Abstract
Objective
This study aimed to evaluate the impact of anti-TNF (biological) therapies on the incidence and progression of diabetic retinopathy.
Materials and methods
A cross-sectional analysis of 50 diabetic patients with rheumatic diseases (group 1) was performed. An age-, sex-, and HbA1c-matched control group (group 2) was formed from a pool of diabetic patients who underwent regular eye examinations. The presence or absence of diabetic retinopathy was also assessed. Comorbidities such as hypertension, coronary artery disease, and hyperlipidemia were also evaluated as possible confounding factors.
Results
Hundred eyes of 50 patients were evaluated in each group. Only three patients in group 1 had non-proliferative retinopathy. The median duration of rheumatic disease was 9 years, whereas that of diabetes was 11 years. The mean duration of anti-TNF therapy was 4 years. In the control group of diabetes-only patients, 13 patients developed some form of newly diagnosed diabetic retinopathy during the last five years. The calculated retinopathy occurrence between the groups was statistically significant (p < 0.05). In this study, the incidence rate ratio for patients receiving anti-TNF treatment was calculated as 0.4 in the study.
Conclusion
TNF inhibitors, with their anti-inflammatory effects, positively impact diabetic complications by reducing the incidence of retinopathy. To our knowledge, this is the first study to evaluate retinopathy development after anti-TNF therapy.
Key messages
What is Known:
-
• Inhibition of TNF? is known to be beneficial in reducing the risk of diabetes itself in rheumatic disease patients.
-
• Disorders related to TNF? and its pathways are critical contributors to microvascular complications, such as prolif?erative retinopathy.
What is New:
-
• Our preliminary data shows that TNF inhibitors positively impact retinal microvasculature, lowering diabetic reti?nopathy incidence.
-
• Glycemic control is potentially the most critical parameter of the development of diabetic complications in rheumatic disease patients, even under effective anti-inflammatory treatment.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
The role of anti-inflammatory drugs in treating diabetes and its complications has been a focal point of diabetes research since the 1870s [1]. The novel findings of animal studies demonstrating that TNF-α has a direct role in the pathogenesis of diabetes and insulin resistance have opened the door for new studies in this field [2]. However, dietary habits and lifestyle changes throughout the century have resulted in a quarter of the global population develo** diabetes [3, 4]. Since the annual incidence of retinopathy development and progression in diabetic patients is–2–12%, diabetic retinopathy (DR) has become one of the costliest visual impairments worldwide [5]. Although TNFα is still a critical factor in the pathogenesis of diabetic retinopathy, among other inflammatory mediators, controversial data restrict its widespread use [6, 7]. Impaired TNFα production is an essential factor leading to microvascular complications, especially proliferative diabetic retinopathy [8]. Currently, the main treatment options are intravitreal use of anti-vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) agents [3, 5].
Infliximab and adalimumab, the first FDA-approved anti-TNF-α agents, have been used in various rheumatic and dermatologic disorders, such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS), for over two decades with proven efficacy and safety [9]. TNF-α antagonism has also been shown to reduce the incidence of DM in these patients by nearly halving the risk of diabetes [10]. To our knowledge, the incidence and severity of diabetic retinopathy in patients receiving anti-TNF treatment have not been evaluated.
In this study, we examined the effect on the development of diabetic retinopathy by reviewing the course of cases treated with biological agents (adalimumab, infliximab, etanercept, golimumab, and certolizumab), which are the first choice in rheumatology practice in patients unresponsive to conventional therapies.
Materials and methods
We screened 2558 diabetic patients (1617 male and 941 female) who were followed up with OCT in our hospital. Patients with no retinopathy at baseline evaluation were selected, including OCT and a thorough clinical examination. Similarly, patients with rheumatologic diseases with detailed baseline eye examinations were scanned. Patients with overlap** diagnoses of diabetes and rheumatic diseases were analyzed, and the subjects treated with TNFi were recruited. After applying the exclusion and regular follow-up criteria, the remaining 121 diabetic subjects without known rheumatic disease were randomized according to age, gender, and HbA1c criteria to be matched with the TNFi-treated cases.
