# Emerging Trends and Management for Sjogren Syndrome-Related Dry Eye Corneal Alterations
## 4 Extragalundular Corneal Complications
### Therapeutic Interventions
Polycarboxoxymethylglucosesulphate is a bioengineered molecule with reparative and regenerative properties, whose administration as eyedrops has shown to improve healing of SS-related corneal melting [86]. Lacripep is a molecule with anti-inflammatory/immunoregulatory effects on the ocular surface [127]; rapamycin is a new immunosuppressor whose topical administration has improved tear secretion and ocular surface damage in a PSS animal model [128]. Experimental therapeutic strategies to manage SS include various biological drugs that target different inflammation signaling pathways related to the activation of B and T cells and the regulation of several proinflammatory cytokine expressions. To date, several biologic drugs have been shown to significantly improve clinical systemic manifestations in pSS patients in randomized placebo-controlled clinical trials, including rem brtutinib, dazodalibep, epratuzumab, iguratimod, inalalumab, leflfunomide associated with hydroxychloroquine, iscalimab, sequential administration of belimumab and rituximab, baricitinib, low doses of interleukin-2, interferon alfa-2b, and ROS459072 [118; 45; 120]. Unfortunately, data about the efficacy of these drugs on the SS-related glandular and extragalundular ocular manifestation are generally unavailable [118; 120]. Diet supplements, including omega-3 and omega-6 fatty acids, oral hyaluronic acid, astaxanthin, maquibherry extract, and bilberry extract, having well-known anti-oxidant, anti-inflammatory, anti-apoptotic, and immunomodulatory effects, have shown poor-to-moderate therapeutic efficacy in improving signs and/or symptoms in DED patients [57; 58; 129; 130]. Their assumption as a supplementary therapy in DED patients is endorsed by recent investigations [130]. Nevertheless, no specific data on SS patients are currently available. Microbiota transfer therapy has shown promising results in animal models. Germ-free mice colonized with human intestinal microbiota derived from healthy subjects showed higher levels of CD4+T-regulatory cells in the ocular draining cervical lymph nodes and a lower tendency of corneal barrier disruption when compared with germ-free mice colonized with intestinal microbiota of pSS patients [131]. The transplantation of allogenic mesenchymal stem cells or multipotent hematopoietic stem cells, having trophic and immunomodulatory properties, is under examination  
\begin{table}
\begin{tabular}{c c c} \hline \hline
**Therapeutic Agent/Approach** & **Therapeutic Effects** & **Scientific Evidences** \\ \hline \multirow{8}{*}{**Stem cells transplantation (pSS animal models)**} & & Mesenchymal stem cells or allogenic multipotent hematopoietic stem cells transplantation on the ocular surface has shown promising results in increasing tear secretion, tear film stability, and epithelial and goblet cells regeneration and in reducing ocular surface flogosis [132]. The administration of mesenchymal stem cells by intra-lacimal gland and subconjunctival injections has proven to inhibit epithelial cells autophagy, to reduce lymphocytic infiltration, and to decrease the objective signs of dry eye [133]. \\ \hline \multirow{8}{*}{**Gene transfer (animal models and human clinical trials)**} & & Adenoviral-mediated gene transfer or ultrasound assisted non-viral gene transfer of the AQP1 gene into damaged salivary glands are under investigation in several animal models [134] and in few clinical trials [135] and have shown promising preliminary results in increasing the parotid salivary flow. \\ \hline \multirow{8}{*}{**Gene transfer (animal models and human clinical trials)**} & & Adenoviral-mediated gene transfer or ultrasound assisted non-viral gene transfer of the AQP1 gene into damaged salivary glands are under investigation in several animal models [134] and in few clinical trials [135] and have shown promising preliminary results in increasing the parotid salivary flow. because high rates of graft rejection counterbalance their promising results despite local immunosuppression [120].