Effectiveness of a New Active Tear Substitute Containing 0.2% Hyaluronic Acid and 0.001% Hydrocortisone on Signs and Symptoms of Dry Eye Disease by Means of Low- and High-Tech Assessments

Dry eye disease (DED) is a chronic, multifactorial disease of the ocular surface (OS), characterized by either decreased tear production or increased evaporation [1, 2]. DED alters OS homeostasis, causing reduced tear production, increased evaporation, OS inflammation, increased tear film osmolarity, and tissue damage [2]. This mechanism tends to perpetuate by creating the vicious circle of dry eye [3]. DED presents with a range of symptoms that vary in severity in each patient, and include eye irritation, stinging and foreign body sensations, ocular fatigue and vision impairment [1]. Although DED is one of the most common ocular disorders, with a prevalence range from 5 to 50% depending on the geographic region, it is still underdiagnosed and undertreated [4‐8]. Some risk and predisposing factors for DED can be identified, such as ocular allergy, cataract surgery, preserved eye drops, and meibomian gland dysfunction (MGD) among others [9‐12].

Traditionally, common clinical measures used for diagnosing DED and OS impairment are fluorescein tear breakup time (TBUT), OS fluorescein staining, Schirmer test and hyperemia assessment [13, 14]. However, both TBUT and Schirmer test are limited by their invasiveness, which affects the OS response and may lead to increased tearing reflex. Moreover, different patterns of tear rupture can be seen in DED, making TBUT difficult to interpret, with consequent low repeatability and reproducibility [15, 16]. TBUT is also a subjective test whose cut-off values are not fully validated: generally, 10 s is an accepted cut-off [13], but it has been suggested that if the volume of fluorescein used is lower (a desirable strategy because it induces less OS modifications) 5 s would be a proper cut-off [17]. Likewise, the assessment of hyperemia can be influenced by the subjectivity of the operator. In addition, these parameters can be poorly related to symptoms and, sometimes, poorly responsive to adequate treatment [18, 19]. Otherwise, the ocular discomfort symptoms of DED are effectively measured with questionnaires, among which the OSDI (Ocular Surface Disease Index) score is the most validated [20].

Recently, new tools for the instrumental diagnosis and monitoring of DED have been introduced in the clinical practice [21]. Among these, Keratograph^® is an all-in-one device increasingly used for the study of OS diseases, as it allows automated, non-eye contact evaluation of noninvasive Keratograph tear breakup time (NIKBUT), tear meniscus height (TMH), eyelid meibography, conjunctival hyperemia, and conjunctival folds as a sign of conjunctivochalasis (hereafter conjunctivochalasis) [16, 22].

The use of tear substitutes to lubricate the OS is regularly prescribed in the case of DED, representing the mainstay of treatment [4]. Most products on the market contain hyaluronic acid (HA) as their main component, which has important lubricating and moisturizing properties able to improve the stability of the tear film thanks to the specific strong interactions with the mucus layer in the ocular surface [23‐25]. HA also promotes wound healing thanks to its specific activity on CD44 receptors expressed by corneal epithelium [26]. Other products contain carboxymethylcellulose and polyethylene glycol [4]. However, traditional lubricating eye drops can relieve the symptoms of DED but are poorly effective in counteracting specifically the main underlying pathological mechanism, namely dysregulated parainflammation, which has recently been recognized as an important pathogenetic step in the progression of tear dysfunction in DED [27, 28]. Therefore, to act on this pathological factor as well, an innovative HA-based eye drops formulation has recently been placed on the market (Idroflog^®, Alfa Intes, Italy; class III medical device) [29]. In addition to the presence of 0.2% HA, this innovative product contains a low concentration of hydrocortisone (0.001%; hereafter termed hyaluronic acid and low-hydrocortisone eye drops, HALH), a synthetic analogue of cortisol, which is normally produced at the level of the OS to provide the first line of defense to potential exogenous, pro-inflammatory triggers and restore the homeostasis [30]. According to a recently published clinical study, the treatment with HALH proved to control macrophage infiltration, reducing the immune system involvement and leading to an easier recovery of OS homeostasis [31]. Therefore, the product has the advantage not only of lubricating and moisturizing the OS but also of controlling the sub-clinical inflammatory component [31].

