Anterior and Posterior Ocular Changes in Patients with Active and Inactive Ankylosing Spondylitis

Introduction

Ankylosing spondylitis (AS) is an immune-mediated rheumatic disease characterized by chronic inflammation mainly affecting the spine and vertebra [1]. The global prevalence of AS ranges between 0.1 and 1.4% [2]. Systemic autoimmune reactions can cause some articular and extra-articular manifestations effecting the eyes, gastrointestinal tract, and heart [3]. The most common ocular manifestations of AS are anterior uveitis and Sjögren’s syndrome [4,5]. Previous studies showed uveitis was mostly nongranulomatous and recurrent and was seen in 25–40% of AS patients [6,7]. Other studies have shown that anterior uveitis seen in AS is typically associated with HLA-B27-positivity, more commonly in long-term AS patients, and responds well to topical corticosteroids and noncorticosteroid anti-inflammation drugs [6,8]. Other less common ocular manifestations include superficial keratitis, scleritis, episcleritis, papillitis, retinal vasculitis, vitritis, epiretinal membranes, and cystoids macular edema [9,10]. Disease activity of AS patients was investigated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [11]. BASDAI is widely used in clinical practice and research because it is a useful test for evaluating key aspects of AS, monitoring disease activity, guiding treatment decisions, and predicting long-term outcomes. In AS patients, the main treatment aim is to relieve symptoms and to prevent poor posture and disease progression. For these purposes, treatment includes exercise, physiotherapy, and drugs such as analgesics, nonsteroidal anti-inflammatory drugs, corticosteroids, and disease-modifying anti-rheumatic drugs [12].

In previous studies, corneal thickness has been evaluated in patients with AS [13–15]. Oltulu et al and Ortak et al reported that that Schirmer test and TBUT values were lower, while OSDI scores were significantly higher in AS patients [16,17]. Kola et al reported that the mean choroidal thickness was higher in patients with AS [18]. However, alterations in corneal endothelium and in anterior segment or posterior segment parameters were not investigated in detail in patients with AS. In this study, we aimed to investigate the anterior and posterior segment parameters with Scheimpflug imaging, specular microscopy, optic biometry, and optic coherence tomography (OCT) in patients with AS and to compare those findings with healthy controls. We also aimed to investigate the association of ocular findings with disease severity and activity in AS patients.

Material and Methods

DESIGN AND STUDY POPULATION:

This study was approved by the Erzincan University Clinical Studies and Ethics Committee (Approval Date: 15/02/2018, Approval number: 33216249-604.01.02-E.9207). The written informed consent forms were signed by all participants. The study was conducted prospectively in Erzincan Mengücek Gazi Education and Research Hospital between March 2018 and May 2020. Seventy-eight AS patients diagnosed according to modified New York criteria [19] and 70 control subjects who came for routine examinations without any musculoskeletal system concerns were enrolled in this cross-sectional study. We excluded patients with active anterior uveitis or any history of uveitis, posterior synechia, cataract, or keratitis precipitates, which are the indirect signs of a previous uveitis attack. We also excluded patients with refractive errors more than ± 4.0 diopters (D), contact lens use, ocular surgery or trauma, glaucoma, anterior segment disease, active corneal infection, keratoconus, dry eye, or diabetes mellitus, as well as patients receiving systemic drugs with corneal toxicities or topical ophthalmic medications.

RHEUMATOLOGICAL EXAMINATIONS:

Seventy-eight patients included in the study were diagnosed with AS according to the modified New York criteria. Disease activity of these patients was investigated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [11], which is widely used in clinical practice and research because it is a useful test for evaluating key aspects of AS, monitoring disease activity, guiding treatment decisions, and predicting long-term outcomes. In assessment using BASDAI, patients were asked to evaluate their symptoms by answering 6 questions regarding fatigue, spinal pain, joint pain/swelling, areas of localized tenderness, duration of morning stiffness, and severity of morning stiffness. Each question is scored on 0 to 10, where 0 represents no problem, and 10 represents the worst possible problem. The final BASDAI score is the average of questions 1–4 plus the average of questions 5 and 6 (morning stiffness) divided by 2. In addition to the human leukocyte antigen (HLA)-B27 test, inflammatory markers such as erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were also recorded.

