From the Guidelines
Leflunomide should be used with caution in patients at risk of gastrointestinal bleeding, and if a GI bleed occurs, the medication should be discontinued immediately and appropriate medical attention sought. Leflunomide can potentially increase the risk of gastrointestinal bleeding, particularly in patients with pre-existing risk factors, such as a history of peptic ulcer disease, concurrent use of NSAIDs, corticosteroids, or anticoagulants 1. Symptoms of GI bleeding may include black tarry stools, bright red blood in vomit or stool, abdominal pain, and dizziness or lightheadedness. To reduce the risk of GI bleeding while on leflunomide, patients should take the medication with food, avoid alcohol, and consider gastroprotective agents like proton pump inhibitors if they have risk factors. The mechanism behind leflunomide-associated GI bleeding involves its inhibition of pyrimidine synthesis and potential effects on the mucosal lining of the GI tract 1. Regular monitoring of hemoglobin levels and stool occult blood testing may be warranted in high-risk patients. According to the American College of Gastroenterology practice guidelines, overt GI bleeding refers to patients who present with melena or hematochezia with a source of bleeding that is identified, and occult GIB is defined as patients who present with iron-deficiency anemia with or without guaiac-positive stools who are found to have a source of bleeding 1. If severe bleeding occurs, cholestyramine washout (8g three times daily for 11 days) can be used to rapidly eliminate leflunomide from the body.
Some key points to consider when managing patients on leflunomide who are at risk of GI bleeding include:
- Aggressive volume resuscitation and maintenance of hemodynamic stability are the first priorities in patients presenting with substantial UGIB 1
- Upper endoscopy and video capsule endoscopy (VCE) are important diagnostic techniques in the investigation of UGIB, with endoscopy being the most appropriate in this clinical scenario 1
- Patients with a history of peptic ulcer disease, concurrent use of NSAIDs, corticosteroids, or anticoagulants are at higher risk of GI bleeding while on leflunomide 1
- Regular monitoring of hemoglobin levels and stool occult blood testing may be warranted in high-risk patients 1
From the Research
Leflunomide and Gastrointestinal Bleeding
- There is no direct evidence in the provided studies that links leflunomide to gastrointestinal (GI) bleeding 2, 3, 4, 5, 6.
- However, the study by 6 mentions that new GI complaints were more common with methotrexate compared to leflunomide, suggesting that leflunomide may have a lower risk of GI side effects.
- Another study 5 reports cases of severe infections, including abdominal sepsis and gastroenteritis, in patients taking leflunomide, but these cases were often associated with concomitant use of corticosteroids or methotrexate.
Management of GI Bleeding
- The European Society of Gastrointestinal Endoscopy (ESGE) guidelines 3 recommend an initial assessment of patients presenting with acute lower GI bleeding, including a history of co-morbidities and medications that promote bleeding.
- The guidelines also recommend a restrictive red blood cell transfusion strategy in hemodynamically stable patients with acute lower GI bleeding and no history of cardiovascular disease.
- In patients with major acute lower GI bleeding, colonoscopy should be performed sometime during their hospital stay, and computed tomography angiography may be used to locate the site of bleeding in patients with hemodynamic instability.
Leflunomide Safety Profile
- The study by 2 reports that the most common adverse events associated with leflunomide were diarrhea, respiratory infections, nausea, headache, rash, increased serum hepatic aminotransferases, dyspepsia, and alopecia.
- Monitoring of serum hepatic enzyme levels is recommended in patients receiving leflunomide 2.
- The study by 6 found that leflunomide was linked to a greater increase in liver enzymes compared to methotrexate.