Epi-off riboflavin with vitamin E TPGS (Ribocross) cross-linking: One-year outcome

Epi-off riboflavin with vitamin E TPGS (Ribocross) cross-linking: One-year outcome | 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 Epi-off riboflavin with vitamin E TPGS (Ribocross) cross-linking: One-year outcome Pietro Paolo Saba, Alessandro Feo, Luca Pagano, Paolo Vinciguerra, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3952065/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Nov, 2024 Read the published version in International Ophthalmology → Version 1 posted 11 You are reading this latest preprint version Abstract Purpose: To assess the short and mid-term outcomes of epi-off corneal collagen cross-linking using Riboflavin with Vitamin E TPGS (Epi-off Ribocross® CXL) for progressive keratoconus Design: Retrospective, single-center noncomparative interventional study. Methods: Patients with progressive keratoconus who underwent CXL using Riboflavin with Vitamin E TPGS (Ribocross®) from May 2021 to May 2022 who completed at least 12 months of follow-up in Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Corrected distance visual acuity (CDVA), tomographic parameters (Belin ABCD) and topographic parameters were evaluated at baseline and at last follow up. Results: Twenty eyes of 20 patients fulfilled inclusion criteria. CDVA remained stable at last follow up (0,88 ± 0,19 from 0,83 ± 0,21, p=0.45) with a significant reduction in cylinder (1,97 ± 1,69 from 2,78 ± 2,19, p=0.03). Kmax significantly improved from 53.18D ± 6.32 to 50.96 ± 5.3D (p= 0.005). At the last follow up, no case of progression was noted. Conclusions: Epi-off Ribocross® CXL proved to be a safe treatment for progressive KC, with a stabilisation of all cases at the one year follow up. Further studies are needed to confirm long-term stability. INTRODUCTION Keratoconus (KC) is a condition characterized by progressive corneal thinning and steepening, leading to irregular astigmatism and vision deterioration 1 . Typically diagnosed in adolescence, it advances until the fourth decade of life 2 . To combat this, Riboflavin-ultraviolet A-induced corneal cross-linking (CXL) is commonly utilized to enhance corneal biomechanical strength and halt disease progression. The gold standard approach, known as standard epithelium-off CXL (epi-off CXL) according to the Dresden protocol, involves epithelium removal to facilitate riboflavin penetration into the corneal stroma before UVA irradiation 3 , 4 . Conversely, transepithelial CXL techniques have emerged, eliminating the need for epithelium removal to enhance riboflavin penetration 5 . However, commercial transepithelial CXL protocols often achieve lower riboflavin concentrations in the anterior corneal stroma compared to epi-off CXL, potentially compromising efficacy 6 . One such transepithelial method involves using riboflavin combined with vitamin E tocopherol polyethylene glycol succinate (TPGS), aimed at enhancing epithelium penetration, which is commercially referred to as Ribocross®. TPGS acts as an effective permeation enhancer, facilitating drug adsorption through biological barriers 7 . Additionally, as a member of the tocopherol pro-drugs group, TPGS provides protective effects against free-radical damage released during CXL treatment 7 . Nevertheless, the effectiveness and safety of transepithelial CXL riboflavin preparations in the standard epi-off CXL procedure remain unclear. Our study aims to evaluate the safety and effectiveness of epi-off CXL using Ribocross® in progressive KC. PATIENTS AND METHODS Population The study included twenty patients treated with epi-off CXL with Vitamin E TPGS for progressive keratoconus from May 2021 to May 2022 who completed at least 12 months of follow-up at the Eye Center of Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Progression of keratoconus was defined based on Italian national health system criteria (differential maps demonstrating a change in curvature in the area corresponding to the conical component of a minimum of 1.0 dioptres obtained with an instantaneous map or a reduction of more than 20µm in minimal pachymetry) and was later confirmed with Belin ABCD Grading and Progression Display 8 , 9 . Exclusion criteria included: minimum pachymetry inferior to 400 µm, corneal infections, history of herpetic keratitis, severe dry eye, previous ocular surgery, and pregnancy or breast-feeding. The Institutional Review Board (IRB) ruled that formal approval was not required for this record review study which was conducted according to the ethical standards set in the 1964 Declaration of Helsinki, as revised in 2013. All patients signed an informed consent, for both the treatment and use of their de-identified clinical data for publication. At baseline and after 6 months, 12 and 24 (when available) after the CXL procedure, all patients underwent the following examinations: best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, Goldmann tonometry, dilated funduscopy, and corneal tomography with Pentacam HR (OCULUS Optigeräte GmbH), and anterior-segment optical coherence tomography (AS-OCT) with Solix device (Optovue, USA). Evaluated parameters The following parameters were recorded: age, gender, BCVA, refraction, Kmax, thinnest point. Atopy was defined according to the American Academy of Allergy, Asthma, and Immunology as a clinical history of allergic rhinitis, asthma, or atopic dermatitis 10 . The ABC values of the Belin ABCD progression display system of the Pentacam were also recorded. The ABCD display measures average anterior (ARC) and posterior (PRC) curvature values in a 3-mm optical zone centred on the thinnest point of the cornea and the thinnest pachymetry 9 . Additionally, the following Pentacam-derived parameters, resulting from Fourier decomposition of keratometry data, were evaluated: spherical component and eccentricity, maximum decentration, regular astigmatism in the centre and in the periphery, and irregularities. Finally, the postoperative demarcation line depth (DLD) was measured on AS-OCT 11 . CXL Procedure CXL surgery entailed the use of riboflavin solution with 0.1% riboflavin, with the addition of Vitamin E TPGS as enhancer (Ribocross®, SERVImed, Rome, Italy). After epithelial removal, riboflavin was applied to the cornea at regular intervals (typically every 2 min) for 25 min. Then, UV-A irradiation (UV-A power = 9.60 mW/cm 2 ) was performed for 10 min (fluence = 5.4 J/cm 2 ). At the end of the surgery, a soft therapeutic contact lens was applied. Post-operatively, an ophthalmic gel with 0.3% netilmicin (Xanternet; SIFI