REVIEW

CURRENT
OPINION Dermatologic complications of anti-PD-1/PD-L1
immune checkpoint antibodies
Vincent Sibaud a,b, Nicolas Meyer b, Laurence Lamant c,
Emmanuelle Vigarios d, Julien Mazieres e, and Jean Pierre Delord a

Purpose of review
The therapeutic use of anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab) is rapidly increasing. Given
their mechanism of action that triggers T-cell activation, these immune checkpoint inhibitors induce specific
adverse events that are mostly of immunologic origin. In this way, cutaneous toxicities represent the most
frequent immune-related adverse events (irAEs). The purpose of this review is to summarize the most
prevalent dermatologic complications induced by PD-1/PD-L1 immune checkpoint-blocking antibodies and
to compare their dermatologic safety profile with anti-CTLA-4 ipilimumab.
Recent findings
More than 40% of melanoma patients treated with anti-PD-1 therapy are faced with dermatologic irAEs.
However, these cutaneous complications usually remain self-limiting and readily manageable. Nonspecific
macular papular rash and pruritus represent the most common manifestations. More characteristic lichenoid
dermatitis or psoriasis may also develop. Vitiligo is also frequent in patients with melanoma but has not
been reported in other types of solid cancers. Mucosal involvement may also occur, including xerostomia
and lichenoid reactions. Although available data remain scarce, anti-PD-L1 antibodies present a similar
dermatologic safety profile.
Summary
Dermatologic irAEs induced by PD-1 or PD-L1 blockade therapy rarely result in significant morbidity or
permanent discontinuation of treatment. However, early recognition and appropriate management are
crucial for restricting dose-limiting toxicities.
Keywords
anti-PD-1/PD-L1, lichenoid, mucosa, psoriasis, skin toxicities

INTRODUCTION Immune checkpoint inhibitors present a

Immune checkpoint inhibitors represent one of
the major oncologic breakthroughs and now offer
a new paradigm for the treatment of different types
of advanced solid cancers. Ipilimumab, a human-
ized monoclonal antibody inhibiting the CTLA-4
pathway (cytotoxic T-lymphocyte antigen-4),
favorable overall benefit-to-risk profile. However,
given their mechanism of action as immune-
modulating agents that trigger T-cell activation,
these monoclonal antibodies are associated with
a specific toxicity profile, entailing a new spectrum
of adverse events that are mostly of mechanism-
& &

was the first-in-class immune checkpoint-blocking
antibody, which has been licensed in advanced
melanoma. Anti-PD-1 agents nivolumab and pem-
brolizumab bind to a distinct inhibitory immune
checkpoint receptor, programmed cell death
protein 1 (PD-1), which is also expressed on T cells
and other immune cells. They were recently granted
accelerated approval by the EMA and FDA in
advanced melanoma and/or non-small-cell lung
cancer and are being evaluated in other types of
advanced cancers. Anti-PD-L1 antibodies (atezolizu-
mab, BMS-936559), which target the main PD-1
ligand, are still under clinical evaluation.
based immune nature [1 ,2 ]. Although ad-hoc
a
Department of Medical Oncology and Clinical Research, bDepartment
of Oncodermatology, cDepartment of Pathology, dDepartment of Oral
Medicine, Institut Claudius Regaud, Institut Universitaire du Cancer,
Toulouse Oncopole and eDepartment of Oncopneumology, Hopital
Larrey, Toulouse University, Toulouse, France
Correspondence to Vincent Sibaud, Departments of Oncodermatology
and Medical Oncology, Institut Claudius Regaud, Institut Universitaire du
Cancer, Toulouse Oncopole, 1 rue Irene Joliot-Curie – 31059 Toulouse,
Cedex, France. Tel: +33 6 31 53 39 49; fax: +33 5 31 15 60 29;
e-mail: sibaud.vincent@iuct-oncopole.fr
Curr Opin Oncol 2016, 28:254–263
DOI:10.1097/CCO.0000000000000290

