Sjögren’s Syndrome and Ocular Inflammation: Pathophysiology, Clinical Manifestation and Mitigation Strategies

Abstract

Sjögren’s syndrome (SS) is a chronic autoimmune disease primarily affecting the lacrimal and salivary glands, characterized by ocular and oral dryness. Beyond exocrine dysfunction, SS may also involve multiple organs and systems, contributing to systemic complications that impair a patient’s quality of life. Among these, ocular inflammation represents a significant clinical challenge, manifesting as dry eye disease and other vision-affecting complexities. Despite advances in SS understanding, the inflammatory mechanisms driving ocular manifestations remain incompletely elucidated. This review aims to clarify the key inflammatory pathways underlying ocular complications in SS and the clinical implications. Additionally, it discusses both conventional and novel therapeutic strategies focusing on mitigating SS-associated ocular inflammation, including targeted immunomodulatory agents, regenerative medicine, and innovative drug delivery systems. By integrating current knowledge from recent studies, this review attempts to provide researchers and clinicians with a comprehensive resource for optimizing SS treatment approaches. The advancement of targeted therapies and emerging mitigation strategies holds promise for improving patient outcomes and enhancing SS management.

1. Introduction

Sjögren’s syndrome (SS) is a systemic autoimmune disease primarily characterized by the involvement of exocrine glands, particularly the salivary and lacrimal glands, resulting in sicca symptoms, including dryness of the mouth (xerostomia) and eyes (xerophthalmia). This disease occurs primarily in middle-aged women but also in men, children, and the elderly, less frequently [1,2]. SS prevalence and affection in the female gender follows a 9:1 ratio, and most diagnoses occur between the 4th and 5th decades of life. In contrast, its prevalence is approximately 0.5–1.5% of the general population [3,4], a difference related to the immunoregulatory properties of female sex hormones [2,5,6].

SS is a widespread rheumatoid condition; however, many aspects of this disease have not yet been fully elucidated. SS may occur either alone (primary Sjögren’s syndrome, pSS) or combined with other autoimmune and inflammatory diseases (secondary Sjögren’s syndrome, sSS). In addition to eye and mouth dryness (98% of pSS patients report at least one symptom, 89% present both symptoms) [7], highly prevalent clinical pSS features are fatigue (>70%) [8] and arthralgia (>75%) [7]. A relatively low, but important risk of lymphoma occurrence is also observed [6,9,10,11], as the risk of non-Hodgkin B-cell lymphoma, particularly mucosa-assisted lymphoid tissue (MALT), is 10- to 19-fold higher in pSS patients [12] (5–10% prevalence) [13]. While sSS syndrome presents mostly the same symptoms as pSS, it results from a combination with other autoimmune diseases, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) [2,6].

Regarding the causes and symptoms of SS, debilitating inflammation is induced by autoantibody production and lymphocyte infiltration [11,14], but like all autoimmune diseases, it can also be caused due to several external (i.e., lifestyle, stress, smoking), biological (i.e., viral infections, hormones) and genetic factors [2,11,15,16]. The first report including SS manifestations was made in 1933 by Dr. Henrik Sjögren, who studied 19 women with severe symptoms of dry eyes and mouth, who presented systemic complications and lymphocytic infiltrations of the salivary and lacrimal glands [11,14]. In SS, symptoms like fatigue and arthralgia are often associated with the respiratory, nervous, and vascular systems, thus inducing complications like pulmonary embolism or vasculitis [2,6,9,15,17].

The most commonly recorded ocular effect in SS patients is systemic destruction of the lacrimal gland associated with ocular inflammation and characterized mainly by dry eye disease (DED), as well as tear production deficiency. DED is divided into two main subtypes, namely the aqueous-deficient dry eye (ADDE) caused by lacrimal gland issues and the evaporative dry eye (EDE), initiated by lacrimal gland damage [2,15,18,19,20,21]. SS pathogenesis is mainly ascribed to the activation of the type I and II interferons, cytokine production, and autoantibodies secretion by the activation, shedding, and destruction of gland-present B and T lymphocytes [9,16]. Such manifestations drive changes in the ocular surface and destroy the neural network, which in turn induces the reflexive secretion of tears [22,23]. DED has been a global public health problem for years, but no standard cure has yet been found. Symptoms vary from itching and burning to light sensitivity, blurred vision, broken eyelashes, sensation of a foreign object in the eye, etc., provoking daily discomforts for SS patients, such as difficulty in reading or driving and fatigue [18,20,24].

SS diagnosis is established based on an evaluation of specific criteria and the utilization of several diagnostic tools. Clinical techniques such as the measurement of tear volume by Schirmer’s test, sialometry (for measuring xerostomia by indicating low unstimulated salivary flow rate), and tear break-up time measurement are tests used to diagnose SS in ocular inflammation [25,26,27]. More precisely, an SS-related ophthalmologic examination should include an assessment of tear production (Schirmer’s test), ocular surface staining, as well as the integrity of meibomian glands. Evaluation of the ocular surface with vital dyes is typically performed with lissamine green, which stains devitalized conjunctival cells and has replaced the outdated Rose Bengal drops method, and fluorescein, which reveals defects in the corneal epithelium [28,29,30].

SS classification criteria rely on a combination of clinical and serological features. The 2016 American College of Rheumatology (ACR)—European League Against Rheumatism (EULAR) criteria define SS classification based on a weighted scoring system, where a total score of ≥4 is required. Key diagnostic components include ocular signs such as an ocular surface staining score (OSS) ≥ 5 or a van Bijsterveld score ≥ 4, and objective measures of salivary gland dysfunction, like a Schirmer test ≤ 5 mm in 5 min in at least one eye. The presence of anti-Ro/SSA antibodies, focal lymphocytic sialadenitis (focus score ≥ 1 focus/4 mm² on labial salivary gland biopsy), and the unstimulated whole saliva flow rate of ≤0.1 mL/min also contribute to the diagnosis. These criteria emphasize autoimmune involvement and help differentiate SS from other causes of sicca symptoms [29,31,32].

Relative mitigation techniques are constantly updated to achieve the most effective SS treatment solution. A range of therapeutic interventions including ocular therapeutic drops, administration of anti-inflammatory drugs, mainly corticosteroids, cyclosporine A (CyA), tetracyclines and derivatives, fatty acids, vitamins, or anti-inflammatory therapies [23,25,26,33,34,35], are employed, usually involving a marked opening of the tear ducts and the insertion of collagen or silicone plugs that block and prevent tear drainage [19].

This review aims to demonstrate a comprehensive approach to the pathophysiology of SS and its association with ocular inflammation. For this purpose, hormones affecting the lacrimal glands, several genetic, epigenetic, environmental, and pathophysiological agents, as well as autoimmune mechanisms, inflammatory markers, and autoantibodies linked to SS manifestation, are thoroughly discussed. Furthermore, emphasis is also given to the clinical manifestations of SS along with treatment and mitigation interventions utilized for combating this disease, which are also extensively analyzed. The main highlights and key points of this research are illustrated in Figure 1.

2. Materials and Methods

All data included in this review were collected from scientific articles and reviews published in online databases like Scopus, MDPI, Science Direct, PubMed, and Google Scholar. Some of the main keywords and key phrases utilized in this review are the following: “Sjögren’s syndrome”, “ocular inflammation”, “dry eye disease”, “lacrimal glands”, “hormones”, “ Sjögren’s syndrome pathogenesis”, “autoimmune mechanisms”, “inflammatory mechanisms”, “type I interferon system”, “B cells”, “autoantibodies”, “genetic factors”, “epigenetic factors”, “environmental factors”, physiological factors”, “microRNA”, “clinical manifestations”, “mitigation techniques”, “topical lubricants”, “cyclosporine A”, “omega-3 fatty acids”, “omega-6 fatty acids”, “vitamin A”, “vitamin D”, “vitamin E”, “innate immunity”, “therapeutic contact lenses”, with the use of combinations of these keywords by using the AND and/or OR terms in each query, in every scientific database mentioned.

This research process was conducted from October 2024 to February 2025, considering relative data obtained from articles published mainly over the last 5–10 years. The eligible review studies met pre-established criteria, including mostly research articles, written in the English language, and being published between 2015–2025. A limited number of important articles that contained important information not mentioned in more recent publications, but that were published before 2018, were also included. Duplicates and articles published in non-eligible or invalid scientific databases were strictly excluded, while conference papers, book chapters, short surveys, newspaper or magazine articles, theses, or non-academic reports were mostly excluded as well (under the PRISMA guidelines).

All articles included were thoroughly evaluated by reviewing primarily their titles, abstracts, and keywords, involving only those that contained pertinent information. Statistical data, study outcomes, and research processes were analyzed and then presented to achieve a practical demonstration of the severity of Sjögren’s syndrome (Figure 2).

