Letter to the editor: ‘topical preservative-free ophthalmic treatments an unmet clinical need’

In their interesting review published online Figus and coworkers [1] address the important topic of the value of topical preservative-free (PF) ocular medications placing emphasis on their role in the management of dry eye disease (DED) and glaucoma. We wish to highlight certain key issues, which in our opinion would complement this review. It is surprising that the author’s comprehensive literature search failed to identify two pertinent reviews [2,3] and a research publication [4] from our group published well before the closure of the authors’ data collection (April 2020). This omission unfortunately occurred despite their claim that ‘all available articles in the English language, up to April 2020, were reviewed.’ It can be argued that our work [2–4] would have reinforced the argument for the superiority of PF medications. Of note, in section 3.2.2 of this review the term ‘glaucoma related-ocular surface disease’ is employed, a term almost identical to the term ‘glaucoma therapy-related ocular surface disease’ we have introduced in the literature in 2018[2]. Primarily, in such a review we feel it is essential to understand the biological properties and mechanism of cumulative toxicity of the commonest preservative in topical eye medications: benzalkonium chloride, (BAK). In section 1 the authors state that ‘due to the rapid BAK concentration clearance in the tear film, the severity of BAK toxicity may be mostly due(?) to the duration of the exposure to the treatment.’ They support this statement with reference #28 by Lemij and coworkers, which is a study exploring patient satisfaction with glaucoma therapy. In fact, one of the most problematic aspects of BAK toxicity is the progressive slow accumulation of this preservative within ocular tissues [2,3,5]. In the same section, they write ‘presumed advantages of newer preservatives such as SofZia®, Purite®, or Polyquad over BAK, are still uncertain.’ Again they support their argument with a reference (#30), which is inconsistent since it states the exact opposite: ‘Cellular viability was moderately reduced by perborate and polyquad-preserved tear substitutes and dramatically reduced by BAK.’ We fully agree however with their statement on the same subject in section 3.2.2. that ‘study lengths are short, whereas the use of BAK in eyedrops is often lifelong.’ This point however, in our view undermines the overall argument for the use of BAK-preserved medications they describe in section 1. In section 3.1 the authors provide convincing evidence showing that preservatives negatively affect the outcome of DED therapy, inducing tear film instability, goblet cell death, and inducing oxidative and inflammatory ocular surface damage. Yet, in the concluding paragraph of this section they state: ‘the literature does not prove that PF artificial tears are more effective than preserved artificial tears for the treatment of DED.’ They are therefore reluctant to support the advantages of only using PF eyedrops in DED management due to a perceived lack of comparative trials. In reality, however, there is abundant evidence, summarized by the consensus recommendations of the Tear Film and Ocular Surface Society Dry Eye Workshop II [6] which categorically states that sufficient evidence exists to confirm that DED patients, particularly those with severe DED should avoid the use of ocular lubricants preserved with BAK when they need to use them frequently, or need other chronic topical therapies, such as glaucoma medications, because BAK toxicity represents a considerable burden over time. [6] This evidence has shifted the scientific community and industry toward launching and using PF artificial tear drops. Hence, today there is no justification to consider long-term therapy with preserved lubricants. Our primary target is to enhance comfort and safety by eliminating preservatives, and has nothing to do with efficacy. Contrary to the author’s statement in section 3.2.1 that ‘BAK is rapidly diluting because of tear film clearance,’ the opposite is true, because BAK progressively accumulates in ocular tissues and its toxicity progressively increases over time [2,5,7]. Exposure to BAK exacerbates allergy and inflammation, negatively impacting anti-allergic therapy, and should be avoided [8] as PF medications for inflammatory and allergic conditions are less toxic and more effective. Progressive GTR-OSD affects the quality of life of millions of patients worldwide and reduces the success of medical and surgical glaucoma therapy [2,5,9,10]. The causative GTR-OSD, often goes under-recognized and undertreated [10], is fast becoming a major health concern, with 45–60% of patients using glaucoma eyedrops reportedly being affected by toxicity [2,9,10]. The authors clearly describe the key role of preservative toxicity in the development of this condition and provide