The patient’s story began after six cycles of pembrolizumab, an anti-PD-1 antibody administered every three weeks for squamous carcinoma of the skin that had spread to the retroperitoneum, the space behind the abdominal cavity. Ten days into a new set of symptoms, she presented with pustules and crusting on her lips, erosion of the buccal mucosa inside her mouth, and target-like lesions across her face, trunk, and limbs, some of which developed central blisters. The rash was accompanied by severe itching. Clinicians diagnosed erythema multiforme, a cutaneous immune-related adverse event, and prescribed oral thalidomide and compound glycyrrhizin tablets, with a follow-up appointment scheduled two weeks later. Crucially, during that interval, she received another infusion of pembrolizumab, a seventh cycle that would prove pivotal to the case.

At follow-up, the picture had changed dramatically. The target-like lesions had progressed into disseminated erythematous nodules with erosions and scaling, a morphology that no longer fit the initial diagnosis. A skin biopsy was obtained and examined under the microscope, revealing acanthosis, a thickening of the epidermis’s spinous layer, along with hyperkeratosis, an accumulation of excess keratin at the skin surface, and an inflammatory infiltrate dominated by lymphocytes. Supplementary histopathological findings included basal cell liquefaction and degeneration, pigment incontinence, and lymphocyte-predominant inflammation in the superficial dermis. These features pointed away from simple erythema multiforme and toward a subepidermal blistering disorder, prompting immunoserological investigation of the patient’s peripheral blood.

The laboratory results were decisive. The woman’s serum contained high titers of anti-BP180 antibodies, measured at 40.96 units per milliliter against a normal threshold of less than 9.0 units per milliliter. BP180, also known as type XVII collagen, is a structural component of hemidesmosomes, the molecular anchors that fasten the basal layer of the epidermis to the underlying basement membrane. Autoantibodies against BP180 are the hallmark of bullous pemphigoid, and their presence, combined with the nodular clinical presentation, secured a diagnosis of pemphigoid nodularis. Interestingly, direct immunofluorescence testing on the skin biopsy was negative, a detail the authors emphasize as a caution: when pemphigoid nodularis is suspected, both direct and indirect immunofluorescence should be performed, because relying on a single technique can miss the diagnosis entirely.

Pemphigoid nodularis is so rare that most dermatologists will never encounter a single case in their careers. It presents clinically as prurigo nodularis, with intensely itchy, firm, dome-shaped nodules, yet immunologically it behaves like bullous pemphigoid, with autoantibodies targeting the dermal-epidermal junction. A substantial proportion of reported cases have been linked to drugs, although the precise etiology remains uncertain. What makes this case particularly notable is the temporal relationship: the eruption began after six cycles of pembrolizumab and worsened into nodular disease following a seventh cycle. That chronological association, backed by the markedly elevated anti-BP180 levels, led the authors to conclude that the checkpoint inhibitor was the most likely trigger.

The mechanism by which pembrolizumab might provoke such an autoimmune reaction lies at the heart of how these drugs work. Pembrolizumab blocks the PD-1 receptor on T cells and its ligand, PD-L1, on tumor and other cells, releasing a molecular brake that tumors exploit to evade immune destruction. The same unleashing of T-cell activity that shrinks tumors can also erode immune tolerance to self-antigens, producing autoimmune-like conditions known as immune-related adverse events. For pemphigoid nodularis specifically, the authors point to two leading pathogenetic hypotheses: molecular mimicry, in which an immune response against tumor antigens cross-reacts with BP180 because of structural similarity between the two proteins, and bystander activation, in which the broadly stimulated immune environment inadvertently activates autoreactive B cells that were previously quiescent. Both mechanisms align with the current understanding of how checkpoint blockade can tip the immune system into autoimmunity.

Treatment proceeded along established protocols for severe cutaneous immune-related adverse events. The patient received short-term intravenous methylprednisolone at a maximum dose of 40 milligrams, supplemented with topical compound polymyxin B and neomycin ointment for the eroded skin, sodium bicarbonate solution gargles for the oral involvement, and oral minocycline, a tetracycline antibiotic with anti-inflammatory properties often used as an adjuvant in blistering diseases. The response was rapid, and within two months all skin lesions had completely regressed, leaving only residual post-inflammatory hyperpigmentation. The speed of resolution underscores a central message of the report: early recognition and prompt differentiation of pemphigoid nodularis from other dermatological conditions can prevent disease progression and the need for more aggressive immunosuppression.

Perhaps the most consequential clinical question raised by the case is whether pembrolizumab should have been stopped at all. Guidelines generally recommend discontinuing immune checkpoint inhibitors in patients who develop high-grade immune-related adverse events, and a blistering autoimmune disease would seem to qualify. Yet the calculus is rarely simple, because these drugs can deliver durable tumor control that no other therapy matches. In this patient, the treating team managed to have it both ways: she has continued pembrolizumab for two years since the episode, with stable tumor control and no recurrence of the skin rash. The authors suggest that the immune activation driving her pemphigoid nodularis was distinct from the antitumor immune response, allowing suppression of the former without sacrificing the latter. Their observation also fits a growing body of evidence that patients who develop early-onset immune-related adverse events, particularly dermatologic ones, may experience improved survival outcomes, possibly reflecting a robust overall immune activation directed against both tumor antigens and self-antigens.

For oncologists and dermatologists, the case is a reminder that cutaneous immune-related adverse events can present in atypical and evolving forms that defy initial diagnoses. A rash labeled erythema multiforme in a patient on a PD-1 inhibitor deserves close surveillance, especially if it changes character after subsequent treatment cycles. Regular follow-up with comprehensive laboratory assessments, including immunoserological panels for basement membrane zone antibodies, and timely histopathological analysis can sharpen diagnostic accuracy and guide management. The successful outcome in this patient also highlights the value of a multidisciplinary approach, in which oncologists, dermatologists, and pathologists coordinate to balance toxicity control against the imperative of continued cancer therapy.

Beyond the individual patient, the report speaks to a broader frontier in immuno-oncology. Immune checkpoint inhibitors have transformed the prognosis of advanced melanoma and many other malignancies, but their benefit comes with an expanding catalog of immune-mediated toxicities affecting virtually every organ system, and the skin is the most commonly affected. Researchers are now working to elucidate the mechanisms underlying these adverse events and to identify biomarkers that could predict, before treatment begins, which patients will respond to therapy and which will develop toxicity. Such tools would enable more individualized and safer administration of checkpoint blockade, preserving its remarkable antitumor power while anticipating and defusing the autoimmune collateral damage that cases like this one so dramatically illustrate.

Subject of Research: Pembrolizumab-induced pemphigoid nodularis as an immune-related adverse event in a patient with metastatic cutaneous squamous carcinoma

Article Title: Pembrolizumab-induced pemphigoid nodularis manifesting as an erythema multiforme-like eruption: a case report

Article References: Kang, L., & Yang, J. (2025). Pembrolizumab-induced pemphigoid nodularis manifesting as an erythema multiforme-like eruption: a case report. Clinical Cancer Bulletin, 4(1), Article 7. https://doi.org/10.1007/s44272-025-00032-4

Image Credits: AI Generated

DOI: 10.1007/s44272-025-00032-4

Keywords: pembrolizumab, pemphigoid nodularis, immune checkpoint inhibitors, immune-related adverse events, erythema multiforme, anti-BP180 antibodies, bullous pemphigoid, PD-1, dermatologic toxicity, skin cancer, immunotherapy, case report