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Drug-induced lupus erythematosus following immunotherapy with anti-programmed death-(ligand) 1
We read with interest the study of Kostine et al describing rheumatic immune-related adverse events (irAE), which occur in 6.6% of patients treated for cancer by anti-programmed death-(ligand) 1 (PDL1).1 These new adverse effects pose signif-icant challenges to patient care in terms of optimal management of these autoimmune damaging toxicities, while allowing effec-tive antitumor therapy to continue.
The PD(L)1 pathway is involved in the maintenance of immune tolerance, and the blockage of this axis by anticancer immunotherapy could trigger autoimmune diseases and espe-cially lupus.2 3 We then searched in the pharmacovigilance register of our institution—the ‘Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC)’—whether cases of drug-induced lupus erythematosus (DI-LE) were reported following anti-PD(L)1 immunotherapies.
Between October 2013 and July 2017, five cases of DI-LE were recorded in REISAMIC. Given the number of patients having received anti-PD(L)1 during the same period (n=1044), the estimated incidence of DI-LE was 0.48%. All patients gave their written informed consent for the use of their data in this report. The patients’ characteristics are summarised in table 1. The patients had developed DI-LE at a median (range) age of 63 (48–80) years. None of the patients had a history of autoim-mune disease before starting anti-PD(L)1. The most specific sign of DI-LE was subacute cutaneous lupus erythematous (SCLE) in four patients and chilblain lupus in the remaining patient. One patient having SCLE had also declared a systemic lupus erythematosus (SLE) according to the Systemic Lupus Interna-tional Collaborating Clinics criteria.4 The DI-LE was revealed by a frank maculopapular rash in the four patients with SCLE (figure 1). The median time of DI-LE occurrence was 10 (range: 4–22) weeks after the initiation of immunotherapy. Antinuclear antibodies in serum were found positive for two (40%) out of the five patients and were specifically positive for anti-Sjögren’s syndrome-related antigen A (SSA). These two SSA-positive patients had SCLE but no eye or mouth dryness symptoms suggestive of Sjögren’s disease. A skin biopsy was performed in all cases except the chilblain lupus. The skin biopsies revealed a lymphocytic infiltrate of the dermis, predominantly around adnexal sites. Alcian blue staining revealed mucin deposits in all patients. Direct immunofluorescence assays for IgG or C3 in skin biopsy were positive in two of the four patients tested (50%). The treatment of DI-LE was based on topical cortico-steroids in all cases, with the antimalarial hydroxychloroquine added in the SLE case, and the outcome was favourable with a resolution in all cases.
This report is the first series of cases of lupus erythema-tosus induced by anti-PD(L)1 immunotherapy. A recent similar case report of pembrolizumab-related subacute cutaneous lupus erythematosus was provided.5 The DI-LE has been variously reported after drug exposure such as hydralazine, procainamide, quinidine, oestrogen, tumour necrosis factor inhibitors, chlor-promazine, isoniazid, practolol, penicillamine and minocycline.6 We believe that anti-PD(L)1 immunotherapies should also now be added to this list.
