Immune-related cystitis due to immune checkpoint inhibitors: a case report

Immune-related cystitis due to immune checkpoint inhibitors: a case report | 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 Immune-related cystitis due to immune checkpoint inhibitors: a case report WenLai Li, Kezhi Shi, Xuanwei Li, Yue Li, Congyuan Ma, Ping Zhu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2742084/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background： Immune checkpoint inhibitors (ICIs) have been proven to be beneficial in multiple advanced malignancies. However, the widespread use of ICIs also occurred with various immune-related adverse events (irAEs). However, while various immune-related adverse events related to immune checkpoint inhibitors have been reported, there are few reports of lower urinary tract symptoms. Case presentation： A 42-year-old woman with lung cancer who was being treated with sintilimab, anlotinib, and denosumab presented to the nephrology department with frequent micturition, urgency, odynuria and gross hematuria. Initial laboratory tests did not reveal bacteria, but CT examination suggested cystitis. After empiric antiinfective therapy, the above symptoms did not improve significantly. The patient stopped taking sinlizumab and completed cystoscopy. Based on the combined clinical manifestations and laboratory findings, he was diagnosed with immune-related cystitis. Symptomatic relief was achieved via steroid treatment. Thereafter, the patient has been followed for 3 months without any symptoms or recurrence of immune-related cystitis Conclusions: immune-related cystitis is a commonly misdiagnosed disease. However, early diagnosis, treatment and prophylaxis through accumulated clinical data can help patients achieve a good prognosis. Therefore, clinicians need to be well aware of the variety of clinical characteristics and treatment options of this disease. immune checkpoint inhibitors immune-related cystitis lung cancer hematuria Case report Figures Figure 1 Figure 2 Figure 3 Introduction The appearance of immune checkpoint inhibitors (ICIs) is of epoch-making significance in oncology. The application of ICIs significantly prolongs the survival time of patients and is widely used in clinical practice. With the wide application of ICIs, immune-related adverse events (irAEs) have been gradually reported. This article reports a case of immune-related cystitis after sindilizumab, anlotinib and denosumab immunotherapy to provide reference for clinical treatment. Case Report A 42-year-old female patient visited The First College of Clinical Medical Science, China Three Gorges University in October 2019 with multiple nodules on the left neck, irritable dry cough and headache. The patient was diagnosed with "malignant tumor of the right lung" and admitted to hospital for treatment. After receiving multi-line treatment, including chemotherapy, and targeted therapy, among others, the effect was not good and the patient's disease progressed. On April 26, 2022, the patient was treated with Sintilimab, Anlotinib and Denosumab, a few days The patient experienced gross hematuria with frequent micturition, urgency and odynuria. She did not receive any treatment until she was re-admitted to the hospital on May 24,2022. We performed a routine urine examination, the results showed urobilinogen 2+, urine occult blood 1+, urine protein 2+, white blood cells 3+, sediment red blood cells 51.6 cells/ul. We also did a urine culture, but it didn't show any bacteria. In addition, the white blood cell count, neutrophil count, C-reactive protein and procalcitonin were not abnormal. CT(Computed Tomography) examination of the patient 's urinary system: the bladder wall is thickened, the surrounding fat space is blurred, considering inflammation (Fig. 1 ), giagnosis: Cystitis. At first, we considered the possibility of cystitis caused by bacteria. So, we treated the disease with amoxicillin and clavulanate potassium, 10 days later (From 25 May to 4 June), we rechecked the patient's urinalysis, the result show that occult blood 2+, white blood cells 3+, sediment red blood cells 85.9(cells/ul), sediment white blood cells 1486.2(cells/ul). According to the examination results, it show that the treatment effect was not good. After consultation with oncologist, it was considered to be related to sinlizumab, and it was suggested to discontinue tumor drugs to complete cystoscopy. The drug was switched to Piperacillin Sodium and Tazobactam Sodium for Injection (June 5 to June 10). During this time we again urine culture, the result is still negative. The patient's symptoms of frequent micturition, urgency and odynuria were improved than before, but there's still hematuria. The reexamination results showed that occult blood 1+, white blood cell 3+, sediment red blood cell 35.8(cells/ul), sediment white blood cell 1638.2(cells/ul). In this patient with limited response to anti-infective therapy. So, we performed cystoscopy, which showed hyperemia and redness of bladder mucosa, bilateral ureteral orifices, and no neoplasm in bladder. It suggest immune-related cystitis or radiation-related cystitis (Fig. 2 ). Combined with the patient's urine routine, blood test, urinary CT, medication information and cystoscopy results, we considered the diagnosis of immune-related