GENERAL OPHTHALMOLOGIC EXAMINATIONS:

All patients underwent a detailed ophthalmic examination. All measurements were performed from 10: 00 AM to 2: 00 PM to minimize the effects of diurnal variation of cornea. The right eye was examined in all patients. Assessment of intraocular pressure (IOP) was performed with a Goldmann applanation tonometer. Visual acuity testing was performed by using a Snellen chart. The results of the visual acuity test were converted to a logarithm of minimum angle of resolution (logMAR) units before statistical analysis. Fundus examination was performed by using a 90 D biomicroscopy lens.

SPECULAR MICROSCOPY EXAMINATIONS:

Endothelial cell density (cells/mm²) (ECD), percentage of hexagonal cells of corneal endothelial cells (HEX), coefficient of variation (CV), and average cell size (AVG) of endothelial cells were measured using noncontact specular microscopy (CEM-530 Specular Microscope, NIDEK, Japan).

SCHEIMPFLUG IMAGING EXAMINATIONS:

Corneal volume, Keratometry1 (K1), Keratometry2 (K2), Keratometry Mean (KM), Anterior Chamber Depth (ACD), Anterior Chamber Angle (ACA), Anterior Chamber Volume (ACV), were measured by Scheimpflug imaging (CSO Sirius Topographer, CSO, Firenze, Italy). Right eyes of all subjects were measured under miosis by the same ophthalmologist. Averages of 3 successive measurements were used for analysis.

OPTIC COHERENCE TOMOGRAPHY EXAMINATIONS:

Ganglion cell complex (GC) (superior and inferior) thickness, Macular volume, Subfoveal Choroidal thickness, Choroidal thickness at 1000 microns and 2000 microns nasal to the fovea (1000 N, 2000 N), at 1000 microns and 2000 microns temporal to the fovea (1000 T, 2000 T) were all recorded using enhanced deep imaging optic coherence tomography (RS-3000 Advance, Nidek Co, Gamori, Japan). Axial length was measured by optical biometry (Nidek AL-Scan, Nidek, Gamagori, Japan). Choroidal thickness was measured by the same experienced ophthalmologist.

OPTICAL BIOMETRY EXAMINATIONS:

Axial length (AL) was measured by optical biometry (Nidek AL-Scan, Nidek, Gamagori, Japan).

DRY EYE-RELATED PARAMETERS EXAMINATIONS:

Schirmer test, tear break-up time (TBUT), corneal fluorescein staining, and Ocular Surface Disease Index (OSDI) scores were also evaluated. The OSDI is a questionnaire consisting of 12 questions subdivided into 3 main sections: ocular symptoms of dry eye disease, ocular symptoms during vision-related function, and ocular symptoms induced by environmental triggers. The OSDI questionnaire is graded on a scale from 0 to 4, where 0 indicates none of the time; 1, some of the time; 2, half of the time; 3, most of the time; and 4, all of the time. The total score of OSDI is calculated by multiplying the sum of scores obtained from 12 questions by 25, divided by number of questions answered. The patients were subdivided into 3 groups according to their OSDI scores, as normal (OSDI: 0–12 points), mild (OSDI: 13–22 points), moderate (OSDI: 23–32 points), and severe (OSDI: 33–100 points).

