Inflammatory Ocular Surface Disease Research Articles

Outcomes of Cyclosporine Ophthalmic Emulsion 0.05% Use in Pediatric Blepharokeratoconjunctivitis

Purpose: Pediatric blepharokeratoconjunctivitis (BKC) is a chronic ocular surface inflammatory disease. In this article, we report our experience using low-dose topical cyclosporine (CsA) 0.05% for the treatment of pediatric BKC. Methods: A retrospective review was conducted on pediatric patients treated with topical CsA 0.05% for BKC between 2018 and 2022 at a single academic institution. Patients with less than 6 weeks of follow-up, a history of ocular infectious disease, or previous usage of topical/systemic immunomodulators (except corticosteroids) were excluded. The primary outcome was the change in the number of episodes of disease reactivation (flare) before and after the use of CsA 0.05%. Secondary outcomes included the number of clinic visits per year, success rate in corticosteroid tapering, and usage of rescue topical corticosteroid. Results: A total of 21 patients (13 male patients and 8 female patients) treated with CsA 0.05% twice daily were included in this study. The mean age of patients was 9.7 ± 4.2 years, and the mean follow-up period was 62.2 ± 62.5 weeks. The median number of flares per year was 5.6 (95% CI, 3.9–7.3) before treatment with CsA 0.05%, which reduced to 0.0 (95% CI, 0.0–0.9) while on CsA 0.05% (P = 0.01). The median number of clinic visits significantly reduced from 9.5 (95% CI, 7.3–11.7) to 4.5 (95% CI, 3.7–6.8) visits per year (P < 0.0001). After 3.5 ± 2.7 weeks, 90.4% of patients using topical CSs concomitantly with topical CsA 0.05% could be successfully tapered off their topical CSs. Of the patients who tapered off their topical CSs, 3 patients (15%) later required rescue topical CSs despite ongoing CsA 0.05% treatment because of acute flare episodes. No adverse effects were reported with CsA use. Conclusions: This study demonstrates the efficacy of low-dose topical CsA 0.05% in reducing the frequency of acute flares and clinic visits per year in pediatric BKC.

The role of inflammatory periocular, ocular surface and systemic diseases in involutional ectropion.

This study investigated the association between involutional ectropion and chronic inflammatory diseases of the eyelid and ocular surface, and other systemic diseases. This case-control study was conducted using electronic medical records from Clalit Health Services in Israel, 2001-2022. Patients diagnosed with involutional ectropion were compared to two control groups: one with senile cataracts and another with other ophthalmic diseases. The groups were matched 1:3 by birth year, sex, and ethnicity. Mixed models were used to assess differences in demographics, periocular, ocular, and systemic diseases between the groups. Conditional logistic regression was used to estimate the odds ratios (OR) and adjust for confounders. A total of 1786 patients with involutional ectropion and 5358 matched individuals in each control group were included. The average age of the patients with involutional ectropion was 77 ± 10 years, and 60% were men. Significant associations were found between involutional ectropion and several inflammatory diseases: blepharitis (OR 4.25, 95% confidence interval [CI]: 3.68-4.91), chalazion (OR 3.01, 95% CI: 2.3-3.94), hordeolum (OR 2.27, 95% CI: 1.8-2.86), dermatitis of the eyelid (OR 1.69, 95% CI: 1.16-2.47), chronic conjunctivitis (OR 3.49, 95% CI: 2.86-4.26), pterygium (OR 2.21, 95% CI: 1.71-2.86), hypertension (OR 1.5, 95% CI: 1.31-1.72), dyslipidaemia (OR 1.46, 95% CI: 1.3-1.64), and rheumatic disease (OR 1.9, 95% CI: 1.5-2.4). Periocular, ocular surface, and systemic inflammatory diseases are independent risk factors for involutional ectropion. Further research is necessary to fully understand these associations.

The evolution of cyclosporine treatments for treatment of ocular surface diseases.