3. Pathophysiology of SS and Ocular Inflammation

In SS incidence, inflammatory processes occur primarily through the glandular epithelial cells, which are involved in the expression of antigen proteins, promote adhesion, and stimulate T lymphocytes. Certain cytokines, such as interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), several interleukins (e.g., IL-1β, IL-6, IL-10), and the tumor growth factor beta (TGF-β), enhance the antigen-presenting function or induce the apoptosis of epithelial cells of the lacrimal and salivary glands [36,37].

3.1. Lacrimal Glands

Tears, which lubricate, clean, and protect the eye surface, are produced by the lacrimal gland, a compound, tubuloalveolar serous gland that opens at the inner surface of the palpebra and lubricates the ocular surface. Lobules that emerge from a connective tissue capsule and are divided by connective tissue septa make up the gland [38,39]. The predominant tear glands are located in the upper outer part of the orbit, within the lacrimal fossa of the frontal bone, and consist of two parts: the ocular, higher up in the cavity, and the buccal part, closer to the eyeball. The orbital lobe is larger among the two tear glands, while the size of the primary lacrimal gland varies significantly (comprising two lobes of about 20 × 12 × 5 mm). Differences between the symmetries of the right and left glands indicate an underlying pathology [40,41]. The lacrimal receives its arterial blood supply for both the upper and lower eyelids primarily from the lacrimal branch of the suboccipital artery, and occasionally from the recurrent meningeal artery. Finally, the lacrimal vein, which traverses the gland, drains into the superior ophthalmic vein [41,42].

The structure and function of the lacrimal gland are influenced by hormones produced in the pituitary and hypothalamus regions. Such hormones are α-melanocyte-stimulating hormone (α-MSH), prolactin, androgens, adrenocorticotropic hormone (ACTH), estrogen and progesterone, as well as retinoic acid, insulin, glucagon, and glucocorticoids (Figure 3) [21,43,44]. Hundreds of factors that protect the ocular surface, such as growth factors (e.g., epidermal growth factors (EGFs)), anti-inflammatory agents (e.g., interleukin 1 receptor antagonist (IL-1RA)), mucins, etc., are produced by lacrimal glands and in fact, decreased concentrations of these factors have been recorded in SS patients [45,46]. When the tear functional unit becomes inflamed, dry eye develops, causing dysfunction and epithelial cell death, leading to the secretion of tears into the gland and conjunctiva. Lacrimal gland dysfunction is attributed to various mechanisms, such as the cholinergic blockade by autoantibodies attacking the muscarinic acetylcholine 3 receptors (mAChRs, M₃), a mediation of cytokines causing epithelial cell death, inflammatory cytokine action such as IL-1 [45,46,47,48], neurotransmission disorders [45,49], oxidative stress [50], B-lymphocyte self-reactivity [51] and angiogenesis-related disorders. An overexpression of the vascular endothelial growth factor (VEGF), which alters lacrimal gland vasculature morphology, induces inflammation and hypoxia [48,52,53]. However, these are only a few of the known mechanisms considering tear gland dysfunction that have been extensively studied.

3.2. Autoimmune and Inflammatory Mechanisms

The lacrimal gland may become an immune-disease target for SS, as a result of aging, ocular inflammation, genetic predispositions, and/or external factors. Extensive research on SS autoimmune mechanisms, mainly on the relative cytokines, chemokines, and their roles in exocrine glands, is currently conducted [45,47,54]. SS development is ascribed to a disruption of innate immune barriers, accomplished by a mechanism involving the interferon (IFN) pathway [7]. More specifically, key cytokines involved in the pathogenesis of autoimmune diseases like pSS are IFNs, which are produced by the body’s cells in response to viral infections, pathogens, or abnormal cellular processes. IFN’s overexpression enhances the growth and progression of pSS [55]. IFNs are divided into three categories: type I, II, and III. Type I IFNs mobilize innate immune responses by enhancing antigen presentation and cytotoxicity while restraining the magnitude of inflammation to prevent toxicity [56]. IFN-I consists of 13 IFN-α subtypes (-α1, -α2, -α4, -α5, -α6, -α7, -α8, -α10, -α13, -α14, -α16, -α17 and -α21), IFN-β, IFN-k, IFN-ε, IFN-d and IFN-ω. IFN-α, IFN-β, IFN-γ, IFN-e, IFN-k, and IFN-ω are traced in humans, whereas IFN-d and IFN-t have been found only in pigs and cattle, respectively [2,55,57]. SS patients have exhibited an increased expression of IFN-I genes (IFN signature), found mainly in blood mononuclear cells and tissues. The presence of the IFN signature indicates an ongoing activation of the IFN-I pathway, which accelerates autoimmune activity. In pSS, an IFN signature signifies disease activity, whereas in RA, it defines a specific disease subset related to poor clinical outcomes and resistance to B-cell depletion therapy (Figure 4) [55,58].

3.2.1. Type I Interferon System in Primary SS (pSS): An Interplay Between Innate Immunity, Inflammation, and pSS Exacerbation

To fully elucidate how the pSS-IFN-I system synergy, it is necessary to present the IFN action mechanisms in SS formation and immune system activation against the exocrine glands [2,55,57]. Both salivary and lacrimal glands express ligands, receptors, and cytokines, capable of activating several innate immune cells like natural killer (NKs), dendritic (DCs), and mast cells (MCs), as well as macrophages, type 3 innate lymphoid cells (ILC3s), antigen-presenting cells (APCs) and B or T regulatory cells. MCs induce fibrosis and salivary gland infiltration, whereas the mucosa-associated invariant T cells (MAITs) exhibit impaired activation and formation of protective cytokines, interacting with APCs. Macrophages are activated by IFN-γ, releasing IL-22 that exacerbates immune signaling, while T cells are triggered by DCs and inflammatory cytokines, for further IFN-γ production. IFN-α enhances B cell activating factor (BAFF) release, B cell survival, and autoantibody formation as concurrently, as ILC3s interact with B cells via BAFF [9,11,54].

IFN-I system activation is primarily attributed to viral infection or other environmental factors that cause inflammation and trigger plasmacytoid DCs (PDCs) activation in the lacrimal glands. PDCs produce IFN-α, which leads to epithelial cell apoptosis and also autoantigen release (anti-Sjögren’s-syndrome-related antigen A (Ro/SSA) and B (La/SSB)). Such autoantigens preserve IFN-α production, activating a self-perpetuating cycle. After being exposed during epithelial cell apoptosis, they are recognized by immune B-cells, leading to the production of autoantibodies against the autoantigens SSA/Ro and SSB/La (anti-Ro/SSA and anti-La/SSB, respectively) [11,59,60].

Immune complexes activate PDCs through binding to the FcγRIIa receptor (cluster of differentiation 32 (CD32)), promoting the formation of germinal center (GC)-like structures. This binding triggers toll-like receptors (TLRs), particularly TLR7 and TLR9, which recognize RNA and DNA within the complexes, leading to enhanced IFN-α production and further inflammation. IFN-α marker, in turn, induces major histocompatibility complex (MHC) class I and II expression in lacrimal gland epithelial cells, enabling them to present antigens. Concurrently, chemokines such as the C-X-C motif chemokines 12, 9, and 10 (CXCL12, CXCL9, and CXCL10, respectively), exacerbate inflammation by recruiting T-cells, B-cells, and additional PDCs to the site [9,11,54].

Aberrant VEGF expression drives chaotic neoangiogenesis, with the upregulation of the intracellular adhesion molecule 1 (ICAM-1) on endothelial cells, facilitating immune innate cell infiltration [9,11,54]. Sustained IFN-α maintains inflammation and increases epithelial autoantigen expression (e.g., Ro52), perpetuating the autoimmune cycle. Progressive epithelial cell and immune-mediated tissue destruction ultimately impair exocrine gland function, leading to keratoconjunctivitis sicca, the hallmark ocular manifestation of Sjögren’s syndrome [9,11,54]. The main impact of cytokines and chemokines involved in SS is presented in

Table 1. Effects and Roles of Cytokines and Chemokines Involved in SS Autoimmune Mechanisms.

