To compare the corneal topographic parameters and ocular surface parameters of ocular rosacea (OR) patients across skin subtypes of the disease and healthy controls.

This prospective study included 180 eyes of 90 OR patients and 60 eyes of 30 healthy controls. Among the OR patients, 30 had phymatous (60 eyes), 30 had erythematotelangiectatic (60 eyes) and 30 had papulopustular skin types (60 eyes). We measured the mean keratometry (Kmean), maximum keratometry (Kmax), thinnest corneal thickness (TCT), central corneal thickness (CCT) and corneal volume (CV) with a topography device (Sirius, Italy). Additionally, we measured tear-film breakup time (TBUT), Meiboscore and Schirmer's test from all participants. We compared parameters across OR skin groups as well as with controls.

Kmean and Kmax were significantly steeper in the OR group compared to controls (p
                     <0.05). We found significant correlations between “Kmean-Kmax”, “CV-TCT”, “CV-CCT”, and “TCT-CCT” in both groups, while significant correlations between “age-Kmean”, “age-Kmax”, and “Meiboscore-Kmax” were present only in OR patients. When patients were divided into subgroups according to their skin subtypes, the papulopustular and phymatous subgroups had steeper Kmean and Kmax compared to the erythematotelangiectatic and control groups (P
                     <0.05). The papulopustular subgroup had lower CCT, lower TBUT and higher Meiboscore compared to the phymatous, erythematotelangiectatic and control groups but lower TCT compared to controls (P
                     <0.05). In addition, there were significant correlations between “Kmax-CV”, “Kmax-TCT”, and “Kmax-meiboscore” only in the papulopustular subgroup (P
                     <0.05).

It appears that the corneas of OR patients are steeper than those of healthy controls; corneal thinning and abnormalities of ocular surface parameters are more pronounced in papulopustular skin types.

Comparer les paramètres topographiques cornéens et les paramètres de la surface oculaire des patients atteints de rosacée oculaire (RO) selon les sous-types cutanés de la maladie et des témoins sains.

Cette étude prospective a inclus 180 yeux de 90 patients RO et 60 yeux de 30 témoins sains. Parmi les patients RO, 30 avaient une peau phymateuse (60 yeux), 30 une peau érythémato-télangiectasique (60 yeux) et 30 une peau papulo-pustuleuse (60 yeux). Nous avons mesuré la kératométrie moyenne (Kmean), la kératométrie maximale (Kmax), l’épaisseur cornéenne la plus fine (TCT), l’épaisseur cornéenne centrale (CCT) et le volume cornéen (CV) avec un appareil topographique (Sirius, Italie). De plus, nous avons mesuré le temps de rupture des larmes (TBUT), le meiboscore et faire le test de Schirmer de tous les participants. Nous avons comparé les paramètres des groupes de peau OR et des contrôles.

Kmean et Kmax étaient significativement plus raides dans le groupe OR que dans le groupe témoin (p
                     <0,05). Nous avons trouvé des corrélations significatives entre « Kmean-Kmax », « CV-TCT », « CV-CCT », « TCT-CCT » dans les deux groupes, tandis que des corrélations significatives entre « âge-Kmean », « âge-Kmax » et « Meiboscore-Kmax » n’étaient présents que chez les patients RO. Lorsque les patients ont été divisés en sous-groupes selon leurs sous-types decutanés, les sous-groupes papulopustulaires et phymateux présentaient une Kmoyenne et un Kmax plus raides que les groupes érythémato-télangiectatiques et témoins (p
                     <0,05). Le sous-groupe papulopustuleux présentait un CCT inférieur, un TBUT inférieur et un Meiboscore plus élevé par rapport aux groupes phymateux, érythémato-télangiectatiques ou témoins, tandis que le TCT était inférieur à celui des témoins (p
                     <0,05). En outre, il y avait des corrélations significatives entre « Kmax-CV », « Kmax-TCT » et « Kmax-meiboscore » uniquement dans le sous-groupe papulopustulaire (p
                     <0,05).

Il apparaît que les cornées des patients atteints de RO soient plus courbes que celles des témoins sains, l’amincissement de la cornée et l’altération des paramètres de la surface oculaire sont plus prononcés dans les types de peau papulopustulaires.

# Introduction

Rosacea is a chronic inflammatory skin disorder observed in more than 10% of the population. Symptoms are frequently reported around the head and neck area. In the region, it mainly affects the central facial area, including cheeks, chin, nose and center of the forehead. It is characterized by flushing, some transient or permanent rashes, inflammatory papules and pustules, telangiectasia, and ocular symptoms that constitute ocular rosacea (OR) [1]. According to epidemiological data, extrinsic and intrinsic factors play a role in the pathogenesis of rosacea, alongside the influence of genetic predisposition [2,3].

