Advances in Clinical Pharmacogenomics and Prevention of Severe Cutaneous Adverse Drug Reactions in the Era of Precision Medicine

Abstract

Severe cutaneous adverse drug reactions (SCARs), including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but severe life-threatening adverse drug reactions. Although their incidence is rare, the mortality rates are as high as 10% for DRESS, 1–5% for SJS and 25–50% for TEN. Recent studies have suggested that HLA genes are associated with SCARs during treatment with causative medicines. The HLA gene is located on chromosome 6p21.1–21.3 and consists of HLA class I, II and III. Interestingly, HLA-pharmacogenomic markers influence these mechanisms of immunopathogenesis in culprit drug-induced SCARs. However, due to genetic differences at the population level, drug-induced SCARs are varied; thus, the specific pharmacogenomic markers for ethnicity might differ among populations. For instance, the HLA-A*31:01 allele is associated with carbamazepine-induced SCARs in Europeans and Japanese individuals, while the HLA-B*15:02 allele is associated with carbamazepine-induced SJS-TEN among Thais, Han Chinese, Taiwanese and Southeast Asians populations. Such differences pose a major challenge to preventing SCARs. Therefore, knowledge of the pharmacogenomics, mechanisms of immunopathogenesis and ethnic-specific genetic variation related to drug-induced SCARs is needed.

1. Introduction

Over the last decade, precision medicine has developed diagnostic methods and focused on delivering the right treatments to individual patients by the integration of big data, artificial intelligence, genetics, omics, pharma, cogenomics, and environmental and social factors [1, 2]. In addition, physicians, pharmacists, health systems, policymakers and patients have recognized advances in precision medicine and led to powerful discoveries of genetic variations with interindividual differences [3]. Interestingly, the knowledge of pharmacogenomics has been associated with causative drug-induced severe cutaneous adverse reactions (SCARs) as a biomarker in clinical precision medicine and innovation for therapeutic decisions in many countries [4, 5, 6, 7].

Severe cutaneous adverse reactions (SCARs) are a delayed type of T-cell-mediated adverse drug reaction and are a major cause of morbidity and life-threatening [8]. SCARs include drug-induced hypersensitivity syndrome (DIHS), drug reactions with eosinophilia and systemic symptoms (DRESS), hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalized exanthematous pustulosis (AGEP) [9, 10, 11]. Previous studies have suggested that drug-induced SCARs are genetically influenced by human leukocyte antigen (HLA), peptide and T lymphocytes [12, 13, 14]. Particularly, the function of HLA genes is to present antigen or peptide to T lymphocytes. Research on the HLA genes and phenotypes of drug-induced SCARs has confirmed the use of pharmacogenomic biomarkers for screening in many populations. Therefore, we focused on clinical pharmacogenomics and causative drug-induced severe cutaneous adverse reactions over the past decade. Moreover, we discuss the influence of human leukocyte antigen (HLA) genes related to pharmacogenomic markers, mechanisms of immunopathogenesis in drug-induced SCARs, and ethnic-specific genetic variation and provide a rationale for predicting clinical precision medicine and therapeutic decisions.

2. Severe cutaneous adverse drug reactions (SCARs): epidemiology, etiology and clinical manifestations

Severe cutaneous adverse drug reactions (SCARs) represent a collection of rare but potentially fatal dermatological conditions that have garnered increasing attention in both clinical and research settings. SCARs arising from drug use are linked to significant health issues, increased mortality rates, elevated healthcare expenses, and substantial challenges in drug development. Epidemiological studies have revealed that SCARs encompass a wide range of conditions, primarily Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reactions with eosinophilia and systemic symptoms (DRESS) and acute generalized acute pustulosis (AGEP) syndrome, which are characterized by a low incidence rate but a high mortality rate, making them a significant concern for healthcare providers [15, 16].