Cytokines and Chemokines	Main Producer(s)	Effect(s)/Role(s)	Pathogenesis Association	Clinical Significance	References
IFN-γ	T cells Monocytes Macrophages	Pro-inflammatory regulation of MHC class I and II	Increases the expression of autoantigens, facilitating the immune response	Associated with increased T-cell infiltration	[54,61]
IL-1, IL-2, IL-6, TNF	T cells Monocytes Macrophages	Pro-inflammatory	They activate inflammatory pathways and contribute to the destruction of glandular cells.	Associated with increased dry eyes and dry mouth	[54,62]
IL-10, TGF-β	Τ cells	Anti-inflammatory	They regulate the immune response, reducing autoimmunity	Their reduced expression may contribute to autoimmunity	[54,63]
IFN-α	PDCs Monocytes	Antiviral, anti-cancer, pro-inflammatory	Triggers the production of autoantibodies and the release of chemokines	Associated with relapse and extraneous events	[54,55,64]
CXCL12	Epithelial cells	Binds to CXCR4 on T cells and PDCs	Attracts immune cells to the area of the glands	Promotes chronic inflammation and fibrosis	[54,65]
CXCL13	Activated and upgraded epithelium	Associated with CXCR5 in B cells	Promotes the accumulation of B cells and the formation of ectopic lymphocytes	Associated with the likelihood of developing lymphoma	[54,65]
CXCL9, CXCL10, CXCL11	Upgraded epithelium	Associated with CXCR3 in T cells and PDCs	Enhances cell entry and maintenance in the inflammatory microenvironment	Can serve as a biomarker of disease activity	[37,54,65,66,67]

, while an interplay between innate immunity, inflammation, and pSS is thoroughly depicted in Figure 4.

Most inflammation-related chemokines and cytokines also contribute to oxidative stress, neuroinflammation, and ocular damage. In SS, oxidative stress is promoted via the generation of reactive oxygen species (ROS) and lipid peroxidation products, leading to tear film instability, altered tear composition, epithelial damage, and the release of additional pro-inflammatory mediators, thereby exacerbating DED symptoms. Increased oxidative stress in SS is supported by increased malondialdehyde (MDA) levels and reduced activity of antioxidant enzymes [68,69,70]. Moreover, emerging evidence suggests a critical role for neuroinflammation in SS-associated ocular complications. Disruption of the autonomic nervous system (ANS) signaling—particularly reduced parasympathetic input—has been linked to lacrimal gland dysfunction and impaired tear secretion. Corneal hypoesthesia and aggravating ocular discomfort have been associated with inflammatory cytokines (e.g., IL-6, TNF-α), which may impair corneal nerve density. Therapeutic strategies targeting both oxidative stress and neuroinflammatory mechanisms may offer promising interventions for SS-related ocular manifestations (Figure 4) [2,11,71,72,73].

3.2.2. Role of B-Cells in SS

Ongoing research into SS pathophysiology underscores the central role of B cells in disease onset and progression, particularly in pSS. These cells contribute to the formation of ectopic GC-like structures within exocrine glands and are implicated in extra-renal manifestations. Regulatory B (B_reg) cells are especially important in pSS development due to their immunomodulatory functions, including the secretion of cytokines such as IL-10, IL-35, and Granzyme B (GrB) [74,75,76,77,78]. Memory B Cells (MBCs) are also implicated in SS pathogenesis, accumulating in the lacrimal and salivary glands where they promote local autoimmune responses [74]. Their activation leads to autoantibody production and the release of pro-inflammatory cytokines, thereby intensifying ocular inflammation [79]. Targeting MBCs has emerged as a promising therapeutic strategy for managing SS-related ocular complications [77,80]. The key roles of B-cell subtypes in SS pathogenesis are presented in

Table 2. Effects and Roles of Active Molecules produced by B_reg cells.

Breg Cell Derivative	Main Producer(s)	Effect(s)/Role(s)	References
IL-10	Generated by nearly all immune cell types	B-cell growth factor Immunosuppression Effective suppression of Th17 cell response Inflammation reduction Tissue destruction Inhibition of Th cell development via the IL-10-dependent mechanism of STAT5 phosphorylation enhancement Key regulatory factor in the suppression of pSS autoimmunity Cell Dysfunction Decrease in IL-10 production, associated with disease exacerbation	[9,26,74,81]
IL-35	Immunosuppressive cytokines	Restriction of inflammatory response caused by increased Th1/Th17 activity Reduction of destruction of salivary and lacrimal glands Induction of Treg cells, essential for the maintenance of immune tolerance	[26,74,82]
GrB	Perforin-induced apoptosis of target cells by a serine protease family	GrB uses an independent of perforin-mechanism to stop CD4+ T cells’ growth Potent variations in the frequency of Breg cells producing GrB across various autoimmune disorders pSS individuals’ peripheral blood contains more CD19+/CD5+ B cells that produce GrB They exhibit greater expression of the IL-21 receptor (IL-21R), as well as more unaltered IL-21-producing NK T cells	[19,74,83]

, while the interplay between B-cell innate immunity, inflammation, and SS pathophysiology is illustrated in Figure 5.

3.3. Main Autoantibodies in SS: Their Role in Inflammation, Clinical Significance, and Diagnostic Value in SS

Autoantibodies play a variety of roles in SS and are of high diagnostic significance. Among the most clinically important antibodies are the anti-Ro/SSA and anti-La/SSB ones, which are often associated with early-onset disease (younger individuals), severe exocrine dysfunction, intense lymphocytic infiltration of minor salivary glands, and prolonged disease duration. Their detection is commonly performed through ELISA, although assay performance varies depending on the antigen source. The sensitivity and specificity for SSA/SSB antibodies range from 39–77% and 79–100%, respectively, while Line Immunoassay (LIA) has shown superior sensitivity (91.4%) and specificity (87%) [84,85].

B-cell hyperactivity in SS underlies the production of these and other autoantibodies, contributing to diagnosis and clinical manifestations. Anti-Ro/SSAs and anti-La/SSBs, while not disease-specific, remain valuable biomarkers in routine evaluation [84,85,86]. The key autoantibodies and their immunological and diagnostic relevance are described in the following subsections. Their roles in SS-linked inflammation are depicted in Figure 4.

3.3.1. Anti-Ro/SSA Autoantibodies

The Ro/SSA antigen is a ribonucleoprotein complex that comprises two major immunogenic proteins: Ro52 (52 kDa) and Ro60 (60 kDa). Ro60 binds non-coding Y-RNA and forms cytoplasmic ribonucleoprotein particles, whereas Ro52 can localize independently in the nucleus. Both proteins are targeted by autoantibodies in SS and are upregulated by innate immune stimuli such as TLR3. Dysregulated expression may also result from microRNA post-transcriptional mechanisms [87,88]. These autoantibodies are closely linked to SS-related inflammation and are frequently used as primary diagnostic markers.

3.3.2. Anti-La/SSB Autoantibodies

The La/SSB antigen is a 48 kDa phosphorylated protein that associates with nascent RNA transcripts, playing roles in RNA metabolism, including 3′ end protection of RNA polymerase III transcripts and pre-tRNA processing. It functions as an RNA chaperone and is localized in both the nucleus and cytoplasm. Anti-La/SSB autoantibodies are typically detected alongside immunoglobulin G (IgG) and anti-Ro/SSAs, and their isolated presence is not strongly affiliated with SS phenotypic features. Similar to Ro/SSA antigens, La/SSBs expression is modulated by TLR signaling and specific miRNAs, especially under apoptotic stress or via exosome release from epithelial cells [2,15,85,87,88].

3.3.3. Rheumatoid Factor (Rf), Complement System, and Cryoglobulins

Serological positivity for anti-Ro/SSAs and anti-La/SSBs is linked to Rf, which is frequently observed in SS patients. Research has indicated that Rf is one of the few indicators associated with severe illness and exocrine gland symptoms, necessitating further monitoring [86,89]. Rf, particularly the IgM class, targets the Fc region of IgG antibodies and is present in a significant proportion in SS patients. While classically linked to RA, Rf may also be elevated in other autoimmune disorders, including SLE and mixed connective tissue disease, largely due to chronic immune activation. Its presence warrants monitoring due to its correlation with disease severity [60,78,90].

Complement proteins and cryoglobulins are also important contributors to SS pathogenesis, particularly in systemic and vasculitic manifestations. Hypocomplementemia, especially low C3 and C4 levels, has been correlated with increased SS activity and risk of lymphoma. Cryoglobulinemia, the presence of circulating immunoglobulins that precipitate at low temperatures, occurs in a subset of SS patients and is often linked to systemic vasculitis, purpura, peripheral neuropathy, and glomerulonephritis. Both biomarkers hold diagnostic and prognostic value and share clinical relevance with Rf [91].

3.3.4. Cyclic Citrullinated Peptide Antibodies (Anti-CCP)

Patients who tested positive for anti-CCP and RF showed progressively worse ocular inflammation, providing a diagnostic tool and useful information for patients with severe inflammatory eye disease [92]. Anti-CCP antibodies, although primarily affiliated with RA, have also been detected in approximately 22.1% of patients diagnosed with pSS, even in the absence of clinically established RA. Their presence in SS may serve as a predictive marker for future arthritis development, thus providing useful prognostic information and supporting early monitoring for potential RA transition [11,92,93].

