ARTICLE
Corneal Biomechanical Properties in Rheumatoid Arthritis Mehmet Erol Can, M.D., Sukran Erten, M.D., Gamze Dereli Can, M.D., Hasan Basri Cakmak, M.D., Ph.D., Ozge Sarac, M.D., and Nurullah Cagil, M.D.
Purpose: To investigate the variations in biomechanical properties of the cornea in rheumatoid arthritis (RA) patients. Methods: A total of 53 RA patients, and 25 healthy individuals (control group) were enrolled. Rheumatoid arthritis patients were classified as in active phase (group 1; n¼24) or in remission phase (group 2; n¼29). Corneal biomechanical parameters including corneal hysteresis (CH), corneal resistance factor (CRF), corneal compensated intraocular pressure (IOPcc), and Goldmann-correlated IOP (IOPg) were measured with the Reichert Ocular Response Analyzer. Topographical measurements, including central corneal thickness (CCT), anterior chamber depth, iridocorneal angle, and corneal volume were measured using a Sirius corneal topographer. Results: The mean CH was 9.4361.17 mm Hg in group 1, 9.4261.84 mm Hg in group 2, and 10.4761.68 mm Hg in the control group (P¼0.03). The mean IOPcc was 17.8563.2 mm Hg in group 1, 17.9563.49 mm Hg in group 2, and 15.3663.11 mm Hg in the control group (P¼0.008). The CH showed a significant positive correlation with CRF (P¼0.000, r¼0.809) and CCT (P¼0.000, r¼0.461), and a significant negative correlation with IOPcc (P¼0.000, r¼20.469). Conclusions: Decrease in the mean CH measurements indicates that ultrastructural changes in the cornea may occur in the active phase, and these changes persist in the remission period. In addition, IOPcc is significantly affected by the corneal biomechanical properties. In RA patients, it is important to control the corneal parameters and IOP measurements against the irreversible changes on the optic nerve. Key Words: Corneal biomechanics—Corneal hysteresis—Active rheumatoid arthritis—Remission rheumatoid arthritis. (Eye & Contact Lens 2015;41: 382–385)
R
heumatoid arthritis (RA) is a common and chronic autoimmune disease affecting many organs.1,2 The prevalence of RA is around 0.8% of the population.1,2 Females are affected approximately three times more often than males.1,2 The main feature of RA is persistent inflammatory synovitis, which usually involves peripheral joints in a symmetric distribution, From the Department of Ophthalmology (M.E.C.), Ankara Kecioren Training and Research Hospital, Ankara, Turkey; Departments of Rheumatology (S.E.), and Ophthalmology (G.D.C., O.S., N.C.), Ankara Ataturk Training and Research Hospital, Yildirim Beyazit University, Ankara, Turkey; and Department of Ophthalmology (H.B.C.), Hacettepe University, Faculty of Medicine, Ankara, Turkey. The authors have no funding or conflicts of interest to disclose. Address correspondence to Gamze Dereli Can, M.D., Department of Ophthalmology, Ankara Ataturk Training and Research Hospital, Yildirim Beyazit University, Bilkent, Ankara, 06800 Turkey; e-mail: dereli_ [email protected] Accepted January 11, 2015. DOI: 10.1097/ICL.0000000000000142
382
although it has a variety of systemic manifestations. The most common extra articular manifestations of RA are anemia, fatigue, subcutaneous (“rheumatoid”) nodules, pleuropericarditis, neuropathy, ophthalmic involvement, splenomegaly, Sjögren syndrome, vasculitis, renal disease, and ocular involvement.1,2 Ocular manifestations generally occur in 25% of the patients.3 Although the most common ocular manifestation in RA is keratoconjunctivitis sicca; corneal infection, episcleritis, scleritis, anterior uveitis, or different types of corneal inflammation, such as stromal keratitis, sclerosing keratitis, keratolysis, peripheral ulcerative keratitis, and corneal melting could arise during its chronic course.3,4 The corneal stromal layer, mainly composed of the regular lamella of type 1 collagen fibril, plays a substantial role in the acquisition of much of the corneal flexibility and achievement of a large refractive power.5 Stromal changes, occurring in natural processes like aging, could appear in pathological conditions as a manifestation of some systemic diseases of connective tissue, which may affect corneal stroma. Measurement of the corneal biomechanical parameters, in those disease states, is essential to understand the extent of ocular involvement.6,7 Rheumatoid arthritis has a protracted clinical course with active and remission periods. Ocular inflammatory signs could be observed in active periods, if an ocular involvement is present. However, occult tissue changes might take place without any apparent ocular signs during a routine ophthalmological examination. Detection of these occult tissue changes could help to differentiate active phase from remission phase. In this study, the main aim was to investigate whether there were any changes occurring in corneal biomechanical parameters in RA patients compared with healthy subjects. The second aim was to answer this critical question: If there is a change in the RA group, is it associated with the disease phase?
MATERIALS AND METHODS Study Population and Design This was a prospective, cross-sectional comparative trial conducted at Ataturk Training and Research Hospital, Ankara, Turkey, according to the Tenets of the Declaration of Helsinki. Approval was obtained from the local ethics committee, and written informed consent was obtained from all participants before enrollment in the study. The study consisted of 53 RA patients (study group) and 25 healthy individuals (control group). Study group was further Eye & Contact Lens Volume 41, Number 6, November 2015
Copyright @ Contact Lens Association of Opthalmologists, Inc. Unauthorized reproduction of this article is prohibited.
