Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.
OBJECTIVE
Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.


METHODS
We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours.


RESULTS
We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.


CONCLUSIONS
As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.
Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Laura C
LC
Cappelli
Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Anna Kristina
AK
Gutierrez
Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Alan N
AN
Baer
Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Jemima
J
Albayda
Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Rebecca L
RL
Manno
Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Uzma
U
Haque
Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
Evan J
EJ
Lipson
Department of Radiology, Johns Hopkins University, Baltimore, Maryland, USA.
Karen B
KB
Bleich
Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Ami A
AA
Shah
Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
Jarushka
J
Naidoo
Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
Julie R
JR
Brahmer
Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
Dung
D
Le
Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Clifton O
CO
Bingham
D000328:Adult; D000368:Aged; D000974:Antibodies, Antinuclear / Q000097:blood; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001168:Arthritis / Q000139:chemically induced* / Q000188:drug therapy; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D012859:Sjogren's Syndrome / Q000139:chemically induced* / Q000188:drug therapy; D013585:Synovitis / Q000139:chemically induced* / Q000188:drug therapy
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab; D000077594:Nivolumab
Arthritis; Autoimmune Diseases; Inflammation; Sjøgren's Syndrome