nutrients Review A Review of Topical and Systemic Vitamin Supplementation in Ocular Surface Diseases Paolo Fogagnolo 1,*, Stefano De Cilla’ 2, Micol Alkabes 2, Pierfilippo Sabella 1 and Luca Rossetti 1 1 Ophthalmology Unit, Department of Health Sciences, San Paolo Hospital, Università degli Studi di Milano, 20142 Milan, Italy; pierfi[email protected] (P.S.); [email protected] (L.R.) 2 Ophthalmology Unit, Ospedale Maggiore della Carita, 28100 Novara, Italy; [email protected] (S.D.C.); [email protected] (M.A.) * Correspondence: [email protected] Abstract: In the homeostasis of the ocular surface, vitamins play a critical role in regulating inflam- matory responses and promoting cell differentiation, development and correct function. Systemic vitamin supplementation has been available for many decades; in recent years, thanks to pharma- cological advancements, topical vitamin delivery has also become available in an attempt to better treat ocular surface disease (OSD) and dry eye disease (DED). In this paper, we reviewed the current evidence on the role of vitamin supplementation in OSD and DED. We originally searched the PubMed archive, inspected the references and restricted the search to pertinent papers. The body of evidence was evaluated using the amelioration of both signs and symptoms as the outcome, when available. We found that in patients with vitamin deficiency, systemic supplementation of Vitamin A is effective in treating OSD, reducing both DED signs and symptoms. Additionally, systemic supplementation of vitamin D is useful in reducing DED symptoms and increasing tear volume. Citation: Fogagnolo, P.; De Cilla’, S.; Vitamin A is also effective in reducing DED signs and symptoms when administered locally. The Alkabes, M.; Sabella, P.; Rossetti, L. A efficacy of supplementation with other vitamins is still not fully proven. In conclusion, the inclusion Review of Topical and Systemic of vitamins into the treatment strategies for OSD and DED allows for better treatment customization Vitamin Supplementation in Ocular and better outcomes in these patients. Surface Diseases. Nutrients 2021, 13, 1998. https://doi.org/10.3390/ Keywords: ocular surface disease; dry eye disease; goblet cells; vitamin A; vitamin D; Sjogren nu13061998 syndrome; diabetes; neuropathic ocular pain; glaucoma Academic Editor: Jean-François Landrier 1. Introduction Received: 18 April 2021 Ocular surface disease (OSD) is an inclusive term encompassing the abnormalities of Accepted: 8 June 2021 Published: 10 June 2021 the ocular surface (OS) as a functional unit, including multiple epitheliopathies, inflamma- tion, surface abnormalities and distortions, which all affect tear dynamics. It also includes Publisher’s Note: MDPI stays neutral dry eye disease (DED), a multifactorial disease characterized by loss of homeostasis of the with regard to jurisdictional claims in tear film, OS inflammation and damage, and neurosensory abnormalities. In DED, these published maps and institutional affil- changes are accompanied by increased tear evaporation and hyperosmolarity, and typical iations. symptoms [1]. DED may also be caused by dysregulation of the immune system, such as Sjogren syndrome (SS). In the homeostasis of the OS, vitamins play a critical role. Vitamins A, C, and E are physiologically present in the OS and are essential for cell differentiation, development, and correct function [2]. Vitamin D and B have a key regulation activity of the immune and Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. nervous systems, respectively [2]. Vitamin deficiencies are frequently associated with both This article is an open access article OSD and DED, and systemic supplementation has proved to be beneficial in subgroups of distributed under the terms and patients with low vitamin intake. conditions of the Creative Commons The treatment of DED is stepwise and aims at controlling its risk factors and specific Attribution (CC BY) license (https:// pathophysiological patterns. Lubrication is a mainstay of DED treatment at all stages [3]. creativecommons.org/licenses/by/ Recently, many lubricating eyedrops have been enriched with compounds (amino acids, 4.0/). sugars, vitamins) in an attempt to promote OS homeostasis and control local inflammation. Nutrients 2021, 13, 1998. https://doi.org/10.3390/nu13061998 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, x FOR PEER REVIEW 2 of 13 sugars, vitamins) in an attempt to promote OS homeostasis and control local inflamma- Nutrients 2021, 13, 1998 2 of 12 tion. However, the usefulness of topical and systemic vitamin supplementation in DED is still controversial. The objective of this review is to address whether topical and systemic vitamin sup- plementationHowever, the are usefulness