cystitis. Hormone therapy is recommended according to CTCAE grade 2 and above, so we treat it with steroids from June 11(methylprednisolone hemisuccinate 40mg, intravenous drip for 3 days). After steroid treatment the symptom of frequent micturition, urgent micturition and dysuria disappeared, and hematuria also disappear. So the patient was discharged without incident, the patient was told to change the methylprednisolone hemisuccinate to prednisolone (PSL) maintenance dose of 1.0 mg/kg and taper. Final maintenance dose was 10mg daily until 28 July 2022, the patient's re-examination of urine routine showed no abnormality, so prednisolone was discontinued(Fig. 3 ). During the follow-up on August 10, 2022, the urine routine of the patient remained normal. Discussion ICIs are monoclonal antibodies directed against negative regulatory components of T cells. These monoclonal antibodies work by blocking internal down-regulators of the immune system, so-called "immune checkpoints." ICIs restore the tumor-killing activity of T lymphocytes by blocking the signaling pathways of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) or programmed death protein 1(PD-1) and programmed death ligand 1 (PD-L1)[ 1 ]. There are three major categories of ICIs currently used in clinical practice:CTLA-4,PD-1 and PD-L1.With the increasing use of immune checkpoint inhibitors, adverse reactions have been reported[ 1 ]. The most common adverse reactions are skin, intestinal, endocrine, pulmonary and musculoskeletal adverse reactions[ 2 ]. The mechanism of immune-related adverse reactions remains unclear. Some potential mechanisms include increased activity of T cells against antigens present on tumors and normal tissues; Increased concentration of pre-existing autoimmune antibodies; Increased levels of inflammatory cytokines; enhanced immune response mediated by components of CTLA-4 antibody directly bound to normal tissues expressing CTLA-4 antibody[ 3 ]. It has been reported that combination therapy with immune checkpoint inhibitors may lead to an increased incidence and earlier onset of irAEs, coincidentally, this patient was treated with a combination of immune checkpoint inhibitors[ 4 ]. To our knowledge, current reports of immune-related cystitis are rare in irAEs. The patient's urine routine, urine cytology and urinary CT showed cystitis, which was ineffective after treatment with multiple anti-infective drugs, so it should not be considered as the pathogenic bacteria of urinary tract infection. The patient's urinary symptoms were improved than before when using steroid hormone, and the reexamination of urine routine showed gradual improvement, so it was considered as immune-related cystitis. Studies have shown that steroid therapy does not affect the efficacy of immune checkpoint inhibitor therapy[ 5 ]. Treatment of irAEs of CTCAE Grade 2 or higher requires dose delay or discontinuation and symptomatic treatment. Steroids are recommended for Grade 2 irAEs and Grade 3 or higher irAEs that persist for more than 1 week[ 6 ].This patient was CTCAE Grade 3, steroids were administered as prescribed and were gradually reduced and eventually discontinued as symptoms improved. If urinary tract irritation symptoms occur during ICIs, multiple etiological examinations have no evidence of infection, and anti-infection treatment is ineffective, it is necessary to be alert to the possibility of immune-related cystitis. In this case, the symptoms were relieved in a short time after stopping ICIs and using hormone therapy, which confirms that hormone therapy is effective for immune-related cystitis. At present, there are few case reports of immune-related cystitis, so it is impossible to further analyze the high risk factors, severity of disease, hormone treatment dose, prognostic factors and so on. We believe that these problems will be solved gradually in future research. We reported a case of immune-related cystitis following treatment with ICIs. This case reminds us of the need to consider the possibility of irAEs for any symptoms that develop during the treatment period of ICIs. The possibility of immune-related cystitis should be considered as soon as possible when there are urinary system symptoms, urine routine, urine cytology, etc. indicating inflammatory changes, but there is no evidence of infection and tumor, and anti-infective treatment is ineffective. In addition, we need to cooperate with professional oncologists to help diagnose irAEs timely and accurately. This case also suggests that early steroid therapy may help to control the progression of immune-related cystitis and reduce the total dose and time of steroids. Abbreviations IRAE immune-related adverse event ICIs immune checkpoint inhibitors irAEs immune-related adverse events CT computed tomography CTCAE common terminology criteria for adverse events PSL prednisolone CTLA-4 cytotoxic T lymphocyte associated antigen 4 PD-1 programmed death protein 1 PD-L1 programmed death ligand 1 Declarations Acknowledgements Not applicable. Authors’ contributions WLL, KZS, XWL and PZ were involved in diagnosis, management and follow‑up of the patient at all stages. CYM and YL contributed substantially and significantly to the literature review, drafting of the initial manuscript, critical revision and preparation of the final version. All