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Excerpt from TFOS DEWS II iatrogenic dry eye report
4.1.2 Systemic drugs with a known or suspected link to dry eye
Isotretinoin is listed in Table 3, "Known or suspected systemic medications causing, contributing to, or aggravating dry eye."
4.1.3 Mechanicsm
[38] Samarawickrama C, Chew S, Watson S. Retinoic acid and the ocular surface. Surv Ophthalmol 2015 May-Jun;60(3):183–195.
[39] Caffery BE, Josephson JE. Ocular side effects of isotretinoin therapy. J Am Optom Assoc 1988;59(3):221–224.
[40] Mathers WD, Shields WJ, Sachdev MS, Petroll WM, Jester JV. Meibomian gland morphology and tear osmolarity: changes with Accutane therapy. Cornea 1991;10(4):286–290.
[41] Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Investig Ophthalmol Vis Sci 2011;52(4):1938–1978.
[42] Kremer I, Gaton DD, David M, Gaton E, Shapiro A. Toxic effects of systemic retinoids on meibomian glands. Ophthalmic Res 1994;26(2):124–128.
[43] Bolekova A, Kluchova D, Tomasova L, Hvizdosova N. Effect of retinoic acid on the nitrergic innervation of meibomian glands in rats. Eur J Histochem 2012;56:e50.
[44] Ding J, Kam WR, Dieckow J, Sullivan DA. The influence of 13-cis retinoic acid on human meibomian gland epithelial cells. Investig Ophthalmol Vis Sci 2013;54(6):4341–4350.
[45] Ubels JL, Veenstra E, Ditlev J, Ingersoll K. Interactions of testosterone and all-trans retinoic acid in regulation of androgen receptor expression in rat lacrimal gland. Exp Eye Res 2003;77(6):741–748.
[46] Ubels JL, Wertz JT, Ingersoll KE, Jackson 2nd RS, Aupperlee MD. Down-regulation of androgen receptor expression and inhibition of lacrimal gland cell proliferation by retinoic acid. Exp Eye Res 2002;75(5):561–571.
[47] Bozkurt B, Irkeç MT, Atakan N, Orhan M, Geyik PO. Lacrimal function and ocular complications in patients treated with systemic isotretinoin. Eur J Ophthalmol 2002 May-Jun;12(3):173–176.
Excerpt from TFOS DEWS II iatrogenic dry eye report
4.1.2 Systemic drugs with a known or suspected link to dry eye
Isotretinoin is listed in Table 3, "Known or suspected systemic medications causing, contributing to, or aggravating dry eye."
4.1.3 Mechanicsm
Normal vitamin A is needed for corneal epithelial differentiation, increasing corneal wound healing and strength and reducing corneal and conjunctival epithelial keratinization [38]. However, excess retinoic acid (RA), used in the treatment of severe acne, cancer chemotherapy and anti-aging can cause dry eye and blepharitis; as isotretinoin is secreted in tears by the lacrimal gland, and is attributed to inducing atrophy of the meibomian glands, it can lead to changes in lipid secretion, tear osmolality and tear film stability[39,40].
In terms of the mechanism of high-dose RA-induced dry eye, there are several possible ocular surface target tissues, including the lacrimal glands, meibomian glands, cornea and conjunctiva. High-dose RA is known to cause meibomian gland atrophy, reduced quality of meibum, reduced tear film breakup time, increased tear osmolarity and dry eye symptoms [41]. It induces tissue necrosis and keratinization in adult animal meibomian glands [42] and disrupts meibomian gland development if given during the prenatal developmental period [43]. At the molecular and cellular level, RA inhibits meibomian gland epithelial cell proliferation, increases cell death, alters the expression of more than 6000 genes including IL-1β and matrix metalloproteinase 9 (MMP-9) and inactivates AKT signaling pathway that is important for cell survival and proliferation [44]. Similarly, high-dose RA also inhibits rat lacrimal gland epithelial cell proliferation and down-regulates androgen receptors [45,46]. However, RA does not appear to affect human lacrimal gland secretion clinically. One study found that Schirmer test scores were not significantly different before or after 2 months of isotretinoin treatment, even though reduced TBUT, increased blepharitis and subjective dryness, itching and CL intolerance did increase significantly after treatment [47]. This indicates that dry eye induced by RA is more likely secondary to MGD than to reduced lacrimal gland secretion. It is not clear why the clinical data show discrepancies from the animal and cell experimental data on the effect of high-dose RA on lacrimal glands. However, it appears that MGD is a major mechanism of RA-induced dry eye in both human, animal and cell culture studies. In terms of the cornea and conjunctiva, high-dose RA has been used to promote corneal wound healing and reduce conjunctiva keratinization; these tissues seem to be quite tolerant of high levels of RA and therefore not contributory to dry eye induced by RA [38].