3.3.5. Anti-Centromere Antibody (ACA)

ACAs, targeting centromere proteins (CENPs), are observed in a minority of SS patients (17% of ACA-positive autoimmune diseases were SS). Since this discovery, ACA’s presence in SS has reached 3.7–27.4%, and they are associated with severe sicca symptoms and extensive lymphocytic infiltration of the salivary glands. Although more commonly linked to limited systemic sclerosis, their detection in SS suggests a distinct clinical subset with possible overlap features [83,94,95,96].

3.4. Genetic, Epigenetic, Environmental, and Physiological Factors Triggering SS Development

SS onset and progression are driven by a wide combination of genetic and epigenetic mechanisms, physiological alterations, environmental triggers, as well as gut microbiota dysbiosis, with the gut-lacrimal axis also playing a key role. These elements interact with innate immunity and chronic inflammation, as illustrated in Figure 4.

3.4.1. Genetic-Epigenetic Factors

Recent transcriptomic studies in salivary glands and peripheral blood suggest that genetic polymorphisms and epigenetic alterations, especially those affecting immune-related pathways (e.g., microRNA pathways), play a critical role in SS susceptibility. Key mechanisms include the activation of the IFN-I axis, Th1-related cytokines (IL-12, IFN-γ), and dysregulation of chemokine receptors like CXCR5 [19]. Epigenetically, various modifications, like DNA methylation, histone modifications, non-coding RNA, and IFN gene hypomethylation, lead to increased B-cell expression [19,64,75]. Hypomethylation of IFN-regulated genes in epithelial cells and immune cells like peripheral blood mononuclear cells (PBMCs) contributes to a persistent IFN-I signature [55,58,66], while altered histone acetylation enhances pro-inflammatory cytokine expression (e.g., IL-6, TNF-α) [2,9].

microRNAs Implication

MicroRNAs (miRNAs), single-stranded, non-coding RNAs regulating over 60% of protein-coding genes, play a major role in immune regulation (such as T and B-cell function) by targeting mRNAs for degradation or translational inhibition [97]. Specifically, aberrant expression of miRNAs, like upregulated miR-146a/miR-155 and downregulated miR-181a levels, is linked to dysfunctional B and T-cell responses in SS. These patterns, consistently observed in exocrine glands and PBMCs, highlight the emerging role of miRNAs as both biomarkers and potential therapeutic targets in SS (

Table 3. Some miRNAs involved in the Onset and Development of Sjögren’s Syndrome.

Differently Expressed miRNAs	Correlation with SS	References
miR-146a	Increased expression in SS Phagocytosis enhancement Suppression of the production of inflammatory cytokines mi5-146a dysfunction may contribute to: chronic inflammation and SS autoimmunity	[98]
miR-155	Increased SS Role in innate and adaptive immunity Its abnormal expression leads to inflammatory autoimmune diseases Its inhibition may mitigate SS symptoms, indicating that miR-155 is a potential therapeutic target	[97,99]
miR-181a	Role in the regulation of SS immune response Increased expression in peripheral monocytes, is associated with immune overactivity Decreased expression in salivary glands is associated with their dysfunction	[100]

) [19,97,98,99,100].

3.4.2. Psychological Factors

Psychological distress, such as anxiety, depression, and chronic stress, is highly prevalent among pSS patients and contributes to both symptom burden and disease progression [101]. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis due to adrenal autoimmunity and altered levels of IL-1, IL-36a, and humoral immunity markers are associated with fatigue and neuroinflammation [102]. Depression has been correlated with neurotransmitter imbalances, neurotrophic factor disruption, and the presence of autoantibodies targeting neuropeptides. Additionally, α-MSH autoantibodies and BAFF may synergistically contribute to anxiety, brain inflammation, neuronal damage, and hippocampal dysfunction [103]. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) may mitigate depressive symptoms by reducing neuroinflammation. Emerging therapeutic interventions like dazodalibep (CD40 ligand antagonist), RSLV132 (RNaseFc fusion protein), and belimumab against fatigue symptoms show promise in addressing SS-related neuropsychiatric complications [37,55,102,103,104,105].

3.4.3. Environmental Factors

Environmental triggers such as viral infections (e.g., Epstein-Barr virus (EBV), human T-lymphotropic virus 1 (HTLV-1), cytomegalovirus (CMV), and hepatitis C virus (HCV)), play a pivotal role in SS pathogenesis, particularly through chronic persistence in salivary glands and molecular mimicry mechanisms that lead to loss of self-tolerance and autoimmunity [2,26,106,107]. Moreover, although there is emerging evidence suggesting a possible link between SS and COVID-19, post-COVID-19 SS is not yet definitely established. Studies however, indicate that SARS-CoV-2 may trigger or exacerbate SS-like symptoms or autoantibodies in certain individuals, but further research is necessitated to confirm an exact causal relationship [108,109,110].

Exposure to pollutants such as heavy metals (e.g., mercury, lead, chromium, cadmium) [111,112] and organic solvents like perfluoroalkyl acids) [113], has been associated with SS onset via oxidative stress and epigenetic modifications. In addition, lifestyle factors, including chronic ultraviolet (UV) radiation exposure, smoking, and dietary patterns, may also modulate risk. Notably, the role of smoking remains controversial, with both protective and detrimental effects reported on pSS risk. Some studies indicate nicotine’s ability to suppress B cell hyperactivity (lower pSS risk), and others suggest that it triggers exocrine gland dysfunction and oxidative stress (higher pSS risk). However, further studies are required to support this observation [114].

3.4.4. Role of Gut Dysbiosis and Gut-Lacrimal Axis

Gut microbiota dysbiosis has been increasingly implicated in SS through its impact on T-cell differentiation, mucosal immunity, and ocular inflammation. SS patients commonly display reduced microbial diversity, altered Firmicutes/Bacteroidetes (F/B) ratios, and decreased levels of short-chain fatty acid (SCFA)-producing bacteria, like Faecalibacterium prausnitzii and Bifidobacterium spp., contributing to epithelial barrier dysfunction [115,116,117]. Disruption of the gut-lacrimal axis can further aggravate DED via systemic endotoxin leakage and cytokine-driven lacrimal gland inflammation. Therapeutic strategies such as probiotic supplementation, dietary interventions, and fecal microbiota transplantation (FMT) are under investigation as adjunctive treatments (Figure 4) [115,116,117].

4. Clinical Manifestations of SS

4.1. Clinical Manifestations of SS: Sicca Symptoms and More

SS presents with a wide spectrum of clinical features, broadly categorized into glandular and extraglandular manifestations. Glandular dysfunction arises from lymphocytic infiltration and destruction of exocrine glands (primary salivary and lacrimal ones) and include xerostomia (dry mouth), keratoconjunctivitis sicca (dry eyes), parotid gland enlargement, and dryness of other mucosal surfaces (e.g., vaginal or nasal dryness, dry skin (xerosis)). Over 90% of SS patients report dry mouth, making sicca syndrome the hallmark of SS, along with DED (80% experience sicca symptoms) [118]. Extraglandular manifestations stem from systemic immune dysregulation and may involve musculoskeletal (e.g., arthralgia, myalgia), pulmonary (e.g., interstitial lung diseases (ILDs)), renal (e.g., tubulointerstitial nephritis), neurological (e.g., peripheral neuropathy), hematological (e.g., MALT lymphoma), vascular (e.g., systemic vasculitis), gastrointestinal and hepatic systems, often accompanied by constitutional symptoms (e.g., fever, fatigue) and cutaneous lesions [119,120]. Furthermore, SS may have serious systemic consequences, including lymphoma, cardiovascular disease, and increased mortality in certain subgroups. Notably, although SS affects women predominantly, men exhibit a nearly 3-fold higher mortality rate, potentially due to more severe systemic involvement [121,122].

Pulmonary complications occur in 9–20% of SS patients, most frequently as respiratory impairment like chronic ILDs and tracheobronchial disease [9,15,20,123]. ILDs include non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), lymphocytic interstitial pneumonia (LIP), and cryptogenic organizing pneumonia (COP). NSIP is the most common ILD pattern in SS (~45%), characterized by ground-glass opacities and reticular changes. It can be either cellular (inflammatory, better prognosis) or fibrotic (progressive, worse outcome) [124,125]. UIP is less common (~17%) but more severe, presenting with progressive fibrosis, honeycombing, as well as subpleural fibrosis on high-resolution CT (HRCT) [126,127]. Plus, LIP is strongly associated with SS (25%), though rare, marked by diffuse lymphocytic infiltration, cystic lung disease, and risk of lymphoma [128,129]. Finally, COP involves alveolar and small airway inflammation, leading to patchy consolidations and scarring. The pSS-COP link is extremely rare [130].

