Kathleen L. Krenzer

Androgens and Dry Eye in Sjögren's Syndromea

ABSTRACT: Sjögrens syndrome is an extremely complex and currently incurable autoimmune disorder, which occurs primarily in females, and is associated with lacrimal gland inflammation, meibomian gland dysfunction, and severe dry eye. We hypothesize that androgen deficiency, which reportedly occurs in primary and secondary Sjögrens syndrome (e.g., systemic lupus erythematosus, rheumatoid arthritis), is a critical etiologic factor in the pathogenesis of dry eye syndromes. We further hypothesize that androgen treatment to the ocular surface will promote both lacrimal and meibomian gland function and alleviate both “aqueous‐deficient” and “evaporative” dry eye. Our results demonstrate that androgens regulate both lacrimal and meibomian gland function, and suggest that topical androgen administration may serve as a safe and effective therapy for the treatment of dry eye in Sjögrens syndrome.

Is Complete Androgen Insensitivity Syndrome Associated with Alterations in the Meibomian Gland and Ocular Surface

Purpose. This studys purpose was to determine whether complete androgen insensitivity syndrome (CAIS) is associated with alterations in the meibomian gland and ocular surface. Methods. Individuals with CAIS, as well as age-matched female and male controls, completed questionnaires which assessed dry eye symptoms and underwent slit lamp evaluations of the tear film, tear meniscus, lids and lid margins and conjunctiva. The quality of meibomian gland secretions was also analyzed. Results. Our results demonstrate that CAIS is associated with meibomian gland alterations and a significant increase in dry eye signs and symptoms. Clinical assessment revealed that CAIS women, as compared to controls, had a significant increase in telangiectasia, keratinization, lid erythema and orifice metaplasia of the meibomian glands, and a significant decrease in the tear meniscus and quality of meibomian gland secretions. Questionnaire results showed that dry eye symptoms were increased over twofold in CAIS individuals, as compared to controls, including a significant increase in the sensations of dryness, pain and light sensitivity. Conclusion. Our results suggest that androgen insensitivity may promote meibomian gland dysfunction and an increase in the signs and symptoms of dry eye.

Alternative reference values for tear film break up time in normal and dry eye populations.

In several tissues and cell lines, including epithelial cells of the prostate, breast and seminal vesicles, and in acinar cells of the meibomian and other sebaceous glands, androgens have a major stimulatory effect on the production, accumulation and/or secretion of lipids.1–11 In most of these tissues and cell lines, the composition of these lipids is complex. Accumulating lipids include cholesterol esters, diacylglycerides, triglycerides and wax esters. Depending on the tissue type, these lipids may have different physiological functions and dysregulation of their production is related to pathological conditions as diverse as acne, dry eye syndromes and cancer. In acne and dry eye syndromes local modulation of androgen action may provide an effective therapy.7,12

Sex steroids, the meibomian gland and evaporative dry eye.

Our recent research has led to our hypothesis that gender and sex steroid hormones are critical factors in the regulation of the meibomian gland and pathogenesis of evaporative dry eye. The objective of this article is to briefly summarize the experimental basis for this hypothesis.

Identification and Hormonal Control of Sex Steroid Receptors in the Eye

During the past several decades, it has become quite evident that androgens, estrogens and progestins may exert a significant influence on the structure and/or function of a variety of ocular tissues, including the lacrimal gland, meibomian gland, conjunctiva, goblet cells, cornea, anterior chamber, lens and/or retina.1,2 The nature of these sex steroid effects appears to involve modulation of such ocular parameters as tissue morphology, gene expression, protein synthesis, lipid production, mucous secretion, aqueous tear output, tear film stability, immunological activity, corneal curvature, aqueous humor outflow and visual acuity.1,2 In addition, these hormones have been proposed as topical therapies for such conditions as dry eye syndromes (both aqueous-deficient and evaporative), corneal wound healing and high intraocular pressure.1,3,4 However, despite these findings, very little information exists concerning the precise target cells for sex steroid action, the specific ocular processes controlled by these hormones, or the mechanisms (e.g. classical vs. non-classical) underlying potential sex steroid-eye interactions.

Emedastine ophthalmic solution 0.05% versus levocabastine ophthalmic suspension 0.05% in the treatment of allergic conjunctivitis using the conjunctival allergen challenge model.