Although rare, according to a review article by Wen-Hung CHUNG and it impacts approximately 2% of patients admitted to hospitals, with an annual occurrence ranging from 2 to 7 cases per million for SJS/TEN and 1 in 1000 to 1 in 10,000 instances of exposure to the causative agents in DRESS [9]. However, the mortality rates for these conditions differ, with approximately 5–10% for SJS, 10–25% for SJS/TEN overlap, 25–50% for TEN, and 10% for DRESS [17, 18, 19]. The etiology of SCARs is multifactorial and involves a complex interplay of genetic predisposition, immune dysregulation, and exposure to specific medications, with a range of drugs implicated as potential culprits. Interestingly, this diversity of genetics in causal agents has made it complicated to predict and prevent SCARs in clinical practice.

Clinically, SCARs manifest with a spectrum of severe cutaneous and mucosal manifestations, including blistering, epidermal detachment, and mucous membrane involvement, frequently accompanied by systemic symptoms. Epidemiological trends, underlying etiological factors, and the clinical presentation of SCARs, shed light on the difficulties and necessity of early diagnosis and treatment in managing these rare yet devastating drug-induced SCARs [11].

2.1 Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and its more severe form the Toxic epidermal necrolysis (TEN) is a rare yet life-threatening dermatological condition characterized by severe cutaneous adverse reactions (SCARs) characterized by extensive skin detachment and mucous membrane involvement. SJS is was defined as skin detachment of less than 10% of the total body surface area (BSA). SJS/TEN overlapping involved skin detachment of 10–30% of the BSA (Figure 1), while TEN is considered detachment of greater than 30% of the total BSA [17, 20]. Furthermore, approximately 50–95% of SJS-TEN cases are related to medication exposure. Symptoms of SJS and TEN usually occur 4–28 days after exposure to drugs, such as antiepileptic drugs (AEDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and specific antibiotics [21]. However, the incidence rate of SJS-TEN differs among ethnicities.

Figure 1.

Clinical presentations of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlapping were performed by focusing on skin detachment of 10–30% of BSA. The prodromal phase is the first symptom and consists of fever, malaise (flu-like) and stinging eyes, sore throat and multiple internal organs.

However, the prevalence in the East Asian population is greater than that in other populations (11). According to the data from the incidences reported from Korea during 2010–2013, SJS and TEN were 3.96–5.03 and 0.94–1.45, respectively [22]. The characteristics of SJS-TEN are painful blistering skin detachment, stinging eyes, malaise, fever, headache, sore throat and multiple internal organ involvement (cardiovascular, pulmonary, gastrointestinal, and genitourinary system) [21, 23]. Erythrodermic rash eruption first affects the face, upper torso, and proximal extremities. Erythematous, purpuric macules with irregular or dusky-red macules and atypical target lesions are the initial lesions identified (typically beginning to appear approximately 4–28 days after treatment initiation in drug) that develop into fluid-filled bullae and necrotic keratinocytes and epidermal separation from the dermis, referred to as a positive Nikolsky sign [24, 25, 26]. Furthermore, other factors that increase the risk of developing SJS and TEN are HIV infection, Mycoplasma pneumoniae infection, other viruses (such as herpes simplex virus, HSV; cytomegalovirus, CMV; and human herpes virus 6, HHV-6) and hematologic malignancies [21]. The most significant factors contributing to mortality in the initial stages of the disease seem to be the severity of the illness, the onset of the reactions, advanced age, underlying disease and the number of skin detachment conditions, which are the primary factors associated with higher mortality rates.

Individuals who survive reactions such as SJS/TEN face a substantial risk of enduring complications that affect various bodily systems, including the dermatological system, eyes, mucous membranes, and respiratory, renal, and hepatic systems [27]. In light of these multifaceted challenges and the profound impact of SCARs on individuals and healthcare systems, there is a pressing need for continued pharmacogenomic research and clinical vigilance.

