Biomolecules & Therapeutics 2024; 32(1): 1-12  https://doi.org/10.4062/biomolther.2023.170
Immunological Mechanisms in Cutaneous Adverse Drug Reactions
Ai-Young Lee*
Department of Dermatology, Dongguk University Ilsan Hospital, Goyang 10326, Republic of Korea
*E-mail: lay5604@naver.com
Tel: +82-31-961-7250, Fax: +82-31-961-7695
Received: September 22, 2023; Revised: October 10, 2023; Accepted: October 23, 2023; Published online: January 1, 2024.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Adverse drug reactions (ADRs) are an inherent aspect of drug use. While approximately 80% of ADRs are predictable, immune system-mediated ADRs, often unpredictable, are a noteworthy subset. Skin-related ADRs, in particular, are frequently unpredictable. However, the wide spectrum of skin manifestations poses a formidable diagnostic challenge. Comprehending the pathomechanisms underlying ADRs is essential for accurate diagnosis and effective management. The skin, being an active immune organ, plays a pivotal role in ADRs, although the precise cutaneous immunological mechanisms remain elusive. Fortunately, clinical manifestations of skin-related ADRs, irrespective of their severity, are frequently rooted in immunological processes. A comprehensive grasp of ADR morphology can aid in diagnosis. With the continuous development of new pharmaceuticals, it is noteworthy that certain drugs including immune checkpoint inhibitors have gained notoriety for their association with ADRs. This paper offers an overview of immunological mechanisms involved in cutaneous ADRs with a focus on clinical features and frequently implicated drugs.
Keywords: Adverse drug reactions, Skin, Immunological mechanisms, Clinical features, Culprit drugs
INTRODUCTION

The skin serves as the human body’s initial defense against environmental hazards, serving not only as a physical barrier but also as an active immune organ. Immune responses originating in the skin can be categorized into innate inflammatory reactions and adaptive reactions (Bangert et al., 2011; Sharma et al., 2019). The former involves the recognition of microbial compounds by specific receptors like Toll-like receptors, followed by the activation of signaling pathways. These responses are relatively non-specific and lack memory. Conversely, the latter responses, relying on antigen-presenting cells, T cells, and B cells, exhibit a high level of specificity and memory. T cells play a pivotal role in orchestrating host immune reactions in the skin (Ho and Kupper, 2019). Dendritic cells, encompassing epidermal Langerhans cells and dermal dendritic cells, serve as antigen-presenting cells. They capture exogenous antigens, migrate to draining lymph nodes, and present the processed antigens to T cells, thereby driving T-cell differentiation and activation (Loser and Beissert, 2007). The generation of antigen-specific effector T cells is required for effective immune reactions.

Drugs are chemical substances administered for the investigation, prevention, or treatment of diseases or symptoms. Drug exposure can lead to various adverse reactions that impact different body organs and systems, such as the liver, kidneys, respiratory tract, hematologic system, nervous system, and skin. Adverse drug reactions (ADRs) can be categorized based on the number of involved body organs (single organ-specific or multiple), their dependence on drug dosage (dose-related or dose-unrelated), or their underlying mechanism (immunological or non-immunological) (Brockow and Romano, 2008; Kuljanac, 2008). ADRs are further classified as immediate and non-immediate (delayed) based on the time elapsed from the last drug administration to the onset of symptoms. Non-immediate ADRs are defined differently, occurring at least 1 h or more than 6 h after the initial drug administration (Limsuwan and Demoly, 2010; Rodilla et al., 2010; Romano et al., 2017; Lehloenya et al., 2020). Approximately 80% of ADRs are predictable, showing an association with the prescribed dose and the known pharmacological actions of the drug. Conversely, unpredictable reactions are dose-independent and unrelated to the drug’s pharmacological actions.

Drugs are typically designed to minimize interactions with the immune system. However, in some cases, drugs can inadvertently trigger an immune system-mediated response (Redwood et al., 2018), leading to what is known as a drug hypersensitivity reaction or drug allergy. Immunological ADRs are inherently unpredictable, dose-unrelated, and sensitization to causative drugs-required, while non-immunological drug reactions can either be predictable or unpredictable (Table 1). Notably, the skin is the most commonly affected organ, accounting for approximately 45% of all ADRs (Zhang et al., 2019; Del Pozzo-Magaña and Liy-Wong, 2022). Cutaneous ADRs occur in 2-3% up to 10% of hospitalized patients (Bigby et al., 1989; Babu and Belgi, 2002; Hussein, 2016; Zalewska-Janowska et al., 2017). These cutaneous ADRs typically involve off-target reactions with immunological mechanisms. In recent years, the use of immune checkpoint inhibitors (ICIs) has seen rapid growth due to their effectiveness in cancer treatment. However, these drugs can lead to immune-related adverse events (irAEs), with cutaneous ADRs being the most common (Sibaud et al., 2016; Plachouri et al., 2019; Bhardwaj et al., 2022; Seervai et al., 2022; Watanabe and Yamaguchi, 2023). This highlights the substantial evidence supporting the involvement of immunologic mechanisms in cutaneous ADRs. Additionally, human immunodeficiency virus (HIV) can disrupt the immune system. During HIV infection, delayed immune-mediated adverse reactions are up to 100 times more common, with the skin being the most affected organ (Chimbetete et al., 2023). This further underscores the close relationship between cutaneous ADRs and immune mechanisms. This review explores the immunological mechanisms associated with ADRs in the skin.

Table 1 Immunological ADRs vs non-immunological ADRs

ADRs
ImmunologicalNon-immunological
IncidenceUncommonCommon
Sensitization to causative drugsRequiredNot required
Dose-dependencyIndependentDependent or independent
PredictabilityUnpredictablePredictable or unpredictable

GENERAL OVERVIEW OF IMMUNOLOGICAL MECHANISMS IN ADRS

To trigger an immune response, antigens are necessary to stimulate the immune system. However, drugs are generally too small to qualify as complete antigens. Drugs fall into two categories: chemically reactive substances (known as haptens) or chemically non-reactive small compounds (referred to as prohaptens). Prohaptens must undergo metabolic transformations to convert into chemically reactive haptens, which can then form complexes with endogenous proteins or peptides. These hapten-protein or hapten-peptide complexes are taken up by antigen-presenting cells, processed, and subsequently covalently bound to major histocompatibility complex (MHC) molecules. They are then presented to specific T cells, inciting cellular and/or humoral immune responses. In addition to forming hapten-biomolecule conjugates, drugs and/or metabolites can also directly interact with MHC molecules and T-cell receptors through non-covalent interactions, leading to immune responses. This latter explanation, which departs from the classical hapten theory, is referred to as the pharmacological interactions with immune receptor (p-i) concept (Fig. 1) (Roujeau, 2006; Brockow and Romano, 2008; Pavlos et al., 2015; Pirmohamed et al., 2015; Chen et al., 2018; Pichler, 2019; Han et al., 2022; Wilkerson, 2022; Wuillemin et al., 2022).

Figure 1. Proposed mechanisms to provoke immune reactions in immunological ADRs. Hapten theory (left): Covalent binding between drug antigens (hapten-protein or hapten-peptide complexes) and MHC molecules in antigen-presenting cells (APC) is necessary to present to specific T cells. P-I concept (right): Drugs and/or metabolites directly interact with MHC molecules and T cell receptors (TCRs) via non-covalent interaction.

There are four types of hypersensitivity reactions classified by Gell and Coombs (Dispenza, 2019). Immune-mediated ADRs can be classified based on the primary immune cell involved (Redwood et al., 2018) and the Gell and Coombs classification (Wilkerson, 2022). B-cell-mediated reactions correspond to Gell-Coombs types I-III, while T-cell-mediated reactions correspond to Gell-Coombs type IV (Roujeau, 2006; Brockow and Romano, 2008; Pichler, 2019; Han et al., 2022; Wilkerson, 2022). Type I reactions are characterized by immunoglobulin E (IgE)-mediated immediate responses (Fig. 2A, 2B), whereas type IV reactions involve drug-reactive T cells, resulting in delayed hypersensitivity reactions (Fig. 3). Type II reactions entail complement-dependent cellular cytotoxicity reactions mediated by specific IgG or IgM on the surface of erythrocytes, leukocytes, and/or platelets, potentially leading to hemolytic anemia, granulocytopenia, and thrombocytopenia depending on the target cells. Type III reactions are immune complex-mediated, involving the binding of specific IgG or IgM with drugs. These complexes can accumulate in host tissues and activate complements, giving rise to conditions such as vasculitis, arthralgia, or serum sickness. The distinction between Gell-Coombs types I and IV is useful for estimating the immunological mechanisms involved, particularly in terms of the time elapsed between the last drug administration and the onset of symptoms, whether immediate or non-immediate.