authors have participated sufficiently in the work to take public responsibility for the presented content. All the authors have contributed, read and approved the final and revised version of the manuscript. Funding This study was supported by Scientific Research project of Education Department of Hubei Province (grant. no. B2017024) and the Natural Science Foundation of Yichang City (grant.no. A20-2-002). This funding source had no role in the report of this case and did not have any role during its interpretation, or decision to submit report. Records and data pertaining to this case are in the patient’s secure medical records in the First College of Clinical Medical Science, China Three Gorges University. If needed, the relevant material can be provided by corresponding author on reasonable request. Declarations Ethics approval and consent to participate Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Consent for publication Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. Availability of data and materials The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. References Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50(12):1–11. 10.1038/s12276-018-0191-1 . Brahmer JR, Abu-Sbeih H, Ascierto PA, Brufsky J, Cappelli LC, Cortazar FB, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6). 10.1136/jitc-2021-002435 . Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018;378(2):158–68. 10.1056/NEJMra1703481 . Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology: official journal of the European Society for Medical Oncology. 2017;28(suppl4):iv119–iv42. 10.1093/annonc/mdx225 . Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, et al. Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin oncology: official J Am Soc Clin Oncol. 2015;33(28):3193–8. 10.1200/jco.2015.60.8448 . Ozaki K, Takahashi H, Murakami Y, Kiyoku H, Kanayama H. A case of cystitis after administration of nivolumab. Int cancer Conf J. 2017;6(4):164–6. 10.1007/s13691-017-0298-6 . Additional Declarations No competing interests reported. Supplementary Files CAREchecklist.pdf Cite Share Download PDF Status: Posted Version 1 posted 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-2742084","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":192264079,"identity":"49b2b04f-c9d9-4a97-a2c6-5fd3876646c6","order_by":0,"name":"WenLai Li","email":"","orcid":"","institution":"Three Gorges University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"WenLai","middleName":"","lastName":"Li","suffix":""},{"id":192264080,"identity":"3121fdb2-c4c7-4603-acfa-74613e0c8ad7","order_by":1,"name":"Kezhi Shi","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kezhi","middleName":"","lastName":"Shi","suffix":""},{"id":192264081,"identity":"24f4a7f6-9803-4195-ba2a-f4a2a301649b","order_by":2,"name":"Xuanwei Li","email":"","orcid":"","institution":"Three Gorges University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xuanwei","middleName":"","lastName":"Li","suffix":""},{"id":192264082,"identity":"1a7f836b-60f2-43e0-b643-b73e1f043e19","order_by":3,"name":"Yue Li","email":"","orcid":"","institution":"The Renhe Hospital of Three Gorges University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Li","suffix":""},{"id":192264083,"identity":"05233b33-8d77-44d7-9319-a76f02a7b9ec","order_by":4,"name":"Congyuan Ma","email":"","orcid":"","institution":"Three Gorges University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Congyuan","middleName":"","lastName":"Ma","suffix":""},{"id":192264084,"identity":"c8d2cee8-0d70-4907-ad7b-4924aab0d534","order_by":5,"name":"Ping Zhu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYPACGx42ZuYDBz78IEItD4RKk+Nnb0s8OLOHeC2HjSV7zhgf5mAjQos9e+/hFz93MCduuJHz4TDQBHl+sQMEbOE5l2bZe4YNqCV3w+ECCwbDmbMTCGiRyDEz4G3jgWiZwcOQYHCbCC2Gf9skQA57cJiHjTgtxo952wxA3mcgUsuZc2nMsm0JoEA2AAayBGG/sLf3Hv74tu0/KCoff/jww0aeX5qAFqA9bBJIPAmc6pC1MH8gRtkoGAWjYBSMYAAAYS1G5cXtR2oAAAAASUVORK5CYII=","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Zhu","suffix":""}],"badges":[],"createdAt":"2023-03-27 12:44:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2742084/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2742084/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":35967092,"identity":"6b808439-16b4-4119-b27c-2c99fbebc491","added_by":"auto","created_at":"2023-04-18 22:52:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":138062,"visible":true,"origin":"","legend":"\u003cp\u003eUrinary CT: Bladder wall is thickened and the surrounding fat space is blurred.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2742084/v1/773a6ac085e69af8e53ab89d.png"},{"id":35966355,"identity":"1ea2e302-a293-4228-b74a-3c3323674658","added_by":"auto","created_at":"2023-04-18 22:44:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":238454,"visible":true,"origin":"","legend":"\u003cp\u003eCystoscope view: hyperemia and redness of bladder mucosa, bilateral ureteral orifices, and no neoplasm in bladder.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2742084/v1/a77f6bfae6b58abcdc9b9ff5.png"},{"id":35966351,"identity":"3264ab3a-0c82-4662-a900-08b3d2083933","added_by":"auto","created_at":"2023-04-18 22:44:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":46646,"visible":true,"origin":"","legend":"\u003cp\u003eChanges of RBCs and WBCs in patients treated with drugs. From 25 May to 4 June, we used amoxicillin and clavulanate potassium; From June 5 to June 10, we used Piperacillin Sodium and Tazobactam Sodium; From June 11 to June 15, we used steroids.