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KEY POINTS
 Cutaneous manifestations represent the most prevalent
immune-related adverse events induced by anti-PD-1
immune checkpoint antibodies.
 Skin toxicities mainly manifest in the form of
maculopapular rash and pruritus.
 More characteristic dermatologic complications can
also occur, including vitiligo, lichenoid dermatitis,
exacerbated psoriasis, or mucosal involvement (e.g.
lichenoid reaction, xerostomia).
 The dermatologic safety profile appears very similar
between anti-PD-1 and anti-PD-L1 or anti-CTLA-
4 antibodies.
 Dermatologic toxicities are usually mild, readily
manageable, and rarely result in significant morbidity.
Early management, however, is crucial for limiting
treatment discontinuation.
prospective dermatologic studies or meta-analyses
are still lacking, it is clearly apparent that
cutaneous manifestations represent the most
frequent immune-related adverse events (irAEs)
of any grade induced by anti-PD-1 agents, affecting
more than 40% of patients with melanoma
& & &
[3 ,4,5 ,6 ]. As pembrolizumab and nivolumab
therapy both act by blocking the PD-1 receptor
and are structurally similar, their profiles of
dermatologic adverse events do not differ signifi-
cantly and correspond to a class effect. Although
their global toxicity profile compares favorably
with anti-CTLA-4 (ipilimumab, tremelimumab),
the overall incidence of dermatologic irAEs
appeared roughly similar in comparative studies
& &
without new safety signals [5 ,7 ]. Data available
on anti-PD-L1 therapy-related dermatologic
toxicities remain scarce. However, their skin safety
profile also appears very similar to that reported
with anti-PD-1 antibodies [8,9 ,10].
&
Pathophysiological mechanisms governing skin
toxicities of immune checkpoint inhibitors are
largely unknown, even if they are mainly T-cell
mediated. It is possible to speculate that they are
related to an aberrant targeting of antigens into the
dermis/epidermis by reactivated CD4þ/CD8þ T cells,
generating an inflammatory process after cross-
reaction with normal skin. However, the specific
self-antigens driving T-cell infiltration into the skin
have not been identified.
The majority of dermatologic complications
occurring with PD-1 /PD-L1 blockade therapy are
mild, reversible, and readily manageable with sup-
portive care. They uncommonly result in significant
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Anti-PD-1/PD-L1 antibodies and skin Sibaud et al.
morbidity and permanent discontinuation is
seldom required (less than 5%) [1 –3 ,8,9 ,11 ].
& & & &
However, early recognition and management are
of paramount importance in restricting dose-limit-
ing toxicities and preventing a deleterious impact
on a patient’s health-related quality of life. It may be
noted that these dermatologic irAEs have a shorter
time to onset than those affecting other organs.
Furthermore, the risk of developing cutaneous
adverse events does not seem directly correlated
with the different dose regimens of ipilimumab,
pembrolizumab, nivolumab, or anti PD-L1 therapy
& &
evaluated [6 ,11 ,12–14]. Finally, it has recently
been suggested that the occurrence of dermatologic
irAEs with anti-PD-1 antibodies may represent
& & &
a positive prognostic factor [6 ,11 ,15 ,16] with
a higher survival benefit or objective response rate.
The aim of this article is to extensively review
the available data on dermatologic complications of
anti-PD-1 and anti-PD-L1 antibodies, comple-
mented by our own multidisciplinary experience,
and to compare its profile of dermatologic irAEs
with those of other immune checkpoint inhibitors
such as anti-CTLA-4 ipilimumab.
SKIN RASHES
Overall incidence and clinical grading
The incidence of all-grade skin rash with anti-PD-1
& & &
agents ranges from 13 to 22% [4,5 ,7 ,14,17,18 ]
(Table 1) in patients with melanoma and appears
roughly similar for nivolumab and pembrolizumab
therapy. In a large majority of cases, skin rash
remains self-limiting, with less than 2% of treated
patients affected by grade 3 (or higher) toxicity
& & &
[4,5 ,7 ,14,17,18 ] (Table 1). By comparison, the
overall incidence determined by meta-analysis was
slightly higher with anti-CTLA-4 ipilimumab
(24.3%; 95% CI, 21.4–27.6%), with a relative risk
of 4.00 (95% CI, 2.63–6.08, P < 0.001) [13]. More
recently, however, the percentage of patients devel-
oping a skin rash appeared closely comparable
between nivolumab or pembrolizumab and ipilimu-
& &
mab in head-to-head studies [5 ,7 ].
By contrast, the overall rate of rash reported by
patients treated with pembrolizumab or nivolumab
&
for other types of advanced cancer [19,20 ,21–23]
was significantly lower and less than 10%. This may
be related, at least in part, to the investigator’s
profile and a more systematic complete skin exam-
ination performed by dermatologists.
The incidence of anti-PD-L1-related skin rash
remains to be more accurately determined but seems
to be slightly lower than with PD-1, at between
&
9 and 14% [8,9 ,10].
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Supportive care

