ORIGINAL PAPER

Decreased central corneal thickness in ankylosingspondylitis

Huseyin Ortak • Ahmet Inanır • Selim Demir •

Alper Uysal • Safak Sahin • Mustafa Sagcan •

Yalcın Onder • Sait Alim • Ayse Kevser Demir

Received: 23 May 2013 / Accepted: 3 July 2013

� Springer Science+Business Media Dordrecht 2013

Abstract Central corneal thickness and dry eye tests

were evaluated in a study population consisting of 68

ankylosing spondylitis patients diagnosed according

to the modified New York criteria, and 61 age-

matched controls without ankylosing spondylitis.

A full ophthalmological evaluation was performed

on each subject. All subjects were screened for age,

gender, HLA-B27, tear break-up time test, Schirmer

test, and duration of disease. Central corneal thickness

was measured under topical anesthesia with an ultra-

sonic pachymeter. The mean central corneal thickness

was 537.3 ± 30.6 lm, range 462–600 lm, in anky-

losing spondylitis patients, whereas it was 551.7 ±

25.2 lm, range 510–620 lm, in controls (p = 0.005).

The Schirmer test result was 7.3 ± 5.9 mm for the

ankylosing spondylitis patients and 11.7 ± 5.8 mm

for the control group (p = 0.002). Tear break-up time

was 7.3 ± 3.2 s for the ankylosing spondylitis patients

and 14.0 ± 4.5 s for the control group (p \ 0.001).

The possibility of a thinner cornea should be taken into

consideration in ankylosing spondylitis. In addition,

attention must be given to lower dry eye tests in

surgical interventions such as photorefractive keratec-

tomy and laser in situ keratomileusis in ankylosing

spondylitis patients.

Keywords Ankylosing spondylitis � Central corneal

thickness � Tear dysfunction

H. Ortak (&) � S. Demir � A. Uysal

Department of Ophthalmology, Gaziosmanpasa

University Faculty of Medicine, Tokat, Turkey

e-mail: huseyin.ortak@hotmail.com

A. InanırDepartment of Physical Medicine and Rehabilitation,

Gaziosmanpasa University Faculty of Medicine,

Tokat, Turkey

S. Sahin � M. Sagcan

Department of Internal Medicine, Gaziosmanpasa

University Faculty of Medicine, Tokat, Turkey

Y. Onder

Department of Public Health, Gaziosmanpasa University

Faculty of Medicine, Tokat, Turkey

S. Alim

Department of Ophthalmology, Tokat State Hospital,

Tokat, Turkey

A. K. Demir

Department of Internal Medicine, Turhal State Hospital,

Tokat, Turkey

123

Int Ophthalmol

DOI 10.1007/s10792-013-9827-2

Introduction

Ankylosing spondylitis (AS) is a chronic inflammatory

disease usually affecting young people and starts in the

second or third decade of life [1, 2]. The pathogenesis

of AS is unknown, but the most prevalent hypothesis is

an immune-mediated mechanism that affects the

secretion of tumor necrosis factor-a, interferon-c,

interleukin-10, and other factors such as genetic and

environmental factors [3]. AS is a disease that primar-

ily affects the sacroiliac joints and the spine. In

addition, AS affects extra-articular organs such the

eyes, skin, and cardiovascular system. The most

frequent extra-articular manifestation is anterior uve-

itis, which is associated with HLA-B27 positivity [1].

Central corneal thickness (CCT) measurement is

clinically important in ophthalmology, especially in

refractive surgery and glaucoma. Corneal pachymetry

is used to diagnose and monitor the progression of

glaucoma, as well as aid in the preoperative evaluation

of patients undergoing refractive surgery [4]. Although

ultrasound pachymetry (UP) can have a high intra- and

inter-individually variability, it is still the most com-

monly used method of measuring CCT due to its cost-

effectiveness, ease of use, and high repeatability [5, 6].

Moreover, CCT measurement by UP is similar to and

highly correlated with the Galilei dual-Scheimpflug

analyzer, which is considered highly reliable for

corneal thickness measurement [7, 8].