SpA, Catania, Italy) was prescribed 4 times a day until re-epithelization process was complete (usually at day 3) and, following removal of contact lens, dexamethasone 21-phosphate 0.15% drops (Etacortilen, Sifi, Lavinaio, Italy) twice daily for 10 days, and 0.15% sodium hyaluronate drops (BluYal, Sooft, Montegiorgio, Italy) 6 times daily for 45 days. Furthermore, all patients received oral amino acid supplements (Aminoftal, Sooft, Montegiorgio, Italy) for 7 days. Data Analysis The statistical analysis was performed with SPSS, version 28 (IBM Corp). All data are reported as means ± SD. The Mann-Whitney test for unpaired data was applied to evaluate the significance level of respective differences between baseline and follow-up values. The level of statistical significance was set at a P value of less than .05. RESULTS 20 eyes of 20 patients (18 M, 2 F) with an average age of 27 ± 11.2 year were observed for an average of 13 months after the CXL. 2 patients had a history of atopy. BCVA remained stabile with a non statistically significant improvement (from 0,83 ± 0,21 to 0,88 ± 0,19 decimal, p=0.45). Sphere remained substantially the same, while we observed a significant reduction in cylinder, decreasing from -2.78 ± 2.19 to -1.97 ± 1.69 (p = 0.028). (Table 1) Analyzing the tomographic data from the Pentacam, the ARC (Anterior radius curvature taken from the 3 mm cone centered on the thinnest point) exhibited a change from 6.92 ± 0.64 to 7.40 ± 0.77 (p = 0.001), the PCR (Posterior radius curvature taken from the 3mm cone centred on the thinnest point) significantly decreased from 5,08 ± 0,61 to 4,91 ± 0,60 (p=0.02) and the thinnest pachymetry reduced from 476,05 ± 41,27 to 434,88 ± 57,88 µm (p=0.02). The demarcation line measured on AS-OCT was 312 ± 63 µm. Topographic parameters revealed a significant decrease in the Kmax from 53.18D ± 6.32 to 50.96 ± 5.3D (p = 0.005), with a delta of 2.2 ± 1 µm. Similarly SimK1 reduced from 44,17 ± 3,05 D to 42,45 ± 2,72 D (p= 0.001). Additionally, several parameters indicating corneal irregularity showed significant changes: ISV decreased from 84.26 ± 36.52 to 73.83 ± 28.56 (p = 0.05), KI reduced from 1.23 ± 0.12 to 1.19 ± 0.11 (p = 0.03), CKI decreased from 1.04 ± 0.06 to 1.00 ± 0.05 (p = 0.049), IHD showed a decrease from 0.13 ± 0.069 to 0.11 ± 0.05 (p = 0.024), and Rmin changed from 6.42 ± 0.70 to 6.69 ± 0.67 (p = 0.001) (Table 2). DISCUSSION Corneal cross-linking with removal of the epithelium is today considered the gold standard for the treatment of progressive keratoconus 12 . The enzymatic reaction induced by the stromal concentration of riboflavin and ultraviolet A (UV-A) light leads to the photopolymerization process of the stromal collagen chains and by modulating these two parameters it is possible to personalize the treatment based on the patient's corneal thickness and degree of evolution of keratoconus 13 , 14 . Although the corneal epithelium and Bowman's basal lamina represent a physical barrier against the penetration of both riboflavin and UV light 15 , over time techniques have been developed that allow the integrity of these anatomical structures to be maintained, reducing the risks of epithelium removal related postoperative complications 16 – 18 . However, many studies demonstrate that standard transepithelial CXL does not lead to long-term stabilization of the disease, since the demarcation line is too superficial, often requiring additional treatments 18 , 19 . Vitamin E tocopherol polyethylene glycol succinate (TPGS) has been added to Riboflavin, facilitating drug adsorption through biological barriers and offering enhanced transepithelial penetration. Additionally, it has also been reported to provide protective effects against free-radical damage released during CXL treatment as well as showing a synergistic effect of TPGS with riboflavin, which should induce a more powerful crosslinking effect 7 . The first idea is supported by an in-vivo study carried out on rabbit eyes, which demonstrated that the topical application of eye drops containing riboflavin/TPGS was able to counteract the oxidant corneal damage caused by UV rays 20 . The synergistic effect was proposed in a paper on CXL of dental collagen, where the association of Riboflavin/TPGS was observed to induce a greater structural integrity and conformational stability of dentin-collagen fibrils 21 . Hence, in our study we analyzed the result of epi-off CXL with Riboflavin/TPGS, showing comparable results in stopping keratoconus progression at the 1-year follow-up compared to other CXL epi-off methods. The most used keratoconus progression parameter is Kmax. An abnormal anterior surface of the keratoconus cornea with a high Kmax already implies some degree of visual impairment. It was noted that the Kmax in our study had a strong, statistically significant reduction, going from 53.18D ± 6.32 to 50.96 ± 5.3D with a p-value of 0.005 and a delta of 2.22 ± 1D. When comparing this value with other published studies, our Kmax reduction was equal or superior to the others. In fact, reported studies 22 , 23 , 24 , 25 using standard Riboflavin solutions showed 1-year Kmax reduction ranging from 1.18 to 1.6 D, while the only other reported study 26 using the combination of Riboflavin/TPGS showed a much higher 1-year reduction (3.6D). These results could potentially represent a stronger CXL effect of Riboflavin/TPGS; however, this finding should be confirmed with a randomized controlled trial. In our study, we also found a significant reduction in the ARC measured via the Pentacam (from 6.92 ± 0.64 to 7.40 ± 0.77, p-value of 0.001), which, obviously, is directly correlated with the Kmax reduction 8 . Other statistically significant data include a reduction in ISV, KI, CKI, RI and IHI, which are all useful parameters for evaluating the regularity of the cornea, in fact, they increase not only in the presence of keratoconus but also in the presence of scars or corneal aberrations. Following the CXL treatment, their reduction is a consequence of the flattening of the apex of the cone and reflects a greater regularization of the cornea. Similarly, we also noted a significant reduction in the cylinder (going from − 2.78 ± 2.19 to -1.97 ± 1.69). Another finding worth mentioning is the safety of the modified solution, with no documented adverse events or intra- and post-operative complications. Study limitations include the limited number of patients and the 1-year follow-up time, which may restrict the generalizability and long-term assessment of our findings. Additionally, the retrospective nature of