2.2 Drug reaction with eosinophilia and systemic symptoms (DRESS)

DRESS syndrome is a rare but potentially life-threatening drug-induced hypersensitivity syndrome distinguished by a collection of clinical symptoms, including fever (ranging from 38 to 40°C), widespread skin rash, facial edema, lymphadenopathy, hematological abnormalities (eosinophilia and atypical lymphocytes are usually found in more than 90 and 50% of cases, respectively) and the involvement of one or multiple organ systems, such as hepatitis, interstitial nephritis, myocarditis, pneumonitis and neurological involvement [19, 28]. Due to its extensive clinical presentation, DRESS rash is often polymorphic and includes maculopapular exanthema, which is the most common initial skin manifestation; purpuric, lichenoid, exfoliative, urticarial, and eczema-like lesions; blisters; and pustular lesions [29, 30]. In previous studies, we found that the estimated incidence of DRESS ranged from 1 in 1000 to 1 in 10,000 after drug exposure [31]. DRESS typically develops 2–8 weeks (average 22.2 days) after exposure to the culprit medication or many months after the drug has been discontinued, and the mortality rate is 10% [11, 32]. Additionally, the clinical presentation of DRESS was not significantly different between children and adults [30]. In clinical practice, the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring system has been used to establish diagnoses for DRESS syndrome [33]. Against this backdrop, the RegiSCAR scoring system has emerged as an indispensable tool in the field of DRESS syndrome diagnosis and classification. Its fundamental purpose is to stratify DRESS cases into four discrete tiers, namely, “no,” “possible,” “probable,” or “definite” cases, based on a comprehensive evaluation of clinical presentation and laboratory findings with drug causality assessment [34, 35]. This systematic categorization not only refines the diagnostic process but also enhances our ability to differentiate DRESS from related severe cutaneous adverse reactions, a critical aspect of accurate patient management. Furthermore, the incidence of common culprit drug-induced DRESS caused by anticonvulsants has been reported. (phenytoin, carbamazepine, lamotrigine and phenobarbital), allopurinol, antibiotics (amoxicillin, ampicillin, azithromycin, levofloxacin, minocycline and vancomycin), sulfonamides (sulfamethoxazole-trimethoprim, dapsone and sulfasalazine) and antiviral drugs (abacavir and nevirapine) [11, 36]. Nevertheless, the impact of viral infection influences the pathophysiology, perturbation of the immune response and cause of DRESS syndrome caused by viruses such as human herpesvirus (HHV-6 and HHV-7), Epstein–Barr virus (EBV), cytomegalovirus (CMV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [31, 36, 37].

2.3 Acute generalized exanthematous pustulosis (AGEP)

Acute generalized exanthematous pustulosis (AGEP) is an uncommon severe adverse cutaneous reaction distinguished by the prompt emergence of numerous nonfollicular, aseptic pustules that are primarily located within the epidermal layer [38]. Furthermore, patients afflicted by AGEP typically exhibit accompanying clinical features, including fever (more than 38°C), leukocytosis (greater than 10,000 cells/mm³), and neutrophilia (greater than 7000 cells/mm³), which are commonly observed elements of this condition. Moreover, we detected clinical manifestations such as eosinophilia (approximately 30% of patients), hepatic dysfunction, renal failure, acute respiratory distress syndrome and lymphadenopathy [11, 39]. Compared with SJS-TEN and DRESS, AGEP is typically regarded as having a less severe clinical course, with a mortality rate less than 5% and an incidence of 1–5 patients per million per year [40, 41]. The onset of AGEP typically occurs within 24–48 hours after treatment starts with the causative drug [42].

Additionally, the most common medications that frequently triggered AGEP in the Asian population are penicillins, cephalosporins (ceftriaxone and cefuroxime), vancomycin and quinolones [40]. According to the data from spontaneous reports from 1984 to 2021 by the Health Product and Vigilance Center of Thailand, the culprit medications causing AGEP include ceftriaxone, clindamycin, ceftazidime, meropenem and amoxicillin-clavulanic acid. (https://hpvcth.fda.moph.go.th/spontaneous-2021/).

