-
The Oncologist Dec 2016: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered... (Review)
Review
UNLABELLED
: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated.
IMPLICATIONS FOR PRACTICE
High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.
Topics: Acute Kidney Injury; Antimetabolites, Antineoplastic; Bone Marrow; Chemical and Drug Induced Liver Injury; Crystallization; Humans; Leucovorin; Methotrexate; Mucositis; gamma-Glutamyl Hydrolase
PubMed: 27496039
DOI: 10.1634/theoncologist.2015-0164 -
Clinical Medicine (London, England) May 2021Psoriasis is a clinically heterogeneous lifelong skin disease that presents in multiple forms such as plaque, flexural, guttate, pustular or erythrodermic. An estimated...
Psoriasis is a clinically heterogeneous lifelong skin disease that presents in multiple forms such as plaque, flexural, guttate, pustular or erythrodermic. An estimated 60 million people have psoriasis worldwide, with 1.52% of the general population affected in the UK. An immune-mediated inflammatory disease, psoriasis has a major genetic component. Its association with psoriatic arthritis and increased rates of cardiometabolic, hepatic and psychological comorbidity requires a holistic and multidisciplinary care approach. Psoriasis treatments include topical agents (vitamin D analogues and corticosteroids), phototherapy (narrowband ultraviolet B radiation (NB-UVB) and psoralen and ultraviolet A radiation (PUVA)), standard systemic (methotrexate, ciclosporin and acitretin), biologic (tumour necrosis factor (TNF), interleukin (IL)-17 and IL-23 inhibitors) or small molecule inhibitor (dimethyl fumarate and apremilast) therapies. Advances in the understanding of its pathophysiology have led to development of highly effective and targeted treatments.
Topics: Acitretin; Humans; Immunosuppressive Agents; Methotrexate; Phototherapy; Psoriasis
PubMed: 34001566
DOI: 10.7861/clinmed.2021-0257 -
Cell Research Apr 2020The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors,... (Review)
Review
The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.
Topics: Anti-Inflammatory Agents; Autoimmune Diseases; Dimethyl Fumarate; Glycolysis; Humans; Immunomodulation; Immunosuppressive Agents; Inflammation; Metformin; Methotrexate; Sirolimus
PubMed: 32132672
DOI: 10.1038/s41422-020-0291-z -
Biomedicine & Pharmacotherapy =... Jun 2022Methotrexate (MTX) has been used for the treatment of rheumatoid arthritis (RA) for about forty years and to date MTX remains the part of global standard of treatment... (Review)
Review
Methotrexate (MTX) has been used for the treatment of rheumatoid arthritis (RA) for about forty years and to date MTX remains the part of global standard of treatment for RA. The efficacy of MTX in RA is the result of multiple mechanisms of action. In order to summarize the possible pharmacological mechanisms of MTX in the treatment of RA, this review will elaborate on folate antagonism, promotion of adenosine accumulation, regulation of inflammatory signaling pathways, bone protection and maintenance of immune system function.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Methotrexate
PubMed: 35658215
DOI: 10.1016/j.biopha.2022.113074 -
Actas Dermo-sifiliograficas 2014Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958, scientific evidence for this indication has been scant until... (Review)
Review
Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958, scientific evidence for this indication has been scant until quite recently. We now have new data on the pharmacokinetics and mechanism of action of methotrexate and new subcutaneous formulations that have improved the bioavailability, efficacy, and ease of administration of the drug. The results of recent clinical trials comparing methotrexate with several biologic agents have shown it to be the first-line therapy among the classic systemic treatments for psoriasis. Moreover, the incremental cost-effectiveness ratio for subcutaneous methotrexate has been shown to be superior to that of ciclosporin, adalimumab, and infliximab.
Topics: Dermatologic Agents; Humans; Methotrexate; Psoriasis
PubMed: 23434058
DOI: 10.1016/j.ad.2012.11.017 -
International Journal of Molecular... Oct 2019Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying... (Review)
Review
Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses-including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus-have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients' immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.
Topics: Adenosine; Alarmins; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis; Arthritis, Rheumatoid; Cytokines; Folic Acid; HMGB1 Protein; Humans; Immunity, Innate; Inflammation; Matrix Metalloproteinases; Methotrexate; NF-kappa B; Polyamines; Prostaglandins; Reactive Oxygen Species
PubMed: 31658782
DOI: 10.3390/ijms20205023 -
Annals of Internal Medicine Mar 2020Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred.
OBJECTIVE
To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo.
DESIGN
Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333).
SETTING
North America.
PARTICIPANTS
Adults with known cardiovascular disease and diabetes or metabolic syndrome.
INTERVENTION
Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week.
MEASUREMENTS
Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication.
RESULTS
After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]).
LIMITATION
The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period.
CONCLUSION
Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased.
PRIMARY FUNDING SOURCE
National Institutes of Health.
