Sterile Neutrophilic Pseudomembranous Conjunctivitis Associated with Tisotumab Vedotin: Clinical and Cytological Evidence from Two Cases

Sterile Neutrophilic Pseudomembranous Conjunctivitis Associated with Tisotumab Vedotin: Clinical and Cytological Evidence from Two Cases | 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 Case Report Sterile Neutrophilic Pseudomembranous Conjunctivitis Associated with Tisotumab Vedotin: Clinical and Cytological Evidence from Two Cases Kaoru Araki-Sasaki, Shogen Boku, Megumi Kitamura, Hiroshi Shiraga, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8947841/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Tisotumab vedotin-tftv (TV), an antibody-drug conjugate (ADC), represents a significant advancement in cancer therapy but carries the potential to induce ocular surface toxicity. Having encountered ocular side effects with TV and obtained intriguing findings from histological examination, we discuss the pathophysiology and management approaches. Cases: Two female patients with advanced cervical cancer receiving TV therapy developed pseudomembranous conjunctivitis after 2 to 3 doses. Both cases presented with conjunctival hyperemia and pseudomembrane formation on the tarsal conjunctiva. One case additionally exhibited multiple epithelial erosions on the inferior conjunctiva. Cytology of the pseudomembrane showed neutrophilic infiltration but no detectable microorganisms. This suggested an immune-mediated erosion, such as a tissue factor-mediated reaction in the conjunctival epithelium. Complete remission was achieved within two weeks with topical corticosteroids (dexamethasone eye drops: 4–5 times daily) and lubricants. In both cases, after achieving grade 0 by extending the treatment interval, re-treatment was performed; however, ocular side effects recurred in Case 1. Four days of prophylactic steroid eye drops failed to prevent side effects, but intensifying steroid eye drops allowed inflammation to resolve without sequelae. However, intraocular pressure increased after the seventh dose. In Case 2, after side effects appeared, TV administration was resumed with extended intervals and reduced dosage; no conjunctivitis side effects were observed under the recommended prophylactic protocol. Both patients have now completed the seventh dose. Conclusions TV may cause pseudomembranous conjunctivitis with conjunctival erosion characterized by non-infectious neutrophilic infiltration, suggesting off-target cytotoxicity. Further case accumulation is necessary for the appropriate management of TV-induced ophthalmic side effects. tisotumab vedotin tissue factor antibody–drug conjugate (ADC) pseudomembranous conjunctivitis ocular toxicity Figures Figure 1 Figure 2 Introduction Antibody–drug conjugates (ADCs) enable targeted delivery of cytotoxic agents to tumor cells; however, they may also cause off-target effects in normal tissues expressing the same receptor [ 1 – 4 ]. Tisotumab vedotin-tftv (TV), which targets tissue factor (TF) and is conjugated with monomethyl auristatin E (MMAE), was approved for the treatment of recurrent cervical cancer in 2025. Because TF is expressed in various epithelial tissues, including conjunctival epithelial cells ( https://eye-transcriptome.com/search_latest.php ), ocular adverse effects were anticipated and have been reported. Prophylactic eye care measures, such as preventive eye drops and cooling packs, are recommended during TV therapy. Nevertheless, ocular surface disorders have occurred despite these measures [ 5 – 8 ]. Previous reports described pseudomembranes, fibrosis, erosions, scarring, and punctate epithelial keratitis; however, detailed histopathological findings remain limited. Here, we describe the clinical and pathological features of two cases of TV-induced pseudomembranous conjunctivitis and discuss their management to promote the safe use of this ADC. Case reports Case 1 A 40-year-old woman with recurrent cervical squamous cell carcinoma (stage IIIC1) developed unilateral redness and discharge after the third administration of TV. Slit-lamp examination revealed conjunctival hyperemia and a removable pseudomembrane on the upper palpebral conjunctiva (Fig. 1A, B). The membrane appeared slightly hardened and scar-like. Although the presentation resembled epidemic keratoconjunctivitis, adenoviral antigen testing was negative and no preauricular lymphadenopathy was noted. The pseudomembrane was excised and examined histologically. Giemsa staining demonstrated numerous segmented neutrophils, consistent with acute inflammation (Fig. 1C). No microorganisms were identified on smear or culture. Topical dexamethasone (six times daily) and lubricants resulted in complete resolution within two weeks, and the steroid was tapered over an additional one week. TV therapy was resumed after a one-month interval. Despite continuous prophylactic fluorometholone (three times daily), marked conjunctival hyperemia without membrane formation recurred one week after the fourth administration (Fig. 1D). The inflammation again responded to topical dexamethasone (three times daily). Dexamethasone was tapered to once daily and