Anti–PD1 Immune Checkpoint Inhibitor–Induced Bullous Pemphigoid in Metastatic Melanoma and Non–Small Cell Lung Cancer
Anti–programmed cell death 1 (PD1) targeted immune checkpoint inhibitors such as nivolumab and pembrolizumab are increasingly used to treat advanced malignancies such as melanoma, non–small cell lung cancer, urothelial cancer, and renal cell carcinoma. A rare but increasingly reported adverse effect of anti-PD1 therapy is bullous pemphigoid (BP), an autoimmune blistering disease directed against BP antigen 1 and BP antigen 2 in the basement membrane of the epidermis. We present 3 cases of BP secondary to anti-PD1 immunotherapy in patients with melanoma and non–small cell lung cancer to highlight the diagnosis and treatment of this condition and emphasize the importance of the dermatologist in the care of patients with immunotherapy-related skin disease.
Practice Points
- Anti–programmed cell death 1 (PD1) targeted therapies improve survival in solid and hematologic malignancies but are associated with autoimmune side effects, with bullous pemphigoid (BP) being the newest reported.
- Bullous pemphigoid can develop months into immunotherapy treatment.
- Bullous pemphigoid should be on the differential diagnosis in a patient who is on an anti-PD1 immune checkpoint inhibitor and develops 1 or more of the following: pruritus, dermatitis, and vesicles.
- Early diagnosis of BP is essential for keeping patients on immunotherapy because its severity often results in temporary or permanent discontinuation of treatment.
Comment
Immunotherapy with immune checkpoint blockade represents a successful application of immune recognition to treat metastatic cancers, including melanoma, non–small cell lung cancer, urothelial cancer, and renal cell carcinoma.
Anti-PD1 targeted therapies improve survival in solid and hematologic malignancies, with a response rate as high as 40% in melanoma.2 Although these medications can prolong survival, many are associated with loss of self-tolerance and severe autoimmunelike events that can limit therapy.3 An exception is PD1-induced vitiligo, which patient 1 developed and has been associated with a better response to therapy.4
Anti-PD1–induced BP is a newly reported adverse effect. In its early stages, BP can be difficult to differentiate from eczematous or urticarial dermatitis.5-8 Discontinuation of immunotherapy has been reported in more than 70% of patients who develop BP.1 There are reports of successful treatment of BP with a course of a PD1 inhibitor,9 but 2 of our patients had severe BP that led to discontinuation of immunotherapy.
Consider Prescreening
Given that development of BP often leads to cessation of therapy, identifying patients at risk prior to starting an immune checkpoint inhibitor might have clinical utility. Biopsy with DIF is the gold standard for diagnosis, but serologic testing can be a useful adjunct because enzyme-linked immunosorbent assay for BP antigen 1 and BP antigen 2 has a reported sensitivity and specificity of 87% and 98%, respectively.10 Serologic testing prior to starting therapy with an immune checkpoint inhibitor can provide a baseline for patients. A rise in titer, in conjunction with onset of a rash, might aid in earlier diagnosis, particularly because urticarial BP can be difficult to diagnose clinically.
Further study on the utility vs cost-benefit of these screening modalities is warranted. Their predictive utility might be limited, however, and positive serologic test results might have unanticipated consequences, such as hesitation in treating patients, thus leading to a delay in therapy or access to these medications.
Conclusion
The expanding use of immune checkpoint inhibitors is increasing survival in patients with metastatic melanoma and other malignancies. Adverse effects are part of the continuum of immune system stimulation, with overstimulation resulting in dermatitis; thyroiditis; pneumonitis; and less commonly hypophysitis, vitiligo, and colitis.
Rarely, immune checkpoint inhibition induces BP. Development of BP leads to discontinuation of therapy in more than half of reported cases due to lack of adequate treatment for this skin disease and its impact on quality of life. Therefore, quick diagnosis of BP in patients on immunotherapy and successful management techniques can prevent discontinuation of these lifesaving cancer therapies. For that reason, dermatologists play an important role in the management of patients on immune checkpoint inhibitors for cancer.
