Discussion
Our study showed for the first time the simulated benefits of utilizing
pre-stored HLA information to prevent type B ADRs or SCARs without
additional testing in a real-life setting. Consistent with the findings
of previous studies, the risk of developing SCARs due to allopurinol and
carbamazepine use was significantly higher in patients with the risk
alleles. In addition, type B ADRs due to allopurinol, carbamazepine, and
oxcarbazepine use were more common in patients with the risk alleles.
Conversely, if the data on the HLA PGx alleles were available before
prescribing the risk drugs to the patients, a significant number of
SCARs and type B ADRs could have been prevented, resulting in improved
patient safety and cost effectiveness.
Our findings support the claim that PGx information should be integrated
into EMRs using a clinical decision support
system.5,15 In case of organ transplantation patients
who have already undergone tests for HLA genotyping, physicians could
use this HLA PGx information to reduce ADR risks. Although our study did
not find statistically significant differences in the rate of ADRs for
some drugs, possibly owing to the small number of the study population
who took them, the available HLA data could be useful in preventing
ADRs.
In addition to the data on the HLA PGx alleles, other readily available
HLA allele data can be used to diagnose and identify individuals at a
risk of various autoimmune diseases.16,17 Associations
between certain HLA alleles and autoimmune diseases, such as HLA-DRB1
for rheumatoid arthritis, HLA-B51 for Behcet’s disease, HLA-B27 for
ankylosing spondylitis, HLA-DQ2/DQ8 for celiac disease, and
HLA-DQB1*06:02 for narcolepsy, are widely known. A broadened screening
of pre-stored HLA information to detect disease-associated variants of
HLA alleles may enable early identification of susceptible patients,
which may facilitate early diagnosis of diseases.
The exact incidence of SCARs is unknown; however, the incidence of
SJS/TEN is estimated at 1–2 cases per 1,000,000 people per
year.18 Although the incidence of SCARs is very low,
it carries significant morbidity, and the mortality rates are 10% for
SJS, 30% for SJS/TEN overlap, 50% for TEN, and 5% for
DRESS.18 Furthermore, SCARs may severely damage the
affected mucosa or skin and leave permanent sequelae. Therefore,
although the absolute risk reduction is small owing to its rare
occurrence, the potential benefits of preventing SCARs are substantial.
Considering patient data for the HLA PGx alleles is already available,
it is reasonable to integrate this data and ensure its availability for
clinicians at the point-of-care to help prevent SCARs. To achieve this,
a clinical decision support system that instantly informs the
personalized estimated risk to physicians by automatically linking the
existing genetic information with the prescription should be
implemented.
Pharmacogenomic studies showed that certain HLA genotypes induce T cell
activation to a specific drug, resulting in the development of a SCAR.
In 2005, the HLA-B*58:01 allele was first reported to be strongly
associated with allopurinol-induced SCAR in a case–control study of the
Han Chinese population in Taiwan (OR = 580.3).19 In
Korea, the HLA-B*58:01 allele was also strongly associated with
allopurinol-induced SCAR (OR = 97.8).20 This study is
consistent with these findings, confirming the usefulness of detecting
the HLA-B*58:01 allele in actual clinical practice.
However, the association between a specific allele and a particular
drug-induced hypersensitivity varies between ethnicities. For example,
100% of carbamazepine-induced SJS patients were positive for the
HLA-B*15:02 allele, whereas only 3% of the tolerant patients were
positive (OR = 2,504) in the Han Chinese population, in which the
HLA-B*15:02 allele frequency is relatively high.21This strong association between the occurrence of carbamazepine-induced
SJS/TEN and HLA-B*15:02 was not replicated in Koreans, in whom the
HLA-B*15:02 allele frequency is low.22 Instead,
HLA-B*15:11 has been proposed as an additional allele type associated
with carbamazepine-induced SJS in Koreans.23 In
patients with carbamazepine-induced DRESS, the HLA-A*31:01 allele was
reported as a risk marker in Europeans, Japanese, and
Koreans.23 Oxcarbazepine, a 10-keto analog of
carbamazepine, has also been associated with the HLA-B*15:02 and
HLA-A*31:01 alleles in the development of SJS/TEN and maculopapular
rash, respectively.24
Methazolamide, a carbonic anhydrase inhibitor used as an intraocular
pressure-lowering drug to treat glaucoma, was found to be associated
with SJS/TEN in individuals with the HLA-B*59:01 allele in Northeast
Asia, including Korea, Japan, and China.25 However, we
did not find significant results regarding methazolamide because its use
was minimal in our study. Dapsone, an antimicrobial agent used in the
treatment of leprosy or Pneumocystis jirovecii pneumonia, can
induce a hypersensitivity syndrome similar to DRESS
syndrome,26 and it was significantly associated with
the HLA-B*13:01 allele in Chinese, Thai, and
Koreans.27 Recently, the HLA-A*32:01 allele was
reported to be strongly associated with vancomycin-induced DRESS.