Figure 2. Overviews of IgE-mediated immediate hypersensitivity reaction. (A) Proliferation and differentiation of B cells by antigen-specific T cells. (B) Differentiation of B cells into IgE-secreting plasma cells with the help of type 2 helper (Th2) cells. Crosslinking of specific IgE, which attaches on the surface of mast cells, by antigens induces type I hypersensitivity reaction.

Figure 3. Overviews of T-cell-mediated delayed hypersensitivity reaction. Specific T cells instead of B cells are activated by antigen-specific T cells.

Cutaneous ADRs often involve immunological mechanisms. In these cases, skin symptoms can occur either in isolation or alongside symptoms affecting several other organs. Cutaneous ADRs manifest in various clinical forms. The most common types include exanthematous (maculopapular or morbilliform) eruptions and urticarial eruptions (Bigby et al., 1989; Heinzerling et al., 2012; Noguera-Morel et al., 2014; Wang et al., 2017). Less frequently, they can mimic a wide range of skin conditions (Nigen et al., 2003), including fixed eruptions, photosensitivity, acneiform and pustular eruptions, eczematous eruptions, bullous eruptions, erythema multiforme, erythema nodosum, lichenoid eruptions, purpura, vasculitis, lupus erythematosus-like reactions, scleroderma-like reactions, pityriasis rosea-like eruptions, pigmentation changes, hypertrichosis, hair loss, or nail abnormalities. These skin reactions may coincide with fever and the involvement of internal organs like the liver and kidneys, indicating more serious reactions. Severe cutaneous ADRs encompass conditions such as anaphylaxis, acute generalized exanthematous pustulosis (AGEP), drug-induced hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Among these clinical features, urticaria and anaphylaxis are typically immediate reactions caused by IgE-mediated type I hypersensitivity reactions. In contrast, exanthematous eruptions and severe cutaneous ADRs other than anaphylaxis are delayed reactions involving T-cell-mediated type IV hypersensitivity reactions (Table 2) (Roujeau, 2006; Limsuwan and Demoly, 2010; Peter et al., 2017; Romano et al., 2017; Wang et al., 2018; Bellon, 2019; Lehloenya et al., 2020; Vocanson et al., 2020; Copaescu et al., 2022; Wilkerson, 2022; Wuillemin et al., 2022). The isolation of drug-reactive T cells and their association with human leukocyte antigen (HLA) in delayed ADRs provide further support for T cell-mediated reactions as the underlying immunological mechanism (Pavlos et al., 2015; Pirmohamed et al., 2015; White et al., 2015). These findings underscore the connection between clinical features and the immunological mechanisms of ADRs (Barbaud, 2009).

Table 2 Generally accepted immunological mechanisms in different types of ADRs in the skin

Cutaenous ADRs
Single organMultiple organ

IgE-mediated

Immediate

UrticarialAnaphylaxis

T cell-mediated

Delayed

ExanthematousAGEP
DIHS
SJS/TEN


ADRs are an inherent risk of drug use and the drugs that commonly cause them can vary across different age groups. However, it is important to note that age alone is not a significant risk factor for ADRs (Hoigne et al., 1990). Other factors, including individual characteristics and the frequency of drug prescriptions, may contribute to these variations. As the quantity of the drugs prescribed can influence the incidence of ADRs (Santos Andrade et al., 2017; Wang et al., 2017; Zazzara et al., 2021), the drugs most commonly associated with ADRs may change over time and from place to place (Wang et al., 2017; Balsamo et al., 2022). Nevertheless, certain drugs have consistently been linked to ADRs. These include nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and anticonvulsants (Bigby et al., 1989; Clavenna and Bonati, 2009; Heinzerling et al., 2012; Oscanoa et al., 2017; Wang et al., 2017).

These findings highlight the connection between the immunological mechanisms of ADRs, the time from the last drug administration to onset, and clinical features. While several factors can influence the drugs commonly associated with ADRs, NSAIDs, antibiotics, and antiepileptics have consistently emerged as primary causative drugs (Del Pozzo-Magaña and Liy-Wong, 2022). Therefore, this review delves into the immunological mechanisms involved in common cutaneous ADRs such as exanthematous eruptions, urticarial eruptions, and severe cutaneous ADRs. Furthermore, it provides a more detailed exploration of these mechanisms based on the drugs most frequently implicated.

IMMUNOLOGICAL MECHANISMS OF CUTANEOUS ADRS BASED ON CLINICAL FEATURES

Exanthematous eruption

Clinical symptoms resembling viral exanthems, which are skin eruptions caused by viral infection (Fig. 4), can complicate the diagnosis of exanthematous ADR; distinguishing it from viral exanthems is often necessary (Yazıcıoğlu, 2014). While these symptoms can range from being confined to the skin to accompanying systemic symptoms, especially in severe ADRs, exanthematous ADR is the most common form of cutaneous ADR (Babu and Belgi, 2002). Typically, the skin lesions develop at least 1 h after the initial drug administration (Christiansen et al., 2000; Rozieres et al., 2009; Torres et al., 2009; Rodilla et al., 2010; Phillips et al., 2019; Pérez-Sánchez et al., 2020).

Figure 4. Clinical features of exanthematous ADRs vs viral exanthem. Clinical features of exanthematous ADRs, showing symmetrically-distributed, generalized erythematous maculopapular eruptions accompanied by itching (left), and viral exanthem (right).

Drug-reacting T cells have been successfully isolated from patients with exanthematous ADR (Ye et al., 2017; Wuillemin et al., 2022). As illustrated in Fig. 3, hapten-carrier (drug-protein or drug-peptide) conjugates can activate T cells (Wuillemin et al., 2022). Consequently, an immunological mechanism involving T cells, specifically T cell-mediated Gell-Coombs type IV hypersensitivity, has been proposed, albeit with ongoing controversies (Christiansen et al., 2000; Rozieres et al., 2009; Torres et al., 2009; Romano et al., 2017; Phillips et al., 2019). Studies examining the phenotype and functions of both CD4+ and CD8+ T cells within skin lesions have highlighted the significant role of CD8+ T cells (Rozieres et al., 2009). Moreover, type 1 helper (Th1) T cell responses have been suggested as a primary immunological mechanism, evidenced by the production of cytokines like interferon-gamma, tumor necrosis factor-alpha, interleukin 2, and cytotoxic molecules such as perforin and granzyme B (Torres et al., 2009). An investigation into the interaction between the checkpoint inhibitor Tim3 and its physiological ligand galectin-9 (Gal9) supported the involvement of Th1 CD4+ T-cell proliferation and the suppression of regulatory T cells (Tregs) due to impaired Gal9 expression in exanthematous ADR (Fernandez-Santamaría et al., 2019).

Urticarial eruption and anaphylaxis

Clinical manifestations of urticaria are characterized by wheals or hives, which can greatly vary in size and shape and typically resolve within 24 h, returning the skin to its normal state (Fig. 5). In severe cases where urticaria affects multiple organs, manifesting as myocardial dysfunction, breathing difficulties, dizziness, and syncope, it is diagnosed as anaphylaxis, a potentially fatal ADR. Wheals, a common skin symptom in both urticaria and anaphylaxis, result from mediators released primarily from mast cells and basophils. The underlying mechanisms for urticaria and anaphylaxis share similarities, encompassing both immunological and non-immunological components (Macy, 2016; Montañez et al., 2017; Schettini et al., 2023). The immunological mechanisms can be IgE-dependent or IgE-independent. Like in exanthematous ADRs, hapten-carrier conjugates play a role in the immunological pathway. However, in this case, drug-protein conjugates produce antibodies, as demonstrated in Fig. 2A and 2B, instead of T cell activation (Martin-Serrano et al., 2016). The IgE-mediated pathway involves Th2 cell activation, IgE antibody production by B cells, and crosslinking of specific IgE antibodies on the surfaces of mast cells or basophils, as illustrated in Fig. 2B (Montañez et al., 2017; Nguyen et al., 2021). Allergen-specific IgG antibodies can also contribute to IgE-independent immunological mechanisms. IgG antibodies activate Fc gamma receptors in monocytes/macrophages, neutrophils, and platelets, ultimately leading to vascular integrity loss and vascular leakage through the release of potent mediators like platelet-activating factor (Beutier et al., 2018; Jönsson et al., 2019). Non-immunological mechanisms can occur through the direct stimulation of mast cell degranulation. The mast cell receptor, Mas-related G protein-coupled receptor member X2, has been identified as a mediator of mast cell degranulation via non-immunological mechanisms (Spoerl et al., 2017; Mackay et al., 2021; Zhu et al., 2022). An imbalance in lipid mediators, such as leukotrienes and prostaglandins due to the inhibition of the cyclooxygenase-1 (COX-1) enzyme, can also induce urticarial symptoms, irrespective of the immunological mechanism (Blanca-López et al., 2015; Stevens et al., 2015; Hermans et al., 2018). This mechanism is particularly relevant for NSAIDs but not for other drugs that do not inhibit COX-1.