useful in of improving topical and signs systemic and vitaminsymptoms supplementation in patients with in DEDDED isand, morestill controversial. in general, OSD. The objective of this review is to address whether topical and systemic vitamin sup- plementation are useful in improving signs and symptoms in patients with DED and, more 2. Materials and Methods in general, OSD. This review was performed at the Department of Health Sciences, Università degli Studi2. Materials di Milano, and San Methods Paolo Hospital, Milan, Italy. We originally searched the PubMed ar- chiveThis on 01 review March was 2021 performed with the at keywords the Department “vitamin” of Health AND Sciences,“ocular surface Universit disease”à degli OR “dryStudi eye di Milano,disease”. San We Paolo inspected Hospital, the Milan, results Italy. of 4230 We originallypapers and searched identified the PubMed254 papers, providingarchive on the 01 following March 2021 useful with information: the keywords (1) “vitamin” preclinical AND evidence “ocular of surfaceefficacy; disease” (2) clinical evidenceOR “dry eyeof efficacy. disease”. Two We inspectedevaluators the indepen resultsdently of 4230 inspected papers and the identified full text and 254 papers,references toproviding retrieve therelevant following papers. useful Excluded information: were repo (1) preclinicalrts with duplicated evidence of results, efficacy; case (2) series clinical with 10evidence patients of or efficacy. less, papers Two evaluators with no abstract independently or papers inspected not written the in full En textglish. and No references restrictions onto retrievethe presence relevant of a papers. control Excluded group or were length reports of follow-up with duplicated were applied. results, In case the series end, 55 studieswith 10 were patients analyzed or less, in papers this review. with no abstract or papers not written in English. No restrictions on the presence of a control group or length of follow-up were applied. In the end, 55 studies were analyzed in this review. 3. Results 3.1.3. Results Vitamin A 3.1.1.3.1. Vitamin Preclinical A Evidence 3.1.1. Preclinical Evidence There is large preclinical evidence supporting the beneficial effects of vitamin A ad- ministrationThere is (either large preclinicalsystemically evidence or topically) supporting on the the ocular beneficial surface. effects The of mechanisms vitamin A of administration (either systemically or topically) on the ocular surface. The mechanisms of action of vitamin A on the OS are reported in Figure 1. Vitamin A increases conjunctival action of vitamin A on the OS are reported in Figure1. Vitamin A increases conjunctival mucin expression and promotes correct corneal and conjunctival wound healing, reduc- mucin expression and promotes correct corneal and conjunctival wound healing, reducing ingkeratinization. keratinization. These These effects effects have have been been shown shown by several by several studies studies using differentusing different animal ani- malmodels models of DED: of DED: vitamin vitamin A promotes A promotes wound wound healing healing [4] by directly [4] by improvingdirectly improving epithelial epi- thelialrepair [repair5,6], and [5,6], reducing and reducing cell apoptosis cell apoptosis [7] and corneal [7] and keratinization corneal keratinization [8]. These effects [8]. are These effectsmediated are bymediated an increase by an in increase tear volume in tear [9, 10volume] and quality [9,10] and [5]. Onquality a rabbit [5]. On model a rabbit of OSD, model ofdue OSD, to antiglaucoma due to antiglaucoma treatments, treatments, topical vitamin topical A wasvitamin as effective A was asas topicaleffective cyclosporine as topical cy- closporinein reducing in OS reducing inflammation, OS inflammation, as evaluated as by evaluated impression by cytology impression [11]. cytology [11]. Figure 1. Effects of vitamin A supplementation on the ocular surface. Nutrients 2021, 13, 1998 3 of 12 The mechanism of action of vitamin A is complex. It upregulates the cytochrome P450 synthesis of eicosanoids in in vitro models of human conjunctival and cornea cells [12]. Eicosanoids exhibit potent inflammatory and angiogenic properties, and upregulate se- cretory phospholipase A (2) group IIA genes, which are responsible for increased mucin 16 expression [13]. Expression of mucin 16 in the cornea glycocalyx provides a protec- tive barrier for the epithelium [13]. Vitamin A also stimulates the synthesis of mucin 4 (physiologically absent on human OS), but not directly the synthesis of mucin 1 (one of the most expressed mucin on the OS secreted by goblet cells) [14]. Finally, vitamin A also down-regulates androgen receptor expression on the ocular surface [15]. 3.1.2.