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Published: June 2013Print Record of Viewing
Hyperuricemia-related diseases such as gout, Lesch-Nyham syndrome, and urate kidney stones are commonly treated with allopurinol. However, with widespread use of the drug has come the recognition of allopurinol hypersensitivity syndrome. This syndrome, which includes skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, eosinophilia, vasculitis, and other reactions, has a reported mortality rate of 20% to 25%. The presence of an HLA-B allele, specifically HLA-B*5801, has been associated with the hypersensitivity cutaneous reactions. This allele is found in varying frequencies among ethnicities but in all studies, regardless of ethnicity, the presence of and the allele greatly increases the risk of severe skin reactions in response to the use of allopurinol. Guidelines have been published on the use of HLA-B*5801 testing in patients getting allopurinol, but these guidelines vary. Some suggest testing all patients who are to be administered allopurinol, while others specifically target high-risk populations for testing. Two new tests, one for blood specimens and another for saliva, offer rapid detection of the HLA-B*5801. In this presentation, Dr. Black reviews the current knowledge on allopurinol severe cutaneous adverse reactions, recommendations on testing, and the use of these 2 new tests.
Presenter: John Logan Black, MD
I’ll be talking today about HLA-B*5801 testing for allopurinol. Allopurinol induces a variety of hypersensitivity reactions, among those being severe cutaneous adverse reactions, and the testing that I’ll be discussing with you today relates to that.
I have no disclosures.
By way of background, hypersensitivity reactions to medications have been found to be associated with various HLA-B alleles. For example, Abacavir hypersensitivity reactions have been associated with HLA-B*5701; carbamazepine, and possibly phenytoin, fosphenytoin, and Lamictal also can induce hypersensitivity reactions, and they are associated with HLA-B*1502. Finally, today, we’ll be talking about allopurinol hypersensitivity reactions, which have been found to be associated with HLA-B*5801.
HLA-B is a member of the major histocompatibility complex, so-called MHC gene family, which consists of classes I, II, and III.
The HLA-B gene product is a member of the HLA class I molecules and is expressed on nearly all cells. HLA-B is responsible for presenting peptides to the immune system. The HLA genes are numerous and highly polymorphic. There are over 1500 HLA-B alleles that are known, and they’re constantly finding some additional alleles as time goes by.
In most cases, peptides presented by class I molecules are just break-down products of normal “self” proteins, and so they’re recognized as “self” and they don’t induce an immunologic reaction. If a cell becomes infected with a pathogen, some of the peptides presented by the class I molecule will be “non-self” and these will trigger an immune response.
Pharmaceuticals can rarely produce immune-mediated hypersensitivity reactions, apparently through interaction with MHC molecules, which then leads to T-cell activation and the observed immune response. There are 3 theories to explain this. The first one is the so-called hapten hypothesis, and this is where a drug binds to a peptide, probably covalently, and that causes a complex to interact with the HLA-B molecule. The second one is the so-called p-i concept, and that’s where a drug interacts directly with HLA-B molecules, in general. And the third one, which is borne out by recent research showing these interactions, these associations between drugs and specific HLA molecules, the third one relates to drugs that interact directly with a specific HLA, and in this case, HLA-B allele.
Allopurinol is used widely for hyperuricemia-related diseases such as gout, Lesch-Nyhan syndrome, and urate kidney stones. It is associated with a spectrum of reactions called allopurinol hypersensitivity syndrome. Skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis are among those hypersensitivity reactions, but there are others including eosinophilia, vasculitis, rash, and major end-organ disease. The morality rate has been quoted to be 20% to 25%.
Research has largely been restricted to the incidence of severe cutaneous adverse reactions. Among Han Chinese studies, mainly in Taiwan, the HLA-B*5801 allele was present in 100% of patients with allopurinol-induced skin reactions but only 15% of individuals who received allopurinol and were tolerant; they were called allopurinol-tolerant controls. In the Thai population, the HLA-B*5801 allele was present in 100% of patients with allopurinol-induced skin reactions but only 13% of allopurinol-tolerant controls. In the Korean population, HLA-B*5801 was present in 80% of patients with allopurinol-induced skin reactions but only 12% of healthy controls. These were not individuals that were necessarily exposed to allopurinol.
