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. Author manuscript; available in PMC: 2018 Nov 1.
Published in final edited form as: Arthritis Care Res (Hoboken). 2017 Sep 21;69(11):1751–1763. doi: 10.1002/acr.23177

Table 1.

Characteristics of clinical trials and incidence of reported musculoskeletal and rheumatic IRAE.

Author,
year		 Trial
phase		 Indication Number
exposed		 Drug/s Dose Arthralgia Arthritis Dry eyes Dry
mouth		 Myalgia Muscle
weakness		 Vasculitis Other
Anti-CTLA-4
Bashey
2009		 1 Relapse after
hematopoetic
stem cell
transplant		 29 Ipilimumab Dose
escalation		 NR 2 (7%) NR NR NR NR NR “bone pain”: 1
(3%); “muscle
cramps”: 1
(3%)
Downey
2007		 2 Metasatic
melanoma		 139 Ipilimumab (+/−
peptide vaccine)		 3 mg/kg in
one group,
dose
escalation
in other		 10/73 (13.7%) with
peptide; 4/66
(without peptide		 NR NR NR NR NR NR NR
Hersh
2014		 2 Advanced
melanoma		 72 Ipilimumab +/−
dacarbazine		 3 mg/kg NR NR NR NR NR NR 1/35 (3%) in
ipi +
dacarbazine		 NR
Hodi 2014
(1) Cancer
Immunol
Res		 1 Metasatic
melanoma		 46 Ipilimumab +/−
bevacizumab		 3 mg/kg or
10 mg/kg		 13 (28%)
“joint pain”		 NR 2 (4%) NR 6 (13%)
“muscle
pain”		 NR 1 (2%) with
GCA		 “joint
function”
problems: 1
(2%)
Hodi 2014
(2) JAMA* 		2 Metasatic
melanoma		 245 Ipilimumab +/−
sargramostim		 10 mg/kg 3/118 (3%) in
combination;
1/120 (1%) in ipi
alone		 1/118 (1%) in
combination		 NR NR 2/118 (2%)
combinatio
n;
4/120 (3%)
ipi alone		 1/118
(1%)
combinati
on;
1/120
(1%) ipi
alone		 NR “autoimmune
disease”:
4/120 (3%) in
Ipi alone
Kwon
2014		 3 Metastatic
prostate cancer		 399 Ipilimumab +
radiation		 10 mg/kg 44/393 (11%) NR NR NR NR NR NR MSK pain: 32
(8%)
Le
2013		 1 Pancreatic cancer 30 Ipilimumab +/−
GVAX		 10 mg/kg Ipi + GVAX: 1/15
(75)		 NR Ipi: 1/15
(7%)		 NR NR NR NR NR
Lynch
2012		 3 NSCLC 138 Ipilimumab +
carboplatin,
paclitaxel
(concurrent or
phased)		 10 mg/kg Concurrent: 16/71,
(22.5%) phased:
12/67 (18%)		 NR NR NR NR NR NR NR
Merchant
2015		 1 Advanced solid
tumors
(pediatric)		 33 Ipilimumab Dose
escalation		 NR NR NR NR 1/33 (3%) NR NR NR
Prieto
2012* 		1/2 Metastatic
melanoma		 177 Ipi + peptide
vaccine; Ipi + IL-
2, Ipi dose
escalation +
peptide vaccine		 various NR 1/36 (3%) in
Ipi + IL-2; 1/85
(1%) in Ipi DE
+ peptide
vaccine		 NR NR NR NR NR NR
Reck 2013 2 Extensive disease
small cell lung CA		 85 Ipilimumab +
chemotherapy,
concurrent or
phased		 10 mg/kg 24% in concurrent;
46% in phased		 NR NR NR NR NR NR NR
Robert
2011		 Metastatic
melanoma		 247 Ipilimumab +
dacarbazine		 NR NR NR NR NR NR NR NR Back pain
28/247
(11.3%)
Sarnaik
2010		 2 Stage III/IV
melanoma		 75 Ipilimumab +
peptide vaccine		 3 mg/kg,
10 mg/kg		 Arthritis/arthralgia
17/75 (23%)		 2/75
(3%)		 NR Myositis/
myalgia
16/75
(21%)		 NR NR NR
Weber
2008* 		1/2 Metastatic
melanoma		 88 Ipilimumab Various 1/88 (1%) NR NR NR NR NR NR Pain in
extremity:
1/88 (1%)
Yamazaki
2015		 2 Previously
untreated
advanced
melanoma		 15 Ipilimumab +
dacarbazine		 10 mg/kg NR NR NR NR NR NR NR Back pain:
4/15 (27%)
Yang 2007 2 Metastatic RCC 47 Ipilimumab Various 1/47 (2%) NR NR NR NR NR NR NR
Calabro
2014		 2 Malignant
mesothelioma		 29 Tremelimumab Dose
escalation		 4 (14%) NR NR NR NR NR NR NR
Ralph
2010		 2 Advanced gastric
and esophageal
adenocarcinoma		 18 Tremelimumab 15 mg/kg 3/18 (17%) NR NR NR NR NR NR NR
Sangro
2013		 2 HCC and hepatitis
C		 21 Tremelimumab 15 mg/kg NR 1/21 (5%) NR NR NR NR NR NR
Anti-CTLA-4 vs. Anti-PD-1
Robert
2015 (2)
Pembro		 3 Advanced
melanoma		 811 Ipilimumab vs.
Pembrolizumab		 Pembro:
10 mg.kg
Ipi: 3
mg/kg		 26/278 (9%) in
q2week Pembro,
32/277 (12%) in
q3week Pembro,
13/256 (5%) in Ipi		 5/278 (2%) in
q2week,
1/277 (.450 in
q2week		 MR 20/278
(8%) in
q2week
pembro,
11/277
(4%) in
q3week
pembro,
1/2576
(.4%) in
ipi		 19/278
(7%) in
q2week,
6/277 (2%)
in q3week,
2/256 (2%)
in ipi		 NR NR Myositis:
2/277 (1%) in
q3week, 1/256
(0.5%) in Ipi

