with close follow-up; however, expectant management should be provided in that subsequent dosing could flare up cutaneous disease. While with grade 3 reactions there is room to harness control of cirAEs and treat through immunotherapy after brief interruption, grade 4 reactions should prompt immediate ICI discontinuation and urgent care should be sought.
Pruritus
ICI-related pruritus occurs in nearly half of patients and can be found in isolation or association with any cutaneous finding. With the former, secondary skin changes including excoriations and hyperpigmentation are frequently seen. Regardless of cutaneous associations, ICI-related pruritus is most common on the scalp, trunk, and extremities, with relative sparing of the head, neck, and acral surfaces. Notably, ICI-related pruritus has been demonstrated to be independently associated with lower patient quality of life.30
Treatment of pruritus of any severity includes oral antihistamines and frequent application of emollients. Topical corticosteroids may also be used, and intralesional corticosteroids can be helpful for secondarily developed prurigo nodules. While these measures are typically sufficient for mild-moderate pruritus, more severe disease necessitates additional systemic therapy, including oral agents like gabapentin/pregabalin (neuronal calcium channel inhibitors), naloxone/naltrexone (mu-opioid antagonists), and aprepitant (neurokinin-1 receptor antagonist). Dupilumab (anti-IL4-Ra monoclonal antibody), which is an injectable performed either in office or at home, is an alternative. Phototherapy with narrowband ultraviolet B, typically initiated at 2 to 3 times per week, may also provide benefit and is a useful option in patients motivated to avoid additional systemic therapeutics or when they are contraindicated. Systemic corticosteroids are only necessary in debilitatingly severe cases or those unresponsive to all above measures, which is uncommon.25,31-34
Bullous Eruption
Maculopapular Eruption
Maculopapular or eczematous eruptions occur in ~25% of patients treated with anti-CTLA-4 therapy and ~10% to 20% treated with anti-PD-1/PD-L1 therapy, occurring early in treatment and within a dose-dependent manner. These cutaneous reaction patterns have historically been discussed jointly; however, given morphologic, histologic, and therapeutic differences, it is helpful to consider them as related yet distinct entities, as we will here.
Maculopapular eruptions are reminiscent of a morbilliform exanthem with coalescing erythematous macules and papules, which may become confluent. The trunk and extremities are most commonly involved, and patients often report pruritus. A subset of these patients may go on to develop lichenoid, psoriasiform, or eczematous reactions. As with other drug-induced maculopapular eruptions, it is prudent to monitor for progression into a severe cutaneous adverse reaction such as drug reaction with eosinophilia and systemic symptoms (DRESS) or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).5,13,25,32 Treatment of maculopapular eruptions relies on topical corticosteroids for symptomatic management and hastened resolution. Systemic steroids are reserved for the mentioned severe cutaneous adverse reactions. Tocilizumab, a monoclonal antibody against IL-6R, has also demonstrated efficacy in managing severe, refractory ICI hypersensitivity reactions.35
Eczematous Eruption
Eczematous eruptions present with pruritic erythematous papules and plaques with scale, which may appear like atopic, asteatotic, or nummular dermatitis. These reactions typically occur on the trunk and extremities and may become confluent.5,25 Topical therapies, including moderate potency corticosteroids and calcineurin inhibitors, are the therapeutic mainstay for mild-moderate disease, which are used adjunctively with liberal application of emollient. Systemic antihistamines may benefit associated pruritus. More severe reactions can be addressed with dupilumab or narrowband UVB phototherapy in addition to increased potency of topical corticosteroids. Oral steroids should only be considered when persistent or severe.
Bullous Eruption
Bullous disorders are rare cirAEs, but they present more frequently in patients treated with anti-PD-1/PD-L1 therapy.5 Mean time to onset is 14 weeks after ICI initiation, which is delayed compared with other cutaneous reactions.13 Affected patients often develop intense pruritus followed by characteristic tense bullae and/or non-bullous urticarial or eczematous plaques (Figure 2).
The oral mucosa is involved in less than one-third of cases.36,37 Diagnostic evaluation is akin to classic disease, which includes identification of a subepidermal split and numerous eosinophils on histopathology, linear deposition of immunoglobulin G and C3 along the basement membrane on direct immunofluorescence, and peripheral detection of antibodies against hemidesmosomal proteins (BP180 and BP230).13,25
