“HLA polymorphisms and their
involvement in drug induced
hypersensitivity reactions”
Written by Maria Flores
Student number 3557928
Supervisors:
PhD. Raymond Pieters
PhD. Janine Ezendam (RIVM)
1
2. INDEX
Page(s)
1.
2.
3.
4.
5.
Index………………………………………………………………………………………………..….2-3
Introduction…………………………………………………………………………………….…4-5
Abbreviation list……………………………………………………………………………….……6-7
Thesis hypothesis………………………………………………………………….…………….……8
HLA and DHR……………………………………………………………………………………...9-15
5.1.Type of HLA associations with DHR……………………………………………..…..…9-13
5.1.1.MHC class I associations…………………………………………..……………………9-10
5.1.2.MHC class II associations…………………………………………….………….…..10-11
5.1.3.Mixed associations……………………………………………….…………………….12-13
5.2 Immunological mechanisms and concepts involved in DHRs……………..13-14
5.2.1 concepts suggested in drug recognition by T cells………………………..14-15
6. Factors
involved
in
the
predisposition
of
drug
induced
hypersensitivity…………………………………………………………………………….……16-22
6.1. Gender and DHRs…………………………………………………………………………...….16-17
6.2. Age and DHRs…………………………………………………………………………………….17-18
6.3. Viral infections and DHRs……………………………………………………………………18-19
6.4. Other MHC gene polymorphisms and DHRs…………………………………………..20-21
6.5. Metabolic polymorphisms and ADRs……………………………………………………..21-22
7. Discussion…………………………………………………………………………………………..23-25
8. Conclusion
and
future
directions……………………………………………………………………………………………...26
9. Annex: Strongest genetic associations of DHRs……………………….………27-31
9.1 Carbamazepine………………………………………………………………………………..27-28
9.2 Allopurinol…………………………………………………………………………….………28-29
2
9.3 Abacavir…………………………………………………………………………………..……..29-30
9.4 Nevirapine………………………………………………………………………………..……30-31
10.References……….………………………………………………………………..…………………32-40
3
1. INTRODUCTION
Drug induced hypersensitivity reactions (DHRs) are a major clinical problem. DHRs
might present life-threatening conditions affecting the skin or other organs such as liver
and renal injury, bone marrow suppression, pneumonitis among others 1. The most
common observed DHR condition in the clinic are severe cutaneous reactions.
Severe cutaneous adverse reactions usually include the Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic
symptoms (DRESS) 1. SJS and TEN have an average mortality of 1-35% on those
patients who developed the condition. Patients suffering from DRESS generally present
skin eruptions and lymphadenopathy and fever. The mortality of patients suffering
from DRESS is reported to be 10% 1,5.
Almost all drugs have been reported to induce DHR, but anti-convulsing agents, nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics report more DHR cases than
any other pharmaceutical group 74. Idyosincratic DHRs are typically dose-independent
and unpredictable. DHRs are the consequence of an exaggerated life-threatening
immune mediated reaction. An individual is pre-sensitized at the initial exposure to the
drug. A second exposure would lead to a rapid and severe reaction 1,2.
Recent findings have found human leukocyte antigens (HLA) as mediators of DHRs by
specific drugs such as the case of carbamazepine and nevirapine leading to life
threatening conditions. HLA genes are highly polymorphic and their function is to
present antigens to T-cells. Race and genetics are the known risk factors of DHRs. The
frequency of specific HLA polymorphisms is higher in some populations than others as
they have inherited the HLA polymorphisms by their ancestors. This would explain the
higher incidence of DHRs in a particular population by one drug. One example would be
the high frequency of HLA-B*1502 in the HAN Chinese, which mediates carbamazepine
induced SJS/TEN and explains the high prevalence of these reactions in this ethnic
group 8-10.
Although studies confirm HLA polymorphisms as important factors involved in DHRs, not
every single patient carrying the studied polymorphisms developed the DHRs,
suggesting unknown underlying factors as important pieces in the physiopathology of
the disease.
4
The relevance of these reactions urges the need of discovering other biomarkers of
DHRs and to elucidate all other factors involved in DHR pathogenesis to prevent DHR
onset pre-clinically. Factors such as age, gender, viral infections among others are
thought to play a role in DHR onset. The aim of this thesis is to find whether other
factors rather than HLA polymorphisms might be involved in DHR onset.
5
3. ABBREVIATION LIST
ADR……………………………………………………………………………………..Adverse drug reactions
AIDS………………………………………………………………Acquired immune deficiency syndrome
ALT……………………………………………………………………..…………...Alanine aminotransferase
APC…………………………………………………………………………………….Antigen presenting cells
CIA……………………………………………………………………...Clozapine-induced agranulocytosis
CXCL8………………………………………………………………………………………….……..Interleukin 8
DHR……………………………………………………………………Delayed hypersensitivity reactions
DRESS………………………………………..Drug rash with eosinophilia and systemic symptoms
EMA…………………………………………………….………………………….European medicine agency
GM-CSF………………………………………...Granulocyte-macrophage colony stimulating factor
GWA……………………………………………………………………………….…genome wide association
HIV………………………………………………………………………..…Human immunodeficiency virus
HLA……………………………………………………………..……………………Human leukocyte antigen
HSS…………………………………………………………………………………Hypersensitivity syndrome
IL………………………………………………………………………………………………………....Interleukin
MHC……………………………………………………………………….Major histocompatibility complex
MHCI…………………………………………………………...Major histocompatibility complex class I
MHCII………………………………………………………….Major histocompatibility complex class II
MPE…………………………………………………………………………………...Maculopapular eruptions
NSAIDs……………………………………………………....Non-steroidal anti-inflammatory drugs
6
OR……………………………………………………………………………………………………….…Odds ratio
SCARs………………………………………………………………..Severe cutaneous adverse reactions
SJS…………………………………………………………………………..…...Stevens-Johnson syndrome
SLE…………………………………………………………………………….Systemic lupus erythematosus
SMX-NHOH……………………………………………………………….Sulfamethoxazol-hydroxylamine
SNPs……………………………………………………………………...Single nucleotide polymorphisms
TCR………………………………………………………………………………………..………..T-cell receptor
TEN…………………………………………………………………………………Toxic epidermal necrolysis
Th1………………………………………………………………………………………....T-helper cells type 1
7
4. THESIS HYPOTHESIS
Current research on DHRs has identified HLAs polymorphisms as the main mediators of
DHRs. Although susceptible individuals might carry the HLA in question, not every
single individual develops the DHR. The hypothesis of this thesis is:
Underlying factors other than race and genetics are also found in combination with HLA
polymorphisms for the final establishment of DHRs.
