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

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. 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. 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.近四分之一接受免疫检查点抑制剂（immune checkpoint inhibitor, ICI）治疗的患者会出现干燥症候群（sicca syndrome），而原发性干燥综合征（Sjögren’s disease, SjD）的患病率估计为0.3%~2.5%，且可能存在漏报情况。本叙述性综述检索了截至2024年1月31日的Medline与Embase数据库文献，旨在探讨与ICI相关的干燥症候群/SjD的病理生理学机制、发病率、人口学与临床特征、生物标志物、唇腺活检（labial salivary gland biopsy, LSGB）、特发性SjD（idiopathic SjD, iSjD）分类标准符合情况、鉴别诊断及诊疗方案。与ICI相关的SjD存在诊断不足的问题，因开展了强制性SjD筛查的研究显示，40%~60%的ICI相关性干燥症候群患者符合iSjD分类标准。唇腺活检在识别此类病例中发挥了关键作用，因为这类患者多数抗Ro/SS-A抗体（anti-Ro/SS-A antibody）检测结果为阴性。尽管唇腺活检样本中可见局灶性淋巴细胞性涎腺炎（focal lymphocytic sialoadenitis），与iSjD的病理表现相似，但免疫组织化学分析（immunohistochemical analysis）证实，与iSjD相比，ICI相关性干燥症候群/SjD具有独特的病理模式，其特征为B淋巴细胞浸润匮乏，而B淋巴细胞浸润正是iSjD的标志性病理表现。此外，与iSjD患者相比，ICI相关性干燥症候群/SjD患者在人口学特征、临床表现、血清学指标及治疗反应方面均存在差异。此类患者的干燥症状较iSjD更为急性，且以口干症（xerostomia）为主，眼干燥症（xerophthalmia）次之，对糖皮质激素治疗可产生部分或完全应答。对于接受ICI治疗的患者，若出现干燥症状，应及时开展SjD相关筛查。