Contribution of the Skin–Gut Axis to Immune-Related Adverse Events with Multi-System Involvement

Abstract

Immune-related adverse events (irAEs) frequently complicate treatment with immune checkpoint blockade (ICB) targeting CTLA-4, PD-1, and PD-L1, which are commonly used to treat solid and hematologic malignancies. The skin and gastrointestinal (GI) tract are most frequently affected by irAEs. While extensive efforts to further characterize organ-specific adverse events have contributed to the understanding and management of individual toxicities, investigations into the relationship between multi-organ toxicities have been limited. Therefore, we aimed to conduct a characterization of irAEs occurring in both the skin and gut. A retrospective analysis of two cohorts of patients treated with ICB at Memorial Sloan Kettering Cancer Center was conducted, including a cohort of patients with cutaneous irAEs (ircAEs) confirmed by dermatologists (n = 152) and a cohort of patients with biopsy-proven immune-related colitis (n = 246). Among both cohorts, 15% (61/398) of patients developed both skin and GI irAEs, of which 72% (44/61) patients had ircAEs preceding GI irAEs (p = 0.00013). Our study suggests that in the subset of patients who develop both ircAEs and GI irAEs, ircAEs are likely to occur first. Further prospective studies with larger sample sizes are needed to validate our findings, to assess the overall incidence of co-incident irAEs, and to determine whether ircAEs are predictors of other irAEs. This analysis highlights the development of multi-system dermatologic and gastrointestinal irAEs and underscores the importance of oncologists, gastroenterologists, and dermatologists confronted with an ircAE to remain alert for additional irAEs.

Cutaneous Adverse Events of Systemic Melanoma Treatments: A Retrospective Single-Center Analysis

“…For example, phototherapy with UVBnb or specific biologics (e.g., TNF-blockade or apremilast) will be preferred for psoriasiform skin AE. In the case of Grade 2 or higher pruritus, GABA analogues, such as pregabaline or gabapentine can be introduced starting at low initial doses [ 31 ]. In acneiform rashes, topical antibiotics such as clindamycin or oral tetracyclines will be prioritized over topical corticosteroids [ 32 ].…”

A Review of Bullous Dermatologic Adverse Events Associated with Anti-Cancer Therapy

“…Treatment is based on the grade of ICI-BP. The treatment approach recommended is to continue ICI treatment in grade 1 DAEs and provide BP-specific medications; however, if grade 2 or higher, anti-cancer therapy should be held until the DAE resolves to grade 0 or 1 [81,82]. Medications include topical corticosteroids, oral corticosteroids, and sys-temic steroid-sparing drugs such as methotrexate, dapsone, azathioprine, mycophenolate mofetil, omalizumab, dupilumab, rituximab, or IVIg [4,[83][84][85][86].…”

Cutaneous immune‐related adverse events from immune checkpoint inhibitor therapy: Moving beyond “maculopapular rash”

“…The importance of these teams becomes even more evident when exploring the relationships between ciRAEs, irAEs in other organs, and patterns of malignancy response and resistance.Novel single-cell RNA sequencing and multi-spectral flow cytometry have recently been reported in relation to ICI-induced colitis. The correlation between the skin-gut axis with immune-related adverse events has been well described,44 and the study of the molecular mechanisms of irAEs affecting the gastrointestinal tract can have important implications relating to cirAEs. Using TCRαβ analysis, Luoma et al demonstrated a connectivity between CD8+ tissueresident memory T cells in the gastrointestinal tract and emergence of cytotoxic effector cells in patients with checkpoint inhibitorinduced colitis.…”