SJS is a rare but potentially life-threatening adverse drug reaction characterized by mucocutaneous involvement, including severe ocular complications [[1], [2], [3], [4]]. Detailed ophthalmic consultation is warranted in all stages of SJS including the inflammatory acute stage (day of onset to 2 month), sub-chronic (2 months to 6months from onset) and the cicatricial chronic (more than 6 months from onset of SJS) [5]. Various topical (topical corticosteroid, lubricants) and surgical measures (amniotic membrane grafting (AMG), limbal stem cell transplantation (LSCT), cultivated oral mucosal epithelial transplantation (COMET), mucous membrane grafting (MMG)) help contain the persistent inflammatory episodes on the ocular surface, restore visual acuity and improve the quality of life to an extent [[6], [7], [8], [9], [10], [11], [12]].

The pathophysiology of SJS in the ocular surface is not fully understood. Literature suggests that in the acute phase, there is the presence of a severe cytokine storm and pro-inflammatory mediators in tears and serum [13,14]. As the disease progresses into the chronic phase, the ocular surface displays persistent underlying inflammation triggered by various combined immune mechanisms [15]. The mystery behind the underlying immunopathogenesis in the ocular surface necessitates the need for novel treatment modalities for SJS related ocular complications.

Neutrophils are widely established to be key mediators of inflammation, infection and stress in human body and ocular surface [[16], [17], [18], [19]]. Activated neutrophils release extracellular chromatin webs composed of DNA, histones and granular proteins together known as neutrophil extracellular traps (NETs) in response to diverse stimuli [20]. Elevated NETs have been reported in tears in Sjogren's syndrome, chronic oGVHD, non-Sjogren's DED and ocular cicatricial pemphigoid [16,19,21]. This process of excessive NETs formation (called Netosis) could be activated due to increased tear hyperosmolarity induced stress on the ocular surface in dry eye disease [22]. Hyperosmolar stress, alone, can also induce NETosis in healthy neutrophils, even in the absence of other NETosis inducers on ocular surface [22]. Elevated NETs are also associated with systemic autoimmune and inflammatory disorders [23]. Myeloperoxidase (MPO)-DNA complexes has become the most commonly used quantitative assay for assessing NET formation [24]. Several immune pathway genes have been associated with NETs formation include Toll-like receptor 9 (TLR9) [[25], [26], [27]], Myeloid differentiation primary response 88 (MyD88) [28], Interleukin 8 (IL-8) [29], Tumor necrosis factor superfamily member 14 (TNFSF14) [30]and complement component 3a (C3a) [31].

Unfractionated Heparin, a glycosaminoglycan widely known for its anticoagulant capabilities in surgical and medical management for multiple diseases, is slowly emerging as a therapeutic entity from the ophthalmic perspective. Heparin eye drops has previously known to reduce the recurrence of pseudo-membranes in ocular chemical injury cases [32]. Heparin eye drops administered post operatively in cases of extracapsular cataract extraction has been reported to reduce the occurrence of posterior capsular opacification (PCO) [33]. In SJS, drug specific T-cells released in the acute onset systemically, are capable of releasing cytokines and interferons which can activate eosinophils, basophils and neutrophils [34]. There are no previous studies documenting presence of NETs on ocular surface in SJS. This study aims to identify NETs present in SJS eyes, assess the efficacy of topical LDH in chronic and sub-chronic SJS cases, and correlate these findings with the expression of immune pathway genes.