In the present paper, the effectiveness of HALH was retrospectively evaluated and compared with standard lubrication to test the hypothesis that treating OS parainflammation might give a clinical advantage over standard lubrication on different subtypes of DED. A positive result of the study would allow a better customization of DED treatment. We also studied the impact of low- and high-tech measures on measuring OS changes over time after each therapy, thus proving further real-life data on the possible advantage of using high-tech imaging on DED management.

The noninvasive diagnostic workup of DED using high-tech, all-in-one devices, such as Keratograph^®, have been recommended by experts and is gaining popularity in many settings thanks to several major advantages [32]. Indeed, the procedure is operator-independent, contactless, and no dyes are required. Aside from the request not to blink during the video recording of NIKBUT analysis, which may lead to increased tearing reflex, OS homeostasis is by far less altered than with low-tech measures, thus providing a more objective assessment of DED parameters than low-tech measures [16].

Keratograph^® has been successfully used for the diagnosis and monitoring of various OS diseases in recent studies [21, 33‐37], the most commonly studied parameter being NIKBUT. A recent randomized trial showed that the discriminative ability of NIKBUT in detecting dry eye is significantly higher than TBUT (area under the receiver operating characteristic curve of 0.68 and 0.57, respectively) [38]. At the same time, the reproducibility of this measure is still debated: it has been reported that it may be high in some patients (even higher than TBUT) [39], although other reports suggested that TBUT is more reproducible than NIKBUT [16, 40, 41].

In this study, we retrospectively evaluated the activity of HALH versus standard lubricating eye drops in the most common types of DED (post-cataract surgery, MGD, allergy and glaucoma medications). Overall, the efficacy of HALH and STS in treating DED was confirmed by both high- and low-tech measures. Yet, HALH treatment achieved higher significance than STS when changes were inspected by Keratograph^® NIKBUT-first (p < 0.001 and p < 0.05, respectively; Table 2). NIKBUT-first showed a significant improvement in the HALH group versus STS at 15 days, whereas such a difference was latent with TBUT until 45 days.

The superiority of high-tech measures in detecting changes at follow-up was previously supported [34] while refuted elsewhere [35, 42]. Using Keratograph^®, we were able to report early and additional significant differences among treatments compared with the use of low-tech assessments and to report the enhanced activity of the HALH treatment even in specific DED subgroups: NIKBUT-first in the HALH group was enhanced in patients with MGD after 15 days of treatment and in patients who had undergone cataract surgery after 45 days of treatment. Moreover, only patients in the HALH group reported a statistically significant improvement in the NIKBUT class after 45 days of treatment.

Such a feature was also reported by comparing other parameters. TMH and Schirmer are noninvasive and invasive tests for quantitatively evaluating tears amount, respectively [43]. In this study, both parameters significantly improved at follow-up; however, only TMH was able to identify earlier and more frequent changes than the Schirmer test, which were all in favor of HALH. Nevertheless, results on TMH and Schirmer test should be interpreted with caution because the tearing reflex may have been stimulated during the study examination, particularly in the context of a retrospective, clinical-based study.

Conjunctival hyperemia is an important sign of OS irritation and inflammation [44]. Both STS and HALH treatments improved conjunctival hyperemia and reduced the percentage of patients reporting epithelial alterations. When considering hyperemia in patients with DED after cataract surgery treated with HALH, the improvement was significant compared with baseline at both time points (p = 0.008 and p < 0.001, respectively), although without differences between groups. Low-tech measures supported this result, reporting a significant improvement in the hyperemia stage at both 15 days (36% of patients improved their stage) and 45 days (48% of patients improved their stage) of treatment in the HALH group. Regarding epithelial damage, a significant improvement was reported only in the STS group, although the difference at 45 days was not statistically significant between treatments. Moreover, it must be considered that the severity of epithelial damage at baseline was different in the two groups (27% for HALH versus 43% for STS), making recovery more likely in the STS group.