Eye & Contact Lens Volume 41, Number 6, November 2015 grouped into 2 subgroups: group 1 (n¼24) or group 2 (n¼29) using a Disease Activity Score (DAS) by Rheumatology specialist.8 The DAS combines single measures into an overall continuous measure of RA disease activity. It includes the Ritchie Articular Index, a 44-joint swollen joint count, erythrocyte sedimentation rate, besides a general health assessment on a visual analog scale. A DAS less than 1.6 corresponds with being in remission according to American Rheumatism Association criteria.8 A comprehensive evaluation of patients was undertaken, including patients’ age, gender, and medical and ocular history. Exclusion criteria included having a history of contact lens use, corneal or intraocular surgery, glaucoma, corneal scar, keratitis, dry eye disease, or active corneal inflammation.
Examination Protocol and Measurements All of the subjects underwent a complete ophthalmological examination, including visual acuity testing, slitlamp examination, intraocular pressure (IOP) measurement with Goldmann applanation tonometer, and fundus examination. The Ocular Response Analyzer (Reichert Ophthalmic Instruments, Buffalo, NY) was used to measure the biomechanical properties of the cornea with a standard technique.9 It gives a great amount of information for in vivo evaluation of corneal biomechanical properties.9 Besides yielding many other parameters to analyze biomechanical properties of the cornea, this instrument measures two important parameters: corneal hysteresis (CH) and corneal resistance factor (CRF). The CH depends on the corneal viscoelasticity, whereas CRF shows the overall resistance of the cornea.9 The CH, CRF, corneal compensated IOP (IOPcc), and Goldmann-correlated IOP (IOPg) were measured while performing the ORA measurement. All the subjects were asked to look at a target light with the same room temperature and light level. Three consecutive measurements, having a Waveform Scores $7, were obtained for each eye, and the average value of these measurements was used. Central corneal thickness (CCT), anterior chamber depth (ACD), temporal iridocorneal angle (ICA), corneal volume (CV), and anterior chamber volume (ACV) were measured using a Scheimpflug camera combined with a Placido disk corneal topographer (Sirius; C.S.O., Firenze, Italy) with a standard method according to manufacturers’ directives.10 During scanning of 25 Scheimpflug images and 1 placido image, all the subjects asked to fix at the placido disk for 1 to 3 sec. After the image acquisition, the image, which is free of artifact, and allows visualization of the entire anterior chamber structures was selected. All measurements were performed by a single clinician (M.E.C.).
Active or Remission Rheumatoid Arthritis
RESULTS Demographic Characteristics All participants were women. The mean age was 54.88615.01 (range, 18–76) years in group 1, 51.24610.04 (range, 24–67) years in group 2, and 50.4469.49 (range, 39–72) years in the control group. There is no statistically significant difference between the three groups (P¼0.36).
Results of ORA Examinations The mean CH was 9.4361.17 mm Hg in group 1, 9.4261.84 mm Hg in group 2, and 10.4761.68 mm Hg in the control group. The difference between the three groups was found to be significant with the ANOVA test (P¼0.03). Post hoc tests revealed that the difference between groups 1 and 2 was not significant (P¼0.99). However, the mean CH in the control group was significantly different from group 1 (P¼0.04). In the comparison of the control group and group 2, the mean CH did not show any significant difference (P¼0.09). The mean IOPcc was 17.8563.2 mm Hg in group 1, 17.9563.49 mm Hg group 2, and 15.3663.11 mm Hg in the control group (P¼0.008). In the control group, the mean IOPcc was significantly lower than groups 1 and 2 (P¼0.02, P¼0.01, respectively). However, there was no significant difference between groups 1 and 2 (P¼0.99). The ANOVA analysis of CH, CRF, IOPcc, and IOPg measurements were summarized in Table 1. The CH showed a significant positive correlation with the CRF (P¼0.000, r¼0.809) and the CCT (P¼0.000, r¼0.461), and a significant negative correlation with the IOPcc (P¼0.000, r¼20.469). There was no statistically significant correlation between the CH and IOPg (P¼0.65, r¼0.052) and the IOP measured by Goldmann tonometer (P¼0.941, r¼0.009).
Results of Sirius Examinations
The mean CCT was 532.38637.5 mm in group 1, 535.38632.53 mm in group 2, and 529.48636.87 mm in the control group (P¼0.83). Similarly, the mean ACD, temporal ICA, CV, and ACV were not statistically significant within three groups. All Sirius examination findings were summarized in Table 2.