Table 1. All-grade and high-grade skin toxicities of anti-PD-1 and anti-CTLA-4 immune checkpoint antibodies reported in
pivotal studies conducted in melanoma patientsa
Treatment-related
select skin adverse Nivolumab/ipilimumab
events (% grade 3) Pembrolizumab Nivolumab Ipilimumab in combination

Skin select adverse Data missing 37.4–41.9% (1.5–1.6) 43.5–58.7% (0–2.9) 58.7–71.3% (4–9.6)
events
Rash 13.4–20.7% (0–2) 15–21.7% (0.3–0.5) 14.5–26.1% (0–1.6) 28.4–55% (2.9–5.3)
Rash maculopapular 1.5–3.6% (0–0.4) 2.5–4.2% (0.3) 2.7–17.4% (0–0.4) 11.8–16% (1.6–3.2)
Pruritus 14.1–20.7% (0–1) 17–18.8% (0–0.5) 24.4–35.4% (0–0.4) 33.2–47% (0–1.9)
Vitiligo 8.9–11% (0) 7.3–10.7% (0–0.3) 1.6–8.7% (0) 6.7–11% (0)

a & & &

Adapted from [4,5 ,7 ,14,17,18 ].

Clinical presentations be systematically recommended in the case of

Maculopapular rashes
A predominantly nonspecific macular papular rash
represents the most prevalent cutaneous adverse
event induced by anti-PD-1 therapy [11 ]. Patients
&
generally develop eruptions after the first doses
& & &
[2 ,6 ,11 ], but lesions can also worsen after each
treatment cycle.
Lesions are mainly located on the trunk and
extremities, usually sparing the face. Acral involve-
&
ment is also possible [11 ]. The extent of skin surface
involved varies, but lesions usually remain self-lim-
iting (grade 1 or 2, covering less than 30% of body
surface area). Lesions chiefly consist of faint eryth-
ematous macules and/or papules (Fig. 1a and b),
with or without discrete scaling. Itching or a burn-
ing sensation are commonly associated. A predom-
inantly photoexposed distribution has also been
mentioned recently but needs to be confirmed [11 ].
&
Histopathologic changes are not clearly charac-
terized with PD-1/PD-L1 blocking antibodies. By
contrast, the most relevant histopathologic findings
with anti-CTLA-4 ipilimumab are perivascular
superficial CD4þ T-cell infiltrates, with or without
epidermal spongiosis and eosinophilic infiltrates
in the upper dermis [13]. A skin biopsy should
atypical lesions or persistent/recurrent grade 2 or
grade 3 exanthematous rash. Indeed, more specific
histologic features can occasionally be isolated (e.g.
psoriasiform or lichenoid patterns).
Early intervention and adequate monitoring are
crucial in order to restrict exacerbation of the
lesions, to ensure consistent dosing, and to limit
the decrease in quality of life. Symptomatic manage-
ment depends on severity and clinical grading but
mainly includes prescription of oral antihistamines,
topical steroids (e.g., betamethasone or clobetasol
propionate, cream or ointment), and/or moisturiz-
ing ointments. However, a cutaneous infection
should be ruled out before applying topical steroids.
In a large majority of cases, management of macular
papular rash does not require skipping a cycle or
permanent discontinuation. Nevertheless, immu-
notherapy should be delayed and oral corticoste-
roids considered (0.5–2 mg/kg/day) in the case of
persistent or intolerable grade 2 and grade 3 rash
(Fig. 2). Once improving, systemic steroids should
be tapered over 1 month and immunotherapy
resumed within 12 weeks of the last dose and
when the steroid dose is less than 10 mg prednisone
equivalent. Management algorithm is summarized
in Fig. 2.

(a) (b)

FIGURE 1. (a) Grade 1 and (b) grade 2 pruritic maculopapular rash (anti-PD-1 antibodies).

