Effects of Anti-TNF and NSAID Therapy on Choroidal and Macular Thickness in Ankylosing Spondylitis: An OCT-Based Evaluation of Subclinical Inflammation

Effects of Anti-TNF and NSAID Therapy on Choroidal and Macular Thickness in Ankylosing Spondylitis: An OCT-Based Evaluation of Subclinical Inflammation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Anti-TNF and NSAID Therapy on Choroidal and Macular Thickness in Ankylosing Spondylitis: An OCT-Based Evaluation of Subclinical Inflammation Zarife Ekici Gök¹, Mehmet Şakir Altuner², Kayhan Mutlu³ This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8234375/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Jan, 2026 Read the published version in BMC Ophthalmology → Version 1 posted 12 You are reading this latest preprint version Abstract This study aimed to evaluate the effects of non-steroidal anti-inflammatory drugs (NSAIDs) and anti–tumor necrosis factor-α (anti-TNF-α) therapy on retinal and choroidal thickness in ankylosing spondylitis (AS) patients without uveitis and to compare these findings with healthy controls. A total of 65 AS patients and 30 age- and sex-matched healthy controls were included. Macular thickness, retinal nerve fiber layer (RNFL) thickness, and subfoveal choroidal thickness were measured using spectral-domain optical coherence tomography (SD-OCT). Patients receiving NSAIDs and/or sulfasalazine (Group 1, n = 30) were compared with patients receiving anti-TNF-α therapy (Group 2, n = 35) and with healthy controls (Group 3, n = 30). Mean subfoveal choroidal thickness was significantly greater in Group 1 compared with Group 2 and controls (p < 0.05). Nasal inner (p = 0.008) and nasal outer (p = 0.003) macular subfield thicknesses were significantly lower in both AS groups compared with controls, while RNFL thickness did not differ significantly among groups (p = 0.069). Covariance analysis showed that age and disease duration had no significant effect on these outcomes. These findings suggest that choroidal and macular thickness may be altered by subclinical inflammation in AS even in the absence of uveitis, and that anti-TNF-α therapy may provide superior suppression of inflammation compared with NSAIDs. OCT-based choroidal assessment may serve as a useful indicator for monitoring inflammatory activity and treatment response in AS. Ankylosing spondylitis Optical coherence tomography Choroid Macular thickness Anti-TNF therapy Figures Figure 1 Figure 2 Figure 3 Introduction Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that primarily affects the spine, peripheral joints, and entheses[ 1 ]. Uveitis represents the most frequent extra-articular manifestation, and the reported prevalence of anterior uveitis in AS ranges between 30% and 40% [ 2 ]. Although uveal involvement in spondyloarthropathies is predominantly characterized by anterior uveitis, the choroid—being a major vascular component of the uveal tract—may also be affected by systemic inflammation. Imaging this layer with spectral-domain optical coherence tomography (SD-OCT) provides a noninvasive, repeatable, and effective method for detecting choroidal alterations [ 3 ]. In clinical practice, OCT is widely used to evaluate posterior segment structures, including macular thickness, retinal volume, retinal nerve fiber layer (RNFL) thickness, and choroidal thickness [ 4 ]. Cytokines including TNF-α, IL-1, IL-6, IL-17, and IL-23 play key roles in the pathogenesis of AS. Among these, TNF-α is strongly associated with inflammatory, exudative, neovascular, and neurodegenerative ocular responses [ 5 ]. Anti-TNF agents have demonstrated significant success in controlling both systemic and ocular inflammation [ 6 – 8 ]. Current treatment strategies aim to relieve pain and suppress inflammation, and TNF-α inhibitors such as infliximab, etanercept, adalimumab, and golimumab are widely preferred in patients with inadequate response to NSAIDs or conventional agents like sulfasalazine [ 9 ]. The aim of this study was to evaluate posterior segment alterations in AS patients without uveitis and to compare the effects of different anti-inflammatory treatments, including NSAIDs, sulfasalazine, and anti-TNF-α therapy, with those of healthy controls. Materials and Methods This cross-sectional study included 95 participants: 65 ankylosing spondylitis (AS) patients and 30 healthy controls. AS patients were recruited from the rheumatology clinic during routine follow-up and referred for ophthalmologic evaluation. Group 1 consisted of 30 patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) and/or sulfasalazine, Group 2 included 35 patients receiving anti-TNF-α therapy, and Group 3 consisted of 30 age- and sex-matched healthy individuals. All AS diagnoses were made by a rheumatologist according to the modified New York criteria [ 10 ]. Only patients in clinical remission were included, defined as absence of active uveitis, no ocular symptoms, and an Ankylosing Spondylitis Disease Activity Score (ASDAS) < 2.1, corresponding to low disease activity. Systemic treatment had to be stable for at least three months prior to imaging. Written informed consent was obtained from all participants, and the study adhered to the Declaration of Helsinki. Approval was obtained from the XXX Clinical Research Ethics Committee (protocol number: 2022/55). A comprehensive ophthalmologic examination was performed by the same ophthalmologist, including best-corrected visual acuity assessment using Snellen charts, slit-lamp biomicroscopy, intraocular pressure measurement, and dilated fundus examination with a + 90D non-contact lens. Spectral-domain optical coherence tomography (SD-OCT) was used to measure macular thickness, peripapillary retinal nerve fiber layer (RNFL) thickness, and subfoveal choroidal thickness. All measurements were obtained between 09:00 and 12:00 to minimize diurnal variation. Subfoveal choroidal thickness was measured manually using enhanced depth imaging mode. To avoid inter-eye correlation, only the right eye was included in the analysis [ 11 ]. Inclusion criteria Age 18–50 years Best-corrected visual acuity ≥ 20/20 Spherical equivalent < ± 3.0 diopters Axial length < 25 mm No previous ocular surgery No ocular or neurological disease Clinical remission at imaging At least three months since last uveitis episode, if present Stable systemic treatment for ≥ 3 months Minimum six months of NSAID, sulfasalazine, or anti-TNF therapy Exclusion criteria Spherical equivalent ≥ ± 3.0 diopters Glaucoma, ocular hypertension, optic neuropathy Retinopathy or other retinal disease Ocular trauma or intraocular surgery Systemic corticosteroid use Other systemic inflammatory or vascular disease At the time of diagnosis, acute-phase reactant levels may differ among AS patients. 