Cyclosporine is a versatile immunomodulatory drug commonly employed in modern medicine. Although cyclosporine was initially used to prevent solid organ transplant rejection, its indications have extended to treat many inflammatory or autoimmune diseases. Cyclosporin is available for use in oral, intravenous, and topical forms, including eye drops to treat corneal and ocular surface conditions. It is naturally advantageous to administer cyclosporin directly into the eye, avoiding potential and dose limiting systemic adverse effects. However, the transition from systemic to topical administration has been a challenging one. This report reviews the evolution of ophthalmic cyclosporine treatment and explores its clinical impacts and future research directions. Latest advancements in formulations - from oil-based solutions to nanomicelle and gel systems and waterless formulations - have improved the therapeutic efficacy and tolerability of topically applied cyclosporine, demonstrating greater effectiveness in treating ocular surface parameters compared to oil-based solution. Cyclosporine continues to be a safe and effective immunomodulatory drug in the field of ophthalmology to treat various chronic inflammatory ocular surface diseases and dry eye. Currently, there are several commercially available topical preparations available for ophthalmic use each with unique formulation and clinical outcomes.

Atopic Keratoconjunctivitis: Pathophysiology, Clinic, and Potential New Therapeutic Concepts.

Atopic dermatitis (AD) is a chronic recurrent inflammatory skin disease with a bipolar age distribution in childhood, adolescence and middle adulthood. Up to 50% of AD patients show ocular involvement, which can be potentially sight threatening. Clinically, the majority of cases present with atopic blepharo(kerato)conjunctivitis or atopic keratoconjunctivitis (AKC); other clinical variants from this group of inflammatory ocular surface diseases are keratoconjunctivitis vernalis in childhood and adolescence and allergic conjunctivitis. In addition to the aforementioned blepharitis, keratitis and conjunctivitis, AD is also associated with eyelid involvement with subsequent eyelid malposition, limbal insufficiency with the development of pseudopterygia, (chronic) cicatrizing conjunctivitis with symblephara formation and fornix shortening, as well as ocular surface malignancies such as conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma. In addition, an association with AD or AKC has been described for keratoconus. Whereas the therapy of AD in dermatology has made revolutionary advances in recent years through the use of biologicals, the primary use of these biologicals in ophthalmological complications is still very hesitant. Treatment here is often provided using topical steroids and calcineurin inhibitors. The following article summarises recent developments in basic and clinical dermatological research and discusses them in the context of current concepts for ophthalmological therapy.

Lessons Learned From Ocular Graft versus Host Disease: An Ocular Surface Inflammatory Disease of Known Time of Onset.

The ocular surface inflammatory disorders (OSIDs) comprise a group of conditions characterized by persistent inflammation of the ocular surface and adnexal tissues. Systemic autoimmune diseases and hypersensitivity reactions cause them, and, if left untreated, can result in severe inflammatory dry eye, corneal damage, and vision loss. Ocular graft-versus-host disease (oGVHD) forms part of the ocular surface inflammatory disease umbrella. It is a condition occurring after allogeneic hematopoietic stem cell or bone marrow transplantation, usually in chronic graft-versus-host disease. oGVHD can virtually affect any ocular adnexal tissue, especially the meibomian glands, and cause persistent inflammation, tissue fibrosis, and subsequent chronic, severe dry eye disease. Among the OSIDs, oGVHD has the particularity that it has a "time zero," meaning we know when the disease started. As such, preclinical models have leveraged this to investigate the molecular mechanisms involved in the damage oGVHD causes to the ocular surface. In oGVHD, establishing a "time zero" allows for predicting the clinical course and establishing adequate treatment. This is also possible because the inflammatory infiltration occurs in ocular surface tissues, which are readily accessible. Using oGVHD, we might be able to understand the immune response mechanisms in other OSIDs better (i.e., Sjögren syndrome, Stevens-Johnson syndrome, among others). This review presents an up-to-date overview of the pathogenesis, clinical presentation, and treatment of oGVHD. In addition, we will discuss the value of the "time zero" concept in the study of oGVHD.

Allogeneic limbo-deep anterior lamellar keratoplasty (Limbo-DALK)-A novel surgical technique in corneal stromal disease and limbal stem cell deficiency.

