Discussion
This study summarized data on 42 cases of irAEs. Several retrospective studies and reviews summarized the clinical and histopathological features of cutaneous irAEs, but none of these studies examined Asians. Our study is the first report of a detailed examination of the clinical and histopathological findings of cutaneous irAEs in a relatively large cohort experienced in Japan. The most common cutaneous irAEs was maculopapular rash, but ICIs caused virtually every type of skin rash, including erythema multiforme, lichenoid reaction, psoriasiform reaction, autoimmune diseases such as scleroderma-like reaction and bullous pemphigoid, and severe drug eruptions such as SJS. Interestingly, cutaneous irAEs shared clinical and histopathological features with classical inflammatory eruptions. Although not observed in our study, there have been reports of sarcoidosis,13Grover’s disease,14–16 granuloma annulare,17 dermatomyositis,18, 19Sjögren’s syndrome,20 pityriasis rubra pilaris,21 or acute generalized exanthematous pustulosis22, 23 induced by ICIs.
The incidence of ICI-induced inflammatory eruptions is the highest among irAEs, with anti–PD-1 and anti-CTLA-4 antibodies causing events in 20–30 and nearly 50% of patients, respectively.7, 8However, most events are self-limiting (grades 1–2). In this study, 39 of 42 (92.9%) rashes were grades 1–2, covering less than 30% of the BSA, and grade 3 or higher rashes accounted for 7.1% of all rashes. These findings are consistent with previous reports.4, 7, 8, 24 In this study, one case of grade 3 cutaneous irAEs was attributable to combination treatment with anti–PD-1 and anti–CTLA-4 antibodies, and the combination therapy tended to cause more severe inflammatory eruptions than anti–PD-1 or anti-CTLA-4 antibody monotherapy. Thus, combination therapy may increase the grade of rash and the frequency of cutaneous irAE.
Cutaneous irAEs may occur first among all irAEs,7, 8and the onset of rash varies by rash type. In our study, maculopapular rash, erythema multiforme, and SJS had a relatively early onset, with most of them occurring within 3 months after the first ICI dose. Conversely, lichenoid reactions and autoimmune diseases such as bullous pemphigoid and scleroderma-like reactions occurred relatively late, emerging 4–8 months after treatment initiation. Previous case reports and reviews indicated that maculopapular rash often develops 3–6 weeks after the first use of ICIs,7, 8, 24, 25 lichenoid reactions occur after 6–12 weeks,5, 7, 8, 25–27 and bullous pemphigoid appears after approximately 14 weeks,5, 27 roughly consistent with our results. Although previous reports suggested a relatively early onset of psoriasiform reactions,28, 29 this event occurred approximately 26 weeks after treatment initiation in our patient. Excluding the maculopapular type, only a few cases were included in each rash type, and further accumulation of cases is required.
Cutaneous irAEs were treated according to the rash grade. More than half of grade 2 rashes were treated with systemic steroids, and patients with grade 3 or higher rashes were often treated with high-dose prednisolone (≥1 mg/kg). In the case of psoriasiform reaction, topical active vitamin D was added to the treatment; however, there was no apparent difference in the choice of treatment by rash type. Among patients with grade 1 rash, ICIs were permanently discontinued in some patients because of irAEs in other organs. Meanwhile, ICIs can be continued and the skin rash will be improved without exacerbation following dermatologic treatments (e.g., topical steroids, oral antihistamines, moisturizers) in most cases. ICIs can be resumed after tentative interruption. Importantly, cutaneous irAEs are not dose-dependent,8and dose reduction may not be an appropriate management.
This study had several limitations. First, this was a retrospective, single-institutional study. Patients were evaluated only when they were referred to our dermatology department for expert advice and skin biopsy. Mild cases in which a skin biopsy was unnecessary were not evaluated. Thus, our cohort may represent more severe inflammatory eruptions at our institution. In addition, only one or two cases of minor skin rash were included. Further accumulation of cases is needed to compare the timing of onset and grade of rash.
In conclusion, we summarized the clinical characteristics and histopathological findings of 42 cases of biopsy-proven cutaneous irAEs induced by ICIs. Although various inflammatory eruptions occur in the treatment of ICIs, the inflammatory eruptions induced by ICIs share similar clinical and histopathological features with classical inflammatory eruptions. Differing from irAEs in other organs, cutaneous irAEs may be equivalent to conventional drug eruptions. Further research is warranted.