5 . Due to heterogeneity in acute-phase reactant values at diagnosis and the fact that all measurements were performed during remission, CRP and ESR were not included in comparative analyses Demographic data, disease duration, treatment type (NSAIDs/sulfasalazine or specific anti-TNF-α drugs such as etanercept, adalimumab, infliximab), and history of uveitis were recorded. All OCT findings were analyzed in relation to these variables. Macular, RNFL, and Subfoveal Choroidal Thickness Measurements All measurements were obtained using spectral-domain OCT (SD-OCT; RS-3000 Advance, NIDEK, Japan). For each participant, the scan with the highest signal strength (≥ 7) was selected for analysis. Peripapillary RNFL thickness was measured using a 6 × 6 mm² scan centered on the optic nerve head, and the global average RNFL value was used for statistical evaluation. Macular thickness measurements were obtained in nine areas defined by the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, using the software of the SD-OCT device. Subfoveal choroidal thickness was measured using enhanced depth imaging OCT (EDI-OCT). The central subfoveal choroidal thickness (CSCT) was defined as the vertical distance from the hyperreflective line of Bruch’s membrane to the hyperreflective line of the inner surface of the sclera. All images were obtained by the same experienced technician. Statistical Analysis For the analysis of the data obtained in this study, SPSS software (IBM SPSS Statistics, v23) and Jamovi software (The Jamovi Project, v2.4) were used. The distribution of variables was assessed with the Shapiro–Wilk test in order to determine the appropriate statistical tests for intergroup comparisons. Parametric tests were applied to variables that met the normality assumption, while non-parametric tests were applied to those that did not. The level of statistical significance was accepted as 0.05. For variables with normal distribution, ANOVA was used, whereas for those without normal distribution, the Kruskal–Wallis test was applied. Following ANOVA, post hoc group comparisons were performed with the Bonferroni test, while for the Kruskal–Wallis test, pairwise comparisons were conducted with the Bonferroni-corrected Mann–Whitney U test. Power Analysis An a priori power analysis using G*Power (effect size d = 0.6, α = 0.05) demonstrated that a minimum of 27 participants per group was required to achieve 80% power. The study exceeded this requirement for all groups. A p-value < 0.05 was considered statistically significant. Results There were no statistically significant differences among the groups in terms of age, sex distribution, smoking status, intraocular pressure, or spherical equivalent values (p>0.05 for all). The mean ages were 38.03 years in Group 1, 40.2 years in Group 2, and 31 years in Group 3. Demographic characteristics are summarized in Table 1. Only one patient in the anti-TNF-α group had a history of uveitis. In Group 1, 9 patients used sulfasalazine in combination with NSAIDs, whereas 21 used NSAIDs alone. In Group 2, the distribution of anti-TNF-α agents was as follows: certolizumab pegol (n=4), golimumab (n=9), adalimumab (n=20), etanercept (n=1), and infliximab (n=1). The mean subfoveal choroidal thickness values were 353.23 ± 38.14 μm in Group 1, 328.80 ± 53.23 μm in Group 2, and 322.63 ± 43.35 μm in Group 3. The overall difference among groups was significant (p=0.026), and pairwise comparisons showed that Group 1 had significantly greater choroidal thickness than both Group 2 and Group 3. RNFL thickness did not differ significantly among the groups (p=0.069), with mean values of 108.23 ± 12.13 μm in Group 1, 111.40 ± 10.11 μm in Group 2, and 114.77 ± 10.14 μm in Group 3. Regarding macular thickness, significant intergroup differences were observed in the nasal inner (p=0.008) and nasal outer (p=0.003) ETDRS subfields. In both AS groups, these regions were significantly thinner compared with controls. Table 2 presents macular, RNFL, and choroidal measurements, while Tables 3–5 display intergroup comparisons. Rank ANCOVA was performed to assess whether the significant variables were independent of potential confounders such as age and disease duration. Choroidal thickness and nasal outer macular thickness remained significantly different among the groups after adjustment, and age and disease duration showed no significant effects (p>0.05 for all). These results indicate that, independent of age and disease duration, the type of anti-inflammatory treatment appears to have a meaningful effect on subfoveal choroidal thickness and nasal macular thickness in AS patients. Discussion The uveal tissue, as the vascular layer of the eye, is susceptible to systemic inflammation in ankylosing spondylitis (AS), most commonly presenting clinically as acute anterior uveitis [ 12 ]. Although anterior uveitis represents the hallmark ocular manifestation of AS, several studies have demonstrated that posterior segment structures may also be affected, even when anterior segment findings are normal. In some cases, macular edema or subtle posterior changes have been detected by OCT despite a quiet anterior chamber, suggesting the presence of subclinical inflammation extending beyond the anterior uveal tract [ 13 , 14 ]. The choroid, which contains fenestrated vessels, stromal melanocytes, fibroblasts, and a dense resident network of macrophages and dendritic cells, plays a fundamental role in maintaining ocular immune homeostasis. These immune cells regulate inflammatory responses and contribute to the control of retinal and choroidal inflammation [ 15 ]. Additionally, the choroidal vasculature is capable of autoregulating blood flow in response to systemic blood pressure, intraocular pressure, and autonomic input, making it particularly sensitive to systemic inflammatory conditions [ 16 ]. Consistent with this, previous studies have shown that the choroid may be altered in a wide spectrum of ocular and systemic diseases, and that inflammatory stimuli—such as acute anterior uveitis—can cause measurable increases in both choroidal and macular thickness [ 17 – 19 ]. In AS patients without uveitis, increased subfoveal choroidal thickness compared with healthy individuals has been previously demonstrated [ 20 ]. In our study, choroidal thickness was significantly higher in patients treated with NSAIDs and sulfasalazine compared with those receiving anti-TNF-α therapy, supporting the hypothesis that inflammation contributes to choroidal thickening in AS. If increased choroidal thickness is considered an indicator of subclinical inflammation, our findings suggest that anti-TNF-α agents suppress this inflammation more effectively than NSAIDs, resulting in reduced choroidal thickness. This study also showed that AS patients receiving anti-TNF therapy had significantly lower subfoveal choroidal thickness (SFCT) compared with both NSAID users and healthy controls, suggesting a greater degree of suppression of posterior segment inflammation. Although none of the patients exhibited active uveitis at the time of imaging, these structural differences support the concept that the choroid is a sensitive biomarker of systemic inflammatory burden, even during clinical remission. In another study comparing uveitic eyes, fellow non-uveitic eyes, and healthy controls during both active and remission phases, subfoveal choroidal thickness was significantly greater in the active phase but showed