To describe a novel corneal surgical technique combining Deep Anterior Lamellar Keratoplasty (DALK) with grafting of allogeneic limbus (Limbo-DALK) for the treatment of eyes with corneal stromal pathology and limbal stem cell deficiency (LSCD). Clinical records of six Limbo-DALKs performed in five patients diagnosed with LSCD and corneal stromal pathology requiring keratoplasty were retrospectively reviewed. All patients were diagnosed with LSCD due to various pathologies including thermal and chemical burns, congenital aniridia or chronic inflammatory ocular surface disease. Parameters analysed included demographics, diagnoses, clinical history, thickness measurements using anterior segment OCT, visual acuity, and epithelial status. Regular follow-up visits were scheduled at 6 weeks as well as 3, 6, 9, and 12 and 18 months postoperatively. Main outcome measures were time to graft epithelialisation and the occurrence of corneal endothelial decompensation. Two grafts showed complete epithelial closure at 2 days, two at 14 days. In one eye, complete epithelial closure was not achieved after the first Limbo-DALK, but was achieved one month after the second Limbo-DALK. No endothelial decompensation occurred except in one patient with silicone oil associated keratopathy. Endothelial graft rejection was not observed in any of the grafts. Based on the data from this pilot series, limbo-DALK appears to be a viable surgical approach for eyes with severe LSCD and corneal stromal pathology, suitable for emergency situations (e.g. corneal ulceration with impending corneal perforation), while minimising the risk of corneal endothelial decompensation.

Definition and Diagnostic Criteria for Pediatric Blepharokeratoconjunctivitis

Pediatric blepharokeratoconjunctivitis (PBKC) is a chronic, sight-threatening inflammatory ocular surface disease. Due to the lack of unified terminology and diagnostic criteria, nonspecific symptoms and signs, and the challenge of differentiation from similar ocular surface disorders, PBKC may be frequently unrecognized or diagnosed late. To establish a consensus on the nomenclature, definition, and diagnostic criteria of PBKC. This quality improvement study used expert panel and agreement applying the non-RAND modified Delphi method and open discussions to identify unified nomenclature, definition, and definitive diagnostic criteria for PBKC. The study was conducted between September 1, 2021, and August 14, 2022. Consensus activities were carried out through electronic surveys via email and online virtual meetings. Of 16 expert international panelists (pediatric ophthalmologists or cornea and external diseases specialists) chosen by specific inclusion criteria, including their contribution to scientific leadership and research in PBKC, 14 (87.5%) participated in the consensus. The name proposed was "pediatric blepharokeratoconjunctivitis," and the agreed-on definition was "Pediatric blepharokeratoconjunctivitis is a frequently underdiagnosed, sight-threatening, chronic, and recurrent inflammatory eyelid margin disease associated with ocular surface involvement affecting children and adolescents. Its clinical spectrum includes chronic blepharitis, meibomitis, conjunctivitis, and corneal involvement ranging from superficial punctate keratitis to corneal infiltrates with vascularization and scarring." The diagnostic criteria included 1 or more suggestive symptoms accompanied by clinical signs from 3 anatomical regions: the eyelid margin, conjunctiva, and cornea. For PBKC suspect, the same criteria were included except for corneal involvement. The agreements on the name, definition, and proposed diagnostic criteria of PBKC may help ophthalmologists avoid diagnostic confusion and recognize the disease early to establish adequate therapy and avoid sight-threatening complications. The diagnostic criteria rely on published evidence, analysis of simulated clinical cases, and the expert panel's clinical experience, requiring further validation with real patient data analysis.

Epidemiology of Pediatric Ocular Surface Inflammatory Diseases in the United States Using the Optum Labs Data Warehouse

To benchmark the epidemiologic features of pediatric ocular surface inflammatory diseases (POSID). Retrospective cohort study. Patients 18 years of age or younger with a medical claim for a diagnosis of POSID in the Optum Labs Data Warehouse between 2007 and2020. Patients with claims of blepharokeratoconjunctivitis (BKC), herpes simplex keratoconjunctivitis (HSK), or vernal keratoconjunctivitis (VKC) were included. Those with less than 6 months of follow-up before the initial diagnosis of POSID were excluded. Odds ratios (ORs) were derived from multivariable logistic regression analyses evaluating the associations between epidemiologic variables and POSID development. The primary outcome was the estimated prevalence of POSID. Prevalence of POSID subtypes and changes in prevalence over time were also evaluated. Two thousand one hundred sixty-eight patients with POSID were identified from 2018 through 2019, yielding an estimated prevalence of 3.32 per 10 000. The prevalence of POSID was higher among children between 5 and 10 years of age, male children, those of Asian descent, and those living in the Northeast and the West census regions of the United States. The prevalence (per 10 000) of BKC, HSK, and VKC in the same period were 0.59 (95% confidence interval [CI], 0.53-0.65), 0.74 (95% CI, 0.68-0.81), and 1.99 (95% CI, 1.88-2.10), respectively, and significant differences were found in terms of age, sex, racial, ethnic, and regional distributions among the diagnoses. Between 2008 through 2009 and 2018 through 2019, a significant increase in POSID was noted among Asians (from 6.26 [95% CI, 5.28-7.36] to 11.80 [95% CI, 10.40-13.34]) driven by changes in VKC. Multivariable analysis demonstrated that age older than 5 years (OR, 2.57-3.75; 95% CI, 2.17-4.34), male sex (OR, 1.38; 95% CI, 1.26-1.50), Asian descent (OR, 3.12; 95% CI, 2.70-3.60), and Black or African American descent (OR, 1.26; 95% CI, 1.02-1.55) were associated with POSID development. This study provides an estimated prevalence of POSID and its 3 common subtypes in the United States, with important epidemiologic differences among them. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Application of topical 2% cyclosporine A in inflammatory ocular surface diseases.