Taken together, our results support the effectiveness of the new tear substitute containing HA and a low hydrocortisone concentration compared with STS in the qualitative and quantitative improvement in the tear film in patients with different types of DED. Yet, it is essential to highlight that statistically significant differences may not always be clinically relevant and, thus, caution in data interpretation is mandatory. In fact, in the literature there is paucity of studies that evaluate if the changes in OS parameters are clinically meaningful. To the best of our knowledge, only one study measured the minimal clinically important difference for OSDI [45]. Assuming as clinically relevant a change of OSDI score in mild DED ranging from 4.5 to 7.3 units, both HALH and STS were clinically effective in the whole study population and in all subgroups.

Recent literature suggests that several degenerative changes in the OS occur with age, within a process called inflammaging [46, 47]. It is a chronic, subclinical form of dysregulated parainflammation that arises with aging and includes tear instability, decreased tear production, increased OSDI score, and inflammatory markers [48]. With aging, parainflammatory compensatory mechanisms fail to adequately restore OS homeostasis. This leads to a persistent asymptomatic inflammatory state, particularly evident following an insult, such as cataract surgery [48]. Low-concentration use of hydrocortisone can help the system to recover more effectively than STS [31]. From a speculative point of view, this may explain the observed enhanced activity of the HALH treatment, particularly in patients with surgically-related DED, who were older than other subgroups, and thus may be mainly involved in inflammaging processes.

Our findings related to the use of STS agree with previous studies evaluating the effectiveness of these treatments by assessing the OSDI score and TBUT value [49‐52]. At the same time, high-tech parameters, such as NIKBUT, were previously used on DED subjects to assess the activity of STS [33, 42, 53‐55].

Our data are consistent with previous findings that highlighted the possible advantages of high technology to better diagnose and monitor patients with DED. Nonetheless, the clinical advantage of high-tech still needs to be fully verified and more extensive research with head-to-head studies as well as meta-analyses are needed to draw firmer conclusions. In particular, the best NIKBUT parameter (first, average, or class) to use has not yet been defined, nor is the agreement between high- and low-tech measures. For instance, in our cohort, patients ameliorating one NIKBUT class (n = 43) or more had a decrease in the OSDI score from 29 ± 16 at baseline to 17 ± 7 at day 45 (p < 0.001). The OSDI score for patients with stable NIKBUT class (n = 94) was 27 ± 13 at baseline and 18 ± 9 at day 45 (p < 0.001). The OSDI score for patients who worsened NIKBUT class (n = 16) was 35 ± 17 at baseline and 21 ± 12 at day 45 (p = 0.007). The lack of significant correlation between low- and high-tech measures and the OSDI score, as well as the poor correlation between low- and high-tech measures, has already been reported using a cross-sectional dataset [35]. These aspects will be addressed in a subsequent paper, exploring the correlation occurring in DED measures during follow-up.

This study has some limitations, mainly related to the retrospective design and the lack of patient randomization. The sample size was large enough to provide robust statistics, but the glaucoma group was poorly represented and therefore not analyzed separately. In addition, the study duration was limited; despite the progressive amelioration of parameters in both groups at 45 days, it is reasonable to hypothesize that further improvement could have been achieved with a longer follow-up. However, our dataset reflects the multicenter, real-life clinical practice use of HALH and STS, which can be considered a study's strength potentially improving the generalizability of the results.

Our study combines, for the first time, low- and high-tech measures to retrospectively compare the activity of HALH treatment versus STS. Obtained results suggest its effectiveness in all DED subtypes, especially in patients who had undergone cataract surgery, and its superiority in terms of tear film stability improvement.

Moreover, our data showed that the beneficial effects of HALH treatment are progressive over the observation period. Considering the concept of inflammaging, prolonged use is needed to fully recover system homeostasis. From this viewpoint, it is also possible that longer treatment will highlight further differences in terms of activity between HALH and STS.

Based on the variation in latency shown by low-tech versus high-tech measures, we recommend longer observation (i.e., 3–6 months) to fully ascertain whether the early improvement documented by means of high-tech measures will be confirmed at subsequent time points using low-tech tests.