maintained during subsequent cycles. Mild conjunctival hyperemia developed approximately one week after each TV administration thereafter. When a 3-week TV treatment cycle was repeatedly administered alongside prophylactic steroid eye drops, intraocular pressure increased after the 7th cycle. To avoid steroid-induced glaucoma, topical tacrolimus (twice daily) was initiated after the seventh cycle with the patient’s consent. The eighth cycle is currently planned. Table1 illustrates the administration dates of Tv and the onset dates of adverse effects for Cases 1 along with the corresponding treatments. Case 2 A 30-year-old woman with stage IVB cervical adenocarcinoma developed bilateral conjunctival redness and serous discharge one week after the second administration of TV (Fig. 2A). Adenoviral testing was negative. A pseudomembrane was observed on the upper palpebral conjunctiva (Fig. 2B); it was thin, fibrous, and soft. Fluorescein staining revealed multiple erosions on the temporal bulbar conjunctiva of the left eye (Fig. 2C), clearly distinct from herpetic dendritic lesions. The pseudomembrane was easily removed using Millipore filters (0.45 µm and 0.22 µm), fixed in 95% ethanol, and stained with PAS. Impression cytology demonstrated numerous segmented neutrophils without detectable microorganisms (Fig. 2D). The lesions improved with topical 1% dexamethasone (five times daily) and frequent preservative-free lubricants. Dexamethasone was tapered over two weeks and discontinued. After extending the dosing interval and reducing the TV dose, no recurrence of conjunctival hyperemia was observed. The seventh cycle has recently been completed. The clinical course of case 2 was summarized in table 2. Both patients had no abnormalities in the pre-treatment ophthalmic screening examinations and received prophylactic 0.1% fluorometholone eye drop, brimonidine eye drop, and artificial tears at the time of TV administration according to a suggested protocol. Topical steroids were administered for four days starting the day before TV infusion. Brimonidine hydrochloride was administered on the day of TV administration, and artificial tears were continued for 30 days thereafter. Throughout the observation period, best-corrected visual acuity and intraocular pressure remained stable. Discussion As the application of antibody-drug conjugates (ADCs) broadens, ocular toxicities such as conjunctivitis and keratopathy are increasingly identified [ 1 – 4 ]. The pathogenesis of tisotumab vedotin (TV)-induced pseudomembranous conjunctivitis might involve on-target and off-target effects. Considering the amount of tissue factor (TF) expression in the conjunctival epithelium, it is speculated that on-target adverse event is main cause of pseudo-membranous conjunctivitis wit neutrophil-dominant inflammation. Although previous studies [ 5 – 8 ] have focused on the incidence and clinical presentation of conjunctivitis and pseudo-membrane formation associated with TV, this is the first time to investigate the cellular composition or clarify whether inflammation was infectious or sterile. The formation of pseudomembranes typically suggests an acute and cumulative inflammatory response. In our cases, the absence of microorganisms and the rapid response to steroids suggest an immune-mediated reaction rather than infection. From the findings of multiple conjunctival epithelial erosions shown in case 2, we hypothesize that the sterile inflammatory necrotic process underlying TV-induced on and off -target ocular toxicity. The clinical phenomenon of TV-induced ocular toxicity resembles the epithelial damage-induced immune response seen in drug-induced pseud-ocular pemphigoid (drug-induced pseud-ocular pemphigoid), which causes neutrophil accumulation and chronic inflammation [ 9 , 10 ]. At present, at our affiliation, among 8 patients receiving TV, severe ocular side effects are seen only in two cases. Therefore, some other epigenetic effects like anti-cancer drugs or eye drops previously administered which resulted in weak ocular surface might be a trigger of adverse ocular events. This is further investigation to clarify the prognosis of the adverse events. Past reports have indicated that some TV-related ocular adverse events were associated with infections [ 7 ]. Our case series also requires differentiation from infections. However, our cases were diagnosed as non-infectious because smear and culture tests were negative for microorganisms, and no purulent ocular discharge was observed in the patients. Nevertheless, we consider that corneal infections may occur as secondary events following adverse events caused by ADCs. The occurrence of ophthalmic adverse events despite prophylactic steroid eye drops suggests that current prevention strategies may be inadequate. Early steroid treatment upon onset of side effects was useful for preventing scar formation and maintaining ocular surface integrity. However, continued use of steroid eye drops also caused problems with elevated intraocular pressure. Reducing the dosage of anticancer drugs is a safe approach; however, when this is not feasible due to the patient's general