Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint Inhibitors: A Review of the Literature

Abstract

Background:
Immune checkpoint inhibitors are a new promising class of antitumor drugs that have been associated to a number of immune-related adverse events (AEs), including musculoskeletal and rheumatic disease.

Methods:
We searched Medline reviewing reports of musculoskeletal and rheumatic AEs induced by immune checkpoint inhibitors.

Results:
Several musculoskeletal and rheumatic AEs associated with immune checkpoint inhibitors treatment are reported in literature. In particular, arthralgia and myalgia were the most common reported AEs, whereas the prevalence of arthritis, myositis and vasculitis is less characterized and mainly reported in case series and case reports. Other occasionally described AEs are sicca syndrome, polymyalgia rheumatica, systemic lupus erythematosus and sarcoidosis.

Conclusions:
Newly induced musculoskeletal and rheumatic diseases are a frequent adverse event associated with immune checkpoint inhibitors treatment.

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Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint
Inhibitors: A Review of the Literature
Devis Benfaremo, Lucia Manfredi, Michele Maria Luchetti* and Armando Gabrielli
Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
!
A R T I C L E H I S T O R Y!
Received: March 02, 2018
Revised: April 24, 2018
Accepted: May 01, 2018
DOI:
10.2174/1574886313666180508122332
!
Abstract: Background: Immune checkpoint inhibitors are a new promising class of antitumor drugs
that have been associated with a number of immune-related adverse events (AEs), including
musculoskeletal and rheumatic disease.
Methods: We searched Medline reviewing reports of musculoskeletal and rheumatic AEs induced by
immune checkpoint inhibitors.
Results: Several musculoskeletal and rheumatic AEs associated with immune checkpoint inhibitors
treatment are reported in the literature. In particular, arthralgia and myalgia were the most common
reported AEs, whereas the prevalence of arthritis, myositis and vasculitis is less characterized and
mainly reported in case series and case reports. Other occasionally described AEs are sicca syndrom e,
polymyalgia rheumatica, systemic lupus erythematosus and sarcoidosis.
Conclusions: Newly induced musculoskeletal and rheumatic diseases are a frequent adverse event
associated with immune checkpoint inhibitors treatment. !
Keywords: Immune checkpoint inhibitors, anti-PD1, anti-CTLA4, nivolumab, pembrolizumab, ipilimumab, rheumatic dis-
eases, musculoskeletal diseases.
1. INTRODUCTION
Immune checkpoint inhibitors (ICIs) are a new promising
class of anti-tumor drugs that block negative costimulation
of T-cells leading to an enhanced anti-tumor immune re-
sponse. Targets of these therapies include cytotoxic T-
lymphocyte associated protein-4 (CTLA-4), programmed
cell death protein-1 (PD-1), and programmed death ligand-1
(PD-L1). CTLA-4 and PD-1 are negative regulatory recep-
tors expressed on T-cells. ICIs block the negative interac-
tions between T-cells, antigen presenting cells and tumors,
allowing positive costimulation to occur and T-cells to be-
come activated [1].
In early trials, treatment with both CTLA-4 and PD1 in-
hibitors showed a remarkable benefit in promoting durable
anti-tumor immune responses, and this success led to the
approval by the US Food and Drug Administration (FDA) of
the monoclonal antibodies ipilimumab (anti-CTLA4),
nivolumab (anti-PD1), pembrolizumab (anti-PD1), atezoli-
zumab (anti-PDL1), avelumab (anti-PDL1) and durvalumab
(anti-PDL1) for therapeutic use in a variety of cancers,
including melanoma, non-small-cell lung cancer (NSCLC),
head and neck squamous cell carcinoma, renal cell
carcinoma, Hodgkin lymphoma, bladder cancer, Merkel cell
*Address correspondence to this author at the Dipartimento di Scienze
Cliniche e Molecolari, Università Politecnica delle Marche, Ancona,
Italy; Tel: 00390715964200; Fax: 00390715964225;
E-mail: m.luchetti@staff.univpm.it
carcinoma and microsatellite instability high or mismatch
repair-deficient adult and pediatric solid tumors [2].
Notwithstanding their therapeutic promise, significant
toxicity, particularly consisting in immune-related adverse
events (IRAEs), has been observed with both classes of ICIs,
with higher rates occurring when PD1-targeted therapy is
used in combination with CTLA4-targeted therapy. IRAEs
may involve any organ system, including gastrointestinal
tract, endocrine glands, skin, liver, cardiovascular and pul-
monary systems, and may lead to significant morbidity and,
to a lesser extent, mortality (Table 1) [3].
Musculoskeletal and rheumatic diseases are among the
less frequently reported IRAEs associated to ICIs treatment,
but they are burdened with significant morbidity. In this nar-
rative review, we will summarize the current evidence of
rheumatic IRAEs associated with ICIs treatment.
2. METHODS
For the purpose of this narrative review, we conducted a
MEDLINE database search for the following words: “ar-
thralgia”, “xeroftalmia”, “xerostomia”, “sicca syndrome”,
“vasculitis”, “myalgia”, “myositis”, “enthesitis”, “arthritis”,
“systemic lupus erythematosus”, “lupus”, “polymyalgia
rheumatica”, “sarcoidosis”, “musculoskeletal”, “rheumatic”
and “anti-PD1”, “anti-PDL1”, “anti-PD1 antibody”, “anti-
CTLA4”, “CTLA4 antibody”, “ipilimumab”, “avelumab”,
“nivolumab”, “atezolizumab”, “pembrolizumab”, “durvalu-