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 Anti-PD-1/PD-L1 antibodies and skin Sibaud et al.

Symptomatic management: topical moisturizers applied to full body surface, moderate or high-potency
topical steroids applied on affected areas, oral antihistamines
Grade 1
Macules/papules covering <10% BSA with or
without symptoms (e.g. pruritus, burning,
tightness)
Continue anti-PD-1/PD-L1 antibodies

Reassess after 2 weeks and monitor for change in severity

Symptomatic management: topical moisturizers applied to full body surface (if tolerated), high-potency
topical steroids applied to affected areas, oral antihistamines

Grade 2*
Continue anti-PD-1/PD-L1 antibodies, reassess after 1–2 weeks and monitor for
Macules/papules covering 10%-30% BSA with or change in severity:
without symptoms (e.g. pruritus, burning,
tightness)
limiting instrumental activities of daily living - If persistent (or intolerable grade 2), delay immunotherapy and consider oral corticosteroids (0.5–1 mg/kg
(ADL) /day). Once improved, taper steroids over 1 month and resume immunotherapy when systemic steroid dose is
< 10 mg prednisone equivalent

- if worsened manage as grade 3

*: A skin biopsy should be performed in the case of atypical lesions, persistent grade 2 and grade 3 or life-threatening skin reactions

Symptomatic management: topical moisturizers (if tolerated), high or very high-potency topical steroids
(e.g.clobetasol), oral antihistamines, oral steroids (1 mg/kg/day)

Grade 3* Delay immunotherapy,reassess after several days and monitor for change in severity:
Macules/papules covering >30% BSA with or
without symptoms (e.g. pruritus, burning,
tightness) limiting self-care ADL -if persistent or worsened: permanently discontinue immunotherapy and supportive measures

-if improved to grade 1: taper steroids over 1 month and resume immunotherapy when systemic steroid dose
is < 10 mg prednisone equivalent – close follow-up

Life-threatening reactions*
(blisters and exfoliative rash, fever, mucosal Permanently discontinue – supportive measures
ulcerations, facial oedema, nikolsky sign, etc.)

FIGURE 2. Modified management algorithm for skin rash.

& &
Macular papular rash may also represent the first pembrolizumab or nivolumab [5 ,7 ] (Table 1).
manifestation of a more severe skin toxicity. Life- Pruritus also develops rapidly after the start of
threatening skin reactions, including Stevens–John- immunotherapy, either alone or associated with a
&
son’s syndrome and toxic epidermal necrolysis, skin rash [11 ]. Supportive management should be
have been reported with ipilimumab [24]. Although advised, including oral antihistamines, topical
no similar observations have been published until steroids, and/or moisturizers.
now, the occurrence of such severe skin reactions
with pembrolizumab and nivolumab therapy has Lichenoid dermatitis
already been recorded in pharmacovigilance data- Maculopapular rashes can sometimes correspond to
bases. Therefore, patients should be systematically a lichenoid reaction. Lichenoid dermatitis has been
& &
monitored for the development of clinical symp- very sporadically reported [25,26 ,27 ] but is not rare
toms suggestive of potentially life-threatening skin in clinical practice, either with anti-PD-1 or with
reactions (blisters, Nikolsky sign, mucosal ulcera- anti-PD-L1 therapy and is probably underestimated.
tions, associated fever, skin pain, and so on). Immu- The lesions are more often confined to the
notherapy should be permanently discontinued in trunk, but the limbs can also be involved (Fig. 3a
this situation. and b). Pruritus can be very severe. Onset of the
lesions can be delayed compared with the other
Pruritus forms of maculopapular rash [25]. A systematic
Pruritus is also common with anti-PD-1/PD-L1 mucosal examination should also be performed
agents and can severely impact on health-related (see ‘Mucosal involvement’).
quality of life. It affects between 11 and 21% of Histopathologic features include a lichenoid
treated patients with a rate of high-grade lesions interface dermatitis with marked superficial band-
& & & &
of less than 1% [3 ,4,7 ,9 ,11 ,14]. By contrast, ipi- like T-cell infiltrates in the upper dermis. Vacuolar
limumab induces pruritus more frequently than degeneration with partial disruption of the basal

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Supportive care

(a) (b)

FIGURE 3. (a) Diffuse and (b) localized lichenoid dermatitis induced by anti-PD-1 antibodies.

