Ocular Surface Keratinization Research Articles

Retinol palmitate in management of chronic Steven-Johnson Syndrome with ocular surface keratinization

PurposeTo study the outcomes of topical Retinol Palmitate ophthalmic solution in chronic Stevens-Johnson Syndrome with ocular surface keratinisation. MethodsIt was a comparative interventional study conducted at Rajendra Prasad Centre for Ophthalmic Sciences, Delhi, India from 2020 to 2022 evaluating outcomes of addition of topical Retinol Palmitate to conventional treatment objectively as well as subjectively from baseline up to 12 weeks. ResultsA statistically significant improvement was seen in patients who received topical Retinol palmitate at 12 weeks in terms of Schirmer-1 test(p=<0.01), tear prism height on ASOCT(p = 0.02), Rose Bengal staining score of cornea(p = 0.01) and conjunctiva (p < 0.01), reduction of ocular surface keratinisation on impression cytology(p = 0.01) and subjective evaluation using OSDI questionnaire(p = 0.04).Impression cytology revealed goblet cells in Retinol palmitate group at 1 week after initiation of therapy, which increased further at 1 month follow up but reduced at 3 months. No goblet cells were seen in control group at any follow-up. No significant difference was noted between the two groups in terms of visual acuity, tear film breakup time, inflammatory cells on impression cytology and inflammatory markers in tears. ConclusionTopical Retinol palmitate is a safe and effective drug in cases of chronic SJS with ocular surface keratinisation. It has the potential to reverse keratinisation of the ocular surface and promote development of goblet cells. However, the survival of goblet cells is not long lasting.

Isolated alacrimia associated with microblepharon

Isolated alacrimia is a rare condition often reported with salivary gland agenesis in the literature. Children with the isolated absence of the lacrimal gland can have normal tear film but not during emotional stimuli. Microblepharon is a congenital anomaly with abnormally small eyelids due to vertical shortening, which leads to incomplete blink, exposure keratopathy, and corneal ulceration. The combined occurrence of both the conditions in our case led to ocular surface keratinization and visual impairment. Here, we report a case of isolated lacrimal gland agenesis in association with microblepharon in a 2-year-old child.

Regeneration of Lacrimal Gland Function to Maintain the Health of the Ocular Surface.

Dry eye is a multifactorial disease that is one of the most common diseases worldwide. A major cause of dry eye is the deficiency of aqueous tears, which are mainly secreted from the lacrimal gland. The lacrimal gland plays an important role in maintaining the health of the ocular surface and protecting it from environmental exposure. Dry eye can lead to ocular irritation and discomfort, as well as severe ocular surface diseases (e.g., ocular infections, corneal ulcerations, and ocular surface keratinization). These severe diseases can be induced by an atrophied or injured lacrimal gland; current therapies cannot completely restore the function of lacrimal gland. To develop more definitive therapies, it is important to understand lacrimal gland biology at the molecular level, as well as inflammatory processes affecting the function of the gland. During severe inflammation, the tissue structure of the lacrimal gland is destroyed; it is replaced by scar formation during wound healing, which leads to lacrimal gland dysfunction. Using an animal model of lacrimal gland dysfunction, many investigators have studied molecular mechanisms of inflammation in the lacrimal gland. To restore lacrimal gland function, the lacrimal acini must be restored in their niche. Notably, organ transplantation therapies have been reported to restore lacrimal gland function, directly or indirectly, in animal models. In this review, we describe the current understanding of the lacrimal gland as the therapeutic target for dry eye diseases, as well as recent advances in the field of lacrimal gland cell-based therapy to treat severe dry eye diseases.

Efficacy and adverse reactions of methotrexate in the treatment of ocular cicatricial pemphigoid: A case series study.