no difference during remission [ 21 ]. A separate prospective study investigating the effects of nine months of anti-TNF-α therapy on RNFL, central macular thickness (CMT), and macular layers in AS patients reported no significant structural changes [ 22 ]. Similarly, Tuzcu et al. found no significant differences in central macular thickness or RNFL thickness in AS patients without uveitis. Their study reported a negative correlation between disease duration and temporal RNFL thickness, along with thinning of the ganglion cell layer, particularly in patients with a BASDAI score of 4 [ 23 ]. Another study on AS patients with acute anterior uveitis but no posterior involvement demonstrated retinal thinning, suggesting subclinical posterior segment involvement possibly related to previous mild or undetected inflammatory episodes [ 24 ]. Further supporting our findings, a recent study demonstrated a decreased incidence of diabetic retinopathy in patients receiving anti-TNF therapy [ 25 ]. This observation aligns with the role of TNF-α in retinal and choroidal inflammation and reinforces the biological plausibility of our finding that anti-TNF treatment is associated with decreased choroidal thickness. The protective effect seen in diabetic patients supports the concept that TNF inhibition may modulate microvascular inflammation. In our study, statistically significant thinning of the nasal macular subfields was observed in AS patients compared with controls. Given that the BASDAI score in our cohort averaged 2 and only one patient had a history of uveitis, no apparent clinical factor could account for this finding. Retinal thinning in the nasal macular quadrant may reflect subclinical inflammatory changes in posterior tissues. The higher choroidal thickness in NSAID users further suggests that anti-TNF-α therapy provides superior suppression of inflammatory activity. The nasal macula is anatomically adjacent to the optic nerve head and contains a higher density of retinal nerve fiber layers, rendering it potentially more vulnerable to microvascular or inflammatory alterations [ 26 , 27 ]. Studies evaluating choroidal and retinal perfusion have also demonstrated distinct autoregulatory properties in the nasal macula, suggesting that this region may respond differently to systemic inflammatory or autonomic influences [ 28 ]. The selective thinning observed in nasal ETDRS subfields in our study may therefore represent region-specific susceptibility of the posterior segment in AS patients, even during remission. Covariance analysis confirmed that age and disease duration did not significantly influence choroidal or nasal macular thickness, indicating that differences between treatment groups reflected the effects of the treatments themselves rather than demographic or disease-related factors. Several additional studies have investigated the effects of anti-TNF therapy on retinal layers. One reported no significant differences in ganglion cell or retinal layer thickness before and after treatment [ 22 ]. Another study comparing NSAID, sulfasalazine, and anti-TNF-α therapy groups found no significant differences in RNFL thickness [ 29 ]. Consistent with these findings, our study also did not demonstrate significant RNFL differences among treatment groups. This study has several limitations. The relatively small sample size restricted our ability to perform subgroup analysis of individual anti-TNF agents. Although agents such as adalimumab, certolizumab, and golimumab differ in molecular structure and pharmacological properties, all function via TNF-α blockade. Therefore, the trend toward reduced choroidal thickness likely reflects a class effect rather than drug-specific differences. Additionally, the cross-sectional study design prevented evaluation of longitudinal structural changes. Future studies with larger sample sizes and prospective follow-up are needed to explore the temporal effects of various biologic agents on choroidal and retinal structures and to further clarify the mechanisms underlying posterior segment involvement in AS. Conclusion In conclusion, this study suggests that choroidal and retinal thickness may be influenced by the inflammatory process of AS even in the absence of uveitis, and that the effects of anti-inflammatory treatments differ. OCT-based assessment of the choroid may serve as a useful marker for evaluating treatment response and detecting subtle inflammatory activity. These findings support the potential role of OCT in the routine follow-up of AS patients and in identifying those at risk of inflammation-related ocular involvement. Larger prospective studies are needed to validate these results Abbreviations AS Ankylosing spondylitis OCT Optical coherence tomography CMT Central macular thickness RNFL Retinal nerve fiber layer SFCT Subfoveal choroidal thickness NSAID Non-steroidal anti-inflammatory drug TNF-α Tumor necrosis factor-alpha. Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Malatya Turgut Özal University, Faculty of Medicine (Approval No: 2022/122). All procedures were conducted in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to inclusion in the study. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contribution ZEG and MŞA conceived and designed the study. ZEG collected and analyzed the data. KM contributed to data interpretation and manuscript revision. All authors read and approved the final version of the manuscript. Acknowledgements The authors would like to thank the staff of the Ophthalmology Department, Malatya Turgut Özal University, for their technical assistance and support. Data Availability The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. References Gran JT, Skomsvoll JF. The outcome of ankylosing spondylitis: a study of 100 patients. Br J Rheumatol. 1997;36(7):766–71. Zagora SL, McCluskey P. Ocular manifestations of seronegative spondyloarthropathies. Curr Opin Ophthalmol. 2014;25(6):495–501. Kal A, Duman E, Sezenöz AS, Ulusoy MO, Kal Ö. Evaluation of retrobulbar blood flow and choroidal thickness in patients with rheumatoid arthritis. Int Ophthalmol. 2017;37(6):1311–18. Chakraborty R, Read SA, Collins MJ. 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Ocul Immunol Inflamm. 2014;22(6):434–8. Basarir B, Celik U, Altan C, Celik NB. Choroidal thickness changes determined by EDI-OCT on acute anterior uveitis in HLA-B27-positive ankylosing spondylitis. Int Ophthalmol. 2018;38(1):307–12. Ilhan N, Ustun N, Tuzcu EA, Coskun M, Yagiz AE, Ilhan O, et al. Spectral-domain optical coherence tomographic findings in patients with ankylosing spondylitis under anti-TNF-α therapy. Cutan Ocul Toxicol. 2015;34(3):222–6. Tuzcu E, Ustun N, Ilhan N, Coskun M, Yagiz AE, Ilhan O, et al. Peripapillary RNFL and GCL-IPL thickness in ankylosing spondylitis. Ocul Immunol Inflamm. 2014;22(6):429–33. Buttanrı İB, Kurtuluş D, Serin D. Eye involvement in patients with ankylosing spondylitis. Glo-Kat. 2014;9(4):267–9. Uçar Baytaroğlu İM, Baytaroğlu A, Uçar Toros M, Daldal H. Incidence of diabetic retinopathy in anti-TNF treated rheumatic disease patients with type 2 diabetes. Graefes Arch Clin Exp Ophthalmol. 