To report our experience with the 2% cyclosporin A (CsA) in a series of challenging inflammatory ocular surface diseases due to different etiologies. The records of patients who received topical 2% CsA for different indications were reviewed retrospectively. Demographic characteristics, indications for treatment, patient symptoms and clinical findings were recorded. Fifty-two eyes of 52 patients were included. Mean age was 43.2 ± 14.3 (11-66) years with a F/M ratio of 34/18. Indications included pediatric acne rosacea (n = 4), adenoviral corneal subepithelial infiltrates (n = 12), filamentary keratitis (n = 14), pterygium recurrence (n = 15), herpetic marginal keratitis (n = 2) and graft versus host disease (n = 5 patients). Mean duration of treatment was 7.3 ± 2.8 (3-10) months. Forty-three (83%) patients reported favorable outcome with improvement in symptoms after a mean time of 4.4 ± 2.7 (2-6) months. Topical 2% CsA may address the needs of different cases with ocular surface inflammation, as a safe option for long-term therapy.

Long-term effects of meteorological factors and extreme weather on daily outpatient visits for conjunctivitis from 2013 to 2020: a time-series study in Urumqi, China.

Conjunctivitis is a common multifactorial inflammatory ocular surface disease characterized by symptoms such as congestion, edema, and increased secretion of conjunctival tissue, and the potential effects of meteorological factors as well as extreme meteorological factors on conjunctivitis and their lagging effects have not been fully evaluated. We obtained the electronic case information of 59,731 outpatients with conjunctivitis from the Ophthalmology Department of the First Affiliated Hospital of Xinjiang Medical University (Urumqi, Xinjiang, China) for the period from January 1, 2013, to December 31, 2020. Meteorological data for daily mean temperature (°C), daily relative humidity (%), daily average wind speed (m/s), and atmospheric pressure (hPa) were obtained from the China Meteorological Data Sharing Service. The air pollutant data were obtained from 11 standard urban background fixed air quality monitors. A time-series analysis design and a quasi-Poisson generalized linear regression model combined with a distributed lagged nonlinear model (DLNM) were used to fit the effects of exposure to different meteorological factors and extreme weather on conjunctivitis outpatient visits. Subgroup analyses were performed on gender, age and season, and type of conjunctivitis. Univariate and multifactorial model results indicated that each 10-unit increase in mean temperature and relative humidity was associated with an increased risk of conjunctivitis outpatient visits, while each 10-unit increase in atmospheric pressure was associated with a decreased risk. The results of the extreme weather analysis suggested that extremely low levels of atmospheric pressure and relative humidity as well as extreme levels of temperature were associated with an increased risk of outpatient conjunctivitis visits, and extreme wind speeds were associated with a decreased risk. The results of the subgroup analysis suggested gender, age, and seasonal differences. We conducted the first large sample size time-series analysis in the large city furthest from the ocean in the world and confirmed for the first time that elevated mean temperature and extreme low levels of relative humidity in Urumqi were risk factors for local conjunctivitis outpatient visits, while elevated atmospheric pressure and extreme low levels of wind speed were protective factors, and there were lagged effects of temperature and atmospheric pressure. Multicenter studies with larger sample sizes are needed.