Although vancomycin is one of the main culprit drugs of SCARs in Korea,
the HLA-A*32:01 allele is unlikely to be used as a screening test
considering its rare genotype frequency in Koreans, which is at
0.6%.27 Further studies to investigate the risk
alleles of vancomycin-induced DRESS in the Korean population are
warranted. Nonetheless, if pre-stored data on HLA-A*32:01 were readily
available, it could still be used to minimize vancomycin prescription in
susceptible patients with the HLA-A*32:01 allele.
Abacavir, a nucleoside analog used to treat HIV infections, can cause
severe delayed systemic hypersensitivity reactions in association with
the HLA-B*57:01 allele. However, the use of the HLA-B*57:01 allele as a
screening test has no clinical relevance owing to its very low allelic
frequency (0.2%) in Koreans.28 Our results are
consistent with this observation.
Of the 4,092 individuals with 8 HLA PGx alleles identified in our study,
1,597 (39%), or 13% of the total number of study subjects, were
prescribed one or more of the seven drugs associated with these alleles.
If all these patients had their HLA test results evaluated at the time
of drug prescription, doctors could have made better therapeutic
decisions, including whether to prescribe alternative drugs, change the
dose, or carefully monitor the patients according to their individual
PGx profile. In addition, if a prescription was changed by a physician
due to an automatic PGx warning at the time of prescription, not only
SCARs but also a considerable number of type B ADRs, specifically 15.3%
(53/347) for allopurinol, 33.3% (3/9) for carbamazepine, 23.5% (4/17)
for oxcarbazepine, 66.7% (2/3) for dapsone, and 2.6% (9/341) for
vancomycin, could have been prevented.
Our study is a retrospective study and the preventative effects proposed
need to be assessed further in prospective studies and real clinical
practice. Nonetheless, the proposed approach has clear benefits because
it utilizes pre-tested HLA data to prevent ADR occurrences without
additional costs or patient discomfort. Given the rapid increase in the
genomic data collection for research and clinical purposes, timely use
of these valuable genomic data in clinical practice should be
prioritized.29,30 For the secondary use of the
point-of-care of genomic tests, it is necessary to evaluate and confirm
the clinical validity of the tests for the specific uses other than the
primary purpose. Additionally, it is necessary to devise an effective
and safe approach to deliver genomic information at the right time and
in the right manner. The most appropriate method so far is to design and
use a clinical decision support system that integrates the personal
genomic information of the patient at the time of drug prescription and
provides an appropriate PGx warning. Considering the diversity of
genetic tests, various drugs, and individual genetic variations, it is
necessary to design an optimal system to ensure efficiency and safety in
clinical practice.
Although this study provided important results, there are several
limitations. First, the HLA genotypes selected in this study were
obtained from results accumulated over a long period using various HLA
testing methods. Therefore, the results of the lower resolution HLA
tests were converted to the matched 4-digit results based on the
previously reported population-wise allele frequencies. This means that
some results may not be accurate in some patients. However, this is
unlikely to result in significant error based on the allele frequency
data.28 For example, the HLA-B58 status was also shown
to be strongly associated with allopurinol hypersensitivity and
HLA-B*58:01 is the only HLA-B58 allele in the Korean
population.31
Second, the causal relationships in this study were not assessed by
confirmative tests, and therefore, misdiagnosis and overestimation are
possible. In our analysis, we assumed that the reported SCARs or type B
ADRs were related to the prescribed drug. Therefore, SCARs reported in
an individual could have been caused by another drug other than the risk
drug associated with the HLA PGx alleles. The study relied on ADR
reporting, and thus, under-reporting could have been a problem.
Nonetheless, our study could replicate the significant associations
between the HLA-B*58:01 allele and allopurinol and the HLA PGx alleles
for carbamazepine, suggesting that our overall findings are valid.
In summary, the results of this study highlight the importance of
utilizing pre-stored HLA data to predict potential ADRs in a clinical
setting. Because HLA PGx alleles are already available, no additional
cost is required; moreover, if these HLA PGx alleles were readily
available at the point-of-care, some SCARs and type B ADRs could have
been prevented. Therefore, further
studies are needed to integrate HLA data and existing EMRs to achieve a
personalized medicine approach.