3. Human leukocyte antigen (HLA) gene and immune response

The human leukocyte antigen (HLA) is a substantial genetic entity, holding a pivotal position within the immune system. In humans, the HLA gene resides on the short arm of chromosome 6 (6p21.1–21.3), boasts an extensive repertoire of genes exceeding a count of 200 and belongs to the major histocompatibility complex (MHC) protein family [43, 44]. HLAs are classified by structure and function and are composed of HLA class I, II and III, as shown in Figure 2 [45]. However, only two primary classes exist: HLA class I and HLA class II genes, which are strongly associated with drug-induced SCARs [46, 47, 48].

Figure 2.

Human leukocyte antigen (HLA) is a group of highly polymorphic genes located on chromosome 6p21.1–21.3. The HLA gene consists of HLA class I, II and III. In particular, HLA class I (HLA-A, HLA-B, and HLA-C) and II (HLA-DP, HLA-DQ and HLA-DR) genes were associated with drug-induced SCARs. The structure of HLA class I (comprising the alpha chain; α1, α2, α3 and beta-2 microglobulin; β2 m) and HLA class II (comprising the alpha chain; α1, α2 and the beta chain; β1, β2).

HLA class I molecules are located on nucleated cell surfaces and serve as media tors for presenting intracellular pathogen-derived antigens (e.g., viruses, certain bacteria, drugs) to cytotoxic T lymphocytes (CD8+ T lymphocytes) [49]. Their structure comprises a heavy chain (α-chain) consisting of three domains (α1, α2, and α3), with α1 and α2 forming a peptide-binding groove for antigenic peptide accommodation.

Beta-2 microglobulin (β2 m), a smaller non-HLA-encoded protein, associates with the α3 domain, ensuring HLA class I molecule stability (Figure 2). These molecules specifically bind short peptide antigens (usually 8–10 amino acids) from intracellular pathogens, which are inserted into the peptide-binding groove created by the α1 and α2 domains of the heavy chain [50]. The HLA class I alleles, which present molecules for CD8+ T lymphocytes, are further split into HLA-A, HLA-B, and HLA-C genes [51].

HLA class II molecules are primarily located on antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells. They facilitate the presentation of antigens from extracellular pathogens to helper T lymphocytes (CD4+) [52]. HLA class II structures are more intricate than HLA class I structures and consist of two chains, the alpha chain (α-chain), which is encoded by HLA-D genes and features α1 and α2 domains that form a peptide-binding groove, and the beta chain (β-chain), which is encoded by the HLA-DP, HLA-DQ and HLA-DR genes and consists of the β1 and β2 domains (Figure 2). Peptide antigens sent by HLA class II are generally longer (typically 13–25 amino acids) and originate from extracellular pathogens digested by antigen-presenting cells [53]. Both HLA class I and class II molecules exhibit significant genetic diversity among individuals, enabling the immune system to recognize a broad array of pathogens. Recognition of antigens by T-cell receptors on T lymphocytes, based on HLA presentation, can initiate immune responses to eliminate infected cells or coordinate immune actions, depending on the type of T lymphocytes involved (CD8+ or CD4+) [54].