Based on our experience and the present case series, DI-LE induced by anti-PD(L)1 was characterised by an extensive,
non-itchy and frankly macular or papular erythematous rash. The DI-LE diagnosis relies on the combination of the dermato-logical presentation associated with pathological features char-acterised by a lymphocytic dermal infiltration predominantly located at periadnexal sites, and mucin deposits.7 The confron-tation between the clinical appearance and the pathological aspects is often useful to differentiate between DI-LE and other non-specific cutaneous irAEs, or other specific autoimmune skin diseases that can be induced by anti-PD(L)1 such as psoriasis, toxic epidermal necrolysis, lichen planus, bullous dermatitis and dermatomyositis.8
These new cases of lupus induced by anti-PD(L)1 should incite rheumatologist and internists to dedicate further prospective study for irAE. Investigation of potential biomarkers of irAEs such as the genetic background, serum
Correspondence
Figure 1 Photographs and histologic assessment of skin biopsies of cutaneous lupus erythematosus lesions induced by treatment with anti-PD(L)1. (A) Patient 4, erythematous papules and plaques with an annular, polycyclic configuration: generalised subacute lupus erythematous. (B) Patient 1, erythematous macules on the neck: subacute cutaneous lupus erythematosus. (C) Patient 2, symmetric papulosquamous erythematous rashes on the lower limbs. (D) Patient 3, erythematous macules and plaques on the back: subacute cutaneous lupus erythematosus. (E) Skin biopsy from patient 1, haematoxylin eosin saffron (HES) staining, ×2.5: peripheral and periadnexal monomorphic lymphocytic inflammatory infiltrate over the entire dermis. (F) Skin biopsy from patient 4, HES staining, ×5: lichenoid dermatosis with staged apoptotic bodies in the epidermis. Peripheral inflammatory mononuclear infiltrate in the upper dermis. (G) Skin biopsy from patient 3, Alcian blue staining, ×10: mucin deposits in the dermis.
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Tabl
e 1
Char
acte
ristic
s of
the
patie
nts
havi
ng d
evel
oped
DI-L
E fo
llow
ing
trea
tmen
t with
ant
i-PD(
L)1
imm
unot
hera
py
Gen
der,
age,
can
cer
hist
olog
yPr
evio
us c
ance
r tr
eatm
ents
Dru
gCa
usal
rel
atio
nshi
p
Tim
e to
oc
curr
ence
of
DI-L
E*
(in w
eeks
)D
I-LE
form
†Se
veri
ty
grad
e
His
topa
thol
ogic
al
char
acte
rist
ics
of a
ski
n bi
opsy
Dir
ect
imm
unofl
uore
scen
ce in
sk
in b
iops
yA
utoi
mm
une
biol
ogy
in s
erum
‡
Seru
m c
reat
ine
kina
se (n
orm
al
valu
e <
145
IU/L
)O
ther
irA
Es
Trea
tmen
t fo
r cu
tane
ous
lupu
s, an
d ou
tcom
eBe
st o
vera
ll an
titu
mou
r re
spon
se, a
nd r
eint
rodu
ctio
n of
PD
(L)1
(or
reas
on fo
r w
ithd
raw
al)
Patie
nt 1
, wom
an, 4
8 ye
ars
old,
trip
le-
nega
tive
brea
st
carc
inom
a
Farm
orub
icin
e-en
doxa
n-5-
fluor
oura
cil;
erib
ulin
, cap
ecita
bine
; ge
mci
tabi
ne
Atez
oliz
umab
Like
ly6
SCLE
Clin
ical
asp
ect a
nd
loca
tion:
ery
them
atos
us, n
eckl
ine
1In
flam
mat
ory
mon
omor
phic
ly
mph
ocyt
e in
filtr
ate
in
periv
ascu
lar a
nd p
eria
dnex
al
site
s th
roug
hout
the
derm
is.
Alci
an b
lue
stai
ning
reve
aled
m
ucin
dep
osits
in th
e de
rmis.
Posi
tive
for I
gG, l
inea
r, m
oder
ate,
ep
ider
mal
der
mal
junc
tion
Neg
ativ
e fo
r C3d
Neg
ativ
eTi
tre
for A
NA
nega
tive
(<1/
80),
aDN
A<10
, EN
A ne
gativ
e co
mpl
emen
t in
norm
al ra
nge
(C3=
1.73
; C4
=0.
