The underlying etiology of Sjögren syndrome is not clearly elucidated; however, genetic, hormonal, and environmental factors are thought to be involved. As with other autoimmune disorders, extrinsic or intrinsic stimuli in genetically predisposed individuals are thought to be responsible for disease manifestation [4]. Perimenopausal women are more commonly affected by SS, suggesting an immunoregulatory effect of sex hormones on the development of disease, likely related to an imbalance of the estrogen-androgen ratio [3, 24]. Animal models have demonstrated acceleration of pathologic changes including lymphocyte infiltration and apoptosis in genetically predisposed animals following removal of ovarian sex hormones and conversely prevention following sex hormone replacement [25]. Viral triggers have also been proposed, with activation of immune mechanisms through the type I IFN system, which has been widely implicated in autoimmune disorders [4]. MHC class II genes are associated with pSS, in particular HLA-DR and DQ alleles [3]. Polymorphisms of the IRF-5 and STAT4 genes, as well as the increase in copy of immunoregulatory genes FCGRB and CCL3L1, may increase disease susceptibility [4, 26–30]. Autoantibody production including anti-SSA/Ro and anti-La/SSB La is associated with early onset and longer duration of disease, as well as more intense immune cell infiltration, higher frequency of extraglandular manifestation, and parotid gland enlargement [3].

The underlying histopathology of SS includes periductal lymphocytic infiltration of salivary and lacrimal glands and destruction of tissues [31]. Infiltrates generally consist of CD4+ T cells, CD8+ T cells, B cells, and macrophages [8]. While the majority of the infiltrating cell population is comprised of T cells, B cell autoreactivity is thought to play an important role in both preclinical and clinical disease [8, 25]. Apoptosis of acinar cells is also a prominent feature, leading to hypofunction and hyposecretion of fluids, and in animal studies has been shown to occur after immune cell infiltration following oophorectomy [25]. There continues to remain some debate as to whether apoptosis follows the inflammatory phase, and some authors suggest that apoptosis may have a role in initiating the disease process in genetically susceptible individuals [24]. Non-apoptotic mechanisms may also play a role, leading to hypofunction of secretory mechanisms. These include neural dysregulation via inhibition of neurotransmitter release by cytokines, increased levels of cholinesterase leading to reduced Ach, and M3R antimuscarinic antibody blockade [8, 24]. Changes in the expression and distribution of aquaporin5 in the acini of salivary glands are thought to contribute to reduced fluid secretion, both in the inflammatory and noninflammatory phases [24].

Tears are crucial for the maintenance of a healthy ocular surface. Not only do they provide lubrication but contain a host of growth factors, vitamins, and neuropeptides that promote a healthy environment for the ocular surface epithelium [32]. Ocular signs and symptoms related to pSS are a result of immune cell infiltration and destruction of the lacrimal gland, leading to aqueous tear deficiency and the secondary effects of this, sicca syndrome. Patients may complain of dryness, foreign body sensation, redness, fatigue, itching, reduction in vision, and reflex tearing. Deficiency of tears also leads to a proinflammatory response, immune cell infiltration, loss of surface epithelial integrity, and eventually keratinization of the ocular surface [33]. This latter process is known as squamous metaplasia. In addition, meibomian gland dropout may occur and lead to increased tear evaporation, compounding the effect of reduced tear production and leading to increased fluorescein and rose Bengal staining that is seen in SS-related ATD (aqueous tear deficiency) vs. non-SS ATD [34, 35]. In severe cases, persistent corneal epithelial defects or ulceration may also occur, putting patients at risk for corneal infection.

