Bullous Pemphigoid
BP is an autoimmune disease mediated by IgG and IgE autoantibodies
against hemidesmosome proteins which are responsible for the adhesion
between the epidermis and dermis. In bullous pemphigoid appearance of
tense bullae and blisters over urticarial plaques can arise on the
cutaneous layer which is accompanied by intense pruritus82.
Pathogenesis: The hypothesized mechanism of immunotherapy-induced
BP is dysregulation of T cell immune response and synthesis of IgG and
IgE autoantibodies against hemidesmosome proteins bullous pemphigoid
antigen 2 [BPAG2] or BP180, and a plakin family protein BP230 or
bullous pemphigoid antigen1(BPAG1). Both the antigens are specific for
the hemidesmosomes which are responsible for the degradation of the
basement membrane zone and increased inflammatory cell infiltration at
hemidesmosomes found in keratinocytes 82. It is a
humorally mediated autoimmune disease, but auto-reactive T cells and T
regulatory (Tregs) cells have also been found to play a role. The
termination of immune response involves both Tregs and PD-1 and PD-L1
pathway, and elimination of any one of these results in tolerance
breakdown and autoimmunity development83.
Clinical incidence : Twenty-nine cases of bullous pemphigoid were
reported with the anti-PD-1/PD-L1 immunotherapy where thirteen cases
were associated with pembrolizumab84-93, twelve with
nivolumab92-97, three with
atezolizumab93, 98, 99, and one with durvalumab
therapy 93. The occurrence of BP was found in 16-30%
of patients receiving anti-PD-1/PD-L1 immunotherapy and is generally
longer than that of other cutaneous toxicities. It generally has an
onset of 3 weeks-6 years. Most patients were clinical, histologic, and
immunologic features of classic bullous pemphigoid which manifest with
tense blisters over urticarial plaques seen on the trunk and extremities
escorted by intense pruritus93, 100. Before the
expansion of bullae, patients developed pruritus with nonspecific
cutaneous lesions. A total of four cases with nivolumab (n=1) and
pembrolizumab (n=3) developed non-bullous pemphigoid (NBP), severe
pruritus with eczematous patches or urticarial plaques92. A patient with metastatic RCC developed bullous
pemphigoid subsequently with a single dose of 480 mg iv of nivolumab
therapy96.
Treatment: Bullous pemphigoid was the most common extensive
blistering skin disorder in which treatment with systemic prednisolone
was effective in the majority of reported cases. Other reported
treatments include daily topical clobetasol
propionate84, betamethasone 0.05%
ointment86, doxycycline and
niacinamide98, topical fusidic acid plus betamethasone
valerate cream94. In a reported case series, the
development of non-bullous pemphigoid has been treated with 300 mg
omalizumab q4w and rituximab 325 mg/m2 for 4 weeks and there is complete
resolution of the eruption and significant resolution after treatment
with omalizumab and Rituximab 92.