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Fertility and Sterility Sep 2023
Topics: Humans; Methotrexate; Fathers; Reproductive Health
PubMed: 37429405
DOI: 10.1016/j.fertnstert.2023.07.004 -
Cell Chemical Biology Feb 2024Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate...
Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate undergoes folylpolyglutamate synthetase-mediated γ-glutamylation, which affects cellular retention and target specificity. Mechanisms of MTX resistance in cancers include a decrease in MTX poly-γ-glutamylation and an upregulation of DHFR. Here, we report a series of potent MTX-based proteolysis targeting chimeras (PROTACs) to investigate DHFR degradation pharmacology and one-carbon biochemistry. These on-target, cell-active PROTACs show proteasome- and E3 ligase-dependent activity, and selective degradation of DHFR in multiple cancer cell lines. By comparison, treatment with MTX increases cellular DHFR protein expression. Importantly, these PROTACs produced distinct, less-lethal phenotypes compared to MTX. The chemical probe set described here should complement conventional DHFR inhibitors and serve as useful tools for studying one-carbon biochemistry and dissecting complex polypharmacology of MTX and related drugs. Such compounds may also serve as leads for potential autoimmune and antineoplastic therapeutics.
Topics: Humans; Antineoplastic Agents; Carbon; Folic Acid Antagonists; Methotrexate; Neoplasms; Proteolysis Targeting Chimera; Tetrahydrofolate Dehydrogenase
PubMed: 37875111
DOI: 10.1016/j.chembiol.2023.09.014 -
The American Journal of Medicine Dec 2023Mortality in rheumatoid arthritis is increased, about twice vs controls, and cardiovascular diseases are a major cause. The pathogenesis is primarily accelerated... (Review)
Review
Mortality in rheumatoid arthritis is increased, about twice vs controls, and cardiovascular diseases are a major cause. The pathogenesis is primarily accelerated atherosclerosis of the coronary, cervical, and cerebral arteries, which is premature, pervasive, and progressive, but often occult, under-recognized, and under-treated. It is mostly driven by the chronic, systemic autoimmune inflammation, but increased prevalence of traditional risk factors and adverse effects of treatments are also very important. Inflammatory markers, disease severity, and duration are major determinants of the cardiovascular risk in rheumatoid arthritis, which is underestimated by usual methods. Cardiovascular protection is best achieved by suppressing inflammation and disease activity as early as possible ("treat-to-target"), and striving to achieve and maintain remission or lowest disease activity. Secondly, identifying and addressing the whole spectrum of traditional risk factors, currently often neglected, is necessary. Because long-term glucocorticoid exposure ≥5 mg/d may be associated with cardiovascular events and other harm, more intensive treatment, especially useful for bridging with methotrexate at the outset of treatment, needs to be limited in time and dosage. A multipronged approach may improve cardiovascular outcomes of RA patients in future studies.
Topics: Humans; Arthritis, Rheumatoid; Risk Factors; Inflammation; Atherosclerosis; Methotrexate; Cardiovascular Diseases
PubMed: 37742851
DOI: 10.1016/j.amjmed.2023.09.004 -
JAMA Network Open Oct 2023This is the first network meta-analysis to assess outcomes associated with multiple conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
This is the first network meta-analysis to assess outcomes associated with multiple conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid.
OBJECTIVE
To analyze clinical outcomes after treatment with conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid among patients with rheumatoid arthritis.
DATA SOURCES
With no time restraint, English language articles were searched in MEDLINE, Embase, Cochrane Central, ClinicalTrials.gov, and reference lists of relevant meta-analyses until September 15, 2022.
STUDY SELECTION
Four reviewers in pairs of 2 independently included controlled studies randomizing patients with rheumatoid arthritis to mono-conventional synthetic disease-modifying antirheumatic drugs, glucocorticoid, placebo, or nonactive treatment that recorded at least 1 outcome of tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein level. Of 1098 assessed articles, 130 articles (132 interventions) were included.