Figure 5. Clinical features of urticarial ADRs. Characteristic findings are wheals or hives, which greatly vary in size and shape and last less than 24 h before the skin returns to its normal state.

AGEP

AGEP is a severe ADR characterized by a pustular skin disorder with systemic involvement (Szatkowski and Schwartz, 2015). Skin symptoms manifest as an acute onset of non-follicular, pinhead-sized sterile neutrophilic pustules on an erythematous base (Fig. 6). AGEP is considered a delayed reaction, typically emerging within 48 h after the ingestion of causative medication. With the exception of anaphylaxis, other severe ADRs, including AGEP, are driven by T cell-mediated type IV hypersensitivity reactions. Various T cell subpopulations, such as cytotoxic T cells, Th1 cells, Th2 cells, Th17 cells, and Tregs, can participate in the development of severe ADRs. Subpopulations involved in the innate immune system and tissue-resident cells, including keratinocytes, can also contribute to the development of these reactions (Roujeau, 2006; Limsuwan and Demoly, 2010; Peter et al., 2017; Romano et al., 2017; Wang et al., 2018; Bellon, 2019; Lehloenya et al., 2020; Vocanson et al., 2020; Copaescu et al., 2022; Wilkerson, 2022; Wuillemin et al., 2022). However, the mechanism underlying neutrophilic skin inflammation, a hallmark of AGEP, remains unclear. The interleukin 17(IL-17) family, consisting of IL-17A-F, known to be involved in various skin inflammatory disorders, has been found to be highly expressed in neutrophils and mast cells in AGEP (Kakeda et al., 2014). While T helper 17 (Th17) cells are known to produce IL-17A and promote type II immune responses, multiple sources, ranging from immune cells to non-immune cells, can be involved in the production of IL-17A and other IL-17 family cytokines (Gu et al., 2013). Upregulation of IL-17E (IL-25) has been identified in neutrophil-rich inflammatory skin diseases, including AGEP, and IL-17E has been shown to promote the recruitment of innate immune cells, particularly neutrophils (Senra et al., 2019). Furthermore, the more frequent detection of mutations in 36RN (the gene encoding the IL-36 receptor antagonist) in AGEP suggests a role for IL-36 gamma, which is released by keratinocytes and macrophages, in neutrophilic skin inflammation (Meier-Schiesser et al., 2019).

Figure 6. Clinical features of acute generalized exanthematous pustulosis (AGEP). Non-follicular, pinhead-sized sterile neutrophilic pustules are shown on the erythematous base.

DIHS

DIHS, also known as drug reaction with eosinophilia and systemic symptoms syndrome, is a severe ADR characterized by fever, a widespread exanthem, facial edema (Fig. 7), lymphadenopathy, hematologic abnormalities, multiorgan involvement, and viral reactivation. This condition typically occurs several days or weeks after drug initiation or discontinuation. Similar to other delayed severe ADRs, it is believed to result from T cell-mediated type IV hypersensitivity reactions (Roujeau, 2006; Limsuwan and Demoly, 2010; Peter et al., 2017; Romano et al., 2017; Wang et al., 2018; Bellon, 2019; Lehloenya et al., 2020; Vocanson et al., 2020; Copaescu et al., 2022; Wilkerson, 2022; Wuillemin et al., 2022). Rather than the hapten theory, the prevailing view is that the main mechanism involves a direct non-covalent interaction between drugs and MHC molecules and T cell receptors (the p-i reactions) (Pichler, 2019; Sueki et al., 2022; Wuillemin et al., 2022). A distinctive feature of DIHS, setting it apart from other ADRs, is the reactivation of viruses, particularly Herpesviridae. This viral reactivation can enhance and sustain aberrant T cell and eosinophil responses to both drugs and viruses (Ushigome et al., 2018; Anci et al., 2021; Ramirez et al., 2023). In fact, reactivation of human herpesvirus-6 has been associated with greater DIHS severity (Zhu and Ren, 2023). Another unique aspect of DIHS, not commonly observed in other ADRs, is the development of autoimmune sequelae (Morita et al., 2018; Shiohara and Mizukawa, 2019; Miyagawa and Asada, 2021; Wei et al., 2023). Although the mechanisms behind these autoimmune sequelae remain unclear, there is evidence suggesting a progressive loss of suppressive function in Tregs as they shift toward Th17 cells (Ushigome et al., 2018; Shiohara and Mizukawa, 2019; Miyagawa and Asada, 2021).

Figure 7. Clinical features of drug-induced hypersensitivity syndrome (DIHS). Widespread exanthem and facial edema are shown. The skin symptoms are accompanied by fever, lymphadenopathy, hematologic abnormalities, and multiorgan involvement.

SJS and TEN

SJS and TEN are severe mucocutaneous ADRs characterized by widespread skin and mucosal necrosis and detachment (Fig. 8). They represent two ends of the same spectrum of diseases with different severities, which are classified by the percentage of skin detachment area, less than 10% in SJS and more than 30% in TEN (Hasegawa and Abe, 2020). Similar to other delayed severe ADRs, these conditions are T cell-mediated immune disorders. The interaction of drug-specific T cells, cytotoxic T cells activated by the drug, with HLA class I restriction and T cell receptors can play a key role in the immune mechanism (Roujeau, 2006; Limsuwan and Demoly, 2010; Peter et al., 2017; Romano et al., 2017; Wang et al., 2018; Bellon, 2019; Lehloenya et al., 2020; Vocanson et al., 2020; Copaescu et al., 2022; Wilkerson, 2022; Wuillemin et al., 2022). CD8+ T cells exhibit cytotoxicity against keratinocytes, resulting in keratinocyte apoptosis via the perforin/granzyme B, granulysin, or Fas/FasL pathway (Saeed and Chodosh, 2016; Hasegawa and Abe, 2020; Kuijper et al., 2020; Noe and Micheletti, 2020; Chen et al., 2022a). Keratinocyte death stimulates local inflammation, which produces pro-inflammatory molecules, including TNF-alpha, through the activation of other immune cells and downregulation of regulatory T cells (Kuijper et al., 2020). CD14+ monocytes release annexin A1 to induce formyl peptide receptor 1 (FPR1) in keratinocytes, which makes keratinocytes vulnerable to necroptosis, so-called programmed necrosis (Hasegawa and Abe, 2020; Kuijper et al., 2020; Kinoshita et al., 2021). Keratinocyte necroptosis contributes to mucocutaneous necrosis and detachment, along with keratinocyte apoptosis (Hasegawa and Abe, 2020; Kuijper et al., 2020). In addition to monocytes, CD8+ T cells can also be involved in necroptosis by producing lipocalin 2, which triggers the formation of neutrophil traps. LL-37, a microbial peptide, can induce FPR1 in keratinocytes (Kinoshita et al., 2021). Keratinocyte death stimulates local inflammation, which produces pro-inflammatory molecules, including TNF-alpha, through the activation of other immune cells and downregulation of regulatory T cells (Kuijper et al., 2020). A schematic diagram is shown in Fig. 9. A randomized clinical trial has also identified the effect of TNF-alpha antagonist on patients with SJS and TEN (Wang et al., 2018).

Figure 8. Clinical features of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Widespread skin and mucosal necrosis and detachment are shown, although the percentage of skin detachment area is lower in SJS (left) and higher in TEN (right).