Other clinical features include hypergammaglobulinemia, often associated with anti-Ro/SSA, anti-La/SSB, and RF antibodies [2,11]. Cutaneous involvement includes dry skin, annular erythema, and vasculitis lesions, often linked to keratin alterations and skin protein dysregulation [131]. Moreover, neurological and systemic complications are increasingly recognized in SS, significantly affecting patients’ quality of life. Common neurological manifestations include peripheral and small fiber neuropathy, as well as cognitive impairment, and are often linked to B-cell hyperactivity, altered lipid metabolism, and chronic IFN-driven, neuroinflammation-related demyelination. Additionally, metabolic syndrome, pulmonary involvement, renal dysfunction, and elevated cardiovascular risk further deteriorate the SS burden. These manifestations may progress silently, and thus early detection prevents long-term morbidity [9,15,20,64,123,132,133]. Figure 5 provides a schematic overview of the most common clinical symptoms experienced by SS patients.

4.2. Dry Eye Diseases of SS

DED is one of the most prevalent and early ocular manifestations in SS patients, driven by autoimmune-mediated destruction of the lacrimal glands and chronic inflammation of the ocular surface. It is also commonly observed in other systemic or ocular conditions, such as diabetes mellitus, graft versus host disease, and Graves’ orbitopathy. In SS, DED typically presents with reduced tear production, epithelial damage, and destabilization of the tear film due to goblet cell loss, leading to symptoms such as burning, grittiness, blurred vision, and photosensitivity [134].

Diagnostic evaluation of DED includes a combination of subjective and objective assessments, such as the ocular surface disease index (OSDI), Schirmer’s test (ST), tear film break-up time (TFBUT), and corneal fluorescein staining (CFS). These tests help characterize the severity and impact of dry eye but cannot be used to distinguish pSS from sSS, as both forms exhibit similar ocular involvement, and pSS-sSS distinction is based on the presence of another well-defined autoimmune disease (e.g., RA, SLE) [134].

DED in SS significantly impacts the quality of life. Recent studies report that patients with severe DED symptoms experience a four-fold reduction in daily functionality compared to individuals without symptoms. Moreover, such patients are more than twice as likely to suffer from emotional distress, increased financial burden, and social limitations. Painful dry eye is more frequently observed in women, older individuals, and patients with corneal epithelial injury. Notably, photosensitivity affects ~50% of SS patients, while 25% report painful photosensitivity [14,23,42,135].

4.3. Ocular Inflammatory Complications

Beyond the classic symptoms of DED, SS may involve a range of inflammatory ocular complications, including sterile corneal ulcer, scleritis, optic neuritis, and uveitis as illustrated in Figure 6. These conditions may pose significant threats to vision and require prompt diagnosis and management [121,135,136,137].

4.3.1. Sterile Corneal Ulcers

Sterile corneal ulcers affect ~2.5–3.6% of SS patients and are considered vision-threatening complications. They are not caused by infections but rather by immune-mediated disorders such as SS or RA. Such ulcers may worsen after procedures like cataract surgery, especially if the underlying ocular surface is poorly controlled. In these cases, pre-operative immunosuppression is often recommended to minimize risks [138]. Additional contributing factors include the use of contaminated contact lenses (e.g., Gram-negative organisms), poor lens hygiene, or chemical exposure. Gram-negative keratitis presents with red, painful eyes and is mostly linked to contact lens damage [18,139,140]. Furthermore, topical corticosteroids, although used to suppress inflammation, can paradoxically exacerbate sterile corneal ulcers, especially with prolonged use. While they aid in modulating immune response, their use should be carefully monitored (Figure 6) [141].

4.3.2. Scleritis

Scleritis is a severe ocular inflammation affecting the sclera—the outer protective layer of the eye—whose vascular structure is particularly prone to inflammatory responses. Due to its dense and fibrous composition, the sclera does not easily eliminate harmful agents, making it susceptible to prolonged inflammatory reactions. Scleritis is typically observed in middle-aged patients (diagnosed between 47–60 years of age), and is frequently correlated with systemic autoimmune diseases like SS, rather than infectious causes. Although rare, it can also be triggered by bacterial, viral, or fungal infections [19,142,143]. It is considered a heterogeneous condition, in both terms of pathogenesis and etiology, and is increasingly viewed as an autoimmune disorder in which T- and B-cell cytokines play a central role. Treatment often involves topical or systemic corticosteroids, anti-TNF, and anti-B-cell-targeted therapies. However, these treatments can be linked to notable ocular side effects and carry potential risks to vision, further compromising the patient’s quality of life (Figure 6) [24,94,144].

4.3.3. Optic Neuritis

In some cases, optic neuritis may be the first SS manifestation, even in the absence of classic complicating the diagnostic process. The condition is linked to autoimmune activity, with antibodies such as anti-Ro/SSA, anti-La/SSB, and anti-aquaporin-4 antibodies being often detected [145]. Although usually idiopathic, optic neuritis may also be triggered by infections or systemic inflammation. It presents with retro-orbital pain, unilateral vision loss, and photosensitivity requiring prompt management (Figure 6) [145,146,147].

4.3.4. Uveitis

Uveitis is an inflammatory condition that affects the eye’s uvea, which consists of the iris, ciliary body, and choroid. It may result from infections, trauma, or immune-mediated response complications [11,148]. Although corticosteroids are widely used as the primary treatment and are often effective, they can lead to significant side effects, and their long-term use should be approached with caution. Uvea is a highly heterogeneous condition. When associated with immunobiological responses, it is linked to dysregulation between immune suppression and pro-inflammatory cascades. Regulatory T lymphocytes and their produced cytokines (e.g., IL-10, IL-27 (retinal cells), TGF-β), play a pivotal role in disease modulation (Figure 6) [11,148].

5. Common Conventional and Newly-Emerged Treatment and Mitigation Techniques for SS and DED Management

Several conventional techniques have been developed and are currently employed, paving the way for more effective and resilient innovative treatment approaches to ensure better patient compliance in SS management. The most common strategy adopted by contact lens users for symptom relief is the use of tear substitutes, which play a crucial role in restoring ocular moisture. While many contact lenses contain preservatives that can cause irritation and complications, tear substitutes are typically preservative-free and better tolerated [36]. Current DED treatments in the context of SS aim to lubricate the ocular surface, prolong tear film stability, and target ocular inflammation through specific therapeutic agents. Treatment selection depends largely on the severity of the disease, as DED can present with varying levels of discomfort and damage. A major challenge in both selecting treatments and interpreting outcomes lies in the common misclassification of DED as a uniform condition, despite its multifaceted clinical manifestations, pathogenetic mechanisms, and outcomes [11,36,60,62,103,149]. All conventional topical, systemic, interventional, adjunctive, and nutritional SS therapies used are depicted in Figure 7 and Figure 8.

5.1. Conventional Topical and Systemic Treatments

5.1.1. Topical Lubricants: Artificial and Biologic Tear Substitutes

A wide range of substances is utilized in the manufacture and administration of commercial artificial lubricants designed to alleviate dry eye symptoms. These formulations typically include demulcents, which lubricate the ocular surface, and emollients that slow tear evaporation, often involving sodium hyaluronate (SH), known for its capacity to hydrate and protect the corneal endothelium. Administration of hyaluronic acid (HA) and its sodium salt, SH, in SS patients has led to significant improvement in tear film break-up time (TBUT), cytology, and corneal staining after 2 weeks of treatment [150,151,152]. Artificial tear substitutes are mainly intended for temporary relief and symptom control in patients with mild SS symptoms. While generally safe and effective, their utility is limited in chronic or moderate-to-severe SS, due to the need for frequent dosing [23,150,151,152]. In addition, lipid-based formulations used in SS treatment vary in viscosity and hydration levels, which may present clinical challenges. For instance, more viscous formulations like ointments offer extended relief and increased ocular surface retention time, but may impair visual acuity by inducing blurred vision. The use of corticosteroids in ophthalmic solutions should also be avoided, as they can increase the risk of corneal infection and degradation. Likewise, eye drop preservatives (e.g., benzalkonium chloride, sodium chlorate), though effective, may cause ocular surface damage upon repeated use [22,23,25].

In contrast, biologic tear substitutes, such as autologous serum and allogeneic platelet-rich plasma (PRP) eye drops, deliver essential nutrients and regenerative factors that artificial lubricants lack. Such formulations contain potent anti-inflammatory and tissue repair agents, such as EGF, fibronectin, TGF-β1, and platelet-derived growth factor-AB (PDGF-ΑΒ), making them suitable for severe SS-related DED management. Notably, PRP drops have demonstrated superior efficacy compared to artificial lubricants, particularly in SS cases. However, challenges including high cost, storage conditions, and frequent dosing needs, limit their broader clinical use (Figure 7) [153,154,155,156,157].

