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Lid margin keratinization in Stevens-Johnson syndrome: Review of

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DOI: 10.1016/j.jtos.2021.03.011

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journal homepage: www.elsevier.com/locate/jtos

Lid margin keratinization in Stevens-Johnson syndrome: Review of

pathophysiology and histopathology
Swati Singh a, b, Saumya Jakati c, Swapna S. Shanbhag d, Abdelrahman M. Elhusseiny e,
Ali R. Djalilian e, *, Sayan Basu a, b, d, **
a
Centre for Ocular Regeneration (CORE), L V Prasad Eye Institute, Hyderabad, Telangana, India
b
Brien Holden Eye Research Centre (BHERC), L V Prasad Eye Institute, Hyderabad, Telangana, India
c
Ophthalmic Pathology Laboratory, L V Prasad Eye Institute, Hyderabad, Telangana, India
d
The Cornea Institute, L V Prasad Eye Institute, Hyderabad, Telangana, India
e
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States

A R T I C L E I N F O A B S T R A C T

Keywords: Lid margin keratinization (LMK) is a chronic ocular sequela of Stevens-Johnson syndrome (SJS), which causes lid
Stevens-Johnson syndrome wiper epitheliopathy and progressive ocular surface damage. The exact etiopathogenesis of LMK, however, re­
Lid margin mains elusive. This review summarizes the potential pathophysiological mechanisms of LMK and describes its
Lid margin keratinization
histopathological features. A literature search of articles discussing the pathophysiology of LMK in SJS was
Meibomian glands
Tarsal keratinization
performed. The possible pathophysiologic mechanisms contributing to LMK, as identified on the literature re­
Lip-wiper epitheliopathy view, included loss of the muco-cutaneous junction barrier leading to epidermalization, dyskeratosis involving
the meibomian gland orifices, altered lid margin microbiome, and de novo squamous metaplasia of the marginal
conjunctival epithelium. Based on these mechanisms, the possible sources of keratinized epithelium at the
posterior lid margin in SJS could be the adjacent anterior eyelid skin, hyperkeratinized epithelium from the
meibomian gland ductal orifices, or the inflamed marginal conjunctiva. The epithelial, sub-epithelial, and
stromal changes seen in keratinized posterior lid margins in SJS patients undergoing mucous membrane grafting
were also investigated. The findings revealed keratinizing squamous metaplasia of the posterior lid margin
accompanied by subepithelial infiltration of helper T cells predominantly on the conjunctival side. The visible
meibomian gland orifices had ductal hyperkeratinization and plugging. These findings support a role for
inflammation in the pathogenesis of LMK in SJS. Future research can be directed at delineating the pathways that
lead to LMK by studying the changes in the lid margin microbiome, and the molecular mechanisms regulating
keratinization in the conjunctiva and the meibomian gland orifices in eyes affected by SJS.

1. Introduction
Stevens-Johnson syndrome (SJS) is an immunologic dermato-
inflammatory disease that targets the skin and the mucosal surfaces
[1,2]. The ocular surface damage during the acute stage includes
conjunctival ulcerations, membrane formation, and sloughing of surface
epithelium including the lid margin [1]. The chronic sequelae are pre­
dominantly a result of dry eyes, conjunctival scarring/deficiency, loss of
limbal epithelial stem cells, and lid margin keratinization (LMK) [2].
The normal lid margin has a convex inner border, and the keratinized
epidermis stops abruptly behind the meibomian orifices’ posterior
margin [3]. Then begins the mucocutaneous junction (MCJ), followed
by the lid wiper zone that comes into contact with the ocular surface.
Keratinization of the lid margin is a common sequela of SJS/toxic
epidermal necrolysis (TEN) resulting in the formation of whitish keratin
deposits over the lid wiper zone and palpebral conjunctiva. LMK can
result in chronic epitheliopathy and ultimately loss of integrity of the
epithelium, and thus is strongly correlated with the corneal disease and

* Corresponding author. Stem Cell Therapy and Corneal Tissue Engineering Laboratory, Illinois Eye and Ear Infirmary, 1855 W. Taylor Street, M/C 648, Chicago,
IL, 60612, United States.