The application of methotrexate (MTX) in the treatment of autoimmune diseases has been gradually increasing, but reports of MTX treatment for advanced ocular cicatricial pemphigoid (OCP) are extremely rare. This study investigated the efficacy and adverse reactions of low-dose MTX in patients with OCP.This was a retrospective, noncontrolled, case series study. Eleven patients diagnosed with advanced OCP (4 cases in stage III and 7 cases in stage IV) were enrolled. Treatment by oral administration of MTX (7.5 ± 2.5 mg) alone was performed. Visual acuity of the patients, conjunctival inflammation, cicatrization, ocular surface keratinization, and toxic side effects of drugs were evaluated.All patients enrolled in this study were females aged 32 to 83 years. Patients were followed up for 4 to 33 months. Low-dose MTX improved visual acuity of 3 cases (6 eyes, 27.3%). Conjunctival inflammation of 5 patients (10 eyes) rested after treatment, and conjunctival inflammation of 3 cases (6 eyes, 27.3%) was decreased with an effective rate of 72.7%. Cicatrices of 8 cases (15 eyes) showed degeneration after treatment with an effective rate of 71.4% (15/21). Ocular surface keratinization receded in 4 cases with an effective rate of 66.7%. None of the patients discontinued the treatment due to severe toxic side effects. All patients tolerated mild drug-induced gastrointestinal reactions. Three patients terminated the treatment in advance after 4 to 6 months due to no improvement in the disease condition.Observation of clinical efficacy and safety findings demonstrated that low-dose MTX can be used to treat patients with advanced OCP.

Clinical features and in vivo confocal microscopy assessment in 12 patients with ocular cicatricial pemphigoid.

To describe the clinical features and microstructural characteristics assessed by in vivo confocal microscopy (IVCM) in patients with ocular cicatricial pemphigoid (OCP). A descriptive, uncontrolled case series study. Patients diagnosed with OCP were examined by clinical history, slit-lamp biomicroscopy features and IVCM images. The results of direct immunofluorescence (DIF) biopsies and indirect immunofluorescence (IIF) were also recorded. Local and systemic immunosuppressive therapy were administered and adjusted according to response. A total of 12 consecutive OCP patients (7 male, 5 female; mean age 60.42±10.39y) were recruited. All patients exhibited bilateralprogressive conjunctival scarring and recurrent chronic conjunctivitis was the most frequent clinical pattern. The mean duration of symptoms prior to diagnosis of OCP was 2.95±2.85y (range: 5mo to 10y). The Foster classification varied from stage I to IV and 20 eyes (83%) were within or greater than Foster stage III on presentation. Two of the 12 patients (17%) demonstrated positive DIF; 3 of the 12 (25%) patients reported positive IIF. The mean duration of the follow-up period was 20.17±11.88mo (range: 6 to 48mo). IVCM showed variable degrees of abnormality in the conjuctiva-cornea and conjuctival scarring was detected in all the involved eyes. Corneal stromal cell activation and dendritic cell infiltration presented as ocular surface inflammation, ocular surface keratinization along with the destroyed Vogt palisades was noted in eyes with potential limbal stem cell deficiency. After treatment, remission of ocular surface inflammation was achieved in all the patients, 18 eyes (75%) remained stable, 6 eyes (25%) had recurrent conjunctivitis and cicatrization in 2 eyes (8%) was progressing. As an autoimmune disease, OCP manifests as variable degrees of clinical and laboratory abnormalities with both local and systemic immunosuppressive treatment playing important roles in disease therapy. IVCM can be as a valuable non-invasive technique to assess ocular surface changes in a cellular level with a potential value for providing diagnostic evidence and monitoring therapeutic effects during follow-up.

Ocular Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and some- times life-threatening hypersensitivity mucocutaneous disease triggered mostly by medi- cation and infections Major involving tissues are the mucous membranes of oral, gastroin- testinal, respiratory, integument, and gynecologic tissues. Even after recovering from skin problems without sequelae, survivors can have serious ocular complications leading to blindness despite local and systemic therapy. There is no definite effective systemic and lo- cal treatment for SJS/TEN. Early detection and aggressive treatment are important for the long-term prognosis of the eye. Eyelid margin and palpebral conjunctiva and fornix should be checked thoroughly to detect the cicatrical changes that make chronic ocular surface failure such as limbal cell deficiency and complete ocular surface keratinization. Amniotic membrane transplantation and cultivated oral mucosal graft are beneficial to reduce the risk of ocular surface failure.