DISCUSSION This study evaluated the biomechanical and topographical properties of the cornea in RA patients’ active or remission phases. The results showed that RA patients had lower CH values compared with controls, whereas the CRF values did not show any difference. The mean IOPcc values were lower in healthy subjects
Statistical Analysis of the Data Statistical analysis was performed using Statistical Package for the Social Sciences software version 20.0 (SPSS Inc, Chicago, IL). All continuous variables were tested for normality. The Levene test for equal variances was performed before comparison of groups by an analysis of variance (ANOVA) test. The ANOVA was carried out to compare mean values of continuous variables among groups. The Tukey HSD test was used to make post hoc comparisons after ANOVA. The Pearson correlation analysis was used to test bivariate correlations among variables. All the results were given as mean6standard deviation. A P#0.05 was considered statistically significant. © 2015 Contact Lens Association of Ophthalmologists
TABLE 1. Comparison of the Mean Ocular Response Analyzer Measurements in the Active RA, Remission RA, and Control Groups
CH (mm Hg) CRF (mm Hg) IOPcc (mm Hg) IOPg (mm Hg)
Active RA
Remission RA
Control
Pa
9.4361.17 9.8661.8 17.8563.2 16.4463.99
9.4261.84 9.8561.8 17.9563.49 16.5263.26
10.4761.68 10.3261.79 15.3663.11 14.963.27
0.03 0.57 0.008 0.18
a
ANOVA test.
CH, corneal hysteresis; CRF, corneal resistance factor; IOPcc, corneal compensated intraocular pressure; IOPg, Goldmann-correlated intraocular pressure; RA, rheumatoid arthritis.
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Eye & Contact Lens Volume 41, Number 6, November 2015
M. E. Can et al. TABLE 2.
Comparison of the Mean Sirius Measurements in the Active RA, Remission RA, and Control Groups Active RA
CCT (mm) ACD (mm) ICA temporal (degrees) CV (mm3) ACV (mm3)
532.38637.5 3.1760.33 40.7166.53
Remission RA
Control
Pa
535.38632.53 529.48636.87 0.83 3.2360.35 3.2360.38 0.82 42.6267.12 41.8865.65 0.56
57.1763.50 56.9463.55 57.1664.12 124.71628.02 128.34626.64 126.16626.7
0.96 0.88
a
ANOVA test.
ACD, anterior chamber depth; ACV, anterior chamber volume; CCT, central corneal thickness; CV, corneal volume; ICA Temporal, temporal iridocorneal angle; RA, rheumatoid arthritis.
than RA patients, both in groups 1 and 2. Rheumatoid arthritis is a chronic multisystem disease, in which ocular involvement might occur, and in some cases it can cause serious visual loss.11 Corneal stromal changes, such as corneal thinning with keratolysis, stromal corneal opacities with peripheral neovascularization and associated iridocyclitis, lower density of superficial epithelial cells, fewer subbasal nerves, and greater nerve tortuosity have been demonstrated in RA patients.12,13 In RA, the corneal morphological findings are associated with increased apoptotic and proteolytic activity.13 It has been thought that these corneal stromal changes have an effect on biomechanical properties of the cornea. The ORA provides the measurement of corneal biomechanical parameters including CH and CRH that depend on corneal viscoelasticity.9 The CH is the strain rate–dependent parameter and symbolizes the cumulative effects of all factors, such as corneal thickness, hydration, and rigidity, which are essential in the determination of corneal biomechanics. The CH projected the viscous damping property of the cornea, showing its ability of absorption and dissemination of the energy. However, CRF shows overall corneal resistance to any applied force. It has been reported that CH and CRF were related to corneal shape and thickness.14 A decrease in CH and CRF was reported in disorders with disorganization in corneal collagen lamella, like keratoconus and post-LASIK ectasia.15 Previous studies have demonstrated that the corneal biomechanical properties, such as corneal viscoelasticity and resistance, are changed in some corneal disorders, autoimmune or systemic diseases, or hormonal fluctuations.16–23 In RA patients, few articles have reported the corneal biomechanical properties. Prata et al.24 reported lower CH levels in RA patients when compared with healthy subjects, which was very similar with our results. Tas et al.25 demonstrated a decrease in both CH and CRF levels in RA patients. In RA, the disease process causes tissue changes both in corneal epithelium and corneal stroma.13,26 Villani et al.13 investigated corneal involvement in RA with in vivo confocal microscopy. They found a higher amount of hyperreflective activated keratocytes, indicating an inflammatory process in RA. Adachi et al.26 examined ultrastructural alterations in the corneal stroma in RA patients and reported that there were alterations in both the corneal extracellular matrix and collagen, which might cause a structural weakening. The inflammatory process and ultrastructural alterations in corneal stroma contributed to a decrease in CH in RA patients. To the best of our knowledge, this study is the first one comparing the biomechanical properties of the cornea in active or inactive RA patients. In previous studies, neither RA patients were 384
