What is the risk of gastrointestinal (GI) bleeding associated with Methotrexate (MTX) therapy?

From the Guidelines

Methotrexate should be immediately discontinued in patients who develop a GI bleed, and urgent medical attention should be sought to manage the bleeding and prevent further complications. The management of GI bleeding in patients on methotrexate includes fluid resuscitation, blood transfusion if necessary, and endoscopic evaluation to identify and treat the bleeding source 1. Methotrexate causes GI bleeding through direct mucosal injury and by inhibiting folate metabolism, which impairs cell division and repair in the GI tract. Patients with pre-existing GI conditions, those taking NSAIDs concurrently, or those with renal impairment are at higher risk of GI bleeding while on methotrexate 1.

Some key points to consider in the management of methotrexate-induced GI bleeding include:

• The importance of prompt recognition and treatment of GI bleeding to prevent morbidity and mortality
• The need for regular monitoring of complete blood count, liver function, and renal function to detect early signs of toxicity 1
• The potential benefits of folate supplementation in reducing the risk of GI bleeding and other adverse effects of methotrexate 1
• The consideration of alternative medications if the risk of recurrent bleeding is high

It is essential to weigh the benefits and risks of restarting methotrexate after a GI bleed, potentially at a lower dose or with added folate supplementation, and to consider alternative treatments if necessary 1. Regular monitoring and follow-up are crucial to prevent and manage potential complications associated with methotrexate use.

From the FDA Drug Label

Alimentary System - gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis The FDA drug label mentions that methotrexate can cause gastrointestinal toxicity, including gastrointestinal ulceration and bleeding, which can be a cause of GI bleed.

• Gastrointestinal ulceration and bleeding are listed as potential adverse reactions under the Alimentary System.
• The label also mentions that diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
• Additionally, unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs) 2.

From the Research

Methotrexate and Gastrointestinal Bleeding

• Methotrexate (MTX) is a folic acid antagonist used to treat various conditions, including rheumatoid arthritis, but it can cause adverse effects such as gastrointestinal mucosal injury, intestinal mucositis, bleeding, and peptic ulcers 3.
• A case study reported a rare instance of severe gastrointestinal mucosal necrosis in an 82-year-old woman after 8 years of low-dose MTX treatment, highlighting the importance of monitoring patients for potential drug-induced adverse effects 3.
• While MTX can cause gastrointestinal bleeding, the overall incidence of this adverse effect is not well-established in the provided studies.

Gastrointestinal Bleeding in General

• Acute gastrointestinal bleeding is a common and potentially life-threatening condition that requires prompt diagnosis, risk assessment, and management 4.
• The goals of care for gastrointestinal bleeding include preventing end-organ injury, managing comorbid illnesses, identifying the source of bleeding, stopping continued bleeding, supporting oxygen-carrying capacity, and preventing rebleeding 4.
• Other studies have investigated the risk of gastrointestinal bleeding in patients with severe sepsis or septic shock, but these studies focused on the use of proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) for stress ulcer prophylaxis, rather than MTX 5, 6.

Methotrexate Safety and Toxicity

• Methotrexate has been shown to be effective in the long-term treatment of various conditions, but its chronic administration can raise concerns about safety 7.
• Serious side effects of MTX include hepatic, hematologic, and pulmonary toxicity, which can be minimized or prevented with careful monitoring of patients' symptoms and laboratory tests 7.
• However, the provided studies do not establish a clear link between MTX and gastrointestinal bleeding, and more research is needed to fully understand the risks associated with MTX treatment 3, 7.