** Corresponding author. Brien Holden Eye Research Centre (BHERC) and Centre for Ocular Regeneration (CORE), L V Prasad Eye Institute, Road No.2, Banjara
Hills, Hyderabad, 500034, Telangana, India.
E-mail addresses: adjalili@uic.edu (A.R. Djalilian), sayanbasu@lvpei.org (S. Basu).

https://doi.org/10.1016/j.jtos.2021.03.011
Received 19 September 2020; Received in revised form 2 March 2021; Accepted 29 March 2021
Available online 3 April 2021
1542-0124/© 2021 Elsevier Inc. All rights reserved.

Please cite this article as: Swati Singh, The Ocular Surface, https://doi.org/10.1016/j.jtos.2021.03.011
S. Singh et al.
its progression in chronic SJS [4,5]. The incidence of LMK in patients
with chronic ocular SJS/TEN is unclear, however, among a cohort of
patients who were followed up from the acute to the chronic phase, LMK
was observed in 22%–100% of patients with variable degrees of severity,
with a median time of three months to the occurrence of this compli­
cation [5–7]. In the chronic phase, LMK with variable degrees of severity
was observed in 62–88% eyes of patients, who underwent amniotic
membrane transplantation (AMT) in the acute phase. The median time
to the occurrence of this complication was also three months [6,8].
Although the exact etiopathogenesis of LMK has not been clearly
elucidated, a number of potential mechanisms have been proposed [5,
9]. Likewise, there are very limited studies on the histopathological
findings of the lid margins in chronic SJS [10]. Understanding the eti­
ology behind LMK in chronic SJS could open avenues for preventive and
therapeutic strategies. The current review provides an overview of the
various possible pathophysiological mechanisms involved in LMK along
with new data from immunohistochemical studies of the keratinized lid
margins in chronic SJS patients.
2. Methods
2.1. Literature review
A systematic Medline search was performed on PubMed using the
terms “lid margin keratinization”, “Stevens-Johnson syndrome” and
“Ocular”, “conjunctival keratinization”, and “chronic Stevens-Johnson
syndrome sequelae”. Articles published in the English language till
September 2020 were included for the review purpose. Two observers
(S.S., S.B.) reviewed the articles independently, and 25 relevant articles
discussing the pathology of LMK were evaluated in detail.
2.2. Tissue biopsy and histopathology
The excised keratinized lid margins obtained from SJS patients
(diagnosed and categorized as per the published criteria) undergoing lid
mucous membrane grafting (MMG) for LMK at a tertiary eye care center
between June 2019 and June 2020 were analyzed histopathologically
[11,12]. The details of tissue processing, staining and immunohisto­
chemistry are provided in the Supplementary Appendix.
Analyzed parameters included descriptive morphology of the
epithelium, (keratinization, granular cell layer, metaplasia), conjunc­
tival layer (goblet cell loss, parakeratosis), degree of the mononuclear
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cell infiltrate (qualitatively graded from 0 to 4), infiltrate pattern
(described as superficial perivascular, superficial perivascular and
interstitial, periadnexal), location of the infiltrate (intraepithelial, sub­
epithelial, stromal) and stromal fibrosis. Also, the ductal orifices of the
meibomian glands (if visible) and the presence of ectopic sebaceous
glands were studied. The epithelial lining of the lid margin was studied
in two zones: skin and the lid wiper zone (conjunctival side). Keratini­
zation was not considered as a differentiating factor for dividing the
various zones. The skin zone had an area consisting of six to eight rows
of normal cutaneous epithelium having stratum granulosum, rete pegs,
and anucleate, cornified cells of the epidermis superiorly (Fig. 1).