the study and the absence of a control group undergoing standard Epi-off treatment introduce potential biases and limit the ability to draw direct comparisons between treatment modalities. These limitations underscore the need for further prospective, controlled studies with larger sample sizes and longer follow-up periods to validate the efficacy and safety of epi-off CXL using Ribocross® in progressive KC. CONCLUSION In conclusion, our study underscores the safety and efficacy of Epi-off Ribocross® CXL in halting the progression of keratoconus, as evidenced by the stabilization of all cases at the one-year follow-up. While promising, further investigations are warranted to validate the long-term stability and compare the effectiveness of Epi-off Ribocross® CXL with standard CXL utilizing normal riboflavin preparation. These findings contribute to the ongoing refinement and optimization of treatment strategies for progressive keratoconus, aiming to enhance patient outcomes and quality of life. Declarations All authors declare that they have no conflicts of interest. Paolo Vinciguerra and Riccardo Vinciguerra are consultant for Oculus® The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. This study was performed in line with the principles of the Declaration of Helsinki. Informed consent, including consent for publication of the images, was obtained from the patients. Author Contribution Pier Paolo Saba and Alessandro Feo should be considered equally contributing first author References Santodomingo-Rubido J, Carracedo G, Suzaki A, Villa-Collar C, Vincent SJ, Wolffsohn JS. Keratoconus: An updated review. Cont Lens Anterior Eye. 2022;45(3):101559. doi: 10.1016/j.clae.2021.101559 Romano V, Vinciguerra R, Arbabi EM, et al. Progression of Keratoconus in Patients While Awaiting Corneal Cross-linking: A Prospective Clinical Study. J Refract Surg. 2018;34(3):177–180. doi: 10.3928/1081597X-20180104-01 Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg. 2003;29(9):1780–1785. doi: 10.1016/s0886-3350(03)00407-3 Zweifel SA, Spaide RF, Curcio CA, et al. Reticular Pseudodrusen Are Subretinal Drusenoid Deposits. Ophthalmology. 2010;117(2):303–312.e1. doi: 10.1016/j.ophtha.2009.07.014 Vinciguerra P, Montericcio A, Catania F, et al. New perspectives in keratoconus treatment: an update on iontophoresis-assisted corneal collagen crosslinking. Int Ophthalmol. 2021;41(5):1909–1916. doi: 10.1007/s10792-021-01713-4 Gore DM, O’Brart D, French P, Dunsby C, Allan BD. Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model. Invest Ophthalmol Vis Sci. 2015;56(8):5006–5011. doi: 10.1167/iovs.15-16903 Ostacolo C, Caruso C, Tronino D, et al. Enhancement of corneal permeation of riboflavin-5’-phosphate through vitamin E TPGS: a promising approach in corneal trans-epithelial cross linking treatment. Int J Pharm. 2013;440(2):148–153. doi: 10.1016/j.ijpharm.2012.09.051 Vinciguerra R, Belin MW, Borgia A, et al. Evaluating keratoconus progression prior to crosslinking: maximum keratometry vs the ABCD grading system. J Cataract Refract Surg. 2021;47(1):33–39. doi: 10.1097/j.jcrs.0000000000000475 Belin MW, Duncan JK. Keratoconus: The ABCD Grading System. Klin Monbl Augenheilkd. 2016;233(6):701–707. doi: 10.1055/s-0042-100626 Bellanti JA, Settipane RA. The atopic disorders and atopy … strange diseases” now better defined! Allergy asthma Proc . 2017;38(4):241–242. doi: 10.2500/aap.2017.38.4074 Vinciguerra R, Tzamalis A, Romano V, Arbabi EM, Batterbury M, Kaye SB. Assessment of the Association Between In Vivo Corneal Biomechanical Changes After Corneal Cross-linking and Depth of Demarcation Line. J Refract Surg. 2019;35(3):202–206. doi: 10.3928/1081597X-20190124-01 Mazzotta C, Traversi C, Baiocchi S, et al. Corneal Collagen Cross-Linking With Riboflavin and Ultraviolet A Light for Pediatric Keratoconus: Ten-Year Results. Cornea. 2018;37(5):560–566. doi: 10.1097/ICO.0000000000001505 Schumacher S, Mrochen M, Wernli J, Bueeler M, Seiler T. Optimization model for UV-riboflavin corneal cross-linking. 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Refractive and topographic results of benzalkonium chloride-assisted transepithelial crosslinking. J Cataract Refract Surg. 2012;38(6):1000–1005. doi: 10.1016/j.jcrs.2012.01.024 Weadock K, Olson RM, Silver FH. Evaluation of collagen crosslinking techniques. Biomater Med Devices Artif Organs. 11(4):293–318. doi: 10.3109/10731198309118815 Palazzo M, Vizzarri F, Ondruška L, et al. Corneal UV Protective Effects of a Topical Antioxidant Formulation: A Pilot Study on In Vivo Rabbits. Int J Mol Sci. 2020;21(15). doi: 10.3390/ijms21155426 Daood U, Matinlinna JP, Fawzy AS. Synergistic effects of VE-TPGS and riboflavin in crosslinking of dentine. Dent Mater. 2019;35(2):356–367. doi: 10.1016/j.dental.2018.11.031 Grišević S, Gilevska F, Biščević A, et al. Cross-linking treatment for better visual acuity. Med Glas Off Publ Med Assoc Zenica-Doboj Canton, Bosnia Herzegovina. 2020;17(1):123–128. doi: 10.17392/1071-20 Greenstein SA, Hersh PS. Corneal Crosslinking for Progressive Keratoconus and Corneal Ectasia: Summary of US Multicenter and Subgroup Clinical Trials. Transl Vis Sci Technol. 2021;10(5):13. doi: 10.1167/tvst.10.5.13 Seiler TG, Fischinger I, Koller T, Zapp D, Frueh BE, Seiler T. Customized Corneal Cross-linking: One-Year Results. Am J Ophthalmol. 2016;166:14–21. doi: 10.1016/j.ajo.2016.02.029 Akram S, Momin S, Malik B, Sirang Z. Outcomes of Epi-On Collagen Cross-Linkage Procedure Assessed in Progressive Keratoconus Patients. Cureus. 2022;14(10):e30664. doi: 10.7759/cureus.30664 Caruso C, Epstein RL, Troiano P, et al. Topography and Pachymetry Guided, Rapid Epi-on Corneal Cross-Linking for Keratoconus: 7-year Study Results. Cornea. 