The classification system developed by the National Rosacea Society Expert Committee is widely accepted. Clinical subtypes and variants of skin rosacea is standardized [4]. This committee defines four disease subtypes based on phenotypes: erythematotelangiectatic, papulopustular, phymatous and OR. Although phenotypes can often coexist, rosacea is mainly distinguished by the predominant phenotype [4].

It is estimated that OR affects 58 to 72% of patients with skin rosacea [5]. Ocular involvement is typically bilateral and asymmetric [6]. Most commonly, OR presents as a chronic blepharoconjunctivitis with eyelid margin inflammation, telangiectasias and meibomian gland dysfunction (MGD) [7]. Ocular symptoms, such as dryness, redness, watering, burning, foreign body sensation, light sensitivity, and blurred vision can be observed in 50–75% of patients [8]. These symptoms may also occur ahead of dermatological symptoms, posing challenges to diagnose the disease [9]. Although early symptoms usually involve eyelids, they progress to the corneal area in 41% of the cases [6]. The inferior cornea is usually involved, but central corneal involvement may also occur, with the circumferential progression of the disease [6]. Corneal involvement can manifest in a broad spectrum from punctate erosions to corneal perforation [10].

Dysregulations in the inflammatory system play a pivotal role in the OR pathogenesis [2]. The inflammation cascade initiates with the cell infiltration and release of proinflammatory factors, particularly associated with high level of toll-like receptor expressions [11,12]. In the context of an irregularity of the corneal surface, it is worth considering topography as an additional help to patient's examination. Unfortunately, anterior segment parameters and corneal biomechanics seem modified by OR. The chronic inflammation of the ocular surface is incriminated [13]. Dursun et al. even further discuss how much rosacea could change topography by mimicking keratoconus patterns [14]. Actually as a matter of fact, the pleiomorphic presentation of the OR jeopardizes the analysis of topography in our routine clinical practice.

Aiming at analyzing topography with an acceptable level of accuracy in OR patients, we failed to read any case control study comparing topographic indices of normal corneas versus cornea of OR patients, such as the thinnest corneal thickness (TCT) and maximum keratometry (Kmax). Additionally, how OR skin subtypes are interfering with topographic values and ocular surface parameters are still ill defined.

In this study, we aim to compare some main topographic and ocular surface parameters of OR patients with healthy controls considering rosacea skin subtypes.

# Material and methods

This prospective cross-sectional study included 180 eyes of 90 rosacea patients having both cutaneous and ocular involvement and 60 eyes of 30 healthy controls. This study was conducted by following the principles of the Declaration of Helsinki. The local ethics committee approved the study and we obtained a written informed consent from the participants.

Rosacea patients were referred to our cornea clinic by an experienced dermatologist (A. A.), with respect to their skin phenotypes according to the ROSCO consensus [15]. The presence of OR was determined by a single senior cornea specialist (N. Y.), following a comprehensive ophthalmological examination which included the best-corrected visual acuity, both biomicroscopic anterior and posterior segment examinations and the measurement of intraocular pressure. Only patients with mild-to-moderate OR (i.e. having lid margin telangiectasia, blepharitis, blepharoconjunctivitis, and meibomian gland dysfunction) were included. Patients with a history of other ocular or systemic disease, history of ocular surgery, severe ocular rosacea findings (i.e. corneal scar or corneal infiltrates, stem cell deficiency, sclerokeratitis), pregnancy, ocular or systemic medication, contact lens usage, or smoking were excluded from the study.

Demographics, ophthalmological examination features, tear breakup time (TBUT), Schirmer-1 test results and meibomian gland dysfunction score (meiboscore) were recorded from all participants. The meiboscore was obtained by taking infrared meibography images of the inferior eyelids with the Sirius topography device (Sirius, CSO, Florence, Italy) and grading the loss rate in the glands on a scale of 0 to 4 (grade 0: <10% loss; grade 1: 10–25% loss; grade 2: 25–50% loss; grade 3: 50–75% loss; grade 4: >75% loss). Same sirius topography was used to measure the mean keratometry (Kmean), maximal keratometry (Kmax), thinnest corneal thickness (TCT), central corneal thickness (CCT), and corneal volume (CV) parameters for all participants.

SPSS version 22 (SPSS Inc. Chicago, USA) was used for statistical analysis. Descriptive statistics consisted of reporting global data as mean±standard deviations. We tested normality of values with the Shapiro–Wilk. For normally distributed values, we compared groups using the independent sample t-test and one-way ANOVA. If not normally distributed, we compared values using the Mann-Whitney U and Kruskal Wallis tests among groups. For correlation analysis, the Pearson test was carried out for normally distributed values, while the Spearman test was carried out for not normally distributed values. We set the statistical significance level at P
                     ≤0.05.