Figure 9. Schematic diagram for pathogenesis involved in SJS/TEN. Cytotoxic T cells activated by the interaction of drug antigens with drug-specific T cells induce keratinocyte apoptosis via perforin/granzyme B, granulysin, or the Fas/FasL pathway. Keratinocyte death downregulates regulatory T cells (Tregs) but activates immune cells, which induce formyl peptide receptor 1 (FPR1) in keratinocytes, leading to keratinocyte necroptosis.
IMMUNOLOGICAL MECHANISMS IN CUTANEOUS ADRS DEPENDING ON THE IMPLICATED DRUGS

NSAIDs

Therapeutic activities of NSAIDs occur through the inhibition of COX, the enzyme responsible for producing prostaglandins (Vane and Botting, 2003). There are two isoforms of the COX enzyme, COX-1 and COX-2. Due to the common action mechanism of NSAIDs, cross-hypersensitivity reactions associated with COX-1 inhibition can trigger NSAID-exacerbated respiratory disease, NSAID-exacerbated cutaneous disease, and NSAID-induced urticaria/angioedema (Ayuso et al., 2013; Blanca-López et al., 2014; Hermans et al., 2018; Doña et al., 2020; Pérez-Sánchez et al., 2020). These three phenotypes are peculiar ADRs to NSAIDs related to their action mechanisms regardless of immunological mechanisms. Immunological mechanisms are involved in the other two phenotypes of ADRs caused by NSAIDs, single-NSAID-induced urticaria/angioedema/anaphylaxis and single-NSAID-induced delayed reactions (Ayuso et al., 2013; Doña et al., 2020; Pérez-Sánchez et al., 2020). The former reactions are immediate ADRs mediated by drug-specific IgE, whereas the latter reactions are delayed ADRs mediated by drug-specific T cells (Ayuso et al., 2013; Aun et al., 2014; Torres et al, 2014a; Pérez-Sánchez et al., 2020). The schematic diagram is shown in Fig. 10. As mentioned above, ADRs caused by NSAIDs are more complex than other drugs in terms of the number and types of reactions elicited and mechanisms involved (Blanca-López et al., 2014). Besides these various phenotypes of ADRs, their frequent prescription and consumption can contribute to NSAIDs being leading causes of ADRs even in cases of drug-induced anaphylaxis (Aun et al., 2014; Mota et al., 2018).

Figure 10. Overviews of mechanisms involved in five different types of NSAID-induced ADRs.

Antibiotics

Along with NSAIDs, antibiotics are one of the most common causes of ADRs (Del Pozzo-Magaña and Liy-Wong, 2022). Causative drugs have the ability to form novel antigens through haptenization and to provoke various immune-mediated ADRs (Ariza et al., 2015; Goh et al., 2021). In particular, beta-lactam antibiotics, which include penicillins, cephalosporins, monobactams, carbapenems, and clavams, are the most frequent cause of ADRs mediated by immunological mechanisms (Rodilla et al., 2010; Torres et al., 2014b; Ariza et al., 2015; Fernandez et al., 2017). Beta-lactam antibiotics with common R1 side chains can induce immunological cross-reactions (Khan et al., 2019). Immediate reactions mediated by IgE typically present with urticaria and anaphylaxis as the most common symptoms, while non-immediate reactions mediated by T cells often manifest as exanthem and urticaria (Torres et al., 2014b; Romano et al., 2017). In comparison to beta lactams, non-beta lactams such as fluoroquinolones, vancomycin, macrolides, and tetracyclines are relatively safer in immune-mediated ADRs. However, their prevalence is on the rise. Immediate reactions are more frequent than non-immediate reactions in fluoroquinolones, whereas non-immediate reactions are predominant in tetracyclines. Both immediate and non-immediate reactions can occur with macrolides (Zhu et al., 2022). Cross-reactivity also occurs among different fluoroquinolones (Neuman et al., 2015).

Antiepileptics

Compared with non-aromatic antiepileptic drugs, aromatic antiepileptic drugs, including carbamazepine, oxycarbazepine, lamotrigine, phenobarbital, phenytoin, primidone, and zonisamide, significantly increase the risk of developing ADRs (Błaszczyk et al., 2015; Atanasković-Marković et al., 2019; Mani et al., 2019). Skin symptoms usually include exanthematous eruption and delayed urticaria (Atanasković-Marković et al., 2019). Aromatic antiepileptic drugs also can be an important cause of severe ADRs such as DIHS, SJS, and TEN (Wang et al., 2015; Al-Quteimat 2016; de Filippis et al., 2020). Enhanced granzyme B release and intracellular granulysin expression involved in SJS and TEN occurrence have been detected in peripheral blood mononuclear cells from patients with exanthematous eruption induced by antiepileptic drugs (Porębski et al., 2015). ADRs are mostly delayed reactions. Thus, T cell-mediated immune responses are involved in them. Genetic variation in the HLA loci has been associated with the risk of ADRs by carbamazepine (Shen et al., 2020; Min et al., 2022), indicating the importance of T cell immune responses (White et al., 2015; Illing et al., 2017). The alteration of the repertoire of endogenous peptides by HLA may be a mechanism of HLA-linked ADRs (Min et al., 2022). Although there is no evidence of cross-sensitivity to other aromatic structures, a high degree of cross-sensitivity to other antiepileptic drugs, particularly among aromatic antiepileptics, has been identified (Błaszczyk et al., 2015; Mani et al., 2019).

ICIs in new drugs

ICIs are monoclonal antibodies that block key mediators of tumor-mediated immune evasion such as programmed cell death protein 1, PD ligand 1, and cytotoxic T lymphocyte-associated protein 4. ICIs can activate cytotoxic T cells, inhibit Treg function, and alter cytokine balance, enhancing antitumor activities. Thanks to the high response rates and extended survival of patients with advanced and metastatic malignancies, the use of ICIs for cancer therapy has been increasing rapidly. However, alterations in the immune system can also induce irAEs dose-independently (Han et al., 2021; Okiyama and Tanaka, 2022; Pach and Leventhal., 2022; Yamamoto, 2022; Watanabe and Yamaguchi, 2023). Multiple organs can be affected in irAEs. However, skin is the most common and the first organ to develop irAEs, with incidences ranging between 35% and 60% (Muntyanu et al., 2021; Patel and Pacha, 2021; Chen et al., 2022b). Many different skin symptoms have been presented (Geisler et al., 2020; Gault et al., 2021; Quach et al., 2021; Pach and Leventhal, 2022). The most common manifestations include exanthematous eruptions, pruritus, lichenoid eruptions, and vitiligo. Severe ADRs such as SJS, TEN, DIHS, and AGEP develop less frequently. Various rheumatologic adverse reactions such as scleroderma, dermatomyositis, and cutaneous lupus erythematosus can also occur. The reactions are delayed responses with the most prevalent exanthematous rash presenting within the first 6 weeks after the initial ICI dose.

CONCLUSIONS

ADRs affect several different body organs and systems. The skin as an active immune organ is the most common organ developing ADRs, particularly immunological ones. The immunological mechanisms involved in cutaneous ADRs remain unclear. However, urticarial eruption and anaphylaxis are mostly caused by IgE-mediated Gell-Coombs type I immune reactions, whereas exanthematous eruptions and severe ADRs are caused by T cell-mediated Gell-Coombs type IV immune reactions. Although certain drugs frequently cause ADRs, the immunological mechanisms are mainly associated with clinical features induced by culprit drugs and not by the drugs themselves. The ADR diagnosis is important. Although systemic provocation is the most reliable method for the diagnosis, it may be challenging. On the other hand, understanding the pathomechanisms of ADRs can provide a proper pathway for the diagnosis.

CONFLICT OF INTEREST

None.