2 Current Drug Safety, 2018, Vol. 13, No. 3 Benfaremo et al.
mab”, “anti-programmed death 1 monoclonal antibody”,
“immune checkpoint inhibitor”.
3. RESULTS
Globally considered, rheumatic and musculoskeletal
IRAEs appear to be rarer than other more frequent and bur-
densome ones, like pneumonitis, hypophysitis and colitis. In
a French registry of grade ≥2 IRAEs occurring in 908 ICI-
treated patients, 21 (2.3%) experienced an event, excluding
arthralgia and myalgia, which are more commonly reported
and may rather represent a manifestation of the neoplastic
disease itself (4]. In another single-center registry of 400 pa-
tients treated with ICIs, only 14 (3.5%) developed rheumatic
diseases [5].
Tables 2 and 3 summarize the findings of the rheumatic
and musculoskeletal IRAEs occurring in the ICI-treated pa-
tient, as reported by observational studies, case series and case
reports.
3.1. Arthralgia and Inflammatory Arthritis
Arthralgia is among the most commonly reported AEs,
both in clinical trials, observational studies and case reports.
The incidence of arthralgia is around 9-12% and 6-8% for
patients receiving pembrolizumab and nivolumab, 5% for
patients receiving ipilimumab and 11% for patients receiving
the combination therapy of nivolumab and ipilimumab [6].
In a recent systematic review that included 33 clinical tri-
als of all ICIs in different types of cancer, articular pain was
the most commonly reported musculoskeletal complaint (1-
43% of participants), whereas a true inflammatory arthritis
was reported in only five trials, with a prevalence of 1-7%
[1].
The same authors described 13 patients with rheuma-
tologic events following nivolumab, ipilimumab or combina-
tion therapy. Inflammatory arthritis was seen in 9 patients,
with synovitis confirmed in 4 patients by imaging tech-
niques. Some patients required biologic treatment with etan-
ercept, adalimumab or infliximab to achieve mostly a partial
response [7].
In another retrospective chart review, the authors re-
ported four cases of inflammatory polyarthritis, four patients
with oligoarthritis and two with tenosynovitis. Six of them
were ANA positive and two had anti-citrullinated protein
(anti-CCP) antibodies. All patients were treated with sys-
temic corticosteroids, even at a small dose, and five patients
received steroid-sparing agents. Even so, in some of the
patients, the joint symptoms persisted for months [8].
In another retrospective study, conducted in metastatic
melanoma treated with pembrolizumab or nivolumab and
ipilimumab, 13.3% of patients developed arthralgia. Most
frequently, arthralgia involved large joints (shoulders, knees)
in a predominantly symmetrical pattern. Only two patients
were seropositive for rheumatoid factor and/or anti-CCP
antibodies. Ten patients developed a frank inflammatory
arthritis. The majority of patients was treated with non-
steroidal anti-inflammatory drugs (NSAIDs), 23.1% required
additional low-dose corticosteroids and 7.6% of patients re-
ceived immunosuppressive treatment [9].
Inflammatory arthritis may affect both large and small
joints, and may present with different clinical phenotypes,
sometimes as oligoarthritis, sometimes as additive arthritis
but also as severe polyarthritis [7, 10].
A French retrospective study reported that a polyarthritis
resembling rheumatoid arthritis (RA) developed in six pa-
tients receiving ICIs; all six were positive for anti-CCP anti-
bodies and four for rheumatoid factor. The median time to
the event after exposure to the drug was 1 month (range 1–9
months). Three patients needed to be treated with disease-
modifying anti-rheumatic drugs (DMARDs); the others re-
ceived corticosteroids or NSAIDs [11].
In the French registry including 908 patients, the preva-
lence of RA was very low (0.2%), whereas that of non-RA
inflammatory polyarthritis was slightly higher (1.2%), reach-
ing 2.5% when ICIs were used in combination [4]. In another
single-center registry, polyarthritis was seen in 10 out of 400
patients (2.5%), oligoarthritis in one patient and monoarthri-
tis in another one [5].
Among non-RA inflammatory arthritis, de-novo psoriasis
and psoriatic arthritis (PsA) were reported to be induced by
Table 1. Therapeutic indications and commonly reported adverse events of the main ICIs.
Drug
ICI Target
Therapeutic Indications
Commonly Reported Adverse
Events
Ipilimumab
CTLA-4
Metastatic melanoma
Fatigue, rash, colitis (+), hepato-
toxicity, pneumonitis (-), hypo-
physitis (+), hypothyroidism
Pembrolizumab
PD-1
Metastatic melanoma, NSCLC, Head
and neck cancer, Hodgkin’s lym-
phoma, urothelial carcinoma, gastric
cancer
Fatigue, rash, colitis (-), hepatotox-
icity, pneumonitis (+), hypophysi-
tis (-), hypothyroidism
Nivolumab
PD-1
Metastatic melanoma, NSCLC,
Renal cell carcinoma, Hodgkin’s
lymphoma, head and neck cancer,
urothelial carcinoma, colorectal
cancer, hepatocellular carcinoma
Fatigue, rash, colitis (-), hepatotox-
icity, pneumonitis (+), hypophysi-
tis (-), hypothyroidism
Atezolizumab
PD-L1
NSCLC, locally advanced or metas-
tatic urothelial carcinoma
Fatigue, rash, hepatotoxicity, hy-
pophysitis (+), hypothyroidism

Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint Inhibitors Current Drug Safety, 2018, Vol. 13, No. 3 3
Table 2. Published case reports and case series of musculoskeletal IRAEs induced by ICIs.
Reference
Drug
Indication
Clinical Presentation
Withdrawal
of Drug
Treatment and outcome
Type of
Study
Hunter 2009
[31]
Ipilimumab
Melanoma
Dysphagia, dysarthria, dif-
fuse muscle weakness, ele-
vation of CK.
Diagnosis of acute polymy-
ositis
No (symptoms
appeared after
the end of
therapy)
Corticosteroid and intravenous
Ig
Response to therapy and heal-
ing of melanoma
Case
report
Fadel 2009
[36]
Ipilimumab
Melanoma
After two injections, the
patient developed signs and
symptoms of lupus nephritis
Yes
Corticosteroid therapy with
clinical improvement
Case
report
Manousakis
2013 [43]
Ipilimumab
Metastatic
melanoma
Asymmetric, severe weak-
ness involving all limbs,
respiration, and cranial
nerves, which was progres-
sive over 2 weeks.
EMG/NCS showed an ax-
onal polyradiculoneuropathy
with multifocal motor con-
duction blocks.
Nerve pathology showed
inflammation around the
endoneurial microvessels
and subperineurial edema
and inflammation.
Yes
Improvement over months
without further treatment
Case
report
Minor 2013
[45]
Ipilimumab
Melanoma
Uterine lymphocytic vascu-
litis presenting with a mass
in uterus and pelvic lympha-
denopathy
No (therapy
just finished)
Hysterectomy due to concern
for malignancy
No further treatment
Case
report
Goldstein
2014 [46]
Ipilimumab
Melanoma
Two patients developed
polymyalgia rheumatica
w/o giant cell arteritis
Yes
High dose corticosteroid ther-
apy
After six months one patient
died
Case
series
Chan 2015
[17]
Pembrolizumab
Melanoma
First case: knee arthritis
Second case: polyarthritis
and myalgia diagnosed as
seronegative inflammatory
arthritis
Yes
(in the first
case drug was
restarted after
symptoms
resolution)
First case: steroid therapy with
resolution of symptoms
Second case: naproxen, hy-
droxychloroquine and
paracetamol
Case
series
Sheik 2015
[30]
Ipilimumab
Melanoma
Erythematous rash with
Gottron’s papules and pro-
ximal muscle weakness
Diagnosis: dermatomyositis
Yes
Prednisone 80 mg daily ta-
pered over 8 weeks.
Only a minimal clinical re-
sponse was achieved.
Case
report
Yoshioka
2015 [27]
Nivolumab
Melanoma
Shortness of breath with
CPK elevation.
Diagnosis: myositis compli-
cated by respiratory distress
Yes
Complete recovery after sev-
eral weeks
Case
report
Garel 2016
[48]
Pembrolizumab
Metastatic
melanoma
Two patients presenting with
pain of the shoulders and hip
girdles, morning stiffness
Diagnosis: polymyalgia
rheumatica
No (partial in
one case)
Fast improvement 48 hours
after the beginning of oral
prednisone.
Disease remission at one
month.
Case
report
De Velasco
2016 [19]
Nivolumab
Metastatic clear
cell renal cell
carcinoma
Autoimmune uveitis and
Jaccoud’s arthropathy
Yes
Improvement of uveitis with
corticosteroid treatment.
Not reported the outcome of
arthropathy.
Case
report
Khoja 2016
[35]
Pembrolizumab
Melanoma
Eosinophilic fasciitis
No (symptoms
appeared after
the end of
therapy)
Corticosteroid therapy with
clinical improvement
Case
report
(Table 2) Contd…