2024;262(11):3559–65. 10.1007/s00417-024-06529-3 . Hood DC, Raza AS. On improving the use of OCT imaging for detecting glaucomatous damage. Br J Ophthalmol. 2014;98(Suppl 2):ii1–9. Curcio CA, Allen KA. Topography of ganglion cells in human retina. J Comp Neurol. 1990;300(1):5–25. Park HY, Park SH, Park CK. Choroidal microvasculature dropout is associated with parafoveal thinning in glaucoma. Ophthalmology. 2017;124(9):1386–94. Kal A, Ulusoy MO, Ozturk C. Spectral domain OCT findings in ankylosing spondylitis. Int Ophthalmol. 2020;40(10):2727–34. Tables Table 1 to 5 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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00:44:41","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":106613,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8234375/v1/039e79c84c85900285d2e008.html"},{"id":98423229,"identity":"79abca00-8906-4f06-8148-134b5ad7cdc7","added_by":"auto","created_at":"2025-12-17 16:31:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":53050,"visible":true,"origin":"","legend":"\u003cp\u003eBox plot showing the comparison of subfoveal choroidal thickness in the eyes among the three study groups (Control, Group 1: NSAIDs, Group 2: Anti-TNF-α). The central line represents the median; the box, the interquartile range; and the whiskers, the minimum and maximum values.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8234375/v1/f7e3cae5c1bbfda88742ee00.png"},{"id":97932409,"identity":"ba6db00c-5a9a-44c8-aa4b-b242c98c5140","added_by":"auto","created_at":"2025-12-11 00:44:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":58189,"visible":true,"origin":"","legend":"\u003cp\u003eBox plot showing the comparison of subfoveal choroidal thickness in the eyes among the three study groups (Control, Group 1: NSAIDs, Group 2: Anti-TNF-α). The central line represents the median; the box, the interquartile range; and the whiskers, the minimum and maximum values.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8234375/v1/e7ddb58ef009f088fbf12271.png"},{"id":97932410,"identity":"920fa15b-24b0-4ac1-bfa4-8d81cc2acd49","added_by":"auto","created_at":"2025-12-11 00:44:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":56160,"visible":true,"origin":"","legend":"\u003cp\u003eBox plot showing the comparison of nasal outer macular thickness in the eyes among the three study groups (Control, Group 1: NSAIDs, Group 2: Anti-TNF-α). The central line represents the median; the box, the interquartile range; and the whiskers, the minimum and maximum values. Outliers are displayed as separate points.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8234375/v1/c526bab8a06e2faf2c4af5e7.png"},{"id":100617888,"identity":"2db8d078-30ef-4c61-a32e-9b6fa43ce21e","added_by":"auto","created_at":"2026-01-19 17:57:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":642923,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8234375/v1/7c84a10d-4832-45ec-9204-1f183d57ff60.pdf"},{"id":98421553,"identity":"1be7965a-5371-4faf-9022-c286e3569516","added_by":"auto","created_at":"2025-12-17 16:28:25","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":35333,"visible":true,"origin":"","legend":"","description":"","filename":"TablesAS.docx","url":"https://assets-eu.researchsquare.com/files/rs-8234375/v1/06776170c11c81d6435c5664.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of Anti-TNF and NSAID Therapy on Choroidal and Macular Thickness in Ankylosing Spondylitis: An OCT-Based Evaluation of Subclinical Inflammation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnkylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that primarily affects the spine, peripheral joints, and entheses[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Uveitis represents the most frequent extra-articular manifestation, and the reported prevalence of anterior uveitis in AS ranges between 30% and 40% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although uveal involvement in spondyloarthropathies is predominantly characterized by anterior uveitis, the choroid\u0026mdash;being a major vascular component of the uveal tract\u0026mdash;may also be affected by systemic inflammation. Imaging this layer with spectral-domain optical coherence tomography (SD-OCT) provides a noninvasive, repeatable, and effective method for detecting choroidal alterations [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In clinical practice, OCT is widely used to evaluate posterior segment structures, including macular thickness, retinal volume, retinal nerve fiber layer (RNFL) thickness, and choroidal thickness [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCytokines including TNF-α, IL-1, IL-6, IL-17, and IL-23 play key roles in the pathogenesis of AS. Among these, TNF-α is strongly associated with inflammatory, exudative, neovascular, and neurodegenerative ocular responses [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Anti-TNF agents have demonstrated significant success in controlling both systemic and ocular inflammation [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Current treatment strategies aim to relieve pain and suppress inflammation, and TNF-α inhibitors such as infliximab, etanercept, adalimumab, and golimumab are widely preferred in patients with inadequate response to NSAIDs or conventional agents like sulfasalazine [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe aim of this study was to evaluate posterior segment alterations in AS patients without uveitis and to compare the effects of different anti-inflammatory treatments, including NSAIDs, sulfasalazine, and anti-TNF-α therapy, with those of healthy controls.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis cross-sectional study included 95 participants: 65 ankylosing spondylitis (AS) patients and 30 healthy controls. AS patients were recruited from the rheumatology clinic during routine follow-up and referred for ophthalmologic evaluation. Group 1 consisted of 30 patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) and/or sulfasalazine, Group 2 included 35 patients receiving anti-TNF-α therapy, and Group 3 consisted of 30 age- and sex-matched healthy individuals.\u003c/p\u003e\u003cp\u003eAll AS diagnoses were made by a rheumatologist according to the modified New York criteria [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Only patients in clinical remission were included, defined as absence of active uveitis, no ocular symptoms, and an Ankylosing Spondylitis Disease Activity Score (ASDAS)\u0026thinsp;\u0026lt;\u0026thinsp;2.1, corresponding to low disease activity. Systemic treatment had to be stable for at least three months prior to imaging.\u003c/p\u003e\u003cp\u003e Written informed consent was obtained from all participants, and the study adhered to the Declaration of Helsinki. Approval was obtained from the XXX Clinical Research Ethics Committee (protocol number: 2022/55).