CCT is affected by conditions such as diabetes,

uveitis, high altitude, trachomatous dry eye, Sjogren

autoimmune syndrome, and rheumatoid arthritis. It

has been found that the CCT of diabetic patients is

thicker than that of non-diabetic patients. It is

suggested that corneal endothelial dysfunction and

increased corneal hydration may be responsible for

increased corneal thickness in diabetics [9]. Measure-

ments of CCT in uveitic eyes with Behcet disease

(BD) was significantly greater than in age- and sex-

matched healthy controls [10]. In addition, the corneal

thickness of the central and mid-peripheral cornea was

significantly decreased in dry eyes. Regarding changes

in CCT, it is suggested that the chronic state of

desiccation and immune activation in dry eye may

contribute to corneal thinning [11].

The corneal effects of AS, with its complex and

autoimmune nature, are little known. For this reason,

the aim of this study was to evaluate CCT in AS

patients and age-matched controls.

Materials and methods

Study population

A total of 129 subjects who presented to the ophthal-

mology clinic at Gaziosmanpasa University Hospital

were enrolled in the study. The study population

consisted of 68 AS patients diagnosed according to the

modified New York criteria [12] and 61 age-matched

controls without AS. Subjects with diabetes mellitus,

glaucoma, keratoconus, contact lens wear, corneal

dystrophy and keratitis, active and chronic uveitis,

systemic therapy with pharmaceutical drugs with

known corneal toxicity, patients receiving topical

therapy with antiglaucoma drugs and who had a

previous history of ophthalmic surgery were excluded

from this study. The control group comprised subjects

who came for routine examination without any

complaints. A full ophthalmological evaluation was

performed on each subject. All subjects were screened

for age, gender, HLA-B27, duration of disease, tear

break-up time (TBUT), Schirmer test under topical

anesthesia, and measurement of the CCT with an

ultrasonic pachymeter. The hospital ethics committee

approved the study, and written informed consent was

obtained from each patient after the nature and

purpose of the study was fully explained to them.

All experiments were performed in accordance with

the Declaration of Helsinki.

Corneal thickness measurements and dry eye

detection

The cornea was anesthetized with topical proparacaine

hydrochloride 0.5 % (Alcon-Couvreur; Puurs, Bel-

gium), and CCT measurements were taken with an

ultrasonic pachymeter and repeated three times (Op-

tikon 2000 SPA; Pacline, Roma, Italy). The subject sat

on the chair and was asked to fixate on a distant target,

while the ultrasound probe was aligned perpendicular

to the mid-pupillary axis of the cornea in the undilated

eye and placed gently in contact with the cornea. The

CCT was measured by a single ophthalmologist. One

eye from each subject was randomly used for the

statistical analyses.

The tear break-up test was carried out with a sterile

fluorescein strip that was placed in the lower eyelid

fornix. The patient was asked to blink twice and then

look straight ahead, without blinking. The time before

Int Ophthalmol

123

the first defect appeared in the stained tear film was

measured as the tear film TBUT. The mean of three

consecutive tear break-up tests was obtained.

The Schirmer test was carried out with anesthesia.

Three minutes after two proparacaine hydrochloride

0.5 % eye drops were instilled, the lid margin was

dried with cotton. The Schirmer test strip was placed

in the lower temporal fornix in the junction of the

middle and lateral one-third of the eyelid. The patient

was asked to keep both eyes immobile, and 5 min later

the strip was removed and the amount of wetting in

millimeters was recorded from the strips. The dry eye

tests were performed in the same time interval (from

10.00 to 14.00 h) at a temperature that ranged from 20

to 25 �C and relative humidity that ranged from 35 to

45 %.

Statistical analyses

After coding the data obtained during the investiga-

tion, the data were analyzed using SPSS 15.0.

Normality tests were applied to all measurement

variables. Normally distributed continuous variables

were defined by mean ± standard deviation, while

frequency data were defined as percentages (%). The

variables with a normal distribution were evaluated

using the t test, while non-normally distributed

variables were evaluated by the Kruskal–Wallis test.

