Our results did not indicate any significant differences in the incidence of rashes upon treatment with anti-EGFR antibodies between the S and W groups. On the other hand, although a sex-based evaluation suggested that men were significantly more prone to skin rash than women in summer, there was no significant association between the incidence of rash and sex of the patients treated in winter. The tissue concentrations of EGF and EGF receptors are regulated by sex hormones such as estrogen and testosterone, which may contribute to sex differences in the development of skin rashes induced by anti-EGFR antibodies . The higher incidence of skin rashes in men during summer may be attributed to the effects of ultraviolet (UV) light, lack of skincare, male hormones, and secretion of anti-EGFR antibodies into the sweat.
UV rays are classified as UV-A, UV-B, and UV-C, based on their wavelengths. When the skin is exposed to UV-B radiation, photochemical reactions form cyclobutane-type pyrimidine dimers and (6-4)-adducts, which induce DNA damage and inflammatory reactions, thus decreasing epidermal barrier function [15,16]. Reduced epidermal barrier function leads to increased sensitivity to UV-B, making erythema more likely to develop even at low UV-B doses . Moreover, the average UV-B levels and UV index in Japan (Tsukuba, 2014–2019) were reported to be 23.9 kJ/m2 and 6.7, respectively, in summer and 6.3 kJ/m2 and 2.0, respectively, in winter (Fig. 1b) . Therefore, summer had higher UV-B levels and UV index than did winter. The UV index is formulated using the International Commission on Illumination reference action spectrum for UV-induced erythema on the human skin. For the average person, a UV index of 0 to 2 means low danger from the sun’s UV rays. Moreover, a UV index of 6 to 7 means a high risk of harm from unprotected sun exposure . The use of sunscreen can prevent erythema, DNA photodamage, and contact hypersensitivity . Additionally, the application of sunscreen and general skincare products is significantly lower in men than in women [21,22].
Epithelial cells of sebaceous glands express androgen receptors, and sebaceous glands are target tissues for androgens . Hence, androgenic species have been reported to interfere with the accumulation of structural proteins that rebuild damaged skin . Furthermore, testosterone levels in men vary with season, with testosterone levels being lower in colder months than in hotter months . Moreover, plasma testosterone levels in men are higher than those in women .
Based on the abovementioned findings, we hypothesized that factors such as increased UV radiation, lack of skincare, and high testosterone levels in summer could be responsible for the higher incidence of rashes in men than in women in summer. If these hypotheses are valid, skincare during the summer months is essential. Thus, focused patient education on the importance of skincare, particularly in the summer, may reduce the rash severity in patients, especially men, with CRC or HNC being treated with anti-EGFR antibodies.
Our retrospective study had several limitations. First, we could not investigate adherence to topical moisturizers and oral antibiotics, such as minocycline. However, we believe that patient adherence was acceptable, as we repeatedly explained the need for moisturizers and oral antibiotics at the start and continuation of treatment with anti-EGFR monoclonal antibodies. Second, there was a lack of information on the skin moisture content, sunscreen use, and testosterone levels of the included patients. Though our retrospective study examined as many factors as possible given the available resources, additional studies that consider the factors of adherence, skin moisture content, sunscreen use, and testosterone levels are needed to expand upon the findings of our study.
The novelty of our study is that we identified no difference in the incidence of rashes caused by treatment with anti-EGFR antibodies between the summer and winter months. However, men during the summer may be more prone to developing rashes than women during the summer as well as men and women during the winter.
The topic of our study is relevant to the current situation, as an increasing number of patients are receiving anti-EGFR therapy, making them susceptible to rashes. Rashes tend to be more frequent in men during summer. This information should help healthcare staff and patients take the necessary actions, such as education and practice of moisturizing, sunscreen use, and skin cleansing. However, rash mechanisms and preventive methods still remain unclear. We anticipate that the findings of our study on the relationship between rash and seasonal climate change will assist in the elucidation of rash mechanisms and establishment of preventive measures.