Overview                                                          

Tumour Necrosis Factor alpha (TNFα) inhibitors have been used in the treatment of chronic inflammatory diseases such as rheumatoid arthritis and Crohn’s disease.¹ As TNFα is naturally crucial in mediating the inflammatory response at physiological levels, the inhibition of TNFα may lead to an increased risk of severe infections or malignancies.

Kaposi’s sarcoma (KS) is an angioproliferative disorder of endothelial and immune cells which are infected with human herpes virus type 8 (HHV-8), also known as Kaposi’s Sarcoma herpes virus (KSHV).^2,3

According to the aetiology, KS is classified into four (4) types:

• Classic KS, which typically presents in middle-aged or old patients;
• Endemic KS, which are prominently occurring in sub-Saharan indigenous Africans;
• Iatrogenic KS, which is associated with immunosuppressant therapy and among the organ transplant recipients;
• Epidemic KS, which is associated with acquired immune deficiency syndrome (AIDS).^3,4

Background of the safety issue

In August 2020, the National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) on the risk of Kaposi’s sarcoma associated with TNFα inhibitors.⁵ 

The signal of Kaposi’s sarcoma was initially identified for infliximab, based on the five (5) case reports of KS identified in the Spanish national database. After considering all available evidence from case reports and literature, EMA extended the scope of analysis and evaluation to other TNFα inhibitors such as adalimumab, etanercept, certolizumab and golimumab.⁶ 

Following EMA’s safety review, it was concluded that the risk of Kaposi’s sarcoma is applicable to all TNFα inhibitors and that the information related to Kaposi’s sarcoma should be added into all TNFα inhibitors’ package inserts. 

Adverse Drug Reaction (ADR) Reports: 

NPRA has received 314 ADR reports with 556 adverse events suspected to be related to TNFα inhibitors. There were 63 infection-related adverse events such as tuberculosis (25) and pneumonia (10). However, no event related to Kaposi’s sarcoma has been reported locally for all TNFα Inhibitors.⁷  

Advice for Healthcare Professionals: 

• Be alert on the risk of Kaposi’ sarcoma associated with the use of TNFα inhibitors.
• Please report all adverse events suspected to be related to the use of TNFα inhibitors to NPRA.

References

1. Cohen CD., Horster S., Sander CA., Bogner JR. Kaposi’s sarcoma a.ssociated with tumour necrosis factor a neutralising therapy. Ann Rheum [Internet]. 2003 [Cited 2020 September 17]; 62(7):684. Available from: https://www.pubmed.ncbi.nlm.nih.gov/12810439/
2. Jessica K. Kaposi Sarcoma [Internet]. Medscape; 2019 [updated 2019 April 11]. Available from: https://emedicine.medscape.com/article/279734-overview.
3. Yusuf K., Sercan A., Ibrahim G. Kaposi’s Sarcoma epidemiology, risk factors, staging and treatment: an overview. Acta Oncologica Turcica [Internet]. 2017 [Cited 2020 September 17]; 50(2):148-159. Available from: https://www.journalagent.com/aot/pdfs/AOT_50_2_148_159.pdf.
4. Susan EK., Jasmeet CS. Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment [Internet]. UpToDate. 2019 April 1 [Cited on 2020 September 17]. Available from https://www.uptodate.com/contents/classic-kaposi-sarcoma-epidemiology-risk-factors-pathology-and-molecular-pathogenesis?%20topicRef=7729&source=see_link
5. European Medicines Agency (EMA). PRAC recommendations on signals. 2020 August 3 [Cited 2020 September 17]. EMA/PRAC/367621/2020
6. European Medicines Agency (EMA). Minutes of PRAC meeting on 28-31 October 2019: [Internet]. 2019 November 28 [Cited 2020 September 17]. EMA/PRAC/107813/2020
7. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2020 [Cited 2020 September 17]. Available from: https://www.npra.gov.my