Though the continuous layer of parakeratinized cells characterizes the
mucocutaneous junction (MCJ) in the normal lid margin, many cases did
not have a stark differentiation between the MCJ and the lid wiper area
due to squamous metaplasia of the latter. The normal lid wiper con­
junctiva (LWC) constitutes an area of transitional histomorphology,
(Supplementary Figure) and extends between the MCJ and the tarsal
conjunctiva. It features smaller, cuboidal cells with goblet cell expres­
sion in normal lid margin.
3. Mechanisms of lid margin keratinization in SJS/TEN
Keratinization is a protective mechanism displayed by epithelia
under distress or chronic inflammation. Keratinization of the tarsal and
bulbar conjunctival epithelium has been observed in vitamin A defi­
ciency, long-standing ectropion/exposure, and in severe dry eyes such as
graft-versus-host disease and SJS/TEN [13–16]. LMK seen in SJS/TEN
with exuberant amounts of overlying keratin is visibly different from the
keratinization seen on the bulbar conjunctiva. This could be attributed
to the differences in the conjunctival morphology at the two locations,
presence of the MCJ and meibomian glands at the lid margin, or because
of the differences in the mechanisms responsible for keratinization.
The exact mechanism of LMK in SJS/TEN remains unknown. The
possible sources of keratinized epithelium at the posterior lid margin in
SJS could be the adjacent anterior eyelid epidermis, hyperkeratinized
epithelium from the meibomian gland ductal orifices or de novo meta­
plasia of the conjunctival epithelium (Fig. 2). In the following sections,
we discuss the possible mechanisms and the existing evidence that
supports each hypothesis, followed by a detailed description of the
histopathological findings in LMK.
Fig. 1. Overview of a section through the center of
an upper normal lid margin of a 30-year-old-male.
A &B, the epidermis has rete pegs lining narrow
dermal papillae and a distinct granular layer covered
by the stratum corneum. The mucocutaneous junction
(MCJ) area contains parakeratinized cells and squa­
mous surface epithelium without any stratum gran­
ulosum (B, marked with an arrow). At the start of the
lid wiper (A, C) a conjunctival epithelial structure
with cuboidal surface cells and goblet cells (shaded
circle) start appearing.
S. Singh et al.
Fig. 2. Summary of the possible mechanistic explanations for posterior lid margin keratinization in eyes of patients suffering from chronic ocular sequelae of Stevens-
Johnson syndrome (SJS). (MCJ; mucocutaneous junction).
3.1. Epidermalization from the adjacent skin epidermis
The MCJ barrier normally inhibits epidermal cells from progressing
to the conjunctival side [3]. Its existence has been proposed to be
analogous to the limbal stem cell barrier, disruption of which results in
conjunctivalization of the cornea. The MCJ barrier may be lost sec­
ondary to ulceration in the acute phase of SJS because of the damage to
the putative conjunctival stem cells [17]. The MCJ is considered as the
site for mucosal epithelial cell differentiation activities and there is a
potential possibility of aberrant response of this region to the inflam­
matory insult during the acute phase of SJS. The healthy MCJ area of the
normal lid margin has a distinct histology with absence of stratum
granulosum, and stratum corneum compared to the skin epidermis. The
histopathological appearance of LMK, shows posterior migration of the
keratinized epithelium with diffuse subepithelial lymphocytic infiltra­
tion [18]. The interfollicullar epidermis is supposed to contain stem cells
that differentiate into keratinized epithelium or sebocytes under c-myc
factor influence [19]. The aberrant activation or dysregulation of these
stem cells might result in hyperkeratinization drive spilling onto the
LWC. Future studies on the expression of various cytokeratins and
keratinization related genes in LMK can help ascertain the source of the
keratinized epithelium.