4 Current Drug Safety, 2018, Vol. 13, No. 3 Benfaremo et al.
Reference
Drug
Indication
Clinical Presentation
Withdrawal
of Drug
Treatment and outcome
Type of
Study
Law-ping-
man 2016
[14]
Nivolumab
NSCLC
After eight infusion of drug,
the patient developed psori-
atic arthritis
Yes (for 4
weeks)
Corticosteroid and MTX therapy
with improvement of skin le-
sions and arthritis and subse-
quent stop of steroid and MTX
Case
report
Kimura
2016 [28]
Nivolumab
Melanoma
Two months after the first
dose acute polymyositis
developed
Yes
Corticosteroids, intravenous
immunoglobulin, PLEX with
significant benefit
Case
report
Schmutz
2016 [12]
Nivolumab
NSCLC
After eight infusions, the
patient developed psoriatic
arthritis
Yes
Corticosteroid and MTX were
started.
Nivolumab was restarted after
response of skin lesions
Case
report
Fox 2016
[25]
Nivolumab
Melanoma
After the second dose of
drug, severe muscle pain,
difficulty breathing, short-
ness of breath, and an inabil-
ity to lift the legs with CPK
elevation.
Diagnosis: myositis
Yes
Corticosteroids with normali-
zation of CK within one week.
Case
report
Vallet 2016
[34]
Pembrolizumab
Melanoma
After two injections, proxi-
mal bilateral limb weakness
and dysphonia with CPK
elevation.
Diagnosis: myositis.
Yes
Corticosteroids followed by
two cycles of PLEX, followed
by one PLEX per week for 3
weeks.
One month after the onset of
symptoms, patient had a near
complete clinical recovery. No
relapses at 3 months of follow-
up.
Case
report
Konoeda
2017 [21]
Nivolumab
Advanced colon
cancer
Bilateral ptosis, limb and
neck weakness, dyspnea, and
myalgia in two weeks.
Diagnosis of myasthenia
gravis and myositis
Yes
Oral prednisolone, intravenous
immunoglobulin and plasma
exchange with noninvasive
positive-pressure ventilation.
Case
report
Haddox
2017 [33]
Pembrolizumab
Melanoma
Progressive dysarthria, bilat-
eral ptosis, neck weakness,
dysphagia, diffuse myalgia,
and mild proximal muscle
weakness in both the upper
and lower extremities.
Diagnosis of immune-
mediated necrotizing myopa-
thy over a NMJ disorder.
Yes
Prednisone and PLEX (three
sessions) were started but
patient continued to deteriorate
and died for respiratory fail-
ure. An autopsy was per-
formed, which revealed dif-
fuse necrotic myositis of the
diaphragm and lymphohistio-
cytic myocarditis.
Case
report
Teyssonneau
2017 [41]
Pembrolizumab
Left parotid
acinic cell car-
cinoma with
adrenal gland
and lung metas-
tases
Dry-eye syndrome, conjunc-
tival hyperemia, xerostomia
and skin rash on both hands
identified as Gougerot-
Sjogren like syndrome
No
Daily dose of 10 mg predni-
sone, betamethasone cream for
the hands, artificial tear drops
and artificial saliva. For dry-eye
syndrome and the xerostomia,
which significantly affected the
patient’s daily life, treatment
with pilocarpine.
Case
report
Behling
2017 [29]
Nivolumab
Melanoma
Moderate pain in the proxi-
mal muscle groups of the
upper limbs and a slight
worsening of a pre-existing
dyspnea (started 10 days
after the first infusion).
Three days later dyspnea,
dysphagia, and worsened
muscle pain lead to hospi-
talization. Increase of CPK,
myoglobin, troponin I, ANA
positive.
Diagnosis of autoimmune-
induced myositis.
No
Immunosuppressive therapy
with iv prednisone.
After four days of hospitaliza-
tion, a third-degree atrioven-
tricular block with a bradycar-
dia of 44 bpm and a systolic
blood pressure up to 200
mmHg developed. The patient
died after 26 days of treat-
ment.
Case
report
(Table 2) Contd…

Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint Inhibitors Current Drug Safety, 2018, Vol. 13, No. 3 5
Reference
Drug
Indication
Clinical Presentation
Withdrawal
of Drug
Treatment and outcome
Type of
Study
Bernier
2017 [47]
Nivolumab
NSCLC
Diffuse joint pain that oc-
curred suddenly.
Diagnosis of polymyalgia
rheumatica
Yes
(Drug was
restarted after
resolution of
joint pain in
association
with steroid
therapy)
Good response to corticoster-
oid therapy
Case
report
Chen 2017
[26]
Nivolumab
NSCLC
Ptosis, diplopia, drop head,
and general weakness 5 days
after a third drug infusion
conducted to a diagnosis of
nivolumab-related myasthe-
nia and myositis
Yes
Steroid treatment with meth-
ylprednisolone 1mg/kg/d and
pyridostigmine 60mg twice a
day was administered begin-
ning at admission; however,
the patient’s condition pro-
gressively worsened, despite
treatment. Respiratory failure
developed 2 weeks after ad-
mission. The patient died on
day 27 after the third nivolu-
mab infusion.
Case
report
Dasanu
2017 [18]
Ipilimumab
Melanoma
Swelling and pain involving
the right knee with signs of
synovial inflammation and
an important joint effusion;
moderate bilateral pleural
effusions and enlarged heard
silhouette; large pericardial
effusion
Just com-
pleted
Steroid therapy was initiated
with remarkable clinical im-
provement over the next 24h
and then was tapered over the
next six weeks with resolution
of pericardial and pleural
effusions two weeks later.
Eight months after completing
ipilimumab therapy, the right
knee effusion re-accumulated
and prednisone was restarted.
Case
report
Gauci 2017
[50]
Nivolumab
Melanoma
After three drug infusions,
the patient developed a
variant of polymyalgia
rheumatica
Yes
Corticosteroid therapy. After
achieving remission, nivolu-
mab was recommenced with-
out any flare of arthritis.
Case
report
Liu 2017
[39]
Nivolumab
NSCLC
After five months of
nivolumab therapy, the
patient developed subacute
cutaneous lupus erythemato-
sus
Yes
Corticosteroids, hydroxy-
chloroquine, aspirin with
improvement.
Nivolumab was restarted after
5 months
Case
report
Mahmoud
2017 [15]
Pembrolizumab
Melanoma
Knee inflammatory synovitis
No
Prednisone and infliximab
Case
report
Push-
karevskaya
2017 [32]
Ipilimumab
Melanoma
First case: after four months
diagnosis of ocular myositis
Second case: after two cy-
cles of drug diagnosis of
ocular myositis
Yes
First case: Corticosteroid
therapy and mycophenolate
mofetil and immunoglobulin
Second case: Corticosteroid
therapy and mycophenolate
mofetil.
Both resolution of myositis.
Case
report
Ruiz-
Bañobre
2017 [13]
Nivolumab
NSCLC
Diagnosis of psoriatic arthri-
tis after the 11th course of
nivolumab
No
Corticosteroid and NSAIDS
therapy and then MTX with
nivolumab.
Minimal disease activity was
achieved
Case
report
Saini 2017
[24]
Nivolumab
Hodgkin lym-
phoma and then
acute myeloid
leukemia
Diffuse edema with
subsequent diagnosis of
autoimmune myositis
No
Corticosteroid therapy.
The patient died after six
months from diagnosis
Case
report
Salmon
2017 [16]
Pembrolizumab
Melanoma
After nine infusions, the
patient developed polyarthri-
tis and fever
No
Corticosteroid therapy and
then MTX were prescribed
with moderate benefit
Case
report
(Table 2) Contd…