References
  1. Al-Quteimat, O. M. (2016) Phenytoin-induced toxic epidermal necrolysis: review and recommendations. J. Pharmacol. Pharmacother. 7, 127-132.
    Pubmed KoreaMed CrossRef
  2. Anci, E., Braun, C., Marinosci, A., Rodieux, F., Midun, E., Torres, M. J. and Caubet, J. C. (2021) Viral infections and cutaneous drug-related eruptions. Front. Pharmacol. 11, 586407.
    Pubmed KoreaMed CrossRef
  3. Ariza, A., Mayorga, C., Fernandez, T. D., Barbero, N., Martín-Serrano, A., Pérez-Sala, D., Sánchez-Gómez, F. J., Blanca, M., Torres, M. J. and Montanez, M. I. (2015) Hypersensitivity reactions to β-lactams: relevance of hapten-protein conjugates. J. Investig. Allergol. Clin. Immunol. 25, 12-25.
    Pubmed
  4. Atanasković-Marković, M., Janković, J., Tmušić, V., Gavrović-Jankulović, M., Veličković, T. Ć., Nikolić, D. and Škorić, D. (2019) Hypersensitivity reactions to antiepileptic drugs in children. Pediatr. Allergy Immunol. 30, 547-552.
    Pubmed CrossRef
  5. Aun, M. V., Blanca, M., Garro, L. S., Ribeiro, M. R., Kalil, J., Motta, A. A., Castells, M. and Giavina-Bianchi, P. (2014) Nonsteroidal anti-inflammatory drugs are major causes of drug-induced anaphylaxis. J. Allergy Clin. Immunol. Pract. 2, 414-420.
    Pubmed CrossRef
  6. Ayuso, P., Blanca-López, N., Doña, I., Torres, M. J., Guéant-Rodríguez, R. M., Canto, G., Sanak, M., Mayorga, C., Guéant, J. L., Blanca, M. and Cornejo-García, J. A. (2013) Advanced phenotyping in hypersensitivity drug reactions to NSAIDs. Clin. Exp. Allergy 43, 1097-1109.
    Pubmed CrossRef
  7. Babu, K. S. and Belgi, G. (2002) Management of cutaneous drug reactions. Curr. Allergy Asthma Rep. 2, 26-33.
    Pubmed CrossRef
  8. Balsamo, C., Bono, C. D., Pagano, G., Valastro, V., Ghizzi, C. and Lombardi, F. (2022) Pediatric adverse drug reactions: an observational cohort study after health care workers' training. J. Pediatr. Pharmacol. Ther. 27, 324-329.
    Pubmed KoreaMed CrossRef
  9. Bangert, C., Brunner, P. M. and Stingl, G. (2011) Immune functions of the skin. Clin. Dermatol. 29, 360-376.
    Pubmed CrossRef
  10. Barbaud, A. (2009) Skin testing in delayed reactions to drugs. Immunol. Allergy Clin. North Am. 29, 517-535.
    Pubmed CrossRef
  11. Bellón, T. (2019) Mechanisms of severe cutaneous adverse reactions: recent advances. Drug Saf. 42, 973-992.
    Pubmed CrossRef
  12. Beutier, H., Hechler, B., Godon, O., Wang, Y., Gillis, C. M., de Chaisemartin, L., Gouel-Chéron, A., Magnenat, S., Macdonald, L. E., Murphy, A. J., Chollet-Martin, S., Longrois, D., Gachet, C., Bruhns, P. and Jönsson, F.; NASA study group (2018) Platelets expressing IgG receptor FcγRIIA/CD32A determine the severity of experimental anaphylaxis. Sci. Immunol. 3, eaan5997.
    Pubmed CrossRef
  13. Bhardwaj, M., Chiu, M. N. and Sah, S. P. (2022) Adverse cutaneous toxicities by PD-1/PD-L1 immune checkpoint inhibitors: pathogenesis, treatment, and surveillance. Cutan. Ocul. Toxicol. 41, 73-90.
    Pubmed CrossRef
  14. Bigby, M., Stern, R. S. and Arndt, K. A. (1989) Allergic cutaneous reactions to drugs. Prim. Care 16, 713-727.
    Pubmed CrossRef
  15. Blanca-López, N., Barrionuevo, E., Andreu, I. and Canto, M. G. (2014) Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: from phenotyping to genotyping. Curr. Opin. Allergy Clin. Immunol. 14, 271-277.
    Pubmed CrossRef
  16. Blanca-López, N., Cornejo-García, J. A., Pérez-Alzate, D., Pérez-Sánchez, N., Plaza-Serón, M. C., Doña, I., Torres, M. J., Canto, G., Kidon, M., Perkins, J. R. and Blanca, M. (2015) Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs in children and adolescents: selective reactions. J. Investig. Allergol. Clin. Immunol. 25, 385-395.
    Pubmed
  17. Błaszczyk, B., Lasoń, W. and Czuczwar, S. J. (2015) Antiepileptic drugs and adverse skin reactions: an update. Pharmacol. Rep. 67, 426-434.
    Pubmed CrossRef
  18. Brockow, K. and Romano, A. (2008) Skin tests in the diagnosis of drug hypersensitivity reactions. Curr. Pharm. Des. 14, 2778-2791.
    Pubmed CrossRef
  19. Chen, C. B., Abe, R., Pan, R. Y., Wang, C. W., Hung, S. I., Tsai, Y. G. and Chung, W. H. (2018) An updated review of the molecular mechanisms in drug hypersensitivity. J. Immunol. Res. 2018, 6431694.
    Pubmed KoreaMed CrossRef
  20. Chen, C. B., Wang, C. W. and Chung, W. H. (2022a) Stevens-Johnson syndrome and toxic epidermal necrolysis in the era of systems medicine. Methods Mol. Biol. 2486, 37-54.
    Pubmed CrossRef
  21. Chen, C. H., Yu, H. S. and Yu, S. (2022b) cutaneous adverse events associated with immune checkpoint inhibitors: a review article. Curr. Oncol. 29, 2871-2886.
    Pubmed KoreaMed CrossRef
  22. Chimbetete, T., Buck, C., Choshi, P., Selim, R., Pedretti, S., Divito, S. J., Phillips, E. J., Lehloenya, R. and Peter, J. (2023) HIV-associated immune dysregulation in the skin: a crucible for exaggerated inflammation and hypersensitivity. J. Invest. Dermatol. 143, 362-373.
    Pubmed KoreaMed CrossRef
  23. Christiansen, C., Pichler, W. J. and Skotland, T. (2000) Delayed allergy-like reactions to X-ray contrast media: mechanistic considerations. Eur. Radiol. 10, 1965-1975.
    Pubmed CrossRef
  24. Clavenna, A. and Bonati, M. (2009) Adverse drug reactions in childhood: a review of prospective studies and safety alerts. Arch. Dis. Child. 94, 724-728.
    Pubmed CrossRef
  25. Copaescu, A. M., Ben-Shoshan, M. and Trubiano, J. A. (2022) Tools to improve the diagnosis and management of T-cell mediated adverse drug reactions. Front. Med. (Lausanne) 9, 923991.
    Pubmed KoreaMed CrossRef
  26. de Filippis, R., Soldevila-Matías, P., De Fazio, P., Guinart, D., Fuentes-Durá, I., Rubio, J. M., Kane, J. M. and Schoretsanitis, G. (2020) Clozapine-related drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a systematic review. Expert Rev. Clin. Pharmacol. 13, 875-883.
    Pubmed CrossRef
  27. Del Pozzo-Magaña, B. R. and Liy-Wong, C. (2022) Drugs and the skin: a concise review of cutaneous adverse drug reactions. Br. J. Clin. Pharmacol.. doi: 10.1111/bcp.15490 [Online ahead of print].
    Pubmed CrossRef
  28. Dispenza, M. C. (2019) Classification of hypersensitivity reactions. Allergy Asthma Proc. 40, 470-473.
    Pubmed CrossRef
  29. Doña, I., Pérez-Sánchez, N., Eguiluz-Gracia, I., Muñoz-Cano, R., Bartra, J., Torres, M. J. and Cornejo-García, J. A. (2020) Progress in understanding hypersensitivity reactions to nonsteroidal anti-inflammatory drugs. Allergy 75, 561-575.
    Pubmed CrossRef
  30. Fernandez-Santamaría, R., Palomares, F., Salas, M., Doña, I., Bogas, G., Ariza, A., Rodriguez-Nogales, A., Plaza-Seron, M. C., Mayorga, C., Torres, M. J. and Fernández, T. D. (2019) Expression of the Tim3-galectin-9 axis is altered in drug-induced maculopapular exanthema. Allergy 74, 1769-1779.
    Pubmed CrossRef
  31. Fernandez, T. D., Mayorga, C., Salas, M., Barrionuevo, E., Posadas, T., Ariza, A., Laguna, J. J., Moreno, E., Torres, M. J., Doña, I. and Montañez, M. I. (2017) Evolution of diagnostic approaches in betalactam hypersensitivity. Expert Rev. Clin. Pharmacol. 10, 671-683.