We managed to analyze the data from 100 eyes of 50 patients with type 2 diabetes who were taking biologics for various rheumatic diseases. As meta-analyses have shown, the most determinant factors associated with diabetic retinopathy are HbA1c levels, nephropathy, lipid profiles, and cardiovascular status [11, 13]. Fundus fluorescein angiography (FFA) was also conducted on a clinical basis. All subjects underwent comprehensive dilated initial eye examinations following the diagnosis of type 2 diabetes. All HbA1c values included in the study were measured by ion-exchange high-performance liquid chromatography (HPLC) using a Bio-Rad Variant Turbo instrument (Siemens).
The sample size was calculated using G*Power Version 3.1.6. In Turkey, Taş et al. [14] conducted a multicenter study on the epidemiology of DR in 2362 patients and found a DR prevalence of 30.5%. Considering the difference as a threefold drop in the expected incidence of DR in Group 1, the sample size was calculated as approximately 49 in the groups and 98 patients in total for an alpha significance level of 0.05 for 0.8 power.
PASW for Windows (version 15.0, SPSS Inc., Chicago, IL, USA) was used for the statistical analyses. Descriptive statistics were presented as numbers and percentages for categorical variables and medians and interquartile ranges for numerical variables. The proportions in the groups were compared using the chi-squared test. Because continuous variables did not follow a normal distribution, two independent group comparisons were made using the Mann–Whitney U test. Risk factors were analyzed using a logistic regression analysis. The statistical significance level was set at P < 0.05.
Results
There was no significant difference between the two groups regarding age, gender, and duration of diabetes. There was also no significant difference between the groups regarding glycemic control, renal function, or other comorbidities. The demographic features of both groups are summarized in Table 1.
In the rheumatic disease group (group-1) twenty-four (48%) patients were diagnosed with rheumatoid arthritis, 20 (40%) with ankylosing spondylitis, and 6 (12%) with psoriatic arthritis. Fourteen patients were treated with etanercept or adalimumab. Twelve patients received infliximab, and five patients each were taking golimumab and certolizumab, and the median rheumatic disease duration was 9 (6–12) years. The median duration of TNFi use was 3.5 (2–5) years.
The retinal evaluation revealed median foveolar thickness and macular thickness as 255 μm (245–274) and 301 μm (286–315) in group 1 compared to 264 μm (246–278) and 295 μm (286–310) in group 2 (p = 0.28/p = 0.71). In approximately 5 years of retinal follow-up, non-proliferative DRP developed in only 5 of 100 eyes (3 patients), and macular edema was found in only one eye treated with focal laser photocoagulation (Table 2). Retrospectively, 43% (21) of the patients had FFA in group 1, but none showed any evidence of proliferative retinopathy. However, in Group 2, 24 eyes of 13 patients developed some form of diabetic retinopathy during the last five years. Nine patients had background diabetic retinopathy changes such as microaneurysm, hard exudate, or dot-blot hemorrhages, and four patients were diagnosed with diabetic macular edema and needed intravitreal treatments.
Although it is noteworthy that all patients with retinopathy in both groups had a diabetes duration of ≥ 5 years, it was calculated that the duration of diabetes did not significantly affect the development of retinopathy in our study (p = 0.09). However, diabetes duration had a weak but statistically significant positive correlation with macular thickness in both eyes (p = 0.04/p = 0.013/r:0.25). DR development was significantly higher in patients with HbA1c > 7.45 when all cases were considered (p = 0.006). In the univariate analysis of the risk factors for DR, an increase in HbA1c and creatinine levels were found to be a risk factor, whereas TNF inhibition was found to be a protective factor (p < 0.001 p = 0.020 p = 0.012). In the multivariate logistic regression analysis (Table 3), only increased HbA1c level was seen as a risk factor, but the protective effect of TNF inhibition was sustained (p < 0.001, p = 0.01). A chi-square test was conducted to evaluate the occurrence of retinopathy, which yielded statistically significant results (p = 0.006). The incidence rate ratio in our study was calculated as 0.4 in our study.
Discussion
The lower risk rate calculated in the anti-TNF treatment group supports the basis of intravitreal drug studies in this field [9]. In a series of longstanding DM cases over 20 years, high TNFα receptor levels were particularly associated with develo** proliferative changes. As the disease progressed, TNFα production doubled and was correlated with the severity of retinopathy [8, 15]. Our study with a limited sample size investigated the effects of TNF inhibitors for an average of 4 years. Although the groups did not differ in retinal thickness measurements, vascular changes, or related findings, it revealed an increased incidence of diabetic retinopathy.