condition, consideration should be given to the use of brimonidine eye drops or tacrolimus eye drops, in addition to steroids, for reducing congestion and inflammation. The accumulation and sharing of cases of ocular adverse events associated with antibody drugs, along with the exploration of appropriate management strategies, is an urgent priority. Conclusion TV can cause pseudomembranous conjunctivitis characterized by neutrophil infiltration even with current preventive measures, necessitating early detection and prompt anti-inflammatory therapy. To ensure the safe long-term use of this drug, it is essential to accumulate case data and investigate optimal preventive and management strategies. Declarations Ethics approval and consent to participate Ethics approval was not required for this case report in accordance with institutional policy. Written informed consent was obtained from both patients for participation and publication. Consent for publication Written informed consent for publication of clinical details and images was obtained from the patients. Availability of data and materials All relevant data supporting the findings of this study are included within the article. Competing interests All authors declare that they have no competing interests. Funding The authors received no specific funding for this work. Authors’ contributions K.A-S and S.B conceived the study and drafted the manuscript. A.I and H.S collected clinical data. M.K performed cytological analysis. H.I supervised the study. All authors reviewed and approved the final manuscript. Acknowledgements English language refinement was assisted using ChatGPT (OpenAI, San Francisco, CA, USA) and Deep L (DeepL SE, Cologne, Germany). All authors reviewed and approved the final manuscript and take full responsibility for its content and accuracy. References Ho WL, Yau T, Wong H. The ophthalmological complications of targeted agents in cancer therapy: what do we need to know as ophthalmologists? Acta Ophthalmol, 2013;91:604-609. Marshall RF, Xu H, Berkenstock M. Ocular toxicities associated with antibody drug conjugates. Curr Opin Ophthalmol, 2024;35:494-498. Fortes BH, Tailor PD, Dalvin LA. Ocular toxicity of targeted anticancer agents. Drugs, 2021;81:771-823. Bates D, Eastman A. Microtubule destabilizing agents: far more than just antimitotic anticancer drugs. Br J Clin Pharmacol, 2017;83:255-268. Vergote I, González-Martín A, Fujiwara K, et al. Tisotumab vedotin as second- or third-line therapy for recurrent cervical cancer. N Engl J Med, 2024;391:544-556. Bouguerra ZB, Rousseau F, Fauquier S, et al. Practical clinical management of ocular adverse events related to antibody-drug conjugates in gynecological malignancies. Cancer Treat Rev, 2025;134:102867. Lent-Schochet D, Tauber S, Seagrave Z, et al. Ocular surface disease related to tisotumab vedotin-tftv. Gynecol Oncol Rep, 2025;57:101676. Parikh AA, Hanna J, Shah AP. Acute keratoconjunctivitis associated with tisotumab vedotin-tftv for metastatic cervical cancer. Am J Ophthalmol Case Rep, 2023;33:101979. Bremer T, Murthy S, Patzelt S, et al. The receptor BLT1 is essential on neutrophils in a mouse model of mucous membrane pemphigoid. JCI Insight, 2025;10:e173914. Du G, Patzelt S, van Beek N, Schmidt E. Mucous membrane pemphigoid. Autoimmun Rev. 2022; 21:103036. doi: 10.1016/j.autrev.2022.103036. Tables Table 1. Clinical Course of Case 1 Cycle Tv Administration Date (Day) Ocular Prophylaxis Dose of TV Ocular Adverse Events Management 1 July 14, 20XX (Day 0) DEX x4/day 100% None — 2 Aug 4, 20XX (Day 21) DEX x4/day 100% Left pseudomembranous conjunctivitis (Aug 12, 20XX) DEX ×6/day, tapered and discontinued 3 Sept 22, 20XX (Day 70) DEX ×4/day 80% None — 4 Oct 20, 20XX (Day 98) FLM ×4/day 80% Left conjunctivitis (Oct 28, 20XX) DEX ×3/day → DEX ×1/day until next cycle 5 Nov 10, 20XX (Day 119) DEX ×1/day continued 80% Bilateral conjunctivitis (Nov 18, 20XX) DEX ×2/day → FLM ×2/day until next cycle 6 Dec 1, 20XX (Day 140) FLM ×4/day continued 80% Right conjunctivitis (Dec 9, 20XX) FLM ×4/day until next cycle 7 Dec 22, 20XX (Day 161) FLM ×4/day continued 80% Bilateral conjunctivitis (Dec 30, 20XX) DEX ×6/day, tapering Abbreviations: DEX, dexamethasone ophthalmic solution; FLM, fluorometholone ophthalmic suspension; TV, tisotumab vedotin. Table 2. Clinical Course of Case 2 Cycle Tv Administration Date (Day) Ocular Prophylaxis Dose of TV Ocular Adverse Events Management Outcome 1 Aug 7, 20XX (Day 0) DEX ×4/day 100% None — — 2 Aug 28, 20XX (Day 21) 100% None — — 3 Sept 18, 20XX (Day 42) 100% Eye discharge; pseudomembranous conjunctivitis (Sept 26, 20XX) DEX ×5/day, tapered Resolved within 1 week 4 Oct 31, 20XX (Day 85) 80% None — — 5 Nov 21, 20XX (Day 106) 80% None — — 6 Dec 26, 20XX (Day 141) 80% None — — 7 Jan 16, 20XX+1 (Day 162) 80% None — — Abbreviations: DEX, dexamethasone ophthalmic solution; FLM, fluorometholone ophthalmic suspension; TV, tisotumab vedotin. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 08 Apr, 2026 Reviewers agreed at journal 28 Mar, 2026 Reviewers invited by journal 25 Mar, 2026 Editor invited by journal 03 Mar, 2026 Editor assigned by journal 02 Mar, 2026 Submission checks completed at journal 02 Mar, 2026 First submitted to journal 23 Feb, 2026 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8947841","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":612296629,"identity":"4aa65674-f9fc-469a-aa26-c2a04f5a7b95","order_by":0,"name":"Kaoru Araki-Sasaki","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIie2RsWrDMBCGf2NQF7ddawrVK1wIBPo2Eh28JGkhS4ZiDAVnCXj11lfQG9RgUBc/gLvZBNqlQ7MlEGgVuriDknQLQd9yIO4T/90BDseR4iWEG8Avuo9sr9I3TaLbvE8BZIKADvkf4LPXdpk/xNHzrCBvNcX4kies+cLF2KZQNeyHisqRqoTwgwqTMMVZLwebWBUMETZUjBRE4Xvpt1Qa7DoAM1EtwbKPxbqhOOJZm3jrFPJlq2x2KKjFwATzBeo74NwoihkFOxSqPwe3OZU9Vb+jNLPIXMs0nJN9Fp5Fi7f5JuY8u1+2ZmMyeyr11WqqrRv7Q/FbtnciLQ5Sujz+X3E4HI5T5QeIl1VS8cC+JQAAAABJRU5ErkJggg==","orcid":"","institution":"Kansai Medical University","correspondingAuthor":true,"prefix":"","firstName":"Kaoru","middleName":"","lastName":"Araki-Sasaki","suffix":""},{"id":612296630,"identity":"51ddfe7f-f651-4e11-a739-496bfc6e91a1","order_by":1,"name":"Shogen Boku","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shogen","middleName":"","lastName":"Boku","suffix":""},{"id":612296631,"identity":"ab9d7f3f-0800-427d-a6eb-2cd3eb25a231","order_by":2,"name":"Megumi Kitamura","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Megumi","middleName":"","lastName":"Kitamura","suffix":""},{"id":612296632,"identity":"58dad043-519a-4008-adf9-c791a576cb22","order_by":3,"name":"Hiroshi Shiraga","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Shiraga","suffix":""},{"id":612296635,"identity":"bf6c342c-136e-4d18-96c0-aac6d451d259","order_by":4,"name":"Hiromi Murata","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hiromi","middleName":"","lastName":"Murata","suffix":""},{"id":612296643,"identity":"06872cff-060b-46a3-abdb-e68129f9f39a","order_by":5,"name":"Atsuko Ishimoto","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Atsuko","middleName":"","lastName":"Ishimoto","suffix":""},{"id":612296661,"identity":"6f4d5a35-b633-4779-8368-6c9ada23f9ce","order_by":6,"name":"Hisanori Imai","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hisanori","middleName":"","lastName":"Imai","suffix":""}],"badges":[],"createdAt":"2026-02-23 13:53:51","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8947841/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8947841/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105548661,"identity":"46fda547-f3a4-4bfe-8b6c-28093077a060","added_by":"auto","created_at":"2026-03-27 09:34:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1076732,"visible":true,"origin":"","legend":"\u003cp\u003ea Conjunctival hyperemia and edema with epiphora after the third administration of TV\u003c/p\u003e\n\u003cp\u003eb White pseudo-membrane on the upper palpebral conjunctiva\u003c/p\u003e\n\u003cp\u003ec Cytology showing dense neutrophilic infiltration (cells with segmented nuclei) without microorganism (Giemsa staining)\u003c/p\u003e\n\u003cp\u003ed Mild conjunctivitis recurrence upon re-administration of TV despite suggested regime and ongoing fluorometholone\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8947841/v1/d2d7cb36bb9aa1b18c82ab87.jpg"},{"id":105548662,"identity":"19e109f4-477b-4b5f-83e8-af88bd2e0356","added_by":"auto","created_at":"2026-03-27 09:34:33","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":967470,"visible":true,"origin":"","legend":"\u003cp\u003ea Bilateral conjunctival hyperemia after the second administration of TV\u003c/p\u003e\n\u003cp\u003eb Extensive pseudo-membrane formation on the upper palpebral conjunctiva\u003c/p\u003e\n\u003cp\u003ec Fluorescein staining showing multiple conjunctival erosions on the temporal bulbar conjunctiva of the left eye; the white circle indicates the cornea\u003c/p\u003e\n\u003cp\u003ed Impression cytology of the pseudo-membrane revealing numerous neutrophils with segmented nuclei (PAS stain)\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8947841/v1/64f384e513d1d084b25a7198.jpg"},{"id":105548663,"identity":"88d97331-0b38-426e-b173-8f27c0d41e28","added_by":"auto","created_at":"2026-03-27 09:34:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2496319,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8947841/v1/10c8bead-14c0-4d34-a329-525a22784313.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Sterile Neutrophilic Pseudomembranous Conjunctivitis Associated with Tisotumab Vedotin: Clinical and Cytological Evidence from Two Cases","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAntibody\u0026ndash;drug conjugates (ADCs) enable targeted delivery of cytotoxic agents to tumor cells; however, they may also cause off-target effects in normal tissues expressing the same receptor [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Tisotumab vedotin-tftv (TV), which targets tissue factor (TF) and is conjugated with monomethyl auristatin E (MMAE), was approved for the treatment of recurrent cervical cancer in 2025. Because TF is expressed in various epithelial tissues, including conjunctival epithelial cells (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://eye-transcriptome.com/search_latest.php\u003c/span\u003e\u003cspan address=\"https://eye-transcriptome.com/search_latest.php\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003cp\u003e), ocular adverse effects were anticipated and have been reported. Prophylactic eye care measures, such as preventive eye drops and cooling packs, are recommended during TV therapy. Nevertheless, ocular surface disorders have occurred despite these measures [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Previous reports described pseudomembranes, fibrosis, erosions, scarring, and punctate epithelial keratitis; however, detailed histopathological findings remain limited. Here, we describe the clinical and pathological features of two cases of TV-induced pseudomembranous conjunctivitis and discuss their management to promote the safe use of this ADC.