- Email: [email protected]
Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren's syndrome and healthy subjects
+Model
ARTICLE IN PRESS
JFO-2075; No. of Pages 7
Journal français d’ophtalmologie (2018) xxx, xxx—xxx
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
ORIGINAL ARTICLE
Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects Comparaison des propriétés biomécaniques de la cornée chez des patients ayant des yeux secs associés au syndrome de Sjögren et chez des sujets sains L. Borrego-Sanz a,∗, F. Sáenz-Francés San Baldomero a, D. Díaz Valle a, E. Santos Bueso a, R. Sánchez Jean a, J.M. Martínez de la Casa a, J.M. Benítez del Castillo a, J. García Feijóo a, L. Rodríguez Rodríguez b a
Department of Ophthalmology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense de Madrid, Madrid, Spain b Department of Rheumatology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense de Madrid, Madrid, Spain Received 19 November 2017; accepted 19 February 2018
KEYWORDS Sjögren’s syndrome; Corneal biomechanics; Intraocular pressure; Ocular response analyser
∗
Summary Purpose. — The goal of this study is to determine whether any difference in corneal biomechanical properties exists between Sjögren’s syndrome dry eye patients and healthy subjects. Methods. — Thirty-one patients diagnosed with Sjögren’s syndrome and associated dry eye manifestations and 44 healthy individuals were included in the study. Ultrasonic pachymetry (UP) was used to measure central corneal thickness (CCT). Corneal biomechanical parameters were obtained using ocular response analyzer (ORA). The main parameters assessed were corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann correlated intraocular pressure (IOPg) and corneal compensated IOP (IOPcc). A Student’s t-test for independent groups was performed to compare the mean of these variables between both groups.
Corresponding author. Avda Prof. Martín Lagos s/n, 28040 Madrid, Spain. E-mail address: [email protected] (L. Borrego-Sanz).
https://doi.org/10.1016/j.jfo.2018.02.015 0181-5512/© 2018 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
2
L. Borrego-Sanz et al. Results. — Mean CH values in Sjögren’s syndrome and healthy subject eyes were 10.1 mmHg and 11.18 mmHg respectively, representing a statistically significant difference (P = 0.003). No other variable measured differed between cases and controls (P > 0.05). Mean CRF values were 9.51 mmHg and 10.37 mmHg respectively, and mean CCT measured by UP in cases and controls was 527.41 m and 552.51 m respectively. Conclusions. — Sjögren’s syndrome can influence corneal biomechanical properties, specifically CH. ORA measurements should be considered of interest in the evaluation of Sjögren syndrome subjects. © 2018 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Syndrome de Sjögren ; Biomécanique de la cornée ; Pression intraoculaire ; Analyseur de la réponse oculaire
Résumé Objectif. — Déterminer s’il existe des différences dans les propriétés biomécaniques de la cornée entre les patients présentant une sécheresse oculaire associée au syndrome de Sjögren et les sujets sains. Méthodes. — Trente et un patients diagnostiqués avec un syndrome de Sjögren et les manifestations oculaires associées à la sécheresse oculaire et 44 personnes en bonne santé ont été inclus dans cette étude. La pachymétrie à ultrasons (PU) a été utilisée pour mesurer l’épaisseur de la cornée centrale (ECC). Les paramètres biomécaniques de la cornée ont été obtenus à l’aide de l’analyseur de réponse oculaire (ARO). Les principaux paramètres évalués étaient l’hystérésis cornéenne (HC), le facteur de résistance cornéen (FRC), la pression intraoculaire corrélée avec Goldmann (PIOg) et la pression intraoculaire compensée cornéenne (PIOcc). Un test-t de Student a été réalisé pour des groupes indépendants afin de comparer la moyenne de ces variables entre les deux groupes. Résultats. — Les valeurs moyennes de HC chez les patients atteints du syndrome de Sjögren et chez les sujets sains étaient respectivement de 10,1 mm Hg et 11,18 mm Hg, et leur différence était statistiquement significative (p = 0,003). Aucune autre variable ne présentait de différences significatives entre les cas et les témoins (p > 0,05). Les valeurs moyennes de FRC étaient de 9,51 mm Hg et 10,37 mm Hg, respectivement, et le ECC moyen mesuré par PU dans les cas et les contrôles était de 527,41 m et 552,51 m, respectivement. Conclusions. — Le syndrome de Sjögren peut influencer les propriétés biomécaniques de la cornée, en particulier dans les HC. Les mesures d’ARO devraient être considérées d’intérêt dans l’évaluation des patients atteints du syndrome de Sjögren. eserv´ es. © 2018 Elsevier Masson SAS. Tous droits r´
Introduction Sjögren’s syndrome (SS) is a chronic autoimmune disorder characterized by lymphoplasmocytic infiltration of the exocrine glands, producing particularly hypofunction of the salivary and lacrimal glands. Dry eye and mouth are considered the most common and earlier symptoms of the disease although other systemic complications may also appear. In fact, the wide range of clinical manifestations displayed, sometimes contribute to a delay in the diagnosis [1,2]. Typically, the important eye-involvement associated with this disease often lead to more severe signs of ocular surface damage and sequels than those observed in common dry-eye syndrome, varying the prevalence of SS disorder greatly, from 0.09% to 2.7% according to different reports [2—4]. A healthy corneal surface is of paramount importance to maintain stability of corneal biomechanics since impairment
and disruption of corneal epithelium observed in dry eye syndrome has been shown to alter these properties [5—8]. The etiology of SS may be a consequence of genetic, environmental and hormonal factors or a combination of them, whereas immune-mediated processes are implicated in the basis of the physiopathology of this condition causing, through inflammation, alterations in the function of exocrine glands which results on reduced secretory function [9]. Furthermore, local antigen-antibody reaction in the tear of subjects suffering from SS may also produce a direct damage, not only in the corneal epithelium but in de subjacent stroma as well [6,9]. Cytokines and reactive oxidative cells observed in ocular surface and tear levels of SS patients are also supposed to be linked to the characteristic corneal damage of SS, which through its impact on corneal structural component, could well affect corneal biomechanical and viscoelastic properties [6,9,10]. The ocular response analyzer (ORA) is a non-contact tonometer that measures the corneal biomechanical
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
Corneal biomechanical characteristics in Sjögren’s syndrome dry eyes properties of corneal hysteresis (CH) and corneal resistance factor (CRF), in addition to measure the biphasic corneal response to generate a cornea compensated intraocular pressure (IOPcc). CRF reflects the overall resistance of the cornea being partially independent of IOP, and CH evidence the viscoelastic properties of the corneal tissue showing the changes in the organization of collagen lamellae. Both CH and CRF have proved to be rather good indicators of corneal biomechanical behavior [11]. The aim of this study is to determine whether any difference in corneal biomechanical properties exists between patients suffering from Sjögren’s syndrome associated dry eye and healthy subjects.