\u003c/p\u003e\u003cp\u003eA comprehensive ophthalmologic examination was performed by the same ophthalmologist, including best-corrected visual acuity assessment using Snellen charts, slit-lamp biomicroscopy, intraocular pressure measurement, and dilated fundus examination with a\u0026thinsp;+\u0026thinsp;90D non-contact lens. Spectral-domain optical coherence tomography (SD-OCT) was used to measure macular thickness, peripapillary retinal nerve fiber layer (RNFL) thickness, and subfoveal choroidal thickness. All measurements were obtained between 09:00 and 12:00 to minimize diurnal variation. Subfoveal choroidal thickness was measured manually using enhanced depth imaging mode. To avoid inter-eye correlation, only the right eye was included in the analysis [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eInclusion criteria\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eAge 18\u0026ndash;50 years\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eBest-corrected visual acuity\u0026thinsp;\u0026ge;\u0026thinsp;20/20\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSpherical equivalent\u0026thinsp;\u0026lt;\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0 diopters\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAxial length\u0026thinsp;\u0026lt;\u0026thinsp;25 mm\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eNo previous ocular surgery\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eNo ocular or neurological disease\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eClinical remission at imaging\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAt least three months since last uveitis episode, if present\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStable systemic treatment for \u0026ge;\u0026thinsp;3 months\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMinimum six months of NSAID, sulfasalazine, or anti-TNF therapy\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eExclusion criteria\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eSpherical equivalent\u0026thinsp;\u0026ge;\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0 diopters\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eGlaucoma, ocular hypertension, optic neuropathy\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eRetinopathy or other retinal disease\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eOcular trauma or intraocular surgery\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSystemic corticosteroid use\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eOther systemic inflammatory or vascular disease\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eAt the time of diagnosis, acute-phase reactant levels may differ among AS patients.\u003csup\u003e5\u003c/sup\u003e. Due to heterogeneity in acute-phase reactant values at diagnosis and the fact that all measurements were performed during remission, CRP and ESR were not included in comparative analyses\u003c/p\u003e\u003cp\u003eDemographic data, disease duration, treatment type (NSAIDs/sulfasalazine or specific anti-TNF-α drugs such as etanercept, adalimumab, infliximab), and history of uveitis were recorded. All OCT findings were analyzed in relation to these variables.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eMacular, RNFL, and Subfoveal Choroidal Thickness Measurements\u003c/h2\u003e\u003cp\u003eAll measurements were obtained using spectral-domain OCT (SD-OCT; RS-3000 Advance, NIDEK, Japan). For each participant, the scan with the highest signal strength (\u0026ge;\u0026thinsp;7) was selected for analysis. Peripapillary RNFL thickness was measured using a 6 \u0026times; 6 mm\u0026sup2; scan centered on the optic nerve head, and the global average RNFL value was used for statistical evaluation.\u003c/p\u003e\u003cp\u003eMacular thickness measurements were obtained in nine areas defined by the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, using the software of the SD-OCT device. Subfoveal choroidal thickness was measured using enhanced depth imaging OCT (EDI-OCT). The central subfoveal choroidal thickness (CSCT) was defined as the vertical distance from the hyperreflective line of Bruch\u0026rsquo;s membrane to the hyperreflective line of the inner surface of the sclera. All images were obtained by the same experienced technician.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eFor the analysis of the data obtained in this study, SPSS software (IBM SPSS Statistics, v23) and Jamovi software (The Jamovi Project, v2.4) were used. The distribution of variables was assessed with the Shapiro\u0026ndash;Wilk test in order to determine the appropriate statistical tests for intergroup comparisons. Parametric tests were applied to variables that met the normality assumption, while non-parametric tests were applied to those that did not. The level of statistical significance was accepted as 0.05.\u003c/p\u003e\u003cp\u003eFor variables with normal distribution, ANOVA was used, whereas for those without normal distribution, the Kruskal\u0026ndash;Wallis test was applied. Following ANOVA, post hoc group comparisons were performed with the Bonferroni test, while for the Kruskal\u0026ndash;Wallis test, pairwise comparisons were conducted with the Bonferroni-corrected Mann\u0026ndash;Whitney U test.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePower Analysis\u003c/h3\u003e\n\u003cp\u003eAn a priori power analysis using G*Power (effect size d\u0026thinsp;=\u0026thinsp;0.6, α\u0026thinsp;=\u0026thinsp;0.05) demonstrated that a minimum of 27 participants per group was required to achieve 80% power. The study exceeded this requirement for all groups.\u003c/p\u003e\u003cp\u003eA p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThere were no statistically significant differences among the groups in terms of age, sex distribution, smoking status, intraocular pressure, or spherical equivalent values (p\u0026gt;0.05 for all). The mean ages were 38.03 years in Group 1, 40.2 years in Group 2, and 31 years in Group 3. Demographic characteristics are summarized in Table 1.\u003c/p\u003e\n\u003cp\u003eOnly one patient in the anti-TNF-\u0026alpha; group had a history of uveitis. In Group 1, 9 patients used sulfasalazine in combination with NSAIDs, whereas 21 used NSAIDs alone. In Group 2, the distribution of anti-TNF-\u0026alpha; agents was as follows: certolizumab pegol (n=4), golimumab (n=9), adalimumab (n=20), etanercept (n=1), and infliximab (n=1).\u003c/p\u003e\n\u003cp\u003eThe mean subfoveal choroidal thickness values were 353.23 \u0026plusmn; 38.14 \u0026mu;m in Group 1, 328.80 \u0026plusmn; 53.23 \u0026mu;m in Group 2, and 322.63 \u0026plusmn; 43.35 \u0026mu;m in Group 3. The overall difference among groups was significant (p=0.026), and pairwise comparisons showed that Group 1 had significantly greater choroidal thickness than both Group 2 and Group 3.\u003c/p\u003e\n\u003cp\u003eRNFL thickness did not differ significantly among the groups (p=0.069), with mean values of 108.23 \u0026plusmn; 12.13 \u0026mu;m in Group 1, 111.40 \u0026plusmn; 10.11 \u0026mu;m in Group 2, and 114.77 \u0026plusmn; 10.14 \u0026mu;m in Group 3.