8
5. HLA and DHRs.
The major histocompatibility complex (MHC) genes, are also known as human leukocyte
antigen (HLA). HLA are genes that encode for cell receptors The goal of HLA is to
capture and present self and pathogen-derived peptides to immune cells (T-cells) as
part of immune alertness 5. MHC class I (MHCI) and MHC class II (MHCII) are the two
types of the classical MHC molecules mediating these processes.
MHCI molecules are present in nucleated cells, while MHCII molecules are only present
only in specialized APC. MHCI molecules are responsible for presenting peptides to
cytotoxic or killer CD8+, while MHCII present peptides to helper or regulatory CD4+.
The classical MHCI molecules are encoded by the loci HLA-A, HLA-B and HLA-C. MHCII
molecules are encoded by the loci HLA-DR, HLA-DQ and HLA-DP 5.
HLA genes are also referred as “immune response” genes in regards of its critical role in
regulating specific immunity. HLA genes are highly polymorphic where a single locus
can possess more than 1000 alleles, as in the case of HLA-B. HLA allotypes variation
can range between 1-30 residues 5. In this chapter, we address MHCI, MHCII and the
mixed association so far reported.
5.1. Types of HLA association with DHR.
5.1.1 MHCI associations:
MHCI associations appear to be the most reported and studied associations.6-14. They
also show the strongest associations of DHRs when compared to MHCII associations.
The strongest associations of DHRs are observed in allopurinol (OR=580) abacavir
(OR=960) and carbamazepine (OR=2500) 6-14. The association strength observed in
MHCI studies have led to the discovery of important biomarkers for drug induced
hypersensitivity reactions. The biomarkers are HLA-B*1502 for carbamazepine, HLAB*5701 for abacavir and HLA-B*5801 for allopurinol. All three biomarkers are currently
used to predict possible drug related hypersensitivity reactions prior to the start of
9
treatment 6-10. In MHCI association, antibiotics and anticonvulsants are the most
observed pharmaceuticals groups involved in the onset of DIH 6-14.
With only a few exceptions, DHRs mediated by MHCI allele polymorphism primary
targets the skin with syndromes such as SJS, TEN and MPE. 13-14. SJS and TEN are
frequently found together in a single case and it is a common cause of death 7-10,14..
After skin reactions, the liver is the second most common target of MHCI associations,
as observed in flucloxacillin by HLA-B*5701-induced hepatotoxicity 11.
The prevalence of MHCI associations appears to be well distributed in different ethnic
populations around the world, but is frequently observed in the Asian population 7-10,14.
The association strength of MHCI allele polymorphisms with the resulting phenotype
suggests Asians at higher risk to develop drug induced SJS/TEN than any other
ethnicity. Likewise, the offending drugs are physician first choice in the clinic, which
encourages to establish rapid methods of biomarker detection prior to the start of
treatment, especially in Asian communities. In Table I we summarized the most
relevant findings in MHCI associations with DHR.
Table I. Overview of drugs associated with MHCI DIH reactions
Drug
Abacavir
Allopurinol
Carbamazepine
Feprazone
Flucloxacillin
Oxicam
Phenytoin
Sulfamethoxazole
Sulfonamides
Phenotype
HSS
SJS/TEN
SJS
Fixed drug eruption
Hepatotoxicity
TEN
SJS/TEN
SJS/TEN
TEN
Levamisole
Agranulocytosis
HSS: hypersensitivity syndrome.
HLA association
HLA-B*5701
HLA-B*5801
HLA-B*1502
HLA-B22
HLA-B*5701
HLA-A2, HLA-B12
HLA-B*1502
HLA-B55
HLA-A29, HLA-B12
& HLA-DR7
HLA-B27
References
6
7,8
8,9,10
15
11
13
14
12
16
17
5.1.2 MHCII associations:
MHCII associations seem to involve a wider range of immune mediated diseases such
as systemic lupus erythematosus, asthma, anaphylactoid reactions and hepatotoxicity
(Table II) In comparison with MHCI associations which mainly induce skin pathologies,
18-23.
10
MHCII associations are induced in most cases by non-steroidal anti-inflammatory drugs
(NSAIDs). NSAIDs are drugs with anti-inflammatory, analgesic and anti-pyretic effect.
The most prominent NSAIDs are aspirin, ibuprofen and naproxen all available over-thecounter. NSAIDs are implicated in cases of asthma, SJS/TEN and anaphylactoid
reactions.
In 1997, DPB1*0301 was discovered to be the allele involved in the onset of aspirin
induced asthma (Dekker et al). The frequency of this allele was found to be increased
in those patients who developed asthma during aspirin treatment (19.5% vs. 5.2% of
the controls, OR=4.4 P=0.002). Such discovery gave the first clues of immune
recognition of an unknown antigen as part of an etiology 18. DPB1*0301 allele was
found to be carried by patients from different ethnic backgrounds (e.g. Caucasian and
Asian) all of whom developed asthma after aspirin treatment. Such results suggests
DPB1*0301 as necessary for the onset of aspirin-induced asthma in different
populations 18-19. More HLA markers of NSAID-DHRs have been discovered during the
past years 22. Table II gives an overview of all those MCHII alleles involved in DHRs.