Material and methods We performed a group-matched case control study. Cases were patients diagnosed with Sjögren’s syndromeassociated dry eye and treated in the ocular surface department of our institution whereas controls were healthy volunteers recruited amongst the staff and staff’s relatives of the same institution. Cases and controls were groupmatched according to age and sex; group matching criteria was: mean age difference between cases and controls below 1 year and sex difference between cases and controls below 5%. To be considered as a case, a subject must exhibit a complete Sjögren’s syndrome diagnosis as required by the American College of Rheumatology Classification Criteria for Sjögren’s Syndrome (comprising at least 2 out of the following 3): • positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and ≥ ANA 1:320); • ocular staining score ≥ 3 (using lissamine green and fluorescein) to diagnose keratoconjunctivitis sicca; • presence of focal lymphocytic sialadenitis with focus score ≥ 1 focus/4mm2 in labial salivary gland biopsies. Fulfilment of criterion number 2 was a mandatory requirement in the case group. As cases, these subjects were required to show moderate to severe dry-eye according to tear film evaluations consisting in a tear break-up time (TBUT), Schirmer I test, and corneal staining score (CSS) examination collected by a masked investigator. Exclusion criteria includes the following for both cases and controls: any prior ophthalmologic surgery, any other ocular disease (apart from the dry eye as produced by the Sjögren’s syndrome for the cases), a spherical equivalent greater than 5 diopters or 3 or more dioptres of astigmatism, a best corrected visual acuity lower than 20/25, any systemic disease apart from mild hypertension or hypercolesterolemia (and primary Sjogren’s syndrome in the case group). All the study participants underwent comprehensive ophthalmologic examination including an ultrasound pachymetry examination (Dicon P55, Paradigm Medical Industries Inc., Salt Lake City, UT, USA), which is currently the clinical gold standard method to measure CCT for its repeatability, accuracy and quick measurement time. Also, patients underwent ORA measures (Reichert Ophthalmic Instruments, Buffalo, NY, USA) and Goldmann applanation
3
tonometry (Haag-Streit AG, Gartenstadtstrasse 10, 3098 Koeniz, Switzerland). All the examinations were performed by the same ophthalmologist, though, to avoid the introduction of observer bias, the ophthalmologist was masked to the results of all the devices which were collected by other examiner. Given it is a non-contact procedure, the ORA evaluations were performed in first place prior to the instillation of any eye-drop. All patients accorded not to instill any artificial tears or ointments used to treat dry eye related symptoms one day before measurements. For each group (cases and controls) mean CH, CRF, IOP cc and IOP g measured by ORA, CCT measured by UP and IOP measured with Goldmann applanation tonometry (GAT) were determined along with their standard deviations. A Student’s t-test for independent groups was performed to test the evidence against the null hypothesis of no mean difference of all the variables between both groups. Sample size was calculated in order to provide 90% power to detect a mean difference of corneal hysteresis equal to or greater than 0.25 mmHg assuming an ␣ risk of 95%. Pairwise correlations between ORA parameters (CH, CRF) and baseline characteristics of tear film (Schirmer I test, CSS and TBUT) in SS subjects were assessed through Pearson correlation coefficient (r). One eye per subject was examined; the decision to choose the right or left eye was made according to an automatic randomization procedure (www.randomization.com).
Results Thirty-one subjects per group were required in order to provide 90% power to detect a mean difference of corneal hysteresis equal or greater than 0.25 mmHg assuming an ␣ risk of 95%. Finally, 31 cases and 44 controls were recruited. Mean age was 48.16 years (standard deviation (SD): 4.98 years) in the case group and 47.25 (SD: 3.25 years) in the control group whereas the distribution for sex was 90.9% females and 9.1% males. Corneal biomechanical parameters were calculated by three consecutive measurements taken within 5 minutes. Mean CH in the case group was 10.1 mmHg (SD: 0.32 mmHg) whereas for the controls was 11.18 mmHg (SD: 0.18 mmHg). Fig. 1 depicts corneal hysteresis distribution in both groups using box-plots. According to a Student’s t-test for independent means, there is strong evidence against the null hypothesis of no difference in mean hysteresis between both groups: mean difference: 1.08 mmHg (lower in the case group); P = 0.003; 95% confidence interval of the difference: 0.37—1.78 mmHg. Mean CRF was 10.75 mmHg (SD: 0.28 mmHg) in the SS group and 10.70 mmHg (SD: 0.26 mmHg) in the control group, respectively. There was no statistically significant difference between the two groups (P ≥ 0.05). The remaining variables studied (mean IOP cc, IOP g, CCT measured by UP and IOP measured by GAT) were also compared between groups though not any further statistically significant difference arose to the 95% level of signification. Table 1 show the mean and standard deviation of the variables studied in cases and controls. Table 2 presents the correlations coefficients (Pearson correlation coefficient) between ORA parameters (CH, CRF) and baseline characteristics of the tear film (Schirmer I test,
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
4
L. Borrego-Sanz et al.
Figure 1. Corneal hysteresis distribution in cases and controls using box-plots. The median for each group is marked by the centerline and the minimum and maximum values of all the data with the bars.
CSS and TBUT) in SS subjects. Only CH showed a significantly weak correlation with CSS (r = −0.19, P = 0.04). Any further statistically significant difference was evidenced.
Discussion Sjögren’s syndrome (SS) is a relatively common systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine secretory glands [1]. This process leads to sicca syndrome, which combines dryness of the eyes, oral cavity, pharynx, larynx and/or vagina. More specifically, ocular findings may include punctate keratitis, filaments,
Table 1
recurrent erosions, corneal vascularization, ulceration, corneal opacity and scarring [6]. Approximately, half of the patients develop extraglandular manifestations, including cutaneous, musculoskeletal, pulmonary, renal, hematological and neurological involvement [12]. Although it may affect both sexes, a strong propensity among women has been described, with a female/male ratio as high as 20:1 in some populations [13]. SS is a world-wide distributed disease that may appear in all ages. However, the incidence peak occurs in the fourth and fifth decades of life, time characterized by changes in estrogen levels in women, which are considered as a factor that contribute to autoimmunity [9]. Besides, androgens and specifically dehydroepiandrosterone (DHEA) decline with age and are 40—50% lower in SS patients than in healthy controls. The imbalance between androgen—estrogen values has been suggested to increase the risk of suffering from this disease [9]. While pathogenesis of SS is not completely understood, significantly increased activation of circulating B cells followed by autoantibody production and immune complex formation are associated with increased disease severity [14]. T cell mediated autoimmune responses in the glandular tissue as well as dysregulated apoptosis due to chronic inflammatory mechanisms are currently considered crucial in this exocrinopathy [9,10]. One of the most severely affected tissues in SS is the cornea, where changes in tear film layer, epithelium and stroma sometimes produce sight-threatening complications and might alter corneal biomechanical properties [6]. In this regard, previous studies have reported SS to be significantly associated with corneal ectasias as pellucid marginal degeneration [15]. Direct inflammation of the corneal stroma as that observed in connective tissue disorders and other rheumatological diseases, could play a role in the development of the aforementioned situations [16].
Mean and standard deviation of the variables studied in cases and controls.