A Combined Approach of Amniotic Membrane and Oral Mucosa Transplantation for Fornix Reconstruction in Severe Symblepharon

To evaluate the results of a combined approach of cicatrix lysis, intraoperative mitomycin C (MMC) application, oral mucosal transplantation (OMT), and amniotic membrane transplantation (AMT) for surgery of severe symblepharon. This prospective study included 32 eyes with severe symblepharon in which after cicatrix lysis the residual conjunctiva was not enough to cover the tarsus (grade III symblepharon) or there was no residual conjunctiva (grade IV symblepharon). After symblepharon lysis and MMC application, OMT was used to cover the tarsus throughout to fornix, and AMT with fibrin glue was performed to cover the exposed sclera. Outcome was defined as complete success (restoration of an anatomically deep fornix), partial success (focal recurrence of scar), or failure (return of symblepharon). Etiology of symblepharon included chemical burn (n = 16), thermal burn (n = 7), Stevens-Johnson syndrome (n = 5), mucous membrane pemphigoid (n = 2), xeroderma pigmentosum (n = 1), and graft-versus-host disease (n = 1). Motility restriction was present in 87.5% preoperatively. After a mean follow-up of 16.4 ± 7.6 months, the anatomical outcome included complete success in 84.4%, partial success in 9.4%, and failure in 6.2%. In grades III and IV symblephara, the outcomes were complete success in 89.5% and 76.9%, partial success in 10.5% and 7.7%, and failure in none and 15.4%, respectively. No motility restriction was noted in any eye postoperatively. Complications included entropion (n = 2), ocular surface keratinization (n = 1), and pyogenic granuloma (n = 4). In severe symblepharon, a combined approach of cicatrix lysis, MMC application, OMT, and sutureless AMT was a safe and effective technique for fornix reconstruction.

Interleukin-1 receptor mediates the interplay between CD4+ T cells and ocular resident cells to promote keratinizing squamous metaplasia in Sjögren's syndrome

Keratinizing squamous metaplasia (SQM) of the ocular mucosal epithelium is a blinding corneal disease characterized by the loss of conjunctival goblet cells (GCs), pathological ocular surface keratinization and tissue recruitment of immune cells. Using the autoimmune regulator (Aire)-deficient mouse as a model for Sjögren's syndrome (SS)-associated SQM, we identified CD4+ T lymphocytes as the main immune effectors driving SQM and uncovered a pathogenic role for interleukin-1 (IL-1). IL-1, a pleiotropic cytokine family enriched in ocular epithelia, governs tissue homeostasis and mucosal immunity. Here, we used adoptive transfer of autoreactive CD4+ T cells to dissect the mechanism whereby IL-1 promotes SQM. CD4+ T cells adoptively transferred from both Aire knockout (KO) and Aire/IL-1 receptor type 1 (IL-1R1) double KO donors conferred SQM to severe-combined immunodeficiency (scid) recipients with functional IL-1R1, but not scid recipients lacking IL-1R1. In the lacrimal gland, IL-1R1 was primarily immunolocalized to ductal epithelium surrounded by CD4+ T cells. In the eye, IL-1R1 was expressed on local mucosal epithelial and stromal cells, but not on resident antigen-presenting cells or infiltrating immune cells. In both tissues, autoreactive CD4+ T-cell infiltration was only observed in the presence of IL-1R1-postive resident cells. Moreover, persistent activation of IL-1R1 signaling led to chronic immune-mediated inflammation by retaining CD4+ T cells in the local microenvironment. Following IL-1R1-dependent infiltration of CD4+ T cells, we observed SQM hallmarks in local tissues—corneal keratinization, conjunctival GC mucin acidification and epithelial cell hyperplasia throughout the ocular surface mucosa. Proinflammatory IL-1 expression in ocular epithelial cells significantly correlated with reduced tear secretion, while CD4+ T-cell infiltration of the lacrimal gland predicted the development of ocular SQM. Collectively, data in this study indicated a central role for IL-1 in orchestrating a functional interplay between immune cells and resident cells of SS-targeted tissues in the pathogenesis of SQM.

