Monoclonal antibodies directed against immune checkpoint inhibitor proteins cytotoxic T-lymphocyte antigen-4 (CTLA-4, such as ipilimumab and tremelimumab), programmed cell death-1 (PD-1, such as nivolumab and pembrolizumab) and programmed cell death ligand-1 (PDL-1, such as atezolizumab, avelumab, and durvalumab) have now been recognized as the fourth pillar in cancer treatment by enhancing the immune system. During therapy with these novel therapies, a unique set of adverse effects may develop called immune-related adverse events (irAEs). These can be of varying degrees of severity and include the development of rashes (which can progress to life-threatening toxic epidermal necrolysis), colitis, hepatitis, hypophysitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies (including motor axonal neuropathy), nephritis, myocarditis, and pneumonitis. Life-threatening reactions remain rare and are estimated to occur with an incidence between 0.3%-1.3%.

The frequency of each type of irAE varies with the immune checkpoint inhibitor used and the condition for which it is used. PD-1and PDL-1 inhibitors have a lower incidence of irAE compared to inhibitors of CTLA- 4.

In one recent meta-analysis, colitis was the most frequent severe irAE in patients receiving anti-CTLA-4 antibodies seen in 70% of deaths with those agents, whereas pneumonitis (35%), hepatitis (22%), and neurotoxic effects (15%) were seen in deaths associated with PD-1 or PD-L1 antibodies. The highest fatality rates are associated with irAE-associated myocarditis.

IrAEs of any grade occur in up to 60% of patients receiving ipilimumab (an anti-CTLA-4 Ab), with 10%-30% of these being serious. IrAEs with ipilimumab appear to be dose dependent. Diarrhea and colitis are the most common and occur within 8-12 weeks of starting treatment. Less common irAEs with this therapy include pruritus, hepatitis, and endocrinopathies.

IrAEs related to PD-1 inhibitors are less frequent in comparison. Only 10% will have severe irAEs. Less-severe irAEs such as fatigue, headache, arthralgias, rash, pruritus, pneumonitis, diarrhea, and/or colitis and endocrinopathies occur in between 5%-20% and within the first 6 months of therapy. The most common irAEs with nivolumab were endocrinopathies (thyroiditis), pneumonitis, hepatitis, diarrhea, and colitis. There has been a case in which severe autoimmune enteritis developed in an otherwise healthy infant after in-utero exposure to pembrolizumab.

Numerous cutaneous side effects of immune checkpoint inhibitors have been recognized. Morbilliform eruptions are more common with anti-CTLA-4 therapy than with anti-PD-1 and anti-PDL-1 inhibitors with a median time to onset of 2 months. Pruritus, eczematous (median time to onset 2 months) and lichenoid eruptions (median onset 4 months), psoriasis, and vitiligo (median onset 5-6 months) have also been seen. Bullous pemphigoid (anti-PD-1, anti-PDL-1 induced, median time to onset 5-6 months) and granulomatous reactions (anti-PD-1 induced) are rarer. A Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN)-like generalized bullous eruption is also rare. It may occur up to months after initiation of therapy and may develop in a background of an existing eczematous, lichenoid, urticarial, or morbilliform eruption, 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.

Related topic: cutaneous adverse effects of anti-PD-1 and anti-PD-L1 therapy