Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy

Background The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy. Subjects, Materials, and Methods Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or...

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Published in:	The oncologist (Dayton, Ohio) Ohio), 2019-09, Vol.24 (9), p.1259-1269
Main Authors:	Warner, Blake M., Baer, Alan N., Lipson, Evan J., Allen, Clint, Hinrichs, Christian, Rajan, Arun, Pelayo, Eileen, Beach, Margaret, Gulley, James L., Madan, Ravi A., Feliciano, Josephine, Grisius, Margaret, Long, Lauren, Powers, Astin, Kleiner, David E., Cappelli, Laura, Alevizos, Ilias
Format:	Article
Language:	eng
Subjects:	Adult Aged Antibodies, Monoclonal, Humanized - administration & dosage Antineoplastic Agents, Immunological - administration & dosage Antineoplastic Agents, Immunological - adverse effects Cohort Studies Female Humans Immune checkpoint inhibitor Immune‐related adverse event Immuno‐Oncology Male Middle Aged Neoplasms - drug therapy Neoplasms - immunology Neoplasms - pathology Nivolumab - administration & dosage Papillomavirus Infections - drug therapy Papillomavirus Infections - immunology Papillomavirus Infections - pathology Programmed cell death 1/programmed cell death ligand 1 pathway Respiratory Tract Infections - drug therapy Respiratory Tract Infections - immunology Respiratory Tract Infections - pathology Sialadenitis Sicca syndrome Sjogren's Syndrome - chemically induced Sjogren's Syndrome - immunology Sjogren's Syndrome - pathology Sjögren's syndrome Xerostomia
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Summary:	Background The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy. Subjects, Materials, and Methods Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB). Results Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD‐L1) and transforming growth factor ß (n = 1). Four had pre‐existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti‐Sjögren's Syndrome‐related Antigen A (Anti‐SSA) were both positive in two subjects. LSGB showed mild‐to‐severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD‐L1) were variably positive. In direct response to the advent of the sicca immune‐related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low. Conclusion ICI therapy is associated with an autoimmune‐induced sicca syndrome distinct from Sjögren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term. Implications for Practice Sicca syndrome has been reported as an immune‐related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild‐to‐severe sialaden
ISSN:	1083-7159 1549-490X