Singapore Dermatologist Suspended After Patient Hospitalised From Immunosuppressant Use

A Singapore dermatologist has been suspended for 14 months after a patient was hospitalised from a rare but serious reaction to azathioprine, an immunosuppressant prescribed for a persistent skin rash.

What happened?

In April 2020, the patient consulted Dr Khoo Boo Peng at Naaman Skin and Laser Centre for a rash he had for eight months. Dr Khoo diagnosed him with prurigo nodules or papules, a chronic, itchy skin condition, and initially treated him with a steroid injection.

Approximately two weeks later, the patient was prescribed a combination of cyclosporin and methotrexate when the rash persisted. By June 2020, the symptoms returned. This time, Dr Khoo switched the patient to azathioprine (2 mg/kg per day) and prednisolone, a corticosteroid.

Within two weeks, the patient reported swelling, darkened skin, hair loss and mouth sores. Dr Khoo initially attributed these to steroid-related fluid retention and did not stop azathioprine until repeated email updates showed worsening symptoms.

The patient was eventually hospitalised for 10 days and diagnosed with pancytopenia, a dangerous drop in blood cells caused by bone marrow suppression. It is a known but rare complication of azathioprine in patients who cannot metabolise the drug properly.

The Singapore Medical Council (SMC) found that Dr Khoo failed to:

1. Explain the risks of azathioprine to the patient,
2. Arrange mandatory blood tests to check for early toxicity, and
3. Screen for metaboliser status before prescribing a high dose

He later pleaded guilty to two counts of professional misconduct.

This might seem like an extreme reaction for a rash, so what exactly was the skin condition the patient had, and why was such a strong drug prescribed? How did things go so wrong? Let’s take a closer look.

What are Prurigo Nodules?

Prurigo refers to a reactive skin disease characterised by prurigo papules or nodules. Prurigo nodules, also called prurigo nodularis, are hard, intensely itchy bumps that develop on the skin due to repeated scratching or rubbing.

They are often found on the arms, legs, or trunk and can significantly affect sleep and quality of life.

The condition is linked to an itch–scratch cycle: scratching worsens inflammation, which in turn creates more itching and nodules. It is often associated with eczema, psoriasis, liver or kidney disease, and sometimes systemic conditions like thyroid disorders or HIV.

What is Azathioprine?

Azathioprine is an immunosuppressive medication. It is used to calm overactive immune responses in:

• Severe eczema or prurigo nodularis
• Autoimmune diseases (e.g. lupus, rheumatoid arthritis)
• Inflammatory bowel disease (Crohn’s disease, ulcerative colitis)
• Organ transplant patients to prevent rejection

How Does the Body Process Azathioprine?

The body metabolises this Azathioprine into active metabolites mercaptopurine (6-MP) and thioguanine (6-TGN). These metabolites incorporate into the DNA and RNA of immune cells, disrupting their proliferation and dampening the immune response.

Azathioprine metabolism depends on three key enzymes. If they do not work properly, toxic levels of azathioprine can arise.

Thiopurine methyltransferase (TPMT) converts active 6-MP into inactive metabolites. Low TPMT activity means higher levels of active compounds, which increases toxicity risk.

Xanthine oxidase (XO) converts 6-MP into inactive metabolites. Common drugs like allopurinol (used in gout) can affect this pathway and create dangerous drug-drug interactions.

In addition, Nudix hydrolase 15 (NUDT15) is an enzyme that breaks down active metabolite TGNs. Individuals with reduced enzyme activity accumulate higher levels of TGNs and face a higher risk of toxicity. This risk is especially relevant in Asian populations, where NUDT15 variants occur more often and significantly increase toxicity.

Studies show that genetic screening for high-risk NUDT15 variants reduces toxicity risk and should be used when available.

In the patient’s case, who allegedly declined testing, the doctor should adopt a cautious approach and start the patient on a lower dosage of 1mg/kg per day, to test the patient’s susceptibility to the drug.

Azathioprine Side Effects

Common side effects of the drug include nausea, vomiting, fatigue, and hair thinning.

Complications of Azathioprine use can be related to its drug toxicity:

• Bone marrow suppression – causing thrombocytopenia (decrease in platelets), leukopenia (decrease in white blood cells) and pancytopenia (decrease in platelets, white blood cells and red blood cells)
  • This can cause a range of symptoms, including fatigue, shortness of breath, dizziness, and an increased risk of infections and bleeding
• Liver injury, as the medication is metabolised by the liver
• Kidney damage, as the medication is excreted via the kidneys

In the patient’s case he experienced swelling of the lips, blisters and mouth sores. These are indications of drug toxicity, bone marrow suppression and injury to mucosal epithelial cells.

What Went Wrong in This Case?

The tribunal highlighted several lapses:

1. Dr Khoo did not perform metaboliser testing: Doctors should test patients for TPMT/NUDT15 enzyme activity before starting azathioprine.
2. He prescribed a high starting dose: When testing is declined, guidelines recommend starting at 1 mg/kg/day and increasing slowly, but Dr Khoo started the patient on 2 mg/kg/day.
3. No regular monitoring: Regular blood counts and liver tests in the first 4-6 weeks are standard to catch toxicity early. Closer monitoring could have detected the reaction sooner, preventing hospitalisation.
4. He failed to respond urgently: When the patient developed mouth sores and swelling, Dr Khoo should have stopped the drug immediately and arranged an urgent review.

For most people, rashes are harmless and easy to treat. But for stubborn conditions, treatment can become complex, and medications may carry higher risks. This is why clear communication, informed consent, and proper follow-up are all part of safe care.

External References

1. Zhou S. (2006). Clinical pharmacogenomics of thiopurine S-methyltransferase. Current clinical pharmacology, 1(1), 119–128. https://doi.org/10.2174/157488406784111627
2. Moyer A. M. (2021). NUDT15: A bench to bedside success story. Clinical biochemistry, 92, 1–8. https://doi.org/10.1016/j.clinbiochem.2021.02.007
3. Wang, C. W., Chi, M. H., Tsai, T. F., Yu, K. H., Kao, H. W., Chen, H. C., Chen, C. B., Lu, C. W., Chen, W. T., Chang, Y. C., Chang, C. J., Chang, Y. T., Jan Wu, Y. J., Chang, C. J., Huang, Y. H., Ng, C. Y., Huang, P. W., Lin, Y. J., Hui, R. C., Chung, W. H., … Taiwan/Asian Severe Cutaneous Adverse Reaction Consortium (2022). Implementation of NUDT15 Genotyping to Prevent Azathioprine-Induced Leukopenia for Patients With Autoimmune Disorders in Chinese Population. Clinical pharmacology and therapeutics, 112(5), 1079–1087. https://doi.org/10.1002/cpt.2716
4. Mohammadi O, Kassim TA. Azathioprine. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542190/