DATA EXTRACTION AND SYNTHESIS
The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, and data quality was assessed by the Cochrane risk of bias tool RoB 2. Data were extracted by a single author and checked independently by 2 authors. Data were analyzed using a random effect model, and data analysis was conducted from June 2021 to February 2023.
MAIN OUTCOMES AND MEASURES
A protocol with hypothesis and study plan was registered before data recording. The most complete of recorded outcomes (tender joint count) was used as primary outcome, with imputations based on other outcomes to obtain a full analysis of all studies. Absolute change adjusted for baseline disease activity was assessed.
RESULTS
A total of 29 interventions in 275 treatment groups among 132 randomized clinical trials (mean [range], 71.0% [27.0% to 100%] females in studies; mean [range] of ages in studies, 53 [36 to 70] years) were identified, which included 13 260 patients with rheumatoid arthritis. The mean (range) duration of RA was 79 (2 to 243) months, and the mean (range) disease activity score was 6.3 (4.0 to 8.8). Compared with placebo, oral methotrexate was associated with a reduced tender joint count by 5.18 joints (95% credible interval [CrI], 4.07 to 6.28 joints). Compared with methotrexate, glucocorticoid (-2.54 joints; 95% CrI, -5.16 to 0.08 joints) and remaining drugs except cyclophosphamide (6.08 joints; 95% CrI, 0.44 to 11.66 joints) were associated with similar or lower tender joint counts.
CONCLUSIONS AND RELEVANCE
This study's results support the present role of methotrexate as the primary reference conventional synthetic disease-modifying antirheumatic drug.
Topics: Female; Humans; Male; Antirheumatic Agents; Arthritis, Rheumatoid; Glucocorticoids; Methotrexate; Network Meta-Analysis; Adult; Middle Aged; Aged
PubMed: 37801318
DOI: 10.1001/jamanetworkopen.2023.35950 -
International Journal of Rheumatic... May 2024
Topics: Humans; Methotrexate; Japan; Antirheumatic Agents; Drug Dosage Calculations; Treatment Outcome; Arthritis, Rheumatoid
PubMed: 38720411
DOI: 10.1111/1756-185X.15176 -
Annals of Internal Medicine May 2024Many patients with rheumatologic conditions receive care from physicians other than rheumatologists. Here we note key findings from 6 studies in rheumatology published... (Review)
Review
Many patients with rheumatologic conditions receive care from physicians other than rheumatologists. Here we note key findings from 6 studies in rheumatology published in 2023 that offer valuable insights for internal medicine specialists and subspecialists outside of rheumatology. The first study investigated the effect of low-dose glucocorticoids on patients with rheumatoid arthritis (RA) over 2 years and challenged existing perceptions about the risks of glucocorticoids in this setting. The second study focused on the updated guideline for preventing and treating glucocorticoid-induced osteoporosis. With the chronic and widespread use of glucocorticoids, the American College of Rheumatology emphasized the importance of assessing fracture risk and initiating pharmacologic therapy when appropriate. The third study explored the potential use of methotrexate in treating inflammatory hand osteoarthritis, suggesting a novel approach to managing this challenging and common condition. The results of the fourth article we highlight suggest that sarilumab has promise as an adjunct treatment of polymyalgia rheumatica relapse during glucocorticoid dosage tapering. The fifth study evaluated sublingual cyclobenzaprine for fibromyalgia treatment, noting both potential benefits and risks. Finally, the sixth article is a systematic review and meta-analysis that assessed the therapeutic equivalence of biosimilars and reference biologics in the treatment of patients with RA. Knowledge of this recent literature will be useful to clinicians regardless of specialty who care for patients with these commonly encountered conditions.