Variables
Sjögren group (n = 31)
Healthy group (n = 44)
P
Age TBUT (s) CSS (score) Schirmer I test (mm) CH (mmHg) CRF (mmHg) IOPcc (mmHg) IOPg (mmHg) IOP by GAT (mmHg) CCT by UP (m)
48.16 ± 4.98 3.11 ± 0.16 3.29 ± 0.29 2.69 ± 0.36 10.1 ± 0.32 9.51 ± 2.16 14.38 ± 3.39 13.26 ± 3.91 15.34 ± 2.74 527.41 ± 40.65
47.25 ± 3.25 11.2 ± 0.53 0.05 ± 0.02 14.22 ± 0.72 11.18 ± 0.18 10.37 ± 1.70 13.17 ± 2.83 13.19 ± 2.78 14.11 ± 1.85 552.51 ± 34.21
0.56 < 0.001 < 0.001 < 0.001 0.003 0.051 0.057 0.91 0.052 0.054
Table 2 Correlation coefficient (r) with level of significance (P) between ORA parameters and characteristics of tear film in SS subjects. Parameters
r (P) of CH in SS
r (P) of CRF in SS
Schirmer I test (mm) TBUT (s) CSS (score)
0.15 (0.11) 0.17 (0.07) −0.19 (0.04)
0.12 (0.20) 0.09 (0.35) −0.13 (0.18)
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
Corneal biomechanical characteristics in Sjögren’s syndrome dry eyes In this study we aimed to determine whether any difference in corneal biomechanical properties measured by ORA and specifically in corneal hysteresis, exists between patients suffering from SS and healthy subjects. We observed a significant reduced CH in the cases group. Many arguments could be invoked to explain our findings. The corneal stroma is responsible for the mechanical and refractive properties of the eye. Bowman’s layer and stroma are composed mainly of an arrangement of collagen fibrils which contribute to the biomechanical corneal behavior [6]. As a matter of fact, matrix metalloproteinase 9 (MMP-9), interleukin 6 (IL-6) and transglutaminase 2 (TG-2), which are involved in the degradation of extracellular matrix components playing an important role in inflammation, wound healing and tissue remodeling, were shown to be elevated in the tear of dry eye related to SS subjects [17,18]. These findings would support the hypothesis that the more severe corneal damage in SS patients compared to that suffering from common dryeye syndrome is due to collagen lysis processes caused by a tear film charged with higher level of cytokines immune complexes and reactive oxygen species, and a shorter telomere length in the lacrimal gland as described by Kawashima et al. [19]. That could affect not only the corneal surface but also the ultrastructure and architecture of the subjacent stroma, producing changes in biomechanical properties of the cornea. On the contrary, Firat et al. reported that dry eye syndrome causes severe symptoms but does not alter biomechanical characteristics [8]. However, these authors did not classify their patients according to different grade of severity of dry eye. Furthermore, Luce et al. showed decreased CH measurements in eyes having laser-assisted in situ keratomileusis (LASIK) and Fuchs dystrophy [11]. Pedersen et al. reported similar reduction in corneal biomechanics after LASIK, refractive lenticule extraction (ReLex) and small incision lenticule extraction (SMILE) when evaluated by CorVis ST probably related to corneal tissue removal following these surgeries [20]. Thus, biomechanical corneal assessment provides valuable information about structural changes in the ground substance of the cornea, especially those resulting after refractive surgical procedures or in pathological corneal conditions such as keratoconus, edema, glaucoma or high myopia in which an impact on CH and CRF has been widely showed [21]. Our results suggest that the native characteristics of the cornea in SS subjects cause also changes in biomechanical properties, specifically in CH and it should be taken into account cautiously when evaluating patients prior to surgeries or in concomitant conditions, in order to identify risk factors and susceptible individuals which may develop added complications. The biomechanical properties of the cornea in patients with systemic connective tissue diseases have not been widely analyzed. Tas. et al. revealed lower CH and CRF values in patients with rheumatoid arthritis (RA) compared with controls, and higher IOPg and IOPcc in the same group [22]. Celik et al., showed in patients with psoriasis, lower CH and CRF values compared with healthy subjects and that was also observed by Yacizi et al. in patients with systemic lupus erythematosus [23,24]. Besides, lower CH and CRF have been seen in advanced stages of Marfan syndrome, a genetic disorder of the connective tissue [25]. Although we
5
only incorporated primary SS patients in our study in order to avoid biases produced to include autoimmune diseases associated with SS such as RA or systemic sclerosis, our results show that these patients share a different corneal behavior suggested by the HC differences observed with respect to healthy subjects, an observation which is in consonance with that reported by Long et al., who also found less corneal ‘‘stiffness’’ in SS patients measured by Corvis ST [6]. Similarly with these authors, our finding suggest that a greater corneal surface damage as that seen in SS subjects results in a more compliant corneal behavior. However, our study reflects the association specifically in CH but not in CRF. We are unaware of the reason underneath the lack of significant differences of CRF between cases and controls. However, as CH represents overall corneal viscous properties whereas CRF is an indicator of the overall resistance of the cornea, therefore, we could hypothesize that viscous properties might be better related to the corneal damage seen in SS subjects [11]. Nonetheless, further studies should be performed to assess whether this finding is consistent. Unlike Long et al., our measurements were obtained by ORA instead of Corvis ST, and probably some differences could be explained by the different operating principle that guides each device. Both apply an air pulse on the anterior surface causing corneal deformity, but while ORA measures the intensity of the reflected infrared light from deforming corneal surface, Corvis ST depends on the Scheimpflug principle to record images of a cross-section corneal displacement. Thus, differences in spectral analysis waveforms and biomechanical results between these devices have been showed that both instruments are not completely interchangeable [26]. With respect to CCT, it has been reported to be decreased in dry eye, probably due to the hypertonic osmolality of tear film. However, a rapid increase in the parameter after administration of artificial tear has been described [27]. In contrast, we did not detect statistically significant differences in mean CCT between the two groups, in agreement with the studies by Firat et al. and Long et al. [7,8]. Regarding to IOP measurements, we did not find significant differences either in IOP cc, IOP g and IOP measured by GAT between both groups. These findings would support the hypothesis that although surface tension of the tear film has been described as a factor influencing GAT, accuracy of IOP measurements seems not to be affected by increased tear deficiency, and that IOP measures using ORA are less influenced by corneal parameters [28,29]. Our study had some limitations. We did not take into account the possible influence of the different ophthalmic therapies employed to treat ocular manifestations in these patients along the recruitment and this could be an issue, since it is known that biomechanical properties may be affected by corneal hydration as produced by artificial tears [30]. Notwithstanding and with regard to the aforementioned, patients accorded not to instill eye drops 1 day before ORA measurements and although we think that the impact of topical drops is not enough to explain the significant differences observed in both groups, is difficult to eliminate completely the influence caused by their use. Moreover, our sample is limited to a homogeneous Caucasian population and variations in CCT between different ethnic groups could also play a role in biomechanical changes
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
6
L. Borrego-Sanz et al.
and therefore, should be considered of interest in future research. To the best of our knowledge, this study is the first investigating the corneal biomechanical properties measured by ORA in SS-associated dry eye subjects. Our findings regarding CH differences between cases with SS and healthy controls allow us to speculate that changes in biomechanical properties, specifically lower HC in the patient group, might be caused by corneal alterations related to dry eye associated disease in SS subjects and inflammatory phenomena produced either by corneal changes induced by a tear rich in immune complex, cytokines and active oxygen species, as well as direct inflammation of the stroma. These findings suggest that ORA measurements should be considered of interest in the evaluation of SS subjects, mainly if corneal morphological characteristics are simultaneously altered such as in keratoconus, glaucoma, high myopia or after refractive surgery, where a greater decrease in corneal biomechanical properties might be expected. In conclusion, SS affects corneal structure and causes biomechanical changes specifically in CH which can be observed by ORA, in addition to originate severe ocular symptoms. These corneal biomechanical changes should be considered when evaluating patients with SS, especially before planning ophthalmologic surgical procedures or in concomitant conditions such as glaucoma or corneal ectasias.