A statistical significance level of p \ 0.05 was

accepted for all the tests.

Results

The study population consisted of 68 patients with AS

who presented to the ophthalmology clinic at Gazios-

manpasa University Hospital and 61 sex- and age-

matched controls. No statistically significant differ-

ences were found in terms of age and sex between the

study and control groups (p = 0.173 and 0.594,

respectively). The mean age was 40.9 ± 8.8 years

for the control group and 38.5 ± 10.3 years for the

patient group. The duration of disease was 5.42 years

(age range 1–25). Of the 68 AS patients, 38 patients

were HLA-B27(?) and 30 patients were HLA-B27

(-). Nonsteroidal anti-inflammatory drugs, sulfasala-

zine, etanercept, infliximab, and adalimumab have

been used for the treatment of AS. Co-morbidities

associated with AS included the following diseases:

Graves disease (eight patients), bronchial asthma (five

patients), diabetes (four patients), familial Mediterra-

nean fever (one patient), sarcoidosis (one patient), and

peptic ulcer (one patient). There were 32 men and 36

women in the patient group and 25 men and 36 women

in the control group. The descriptive features of all

patients are shown in Table 1.

The spherical refraction value was -0.75 ± 0.85

(range from 1.25 to -2.50 D) for the AS patients and

-0.52 ± 0.45 (range 0.50 to -2.00 D) for the control

group. The cylindrical refraction value was -0.45 ±

0.30 (range 1.25 to -1.50 D) for the AS patients and

-0.52 ± 0.34 (range 1.00 to -2.00 D) for the control

group. There were no statistically significant differ-

ences between the two groups for spherical and

cylindrical refraction (p [ 0.05). The mean CCT

was 537.3 ± 30.6 lm with a range between 462 and

600 lm in AS patients, but 551.7 ± 25.2 lm with a

range between 510 and 620 lm in controls

(p = 0.005). The Schirmer test result was 7.3 ±

5.9 mm for the AS patients and 11.7 ± 5.8 mm for

the control group (p = 0.002). Tear break-up time was

7.3 ± 3.2 s for the AS patients and 14.0 ± 4.5 s for

the control group (p \ 001); see Table 2.

No statistically significant differences were found

between duration of disease and CCT, TBUT and

Schirmer test in the AS group. Data are shown in

Table 3.

Discussion

Central corneal thickness is a crucial ophthalmic

parameter that should be measured in clinical practice

in cases of glaucoma, photorefractive keratectomy,

Table 1 Descriptive features of ankylosing spondylitis

patients and control group

Patients Control p*

(n = 68) (n = 61)

Gender (male) 32 (47.1 %) 25 (41.0 %) 0.594

Age (years) 38.5 ± 10.3 40.9 ± 8.8 0.173

HLA B27 (±) 38/30

Duration of disease

(years)

5.42 (1–25)

Data are shown as n (%) and mean ± standard deviation

* T test was used for statistical evaluation

Int Ophthalmol

123

and laser in situ keratomileusis (LASIK). The collagen

types, corneal hydration, and extracellular matrix may

vary in the different corneal diseases, and these factors

can change CCT [13]. In addition, CCT can be

associated with age, ethnic group, and diurnal varia-

tions [14]. In our study, we found significantly thinner

CCT measurements in AS patients’ eyes than control

eyes. In addition, the TBUT and Schirmer test results

were lower in AS patients’ eyes than control eyes. No

correlations were found between variables such as

CCT, TBUT, Schirmer test, and disease duration in the

AS group.

The pathogenesis of AS is not fully understood.

However, the most likely mechanisms of its formation

are an immune-mediated mechanism, inflammation,

and cytokines [3]. Interleukin-17 (IL-17), produced by

Th17 cells, plays critical roles in the pathogenesis of

autoimmune diseases. It has been shown that IL-17 is

increased in the inflammatory tissues of autoimmune

diseases and creates a synergy with some of the

cytokines for the inflammation. In addition, IL-17

activates nuclear factor jB and mitogen-activated

protein kinase (MAPK) pathways [15]. Mattey et al.