Topics: Humans; Glucocorticoids; Osteoporosis; Arthritis, Rheumatoid; Antirheumatic Agents; Methotrexate; Rheumatology; Rheumatic Diseases; Biosimilar Pharmaceuticals; Polymyalgia Rheumatica; Fibromyalgia
PubMed: 38621248
DOI: 10.7326/M24-0678 -
Expert Review of Clinical Immunology 2023Rheumatoid arthritis (RA) is an autoimmune disorder necessitating immunosuppressive therapy. Remarkable progress has been made in the treatment of RA over recent... (Review)
Review
INTRODUCTION
Rheumatoid arthritis (RA) is an autoimmune disorder necessitating immunosuppressive therapy. Remarkable progress has been made in the treatment of RA over recent decades, particularly with the development of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi). Nonetheless, the development of new drugs has been accompanied by concerns regarding the association between these novel therapies and the risk of malignancy.
AREAS COVERED
This narrative review aims to discuss the understanding of RA, conventional synthetic (cs) DMARDs, bDMARDs, JAKi, and their association with malignancy. Furthermore, the review discusses the management of malignancy in patients receiving b/tsDMARDs.
EXPERT OPINION
Although recent studies suggest that the potential risk of malignancy of methotrexate and a JAKi tofacitinib, it is essential to avoid indiscriminate withholding of treatment by those agents, as this may lead functional impairment and increased mortality. Therefore, the adoption of a Treat-to-Target (T2T) approach considering individual patient characteristics, becomes of utmost importance. Rheumatologists should maintain a vigilant stance regarding malignancy in this context, recognizing the importance of early detection and management. Implementing a screening program for malignancies is indispensable, and the use of computed tomography screening may enhance the effectiveness of management strategies.
Topics: Humans; Janus Kinase Inhibitors; Antirheumatic Agents; Arthritis, Rheumatoid; Methotrexate; Neoplasms; Biological Products
PubMed: 37578325
DOI: 10.1080/1744666X.2023.2247158 -
Drug Discovery Today Aug 2023Rheumatoid arthritis (RA) is an inflammatory, autoimmune and connective-tissue arthropathy. The methotrexate (MTX) and aceclofenac (ACL) combination drug regimen is... (Review)
Review
Rheumatoid arthritis (RA) is an inflammatory, autoimmune and connective-tissue arthropathy. The methotrexate (MTX) and aceclofenac (ACL) combination drug regimen is known to regulate the immunological pathways. Also, RA-elicited inflammation is decreased by the combination drug treatment. ACL and MTX combination treatment has been shown to regulate the signaling pathway controlled by NF-κB and FOXO1. The present manuscript reviews the importance of the combination drug regimen to treat and/or manage RA. The combination drug regimen could affect the Th1/Th17 axis to switch the balance toward the immunoregulatory (Th1) phenotype for establishing immune homeostasis. In conclusion, we propose the study of the immunological signaling pathways in experimental humanized RA mice.
Topics: Mice; Animals; Methotrexate; Antirheumatic Agents; Arthritis, Rheumatoid; Inflammation; Arthritis, Experimental; Drug Therapy, Combination
PubMed: 37330038
DOI: 10.1016/j.drudis.2023.103671 -
Journal of Nuclear Cardiology :... Aug 2023
Topics: Humans; Methotrexate; Sarcoidosis; Immunosuppressive Agents; Myocarditis
PubMed: 36609682
DOI: 10.1007/s12350-022-03190-3 -
BMJ Case Reports Feb 2024A large percentage of the US population is either receiving or should be considered for statin therapy. Whether through primary or secondary prevention for...
A large percentage of the US population is either receiving or should be considered for statin therapy. Whether through primary or secondary prevention for atherosclerotic disease, statins remain one of the mainstay options available to physicians. Myalgias are the most commonly reported side effects, though largely self-limited and subjective in nature. Here, we report a case of drug-related myonecrosis following long-term use of atorvastatin. Prompt recognition of the condition and initiation of treatment is paramount to control the disease's progression. While high-dose steroids are first line, quick escalation to methotrexate, IVIG or rituximab should be considered in refractory cases. This decision is guided by monitoring of serum markers such as CK and transaminases. The goal is quick normalisation of these enzymes, signalling cessation of underlying muscle necrosis. Patients may never regain full function and treatment can last months to years.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscular Diseases; Atorvastatin; Methotrexate; Frailty
PubMed: 38316487
DOI: 10.1136/bcr-2023-256956