analyzed separately as in active or remission phase nor RA activation considered in evaluating the biomechanical properties of the cornea. In our study, RA patients had lower CH values than controls, and these results were similar to the previous ones. However, CH did not show any significant difference between patients in active or inactive stage. The persistence of lower CH values in remission phase indicates that the ultrastructural changes that occur in the cornea are irreversible and persistent, although disease activity decreases. Similar changes in corneal biomechanics were observed in other autoimmune diseases.27,28 Emre et al.27 investigated the changes in biomechanical properties of the cornea with the ORA in scleroderma patients and reported that both CH and CRF values were higher in the scleroderma group than in the control group. Yazici et al.28 compared the corneal biomechanical properties in systemic lupus erythematosus (SLE) with age-matched controls and reported that CH and CRF values were found to be lower in the SLE group than in the control group. In this study, we also demonstrated a difference in mean IOPcc values between controls and RA patients. The mean IOPcc values were higher in RA patients than in the control group. However, the mean IOP values measured with Goldmann tonometer were similar between groups. These results were in accordance with the other previous studies and suggest that the IOPcc values are measured higher with ORA because of a change in CH values.24,25 When an evaluation of IOPcc measurements was higher than in normal subjects, the possibility of an incorrectly lower IOPg measurement should always be considered in RA patients. So, further evaluations should be done for the higher IOP measurements, especially for optic nerve damage. In conclusion, this study showed that the corneal biomechanical properties could have been affected and persisted in RA in active or remission disease phase. More studies including large patient groups should be done to support our findings. REFERENCES 1. Grassi W, De Angelis R, Lamanna G, et al. The clinical features of rheumatoid arthritis. Eur J Radiol 1998;27:18–24. 2. Scutellari PN, Orzincolo C. Rheumatoid arthritis: Sequences. Eur J Radiol 1998;27:31–38. 3. Harper SL, Foster CS. The ocular manifestations of rheumatoid disease. Int Ophthalmol Clin 1998;38:1–19. 4. Lemp MA. Dry eye (Keratoconjunctivitis Sicca), rheumatoid arthritis, and Sjögren’s syndrome. Am J Ophthalmol 2005;140:898–899. 5. Fratzl P, Daxer A. Structural transformation of collagen fibrils in corneal stroma during drying. An x-ray scattering study. Biophys J 1993;64:1210– 1214. 6. Nyquist GW. Rheology of the cornea: Experimental techniques and results. Exp Eye Res 1968;7:183–188. 7. Nash IS, Greene PR, Foster CS. Comparison of mechanical properties of keratoconus and normal corneas. Exp Eye Res 1982;35:413–424. 8. Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Kerstens PJSM, et al. DAS-driven therapy versus routine care in patients with recent-onset active rheumatoid arthritis. Ann Rheum Dis 2010;69:65–99. 9. Altan C, Demirel B, Azman E, et al. Biomechanical properties of axially myopic cornea. Eur J Ophthalmol 2012;22:24–28. 10. Savini G, Hoffer KJ, Carbonelli M. Anterior chamber and aqueous depth measurement in pseudophakic eyes: Agreement between ultrasound biometry and scheimpflug imaging. J Refract Surg 2013;29:121–125. 11. Baldassano VF. Ocular manifestations of rheumatic diseases. Curr Opin Ophthalmol 1998;9:85–88. 12. Reddy SC, Rao UR. Ocular complications of adult rheumatoid arthritis. Rheumatol Int 1996;16:49–52.
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Eye & Contact Lens Volume 41, Number 6, November 2015 13. Villani E, Galimberti D, Viola F, et al. Corneal involvement in rheumatoid arthritis: an in vivo confocal study. Invest Ophthalmol Vis Sci 2008;49:560–564. 14. Martinez-de-la-Casa JM, Garcia-Feijoo J, Fernandez-Vidal A, et al. Ocular response analyzer versus Goldmann applanation tonometry for intraocular pressure measurements. Invest Ophthalmol Vis Sci 2006;47:4410–4414. 15. Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005;31:156–162. 16. Nemet AY, Vinker S, Bahar I. The association of keratoconus with immune disorders. Cornea 2010;29:1261–1264. 17. Fernández-Barboza F, Verdiguel-Sotelo K, Hernández-López A. Pellucid marginal degeneration and corneal ulceration, associated with Sjögren syndrome [in Spanish]. Rev Med Inst Mex Seguro Soc 2009;47:77–82. 18. Shah S, Laiquzzaman M, Bhojwani R, et al. Assessment of the biomechanical properties of the cornea with the ocular response analyzer in normal and keratoconic eyes. Invest Ophthalmol Vis Sci 2007;48:3026–3031. 19. Johnson RD, Nguyen MT, Lee N, et al. Corneal biomechanical properties in normal, forme fruste keratoconus, and manifest keratoconus after statistical correction for potentially confounding factors. Cornea 2011;30:516–523. 20. Del Buey MA, Cristóbal JA, Ascaso FJ, et al. Biomechanical properties of the cornea in Fuchs’ corneal dystrophy. Invest Ophthalmol Vis Sci 2009;50: 3199–3202. 21. Hager A, Loge K, Füllhas M-O, et al. Changes in corneal hysteresis after clear corneal cataract surgery. Am J Ophthalmol 2007;144:341–346.