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2742084/v1/2abd7b57f151a9d525755bc0.png"},{"id":47431972,"identity":"2620c045-3ee4-4bed-8c54-3373a1f888ee","added_by":"auto","created_at":"2023-12-01 10:07:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1145416,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2742084/v1/badc39c7-d59b-4516-af74-43afd1ac76e5.pdf"},{"id":35966357,"identity":"e36f81c6-cf87-438b-8b33-d1ac478e960b","added_by":"auto","created_at":"2023-04-18 22:44:16","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":183840,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2742084/v1/a7d0e73e48ca56e1d1bee01e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Immune-related cystitis due to immune checkpoint inhibitors: a case report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe appearance of immune checkpoint inhibitors (ICIs) is of epoch-making significance in oncology. The application of ICIs significantly prolongs the survival time of patients and is widely used in clinical practice. With the wide application of ICIs, immune-related adverse events (irAEs) have been gradually reported. This article reports a case of immune-related cystitis after sindilizumab, anlotinib and denosumab immunotherapy to provide reference for clinical treatment.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 42-year-old female patient visited The First College of Clinical Medical Science, China Three Gorges University in October 2019 with multiple nodules on the left neck, irritable dry cough and headache. The patient was diagnosed with \"malignant tumor of the right lung\" and admitted to hospital for treatment. After receiving multi-line treatment, including chemotherapy, and targeted therapy, among others, the effect was not good and the patient's disease progressed. On April 26, 2022, the patient was treated with Sintilimab, Anlotinib and Denosumab, a few days The patient experienced gross hematuria with frequent micturition, urgency and odynuria. She did not receive any treatment until she was re-admitted to the hospital on May 24,2022. We performed a routine urine examination, the results showed urobilinogen 2+, urine occult blood 1+, urine protein 2+, white blood cells 3+, sediment red blood cells 51.6 cells/ul. We also did a urine culture, but it didn't show any bacteria. In addition, the white blood cell count, neutrophil count, C-reactive protein and procalcitonin were not abnormal. CT(Computed Tomography) examination of the patient 's urinary system: the bladder wall is thickened, the surrounding fat space is blurred, considering inflammation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), giagnosis: Cystitis. At first, we considered the possibility of cystitis caused by bacteria. So, we treated the disease with amoxicillin and clavulanate potassium, 10 days later (From 25 May to 4 June), we rechecked the patient's urinalysis, the result show that occult blood 2+, white blood cells 3+, sediment red blood cells 85.9(cells/ul), sediment white blood cells 1486.2(cells/ul). According to the examination results, it show that the treatment effect was not good. After consultation with oncologist, it was considered to be related to sinlizumab, and it was suggested to discontinue tumor drugs to complete cystoscopy. The drug was switched to Piperacillin Sodium and Tazobactam Sodium for Injection (June 5 to June 10). During this time we again urine culture, the result is still negative. The patient's symptoms of frequent micturition, urgency and odynuria were improved than before, but there's still hematuria. The reexamination results showed that occult blood 1+, white blood cell 3+, sediment red blood cell 35.8(cells/ul), sediment white blood cell 1638.2(cells/ul). In this patient with limited response to anti-infective therapy. So, we performed cystoscopy, which showed hyperemia and redness of bladder mucosa, bilateral ureteral orifices, and no neoplasm in bladder. It suggest immune-related cystitis or radiation-related cystitis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Combined with the patient's urine routine, blood test, urinary CT, medication information and cystoscopy results, we considered the diagnosis of immune-related cystitis. Hormone therapy is recommended according to CTCAE grade 2 and above, so we treat it with steroids from June 11(methylprednisolone hemisuccinate 40mg, intravenous drip for 3 days). After steroid treatment the symptom of frequent micturition, urgent micturition and dysuria disappeared, and hematuria also disappear. So the patient was discharged without incident, the patient was told to change the methylprednisolone hemisuccinate to prednisolone (PSL) maintenance dose of 1.0 mg/kg and taper. Final maintenance dose was 10mg daily until 28 July 2022, the patient's re-examination of urine routine showed no abnormality, so prednisolone was discontinued(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). During the follow-up on August 10, 2022, the urine routine of the patient remained normal.