Japanese studies have also been done, and they have shown that the HLA-B*5801 allele was present in 56% of allopurinol-induced skin reaction cases vs. 0.61% of healthy controls. There are 2 European studies to date. The first one states that HLA-B*5801 was present in 55% of allopurinol-induced severe skin reaction cases vs. 1.5% of controls tested positive for the allele. In the second study, HLA-B*5801 was present in 100% of allopurinol-induced severe skin reaction cases compared to 1.5%, which is the population frequency for the allele.
A meta-analysis was done, which considered all published studies at the time that the analysis was done. An odds ratio of 73 was found comparing those with severe skin reactions to healthy controls, and an odds ratio of 165 was found comparing those with severe skin reactions to allopurinol-tolerant controls.
Now the HLA-B*5801 allele frequency, not surprisingly, varies by population ethnicity. Around 2% to 4% of individuals in African populations carry this allele; 3% to 15% of individuals in the Asian/Indian population have this allele. Around 12% of Koreans carry this allele, 0.61% of Japanese individuals carry this allele, and about 1.5% of individuals of European extraction carry this allele.
Recently, guidelines have been published to help clinicians know what to do with this information. The Clinical Pharmacogenomic Implementation Consortium, called CPIC, has published an article that implies that genotyping be performed on those getting allopurinol, although they don’t directly state that anywhere in the article. They recommend that the drug should not be administered to patients with the HLA-B*5801 allele. Similarly, the American College of Rheumatology has published guidelines for the management of gout utilizing allopurinol among other medications. They recommend that testing for selected subpopulations occur, specifically individuals of Korean descent, especially those in stage 3 renal failure should be tested, and Han Chinese and individuals of Thai extraction should be tested, irrespective of renal function.
Taken together, the safest position may be to consider testing all individuals who will be given allopurinol, although this is a decision that needs to be made by individual practitioners and clinics because it does add expense to the administration of this medication. Whether testing should be done on those previously prescribed the drug, without a skin reaction, who have had a break in therapy and now the therapy is being restarted, is unknown. There is simply no data out there that tells us whether we should test such individuals who have been tolerant to the medication in the past or not.
With regard to the actual test, the method involves extracting genomic DNA either from blood or saliva, and then the specific allele is amplified with a control gene to ensure that the reaction is working properly, utilizing a real-time polymerase chain reaction in the presence of SYBR Green, which fluoresces when bound to double-stranded DNA, and so the growth rate of the DNA that is amplified is measured, and that tells us whether the allele is present or not.
The test is useful for predicting increased risk for severe skin reactions caused by allopurinol, an interpretation is provided after testing to indicate whether there was a presence or absence of the HLA-B*5801 allele with a relevant discussion.
As always, there are cautions. There are unreported HLA-B*58 alleles that may exist, and these may or may not interfere with this assay. This assay also detects closely related, but rare, alleles as is depicted on this slide. There are, as yet, no data indicating whether these subtypes are associated with hypersensitivity reaction of any kind.
Some cautions include that allogeneic bone marrow or stem cell transplants will interfere with this testing. In fact, we’re not certain how to handle these. There is no research that will tell us whether an individual who has had a transplant, who now has been transplanted, to receive, to have, HLA-B*5801 allele, is at increased risk. We do know that individuals who genetically originally have the HLA-B*5801 allele present that allele on most of their cells, and whether this still imparts the risk of developing hypersensitivity reaction after transplant is unknown. Heterologous transfusions of blood that have not been depleted of leukocytes may also interfere with testing up to 4 to 6 weeks after receiving that transfusion. DNA obtained from white cells may not provide useful information for patients who receive a recent transfusion of blood that was not leukocyte-reduced. It is best to wait 4 to 6 weeks until transfused cells have left the patient’s circulation before drawing the patient’s blood specimen for genotype testing or simply provide a saliva sample for DNA extraction, which will contain the patient’s native DNA.
Other unknown factors may also lead to allopurinol hypersensitivity reactions, so a negative result doesn’t guarantee that the patient will never get a cutaneous reaction. As always, clinical monitoring is needed in all cases regardless of the result that you obtain from this testing. Allopurinol should be discontinued if an allopurinol hypersensitivity reaction occurs or is suspected, and should not be restarted in the future.
So, this has been a discussion about the use of HLA-B*5801 testing as it refers to patients who are receiving allopurinol.