Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) functions as an immune checkpoint in negatively regulating T-cell function. T-cell activation requires costimulation via binding of B7 molecules with CD28 on the T-cell surface. CTLA-4 acts as a homolog with greater binding affinity for B7 than CD28, preventing downstream effects of T-cell activation including proliferation, survival, and differentiation.¹ Inhibitors of CTLA-4, such as ipilimumab and tremelimumab, activate the immune system to target cancer cells and have been approved for use in metastatic melanoma with significantly improved survival outcomes.¹

Despite these benefits, CTLA-4 inhibitors remain hindered by immune-related adverse events (irAEs); cutaneous irAEs are the most commonly experienced in nearly 45% of patients across pooled clinical trials.² In addition, combination therapy with other immune checkpoint inhibitors (ICIs) results in more frequent eruptions, more severe and longer-lasting cutaneous irAEs.³,⁴ In metastatic melanoma patients, anti-CTLA-4 therapy demonstrated a dose-dependent relationship with higher-grade irAEs overall.⁵

A pruritic morbilliform rash is one of the most frequent cutaneous irAEs observed with CTLA-4 inhibitors, with an estimated overall incidence of 24.3% for ipilimumab users (Figure 40.1). These rashes have been described as similar in appearance to morbilliform eruptions associated with common medications, such as antibiotics.² Rashes associated with CTLA-4 inhibitors have also been morphologically described as reticular, erythematous, and edematous, affecting both the trunk and extremities.²

Other specific unique cutaneous irAEs reported with anti-CTLA-4 agents include psoriasis, Grover’s disease, eczematous eruptions (Figure 40.2), dermatomyositis, sarcoidosis, panniculitis (Figure 40.3), Sweet’s syndrome (Figure 40.4), lymphomatoid papulosis-like eruptions (Figure 40.5), and acneiform eruptions, although the relative incidences are not well established.³ These cutaneous eruptions may either be de novo or represent exacerbation of preexisting skin disease. In addition, relative to other ICIs, anti-CTLA-4 toxicities are less likely to affect the oral mucosa.³