Disclosure of interest The authors declare that they have no competing interest.
References [1] Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, et al. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64:475—87. [2] Both T, Dalm V, van Hagen PM, van Daele PL. Reviewing primary Sjögren’s syndrome: beyond the dryness. From pathophysiology to diagnosis and treatment. Int J Med Sci 2017;14:191—200. [3] Jonsson R, Moen K, Vestrheim D, Szodoray P. Current issues in Sjögren’s syndrome. Oral dis 2002;8:130—40. [4] Patel R, Shahane A. The epidemiology of Sjögren’s syndrome. Clin Epidemiol 2014;6:247—55. [5] Elsheikh A, Alhasso D, Rama P. Assessment of the epithelium’s contribution to corneal biomechanics. Exp Eye Res 2008;86:445—51. [6] Long Q, Wang JY, Xu D, Li Y. Comparison of corneal biomechanics in Sjögren’s syndrome and non-Sjögren’s syndrome dry eyes by Scheimpflug based device. Int J Ophthalmol 2017;10:711—6. [7] Long Q, Wang J, Yang X, Jin Y, Ai F, Li Y. Assessment of corneal biomechanical properties by Corvis ST in patients with dry eye and in healthy subjects. J Ophthalmol 2015;2015, http://dx.doi.org/10.1155/2015/380624 [380624]. [8] Firat PG, Doganay S. Corneal hysteresis in patients with dry eye. Eye (Lond) 2011;25:1570—4. [9] Nikolov NP, Illei GG. Pathogenesis of Sjögren’s syndrome. Curr opin Rheumatol 2009;21:465—70.
[10] Kiripolsky J, McCabe LG, Kramer JM. Innate immunity in Sjögren’s syndrome. Clin Immunol 2017;182:4—13, http://dx.doi.org/10.1016/j.clim.2017.04.003 [Epub ahead of print]. [11] Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005;31:156—62. [12] García-Carrasco M, Ramos-Casals M, Rosas J, Pallarés L, CalvoAlen J, Cervera R, et al. Primary Sjögren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine (Baltimore) 2002;81:270—80. [13] López-Miguel A, Tesón M, Martín-Monta˜ nez V, Enríquez de Salamanca A, Stern ME, González-García MJ, et al. Clinical and molecular inflammatory response in Sjögren syndromeassociated dry eye patients under desiccating stress. Am J Ophthalmol 2016;161:133—41. [14] Cornec D, Devauchelle-Pensec V, Tobón GJ, Pers JO, JousseJoulin S, Saraux A. B cells in Sjögren’s syndrome: from pathophysiology to diagnosis and treatment. J Autoimmun 2012;39:161—7. [15] Fernández-Barboza F, Verdiguel-Sotelo K, Hernández-López A. Pellucid marginal degeneration and corneal ulceration, associated with Sjögren syndrome. Rev Med Inst Mex Seguro Soc 2009;47:77—82. [16] Hyams SW, Kar H, Neumann E. Blue sclerae and keratoglobus. Ocular signs of a systemic connective tissue disorder. Br J Ophthalmol 1969;53:53—8. [17] Aragona P, Aguennouz M, Rania L, Postorino E, Sommario MS, Roszkowska AM, et al. Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different dorms of dry eye disease. Ophthalmology 2015;122:62—71. [18] Van Doren SR. Matrix metalloproteinase interactions with collagen and elastin. Matrix Biol 2015;44—46:224—31. [19] Kawashima M, Kawakita T, Maida Y, Kamoi M, Ogawa Y, Shimmura S, et al. Comparison of telomere length and association with progenitor cell markers in lacrimal gland between Sjogren syndrome and non-Sjogren syndrome dry eye patients. Mol Vis 2011;17:1397—404. [20] Pedersen IB, Bak-Nielsen S, Vestergaard AH, Ivarsen A, Hjortdal J. Corneal biomechanical properties after LASIK, ReLEx flex, and ReLEx smile by Scheimpflug-based dynamic tonometry. Graefes Arch Clin Exp Ophthalmol 2014;252: 1329—35. [21] Terai N, Raiskup F, Haustein M, Pillunat LE, Spoerl E. Identification of biomechanical properties of the cornea: the ocular response analyzer. Curr Eye Res 2012;37:553—62. [22] Tas. M, Öner V, Özkaya E. Durmus. M. Evaluation of corneal biomechanical properties in patients with rheumatoid arthritis: a study by ocular response analyzer. Ocul Immunol Inflamm 2014;22:224—7. [23] Celik U, Aykut V, Celik B, Tas M, Yazgan S, Kaldrm H, et al. A comparison of corneal biomechanical properties in patients with psoriasis and healthy subjects. Eye Contact Lens 2015;41:127—9. [24] Yazici AT, Kara N, Yüksel K, Altinkaynak H, Baz O, Bozkurt E, et al. The biomechanical properties of the cornea in patients with systemic lupus erythematosus. Eye (Lond) 2011;25:1005—9. [25] Kara N, Bozkurt E, Baz O, Altinkaynak H, Dundar H, Yuksel K, et al. Corneal biomechanical properties and intraocular pressure measurement in Marfan patients. J Cataract Refract Surg 2012;38:309—14. [26] Tejwani S, Shetty R, Kurien M, Dinakaran S, Ghosh A, Sinha Roy A. Biomechanics of the cornea evaluated by spectral analysis of waveforms from ocular response analyzer and Corvis-ST. Plos One 2014;9, http://dx.doi.org/10.1371/journal.pone.0097591 [e97591].
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
Corneal biomechanical characteristics in Sjögren’s syndrome dry eyes [27] Dayanair V, Sakarya V, Ozcura F, Kir E, Aktunc ¸ T, Ozkan BS, et al. Effect of corneal drying on central corneal thickness. J Glaucoma 2004;13:6—8. [28] Damji KF, Muni RH, Munger RM. Influence of corneal variables on accuracy of intraocular pressure measurement. J Glaucoma 2003;12:69—80.
7
[29] Medeiros FA, Weinreb RN. Evaluation of the influence of corneal biomechanical properties on intraocular pressure measurements using the ocular response analyzer. J Glaucoma 2006;15:364—70. [30] Pi˜ nero DP, Alcón N. Corneal biomechanics: a review. Clin Exp Optom 2015;98:107—16.