AAV-mediated expression of HLA-G for the prevention of experimental ocular graft vs. host disease

Ocular graft versus host disease (OGvHD) develops after allogeneic hematopoietic stem cell transplantation (HSCT) and manifests as ocular surface inflammatory disease. This study evaluated the efficacy of adeno-associated virus (AAV) gene therapy encoding human leukocyte antigen G (HLA-G) to inhibit OGvHD. A major histocompatibility mismatch chronic OGvHD murine model was evaluated. 7days after HSCT, mice were dosed subconjunctivally with scAAV8-HLA-G1/5 (1 x 109 vg/eye), topical cyclosporine (twice daily), or left untreated. Body weights and tear production (red thread test) were recorded, and eyelid, corneal opacity, and corneal fluorescein retention were scored through day 44 after HSCT. Tissues were collected for vector biodistribution, ocular histology, and immunofluorescence. Compared with untreated HSCT eyes, those dosed with scAAV8-HLA-G1/5 had significantly reduced clinical inflammatory signs of OGvHD. On histology, eyes that received scAAV8-HLA-G1/5 or cyclosporine had a significantly lower mean limbal mononuclear cell count when compared with non-treated HSCT eyes. HLA-G immunofluorescence was detected in the subconjunctiva and peripheral cornea in HSCT animals treated with scAAV8-HLA-G1/5. Vector genomes were detected in the lacrimal gland, but not in the other tested organs. These results provide evidence that subconjunctival AAV targets ocular surface and corneal disease and support that HLA-G-based gene therapy may be an effective treatment for OGvHD.

Celastrol-based nanoporous membranes prevent subconjunctival fibrosis by activating autophagy

Subconjunctival fibrosis is the final manifestation of various ocular surface injuries and inflammatory diseases; however, clinical treatment is not currently available to prevent or reverse this condition. Celastrol, a triterpene derived from Tripterygium wilfordii, is a potent antifibrotic agent. However, the underlying mechanism of the effect of celastrol on subconjunctival fibrosis remains unknown. It is difficult to choose the method of administration to improve the antifibrotic effect of drugs on subconjunctival fibrosis. In this study, we developed a class of porous nanofibrous membranes loaded with celastrol for sustainable release and hyaluronic acid as a coating layer to prevent burst release. The SEM images indicated that the nanopores and coating layer were clearly observed. In addition, Western blot and confocal microscopic analysis of human pterygium fibroblasts revealed that celastrol induced autophagy. Moreover, celastrol increased the expression of LC3 II in subconjunctival tissue and inhibited the expression of FN and COLⅠ in rats. This finding suggests that autophagy induction by celastrol protects against subconjunctival fibrosis. Furthermore, we revealed that celastrol activated autophagy by inhibiting the PI3K/Akt/mTOR pathway. Moreover, the porous nanofibrous membrane exhibited excellent biocompatibility for potential application in future clinical translation. Thus, this study reveals the importance of autophagy as a possible therapeutic target and celastrol as a potential candidate drug against subconjunctival fibrosis, demonstrating an alternative to inhibit fibrosis, and extend ocular sustainable delivery of various drugs to treat eye diseases.

Targeting Noncanonical Pyroptosis With a Small Molecular Inhibitor Alleviates Inflammation in the LPS-Induced Keratitis Mouse Model.

Pyroptosis, a novel proinflammatory programmed cell death, has been implicated in some ocular diseases. Of special note is the noncanonical pyroptosis that has recently been recognized to play a critical role in microbial keratitis. We previously discovered a new potent small molecular pyroptosis inhibitor, J114. In this investigation, we will explore whether J114 is able to inhibit the noncanonical pyroptosis and the underlying mechanism. Then a lipopolysaccharide (LPS)-induced keratitis mouse model will be used to evaluate the therapeutic effect of J114 in vivo. In vitro, macrophages originating from humans or mice were stimulated with intracellular LPS to induce noncanonical pyroptosis activation. in vivo, acute keratitis in mouse was induced by LPS intrastromal injection. We verified the protective effect of J114 on noncanonical pyroptosis. Clinical scoring, histological observation, macrophage localization, and quantification of pyroptotic markers in the cornea were used to characterize the therapeutic effects. J114 substantially inhibited the noncanonical pyroptosis and the release of inflammatory cytokines by suppressing the activation of caspase-4/5/11 and the noncanonical NLRP3 inflammasome through blocking the NLRP3-ASC interaction. in vivo, J114 protected against LPS-induced noncanonical pyroptosis of acute keratitis, as manifested by alleviated clinical manifestations and histological disorders, and relieved inflammatory reactions. In this study, we found that J114 could efficiently inhibit LPS-induced noncanonical pyroptosis and revealed the underlying mechanism. This compound displayed significant anti-inflammatory activity in the LPS-induced keratitis mouse model. All the findings indicated that J114 could be a potential lead compound for drug development against inflammatory ocular surface diseases.