\u003c/p\u003e"},{"header":"Case reports","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCase 1\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 40-year-old woman with recurrent cervical squamous cell carcinoma (stage IIIC1) developed unilateral redness and discharge after the third administration of TV. Slit-lamp examination revealed conjunctival hyperemia and a removable pseudomembrane on the upper palpebral conjunctiva (Fig. 1A, B). The membrane appeared slightly hardened and scar-like. Although the presentation resembled epidemic keratoconjunctivitis, adenoviral antigen testing was negative and no preauricular lymphadenopathy was noted.\u003c/p\u003e\n\u003cp\u003eThe pseudomembrane was excised and examined histologically. Giemsa staining demonstrated numerous segmented neutrophils, consistent with acute inflammation (Fig. 1C). No microorganisms were identified on smear or culture.\u003c/p\u003e\n\u003cp\u003eTopical dexamethasone (six times daily) and lubricants resulted in complete resolution within two weeks, and the steroid was tapered over an additional one week. TV therapy was resumed after a one-month interval.\u003c/p\u003e\n\u003cp\u003eDespite continuous prophylactic fluorometholone (three times daily), marked conjunctival hyperemia without membrane formation recurred one week after the fourth administration (Fig. 1D). The inflammation again responded to topical dexamethasone (three times daily). Dexamethasone was tapered to once daily and maintained during subsequent cycles.\u003c/p\u003e\n\u003cp\u003eMild conjunctival hyperemia developed approximately one week after each TV administration thereafter. When a 3-week TV treatment cycle was repeatedly administered alongside prophylactic steroid eye drops, intraocular pressure increased after the 7th cycle. To avoid steroid-induced glaucoma, topical tacrolimus (twice daily) was initiated after the seventh cycle with the patient\u0026rsquo;s consent. The eighth cycle is currently planned.\u003c/p\u003e\n\u003cp\u003eTable1 illustrates the administration dates of Tv and the onset dates of adverse effects for Cases 1 along with the corresponding treatments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCase 2\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 30-year-old woman with stage IVB cervical adenocarcinoma developed bilateral conjunctival redness and serous discharge one week after the second administration of TV (Fig. 2A). Adenoviral testing was negative. A pseudomembrane was observed on the upper palpebral conjunctiva (Fig. 2B); it was thin, fibrous, and soft.\u003c/p\u003e\n\u003cp\u003eFluorescein staining revealed multiple erosions on the temporal bulbar conjunctiva of the left eye (Fig. 2C), clearly distinct from herpetic dendritic lesions. The pseudomembrane was easily removed using Millipore filters (0.45 \u0026micro;m and 0.22 \u0026micro;m), fixed in 95% ethanol, and stained with PAS. Impression cytology demonstrated numerous segmented neutrophils without detectable microorganisms (Fig. 2D).\u003c/p\u003e\n\u003cp\u003eThe lesions improved with topical 1% dexamethasone (five times daily) and frequent preservative-free lubricants. Dexamethasone was tapered over two weeks and discontinued. After extending the dosing interval and reducing the TV dose, no recurrence of conjunctival hyperemia was observed. The seventh cycle has recently been completed.\u003c/p\u003e\n\u003cp\u003eThe clinical course of case 2 was summarized in table 2.\u003c/p\u003e\n\u003cp\u003eBoth patients had no abnormalities in the pre-treatment ophthalmic screening examinations and received prophylactic 0.1% fluorometholone eye drop, brimonidine eye drop, and artificial tears at the time of TV administration according to a suggested protocol. Topical steroids were administered for four days starting the day before TV infusion. Brimonidine hydrochloride was administered on the day of TV administration, and artificial tears were continued for 30 days thereafter. Throughout the observation period, best-corrected visual acuity and intraocular pressure remained stable.