26)
Nor
mal
(75
IU/L
)N
oTo
pica
l ste
roid
s, re
solu
tion
in
2 w
eeks
PR No
inte
rrup
tion
of a
tezo
lizum
ab
Patie
nt 2
, wom
an, 8
0 ye
ars
old,
diff
use
larg
e B-
cell
lym
phom
a
R-CH
OP;
R-G
EMOX
; R-
lena
lidom
ide
Niv
olum
abLi
kely
14SC
LECl
inic
al a
spec
t and
lo
catio
n: p
apul
osqu
amou
s er
ythe
mat
ous
in th
e lo
wer
lim
bs, s
ymm
etric
al
2In
flam
mat
ory
periv
ascu
lar
lym
phoc
ytic
infil
trat
e of
the
uppe
r and
mid
dle
derm
is.
Alci
an b
lue
stai
ning
reve
aled
m
ucin
dep
osits
.
Neg
ativ
eN
egat
ive
Titr
e fo
r AN
A<1/
80;
aDN
A<10
; EN
A ne
gativ
eLo
w c
ompl
emen
t C4
and
CH50
but
nor
mal
C3
(C3=
1.53
; C4<
0.02
; CH
50<
10)
Nor
mal
(28
IU/L
)Ye
s: he
patit
is
grad
e 2
Topi
cal s
tero
ids,
reso
lutio
n in
3
wee
ks
PD Tem
pora
ry w
ithdr
awal
of i
mm
unot
hera
py d
ue to
lupu
s, an
d th
en d
efini
tive
with
draw
al o
f niv
olum
ab d
ue to
di
seas
e pr
ogre
ssio
n
Patie
nt 3
, wom
an,
66 y
ears
old
, ca
rcin
oma
epid
erm
oid
Radi
othe
rapy
; ca
rbop
latin
-cet
uxim
ab-
5-flu
orou
raci
l; pa
clita
xel-c
etux
imab
; m
etho
trex
ate-
carb
opla
tine
Niv
olum
abLi
kely
4SC
LECl
inic
al a
spec
t and
loca
tion:
er
ythe
mat
osus
on
the
trun
k, b
ack
and
face
2Pe
rivas
cula
r lym
phoc
ytic
in
filtr
ate
of th
e up
per d
erm
is
with
dis
cret
e va
cuol
isat
ion
of th
e ep
ider
mal
bas
al la
yer.
Alci
an b
lue
stai
ning
reve
aled
m
ucin
dep
osits
in th
e de
rmis.
Neg
ativ
ePo
sitiv
e w
ith
ANA+
and
SSA+
Titr
e fo
r AN
A=1/
640;
aD
NA<
10;
ENA=
1.5
wea
kly
posi
tive;
SSA
=94
U/
mL,
com
plem
ent i
n no
rmal
rang
e (C
3=1.
42;
C4=
0.2;
CH5
0 no
t do
ne)
Nor
mal
(30
IU/L
)N
oTo
pica
l ste
roid
s, re
solu
tion
in
2 w
eeks
SD Tem
pora
ry w
ithdr
awal
of i
mm
unot
hera
py d
ue to
lupu
s
Patie
nt 4
, man
, 63
year
s ol
d, m
elan
oma
Non
ePe
mbr
oliz
umab
Cert
ain
22SC
LECl
inic
al a
spec
t and
loca
tion:
gen
eral
ised
, cl
early
ery
them
atos
us, p
apul
ar a
nd
mac
ular
asp
ects
on
the
trun
k, b
ack,
ab
dom
en a
nd th
orax
Syst
emic
lupu
s er
ythe
mat
osus
(SLI
CC
crite
ria4 w
ere
SCLE
+ar
thra
lgia
+po
sitiv
e se
rum
ant
ibod
ies)
3Li
chen
oid
derm
atos
is w
ith
stag
ed a
popt
otic
bod
ies
in
the
epid
erm
is. P
erip
hera
l in
flam
mat
ory
mon
onuc
lear
in
filtr
ate
in th
e up
per d
erm
is.
Alci
an b
lue
stai
ning
did
not
re
veal
any
muc
in d
epos
its in
th
e de
rmis.