3.2. Meibomian gland dyskeratosis and lid margin microbiome alteration
The dry eye disease in SJS is of mixed etiology involving both
aqueous deficiency and meibomian gland dysfunction (MGD). Severe
MGD is known to occur in SJS with no expressible glands observed in as
many as 71% patients [20]. The presence of dense keratin-like material
within the orifices at the lid margin point to the meibomian glands being
another possible source of keratinization. This hyperkeratinization at
the ductal orifice could be due to a reactive immune mediated process
and/or because of alteration of the microbial flora of the lid margin. Loss
of the oil barrier and meibomian glands has been shown to trigger LMK
along with keratinization in Notch1 knockout mice [21]. Also, the
altered ocular microbiome in SJS patients with predominance of path­
ogenic bacteria could lead to lid margin changes like the obstructive
variety of MGD [22,23]. This interplay of altered lid margin microbial
flora and loss of meibomian glands could incite the hyperkeratinization
secondary to free fatty acids produced by bacterial enzymes. However,
the changes observed at the gland orifices could simply be secondary to
the keratinization process itself, as an effect rather than a cause.
Another aberrant effect on the meibomian glands is observed in the
3
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form of ectopic sebaceous glands. Iyer et al. clinically studied lid mar­
gins of SJS patients for whitish papules that were labeled as ectopic
sebaceous glands and reported their presence in 70% of the examined lid
margins [10]. The occurrence of ectopic sebaceous glands on the skin
has been rarely reported following SJS/TEN attack [24,25]. The etio­
pathogenesis and clinical relevance of ectopic sebaceous glands is still
unclear however they have been considered to be similar to Fordyce
spots which is a reactive phenomenon [10]. This in turn indicates the
possibility of aberrant response of interfollicular epidermis in differen­
tiating into sebocytes in the areas otherwise devoid of sebaceous glands.
3.3. Squamous metaplasia
Squamous metaplasia of the conjunctiva is the pathologic trans­
formation of the normal non-keratinized stratified columnar goblet cells
containing epithelium into keratinized non-secretory squamous epithe­
lium. It may occur as a result of chemical/thermal burns, dry eye,
vitamin A deficiency, mucous membrane pemphigoid and SJS [26].
Several studies have studied the pathogenesis of squamous conjunctival
metaplasia in SJS. As noted above, inflammation likely plays an
important role in many of these cases. The MCJ is rich in lymphocytes
and is supposed to constitute a part of the eye-associated lymphoid tis­
sue (EALT) [27]. Although the increased population of lymphocytes
observed in this area in SJS patients could be due to the activation of
EALT, the exact pathogenesis of this unregulated activation in the
chronic phase is unclear. Lymphocytes are the predominant cell types
seen in both acute and chronic stages of SJS [2,18,28]. Mieno et al.
noted some interesting differences in the inflammatory cell infiltration
based on the EP3 protein expression (which suppresses cytokine pro­
duction) in the lid epidermis and bulbar conjunctival epithelium of
patients with SJS [29]. They found the EP3 expression was preserved in
the epidermis but downregulated in the bulbar conjunctiva. They pro­
posed that downregulation of EP3 expression in the conjunctiva was
responsible for the ocular surface inflammation. However, the relative
expression of EP3 at the MCJ on the skin and conjunctival side remains
unknown. Nakamura et al. have demonstrated the strong presence of
TGase 1 mRNA in the suprabasal epithelium of keratinized bulbar con­
junctiva located near the dense subepithelial inflammatory infiltration
containing cytokines like interferon γ [13]. Inflammation was postu­
lated as a reason for expression of TGase 1 and abnormal keratins in the
keratinized ocular surface. Histopathologic examination of keratinized
epithelium of the conjunctiva and cornea has demonstrated all the
classic epidermal differentiation markers including filaggrin,
S. Singh et al.
transglutaminase 1 (TGase 1), involucrin, and cytokeratins 1/10 [13,
30]. Likewise, the expression of transglutaminase 1 gene is observed to
accompany pathologic keratinization in severe SJS [13].