Table II. Overview of drugs associated with MHCII DHRs.
Drug
Phenotype
HLA
association
Odds
Ratio
(OR)
Ethnicity
Reference
Aspirin
Asthma
DPB1*0301
OR=5.2
Korean
18,19
Hydralazine
SLE
HLA-DR4
N/D
N/S
20
Lapatinib
DILI
HLADQA1*02:01
OR=9
N/S
21
NSAIDs
Anaphylactoid
reactions
HLA-DR11
OR=7.3
N/S
22
Ximelagatran
DILI
HLA-DRB1*01,
HLA-DQA1*02
N/D
Caucasian
(northern
European)
23
SLE: systemic lupus erythematosus. DILI: drug induced liver injury. N/D=Not
determined. N/S= not specified.
11
5.1.3 Mixed associations of DHR
Mixed association of DHRs include multiple alleles from both MHCI and MHCII genes,
which in combination induce one DHR phenotype (Table III). The most common drug
showing these associations is nevirapine. Nevirapine is a non-nucleoside reverse
transcriptase inhibitor used as physicians first choice for the treatment of HIV-1
infection and AIDS patients. The most common adverse effect of nevirapine is the
development of mild to moderate rash (15%). Severe or life threatening skin conditions
(SJS, TEN) have been observed in 1.5% of the patients under nevirapine treatment 2627.
Several HLA alleles are associated with nevirapine induced hypersensitivity reactions.
These HLA alleles vary from population to population. In the Thai population, HLA-Cw4
and HLA-B*3505 have been linked with cutaneous adverse reactions, such as SJS and
TEN 26, 27. In Sardinian population HLA-Cw8 and HLA-B*14 were associated with
hypersensitivity syndrome, while HLA-DRB1*0101 was associated with DILI in
Australian population and cutaneous reactions in the French population 28, 29, 30. Such
findings suggest nevirapine DHR as allele and race specific. Table III shows more drugrelated HLA mixed associations and its phenotype.
Table III. Overview of drugs associated with mixed MHCI and MHCII DHRs.
Drug
Phenotype
HLA
association
Odds
ratio
(OR)
Ethnicity
Reference
Aminopenicillins
HSS
HLA-DR4,
HLA-A2,
HLA-DRw52
N/D
N/S
24
Clozapine
Agranulocytosis
HLA-DQB1,
HLA-C, HLADRD1
N/D
N/S.
25
12
Nevirapine
SJS/TEN, HSS
HLA-Cw4,
HLA-Cw8,
HLAB*3505,
HLA-B*14
OR=18.9
Thai (HLACw4, HLAB*3505)
26-30
Caucasian
Italian
(HLA-B*14,
HLA-Cw8)
HSS: Hypersensitivity syndrome. N/D: not determined. N/S: Not specified.
5.2. Immunological mechanisms and concepts involved in DHRs.
According to the Gell and Coombs classification system, DHRs are classified as Type IV
reactions which are subdivided into four types: IVa, IVb, IVc and IVd. Each type of
reaction is mediated by different cytokine patterns although all DHRs are mediated by
drug specific T lymphocytes. T lymphocytes are responsible for tissue
damage/infiltration or the activation of cytokines 3, 57. Each type of allergic is briefly
described in table IV.
Table IV. DHR types and their mechanism
Type
Cells mediating
DHR
Example
References
IVa
interferon-Ɣ leads
to the activation of
macrophages by
Th1 cells, as a
result inflammation
takes place.
Contact dermatitis
3,57
IVb
Th2 cells secrete
interleukines (IL)
The secretion of IL
promotes B cell
production of IgE
Eosinophile rich
maculopapular
exanthema, rinitis
and asthma
3,57
13
and IgG.
IVc
Eosinophils,
monocytes or
polynuclear cell
recruitment
activates CD8+ Tcells which migrate
to tissues, killing
their cells.
DILI, SJS, TEN
3,57
IVd
T-cells is generated
by CXCL8 and
granulocytemacrophage colony
stimulating factor
(GM-CSF). As a
result, neutrophils
are recruited.
Dermatosis,
exanthematous
pustulosis, Behcet
disease
3,57
5.2.1 Concepts involved in drug recognition by T cells.
The specific mechanism by which a chemical or drug antigen is presented is still a
subject to debate. It is believed that the chemical characteristic of the offending drug
play an important role in its immunogenicity. Three pathways are considered viable for
chemical stimulation of T-cells: The hapten concept, the pro-hapten concept and the
pharmacological interaction with immune receptors concept (p-i concept) 3, 57, 58.
Regardless of the pathway, the main feature is the recognition of peptides bound to
MHC molecules by T-cells. Each concept is summarized in this section.
a) The hapten concept.
14
Small molecules (<1000 D) are not considered antigenic, therefore they cannot interact
with the immune system. The hapten concept explains how a small molecule can
become recognizable to the immune system. This concept suggests a small molecule
must bind to a high molecular weight molecule, such as a protein, in order to become
presented by HLA molecules and therefore, be antigenic 3, 57, 58.
Haptens are chemically reactive small molecules. They are able to bind covalently to
peptides (e.g. membrane proteins, enzymes, soluble extracellular proteins, etc.). Some
drugs specifically bind to a particular aminoacid, such as lysine residues of serum
albumin (e.g. penicillin). 3, 57, 58.
b) The pro-hapten concept.