5.1.2. Topical Cyclosporine A (CyA) Immunosuppressive Treatment

CyA is a potent immunosuppressive agent that inhibits the activation and proliferation of T cells. In the context of abnormal activation of Th17 observed in SS, CyA acts as a key mitigation agent [158]. By binding to cyclophilin D and preventing T-lymphocyte activation, CyA reduces inflammation (DED contributing factor). Furthermore, CyA helps preserve conjunctival epithelial cell integrity by inhibiting the opening of the mitochondrial permeability transition (MPT) pore, a process that otherwise leads to cell death. This inhibition results in decreased tear production as inflammation subsides. CyA improves tear secretion and lacrimal gland function by lowering the expression of pro-inflammatory markers like IFN-γ and IL-1, both elevated in SS [159]. One of the most commonly used commercial formulations of CyA is marketed under the brand name “Restasis^®”, which contains 0.05% CyA along with preservatives. Other formulations used in artificial tear preparations may contain lower CyA concentrations (0.5 and 0.1%) depending on disease severity [34]. Clinical studies have reported an increase in Schirmer scores and notable symptomatic relief following CyA treatment. Improvements have also been observed in tear film stability, evidenced by increased tear meniscus height, volume, and round cell density [158]. Importantly, CyA therapy has been associated with a significant increase in goblet cell density, enhancing mucin production and providing better protection for the ocular surface. However, CyA may also lead to many adverse effects during therapy, like burning and stinging sensations, which may affect patient compliance and limit widespread use (Figure 7) [22,34,158,159].

5.1.3. Conventional Systemic Corticosteroids, Disease-Modifying Anti-Rheumatic Drugs (DMARDs) and Immunosuppressants

While topical therapies provide symptomatic relief for ocular SS manifestations, systemic treatments play a vital role in controlling the underlying autoimmune pathology and preventing SS progression. Selecting a systemic therapy is guided by SS severity, extent of systemic involvement, and patient treatment response. Systemic corticosteroids, such as prednisone and methylprednisolone, are widely used for short-term management of SS-induced acute inflammation. They function by suppressing pro-inflammatory cytokines (e.g., TNF-α, IL-6, IFN-γ), thus limiting immune cell infiltration and associated tissue damage. However, due to significant long-term side effects, like osteoporosis, hyperglycemia, hypertension, and adrenal suppression, they are generally prescribed at the lowest effective dose and for a limited duration [23,33,160].

Conventional synthetic DMARDs (csDMARDs) are standard therapy for systemic autoimmune diseases such as SS, mostly in cases presenting with arthritis, systemic inflammation, or extraglandular complications. Among these, hydroxychloroquine, an antimalarial agent, is widely favored due to its B-cell modulating capacity, autoantibody suppression, and inhibition of TLR signaling. Clinical trials suggest that it may alleviate systemic inflammation, fatigue, and sicca symptoms, while also offering cardiovascular protection [23,33,161]. Methotrexate, a folate antagonist, is often considered in SS patients with arthritis and systemic inflammatory symptoms because of its immunosuppressive and anti-inflammatory properties. Interestingly, studies suggest that anti-Ro/SSA-positive patients with RA exhibit notably lower disease activity scores (score-28 C-reactive protein (DAS28-CPR)) when treated with methotrexate, compared to anti-Ro/SSA-negative individuals. However, this finding paradoxically correlates with a poorer overall therapeutic response, suggesting that anti-Ro/SSAs may serve as predictive markers of refractoriness to methotrexate in RA and potentially in SS patients as well. When methotrexate is contraindicated, leflunomide is preferred; however, scientists should consider its adverse effects beforehand [69,162]. Moreover, the macrophage migration inhibitory factor (MIF), which binds to nuclear factor-kappa beta (NF-κΒ), reduces pro-inflammatory cytokines and exerts a significant rebalancing effect on Th1, Th17, and T regulatory cells [163]. While not yet widely applied as a therapy, its involvement in TLR modulation and innate immunity regulation suggests its potential as a future treatment SS target [149,163,164].

Regarding patients with severe systemic SS or unresponsive to csDMARDs, stronger immunosuppressants (like cyclophosphamide) may be required [165]. Mycophenolate mofetil (MMF) and azathioprine suppress lymphocyte proliferation and are often used in cases of SS-related vasculitis or ILD. MMF has also been used intravenously, often in conjunction with immunoglobulin therapy after rituximab, to manage refractory sensory neuropathy in pSS patients [166]. Systemic CyA and tacrolimus, which block T-cell activation via calcineurin inhibition, can suppress ocular inflammation and modulate Th1 cytokine activity. Despite their potential in tear gland preservation, systemic administration is limited due to risks of nephrotoxicity and hypertension (Figure 7) [166,167].

5.2. Conventional Interventional Procedures

5.2.1. Punctal Occlusion

Punctal occlusion, using temporary collagen or permanent silicone plugs, is a well-adopted method to reduce tear drainage, thus enhancing tear film stability and ocular surface hydration in patients with SS-related DED. While effective, side effects such as plug extrusion, infection, and local inflammation are common (Figure 7) [19,23,94,168].

5.2.2. Therapeutic Contact Lenses (CLs)

One of the most common therapeutic options is the Therapeutic Hyper-CL^TM, a soft contact lens designed to prolong the residence time of eye drops on the ocular surface. This is achieved by creating a reservoir between the lens and cornea, where active agents are trapped and slowly released [169]. Scleral lenses, which vault over the cornea, create a moisture chamber that protects the epithelium and enhances tear film retention, displaying notable benefits in refractory DED in SS patients [170,171]. A particularly promising strategy for severe dry eye in SS is the use of silicone-hydrogel bandage contact lenses (BCL), which improve visual acuity, ocular surface healing, and overall quality of life. In a recent comparative study, SS patients treated with BCLs for six weeks exhibited greater visual improvements than those using lubricating eye drops eight times daily. Notably, the BCL group showed sustained improvements even after therapy discontinuation, without reports of pain or keratitis (Figure 7) [172].

5.2.3. Surgical Interventions

For severe refractory SS cases with corneal damage or glandular dysfunction, surgical options become necessary. Tarsorrhaphy, the partial or complete surgical closure of the eyelids, is a traditional yet effective technique to minimize tear evaporation and protect the ocular surface [18,30,151]. Innovative procedures include minor salivary gland auto-transplantation to the conjunctival fornix, which serves as a natural tear substitute, and amniotic membrane transplantation (AMT), used for epithelial regeneration and healing of severe ocular surface defects (Figure 7) [151].

5.3. Adjunctive and Nutritional Therapies

5.3.1. Oral Administration: Omega-3 and/or Omega-6 Fatty Acid Supplementation

Essential omega-3 and omega-6 fatty acids (FAs), obtained through the diet, are important regulators of inflammation and contribute to the integrity of cell membranes. Certain omega-3 FAs, like eicosapentaenoic acid (EPA) derived from fish oil, inhibit the production of pro-inflammatory cytokines (e.g., IL-1, TNF-α). Several studies have consistently pointed out that oral administration, twice daily, of linoleic and γ-linoleic FAs, leads to significant improvement of ocular irritation symptoms and accelerates tear secretion. Similarly, preclinical trials in mice have exhibited that resolvin E1, a metabolite of EPA, effectively mitigates inflammation [25,173,174]. Compared to healthy individuals, pSS patients demonstrate lower levels of omega-3 and omega-6 FAs. The beneficial impact of omega-3 FAs is likely attributed to their conversion into resolvins and other potent anti-inflammatory mediators, such as docosahexaenoic acid (DHA) and EPA, which collectively reduce inflammation and tissue damage. Moreover, SS patients often experience dry mouth and dysgeusia, which can alter their eating behavior and lead to nutritional deficiencies, including reduced intake of vitamins and omega-3 FAs. Supplementation with omega-3 and/or omega-6 FAs has shown beneficial effects on TBUT and Schirmer’s levels, improving the overall quality of life in SS patients (Figure 7) [25,173,174].

5.3.2. The Role of Vitamins in SS Mitigation

Vitamin A

Vitamin A is actively involved in immune regulation and epithelial homeostasis. In the form of all-trans-retinoic acid in animal models, it has been shown to reduce the levels of Th1 (e.g., IL-2, IFN-γ) and Th2 cytokines (e.g., IL-4), hence exerting anti-inflammatory effects. Vitamin A deficiency is associated with the progression of systemic manifestations and disease severity in SS, while it also contributes to the instability of epithelial and mucosal barriers, exacerbating symptoms like dry eyes (Figure 7 and Figure 8) [151,175,176].