There is also a possibility that some autoantigen at the lid margin is
exposed during SJS, which triggers an autoimmune inflammatory
response. It is quite possible that there is some interplay between these
proposed mechanisms with an altered vitamin A metabolism [15,16],
exposure, ocular surface dryness and desiccation acting as additional
influences. Conjunctivalized corneas of SJS patients showed sub­
epithelial infiltration with macrophages, CD4 and CD8 positive T cells
[28]. These biopsies had a substantial inflammatory cell infiltration
despite little or no inflammation noted clinically. This ongoing subtle
inflammation has been demonstrated around the hair follicles in the lids
of chronic SJS patients that seemed quiet clinically [31]. The exact
reason behind this persistent inflammation during the chronic phase of
SJS is unclear. Kawasaki et al. postulated it as a secondary reaction to
limbal stem cell deficiency and dry eyes [28]. Dry eye disease induced
conjunctival squamous metaplasia has been noted in mouse models
where T cell infiltration and goblet cell loss were mediated by interferon
γ [14]. Therefore, it is quite possible that LMK occurs due to a process
similar to bulbar conjunctival keratinization, which is a result of squa­
mous metaplasia. However, it is interesting to note that LMK can occur
both in the absence of bulbar keratinization and dryness.
4. Histopathological findings
Fifty-five posterior lid margins of 40 (24 female and 16 male) pa­
tients were analyzed. The demographics, clinicopathological data, and
results of immunohistochemistry staining are summarized in Supple­
mentary Tables 1 and 2 All patients had chronic ocular sequelae of SJS
with a mean lid complication score of 9.5 (range: 8 to 11), and a mean
corneal complication score of 6 (range: 4 to 12). Schirmer I test values
were available for 37 eyes (median 2 mm, range: 0 to 30), of which 14
eyes had zero tear secretion. The various histopathological findings
observed in the excised lid margins are illustrated in Figs. 3 and 4.
4.1. Light microscopy findings
In all specimens, the appearance of the MCJ was distorted and not
4
The Ocular Surface xxx (xxxx) xxx
clearly discernible. There was parakeratosis of lid wiper zone with
acellular superficial layers of epithelium shedding keratin beyond the
normally keratinized skin epithelium. The keratinizing squamous
metaplasia of the LWC was devoid of keratohyaline granules in 76%
(42/55) specimens but the superficial acellular layer containing keratin
(stratum corneum) was present in all specimens. Goblet cells within the
LWC were seen in only 23% (12/53) of the samples. Two margins with
previously placed MMG were excluded from the epithelial analysis.
The predominant histopathological change was diffuse subepithelial
inflammatory infiltration involving the lid margin at and beyond the
MCJ area in 98% (54/55) of the lid margins. There was a clear demar­
cation of the beginning of the inflamed zone in 78.2% (43/55) of the lid
margins, where the keratinized skin epidermis stopped. The inflamma­
tory infiltration involved both the sides (skin and conjunctiva) in 20%
(11/55) of the lid margins, and no inflammation was noted in 1.8% (1/
55) of the lid margins. The grades of inflammation were different on the
skin and conjunctival side. Inflammation grade was 4 in 32% (17/54), 3
in 32% (17/54) and 2 in 14% (8/54) and 1 in 22% (12/54) of the lid
margins on the conjunctival side whereas the cutaneous side had grades
1 (18%, 2/11) and 2 (82%, 9/11) only.
The other epithelial changes noted were branching and long rete
ridges in 20% (11/55), basal cell vacuolar degeneration in 1.8% (1/55),
and epithelial down growth in 31% (17/55) of the lid margins. Meibo­
mian glands acini were identified in 88.7% (47/53) of the biopsies
where the central duct was identified in 18% (13/53) of the lid margins
and showed occluded orifices in 77% (10/13) of the glands. Ectopic
sebaceous glands were identified histopathologically in 22% (12/53) of
the lid margins, whereas clinically visible whitish spots could be seen in
16% (9/53) of the lids. In some specimens, it appeared as if the ectopic
sebaceous glands were migrated meibomian glands reaching near the
terminal portion of the central duct as shown in Fig. 4G. The deeper
sections revealed the apparent ectopic sebaceous glands in 20 lid mar­
gins which continued either into meibomian glands or were associated
with the hair follicle, hence labeled as glands of Zeis. Stromal changes in
the form of fibrosis, dilated and proliferating blood vessels, and stromal
lymphocytes were present in 65% (36/55), 34.5% (19/55), and 36.3%
(20/55) of the lid margins, respectively.