6 Current Drug Safety, 2018, Vol. 13, No. 3 Benfaremo et al.
Reference
Drug
Indication
Clinical Presentation
Withdrawal
of Drug
Treatment and outcome
Type of
Study
Gambichler
2017 [44]
Nivolumab +
ipilimumab
Melanoma
After three weeks, the patient
developed progressive
erythema, paresthesia and pain
on the fingertips of both hands.
Diagnosis: acral vascular
syndrome
Histopathology did not reveal
evidence for vasculitis
No
Treatment with corticosteroids
and prostacyclin.
The patient died for cancer
progression.
Case
report
Firwana
2017 [54]
First case: Ipilimu-
mab
Second case: ipili-
mumab
Third case:
ipilimumab fol-
lowed by pembroli-
zumab
Melanoma
First case: tender retroauricular,
occipital, cervical, and axillary
lymphadenopathy. PET CT
showed substantial bilateral
cervical, axillary, hilar, medi-
astinal, iliac, and inguinal lym-
phadenopathy.
Second case: PET CT showed
diffuse hilar and mediastinal
lymphadenopathy. Pathology
revealed multiple poorly
formed epithelioid granulomas
with multinucleated giant
cells, focal necrotic debris, and
abundant small lymphocytes,
but no evidence of melanoma.
Third case: the patient de-
veloped a granulomatous
skin lesion on right forearm.
A biopsy of the lymph node
confirmed a systemic granu-
lomatous process.
First case: Yes
Second case:
not reported
Third case:
Yes, but not
immediately
First case: No corticosteroids
were prescribed.
Follow-up PET CT obtained
three months later showed
complete resolution of the
lymphadenopathy
Second case: not reported
Third case: symptoms re-
solved spontaneously in few
weeks without any treatment.
PET-CT imaging obtained two
months after stopping pem-
brolizumab showed stable
lymphadenopathy
Case
series
Lainez 2017
[59]
Nivolumab
NSCLC
After 8 injections of nivolu-
mab, a new CT and PET scan
revealed massive growth and
increase in metabolism of hilar
and mediastinal lymph nodes.
EBUS-TBNA showed an
epithelioid cell reaction
compatible with sarcoidosis
No
Stability of disease at 12
months without treatment
Case
report
Reuss 2017
[60]
Nivolumab plus
ipilimumab
Metastatic
melanoma
PET-CT scan revealed new
supraclavicular, mediastinal,
right hilar and left iliac ade-
nopathy, as well as subcutane-
ous left pretibial and right calf
nodules. Histology showed
non-caseating granulomas.
Diagnosis of sarcoidosis
Partial: nivo-
lumab
monotherapy
was main-
tained
Stable disease without treat-
ment
Case
report
Reddy 2017
[58]
Ipilimumab plus
pembrolizumab (1
case)
Ipilimumab plus
nivolumab (1 case)
Metastatic
melanoma
Mediastinal and hilar lym-
phadenopathy and multiple
subcentimeter pulmonary
nodules in the bilateral upper
and lower lobes of the lungs
and skin lesion consistent
with sarcoidosis (1 case)
Mediastinal and hilar lymphade-
nopathy as well as mild nonspe-
cific nodularity in the right lower
lung and several subcutaneous
nodules that on biopsy showed a
granulomatous infiltrate within
the dermis and subcutaneous fat,
composed of well-formed
noncaseating granulomas with
multinucleated giant cells and
scattered lymphocytes. The final
diagnosis was sarcoidosis.
Yes (tempo-
rary with-
drawal)
Improvement with corticoster-
oids
Case
report
(Table 2) Contd…

Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint Inhibitors Current Drug Safety, 2018, Vol. 13, No. 3 7
Reference
Drug
Indication
Clinical Presentation
Withdrawal
of Drug
Treatment and outcome
Type of
Study
Lomax 2017
[57]
One case: Nivolu-
mab vs ipilimumab
Two cases: Pem-
brolizumab
Melanoma
Hilar and mediastinal ade-
nopathy and subcutaneous
nodules.
Diagnosis of sarcoidosis.
Yes (2 cases)
No (1 case)
No treatment (1 case) with
improvement
Corticosteroid therapy (2
cases) with improvement
Case
series
Zhang 2017
[56]
Nivolumab
Metastatic clear
cell renal carci-
noma
PET CT showed asympto-
matic bilateral mediastinal
and hilar lymphadenopathy.
Histopathology examination
revealed epithelioid granu-
lomas consistent with sar-
coidosis.
Not reported
Not reported
Case
report
Nakamagoe
2017 [49]
Nivolumab
Metastatic
melanoma
After 2 months, generalized
joint pain and weakness of
proximal muscles developed.
A diagnosis of polymyalgia
rheumatica was made.
Yes
Oral corticosteroid with
marked improvement with 24
hours and resolution of symp-
toms after 3 weeks.
Case
report
Tan 2017
[23]
Nivolumab
NSCLC
Immune-mediated myasthe-
nia gravis and myositis with
respiratory failure
No
Treatment with pyridostig-
mine, methylprednisolone (1 g
daily for 3 days), and immune
globulin (400 mg/kg/d for 5
days) with benefit
Case
report
Aya 2017
[42]
Pembrolizumab
Melanoma
Bilateral paresthesia in glove
and stocking distribution that
rapidly progressed with
severe weakness in her lower
limbs and diplopia (6th
cranial nerve palsy). Elec-
tromyography and nerve
conduction study showed a
moderate sensory peripheral
polyneuropathy.
Muscle and nerve biopsy
showed some angulated
atrophic muscle fibers and
perivascular infiltration of
mononuclear cells of small
endoneural vessels.
Yes
Pulses of corticosteroids, then
oral prednisone at 1 mg/kg
slowly tapered over 6 months
until 5 mg/day and then dis-
continued.
Complete functional recovery
over 6 months.
Case
report
Nandavaram
2017 [52]
Ipilimumab
Melanoma
Asymptomatic mediastinal
and hilar nodes bilaterally.
Histopathological examina-
tion revealed non-caseating
granulomatous lymphadeni-
tis characterized by aggre-
gates of epithelioid macro-
phages consistent with sar-
coidosis.
Yes
Improvement without further
treatment
Case
report
Kim 2017 []
Ipilimumab
Pembrolizumab
Metastatic
melanoma
Three cases of symmetric
polyarthritis involving small
joints that developed be-
tween the second and the
fourth infusion of the drug
No
All patients received corticos-
teroids and IL-6 receptor an-
tagonist (tocilizumab) with
articular response.
One patient discontinued
tocilizumab because of adrenal
insufficiency.
Case
series
Shao 2018
[38]
Pembrolizumab
Melanoma
Erythematous and non-
pruritic eruption of edema-
tous papules coalescing into
plaques on his back, chest,
lateral arms, thighs, and
abdomen.
Histological findings of
papules were interpreted as a
lupus-like medication reac-
tion.
Yes
Within one month, the rash
completely resolved without
use of topical steroids or other
topical medications.
Case
report
(Table 2) Contd…