[16] also showed that higher disease activity of AS is

associated with increased serum levels of MMP-8,

MMP-9, and cytokines.

Tear dysfunction is one of the most common

ophthalmic problems, affecting many patients all over

the world. It is suggested that tear dysfunction

involves changes in tear composition rather than tear

volume [17]. The tear fluid functions as both a

lubricant and a conduit for regulatory molecules in

the cornea, and interactions between cornea and tear

fluid play an important role in the regulation of corneal

structure and functions. The development of molec-

ular biology has raised the notion that cell–cell and

cell–extracellular matrix interactions, as well as

cytokines, contribute to the corneal structure [18]. It

has been shown that several tear cytokines increase in

tear dysfunction and dry eye disease [19, 20]. Ocular

surface stress of dry eyes stimulates the release of

proinflammatory cytokines mediated by MAPK [21].

MMP-9 exists predominantly in an inactive form in

eyes with normal tear production [22]. Tear MMP-9

activity was significantly higher in patients with

dysfunctional tear syndrome. In addition, the activity

of tear MMP-9 was shown to have a significant

correlation with parameters such as TBUT, as well as

corneal and conjunctival fluorescein staining [23].

Proteinases have an important role in maintenance and

repair of corneal stromal extracellular matrix (ECM)

[24]. There is a balance between proteinases and

natural proteinase inhibitors in preocular tear film and

cornea. MMP-2 and MMP-9 are major functional

proteinases for the remodeling and degradation of the

corneal stromal collagen. When there is an imbalance

Table 2 Mean CCT, TBUT, and Schirmer test values in ankylosing spondylitis patients and control group

Patients Control p*

(n = 68) (n = 61)

Corneal thickness (lm) 537.3 ± 30.6 (462–600) 551.7 ± 25.2 (510–620) 0.005

Tear break-up time (s) 7.3 ± 3.2 (0–15) 14.0 ± 4.5 (3–20) \0.001

Schirmer test (mm/5 min) 7.3 ± 5.9 (1–24) 11.7 ± 5.8 (1–25) 0.002

Data are shown as mean ± standard deviation (range)

* T test was used for statistical evaluation

Table 3 Relationship between disease duration and CCT, TBUT, and Schirmer test values

Disease duration Corneal thickness (l) Tear break-up time (s) Schirmer (mm/5 min)

\5 years (n = 39) 543.6 ± 32.3 7.4 ± 3.0 4.6 ± 3.6

5–10 years (n = 16) 552.9 ± 39.6 6.5 ± 3.3 8.0 ± 7.2

[10 years (n = 13) 558.6 ± 26.4 7.2 ± 3.2 8.8 ± 3.4

p* 0.412 0.559 0.212

Data are shown as mean ± standard deviation

* Kruskal–Wallis test was used for statistical evaluation

Int Ophthalmol

123

between proteinases and proteinase inhibitors, there

may be a pathological degradation of stromal collagen

and proteoglycans in the cornea [25].

Keratoconus is characterized by corneal thinning

and ectasia due to increased degradation of the ECM

[26]. In this regard, Balasubramanian et al. [27]

reported that tears of people with keratoconus had

1.9-fold higher levels of proteolytic activity and

increased expression of several MMPs and cytokines

compared with tears from controls. Inflammatory

mediators produced by inflammatory/immune cells

were found to contribute to developing corneal

epithelial disease in dry eye. It has been shown that

exposure to desiccating stress recruits activated

CD4 ? T cells of the Th1 and Th17 lineages to the

ocular surface. IL-17 produced by Th17 cells stimu-

lated production of MMPs 3 and 9 by the corneal

epithelium [28]. Consequently, it is reasonable to

expect prominently thinner central corneas in AS

patients’ eyes.

Seronegative spondyloarthropathies co-morbid

with Sjogren syndrome are rare. However, photore-

fractive keratectomy and LASIK can induce dry eye

after surgery and then lead to abnormal results of dry

eye tests such as the Schirmer test and TBUT [29].

