From the Guidelines
Leflunomide should be immediately discontinued in patients who experience a gastrointestinal (GI) bleed, and aggressive management including fluid resuscitation, blood transfusions if needed, and acid suppression therapy with proton pump inhibitors should be initiated. The risk of GI bleed with leflunomide is a significant concern, particularly in patients with pre-existing risk factors, as it can increase the risk of morbidity and mortality 1. According to the guidelines for nonvariceal upper gastrointestinal bleeding, aggressive volume resuscitation and maintenance of hemodynamic stability are the first priorities in managing UGIB 1.
Management of Leflunomide-Induced GI Bleed
- Discontinue leflunomide immediately in patients who experience a GI bleed
- Initiate aggressive management including fluid resuscitation, blood transfusions if needed, and acid suppression therapy with proton pump inhibitors
- Consider cholestyramine washout therapy (8g three times daily for 11 days) to rapidly eliminate leflunomide from the body, as its active metabolite has a long half-life of 1-4 weeks
- After resolution, alternative disease-modifying antirheumatic drugs should be considered based on the patient's underlying condition, and if leflunomide must be restarted, gastroprotective agents should be co-prescribed and regular monitoring implemented.
Risk Factors for GI Bleed with Leflunomide
- Pre-existing gastrointestinal conditions, such as ulcers or erosive gastritis
- Concomitant use of NSAIDs, corticosteroids, or anticoagulants
- Advanced age
- History of gastrointestinal bleeding
The guidelines for the management of psoriasis and psoriatic arthritis with traditional systemic agents, including leflunomide, highlight the potential toxicities of leflunomide, including gastrointestinal irritation, elevated liver enzymes, leukopenia, increased risk of infections, and teratogenicity 1. However, the most recent and highest quality study on nonvariceal upper gastrointestinal bleeding provides the best guidance on managing GI bleed in patients taking leflunomide 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.
- The study by 6 found that leflunomide was linked to a greater increase in liver enzymes, but there were fewer GI complaints compared to methotrexate.
- Overall, the safety profile of leflunomide suggests that it is generally well-tolerated, but monitoring of serum hepatic enzyme levels is recommended, and the drug is not recommended in female patients who are or may become pregnant 2.