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs the application of antibody-drug conjugates (ADCs) broadens, ocular toxicities such as conjunctivitis and keratopathy are increasingly identified [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The pathogenesis of tisotumab vedotin (TV)-induced pseudomembranous conjunctivitis might involve on-target and off-target effects. Considering the amount of tissue factor (TF) expression in the conjunctival epithelium, it is speculated that on-target adverse event is main cause of pseudo-membranous conjunctivitis wit neutrophil-dominant inflammation. Although previous studies [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] have focused on the incidence and clinical presentation of conjunctivitis and pseudo-membrane formation associated with TV, this is the first time to investigate the cellular composition or clarify whether inflammation was infectious or sterile.\u003c/p\u003e \u003cp\u003eThe formation of pseudomembranes typically suggests an acute and cumulative inflammatory response. In our cases, the absence of microorganisms and the rapid response to steroids suggest an immune-mediated reaction rather than infection. From the findings of multiple conjunctival epithelial erosions shown in case 2, we hypothesize that the sterile inflammatory necrotic process underlying TV-induced on and off -target ocular toxicity.\u003c/p\u003e \u003cp\u003eThe clinical phenomenon of TV-induced ocular toxicity resembles the epithelial damage-induced immune response seen in drug-induced pseud-ocular pemphigoid (drug-induced pseud-ocular pemphigoid), which causes neutrophil accumulation and chronic inflammation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAt present, at our affiliation, among 8 patients receiving TV, severe ocular side effects are seen only in two cases. Therefore, some other epigenetic effects like anti-cancer drugs or eye drops previously administered which resulted in weak ocular surface might be a trigger of adverse ocular events. This is further investigation to clarify the prognosis of the adverse events.\u003c/p\u003e \u003cp\u003ePast reports have indicated that some TV-related ocular adverse events were associated with infections [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Our case series also requires differentiation from infections. However, our cases were diagnosed as non-infectious because smear and culture tests were negative for microorganisms, and no purulent ocular discharge was observed in the patients. Nevertheless, we consider that corneal infections may occur as secondary events following adverse events caused by ADCs.\u003c/p\u003e \u003cp\u003eThe occurrence of ophthalmic adverse events despite prophylactic steroid eye drops suggests that current prevention strategies may be inadequate. Early steroid treatment upon onset of side effects was useful for preventing scar formation and maintaining ocular surface integrity. However, continued use of steroid eye drops also caused problems with elevated intraocular pressure. Reducing the dosage of anticancer drugs is a safe approach; however, when this is not feasible due to the patient's general condition, consideration should be given to the use of brimonidine eye drops or tacrolimus eye drops, in addition to steroids, for reducing congestion and inflammation.\u003c/p\u003e \u003cp\u003eThe accumulation and sharing of cases of ocular adverse events associated with antibody drugs, along with the exploration of appropriate management strategies, is an urgent priority.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTV can cause pseudomembranous conjunctivitis characterized by neutrophil infiltration even with current preventive measures, necessitating early detection and prompt anti-inflammatory therapy. To ensure the safe long-term use of this drug, it is essential to accumulate case data and investigate optimal preventive and management strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was not required for this case report in accordance with institutional policy. Written informed consent was obtained from both patients for participation and publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of clinical details and images was obtained from the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll relevant data supporting the findings of this study are included within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no specific funding for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eK.A-S and S.B conceived the study and drafted the manuscript.\u003cbr\u003e\u0026nbsp;A.I and H.S collected clinical data.\u003cbr\u003e\u0026nbsp;M.K performed cytological analysis.\u003cbr\u003e\u0026nbsp;H.I supervised the study.\u003cbr\u003e\u0026nbsp;All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEnglish language refinement was assisted using ChatGPT (OpenAI, San Francisco, CA, USA) and Deep L (DeepL SE, Cologne, Germany). All authors reviewed and approved the final manuscript and take full responsibility for its content and accuracy.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eHo WL, Yau T, Wong H. The ophthalmological complications of targeted agents in cancer therapy: what do we need to know as ophthalmologists? Acta Ophthalmol, 2013;91:604-609.\u003c/li\u003e\n \u003cli\u003eMarshall RF, Xu H, Berkenstock M. Ocular toxicities associated with antibody drug conjugates. Curr Opin Ophthalmol, 2024;35:494-498.