Genetic Testing For Allopurinol And The Risk Of Severe Skin Reactions

Gail asked

My husband has been put on allopurinol for gout. His genetic profile from 23andMe and reported through Promethease shows he has an SNP and is positive for the HLA-B*5801 allele. According to the website, the HLA-B*5801 allele is a genetic marker that may put him more at risk for severe cutaneous adverse reactions caused by allopurinol. Should he be taking the drug?

Answer

This is a great question, but unfortunately, there is no simple or concrete answer.

It requires a discussion of the relatively new field of 'pharmacogenomics', and how someone's genetic profile can be utilized to find (or avoid) drugs that may be especially beneficial or potentially harmful. Using someone's genetic profile to determine drug therapy is sometimes referred to as 'personalized medicine'.

Although I say this is a relatively new field, there are a number of drugs that have detailed pharmacogenomic information in their FDA-approved labeling. Some drugs even require genetic tests before they are prescribed.

One such drug is Herceptin, which is used to treat certain forms of cancer. Patients should undergo genetic testing to ensure they express a certain protein, known as HER2. If they do not have that protein, the drug would likely be ineffective.

If you are interested in which drugs have pharmacogenomic information published in their drug labeling (i.e. prescribing information), a full table can be found on the FDA website.

Concerning allopurinol, the FDA provides no guidance on it in regard to genetic testing, but there is a fairly strong link between a certain generic factor in some populations and the risk of rare, but serious skin reactions.

Allopurinol Pharmacogenomics

There is fairly extensive information published regarding how a variant allele (a form of a gene) of the human leukocyte antigen (HLA)-B, known as HLA-B*58:01, is an indicator of allopurinol-induced severe skin reactions.

These skin reactions include:

• Toxic epidermal necrolysis
• Exfoliative lesions
• Stevens-Johnson Syndrome

All of these skin reactions are known as SCARs, or severe cutaneous adverse reactions. They are not common (<0.5% incidence rate) but are extremely serious if they do occur. In fact, the mortality rate of toxic epidermal necrolysis alone is around 25%.

In 2013, and even before then, research began to emerge that individuals with certain genetic factors (e.g. those with HLA-B*58:01 as discussed above) are at a higher risk of these serious reactions versus those who do not have this variant allele.

While the FDA doesn't provide any pharmacogenetic guidance for allopurinol specifically, other reputable organizations do.

Recommendations

One such organization, CPIC (Clinical Pharmacogenetics Implementation Consortium), which is not part of the FDA but provides clinical guidance based on evidence-based scientific research, has published fairly extensive guidelines on allopurinol use in those with the variant allele in question, HLA-B*58:01 (sometimes referred to as HLA-B*5801). Those guidelines can be found here.

CPIC makes a strong recommendation for avoiding allopurinol in those with HLA-B*58:01:

"...given the high specificity for allopurinol-induced SCAR, allopurinol should not be prescribed to patients who have tested positive for HLA-B*58:01. Alternative medication should be considered for these patients to avoid the risk of developing SCAR. For patients who have tested negative, allopurinol may be prescribed as usual."

This recommendation is based on data collected from numerous studies showing that those who experienced allopurinol-induced SCARs are far more likely to have the HLA-B*58:01 allele.

In one such study, every individual who had an allopurinol-included SCAR had the variant allele, and in another, close to 80% had it.

The CPIC guidelines do include the caveat that there are likely numerous other factors at play in allopurinol-induced SCAR cases (e.g. ethnicity and kidney function) and that the majority of individuals carrying the allele will not develop a SCAR when taking allopurinol.

Having the HLA-B*58:01 allele likely only increases your risk of a SCAR occurring (which is small, to begin with). It absolutely doesn't mean that you will experience a SCAR.

It is important to remember that the recommendations from CPIC are not in the FDA-approved labeling for allopurinol.

In fact, the FDA has released a number of warnings to consumers regarding the dangers of utilizing unapproved genetic tests to enhance drug therapy. One such warning states the following:

"The FDA is alerting patients and health care providers that claims for many genetic tests to predict a patient's response to specific medications have not been reviewed by the FDA, and may not have the scientific or clinical evidence to support this use for most medications. Changing drug treatment based on the results from such a genetic test could lead to inappropriate treatment decisions and potentially serious health consequences for the patient."

Now, even though the FDA isn't yet on board with genetic testing for allopurinol, as discussed in the sections above, there is pretty good evidence that genetic testing can be of great benefit in potentially avoiding serious skin reactions.

Similar to the CPIC guidelines, the American College of Rheumatology, in their guidelines for the treatment of gout, recommends considering testing for HLA-B*58:01 in certain populations. They do not recommend universal testing.

They recommend considering testing only in certain high-risk risk populations, such as Koreans with chronic kidney disease since nearly all studies have shown that Asian populations are more at risk (specifically Thai, Han Chinese, and Koreans). There isn't as strong a correlation with Caucasians.

Final Words

The study of pharmacogenomics and how drug therapy can be optimized is still in its early stages.

While we have fairly comprehensive data on some drugs and are confident that genetic testing is of great value, a lot of research and testing still needs to be done.

In the case of allopurinol, there is strong evidence that expressing HLA-B*58:01 is correlated to an increased risk of severe skin reactions but we also know there are other factors at play (e.g. ethnicity, kidney function, etc...).

Even with the benefit of knowing your genetic testing results, it is important to not alter your drug therapy without first speaking to your doctor. They can help you sort through all of the information available pertaining to your medical situation and can adjust therapy as appropriate.

Fortunately, if it is decided that you should try an alternative therapy, there are many other options available for managing gout.