4. Mechanisms of immunopathogenesis in drug-induced SCARs

4.1 Hapten/ProHapten concept

In the late nineteenth century, experiments showed that small, nonimmunogenic molecules could become immunogenic when attached to larger carriers. Karl Landsteiner coined the term “hapten” in the early twentieth century while studying blood groups and these immunogenic compounds. By the mid-twentieth century, the hapten theory became crucial in understanding allergic reactions, explaining how haptens (drugs) create new antigenic determinants when bound to proteins. Today, this theory clarifies immune responses to various substances, including drugs and allergens, especially in drug-induced hypersensitivity reactions and SCARs. The process starts with exposure to a potential hapten-forming drug. Haptens, which are inherently nonimmunogenic small molecules, then covalently attach to endogenous proteins, forming drug-protein complexes (hapten-protein adducts) [55, 56, 57]. These complexes are considered foreign due to their drug or modified drug content. Immune cells, notably T lymphocytes, play has a vital role in recognizing foreign antigens, with T lymphocytes identifying antigenic peptides presented by human leukocyte antigen (HLA) molecules on cell surfaces, as presented in Figure 3. HLA molecules are responsible for presenting antigens to T lymphocytes. In drug-induced immune responses, HLA molecules present drug- protein complexes to T lymphocytes as antigens, especially in SCARs such as SJS and TEN. Cytotoxic CD8+ T lymphocytes are often central to this process, leading to the destruction of skin and mucosal tissues and severe skin and mucosal reactions. Immune-mediated tissue damage is initiated by activated immune cells, mainly cytotoxic T lymphocytes, triggering inflammation in affected cells.

Figure 3.

Mechanisms of immunopathogenesis in drug-induced SCARs consisting of 4 theories of interactions between HLA, drugs, peptides and T lymphocytes: the Hapten theory (model 1), the Prohapten theory (model 2), the pharmacological interaction (p-i) concept (model 3) and the altered peptide repertoire model (model 4). APC, antigen-presenting cell; HLA, human leukocyte antigen; TCR, T-cell receptor.

The prohapten theory extends the hapten theory, which proposes that certain drugs, referred to as prohapten, become immunogenic through metabolic transformations. These changes convert prohapten into highly reactive reactive intermediates that covalently bind to endogenous proteins, forming drug-protein complexes (hapten-protein adducts) [58, 59]. These complexes, considered foreign, contain the drug or its modified forms. T lymphocytes, which are receptors that recognize antigens presented by HLA molecules, are central to this process. In the prohapten.

In theory, HLA molecules present drug-protein complexes to T lymphocytes as antigens, potentially leading to various immune-related conditions, including severe cutaneous adverse drug reactions such as SJS and TEN.

4.2 Pharmacological interaction (p-i) concept

The p-i interaction theory elucidates how certain drugs or their metabolites directly engage the immune system, particularly immune cells such as T lymphocytes. These drugs or metabolites feature chemical structures known as “pharmacophores” capable of binding to specific sites on immune proteins or cell receptors (Figure 3). This interaction, which is typically noncovalent but potent, initiates an immune response involving various immune cells, such as T lymphocytes and B lymphocytes. Immune system activation by pharmacophores can result in immune-mediated effects, including inflammation, cellular damage, and hypersensitivity reactions.

HLA molecules play a role in the presentation of drug-derived antigens to CD4+ T lymphocytes (helper T lymphocytes), further activating immune responses. This coordinated immune response can lead to diverse clinical outcomes, including allergic reactions and hypersensitivity [60, 61, 62, 63].

4.3 Altered peptide repertoire model

In this mechanistic model, the drug engages in a noncovalent interaction with the HLA binding site, subsequently inducing a discernible shift in the chemical landscape of the binding cleft and the repertoire of endogenous peptides. This modification exerts a transformative influence on the selection and presentation of peptide ligands critical for the activation of T-cell receptors (TCRs) [64, 65]. The seminal research by Norcross et al. [66] underscores the noncovalent binding of abacavir to the HLA-B*57:01 molecule, instigating pronounced alterations in the peptide-binding capacity of the HLA-B*57:01 molecule, thereby affecting a profound transformation in the array of endogenous peptides made available for presentation to TCRs, as shown in Figure 3.

5. Pharmacogenomics of drug-induced SCARs

A deeper understanding of the immunopathogenesis mechanisms and HLA genes underpinning drug-induced SCARs, along with the identification of the pharmacogenomic markers in each ethnicity, is needed to improve the risk stratification of culprit drug-induced SCARs for the primary prevention and management of individual patients.