Posi
tive
for I
gG: d
isco
ntin
uous
lo
w-in
tens
ity b
and
and
epid
erm
al
derm
al ju
nctio
n. C
3d p
ositi
ve:
roug
h ba
nd
Posi
tive
with
SSA
+/
SSB+
Titr
e fo
r AN
A>1/
1280
(m
ottle
d as
pect
); aD
NA<
10;
ENA>
28 h
ighl
y po
sitiv
e w
ith S
SA>
241
U/m
L an
d SS
B=86
U/m
L (n
<7)
, com
plem
ent i
n no
rmal
rang
e (C
3=1.
07;
C4=
0.21
; CH5
0>60
)
Elev
ated
:23
8 IU
/L w
hen
lupu
s ap
pear
ed,
then
181
IU/L
15 d
ays
late
r, th
en
retu
rn to
nor
mal
le
vels
Yes:
vitil
igo
univ
ersa
lis,
hepa
titis
gra
de 2
Topi
cal s
tero
ids,
oral
hy
drox
ychl
oroq
uine
, re
solu
tion
in
4 w
eeks
CR Perm
anen
tly d
isco
ntin
ued
due
to th
e ad
vers
e ev
ent
and
the
CR
Patie
nt 5
, man
, 48
year
s ol
d, m
elan
oma
Daca
rbaz
ine-
fote
mus
tine;
ip
ilim
umab
Pem
brol
izum
abCe
rtai
n10
Chilb
lain
lupu
s on
the
toes
1N
ot p
erfo
rmed
Not
per
form
edN
egat
ive
Titr
e fo
r AN
A<1/
80;
aDN
A<10
; EN
A no
t do
ne; c
ompl
emen
t in
norm
al ra
nge
(C3=
1.17
; C4
=0.
2; C
H50=
49.3
)
Nor
mal
(58
IU/L
)Ye
s: vi
tilig
o un
iver
salis
Topi
cal s
tero
ids,
reso
lutio
n in
2
wee
ks
PR No
disc
ontin
uatio
n of
pem
brol
izum
ab
Tota
l:M
edia
n (ra
nge)
age
63
(48–
80) y
ears
––
– M
edia
n (ra
nge)
: 10
(4–2
2) w
eeks
– –
– Po
sitiv
e in
two
of fo
ur c
ases
te
sted
(50%
)AN
A po
sitiv
e in
two
of
five
case
s (4
0%)
– –
– –
*Tim
e be
twee
n th
e fir
st in
fusi
on o
f ant
i-PD(
L)1
and
the
onse
t of s
ympt
oms
of lu
pus
eryt
hem
atos
us.
†Am
ong
Obe
rmos
er e
t al.7
‡Ser
um a
ssay
s fo
r aut
oim
mun
e fa
ctor
s, w
ith n
orm
al v
alue
s in
dica
ted:
AN
A, s
erum
titr
e, n
orm
al <
1/80
; aDN
A, n
orm
al <
10 IU
/mL;
EN
A, ra
tio, n
orm
al <
1.1
(ratio
=sa
mpl
e abs
orpt
ion/
stan
dard
abs
orpt
ion)
; SSA
, nor
mal
<7
U/m
L; S
SB, n
orm
al <
7 U
/mL;
C3,
nor
mal
val
ues=
0.9–
1.80
g/L
; C4,
nor
mal
val
ues=
0.10
–0.4
0 g/
L; C
H50,
nor
mal
val
ue >
31.6
; cre
atin
e ki
nase
(CK)
, nor
mal
val
ues=
0–14
5 IU
/L.
