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.