    Pubmed CrossRef
  32. Gault, A., Anderson, A. E., Plummer, R., Stewart, C., Pratt, A. G. and Rajan, N. (2021) Cutaneous immune-related adverse events in patients with melanoma treated with checkpoint inhibitors. Br. J. Dermatol. 185, 263-271.
    Pubmed CrossRef
  33. Geisler, A. N., Phillips, G. S., Barrios, D. M., Wu, J., Leung, D. Y. M., Moy, A. P., Kern, J. A. and Lacouture, M. E. (2020) Immune checkpoint inhibitor-related dermatologic adverse events. J. Am. Acad. Dermatol. 83, 1255-1268.
    Pubmed KoreaMed CrossRef
  34. Goh, S. J. R., Tuomisto, J. E. E., Purcell, A. W., Mifsud, N. A. and Illing, P. T. (2021) The complexity of T cell-mediated penicillin hypersensitivity reactions. Allergy 76, 150-167.
    Pubmed CrossRef
  35. Gu, C., Wu, L. and Li, X. (2013) IL-17 family: cytokines, receptors and signaling. Cytokine 64, 477-485.
    Pubmed KoreaMed CrossRef
  36. Han, J., Pan, C., Tang, X., Li, Q., Zhu, Y., Zhang, Y. and Liang, A. (2022) Hypersensitivity reactions to small molecule drugs. Front. Immunol. 13, 1016730.
    Pubmed KoreaMed CrossRef
  37. Han, Y., Wang, J. and Xu, B. (2021) Cutaneous adverse events associated with immune checkpoint blockade: a systematic review and meta-analysis. Crit. Rev. Oncol. Hematol. 163, 103376.
    Pubmed CrossRef
  38. Hasegawa, A. and Abe, R. (2020) Recent advances in managing and understanding Stevens-Johnson syndrome and toxic epidermal necrolysis. F1000Res. 9, 612.
    Pubmed KoreaMed CrossRef
  39. Heinzerling, L. M., Tomsitz, D. and Anliker, M. D. (2012) Is drug allergy less prevalent than previously assumed? A 5-year analysis. Br. J. Dermatol. 166, 107-114.
    Pubmed CrossRef
  40. Hermans, M. A. W., Otten, R., Karim, A. F. and van Maaren, M. S. (2018) Nonsteroidal anti-inflammatory drug hypersensitivity: not always an allergy!. Neth. J. Med. 76, 52-59.
  41. Ho, A. W. and Kupper, T. S. (2019) T cells and the skin: from protective immunity to inflammatory skin disorders. Nat. Rev. Immunol. 19, 490-502.
    Pubmed CrossRef
  42. Hoigné, R., Lawson, D. H. and Weber, E. (1990) Risk factors for adverse drug reactions--epidemiological approaches. Eur. J. Clin. Pharmacol. 39, 321-325.
    Pubmed CrossRef
  43. Hussein, M. R. A. (2016) Drug-induced skin reactions: a pathologist viewpoint. Cutan. Ocul. Toxicol. 35, 67-79.
    Pubmed CrossRef
  44. Illing, P. T., Purcell, A. W. and McCluskey, J. (2017) The role of HLA genes in pharmacogenomics: unravelling HLA associated adverse drug reactions. Immunogenetics 69, 617-630.
    Pubmed CrossRef
  45. Jönsson, F., de Chaisemartin, L., Granger, V., Gouel-Chéron, A., Gillis, C. M., Zhu, Q., Dib, F., Nicaise-Roland, P., Ganneau, C., Hurtado-Nedelec, M., Paugam-Burtz, C., Necib, S., Keita-Meyer, H., Le Dorze, M., Cholley, B., Langeron, O., Jacob, L., Plaud, B., Fischler, M., Sauvan, C., Guinnepain, M. T., Montravers, P., Aubier, M., Bay, S., Neukirch, C., Tubach, F., Longrois, D., Chollet-Martin, S. and Bruhns, P. (2019) An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis. Sci. Transl. Med. 11, eaat1479.
    Pubmed CrossRef
  46. Kakeda, M., Schlapbach, C., Danelon, G., Tang, M. M., Cecchinato, V., Yawalkar, N. and Uguccioni, M. (2014) Innate immune cells express IL-17A/F in acute generalized exanthematous pustulosis and generalized pustular psoriasis. Arch. Dermatol. Res. 306, 933-938.
    Pubmed CrossRef
  47. Khan, D. A., Banerji, A., Bernstein, J. A., Bilgicer, B., Blumenthal, K., Castells, M., Ein, D., Lang, D. M. and Phillips, E. (2019) Cephalosporin allergy: current understanding and future challenges. J. Allergy Clin. Immunol. Pract. 7, 2105-2114.
    Pubmed KoreaMed CrossRef
  48. Kinoshita, M., Ogawa, Y., Hama, N., Ujiie, I., Hasegawa, A., Nakajima, S., Nomura, T., Adachi, J., Sato, T., Koizumi, S., Shimada, S., Fujita, Y., Takahashi, H., Mizukawa, Y., Tomonaga, T., Nagao, K., Abe, R. and Kawamura, T. (2021) Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis. Sci. Transl. Med. 13, eaax2398.
    Pubmed KoreaMed CrossRef
  49. Kuijper, E. C., French, L. E., Tensen, C. P., Vermeer, M. H. and Bouwes Bavinck, J. N. (2020) Clinical and pathogenic aspects of the severe cutaneous adverse reaction epidermal necrolysis (EN). J. Eur. Acad. Dermatol. Venereol. 34, 1957-1971.
    Pubmed KoreaMed CrossRef
  50. Kuljanac, I. (2008) Mechanisms of drug hypersensitivity reactions and the skin. Recent Pat. Inflamm. Allergy Drug Discov. 2, 64-71.
    Pubmed CrossRef
  51. Lehloenya, R. J., Peter, J. G., Copascu, A., Trubiano, J. A. and Phillips, E. J. (2020) Delabeling delayed drug hypersensitivity: how far can you safely go?. J. Allergy Clin. Immunol. Pract. 8, 2878-2895.
    Pubmed KoreaMed CrossRef
  52. Limsuwan, T. and Demoly, P. (2010) Acute symptoms of drug hypersensitivity (urticaria, angioedema, anaphylaxis, anaphylactic shock). Med. Clin. North Am. 94, 691-710.
    Pubmed CrossRef
  53. Loser, K. and Beissert, S. (2007) Dendritic cells and T cells in the regulation of cutaneous immunity. Adv. Dermatol. 23, 307-333.
    Pubmed CrossRef
  54. Mackay, G. A., Fernandopulle, N. A., Ding, J., McComish, J. and Soeding, P. F. (2021) Antibody or anybody? Considering the role of MRGPRX2 in acute drug-induced anaphylaxis and as a therapeutic target. Front. Immunol. 12, 688930.
    Pubmed KoreaMed CrossRef
  55. Macy, E. (2016) Practical management of patients with a history of immediate hypersensitivity to common non-beta-lactam drugs. Curr. Allergy Asthma Rep. 16, 4.
    Pubmed CrossRef
  56. Mani, R., Monteleone, C., Schalock, P. C., Truong, T., Zhang, X. B. and Wagner, M. L. (2019) Rashes and other hypersensitivity reactions associated with antiepileptic drugs: a review of current literature. Seizure 71, 270-278.
    Pubmed CrossRef
  57. Martin-Serrano, A., Barbero, N., Agundez, J. A., Vida, Y., Perez-Inestrosa, E. and Montanez, M. I. (2016) New advances in the study of IgE drug recognition. Curr. Pharm. Des. 22, 6759-6772.
    Pubmed CrossRef
  58. Montañez, M. I., Mayorga, C., Bogas, G., Barrionuevo, E., Fernandez-Santamaria, R., Martin-Serrano, A., Laguna, J. J., Torres, M. J., Fernandez, T. D. and Doña, I. (2017) Epidemiology, mechanisms, and diagnosis of drug-induced anaphylaxis. Front. Immunol. 8, 614.
    Pubmed KoreaMed CrossRef
  59. Meier-Schiesser, B., Feldmeyer, L., Jankovic, D., Mellett, M., Satoh, T. K., Yerly, D., Navarini, A., Abe, R., Yawalkar, N., Chung, W. H., French, L. E. and Contassot, E. (2019) Culprit drugs induce specific IL-36 overexpression in acute generalized exanthematous pustulosis. J. Invest. Dermatol. 139, 848-858.
    Pubmed CrossRef
  60. Min, F., Fan, C., Zeng, Y., He, N., Zeng, T., Qin, B. and Shi, Y. (2022) Carbamazepine-modified HLA-A*24:02-bound peptidome: implication of CORO1A in skin rash. Int. Immunopharmacol. 109, 108804.
    Pubmed CrossRef
  61. Miyagawa, F. and Asada, H. (2021) Current perspective regarding the immunopathogenesis of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS). Int. J. Mol. Sci. 22, 2147.
