Association of Bullous Pemphigoid With Immune Checkpoint Inhibitor Therapy in Patients With Cancer

Asdourian, Maria S.; Shah, Nishi; Jacoby, Ted V.; Reynolds, Kerry L.; Chen, Shuo

doi:10.1001/jamadermatol.2022.1624

Cited by 31 publications

(33 citation statements)

References 115 publications

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“…CPI therapy was temporarily held or permanently discontinued in 75% of our study population, a rate higher than with previous observations. 10,24 Two cases flared on reintroduction of the CPI. Delayed irAEs with anti-PD-1-based immunotherapy are being increasingly recognized, 26 and two of our cases presented after completion of the CPI course within 3 months.…”

Section: Discussionmentioning

confidence: 99%

Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study

Kawsar

Edwards

Patel

et al. 2022

British Journal of Dermatology

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Background Checkpoint inhibitor (CPI) therapy has significantly improved overall survival in several cancers including metastatic melanoma (MM) and in the adjuvant setting. Cutaneous immune‐related adverse events (irAEs) secondary to CPIs are commonly observed; however, autoimmune blistering disorders such as bullous pemphigoid (BP) are rare. Objectives To review the prevalence, incidence risk, clinicopathological features and management of toxicity in bullous cutaneous irAEs associated with CPI therapy. Methods A multicentre, retrospective, observational study of CPI‐associated bullous irAEs in adults with all cancers across four UK specialist centres between 2006 and 2019. Results In total, 7391 patients were identified. CPI‐associated bullous irAEs including BP (n = 16) occurred in 0·3% (n = 22). The median age of onset was 76 years, and there was a male predominance. Most patients had cutaneous melanoma (73%, n = 16), of which 81% (13 of 16) were BRAF wildtype. Grade 1, 2, 3 and 4 skin toxicity occurred in 9%, 45%, 41% and 5%, respectively. The mucosae were involved in 27%, and 25% of confirmed cases of BP did not present with bullae. The median time to onset of bullous irAEs was 12 months, with a median total symptom duration of 6 months. Single PD‐1/PD‐L1 agents had a longer time to onset of symptoms than combination therapy (median 12 vs. 7 months, respectively). Overall, 91%, 64% and 9% of patients required one, two or three lines of treatment, respectively. Two cases occurred after completion of CPIs (1 and 3 months). Of the 20 cases that presented while on CPIs this was permanently discontinued in 55% (11 of 20) and temporarily held in 20% (four of 20). In the four held cases of CPI, bullous eruption reflared in 50%. Conclusions CPI‐associated bullous skin toxicity is a rare cutaneous irAE occurring in approximately 0·3% of cases over 13 years of treated patients in this series. Not all cases are diagnostic of BP, but management remains the same. There is a prolonged latency of onset compared with other cutaneous irAEs, with a median time of 12 months, and they can occur after cessation of therapy. Discontinuation of CPIs may be required. Recognizing bullous irAEs promptly and referral to dermatology are essential to optimize management and improve patient outcomes and tumour responses. What is already known about this topic? Checkpoint inhibitor (CPI)‐associated bullous pemphigoid is a rare dermatological immune‐related adverse event (irAE) that has been reported in small case series and reports. What does this study add? This is the largest multicentre, observational study conducted in the UK over the longest period of 13 years, which demonstrates an overall incidence of bullous cutaneous irAEs secondary to CPIs of 0·3%. Clinical presentation is variable, with one‐quarter of patients with bullous pemphigoid presenting without bullae, and mucosal involvement was noted in 27%. Prolonged pruritus is frequently a prodromal symptom. The median time to diagnosis is 12 months and irAEs rarely ...