This concept suggests that an inert chemical/drug may become reactive upon
metabolism. Sulfamethoxazol is the prototype drug of this concept. Sulphamethoxazol is
not chemically reactive itself but becomes reactive once metabolized by CYPP2C9 and
peroxidases in the liver to sulfamethoxazol-hydroxylamine (SMX-NHOH) and
sulphamethoxazol nitroso 57, 59. The most toxic metabolite of sulphamethoxazol is
sulphamethoxazol nitroso, which is produced by auto-oxidation 80. Sulphamethoxazol
nitroso is highly reactive and toxic to immune cells. It binds to cysteine residues on
cellular proteins which leads to the creation of neoantigenic determinants and
therefore, stimulates a T-cell response 81.
c) The p-i concept.
This last concept states that chemically inert drugs are able to activate T-cells if they
possess the affinity to interact with their receptors or with other available MHC
molecules 57, 59. An example of this concept would be aldehyde-fixed APC which is able
to activate specific TCC. In other words, this concept involves a non-covalent, unstable
interaction of the drug with the MHC. These interactions do not require a metabolism or
antigen processing but it states that the p-i activated T-cells arise from previously
sensitized memory T-cells. Afterwards, p-i activated T-cells infiltrate tissues and organs
leading to inflammation 57, 59.
15
6. Factors other than HLA involved in the predisposition of DHRs.
Current literature suggests DHRs incidence are determined by the chemical
characteristics of the drug, the ethnicity of the patient and other host related factors
such as age, gender, among others. In particular, the pathogenesis of cutaneous
adverse drug reactions (ADR) is known to be mediated by genetic and immunological
factors. Here we address the most discussed and suggested factors of DHRs other
than HLA polymorphisms. In Annex I, a summary of the strongest race/genetic
associations of DHRs is given as a complement of this thesis.
6. 1 Gender and DHRs.
Few epidemiology studies have evaluated gender and DHRs incidence. The result of
such studies have shown females as more likely to develop drug induced allergies when
compared to males 32, 65, 67. Tran et al (1998) epidemiology study included 2,367
confirmed cases of ADR in Canadian centers. The results showed up to 70% of
confirmed DHRs cases corresponded to females. This study identified antibiotics
(60.4%) and anticonvulsants (21.5%) as the most common cause of DHRs. In most
cases, the resulting phenotype involved cutaneous adverse reactions such as SJS and
TEN 65. Such results were supported by Spanish and Portuguese epidemiology and
pharmacovigilance studies 32, 65.
The female gender prevailed in ADRs hospital records according to an Alergologica
study (2005) performed by the Spanish society of allergy and clinical immunology.
Females predominated in a 2:1 ratio in first time consult for drug allergies among a
total of 4991 evaluated patients 32. Among them, 732 patients suffered drug allergy
(mean age 41.4 +/- 19.4 years) (62% females and 38% males). This diagnosis was
confirmed in 26.6% of the cases, and among them 75% reported only skin reactions. In
47% of the cases, the trigger drugs were beta-lactams, followed by NSAIDs (29%) and
pyrazolones (10%) 32. The pharmacovigilance study performed by Ribeiro et al (2013)
from the Portuguese pharmacovigilance authority found up to 67% of female cases out
of 16,157 confirmed adult DHRs cases. Contrary to expected based in adult results,
males predominated in the pediatric DHRs confirmed cases (56%) 67.
16
Self-reported allergies are also higher in females. Haddi et al (1990) studied a
population of 2067 adults (20-60 years) which visited a health center for a check-up
examination. The study included a questionnaire related to systemic reactions to drugs
and the determination of IgE presence in blood against aeroallergens presence using
the phadiatop test. Sixty-six percent of females reported reliable history of systemic
reactions to drugs, although the phadiatop test results were similar in patients with or
without systemic reactions to drugs. Such results can be blamed to the high bias
probability on self-reported allergies 61.
The reason why females are especially more predominant in DHRs cases is not fully
elucidated. Epidemiology studies show a broad range of pharmaceutical groups as the
cause of DHRs, but the reason why the female gender shows higher susceptibility to
these drugs is unknown.
6.2 Age and DHRs.
DHRs cases are reported in every life stage, although recent pharmacovigilance studies
suggest more cases of DHR in adulthood. A Portuguese pharmacovigilance retrospective
analysis study comprised a total of 16, 157 confirmed DHRs cases. The patient age
ranged between 7 days up to 96 years. The results showed up to 91% of DHRs cases
as reported in adult patients and only 9% of the cases involved patients under 18
years. The study identified antibiotics (17%) and NSAIDs (13%) as the main offending
drugs 67.
Current children age epidemiological studies are based on community based studies.
Such studies lack of reliable information and are considered too biased to fully identify
the most susceptible population group based on age. Community based studies have
shown high overestimation rates and a lack of allergy categorization as identified by
Bernard et al 2010, where out of 10.2% of parental confirmed DHRs cases, only 6%
resulted as positive based on allergological tests 5.
On the other hand, meta-analysis of prospective studies done in pediatric DHRs cases
have shown and overall DHRs incidence of 1.5% in outpatient children and 10.9% in
hospitalized children. The hospital admission due to DHRs is estimated to be 2.1%.
Antibiotics were detected as the most common cause of DHRs 5. Some countries have
reported up to 20% confirmed cases of SJS/TEN in children between 1 month old up to
16 years old. In most cases attributable to antibiotics and NSAIDs 66 .
17
The most complete and reliable pediatric study was performed by Le et al (2006) who
studied the types and causes of drug allergy in a 10 year retrospective cohort study in
children. The study performed by Le et al 2006 concluded 24% of all DHRs were a
result of drug hypersensitivity. Although this study did not compare children DHR with
those in adults, it lead to important information about the most common causes of
ADRs in children. Antibiotics, narcotic analgesics, and anticonvulsants were the most
common causes of ADR and SJS cases were most attributable to carbamazepine and
phenytoin similar to DHRs in adults 5, 62.