8 Current Drug Safety, 2018, Vol. 13, No. 3 Benfaremo et al.
Reference
Drug
Indication
Clinical Presentation
Withdrawal
of Drug
Treatment and outcome
Type of
Study
Yatim 2018
[55]
Pembrolizumab
Melanoma
PET/CT-scan found at the
thoracic level bilateral new
multiple pleural and paren-
chymal hypermetabolic
lesions and hypermetabolic
enlarged bilateral hilar
lymph nodes and multiple
subcutaneous highly meta-
bolic active nodules ap-
peared on the left flank, right
leg, hypogastric region and
on a laparotomy surgical
scar. Bilateral anterior uvei-
tis was present. The patient
was diagnosed with sarcoi-
dosis.
No (after the
end of ther-
apy)
No treatment. Three months
later another PET/CT-scan
showed complete regression of
the hypermetabolic sarcoidosis
lesions.
Case
report
nivolumab in a few patients with advanced lung cancer [12,
13]. Some of the authors speculated that the induction of
psoriasis may correlate with the therapeutic activity of
nivolumab, since the occurrence of the psoriatic skin lesions
as well as joint symptoms temporally coincided with the
regression of lung cancer lesions [14]. In all the cases the
patients received corticosteroids and methotrexate with sig-
nificant benefit.
Pembrolizumab induced a recurring monoarthritis of both
knees in a woman with metastatic melanoma [15] but was also
responsible for the acute onset of polyarticular inflammatory
arthritis [16, 17]. In two of these patients, pembrolizumab
caused a severe polyarthritis after 14 and 11 months of ther-
apy, respectively. The first patient had tenosynovitis, synovi-
tis, bone marrow edema, and myositis, whereas the second
patient had predominantly synovitis and tenosynovitis. Remis-
sion of symptoms was obtained with bisphosphonates and
salazopyrin.
In a patient treated with ipilimumab for metastatic mela-
noma, acute monoarthritis of the knee with a large effusion
developed two months after completing ICI therapy and re-
curred eight months after treatment discontinuation. At both
occasions, the patient was given systemic corticosteroid with
a moderate benefit. The same patient had pericardial tampo-
nade and bilateral pleural effusions that improved with ster-
oid treatment [18].
A patient treated with nivolumab developed autoimmune
uveitis and Jaccoud’s arthropathy. The drug was discontin-
ued and uveitis was treated with intraocular steroids with
success, but the treatment strategy of the joint disease was
not reported [19].
Given the extreme variability of clinical presentations
and patterns of inflammatory arthritis in patients receiving
ICIs, some authors speculated that one group of patients may
develop non-specific arthritis due to the up-regulation of the
immune system and another group may develop a more spe-
cific form of arthritis, like RA or PsA, based on a genetic or
environmental predisposition [20].
3.2. Myalgia and Inflammatory Myositis
Myalgia was the second most commonly reported muscu-
loskeletal complaint in clinical trials [2-21% of trial partici-
pants) [1]. Nevertheless, several cases of true inflammatory
myositis have been described, especially with anti-PD1
treatment.
Treatment with nivolumab has been associated with the
development of myositis and myocarditis, even of the severe
entity, in a number of case reports and case series, especially
in Eastern Asia [21-25]. A patient treated with nivolumab for
advanced colon cancer received a diagnosis of myasthenia
gravis and myositis for bilateral ptosis, limb and neck weak-
ness, dyspnea and myalgia developing in two weeks. The
patient improved after drug withdrawal and prednisolone and
intravenous immunoglobulin administration. Another patient
developing severe muscle pain, weakness and shortness of
breath after the second dose of nivolumab rapidly improved
with drug discontinuation and prednisone administration. In
the largest retrospective study, among 12 patients with myas-
thenia gravis, 4 had concomitant myositis and 3 had myo-
carditis, with 1 of these patients having both.
In these cases of nivolumab-induced myositis, drug with-
drawal and corticosteroid with or without further immuno-
suppressive therapy were usually effective. Respiratory mus-
cle involvement appeared to be the most fearful complication
of nivolumab-induced myositis, causing the death of the pa-
tient in one case, even though in another case an improve-
ment was seen after drug discontinuation and corticosteroid
administration [26, 27].
Though IRAEs usually present after some months after
drug inception, the onset of severe myositis and myocarditis
has been described even after only one dose of nivolumab.
This patient improved with corticosteroid treatment, intrave-
nous immunoglobulin and plasma exchange after drug dis-
continuation [28].
Finally, nivolumab was also found to induce an autoanti-
body-positive myositis and myocarditis complicated with a
new-onset third-degree atrioventricular block [29].
Ipilimumab-induced dermatomyositis has been described
in a patient with metastatic melanoma. The clinical picture
included erythematosus rash with Gottron’s papules and
proximal muscle weakness. The drug was discontinued and
prednisone 1 mg/kg was started, with minimal clinical re-
sponse [30].

Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint Inhibitors Current Drug Safety, 2018, Vol. 13, No. 3 9
Another patient developed severe autoimmune myositis
following ipilimumab administration, presenting with
dysphagia, dysarthria, diffuse muscle weakness and CK ele-
vation. She was treated with intravenous immunoglobulin
(400/mg/kg) for ten days and high dose methylprednisolone
followed by oral prednisone (1mg/kg daily), with significant
benefit and no cancer recurrence [31].
Ipilimumab has also been associated with the develop-
ment of severe ocular myositis in two patients with metas-
tatic melanoma. In both cases, the condition improved with
the administration of methylprednisolone, mycophenolate
mofetil and, in one patient, intravenous immunoglobulin
[32].
A case of pembrolizumab-induced severe bulbar myopa-
thy and respiratory failure with necrotizing myositis of the
diaphragm was described in a 78-year-old man with metas-
tatic melanoma. This patient developed progressive dyspnea,
bilateral ptosis, neck and limb muscle weakness and
dysphagia. Prednisone and plasma exchange did not improve
his condition and he died for respiratory failure. Interest-
ingly, the autopsy revealed a diffuse necrotic myositis of the
diaphragm and a lymphohistiocytic myocarditis [33].
Other authors reported a case of pembrolizumab-induced
myositis, with the muscle biopsy showing multifocal necro-
sis with adjacent endomysial CD8+ T cell predominant infil-
trates, without inclusion bodies. Pembrolizumab was discon-
tinued and the patient was treated first with corticosteroids
and then with plasma exchange due to intolerance. The pa-
tient experienced a near complete clinical recovery after one
month [34]. Among rarer IRAEs, eosinophilic fasciitis has
been reported following pembrolizumab treatment in a
patient with metastatic melanoma [35].
Myositis was also described in a patient receiving dual
treatment with tremelimumab and durvalumab for non-small
cell lung cancer. The complication arose in about one month
and corticosteroid treatment provided moderate benefit [10].
3.3. SLE and Sicca Syndrome
Systemic Lupus Erythematosus (SLE] is an autoimmune
disease that may involve several organ systems, including
skin, joints, heart, lungs, nervous system and kidneys. In our
literature review, SLE was rarely found to be associated with
ICIs treatment, particularly with ipilimumab.
The first case of lupus-nephritis induced by ipilimumab
was described in 2009 in a patient treated for metastatic
melanoma. The kidney biopsy showed immunoglobulin and
complement complexes in the mesangial space and the se-
rum anti-double-stranded-DNA antibody test was positive,
before treatment with prednisone and ipilimumab discon-
tinuation that eventually improved the nephritis [36].
In a large registry, induction of SLE was reported in only
one patient among 524 that experienced an IRAE while on
ipilimumab treatment [37].
A lupus-like cutaneous reaction in the setting of pem-
brolizumab therapy for metastatic melanoma was described
[38], as well as in a patient receiving nivolumab for metas-
tatic lung cancer [39]. In the latter case, erythematous and
non-pruritic papules developed, with histological findings
suggestive of a lupus-like drug reaction. The skin rash im-
proved after one month without further treatment other than
nivolumab discontinuation.
Dry eyes and dry mouth have been reported as mild AEs
in some ICIs clinical trials, with an incidence ranging from
3-24% [1, 40]. In a large French registry reporting only
grade ≥2 IRAEs occurring in ICI-treated patients, the preva-
lence of true Sjogren’s syndrome was 0.3% [4].
Four out of five patients with sicca syndrome described
in a retrospective study had dry mouth without eye involve-
ment following nivolumab, atezolizumab or combination
treatment. ANA was positive in two of the five patients, and
SSA was positive in one [10].
In another case series, four patients presented sicca
symptoms with severe salivary hypofunction developing on
nivolumab, ipilimumab or combination therapy. On ultra-
sound imaging, one patient had discrete hypoechoic foci
occupying more than 50% of her parotid and submandibular
glands, as it is usually seen in Sjogren’s syndrome. One pa-
tient had also pneumonitis and another had interstitial ne-
phritis and colitis. Three of four sicca patients had positive
ANA; one patient had low titre La/SSB antibodies; none of
the patients had Ro/SSA antibodies [7].
A patient with metastatic parotid carcinoma developed a
sicca syndrome associated with a skin rash on both hands
that was identified as Gourgerot-Sjogren like syndrome [41].
3.4. Vasculitis
Isolated cases of vasculitis have been reported following
the administration of ICIs (ipilimumab in 3 cases, pembroli-
zumab in 2 cases) in a large biologic drug registry [37]. Most
cases of vasculitis induced by biologics present with isolated
cutaneous or neurological (peripheral neuropathy) involve-
ment, and systemic vasculitis appear to be rare. Only two
clinical trials of ICIs reported the onset of vasculitis among
patients receiving these compounds and in one case a giant
cell arteritis was diagnosed [1].
Among isolated vasculitis, cases of peripheral neuropathy
due to histologically proven small vessel vasculitis have
been reported. One was induced by pembrolizumab in a 53-
year-old woman with seropositive RA and metastatic mela-
noma. She was treated with high-dose corticosteroids, fol-
lowed by a gradual tapering, with a complete functional re-
covery over 6-months and minimal residual paraesthesia
[42].
Even though not all cases of asymmetric polyradicu-
loneuropathy described in patients on ICIs are secondary to
vasculitis, an aspecific microvasculopathy underlying the
pathogenesis of the nerve damage has been occasionally de-
scribed [43], as well as an acral vascular syndrome present-
ing with progressive erythema, paresthesia and fingertip
pain, but without histological evidence of vasculitis [44].
Another isolated form of vasculitis involved the uterine
circulation, with lymphocytic infiltration and focal fibrin
deposition. This patient was receiving ipilimumab for metas-
tatic melanoma and presented with an asymptomatic uterine
mass [45].

10 Current Drug Safety, 2018, Vol. 13, No. 3 Benfaremo et al.
Table 3. Published observational studies reporting the incidence of musculoskeletal IRAEs in ICI-treated patients.
Reference
Drugs
Indications
Clinical Presentation
Withdrawal
of Drugs
Treatment and Outcome
Type of
Study
Smith
2017 [8]
Nivolumab
Pembrolizumab
Ipilizumab
Tremelimumab
Melanoma
NSCLC
Anal cancer
Cervical cancer
Merkel cell
carcinoma
Renal cancer
Ten patients, seven treated
with combination therapy and
3 in monotherapy.
4 cases of polyarthritis
4 cases of oligoarthritis
2 cases of tenosynovitis
of which:
6 were ANA positive
2 were anti-CCP positive
No (except
one case)
All patients were treated with
systemic corticosteroids for
their arthritis or tenosynovitis.
Three patients were started on
DMARDs and one patient
required infliximab to allow
tapering of steroids.
Six of the patients had
resolution of musculoskeletal
symptoms and discontinued
treatment an average of 9.2
months after the last dose of
immunotherapy.
Four patients continued to be
treated for their arthritis at the
time of last rheumatology
follow up.
Retrospec-
tive study
Le Burel
2017 [4]
Nivolumab
Nivolumab + Ipili-
mumab
Pembrolizumab
Atezolimumab
Durvalumab
Melanoma
Colon and gas-
tric adenocarci-
noma
Renal cell can-
cer
Lung cancer
Cervical and
urothelial carci-
noma
Brain glioblas-
toma
Out of 908 patients, 30 pa-
tients experienced systemic
immune-related adverse
events: 4 cases of immune
cytopenia (including 3 cases of
immune thrombocytopenia)
10 with connective tissue
diseases (4 cases of Sjogren
syndrome, 3 cases of rheuma-
toid arthritis, and 3 cases of
myositis), 14 with other in-
flammatory arthritic condi-
tions (including 4 cases of
polymyalgia rheumatica, 3
cases of psoriatic arthritis, and
7 cases of seronegative pol-
yarthritis), and 2 with sarcoi-
dosis.
Yes (in 12
cases)
25 patients (83%) received
corticosteroids, and five
patients (17%) received im-
munomodulatory agents
(corticosteroid + MTX or iv
immunoglobulin).
Once the IRAEs had been
detected, the symptoms dis-
appeared in 13 patients
(43%), decreased in 15 pa-
tients (50%), remained stable
in 2 patients (7%) and wors-
ened in none.
French
Registry
Retrospec-
tive Study
Pérez-De-
Lis 2017
[37]
Ipilimumab (524)
Tremelimumab (2)
Nivolumab (225)
Pembrolizumab
(162)
Not declared
Lupus in 1 patient treated with
ipilimumab.
Vasculitis in 3 patients treated
with ipilimumab; 2 patients
treated with pembrolizumab.
Sarcoidosis in 13 patients treated
with ipilimumab; 3 patients treated
with pembrolizumab; 4 patients
treated with nivolumab.
Rheumatoid arthritis in 6 patients.
Not declared
Not declared
Retrospecti
ve study
from BIO-
GEAS
Registry
Suzuki
2017 [22]
Nivolumab
Ipilimumab
Melanoma
Lung cancer
Colon cancer
Twelve myasthenia gravis
cases (0.12%) among 9869
patients with cancer who had
been treated with nivolumab,
but none among 408 patients
treated with ipilimumab
Yes
Immunosuppressive therapy:
high dose corticosteroid
therapy, iv immunoglobulin,
and plasma exchange
Retrospec-
tive study
Belkhir
2017 [11]
Nivolumab
Pembrolizumab
Anti-PDL1
Melanoma
Endometrial
and vagina
adenocarcinoma
Lung
adenocarcinoma
Gastric and
colon carci-
noma
10 patients developed:
rheumatoid arthritis in 6 cases;
polymyalgia rheumatica in 4
cases.
No (except
one case)
Patients with rheumatoid
arthritis: 3 treated with
DMARDS (with good re-
sponse) and 3 with steroid or
NSAIDS (with resolution of
symptoms).
Patients with polymyalgia
rheumatica were treated with
steroid therapy with resolu-
tion of symptoms.
Retrospec-
tive study
(Table 3) Contd…

Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint Inhibitors Current Drug Safety, 2018, Vol. 13, No. 3 11
Reference
Drugs
Indications
Clinical Presentation
Withdrawal
of Drugs
Treatment and Outcome
Type of
Study
Calabrese
2017 [10]
Nivolumab+ ipili-
mumab (7)
Ipilimumab + pem-
brolizumab (1)
Nivolumab (5)
Atezolimumab (1)
Durvalumab (1)
Tremelimumab (1)
Melanoma
NSCLC
Renal cell car-
cinoma
15 patients developed:
sicca syndrome in 5 cases,
arthritis in 7 cases,
myositis in 1 case and
polymyalgia rheumatica in 3
cases.
Lab tests showed:
ANA positivity in 4 cases
FR positivity in 11 cases
Anti-SSA positivity in 1 case
Anti-dsDNA positivity in 1 case
Yes (in 12/15
patients)
Corticosteroid therapy
Infliximab in 2 cases
Etanercept in 2 cases
Adalimumab in 1 case
Methotrexate in 2 cases
These treatments led to sig-
nificant improvement in 6
patients, moderate improve-
ment in 5 patients and only
minimal improvement in 2.
Single
center
retrospec-
tive study
Cappelli
2017 [7]
Nivolumab + ipili-
mumab (8)
Nivolumab or ipili-
mumab (5)
Melanoma
NSCLC
Renal cell car-
cinoma
13 patients developed:
sicca syndrome in 4 cases;
arthritis in 9 cases.
ANA were positive in 5 out of
13 patients.
Yes
These therapies were per-
formed:
Corticosteroid therapy
Infliximab in 2 cases;
Etanercept in 1 case;
Adalimumab in 3 cases;
NSAIDS as needed
Outcome:
stable disease in 5 cases;
partial response in 6 cases;
progressive disease in 1 case;
non measureable in 1 case.
Retrospec-
tive study
Tetzlaff
2018 [53]
Ipilimumab (14)
Nivolumab (3)
Pembrolizumab (5)
Ipilimumab +
nivolumab (3)
Anti-PD-L1 (1)
Melanoma
Prostate adeno-
carcinoma
NSCLC
Hodgkin lym-
phoma
Ovarian cancer
Colorectal
carcinoma
A review of 26 patients (in-
cluding the 3 from this report)
who developed granuloma-
tous/sarcoid-like lesions are
described.
Yes (in 10/26
patients)
Systemic steroids in 12 pa-
tients (44%)
Outcome of sarcoidosis:
Resolution in 14 cases;
Improvement in 9 cases;
Stable in 1 case;
Not reported in 2 cases.
Disease response to ICI:
Stable in 5 cases;
Remission in 10 cases;
Progression in 6 cases;
Not reported in 5 cases.
Retrospec-
tive study
and litera-
ture review
Kostine
2017 []
Nivolumab
Pembrolizumab
Atezolizumab
Avelumab
Anti-PD1+anti-
CTLA4 (5)
Melanoma
Merkel carci-
noma
NSCLC
Renal cancer
35 (6.6%) out of 524 ICI-
treated patients were referred
to the Rheumatology Clinic.
Inflammatory arthritis oc-
curred in 20 cases (3.8%), with
7 cases mimicking rheumatoid
arthritis, 11 cases PMR, 2
cases psoriatic arthritis.
No (except
one case)
All patients required corticos-
teroids (max 30 mg/day),
leading to clinical improve-
ment or remission. Two pa-
tients required DMARDs
(MTX).
After 6 months, 2 patients
were able to discontinue
corticosteroids.
Single
center
prospective
observa-
tional study
Lidar 2018
[5]
Nivolumab (4)
Ipilimumab (1)
Ipilimumab +
nivolumab (1)
Pembrolizumab (8)
Melanoma
Endometrial
cancer
Sinonasal can-
cer
Hodgkin’s
lymphoma
Breast cancer
Polyarthritis in 10 cases
Oligoarthritis in 1 case
Monoarthritis in 1 case
Sarcoidosis in 1 case
Eosinophilic fasciitis in 1 case
No (3 cases)
Withheld (3
cases)
Off therapy
(8 cases)
NSAIDS (11 cases)
Steroid therapy (14 cases)
MTX (8 cases)
Outcomes:
Low disease activity (9 cases)
Moderate (1 case)
Remission (3 case)
Unknown (1 case)
Single
center
registry
(Table 3) Contd….