2020;39(1):56–62. doi: 10.1097/ICO.0000000000002088 Tables Table 1 – Visual acuity and refraction results, showing a stable BCVA and a significant reduction in the cylinder. Refractive parameters T0 T1 p-value BCVA (decimal) 0,83 ± 0,21 0,88 ± 0,19 0,45 sph -0,75 ± 2,51 -1,02 ± 2,89 0,67 cyl -2,78 ± 2,19 -1,97 ± 1,69 0,03 Axis 105,59± 35,70 102,65 ± 33,59 0,63 Table 2 - Topographic and Tomographic results, showing significant reduction in Kmax with a delta of 2.2D. Belin ABC keratoconus staging T0 T1 p-value ARC 6,92 ± 0,64 7,40 ± 0,77 0,001 PRC 5,08 ± 0,61 4,91 ± 0,60 0,02 Thinnest pachi 476,05 ± 41,27 434,88 ± 57,88 0,02 Topographic results T0 T1 p-value Sim K1 (Front) 44,17 ± 3,05 42,45 ± 2,72 0,001 Sim K2 46,78 ± 3,95 44,97 ± 3,63 0,67 Kmax -2,78 ± 2,19 -1,97 ± 1,69 0,0006 Topometric indices T0 T1 p-value ISV 84,23 ± 36,52 73,82 ± 28,56 0,052 IVA 1,01 ± 0,43 0,87 ± 0,35 0,062 KI 1,23 ± 0,12 1,19 ± 0,11 0,032 CKI 3,88 ± 2,51 4,43 ± 2,40 0,074 IHA 19,98 ± 17,28 26,28 ± 17,93 0,310 IHD 0,13 ± 0,07 0,10 ± 0,05 0,024 Rmin 6,42 ± 0,7 6,69 ± 0,67 0,001 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 14 Nov, 2024 Read the published version in International Ophthalmology → Version 1 posted Editorial decision: Revision requested 02 Jul, 2024 Reviews received at journal 26 Jun, 2024 Reviewers agreed at journal 26 Jun, 2024 Reviewers agreed at journal 07 Jun, 2024 Reviews received at journal 01 May, 2024 Reviewers agreed at journal 30 Apr, 2024 Reviewers agreed at journal 29 Apr, 2024 Reviewers invited by journal 26 Apr, 2024 Editor assigned by journal 13 Feb, 2024 Submission checks completed at journal 13 Feb, 2024 First submitted to journal 12 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3952065","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":272603650,"identity":"c2cf63cd-519d-4271-a881-7bd7c62152f1","order_by":0,"name":"Pietro Paolo Saba","email":"","orcid":"","institution":"Humanitas San Pio X Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pietro","middleName":"Paolo","lastName":"Saba","suffix":""},{"id":272603651,"identity":"7fae9022-ff24-48ab-9e4f-b3ce3cc44f27","order_by":1,"name":"Alessandro Feo","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Feo","suffix":""},{"id":272603652,"identity":"aa6000c1-69f7-48c5-86d4-f5e6d39ce2dd","order_by":2,"name":"Luca Pagano","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABB0lEQVRIiWNgGAWjYBACPiQ244OEigNg1oEHDBI4tbAhsZkNHpw5wMAD0pLAIIFTD7IWNsmHbRAtDAkMuK1hk0h++IFxh51d/+zmYxKJ8+7I2Ysdfgi0xaIOt5Y0YwnGM8nJM+4cS7ZI3PbMmEc6zQC/wyRyGCQY25iTGW7kGN5I3HY4sUc6gaAW5h+MbfXJ8jdyDCQS54C0pH8gpIUNaMthO4MbOUYSiQ0gLTkEbOF5ZmaReOZ4guGNtGSDhGOHjXlu5xQcSDCQkGzAoYWfPfnxjY87qu3lbiQffPij5rAc++z0zR8+VNTx47IFDBIbQAgFGODVAEwpDQz2BJSMglEwCkbBSAYAGqRYYUqKpoUAAAAASUVORK5CYII=","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":true,"prefix":"","firstName":"Luca","middleName":"","lastName":"Pagano","suffix":""},{"id":272603653,"identity":"3c78581f-cb66-4caf-9dc9-868d1b6685ec","order_by":3,"name":"Paolo Vinciguerra","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Paolo","middleName":"","lastName":"Vinciguerra","suffix":""},{"id":272603654,"identity":"a7e1aef3-7a20-45a9-a0f7-974054e4e3cc","order_by":4,"name":"Riccardo Vinciguerra","email":"","orcid":"","institution":"Humanitas San Pio X Hospital","correspondingAuthor":false,"prefix":"","firstName":"Riccardo","middleName":"","lastName":"Vinciguerra","suffix":""}],"badges":[],"createdAt":"2024-02-12 22:19:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3952065/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3952065/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10792-024-03354-9","type":"published","date":"2024-11-14T15:57:28+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69274999,"identity":"11ff38e9-43fe-4fb5-813c-a9d25cad8a9b","added_by":"auto","created_at":"2024-11-18 16:43:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":354901,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3952065/v1/2765f049-7119-489f-8b14-f9b33fbcfd08.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Epi-off riboflavin with vitamin E TPGS (Ribocross) cross-linking: One-year outcome","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eKeratoconus (KC) is a condition characterized by progressive corneal thinning and steepening, leading to irregular astigmatism and vision deterioration\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Typically diagnosed in adolescence, it advances until the fourth decade of life\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. To combat this, Riboflavin-ultraviolet A-induced corneal cross-linking (CXL) is commonly utilized to enhance corneal biomechanical strength and halt disease progression. The gold standard approach, known as standard epithelium-off CXL (epi-off CXL) according to the Dresden protocol, involves epithelium removal to facilitate riboflavin penetration into the corneal stroma before UVA irradiation\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Conversely, transepithelial CXL techniques have emerged, eliminating the need for epithelium removal to enhance riboflavin penetration\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, commercial transepithelial CXL protocols often achieve lower riboflavin concentrations in the anterior corneal stroma compared to epi-off CXL, potentially compromising efficacy\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. One such transepithelial method involves using riboflavin combined with vitamin E tocopherol polyethylene glycol succinate (TPGS), aimed at enhancing epithelium penetration, which is commercially referred to as Ribocross\u0026reg;. TPGS acts as an effective permeation enhancer, facilitating drug adsorption through biological barriers\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Additionally, as a member of the tocopherol pro-drugs group, TPGS provides protective effects against free-radical damage released during CXL treatment\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Nevertheless, the effectiveness and safety of transepithelial CXL riboflavin preparations in the standard epi-off CXL procedure remain unclear. Our study aims to evaluate the safety and effectiveness of epi-off CXL using Ribocross\u0026reg; in progressive KC.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePopulation\u003c/h2\u003e \u003cp\u003eThe study included twenty patients treated with epi-off CXL with Vitamin E TPGS for progressive keratoconus from May 2021 to May 2022 who completed at least 12 months of follow-up at the Eye Center of Humanitas Clinical and Research Center, Rozzano, Milan, Italy.\u003c/p\u003e \u003cp\u003eProgression of keratoconus was defined based on Italian national health system criteria (differential maps demonstrating a change in curvature in the area corresponding to the conical component of a minimum of 1.0 dioptres obtained with an instantaneous map or a reduction of more than 20\u0026micro;m in minimal pachymetry) and was later confirmed with Belin ABCD Grading and Progression Display\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eExclusion criteria included: minimum pachymetry inferior to 400 \u0026micro;m, corneal infections, history of herpetic keratitis, severe dry eye, previous ocular surgery, and pregnancy or breast-feeding.\u003c/p\u003e \u003cp\u003e The Institutional Review Board (IRB) ruled that formal approval was not required for this record review study which was conducted according to the ethical standards set in the 1964 Declaration of Helsinki, as revised in 2013.