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
ARTICLE IN PRESS
JFO-2075; No. of Pages 7
Journal français d’ophtalmologie (2018) xxx, xxx—xxx
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
ORIGINAL ARTICLE
Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects Comparaison des propriétés biomécaniques de la cornée chez des patients ayant des yeux secs associés au syndrome de Sjögren et chez des sujets sains L. Borrego-Sanz a,∗, F. Sáenz-Francés San Baldomero a, D. Díaz Valle a, E. Santos Bueso a, R. Sánchez Jean a, J.M. Martínez de la Casa a, J.M. Benítez del Castillo a, J. García Feijóo a, L. Rodríguez Rodríguez b a
Department of Ophthalmology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense de Madrid, Madrid, Spain b Department of Rheumatology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense de Madrid, Madrid, Spain Received 19 November 2017; accepted 19 February 2018
KEYWORDS Sjögren’s syndrome; Corneal biomechanics; Intraocular pressure; Ocular response analyser
∗
Summary Purpose. — The goal of this study is to determine whether any difference in corneal biomechanical properties exists between Sjögren’s syndrome dry eye patients and healthy subjects. Methods. — Thirty-one patients diagnosed with Sjögren’s syndrome and associated dry eye manifestations and 44 healthy individuals were included in the study. Ultrasonic pachymetry (UP) was used to measure central corneal thickness (CCT). Corneal biomechanical parameters were obtained using ocular response analyzer (ORA). The main parameters assessed were corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann correlated intraocular pressure (IOPg) and corneal compensated IOP (IOPcc). A Student’s t-test for independent groups was performed to compare the mean of these variables between both groups.
Corresponding author. Avda Prof. Martín Lagos s/n, 28040 Madrid, Spain. E-mail address: [email protected] (L. Borrego-Sanz).
https://doi.org/10.1016/j.jfo.2018.02.015 0181-5512/© 2018 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
2
L. Borrego-Sanz et al. Results. — Mean CH values in Sjögren’s syndrome and healthy subject eyes were 10.1 mmHg and 11.18 mmHg respectively, representing a statistically significant difference (P = 0.003). No other variable measured differed between cases and controls (P > 0.05). Mean CRF values were 9.51 mmHg and 10.37 mmHg respectively, and mean CCT measured by UP in cases and controls was 527.41 m and 552.51 m respectively. Conclusions. — Sjögren’s syndrome can influence corneal biomechanical properties, specifically CH. ORA measurements should be considered of interest in the evaluation of Sjögren syndrome subjects. © 2018 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Syndrome de Sjögren ; Biomécanique de la cornée ; Pression intraoculaire ; Analyseur de la réponse oculaire
Résumé Objectif. — Déterminer s’il existe des différences dans les propriétés biomécaniques de la cornée entre les patients présentant une sécheresse oculaire associée au syndrome de Sjögren et les sujets sains. Méthodes. — Trente et un patients diagnostiqués avec un syndrome de Sjögren et les manifestations oculaires associées à la sécheresse oculaire et 44 personnes en bonne santé ont été inclus dans cette étude. La pachymétrie à ultrasons (PU) a été utilisée pour mesurer l’épaisseur de la cornée centrale (ECC). Les paramètres biomécaniques de la cornée ont été obtenus à l’aide de l’analyseur de réponse oculaire (ARO). Les principaux paramètres évalués étaient l’hystérésis cornéenne (HC), le facteur de résistance cornéen (FRC), la pression intraoculaire corrélée avec Goldmann (PIOg) et la pression intraoculaire compensée cornéenne (PIOcc). Un test-t de Student a été réalisé pour des groupes indépendants afin de comparer la moyenne de ces variables entre les deux groupes. Résultats. — Les valeurs moyennes de HC chez les patients atteints du syndrome de Sjögren et chez les sujets sains étaient respectivement de 10,1 mm Hg et 11,18 mm Hg, et leur différence était statistiquement significative (p = 0,003). Aucune autre variable ne présentait de différences significatives entre les cas et les témoins (p > 0,05). Les valeurs moyennes de FRC étaient de 9,51 mm Hg et 10,37 mm Hg, respectivement, et le ECC moyen mesuré par PU dans les cas et les contrôles était de 527,41 m et 552,51 m, respectivement. Conclusions. — Le syndrome de Sjögren peut influencer les propriétés biomécaniques de la cornée, en particulier dans les HC. Les mesures d’ARO devraient être considérées d’intérêt dans l’évaluation des patients atteints du syndrome de Sjögren. eserv´ es. © 2018 Elsevier Masson SAS. Tous droits r´
Introduction Sjögren’s syndrome (SS) is a chronic autoimmune disorder characterized by lymphoplasmocytic infiltration of the exocrine glands, producing particularly hypofunction of the salivary and lacrimal glands. Dry eye and mouth are considered the most common and earlier symptoms of the disease although other systemic complications may also appear. In fact, the wide range of clinical manifestations displayed, sometimes contribute to a delay in the diagnosis [1,2]. Typically, the important eye-involvement associated with this disease often lead to more severe signs of ocular surface damage and sequels than those observed in common dry-eye syndrome, varying the prevalence of SS disorder greatly, from 0.09% to 2.7% according to different reports [2—4]. A healthy corneal surface is of paramount importance to maintain stability of corneal biomechanics since impairment
and disruption of corneal epithelium observed in dry eye syndrome has been shown to alter these properties [5—8]. The etiology of SS may be a consequence of genetic, environmental and hormonal factors or a combination of them, whereas immune-mediated processes are implicated in the basis of the physiopathology of this condition causing, through inflammation, alterations in the function of exocrine glands which results on reduced secretory function [9]. Furthermore, local antigen-antibody reaction in the tear of subjects suffering from SS may also produce a direct damage, not only in the corneal epithelium but in de subjacent stroma as well [6,9]. Cytokines and reactive oxidative cells observed in ocular surface and tear levels of SS patients are also supposed to be linked to the characteristic corneal damage of SS, which through its impact on corneal structural component, could well affect corneal biomechanical and viscoelastic properties [6,9,10]. The ocular response analyzer (ORA) is a non-contact tonometer that measures the corneal biomechanical
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
Corneal biomechanical characteristics in Sjögren’s syndrome dry eyes properties of corneal hysteresis (CH) and corneal resistance factor (CRF), in addition to measure the biphasic corneal response to generate a cornea compensated intraocular pressure (IOPcc). CRF reflects the overall resistance of the cornea being partially independent of IOP, and CH evidence the viscoelastic properties of the corneal tissue showing the changes in the organization of collagen lamellae. Both CH and CRF have proved to be rather good indicators of corneal biomechanical behavior [11]. The aim of this study is to determine whether any difference in corneal biomechanical properties exists between patients suffering from Sjögren’s syndrome associated dry eye and healthy subjects.