12 Current Drug Safety, 2018, Vol. 13, No. 3 Benfaremo et al.
Reference
Drugs
Indications
Clinical Presentation
Withdrawal
of Drugs
Treatment and Outcome
Type of
Study
Buder-
Bakhaya
2018 [9]
Pembrolizumab or
Nivolumab ±Ipili-
mumab
Melanoma
195 patients were included
26 patients developed arthral-
gia (mainly large joints).
Of these, 2 were FR ± anti-
CCP positive, 10 developed
arthritis and 5 progressive
osteoarthritis. In 11 patients,
arthralgia could not be speci-
fied.
Yes, in 7.7%
of patients
The majority of patients
(73.1%) received NSAIDs
with benefit.
5 patients (19.2%) further
needed low-dose predniso-
lone.
A patient with RA addition-
ally received sulfasalazine
and hydroxychloroquine.
Outcomes: 5 patients were
able to stop
NSAIDs ± low dose predni-
solone completely, 6 patients
still require NSAIDs ± low
dose steroids.
Retrospec-
tive study
3.5. Polymyalgia Rheumatica
Polymyalgia rheumatica (PMR) almost invariably re-
spond to systemic corticosteroids, even if occurring in pa-
tients receiving ICIs.
Some authors reported the development of PMR in two
patients with metastatic melanoma being treated with
ipilimumab. In one case, a biopsy of the right temporal artery
was performed, showing active arteritis, intimal prolifera-
tion, and disruption of the internal elastic lamina. Both pa-
tients had a brisk response to corticosteroids, with improve-
ment in symptoms and indices of inflammation [46].
In a French retrospective study, PMR was diagnosed in
four patients treated with pembrolizumab and nivolumab ±
ipilimumab, and all patients responded to treatment with
corticosteroids [11].
Another French group reported the development of PMR
in a patient with non–small cell lung cancer after 13 cycles
of nivolumab, with a good response to corticosteroid therapy
[47].
In a case series from the Cleveland Clinic, 3 out of 15 pa-
tients evaluated at the Rheumatology Unit had clinical char-
acteristics compatible with PMR including pain and stiffness
involving the shoulders, hips and neck, with associated se-
vere morning stiffness. None of them had symptoms con-
cerning for giant cell arteritis [10]. Other patients receiving
nivolumab and pembrolizumab developed typical features of
PMR that responded well to corticosteroid treatment [48,
49].
Finally, other authors described a variant of PMR, called
remitting seronegative symmetrical synovitis with pitting
edema syndrome, to be induced by nivolumab in an 80-year-
old man with metastatic melanoma [50].
3.6. Sarcoidosis
Several cases of new-onset sarcoidosis were reported in
patients being treated with ICIs for metastatic melanoma,
including those from a large biologic drugs registry in which
sarcoidosis complicated treatment with ipilimumab (13
cases), nivolumab (4 cases) and pembrolizumab (3 cases)
[37]. In another retrospective study, 5% out of 147 patients
undergoing ipilimumab treatment for melanoma developed
sarcoid-like lymphadenopathy after a median interval time of
3.2 months from the start of ipilimumab. The majority of
patients had mediastinal and hilar lymphadenopathy except
for one patient who had a coexistent intra-abdominal lym-
phadenopathy [51]. Conversely, in a single center registry,
the prevalence of sarcoidosis in patients receiving ICIs was
very low (0.2%) [4].
Notably, some authors observed that in a patient with
ICI-induced sarcoidosis the suspension of the drug alone
achieved the complete resolution of the metabolically active
lymph nodes without the need of additional steroid treatment
[52]. Recently, some authors reviewed the cases of 26 pa-
tients developing granulomatous/sarcoid-like lesions associ-
ated with ICIs. Treatment was discontinued in 38% of pa-
tients and only 44% of the patients were treated with sys-
temic steroids. Almost all of the patients demonstrated either
resolution or improvement of granulomatous/sarcoid-like
lesions irrespective of medical intervention [53].
In other three cases of ICI-related sarcoidosis-like lym-
phadenopathy, two occurring during adjuvant ipilimumab for
stage III surgically resected melanoma and one during pem-
brolizumab for metastatic melanoma, histopathological ex-
amination revealed non-caseating granulomas. Two of the
patients improved with drug discontinuation alone without
the need of corticosteroid treatment [54]. Another melanoma
patient developed sarcoidosis with bilateral anterior uveitis
[55].
Several other reports confirm that sarcoid-like reactions
induced by ICIs are common and often do not require other
treatment than drug discontinuation [56-58], though in some
cases ICI-treatment may be continued without a significant
impact on the patient’s clinical conditions [59, 60].
4. DISCUSSION
Our review suggests that, though rare, musculoskeletal
and rheumatic diseases appear to be associated with ICI-
treatment and demand a prompt recognition to avoid further
impact on morbidity and mortality for cancer patients. The

Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint Inhibitors Current Drug Safety, 2018, Vol. 13, No. 3 13
approach to the management of these patients may require a
tight cooperation between the oncologist and the rheuma-
tologist, that should balance risks and benefits of continuing
or withdrawing anti-tumor treatment and evaluate the need
for a systemic anti-inflammatory or immunomodulating
therapy.
It is difficult to estimate the true incidence and preva-
lence of musculoskeletal AEs in patients receiving ICIs,
given that most of the observational studies are retrospective
and likely biased. Overall, rheumatic complications appear to
involve no more than 10% of the ICIs-treated patients. Most
of the AEs are mild-to-moderate, except for the more severe
forms of myositis that may lead to death due to respiratory
involvement.
There are different treatment options for musculoskeletal
AEs that vary with the extent and the severity of the disease.
Inflammatory arthritis may respond to relatively short
courses of NSAIDs or glucocorticoids, but some of the pa-
tients may need DMARDs and/or biologic treatment due to
refractoriness or disease recurrence upon treatment tapering
or discontinuation [61, 62]. PMR usually responds to gluco-
corticoid treatment that may be tapered as it is usually done
in non-cancer patients. Severe forms of myositis may require
intravenous immunoglobulin and plasma exchange in addi-
tion to corticosteroid treatment. Sarcoidosis and sarcoid-like
reactions are usually managed with treatment discontinuation
and glucocorticoids.
Even if mild AEs may be managed with drug discon-
tinuation alone, continuing ICI treatment while prescribing
other drugs is possible and appears to be safe. Rather, pa-
tients that experience rheumatic AEs while on ICIs showed a
higher tumor response rate compared to the other patients
[61]. There are similar studies reporting the positive associa-
tion of the tumor response rate with the incidence of differ-
ent IRAEs in cancer patients [63].
Since most of the clinical trials of ICIs excluded patients
with preexisting autoimmune disease, little is known about
how these drugs may affect this kind of patients. Available
data on immunotherapy in melanoma patients with preexist-
ing autoimmune diseases are mostly retrospective. Among
30 patients with a variety of autoimmune diseases (from RA
to inflammatory bowel diseases) treated with ipilimumab for
melanoma, only 8 (27%) had an exacerbation of their auto-
immune disease; all flares were medically treated and were
observed within the first 6 weeks after the beginning of ther-
apy [64]. A similar retrospective study analyzed melanoma
patients who were treated with pembrolizumab or nivolumab
after previous failed or intolerant treatment with ipilimumab.
Twenty (38%) patients developed a flare of their autoim-
mune disorder requiring immunosuppression, including
seven out of 13 patients with RA. The majority of the flares
were relatively mild and only two patients required discon-
tinuation of anti-PD1 treatment [65].
As far as we know, ICIs administration in a patient with a
preexisting autoimmune condition is safe enough to warrant
treatment. Rheumatic or autoimmune disease flares can usu-
ally be managed only with steroids, with or without discon-
tinuation of the treatment drug, though rarely they may re-
quire immunosuppressive treatment [66, 67].
CONCLUSION
Immune checkpoint inhibitor treatment has been a break-
through option in several metastatic cancers. As their use is
increasing, the evidence is gathering that they may induce
rheumatic and musculoskeletal conditions or disease flares in
patients with a preexisting autoimmune disorder. A rapid
recognition and a prompt treatment, possibly with a rheuma-
tologist referral, may help to improve the quality of life of
these complicated cancer patients.
LIST OF ABBREVIATIONS
ICIs = Immune Checkpoint Inhibitors
CTLA-4 = Cytotoxic T-lymphocyte Associated Pro-
tein-4
PD-1 = Programmed Cell Death Protein-1
PDL-1 = Programmed Death Ligand-1
NSCLC = Non-small Cell Lung Cancer
IRAEs = Immune-related Adverse Events
NSAIDs = Non-steroidal Anti-inflammatory Drugs
RA = Rheumatoid Arthritis
DMARDs = Disease-modifying Anti-rheumatic Drugs
PsA = Psoriatic Arthritis
SLE = Systemic Lupus Erythematosus
PMR = Polymyalgia Rheumatica.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
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