Sicca syndrome/Sjögren’s disease associated with cancer immunotherapy: a narrative review on clinical presentation, biomarkers, and management

ABSTRACT

Introduction

Almost one-quarter of immune checkpoint inhibitor (ICI) recipients experience sicca syndrome, while Sjögren’s disease (SjD) is estimated at 0.3–2.5%, possibly underreported.

Areas covered

This narrative review (Medline/Embase until January/31/2024) addresses the pathophysiology, incidence, demographic/clinical features, biomarkers, labial salivary gland biopsy (LSGB), fulfillment of the idiopathic SjD (iSjD) classificatory criteria, differential diagnosis, and management of sicca syndrome/SjD associated with ICIs.

Expert opinion

SjD associated with ICIs is underdiagnosed, since studies that performed the mandatory SjD investigation identified that 40–60% of patients with sicca syndrome associated with ICIs meet the iSjD classificatory criteria. LSGB played a fundamental role in recognizing these cases, as most of them had negative anti-Ro/SS-A antibody. Despite the finding of focal lymphocytic sialoadenitis in LSGB samples mimicking iSjD, immunohistochemical analysis provided novel evidence of a distinct pattern for sicca syndrome/SjD associated with ICIs compared to iSjD. The former has scarcity of B lymphocytes, which are a hallmark of iSjD. Additionally, patients with sicca syndrome/SjD associated with ICIs have demographical/clinical/serological and treatment response dissimilarities compared to iSjD. Dryness symptoms are more acute in the former than in iSjD, with predominance of xerostomia over xerophthalmia, and partial/complete response to glucocorticoids. Dryness symptoms in ICI-treated patients warrant prompt SjD investigation.

KEYWORDS:

• Cancer immunotherapy
• CAR-T cell
• checkpoint inhibitors
• dry eye
• sicca syndrome
• Sjogren disease
• Sjogren syndrome
• T-cell engager

Article highlights

• The early identification and management of the immune-related adverse events (irAEs) of cancer immunotherapy are current challenges for oncologists and physicians from different specialties.

• Sicca syndrome is a frequent irAE of cancer treatment with immune checkpoint inhibitors (ICIs) (up to 24%) and it can significantly impair the patient’s health-related quality of life.

• Sjögren’s disease (SjD) associated with ICIs (0.3–2.5%) is underdiagnosed and it can lead to severe systemic manifestations.

• Sicca syndrome symptoms in ICI-treated patients warrant prompt SjD investigation, including the labial salivary gland biopsy (LSGB).

• LSGB is relevant for diagnosis of SjD associated with ICIs, especially in patients with negative anti-Ro/SS-A antibody.

• SjD associated with ICIs is underdiagnosed, since studies that performed the mandatory SjD investigation identified that 40–60% of patients with sicca syndrome associated with ICIs meet the idiopathic SjD (iSjD) classificatory criteria.

• A strong association of SjD associated with ICIs with avelumab was observed. This condition is more often observed with combined ICI therapies than with monotherapies.

• Despite the presence of focal lymphocytic sialoadenitis mimicking iSjD in LSGB specimens from patients with sicca syndrome/SjD associated with ICIs, immunohistochemical analysis discloses scarcity of B cells in the former, in contrast to iSjD. This disparity suggests underlying pathophysiological distinctions between both clinical conditions.

• Sicca syndrome/SjD associated with ICIs has distinct clinical features from iSjD with more acute dryness symptoms, predominance of xerostomia over xerophthalmia, and partial/complete response of these symptoms to glucocorticoid treatment.

• The treatment of sicca syndrome/SjD associated with ICIs includes mainly hydration, topical symptomatic treatment, ocular glucocorticoid/cyclosporine, oral cholinergic agonists, discontinuation of ICI treatment and oral glucocorticoids. These therapeutic options are based upon a low level of evidence.

• Recently, a case was reported involving a patient with preexisting iSjD who developed diffuse large B-cell lymphoma. Following anti-CD19 chimeric antigen receptor (CAR)-T cell therapy, she achieved full remission of both the underlying autoimmune disease and lymphoma.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

S Pasoto, A Franco, C Silva, and E Bonfa conceptualized the article. S Pasoto and A Franco contributed to the literature review, article selection and reading, writing of the manuscript and preparation of tables and figures. C Silva and E Bonfa complemented and critically revised the contents. All authors have read and approved the final version of the manuscript. Public responsibility for the content of the article: S Pasoto, A Franco, C Silva, and E Bonfa.

Acknowledgments

We thank A Darcie, an ophthalmologist who conducted the objective tests for xerophthalmia and provided the images, and G Polho, an oncologist who assisted us in the discussion and provided the oncologist’s perspective on immunotherapy. We also thank L de Camargo Correira for her support in preparing the graphic design for Figure 3. This article, its data or its abstract have not been presented at conferences or similar. The figures in this article were created after the patients authorized the use of the image in accordance with signed informed consent terms.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/1744666X.2024.2370327

Additional information

Funding

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [#303116/2022-6 to SGP, #304984/2020-5 to CAS, and #305242/2019-9 to EB].