layer can also be observed, associated with scattered
& &
apoptotic basal keratinocytes [26 ,27 ] (Fig. 4a–c).
Schaberg et al. [25] recently observed greater histio-
cytic infiltrates compared with control lichenoid
reactions. Conversely, the number of T cells staining
positive for PD-1 was comparable (5–20%). Conser-
vative management with high-potency topical
steroids is generally sufficient and dose interruption
& &
is usually not required [25,27 ].
Psoriasis
Recently, a few sporadic case reports of exacerbation
or occurrence of psoriasis have been reported
&
with nivolumab [28,29,30 ] and pembrolizumab
& &
[11 ,31 ]. This has also been described previously
&
with ipilimumab therapy [32 ]. Patients chiefly
exhibited asymptomatic psoriasiform lesions with
sharply bordered, scaly erythematous plaques
on the trunk and limbs. Immunotherapy was main-
tained in all cases and psoriasis was controlled with
topical steroids, vitamin D3 analogues, or retinoids
&
[28,29,30 ,31 ].
In our experience, we have also observed new
onset psoriasis with anti-PD-L1 agents (unpublished
data). Involvement of palmar areas or inverse
psoriasis with lesions predominantly located

(a) (b)

(c)

FIGURE 4. (a) Histopathological aspects of a lichenoid reaction, demonstrating a vacuolar interface dermatitis with a
predominant superficial band-like T-cell infiltrate and visible scattered apoptotic basal keratinocytes (hemalum eosin, 20); (b)
PD-1 (20% of infiltrate cells); and (c) PD-L1 (15% of infiltrate cells) immunostaining (10, Ventana Ultraview DAB Detection
Kit; clone NAT1054, Cell Marque, Rocklin, California, USA, and clone SP142, Spring Bioscience, Pleasanton, California,
USA).