Material and methods We performed a group-matched case control study. Cases were patients diagnosed with Sjögren’s syndromeassociated dry eye and treated in the ocular surface department of our institution whereas controls were healthy volunteers recruited amongst the staff and staff’s relatives of the same institution. Cases and controls were groupmatched according to age and sex; group matching criteria was: mean age difference between cases and controls below 1 year and sex difference between cases and controls below 5%. To be considered as a case, a subject must exhibit a complete Sjögren’s syndrome diagnosis as required by the American College of Rheumatology Classification Criteria for Sjögren’s Syndrome (comprising at least 2 out of the following 3): • positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and ≥ ANA 1:320); • ocular staining score ≥ 3 (using lissamine green and fluorescein) to diagnose keratoconjunctivitis sicca; • presence of focal lymphocytic sialadenitis with focus score ≥ 1 focus/4mm2 in labial salivary gland biopsies. Fulfilment of criterion number 2 was a mandatory requirement in the case group. As cases, these subjects were required to show moderate to severe dry-eye according to tear film evaluations consisting in a tear break-up time (TBUT), Schirmer I test, and corneal staining score (CSS) examination collected by a masked investigator. Exclusion criteria includes the following for both cases and controls: any prior ophthalmologic surgery, any other ocular disease (apart from the dry eye as produced by the Sjögren’s syndrome for the cases), a spherical equivalent greater than 5 diopters or 3 or more dioptres of astigmatism, a best corrected visual acuity lower than 20/25, any systemic disease apart from mild hypertension or hypercolesterolemia (and primary Sjogren’s syndrome in the case group). All the study participants underwent comprehensive ophthalmologic examination including an ultrasound pachymetry examination (Dicon P55, Paradigm Medical Industries Inc., Salt Lake City, UT, USA), which is currently the clinical gold standard method to measure CCT for its repeatability, accuracy and quick measurement time. Also, patients underwent ORA measures (Reichert Ophthalmic Instruments, Buffalo, NY, USA) and Goldmann applanation
3
tonometry (Haag-Streit AG, Gartenstadtstrasse 10, 3098 Koeniz, Switzerland). All the examinations were performed by the same ophthalmologist, though, to avoid the introduction of observer bias, the ophthalmologist was masked to the results of all the devices which were collected by other examiner. Given it is a non-contact procedure, the ORA evaluations were performed in first place prior to the instillation of any eye-drop. All patients accorded not to instill any artificial tears or ointments used to treat dry eye related symptoms one day before measurements. For each group (cases and controls) mean CH, CRF, IOP cc and IOP g measured by ORA, CCT measured by UP and IOP measured with Goldmann applanation tonometry (GAT) were determined along with their standard deviations. A Student’s t-test for independent groups was performed to test the evidence against the null hypothesis of no mean difference of all the variables between both groups. Sample size was calculated in order to provide 90% power to detect a mean difference of corneal hysteresis equal to or greater than 0.25 mmHg assuming an ␣ risk of 95%. Pairwise correlations between ORA parameters (CH, CRF) and baseline characteristics of tear film (Schirmer I test, CSS and TBUT) in SS subjects were assessed through Pearson correlation coefficient (r). One eye per subject was examined; the decision to choose the right or left eye was made according to an automatic randomization procedure (www.randomization.com).
Results Thirty-one subjects per group were required in order to provide 90% power to detect a mean difference of corneal hysteresis equal or greater than 0.25 mmHg assuming an ␣ risk of 95%. Finally, 31 cases and 44 controls were recruited. Mean age was 48.16 years (standard deviation (SD): 4.98 years) in the case group and 47.25 (SD: 3.25 years) in the control group whereas the distribution for sex was 90.9% females and 9.1% males. Corneal biomechanical parameters were calculated by three consecutive measurements taken within 5 minutes. Mean CH in the case group was 10.1 mmHg (SD: 0.32 mmHg) whereas for the controls was 11.18 mmHg (SD: 0.18 mmHg). Fig. 1 depicts corneal hysteresis distribution in both groups using box-plots. According to a Student’s t-test for independent means, there is strong evidence against the null hypothesis of no difference in mean hysteresis between both groups: mean difference: 1.08 mmHg (lower in the case group); P = 0.003; 95% confidence interval of the difference: 0.37—1.78 mmHg. Mean CRF was 10.75 mmHg (SD: 0.28 mmHg) in the SS group and 10.70 mmHg (SD: 0.26 mmHg) in the control group, respectively. There was no statistically significant difference between the two groups (P ≥ 0.05). The remaining variables studied (mean IOP cc, IOP g, CCT measured by UP and IOP measured by GAT) were also compared between groups though not any further statistically significant difference arose to the 95% level of signification. Table 1 show the mean and standard deviation of the variables studied in cases and controls. Table 2 presents the correlations coefficients (Pearson correlation coefficient) between ORA parameters (CH, CRF) and baseline characteristics of the tear film (Schirmer I test,
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
4
L. Borrego-Sanz et al.
Figure 1. Corneal hysteresis distribution in cases and controls using box-plots. The median for each group is marked by the centerline and the minimum and maximum values of all the data with the bars.
CSS and TBUT) in SS subjects. Only CH showed a significantly weak correlation with CSS (r = −0.19, P = 0.04). Any further statistically significant difference was evidenced.
Discussion Sjögren’s syndrome (SS) is a relatively common systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine secretory glands [1]. This process leads to sicca syndrome, which combines dryness of the eyes, oral cavity, pharynx, larynx and/or vagina. More specifically, ocular findings may include punctate keratitis, filaments,
Table 1
recurrent erosions, corneal vascularization, ulceration, corneal opacity and scarring [6]. Approximately, half of the patients develop extraglandular manifestations, including cutaneous, musculoskeletal, pulmonary, renal, hematological and neurological involvement [12]. Although it may affect both sexes, a strong propensity among women has been described, with a female/male ratio as high as 20:1 in some populations [13]. SS is a world-wide distributed disease that may appear in all ages. However, the incidence peak occurs in the fourth and fifth decades of life, time characterized by changes in estrogen levels in women, which are considered as a factor that contribute to autoimmunity [9]. Besides, androgens and specifically dehydroepiandrosterone (DHEA) decline with age and are 40—50% lower in SS patients than in healthy controls. The imbalance between androgen—estrogen values has been suggested to increase the risk of suffering from this disease [9]. While pathogenesis of SS is not completely understood, significantly increased activation of circulating B cells followed by autoantibody production and immune complex formation are associated with increased disease severity [14]. T cell mediated autoimmune responses in the glandular tissue as well as dysregulated apoptosis due to chronic inflammatory mechanisms are currently considered crucial in this exocrinopathy [9,10]. One of the most severely affected tissues in SS is the cornea, where changes in tear film layer, epithelium and stroma sometimes produce sight-threatening complications and might alter corneal biomechanical properties [6]. In this regard, previous studies have reported SS to be significantly associated with corneal ectasias as pellucid marginal degeneration [15]. Direct inflammation of the corneal stroma as that observed in connective tissue disorders and other rheumatological diseases, could play a role in the development of the aforementioned situations [16].
Mean and standard deviation of the variables studied in cases and controls.
