The existence of keratinizing squamous metaplasia in the posterior lid margins of patients with Stevens-Johnson syndrome indicates a potential role of inflammation in the pathogenesis of lid margin keratinization in Stevens-Johnson syndrome, according to research results published in The Ocular Surface.
Currently, few published studies examine the histopathological and etiopathogenesis of lid margins in chronic Stevens-Johnson syndrome. Researchers therefore conducted a literature review to try and determine the pathophysiological mechanisms involved in lid margin keratinization, as well as to identify new data from immunohistochemical studies.
Twenty-five studies published through September 2020 were identified and included in the review. Studies demonstrated that the exact mechanism of lid margin keratinization in Stevens-Johnson syndrome is unclear, with proposed sources of keratinized epithelium at the posterior lid margin of the adjacent anterior eyelid epidermis, hyperkeratinized epithelium from the meibomian gland ductal orifices, or de novo metaplasia of the conjunctival epithelium.
Dry eye disease in Stevens-Johnson syndrome is “of mixed etiology” and involves both an aqueous deficiency and meibomian gland dysfunction. In Stevens-Johnson syndrome, severe meibomian gland dysfunction can occur with no observed expressible glands in up to 71% of patients, according to the study. Hyperkeratinization at the ductal orifice may also be attributed to reactive immune mediated processes or due to alteration of the microbial flora of the lid margin.
Squamous metaplasia of the conjunctiva may occur resulting from chemical or thermal burns, dry eye, vitamin A deficiency, mucous membrane pemphigoid, and Stevens-Johnson syndrome. Studies have evaluated the pathogenesis of squamous conjunctival metaplasia in Stevens-Johnson syndrome, and — as previously noted — inflammation “likely plays an important role in many of these cases.”
Investigators also noted the possibility that autoantigen in the lid margin is exposed in Stevens-Johnson syndrome, triggering an autoimmune inflammatory response.
In an analysis of 55 posterior lid margins from 40 patients, investigators found that all patients demonstrated chronic ocular sequelae of Stevens-Johnson syndrome with a mean lid complication score of 9.5 and mean corneal complication score of 6. Values for Schirmer I tests were available for 37 eyes, 14 of which had 0 tear secretion. In all specimens, mucocutaneous junction appearance was distorted and not discernable.
Investigators found parakeratosis in the lid wiper zone, with keratin shedding in the acellular superficial layers of the epithelium.
The predominant histopathological changes in these specimens were diffuse subepithelial inflammatory infiltration involving the lid margin in 98% of lid margins. Clear demarcation of the start of the inflamed zone was noted in 78.2% of lid margins. Inflammation generally involved both the skin and conjunctiva sides in 20% of lid margins.
Other epithelial changes included branching and long rete ridges in 20%, basal cell vacuolar degeneration in 1.8%, and epithelial down growth in 31% of lid margins. Meibomian gland acini were noted in 88.7% of biopsies, while the central duct was noted in 18% and demonstrated occluded orifices in 77% of these.
Deeper biopsy sections showed apparent ectopic sebaceous glands in 20 lid margins, which either continued into meibomian glands or which were associated with the hair follicle. Stromal changes — fibrosis, dilated and proliferating blood vessels, and stromal lymphocytes — were noted in 65%, 34.5%, and 36.3% of lid margins, respectively.
Infiltrating immune cells generally included mixed B and T lymphocytes with CD20, CD4, and CD8 positivity. Inflammatory foci showed CD20 positivity in all lid margins with inflammation.
Keratinized posterior lid margins from patients with chronic Stevens-Johnson syndrome showed squamous metaplasia and specific involvement of the mucocutaneous junction and lid wiper conjunctiva, with diffuse subepithelial inflammatory infiltrate abutting the basement membrane area.
Future research must be conducted to understand the pathophysiology of lid margin keratinization, and studies should evaluate expressions of protein kinase C, TGase 1, and cytokeratin 1/10 proteins in the keratinized lid margin epithelium.
“[Lid margin keratinization] is a complication seen in many patients with chronic [Stevens-Johnson syndrome] patients and occurs despite AMT over the lid margins in the acute stage,” according to researchers. “The predominant subconjunctival localization of the inflammation indicates the possible role of inflammation in inducing keratinizing squamous metaplasia.”
Singh S, Jakati S, Shanbhag SS, Elhusseiny AM, Djalilian AR, Basu S. Lid margin keratinization in Stevens-Johnson syndrome: Review of pathophysiology and histopathology. Ocul Surf. Published online April 3, 2021. doi:10.1016/j.tos.2021.03.001