Carbamazepine (CBZ) is commonly prescribed for bipolar disorders, chronic or neuropathic pain and seizures [67], and other studies have shown that it induces patients to suffer from SJS and TEN. Some HLA alleles are commonly known as powerful predictive pharmacogenomic markers for SJS/TEN and DRESS in many populations. SJS/TEN is characterized by skin erythema, severe epidermal detachment, and mucous membrane disintegration. In Southeast Asian populations, the most pronounced marker from CBZ-induced SJS and TEN was found to be HLA-B*15:02 [68]. In particular, the strong association between HLA-B*15:02 and car- bamazepine-induced SJS/TEN in Han Chinese (odds ratio 2504, p value = 3.13 × 10⁻²⁷) [69], Malaysian (odds ratio 221.0, p value = 0.0006) [70], and Indian (odds ratio 71.40, p value = 0.0014) [71] and Thailand (odds ratio 54.43, p value = 2.89 × 10⁻¹²) [72], as presented in Table 1. By comparison, HLA-A*31:01 was the main genetic determinant for carbamazepine-induced SJS, TEN and DRESS in Japanese individuals (odds ratio 10.8, p value = 0.0004) [73] and Europeans (odds ratio 25.93, p value = 8.0 × 10⁻⁵) and (odds ratio 12.41, p value = 0.03), respectively [74]. Previous studies by Rika Yuliwulandari et al. revealed that the HLA-B*15:02 and HLA-B*15:21 alleles in Indonesian patients were members of the HLA-B/5 serotype, which was significantly associated with CBZ-induced SJS/TEN [80]. Oxcarbazepine (OXC) is an antiepileptic drug (AED) and a ketoanalog of CBZ. OXC blocks voltage-dependent sodium channels in the brain. Therefore, OXC is used for the treatment of partial seizures in patients who are unable to tolerate CBZ [81]. Similarly, based on the chemical structures of CBZ and OXC, SJS-TEN can be induced. Previous studies revealed that the cross-reactivity between carbamazepine-induced SJS-TEN and oxcarbazepine-induced SJS was associated with the HLA-B*15:02 allele in an Asian population [75].

Drugs	HLA markers	SCARs	Ethnic	OR (95% CI)	p value	References
Carbamazepine	HLA- B*15:02	SJS/TEN	Han Chinese	2504 (126–49,522)	3.13 × 10^−27	[69]
			Malaysian	221.0 (3.85–12,694.65)	0.0006	[70]
			Indian	71.40 (3.0–1698)	0.0014	[71]
			Thais	54.43 (16.28–181.96)	2.89 × 10^−12	[72]
	HLA- A*31:01	SCARs	Japanese	10.8 (5.9–19.6)	0.0004	[73]
		SJS-TEN	Europeans	25.93 (4.93–116.18)	8.0 × 10^−5	[74]
		HSS		12.41 (1.27–121.03)	0.03
		MPE		8.33 (3.59–19.36)	8.0 × 10^−7
Oxcarbazepine	HLA- B*15:02	SJS	Han Chinese	80.7 (3.8–1714.4)	8.4 × 10^−4	[75]
Allopurinol	HLA- B*58:01	SJS-TEN	Thais	579.0 (29.5–11,362.7)	< 0.001	[76]
		DRESS		430.3 (22.6–8958.9)	< 0.001
		MPE		144.0 (13.9–1497.0)	< 0.001
Abacavir	HLA- B*5/:01	ABC- HSRs	Europeans	29 (6.4–132.3)	< 0.0001	[77]
Cotrimoxazole	HLA- B*15:02	SJS-TEN	Thais	5.16 (1.63–16.33)	0.0075	[78]
	HLA- B*13:01	DRESS		15.20 (3.68–62.83)	7.2 x 10^−5
Dapsone	HLA- B*13:01	DHS	Han Chinese	20.53 (11.55–36.48)	6.84 x 10^−25	[79]
		SCARs	Thais	39.00 (7.67–198.21)	5.3447 × 10^−7
		SJS-TEN		36.00 (3.19–405.89)	2.1657 × 10^−3	[35]
		DRESS		40.50 (6.38–257.03)	1.0784 × 10^−5

Table 1.

