When rashes occur following exposure to immune checkpoint inhibitors (ICIs), those with darker skin tones may face greater diagnostic delays, greater rates of referral to dermatologists, and a higher likelihood of undergoing biopsy, according to a literature review that assessed how cutaneous ICI-related adverse events are managed in skin of color (SoC).
Overall, the collated data suggested that these adverse events are less likely to be recognized in SoC than non-SoC patients and more likely to be referred to a dermatologist when they occur, reported Novia Dattatri, a medical student at the University of California, San Diego (UCSD). Dattatri presented these data at the 22nd Annual Skin of Color Society Scientific Symposium in Denver.
The conclusions are preliminary because only a handful of studies have attempted to directly compare the rate and severity of cutaneous toxicities following ICI cancer treatment by race or skin tone, according to Dattatri, who performed this study in collaboration with her mentor, Grace Y. Kim, MD, an assistant professor in the UCSD Department of Dermatology.
Incomplete Data Exacerbate Diagnostic Uncertainty
The incomplete data may be part of the problem, Dattatri speculated in an interview. The lack of information about whether or how rashes differ in patients with SoC relative to those with White skin may explain the more cautious diagnostic approach, leading to a greater proportion of dermatologic referrals and biopsies performed.
The literature review was confined to publications evaluating rash or other skin toxicities associated with the two most commonly used ICIs: programmed cell death and programmed cell death ligand-1 inhibitors. For inclusion, the publications had to stratify patients by Fitzpatrick skin types (III-VI vs < III) or by non-White vs White race or ethnicity.
The use of race and ethnicity as inclusion criteria in this study reflects how SoC is variably defined in the literature and was intended to ensure comprehensive capture of studies on cutaneous immune-related adverse events across diverse skin tones, Dattatri reported. She said that she and her co-authors “acknowledge race is a social construct that does not accurately reflect genetic ancestry or underlying cutaneous biology, and that skin pigmentation and phototype vary widely within racial categories.”
In the pool of publications including information about checkpoint inhibitor toxicities, 44 met the predefined inclusion criteria. About half were case studies. In total, there was information on 3239 SoC patients exposed to checkpoint inhibitors. Of these, 393 (12.2%) developed a cutaneous adverse event. Most (87%) were mild (grade 1 or 2) when severity was reported.
Only a handful of studies reported the mean time to diagnosis or whether biopsies were performed, but these figures were 34 days and 45%, respectively. Although the proportion of SoC patients who developed toxicities and the proportion of those with severe adverse events were lower than that typically reported, it is difficult to make definitive statements on such limited evidence, according to Dattatri.
On the basis of the published studies, “there appears to be a vast underreporting of these adverse events in SoC,” according to Dattatri, who said this “limits the strength of our conclusions.”
However, the trends of slower diagnoses and uncertainty about a diagnosis of checkpoint inhibitor-related adverse events leading to more dermatology consults and biopsies in SoC was relatively consistent across studies, she reported.
“It is difficult to estimate the overall biopsy rate in the broader population for comparison to the data we collected," Dattatri told Medscape Medical News. “But we do not see a higher rate of severe or unusual presentations among patients with SoC relative to non-SoC populations, which suggests that this does not fully explain why biopsies are performed more often in SoC patients.”
Few Studies of ICI Adverse Events Are SoC-Specific
Only “a handful” of publications included in this literature review focused specifically on differences in ICI-induced cutaneous adverse events between races or skin tones, according to Dattatri. Most included this information within a broader assessment of these side effects, and the details of skin color and interventions were not consistently reported across the literature.
One of the largest and most detailed studies in this review included data on 2447 patients within a single-center patient registry. The findings were summarized in a 2021 letter to the editor in the Journal of the American Academy of Dermatology.
The findings from this registry, of which 10% of the patients were non-White, anticipated those of the larger review. For example, the rate of cutaneous immune-related adverse events as expressed by odds ratio (OR) was about half as great in SoC patients (OR, 0.502; P = .022), whereas referral of these events, when recognized, was more than five times greater (OR, 5.537; P = .006).
To translate this information into clinical relevance, the biggest hurdle is the widespread inconsistencies in reporting of cutaneous adverse events by skin type, Dattatri said. Even though she considers Fitzpatrick skin phototypes — which were developed to characterize risk for sunburns — to be suboptimal given their reliance on clinician perception, she finds them more useful than race.
“We need more objective ways to document skin color,” she said, citing the reproducibility of spectrophotometry as an example. “Standardization of reporting, even if it were to be performed with Fitzpatrick phototype, would be valuable for evaluating whether ICI-related cutaneous toxicities present differently across skin types if performed consistently.”
This problem is not unique to the issue of ICI-related adverse events. Dattatri pointed to other skin toxicities with the potential to differ by skin type, such as radiation-induced dermatitis.
She explained that there are studies suggesting that SoC patients have higher odds of skin changes after radiation but significantly lower odds of recognition of these changes by clinicians.
As more attention is paid to providing equitable care irrespective of race, skin color, or other variables that are not always judged in the same way by different observers, Dattatri suggested that prioritizing patient perspectives might help address diagnostic gaps.
“One key message is to keep patients at the center of care,” she said, advising clinicians to “actively elicit and focus on what patients think has changed about their skin,” which is an approach relevant to more than just ICI-related adverse events.
Dattatri and Kim reported no potential conflicts of interest.