Vitamin E

Vitamin E is a lipid-soluble antioxidant with immunomodulatory properties that can delay the progression of autoimmune diseases. In autoimmune mouse models, a vitamin E-rich diet has shown beneficial effects like reduced lymph node volume, decreased cytokine levels (e.g., IL-6/10/12, TNF-α), and increased IL-1β levels. In SS patients, elevated serum vitamin E levels have been recorded (41.41 μmol/L compared to 33.68 μmol/L in healthy controls), possibly reflecting a compensatory antioxidant immune response. Such findings support vitamin E as a potential adjunctive therapeutic agent in SS symptom management (Figure 7 and Figure 8) [174,175,177].

Vitamin D

Vitamin D, mainly in its active form 1α,25-dihydroxyvitamin D₃ (1α,25-(OH)₂D₃), is known to modulate immune function via various mechanisms. Its deficiency is associated with a higher risk of autoimmune diseases, like RA, SLE, and ILD. Interestingly, the serum concentration of vitamin D in SS patients (79.96 nmol/L) does not markedly differ from that of healthy individuals (71.57 nmol/L). Nevertheless, it plays a key role in regulating immune responses by modulating cytokine production and acting as an acute-phase reactant. Treatment with 1α,25(OH)₂D₃ suppressed the proliferation of Th lymphocytes and memory B cells in SS patients, suggesting its immunosuppressive and anti-inflammatory potential in SS therapy (Figure 7 and Figure 8) [35,73,178,179,180].

5.4. Novel and Emerging Therapies

5.4.1. Biologic Interventions, Targeted Therapies, and Immunomodulators

Advances in biological therapies have opened new avenues for managing SS-associated autoimmune ocular inflammation by targeting specific inflammatory cascades. Several biologic DMARDs (bDMARDs) and cell-based therapies have emerged. Although B cell-targeting SS strategies remain central, therapies focusing on T cells, cytokines, chemokines, and small molecules have also been explored [23,181,182,183].

Rituximab, an anti-CD20 monoclonal antibody, is often used off-label for severe systemic pSS [181]. It depletes B cells and mitigates autoimmunity, though clinical trials show inconsistent efficacy, indicating a need for further research [23,181,182,183]. Belimumab, a BAFF receptor inhibitor (like atacicept), shows promise in reducing autoantibody generation, dryness, and B cell hyperactivity—alone or combined with rituximab—though more data are required [23,105,184,185,186,187]. Additionally, obinutuzumab, as an anti-CD20 antibody, is a good treatment response to rituximab-resistant SS patients without any symptomatic cross-immunity [188]. Abatacept, a soluble fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and a fragment of the Fc portion of human IgG1, binds more strongly to CD80/CD86 than CD28, preventing T-cell activation. Though it showed limited effect on pSS biomarkers [189], it may reduce DED symptoms and systemic activity, especially in SS related to RA [190,191]. Plus, epratuzumab, targeting CD22, may downregulate B-cell receptor signaling and IgM, with promising results in SLE and related SS [188,192]. Baminercept (lymphotoxin β receptor (LTβ-R)-binding) and acazicolcept (CD28-binding in T cells) require further validation [188,193], while iscalimab and dazodalibep (anti-CD40 antibodies) have shown potential in reducing disease activity and dryness [104,194,195]. Ianalumab, a BAFF-R inhibitor, was well tolerated and induced dose-dependent SS activity reduction [196], with sustained B cell depletion and minimal side effects [197]. Similarly, telitacicept, a fusion protein, suppressed B cell maturation and autoantibody secretion, while improving fatigue and exocrine gland function in pSS patients [198].

TNF-α inhibitors present mixed results. Infliximab showed poor response and high discontinuation rates among anti-Ro/SSA-positive patients. Similarly, adalimumab, although potentially beneficial for SS patients who also suffer from Crohn’s disease, like etanercept and infliximab, can lead to anti-drug antibody development and does not improve SS dryness or salivary flow, discouraging further investigation [23,188,199].

Cytokine pathway targeting (e.g., IL-6, IL-17) shows promise. Secukinumab (IL-17 inhibitor) and tocilizumab (IL-6 inhibitor) are currently under investigation for their ability to suppress systemic fatigue, glandular dysfunction, systemic and ocular inflammation in SS patients. Secukinumab downregulates IL-1RA and IL-38, modulating T_reg/Th17 signaling [200]. Lung involvement has been recorded in 10–20% of SS patients, hence, tocilizumab could be an alternative therapeutic strategy, used for SS-associated refractory organizing pneumonia [201]. Nevertheless, it showed limited effect on immunoglobulins, symptom relief, complement, and systemic SS activity [23,202].

Selective phosphoinositide 3-kinase (PI3K) pathway inhibitors like seletalisib, leniolisib, and parsaclisib are also promising agents in regulating SS-related B cell activation and inflammatory cytokines, as they suppressed autoantibody production, Th17 activation, type I IFN signaling, and glandular inflammation while improving salivary flow and fatigue in early trials, concurrently pointing to the need for further studies [188,203,204,205].

Bruton’s tyrosine kinase (BTK) inhibitors, namely remibrutinib and tirabrutinib, and other kinase inhibitors like lanraplenib (spleen tyrosine kinase (SYK)-binding) and filgotinib (Janus kinase (JAK) inhibitor) are early-phase SS treatment candidates that showed partial efficacy. Remibrutinib reportedly improved gene and protein expression, while tirabrutinib, lanraplenib, and filgotinib failed to meet both primary and secondary endpoints [206,207]. However, JAK inhibitors like tofacitinib and baricitinib displayed suppressive effects on IFN-Is and pro-inflammatory signaling. Tofacitinib reduced IL-6 and autophagy protein 5 (ATG5) expression in labial SG (LSG) epithelial cells of pSS patients, mitigating JAK/signal transducer and activator of transcription (STAT)-driven inflammation [188,208,209,210]. Baricitinib, targeting JAK1/2, shows potential against arthritis, ILD, and skin rash, though further evidence is needed [188,211], whereas there are ongoing trials for other JAK inhibitors as well, including deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor with potential anti-SS behavior [212].

Emerging strategies include interference with IFN-I pathways. Biologics like RSLV-132 and RO5459072 (cathepsin S (CatS)) [213] are under evaluation as immunomodulatory therapies. RSLV-132, a recombinant RNase Fc fusion protein, degrades extracellular RNA, reduces IFN-I gene expression, and alleviates fatigue [188,214]. All aforementioned biological and targeted inhibitors are illustrated in Figure 9.

5.4.2. Anterior and Posterior Segment Ocular Drug-Delivery Technologies

Drug delivery to the anterior eye segment (including the cornea, conjunctiva, and aqueous humor) faces challenges due to tear clearance, corneal barrier resistance, and enzymatic degradation. Non-systemic kinase inhibitors (NSKIs) like TOP1360, the tear glycoprotein lacritin, and thymosin β4 derivative RGN-259 modulate ocular inflammation and protect against focal lymphocyte infiltration. TOP1360 decreases ocular inflammation by targeting upregulated kinases in DED, like p38-α, SYK, sulfiredoxin (Srx), and lymphocyte-specific protein tyrosine kinase (Lck). Clinical trials confirm its safety, tolerability, and efficacy in relieving ocular dryness, discomfort, foreign body sensation, and grittiness [23,94,215]. Furthermore, thymosin β4-derived RGN-259 has demonstrated efficacy in neurotropic keratitis. Patients reported reduced ocular discomfort and improved tear volume production [216]. In murine models, it increased mucin and goblet cell density and reduced inflammatory factors [217]. While primary endpoints (ocular discomfort, inferior corneal staining) were unmet, secondary outcomes supported its safety and potential benefit in managing SS-related DED [23,218].

Lacritin levels are reduced in SS, correlating with corneal neuropathy, DED, reduced nerve fiber density (NFD), and length (NFL). Lacritin supports ocular surface integrity by targeting syndecan-1 (SDC1) during heparinase cleavage, offering strong diagnostic sensitivity and specificity [23,219,220]. In knockout mice, it enhanced tear secretion, lowered K10 expression, and significantly reduced focal CD4⁺ T cell infiltration [221]. Its active 19 amino acid fragment, Lacripep, induced clinically remarkable improvements in corneal and conjunctival staining, marking it as a promising future therapy [219,222].

Drug delivery to the posterior eye segment (comprising the retina, choroid, and vitreous humor) is harder to target than the anterior one, as it is limited by the blood-retinal barrier. Intravitreal biodegradable implants, such as fluocinolone acetonide, allow sustained anti-inflammatory drug release and reduce injection frequency. They show great promise for managing severe autoimmune corneal disease cases (Figure 10) [23,223].

