Ocular Immunology and Inflammation

ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20

Effect of Systemically Used Anti-Tumor Necrosis Factor-α Medication on the Corneal Epithelium and Stroma of Patients with Ankylosing Spondylitis Sedat Arikan MD, Ferhat Gokmen MD, Ismail Ersan MD, Ayla Akbal MD, Hatice Resorlu MD, Baran Gencer MD, Hasan Ali Tufan MD & Selcuk Kara MD To cite this article: Sedat Arikan MD, Ferhat Gokmen MD, Ismail Ersan MD, Ayla Akbal MD, Hatice Resorlu MD, Baran Gencer MD, Hasan Ali Tufan MD & Selcuk Kara MD (2016): Effect of Systemically Used Anti-Tumor Necrosis Factor-α Medication on the Corneal Epithelium and Stroma of Patients with Ankylosing Spondylitis, Ocular Immunology and Inflammation, DOI: 10.3109/09273948.2015.1107592 To link to this article: http://dx.doi.org/10.3109/09273948.2015.1107592

Published online: 05 Jan 2016.

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Date: 29 February 2016, At: 21:41

Ocular Immunology & Inflammation, 2016; 00(00): 1–6 © Taylor & Francis Group, LLC ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2015.1107592

ORIGINAL ARTICLE

Effect of Systemically Used Anti-Tumor Necrosis Factor-α Medication on the Corneal Epithelium and Stroma of Patients with Ankylosing Spondylitis Sedat Arikan, Downloaded by [University of California, San Diego] at 21:41 29 February 2016

MD 1

, Ferhat Gokmen, MD2, Ismail Ersan, MD1, Ayla Akbal, MD2, Hatice Resorlu, , Baran Gencer, MD1, Hasan Ali Tufan, MD1, and Selcuk Kara, MD1

MD

1

2

Department of Ophthalmology, Canakkale Onsekiz Mart University School of Medicine, Canakkale, Turkey and 2Department of Physical Medicine and Rehabilitation, Canakkale Onsekiz Mart University School of Medicine, Canakkale, Turkey

ABSTRACT Purpose: To evaluate the effect of systemically used anti-tumor necrosis factor alpha (TNF-α) medication on the thickness of corneal epithelium and stroma in patients with ankylosing spondylitis (AS). Methods: A total of 125 eyes of 69 participants were included in this retrospective study of three groups: healthy participants (Group 1), AS patients receiving anti–TNF-α medication (Group 2), and AS patients receiving a nonsteroidal anti-inflammatory medication (Group 3). Results: According to anterior segment optical coherence tomography, the mean thickness of the corneal epithelium was significantly thicker in Group 2 than in Group 3 (51.6 ± 3.2 µm versus 50.4 ± 3 µm, p = 0.01), as was that of the stroma (475 ± 33 µm versus 443 ± 29 µm, p = 0.002). Conclusions: Anti–TNF-α medication and/or avoidance of nonsteroidal anti-inflammatory drugs could improve the thickness of both the corneal epithelium and stroma in AS patients. Keywords: Snkylosing spondylitis, AS-OCT, anti–TNF-α medication, NSAIDs, corneal epithelium, corneal stroma

benefits of anti-TNF-α medication in the treatment of recurrent uveitis in an AS patient that was unresponsive to both corticosteroids and immunosuppressive agents.4 Apart from involvement in the pathogenesis of uveitis, TNF-α has also been postulated to play a role in the development of ocular surface inflammation.5 Although corneal involvement in AS patients has not been reported to date, the demonstration of decreased central corneal thickness in AS patients in one study could indicate a possible association.6 That same study also suggested that corneal thinning in AS patients could stem from increased inflammation, proteolytic activity, and tear dysfunction.6 In another recent study, the densities and morphologies of corneal Langerhans cells (LCs), crucial members of the antigen-presenting cell population of the ocular surface,7 were found to be greater in patients with active AS.8

