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.