Interleukin-1 as a Phenotypic Immunomodulator in Keratinizing Squamous Metaplasia of the Ocular Surface in Sjögren’s Syndrome

Chronic inflammation of the ocular surface in Sjögren's syndrome (SS) is associated with a vision-threatening, phenotypic change of the ocular surface, which converts from a nonkeratinized, stratified squamous epithelium to a nonsecretory, keratinized epithelium. This pathological process is known as squamous metaplasia. Based on a significant correlation between ocular surface interleukin (IL)-1beta expression and squamous metaplasia in patients with SS, we investigated the role of IL-1 in the pathogenesis of squamous metaplasia in an animal model that mimics the clinical characteristics of SS. Using autoimmune-regulator (aire)-deficient mice, we assessed lacrimal gland and ocular surface immunopathology by quantifying the infiltration of major histocompatibility complex class II(+) (I-A(d+)) dendritic cells and CD4(+) T cells. We examined squamous metaplasia using a biomarker of keratinization, small proline-rich protein 1B. We used lissamine green staining as a readout for ocular surface epitheliopathy and Alcian blue/periodic acid-Schiff histochemical analysis to characterize goblet cell muco-glycoconjugates. Within 8 weeks, the eyes of aire-deficient mice were pathologically keratinized with significant epithelial damage and altered mucin glycosylation. Although knockdown of IL-1 receptor 1 did not attenuate lymphocytic infiltration of the lacrimal gland or eye, it significantly reduced ocular surface keratinization, epitheliopathy, and muco-glycoconjugate acidification. These data demonstrate a phenotypic modulation role for IL-1 in the pathogenesis of squamous metaplasia and suggest that IL-1 receptor 1-targeted therapies may be beneficial for treating ocular surface disease associated with SS.

Molecular Mechanisms of Keratinizing Ocular Surface Disease

A devastating consequence of autoimmune-mediated, aqueous tear deficiency is pathological keratinization of the ocular surface. It is setoff by an aberrant immune response that promotes a program of altered mucosal epithelial cell differentiation. The management of keratinizing ocular surface disease is challenging. Topical therapies are largely inadequate for acute exacerbations, and progressive disease often requires systemic immunosuppression. A combination of translational and basic science research is necessary to understand the link between aberrant immunity and pathological keratinization. I review recent research and future directions aimed to develop targeted therapies that control or prevent ocular surface keratinization.

Molecular Mechanism of Proinflammatory Cytokine-Mediated Squamous Metaplasia in Human Corneal Epithelial Cells

The cornified envelope protein small proline-rich protein 1B (SPRR1B) is a biomarker for squamous metaplasia. Proinflammatory cytokines IL-1beta and IFN-gamma are potent inducers of ocular surface keratinization and SPRR1B expression. Here the molecular mechanisms controlling SPRR1B gene expression in response to IL-1beta and IFN-gamma are elucidated. A 3-kb fragment of the SPRR1B gene 5'-flanking region was amplified from human chromosome 1, sequentially deleted, and cloned into a luciferase vector. Constructs were transiently transfected into human corneal epithelial cells, and activity was assessed in response to IL-1beta, IFN-gamma, or basal medium. Functional cis-elements responding to IL-1beta and IFN-gamma were characterized by site-directed mutagenesis and gel mobility shift assay. Effects of mitogen-activated protein kinases p38, ERK, and JNK were assessed using inhibitors and dominant-negative mutants. Results were validated by real-time RT-PCR. The first 620 bp of the SPRR1B 5'-flanking region regulated constitutive expression and increased promoter activity in response to IL-1beta and IFN-gamma. Corresponding cis-elements for IL-1beta and IFN-gamma were bound by cAMP response element binding protein (CREB) and zinc-finger E-box binding homeobox 1 (ZEB1), respectively. Inhibition of p38 abolished the stimulatory effects of IL-1beta and IFN-gamma on SPRR1B, whereas inhibition of JNK and ERK had no effect. Dominant-negative mutants targeting p38alpha and p38beta2 blocked cytokine-induced SPRR1B promoter activity and mRNA expression. SPRR1B is upregulated by the proinflammatory cytokines IL-1beta and IFN-gamma via p38 MAPK-mediated signaling pathways that lead to the activation of transcription factors CREB and ZEB1, respectively. These results identify key intracellular signaling intermediates involved in the pathogenesis of immune-mediated ocular surface squamous metaplasia.

