Nivolumab Induced Palmoplantar Keratoderma

Dear Editor, Palmoplantar keratoderma (PPK) comprises a heterogeneous group of disorders that can be acquired or hereditary. Acquired PPK may be seen as a rare cutaneous complication of some medications (iodine, bromides, halogenated pesticides, arsenic) and recently various chemotherapeutic agents like BRAF inhibitors, MEK 1/2 inhibitors, tyrosine kinase inhibitors have been found to induce palmoplantar keratodermas.[1] We describe one patient, who after taking nivolumab developed acquired PPK as an adverse event. A 58-year-old man, known diabetic, hypertensive with coronary artery disease presented with painful hyperkeratotic, thick scaly lesions on both palms and soles for 6 months. He had 24 cycles of nivolumab, one injection every 2 weeks for 1 year as adjuvant chemotherapy after amputation of his right great toe with malignant melanoma. There is no evidence of personal/family history of psoriasis or PPK. He had no medical issues or contact with chemicals known to be related to acquired PPK. After 10 cycles of chemotherapy, he observed scaly hyperkeratotic lesions on both palms and soles. As these lesions were asymptomatic, he continued the remaining cycles. After the completion of 24 cycles, the drug was stopped, the patient attended our clinic one week after stopping the drug as palmoplantar lesions increased in size and number and were painful causing a lot of discomfort while walking. On examination, the right great toe was amputated, thick hyperpigmented, diffuse hyperkeratotic plaques were seen on the plantar aspects of both feet and the lesions were tender and painful, and the patient was not able to walk. In addition, there were focal hyperkeratotic lesions on both palms [Figure 1a and b]. Nails were not affected. There was no regional lymphadenopathy. There were no cutaneous lesions anywhere else on the body and scalp. Systemic examination was normal. Laboratory findings were unremarkable. Lesional biopsy from the palms showed prominent compact hyperkeratosis, with focal parakeratosis, and marked acanthosis with irregular elongation of rete ridges. There were necrotic keratinocytes in the upper spinous layer along with focal, mild lymphocytic basal cell degeneration suggestive of lichenoid drug reaction [Figure 2a and b]. On account of the temporal relationship with the initiation of nivolumab and histopathological findings, a diagnosis of acquired (drug-induced) PPK was made. Based on the Naranjo scale of adverse drug reactions, a score of 4 is given, which indicates possible adverse drug reactions. The patient was treated with topical keratolytics and oral acitretin 25 mg daily for 2 months. As the patient was suffering from severe functional disability, oral acitretin was added to accelerate the healing process in addition to stopping the drug. After 4 weeks of treatment, the majority of the lesions on the palms, a few lesions on the soles regressed, and the patient’s quality of life was improved [Figure 3a and b].Figure 1: (a) Focal hyperkeratotic lesions on both palms. (b) Diffuse hyperkeratotic lesions on both solesFigure 2: (a) Marked epidermal parakeratosis (green arrow), acanthosis (blue arrow) with necrotic keratinocytes (black arrow) in the upper spinous layer (H and E, 100×). (b) Necrotic keratinocytes (black arrow) in the upper spinous layer (H and E, 400×)Figure 3: (a) Post-treatment regression of lesions on both palms. (b) Post-treatment partial improvement of lesions on both solesAccording to the recent systematic review,[1] PPK most frequently developed after treatment with BRAF inhibitors (73.7%), BRAF inhibitors combined with MEK 1/2 inhibitors (15.4%), tyrosine kinase inhibitors (3.2%) or other chemotherapy agents (2.4%). The mean latent period between the initiation of the drugs and the onset of PPK was 7.6 months. PPK also occurred after treatment with olmutinib,[2] tepotinib,[3] and talquetamab.[4] Various clinical types of hyperkeratotic skin adverse events have been reported.[5] These types vary in their clinical presentation: Hand–foot skin reaction or palmoplantar keratoderma, induced psoriasis, keratosis pilaris-like or pityriasis rubra pilaris, Grover’s disease, and contact hyperkeratosis to malignant forms such as squamoproliferative skin neoplasms. Their pathogenesis is mainly related to the disruption of epidermal homeostasis and interaction with keratinocyte proliferation/differentiation or keratinocyte survival. Nivolumab is an oncological drug that belongs to the class of immune checkpoint inhibitors. Nivolumab is an IgG4 monoclonal antibody directed against programmed cell death protein 1 (PD1) by binding to PD-1 antigen, expressed on T cells, nivolumab inhibits the interaction between PD-1 and ligands expressed on dendritic cells, macrophages, and cancer cells and thus enhances anti tumor effect on T cells. Nivolumab is currently FDA-approved for the treatment of metastatic melanoma as a monotherapy or in combination with ipilimumab and several other tumors like non-small cell lung cancer, renal cell carcinoma, and squamous cell carcinoma of the head and neck. Among the various known adverse events of nivolumab, psoriasis is well established.[6] To the best of our knowledge, immune checkpoint point inhibitors induced PPK as an adverse event have not been reported. Our patient had no family history of PPK nor did he have medical issues or contact with medications known to be related to acquired PPK. He developed PPK about 5 months after commencing nivolumab. Therefore, it appears that acquired PPK is a specific adverse effect associated with nivolumab. The pathogenesis of nivolumab-induced PPK remains unclear. The above-mentioned mechanisms like disruption of epidermal homeostasis may play a role. We successfully treated the patient with systemic acitretin and topical keratolytics. In conclusion, with the ever-expanding role of these agents, timely recognition and treatment of adverse cutaneous reactions are important in the management of cancer patients. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.