TNF inhibitors are the mainstay treatment options for autoimmune and autoinflammatory diseases, and autoimmunity is predominantly a feature of type 1 DM. However, inflammation and insulin resistance are observed at different rates in both types of diabetes. The development of long-term organ-damaging complications in type 2 DM is of genetic origin and exhibits wide heterogeneity [16, 17].
The role of TNF in diabetes complications has already been elucidated; for example, increased TNFα levels have been observed in tear samples of diabetic patients, which has also been shown to correlate with retinopathy and nephropathy severity [18]. Another suggested mechanism of action of TNF is that increased TNFα during the inflammatory process in chronic diabetes may cause antibody-mediated retinal pericyte damage by upregulating CD38 [19].
Supporting the role of TNF-α in the pathogenesis of diabetes, cohorts receiving anti-TNF-α therapy, particularly infliximab, have shown significantly lower mean blood glucose levels and reduced insulin resistance. A retrospective study with limited subjects showed that infliximab had a 1% effect on HbA1c levels in the long-term. Nevertheless, the low mean HbA1c level in this study is an important limiting factor [20]. In a recent study, the blood glucose-lowering effect of adalimumab was found to be more pronounced in the psoriatic group than in the rheumatic disease group [21,22,23]. Several mechanisms have been reviewed regarding the glucose-lowering effects of biologics, including reduced TNFα-induced insulin resistance, reduced soluble ICAM1 levels, and increased high-molecular-weight adiponectin [24]. Unfortunately, due to the limited number of patients treated with each anti-TNF agent, we could not demonstrate their effects on glucose levels and the incidence of retinopathy separately. We aimed to homogenize our study group in terms of HbA1c levels rather than compare their current blood glucose levels or diabetes treatments, because we wanted to evaluate the long-term effects of TNF inhibitors. In our study, an HbA1c level of 7.45, despite being low, was found to be an independent risk factor for the development of DR. However, a slightly higher proportion of patients in group 2 using insulin may contribute to increased retinopathy, necessitating tighter glucose control to achieve lower HbA1c percentages. Furthermore, some antihyperglycemic drugs such as pioglitazone have been linked to an increase in diabetic macular edema [25]. However, we assumed that drug-related cases would not be overlooked because there was no significant difference in macular thickness between the groups in our study, and retinal evaluation was already performed with detailed fundoscopic imaging.
Although only 3 patients developed diabetic retinopathy under anti-TNF treatment, we believe that it should not be overlooked that anti-TNF agents activate different autoimmune disease pathways in addition to their presumed protective effects. This TNF inhibitor-induced autoimmune disease spectrum covers a wide range, from mild serologic changes to a full-blown systemic autoimmune disease, causing severe end-organ damage [26]. Infliximab has been shown to cause ANA seropositivity in more than half of cases after the initiation of treatment [27]. Systemic and retinal vasculitis induced by anti-TNF treatment, with or without accompanying retinal vein occlusion, has been reported in approximately 4% in some series [28]. Uveitis and optic neuritis have also been reported as the potential side effects of these treatments. Furthermore, the incidence of DM under anti-TNF therapy from large-scale US data was approximately 6% per 1000 person-years. This effect was more prominent in the infliximab and adalimumab groups than in the abatacept group. They also stated that baseline obesity might be a critical factor contributing to the development of DM with biologics [29]. We did not consider BMI as a confounding factor, as we excluded patients with BMI > 30; however, borderline overweight subjects might have created a bias in favor of a higher retinopathy incidence in group 2. However, a 20-year survey revealed that being slightly overweight did not increase the risk of DM complications, particularly in men [30]. Another potential bias in our study is the occasional and previous use of DMARDs, NSAIDs, and steroids used for acute exacerbations. However, since chronicity is an essential factor in the effect of autoimmunity on the course and complications of diabetes and animal studies have shown that NSAIDs only show anti-TNF-like TNF blockade when used in high doses, we excluded acute exacerbation treatments [31, 32]. But perhaps even more importantly, since anti-TNF therapies were not first-line drugs in any of the diagnostic groups included in the study, it must be accepted that first-line therapies also have a certain level of anti-inflammatory effect. However, when we look at the studies in the literature examining the impact of DMARD use on the development of diabetes in rheumatic disease patients, it is noteworthy that this effect is only evident within the first 2 years of treatment, and the risk reduction is mainly in patients aged > 60 years [33]. This again reiterates that chronicity is a vital determinant in the process.
