Emerging biologic frontiers for Sjogren's syndrome: Unveiling novel approaches with emphasis on extra glandular pathology

Abstract

Primary Sjögren's Syndrome (pSS) is a complex autoimmune disorder characterized by exocrine gland dysfunction, leading to dry eyes and mouth. Despite growing interest in biologic therapies for pSS, FDA approval has proven challenging due to trial complications. This review addresses the absence of a molecular-target-based approach to biologic therapy development and highlights novel research on drug targets and clinical trials. A literature search identified potential pSS treatment targets and recent advances in molecular understanding. Overlooking extraglandular symptoms like fatigue and depression is a notable gap in trials. Emerging biologic agents targeting cytokines, signal pathways, and immune responses have proven efficacy. These novel therapies could complement existing methods for symptom alleviation. Improved grading systems accounting for extraglandular symptoms are needed. The future of pSS treatment may involve gene, stem-cell, and tissue-engineering therapies. This narrative review offers insights into advancing pSS management through innovative biologic interventions.

Keywords: Sjögren’s syndrome; biologic therapies; cytokines and chemokines; extraglandular symptom; primary Sjögren’s syndrome.

FIGURE 1

Overview of the Pathogenesis and Biologic Treatments for Sjögren’ s Syndrome. (A) After environmental stimulation, pDCs secrete IFN-α, while conventional DCs release IL-12. This triggers IFN-γ and GM-CSF production via innate and adaptive immunity. IFN-α and IFN-γ jointly induce BAFF, promoting B cell activation and IL-6 secretion. APRIL, regulated by IFN-α and IFN-γ, contributes to B cell proliferation. (B) CD4+ Th cells, combined with CD80/86, activated by APCs, infiltrate organs, producing cytokines inducing B cell activation. Th1 secretes IFN-γ, Th2 targets B cells and neutrophils, secreting IL-4, IL-21, and IL-25, while Th17, stimulated by IL-23, secretes IL-17 and IL-22. In glands and lymphoid tissues, T and B cells activate with CD40/CD40L. IFN-α, IFN-γ, IL-6, IL-22, and IL-23 use the JAK-STAT pathway for effects. Activation results in gland destruction and extraglandular symptoms, revealing the complex immune interplay causing autoimmune manifestations. Several biologics have been developed to target key factors in this process. Notable examples include rituximab (anti-CD20 monoclonal antibody), epratuzumab (anti-CD22 monoclonal antibody), daratumumab (anti-CD38 monoclonal antibody), belimumab (BAFF inhibitor) and ianalumab (BAFFR inhibitor), telitacicept (BAFF and APRIL inhibitor), iscalimab (anti-CD40 monoclonal antibody), abatacept (anti-CD80/86 monoclonal antibody), infliximab and etanercept (anti-TNF-α monoclonal antibodies), tocilizumab (IL-6R receptor inhibitor), bortezomib (IL-17 receptor inhibitor), ustekinumab (IL-12/23 receptor inhibitor), and baricitinib and filgotinib (JAK inhibitors). These targeted biologics offer specific interventions for autoimmune conditions. Abbreviations: pDCs, plasmacytoid dendritic cells; IFN, interferon; DCs, dendritic cells; GM-CSF, Granulocyte-macrophage colony-stimulating factor; BAFF, B cell-activating factor; IL, interleukin; APRIL, a proliferation-inducing ligand; Th cells, T helper cells; APC, antigen-presenting cell; JAK, Janus kinases; STAT, signal transducer and activator of transcription. In this diagram, white color blocks denote medications not utilized in SS, categorized as unverified. Yellow denotes pharmacological interventions with established efficacy, whereas gray designates medications administered but determined to be ineffective.