\u003c/p\u003e\n\u003cp\u003eRegarding macular thickness, significant intergroup differences were observed in the nasal inner (p=0.008) and nasal outer (p=0.003) ETDRS subfields. In both AS groups, these regions were significantly thinner compared with controls. Table 2 presents macular, RNFL, and choroidal measurements, while Tables 3\u0026ndash;5 display intergroup comparisons.\u003c/p\u003e\n\u003cp\u003eRank ANCOVA was performed to assess whether the significant variables were independent of potential confounders such as age and disease duration. Choroidal thickness and nasal outer macular thickness remained significantly different among the groups after adjustment, and age and disease duration showed no significant effects (p\u0026gt;0.05 for all).\u003c/p\u003e\n\u003cp\u003eThese results indicate that, independent of age and disease duration, the type of anti-inflammatory treatment appears to have a meaningful effect on subfoveal choroidal thickness and nasal macular thickness in AS patients.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe uveal tissue, as the vascular layer of the eye, is susceptible to systemic inflammation in ankylosing spondylitis (AS), most commonly presenting clinically as acute anterior uveitis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although anterior uveitis represents the hallmark ocular manifestation of AS, several studies have demonstrated that posterior segment structures may also be affected, even when anterior segment findings are normal. In some cases, macular edema or subtle posterior changes have been detected by OCT despite a quiet anterior chamber, suggesting the presence of subclinical inflammation extending beyond the anterior uveal tract [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe choroid, which contains fenestrated vessels, stromal melanocytes, fibroblasts, and a dense resident network of macrophages and dendritic cells, plays a fundamental role in maintaining ocular immune homeostasis. These immune cells regulate inflammatory responses and contribute to the control of retinal and choroidal inflammation [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Additionally, the choroidal vasculature is capable of autoregulating blood flow in response to systemic blood pressure, intraocular pressure, and autonomic input, making it particularly sensitive to systemic inflammatory conditions [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Consistent with this, previous studies have shown that the choroid may be altered in a wide spectrum of ocular and systemic diseases, and that inflammatory stimuli\u0026mdash;such as acute anterior uveitis\u0026mdash;can cause measurable increases in both choroidal and macular thickness [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn AS patients without uveitis, increased subfoveal choroidal thickness compared with healthy individuals has been previously demonstrated [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In our study, choroidal thickness was significantly higher in patients treated with NSAIDs and sulfasalazine compared with those receiving anti-TNF-α therapy, supporting the hypothesis that inflammation contributes to choroidal thickening in AS. If increased choroidal thickness is considered an indicator of subclinical inflammation, our findings suggest that anti-TNF-α agents suppress this inflammation more effectively than NSAIDs, resulting in reduced choroidal thickness.\u003c/p\u003e\u003cp\u003eThis study also showed that AS patients receiving anti-TNF therapy had significantly lower subfoveal choroidal thickness (SFCT) compared with both NSAID users and healthy controls, suggesting a greater degree of suppression of posterior segment inflammation. Although none of the patients exhibited active uveitis at the time of imaging, these structural differences support the concept that the choroid is a sensitive biomarker of systemic inflammatory burden, even during clinical remission.\u003c/p\u003e\u003cp\u003eIn another study comparing uveitic eyes, fellow non-uveitic eyes, and healthy controls during both active and remission phases, subfoveal choroidal thickness was significantly greater in the active phase but showed no difference during remission [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A separate prospective study investigating the effects of nine months of anti-TNF-α therapy on RNFL, central macular thickness (CMT), and macular layers in AS patients reported no significant structural changes [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Similarly, Tuzcu et al. found no significant differences in central macular thickness or RNFL thickness in AS patients without uveitis. Their study reported a negative correlation between disease duration and temporal RNFL thickness, along with thinning of the ganglion cell layer, particularly in patients with a BASDAI score of 4 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Another study on AS patients with acute anterior uveitis but no posterior involvement demonstrated retinal thinning, suggesting subclinical posterior segment involvement possibly related to previous mild or undetected inflammatory episodes [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFurther supporting our findings, a recent study demonstrated a decreased incidence of diabetic retinopathy in patients receiving anti-TNF therapy [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This observation aligns with the role of TNF-α in retinal and choroidal inflammation and reinforces the biological plausibility of our finding that anti-TNF treatment is associated with decreased choroidal thickness. The protective effect seen in diabetic patients supports the concept that TNF inhibition may modulate microvascular inflammation.\u003c/p\u003e\u003cp\u003eIn our study, statistically significant thinning of the nasal macular subfields was observed in AS patients compared with controls. Given that the BASDAI score in our cohort averaged 2 and only one patient had a history of uveitis, no apparent clinical factor could account for this finding. Retinal thinning in the nasal macular quadrant may reflect subclinical inflammatory changes in posterior tissues. The higher choroidal thickness in NSAID users further suggests that anti-TNF-α therapy provides superior suppression of inflammatory activity.\u003c/p\u003e\u003cp\u003eThe nasal macula is anatomically adjacent to the optic nerve head and contains a higher density of retinal nerve fiber layers, rendering it potentially more vulnerable to microvascular or inflammatory alterations [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Studies evaluating choroidal and retinal perfusion have also demonstrated distinct autoregulatory properties in the nasal macula, suggesting that this region may respond differently to systemic inflammatory or autonomic influences [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The selective thinning observed in nasal ETDRS subfields in our study may therefore represent region-specific susceptibility of the posterior segment in AS patients, even during remission.