Fig. 3. Lid margins stained with hematoxylin and
eosin (HE) and periodic acid Schiff (PAS). A 38-
year-old male diagnosed with Stevens-Johnson syn­
drome (SJS) since the age of 18 years with keratinized
left lid margin (A) with diffuse presence of inflam­
matory cells in subepithelial region, more on the
conjunctival side (B). (C) PAS staining shows the
keratinized superficial layers of lid wiper region with
dense inflammation. (D to F) Right upper lid margin
of a 22-year-old-female with a history of acute SJS
attack 3 months ago showing distinct mucocutaneous
junction and mild inflammation lying in the superfi­
cial subepithelial region. (G to I) Lid margin of a 14-
year-old-female diagnosed with chronic SJS of two
years duration showing dense inflammation in the
conjunctival subepithelial layer with no inflammation
on the cutaneous side. The stratum granulosum
abruptly ends at the junction of epidermal and
conjunctival side, marked is shown with an arrow (B,
E, H; H&E stain; original magnification x50) (C, F, I;
PAS stain; original magnification x150).
S. Singh et al.
4.2. Immunohistochemistry findings
The population of infiltrating immune cells comprised of mixed B
and T lymphocytes, were identified by CD20, CD4 and CD8 positivity
(Fig. 5). The inflammatory foci demonstrated CD20 positivity in all lid
margins that showed inflammation. The differentiation of T cells into
helper and cytotoxic T cells revealed predominance of CD4 positive
helper T cells. The median CD4:C8 ratio was 7.08 (range, 1.5 to 27.8).
Only three lid margins had lower CD4:CD8 ratio of 1.5, 1.6 and 1.9, and
the rest of the margins had CD4:CD8 ratio of more than 2. There were
Fig. 5. Immunohistochemical staining with CD20, CD4, CD8 and CD68 markers. (A to H) Photomicrographs show diffuse inflammation in the subepithelial and
intraepithelial area of lid wiper conjunctiva (disease duration of 14 and 2 years) with strong CD20 immunoreactivity as well as immunoreactivity to CD4, CD8
markers. (I to L) Lid margin of a 22-year-old-male with history of Stevens-Johnson syndrome (SJS) of 3 months duration. [H&E stain; original magnification ×40 (A,
E, I); Diaminobenzidine chromogen x 400 (B, C, D, F, G, H, J, K, L)].
5
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Fig. 4. Lid margins showing ectopic and normal
sebaceous glands. (A to C) Right lid margin of a 28-
year-old female with history of chronic Stevens-
Johnson syndrome (SJS) showing whitish spots
anterior to and in between meibomian gland orifices
which corresponded histopathologically to the mul­
tiple sebaceous gland acini seen in the basal layers of
epithelium suggestive of ectopic glands. (D to F) Left
lid margin of a 6-year-old-female showing lid margin
keratinization with very few scattered whitish spots
and distichiatic lashes. The histopathological sections
revealed the sebaceous glands along the basal layer of
epithelium opening into central empty follicle space
suggestive of glands of Zeis. (G to I) A 34-year-old-
male with history of SJS of 6 months duration had
visible yellowish meibomian glands on tarsal surface
reaching lid margin that are represented histopatho­
logically as mature sebaceous glands aggregating into
the central duct. [Hematoxylin & Eosin (H&E) stain;
original magnification X100 (B, E, H), X150 (C, F, I)].
scattered CD68 positive mononuclear cells within the inflammatory foci
in all lid margins suggestive of macrophages.
