Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1

Abstract

Monoclonal antibodies (mAb) targeting immune checkpoint pathways such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) may confer durable disease control in several malignancies. In some patients, immune checkpoint mAb cause cutaneous immune-related adverse events. Although the most commonly reported cutaneous toxicities are mild, a subset may persist despite therapy and can lead to severe or life-threatening toxicity. Autoimmune blistering disorders are not commonly associated with immune checkpoint mAb therapy. We report a case series of patients who developed bullous pemphigoid (BP), an autoimmune process classically attributed to pathologic autoantibody formation and complement deposition. Three patients were identified. Two patients developed BP while receiving the anti-PD-1 mAb nivolumab, and one while receiving the anti-PD-L1 mAb durvalumab. The clinicopathologic features of each patient and rash, and corresponding radiologic findings at the development of the rash and after its treatment, are described. Patients receiving anti-PD-1/PD-L1 mAb may develop immune-related bullous pemphigoid. This may be related to both T-cell and B-cell mediated responses. Referral to dermatology for accurate diagnosis and management is recommended.

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.…”

“…Collectively, the patterns of delayed onset, the need for oral corticosteroids in the majority of cases, and the systemic autoimmune effects (Table 1) observed in patients with non-lichenoid eruptions suggest a potential mechanism of systemic inflammation stimulated by immune checkpoint blockade that may persist long after the initial activation event and possibly mediating both sustained antitumor effect and both cutaneous and non-cutaneous irAEs. 12 …”

“…Patients present commonly with nonspecific morbilliform eruptions, but alternate clinical presentations reported with anti-PD-1/PD-L1 include psoriasis, 7–11 bullous pemphigoid (BP), 12–16 sarcoidosis, 17–19 and Stevens Johnson syndrome/toxic epidermal necrolysis. 20 For a detailed, comprehensive review of the broad array of presentations published to date, see Curry, et al 2016.…”

Early B cell changes predict autoimmunity following combination immune checkpoint blockade

“…In prior studies, we showed that administration of anti-PD1 and anti-CTLA4 leads to distinct genomic signatures in T cells and myeloid cells compared with treatment using either drug alone (6), suggesting that combination therapy may be viewed as a unique treatment rather than as a combination of the 2 monotherapies. While some of the IRAEs are thought to be T cell mediated, B cells have also been implicated (7)(8)(9)(10). However, most studies monitoring immune responses following checkpoint blockade have focused on T cells, and systematic analyses of early changes in B cells and their correlation with autoimmunity are lacking.…”

Early Detection of Adverse Drug Reactions in Social Health Networks: A Natural Language Processing Pipeline for Signal Detection (Preprint)

“…Inspire forum posts describing this ADR preceded the 2015 case report by 9 months ( Figure 4A). Blistering reactions with PD-1 inhibitiors were initially published as a case report in June 2015 [35] and 3-case series in May 2016 [36]. Forum descriptions preceded the first case report by 9 months ( Figure 4B).…”