MSK stiffness:
3/278 (1%) in
q2week, 2/277
(1%) in
q3week
Anti-PD-1
Borghaei
2015		 3 NSLC 287 Nivolumab 3 mg/kg 46 (16%) NR NR NR 18 (6%) NR NR MSK pain: 39
(14%)
Brahmer
2010		 1 Refractory solid
tumors		 39 Nivolumab Dose
escalation		 2 (5%) NR NR NR NR NR NR MSK “events”:
6 (15%)
Brahmer
2015		 3 Squamous cell
lung CA		 135 Nivolumab 3 mg/kg 7 (5%) NR NR NR 2 (2%) NR NR NR
Gibney
2014		 1 Resected
metastatic
melanoma		 33 Nivolumab +
peptide vaccine		 Dose
escalation		 14 (43%) NR NR 8 (24%) 6 (18%) 4 (12%) NR “eye
disorders”
(e.g. dry eyes)
8 (24%)
Motzer
2015		 2 Metastatic renal
cell carcinoma		 168 Nivolumab 3 doses:
0.3 mg/kg,
2 mg/kg,
10 mg/kg		 1/60 (2%) in 0.3
mg/kg; 4/54 (7%) in
2 mg/kg; 8/54
(15%) in 10 mg/kg		 NR NR 0.3mg/kg
: 2/60
(3%) in, 2
mg/kg
3/54
(6%), 10
mg/kg
6/54
(11%)		 NR NR NR NR
Rizvi 2015 2 Squamous NSCLC 117 Nivolumab 3 mg/kg NR NR NR 7/117
(6%)		 6/117 (5%) NR NR NR
Robert
2015 (1)
Nivo		 3 Previously
untreated stage
III or IV
melanoma		 206 Nivolumab 3 mg/kg 12/206 (6%) NR NR NR 9/206 (4%) NR NR Pain in
extremity:
6/206 (3%)
Weber
2015		 3 Advanced
melanoma
progressed after
anti-CTLA-4		 268 Nivolumab 3 mg/kg 14/268 (5%) NR NR NR NR NR NR NR
Ribas
2015		 2 Ipilimumab
refractory
melanoma		 357 Pembrolizumab 2 mg/kg,
10 mg/kg		 13/178 (7%) in
lower; 11/179 (6%)
in higher		 NR NR NR 9/178 (5%)
in lower,
7/179 (4%)
in higher		 NR NR NR
Robert
2014* 		1 Metastatic
melnaoma		 173 Pembrolizumab 2 mg/kg,
10 mg/kg		 NR NR NR NR NR 1/89 (1%)
in 2 mg/kg
group		 NR MSK pain:
1/84 (1%) in 10
mg/kg group
Anti-PD-L1
Brahmer
2012		 1 Advanced
cancers		 207 MDX-1105 Dose
escalation		 15 (7%) NR NR NR NR NR NR Sarcoid: 1
(0.5%)
Combination Anti-CTLA-4 and Anti-PD-1
Larkin
2015		 3 State III or IV
melanoma		 945 Ipilimumab,
Nivolumab or
combination		 3 mg/kg
ipi, 3
mg/kg
nivo, 3
mg/kg ipi
+ 1 mg/kg
nvo		 Nivo: 24/313
(7.7%), Ipi 19/311
(6.1%), both
33/313 (10.5%)		 NR NR NR NR NR NR NR
Postow
2015		 1 Metastatic
melanoma		 142 Ipilimumab +/−
Nivoluamb		 Dose
escalation		 10/94 (10%) in
combined, 4/46
(9%) in Ipi		 NR NR NR 9/94 (10%)
combined;
6/46 (13%)
in Ipi		 NR NR NR

NR: Not reported, Ipi: Ipilimumab, DE: dose escalation, Pembro: Pembrolizumab, Nivo: Nivolumab

*

: Only reported grade 3 or higher adverse events.