Based in this information, current literature lack of substantial information to identify
the most susceptible population based on age, but identifies that both age stages can
be subject of DHRs.
6.3 Viral infections and DHRs
Concomitant viral infections such as human herpes virus 6 (HHV6) & 7 (HHV7) , Epstein
barr virus, cytomegalovirus and HIV are linked with DHRs susceptibility, although, the
most frequently reported infection with DHRs is HHV6.
Under unknown mechanisms, the interaction of a concomitant viral infection and a drug
treatment is able to interact with the immune system triggering the onset of DHR. DHR
has been previously shown to be capable of reactivating members of the herpes virus
family, but it remains unknown which condition is the cause and which the effect of
DHR. Some authors refer an allergic pathogenesis in the case of herpes virus, such as
the one proposed by Gentile et al (2010): An allergic reaction to the drug will stimulate
T-cell activation and therefore reactivation of the virus DNA harbored at T-cells
following by a cross-reaction of the drug with virus-stimulated T-cells leading to T-cell
expansion and DHRs onset. Nevertheless, other authors have suggested reactive
metabolites of the offender drug to reactivate and propagate a concomitant virus such
as the case of sulphamethoxazol 63,64. Sulfamethoxazol-induced hypersensitivity in HIV
patients has been suggested to be caused due to metabolic polymorphisms such as
those found by Wang et al (2012). The polymorphism rs761142 in glutamate cysteine
ligase catalytic subunit (GCLC) showed association in the reduced expression of GCLC
mRNA expression and sulfamethoxazole hypersensitivity in a cohort study of 171 HIV
patients (adjusted p value= 0.045). GCLC catalysis a critical step in glutathione
biosynthesis, which protects the body from reactive oxygen species such as free
radicals and peroxides 74. The lack of sufficient GCLC protein production would lead to
18
an increase of toxic compounds damaging cells and causing inflammation, leading to an
immunological response.
In HIV patients, most DHR cases are also linked with genetic factors such as HLA
polymorphisms (e.g. nevirapine and HLA-B*5701) 63-64. Among HIV infected patients,
DHR is frequently observed in the clinic and it is reported to occur 100 times more
frequently than in non-HIV infected patients leading to death in more than 20% of the
cases. In most cases, the main target is the skin with conditions such as SJS and TEN,
but encephalitis and hematological disturbances are also reported 71. The less harmful
symptoms are rash and fever.
Other commonly reported drugs inducing DHR with concomitant viral infections are
trimethoprim, isoniazid, riphampicin and amoxicillin and anti-convulsing drugs. Although
concomitant viral infections have been proven to be important factors in DHRs onset,
the interaction of each factor leading to DHR is unknown. Current literature lacks of
information to elucidate the pathogenesis of viral infections and DHR. Table V
summarizes the concomitant viruses and the drugs reported in DHR.
Table V. Viruses and drugs related to DHR onset.
VIRUS
OFFENDER DRUG(S)
REFERENCE
HV6
Lamotrigine, carbamazepine.
70,73
HV6/HIV
Trimethoprin/sulfamethoxazole
71
Epstain-barr
Allopurinol
72
HIV
Sulfamethoxazole
74
19
6.4 Other MHC gene polymorphisms involved in DHRs
Besides HLA polymorphisms, new studies have discovered other MHC gene
polymorphisms involved in drug allergies as in the case of carbamazepine and aspirin
induced DHRs (Table VI).
HLA-B*1502 is the most reported allele mediating cutaneous ADR under carbamazepine
treatment. However, HLA-DR3-DQ2 haplotype and TNF-ɑ polymorphism was found to
mediate severe cases of SJS/TEN 68.
Another example of non-HLA MHC polymorphisms involved in DHR would be those
discovered in aspirin-induced DHRs. Studies on Aspirin-induced asthma (AIA) have
shown a complex, multifactorial pathogenesis involving several MHC polymorphisms.
Polymorphisms on cysteinyl leukotriene receptors such as CYSLTR1 and CYSLTR2,
enzymes involved in leukotriene and arachidonic acid production, as well as HLADPB1*0301 are blamed in the onset of AIA. Even more, recent findings have also found
an association with AIA in those patients carrying several SNP in promoters such as
COX2, EP2, TBX21, which are enzymes involved in inflammation and pain and Th1
transcription factors respectively.
Moreover, aspirin-induced urticaria also demonstrates a highly complex pathogenesis
which involves several MHC gene polymorphisms. HLA-DRB1*1302 and HLA-DB1*0609
alleles are involved in AIU and are considered genetic markers of AIU. In 2009, Choi et
al demonstrated that TNF-α promoter polymorphisms 1031T>C and 863C>A were also
important factors for the development of AIU 76. Kim et al (2006) discovered
leukotriene related genes such as ALOX5 to be important in AIU onset when found in
combination of HLA-DRB1*1302 and HLA-DB1*0609 alleles 77. Such findings may
indicate the true mechanism of action of DHR, where more than HLA polymorphisms
are needed in the establishment of DHR and might explain why some carriers of
offender HLA do not develop the disease after the exposure to the drug.
Table VI. MHC polymorphisms discovered in carbamazepine and aspirin DHRs
Phenotype
MHC polymorphisms
Reference
Severe cutaneous reactions
HLA-DR3-DQ2
68
20
(SJS/TEN)
TNF-ɑ
AIA
HLA-DPB1*0301
18
CYSLTR1, CYSLTR2
COX2, EP2,TBX21
AIU
HLA-DRB1*1302, HLADB1*0609
76,77
TNF-ɑ, ALOX5
6.5 Metabolic polymorphisms and DHRs.
Metabolic polymorphisms have been implicated in DHRs. Isoniazid-induced
hypersensitivity has been discovered as a result of combined metabolic polymorphisms
and the acetylator state in different populations. CYP2E1 is involved in the oxidative
metabolism of Isoniazid. By increasing its activity it also increases the production of
hepatotoxic metabolites leading to liver toxicity in those patients under isoniazid
treatment.
