Bullous pemphigoid, an autoantibody-mediated disease, is a novel immune-related adverse event in patients treated with anti-programmed cell death 1 antibodies

Abstract

Anti-programmed cell death 1 (anti-PD1) antibodies such as pembrolizumab have shown improved progression-free and overall survival in patients with advanced melanoma. Of 124 patients reviewed in Westmead Hospital from May 2012 to November 2015, treated with pembrolizumab for advanced melanoma, we encountered three cases of bullous pemphigoid (BP). We have previously reported a case of BP. In two recent cases, BP was diagnosed early and treated promptly with potent topical or oral steroid. Patients on anti-PD1 antibodies are at a higher risk of developing cutaneous immune-related adverse events such as lichenoid reactions, eczema and vitiligo. No cases of BP were encountered in the previously published cohort of 260 melanoma patients treated with BRAF inhibitors; as such, it appears that BP is associated with anti-PD1 treatment rather than metastatic melanoma. BP appears to be another immune-related adverse event, and clinicians should have a low threshold for performing cutaneous biopsies and immunofluorescence studies in patients on anti-PD1 therapies.

Development of bullous pemphigoid during nivolumab therapy

“…Both medications are reported to induce several cutaneous immune-related adverse events (IRAE), the most common of which are eczematous and lichenoid eruptions, pruritus, and, in melanoma patients, vitiligo 2 . At the time of submission, development of BP had been reported in 6 other patients treated with anti–PD-1 or programmed death ligand 1 (PD-L1) therapy 2, 3, 4…”

A review of bullous pemphigoid associated with PD‐1 and PD‐L1 inhibitors

“…13,14 Three of 21 patients experienced prolonged courses of BP with intermittent blister recurrence occurring 3 to 12 months following cessation of checkpoint inhibitor. 7,10,11,16,17 Six of 21 patients developed BP with oral mucosal involvement two of these patients experienced progression of their cancer, while the rest either achieved complete remission or maintained stable disease. 7,10,11,16,17 Six of 21 patients developed BP with oral mucosal involvement two of these patients experienced progression of their cancer, while the rest either achieved complete remission or maintained stable disease.…”

“…7,10,11,16,17 Six of 21 patients developed BP with oral mucosal involvement two of these patients experienced progression of their cancer, while the rest either achieved complete remission or maintained stable disease. 7,16 Dose reduction was attempted in one patient; however, pembrolizumab was ultimately discontinued following progression of malignancy and worsening dermatologic toxicity. The median time to cutaneous toxicity was 18 weeks The highest dose of pembrolizumab administered was 10 mg/kg every 2-3 weeks.…”

“…7,8,10,13 Pembrolizumab Ten of 21 BP cases were associated with pembrolizumab ( Table 1). 7 The second patient continued with pembrolizumab therapy after development of BP at cycle 26; however, they only required one additional infusion (cycle 27) before completion of their immunotherapy regimen. Three patients were given this dose, and two of three patients experienced pruritis and nonspecific cutaneous toxicity prior to the development of bullae.…”

Cutaneous Eruptions in Patients Receiving Immune Checkpoint Blockade

“…This finding of delayed immunobullous eruptions is consistent with previous reports. 12,15 Interestingly, our cohort also included patients with vitiligo, granulomatous dermatitis, and an urticarial-type reaction, which also occurred over two months after treatment initiation. Ten of 16 (63%) patients required systemic steroids (again including a number of patients without BP), which is a higher proportion than reported for biopsied lichenoid eruptions.…”