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Active or Remission Rheumatoid Arthritis 22. Goldich Y, Barkana Y, Gerber Y, et al. Effect of diabetes mellitus on biomechanical parameters of the cornea. J Cataract Refract Surg 2009; 35:715–719. 23. Goldich Y, Barkana Y, Pras E, et al. Variations in corneal biomechanical parameters and central corneal thickness during the menstrual cycle. J Cataract Refract Surg 2011;37:1507–1511. 24. Prata TS, Sousa AK, Garcia Filho CAA, et al. Assessment of corneal biomechanical properties and intraocular pressure in patients with rheumatoid arthritis. Can J Ophthalmol 2009;44:602. 25. Taş M, Öner V, Özkaya E, et al. Evaluation of corneal biomechanical properties in patients with rheumatoid arthritis: A study by ocular response analyzer. Ocul Immunol Inflamm 2014;22:224–227. 26. Adachi W, Nishida K, Quantock AJ, et al. Ultrastructural alterations in the stroma adjacent to non-inflammatory corneal perforations associated with long standing rheumatoid arthritis. Br J Ophthalmol 1998;82: 1445–1446. 27. Emre S, Kayikçio glu O, Ateş H, et al. Corneal hysteresis, corneal resistance factor, and intraocular pressure measurement in patients with scleroderma using the reichert ocular response analyzer. Cornea 2010; 29:628–631. 28. Yazici AT, Kara N, Yüksel K, et al. The biomechanical properties of the cornea in patients with systemic lupus erythematosus. Eye (Lond) 2011;25: 1005–1009.
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Corneal Biomechanical Properties in Rheumatoid Arthritis Mehmet Erol Can, M.D., Sukran Erten, M.D., Gamze Dereli Can, M.D., Hasan Basri Cakmak, M.D., Ph.D., Ozge Sarac, M.D., and Nurullah Cagil, M.D.
Purpose: To investigate the variations in biomechanical properties of the cornea in rheumatoid arthritis (RA) patients. Methods: A total of 53 RA patients, and 25 healthy individuals (control group) were enrolled. Rheumatoid arthritis patients were classified as in active phase (group 1; n¼24) or in remission phase (group 2; n¼29). Corneal biomechanical parameters including corneal hysteresis (CH), corneal resistance factor (CRF), corneal compensated intraocular pressure (IOPcc), and Goldmann-correlated IOP (IOPg) were measured with the Reichert Ocular Response Analyzer. Topographical measurements, including central corneal thickness (CCT), anterior chamber depth, iridocorneal angle, and corneal volume were measured using a Sirius corneal topographer. Results: The mean CH was 9.4361.17 mm Hg in group 1, 9.4261.84 mm Hg in group 2, and 10.4761.68 mm Hg in the control group (P¼0.03). The mean IOPcc was 17.8563.2 mm Hg in group 1, 17.9563.49 mm Hg in group 2, and 15.3663.11 mm Hg in the control group (P¼0.008). The CH showed a significant positive correlation with CRF (P¼0.000, r¼0.809) and CCT (P¼0.000, r¼0.461), and a significant negative correlation with IOPcc (P¼0.000, r¼20.469). Conclusions: Decrease in the mean CH measurements indicates that ultrastructural changes in the cornea may occur in the active phase, and these changes persist in the remission period. In addition, IOPcc is significantly affected by the corneal biomechanical properties. In RA patients, it is important to control the corneal parameters and IOP measurements against the irreversible changes on the optic nerve. Key Words: Corneal biomechanics—Corneal hysteresis—Active rheumatoid arthritis—Remission rheumatoid arthritis. (Eye & Contact Lens 2015;41: 382–385)
R
heumatoid arthritis (RA) is a common and chronic autoimmune disease affecting many organs.1,2 The prevalence of RA is around 0.8% of the population.1,2 Females are affected approximately three times more often than males.1,2 The main feature of RA is persistent inflammatory synovitis, which usually involves peripheral joints in a symmetric distribution, From the Department of Ophthalmology (M.E.C.), Ankara Kecioren Training and Research Hospital, Ankara, Turkey; Departments of Rheumatology (S.E.), and Ophthalmology (G.D.C., O.S., N.C.), Ankara Ataturk Training and Research Hospital, Yildirim Beyazit University, Ankara, Turkey; and Department of Ophthalmology (H.B.C.), Hacettepe University, Faculty of Medicine, Ankara, Turkey. The authors have no funding or conflicts of interest to disclose. Address correspondence to Gamze Dereli Can, M.D., Department of Ophthalmology, Ankara Ataturk Training and Research Hospital, Yildirim Beyazit University, Bilkent, Ankara, 06800 Turkey; e-mail: dereli_ [email protected] Accepted January 11, 2015. DOI: 10.1097/ICL.0000000000000142
382
although it has a variety of systemic manifestations. The most common extra articular manifestations of RA are anemia, fatigue, subcutaneous (“rheumatoid”) nodules, pleuropericarditis, neuropathy, ophthalmic involvement, splenomegaly, Sjögren syndrome, vasculitis, renal disease, and ocular involvement.1,2 Ocular manifestations generally occur in 25% of the patients.3 Although the most common ocular manifestation in RA is keratoconjunctivitis sicca; corneal infection, episcleritis, scleritis, anterior uveitis, or different types of corneal inflammation, such as stromal keratitis, sclerosing keratitis, keratolysis, peripheral ulcerative keratitis, and corneal melting could arise during its chronic course.3,4 The corneal stromal layer, mainly composed of the regular lamella of type 1 collagen fibril, plays a substantial role in the acquisition of much of the corneal flexibility and achievement of a large refractive power.5 Stromal changes, occurring in natural processes like aging, could appear in pathological conditions as a manifestation of some systemic diseases of connective tissue, which may affect corneal stroma. Measurement of the corneal biomechanical parameters, in those disease states, is essential to understand the extent of ocular involvement.6,7 Rheumatoid arthritis has a protracted clinical course with active and remission periods. Ocular inflammatory signs could be observed in active periods, if an ocular involvement is present. However, occult tissue changes might take place without any apparent ocular signs during a routine ophthalmological examination. Detection of these occult tissue changes could help to differentiate active phase from remission phase. In this study, the main aim was to investigate whether there were any changes occurring in corneal biomechanical parameters in RA patients compared with healthy subjects. The second aim was to answer this critical question: If there is a change in the RA group, is it associated with the disease phase?