A Protocol for Managing Watery Eyes in Patients with Punctal Stenosis

Purpose • To elucidate all factors resulting in watery eyes in patients with punctal stenosis. • To treat these factors pre-operatively and post-operatively following a horizontal 3-snip punctoplasty to achieve surgical success. Methods: 77 consecutive cases presenting to a tertiary care oculoplastics centre with watery eyes due to punctal stenosis/ occlusion were included. The clinical type of stenois/occlusion was identified. Co-existing factors causing lacrimation and epiphora, besides punctal stenosis, were identified and treated preoperatively. All cases had a rectangular 3-snip punctoplasty followed by repeated punctal dilatation in clinic, weekly for one month, and then 2 monthly for 6 months. The anti-inflammatory therapy was continued post-operatively for 2-4 months. Results: All cases had severe watery eyes (Munk grade 4-5). 69 cases (89.6 %) cases were on steroid-antibiotic topical therapy for recurrent blepharitis, while 12 cases (15.7%) were on anti-glaucoma therapy. 58 cases (75.3%) had previously failed punctoplasty. Ocular surface inflammatory disease (OSD) was present in all 77 cases (100%) causing lacrimation. It was notably severe in cases with pinpoint punctae. Membranous punctal occlusion was more common in the elderly patients with less severe OSD. Repeated punctal dilatation was necessary to maintain punctal patency post-operatively, achieving success rate of 97.4%, and 100% patient satisfaction. Conclusion: Disturbed balance between tear production and its drainage exists in patients with watery eyes. A protocol is suggested to restore that balance in patients with punctal stenosis: • Thorough clinical assessment, identifying factors causing lacrimation and treating them pre-operatively. • Identifying lower lid margin pathology that may be contributing to epiphora besides punctal stenosis and correcting it simultaneously with punctoplasty. • Rectangular 3-snip punctoplasty should be the preferred surgical procedure as it maintains the structure and function of the punctum. • Repeated punctal dilatation post-operatively and continued topical anti-inflammatory therapy to avoid punctal re-stenosis. • Patient education regarding recurrent nature of OSD and its early treatment to prevent punctal re-stenosis

Tear cytokines and their relevance as biomarkers in ocular surface inflammatory diseases

Abstract Ocular surface disorders (OSDs) are complex, multifactorial diseases, often coexisting and with overlapping symptoms leading to discomfort and visual compromise. OSD is driven by chronic inflammation and its pathogenesis involves multiple ocular surface structures such as the cornea, conjunctiva, lacrimal glands, and meibomian glands. Diagnosing and monitoring disease progression based on clinical features is crucial for effective treatment implementation. However, achieving a differential diagnosis solely through clinical features can be challenging. The evaluation of biomarkers can facilitate disease diagnosis, aid in classification, and offer insights into disease progression and treatment effectiveness. There remains an unmet clinical need for biological tools to manage ocular surface diseases (OSDs). Tear fluid serves as a readily accessible source of biological material that has undergone extensive analysis in the quest for biomarkers related to OSD. Numerous studies have contributed to the extensive catalog of biomarkers found in tear fluid for OSD. The objective of this review is to provide a comprehensive and up-to-date overview of the most pertinent biomarkers for various OSDs, with a specific focus on quantitative analyses and their correlations with clinical parameters. To achieve this objective, we conducted a review of the PubMed database from January 2013 to June 2023, including original articles that investigated tear cytokines in various OSD pathologies. These studies unveiled a dysregulated interplay of pro- and anti-inflammatory cytokines within these disease pathologies. Pro-inflammatory interleukins (IL-1β, IL-2, IL-8, and IL-17), tumor necrotic factor (TNF-α), interferon-gamma (IFN-γ), as well as IL-4, IL-5, and IL-13 (Th2 pathway), and chemokines such as CCL5, IP-10 (CXCL10), and CX3CL, appear to represent similar inflammatory mechanisms in OSD pathologies. The cytokines identified through tear fluid analysis can aid in categorizing the disease as either pro-inflammatory or pro-fibrotic based on its severity, or they may serve as potential targets for intervention. This, in turn, can facilitate the planning of appropriate management strategies. The integration of biomarker testing into clinical settings holds the potential to advance personalized medicine and represents the next significant step in managing OSD.