\u003c/p\u003e \u003cp\u003eAll patients signed an informed consent, for both the treatment and use of their de-identified clinical data for publication.\u003c/p\u003e \u003cp\u003eAt baseline and after 6 months, 12 and 24 (when available) after the CXL procedure, all patients underwent the following examinations: best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, Goldmann tonometry, dilated funduscopy, and corneal tomography with Pentacam HR (OCULUS Optiger\u0026auml;te GmbH), and anterior-segment optical coherence tomography (AS-OCT) with Solix device (Optovue, USA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEvaluated parameters\u003c/h2\u003e \u003cp\u003eThe following parameters were recorded: age, gender, BCVA, refraction, Kmax, thinnest point. Atopy was defined according to the American Academy of Allergy, Asthma, and Immunology as a clinical history of allergic rhinitis, asthma, or atopic dermatitis\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe ABC values of the Belin ABCD progression display system of the Pentacam were also recorded. The ABCD display measures average anterior (ARC) and posterior (PRC) curvature values in a 3-mm optical zone centred on the thinnest point of the cornea and the thinnest pachymetry\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAdditionally, the following Pentacam-derived parameters, resulting from Fourier decomposition of keratometry data, were evaluated: spherical component and eccentricity, maximum decentration, regular astigmatism in the centre and in the periphery, and irregularities.\u003c/p\u003e \u003cp\u003eFinally, the postoperative demarcation line depth (DLD) was measured on AS-OCT\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCXL Procedure\u003c/h2\u003e \u003cp\u003eCXL surgery entailed the use of riboflavin solution with 0.1% riboflavin, with the addition of Vitamin E TPGS as enhancer (Ribocross\u0026reg;, SERVImed, Rome, Italy).\u003c/p\u003e \u003cp\u003eAfter epithelial removal, riboflavin was applied to the cornea at regular intervals (typically every 2 min) for 25 min. Then, UV-A irradiation (UV-A power\u0026thinsp;=\u0026thinsp;9.60 mW/cm\u003csup\u003e2\u003c/sup\u003e) was performed for 10 min (fluence\u0026thinsp;=\u0026thinsp;5.4 J/cm\u003csup\u003e2\u003c/sup\u003e).\u003c/p\u003e \u003cp\u003eAt the end of the surgery, a soft therapeutic contact lens was applied. Post-operatively, an ophthalmic gel with 0.3% netilmicin (Xanternet; SIFI SpA, Catania, Italy) was prescribed 4 times a day until re-epithelization process was complete (usually at day 3) and, following removal of contact lens, dexamethasone 21-phosphate 0.15% drops (Etacortilen, Sifi, Lavinaio, Italy) twice daily for 10 days, and 0.15% sodium hyaluronate drops (BluYal, Sooft, Montegiorgio, Italy) 6 times daily for 45 days. Furthermore, all patients received oral amino acid supplements (Aminoftal, Sooft, Montegiorgio, Italy) for 7 days.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData Analysis\u003c/h2\u003e \u003cp\u003eThe statistical analysis was performed with SPSS, version 28 (IBM Corp). All data are reported as means\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. The Mann-Whitney test for unpaired data was applied to evaluate the significance level of respective differences between baseline and follow-up values. The level of statistical significance was set at a P value of less than .05.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e20 eyes of 20 patients (18 M, 2 F) with an average age of 27 \u0026plusmn; 11.2 year were observed for an average of 13 months after the CXL. 2 patients had a history of atopy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBCVA remained stabile with a non statistically significant improvement (from 0,83 \u0026plusmn; 0,21 to 0,88 \u0026plusmn; 0,19 decimal, p=0.45). Sphere remained substantially the same, while we observed a significant reduction in cylinder, decreasing from -2.78 \u0026plusmn; 2.19 to -1.97 \u0026plusmn; 1.69 (p = 0.028). \u003cstrong\u003e(Table 1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalyzing the tomographic data from the Pentacam, the ARC (Anterior radius curvature taken from the 3 mm cone centered on the thinnest point) exhibited a change from 6.92 \u0026plusmn; 0.64 to 7.40 \u0026plusmn; 0.77 (p = 0.001), the PCR (Posterior radius curvature taken from the 3mm cone centred on the thinnest point) \u0026nbsp;significantly decreased from 5,08 \u0026plusmn; 0,61 to 4,91 \u0026plusmn; 0,60 (p=0.02) and the thinnest pachymetry reduced from 476,05 \u0026plusmn; 41,27 to 434,88 \u0026plusmn; 57,88 \u0026micro;m (p=0.02).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe demarcation line measured on AS-OCT was 312 \u0026plusmn; 63 \u0026micro;m.\u003c/p\u003e\n\u003cp\u003eTopographic parameters revealed a significant decrease in the \u0026nbsp;Kmax from 53.18D \u0026plusmn; 6.32 to 50.96 \u0026plusmn; 5.3D (p = 0.005), with a delta of 2.2 \u0026plusmn; 1 \u0026micro;m.\u003c/p\u003e\n\u003cp\u003eSimilarly SimK1 reduced from 44,17 \u0026plusmn; 3,05 D to 42,45 \u0026plusmn; 2,72 D (p= 0.001).\u003c/p\u003e\n\u003cp\u003eAdditionally, several parameters indicating corneal irregularity showed significant changes: ISV decreased from 84.26 \u0026plusmn; 36.52 to 73.83 \u0026plusmn; 28.56 (p = 0.05), KI reduced from 1.23 \u0026plusmn; 0.12 to 1.19 \u0026plusmn; 0.11 (p = 0.03), CKI decreased from 1.04 \u0026plusmn; 0.06 to 1.00 \u0026plusmn; 0.05 (p = 0.049), IHD showed a decrease from 0.13 \u0026plusmn; 0.069 to 0.11 \u0026plusmn; 0.05 (p = 0.024), and Rmin changed from 6.42 \u0026plusmn; 0.70 to 6.69 \u0026plusmn; 0.67 (p = 0.001) \u003cstrong\u003e(Table 2).\u003c/strong\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eCorneal cross-linking with removal of the epithelium is today considered the gold standard for the treatment of progressive keratoconus\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. The enzymatic reaction induced by the stromal concentration of riboflavin and ultraviolet A (UV-A) light leads to the photopolymerization process of the stromal collagen chains and by modulating these two parameters it is possible to personalize the treatment based on the patient's corneal thickness and degree of evolution of keratoconus\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough the corneal epithelium and Bowman's basal lamina represent a physical barrier against the penetration of both riboflavin and UV light\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e, over time techniques have been developed that allow the integrity of these anatomical structures to be maintained, reducing the risks of epithelium removal related postoperative complications\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, many studies demonstrate that standard transepithelial CXL does not lead to long-term stabilization of the disease, since the demarcation line is too superficial, often requiring additional treatments\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVitamin E tocopherol polyethylene glycol succinate (TPGS) has been added to Riboflavin, facilitating drug adsorption through biological barriers and offering enhanced transepithelial penetration.