MATERIALS AND METHODS Study Population and Design This was a prospective, cross-sectional comparative trial conducted at Ataturk Training and Research Hospital, Ankara, Turkey, according to the Tenets of the Declaration of Helsinki. Approval was obtained from the local ethics committee, and written informed consent was obtained from all participants before enrollment in the study. The study consisted of 53 RA patients (study group) and 25 healthy individuals (control group). Study group was further Eye & Contact Lens Volume 41, Number 6, November 2015
Copyright @ Contact Lens Association of Opthalmologists, Inc. Unauthorized reproduction of this article is prohibited.
Eye & Contact Lens Volume 41, Number 6, November 2015 grouped into 2 subgroups: group 1 (n¼24) or group 2 (n¼29) using a Disease Activity Score (DAS) by Rheumatology specialist.8 The DAS combines single measures into an overall continuous measure of RA disease activity. It includes the Ritchie Articular Index, a 44-joint swollen joint count, erythrocyte sedimentation rate, besides a general health assessment on a visual analog scale. A DAS less than 1.6 corresponds with being in remission according to American Rheumatism Association criteria.8 A comprehensive evaluation of patients was undertaken, including patients’ age, gender, and medical and ocular history. Exclusion criteria included having a history of contact lens use, corneal or intraocular surgery, glaucoma, corneal scar, keratitis, dry eye disease, or active corneal inflammation.
Examination Protocol and Measurements All of the subjects underwent a complete ophthalmological examination, including visual acuity testing, slitlamp examination, intraocular pressure (IOP) measurement with Goldmann applanation tonometer, and fundus examination. The Ocular Response Analyzer (Reichert Ophthalmic Instruments, Buffalo, NY) was used to measure the biomechanical properties of the cornea with a standard technique.9 It gives a great amount of information for in vivo evaluation of corneal biomechanical properties.9 Besides yielding many other parameters to analyze biomechanical properties of the cornea, this instrument measures two important parameters: corneal hysteresis (CH) and corneal resistance factor (CRF). The CH depends on the corneal viscoelasticity, whereas CRF shows the overall resistance of the cornea.9 The CH, CRF, corneal compensated IOP (IOPcc), and Goldmann-correlated IOP (IOPg) were measured while performing the ORA measurement. All the subjects were asked to look at a target light with the same room temperature and light level. Three consecutive measurements, having a Waveform Scores $7, were obtained for each eye, and the average value of these measurements was used. Central corneal thickness (CCT), anterior chamber depth (ACD), temporal iridocorneal angle (ICA), corneal volume (CV), and anterior chamber volume (ACV) were measured using a Scheimpflug camera combined with a Placido disk corneal topographer (Sirius; C.S.O., Firenze, Italy) with a standard method according to manufacturers’ directives.10 During scanning of 25 Scheimpflug images and 1 placido image, all the subjects asked to fix at the placido disk for 1 to 3 sec. After the image acquisition, the image, which is free of artifact, and allows visualization of the entire anterior chamber structures was selected. All measurements were performed by a single clinician (M.E.C.).
Active or Remission Rheumatoid Arthritis
RESULTS Demographic Characteristics All participants were women. The mean age was 54.88615.01 (range, 18–76) years in group 1, 51.24610.04 (range, 24–67) years in group 2, and 50.4469.49 (range, 39–72) years in the control group. There is no statistically significant difference between the three groups (P¼0.36).
Results of ORA Examinations The mean CH was 9.4361.17 mm Hg in group 1, 9.4261.84 mm Hg in group 2, and 10.4761.68 mm Hg in the control group. The difference between the three groups was found to be significant with the ANOVA test (P¼0.03). Post hoc tests revealed that the difference between groups 1 and 2 was not significant (P¼0.99). However, the mean CH in the control group was significantly different from group 1 (P¼0.04). In the comparison of the control group and group 2, the mean CH did not show any significant difference (P¼0.09). The mean IOPcc was 17.8563.2 mm Hg in group 1, 17.9563.49 mm Hg group 2, and 15.3663.11 mm Hg in the control group (P¼0.008). In the control group, the mean IOPcc was significantly lower than groups 1 and 2 (P¼0.02, P¼0.01, respectively). However, there was no significant difference between groups 1 and 2 (P¼0.99). The ANOVA analysis of CH, CRF, IOPcc, and IOPg measurements were summarized in Table 1. The CH showed a significant positive correlation with the CRF (P¼0.000, r¼0.809) and the CCT (P¼0.000, r¼0.461), and a significant negative correlation with the IOPcc (P¼0.000, r¼20.469). There was no statistically significant correlation between the CH and IOPg (P¼0.65, r¼0.052) and the IOP measured by Goldmann tonometer (P¼0.941, r¼0.009).
