Active Ingredient: Isotretinoin
The increasing number of patients looking for eye care or cosmetic procedures involving the eyes, together with a better understanding of the pathophysiological mechanisms of dry eye disease DED, have led to the need for a specific report about iatrogenic dry eye within the TFOS DEWS II.
Topical medications can cause DED due to their allergic, toxic and immuno-inflammatory effects on the ocular surface. The systemic drugs identified by large epidemiological studies as increasing the risk for DED together with their associated ORs are listed in Table 2.
Table 3 presents a compilation of known or suspected systemic agents that have been reported to induce or exacerbate dry eye. Among other sources, this listing of drugs has been compiled from a series of extensive reviews, epidemiological studies and the key database from Fraunfelder and colleagues, published in both peer-reviewed journals and every 4—5 years in book form.
A large segment of systemic drugs that have an effect on dry eye symptoms are those with anticholinergic activity.
More specifically, G-protein coupled muscarinic receptors in the lacrimal gland acini and conjunctival mucus-producing cells can be affected, thereby reducing aqueous and mucous tear component production and resultant tear film stability.
Moreover, functional cholinergic receptors have been identified in human meibomian gland epithelial cells and these receptors would also be impacted by anti-cholinergic agents.
The anti-cholinergic class comprises a wide range of therapeutic drug categories including antidepressants, antipsychotics or neuroleptics, anti-Parkinson's, H 1 antihistamines, decongestants and antispasmodics.
Additionally, adrenergic agents, including both beta-blockers and alpha agonists, elicit changes in both tear production and tear film quality i.
Alcohol is also secreted in tears and can contribute to dry eye via hyperosmolarity and shortened tear film breakup time.
Certain chemotherapeutic agents such as methotrexate, mitomycin C and busulfan have been reported to cause alterations in the quality of the tear film or affect reflex tear secretion.
In addition, dysfunctional tear syndrome has been associated with epidermal growth factor inhibitors such as erlotinib and cetuximab based on a hospital chart review of 69 patients. Normal vitamin A is needed for corneal epithelial differentiation, increasing corneal wound healing and strength and reducing corneal and conjunctival epithelial keratinization.
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.
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.
It induces tissue necrosis and keratinization in adult animal meibomian glands and disrupts meibomian gland development if given during the prenatal developmental period. Similarly, high-dose RA also inhibits rat lacrimal gland epithelial cell proliferation and down-regulates androgen receptors.
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.