\u003c/p\u003e\u003cp\u003eCovariance analysis confirmed that age and disease duration did not significantly influence choroidal or nasal macular thickness, indicating that differences between treatment groups reflected the effects of the treatments themselves rather than demographic or disease-related factors.\u003c/p\u003e\u003cp\u003eSeveral additional studies have investigated the effects of anti-TNF therapy on retinal layers. One reported no significant differences in ganglion cell or retinal layer thickness before and after treatment [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Another study comparing NSAID, sulfasalazine, and anti-TNF-α therapy groups found no significant differences in RNFL thickness [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Consistent with these findings, our study also did not demonstrate significant RNFL differences among treatment groups.\u003c/p\u003e\u003cp\u003eThis study has several limitations. The relatively small sample size restricted our ability to perform subgroup analysis of individual anti-TNF agents. Although agents such as adalimumab, certolizumab, and golimumab differ in molecular structure and pharmacological properties, all function via TNF-α blockade. Therefore, the trend toward reduced choroidal thickness likely reflects a class effect rather than drug-specific differences. Additionally, the cross-sectional study design prevented evaluation of longitudinal structural changes. Future studies with larger sample sizes and prospective follow-up are needed to explore the temporal effects of various biologic agents on choroidal and retinal structures and to further clarify the mechanisms underlying posterior segment involvement in AS.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this study suggests that choroidal and retinal thickness may be influenced by the inflammatory process of AS even in the absence of uveitis, and that the effects of anti-inflammatory treatments differ. OCT-based assessment of the choroid may serve as a useful marker for evaluating treatment response and detecting subtle inflammatory activity. These findings support the potential role of OCT in the routine follow-up of AS patients and in identifying those at risk of inflammation-related ocular involvement. Larger prospective studies are needed to validate these results\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAnkylosing spondylitis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOCT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOptical coherence tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCMT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCentral macular thickness\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRNFL\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRetinal nerve fiber layer\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSFCT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSubfoveal choroidal thickness\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNSAID\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNon-steroidal anti-inflammatory drug\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTNF-α\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTumor necrosis factor-alpha.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\u003cp\u003e This study was approved by the Ethics Committee of Malatya Turgut \u0026Ouml;zal University, Faculty of Medicine (Approval No: 2022/122). All procedures were conducted in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to inclusion in the study.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eZEG and MŞA conceived and designed the study. ZEG collected and analyzed the data. KM contributed to data interpretation and manuscript revision. All authors read and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eThe authors would like to thank the staff of the Ophthalmology Department, Malatya Turgut \u0026Ouml;zal University, for their technical assistance and support.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGran JT, Skomsvoll JF. The outcome of ankylosing spondylitis: a study of 100 patients. Br J Rheumatol. 1997;36(7):766\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZagora SL, McCluskey P. Ocular manifestations of seronegative spondyloarthropathies. Curr Opin Ophthalmol. 2014;25(6):495\u0026ndash;501.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKal A, Duman E, Sezen\u0026ouml;z AS, Ulusoy MO, Kal \u0026Ouml;. Evaluation of retrobulbar blood flow and choroidal thickness in patients with rheumatoid arthritis. Int Ophthalmol. 2017;37(6):1311\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChakraborty R, Read SA, Collins MJ. Diurnal variations in axial length, choroidal thickness, intraocular pressure, and ocular biometrics. Invest Ophthalmol Vis Sci. 2011;52(8):5121\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEhrenfeld M, Spondyloarthropathies. Best Pract Res Clin Rheumatol. 2012;26(1):135\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBraun J, Baraliakos X, Brandt J, Listing J, Zink A, Alten R, et al. Persistent clinical response to the anti-TNF antibody infliximab in patients with ankylosing spondylitis over 3 years. Rheumatology (Oxford). 2005;44(5):670\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrandt J, Listing J, Haibel H, Sorensen H, Schwebig A, Rudwaleit M, et al. Long-term efficacy and safety of etanercept after readministration in patients with active ankylosing spondylitis. Rheumatology (Oxford). 2005;44(3):342\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDavis JC Jr, van der Heijde DM, Braun J, Dougados M, Cush J, Clegg D, et al. Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks. Ann Rheum Dis. 2005;64(11):1557\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGouveia EB, Elmann D, Morales MS. Ankylosing spondylitis and uveitis: overview. Rev Bras Reumatol. 2012;52(5):742\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVan der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria. Arthritis Rheum. 1984;27(4):361\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDalgliesh JD, Tariq YM, Burlutsky G, Mitchell P. Symmetry of retinal parameters measured by spectral-domain OCT in normal young adults. J Glaucoma. 2015;24(1):20\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosenbaum JT. Characterization of uveitis associated with spondyloarthritis. J Rheumatol. 1989;16(6):792\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShulman S, Goldenberg D, Habot-Wilner Z, Neudorfer M, Barak A, Baruch K, et al. Optical coherence tomography characteristics of eyes with acute anterior uveitis. Isr Med Assoc J. 2012;14(9):543\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTraill A, Stawell R, Hall A, Zamir E. Macular thickening in acute anterior uveitis. Ophthalmology. 2007;114(2):402.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTerasaki H, Kase S, Shirasawa M, Otsuka H, Nakamura M. TNF-α decreases VEGF secretion in highly polarized RPE cells but increases it in non-polarized RPE cells related to crosstalk between JNK and NF-κB pathways. PLoS ONE. 2013;8(7):e69994.