Results of Sirius Examinations
The mean CCT was 532.38637.5 mm in group 1, 535.38632.53 mm in group 2, and 529.48636.87 mm in the control group (P¼0.83). Similarly, the mean ACD, temporal ICA, CV, and ACV were not statistically significant within three groups. All Sirius examination findings were summarized in Table 2.
DISCUSSION This study evaluated the biomechanical and topographical properties of the cornea in RA patients’ active or remission phases. The results showed that RA patients had lower CH values compared with controls, whereas the CRF values did not show any difference. The mean IOPcc values were lower in healthy subjects
Statistical Analysis of the Data Statistical analysis was performed using Statistical Package for the Social Sciences software version 20.0 (SPSS Inc, Chicago, IL). All continuous variables were tested for normality. The Levene test for equal variances was performed before comparison of groups by an analysis of variance (ANOVA) test. The ANOVA was carried out to compare mean values of continuous variables among groups. The Tukey HSD test was used to make post hoc comparisons after ANOVA. The Pearson correlation analysis was used to test bivariate correlations among variables. All the results were given as mean6standard deviation. A P#0.05 was considered statistically significant. © 2015 Contact Lens Association of Ophthalmologists
TABLE 1. Comparison of the Mean Ocular Response Analyzer Measurements in the Active RA, Remission RA, and Control Groups
CH (mm Hg) CRF (mm Hg) IOPcc (mm Hg) IOPg (mm Hg)
Active RA
Remission RA
Control
Pa
9.4361.17 9.8661.8 17.8563.2 16.4463.99
9.4261.84 9.8561.8 17.9563.49 16.5263.26
10.4761.68 10.3261.79 15.3663.11 14.963.27
0.03 0.57 0.008 0.18
a
ANOVA test.
CH, corneal hysteresis; CRF, corneal resistance factor; IOPcc, corneal compensated intraocular pressure; IOPg, Goldmann-correlated intraocular pressure; RA, rheumatoid arthritis.
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M. E. Can et al. TABLE 2.
Comparison of the Mean Sirius Measurements in the Active RA, Remission RA, and Control Groups Active RA
CCT (mm) ACD (mm) ICA temporal (degrees) CV (mm3) ACV (mm3)
532.38637.5 3.1760.33 40.7166.53
Remission RA
Control
Pa
535.38632.53 529.48636.87 0.83 3.2360.35 3.2360.38 0.82 42.6267.12 41.8865.65 0.56
57.1763.50 56.9463.55 57.1664.12 124.71628.02 128.34626.64 126.16626.7
0.96 0.88
a
ANOVA test.
ACD, anterior chamber depth; ACV, anterior chamber volume; CCT, central corneal thickness; CV, corneal volume; ICA Temporal, temporal iridocorneal angle; RA, rheumatoid arthritis.
than RA patients, both in groups 1 and 2. Rheumatoid arthritis is a chronic multisystem disease, in which ocular involvement might occur, and in some cases it can cause serious visual loss.11 Corneal stromal changes, such as corneal thinning with keratolysis, stromal corneal opacities with peripheral neovascularization and associated iridocyclitis, lower density of superficial epithelial cells, fewer subbasal nerves, and greater nerve tortuosity have been demonstrated in RA patients.12,13 In RA, the corneal morphological findings are associated with increased apoptotic and proteolytic activity.13 It has been thought that these corneal stromal changes have an effect on biomechanical properties of the cornea. The ORA provides the measurement of corneal biomechanical parameters including CH and CRH that depend on corneal viscoelasticity.9 The CH is the strain rate–dependent parameter and symbolizes the cumulative effects of all factors, such as corneal thickness, hydration, and rigidity, which are essential in the determination of corneal biomechanics. The CH projected the viscous damping property of the cornea, showing its ability of absorption and dissemination of the energy. However, CRF shows overall corneal resistance to any applied force. It has been reported that CH and CRF were related to corneal shape and thickness.14 A decrease in CH and CRF was reported in disorders with disorganization in corneal collagen lamella, like keratoconus and post-LASIK ectasia.15 Previous studies have demonstrated that the corneal biomechanical properties, such as corneal viscoelasticity and resistance, are changed in some corneal disorders, autoimmune or systemic diseases, or hormonal fluctuations.16–23 In RA patients, few articles have reported the corneal biomechanical properties. Prata et al.24 reported lower CH levels in RA patients when compared with healthy subjects, which was very similar with our results. Tas et al.25 demonstrated a decrease in both CH and CRF levels in RA patients. In RA, the disease process causes tissue changes both in corneal epithelium and corneal stroma.13,26 Villani et al.13 investigated corneal involvement in RA with in vivo confocal microscopy. They found a higher amount of hyperreflective activated keratocytes, indicating an inflammatory process in RA. Adachi et al.26 examined ultrastructural alterations in the corneal stroma in RA patients and reported that there were alterations in both the corneal extracellular matrix and collagen, which might cause a structural weakening. The inflammatory process and ultrastructural alterations in corneal stroma contributed to a decrease in CH in RA patients. To the best of our knowledge, this study is the first one comparing the biomechanical properties of the cornea in active or inactive RA patients. In previous studies, neither RA patients were 384