Apart from their systemic use, etanercept, adalimumab, and infliximab have been trialed as intravitreal therapeutic agents for various inflammatory conditions. Etanercept, which has a shorter half-life than the other drugs, works as a trap receptor, binds to TNF1-2 receptors, and inhibits TNF-mediated pathways. Although its intraocular anti-inflammatory effect has been evaluated and shown to reduce PVR in rabbit eyes, no successful outcomes have been observed in human studies of diabetic retinopathy [9, 34, 35]. Adalimumab, a human monoclonal antibody in IgG1 form, has been FDA-approved since 2002. Arevalo et al. achieved three ETDRS lines of visual gain in a series of seven patients in whom the intravitreal use of adalimumab combined with bevacizumab (anti-VEGF) was tested [6]. Infliximab, another monoclonal IgG1 antibody with a chimeric structure, has been tested in various diseases such as wet age-related macular degeneration, posterior uveitis, and diabetic macular edema. However, except for a 1-month transient effect in chronic uveitis, especially in Behçet’s disease, and up to a 45% reduction in macular edema in a limited number of cases unresponsive to focal therapy, it failed to provide an established impact in long-term intravitreal use [9, 36, 37]. Conversely, infliximab and etanercept have been shown to induce uveitis and retinal toxicity. Intravitreal studies of adalimumab and infliximab by the Pan-American Collaborative Retina Study Group also revealed unfavorable results [7, 9].
As a result, in support of the literature, anti-TNF medication seems to reduce the incidence of diabetic retinopathy independent of its glucose-lowering effect. Although the outcomes of direct intravitreal administration studies have been controversial, with the increasing and widespread use of anti-TNFs, their anti-inflammatory role in the pathophysiology of diabetes and its complications has become a hot research topic. This effect can be attributed to its anti-inflammatory role in diabetes pathogenesis. Further prospective studies with larger cohorts are necessary to establish the long-term impact of biologics on the development and treatment of DR.
Limitations
The primary drawback of our study is its retrospective design; however, the design of a large prospective study to evaluate the intersection of two different complicated disease groups in which many environmental and genetic factors are involved and at the same time, many different biomarkers need to be monitored will only be possible with a nationwide collaboration. Therefore, we believe the relatively limited amount of data available for such a group, which is challenging to match, is valuable.
Another limitation of our study was that we ignored the effect of treatment on patients’ comorbidities. For example, fenofibrate, which is used to treat hypertriglyceridemia, has been reported to reduce retinal inflammation, and randomized controlled trials have shown that this moderate-certainty effect is only at the level of reducing progression in patients with existing retinopathy [38] (Table 3).
