Nivolumab PD-1 inhibitor immunotherapy associated with vulvar, perineal and perianal lichen sclerosus

Nivolumab is a programmed cell death (PD)‐1 ligand inhibitor, licensed for the treatment of melanoma, renal cell carcinoma and nonsmall‐cell lung cancer. It works by inhibiting immune checkpoints and disrupting T‐cell activation to enhance the immune response. Immune‐related toxicities are commonly described, including colitis, hepatitis, thyroiditis and diabetes. Lichenoid dermatoses are also frequently observed on the skin and mucous membranes, but an association with genital lichen sclerosus (LS) has not been reported.1 We describe a patient with metastatic melanoma treated with nivolumab, who developed typical features of genital LS. A 74‐year‐old white woman was diagnosed with metastatic melanoma following excision of a pelvic lesion. The primary melanoma had been excised from the right upper arm 16 years earlier. Positron emission tomography–computed tomography (PET‐CT) demonstrated four peritoneal and omental deposits, but no other disease. Mutation analysis showed that the patient was BRAF wildtype. The patient was commenced on nivolumab 3 mg/kg immunotherapy fortnightly. However, 6 months after initiation, she presented with a 2‐month history of a pruritic vulval and perineal rash, with flares of pruritus and discomfort that occurred after each injection of nivolumab. She had no history of skin disease other than melanoma, but she had experienced a short‐lived postmenopausal vulval itch, which was reviewed in primary care and responded to simple emollients. On physical examination, extensive white atrophic patches were seen, affecting the genitocrural folds, perianal skin, labia majora and outer labia minora (Fig. 1a,b). Cigarette‐paper atrophy and ecchymosis were also noted. Histological examination of a biopsy taken from the perianal skin confirmed histological features of LS. (a) Extensive pallor and atrophy of the vulva, extending onto the genitocrural folds; (b) pallor and atrophy extending onto the perianal skin and gluteal cleft. A tapering course of 0.05% clobetasol proprionate (Dermovate; GlaxoSmithKline, Uxbridge, Middlesex, UK) ointment was commenced, initially once daily, leading to rapid resolution of symptoms. This was reduced to alternate daily applications after a month and then twice weekly for a third month. Good control of the LS was maintained with this regimen during further injections of nivolumab. The immunotherapy was discontinued 4months later following patient request, owing to low‐grade adverse reactions, including diarrhoea and fatigue. She was followed up for an additional 6 months, and during this time applied Dermovate ointment on an as‐required basis, without relapse of more severe symptoms or signs of active disease at time of examination. This case demonstrates typical features of vulvar, perineal and perianal LS developing in a patient commenced on nivolumab, with flares after each injection. Resolution of symptoms and clinical features was observed with standard management of LS with topical clobetasol propionate 0.05%. Skin reactions related to PD‐1 inhibitor therapy are known to occur in 4–27% of patients.1 These typically include lichenoid mucocutaneous eruptions, but also vitiligo (5–11%), lichen planus, psoriasis and bullous pemphigoid.1 One case report has described a relapse of morphoea, but an association with LS has not been described.2 While the exact aetiology of female genital LS has not been fully elucidated, it is known to be a T cell‐mediated disorder, with increasing evidence suggesting an autoimmune pathogenesis, for example the presence of antibodies to extracellular matrix protein 1, increased levels of Th1‐specific cytokines, dense T‐cell infiltrates and enhanced BIC/miR‐155 expression.3 4 It is also reported to occur more commonly alongside other autoimmune conditions such as vitiligo and thyroid disease.5 This would explain an association with PD‐1 inhibitor therapy, as the binding of PD‐1 to its ligands is vital for physiological regulation of the immune system. It therefore plays a major role in inhibiting self‐reactive T cells, which serve to protect against autoimmune diseases. We would like to highlight this potential association, as patients may be hesitant to mention genital AEs to their doctor, which could lead to under‐reporting. A history of vulval symptoms should therefore be considered as part of routine history in these patients, as it responds well to standard treatment. Conflict of interest: the authors declare that they have no conflicts of interest.