The TUBT was evaluated by applying a fluorescein-impregnated strip soaked with sterile saline solution to the inferior conjunctival fornix. The patient was asked to blink several times and then not to blink during evaluation of tear film under a broad beam of cobalt-filtered light. The time from last blink to the first appearance of a dry spot in the tear film was recorded. The average of 3 consecutive measurement was recorded. For corneal fluorescein staining, sodium fluorescein was dropped into the conjunctival sac. After 3 minutes, the corneal fluorescein staining was assessed using the Van Bijsterveld scoring system [20], in which the intensity of staining is scored as 0, no staining; 1, less than one-third; 2, less than two-thirds; and 3, more than two-thirds staining of the cornea. The Schirmer test was performed with topical anesthesia. Three minutes after applying 1 drop of proparacaine 0.5%, a Schirmer test strip was placed behind the lower lid between the temporal and middle one-third of the eyelid. After 5 minutes, the strip was removed and the wet portion of the strip was measured in millimeters.

STATISTICAL ANALYSES:

The statistical analyses were performed using SPSS Statistics, version 21 (IBM Corp., Armonk, NY). Results are presented as mean±SD for continuous variables and as proportions (%) for categorical variables. The t test or the chi-square test was used for comparisons of laboratory data between the active AS group and the inactive AS group. Using one-way ANOVA, differences in specular microscopy findings, Scheimpflug imaging findings, dry eye-related parameters findings, and OCT findings were assessed among the active AS group, the inactive AS group, and the control group. Correlations between ECD, HEX, CV, AVG, CCT, Corneal Volume, BUT, Schirmer Test, Corneal Fluorescent Staining, OSDI Scores and Choroidal Thickness with disease duration, HLA-B27 positivity, CRP and ESR were calculated using Pearson correlation analysis. Statistical significance was set as P<0.05.

Results

RESULTS OF RHEUMATOLOGICAL EXAMINATIONS AND GENERAL OPHTHALMOLOGIC EXAMINATIONS:

The study included 78 ankylosing spondylitis patients and 70 control subjects. Right eyes were analyzed in all participants. According to their BASDAI scores, patients were subdivided into 2 groups – active AS (BASDAI≥4) and inactive AS (convalescent) (BASDAI<4). There was no statistically significant difference between groups regarding age, sex, visual acuity, or IOP.

Laboratory data and HLA B27 positivity of patients having active or inactive disease were compared. Although erythrocyte sedimentation rate and C-reactive protein were significantly higher in the active group; HLA B27 positivity and disease duration were similar between the 2 groups.

RESULTS OF SPECULAR MICROSCOPY EXAMINATIONS:

The findings of noncontact specular microscopy are summarized in Table 1, which shows ECD and HEX decreased, while CV and AVG increased significantly in AS patients compared with the control cases. However, there was no statistically significant difference between active and inactive AS patients regarding these parameters. A specular microscopy image of an AS patient is shown in Figure 1.

RESULTS OF SCHEIMPFLUG IMAGING EXAMINATIONS:

Anterior segment parameters were analyzed between groups (Table 2). Central corneal thickness and corneal volume were lower in AS patients compared with the control subjects, without any difference between active and inactive AS groups. There was no significant difference between groups regarding K1, K2, KMean, ACD, anterior chamber angle, or ACV. A Scheimpflug image of an AS patient is shown in Figure 2.

RESULTS OF OPTIC COHERENCE TOMOGRAPHY EXAMINATIONS:

There was no statistically significant difference between groups regarding superior and inferior ganglion cell complex thickness and macular volume. Choroidal thickness was significantly higher in all 5 points investigated (subfoveal, 1000 N, 2000 N, 1000 T, and 2000 T) in the 2 AS groups compared with the control group. Moreover, choroidal thickness was also significantly higher in the active disease group compared with the convalescent group. An image of choroidal thickness measurement of an AS patient is shown in Figure 3, and an image of ganglion cell complex thickness measurement of an AS patient is shown in Figure 4.

RESULTS OF OPTICAL BIOMETRY EXAMINATIONS:

There was no statistically significant difference between groups regarding AL values.

RESULTS OF DRY EYE-RELATED PARAMETERS EXAMINATIONS:

TBUT and Schirmer test results were lower and the findings of corneal fluorescein staining and OSDI scores were higher in AS patients compared with the control subjects, without any significant differences between the active and inactive AS groups (Table 3).

