Discussion
Principal Findings
Our results indicate that screening Han Chinese patients for HLA-B*58:01 allele before initiating allopurinol treatment, and then withholding allopurinol from those who carry the allele would likely reduce the incidence of allopurinol induced SCARs. In the present study, adverse cutaneous reactions (including oral lesions and rash) that developed in the participants were mild, transient, and localised. In addition, under continuous and systematic monitoring of dermatological symptoms, many HLA-B*58:01 negative patients with transient and mild skin lesions resumed taking allopurinol without a recurrence of symptoms.
We did not identify any participants with SCARs, which indicates that the incidence of allopurinol induced SCARs in HLA-B*58:01 negative patients is quite low. So far, all study participants have been followed up for at least nine months, and no cases of SCARs have been reported. Hence, in this cohort, the incidence of SCARs at two month follow-up is the same as the incidence after nine months. Moreover, we attempted to identify SCARs in our prospective cohort by searching Taiwan's National Health Insurance research database using the unique identification numbers of individual Taiwanese patients; no SCARs were identified by this approach. Therefore, occurrence of allopurinol induced SCARs could be successfully prevented by the use of a genetic screening protocol.
Our results lend support to the use of HLA-B*58:01 screening to prevent allopurinol induced SCARs. However, as for any new pharmacogenomic test, the use and safety of any alternative drug treatments must be documented. Of 569 HLA-B*58:01 carriers in the present study, 354 (62%) were given alternative treatment, whereas the other carriers continued to take their prestudy medication (such as colchicine and non-steroidal anti-inflammatory drugs). Among the 354 HLA-B*58:01 carriers treated with an alternative drug, the only symptom documented during the two month follow-up was mild, transient rash in three (1%) participants.
Implications for Clinical Practice
In addition to the safety benefit to patients, HLA-B*58:01 screening could also be considered a cost effective intervention. Many medical societies worldwide, including the American College of Rheumatology, currently recommend the use of a xanthine oxidase inhibitor with either allopurinol or febuxostat as first line treatment for hyperuricaemia. Benzbromarone is a uricosuric compound that has been used to control hyperuricaemia. It is effective in lowering levels of serum uric acid, especially in patients with low urate excretion. However, benzbromarone has a risk of severe hepatotoxicity as well as acute renal colic, and the drug has been withdrawn from the market or has not been available in some countries (including the United States and some European countries). These are the main reasons why benzbromarone or other uricosuric compounds have not been given to all patients with gout.
There are two potential treatment strategies against gout, which have identical therapeutic efficacy but different costs for government and society. One strategy is global substitution of allopurinol with the new xanthine oxidase inhibitor, febuxostat; the other is to use allopurinol for patients who are HLA-B*58:01 negative and substitute allopurinol with febuxostat in patients who are HLA-B*58:01 positive.
Recently, cost effectiveness analyses carried out in Thai and Korean populations suggested that HLA-B*58:01 testing is a more cost effective measure than global substitution of febuxostat for allopurinol. Because the negative predictive value of HLA-B*58:01 for allopurinol induced SCARs is 100%, the risk of developing allopurinol induced SCARs among HLA-B*58:01 negative patients would be very low. In view of the cost effectiveness or efficacy of other drug treatments for similar indications, not prescribing allopurinol to HLA-B*58:01 positive patients is likely to be prudent, despite the low estimated positive predictive value (2%) of the test.
Potential Impact of Study Findings
In the present study, prospective screening by HLA-B*58:01 genotyping before allopurinol treatment in 2926 people with an indication for allopurinol treatment could successfully reduce the incidence of allopurinol induced SCARs (from seven expected cases of SCARs to none in the 2173 patients who took allopurinol). These results suggest that HLA-B*15:02 screening of about 110 000 new users of allopurinol in Taiwan each year could prevent about 330 cases of allopurinol induced SCARs every year.
Based on our previous experience, this expectation of impact is reasonable. Carbamazepine, which used to be the most common drug causing Stevens-Johnson syndrome and toxic epidermal necrolysis in Taiwan, is now only the eighth most common drug causing these life threatening conditions. This change is attributable to our previous prospective study showing that screening of the allele HLA-B*15:02 could reduce the incidence of carbamazepine induced Stevens-Johnson syndrome or toxic epidermal necrolysis. Subsequent coverage of the genotyping by the Taiwan's National Health Insurance system led to nationwide screening for HLA-B*15:02 by the medical community.
Strengths and Limitations of Study
The development of a reliable pharmacogenomics based approach to prevent adverse reactions with severe complications is a good example to demonstrate that the concept of personalised medicine can be a clinical reality. So far, there have been three critical findings involving adverse drug reactions: allele HLA-B*15:02 for carbamazepine induced Stevens-Johnson syndrome or toxic epidermal necrolysis; HLA-B*57:01 for abacavir induced drug hypersensitivity; and as seen in the present study, HLA-B*58:01 for allopurinol induced SCARs.
These findings show the potential benefits of genetic testing to prevent adverse drug reactions in the clinical setting owing to extremely high negative predictive values. To achieve this goal, solid evidence collected from different clinics and based on reliable laboratory tests is essential, as well as the development of effective strategies to incorporate these tests into routine practice. More importantly, a prospective study to demonstrate that these relevant processes can be performed in clinical settings is also needed. Therefore, the PREDICT-1 study team and our group investigated the use of a prospective screening approach to prevent abacavir induced drug hypersensitivity in 2008 and carbamazepine induced Stevens-Johnson syndrome or toxic epidermal necrolysis in 2011.
Compared with the use of other HLA alleles as biomarkers for preventing drug hypersensitivity, HLA-B*58:01 can be used in a broader spectrum of ethnic groups. The strong association between HLA-B*58:01 and allopurinol induced SCARs has been found in ethnic groups other than the Han Chinese, including Thai, Japanese, Korean, and European groups. Studies in Taiwan, Japan, Europe, and Israel have shown that allopurinol is now a major cause of drug induced SCARs.
In countries where the HLA-B*58:01 is relatively prevalent (for example, the carrier prevalence among Taiwanese population with HLA-B*58:01 is 20%) and where a tight association has been found, screening for this allele could be beneficial for preventing allopurinol induced SCARs. However, the implementation of HLA-B*58:01 screening certainly requires caution in some populations, such as Japanese and European groups, because not all patients with allopurinol induced SCARs carry the allele in those populations. Furthermore, in countries where the allele frequency is low (about 1%), restricting the screening for this allele to a more high risk group of patients (for example, chronic renal failure) could also be a strategy for preventing SCARs.
For countries or populations in which the prevalence is ill defined, further studies to estimate the prevalence are suggested for possible use of this screening. In addition, because the association between the HLA-B*58:01 allele and mild cutaneous adverse reaction induced by allopurinol has been found in mainland China, future investigations might be needed to examine whether screening for the HLA-B*58:01 allele could reduce the prevalence of allopurinol induced maculopapular eruption.