main outcome measures were T cells phenotypes, OCs precursors and inflammatory cytokines. Secondary outcome measure were clinical parameters. In eRA, 25OH vitamin D levels were significantly lower. CD4+/IFNγ+,CD4+/IL4+, CD4+/IL17A+ and CD4+IL17A+IFNγ+, cells were increased in eRA as well as non-classical OCs precursors, whereas T regulatory cells were not altered. TNFα, TGFβ1, RANKL, IL-23 and IL-6 were increased in eRA. Non-classical OCs, IL-23 and IL-6 correlated with disease severity and activity. Standard treatment with MTX and GC ameliorated clinical symptoms and reduced IL-23, whereas it did not affect CD4+ cells sub-sets nor OCs precursors. After 3 months, the combined use of cholecalcipherol significantly ameliorated the effect of treatment on global health. In eRA, a significant imbalance in T CD4+ sub-types accompanied by increased levels of non-classical OCs precursors and pro-inflammatory cytokines was observed. A single dose of cholecalcipherol (300,000 IU) combined with standard treatment significantly ameliorates patients general health.
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The therapeutic effect of probiotics on rheumatoid arthritis: a systematic review and meta-analysis of randomized control trials.
Mohammed, AT, Khattab, M, Ahmed, AM, Turk, T, Sakr, N, M Khalil, A, Abdelhalim, M, Sawaf, B, Hirayama, K, Huy, NT
Clinical rheumatology. 2017;(12):2697-2707
Abstract
Rheumatoid arthritis is an autoimmune disease in which probiotics appears to have an immune modulating action along with decreased inflammatory process. Therefore, we aim to investigate the efficacy of probiotics as an adjuvant therapy for rheumatoid arthritis. A comprehensive literature search was performed using nine databases including PubMed and Web of Science. Interesting data was extracted and meta-analyzed. We assessed the risk of bias using Cochrane Collaboration's tool. The protocol was registered in PROSPERO (CRD 42016036769). We found nine studies involving 361 patients who met our eligibility criteria. Our meta-analysis indicated that pro-inflammatory cytokine IL-6 was significantly lower in the probiotics compared with the placebo group (standardized mean difference = - 0.708; 95% confidence interval (CI) - 1.370 to 0.047, P = 0.036). However, there was no difference between probiotics and placebo in disease activity score (mean difference 0.023; 95% CI - 0.584 to 0.631, P = 0.940). Probiotics lowered pro-inflammatory cytokines IL-6 in RA; however, its clinical effect is still unclear. Hence, many high-quality randomized controlled trials (RCTs) are still needed to prove this effect.