Simultaneous determination of Panax notoginseng total saponins in rabbit tears by UPLC-QqQ-MS/MS and its application to pharmacokinetic study

Panax notoginseng total saponins (PNS), the main bioactive components of the radix and rhizome of Panax notoginseng (Burk.) F.H. Chen, could treat eye disorders. For the treatment of ocular diseases, eye drops are the first choice with the most common, economic and good compliance. So we proposed that PNS might be able to treat inflammatory ocular surface diseases by eye drops based on its anti-inflammatory and antioxidant activities. The short elimination half-life (t1/2) and rapid elimination of PNS after oral or intravenous administration may limit its application for eye disorders. Meanwhile, there is a lack of pharmacokinetic study on trace amount of tear samples with PNS eye drops. Therefore, a simple and sensitive ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UPLC-QqQ-MS/MS) method by multiple reaction monitoring (MRM) in positive ion mode was firstly developed and applied in the pharmacokinetic study of PNS in rabbit tears. Tears samples were prepared by protein precipitation using methanol. The linearity, limit of detection, limit of quantification, specificity, precision, repeatability, stability, recovery, and matrix effect have been investigated and passed their validation criteria. Compared with prior methods, this method has the advantages of rapid analysis, high sensitivity, simple sample preparation and less sample demands. The pharmacokinetic results indicated that PNS eye drops had a slower elimination and a longer t1/2 by topical ocular administration, which is expected to improve the success rate of eye drops in the treatment of anterior segment diseases. The ocular pharmacokinetics of PNS provides an experimental guidance and feasibility basis for in vivo effect verification of PNS eye drops in the future investigation.

Capsanthin from Capsicum annum fruits exerts anti-glaucoma, antioxidant, anti-inflammatory activity, and corneal pro-inflammatory cytokine gene expression in a benzalkonium chloride-induced rat dry eye model.

Dry eye disease (DED) is a complex ocular surface inflammatory disease. Its occurrence varies widely over the world, ranging from 5% to 34%. The use of preservatives, specifically benzalkonium chloride, in the ocular drops worsens the DED conditions. Furthermore, the Covid-19 pandemic increased screen time and the use of face masks and shields. As a result, the number of people suffering from dry eye disease (DED) has increased significantly in recent years. The main objective of our study is to find a solution to manage the dry eye disease (DED) preferably from natural source without any adverse events. In this study, the beneficial effects of capsanthin from Capsicum annum (CCA) were evaluated on benzalkonium chloride (BAC)-induced dry eye disease (DED) in Albino Wistar rats. Oral supplementation of CCA resulted in a statistically significant decrease in intraocular pressure (IOP) (p < .0001), increase in tear break-up time (TBUT) (p < .01), decline in Schirmer test results (p < .01), and decrease in corneal surface inflammation (p < .01). Capsanthin ameliorated in reducing oxidative stress by increasing serum antioxidant levels such as glutathione peroxidase (GPX), nitric oxide (NO), and lactoferrin (LTF) and inhibiting matrix metalloproteinases 2 and 9 (MMP2 and MMP9) (p < .0001). Capsanthin treatment significantly inhibited the expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interleukins (IL-2, IL-4, IL-6), and pro-inflammatory mediator, matrix metalloproteinase-9 (MMP9). Furthermore, the lacrimal gland expressed vascular cell adhesion molecule (VCAM-1), and prostaglandin-endoperoxide synthase 2 (PTGS2) was suppressed by CCA treatment. PRACTICAL APPLICATIONS: Benzalkonium chloride (BAC), a preservative widely used in the topical ocular drug delivery system (ODDS), causes undesirable effects such as dry eye disease as well as ameliorating intraocular pressure leading to optical nerve damage and irreversible vision loss. Capsanthin from Capsicum annum (CCA) can be used to treat symptoms related to dry eye disease such as inflammation, eye irritation, visual disturbance, ocular discomfort with potential damage to the ocular surface. The CCA may be beneficial in the treatment of glaucoma, an elevated intraocular pressure. Capsanthin from C.annum can be useful in managing DED by increasing tear break-up time (TBUT), declining in Schirmer test results and decreasing in corneal surface inflammation.

Signaling Pathways Used by the Specialized Pro-Resolving Mediator Maresin 2 Regulate Goblet Cell Function: Comparison with Maresin 1.