5.4.3. Gene Therapy and Epigenetic Modulation

Advances in gene-editing technologies, particularly CRISPR-Cas9, have opened new avenues for targeting SS pathogenic cytokine expression, aiming to halt disease progression and correct immune dysregulation. Current studies are exploring the genetic silencing of persistently overactive SS patients, with IFN-regulated genes. Gene therapy targeting pro-inflammatory cytokines (e.g., TNF-α, IL-6) is being investigated for its potential to “reprogram” immune responses [188,224]. Moreover, epigenetic therapies that modulate DNA methylation and microRNA expression are promising in reducing autoimmune hyperactivity and restoring lacrimal gland function (Figure 10) [75,97,98,99,100,188,224].

5.4.4. Contact Lens Drug-Delivery and Colloidal Nanocarriers

Conventional treatments for DED and other ocular complications, like eye drops, often face limitations in achieving controlled and effective drug absorption. Therefore, there is a pressing need for targeted and sustained drug delivery systems to enhance therapeutic outcomes. Therapeutic CLs loaded with active agents (e.g., HA, CyA) into their porous matrix offer prolonged contact time, controlled and effective drug release. They can deliver anti-inflammatory (e.g., dexamethasone (Dex)), osmoprotective, and secretagogue substances, alongside rewetting agents, thus improving comfort and treatment adherence. Compared to standard eye drops, therapeutic CLs provide longer drug retention, better patient compliance, and reduced ocular irritation and toxicity [23,225,226].

Colloidal nanocarriers (CNs) represent another innovative approach in ocular drug delivery for SS-related DED. Unlike conventional eye drops that suffer from rapid tear clearance and low bioavailability, CNs enhance corneal penetration, prolong ocular surface retention, and enable controlled drug release. Various CNs under investigation include liposomes that encapsulate both hydrophilic and lipophilic compounds (i.e., azithromycin, CyA), polymeric nanoparticles (NPs) (e.g., polylactic acid (PLA), Dex, chitosan, HA), nano-micelles, nanowafers, microneedles, and dendrimers of high-drug loading capacity, as illustrated in Figure 10 [23,227,228,229,230,231,232,233,234,235].

5.4.5. Stem Cell Therapy and Regenerative Approaches

Emerging regenerative strategies for SS focus on mesenchymal stem cells (MSCs) due to their immunomodulatory and tissue-regenerative properties. MSCs reduce lymphocytic infiltration, enhance anti-inflammatory cytokine production, promote epithelial regeneration, and restore tear and glandular function. Their immunomodulatory effects on T and B cells, DCs, and NKs—partly via regulation of the T cell immunoglobulin and mucin-domain containing-3 (Tim-3) inhibitor—have shown promise in alleviating SS symptoms [236,237,238]. Specifically, MSCs suppress Th1 and Th17 lymphocytes, disrupt T-B cell interplay, downregulate autoantibody formation, and promote survival of injured and inflamed lacrimal and salivary glands [26,236].

Dental pulp-derived stem cells (DPSCs) have exhibited superior effects over bone marrow MSCs (BMMSCs) in reversing hyposalivation, reducing inflammation, and minimizing glandular fibrosis [239,240,241,242,243]. Similarly, umbilical MSCs (UCMSCs) regulate immune activity by promoting CD4⁺/Forkhead box P3 (Fox3⁺) T cells, inducing Th17 apoptosis, and improving T_regs/Th17 balance [244]. UCMSCs also suppressed Vγ4⁺IL-17⁺, increasing saliva flow, regulating T_reg/Th17 immunity, and lowering pulmonary inflammation [245,246]. However, CLs have also been linked to limbal stem cell deficiency (LSCD). Drug-eluting CLs may help prevent or slow LSDC progression [247,248].

A revolutionary approach involves stem cell-coated CLs (often limbal epithelial stem cells) to enhance corneal repair and epithelial regeneration in severe ocular surface disease [238,247,248,249,250]. Advanced high-oxygen, permeable hydrogel CLs coated with UCMSCs have demonstrated long-term retention on the ocular surface, reduction of corneal inflammation, inhibition of Th1/Th17 differentiation, and promotion of T_reg conversion in models of ocular graft-versus-host disease (oGVHD) and potentially SS [251,252]. Nevertheless, broader clinical adoption is hindered by donor compatibility issues and lengthy preparation times, requiring further validation [23,253].

To overcome these challenges, exosome-based therapies (e.g., exosome extracellular vesicles) have emerged as a non-invasive alternative. Stem cell-derived extracellular vehicles (EVs) carry bioactive molecules that promote epithelial healing, immune regulation, and inflammation suppression [253,254]. These exosomes, with stable fatty acid membranes, can cross dense biological barriers and restore glandular function, ensuring stability and structural rigidity [23,148,253]. For example, labial gland-derived MSCs (LGMSCs) and their exosomes reduce inflammation by promoting T_reg differentiation and inhibiting Th17 cells, offering a cell-free SS therapeutic approach [255]. LGMSC-derived exosomal miR-125b has been beneficial towards restoring salivary secretion, reducing CD19⁺CD20⁻CD27⁺CD38^+, and regulating pSS plasma cells by targeting the PR domain zinc finger protein 1 (PRDM1) [255,256,257]. Likewise, olfactory ecto-MSC-derived exosomes ameliorated SS in murine models by modulating myeloid-derived suppressor cells (MDSCs), upregulating arginase expression and ROS levels, thereby mitigating disease progression [258]. Despite these advancements, extensive clinical trials are essential before systemic application of MSCs and their exosomes (Figure 10) [258].

6. Future Directions, Perspectives, and Research

SS is a multifactorial autoimmune disease with substantial unmet clinical needs. A paradigm shift toward precision medicine, targeted immunotherapies, and regenerative strategies is essential. Current treatments such as immunosuppressants, glucocorticoids, and csDMARDs offer symptom relief but do not address the disease’s root cause, which remains unclear. Moreover, SS-specific therapeutics are still lacking, and existing drugs require further validation. Identifying predictive biomarkers like IFN signatures, BAFF levels, and genetic/epigenetic markers may enhance early, individualized diagnosis and predict treatment [9,54,55,56,57,58,61,64]. Novel immunomodulatory agents, including BTK (e.g., remibrutinib, tirabrutinib), PI3K (e.g., seletalisib, parsaclisib), and JAK inhibitors (e.g., tofacitinib, baricitinib), have shown great promise in reducing B-cell hyperactivity, cytokine-driven ocular inflammation, and systemic complications [203,204,206,207,208,209,210,211,227,229]. Further exploration of cytokines such as IL-1β, -6,-17, -23, 38, and TNF-α, and their role in T and B cell regulation, is critical for developing precise immune interventions [22,23,188].

MSCs and exosome-based therapies hold vast potential for restoring exocrine gland function. However, standardized protocols, long-term safety data, and well-structured clinical trials are needed to translate these therapies into routine care [26,237,238,249,253,254,255,256,258]. In the realm of gene and epigenetic therapy, tools like CRISPR-Cas9 and miRNA modulation offer potential for altering SS-related gene expression, but delivery methods and safety profiles must be further refined [97,98,99,100,224,256]. Emerging evidence also highlights the role of gut dysbiosis in SS-related inflammation, indicating potential for microbiota-based adjunct therapies [117]. In parallel, novel approaches such as immune cell engineering, in vitro autoimmune models, immunophenotyping, and artificial intelligence (AI)-driven diagnostic platforms may revolutionize SS research [22,188].

Accelerating the approval of novel therapies will require an optimal clinical trial design, including early predictors of treatment response, biomarkers for drug efficacy evaluation, standardized disease activity scoring, and minimization of background therapy confounding effects. Ultimately, establishing safe, effective, and personalized treatment protocols, based on symptom-specific combination therapies and novel drug candidates, is expected to mark a turning point in SS care and clinical outcomes [22,188].

7. Concluding Remarks

Sjögren’s Syndrome is a chronic systemic autoimmune condition marked by complex ocular and systemic manifestations. Its heterogeneous inflammatory mechanisms, especially in patients with overlapping autoimmune disorders, contribute to important diagnostic and therapeutic challenges. Timely diagnosis and tailored therapeutic strategies are crucial for mitigating complications such as scleritis and corneal damage. Currently, a diverse spectrum of mitigation options—from artificial tears or corticosteroids to advanced biologic agents and surgical interventions—allows for personalized SS management.

Looking ahead, emerging therapies targeting neuroinflammation, oxidative stress, and epigenetic regulation offer hope for more effective treatments of both systemic and ocular SS complications. Nonetheless, large-scale clinical studies remain essential to validate these approaches and integrate them into evidence-based care. Despite notable progress, the underlying immunopathology of SS remains incompletely understood, particularly regarding innate immune activation, cytokine regulation, and lacrimal gland dysfunction. This review sought to elucidate the complex autoimmune mechanisms of SS, critically assess current SS treatment strategies, and highlight innovative remedies with potential clinical impact. As research continues to evolve, the integration of targeted, regenerative, and individualized therapies could pave the way for improving management and long-term outcomes in SS patients.