Bidirectional associations between endometriosis and Sjögren's syndrome in the era of multi-omics

Abstract

We appreciate Zervou and Goulielmos' interest in our research on the bidirectional associations between endometriosis and Sjögren's syndrome (SS). We fully agree that certain genetic factors are critically shared among patients afflicted with both conditions, as these factors could play a pivotal role in identifying potential therapeutic targets for treating both diseases.¹ Understanding these shared genetic influences is essential, given that they may help guide interventions that could significantly improve the quality of life for those affected by endometriosis and SS.

Our population-based cohort study, coupled with our transcriptomics analysis, fortifies this perspective by demonstrating that “dendritic cell maturation” and the “hepatic fibrosis signaling pathway” were significantly enriched in both endometriosis and SS.² These findings suggest that similar underlying mechanisms may drive the pathophysiology of these disorders. Zervou and Goulielmos' observations regarding the upregulation of key proteins such as B-cell activating factor (BAFF), HLA-DQA1, and HLA-DRA in both diseases further underline the importance of adaptive immunity and inflammatory pathways,¹ which we believe are fundamental components that intersect across these conditions.

Moreover, Zervou and Goulielmos' observations highlighted that interleukin (IL)-1 receptor antagonist (IL1-Ra) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) were upregulated in both diseases.¹ This upregulation indicates the complexity of the biological interactions at play, illustrating how interconnected immune responses may contribute to the development of both diseases. We agree that more efforts are always warranted to investigate the effects of other contributing factors on both disease entities. For instance, environmental factors, such as air pollutants, may as well exacerbate primary SS by upregulating inflammatory pathways through the involvement of the IL-6 pathway and NF-kB signaling.³

Collectively, these findings are clinically relevant not only in elucidating the associations between endometriosis and SS but also in providing a solid framework for studying the established links between endometriosis and the long-term risk of other illnesses, including malignancies such as endometrial cancer and uterine sarcoma.⁴ For example, pathways involving CTLA-4 and IL1-Ra have also been implicated in the pathogenesis of endometrial malignancies.^{3, 4} By investigating the shared genetic factors between endometriosis and SS, we may identify novel biomarkers that could predict the onset of these comorbidities in high-risk populations, as well as other long-term conditions.

Additionally, since our transcriptomic analyses were derived from bulk RNA samples, incorporating emerging techniques such as single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics could provide crucial insights. These methods enable detailed profiling of individual cellular populations and their transcriptional states, which would shed light on the heterogeneous endometrial lesions associated with endometriosis.⁵ This enhanced understanding of the complex cellular microenvironment may elucidate the mechanisms underlying comorbidities associated with endometriosis, ultimately facilitating the identification of specific biomarkers for early detection and the development of targeted therapeutic strategies.

As we continue to explore these connections, we envision a more integrated strategy for managing these related autoimmune and inflammatory disorders that will deepen our understanding and enhance therapeutic strategies for patients navigating these complex and challenging diseases.