Specialized pro-resolving mediators (SPMs), including Maresins (MaR)-1 and 2, contribute to tear film homeostasis and resolve conjunctival inflammation. We investigated MaR2′s signaling pathways in goblet cells (GC) from rat conjunctiva. Agonist-induced [Ca2+]i and high-molecular weight glycoconjugate secretion were measured. MaR2 increased [Ca2+]i and stimulated secretion. MaR2 and MaR1 stimulate conjunctival goblet cell function, especially secretion, by activating different but overlapping GPCR and signaling pathways, and furthermore counter-regulate histamine stimulated increase in [Ca2+]i. Thus, MaR2 and MaR1 play a role in maintaining the ocular surface and tear film homeostasis in health and disease. As MaR2 and MaR1 modulate conjunctival goblet cell function, they each may have potential as novel, but differing, options for the treatment of ocular surface inflammatory diseases including allergic conjunctivitis and dry eye disease. We conclude that in conjunctival GC MaR2 and MaR1, both increase the [Ca2+]i and stimulate secretion to maintain homeostasis by using one set of different, but overlapping, signaling pathways to increase [Ca2+]i and another set to stimulate secretion. MaR2 also resolves ocular allergy.

Sutureless Amniotic Membrane Transplantation in Inflammatory Corneal Perforations

Introduction: The aim of this study was to evaluate the efficacy of sutureless amniotic membrane transplantation (SAMT) in patients with corneal perforation secondary to ocular surface inflammatory diseases. Methods: Twelve eyes of eleven patients with corneal perforation associated with Sjögren’s syndrome and ocular cicatricial pemphigoid were included. Surgical procedure consisted in the application of two layers of amniotic membrane covering the corneal perforation and a therapeutic contact lens placed above the two layers, followed by sutureless tarsorrhaphy with Steri-strip applied for 15 days to immobilize the eyelids. All patients underwent slit-lamp examination, fluorescein corneal staining, and anterior segment optical coherence tomography (AS-OCT), preoperatively and post-surgery, weekly for one month, and then every two weeks for three months. Results: All 12 eyes had complete resolution of corneal perforation. Pachymetry measurements improved in all eyes, and complete healing of the corneal ulcer was obtained following treatment and maintained up to 3 months follow-up in all patients. Conclusions: SAMT was proven to be a safe and effective option for the management of inflammatory corneal perforation. The procedure is non-traumatic and easy to perform since the surgical technique is sutureless and does not require topical therapy because it takes advantage of the intrinsic properties of the membrane itself.

Use of Systemic Mycophenolate Mofetil Therapy in Ocular Surface Inflammatory Pathologies at the Initiative and Responsibility of the Ophthalmologist.

The purpose of the study was to evaluate the efficacy and safety of systemic mycophenolate mofetil (MMF) treatment in ocular surface inflammatory diseases. For this retrospective study, patients who were treated with systemic MMF for ocular surface inflammatory diseases between March 2020 and March 2022 were evaluated. Apart from demographic data, examination notes including MMF treatment indication and systemic side effect interrogation and routine laboratory examinations during drug treatment were extracted from the patient records. Detailed staging scores were performed according to the diagnosis including Foster and Mondino for ocular mucous membrane pemphigoid (MMP) and limbal stem cell deficiency scoring for limbal transplantation. For thorough evaluation, anterior segment pictures were used. Fourteen patients were enrolled to the study, with a mean age of 58 ± 12. MMP (6, 42.8%) and limbal allograft transplantation (6, 42.8%) constituted the main indications for the MMF treatment, followed by keratitis-ichthyosis-deafness (KID) syndrome (1, 7.2%) and Mooren's ulcer (1, 7.2%). Five of six patients with MMP regressed according to both staging systems. Only one remained stable which was evaluated as Stage 3. Furthermore, while all limbal transplant groups (6) stabilized and showed regression according to the individualized limbal stem cell deficiency staging system with no rejection during follow-up. Furthermore, patients with Mooren's ulcer and KID syndrome showed control of the inflammation and stabilization after MMF treatment. No significant systemic side effects apart from constipation and nausea (3) were observed in patients whose routine laboratory tests were stable throughout the follow-up. MMF has the potential to be a valuable and safe systemic agent of first choice in the control of ocular surface inflammatory disorders, especially when topical treatment is not effective. With such studies, it is predicted that MMF may reach wider usage areas with the increase in its effectiveness and safety in its use for ocular surface inflammatory pathologies.