\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eICIs are monoclonal antibodies directed against negative regulatory components of T cells. These monoclonal antibodies work by blocking internal down-regulators of the immune system, so-called \"immune checkpoints.\" ICIs restore the tumor-killing activity of T lymphocytes by blocking the signaling pathways of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) or programmed death protein 1(PD-1) and programmed death ligand 1 (PD-L1)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. There are three major categories of ICIs currently used in clinical practice:CTLA-4,PD-1 and PD-L1.With the increasing use of immune checkpoint inhibitors, adverse reactions have been reported[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The most common adverse reactions are skin, intestinal, endocrine, pulmonary and musculoskeletal adverse reactions[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mechanism of immune-related adverse reactions remains unclear. Some potential mechanisms include increased activity of T cells against antigens present on tumors and normal tissues; Increased concentration of pre-existing autoimmune antibodies; Increased levels of inflammatory cytokines; enhanced immune response mediated by components of CTLA-4 antibody directly bound to normal tissues expressing CTLA-4 antibody[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It has been reported that combination therapy with immune checkpoint inhibitors may lead to an increased incidence and earlier onset of irAEs, coincidentally, this patient was treated with a combination of immune checkpoint inhibitors[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. To our knowledge, current reports of immune-related cystitis are rare in irAEs. The patient's urine routine, urine cytology and urinary CT showed cystitis, which was ineffective after treatment with multiple anti-infective drugs, so it should not be considered as the pathogenic bacteria of urinary tract infection. The patient's urinary symptoms were improved than before when using steroid hormone, and the reexamination of urine routine showed gradual improvement, so it was considered as immune-related cystitis.\u003c/p\u003e \u003cp\u003eStudies have shown that steroid therapy does not affect the efficacy of immune checkpoint inhibitor therapy[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Treatment of irAEs of CTCAE Grade 2 or higher requires dose delay or discontinuation and symptomatic treatment. Steroids are recommended for Grade 2 irAEs and Grade 3 or higher irAEs that persist for more than 1 week[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].This patient was CTCAE Grade 3, steroids were administered as prescribed and were gradually reduced and eventually discontinued as symptoms improved. If urinary tract irritation symptoms occur during ICIs, multiple etiological examinations have no evidence of infection, and anti-infection treatment is ineffective, it is necessary to be alert to the possibility of immune-related cystitis. In this case, the symptoms were relieved in a short time after stopping ICIs and using hormone therapy, which confirms that hormone therapy is effective for immune-related cystitis. At present, there are few case reports of immune-related cystitis, so it is impossible to further analyze the high risk factors, severity of disease, hormone treatment dose, prognostic factors and so on. We believe that these problems will be solved gradually in future research.\u003c/p\u003e \u003cp\u003eWe reported a case of immune-related cystitis following treatment with ICIs. This case reminds us of the need to consider the possibility of irAEs for any symptoms that develop during the treatment period of ICIs. The possibility of immune-related cystitis should be considered as soon as possible when there are urinary system symptoms, urine routine, urine cytology, etc. indicating inflammatory changes, but there is no evidence of infection and tumor, and anti-infective treatment is ineffective. In addition, we need to cooperate with professional oncologists to help diagnose irAEs timely and accurately. This case also suggests that early steroid therapy may help to control the progression of immune-related cystitis and reduce the total dose and time of steroids.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIRAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmune-related adverse event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICIs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmune checkpoint inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eirAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmune-related adverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTCAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecommon terminology criteria for adverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePSL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprednisolone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTLA-4\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecytotoxic T lymphocyte associated antigen 4\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogrammed death protein 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD-L1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogrammed death ligand 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWLL, KZS, XWL and PZ were involved in diagnosis, management and follow‑up of the patient at all stages. CYM and YL contributed substantially and significantly to the literature review, drafting of the initial manuscript, critical revision and preparation of the final version. All authors have participated sufficiently in the work to take public responsibility for the presented content. All the authors have contributed, read and approved the final and revised version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Scientific Research project of Education Department of Hubei Province (grant. no. B2017024) and the Natural Science Foundation of Yichang City (grant.no. A20-2-002). This funding source had no role in the report of this case and did not have any role during its interpretation, or decision to submit report.