In terms of the mechanism of high-dose RA-induced dry eye, there are several possible ocular surface target tissues, including the lacrimal glands, meibomian glands, cornea and conjunctiva. High-dose RA is known to cause meibomian gland atrophy, reduced quality of meibum, reduced tear film breakup time, increased tear osmolarity and dry eye symptoms [41]. It induces tissue necrosis and keratinization in adult animal meibomian glands [42] and disrupts meibomian gland development if given during the prenatal developmental period [43]. At the molecular and cellular level, RA inhibits meibomian gland epithelial cell proliferation, increases cell death, alters the expression of more than 6000 genes including IL-1β and matrix metalloproteinase 9 (MMP-9) and inactivates AKT signaling pathway that is important for cell survival and proliferation [44]. Similarly, high-dose RA also inhibits rat lacrimal gland epithelial cell proliferation and down-regulates androgen receptors [45,46]. However, RA does not appear to affect human lacrimal gland secretion clinically. One study found that Schirmer test scores were not significantly different before or after 2 months of isotretinoin treatment, even though reduced TBUT, increased blepharitis and subjective dryness, itching and CL intolerance did increase significantly after treatment [47]. This indicates that dry eye induced by RA is more likely secondary to MGD than to reduced lacrimal gland secretion. It is not clear why the clinical data show discrepancies from the animal and cell experimental data on the effect of high-dose RA on lacrimal glands. However, it appears that MGD is a major mechanism of RA-induced dry eye in both human, animal and cell culture studies. In terms of the cornea and conjunctiva, high-dose RA has been used to promote corneal wound healing and reduce conjunctiva keratinization; these tissues seem to be quite tolerant of high levels of RA and therefore not contributory to dry eye induced by RA [38].
[39] Caffery BE, Josephson JE. Ocular side effects of isotretinoin therapy. J Am Optom Assoc 1988;59(3):221–224.
[40] Mathers WD, Shields WJ, Sachdev MS, Petroll WM, Jester JV. Meibomian gland morphology and tear osmolarity: changes with Accutane therapy. Cornea 1991;10(4):286–290.
[41] Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Investig Ophthalmol Vis Sci 2011;52(4):1938–1978.
[42] Kremer I, Gaton DD, David M, Gaton E, Shapiro A. Toxic effects of systemic retinoids on meibomian glands. Ophthalmic Res 1994;26(2):124–128.
[43] Bolekova A, Kluchova D, Tomasova L, Hvizdosova N. Effect of retinoic acid on the nitrergic innervation of meibomian glands in rats. Eur J Histochem 2012;56:e50.
[44] Ding J, Kam WR, Dieckow J, Sullivan DA. The influence of 13-cis retinoic acid on human meibomian gland epithelial cells. Investig Ophthalmol Vis Sci 2013;54(6):4341–4350.
[45] Ubels JL, Veenstra E, Ditlev J, Ingersoll K. Interactions of testosterone and all-trans retinoic acid in regulation of androgen receptor expression in rat lacrimal gland. Exp Eye Res 2003;77(6):741–748.
[46] Ubels JL, Wertz JT, Ingersoll KE, Jackson 2nd RS, Aupperlee MD. Down-regulation of androgen receptor expression and inhibition of lacrimal gland cell proliferation by retinoic acid. Exp Eye Res 2002;75(5):561–571.
[47] Bozkurt B, Irkeç MT, Atakan N, Orhan M, Geyik PO. Lacrimal function and ocular complications in patients treated with systemic isotretinoin. Eur J Ophthalmol 2002 May-Jun;12(3):173–176.
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