Thursday, 20 Feb 2020

You are here

Azathioprine Adverse Events Associated with TPMT Polymorphisms

Azathioprine (AZA) is widely used in the treatment of several autoimmune diseases. Its use and optimal dosing may be limited by adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in AZA metabolism.

AZA is a pro-drug that is rapidly converted into 6-mercaptopurine (6-MP) via a glutathione-dependent process. TPMT is an important cytoplasmic enzyme catalyzing the methylation of 6-MP leading to the active metabolite 6-TGN.. 

Approximately 4%-11% of individuals are heterozygous for a mutant TPMT allele and have intermediate TPMT activity. Fewer (approximately 1 in 300) will be homozygous or compound heterozygous and have very low or absent TPMT activity. Individuals with intermediate TPMT activity accumulate 50% more 6-TGNs when compared with normal or high TPMT activity and thus at increased risk of AZA-induced ADRs. Patients with deficient TPMT activity rapidly accumulate high doses of 6-TGNs, and are at risk for major bone marrow toxicity.

Although several clinical guidelines recommend determining TPMT genotype or phenotype before initiating AZA therapy, there is no consensus on this issue.  Hence, a metanalysis of 11 published studies and 651 patients with autoimmune diseases studied the associations between AZA TPMT polymorphisms and ADRs.

Of the 384 patients analyzed, 101 patients had ADRs - 14.9% of ADR+ patients were TPMT polymorphism positive and 6.4%  of the 283 no-ADR patients were TPMT polymorphisms positive. TPMT polymorphisms were significantly associated with AZA-induced overall ADRs (OR 3.12; 96%CI 1.48–6.56), bone marrow toxicity (3.76; 1.97–7.17) and gastric intolerance (6.43; 2.04–20.25). These findings were strongest in asians rather than caucasians.  TPMT polymorphisms were not associated with hepatotoxicity.

These studies included patiens with both heterozygous and homozygous TPMT polymorphisms. But, subanalyses indicated that TPMT heterosigosity was also associated with AZA-induced overall bone marrow toxicity.

While a TPMT polymorphism may be associated with an increased risk of AZA-induced ADRs, the presence of normal TPMT genotypes does not preclude the development of ADRs during AZA treatment. TPMT polymorphism explains a variable proportion of AZA-related ADRs, but in no way explain all episodes of ADRs.  Therefore, laboratory monitoring remains an essential measure to ensure AZA safety.


The author has no conflicts of interest to disclose related to this subject

Add new comment

More Like This

Overmedication of America

Recent research from the Lown Institute reports that 750 older Americans are hospitalized daily because of serious side effects from and the core problem is that of polypharmacy, especially in the elderly. 

Best of 2019 - Biologic Safety Guidelines from the British Society for Rheumatology

In the United Kingdom, NICE has looked to the British Society of Rheumatology (BSR) to develop evidence based guidance on the safe use of biologic DMARDs in patients with inflammatory arthritis. This guidance document on biologic safety covers baseline screening, monitoring, effect of co-morbidities, and when or under what circumstances biologic therapy should be interrupted.

Best of 2019 - Methotrexate and the Risk of Lung Disease

Rheumatology has a comprehensive overview of methotrexate (MTX) and the risk of lung injury, MTX-related pneumonitis and interstitial lung disease (RA-ILD) with rheumatoid arthritis (RA). Past reports suggest the frequence of MTX-pneumonitis to be between 0.3 and 11.6%; recent studies suggest it may be much lower.

No Cancer Risk with Systemic Necrotizing Vasculitis

The French Vasculitis Study Group has published that patients with systemic necrotizing vasculitis do not have an increased risk of malignancy; in fact they have a risk that is similar to the general population.

Previous reports have suggested either no risk or a declining risk in the era of better therapies for vasculitis. 

FDA Warns 15 CBD Manufacturers

Today, the U.S. Food and Drug Administration issued warning letters to 15 companies for illegally selling products containing cannabidiol (CBD) in ways that violate the Federal Food, Drug, and Cosmetic Act (FD&C Act).  This warning affirms that the FDA has not determined the many preparations of cannabidiol to be safe or effective.