# Emerging Trends and Management for Sjogren Syndrome-Related Dry Eye Corneal Alterations
## 4 Extragalundular Corneal Complications  
### Clinical Manifestations  
The cornea is the ocular structure most frequently and severely involved in extra-glandular ocular manifestations. Corneal extra glandular complications are the most commonly described vision-threatening SS-related disorders. They have a global prevalence of 2.5-4% among SS patients, are present in 2.5% of cases at disease presentation, are more frequently found in men (90% of cases) and in sSS-RA patients (up to 75% of cases), and are typically associated with other extragalandular ocular complications, especially necrotizing scleritis [2, 6, 7, 8, 9, 12, 13]. Moreover, severe extragalandular corneal complications are linked to higher levels of systemic inflammatory markers (ESR erythrocyte sedimentation rate and CRP C-reactive protein) and to other extragalandular severe systemic manifestations, especially peripheral neuropathy, interstitial nephritis, and vasculitis as well as greater risk of mortality as compared to the other SS patients [8]. These data suggest that extragalandular corneal complications may have a more complex polyautoimmunity pathogenesis [45, 46] and that they may represent a barometer of systemic disease activity, especially in pSS patients [8]. Corneal extragalandular manifestations include the following:  
_A. Sterile central or paracentral corneal scarring/ulcerl melting or keratolysis:_ This is a rare, potentially blinding condition that is occasionally recurrent and may lead to corneal perforation. It can be associated with SS (2.5-3.6% of cases) [8, 9, 10, 12, 13, 86, 10] and with other systemic AI diseases [11]. It is characterized by the development of epithelial defects and progressive reduction in the stromal components in a non-inflamed eye, and it may evolve into descemetocele formation and corneal perforation [10, 13]. The sterile ulcer is typically painless, but in 40% of cases, it may involve the visual axis, inducing blurred vision and reduced visual acuity. The incidence of perforation in sterile ulcers of SS patients is high, reaching 40% of cases, because these ulcers are often painless and have a delayed diagnosis [10, 13]. Several instances of sterile corneal ulcers/melting/impeding corneal perforation or frank perforation associated with SS have been described in the literature, especially in sSS-Ra patients [13, 85], but also as the initial presentation of an undiagnosed pSS [13, 86]. Moreover, several case reports of sterile central/paracentral corneal ulceration/melting/perforation have been described in both pSS and sSS patients typically 2-8 weeks after cataract extraction and associated with a post-operative topical therapy with corticosteroids (CSs) or non-steroidal anti-inflammatory drugs (NSAIDs) [69, 70] and also as the first presentation of an undiagnosed pSS [69, 70]. Topical NSAID- and CS-induced corneal melt/perforations were previously reported [68]. Topical corticosteroids are thought to impair corneal wound healing processes by decreasing new corneal collagen synthesis [68]. On the other hand, topical NSAIDs have been demonstrated to reduce corneal re-epithelialization and corneal ulcer healing with several mechanisms by stimulating the release of the neutrophil collagenases, i.e., the matrix metalloproteinases-8, which seem to play an important role in keratolysis; by decreasing corneal epithelium migration and keratocytes proliferation; and by reducing corneal sensitivity, with consequent neurotrophic epithelliopathy and corneal re-epithelialization impairment [68]. The combination of DED, AI disease, SS-related corneal hyposensitivity with decreased blinking and tear reflex, cataract surgery-inducing inflammation and corneal nerve fiber interruption, and therapy with CSs and NSAIDs seems to be very dangerous for the cornea. It should be considered with extreme caution in SS patients [69, 70]. CSs and NSAIDs should thus be avoided in patients prone to corneal epithelial breakdown, such as SS patients. _B.