During therapy with ICIs, a unique set of adverse effects may develop called immune-related adverse events (irAEs). Pneumonitis, colitis, hepatitis, and immune-related endocrinopathies may be seen (see ICI-related adverse effects for discussion). Cutaneous adverse events are also frequently seen and are often the first irAE that develops. Reported rates of cutaneous adverse events include 20% (anti-PDL-1 monotherapy), approximately 35%-40% (anti-PD-1 monotherapy), approximately 44%-60% (anti-CTLA-4 monotherapy), and about 60%-70% (combination therapy).
A broad array of eruptions and drug-related cutaneous conditions has been reported. "Maculopapular rash" (exanthematous eruption) is reported in 10%-50% of patients undergoing anti-CTLA-4 therapy, and up to 20% of patients on anti-PD-1/anti-PDL-1 therapy. Onset is within 3-6 weeks of drug onset, and the eruption is usually mild and resolves within 2-3 months. A lichenoid reaction occurred in up to 17% of patients taking PD-1 inhibitors in one large study, appearing within days to months and sometimes after a year of therapy initiation. Vitiligo appears in up to 10% of patients around 7 weeks to approximately 9 months. It is usually seen in patients being treated for melanoma, and its presence has been correlated to positive therapy outcomes.
Psoriasis (new onset, median time to onset 91 days; or exacerbation of preexisting psoriasis, median time to onset 50 days) and bullous pemphigoid (time to onset 3-84 weeks) are also associated. Bullous pemphigoid is reported to occur predominantly in males with a history of melanoma or nonmelanoma skin cancer. Its presence has also been correlated with a positive tumor response. Eczema appears within weeks up to around a year (median time: 6 months), predominantly in patients on anti-PD-1 therapy. Isolated pruritus may also occur (pruritus without rash).
Granulomatous reactions (induced by PD-1 inhibitors) and lupus erythematosus are rarer. Severe cutaneous adverse reactions from ICIs include drug-induced hypersensitivity syndrome (DIHS) and Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN). These are rare events and are reported to occur within 3-4 weeks of onset of therapy. A generalized Nikolsky-positive, SJS/TEN-like bullous eruption is also rare. It may occur months after initiation of therapy and may develop in a background of an existing eczematous, lichenoid, urticarial or morbilliform eruption, and often in the setting of the recent addition of another medication, such as allopurinol or trimethoprim-sulfamethoxazole. The term progressive immunotherapy-related mucocutaneous eruption (PIRME) has been proposed for this condition with a milder course and good response to systemic corticosteroids. Sclerosing conditions, including scleroderma, eosinophilic fasciitis and morphea, have been reported. A few cases each of alopecia areata and leukocytoclastic vasculitis have also been reported. Two cases of dermatomyositis that resolved after drug discontinuation have been documented. Cases of lichen sclerosus developing on ICI therapy have been reported.
An increased incidence of co-trimoxazole-induced rash has also been observed in patients receiving checkpoint inhibitors.
Cutaneous irAEs are given grades as follows:
- Grade 1: Rash covers < 10% body surface area (BSA)
- Grade 2: Rash covers 10%-30% BSA or limits self-care activities, or it is a mild rash covering > 30% BSA
- Grade 3: Rash covers > 30% BSA with moderate or severe symptoms, or it limits self-care activities
- Grade 4: Life-threatening rash, requires urgent intervention