Evaluation for ocular involvement in SS begins with a patient history focused on symptoms of dry eye mentioned previously, as well as use of artificial tear substitutes and their effect on alleviating symptoms. Formal scales such as Ocular Surface Disease Index (OSDI) and OCI patient symptom questionnaires may be used. Ophthalmic testing includes Schirmer basal tear secretion testing, evaluation of tear film height, rose Bengal staining and score, fluorescein staining, lissamine green staining, tear breakup time evaluation, assessment of meibomian gland dysfunction, and careful conjunctival and corneal examination to assess for punctate epithelial erosions, corneal filaments, epithelial defects, corneal thinning, ulceration, or squamous metaplasia. Lacrimal scintigraphy is another tool that has been evaluated in SS patients and been shown to correlate closely with rose Bengal staining, Schirmer testing, tear breakup time, and the ocular surface disease index [36]. Other specialized tests may include tear osmolarity testing, tear lactoferrin and lysozyme measurement, and impression cytology for evaluation of goblet cells. More recently, in vivo confocal microscopy of the lacrimal gland has been shown to demonstrate acinar unit dilatation, interstitial fibrosis, and inflammatory cells in SS patients and may aid in the noninvasive evaluation of SS patients [37].

A wide array of treatments have been studied for the management of dry eyes in SS patients including topical lubricants, autologous serum, topical corticosteroids, topical anti-inflammatory therapy, secretagogues, and systemic immunosuppressive agents, as well as interventions such as punctual occlusion with plugs or cautery [38].

Initial treatment strategies for aqueous deficiency in SS begin with aqueous supplementation, generally using artificial tear substitutes, which show consistent improvement in symptoms over baseline [38]. These vary from drops to more viscous gels and ointments. Studies suggest that the use of more viscous lubricants affords greater comfort with reduced frequency of use and increased duration of effect [39]. The use of serum tears has been advocated in the treatment of dye eyes and ocular surface disease due to the presence of growth factors and bactericidal agents, which provide additional benefits to aqueous supplementation in maintaining a healthy ocular surface epithelium [32]. It has been shown, when diluted with saline, to improve both subjective and objective dry eye parameters among SS patients [40].

When aqueous supplementation is insufficient to control sicca symptoms, reduction in tear drainage may be addressed. This can be done via placement of punctual plugs to mechanically occlude one or both puncta on each side or thermal punctual cautery. Placement of Smartplugs in the inferior canaliculi only has been shown to improve Schirmer I testing as well as reduce tear breakup time [41]. Additionally, partial cauterization of the puncta to achieve a punctual opening of 0.5 mm improves clinical signs such as fluorescein staining, rose Bengal staining, tear breakup time, and Schirmer I testing, an effect that is sustained for up to 2 years following treatment [42]. The use of topical anti-inflammatory agents has also been prospectively studied, including corticosteroids and nonsteroidal anti-inflammatory drugs [38]. While varying improvement in subjective and objective parameters has been shown, side effects such as increased intraocular pressure, cataract formation, and corneal epithelial staining may limit their use long term. Topical cyclosporine, in varying concentrations, has been shown in several prospective, randomized controlled trials to improve ocular signs such as surface staining, Schirmer testing, and tear breakup time as well [38]. In one study, a reduction of activated lymphocytes was noted in conjunctival biopsies of SS patients treated with 6 months of topical 0.05 % cyclosporine [43]. Given its relative clinical safety with long-term use, it use should be considered in patients with SS [38].

As described in a recent review of 66 previously published reports regarding the treatment of SS-associated dry eyes, several oral agents have been studied including secretagogues such as pilocarpine and cevimeline [38]. The use of oral pilocarpine has been shown to improve sicca symptoms in SS patients, and in one study of 5 mg twice daily, it showed significantly better subjective outcomes and improved rose Bengal staining compared with artificial tear use or punctual occlusion [44]. In another study, tear meniscus height as measured by Visante OCT was shown to improve following oral administration of pilocarpine, 5 mg twice daily, as were signs and symptoms of dry eye [45]. Cevimeline has also shown promising results in double-blinded, randomized controlled trials, with recommended dosage of 30 mg three times per day [38]. A number of other systemic agents have been studied, including corticosteroids, cyclosporine, hydroxychloroquine, rituximab, infliximab, etanercept, mycophenolic acid, and interferon alpha-2. Although these agents may be beneficial in the treatment of systemic manifestations of SS and for the treatment of SS-associated dry eyes, there is insufficient data to suggest significant improvement with their use [38].