In a patient with sickle cell disease on hydroxyurea who has developed bilateral 1 cm soft, movable, warm nodules over the knees, what is the most likely diagnosis and recommended management?

Hydroxyurea-Induced Leg Ulcers

These bilateral knee nodules are most likely hydroxyurea-induced cutaneous vasculitic toxicities or early leg ulcers, and you should discontinue hydroxyurea immediately and refer to a sickle cell specialist for alternative disease-modifying therapy. 1

Diagnosis

The clinical presentation of bilateral, soft, movable, warm 1 cm nodules over the knees in a sickle cell patient on hydroxyurea is highly concerning for cutaneous vasculitic toxicities associated with hydroxyurea therapy. The FDA drug label explicitly warns that "cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea" 1. While this warning was initially documented in myeloproliferative disorders, the same mechanism applies to sickle cell disease patients.

Key Distinguishing Features to Assess:

• Warmth and tenderness: Suggests active inflammatory/vasculitic process rather than simple sickle cell ulceration
• Bilateral distribution: More consistent with drug-induced vasculitis than typical sickle cell ulcers (which are usually unilateral and over malleoli)
• Soft and movable: Early stage before full ulceration develops
• Location over knees: Hydroxyurea-induced ulcers can occur at various sites, not just the typical malleolar region of sickle cell ulcers

Immediate Management

Discontinue hydroxyurea immediately. The FDA label states: "If cutaneous vasculitic ulcers occur, institute treatment and discontinue hydroxyurea capsules" 1. This is non-negotiable given the risk of progression to disabling ulcers or gangrene.

Specific Steps:

1. Stop hydroxyurea now - do not wait for biopsy confirmation
2. Wound care: Keep areas clean, apply non-adherent dressings, avoid trauma
3. Pain management: NSAIDs or opioids as needed for pain control
4. Monitor for progression: Daily assessment for ulceration, necrosis, or expansion
5. Refer urgently to sickle cell specialist within 1-2 weeks for alternative disease-modifying therapy options

Critical Context from Evidence

Research shows that 29% of sickle cell patients on hydroxyurea develop leg ulcers 2, which is substantially higher than the 9% rate in myeloproliferative disorders. The risk factors identified include:

• Previous history of sickle cell ulcers (80% of those who developed hydroxyurea-induced ulcers had prior SCD ulcers vs 0% without) 2
• Older age (mean age 35.8 years with ulcers vs 23.5 years without) 2
• Duration of therapy (mean 3 years of treatment in affected patients) 2

The mechanism involves hydroxyurea acting synergistically with underlying vascular abnormalities in sickle cell disease, creating a "double hit" to the microvasculature 2.

Alternative Disease-Modifying Therapy

Once hydroxyurea is discontinued, the patient will need alternative therapy to prevent sickle cell complications. According to the 2025 NASCC guidelines, "options for disease modifying therapy in SCD and for participating in clinical research studies if available should be reviewed" 3. Options include:

• Voxelotor (if available in your region)
• Crizanlizumab
• L-glutamine
• Chronic transfusion therapy
• Gene therapy or bone marrow transplant (in select cases)

Common Pitfalls to Avoid

1. Do not continue hydroxyurea "to see if it gets better" - progression to disabling ulcers is well-documented and can be severe
2. Do not assume these are simple sickle cell ulcers - the bilateral presentation and warmth suggest drug-induced vasculitis
3. Do not delay specialist referral - the patient needs alternative disease-modifying therapy to prevent sickle cell complications after stopping hydroxyurea
4. Do not restart hydroxyurea later - these vasculitic toxicities are a contraindication to future use

The FDA explicitly states that hydroxyurea is a "human carcinogen" and warns about multiple serious cutaneous toxicities 1. Given the 40% mortality reduction with disease-modifying therapy in sickle cell disease 3, transitioning to an alternative agent is essential for this patient's long-term survival and quality of life.