4.3. Summary and interpretation of findings
The keratinized posterior lid margins excised from patients with
chronic SJS demonstrated squamous metaplasia, and specific involve­
ment of the MCJ and LWC with diffuse subepithelial inflammatory
infiltrate abutting the basement membrane area. This infiltrate was
composed of macrophages, mixed T and B cell populations with
S. Singh et al.
predominance of helper T cells. Interestingly, the visible meibomian
glands, muscle of Riolan, and skin epithelium were usually devoid of any
inflammation. This indicates either presence of a chronic antigenic
stimulus at the epithelial-subepithelial junction or a sustained secondary
reactive inflammation at the MCJ and conjunctiva continuing even after
the acute phase of SJS was over. Also, the keratinizing squamous
metaplasia of LWC was devoid of the granular cell layer of epidermis in
majority of the specimens and had inflammation localized to the
conjunctival side, suggesting the possibility of de-novo keratinization
process within the conjunctiva mediated by inflammation. However, a
study of cell lineage specific markers and epithelial cell signaling
pathways is needed to further explore this hypothesis.
5. Future research
Understanding the pathophysiology of LMK requires further inves­
tigation into each of the above postulated theories. Studies evaluating
the expression of protein kinase C, TGase 1 and cytokeratins 1/10 pro­
teins in the keratinized lid margin epithelium would assist in delineating
the keratinization pathway. There is a need to explore the progenitor
cells at the MCJ barrier in human lid margins and their regulatory effects
in response to inflammation observed in SJS. For ascertaining the role of
meibomian glands in LMK, evaluation of ductal hyperkeratinization, c-
myc and Notch-1 regulation of ductal epithelial differentiation in LMK
eyes would be desirable. Future research studying the microbiome of
normal lid margin and its alterations in eyes with LMK would provide an
insight into the role microbial flora might play in producing hyper­
keratinized ductal epithelia. Molecular studies exploring the prosta­
glandin E2 expression separately in the cutaneous and conjunctival
segment of the lid margin would highlight the possible mechanism of
persistent inflammation noted on the conjunctival side of these lid
margins. The relationship between inflammation and pathogenesis of
keratinization needs to be studied further. Although keratopathy due to
LMK can be treated with a combination of medical therapy, MMG and
scleral contact lenses, prevention if possible, would be the ideal solution
[32]. The development of such preventive therapy requires under­
standing of the pathophysiology of LMK in SJS. Treatment modalities
aimed at reversal of keratinization or its prevention in the initial stages
with local anti-inflammatory drug applications can be explored.
6. Conclusions
LMK is a complication seen in many patients with chronic SJS pa­
tients and occurs despite AMT over the lid margins in the acute stage.
The possible mechanisms of LMK are epidermalization from the adjacent
eyelid skin, alteration in the lid margin microbiome, meibomian gland
dyskeratosis, or marginal conjunctival squamous metaplasia, though
further studies are still needed. A chronic exaggerated immune reaction
consisting predominantly of helper T cells was observed in SJS patients’
keratinized lid margins long after the acute phase had passed. The
predominant sub-conjunctival localization of the inflammation indicates
the possible role of inflammation in inducing keratinizing squamous
metaplasia. Future studies assessing protein expression in the kerati­
nized lid margin, delineation of the keratinization-inducing pathways
we well as other molecular studies would help in understanding the
immunopathogenesis of LMK in SJS.
Sources of support
This study was supported by the Hyderabad Eye Research Founda­
tion (HERF), Telangana, India.
Author contributions
The corresponding authors state that all authors met three conditions
laid down by ICMJE authorship guidelines. All persons designated as
6
The Ocular Surface xxx (xxxx) xxx
authors qualify for authorship, and all those who qualify are listed. Each
author has participated sufficiently in the work to take public re­
sponsibility for appropriate portions of the content.
Financial disclosure
None.
Declaration of competing interest
None of the authors have any conflicts of interest.
Acknowledgment
The authors wish to thank Mr. G Chenchu Naidu, senior laboratory
technician, Ophthalmic Pathology Laboratory, L V Prasad Eye Institute,
Hyderabad, India for his assistance with tissue processing and staining.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jtos.2021.03.011.
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