Table 3.

Proposed pathogenesis of cutaneous and systemic bullous dermatologic adverse events (DAE).

Type of DAE	Pathogenesis	References
Cutaneous Bullous DAE
Vesiculobullous eczema	-Pathogenesis related to anti-cancer therapy has not yet been postulated. -Idiopathic bullous eczema is hypothesized to result from over-expression of aquaporin 3 and -10 in keratinocytes throughout the mid and upper epidermis, resulting in epidermal fissuring and subsequent vesicle formation secondary to cutaneous water and glycerol outflow.	[23]
Hand–Foot Skin Reaction	-Caused by direct blockade of VEGFR, PDGFR, and EGFR in healthy tissue. -Eccrine excretion of inciting drug is postulated to cause direct dermal toxicity and/or inhibit receptors, leading to impaired wound healing especially in frictional areas. -Some authors have suggested that hand–foot skin reaction may be equivalent to a Koebner phenomenon, which is the development of new skin lesions secondary to trauma.	[26,27,28,29,30]
Bullous Toxic Erythema of Chemotherapy (TEC)	-Pathogenesis of cytotoxic chemotherapy therapy-induced TEC is likely related to drug accumulation in eccrine sweat glands and subsequent local toxicity. -The pathogenesis of TEC secondary to enfortumab vedotin therapy is postulated to be induced by deposition of the cytotoxic monomethyl auristatin E in tissues expressing nectin-4, such as the skin. Enfortumab vedotin induces apoptosis of keratinocytes expressing nectin-4, causing dysfunctional cell-cell adherence and bullae formation.	[31,32,33].
Systemic Bullous DAE
Bullous Pemphigoid (BP)	-Activation of antibody-secreting B cells, inhibition of immunosuppressive regulatory T-lymphocytes, cross-reaction between anti-BP180 antibodies since BP180 is expressed by many tumor cells, or the triggering of clinically undetectable emerging BP by ICI.	[3,8,34,35,36,37]
Bullous Lichenoid Drug Eruption (BLDE)	-Due to exuberant lichenoid dermatitis with CD4+ and CD8+ T cell involvement. -Some have suggested that the pathogenesis of ICI-induced BLDE is similar to that of SJS/TEN, involving apoptosis of basal keratinocytes secondary to activation of CD8+ T cells by the perforin/granzyme pathway.	[38,39]
Lichen Planus Pemphigoides	-ICI may cause lichenoid dermatitis, which leads to BP180 exposure at the DEJ, allowing the host immune system to develop antibodies targeting these exposed BP180 self-antigens. This develops into epitope spreading, leading to autoimmune bullous progression of lichenoid lesions.	[40,41,42]
Pemphigus Vulgaris (PV)	-Immune-mediated T cell reaction secondary to nivolumab, triggering onset or recurrence in susceptible patients. -Spontaneous PV is thought to be the result of circulating IgG to desmoglein-3 and sometimes desmoglein-1, causing dissociation at the epidermal desmosomes and subsequent acantholysis. -It is possible that nivolumab causes an upregulation of these antibodies through a generalized increase in immune function, triggering PV.	[43]
Bullous Erythema Multiforme (BEM)	-Severe immune reaction to antigens as a result of CD4+ and CD8+ T cell imbalance, which may be caused by increased expression of Fas ligand on T cells in response to nivolumab, causing increased keratinocyte apoptosis. -Another theory involves increased differentiation of immature T cells expressing CTLA-4 in response to ipilimumab, causing a hypersensitivity loop of activated T cells to an antigen. -Similar to non-ICI induced BEM, autoreactive T cells and associated cytokines may lead to the pathologic findings of the disease state.	[44]
Linear IgA Bullous Dermatosis (LABD)	-The pathogenesis of anti-cancer drug induced LABD has not been postulated. -Spontaneous LABD involves circulating IgA anti-basement membrane zone antibodies directed against the 97 kDa portion of BP180 in the lamina lucida.	[45]
Bullous Lupus Erythematosus	-Not yet characterized.
Stevens–Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN)	-Delayed-type hypersensitivity reaction in which cytotoxic T cells generate and release granulysin via the Fas/Fas ligand pathway, which leads to disseminated keratinocyte death. -PD-1, PD-L1, or CTCLA-4 inhibition leads to impaired T cell homeostasis in the skin and loss of protection from skin autoimmunity, leading to cytotoxic inflammatory reactions. -With EGFR inhibitors, it is theorized that irreversible inhibition of EGFR leads to interference of epidermal differentiation and re-epithelialization which leads to extensive erosions and the clinical appearance of SJS/TENs.	[8,39,46,47]
SJS/TEN-like Reactions	-The pathophysiology of SJS-like reactions to PD-1 inhibitors is unknown but thought to possibly be initiated by an erosive lichenoid process. The delayed nature may be due to the gradual loss of peripheral tolerance self-antigen directed T cells in the setting of rising checkpoint inhibitor concentrations over time.	[47]

Abbreviations: DAE = dermatologic adverse event; VEGFR = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor receptor; EGFR = epidermal growth factor receptor; ICI = immune checkpoint inhibitor; DEJ = dermal epidermal junction; IgG = Immunoglobulin G; CTLA = cytotoxic T-lymphocyte–associated antigen; IgA = Immunoglobulin A; kDa = kilodalton; PD = programmed cell death protein.