Expert opinion in the management of aqueous Deficient Dry Eye Disease (DED)

The goal of this survey was to characterize the most commonly prescribed treatments for aqueous deficient DED among dry eye specialists and to identify therapeutic options that may be of interest for future study. Our results indicate that while many ophthalmologists are commonly using topical therapies such as steroids and cyclosporine A 0.05 %, they are also turning to oral and other non-topical therapies.

Among topical therapies for aqueous-deficient DED, respondents were most commonly using topical steroids (fluorometholone 0.1 % and loteprednol etabonate 0.5 %), CSA 0.05 %, and autologous serum eye drops. While these practice patterns may reflect respondent experience and interpretation of clinical data, they are also likely affected by local drug availability. The role of inflammation in DED makes topical corticosteroids a natural candidate for therapy, but significant side effects with prolonged corticosteroid therapy, including secondary glaucoma, infection and cataract formation, have limited their use. One randomized controlled trial found loteprednol etabonate 0.5 % to be effective over placebo in patients with moderate clinical inflammation [9]. Topical CSA is an attractive alternative given its relative safety. In addition, it is the only medication approved by the US Food and Drug Administration for moderate to severe DED, and has been well studied in clinical trials [10‐12]. These clinical trials also studied the use of CSA 0.1 %, and many found it to be as efficacious as the 0.05 % formulation as well as safe in both short and long term studies [11, 12]. Respondents in this survey demonstrated an interest in using a stronger formulation of CSA (0.1 %), but are prohibited by its lack of availability. Compounding pharmacies are required to obtain CSA 0.1 % as commercial formulation is undergoing regulatory review in Europe. The optimal duration of therapy with topical CSA is unclear. One study has suggested that after a year of standard twice daily CSA 0.05 % therapy, patients can be successfully weaned to once daily therapy without significant worsening of their symptoms. [13] Respondents of this survey reported most commonly seeing improvements with CSA therapy in shorter time periods (2 weeks to 2 months). ASD are thought to alleviate dry eye by supplying tear components such as various growth factors and vitamins that aid in the maintenance of the ocular surface; it has been studied in a handful of small clinical studies, the majority of which have found it to be more effective than artificial tears [7, 14‐17]. However, there have not been studies comparing ASD to other medications such as CSA. While CSA, topical corticosteroid and ASD appear to have been accepted into the community practice, there is a lack of comparative studies between these agents.

Among non-topical therapies for DED patients, respondents were most commonly using punctal plugs, oral EFA supplements, low-dose oral doxycycline and flaxseed supplements. Punctal plugs have been studied in multiple clinical trials, and a recent Cochrane review found that although the literature did not decisively support its efficacy for dry eye treatment, the data did suggest “usefulness” in DED [18]. EFA supplements are traditionally used to treat evaporative DED or meibomian gland disease. Systemic EFA supplements have been studied in small- to moderate-sized clinical trials; only a few showed improvements for limited measures of DED, with others finding no statistically significant improvement [19‐22]. Doxycycline, an antibacterial with anti-inflammatory effects, gained traction as a therapy for DED when inflammatory pathways were added to the understanding of dry eye pathogenesis [5]. It has primarily been studied in ocular rosacea, but a recent study in a small number of patients suggests doxycycline to be effective in restoring tear film stability in dry eye patients [23‐26]. Despite limited data for both omega fatty acids and doxycycline, both are being used by survey respondents, with significant interest in increasing their use.

Study participants reported significant interest in new topical therapies, particularly diquafosol and vitamin A eye drops. Diquafosol (1–3 %), a P2Y2 receptor agonist thought to promote non-glandular secretion of fluid, is available primarily in East Asian countries due to its approval for use in Japan, but is still undergoing clinical review in the United States. Survey respondents from the Asian/Indian subcontinent did not demonstrate a higher frequency of diquafosol use. Diquafosol has been found in a number of prospective clinical trials to be effective compared with placebo and sodium hyaluronate; there have been no studies comparing its efficacy to CSA 0.05 % [27‐30]. Vitamin A has been identified in natural tears and vitamin A deficiency is thought to cause evaporative DED. Vitamin A drops have been shown in one moderate-sized trial to significantly improve dry eye signs and symptoms over artificial tears, and had similar efficacy to CSA 0.05 % [31]. Respondents also demonstrated interest in two lesser studied medications: topical tacrolimus and resolvin E1 (EFA) eye drops, and appropriately called for more clinical investigations into these medications. Tacrolimus 0.03 %, a macrolide with immunomodulatory properties, was found in small prospective case series to significantly improve signs of dry eye in Sjogren’s syndrome patients and in graft versus host disease patients refractory to topical CSA 0.05 %; it has yet to be studied in a randomized controlled trial setting [6, 32]. A stronger formulation of tacrolimus (0.1 %) has been approved in Japan and is readily available in East Asian countries, though survey respondents from Asia/Indian sub-continent did not report using this treatment more frequently. Resolvin and other topical EFA formulations have only been studied in animal models [33, 34]. While lack of availability was a significant barrier to respondents using all 4 topical therapies, use of vitamin A drops, tacrolimus and topical EFA was also limited by lack of clinical data.

Our results suggest non-topical therapies, such as rituximab and DHEA, are of great interest to clinicians as targets for future research in the treatment of aqueous deficient DED. Rituximab has been reported in case reports for keratoconjunctivitis sicca, but has mostly been studied in clinical trials for primary Sjogren’s. Results are pending from two recent clinical trials, the Tolerance and Efficacy of Rituximab in Sjogren’s Disease trial and the Trial of Anti-B-Cell Therapy in Patients With Primary Sjögren’s Syndrome [35‐39]. Minimal literature exists for the use of sex steroids, such as DHEA, in DED. DHEA supplementation has been studied in Sjogren’s syndrome and has not had promising results [40, 41]. Interestingly, respondents were not interested in cholinerigic agonists such as pilocarpine and cevimeline which have been shown in clinical trials to be effective for dry eye secondary to Sjogren’s syndrome; there was also little interest in hydroxychloroquine, oral cyclosporine or oral steroids [8].

One issue in studying DED is the lack of consensus regarding measures of efficacy in clinical trials. This is compounded by the fact that severity of symptoms do not correlate with exam findings [42]. Outcomes of interest to clinicians in this survey were fluorescein staining of the cornea, reduction in foreign body sensation and reduction in burning sensation. Interestingly, Schirmer type 1 test was not among the top responses despite commonly being used clinically and in clinical trials [42]. The results of this survey may guide the selection of outcomes in future clinical trials.

Limitations of this study include those intrinsic to all surveys, including recall bias and non-response bias. The response rate of 8.6 % is not uncommon and is better than previous dry eye surveys [43, 44]. A strength of the survey is the high proportion of respondents who were corneal specialists, as this is likely to be the population most interested in the topic. Our method of surveying biases toward academic practitioners, and therefore likely represents expert opinion rather than current practices in general. Since the survey did not include traditional therapies such as PFATs, this increased the responses to other therapies such as ASD, which likely does not reflect current practice outside of academic centers. However, this survey is informative about the implementation of newer treatments in DED and is hypothesis generating for future areas of study. The survey could not address all possible potential therapies, which may have prohibited the identification of other treatments of interest. Respondents were given the option to suggest additional therapies, but responses were minimal. Finally, as respondents practice patterns are likely limited by drug availability and local treatment guidelines, the geographic diversity of respondents is a strength of the survey.