Alio et al. reported that 42 eyes (22 patients) known to

have a history of rheumatic diseases (rheumatoid

arthritis, systemic lupus erythematosus, dermatomyo-

sitis, scleroderma, AS, psoriatic arthritis, inflamma-

tory bowel disease, arthritis, or BD) underwent

LASIK. Postoperative follow-up showed development

of a moderate degree of dry eye syndrome in four eyes

(9.5 %) [30]. In addition, Cobo-Soriano et al. [31]

reported similar results in an even larger group of

patients. Therefore, the dry eye tests, as well as CCT,

must be measured before scheduling excimer LASIK

in AS patients.

In conclusion, CCT may have been decreased as a

result of increased inflammation, proteolytic activity,

and tear dysfunction in AS patients. The possibility of

a thinner cornea should be taken into consideration in

AS patients. In addition, attention must be paid to

lower dry eye tests when surgical intervention such as

photorefractive keratectomy and LASIK is proposed.

Acknowledgments No financial support was received for this

submission.

Conflict of interest None of the authors has conflict of interest

with the submission.

References

1. Gouveia EB, Elmann D, Morales MS (2012) Ankylosing

spondylitis and uveitis: overview. Rev Bras Reumatol

52:749–756

2. Ji SX, Yin XL, Yuan RD, Zheng Z, Huo Y, Zou H (2012)

Clinical features of ankylosing spondylitis associated with

acute anterior uveitis in Chinese patients. Int J Ophthalmol

5:164–166

3. Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A (2002)

Ankylosing spondylitis: an overview. Ann Rheum Dis

61:8–18

4. Tai LY, Khaw KW, Ng CM, Subrayan V (2012) Central

corneal thickness measurements with different imaging

devices and ultrasound pachymetry. Cornea 32:766–771

5. Gonzalez-Meijome JM, Cervino A, Yebra-Pimentel E,

Parafita MA (2003) Central and peripheral corneal thickness

measurement with Orbscan II and topographical ultrasound

pachymetry. J Cataract Refract Surg 29:125–132

6. Williams R, Fink BA, King-Smith PE, Mitchell GL (2011)

Central corneal thickness measurements: using an ultrasonic

instrument and 4 optical instruments. Cornea 30:1238–1243

7. Yeter V, Sonmez B, Beden U (2012) Comparison of central

corneal thickness measurements by Galilei Dual-Sche-

impflug analyzer� and ultrasound pachymeter in myopic

eyes. Ophthalmic Surg Lasers Imaging 43:128–134

8. Aramberri J, Araiz L, Garcia A, Illarramendi I, Olmos J,

Oyanarte I, Romay A, Vigara I (2012) Dual versus single

Scheimpflug camera for anterior segment analysis: preci-

sion and agreement. J Cataract Refract Surg 38:1934–1949

9. Ozdamar Y, Cankaya B, Ozalp S, Acaroglu G, Karakaya J,

Ozkan SS (2010) Is there a correlation between diabetes

mellitus and central corneal thickness? J Glaucoma 19:613–

616

10. Ozdamar Y, Berker N, Ertugrul G, Gurlevik U, Karakaya J,

Ozkan SS (2010) Is there a change of corneal thickness in

uveitis with Behcet disease? Cornea 29:1265–1267

11. Liu Z, Pflugfelder SC (1999) Corneal thickness is reduced in

dry eye. Cornea 18:403–407

12. Van der Linden S, Valkenburg HA, Cats A (1984) Evalu-

ation of diagnostic criteria for ankylosing spondylitis: a

proposal for the modification of the New York criteria.

Arthritis Rheum 27:361–368

13. Brandt JD (2004) Corneal thickness in glaucoma screening,

diagnosis, and management. Curr Opin Ophthalmol 15:85–

89

14. Doughty MJ, Zaman ML (2000) Human corneal thickness

and its impact on intraocular pressure measures: a review

and meta-analysis approach. Surv Ophthalmol 44:367–408

15. Zhu S, Qian Y (2012) IL-17/IL-17 receptor system in

autoimmune disease: mechanisms and therapeutic potential.