# Results

The study included 180 eyes of 90 OR patients (32 males, 58 females), who met both inclusion and exclusion criteria, attributing 60 eyes (30 patients) to each skin types. Besides, we included 60 eyes of 30 healthy controls (12 males, 18 females). Mean age was 53.79±7.48 years for OR patients, and 52.12±7.36 years for healthy controls. There was no statistically difference between OR patients and controls for age and gender (P
                     =0.34 and P
                     =0.67) (Table 1
                     ).

Table 1 shows the comparison of Kmean, Kmax, TCT, CCT, CV, TBUT, meiboscore and Schirmer results between OR and control groups. Kmean and Kmax were significantly steeper in the OR group compared to controls (P
                     <0.05). Ocular surface parameters were significantly worse (higher meiboscore, lower TBUT and Schirmer) in the OR group compared to controls (P
                     <0.05). Correlation between demographic, topographic and ocular surface parameters were reported for OR in Table 2
                      and for control group in Table 3
                     . Correlations between “age-Kmean”, “age-Kmax”, “Kmean-Kmax”, “CV-TCT, “CV-CCT”, “TCT-CCT”, “meiboscore-Kmax” and “meiboscore-TBUT” were statistically significant in OR (P
                     <0.05). In control group, only correlations between “Kmean-Kmax”, “CV-TCT”, “CV-CCT”, “TCT-CCT” were statistically significant (P
                     <0.05).

Table 4
                      shows the comparison of Kmean, Kmax, TCT, CCT, CV, TBUT, meiboscore and Schirmer results with respect to skin subgroups (phymatous, erythematotelangiectatic and papulopustular) and controls. Kmean and Kmax values were significantly steeper in papulopustular and phymatous subgroups compared to erythematotelangiectatic and control groups (P
                     <0.05). CCT was significantly thinner in the papulopustular subgroup compared to phymatous, erythematotelangiectatic and control groups (P
                     <0.05), while TCT was also thinner in papulopustular subgroup compared to controls (P
                     <0.05). The TBUT was significantly lower and the meiboscore was significantly higher in the papulopustular subgroup compared to phymatous, erythematotelangiectatic or control groups. Within skin subgroups, we also found a positive correlation between “age-Kmean”, “age-Kmax”, “Kmean-Kmax”, “CV-TCT”, “CV- CCT” and “TCT-CCT” (P
                     <0.05). Additionally, there was a strong positive correlation (P
                     <0.001) between “Kmax-meiboscore” and negative correlations (P
                     <0.05) between “Kmax-CV” and “Kmax-TCT” only in papulopustular subgroup. Fig. 1
                      shows exemplify corneal thickness and keratometry parameters in each group.

# Discussion

Corneal involvement can be seen in OR patients in various forms [16]. Peripheral stromal melting, ulcers, limbal deficiency and fibrotic scars are the most common and advanced stage of corneal involvement which eventually result with vision loss. However, the subclinical progression of the OR on cornea remains poorly documented. As a chronic and inflammatory process, OR places cornea at risk of slow but irreversible damages. Increased matrix metalloproteinase production by corneal stromal fibroblasts and epithelial cells have been shown associated with OR's corneal effects that might lead to corneal structural and biomechanical alterations [16]. These alterations become important even when planning cataract surgery or refractive surgery for patients diagnosed with OR. Surprisingly enough in the context, only few studies are focusing on the effects of rosacea on morphometric corneal patterns.

Onaran et al. compared CCT of 51 OR patients to 51 healthy controls. They found CCT as being significantly lower in OR patients [17]. Yildirim et al. confirmed the observation in 34 OR vs. 34 controls [11]. With a smaller sample of patients (15 OR vs. 15 control), Palamar et al. failed to detect any CCT difference [18]. None of these studies evaluated measurements according to the skin subtypes of rosacea, probably due to the limited sample of patients included. In the present study, we included 180 eyes with OR. Regardless to skin subtypes of rosacea, TCT and CCT did not differed from controls. However, including 60 eyes in each skin type group confer enough statistical power to proceed reasonably for further analysis according to OR skin type. Such a discrimination seems meaningful. We observed a thinner mean CCT in papulopustular subgroup compared to other subgroups and to controls. In addition, the mean TCT of papulopustular subgroup was also thinner vs. controls. Based on such results, we assume that mostly papulopustular phenotype affects corneal thickness. The papulopustular subtype of rosacea is reputed to promote skin inflammation under enhanced susceptibility toward UV, while erythematotelangiectatic subtype preferentially answers to the vascular reactivity side, possibly under neurovascular mechanism. The phymatous feature rather develops inflammation on glandular hyperplasia and evolves toward fibrotic degeneration [19]. We could therefore hypothesize that the subclinical inflammatory process of OR electively preside to the thickness changes observed in the disease and not in normal corneas.