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRecords and data pertaining to this case are in the patient\u0026rsquo;s secure medical records in the First College of Clinical Medical Science, China Three Gorges University. If needed, the relevant material can be provided by corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDarvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50(12):1\u0026ndash;11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s12276-018-0191-1\u003c/span\u003e\u003cspan address=\"10.1038/s12276-018-0191-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrahmer JR, Abu-Sbeih H, Ascierto PA, Brufsky J, Cappelli LC, Cortazar FB, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/jitc-2021-002435\u003c/span\u003e\u003cspan address=\"10.1136/jitc-2021-002435\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePostow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018;378(2):158\u0026ndash;68. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMra1703481\u003c/span\u003e\u003cspan address=\"10.1056/NEJMra1703481\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology: official journal of the European Society for Medical Oncology. 2017;28(suppl4):iv119\u0026ndash;iv42. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/annonc/mdx225\u003c/span\u003e\u003cspan address=\"10.1093/annonc/mdx225\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHorvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, et al. Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin oncology: official J Am Soc Clin Oncol. 2015;33(28):3193\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/jco.2015.60.8448\u003c/span\u003e\u003cspan address=\"10.1200/jco.2015.60.8448\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOzaki K, Takahashi H, Murakami Y, Kiyoku H, Kanayama H. A case of cystitis after administration of nivolumab. Int cancer Conf J. 2017;6(4):164\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s13691-017-0298-6\u003c/span\u003e\u003cspan address=\"10.1007/s13691-017-0298-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"immune checkpoint inhibitors, immune-related cystitis, lung cancer, hematuria, Case report","lastPublishedDoi":"10.21203/rs.3.rs-2742084/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2742084/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground：\u003c/strong\u003eImmune checkpoint inhibitors (ICIs) have been proven to be beneficial in multiple advanced malignancies. However, the widespread use of ICIs also occurred with various immune-related adverse events (irAEs). However, while various immune-related adverse events related to immune checkpoint inhibitors have been reported, there are few reports of lower urinary tract symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation：\u003c/strong\u003eA 42-year-old woman with lung cancer who was being treated with sintilimab, anlotinib, and denosumab presented to the nephrology department with frequent micturition, urgency, odynuria and gross hematuria. Initial laboratory tests did not reveal bacteria, but CT examination suggested cystitis. After empiric antiinfective therapy, the above symptoms did not improve significantly. The patient stopped taking sinlizumab and completed cystoscopy. Based on the combined clinical manifestations and laboratory findings, he was diagnosed with immune-related cystitis. Symptomatic relief was achieved via steroid treatment. Thereafter, the patient has been followed for 3 months without any symptoms or recurrence of immune-related cystitis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e immune-related cystitis is a commonly misdiagnosed disease. However, early diagnosis, treatment and prophylaxis through accumulated clinical data can help patients achieve a good prognosis. Therefore, clinicians need to be well aware of the variety of clinical characteristics and treatment options of this disease.\u003c/p\u003e","manuscriptTitle":"Immune-related cystitis due to immune checkpoint inhibitors: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-04-18 22:44:11","doi":"10.21203/rs.3.rs-2742084/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6988d4dc-464f-4620-a8f0-968623fbc9de","owner":[],"postedDate":"April 18th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-12-01T09:59:33+00:00","versionOfRecord":[],"versionCreatedAt":"2023-04-18 22:44:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2742084","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2742084","identity":"rs-2742084","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}