Variables
Sjögren group (n = 31)
Healthy group (n = 44)
P
Age TBUT (s) CSS (score) Schirmer I test (mm) CH (mmHg) CRF (mmHg) IOPcc (mmHg) IOPg (mmHg) IOP by GAT (mmHg) CCT by UP (m)
48.16 ± 4.98 3.11 ± 0.16 3.29 ± 0.29 2.69 ± 0.36 10.1 ± 0.32 9.51 ± 2.16 14.38 ± 3.39 13.26 ± 3.91 15.34 ± 2.74 527.41 ± 40.65
47.25 ± 3.25 11.2 ± 0.53 0.05 ± 0.02 14.22 ± 0.72 11.18 ± 0.18 10.37 ± 1.70 13.17 ± 2.83 13.19 ± 2.78 14.11 ± 1.85 552.51 ± 34.21
0.56 < 0.001 < 0.001 < 0.001 0.003 0.051 0.057 0.91 0.052 0.054
Table 2 Correlation coefficient (r) with level of significance (P) between ORA parameters and characteristics of tear film in SS subjects. Parameters
r (P) of CH in SS
r (P) of CRF in SS
Schirmer I test (mm) TBUT (s) CSS (score)
0.15 (0.11) 0.17 (0.07) −0.19 (0.04)
0.12 (0.20) 0.09 (0.35) −0.13 (0.18)
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
Corneal biomechanical characteristics in Sjögren’s syndrome dry eyes In this study we aimed to determine whether any difference in corneal biomechanical properties measured by ORA and specifically in corneal hysteresis, exists between patients suffering from SS and healthy subjects. We observed a significant reduced CH in the cases group. Many arguments could be invoked to explain our findings. The corneal stroma is responsible for the mechanical and refractive properties of the eye. Bowman’s layer and stroma are composed mainly of an arrangement of collagen fibrils which contribute to the biomechanical corneal behavior [6]. As a matter of fact, matrix metalloproteinase 9 (MMP-9), interleukin 6 (IL-6) and transglutaminase 2 (TG-2), which are involved in the degradation of extracellular matrix components playing an important role in inflammation, wound healing and tissue remodeling, were shown to be elevated in the tear of dry eye related to SS subjects [17,18]. These findings would support the hypothesis that the more severe corneal damage in SS patients compared to that suffering from common dryeye syndrome is due to collagen lysis processes caused by a tear film charged with higher level of cytokines immune complexes and reactive oxygen species, and a shorter telomere length in the lacrimal gland as described by Kawashima et al. [19]. That could affect not only the corneal surface but also the ultrastructure and architecture of the subjacent stroma, producing changes in biomechanical properties of the cornea. On the contrary, Firat et al. reported that dry eye syndrome causes severe symptoms but does not alter biomechanical characteristics [8]. However, these authors did not classify their patients according to different grade of severity of dry eye. Furthermore, Luce et al. showed decreased CH measurements in eyes having laser-assisted in situ keratomileusis (LASIK) and Fuchs dystrophy [11]. Pedersen et al. reported similar reduction in corneal biomechanics after LASIK, refractive lenticule extraction (ReLex) and small incision lenticule extraction (SMILE) when evaluated by CorVis ST probably related to corneal tissue removal following these surgeries [20]. Thus, biomechanical corneal assessment provides valuable information about structural changes in the ground substance of the cornea, especially those resulting after refractive surgical procedures or in pathological corneal conditions such as keratoconus, edema, glaucoma or high myopia in which an impact on CH and CRF has been widely showed [21]. Our results suggest that the native characteristics of the cornea in SS subjects cause also changes in biomechanical properties, specifically in CH and it should be taken into account cautiously when evaluating patients prior to surgeries or in concomitant conditions, in order to identify risk factors and susceptible individuals which may develop added complications. The biomechanical properties of the cornea in patients with systemic connective tissue diseases have not been widely analyzed. Tas. et al. revealed lower CH and CRF values in patients with rheumatoid arthritis (RA) compared with controls, and higher IOPg and IOPcc in the same group [22]. Celik et al., showed in patients with psoriasis, lower CH and CRF values compared with healthy subjects and that was also observed by Yacizi et al. in patients with systemic lupus erythematosus [23,24]. Besides, lower CH and CRF have been seen in advanced stages of Marfan syndrome, a genetic disorder of the connective tissue [25]. Although we
5
only incorporated primary SS patients in our study in order to avoid biases produced to include autoimmune diseases associated with SS such as RA or systemic sclerosis, our results show that these patients share a different corneal behavior suggested by the HC differences observed with respect to healthy subjects, an observation which is in consonance with that reported by Long et al., who also found less corneal ‘‘stiffness’’ in SS patients measured by Corvis ST [6]. Similarly with these authors, our finding suggest that a greater corneal surface damage as that seen in SS subjects results in a more compliant corneal behavior. However, our study reflects the association specifically in CH but not in CRF. We are unaware of the reason underneath the lack of significant differences of CRF between cases and controls. However, as CH represents overall corneal viscous properties whereas CRF is an indicator of the overall resistance of the cornea, therefore, we could hypothesize that viscous properties might be better related to the corneal damage seen in SS subjects [11]. Nonetheless, further studies should be performed to assess whether this finding is consistent. Unlike Long et al., our measurements were obtained by ORA instead of Corvis ST, and probably some differences could be explained by the different operating principle that guides each device. Both apply an air pulse on the anterior surface causing corneal deformity, but while ORA measures the intensity of the reflected infrared light from deforming corneal surface, Corvis ST depends on the Scheimpflug principle to record images of a cross-section corneal displacement. Thus, differences in spectral analysis waveforms and biomechanical results between these devices have been showed that both instruments are not completely interchangeable [26]. With respect to CCT, it has been reported to be decreased in dry eye, probably due to the hypertonic osmolality of tear film. However, a rapid increase in the parameter after administration of artificial tear has been described [27]. In contrast, we did not detect statistically significant differences in mean CCT between the two groups, in agreement with the studies by Firat et al. and Long et al. [7,8]. Regarding to IOP measurements, we did not find significant differences either in IOP cc, IOP g and IOP measured by GAT between both groups. These findings would support the hypothesis that although surface tension of the tear film has been described as a factor influencing GAT, accuracy of IOP measurements seems not to be affected by increased tear deficiency, and that IOP measures using ORA are less influenced by corneal parameters [28,29]. Our study had some limitations. We did not take into account the possible influence of the different ophthalmic therapies employed to treat ocular manifestations in these patients along the recruitment and this could be an issue, since it is known that biomechanical properties may be affected by corneal hydration as produced by artificial tears [30]. Notwithstanding and with regard to the aforementioned, patients accorded not to instill eye drops 1 day before ORA measurements and although we think that the impact of topical drops is not enough to explain the significant differences observed in both groups, is difficult to eliminate completely the influence caused by their use. Moreover, our sample is limited to a homogeneous Caucasian population and variations in CCT between different ethnic groups could also play a role in biomechanical changes
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
6
L. Borrego-Sanz et al.
and therefore, should be considered of interest in future research. To the best of our knowledge, this study is the first investigating the corneal biomechanical properties measured by ORA in SS-associated dry eye subjects. Our findings regarding CH differences between cases with SS and healthy controls allow us to speculate that changes in biomechanical properties, specifically lower HC in the patient group, might be caused by corneal alterations related to dry eye associated disease in SS subjects and inflammatory phenomena produced either by corneal changes induced by a tear rich in immune complex, cytokines and active oxygen species, as well as direct inflammation of the stroma. These findings suggest that ORA measurements should be considered of interest in the evaluation of SS subjects, mainly if corneal morphological characteristics are simultaneously altered such as in keratoconus, glaucoma, high myopia or after refractive surgery, where a greater decrease in corneal biomechanical properties might be expected. In conclusion, SS affects corneal structure and causes biomechanical changes specifically in CH which can be observed by ORA, in addition to originate severe ocular symptoms. These corneal biomechanical changes should be considered when evaluating patients with SS, especially before planning ophthalmologic surgical procedures or in concomitant conditions such as glaucoma or corneal ectasias.