\u003c/p\u003e \u003cp\u003eAdditionally, it has also been reported to provide protective effects against free-radical damage released during CXL treatment as well as showing a synergistic effect of TPGS with riboflavin, which should induce a more powerful crosslinking effect\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The first idea is supported by an in-vivo study carried out on rabbit eyes, which demonstrated that the topical application of eye drops containing riboflavin/TPGS was able to counteract the oxidant corneal damage caused by UV rays\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. The synergistic effect was proposed in a paper on CXL of dental collagen, where the association of Riboflavin/TPGS was observed to induce a greater structural integrity and conformational stability of dentin-collagen fibrils\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHence, in our study we analyzed the result of epi-off CXL with Riboflavin/TPGS, showing comparable results in stopping keratoconus progression at the 1-year follow-up compared to other CXL epi-off methods.\u003c/p\u003e \u003cp\u003eThe most used keratoconus progression parameter is Kmax. An abnormal anterior surface of the keratoconus cornea with a high Kmax already implies some degree of visual impairment. It was noted that the Kmax in our study had a strong, statistically significant reduction, going from 53.18D\u0026thinsp;\u0026plusmn;\u0026thinsp;6.32 to 50.96\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3D with a p-value of 0.005 and a delta of 2.22\u0026thinsp;\u0026plusmn;\u0026thinsp;1D.\u003c/p\u003e \u003cp\u003eWhen comparing this value with other published studies, our Kmax reduction was equal or superior to the others. In fact, reported studies\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e using standard Riboflavin solutions showed 1-year Kmax reduction ranging from 1.18 to 1.6 D, while the only other reported study\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e using the combination of Riboflavin/TPGS showed a much higher 1-year reduction (3.6D). These results could potentially represent a stronger CXL effect of Riboflavin/TPGS; however, this finding should be confirmed with a randomized controlled trial.\u003c/p\u003e \u003cp\u003eIn our study, we also found a significant reduction in the ARC measured via the Pentacam (from 6.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64 to 7.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77, p-value of 0.001), which, obviously, is directly correlated with the Kmax reduction\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOther statistically significant data include a reduction in ISV, KI, CKI, RI and IHI, which are all useful parameters for evaluating the regularity of the cornea, in fact, they increase not only in the presence of keratoconus but also in the presence of scars or corneal aberrations. Following the CXL treatment, their reduction is a consequence of the flattening of the apex of the cone and reflects a greater regularization of the cornea. Similarly, we also noted a significant reduction in the cylinder (going from \u0026minus;\u0026thinsp;2.78\u0026thinsp;\u0026plusmn;\u0026thinsp;2.19 to -1.97\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69).\u003c/p\u003e \u003cp\u003eAnother finding worth mentioning is the safety of the modified solution, with no documented adverse events or intra- and post-operative complications.\u003c/p\u003e \u003cp\u003eStudy limitations include the limited number of patients and the 1-year follow-up time, which may restrict the generalizability and long-term assessment of our findings. Additionally, the retrospective nature of the study and the absence of a control group undergoing standard Epi-off treatment introduce potential biases and limit the ability to draw direct comparisons between treatment modalities. These limitations underscore the need for further prospective, controlled studies with larger sample sizes and longer follow-up periods to validate the efficacy and safety of epi-off CXL using Ribocross\u0026reg; in progressive KC.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, our study underscores the safety and efficacy of Epi-off Ribocross\u0026reg; CXL in halting the progression of keratoconus, as evidenced by the stabilization of all cases at the one-year follow-up. While promising, further investigations are warranted to validate the long-term stability and compare the effectiveness of Epi-off Ribocross\u0026reg; CXL with standard CXL utilizing normal riboflavin preparation. These findings contribute to the ongoing refinement and optimization of treatment strategies for progressive keratoconus, aiming to enhance patient outcomes and quality of life.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAll authors declare that they have no conflicts of interest. Paolo Vinciguerra and Riccardo Vinciguerra are consultant for Oculus\u0026#174; The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eInformed consent, including consent for publication of the images, was obtained from the patients.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003ePier Paolo Saba and Alessandro Feo should be considered equally contributing first author\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSantodomingo-Rubido J, Carracedo G, Suzaki A, Villa-Collar C, Vincent SJ, Wolffsohn JS. Keratoconus: An updated review. 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Cornea. 2020;39(1):56\u0026ndash;62. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/ICO.0000000000002088\u003c/span\u003e\u003cspan address=\"10.1097/ICO.0000000000002088\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 \u0026ndash; Visual acuity and refraction results, showing a stable BCVA and a significant reduction in the cylinder.