analyzed separately as in active or remission phase nor RA activation considered in evaluating the biomechanical properties of the cornea. In our study, RA patients had lower CH values than controls, and these results were similar to the previous ones. However, CH did not show any significant difference between patients in active or inactive stage. The persistence of lower CH values in remission phase indicates that the ultrastructural changes that occur in the cornea are irreversible and persistent, although disease activity decreases. Similar changes in corneal biomechanics were observed in other autoimmune diseases.27,28 Emre et al.27 investigated the changes in biomechanical properties of the cornea with the ORA in scleroderma patients and reported that both CH and CRF values were higher in the scleroderma group than in the control group. Yazici et al.28 compared the corneal biomechanical properties in systemic lupus erythematosus (SLE) with age-matched controls and reported that CH and CRF values were found to be lower in the SLE group than in the control group. In this study, we also demonstrated a difference in mean IOPcc values between controls and RA patients. The mean IOPcc values were higher in RA patients than in the control group. However, the mean IOP values measured with Goldmann tonometer were similar between groups. These results were in accordance with the other previous studies and suggest that the IOPcc values are measured higher with ORA because of a change in CH values.24,25 When an evaluation of IOPcc measurements was higher than in normal subjects, the possibility of an incorrectly lower IOPg measurement should always be considered in RA patients. So, further evaluations should be done for the higher IOP measurements, especially for optic nerve damage. In conclusion, this study showed that the corneal biomechanical properties could have been affected and persisted in RA in active or remission disease phase. More studies including large patient groups should be done to support our findings. REFERENCES 1. Grassi W, De Angelis R, Lamanna G, et al. The clinical features of rheumatoid arthritis. Eur J Radiol 1998;27:18–24. 2. Scutellari PN, Orzincolo C. Rheumatoid arthritis: Sequences. Eur J Radiol 1998;27:31–38. 3. Harper SL, Foster CS. The ocular manifestations of rheumatoid disease. Int Ophthalmol Clin 1998;38:1–19. 4. Lemp MA. Dry eye (Keratoconjunctivitis Sicca), rheumatoid arthritis, and Sjögren’s syndrome. Am J Ophthalmol 2005;140:898–899. 5. Fratzl P, Daxer A. Structural transformation of collagen fibrils in corneal stroma during drying. An x-ray scattering study. Biophys J 1993;64:1210– 1214. 6. Nyquist GW. Rheology of the cornea: Experimental techniques and results. Exp Eye Res 1968;7:183–188. 7. Nash IS, Greene PR, Foster CS. Comparison of mechanical properties of keratoconus and normal corneas. Exp Eye Res 1982;35:413–424. 8. Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Kerstens PJSM, et al. DAS-driven therapy versus routine care in patients with recent-onset active rheumatoid arthritis. Ann Rheum Dis 2010;69:65–99. 9. Altan C, Demirel B, Azman E, et al. Biomechanical properties of axially myopic cornea. Eur J Ophthalmol 2012;22:24–28. 10. Savini G, Hoffer KJ, Carbonelli M. Anterior chamber and aqueous depth measurement in pseudophakic eyes: Agreement between ultrasound biometry and scheimpflug imaging. J Refract Surg 2013;29:121–125. 11. Baldassano VF. Ocular manifestations of rheumatic diseases. Curr Opin Ophthalmol 1998;9:85–88. 12. Reddy SC, Rao UR. Ocular complications of adult rheumatoid arthritis. Rheumatol Int 1996;16:49–52.
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Eye & Contact Lens Volume 41, Number 6, November 2015 13. Villani E, Galimberti D, Viola F, et al. Corneal involvement in rheumatoid arthritis: an in vivo confocal study. Invest Ophthalmol Vis Sci 2008;49:560–564. 14. Martinez-de-la-Casa JM, Garcia-Feijoo J, Fernandez-Vidal A, et al. Ocular response analyzer versus Goldmann applanation tonometry for intraocular pressure measurements. Invest Ophthalmol Vis Sci 2006;47:4410–4414. 15. Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005;31:156–162. 16. Nemet AY, Vinker S, Bahar I. The association of keratoconus with immune disorders. Cornea 2010;29:1261–1264. 17. Fernández-Barboza F, Verdiguel-Sotelo K, Hernández-López A. Pellucid marginal degeneration and corneal ulceration, associated with Sjögren syndrome [in Spanish]. Rev Med Inst Mex Seguro Soc 2009;47:77–82. 18. Shah S, Laiquzzaman M, Bhojwani R, et al. Assessment of the biomechanical properties of the cornea with the ocular response analyzer in normal and keratoconic eyes. Invest Ophthalmol Vis Sci 2007;48:3026–3031. 19. Johnson RD, Nguyen MT, Lee N, et al. Corneal biomechanical properties in normal, forme fruste keratoconus, and manifest keratoconus after statistical correction for potentially confounding factors. Cornea 2011;30:516–523. 20. Del Buey MA, Cristóbal JA, Ascaso FJ, et al. Biomechanical properties of the cornea in Fuchs’ corneal dystrophy. Invest Ophthalmol Vis Sci 2009;50: 3199–3202. 21. Hager A, Loge K, Füllhas M-O, et al. Changes in corneal hysteresis after clear corneal cataract surgery. Am J Ophthalmol 2007;144:341–346.
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