# Emerging Trends and Management for Sjogren Syndrome-Related Dry Eye Corneal Alterations
## 5 Conclusions and Future Directions  
SS represents one of the systemic disorders that most frequently affects the cornea [10]. Several other systemic diseases, including endocrine, genetic, deposit disorders, virus and bacterial infections, and autoimmune and inflammatory disorders, may have a great impact on corneal health, although they often remain under-evaluated [10,11]. Corneal manifestations may precede the onset of other extraocular features, therefore representing the first sign of an undiagnosed systemic condition. In these cases, the identification of the corneal involvement may provide insight into the pathogenesis of the underlying systemic condition. It may help facilitate early diagnosis and prompt treatment, thus limiting systemic disease progression [10,11]. Several studies in the literature have enhanced our comprehension of SS and its intricate relationship with DED and corneal pathology. The TFOS DEWS II Definition and Classification Report by [PERSON] et al. (2017) [23] offers a thorough and standardized definition of DED, highlighting its multifactorial characteristics and recognizing tear film instability, hyperosmolarity, inflammation, and neurosensory abnormalities as primary etiological factors. This concept has established the basis for much of the ensuing research and clinical categorization of SS-related ocular involvement. New insights onto the pathophysiological mechanisms underlying the SS-related corneal involvement may be extremely relevant in understanding clinical disease manifestations, helping in effective patient counseling and suggesting new customized therapeutic strategies. For example, the corneal nerve abnormalities found in Sjogren's syndrome patients, characterized by diminished nerve density, heightened tortuosity, and atypical reflectivity on in vivo confocal scanning laser microscopy [32,34], may elucidate the paradox often observed in SS patients, whereby considerable corneal staining and epithelial injury coexist with low reported discomfort or where, conversely, neuropathic ocular pain, burning, and photophobia are disproportionate to objective findings [38,40]. Since specific corneal nerve abnormalities have been found to precede other SS clinical manifestations, their detection may be useful in order to anticipate disease diagnosis [32,34]. Furthermore, the comprehension of the role of neuro-inflammation and neuronal degeneration in SS-related DED may direct research towards the use of neuroprotective or neuroregenerative agents (e.g., nerve growth factor-based eyedrops). The upregulation of pro-inflammatory cytokines, including IL-17, IL-8, IFN-\(\gamma\), and TNF-\(\alpha\), is commonly detected in the tear film and ocular surface tissues of DED patients but appears significantly more pronounced in Sjogren's syndrome patients [27]. These cytokines have been demonstrated to worsen lachrymal gland damage, epithelial barrier disruption, goblet cells loss, and degeneration of corneal nerves, resulting in severe eye dryness, persistent ocular surface staining, corneal and conjunctival scarring, and diminished corneal sensitivity. The discovery of their upregulation in SS patients has suggested the use of several topical and systemic anti-inflammatory molecules in the SS-related DED, including steroids [71; 74], cyclosporine A [75], lifitigrast [79; 80], and many systemic immunomodulatory agents [103; 104]. Elevated IL-17 tears levels are associated with more severe corneal pathology and reduced efficacy of standard lubricants, prompting doctors to contemplate the earlier use of biologic medicines or serum eye drops in the treatment protocol [27]. The upregulation of the matrix metalloproteinase (MMP)-9 has been linked to the increased proteolytic activity found in cases of sterile central corneal ulcer [85; 92] and may suggest the use collagenase inhibitors such as acetylcysteine [123] or doxycycline [57]. The frequent and sometimes severe corneal involvement in SS patients may have several explanations.