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(a)
(c)
FIGURE 5. (a) Inverse psoriasiform eruption with anti-PD-L1 therapy (confined to perineal areas). (b, c) Acral lesions of
psoriasis developing with anti-PD-1 agents (courtesy of Professor Caroline Robert for Fig. 5b).
&
in large folds [31 ] can also sometimes be observed
(Fig. 5a–c).
The pathogenesis remains speculative. The
recent demonstration of weak PD-L1 and 2 expres-
sion at mRNA and protein levels in psoriatic
keratinocytes should be underlined [33]. It has also
been clearly demonstrated that psoriasis is strongly
associated with T-helper (Th)17 lymphocytes,
which are, at least in part, downregulated by the
PD-1 pathway. By inhibiting PD-1, these checkpoint
inhibitors may increase Th17 cell activation, induc-
&
ing psoriatic lesions [28,29,30 ]. The true incidence
of anti-PD-1/PD-L-1-induced psoriasis is currently
unknown and prospective studies are underway.
Miscellaneous
(1) The development of follicular acneiform lesions
has been described rarely with pembrolizumab
& &
and atezolizumab therapy [2 ,9 ,21]. It may also
be noted that we personally have observed a
severe exacerbation of papulopustular rosacea
with nivolumab (Fig. 6; unpublished data).
(2) An urticarial reaction can also occur with PD-1/
& &
PD-L1 monoclonal antibodies [2 ].
(3) Several case reports of ipilimumab-induced
Sweet’s syndrome have been reported. PD-1
inhibitors also appear capable of inducing such
&
neutrophilic dermatoses [2 ], and erythema
nodosum (noted in the pembrolizumab ‘Sum-
mary of Product Characteristics’).
(4) Anti-PD-1/PD-L1 antibodies may also reactivate
& &
HSV or herpes zoster infection [3 ,9 ].
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Anti-PD-1/PD-L1 antibodies and skin Sibaud et al.
(b)
VITILIGO
The development of vitiligo represents a well rec-
ognized adverse event in patients with melanoma
treated with anti-CTLA-4 and anti-PD-1/PD-L1 anti-
bodies. Depigmentation may result from induction
of antimelanoma immunity through a cytotoxic
T-cell-mediated response with a cross-reaction
against different epitopes or antigens expressed by
both melanoma cells and normal melanocytes (e.g.
&
MART-1, GP100, TRP1-2, tyrosinase) [15 ,16].
The overall incidence of newly developed viti-
ligo with PD-1 inhibitors varies between 8 and 25%
& & & &
[4,5 –7 ,11 ,15 ]. The relative risk of all-grade
vitiligo with anti-PD-1 and anti-CTLA-4 (pooled
analysis) has been evaluated as 16.3 (95% CI,
3.21–82.8; P ¼ 0.0008) [34 ]. Vitiligoid lesions, how-
&
ever, occur more frequently with anti-PD-1 agents
than with other immunotherapies (overall inci-
dence of 3.4%) [35] previously used in melanoma,
& &
including anti-CTLA-4 [4,5 ,7 ] (Table 1). The inci-
dence with anti-PD-L1 therapies remains to be deter-
mined [10]. Finally, vitiligo has not been described
to date in other types of solid cancers treated
& &
with PD-1/PD-L1 antibodies [9 ,11 ,20 ,21–23],
but a potential underestimation because of a lack
of systematic examination of the entire skin surface
cannot be ruled out.
Vitiligo usually develops after several months
of treatment and does not appear to be dose related.
It can be preceded by erythematous inflammatory
& &
lesions [11 ,15 ]. Lesions are mainly generalized
(Fig. 7a) and bilateral but focal or segmental
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Supportive care
FIGURE 6. Facial papulopustular rash suggestive of a
rosacea (nivolumab).
presentations can also be seen as vitiligoid lesions
localized around skin metastases. Associated hair
depigmentation can be also observed (Fig. 7b; scalp
hair, eyelashes). The main consequence is a psycho-
social impact but vitiligo does not require specific
treatment other than photoprotective measures.
Vitiligo usually persists beyond the completion
of immunotherapy.
It has been recently reported in single-center
studies that disease outcomes (objective response
or overall survival rate) were significantly associated
with a higher occurrence of vitiligo in patients with
melanoma treated with pembrolizumab or nivolu-
& &
mab [6 ,15 ]. However, larger studies are required to
confirm that vitiligo represents a positive prognostic
factor in this context, as has previously been dem-
onstrated with other types of immunotherapy in
patients with melanoma [35].
SKIN XEROSIS
Xerosis occurs in 2–9% of patients with anti-PD-1/
PD-L1 agents
& & &
[4,7 ,9 ,20 ,21]. Dry skin remains
of grade 1–2 but tends to worsen after months
of treatment and potentially triggers pruritus.
(a) (b)
FIGURE 7. (a) Generalized vitiligo with almost complete skin depigmentation (anti-PD-1 antibody). (b) Characteristic eyelash
and eyebrow hair depigmentation occurring with pembrolizumab.
260 www.co-oncology.com
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Therefore, appropriate education and symptomatic
management including long-term use of fragrance-
free topical moisturizers should be systematically
advised to patients.
MUCOSAL INVOLVEMENT
Oral adverse events do not represent major acute
toxicities of immune checkpoint inhibitors [36].
Nonspecific stomatitis or mucosal inflammation
has been sporadically described with both PD-1
& & &
and PD-L1 blockage therapy [6 ,9 ,19,20 ,22],
without reported grade at least 3. In clinical practice,
however, more characteristic oral lesions can some-
times occur with PD-1 or PD-L1 inhibitors.
Oral lichenoid reactions
Lichenoid reactions can also develop on oral muco-
sae. These can be observed with both anti-PD-1 and
& &
PD-L1 antibodies [1 ,25,26 ]. The lesions present as
whitish confluent papules or reticular streaks
consistent with Wickham’s striae (Fig. 8a). Dorsal
or lateral sides of the tongue, the lips, gingiva, hard
palate, or buccal mucosae can be involved. Patients
can report pain or soreness but the lesions can be
asymptomatic. The perianal area or vulva can also be
involved [25]. Although treatment discontinuation
is generally not required, we would emphasize that
the potential for malignant transformation of oral
lichenoid reactions is well established. Although
this remains unknown with anti-PD-1/PD-L1
therapy, systematic and regular oral examination
with long-term surveillance should theoretically
be advised.
Dysgueusia and xerostomia
Dysgueusia and xerostomia have been reported
in less than 5% of patients in pivotal studies
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 Anti-PD-1/PD-L1 antibodies and skin Sibaud et al.