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Section: Discussionmentioning

confidence: 99%

Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study

Kawsar

Edwards

Patel

et al. 2022

British Journal of Dermatology

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“…The latency of bullous disorders due to immunotherapy is generally longer than that of other cutaneous toxicities. In most cases, BP onset is noted concurrently with medication use within 6–8 months of drug initiation ( 8 – 10 ). In this case, however, the bullae first appeared earlier, approximately 3 weeks after the patient’s last infusion.…”

Section: Discussionmentioning

confidence: 99%

“…In most reported cases, BP during ICI therapy has been relatively mild. Systemic and topical corticosteroids were the most common treatments, whereas biologic and targeted agents were used predominantly in cases refractory to treatment with corticosteroids ( 10 ). Our patient exhibited severe and extensive bullous lesions refractory to high-dose corticosteroids (1 mg/kg).…”

Section: Discussionmentioning

confidence: 99%

A case report of steroid-refractory bullous pemphigoid induced by immune checkpoint inhibitor therapy

Guan

Zhang

et al. 2023

Front. Immunol.

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The widespread use of immune checkpoint inhibitors in several malignancies has revealed new immune-related adverse events. Bullous pemphigoid (BP) is an antibody-driven autoimmune disease characterized by skin inflammation and fluid-filled bullae. Herein, a 69-year-old man with lung squamous cell carcinoma developed multiple vesicles and tense bullae 3 weeks after the initiation of a programmed death-1 (PD-1) inhibitor, pembrolizumab, and chemotherapy. Biopsy revealed a subepidermal bulla with lymphocytic and eosinophil infiltration, and immunohistochemical studies predominantly showed CD4+ cells, a few CD8+ cells, and the occasional CD20+ lymphocyte. The serum anti-BP180 antibody level, as well as the interleukin-6 and interleukin-10 levels, were elevated compared to the lower levels of tumor necrosis factor-α. Eosinophil levels were high and consistent with the development of blisters. A diagnosis of BP associated with PD-1 inhibitor therapy was made, and the Common Terminology Criteria for Adverse Events classification was grade 3. Immunotherapy was permanently discontinued, and the patient’s bullous lesions failed to react to high-dose systemic corticosteroids combined with minocycline and niacinamide. Intermittent blister recurrence occurred in 2 months, eventually improving with the administration of two courses of intravenous immunoglobulin. At 5 weeks of follow-up, the patient’s tumor was reduced on a computed tomographic scan. Despite stable BP treatment, however, he repeatedly developed complications due to the complexity of his underlying disease and could not be treated with anti-tumor therapy. Early recognition and management of serious immune-related bullous dermatologic toxicity are essential for patient safety.

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“…All these implications eventually cause bullous pemphigoid. In bullous pemphigoid, the discontinuation of immunotherapy and the addition of steroids are recommended for all grades ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Case report: Bullous pemphigoid associated with sintilimab therapy for pMMR/MSS colorectal cancer

et al. 2023

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Immunotherapy has become a very effective treatment for many cancers. It has a unique set of immune system-related adverse effects, collectively known as immune-related adverse events (irAEs). Skin toxicities are the most common irAEs, of which bullous pemphigoid, although rare, is potentially life-threatening and affects patients’ survival. In this article, we report the treatment of bullous pemphigoid caused by programmed cell death protein-1 (PD-1) in a case of proficient mismatch repair (pMMR)/microsatellite stable (MSS) colorectal cancer. No significant adverse effects were observed in the patient after methylprednisone was tapered to 4 mg twice a day. No new skin lesions occurred recently in the patient and the original skin lesions healed. In particular, the patient’s immunotherapy was not stopped and the best outcome was a partial remission of the disease, lasting for more than 8 months.

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Association of Bullous Pemphigoid With Immune Checkpoint Inhibitor Therapy in Patients With Cancer

Cited by 31 publications

References 115 publications

Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study

Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study

A case report of steroid-refractory bullous pemphigoid induced by immune checkpoint inhibitor therapy

Case report: Bullous pemphigoid associated with sintilimab therapy for pMMR/MSS colorectal cancer

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