N-acetyltransferase 2 (NAT2) polymorphism phenotype is characterized by changes in
the acetylation rates of drugs, making its carriers slow acetylators. Yamada et al (2009)
studied the first reported additive polymorphism of the slow metabolizer genotype NTA2
and the CYP2E1c1/c1 genotype in a diverse Canadian population 78. In combination, the
Odds ratio for isoniazid-induced hepatotoxicity increased from 2.52 up to 7.43 78. Later
studies by Lee et al (2010) confirmed NTA2 polymorphisms as a susceptibility factor for
antituberculose-drug hepatotoxicity while CYP2E1 was associated with the
hepatotoxicity severity in the Chinese 79.
In the Korean population, isoniazid-induced hepatotoxicity is
blamed to NAT2
polymorphisms whereas in the Caucasian population glutathione-S-transferase activity
was observed to cause isoniazid induced hepatotoxicity.
Sulfamethoxazol is also involved in hypersensitivity cases induced by metabolic
polymorphisms. Sulphamethoxazol-induced hepatotoxicity is caused by metabolic
polymorphisms in NT2 and CYP450 enzymes. Sulphamethoxazol undergoes CYP2C921
mediated activation to a hydroxylamine. Polymorphisms on CYP2C9 such as CYP2C9*2
and CYP2C9*3 are thought to have some influence on sulphamethoxazol Nhydroxylation, leading to potential reactive metabolites such as prohaptens, which in
combination with immunological risk factors could be determinant in the onset of the
hypersensitivity phenotype 69. Sulfamethoxazol-induced hypersensitivity risk has been
detected in other populations as linked with the slow acetylator NT2
genotype/phenotype. Zielinska et al (1998) reported a higher risk of idiosyncratic
reactions to cotrimoxazol in Polish infants carrying the NT2 polymorphism when
compared to those infants carrying the wild type allele 75.
A combination of HLA and metabolic polymorphisms have also been reported as a cause
of DHRs. Adverse skin reactions to nevirapine have been reported when metabolic and
HLA polymorphisms are combined. The presence of CYP2B6516G!T is found to be
distributed in different populations around the world, and in combination with HLACw*04 the risk for cutaneous adverse events risen up to OR=18.34 in the general
population. The combination of CYP2B6516G!T and HLA-Cw*3505 is a risk factor for
nevirapine-induced cutaneous adverse events particularly in Asian populations
(OR=5.65) 55. As observed in these findings, it appears that metabolic polymorphisms
are important pieces in DHR pathogenesis, and encourages the study of more possible
metabolic associations in confirmed DHR cases.
22
7.DISCUSSION
In section 6 we have addressed factors other than HLA polymorphisms found to have
an influence in DHRs. Based in current literature, DHRs are determined by a
combination of host and environmental factors proving DHR as a complex, multifactorial
reaction which varies from race to race and among individuals within the same
ethnicity.
Our literature survey identified gender, metabolic conditions/polymorphism, non-HLA
MHC polymorphisms and concomitant viral infections as risk factors of DHR. Although
other factors rather than HLA polymorphisms were found to be associated with DHRs,
the interaction between factors which lead to DHRs remains unknown.
The evidence of age as a risk factor of DHR is not strong enough to determine which
age stage is at higher risk of DHRs. To our knowledge, only one epidemiology study has
reported the incidence of DHR based in life stages, in which adulthood predominated.
Based only in this article, we can speculate adulthood might be at higher risk of DHR
probably because of lack of repeated exposure to the offender drug during childhood,
which is needed for sensitization to take place. Nevertheless, the evidence is not strong
to come to this conclusion. The limited information on children confirmed cases of DHRs
unable to identify the most susceptible age stage and further epidemiology studies are
needed
However, in regards of gender, epidemiology studies have confirmed the female gender
to be a risk factor of DHRs. It can be hypothesized that the frequency of HLA
polymorphism might be higher in woman predisposing them to a higher risk of DHR
when compared to males. Especially, when the prevalence of HLA polymorphisms have
proven to be related to gender, such as the case of HLA-B*5701 in males (89%) and
HLA-DR in females (4:1). The difference of HLA-polymorphisms frequency among
genders would explain the higher cases of specific DHRs in one gender than other, such
as hydralazine induced Lupus erythematosus in females mediated by HLA-DR4 and
abacavir induced SJS/TEN mediated by HLA-B*5701 in males 20,47. Although with the
discovery of ancestral haplotypes, it would be expected that both genders equally
inherit the polymorphisms by their ancestors.
In general, the reported incidence of drug toxicity in clinical trials is higher in females
than males 96. This is blamed to the large differences observed in female
23
pharmacokinetics, in particular the differences in metabolism rate. In part, this can also
be substantiated by findings in the association of metabolic conditions and DHRs. The
slow acetylator (NT2) phenotype is needed for the establishment of DHRs under the
treatment of hydralazine, but is HLA-DR-gender specific. In males HLA-DR2 is needed in
combination of NT2 phenotype while HLA-DR4 mediates hydralazine induced DHR in
females. Both genders developed the DHR only when possessing the NT2 phenotype. If
the HLA-DR polymorphisms was present but not the NT2 phenotype, the DHR was not
established.