In the literature, few studies compare topographical indices for patients suffering from OR, despite the significant prevalence of the disease. Yildirim et al. enlighten a decrease of corneal hysteresis (CH), corneal resistance factor (CRF) and central corneal thickness (CCT) in OR patients compared to controls, but reported no differences for corneal curvatures [13]. Palamar et al. corroborated such results, lacking to analyze keratometry indices [18]. We investigated the most considered indices of topography in a clinical routine. We observed steeper corneal curvatures with higher Kmean and Kmax values in OR patients compared to controls. With respect to their skin subtypes, OR patients with phymatous and papulopustular subtypes were significantly at risk compared to erythematotelangiectatic subtype and the controls. Moreover, corneal thickness of OR patients with papulopustular subgroup decreased compared to others. Corneal thinning is in itself a leading cause of biomechanics alteration. Additionally, Kmax increased while CV and TCT decreased in correlation within the papulopustular subgroup. Taken together, such results are in accordance with the assertion of biomechanical disorders in OR [20], and would strengthen the previous reports of a possible keratoconic-like outcome in such patients [21,22]. From our observations, a specific concern should focus physicians on corneal shape indices when papulopustular or phymatous skin subtype participates to the clinical frame. To our knowledge, we first demonstrate that the patterns of corneal shape differ among skin phenotypes of OR patients, based on simple topographic indices. Rosacea seems at higher risk to alter corneal curvature and thickness particularly in papulopustular subgroup.

Interestingly enough, the steepening K indices only correlated with age in OR eyes. Of note, the corneal biomechanics is reputed to strengthen with age. For instance, keratoconus stops progressing around the 4th decade. In fact, OR is a chronic condition and time accumulates damages of ocular surface in patients. Corneal changes induced by OR do not make any exception. The correlation corroborates that the inflammatory process of OR would rather waken corneal biomechanics with age than the opposite. And logically, the CV positively correlated with corneal thickness indices in both OR and control groups, serving as a supplemental internal control.

In addition, in this study, we investigated the ocular surface parameters that have been previously shown [12] to be closely related to inflammatory factors in OR. We found significantly higher meiboscore results and significantly lower TBUT and Schirmer results in OR patients compared to controls. When we investigated these ocular surface parameters according to skin subtypes, we found significantly lower TBUT and significantly higher meiboscore in papulopustular subtype compared erythematotelangiectatic and phymatous subtypes and there was a strong positive correlation between meiboscore and Kmax only in papulopustular subtype, which may be also explained by the inflammatory process.

Our study inevitably suffers from limitations. We did not consider advanced OR with scarred corneas. Although we take care of such corneas in our routine clinics, we arbitrarily excluded them because it generates artifacts, altering topography indices, which could not be analyzed. Furthermore, late observations after from multiple episodes of acute OR crisis might result from iterative treatments which have contributed to shape the cornea progressively. The skin subgroup of rosacea is no longer the unique feature to discriminate corneal outcomes. Observations would not have provided consistent relationship between OR and corneal topography indices. We have limited our analysis to the most common corneal indices obtained from topography. We did not gather biomechanical data, nor OCT measurements. Comparing data from different devices would have introduced an uncontrolled statistical bias and add to the eventuality of misinterpretation. We chose focusing on topography instead, which is a simple and widespread examination device. Topographical indices are reproducible, reliable in the absence of corneal scar, and provide quantified data.

In conclusion, our study first evaluated the corneal topography and ocular surface parameters among OR skin subtypes. With this approach, we observed that corneal thickness of OR eyes differed from controls. The keratometry indices were steeper in phymatous and papulopustular skin subtypes and corneas were thinner particularly in papulopustular subtype. From ocular surface parameters, TBUT and meiboscore were more effected in papulopustular subtype and meiboscore was found to be strongly associated with the corneal steepness in papulopustular subtype. As a result of this article, it can be suggested that both dermatologists and ophthalmologists should keep in mind the ocular surface and topography parameters and pay more attention to them, especially when faced with the papulopustular subtype. Further studies investigating the association of inflammatory markers with topography parameters in each skin subtype of OR patients are mandatory to enlighten further such observations.

# Disclosure of interest

The authors declare that they have no competing interest.