\u003c/li\u003e\n \u003cli\u003eFortes BH, Tailor PD, Dalvin LA. Ocular toxicity of targeted anticancer agents. Drugs, 2021;81:771-823.\u003c/li\u003e\n \u003cli\u003eBates D, Eastman A. Microtubule destabilizing agents: far more than just antimitotic anticancer drugs. Br J Clin Pharmacol, 2017;83:255-268.\u003c/li\u003e\n \u003cli\u003eVergote I, Gonz\u0026aacute;lez-Mart\u0026iacute;n A, Fujiwara K, et al. Tisotumab vedotin as second- or third-line therapy for recurrent cervical cancer. N Engl J Med, 2024;391:544-556.\u003c/li\u003e\n \u003cli\u003eBouguerra ZB, Rousseau F, Fauquier S, et al. Practical clinical management of ocular adverse events related to antibody-drug conjugates in gynecological malignancies. Cancer Treat Rev, 2025;134:102867.\u003c/li\u003e\n \u003cli\u003eLent-Schochet D, Tauber S, Seagrave Z, et al. Ocular surface disease related to tisotumab vedotin-tftv. Gynecol Oncol Rep, 2025;57:101676.\u003c/li\u003e\n \u003cli\u003eParikh AA, Hanna J, Shah AP. Acute keratoconjunctivitis associated with tisotumab vedotin-tftv for metastatic cervical cancer. Am J Ophthalmol Case Rep, 2023;33:101979.\u003c/li\u003e\n \u003cli\u003eBremer T, Murthy S, Patzelt S, et al. The receptor BLT1 is essential on neutrophils in a mouse model of mucous membrane pemphigoid. JCI Insight, 2025;10:e173914.\u003c/li\u003e\n \u003cli\u003eDu G, Patzelt S, van Beek N, Schmidt E. Mucous membrane pemphigoid. Autoimmun Rev. 2022; 21:103036. doi: 10.1016/j.autrev.2022.103036.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Clinical Course of Case 1\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"973\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003eCycle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eTv Administration Date (Day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eOcular Prophylaxis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eDose of TV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 249px;\"\u003e\n \u003cp\u003eOcular Adverse Events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 266px;\"\u003e\n \u003cp\u003eManagement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eJuly 14, 20XX (Day 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eDEX x4/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 249px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 266px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eAug 4, 20XX (Day 21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eDEX x4/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 249px;\"\u003e\n \u003cp\u003eLeft pseudomembranous conjunctivitis (Aug 12, 20XX)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 266px;\"\u003e\n \u003cp\u003eDEX \u0026times;6/day, tapered and discontinued\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eSept 22, 20XX (Day 70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eDEX \u0026times;4/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 249px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 266px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eOct 20, 20XX (Day 98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eFLM \u0026times;4/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e80%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 249px;\"\u003e\n \u003cp\u003eLeft conjunctivitis (Oct 28, 20XX)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 266px;\"\u003e\n \u003cp\u003eDEX \u0026times;3/day \u0026rarr; DEX \u0026times;1/day until next cycle\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eNov 10, 20XX (Day 119)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eDEX \u0026times;1/day continued\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 249px;\"\u003e\n \u003cp\u003eBilateral conjunctivitis (Nov 18, 20XX)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 266px;\"\u003e\n \u003cp\u003eDEX \u0026times;2/day \u0026rarr; FLM \u0026times;2/day until next cycle\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eDec 1, 20XX (Day 140)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eFLM \u0026times;4/day continued\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 249px;\"\u003e\n \u003cp\u003eRight conjunctivitis (Dec 9, 20XX)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 266px;\"\u003e\n \u003cp\u003eFLM \u0026times;4/day until next cycle\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eDec 22, 20XX (Day 161)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eFLM \u0026times;4/day continued\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 249px;\"\u003e\n \u003cp\u003eBilateral conjunctivitis (Dec 30, 20XX)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 266px;\"\u003e\n \u003cp\u003eDEX \u0026times;6/day, tapering\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: DEX, dexamethasone ophthalmic solution; FLM, fluorometholone ophthalmic suspension; TV, tisotumab vedotin.