PURPOSE To compare a new ocular antihistamine, emedastine difumarate (Emadine Ophthalmic Solution 0.05%; Alcon Laboratories, Fort Worth, Texas), with the marketed ocular antihistamine, levocabastine hydrochloride (Livostin Ophthalmic Suspension 0.05%; CIBA Vision, Atlanta, Georgia), in the treatment of allergic conjunctivitis after conjunctival allergen challenge. METHODS We performed a prospective, double-masked, randomized, contralateral eye study comparing emedastine 0.05% in one eye with levocabastine 0. 05% or emedastine vehicle (placebo) in the contralateral eye. Efficacy was determined 10 minutes and 2 hours after administration of study medications. Ocular itching and redness scores were recorded 3, 5, and 10 minutes after conjunctival allergen challenge. RESULTS A total of 97 subjects with a history of allergic conjunctivitis and a positive response to a diagnostic test were evaluable for safety analysis, and 91 subjects were evaluable for the efficacy analysis. Emadastine 0.05% was statistically significantly more effective than levocabastine 0.05% in reducing ocular itching after conjunctival allergen challenge in both the 10-minute and the 2-hour challenge (P <.05). Emedastine 0.05% and levocabastine 0.05% were statistically equivalent in reducing conjunctival redness after conjunctival allergen challenge, although emedastine tended to be more efficacious than levocabastine at every observation time point. CONCLUSIONS After conjunctival allergen challenge, emadastine 0.05% is significantly more effective than levocabastine 0.05% in reducing ocular itching associated with allergic conjunctivitis. The two compounds are equivalent in controlling the conjunctival redness associated with allergic conjunctivitis.

Conjunctival Impression Cytology from Dogs with Keratoconjunctivitis Sicca

Keratoconjunctivitis sicca (KCS), or dry eye, is a major cause of ocular morbidity in humans and dogs.1,2 Although the cause of KCS in dogs often cannot be determined, as in non-Sjogren’s dry eyes, histopathologic and serologic studies suggest that canine KCS frequently results from immune-mediated lacrimal gland destruction or dysfunction. Tear film deficiencies cause changes in the conjunctival epithelium that may account for many of the clinical symptoms and the corneal morbidity in these cases. The normal conjunctival surface is composed of nonkeratinized, stratified, squamous epithelium with goblet cells. These cells and the products from them, including mucin, are critical for ocular surface integrity. Squamous metaplasia from cuboidal epithelium to increasing keratinization and goblet cell loss is associated with KCS in patients with Sjogren’s syndrome and with ocular problems in postmenopausal women.2–4 Methods for staging squamous metaplasia by impression cytology have been established for use in humans.2,5–7Although KCS in dogs and response to treatment with cyclosporine have been characterized histologically by biopsy of lacrimal glands, there are no reports on conjunctival cytology from dogs with KCS.1,8 Clinical trials in dogs and humans have supported the validity of treating KCS with cyclosporine. In this project we characterized conjunctival cytology from dogs with KCS before and after treatment with cyclosporine in order to determine the effect of topical cyclosporine treatment on the conjunctival epithelium.

Meibomian Gland Dysfunction in Primary and Secondary Sjögren Syndrome

Purpose: We hypothesized that women with primary (pSS) and secondary Sjögren syndrome (sSS; with systemic lupus erythematosus [SLE] or rheumatoid arthritis [RA]) have meibomian gland dysfunction (MGD). We sought to test our hypothesis. Methods: Subjects with pSS, sSS + SLE, sSS + RA, and non-SS-related MGD were recruited from the Sjögren’s Syndrome Foundation or outpatient clinics at Tufts University School of Dental Medicine or Brigham and Women’s Hospital. The control population was recruited from the Greater Boston area. After providing written informed consent, the subjects underwent an eye examination and/or completed two questionnaires that assess symptoms of dry eye disease (DED). Results: Our results demonstrate that pSS and sSS patients have MGD. These subjects had meibomian gland orifice metaplasia, an increased number of occluded meibomian gland orifices, and a reduced quality of meibomian gland secretions. Further, patients with pSS, sSS + SLE, sSS + RA, and MGD had significant alterations in their tear film, lid margin, cornea, and conjunctiva. Symptoms of DED were increased ∼10-fold in all pSS, sSS, and MGD groups relative to controls. Conclusions: Our findings support our hypothesis and show that individuals with pSS, sSS + SLE, and sSS + RA have MGD. In addition, our study indicates that patients with pSS and sSS have both aqueous-deficient and evaporative DED.