Can missing a dose of leflunomide (disease-modifying antirheumatic drug (DMARD)) cause edema?

Missing Leflunomide and Edema: No Direct Relationship

Missing a dose of leflunomide does not cause edema, as there is no evidence in the medical literature establishing edema as a withdrawal effect from leflunomide discontinuation or missed doses. 1

Understanding Leflunomide's Pharmacology

Leflunomide is a conventional synthetic disease-modifying antirheumatic drug (csDMARD) used in the treatment of rheumatoid arthritis and other inflammatory conditions. Its key characteristics include:

• Long half-life of approximately 2 weeks, which means missing a single dose is unlikely to cause sudden physiological changes 2
• Acts by inhibiting dihydroorotate dehydrogenase, an enzyme critical in the production of pyrimidines, thereby affecting activated lymphocyte proliferation 3, 4
• Typically administered at 20mg once daily after an initial loading dose 2

Known Side Effects of Leflunomide

Leflunomide has several documented adverse effects, but edema is not prominently listed among them:

• Common side effects include diarrhea (27%), respiratory infections (21%), nausea (13%), headache (13%), rash (12%), elevated liver enzymes (10%), and alopecia (9%) 2
• More serious but rare adverse events include:
  • Severe skin reactions such as erythema multiforme-like eruptions 5
  • Increased risk of infections, including pulmonary abscess 6
  • Potential hepatotoxicity requiring monthly monitoring of liver enzymes 3

Effects of Missing Doses

When considering missed doses of leflunomide:

• Due to its long half-life (approximately 2 weeks), missing a single dose is unlikely to cause immediate physiological changes or withdrawal symptoms 2
• The 2021 ACR guidelines for rheumatoid arthritis do not mention edema as a consequence of leflunomide discontinuation or missed doses 1
• The guidelines recommend consistent use of DMARDs including leflunomide for optimal disease control, but do not highlight specific withdrawal effects 1

Clinical Implications

For patients on leflunomide therapy:

• If edema occurs in a patient taking leflunomide, clinicians should investigate other potential causes rather than attributing it to missed doses 1
• Patients should be advised to take their missed dose as soon as they remember unless it's almost time for the next dose 3
• Regular monitoring should focus on known adverse effects such as liver function abnormalities rather than edema 3, 2

Important Considerations

• Abrupt discontinuation of leflunomide may require cholestyramine washout in certain situations (e.g., pregnancy planning, severe adverse reactions), but this is not related to edema concerns 2
• If edema develops in patients with rheumatoid arthritis, it's more likely related to the underlying disease activity, cardiovascular comorbidities, or other medications rather than missed leflunomide doses 1