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKiel JW. Modulation of choroidal autoregulation in the rabbit. Exp Eye Res. 1999;69(4):413\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFong AH, Li KK, Wong D. Choroidal evaluation using enhanced depth imaging spectral-domain optical coherence tomography in Vogt\u0026ndash;Koyanagi\u0026ndash;Harada disease. Retina. 2011;31(3):502\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSzepessy Z, Barsi \u0026Aacute;, Kr\u0026aacute;nitz K, Nagy ZZ. The evolution of central retinal and choroidal thickness in acute anterior uveitic patients with spondyloarthropathy. J Ophthalmol. 2018;2018:9136017.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSzepessy Z, Barsi \u0026Aacute;, N\u0026eacute;meth J. Macular changes correlate with the degree of acute anterior uveitis in patients with spondyloarthropathy. Ocul Immunol Inflamm. 2015;23(3):234\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKola M, Kalkisim A, Karkucak M, Turk A, Capkin E, Can I, et al. Evaluation of choroidal thickness in ankylosing spondylitis using optical coherence tomography. Ocul Immunol Inflamm. 2014;22(6):434\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBasarir B, Celik U, Altan C, Celik NB. Choroidal thickness changes determined by EDI-OCT on acute anterior uveitis in HLA-B27-positive ankylosing spondylitis. Int Ophthalmol. 2018;38(1):307\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIlhan N, Ustun N, Tuzcu EA, Coskun M, Yagiz AE, Ilhan O, et al. Spectral-domain optical coherence tomographic findings in patients with ankylosing spondylitis under anti-TNF-α therapy. Cutan Ocul Toxicol. 2015;34(3):222\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTuzcu E, Ustun N, Ilhan N, Coskun M, Yagiz AE, Ilhan O, et al. Peripapillary RNFL and GCL-IPL thickness in ankylosing spondylitis. Ocul Immunol Inflamm. 2014;22(6):429\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eButtanrı İB, Kurtuluş D, Serin D. Eye involvement in patients with ankylosing spondylitis. Glo-Kat. 2014;9(4):267\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eU\u0026ccedil;ar Baytaroğlu İM, Baytaroğlu A, U\u0026ccedil;ar Toros M, Daldal H. Incidence of diabetic retinopathy in anti-TNF treated rheumatic disease patients with type 2 diabetes. Graefes Arch Clin Exp Ophthalmol. 2024;262(11):3559\u0026ndash;65. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00417-024-06529-3\u003c/span\u003e\u003cspan address=\"10.1007/s00417-024-06529-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHood DC, Raza AS. On improving the use of OCT imaging for detecting glaucomatous damage. Br J Ophthalmol. 2014;98(Suppl 2):ii1\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCurcio CA, Allen KA. Topography of ganglion cells in human retina. J Comp Neurol. 1990;300(1):5\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePark HY, Park SH, Park CK. Choroidal microvasculature dropout is associated with parafoveal thinning in glaucoma. Ophthalmology. 2017;124(9):1386\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKal A, Ulusoy MO, Ozturk C. Spectral domain OCT findings in ankylosing spondylitis. Int Ophthalmol. 2020;40(10):2727\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Ankylosing spondylitis, Optical coherence tomography, Choroid, Macular thickness, Anti-TNF therapy","lastPublishedDoi":"10.21203/rs.3.rs-8234375/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8234375/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study aimed to evaluate the effects of non-steroidal anti-inflammatory drugs (NSAIDs) and anti\u0026ndash;tumor necrosis factor-α (anti-TNF-α) therapy on retinal and choroidal thickness in ankylosing spondylitis (AS) patients without uveitis and to compare these findings with healthy controls. A total of 65 AS patients and 30 age- and sex-matched healthy controls were included. Macular thickness, retinal nerve fiber layer (RNFL) thickness, and subfoveal choroidal thickness were measured using spectral-domain optical coherence tomography (SD-OCT). Patients receiving NSAIDs and/or sulfasalazine (Group 1, n\u0026thinsp;=\u0026thinsp;30) were compared with patients receiving anti-TNF-α therapy (Group 2, n\u0026thinsp;=\u0026thinsp;35) and with healthy controls (Group 3, n\u0026thinsp;=\u0026thinsp;30). Mean subfoveal choroidal thickness was significantly greater in Group 1 compared with Group 2 and controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Nasal inner (p\u0026thinsp;=\u0026thinsp;0.008) and nasal outer (p\u0026thinsp;=\u0026thinsp;0.003) macular subfield thicknesses were significantly lower in both AS groups compared with controls, while RNFL thickness did not differ significantly among groups (p\u0026thinsp;=\u0026thinsp;0.069). Covariance analysis showed that age and disease duration had no significant effect on these outcomes. These findings suggest that choroidal and macular thickness may be altered by subclinical inflammation in AS even in the absence of uveitis, and that anti-TNF-α therapy may provide superior suppression of inflammation compared with NSAIDs. OCT-based choroidal assessment may serve as a useful indicator for monitoring inflammatory activity and treatment response in AS.\u003c/p\u003e","manuscriptTitle":"Effects of Anti-TNF and NSAID Therapy on Choroidal and Macular Thickness in Ankylosing Spondylitis: An OCT-Based Evaluation of Subclinical Inflammation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-11 00:44:36","doi":"10.21203/rs.3.rs-8234375/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-16T07:38:33+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-16T07:35:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-14T22:22:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-14T16:24:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"211275445172053498365441743449032849489","date":"2025-12-14T15:21:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"325336388151911437186344684420290593453","date":"2025-12-14T15:00:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"220450903420068233873010415268483840220","date":"2025-12-14T14:53:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-08T06:37:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-02T07:18:55+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-02T04:24:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-01T19:00:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-12-01T18:55:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dfb4e7da-f4fb-4dea-b799-8d6dc6588916","owner":[],"postedDate":"December 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T17:27:14+00:00","versionOfRecord":{"articleIdentity":"rs-8234375","link":"https://doi.org/10.1186/s12886-026-04619-w","journal":{"identity":"bmc-ophthalmology","isVorOnly":false,"title":"BMC Ophthalmology"},"publishedOn":"2026-01-12 16:31:00","publishedOnDateReadable":"January 12th, 2026"},"versionCreatedAt":"2025-12-11 00:44:36","video":"","vorDoi":"10.1186/s12886-026-04619-w","vorDoiUrl":"https://doi.org/10.1186/s12886-026-04619-w","workflowStages":[]},"version":"v1","identity":"rs-8234375","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8234375","identity":"rs-8234375","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}