Commentary to: Cancer and treatment specific incidence rates of immune related adverse events induced by immune checkpoint inhibitors: a systematic review

We read with considerable interest the manuscript by Jayathilaka et al. [1] regarding the adverse events associated with CTLA-4, PD-1, and PD-L1 inhibitors across various phases of cancer treatment. Endocrine, gastrointestinal, and dermatologic toxicities were the most frequently reported immune-related adverse events (irAEs).Notably, mean event rates for specific irAE types were: cutaneous irAEs, 28.7% (95% CI: 22.9–34.6%); endocrine irAEs, 23.9% (95% CI: 18.8–29.1%); gastrointestinal irAEs, 19.4% (95% CI: 14.1–24.6%); pulmonary irAEs, 18.9% (95% CI: 15.1–22.7%); cardiac irAEs, 18.0% (95% CI: 5.9–30.2%); and renal irAEs, 15.5% (95% CI: 7.3–23.7%). The review reported that combination immune checkpoint inhibitors (ICI) therapies resulted in higher irAE frequencies (mean 45.7%) and severity compared to monotherapies (30.5%), emphasizing the importance of tailored patient management strategies.

We thank the authors for providing this valuable systematic review. We would also like to highlight the importance of oral irAEs as a significant and emerging category of toxicities in patients treated with ICIs. Oral irAEs encompass a range of manifestations, including dry mouth, taste disturbances, and oral mucosal lesions [2–4]. These conditions are not only clinically significant but also detrimental to patients’ quality of life, and warrant greater attention in discussions of irAEs. Clinical presentation of oral irAEs poses diagnostic challenges, as their manifestations often resemble other mucocutaneous conditions such as oral lichen planus, erythema multiforme, or Stevens–Johnson syndrome. Accurate differentiation is essential for effective management. Additionally, in a recent report by Xu et al., of patients who experienced oral irAEs, 69% also presented with irAEs in non-oral sites, suggesting a potential relationship between oral and systemic immune dysregulation [5].

We recognize that the literature review by Jayathilaka et al. spanned the years of 2017–2021, and we note that most publications of oral irAEs have been published after 2021. However, two notable studies of oral irAEs seemingly meeting the systematic review inclusion criteria were omitted. These include a 2019 meta-analysis by Yang et al. of 11,465 patients receiving ICI that reported stomatitis in 2.7% of patients [6]. Similarly in 2021, Xu et al. reported that of 468 patients who received ICI, 6.8% developed oral irAEs. These patients presented with xerostomia (68.5%), oral mucosal disorders (33.4%) and dysgeusia (24.5%) [7].

As utilization of immunotherapy continues to increase, so too does the need for early recognition and understanding of its associated adverse events, including those affecting the oral cavity. Recently, Al-Eryani et al. reported that 10.8% of patients treated with ICIs (n = 3768) developed orofacial irAEs, including oral mucosal diseases (41.4%), xerostomia/dry mouth (41.0%), and orofacial neuropathies (17.6%) [8]. A 2024 systematic review and meta-analysis of oral ir-AEs revealed a 5% pool prevalence of xerostomia (95% CI: 4–6%), 3% of mucositis/stomatitis, and 3% (95% CI: 3–4%) of dysgeusia [9]. These data underscore the increasing prevalence and clinical relevance of oral irAEs and highlight the need for their inclusion in systematic reviews of ICI-related toxicities. Additionally, exploring the interplay between oral irAEs and systemic immune responses may provide insights into the broader implications of these adverse events. Such efforts are essential to advancing the field and improving patient care. Despite their significance, oral irAEs remain underrepresented in the literature, especially in systematic reviews and clinical practice guidelines. Future research should focus on developing standardized diagnostic criteria and management strategies for oral irAEs.

In conclusion, the systematic review by Jayathilaka et al. is an informative resource that enhances our understanding of irAEs associated with ICIs. However, the exclusion of oral irAEs represents a significant limitation. Incorporating data on oral toxicities would provide a more comprehensive perspective and facilitate enhanced integration of oral health into oncology practice. As use of ICIs continues to expand, addressing the full spectrum of irAEs, including those affecting the oral cavity, is critical to ensuring holistic and effective cancer care.

Author contributions

AV wrote the manuscript with input from all the other co-authors. BJS, CL, TKO and DEP provided edits and approved the final version of the manuscript.

Competing interests

The authors declare no competing interests.