Resolution of Pembrolizumab‐Associated Steroid‐Refractory Lichenoid Dermatitis with Cyclosporine

Skin rash is a common immune‐related adverse event seen in patients treated with checkpoint inhibitors. This brief communication presents the case of a woman with stage IV lung adenocarcinoma who developed lichenoid dermatitis associated with pruritis on pembrolizumab.

Abstract

Checkpoint inhibitors such as pembrolizumab, an anti‐PD‐1 monoclonal antibody, are a promising new category of oncological therapeutics, associated with a higher risk of immune‐related adverse events including dermatological, autoimmune and endocrine sequelae. Here, we present a case of a woman 76 years of age with stage IV lung adenocarcinoma who developed a severe and steroid‐refractory lichenoid dermatitis associated with pruritus on pembrolizumab. This eruption resolved completely with a short course of oral cyclosporine. Cyclosporine is a promising and effective treatment option for checkpoint inhibitor‐related severe cutaneous eruptions.

Introduction

Pembrolizumab, an anti‐PD‐1 monoclonal antibody, is approved by the U.S. Food and Drug Administration for the treatment of multiple malignancies, including advanced melanoma, non‐small cell lung cancer, Hodgkin's lymphoma, primary mediastinal B‐cell lymphoma, urothelial carcinoma, and head and neck cancer. Recent meta‐analyses have shown that anti‐PD‐1 drugs are associated with a higher risk of rash when compared with conventional treatment such as chemotherapy or targeted therapy [1]. We present a case of a patient on pembrolizumab who developed diffuse steroid‐refractory lichenoid dermatitis associated with severe pruritus that was successfully treated with a short course of oral cyclosporine.

Case Presentation

A woman 76 years of age with stage IV lung adenocarcinoma was initiated on treatment with pembrolizumab and developed an intensely pruritic and violaceous rash on the trunk and extremities after cycle 8. She was initially diagnosed with scabies as she lived in a group facility and was treated twice with permethrin with no improvement. She continued on pembrolizumab through cycle 11, and thereafter, the treatment was held because of significant skin toxicity. She was subsequently referred to dermatology, where she was noted to have a diffuse rash composed of pruritic, purple scaling macules and plaques (Fig. 1). There were no vesicles or bullae noted. Her oral mucosa was clear. She was initially treated with potent topical steroids (clobetasol 0.05% cream), oral antihistamines, and oral dexamethasone for 6 weeks with no improvement, followed by a 3‐week course of oral prednisone 60 mg daily without benefit. The patient continued to exhibit a grade 3 rash with 25% body‐surface‐area involvement. Skin biopsy demonstrated a lichenoid dermatitis with orthokeratosis, numerous dyskeratotic cells, and abundant eosinophils (Fig. 2). Given that her rash was progressing despite discontinuation of pembrolizumab and standard therapies (topical steroids, oral prednisone, and oral antihistamines for pruritus), the patient was started on cyclosporine 100 mg daily in addition to prednisone 40 mg daily. Ten days after starting cyclosporine, her dermatitis improved dramatically, and her pruritus resolved. Complete blood counts, chemistries, and hepatic function panel were within normal limits with no peripheral eosinophilia. As her prednisone was tapered, she had a mild flare that resolved with an increase in her cyclosporine to 125 mg daily. She was eventually tapered off prednisone and discontinued use of topical corticosteroids as well as oral antihistamines. Cyclosporine was discontinued after 4 months of treatment because of sustained resolution of the rash. She remains asymptomatic from her lung adenocarcinoma. A follow‐up computed tomography (CT) scan of the chest 4 months after discontinuation of pembrolizumab revealed enlargement of the dominant right upper lobe nodule (2.3 cm from 1.6 cm), with otherwise stable lung disease and no evidence of widespread disease. A further follow‐up CT 7 months after discontinuing pembrolizumab showed overall improvement in disease, with decreased size of the dominant right upper lobe pulmonary nodule, decreased size and density of numerous small bilateral pulmonary nodules, and no evidence of widespread disease.

Figure 1.

Lichenoid dermatitis after treatment with topical and oral corticosteroids (left) and after 3 months of cyclosporine therapy (right).

Figure 2.

Lichenoid dermatitis with orthokeratosis, numerous dyskeratotic cells, and abundant eosinophils at the dermal‐epidermal junction. Hematoxylin and eosin stain, ×10 magnification.

Discussion

Checkpoint inhibitors are a promising new therapeutic class for the treatment of various malignancies. Skin rash is one of the most common immune‐related adverse events seen in patients treated with either anti‐CTLA4 or anti‐PD‐1 therapies [2] and can limit therapeutic efficacy because the dose may need to be decreased or treatment halted because of the severity of the cutaneous eruption [3]. Specifically, lichenoid drug rash is a common adverse reaction in patients on PD‐1 inhibitors [4]. Mid‐ to high‐potency topical corticosteroids and systemic antihistamines are first‐line treatments of grade 1 and 2 skin toxicities associated with PD‐1 inhibitor therapy. For eruptions classified as grades 3 or 4, or refractory grade 2, discontinuation of the drug and systemic corticosteroids are recommended [5]. The rash in immunotherapy‐mediated dermatitis is thought to be largely mediated by activated T cells [6]. Cyclosporine, a potent T‐cell inhibitor, has been used successfully to treat other immune‐related adverse events such as enterocolitis in patients on PD‐1 inhibitors for treatment of non‐small cell lung carcinoma, and it offers another systemic option for treatment of severe, refractory rash [7]. Additional therapies such as TNF‐α inhibitors have been described for treatment of enterocolitis but require inpatient admission and are thus more cumbersome for management of lichenoid and psoriasiform skin eruptions. Additionally, a potential complication of chronic treatment with TNF‐α inhibitors is that long term use (>12 months) is associated with development or progression of malignancies [8]. Cyclosporine is associated with increased risk of nonmelanoma skin cancer and lymphoproliferative disease; however, it is not associated with increased risk of noncutaneous solid tumors [9]. Furthermore, the risk of malignancy with cyclosporine is highest when used long term (more than 2 years) and/or in patients with additional risk factors [10]. Notably, a prospective cohort study of severe psoriasis patients on long‐term cyclosporine therapy found no increased risk of noncutaneous malignancy compared with the general population [10]. From an oncologic standpoint, despite cessation of pembrolizumab and initiation of cyclosporine treatment, our patient has had a sustained response with overall improvement in lung nodules on 7‐month follow‐up CT. Similar sustained response with stable oncologic disease has been seen in case reports in which cyclosporine was used to treat anti‐PD‐1‐related adverse events [7]. With its ability to be used in a convenient outpatient setting, balanced with its efficacy and rapid‐acting mechanism, cyclosporine is a promising treatment of severe steroid‐refractory cutaneous adverse events associated with anti‐PD‐1 therapy.

Disclosures

The authors indicated no financial relationships.