Based in these results and those found in our review, metabolism seem to be
increasingly important for the establishment of DHR. In our literature review, metabolic
conditions were found alone or in combination with other factors inducing DHR, such as
gender, concomitant viral infections and HLA polymorphisms. CYP450 polymorphisms or
the NT2 metabolic condition (slow acetylator) in combination with HLA polymorphisms
were found reported in DHRs leading to different phenotypes. Surprisingly, not all DHR
involving metabolic conditions included a combination of HLA polymorphisms. Metabolic
conditions/polymorphisms alone are able to exclusively induce DILI. Whereas a
combination of HLA polymorphism and metabolic condition/polymorphism reports both
severe cutaneous adverse reactions and DILI. Based in these observations, it can be
argue that HLA polymorphisms might be mediators of skin adverse drug reactions, and
metabolic polymorphisms alone are able to cause only local damage by the production
of reactive metabolites. Nevertheless, hypersensitivity skin reactions on HIV patients
under sulfamethoxazol treatment were found to be mediated by glutamate cysteine
ligase polymorphisms (OR=2.2) and no HLA associations were found to play a role in
DHR onset.
The role of metabolic conditions/polymorphisms in DHR establishment is thought to be
related by bioactivation of drugs to unstable reactive metabolites or by changes in the
bio-inactivation capacities of metabolic enzymes and last but not least, changes in drug
clearance increasing its toxicity. Although all theories seem logical, these theories need
to be proven in the clinic.
It also appears that a single metabolic condition can be a universal cause of DHR, but
the resulting phenotype is race and HLA dependent. The CYP2BG51GG!T polymorphism
is a universal factor for nevirapine-induced SJS/TEN (OR=1.66). In blacks
CYP2BG51GG!T in combination with HLA-CW*04 mediates SJS/TEN (OR=18.90)
whereas in Asians the same phenotype is observed when CYP2BG51GG!T and HLACW*3505 are found together (OR=3.47-5.65). Such findings corroborates the need in
finding race-specific biomarkers of DHR, as one biomarker should not be considered
24
universal as it would be impossible to extrapolate the same results to other ethnic
groups/populations.
Finally, MHC gene polymorphism other than HLA should also be taken into account in
DHR studies as they were associated with DHRs. In particular, TNFɑ polymorphisms.
Carbamazepine induced DHRs were found to be associated with the haplotype HLADR3-DQ (OR=3.3) in patients under treatment. But only severe cases of cutaneous
ADR where reported in those patients possessing the TNFɑ polymorphisms and the
haplotype HLA-DR3-DQ2. It appears that TNF-ɑ determines the severity of tissue
damage in these patients, but HLA-DR3-DQ2 determines the occurrence of the
hypersensitivity reaction by carbamazepine. The complexity of all factors involved in
DHR urges the need to use genome wide approaches to elucidate underlying factors
and to comprehend the physiopathology of DHR. Such approach will also allow to
assess not only for HLA polymorphisms, but also metabolic conditions and other MHC
gene polymorphisms. These discoveries have shown the complexity of the
pathophysiology of DHR, and suggests for further research focusing not only on HLA
polymorphisms but in other immunologic and metabolic genes as well to fill in the gaps
of the currently unknown pathophysiology of DIH reactions.
25
8. CONCLUSIONS AND FUTURE DIRECTIONS
Based in available literature on DHRs, our thesis hypothesis is accepted. Factors other
than HLA polymorphisms are needed for the establishment of DHRs. Gender,
concomitant viral infections, metabolic conditions/polymorphisms and MHC
polymorphisms other than HLA are all risk factor of DHR. Two or more of these factors
can be found together to elicit an immunological reaction leading to DHR.
The resulting DHR phenotype is race and HLA specific, therefore population-specific
biomarkers should be found by using genome wide approaches. By establishing all the
pieces involved in the physiopathogenesis of the DHRs, a better prevention approach
can be taken to ensure the safety of each patient prior to drug treatment.
Most of the findings mentioned in this thesis were discovered by using the candidate
gene approach which limits the comprehension of the physiopathology of DHR and
other possible underlying factors. By using a broader “omic” approach other genes can
be detected and would facilitate the elucidation of the mechanisms behind every
phenotype. In particular, both metabolic genes and MHC genes should be studied as
were commonly implicated in DHRs. Especial focus should be given to TNF-ɑ
polymorphisms and CYP2 genes.
To again more knowledge on DHR factors and physiopathology, not only efforts in
genomic approaches should be considered but as well in pharmacovigilance and
epidemiology studies. The true incidence and prevalence of DHR might be elucidated in
international pharmacovigilance databases comprising allergologists, toxicologists and
pharmacists and confirmed cases of DHRs from all over the world. With such approach,
the most susceptible population to specific drug/phenotype could be detected to
prevent potential DHR. Also, detecting the most susceptible population would be the
ideal to perform genomic studies as more answers can be obtained.
As well, epidemiology studies should focus in finding the specific differences in
pharmacokinetics and pharmacodynamics among genders and the most susceptible age
stage of DHR, to finally relate such differences in the incidence of DHR. Finally, as part
of preclinical trials, the capacity of a new drug to act as a hapten, prohapten and to
covalently interact with immunological receptors should be evaluated, as it might help
in detecting potential immunotoxic drugs.
26
9.ANNEX I
9.DHRs strongest genetic associations so far discovered
9.1 Carbamazepine:
HLA-B*1502 is the most common HLA polymorphism involved in carbamazepine
induced hypersensitivity reactions and its prevalence is mainly reported in Asian
populations (OR= 2504) 36-42. In the western countries, with mainly Caucasian
population the overall rate of carbamazepine-induce adverse reactions is very low,
estimated to be one to six per 10,000 newly exposed patients and TEN incidence about
0.4-1.2 cases per 10,000 newly exposed patients when compared to Asia 42. The low
frequency of HLA-B*1502 in Caucasians may explain the apparent lower incidence of
carbamazepine-induced SJS/TEN in these populations. Table AI shows the association
of HLA-B*1502 and carbamazepine in DHRs based in ethnicity and Table AII shows the
distribution of the HLA-B*1502 allele among ethnicities.
Table AI. Association of HLA-B*1502 with carbamazepine-induced cutaneous
DHRs ethnicity and phenotype specific.
