Immune checkpoint inhibitor-related dermatologic adverse events

Abstract

Immune checkpoint inhibitors have emerged as a pillar in the management of advanced malignancies. However, nonspecific immune activation may lead to immune-related adverse events, wherein the skin and its appendages are the most frequent targets. Cutaneous immune-related adverse events include a diverse group of inflammatory reactions, with maculopapular rash, pruritus, psoriasiform and lichenoid eruptions being the most prevalent subtypes. Cutaneous immune-related adverse events occur early, with maculopapular rash presenting within the first 6 weeks after the initial immune checkpoint inhibitor dose. Management involves the use of topical corticosteroids for mild to moderate (grades 1-2) rash, addition of systemic corticosteroids for severe (grade 3) rash, and discontinuation of immunotherapy with grade 4 rash. Bullous pemphigoid eruptions, vitiligo-like skin hypopigmentation/depigmentation, and psoriasiform rash are more often attributed to programmed cell death-1/programmed cell death ligand-1 inhibitors. The treatment of bullous pemphigoid eruptions is similar to the treatment of maculopapular rash and lichenoid eruptions, with the addition of rituximab in grade 3-4 rash. Skin hypopigmentation/depigmentation does not require specific dermatologic treatment aside from photoprotective measures. In addition to topical corticosteroids, psoriasiform rash may be managed with vitamin D₃ analogues, narrowband ultraviolet B light phototherapy, retinoids, or immunomodulatory biologic agents. Stevens-Johnson syndrome and other severe cutaneous immune-related adverse events, although rare, have also been associated with checkpoint blockade and require inpatient care as well as urgent dermatology consultation.

Keywords: CTLA-4 inhibitor; PD-1 inhibitor; PD-L1 inhibitor; checkpoint inhibitor; dermatologic adverse event; immune-related cutaneous adverse event; lichenoid eruption; maculopapular rash; pruritus; vitiligo.

Fig 1.

Time to onset of immune-related cutaneous adverse events. DRESS, Drug reaction with eosinophilia and systemic symptoms; irCAE, immune-related cutaneous adverse event; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.

Fig 2.

Maculopapular rash, grade 2. Patient receiving pembrolizumab for stage IV lung adenocarcinoma. Histopathology reveals interface dermatitis with increased dermal mucin. There are many features, including interface changes, mucin and increased basement membrane suggestive of connective tissue disease, and also the possibility of a drug reaction resembling connective tissue disease.

Fig 3.

Lichenoid eruption, grade 2. Patient receiving atezolizumab for multifocal muscle invasive bladder carcinoma. Histopathology reveals interface and perivascular lymphocytic dermatitis with rare eosinophils and evidence of minor vascular damage, consistent with a reaction to treatment.

Fig 4.

Bullous pemphigoid eruption, grade 3. Patient receiving pembrolizumab for stage IV sarcomatoid lung carcinoma. Histopathology shows a subepidermal blister with a superficial dermal lymphocytic infiltrate and scattered eosinophils.

Fig 5.

Skin hypopigmentation/depigmentation, grade 2. Patient receiving pembrolizumab for metastatic melanoma.

Fig 6.

Psoriasiform rash, grade 3. Patient receiving pembrolizumab for metastatic nonesmall cell lung cancer. Histopathology reveals epidermal hyperplasia with elongation of rete ridges, overlying parakeratosis and hypogranulosis, and a superficial perivascular lymphocytic infiltrate.

Fig 7.

Stevens–Johnson syndrome, grade 4. Patient receiving combination therapy with ipilimumab plus nivolumab for melanoma.

Fig 8.

Alopecia and telogen effluvium. Patient receiving combination therapy with ipilimumab plus nivolumab for metastatic melanoma.