References
Rohm TV, Meier DT, Olefsky JM, Donath MY (2022) Inflammation in obesity, diabetes, and related disorders. Immunity 55:31–55. https://doi.org/10.1016/j.immuni.2021.12.013
Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of Tumor Necrosis Factor-α: direct role in obesity-linked insulin resistance. Sci (1979) 259:87–91. https://doi.org/10.1126/science.7678183
Fu P, Huang Y, Wan X et al (2023) Efficacy and safety of pan retinal photocoagulation combined with intravitreal anti-VEGF agents for high-risk proliferative diabetic retinopathy: a systematic review and meta-analysis. Medicine 102:e34856. https://doi.org/10.1097/MD.0000000000034856
Thomas RL, Halim S, Gurudas S et al (2019) IDF Diabetes Atlas: a review of studies utilising retinal photography on the global prevalence of diabetes related retinopathy between 2015 and 2018. Diabetes Res Clin Pract 157:107840. https://doi.org/10.1016/j.diabres.2019.107840
Marques AP, Ramke J, Cairns J et al (2022) The economics of vision impairment and its leading causes: a systematic review. EClinicalMedicine 46:101354. https://doi.org/10.1016/j.eclinm.2022.101354
Arevalo JF, Serrano MA, Wu L (2013) Combined inhibition of tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF) for the treatment of macular edema of various etiologies: a short-term pilot study. Eye 27:569–571. https://doi.org/10.1038/eye.2012.301
Wu L, Hernandez-Bogantes E, Roca JA, INTRAVITREAL TUMOR NECROSIS FACTOR INHIBITORS IN THE TREATMENT OF REFRACTORY DIABETIC MACULAR EDEMA (2011) Retina 31:298–303. https://doi.org/10.1097/IAE.0b013e3181eac7a6
Limb GA, Soomro H, Janikoun S et al (2001) Evidence for control of tumour necrosis factor-alpha (TNF-α) activity by TNF receptors in patients with proliferative diabetic retinopathy. Clin Exp Immunol 115:409–414. https://doi.org/10.1046/j.1365-2249.1999.00839.x
Hasan N, Chawla R, Shaikh N et al (2022) A comprehensive review of intravitreal immunosuppressants and biologicals used in ophthalmology. Ther Adv Ophthalmol 14:251584142210974. https://doi.org/10.1177/25158414221097418
Antohe Jl, Bili A, Sartorius JA et al (2012) Diabetes mellitus risk in rheumatoid arthritis: reduced incidence with anti-tumor necrosis factor α therapy. Arthritis Care Res (Hoboken) 64:215–221. https://doi.org/10.1002/acr.20657
Perais J, Agarwal R, Evans JR et al (2023) Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy. Cochrane Database Syst Reviews 2023. https://doi.org/10.1002/14651858.CD013775.pub2
**e J, Ikram MK, Cotch MF et al (2017) Association of Diabetic Macular Edema and proliferative Diabetic Retinopathy with Cardiovascular Disease. JAMA Ophthalmol 135:586. https://doi.org/10.1001/jamaophthalmol.2017.0988
Wong TY, Sun J, Kawasaki R et al (2018) Guidelines on Diabetic Eye Care. Ophthalmology 125:1608–1622. https://doi.org/10.1016/j.ophtha.2018.04.007
Taş A, Bayraktar MZ, Erdem U et al (2005) Diyabetik Hastalarda retinopati sıklığı ve risk faktörleri. Gülhane Tıp Dergisi 47:164–174
Kuo JZ, Guo X, Klein R et al (2012) Systemic Soluble Tumor Necrosis Factor Receptors 1 and 2 are Associated with Severity of Diabetic Retinopathy in hispanics. Ophthalmology 119:1041–1046. https://doi.org/10.1016/j.ophtha.2011.10.040
Redondo MJ, Hagopian WA, Oram R et al (2020) The clinical consequences of heterogeneity within and between different diabetes types. Diabetologia 63:2040–2048. https://doi.org/10.1007/s00125-020-05211-7
Badenhoop K, Schwarz G, Trowsdale J et al (1989) TNF-? Gene polymorphisms in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 32:445–448. https://doi.org/10.1007/BF00271265
Costagliola C, Romano V, De Tollis M et al (2013) TNF-Alpha levels in tears: a novel biomarker to assess the degree of Diabetic Retinopathy. Mediators Inflamm 2013:1–6. https://doi.org/10.1155/2013/629529
Li Y, Smith D, Li Q et al (2012) Antibody-mediated Retinal Pericyte Injury: implications for Diabetic Retinopathy. Invest Opthalmology Visual Sci 53:5520. https://doi.org/10.1167/iovs.12-10010
Gupta-Ganguli M, Cox K, Means B et al (2011) Does Therapy with Anti–TNF-α improve glucose tolerance and control in patients with type 2 diabetes? Diabetes Care 34:e121–e121. https://doi.org/10.2337/dc10-1334