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"594\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.737373737373737%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRefractive parameters\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.043771043771045%\" valign=\"top\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.946127946127945%\" valign=\"top\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.272727272727273%\" valign=\"top\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.737373737373737%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003eBCVA (decimal)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.043771043771045%\" valign=\"top\"\u003e\n \u003cp\u003e0,83 \u0026plusmn; 0,21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.946127946127945%\" valign=\"top\"\u003e\n \u003cp\u003e0,88 \u0026plusmn; 0,19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.272727272727273%\" valign=\"top\"\u003e\n \u003cp\u003e0,45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.737373737373737%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003esph\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.043771043771045%\" valign=\"top\"\u003e\n \u003cp\u003e-0,75 \u0026plusmn; 2,51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.946127946127945%\" valign=\"top\"\u003e\n \u003cp\u003e-1,02 \u0026plusmn; 2,89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.272727272727273%\" valign=\"top\"\u003e\n \u003cp\u003e0,67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.737373737373737%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003ecyl\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.043771043771045%\" valign=\"top\"\u003e\n \u003cp\u003e-2,78 \u0026plusmn; 2,19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.946127946127945%\" valign=\"top\"\u003e\n \u003cp\u003e-1,97 \u0026plusmn; 1,69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.272727272727273%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.737373737373737%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003eAxis\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.043771043771045%\" valign=\"top\"\u003e\n \u003cp\u003e105,59\u0026plusmn; 35,70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.946127946127945%\" valign=\"top\"\u003e\n \u003cp\u003e102,65 \u0026plusmn; 33,59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.272727272727273%\" valign=\"top\"\u003e\n \u003cp\u003e0,63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 - Topographic and Tomographic results, showing significant reduction in Kmax with a delta of 2.2D. \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.46329526916803%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBelin ABC keratoconus staging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.04404567699837%\" valign=\"top\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.95921696574225%\" valign=\"top\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.46329526916803%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eARC\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003e6,92 \u0026plusmn; 0,64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.04404567699837%\" valign=\"top\"\u003e\n \u003cp\u003e7,40 \u0026plusmn; 0,77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.95921696574225%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.46329526916803%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ePRC\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003e5,08 \u0026plusmn; 0,61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.04404567699837%\" valign=\"top\"\u003e\n \u003cp\u003e4,91 \u0026plusmn; 0,60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.95921696574225%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.46329526916803%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eThinnest pachi\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003e476,05 \u0026plusmn; 41,27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.04404567699837%\" valign=\"top\"\u003e\n \u003cp\u003e434,88 \u0026plusmn; 57,88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.95921696574225%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"610\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.823240589198036%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTopographic results\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.094926350245498%\" valign=\"top\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.04091653027823%\" valign=\"top\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.04091653027823%\" valign=\"top\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.823240589198036%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003eSim K1 (Front)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.094926350245498%\" valign=\"top\"\u003e\n \u003cp\u003e44,17 \u0026plusmn; 3,05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.04091653027823%\" valign=\"top\"\u003e\n \u003cp\u003e42,45 \u0026plusmn; 2,72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.04091653027823%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.823240589198036%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003eSim K2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.094926350245498%\" valign=\"top\"\u003e\n \u003cp\u003e46,78 \u0026plusmn; 3,95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.04091653027823%\" valign=\"top\"\u003e\n \u003cp\u003e44,97 \u0026plusmn; 3,63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.04091653027823%\" valign=\"top\"\u003e\n \u003cp\u003e0,67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.823240589198036%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003eKmax\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.094926350245498%\" valign=\"top\"\u003e\n \u003cp\u003e-2,78 \u0026plusmn; 2,19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.04091653027823%\" valign=\"top\"\u003e\n \u003cp\u003e-1,97 \u0026plusmn; 1,69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.04091653027823%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,0006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"615\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.5974025974026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTopometric indices\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.4025974025974%\" valign=\"top\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.5974025974026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eISV\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.4025974025974%\" valign=\"top\"\u003e\n \u003cp\u003e84,23 \u0026plusmn; 36,52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e73,82 \u0026plusmn; 28,56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0,052\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.5974025974026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eIVA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.4025974025974%\" valign=\"top\"\u003e\n \u003cp\u003e1,01 \u0026plusmn; 0,43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0,87 \u0026plusmn; 0,35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0,062\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.5974025974026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eKI\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.4025974025974%\" valign=\"top\"\u003e\n \u003cp\u003e1,23 \u0026plusmn; 0,12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e1,19 \u0026plusmn; 0,11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,032\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.5974025974026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eCKI\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.4025974025974%\" valign=\"top\"\u003e\n \u003cp\u003e3,88 \u0026plusmn; 2,51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e4,43 \u0026plusmn; 2,40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0,074\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.5974025974026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eIHA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.4025974025974%\" valign=\"top\"\u003e\n \u003cp\u003e19,98 \u0026plusmn; 17,28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e26,28 \u0026plusmn; 17,93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0,310\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.5974025974026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eIHD\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.4025974025974%\" valign=\"top\"\u003e\n \u003cp\u003e0,13 \u0026plusmn; 0,07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0,10 \u0026plusmn; 0,05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,024\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.5974025974026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eRmin\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.4025974025974%\" valign=\"top\"\u003e\n \u003cp\u003e6,42 \u0026plusmn; 0,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e6,69 \u0026plusmn; 0,67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0,001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\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":"international-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"inte","sideBox":"Learn more about [International Ophthalmology](https://www.springer.com/journal/10792)","snPcode":"10792","submissionUrl":"https://submission.nature.com/new-submission/10792/3","title":"International Ophthalmology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3952065/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3952065/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose: To assess the short and mid-term outcomes of epi-off corneal collagen cross-linking using Riboflavin with Vitamin E TPGS (Epi-off Ribocross® CXL) for progressive keratoconus\u003c/p\u003e\n\u003cp\u003eDesign: Retrospective, single-center noncomparative interventional study.\u003c/p\u003e\n\u003cp\u003eMethods: Patients with progressive keratoconus who underwent CXL using Riboflavin with Vitamin E TPGS (Ribocross®) from May 2021 to May 2022 who completed at least 12 months of follow-up in Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Corrected distance visual acuity (CDVA), tomographic parameters (Belin ABCD) and topographic parameters were evaluated at baseline and at last follow up.\u003c/p\u003e\n\u003cp\u003eResults: Twenty eyes of 20 patients fulfilled inclusion criteria. CDVA remained stable at last follow up (0,88 ± 0,19 from 0,83 ± 0,21, p=0.45) with a significant reduction in cylinder (1,97 ± 1,69 from 2,78 ± 2,19, p=0.03). Kmax significantly improved from 53.18D ± 6.32 to 50.96 ± 5.3D (p= 0.005). At the last follow up, no case of progression was noted.\u003c/p\u003e\n\u003cp\u003eConclusions: Epi-off Ribocross® CXL proved to be a safe treatment for progressive KC, with a stabilisation of all cases at the one year follow up. Further studies are needed to confirm long-term stability.\u003c/p\u003e","manuscriptTitle":"Epi-off riboflavin with vitamin E TPGS (Ribocross) cross-linking: One-year outcome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-14 10:28:54","doi":"10.21203/rs.3.rs-3952065/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-02T17:13:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-26T15:36:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"338090957471145950205952615164382900500","date":"2024-06-26T11:13:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"305566387014085630188672263873972808326","date":"2024-06-07T06:26:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-01T15:15:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"269710941908653241771242741106973189363","date":"2024-04-30T13:08:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"29083344487478283941274872400102410465","date":"2024-04-29T05:22:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-27T00:49:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-13T09:55:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-13T08:58:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Ophthalmology","date":"2024-02-12T22:15:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"inte","sideBox":"Learn more about [International Ophthalmology](https://www.springer.com/journal/10792)","snPcode":"10792","submissionUrl":"https://submission.nature.com/new-submission/10792/3","title":"International Ophthalmology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"611c6304-b8e5-45d0-b736-d5e8d406818a","owner":[],"postedDate":"February 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-18T16:01:43+00:00","versionOfRecord":{"articleIdentity":"rs-3952065","link":"https://doi.org/10.1007/s10792-024-03354-9","journal":{"identity":"international-ophthalmology","isVorOnly":false,"title":"International Ophthalmology"},"publishedOn":"2024-11-14 15:57:28","publishedOnDateReadable":"November 14th, 2024"},"versionCreatedAt":"2024-02-14 10:28:54","video":"","vorDoi":"10.1007/s10792-024-03354-9","vorDoiUrl":"https://doi.org/10.1007/s10792-024-03354-9","workflowStages":[]},"version":"v1","identity":"rs-3952065","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3952065","identity":"rs-3952065","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}