Advancements in Therapeutic Approaches and Biomarkers: A New Epoch for Sjögren's Syndrome Management

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease primarily affecting exocrine glands, characterized by symptoms such as dry mouth and eyes, fatigue, and joint pain. It often accompanies other autoimmune disorders like rheumatoid arthritis and lupus [1]. Despite its widespread occurrence and significant effect on quality of life, treatment strategies for pSS have traditionally been limited. These strategies have often focused on providing symptomatic relief rather than addressing the underlying disease process. pSS poses a complex challenge in the field of autoimmune disorders, particularly in terms of diagnosis and management. Traditionally, diagnosis has been reliant on clinical assessments and invasive biopsies, with therapeutic interventions limited to symptomatic relief. However, with new biomarkers and novel therapeutic strategies emerging, we are entering a new epoch in managing pSS. These advancements promise to revolutionize the field, offering targeted treatment regimens that could significantly enhance patient outcomes and quality of life [2].

PSS is characterized by the infiltration of lymphocytes into exocrine glands, which leads to the destruction of glandular tissue and, consequently, functional impairment. The exact cause of the condition remains unclear; however, it is believed that genetic predisposition, environmental triggers, and abnormal immune responses may contribute to its development. PSS is often underdiagnosed or misdiagnosed due to its nonspecific symptoms and overlap with other autoimmune conditions [3]. Traditional diagnostic methods, including subjective dry eye and dry mouth assessments, serological tests for autoantibodies, and salivary gland biopsy, have limitations in terms of invasiveness, specificity, and sensitivity. This underscores the urgent need for reliable, noninvasive biomarkers to improve early diagnosis, assess disease activity, and monitor therapeutic responses [4].

In pSS, biomarkers play an essential role in early diagnosis, assessment of the severity of the disease, and prediction of the prognosis. A summary of pSS biomarkers is shown in Table 1. The presence of autoantibodies such as SSA (Ro) and SSB (La) is a hallmark of pSS, but newer autoantibodies like ANA, RF, Anti-SP-1, Anti-PSP, Anti-CA-6, Anti-AQP5, and Anti-CarPare are garnering attention for their potential role in the early diagnosis of the disease. Elevated levels of cytokines and chemokines in blood samples, such as CXCL10, IL-6, IL-17A, CXCL13, IL-14a, and BAFF (B-cell activating factor), and decreased levels of CCL28 have been linked to early diagnosis and severe conditions. These not only serve as biomarkers for disease progression but also as potential therapeutic targets. The disease biomarkers are not limited to cytokines and chemokines. Detections of gas, receptors, protein, and RNAs also showed optimum disease prediction ability. The increasing levels of NO, Calprotectin, IFI44, SAMD9L, M3R, sST2, hsa_circ_0045800, and in-DC and decreasing levels of BAFF-R indicated a possible diagnosis of pSS and extended tissue damage. The potential of these biomarkers to improve early diagnosis and disease monitoring provides reassurance about the future of pSS management [5].

Tear and salivary fluids are easily accessible biofluids, offering a promising biomarker discovery medium. Advances in proteomics have led to the discovery of salivary biomarkers such as IL-1, IL-10, IL-17, TNF-a, IP-10, MIP-1α, IL-12p40, IL-6, MIG, IL-6, IL-17A, IL-4, IL-2, and RANTES. These biomarkers can facilitate noninvasive diagnostic approaches, reducing the need for labial biopsy. Tear fluid is an attractive source for biomarker discovery due to its direct link to ocular surface health and ease of collection. Tears contain a complex mixture of proteins, lipids, electrolytes, and small molecules reflecting local and systemic changes. However, these biomarkers require a large cohort, extended follow-up, and a more in-depth analysis of their mechanisms to confirm their clinical significance before they can be used in clinical practice. This verification process can be challenging and time-consuming, but it is essential for ensuring the reliability and utility of these biomarkers in a clinical setting [6].

Traditional treatment for pSS is multifaceted. It aims to alleviate symptoms, manage systemic manifestations, and improve overall quality of life. Recent advances in understanding its pathophysiology have catalyzed the development of novel therapeutic strategies. The revolutionary strategy approaches to managing Sjögren's syndrome focus on targeted biologics, small molecules, and innovative symptomatic treatments [7].

Rituximab, a chimeric anti-CD20 monoclonal antibody, depletes B cells, reducing autoantibody production and inflammatory cytokine release. Clinical trials have demonstrated efficacy in improving glandular function and systemic involvement [8]. Belimumab, targeting B-lymphocyte stimulator (BLyS), reduces B-cell survival, improves symptoms, and reduces disease activity scores in patients unresponsive to traditional therapies [8]. Abatacept, by inhibiting T-cell co-stimulation via CTLA-4 Ig, indirectly affects B-cell activity, offering another means of controlling autoimmune activity in pSS [9]. However, the therapeutic approaches of some biological agents were not optimal: thalidomide, oral lozenges of interferon alfa, anakinra, baminercept, and efalizumab were not recommended as their failure outcome in the treatment of pSS [10].

Janus Kinase (JAK) inhibitors, like Tofacitinib and Baricitinib, which impede signaling pathways vital to immune activation and cytokine production, have shown promise in early-phase trials for pSS [11, 12]. Sphingosine-1-Phosphate Receptor Modulators, agents like Fingolimod, modulate lymphocyte trafficking, potentially reducing glandular inflammation [13].

Stem cell therapy, particularly mesenchymal stem cells (MSCs), may offer reparative benefits by promoting tissue regeneration and modulating immune responses. Initial studies indicate improved glandular function and systemic symptoms in pSS patients receiving MSC infusions [14].

Biomarker discoveries enable more personalized treatment regimens, allowing clinicians to tailor interventions based on genetic, serological, and clinical profiles, optimizing therapeutic efficacy and minimizing adverse effects [15]. Chimeric Antigen Receptor T (CAR-T) cells are genetically engineered T cells designed for immunotherapy. Combined CD19/BCMA-targeted CAR-T cells have been developed and are undergoing evaluation in Sjögren's syndrome (SS) (NCT05085431). In conclusion, the evolving landscape of biomarkers and therapeutic strategies in pSS is reshaping how the disease is diagnosed and managed. The potential for improved patient outcomes is unprecedented, with novel biologics and small molecule inhibitor therapy approaches. As research progresses, a more personalized, targeted approach to pSS management will likely become the standard, significantly enhancing the quality of life for those affected and instilling hope for a brighter future in autoimmune diseases.

Xianfei Gao wrote the manuscript. Ping Zeng supervised the project and provided advice for the manuscript. Wen Tang participated in writing some parts of the manuscript.

The authors declare no conflicts of interest.