J Clin Aesthet Dermatol. 2025;18(5):36–37.
by Laura Lomax, MD
Dr. Lomax is with Greensboro Dermatology Associates in Greensboro, North Carolina.
FUNDING: Writing support was provided by Arcutis Biotherapeutics Inc.
DISCLOSURES: The author declares no conflicts of interest relevant to the content of this article.
ABSTRACT: Pembrolizumab is an immune checkpoint inhibitor that is used in the treatment of various cancers. The reported mode of action of pembrolizumab is via binding to the PD-1 receptor which leads to blocking both immune-suppressing ligands, PD-L1 and PD-L2, from interacting with PD-1 to modulate the immune response. A common side effect of immune checkpoint inhibitors is pruritus, reported to occur in 14 to 47 percent of patients, which often reduces overall quality of life. This case report chronicles a patient suffering from significant pruritus and a lichenoid skin eruption after initiation of pembrolizumab treatment that was refractory to topical corticosteroid therapy, narrow band ultraviolet B light, and application of emollients. A topical phosphodiesterase-4 (PDE-4) inhibitor, roflumilast cream 0.3%, was subsequently initiated. Roflumilast is a selective inhibitor of PDE-4, approved by the United States Food and Drug Administration (FDA) in a 0.3% cream vehicle in 2022 for treatment of plaque psoriasis of any severity, and in a 0.3% foam vehicle in 2023 for treatment of seborrheic dermatitis of any severity. In 2024, roflumilast was FDA-approved in a 0.15% cream vehicle for treatment of mild-to-moderate atopic dermatitis in patients six years of age and older. In this adult patient, pruritus was improved within 48 hours after initiation of roflumilast cream 0.3% applied once daily and continued to be effective with use over time.
Keywords: Pruritus, pembrolizumab, checkpoint inhibitor, phosphodiesterase-4 inhibitor, roflumilast cream
Introduction
Pembrolizumab is an immune checkpoint inhibitor that is used in the treatment of various cancers.1 Pembrolizumab binds directly to the PD-1 receptor, thus blocking both immune-suppressing ligands, PD-L1 and PD-L2, from interacting with PD-1 to help regulate the immune response.2 A common side effect of immune checkpoint inhibitors is pruritus, a physically and psychologically bothersome symptom reported to affect 14 to 47 percent of patients. Not surprisingly, the frequent pruritus adversely affects the overall quality of life of the patient.1 In this case report, we report a patient suffering from marked pruritus and a cutaneous lichenoid eruption after initiation of pembrolizumab treatment that was refractory to topical corticosteroid therapy, narrow band ultraviolet B light (NB-UVB), and topical emollient treatment. Roflumilast cream 0.3%, a topical PDE-4 inhibitor, was subsequently started with application once daily and greatly improved the burdensome symptom of itching within 48 hours of initiation. Discontinuing pembrolizumab was not a favorable option due to its importance in treating the urothelial malignancy in this patient. Importantly in this case, repeated use over time of roflumilast cream 0.3% was consistently effective in rapidly controlling pruritus and was not associated with any adverse local or systemic effects.
Case report. We report a case of immune checkpoint inhibitor-induced pruritus in a 71-year-old male patient undergoing treatment with a checkpoint inhibitor, pembrolizumab, for urothelial cancer. He had a past medical history of melanoma in situ, cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, and transient acantholytic dermatosis (Grover’s disease) managed with oral doxycycline 50mg once daily, and topical triamcinolone cream for flares. The patient underwent a total nephrectomy secondary to urothelial cancer of the left renal pelvis in October 2020. In November 2021, a computerized tomography (CT) scan demonstrated enlarged retroperitoneal periaortic lymph nodes. Lymph node biopsy with pathologic examination confirmed recurrence of urothelial cancer. A four-month cisplatin-based chemotherapy trial (December 2021–March 2022) was followed by CT evaluation which showed a lack of treatment response. Pembrolizumab, a checkpoint inhibitor, was initiated in March 2022. At three months, the patient had a partial response to therapy, with complete response at six months, which continues to date. A post-complete response treatment protocol with pembrolizumab was planned to continue for at least an additional year. Within the first three months of the initiation of pembrolizumab, the patient developed significant pruritus and a cutaneous lichenoid eruption involving his posterior thighs and trunk, associated with a substantial negative impact on his quality of life. Topical corticosteroid application twice daily, including triamcinolone cream 0.1% and betamethasone dipropionate cream 0.05%, resulted in a modest but inadequate response. In December 2022, in addition to topical corticosteroid and emollient use, dermatology office-based NB-UVB treatments three times per week were initiated, which led to partial improvement of the pruritus and lichenoid eruption. In April 2023, roflumilast cream 0.3% was initiated with instructions to be applied daily to affected areas of skin. Within the first 48-hours of treatment, the patient reported marked improvement in pruritus. After two weeks of daily applications, NB-UVB therapy and topical corticosteroid use were halted and monotherapy with roflumilast cream 0.3% once daily was continued. The patient achieved better improvement with roflumilast cream 0.3% than he had with either of the topical corticosteroids and NB-UVB. If applications of topical roflumilast were missed, the patient noted that the itching quickly returned, but it was effectively and consistently managed with the continuation or restart of roflumilast cream 0.3% once daily. No adverse effects were noted with use of roflumilast cream 0.3%.
This case report of a 71-year-old male with significant pruritus and a lichenoid skin eruption after initiation of pembrolizumab resulted in a greater improvement of pruritic symptoms following treatment with roflumilast cream 0.3% compared to use of mid-potency and high-potency topical corticosteroids and NB-UVB light therapy. The results in this patient suggest that roflumilast cream 0.3% can be used either as initial treatment of checkpoint inhibitor-induced pruritus or can be initiated in those with persistence of pruritus despite trying other therapies. This case highlights the common difficulty experienced by many patients suffering from checkpoint inhibitor-induced pruritus, with the lack of availability of consistently effective therapeutic options. The rapid and continued reduction in pruritus demonstrated in this case provides some cogent evidence that roflumilast cream 0.3% can be considered to be an effective and safe primary treatment option that can control bothersome pruritus induced by immune checkpoint inhibition.
References
- Phillips GS, Freites-Martinez A, Wu J, et al. Clinical Characterization of Immunotherapy-Related Pruritus Among Patients Seen in 2 Oncodermatology Clinics. JAMA Dermatol. 2019;155(2):249–251. doi:10.1001/jamadermatol.2018.4560
- Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (Keytruda). Hum Vaccin Immunother. 2016 Nov;12(11):2777-2789. doi: 10.1080/21645515.2016.1199310. Epub 2016 Jul 11. PMID: 27398650; PMCID: PMC5137544.