The pharmacogenomic markers associated with drug-induced SCARs.

HLA-A, human leukocyte antigen-A; HLA-B, human leukocyte antigen-B; ABC-HSRs, abacavir hypersensitivity reactions; DRESS, drug reactions with eosinophilia and systemic symptoms; DHS, dapsone hypersensitivity syndrome; HSS, hypersensitivity syndrome; MPE, maculopapular exanthema; SCARs, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. OR, odds ratio; 95% CI, 95% confidence interval;

The p value and probability value were calculated using Fisher’s exact test or the chi-square test.

Allopurinol is a xanthine oxidase inhibitor and is commonly used for treatment of chronic gout, preventing tumor lysis syndrome (TLS) and preventing recurrent calcium nephrolithiasis in hyperuricosuria patients [82, 83]. However, allopurinol is one of the drugs most commonly associated with SJS and TEN [84]. Many studies have shown that the HLA-B*58:01 allele is strongly associated with allopurinol-induced SJS/TEN [85, 86, 87, 88], which is similarly distributed in 7.38% of Asians (6.37%). Of African Americans, 6.38% of which were Thais, which was higher than that of Caucasians (1.13%) and Hispanics (1.07%) [89]. Research revealed an association between the HLA-B*58:01 allele and allopurinol-induced SJS-TEN in Thai patients (odds ratio 579.0). p value <0.001) and allopurinol-induced DRESS (odds ratio 430.3, p value <0.001) and allopurinol-induced MPE (odds ratio 144.0, p value <0.001). Thus, HLA-B*58:01 can be used as a universal pharmacogenomic marker for allopurinol-induced cutaneous adverse drug reactions (CADR) [76].

Abacavir (ABC) is a nucleoside reverse transcriptase inhibitor (NRTI) used to treat human immunodeficiency virus 1 (HIV-1) infection in both adults and children. However, abacavir hypersensitivity reactions (ABC-HSRs) are potentially life-threatening, with a mortality rate of 0.03% [90]. In addition to the clinical manifestations present within 6 weeks, ABC-HSRs usually develop in approximately 5–8% of patients after the initiation of treatment [91]. ABC-HSRs are a multiorgan process that occurs only in patients expressing HLA-B*5/:01 [92]. A previous study reported associations between HLA-B*5/:01 and ABC-HSRs in HIV-infected participants in Western Australia. The HLA-B*5/:01 allele was present in 14 (78%) of the 18 participants with ABC-HSRs and in four (2%) of the 167 abacavir-tolerant participants (odds ratio 117, p value <0·0001) [93]. Furthermore, Dyfrig A. Hughes et al. reported a pooled odds ratio of 29 and a p value <0.0001 [77].

Cotrimoxazole (sulfamethoxazole and trimethoprim) is an antimicrobial used for the treatment and prophylaxis of Pneumocystis jirovecii pneumonia (PJP) in HIV patients and toxoplasmic encephalitis patients [94, 95]. Nonetheless, patients treated with cotrimoxazole reportedly develop cotrimoxazole-induced SCARs (SJS-TEN and DRESS). From 1984 to 2021, the Health Product and Vigilance Center of Thailand reported a list of causative medicines for causing SCARs in Thais, cotrimoxazole was the most common culprit drug causing SCARs, and SJS-TEN was the third most common culprit drug causing DRESS. Associations were found between the HLA-B*15:02 allele and cotrimoxazole-induced SJS/TEN (odds ratio = 5.16, p value = 0.0075) and between the HLA-B*13:01 allele and cotrimoxazole-induced DRSS (odds ratio = 15.20, p value = 7.2x10^–5) in Thai patients (https://hpvcth.fda.moph.go.th/spontaneous-2021/) [78]. Consequently, the HLA-B*13:01 and HLA-B*15:02 alleles are associated with co trimoxazole-induced DRESS and SJS-TEN, respectively.