RESULTS OF CORRELATION ANALYSIS:

The results of correlation analysis are summarized in Table 4, showing a weak negative correlation between ECD and HEX with disease duration, while CV, AVG, and CCT showed a weak positive correlation with disease duration. CCT showed a weak positive correlation with CRP.

Discussion

In this cross-sectional study we evaluated measurements of Specular Microscopy, Scheimpflug Imaging, Optic Coherence Tomography, Optic Biometry, and Dry-Eye Related Parameters of AS patients and compared them with healthy subjects. We found statistically significant differences between study groups. Regarding all those results, we determined the following in patients without acute or previous anterior uveitis: 1) Ankylosing spondylitis did not affect visual acuity, IOP, or AL values in active or inactive disease periods in the absence of uveitis; 2) Central corneal thickness, corneal volume, ECD, and HEX were lower, while CV and AVG were significantly higher in AS patients in both the active and inactive disease periods (ie, AS patients had thinner corneas); 3) TBUT and Schirmer test results were lower and the findings of Corneal fluorescein staining and OSDI scores were higher in AS patients in both the active and inactive disease periods, resulting in tear dysfunction and dry eye disease; 4) Choroidal thickness was significantly higher in AS groups and were significantly higher in the active disease group compared with the inactive group; 5) There was a weak negative correlation between ECD and HEX with disease duration, while CV, AVG, and CCT showed a weak positive correlation with disease duration.

To the best of our knowledge, this is the first study evaluating all these parameters in AS patients, which is the main strength of this study. Because AS is a chronic disease, ocular alterations are highly important in patient follow-up.

In previous literature, diminished visual acuity and elevated intraocular pressure levels was clearly defined in AS patients with acute anterior uveitis [21]. However, in this study we excluded patients with acute or previous anterior uveitis and we did not find any significant difference between AS patients (active or inactive) and control cases regarding visual acuity or IOP values.

Central corneal thickness, corneal volume, ECD, and HEX were lower, while CV and AVG were significantly higher in AS patients in both active and inactive disease periods (ie, AS patients had thinner corneas). Cabuk et al [13] reported that, regarding corneal biomechanical features, there was not any significant difference between AS patients and the control group. They reported a negative correlation between central corneal thickness and BASDAI score, which may result in an underestimate of intraocular pressure readings and thus an inaccurate risk assessment of glaucoma. Caglayan et al [22] also evaluated the corneal biomechanical parameters in patients with AS and reported lower IOP, CCT, and corneal hysteresis values in AS patients compared with the healthy controls. However the mean IOP, CCT, and corneal hysteresis values were higher in active AS patients when compared to the inactive ones. We also found significantly lower CCT and ECD values in AS patients with thinner corneas. We did not find any significant differences between active or inactive disease groups regarding these parameters. Lin et al [14] demonstrated an increased T-cell response in corneas due to expression of the HLA-B27 allele, which may be important in the pathogenesis of thinner cornea development. However, we did not find any correlation between CCT or ECD and HLA-B27 positivity. We found a weak negative correlation between disease duration and CCT, ECD, and HEX, while CV and AVG had a weak positive correlation with disease duration. CCT also showed a weak negative correlation with CRP. However, there was no association of inflammatory markers (ESR or CRP) with ECD, HEX, CV, or AVG. Taken together, these results indicate that the duration of the disease is more important than the severity of inflammation in causing thinner corneas. Especially in cases of prolonged AS, this situation should be taken into consideration in terms of complications that may occur during ocular surgeries.