\u003c/p\u003e\n\u003cp\u003eTable 2. Clinical Course of Case 2\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"976\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eCycle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 206px;\"\u003e\n \u003cp\u003eTv Administration Date (Day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eOcular Prophylaxis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003eDose of TV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003eOcular Adverse Events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003eManagement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 206px;\"\u003e\n \u003cp\u003eAug 7, 20XX (Day 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eDEX \u0026times;4/day\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 206px;\"\u003e\n \u003cp\u003eAug 28, 20XX (Day 21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 206px;\"\u003e\n \u003cp\u003eSept 18, 20XX (Day 42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003eEye discharge; pseudomembranous conjunctivitis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(Sept 26, 20XX)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003eDEX \u0026times;5/day, tapered\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eResolved within 1 week\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 206px;\"\u003e\n \u003cp\u003eOct 31, 20XX (Day 85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 206px;\"\u003e\n \u003cp\u003eNov 21, 20XX (Day 106)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 206px;\"\u003e\n \u003cp\u003eDec 26, 20XX (Day 141)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 206px;\"\u003e\n \u003cp\u003eJan 16, 20XX+1 (Day 162)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: DEX, dexamethasone ophthalmic solution; FLM, fluorometholone ophthalmic suspension; TV, tisotumab vedotin.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"tisotumab vedotin, tissue factor, antibody–drug conjugate (ADC), pseudomembranous conjunctivitis, ocular toxicity","lastPublishedDoi":"10.21203/rs.3.rs-8947841/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8947841/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTisotumab vedotin-tftv (TV), an antibody-drug conjugate (ADC), represents a significant advancement in cancer therapy but carries the potential to induce ocular surface toxicity. Having encountered ocular side effects with TV and obtained intriguing findings from histological examination, we discuss the pathophysiology and management approaches.\u003c/p\u003e\u003ch2\u003eCases:\u003c/h2\u003e \u003cp\u003eTwo female patients with advanced cervical cancer receiving TV therapy developed pseudomembranous conjunctivitis after 2 to 3 doses. Both cases presented with conjunctival hyperemia and pseudomembrane formation on the tarsal conjunctiva. One case additionally exhibited multiple epithelial erosions on the inferior conjunctiva. Cytology of the pseudomembrane showed neutrophilic infiltration but no detectable microorganisms. This suggested an immune-mediated erosion, such as a tissue factor-mediated reaction in the conjunctival epithelium. Complete remission was achieved within two weeks with topical corticosteroids (dexamethasone eye drops: 4\u0026ndash;5 times daily) and lubricants. In both cases, after achieving grade 0 by extending the treatment interval, re-treatment was performed; however, ocular side effects recurred in Case 1. Four days of prophylactic steroid eye drops failed to prevent side effects, but intensifying steroid eye drops allowed inflammation to resolve without sequelae. However, intraocular pressure increased after the seventh dose. In Case 2, after side effects appeared, TV administration was resumed with extended intervals and reduced dosage; no conjunctivitis side effects were observed under the recommended prophylactic protocol. Both patients have now completed the seventh dose.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eTV may cause pseudomembranous conjunctivitis with conjunctival erosion characterized by non-infectious neutrophilic infiltration, suggesting off-target cytotoxicity. Further case accumulation is necessary for the appropriate management of TV-induced ophthalmic side effects.\u003c/p\u003e","manuscriptTitle":"Sterile Neutrophilic Pseudomembranous Conjunctivitis Associated with Tisotumab Vedotin: Clinical and Cytological Evidence from Two Cases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-27 09:34:28","doi":"10.21203/rs.3.rs-8947841/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-08T15:57:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"235076388792694883693957711217183713094","date":"2026-03-29T03:20:49+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-25T05:19:09+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-03T05:56:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-02T11:33:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-02T11:32:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2026-02-23T13:39:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0e524d2e-c6b7-4d94-a76a-41db4b9476af","owner":[],"postedDate":"March 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-27T09:34:28+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-27 09:34:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8947841","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8947841","identity":"rs-8947841","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}