INTRODUCTION Ankylosing spondylitis (AS) is a HLA-B27–related chronic inflammatory disease that primarily involves the spine and sacroiliac joint, although it also affects the peripheral joints, entheses, and eyes to lesser extents. Found in approximately 30% of AS patients, uveitis is the most frequent extra-articular manifestation of the disease.1 Tumor necrosis factor alpha (TNF-α) appears to play an important role in the pathophysiologic mechanism of uveitis observed in AS patients. In fact, increased expression of this proinflammatory cytokine has been detected in either the aqueous humor or serum of patients with uveitis who are also positive for HLA-B27.2 Success using TNF-α antagonists to treat uveitis associated with AS also indicates the significant effect of TNF-α on the uveal tract of AS patients.3 Matsuda et al. even demonstrated the

Received 24 April 2015; revised 9 October 2015; accepted 9 October 2015; published online 6 January 2016 Correspondence: Sedat Arikan, MD, Department of Ophthalmology, Canakkale Onsekiz Mart University School of Medicine, Tip Fakultesi, Goz Hastalıkları AD, Canakkale, Turkey. E-mail: [email protected] Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ioii.

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S. Arikan et al.

Furthermore, an increased number of LCs in the cornea has been related to both poor corneal graft and increased ocular surface prognosis9 inflammation.10 Since TNF-α is reported to be a critical mediator of LC recruitment in the cornea,11 an increased number of LCs in AS patients could plausibly derive from increased expression of TNF-α in the cornea. An increased amount of proinflammatory cytokines, including TNF-α, has been shown to induce corneal epithelial cells to produce matrix metalloproteinases (MMPs), which are responsible for extracellular matrix degradation.12 Given these relationships, it can thus be hypothesized that treatment with antiTNF-α medication might benefit corneal epithelial and stromal thinning in AS patients by suppressing the secretion of MMPs. Currently, anterior segment optical coherence tomography (AS-OCT) is widely used as a reliable method of assessing the thickness of corneal stroma. Moreover, high-definition (HD) ASOCT enables examination of the thickness of the corneal epithelium and stroma separately.13 Taken together, evaluating the thickness of corneal layers in AS patients using HD-AS-OCT could yield important insights into corneal involvement in AS. In addition to this purpose, in this retrospective study we also aimed to assess how the use of anti–TNF-α medication affects the thickness of corneal layers in AS patients, primarily by reviewing the HD-AS-OCT findings for AS patients treated with either anti–TNF-α medication or non-steroidal anti-inflammatory drugs (NSAIDs).

PATIENTS AND METHODS Patients After the local ethics committee approved the study protocol in accordance with the Declaration of Helsinki for research involving human participants, this study was conducted at the Ophthalmology Department of Çanakkale Onsekiz Mart University in Çanakkale, Turkey. The medical records of AS patients who were referred for dry eye disease in the Physical Medicine and Rehabilitation Department to the Ophthalmology Department, and the medical records of healthy individuals who were previously examined in the Ophthalmology Department were retrospectively reviewed. Patients with slit-lamp biomicroscopic findings of anterior segment structures, indirect ophthalmoscopic findings regarding the retina, and available Schirmer I test values, tear breakup time (TBUT) values, and AS-OCT findings in their medical records were included in the study. Excluded from this study were any participants with active ocular inflammation (e.g., uveitis, scleritis, and episcleritis), corneal or conjunctival diseases (e.g., corneal scars), keratoconus, corneal dystrophy,

infectious or noninfectious keratitis (e.g., peripheral ulcerative keratitis, conjunctivitis, conjunctivochalasis, conjunctival dystrophies, pterygium, and pinguecula), and any systemic disease other than AS. Also excluded were all patients with any history of ocular surgery, glaucoma, ocular trauma, contact lens wear, treatment with retinoic acids, and chronic eye drop usage, including that administered as part of therapy for dry eye disease. The healthy participants who formed the control group were selected from patients who were never diagnosed with dry eye disease. All AS patients and healthy participants who had AS-OCT findings available were consecutively reviewed, and those who met all enrollment criteria were assigned to one of three groups: healthy controls and two AS groups. AS patients diagnosed according to modified New York criteria14 were divided into two groups: patients in one group received one of four anti-TNF-α medications (e.g., adalimumab, infliximab, golimumab, or etanercept) and those in the second group received one of three NSAIDs (e.g., 100 mg/d indomethacin, 150 mg/d diclofenac sodium, or 1,500 mg/d naproxen sodium). None of the AS patients in this study received treatment involving both anti–TNF-α medication and NSAIDs at the same time. To evaluate AS activity, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores of the two AS groups were examined. BASDAI is an index used for defining the activity and prognosis of AS, in which a value ≥4 represents active disease.15