    Pubmed KoreaMed CrossRef
  62. Morita, C., Yanase, T., Shiohara, T. and Aoyama, Y. (2018) Aggressive treatment in paediatric or young patients with drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is associated with future development of type III polyglandular autoimmune syndrome. BMJ Case Rep. 2018, bcr2018225528.
    Pubmed KoreaMed CrossRef
  63. Mota, I., Gaspar, Â., Benito-Garcia, F., Correia, M., Chambel, M. and Morais-Almeida, M. (2018) Drug-induced anaphylaxis: seven-year single-center survey. Eur. Ann. Allergy Clin. Immunol. 50, 211-216.
    Pubmed CrossRef
  64. Muntyanu, A., Netchiporouk, E., Gerstein, W., Gniadecki, R. and Litvinov, I. V. (2021) Cutaneous immune-related adverse events (irAEs) to immune checkpoint inhibitors: a dermatology perspective on management. J. Cutan. Med. Surg. 25, 59-76.
    Pubmed CrossRef
  65. Neuman, M. G., Cohen, L. B. and Nanau, R. M. (2015) Quinolones-induced hypersensitivity reactions. Clin. Biochem. 48, 716-739.
    Pubmed CrossRef
  66. Nguyen, S. M. T., Rupprecht, C. P., Haque, A., Pattanaik, D., Yusin, J. and Krishnaswamy, G. (2021) Mechanisms governing anaphylaxis: inflammatory cells, mediators, endothelial gap junctions and beyond. Int. J. Mol. Sci. 22, 7785.
    Pubmed KoreaMed CrossRef
  67. Nigen, S., Knowles, S. R. and Shear, N. H. (2003) Drug eruptions: approaching the diagnosis of drug-induced skin diseases. J. Drugs Dermatol. 2, 278-299.
    Pubmed
  68. Noe, M. H. and Micheletti, R. G. (2020) Diagnosis and management of Stevens-Johnson syndrome/toxic epidermal necrolysis. Clin. Dermatol. 38, 607-612.
    Pubmed CrossRef
  69. Noguera-Morel, L., Hernández-Martín, Á. and Torrelo, A. (2014) Cutaneous drug reactions in the pediatric population. Pediatr. Clin. North Am. 61, 403-426.
    Pubmed CrossRef
  70. Okiyama, N. and Tanaka, R. (2022) Immune-related adverse events in various organs caused by immune checkpoint inhibitors. Allergol. Int. 71, 169-178.
    Pubmed CrossRef
  71. Oscanoa, T. J., Lizaraso, F. and Carvajal, A. (2017) Hospital admissions due to adverse drug reactions in the elderly. A meta-analysis. Eur. J. Clin. Pharmacol. 73, 759-770.
    Pubmed CrossRef
  72. Pach, J. and Leventhal, J. S. (2022) Cutaneous immune-related adverse events secondary to immune checkpoint inhibitors and their management. Crit. Rev. Immunol. 42, 1-20.
    Pubmed CrossRef
  73. Patel, A. B. and Pacha, O. (2021) Skin reactions to immune checkpoint inhibitors. Adv. Exp. Med. Biol. 1342, 319-330.
    Pubmed CrossRef
  74. Pavlos, R., Mallal, S., Ostrov, D., Buus, S., Metushi, I., Peters, B. and Phillips, E. (2015) T cell-mediated hypersensitivity reactions to drugs. Annu. Rev. Med. 66, 439-454.
    Pubmed KoreaMed CrossRef
  75. Pérez-Sánchez, N., Doña, I., Bogas, G., Salas, M., Testera, A., Cornejo-García, J. A. and Torres, M. J. (2020) Evaluation of subjects experiencing allergic reactions to non-steroidal anti-inflammatory drugs: clinical characteristics and drugs involved. Front. Pharmacol. 11, 503.
    Pubmed KoreaMed CrossRef
  76. Peter, J. G., Lehloenya, R., Dlamini, S., Risma, K., White, K. D., Konvinse, K. C. and Phillips, E. J. (2017) Severe delayed cutaneous and systemic reactions to drugs: a global perspective on the science and art of current practice. J. Allergy Clin. Immunol. Pract. 5, 547-563.
    Pubmed KoreaMed CrossRef
  77. Phillips, E. J., Bigliardi, P., Bircher, A. J., Broyles, A., Chang, Y. S., Chung, W. H., Lehloenya, R., Mockenhaupt, M., Peter, J., Pirmohamed, M., Roujeau, J. C., Shear, N. H., Tanno, L. K., Trubiano, J., Valluzzi, R. and Barbaud, A. (2019) Controversies in drug allergy: testing for delayed reactions. J. Allergy Clin. Immunol. 143, 66-73.
    Pubmed KoreaMed CrossRef
  78. Pichler, W. J. (2019) Immune pathomechanism and classification of drug hypersensitivity. Allergy 74, 1457-1471.
    Pubmed CrossRef
  79. Pirmohamed, M., Ostrov, D. A. and Park, B. K. (2015) New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity. J. Allergy Clin. Immunol. 136, 236-244.
    Pubmed KoreaMed CrossRef
  80. Plachouri, K. M., Vryzaki, E. and Georgiou, S. (2019) Cutaneous adverse events of immune checkpoint inhibitors: a summarized overview. Curr. Drug Saf. 14, 14-20.
    Pubmed CrossRef
  81. Porębski, G., Czarnobilska, E. and Bosak, M. (2015) Cytotoxic-based assays in delayed drug hypersensitivity reactions induced by antiepileptic drugs. Pol. Arch. Med. Wewn. 125, 823-834.
    Pubmed CrossRef
  82. Quach, H. T., Johnson, D. B., LeBoeuf, N. R., Zwerner, J. P. and Dewan, A. K. (2021) Cutaneous adverse events caused by immune checkpoint inhibitors. J. Am. Acad. Dermatol. 85, 956-966.
    Pubmed CrossRef
  83. Ramirez, G. A., Ripa, M., Burastero, S., Benanti, G., Bagnasco, D., Nannipieri, S., Monardo, R., Ponta, G., Asperti, C., Cilona, M. B., Castagna, A., Dagna, L. and Yacoub, M. R. (2023) Drug reaction with eosinophilia and systemic symptoms (DRESS): focus on the pathophysiological and diagnostic role of viruses. Microorganisms 11, 346.
    Pubmed KoreaMed CrossRef
  84. Redwood, A. J., Pavlos, R. K., White, K. D. and andPhillips, E. J. (2018) HLAs: key regulators of T-cell-mediated drug hypersensitivity. HLA 91, 3-16.
    Pubmed KoreaMed CrossRef
  85. Rodilla, E. M., González, I. D., Yges, E. L., Múñoz Bellido, F. J., Gracia Bara, M. T. and Toledano, F. L. (2010) Immunological aspects of nonimmediate reactions to beta-lactam antibiotics. Expert Rev. Clin. Immunol. 6, 789-800.
    Pubmed CrossRef
  86. Romano, A., Valluzzi, R. L., Caruso, C., Maggioletti, M. and Gaeta, F. (2017) Non-immediate cutaneous reactions to beta-lactams: approach to diagnosis. Curr. Allergy Asthma Rep. 17, 23.
    Pubmed CrossRef
  87. Roujeau, J. C. (2006) Immune mechanisms in drug allergy. Allergol. Int. 55, 27-33.
    Pubmed CrossRef
  88. Rozieres, A., Vocanson, M., Saïd, B. B., Nosbaum, A. and Nicolas, J. F. (2009) Role of T cells in nonimmediate allergic drug reactions. Curr. Opin. Allergy Clin. Immunol. 9, 305-310.
    Pubmed CrossRef
  89. Saeed, H. N. and Chodosh, J. (2016) Immunologic mediators in Stevens-Johnson syndrome and toxic epidermal necrolysis. Semin. Ophthalmol. 31, 85-90.
    Pubmed CrossRef
  90. Santos Andrade, P. H., da Silva Santos, A., Santos Souza, C. A., Fraga Lobo, I. M. and da Silva, W. B. (2017) Risk factors for adverse drug reactions in pediatric inpatients: a systematic review. Ther. Adv. Drug Saf. 8, 199-210.
    Pubmed KoreaMed CrossRef
  91. Schettini, N., Corazza, M., Schenetti, C., Pacetti, L. and Borghi, A. (2023) Urticaria: a narrative overview of differential diagnosis. Biomedicines 11, 1096.
    Pubmed KoreaMed CrossRef
  92. Seervai, R. N. H., Sinha, A. and Kulkarni, R. P. (2022) Mechanisms of dermatological toxicities to immune checkpoint inhibitor cancer therapies. Clin. Exp. Dermatol. 47, 1928-1942.
    Pubmed CrossRef