Topics: Aged; Antirheumatic Agents; Cardiovascular Diseases; Double-Blind Method; Female; Humans; Male; Methotrexate; Middle Aged; Placebos; Prospective Studies
PubMed: 32066146
DOI: 10.7326/M19-3369 -
Clinical Medicine (London, England) Sep 2019The chikungunya virus (CHIKV) infection epidemic has emerged as a significant public health concern in the last 10-15 years, especially in Asian and south American... (Review)
Review
The chikungunya virus (CHIKV) infection epidemic has emerged as a significant public health concern in the last 10-15 years, especially in Asian and south American countries. However, with ever-expanding tourism and migration, cases have now been reported in north America and Europe. CHIKV infection predominantly causes musculoskeletal symptoms with a chronic polyarthritis which may resemble autoimmune inflammatory arthritis. CHIKV infection should always be suspected in a returning traveller presenting with fever, skin rash and arthralgia. Though first reported in the last century, a series of epidemics since 2004 have substantially improved our knowledge. There has also been a significant increase in our understanding of the immunopathogenesis of chikungunya infection. This knowledge is being used in the development of new treatment strategies and preventive measures. In this narrative review, we discuss some of the recent advances in the epidemiology, immunopathogenesis, and management of CHIKV arthritis.
Topics: Antiviral Agents; Arthritis, Infectious; Chikungunya Fever; Chikungunya virus; Chronic Disease; Humans; Methotrexate
PubMed: 31530685
DOI: 10.7861/clinmed.2019-0035 -
RMD Open Oct 2021In SELECT-PsA 1, a randomised double-blind phase 3 study, upadacitinib 15 mg and 30 mg were superior to placebo and non-inferior to adalimumab in ≥20% improvement... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In SELECT-PsA 1, a randomised double-blind phase 3 study, upadacitinib 15 mg and 30 mg were superior to placebo and non-inferior to adalimumab in ≥20% improvement in American College of Rheumatology (ACR) criteria at 12 weeks in patients with psoriatic arthritis (PsA). Here, we report 56-week efficacy and safety in patients from SELECT-PsA 1.
METHODS
Patients received upadacitinib 15 mg or 30 mg once daily, adalimumab 40 mg every other week for 56 weeks or placebo through week 24 switched thereafter to upadacitinib 15 mg or 30 mg until week 56. Efficacy endpoints included the proportion of patients achieving ≥20%/50%/70% improvement in ACR criteria (ACR20/50/70), ≥75%/90%/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), minimal disease activity (MDA) and change from baseline in modified total Sharp/van der Heijde Score. Treatment-emergent adverse events per 100 patient years (PY) were summarised.
RESULTS
Consistent with results through week 24, ACR20/50/70, PASI75/90/100 and MDA responses were maintained with upadacitinib through week 56 and were generally numerically higher than with adalimumab; inhibition of radiographic progression was also maintained. Patients who switched from placebo to upadacitinib exhibited comparable improvements at week 56 as patients originally randomised to upadacitinib. The rates of serious adverse events were 9.1 events/100 PY with upadacitinib 15 mg and 12.3 events/100 PY with upadacitinib 30 mg. Two deaths were reported in each of the upadacitinib groups.
CONCLUSION
Efficacy across various domains of PsA were maintained with upadacitinib 15 mg and 30 mg through week 56 with no new safety signals observed.
Topics: Antirheumatic Agents; Arthritis, Psoriatic; Heterocyclic Compounds, 3-Ring; Humans; Methotrexate
PubMed: 34663636
DOI: 10.1136/rmdopen-2021-001838 -
British Journal of Clinical Pharmacology May 2022A lot of medication risks related to high-dose methotrexate (HDMTX) therapy still remain to be identified and standardized. This study aims to establish an...
AIMS
A lot of medication risks related to high-dose methotrexate (HDMTX) therapy still remain to be identified and standardized. This study aims to establish an evidence-based practice guideline for individualized medication of HDMTX.
METHODS
The practice guideline was launched by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. The guideline was developed following the WHO handbook for guideline development and the methodology of evidence-based medicine (EBM). The guideline was initially registered in the International Practice Guidelines Registry Platform (IPGRP-2017CN021). Systematic reviews were conducted to synthesize available evidence. A multicentre cross-sectional study was conducted using questionnaires to evaluate patients' perception and willingness concerning individualized medication of HDMTX. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence and to grade the strength of recommendations.
RESULTS
Multidisciplinary working groups were included in this guideline, including clinicians, pharmacists, methodologists, pharmacologists and pharmacoeconomic specialists. A total of 124 patients were involved to integrate patient values and preferences. Finally, the guideline presents 28 recommendations, regarding evaluation prior to administration (renal function, liver function, pleural effusion, comedications, genetic testing), pre-treatment and routine dosing regimen, therapeutic drug monitoring (necessity, method, timing, target concentration), leucovorin rescue (initial timing, dosage regimen and optimization), and management of toxicities. Of these, 12 are strong recommendations.
CONCLUSIONS
We developed an evidence-based practice guideline with respect to HDMTX medication using a rigorous and multidisciplinary approach. This guideline provides comprehensive and practical recommendations involving the whole process of HDMTX administration to health care providers.
Topics: China; Cross-Sectional Studies; Drug Monitoring; Evidence-Based Medicine; Humans; Methotrexate
PubMed: 34729817
DOI: 10.1111/bcp.15134