Phenotype
HLA-B*1502
association
SJS/TEN
SJS/TEN
Positive
Positive
SJS/TEN
SJS/TEN
Positive
Negative in
Caucasians.
Positive in
Asian
ancestry (4/4)
Negative
Positive
Negative
SJS/TEN
HSS/MPE
MPE
# of
patients
showing
association
98% (59/60)
100% (4/4)
100% (6/6)
0% (0/8)
100% (4/4)
0% (0/7)
N/S
100% (0/16)
Ethnicity
Reference
Han Chinese in Taiwan
Han Chinese in Hong
Kong
Thai population
Germany and France;
Vietnam, China,
Cambodia and Reunion
Island
36
14
Japanese
Han Chinese in Taiwan
Han Chinese in Hong
7
37
14
9
40
27
MPE
HSS/MPE
Negative
Negative
Kong
Thai population
Caucasians in United
kingdom
0% (0/9)
N/S
SJS/TEN: Stevens-Johnson/toxic epidermal
Maculopapular eruption. N/S: not specified.
necrolysis.
HSS:
9
43
Hypersensitivity
Syndrome.
MPE:
Table AII. HLA-B*1502 allele frequencies among different populations.
Country
Ethnicity
Taiwan
Hong Kong
Thailand
Malaysia
China
Asian (Han Chinese)
Asian (Han Chinese)
Asian (Thai)
Asian (Malay)
Asian (South
Han/North Han)
Asian (Indian)
Asian (Japanese)
Asian (Korean)
Caucasian
(German/French)
India
Japan
Korea
Europe
HLA-B*1502
Allele frequency
4.3%
7.2%
6.1%
8.4%
7.1%/1.9%
1-6%
0.1%
0.4%
0%
9.2 Allopurinol:
Allopurinol is a drug to treat acid uric excess. The Han Chinese have shown the
strongest genetic predisposition to allopurinol DHRs mediated by HLA-B*5801
(OR=580.30) when compared to Caucasians (OR=80). The most common phenotype is
SJS/TEN and DRESS 8 (Table AIII) . HLA-B*5801 is considered as evenly distributed
among populations 8, 44 (Table AIV).
Table AIII. HLA-B*5801 association with allopurinol-DHRs in different
populations
Ethnicity
Asian (Thai)
Asian (Korean)
Asian
(Japanese)
Asian
(Singapore)
Phenotype
SJS/TEN
Association/OR
Positive (OR
348.3)
SJS/TEN/DRESS
Positive (OR
97.8)
SJS/TEN
Positive
SJS/TEN/DRESS
Positive
Reference
38
45
7
47
28
Asian (Han
Chinese)
Caucasian
(European)
HSS/SJS/TEN
SJS/TEN
Positive (OR
580.3)
Positive (OR 80)
8
40
DRESS= drug rash with eosinophilia and systemic symptoms. HSS=hypersensitivity syndrome. OR=odds
ratio.
Table AIV. HLA-B*5801 distribution among ethnicities.
Ethnicity
HLA-B*5801 frequency
Black (African)
2-4%
Caucasian (European)
1-6%
Japanese
< 1%
Chinese
8.8-10.9%
Other Asians (Indian, Thai)
3-15%
9.3 Abacavir:
Abacavir is a drug used for the treatment of HIV. It is a common cause of SJS/TEN and
HSS in patients under treatment 48 (Table AV). HLA-B*5701 allele was discovered to be
involved in Abacavir DHRs. The Caucasian race has been discovered to be the most
significant factor in abacavir DHRs reactions mediated by HLA-B*5701 (OR=960) 47,50.
HLA-B*5701 can be present in different ethnic groups (frequency <1% in Africans,
Asians) but is mostly reported in White Australian and American populations (Frequency
>3%) for abacavir induced hypersensitivity 47, 48, 50, 54.
Table AV. Populations associated with abacavir-induced severe cutaneous
adverse reactions (SJS/TEN) mediated by HLA-B*5701.
Association
Negative
Country
Korea
Positive
Western
Australia
Population
100%
Korean, 83%
Caucasian,
5% Blacks.
75%
Caucasian.
Reference
51
49
52
29
Positive
UK and
Australia
Positive
USA
Positive
Australia
Positive
USA
9%
Aboriginal,
6% Blacks
84%
Caucasians
14% others.
66%
Caucasians,
19%
Hispanics,
15% Blacks
89%
Caucasian
74%
Caucasians,
11%
Hispanics,
14% Blacks
2% other
53
6
6
47
48
9.4 Nevirapine:
Nevirapine is an antiretroviral drug used for the treatment of HIV. Nevirapine often
causes cutaneous ADR with a frequency of approximately 5% for hypersensitivity
syndrome and 0.3% for SJS/TEN. Several alleles have been discovered in having an
association with nevirapine-induced adverse reaction. Studies show specific HLA
polymorphisms involved in the onset of cutaneous adverse events as race dependent,
particularly HLA-B*3505 in Asians, and HLA-Cw*08 and HLA-DRB*0101 in whites. HLACw*04 has been found in all races inducing DHRs. Table AVI shows all HLA
polymorphisms discovered to mediate nevirapine DHRs.
Table AVI. HLA polymorphism discovered to mediate nevirapine DHRs.
Phenotype
Cutaneous
adverse events
Allele
HLA-Cw*04
Hepatic
adverse effects
HLA-Cw*3505
Ethnicity
All races
(OR=2.5). Blacks
(OR=18.90)
Asians (OR=3.4)
and Thais
(OR=5.65).
Reference
55
30
Cutaneous
adverse events
Cutaneous
adverse events
HLADRB*0101
HLA-Cw*08
Caucasian
(OR=3.02)
Caucasian (6/13)
28
HLA-B*3505
Thai (OR=49.15)
27
31
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