In this study, concomitant with the literature, TBUT and Schirmer test results were lower and the findings of corneal fluorescein staining and OSDI scores were higher in AS patients in both active and inactive disease periods, resulting in tear dysfunction and dry eye disease. We did not find any difference between active or inactive groups nor between dry eye disease parameters and disease duration or inflammatory markers. Our findings agree with the literature. Lee et al reported that AS is significantly correlated with subsequent external eye diseases, mainly dry eye disease and superficial keratopathy [23]. Oltulu et al [16] investigated the ocular surface changes in patients with AS in the inactive period and reported that Schirmer I test and TBUT values were lower, while OSDI scores were significantly higher in the AS group. Gunes et al [15] reported that the mean CCT and the mean corneal volume were significantly lower in AS patients compared to those in healthy controls. The values of TBUT and Schirmer test scores were significantly lower in AS patients, while corneal fluorescein staining and OSDI scores were higher. Ortak et al [17] reported significantly decreased mean CCT, Schirmer test results, and TBUT for ankylosing spondylitis patients compared with control subjects. Marsovszky et al [24] analyzed corneal Langerhans cells (LCs) and dry eye parameters in AS patients and reported that LC densities and central LC morphology were greater in AS patients and the latter was significantly greater in patients with higher disease activity parameters. They also reported that tear production was greatly suppressed in patients with more severe clinical disease. The authors concluded that increased disease activity was correlated with LC density and impaired tear production. In that aspect, corneal Langerhans cells seem to play important roles in development of dry eye disease in AS patients. However, we did not find any significant correlation between dry eye disease parameters and disease activation or duration.

In this study, choroidal thickness was significantly higher in the AS groups, and thickness was significantly greater in the active disease group compared with the inactive group. This finding is also compatible with the literature. Steiner et al reported that AS patients with active AS but without a history of eye inflammation had a thicker choroid than healthy subjects [25]. Kola et al [18] investigated the posterior segment findings in the eyes of patients with AS and reported that the mean choroidal thickness was greater in patients with AS without any significant alterations in peripapillary retinal nerve fiber layer thickness, macular volume, or ganglion cell complex compared with the healthy controls. They also did not find any correlation between choroidal thickness and disease AS activity index or duration. Basarir et al [26] reported greater choroidal thickness in AS patients with acute anterior uveitis; but the central macular thicknesses were not affected on either the active or convalescent periods. Tuzcu et al [27] studied 40 AS patients without any history of acute and/or previous uveitis and found no significant difference between AS patients and control subjects in RNFL thickness or ganglion cell-inner plexiform layers, but the temporal quadrant RNFL thickness and the mean thickness of the ganglion cell-inner plexiform layers were significantly thinner in the AS patients with BASDAI score ≥4. In our study, in the absence of anterior uveitis, choroidal thickness was thicker in AS patients.

Our study has some limitations. The sample size was small because of the many exclusion criteria. Because we did not include the patients with uveitis, we could not investigate its effects on these parameters. We did not sub-grouped our patients regarding their medications, so we could not investigate the effects of medications on these parameters. Arikan et al [28] reported that the mean corneal epithelium thickness was significantly thicker in patients receiving anti-TNF-α medication than in patients receiving a nonsteroidal anti-inflammatory medication. However, Ilhan et al [29] reported that TNF-α blockade does not seem to influence RNFL or macular thickness of patients with AS in the short term. We did not sub-grouped our patients regarding their medications, which is a limitation of this study. Another limitation is the absence of analyses of corneal biomechanical parameters including corneal hysteresis, corneal resistance factor, corneal compensated intraocular pressure, and Goldmann-correlated IOP (IOPg). Because we did not have a Reichert Ocular Response Analyzer, we could not investigate these parameters.

Conclusions

In patients with AS, in the absence of uveitis, visual acuity and IOP are not affected; their corneas are thinner, and they tend to have tear dysfunction and dry eye disease, which are mainly associated with disease duration. In this group of patients, the choroids are thicker, independent of disease duration. Also, this study revealed that corneal endothelial cell numbers, which is critical in corneal health, is negatively affected in AS patients. Ocular alterations in AS patients should be assessed to properly follow-up ocular diseases and to prevent complications during ocular surgeries associated with these alterations.