(a) (b)

FIGURE 8. (a) Lichenoid reaction with visible reticular streaks on the lateral side of the tongue (anti-PD-L1 antibody). (b)
Severe sicca syndrome developing with nivolumab therapy.

& & &

[4,7 ,9 ,20 ,22]. They appear to develop less com-
&
monly with anti-CTLA-4 ipilimumab [7 ]. In rare
cases, these symptoms impact severely on health-
related quality of life (Fig. 8b) and symptomatic
management is then recommended.
Therefore, caution should be taken in patients
suffering from recent or ongoing auto-immune der-
matologic conditions. In all cases, close monitoring
should be set up.

Dual checkpoint blockade

SPECIFIC CONSIDERATIONS Combination blockade of CTLA-4 and PD-1 recep-
tors was shown to be synergistic in increasing
Preexisting autoimmune disorders objective response rate and progression-free sur-
Safety of anti-PD-1 or anti-PD-L1 agents in patients &
vival in advanced melanoma patients [5 ,17,18 ].
&

with preexisting autoimmune diseases is not estab-
lished and some concerns remain. Available data are
lacking because of the fact that patients with base-
line autoimmune conditions were largely excluded
from clinical trials.
It has recently been described retrospectively
that anti-CTLA-4 ipilimumab was able to reactivate
preexisting immune-related diseases, including psor-
&
iasis or sarcoidosis [32 ]. Likewise, the development
of bullous pemphigoid in a patient with melanoma
&
treated with pembrolizumab has been reported [37 ].
We have also noted the exacerbation of preexisting
subacute lupus erythematosus and bullous pemphi-
goid in some of our patients with anti-PD-1 or PD-L1
antibodies (Fig. 9a and b; unpublished data).
As a result, the FDA has recently granted an
accelerated approval to nivolumab and ipilimu-
mab combination. Although the safety profile
appeared acceptable and consistent with previous
experience with nivolumab or ipilimumab in
monotherapy, dermatologic irAEs were notably
increased with a higher rate of all-grade skin
select adverse events (42, 55, and 59–71% for
nivolumab, ipilimumab, and combination,
& &
respectively) [5 ,18 ] (Table 1). However, the pro-
portion of patients developing high-grade
cutaneous adverse events remained below 10% in
both studies. In addition, the number of patients
developing vitiligo was roughly identical in the
nivolumab and combination groups.

(a) (b)

FIGURE 9. (a) Severe exacerbation of preexisting subacute lupus erythematosus, associated with skin superinfection (anti-PD-
L1 agent). (b) Reactivation of bullous pemphigoid with nivolumab therapy.

1040-8746 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-oncology.com 261

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Supportive care
CONCLUSION
Although specific dermatologic studies are still lack-
ing, it is clearly apparent that cutaneous compli-
cations represent the most frequent irAEs induced
by anti-PD-1/PD-L1 antibodies. They are mild and
easily manageable in most cases. Early recognition
and appropriate management, however, are
required for limiting dose concession or treatment
discontinuation and preventing a negative impact
on patients’ quality of life.
Further prospective studies conducted in larger
patient cohorts would be useful to better define
these cutaneous manifestations and to confirm
that development of dermatologic irAEs with PD-
1/PD-L1 blockage therapy may represent a positive
prognostic factor for progression-free and overall
survival, especially for nonvitiligo cutaneous
adverse events (pruritus, rash).
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
E.V. and L.M. have no conflicts of interest to declare; V.S.
has a speaking, consultant, or advisory role with Roche,
GlaxoSmithKline, Pierre Fabre, Merck, Bristol-Myers
Squibb, Bayer, Novartis, and Boehringer Ingelheim.
N.M. has a speaking, consultant, advisory, or investi-
gator role with Roche, GlaxoSmithKline, Novartis, Pierre
Fabre, Merck-Smithline-Dohme, Bristol-Myers-Squibb,
and Amgen. J.M. has a speaking, consultant, or advisory
role with Roche, Bristol-Myers Squibb, PUMA, Pfizer,
Novartis, Astra Zeneca, and Boehringer Ingelheim.
J.P.D. has a speaking or consultant or investigator role
with Roche, GSK, Novartis, BMS, MSD.
Submission Declaration: This manuscript and/or its
contents have not been presented or published elsewhere.
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