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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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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.

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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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