aDN
A, a
nti-D
NA;
AN
A, a
ntin
ucle
ar a
ntib
ody;
CH5
0, 5
0% c
ompl
emen
t hae
mol
ytic
; CR,
com
plet
e re
spon
se; D
I-LE,
dru
g-in
duce
d lu
pus
eryt
hem
atos
us; E
NA,
ext
ract
able
nuc
lear
ant
igen
; irA
E, im
mun
e-re
late
d ad
vers
e ev
ent;
PD, p
rogr
essi
ve d
isea
se; P
R, p
artia
l res
pons
e; R
-CHO
P, rit
uxim
ab-c
yclo
phos
pham
ide
hydr
oxya
dria
myc
ine
onco
vin
pred
niso
ne; R
-GEM
OX, r
ituxi
mab
-gem
cita
bine
oxa
lipla
tine;
SCL
E, s
ubac
ute
cuta
neou
s lu
pus
eryt
hem
atos
us; S
D, s
tabl
e di
seas
e; S
LICC
, Sys
tem
ic L
upus
Inte
rnat
iona
l Col
labo
ratin
g Cl
inic
s4 ; SSA
, Sjö
gren
’s sy
ndro
me-
rela
ted
antig
en A
; SSB
, Sjö
gren
’s sy
ndro
me-
rela
ted
antig
en B
.
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levels of autoimmune factors and cytokines may help better understand these immunological adverse events and autoim-mune conditions in general.
Jean-Marie Michot,1,2 Mathilde Fusellier,1 Stephane Champiat,1,3 Charles Velter,4 Capucine Baldini,1,3 Anne-Laure Voisin,5 Francois-Xavier Danlos,1 Yolla El Dakdouki,1 Maxime Annereau,6 Xavier Mariette,7 Caroline Robert,4 Khadija Cherif,8 Aurélien Marabelle,1 Christine Mateus,4 Olivier Lambotte2,3,9,10
1Medical Oncology and Drug Development Department, Institut Gustave Roussy, Villejuif, France2Department of Internal Medicine and Clinical Immunology, Hôpital Bicêtre, Le Kremlin-Bicêtre, France3University of Paris Sud, Le Kremlin-Bicêtre, France4Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France5Department of Pharmacovigilance, Institut Gustave Roussy, Villejuif, France6Department of Pharmacy, Institut Gustave Roussy, Villejuif, France7Department of Rheumatology, Hôpital Bicêtre, Le Kremlin-Bicêtre, France8Department of Biopathology, Institut Gustave Roussy, Villejuif, France9INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin- Bicêtre, France10Commissariat à l’Energie Atomique (CEA), Fontenay-aux-Roses, France
Correspondence to Dr. Jean-Marie Michot, Drug Development Department, Institut Gustave Roussy, Villejuif F-94805, France; jean- marie. michot@ gustaveroussy. fr
Handling editor Josef S Smolen
Acknowledgements The authors thank David Fraser (Biotech Communication SARL, Ploudalmézeau, France) for copy-editing assistance.
Contributors All authors contributed to the patient care management and manuscript writing. All authors approved the manuscript submitted.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethics Board Committee and Institutional Board of Institut Gustave Roussy.
Provenance and peer review Not commissioned; internally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
To cite Michot J-M, Fusellier M, Champiat S, et al. Ann Rheum Dis 2019;78:e67.
Received 29 April 2018Accepted 1 May 2018Published Online First 1 June 2018
► http:// dx. doi. org/ 10. 1136/ annrheumdis- 2018- 213691
Ann Rheum Dis 2019;78:e67. doi:10.1136/annrheumdis-2018-213677
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2 Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999;11:141–51.
3 Prokunina L, Castillejo-López C, Oberg F, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002;32:666–9.
4 Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677–86.
5 Shao K, McGettigan S, Elenitsas R, et al. Lupus-like cutaneous reaction following pembrolizumab: An immune-related adverse event associated with anti-PD-1 therapy. J Cutan Pathol 2018;45:74–7.
6 Niklas K, Niklas AA, Majewski D, et al. Rheumatic diseases induced by drugs and environmental factors: the state-of-the-art - part two. Reumatologia 2016;54:165–9.
7 Obermoser G, Sontheimer RD, Zelger B. Overview of common, rare and atypical manifestations of cutaneous lupus erythematosus and histopathological correlates. Lupus 2010;19:1050–70.
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