Bower JAJ, O’Flynn L, Kakad R, Aldulaimi D (2021) Effect of inflammatory bowel disease treatments on patients with diabetes mellitus. World J Diabetes 12:1248–1254. https://doi.org/10.4239/wjd.v12.i8.1248
Kiortsis DN (2005) Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 64:765–766. https://doi.org/10.1136/ard.2004.026534
Zhou Y, **e W, Wang L et al (2022) Anti-tumor necrosis factor-alpha therapy and hypoglycemia: a real-world pharmacovigilance analysis. Drug Saf 45:951–959. https://doi.org/10.1007/s40264-022-01210-2
Infante M, Padilla N, Alejandro R et al (2022) Diabetes-modifying antirheumatic drugs: the roles of DMARDs as glucose-lowering agents. Med (B Aires) 58:571. https://doi.org/10.3390/medicina58050571
Saw M, Wong VW, Ho I-V, Liew G (2019) New anti-hyperglycaemic agents for type 2 diabetes and their effects on diabetic retinopathy. Eye 33:1842–1851. https://doi.org/10.1038/s41433-019-0494-z
Usui J, Salvatore SP, Yamagata K, Seshan SV (2023) Clinicopathologic spectrum of renal lesions following Anti-TNF-α inhibitor therapy: a single Center experience. Kidney360 4:363–373. https://doi.org/10.34067/KID.0000000000000063
Lipsky PE, van der Heijde DMFM, St. Clair EW et al (2000) Infliximab and Methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 343:1594–1602. https://doi.org/10.1056/NEJM200011303432202
Ramos-Casals M, Brito-Zerón P, Cuadrado M-J, Khamashta MA (2008) Vasculitis induced by tumor necrosis factor-targeted therapies. Curr Rheumatol Rep 10:442–448. https://doi.org/10.1007/s11926-008-0072-z
Desai RJ, Dejene S, ** Y et al (2020) Comparative risk of diabetes Mellitus in patients with rheumatoid arthritis treated with biologic or targeted synthetic disease-modifying drugs: a Cohort Study. ACR Open Rheumatol 2:222–231. https://doi.org/10.1002/acr2.11124
Gray N, Picone G, Sloan F, Yashkin A (2015) Relation between BMI and diabetes Mellitus and its complications among US older adults. South Med J 108:29–36. https://doi.org/10.14423/SMJ.0000000000000214
Joussen AM, Doehmen S, Le ML et al (2009) TNF-alpha mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations. Mol Vis 15:1418–1428
Joussen M, Poulaki A, Mitsiades V N, et al (2002) Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF‐α suppression. FASEB J 16:438–440. https://doi.org/10.1096/fj.01-0707fje
Baghdadi LR (2020) Effect of methotrexate use on the development of type 2 diabetes in rheumatoid arthritis patients: a systematic review and meta-analysis. PLoS ONE 15:e0235637. https://doi.org/10.1371/journal.pone.0235637
Chen X-F, Du M, Wang X-H, Yan H (2019) Effect of etanercept on post-traumatic proliferative vitreoretinopathy. Int J Ophthalmol 12. https://doi.org/10.18240/ijo.2019.05.06
Tsilimbaris MK, Panagiotoglou TD, Charisis SK et al (2007) The Use of Intravitreal Etanercept in Diabetic Macular Oedema. Semin Ophthalmol 22:75–79. https://doi.org/10.1080/08820530701418243
Sfikakis PP, Grigoropoulos V, Emfietzoglou I et al (2010) Infliximab for Diabetic Macular Edema Refractory to Laser Photocoagulation. Diabetes Care 33:1523–1528. https://doi.org/10.2337/dc09-2372
Farvardin M, Afarid M, Shahrzad S (2012) Long-Term effects of intravitreal infliximab for treatment of sight-threatening chronic noninfectious uveitis. J Ocul Pharmacol Ther 28:628–631. https://doi.org/10.1089/jop.2011.0199
Kataoka SY, Lois N, Kawano S et al (2023) Fenofibrate for diabetic retinopathy. Cochrane Database Syst Reviews 2023. https://doi.org/10.1002/14651858.CD013318.pub2
Funding
No funding was received for this study.
Open access funding provided by the Scientific and Technological Research Council of Türkiye (TÜBİTAK).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of Uşak University (approval number: 199-199-01) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all participants in the study.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Baytaroğlu, İ.M.U., Baytaroğlu, A., Toros, M.U. et al. Incidence of diabetic retinopathy in anti-tnf treated rheumatic disease patients with type 2 diabetes. Graefes Arch Clin Exp Ophthalmol (2024). https://doi.org/10.1007/s00417-024-06529-3
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00417-024-06529-3