  93. Senra, L., Mylonas, A., Kavanagh, R. D., Fallon, P. G., Conrad, C., Borowczyk-Michalowska, J., Wrobel, L. J., Kaya, G., Yawalkar, N., Boehncke, W. H. and Brembilla, N. C. (2019) IL-17E (IL-25) enhances innate immune responses during skin inflammation. J. Invest. Dermatol. 139, 1732-1742.
    Pubmed CrossRef
  94. Sharma, A., Saito, Y., Hung, S. I., Naisbitt, D., Uetrecht, J. and Bussiere, J. (2019) The skin as a metabolic and immune-competent organ: Implications for drug-induced skin rash. J. Immunotoxicol. 16, 1-12.
    Pubmed CrossRef
  95. Shen, M., Er Lim, J. M., Chia, C. and Ren, E. C. (2020) CD39+ regulatory T cells modulate the immune response to carbamazepine in HLA-B*15:02 carriers. Immunobiology 225, 151868.
    Pubmed CrossRef
  96. Shiohara, T. and Mizukawa, Y. (2019) Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): an update in 2019. Allergol. Int. 68, 301-308.
    Pubmed CrossRef
  97. Sibaud, V., Meyer, N., Lamant, L., Vigarios, E., Mazieres, J. and Delord, J. P. (2016) Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr. Opin. Oncol. 28, 254-263.
    Pubmed CrossRef
  98. Spoerl, D., Nigolian, H., Czarnetzki, C. and Harr, T. (2017) Reclassifying anaphylaxis to neuromuscular blocking agents based on the presumed patho-mechanism: IgE-mediated, pharmacological adverse reaction or "innate hypersensitivity"?. Int. J. Mol. Sci. 18, 1223.
    Pubmed KoreaMed CrossRef
  99. Stevens, W., Buchheit, K. and Cahill, K. N. (2015) Aspirin-exacerbated diseases: advances in asthma with nasal polyposis, urticaria, angioedema, and anaphylaxis. Curr. Allergy Asthma Rep. 15, 69.
    Pubmed CrossRef
  100. Sueki, H., Watanabe, Y., Sugiyama, S. and Mizukawa, Y. (2022) Drug allergy and non-HIV immune reconstitution inflammatory syndrome. Allergol. Int. 71, 185-192.
    Pubmed CrossRef
  101. Szatkowski, J. and Schwartz, R. A. (2015) Acute generalized exanthematous pustulosis (AGEP): a review and update. J. Am. Acad. Dermatol. 73, 843-848.
    Pubmed CrossRef
  102. Torres, M. J., Mayorga, C. and Blanca, M. (2009) Nonimmediate allergic reactions induced by drugs: pathogenesis and diagnostic tests. J. Investig. Allergol. Clin. Immunol. 19, 80-90.
  103. Torres, M. J., Barrionuevo, E., Kowalski, M. and Blanca, M. (2014a) Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs. Immunol. Allergy Clin. North Am. 34, 507-524.
    Pubmed CrossRef
  104. Torres, M. J., Mayorga, C., Blanca-López, N. and Blanca, M. (2014b) Hypersensitivity reactions to beta-lactams. Exp. Suppl. 104, 165-184.
    Pubmed CrossRef
  105. Ushigome, Y., Mizukawa, Y., Kimishima, M., Yamazaki, Y., Takahashi, R., Kano, Y. and Shiohara, T. (2018) Monocytes are involved in the balance between regulatory T cells and Th17 cells in severe drug eruptions. Clin. Exp. Allergy, 48, 1453-1463.
    Pubmed CrossRef
  106. Vane, J. R. and Botting, R. M. (2003) The mechanism of action of aspirin. Thromb. Res. 110, 255-258.
    Pubmed CrossRef
  107. Vocanson, M., Naisbitt, D. J. and Nicolas, J. F. (2020) Current perspective of the etiopathogenesis of delayed-type, and T-cell-mediated drug-related skin diseases. J. Allergy Clin. Immunol. 145, 1142-1144.
    Pubmed CrossRef
  108. Wang, C. W., Yang, L. Y., Chen, C. B., Ho, H. C., Hung, S. I., Yang, C. H., Chang, C. J., Su, S. C., Hui, R. C., Chin, S. W., Huang, L. F., Lin, Y. Y., Chang, W. Y., Fan, W. L., Yang, C. Y., Ho, J. C., Chang, Y. C., Lu, C. W. and Chung, W. H.; the Taiwan Severe Cutaneous Adverse Reaction (TSCAR) Consortium (2018) Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions. J. Clin. Invest. 128, 985-996.
    Pubmed KoreaMed CrossRef
  109. Wang, F., Zhao, Y. K., Li, M., Zhu, Z. and Zhang, X. (2017) Trends in culprit drugs and clinical entities in cutaneous adverse drug reactions: a retrospective study. Cutan. Ocul. Toxicol. 36, 370-376.
    Pubmed CrossRef
  110. Wang, X., Xiong, J., Xu, W. H., Yu, S., Huang, X., Zhang, J., Tian, C., Huang, D., Jia, W. and Lang, S. (2015) Risk of a lamotrigine-related skin rash: current meta-analysis and postmarketing cohort analysis. Seizure 25, 52-61.
    Pubmed CrossRef
  111. Watanabe, T. and Yamaguchi, Y. (2023) Cutaneous manifestations associated with immune checkpoint inhibitors. Front. Immunol. 14, 1071983.
    Pubmed KoreaMed CrossRef
  112. Wei, B. M., Fox, L. P., Kaffenberger, B. H., Korman, A. M., Micheletti, R. G., Mostaghimi, A., Noe, M. H., Rosenbach, M., Shinkai, K., Kwah, J. H., Phillips, E. J., Bolognia, J. L., Damsky, W. and Nelson, C. A. (2023) Drug-induced hypersensitivity syndrome / drug reaction with eosinophilia and systemic symptoms. Part I. Epidemiology, pathogenesis, clinicopathological features, and prognosis. J. Am. Acad. Dermatol.. doi: 10.1016/j.jaad.2023.02.072 [Online ahead of print].
    Pubmed CrossRef
  113. White, K. D., Chung, W. H., Hung, S. I., Mallal, S. and Phillips, E. J. (2015) Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response. J. Allergy Clin. Immunol. 136, 219-234.
    Pubmed KoreaMed CrossRef
  114. Wilkerson, R. G. (2022) Drug hypersensitivity reactions. Emerg. Med. Clin. North Am. 40, 39-55.
    Pubmed CrossRef
  115. Wuillemin, N., Ballmer-Weber, B., Schlapbach, C., Jörg, L. and Yerly, D. (2022) The activation pattern of drug-reacting T cells has an impact on the clinical picture of hypersensitivity reactions. Front. Allergy 3, 804605.
    Pubmed KoreaMed CrossRef
  116. Yamamoto, T. (2022) Skin manifestation induced by immune checkpoint inhibitors. Clin. Cosmet. Investig. Dermatol. 15, 829-841.
    Pubmed KoreaMed CrossRef
  117. Yazıcıoğlu, M. (2014) Approach to drug allergies in the childhood. Turk Pediatri Ars. 49, 99-103.
    Pubmed KoreaMed CrossRef
  118. Ye, Y. M., Hur, G. Y., Kim, S. H., Ban, G. Y., Jee, Y. K., Naisbitt, D. J., Park, H. S. and Kim, S. H. (2017) Drug-specific CD4+ T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome. Br. J. Dermatol. 176, 378-386.
    Pubmed CrossRef
  119. Zalewska-Janowska, A., Spiewak, R. and Kowalski, M. L. (2017) Cutaneous manifestation of drug allergy and hypersensitivity. Immunol. Allergy Clin. North Am. 37, 165-181.
    Pubmed CrossRef
  120. Zazzara, M. B., Palmer, K., Vetrano, D. L., Carfì, A. and Onder, G. (2021) Adverse drug reactions in older adults: a narrative review of the literature. Eur. Geriatr. Med. 12, 463-473.
    Pubmed KoreaMed CrossRef
  121. Zhang, C., Van, D. N., Hieu, C. and Craig, T. (2019) Drug-induced severe cutaneous adverse reactions: determine the cause and prevention. Ann. Allergy Asthma Immunol. 123, 483-487.
    Pubmed CrossRef
  122. Zhu, H. and Ren, V. (2023) Immunopathogenic insights on preferential human herpesvirus-6 reactivation in drug rash with eosinophilia and systemic symptoms: a scoping review. J. Cutan. Med. Surg. 27, 388-398.
    Pubmed KoreaMed CrossRef
  123. Zhu, L. J., Liu, A. Y., Wong, P. H. and Arroyo, A. C. (2022) Road less traveled: drug hypersensitivity to fluoroquinolones, vancomycin, tetracyclines, and macrolides. Clin. Rev. Allergy Immunol. 62, 505-518.
    Pubmed KoreaMed CrossRef


This Article


Cited By Articles
  • CrossRef (0)

Services
Social Network Service

e-submission

Archives