Corneal Image Acquisition and Analysis Both eyes of each participant who met the inclusion criteria of this study were examined for measurement of the thickness of the corneal layers using the Anterior Segment 5 Line Raster scanning protocol of Cirrus HDOCT 4000 (Carl Zeiss Meditec Inc., Dublin, CA, USA). This scanning protocol produces five horizontal scan lines 3 mm long and separated by 250 µm, each consisting of 4,096 A scans. This device was used to obtain high-resolution images of the corneal epithelium and stroma in order to evaluate the ocular surface of patients with dry eye disease,16 since this spectraldomain OCT takes 27,000 axial scans per second with 5-µm axial resolution. By manually placement of the caliper tool, the device can also allow the proper measurement of the thickness of anterior and posterior ocular structures. After appropriate corneal images were selected, the thickness of the corneal epithelium and stroma was manually measured with the aid of the OCT caliper tool by two different ophthalmologists (SA and IE), who were both blinded to the measurements obtained from randomized corneal images. The thickness of the corneal epithelium was measured by placing the Ocular Immunology & Inflammation

Anti-TNF Alpha Medication and Corneal Layers caliper tool between the first and second lines of the corneal image, which represent the tear film layer and Bowman’s layer of the cornea, respectively. The second line is clearly visible below the corneal apex. In contrast, the thickness of corneal stroma was measured by placing the caliper tool between the second and third lines of the corneal image, which respectively represent the Bowman’s layer and Descemet’s membrane (Figure 1).

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Statistical Analysis Statistical analysis was performed using the Statistical Package for the Social Sciences version 15 (SPSS Inc., Chicago, IL, USA). To determine whether variables were normally distributed, the data were investigated using visual (i.e., histograms and probability plots) and analytical (i.e., the Kolmogorov–Smirnov and Shapiro–Wilk tests) methods. Descriptive analyses were presented using means and standard deviations for all variables. Since the thickness of the corneal epithelium and stroma were not normally distributed, Kruskal–Wallis tests were administered to compare these parameters among AS patients receiving anti– TNF-α medication, AS patients receiving an NSAID, and healthy participants. The Mann–Whitney U test was performed to test the significance of pairwise differences using Bonferroni correction to adjust for multiple comparisons. An overall 5% type-1 error level was used to infer statistical significance. Since BASDAI scores were not normally distributed, a Mann–Whitney U test was performed to test the significance between the two AS groups in terms of BASDAI scores.

FIGURE 1. OCT image (Cirrus HD- OCT; Carl Zeiss Meditec Inc.) of cornea. The 61-µm vertical distance between the corneal apex and second line represents the thickness of the corneal epithelium; the 506-µm vertical distance between the second and third line represents the thickness of the corneal stroma. © Taylor & Francis Group, LLC

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RESULTS A total 125 eyes of 69 participants were included in this retrospective study. The control group consisted of healthy participants (Group 1, n = 26), whereas AS patients were divided into two groups: Group 2, whose members received one of four anti–TNF-α medications (n = 22) and Group 3, whose members received one of three NSAIDs (n = 21). The number of evaluated eyes in Group 1, Group 2, and Group 3 was 50, 38, and 37, respectively. Eye measurements for two patients in Group 1, three in Group 2, and two in Group 3 who had pterygium in one eye and for three patients in Group 2 and three in Group 3 who had an unsatisfactory corneal image resolution were excluded from this study. In Group 2, 11 AS patients received treatment with adalimumab, five with infliximab, three with golimumab, and three with etanercept. The median duration of anti–TNF-α treatment in Group 2 was 14 months (range 11–25 months). Table 1 presents demographic data and ophthalmologic examination findings of all groups. No statistically significant difference was found between two AS groups in terms of ophthalmologic examination findings, including mean TBUT value, mean Schirmer test value, and mean spherical equivalent (SE) value. However, the mean BASDAI score was significantly lower in Group 2 than in Group 3 (2.7 ± 1.2 versus 5.8 ± 1.5, p