Dapsone is widely used for treating infections (leprosy, Pneumocystis jiroveci pneumonia (PJP) and Toxoplasma gondii encephalitis in patients with HIV infection) and inflammatory disease. Moreover, dapsone-induced DRESS has an important influence on the mortality rate of 9.9% [96]. However, recently, many studies have investigated dapsone-induced DRESS in Thais and Han Chinese people. We found that the HLA-B*13:01 allele was strongly associated with dapsone-induced DRESS (OR = 40.50, p value = 1.0784 × 10⁻⁵) in the Thai population (OR = 20.53, p value = 6.84 × 10⁻²⁵) in Han Chinese [35, 79]. Moreover, the HLA-B*13:01 allele was significantly associated with dapsone-induced SJS-TEN, with an OR of 36.00 (p = 2.1657 × 10^–3) in Thai patients (Table 1).

6. Conclusion

Severe cutaneous adverse reactions (SCARs) are rare and life-threatening in many ethnicities. Notwithstanding the important role of HLA gene pharmacogenomic biomarkers related to drug-induced SCARs, precision medicine has improved the safety, efficacy and therapeutic decision-making process in this decade. Recent studies have shown that pharmacogenomic markers are effective at increasing the number of diagnoses and designing causative drug-induced SCAR protection and supporting clinical pharmacogenomic implementation.

Acknowledgments

This study was supported by grants from the (1) College of Pharmacy, Rangsit University, (2) Research Institute of Rangsit University and (3) Doctor Kasem Foundation (049/2565). The authors would like to acknowledge the staff of the Excellence of Pharmacogenomics and Precision Medicine Centre, College of Pharmacy, Rangsit University, National Biobank of Thailand (NBT) and Pharmacogenomics and Personalized Medicine of Ramathibodi Hospital, Mahidol University. Moreover, we truly appreciate Prof. Chonlaphat Sukasam and Dr. Vorapon Mahakaew for their suggestion and support, participants in our research and Miss Rajira Saisua and Mr. Puripob Warinhomhuan for graphic design of the figures in this manuscript.

Conflicts of interest

The authors have no conflicts of interest to declare.

Abbreviations

ABC-HSRs	abacavir hypersensitivity reactions
AED	antiepileptic drugs
AGEP	acute generalized exanthematous pustulosis
APCs	antigen-presenting cells
BSA	body surface area
CADR	cutaneous adverse drug reactions
CBZ	carbamazepine
CMV	cytomegalovirus
DIHS	drug-induced hypersensitivity syndrome
DRESS	drug reaction with eosinophilia and systemic symptoms
EBV	Epstein–Barr virus
HHV	human herpesvirus
HIV-1	human immunodeficiency virus 1
HLA	human leukocyte antigen
HSS	hypersensitivity syndrome
HSV	herpes simplex virus
MHC	major histocompatibility complex
MPE	maculopapular exanthema
NRTIs	nucleoside reverse transcriptase inhibitors
NSAIDs	nonsteroidal anti-inflammatory drugs
OXC	oxcarbazepine
p-i	pharmacological interaction
PJP	pneumocystis jiroveci pneumonia
RegiSCAR	registry of severe cutaneous adverse reactions SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 (SCARs) severe cutaneous adverse drug reactions
SJS	Stevens–Johnson syndrome
SJS/TEN	overlap Stevens-Johnson syndrome/toxic epidermal necrolysis overlapping
TCR	T-cell receptor
TEN	toxic epidermal necrolysis
TLS	tumor lysis syndrome