Can leflunomide cause foot pain?

Leflunomide and Foot Pain: A Potential Side Effect

Yes, leflunomide can cause foot pain, particularly through peripheral neuropathy, which is a recognized adverse effect of this medication. 1 This side effect should be carefully monitored in patients taking leflunomide for rheumatoid arthritis or psoriatic arthritis.

Mechanism and Presentation

Leflunomide is a disease-modifying antirheumatic drug (DMARD) that works as an immunomodulator by inhibiting pyrimidine synthesis. When it causes foot pain, this typically manifests as:

• Peripheral neuropathy with symptoms including:
  • Paresthesias (tingling, burning sensations)
  • Dysesthesia (abnormal sensations)
  • Progressive decrease in muscle strength
  • Hyporeflexia (decreased reflexes)

Risk Factors for Developing Neuropathy

Patients with the following characteristics are at higher risk for developing peripheral neuropathy while on leflunomide:

• Older age (mean age of neuropathy cases: 69 years vs. 54 years in non-affected patients) 1
• Pre-existing diabetes mellitus (30% of neuropathy cases vs. 2.9% of non-affected patients) 1
• Concurrent use of other potentially neurotoxic medications (20% of neuropathy cases vs. 1.9% of non-affected patients) 1
• Having at least one risk factor (diabetes or neurotoxic drugs) increases the risk substantially (50% of neuropathy cases vs. 4% of non-affected patients) 1

Monitoring and Management

For patients on leflunomide experiencing foot pain:

1. Evaluate for peripheral neuropathy through nerve conduction studies
2. Consider discontinuation if neuropathy is confirmed and attributable to leflunomide
3. Consider cholestyramine washout to accelerate drug elimination, although this may not always improve established neuropathy 2
4. Monitor closely for worsening symptoms

Other Relevant Side Effects of Leflunomide

According to the American Academy of Dermatology guidelines, common side effects of leflunomide include:

• Gastrointestinal symptoms (diarrhea, nausea, loss of appetite) 3
• Weight loss 3
• Headache and dizziness 3
• Liver enzyme elevations 3
• Hematologic abnormalities (rare reports of pancytopenia, agranulocytosis, and thrombocytopenia) 3

Clinical Implications

While foot pain is not specifically listed among the most common side effects in major guidelines, the evidence from pharmacoepidemiological studies clearly indicates that peripheral neuropathy affecting the lower extremities can occur with leflunomide treatment. This is particularly important in patients with pre-existing risk factors.

Monitoring Recommendations

The American Academy of Dermatology recommends:

• Monthly complete blood count with differential and liver function tests for the first 6 months
• Every 6-8 weeks monitoring thereafter 3, 4
• Additional neurological assessment should be considered in patients reporting foot pain or other neuropathic symptoms

Important Caveats

• Peripheral neuropathy may not always be reversible after discontinuation
• Patients with diabetes should have electrophysiological studies before starting leflunomide 2
• The presence of foot pain should prompt thorough neurological evaluation rather than immediate attribution to leflunomide, as other causes may coexist

In summary, while leflunomide is an effective treatment for rheumatoid arthritis and psoriatic arthritis, clinicians should remain vigilant about the potential development of peripheral neuropathy manifesting as foot pain, particularly in patients with pre-existing risk factors.