Small Proline-Rich Protein 1B (SPRR1B) Is a Biomarker for Squamous Metaplasia in Dry Eye Disease

Squamous metaplasia occurs in ocular surface diseases like Sjögren's syndrome (SS). It is a phenotypic change whereby epithelial cells initiate synthesis of squamous cell-specific proteins such as small proline-rich protein 1B (SPRR1B) that result in pathologic keratin formation on the ocular surface. The authors hypothesized that inflammation is a key inducer of pathologic keratinization and that SPRR1B represents an analytical biomarker for the study of the molecular mechanisms. Real-time quantitative RT-PCR and immunohistochemistry were used to examine SPRR1B mRNA and protein in two different mouse models of dry eye and patients with SS. Adoptive transfer of mature lymphocytes from mice lacking the autoimmune regulator (aire) gene was performed to examine the role of inflammation as an inducer of squamous metaplasia. SPRR1B expression in response to several cytokines was examined in vitro, whereas the expression of cytokines IL1beta and IFNgamma was quantified in ocular tissues of aire-deficient mice and patients with SS. SPRR1B was increased across the ocular surface of mice with both desiccating stress and autoimmune-mediated, aqueous-deficient dry eye and in patients with SS. Adoptive transfer of CD4(+) T cells from aire-deficient mice to immunodeficient recipients caused advanced ocular surface keratinization. IL1alpha, IL1beta, IL6, IFNgamma, and TNFalpha induced SPRR1B expression in vitro and the local expression of IL1beta and IFNgamma was elevated in ocular tissues of patients with SS and aire-deficient mice. SPRR1B is a valid biomarker for the study of the molecular mechanisms of squamous metaplasia. There is a definitive link between inflammation and squamous metaplasia in autoimmune-mediated dry eye disease, with IL1beta and IFNgamma likely acting as key participants.

Cicatricial pemphigoid: diagnosis and treatment.

Cicatricial pemphigoid is a systemic autoimmune disease with both ocular and extraocular manifestations. Its effect on the eyes is characterized by chronic cicatrizing conjunctivitis and progressive conjunctival sub-epithelial fibrosis with resultant fornix foreshortening, symblepharon formation, trichiasis, meibomian, and lacrimal duct obstruction resulting in sicca syndrome, ocular surface keratinization, and eventually blindness. Extraocular manifestations include stricture formation of the esophagus, trachea, anus, or vagina. OCP is characterized by deposition of immunoreactants at the conjunctival basement membrane zone, initiating a type II hypersensitivity reaction. Demonstration of this deposition can be done using immunofluorescence or immunoperoxidase technique.

Ocular Surface Keratinization as a Predictor of Response to Topical Retinoic Acid Therapy

To the Editor. —Retinoic acid has improved clinical signs in most cicatrizing dry eye conditions, but not in keratoconjunctivitis sicca.1Even in the absence of cicatrization, it has produced a substantial improvement in some cases of conjunctival and corneal keratinization.2We found that ocular surface keratinization was predictive of response to topical retinoic acid treatment in the course of a randomized, double-masked, placebo-controlled, crossover trial. We quantified conjunctival and corneal keratinization by dividing the ocular surface into 11 zones and scored each area from 0 (no keratinization) to 3 (thick keratin plaque), based on slit-lamp examination and rose bengal staining. The numbers were added to determine a total clinical keratinization score. Conjunctival scrapings were Giemsa stained; an average of 200 to 300 epithelial cells were randomly counted from areas of each slide to determine the percentage of keratinized cells and keratinizing epithelial cells. Report of a Case. —A