Disclosure of interest The authors declare that they have no competing interest.
References [1] Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, et al. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64:475—87. [2] Both T, Dalm V, van Hagen PM, van Daele PL. Reviewing primary Sjögren’s syndrome: beyond the dryness. From pathophysiology to diagnosis and treatment. Int J Med Sci 2017;14:191—200. [3] Jonsson R, Moen K, Vestrheim D, Szodoray P. Current issues in Sjögren’s syndrome. Oral dis 2002;8:130—40. [4] Patel R, Shahane A. The epidemiology of Sjögren’s syndrome. Clin Epidemiol 2014;6:247—55. [5] Elsheikh A, Alhasso D, Rama P. Assessment of the epithelium’s contribution to corneal biomechanics. Exp Eye Res 2008;86:445—51. [6] Long Q, Wang JY, Xu D, Li Y. Comparison of corneal biomechanics in Sjögren’s syndrome and non-Sjögren’s syndrome dry eyes by Scheimpflug based device. Int J Ophthalmol 2017;10:711—6. [7] Long Q, Wang J, Yang X, Jin Y, Ai F, Li Y. Assessment of corneal biomechanical properties by Corvis ST in patients with dry eye and in healthy subjects. J Ophthalmol 2015;2015, http://dx.doi.org/10.1155/2015/380624 [380624]. [8] Firat PG, Doganay S. Corneal hysteresis in patients with dry eye. Eye (Lond) 2011;25:1570—4. [9] Nikolov NP, Illei GG. Pathogenesis of Sjögren’s syndrome. Curr opin Rheumatol 2009;21:465—70.
[10] Kiripolsky J, McCabe LG, Kramer JM. Innate immunity in Sjögren’s syndrome. Clin Immunol 2017;182:4—13, http://dx.doi.org/10.1016/j.clim.2017.04.003 [Epub ahead of print]. [11] Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005;31:156—62. [12] García-Carrasco M, Ramos-Casals M, Rosas J, Pallarés L, CalvoAlen J, Cervera R, et al. Primary Sjögren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine (Baltimore) 2002;81:270—80. [13] López-Miguel A, Tesón M, Martín-Monta˜ nez V, Enríquez de Salamanca A, Stern ME, González-García MJ, et al. Clinical and molecular inflammatory response in Sjögren syndromeassociated dry eye patients under desiccating stress. Am J Ophthalmol 2016;161:133—41. [14] Cornec D, Devauchelle-Pensec V, Tobón GJ, Pers JO, JousseJoulin S, Saraux A. B cells in Sjögren’s syndrome: from pathophysiology to diagnosis and treatment. J Autoimmun 2012;39:161—7. [15] Fernández-Barboza F, Verdiguel-Sotelo K, Hernández-López A. Pellucid marginal degeneration and corneal ulceration, associated with Sjögren syndrome. Rev Med Inst Mex Seguro Soc 2009;47:77—82. [16] Hyams SW, Kar H, Neumann E. Blue sclerae and keratoglobus. Ocular signs of a systemic connective tissue disorder. Br J Ophthalmol 1969;53:53—8. [17] Aragona P, Aguennouz M, Rania L, Postorino E, Sommario MS, Roszkowska AM, et al. Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different dorms of dry eye disease. Ophthalmology 2015;122:62—71. [18] Van Doren SR. Matrix metalloproteinase interactions with collagen and elastin. Matrix Biol 2015;44—46:224—31. [19] Kawashima M, Kawakita T, Maida Y, Kamoi M, Ogawa Y, Shimmura S, et al. Comparison of telomere length and association with progenitor cell markers in lacrimal gland between Sjogren syndrome and non-Sjogren syndrome dry eye patients. Mol Vis 2011;17:1397—404. [20] Pedersen IB, Bak-Nielsen S, Vestergaard AH, Ivarsen A, Hjortdal J. Corneal biomechanical properties after LASIK, ReLEx flex, and ReLEx smile by Scheimpflug-based dynamic tonometry. Graefes Arch Clin Exp Ophthalmol 2014;252: 1329—35. [21] Terai N, Raiskup F, Haustein M, Pillunat LE, Spoerl E. Identification of biomechanical properties of the cornea: the ocular response analyzer. Curr Eye Res 2012;37:553—62. [22] Tas. M, Öner V, Özkaya E. Durmus. M. Evaluation of corneal biomechanical properties in patients with rheumatoid arthritis: a study by ocular response analyzer. Ocul Immunol Inflamm 2014;22:224—7. [23] Celik U, Aykut V, Celik B, Tas M, Yazgan S, Kaldrm H, et al. A comparison of corneal biomechanical properties in patients with psoriasis and healthy subjects. Eye Contact Lens 2015;41:127—9. [24] Yazici AT, Kara N, Yüksel K, Altinkaynak H, Baz O, Bozkurt E, et al. The biomechanical properties of the cornea in patients with systemic lupus erythematosus. Eye (Lond) 2011;25:1005—9. [25] Kara N, Bozkurt E, Baz O, Altinkaynak H, Dundar H, Yuksel K, et al. Corneal biomechanical properties and intraocular pressure measurement in Marfan patients. J Cataract Refract Surg 2012;38:309—14. [26] Tejwani S, Shetty R, Kurien M, Dinakaran S, Ghosh A, Sinha Roy A. Biomechanics of the cornea evaluated by spectral analysis of waveforms from ocular response analyzer and Corvis-ST. Plos One 2014;9, http://dx.doi.org/10.1371/journal.pone.0097591 [e97591].
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015
+Model JFO-2075; No. of Pages 7
ARTICLE IN PRESS
Corneal biomechanical characteristics in Sjögren’s syndrome dry eyes [27] Dayanair V, Sakarya V, Ozcura F, Kir E, Aktunc ¸ T, Ozkan BS, et al. Effect of corneal drying on central corneal thickness. J Glaucoma 2004;13:6—8. [28] Damji KF, Muni RH, Munger RM. Influence of corneal variables on accuracy of intraocular pressure measurement. J Glaucoma 2003;12:69—80.
7
[29] Medeiros FA, Weinreb RN. Evaluation of the influence of corneal biomechanical properties on intraocular pressure measurements using the ocular response analyzer. J Glaucoma 2006;15:364—70. [30] Pi˜ nero DP, Alcón N. Corneal biomechanics: a review. Clin Exp Optom 2015;98:107—16.
Please cite this article in press as: Borrego-Sanz L, et al. Comparison of corneal biomechanical properties of patients with dry eye secondary to Sjögren’s syndrome and healthy subjects. J Fr Ophtalmol (2018), https://doi.org/10.1016/j.jfo.2018.02.015