Clin Sci (Lond) 122:487–511

16. Mattey DL, Packham JC, Nixon NB, Coates L, Creamer P,

Hailwood S, Taylor GJ, Bhalla AK (2012) Association of

cytokine and matrix metalloproteinase profiles with disease

activity and function in ankylosing spondylitis. Arthritis Res

Ther 14:127. doi:10.1186/ar3857

17. Pflugfelder SC (2011) Tear dysfunction and the cornea:

LXVIII Edward Jackson Memorial lecture. Am J Ophthal-

mol 152:900–909

Int Ophthalmol

123

18. Nishida T (2008) The cornea: stasis and dynamics. Nihon

Ganka Gakkai Zasshi 112:179–212

19. Na KS, Mok JW, Kim JY, Rho CR, Joo CK (2012) Corre-

lations between tear cytokines, chemokines, and soluble

receptors and clinical severity of dry eye disease. Invest

Ophthalmol Vis Sci 53:5443–5450

20. Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME,

Pflugfelder SC (2009) Tear cytokine profiles in dysfunc-

tional tear syndrome. Am J Ophthalmol 147:198–205

21. Luo L, Li DQ, Doshi A, Farley W, Corrales RM, Pflugfelder

SC (2004) Experimental dry eye stimulates production of

inflammatory cytokines and MMP-9 and activates MAPK

signaling pathways on the ocular surface. Invest Ophthal-

mol Vis Sci 45:4293–4301

22. Ramaesh T, Ramaesh K, Riley SC, West JD, Dhillon B

(2012) Effects of N-acetylcysteine on matrix metallopro-

teinase-9 secretion and cell migration of human corneal

epithelial cells. Eye (Lond) 26:1138–1144

23. Chotikavanich S, de Paiva CS, de Li Q, Chen JJ, Bian F,

Farley WJ, Pflugfelder SC (2009) Production and activity of

matrix metalloproteinase-9 on the ocular surface increase in

dysfunctional tear syndrome. Invest Ophthalmol Vis Sci

50:3203–3209

24. Zitka O, Kukacka J, Krizkova S, Huska D, Adam V, Ma-

sarik M, Prusa R, Kizek R (2010) Matrix metalloprotein-

ases. Curr Med Chem 17:3751–3768

25. Ollivier FJ, Gilger BC, Barrie KP, Kallberg ME, Plummer

CE, O’Reilly S, Gelatt KN, Brooks DE (2007) Proteinases

of the cornea and preocular tear film. Vet Ophthalmol

10:199–206

26. Collier SA (2001) Is the corneal degradation in keratoconus

caused by matrix-metalloproteinases? Clin Experiment

Ophthalmol 29:340–344

27. Balasubramanian SA, Mohan S, Pye DC, Willcox MD

(2012) Proteases, proteolysis and inflammatory molecules

in the tears of people with keratoconus. Acta Ophthalmol

90:303–309

28. De Paiva CS, Chotikavanich S, Pangelinan SB, Pitcher JD

3rd, Fang B, Zheng X, Ma P, Farley WJ, Siemasko KF,

Niederkorn JY, Stern ME, Li DQ, Pflugfelder SC (2009) IL-

17 disrupts corneal barrier following desiccating stress.

Mucosal Immunol 2:243–253

29. Ang RT, Dartt DA, Tsubota K (2001) Dry eye after

refractive surgery. Curr Opin Ophthalmol 12:318–322

30. Alio JL, Artola A, Belda JI, Perez-Santonja JJ, Munoz G,

Javaloy J, Rodrıguez-Prats JL, Galal A (2005) LASIK in

patients with rheumatic diseases: a pilot study. Ophthal-

mology 112:1948–1954

31. Cobo-Soriano R, Beltran J, Baviera J (2006) LASIK out-

comes in patients with underlying systemic contraindica-

tions: a preliminary study. Ophthalmology 113:1118.e1–

1118.e8

Int Ophthalmol

123