Ocular Manifestations in Adult-Onset Still’s Disease: A Rare Case of Bilateral Uveitis and Updated Literature Review

Ocular Manifestations in Adult-Onset Still’s Disease: A Rare Case of Bilateral Uveitis and Updated Literature Review | 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 Ocular Manifestations in Adult-Onset Still’s Disease: A Rare Case of Bilateral Uveitis and Updated Literature Review Claudio Karsulovic, Cristhian Urzua, Lia Hojman, Alex Castro This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6497504/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 Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disorder with a broad clinical spectrum. Ocular involvement is extremely rare and typically associated with chronic disease or posterior segment inflammation. To date, acute bilateral anterior uveitis has not been reported as an initial manifestation of AOSD. Case presentation We report the case of a 30-year-old patient who presented with fever, urticarial rash, arthralgia, and acute bilateral ocular pain and photophobia. Comprehensive infectious and autoimmune workups were negative. Dermatologic and histopathologic findings, elevated inflammatory markers, and markedly increased IL-6 and sCD25 levels supported the diagnosis of AOSD. The patient responded rapidly to systemic corticosteroids and IL-6 blockade with tocilizumab, achieving full clinical and ophthalmologic remission. Discussion This case represents the first report of acute bilateral anterior uveitis as the initial clinical manifestation of AOSD. The ocular inflammation was likely driven by cytokine dysregulation, particularly IL-6, which may compromise the blood-ocular barrier. The favorable response to tocilizumab further supports IL-6 as a key pathogenic factor. Considering this, we conducted a focused literature review, identifying four additional cases of ocular involvement in AOSD. These cases underline the importance of prompt diagnosis and immunomodulatory treatment to preserve vision and control systemic disease. Conclusion This case expands the known clinical spectrum of AOSD and underscores the need to consider it in patients presenting with bilateral anterior uveitis and systemic inflammatory signs. IL-6 inhibition may be an effective therapeutic approach in such atypical presentations. Figures Figure 1 Figure 2 Introduction Adult-onset Still’s disease (AOSD) is a rare autoinflammatory disorder characterized by systemic inflammation, including spiking fever, arthralgia or arthritis, evanescent rash, and elevated inflammatory markers( 1 ). Although its pathogenesis remains poorly understood, AOSD is believed to result from dysregulated innate immune responses, leading to overproduction of cytokines such as interleukin (IL)-1, IL-6, and IL-18( 2 , 3 ) Ocular involvement in AOSD is exceptionally rare, with uveitis being infrequently reported and primarily associated with chronic disease forms. Previous reports suggest that when uveitis occurs in AOSD, it is often chronic and secondary to the underlying inflammatory state rather than an acute presentation( 1 ). Acute anterior uveitis, particularly bilateral presentations, has not been documented as a clinical manifestation of AOSD to date. This case not only provides a novel perspective on the potential ocular complications of AOSD but also emphasizes its clinical significance by highlighting the need for heightened awareness of atypical presentations that could influence diagnostic strategies and therapeutic approaches. This case describes a patient with acute bilateral anterior uveitis as a unique and previously unreported presenting feature of AOSD, broadening the clinical spectrum of this disease. The potential link between the inflammatory cytokine milieu characteristic of AOSD and uveitis has been suggested, with IL-6 overproduction playing a central role in both systemic and ocular inflammation ( 4 , 5 ) The presence of acute bilateral anterior uveitis poses significant diagnostic challenges, as it requires exclusion of infectious, autoimmune, and systemic inflammatory conditions( 6 ). In this case, extensive evaluations ruled out potential infectious causes such as tuberculosis, syphilis, and viral etiologies, including herpes simplex virus and cytomegalovirus. Autoimmune conditions such as sarcoidosis, Behçet’s disease, and spondyloarthropathies were also excluded through targeted laboratory and imaging studies. This thorough exclusion process ultimately guided the diagnosis towards adult-onset Still’s disease (AOSD) as the underlying cause. In adults, bilateral anterior uveitis is more commonly associated with Behçet’s disease, sarcoidosis, or inflammatory bowel disease. This case demonstrates how elevated inflammatory markers and cytokines, alongside the exclusion of traditional autoimmune or infectious causes, can guide the diagnosis toward AOSD. Moreover, the rapid response to corticosteroids and IL-6 inhibition underscores the potential for targeted therapies in managing such atypical presentations. We identified and analyzed four key publications that reported ocular involvement in AOSD, specifically uveitis or related posterior segment complications. These include two cases of bilateral or unilateral anterior/panuveitis, and two additional cases involving Purtscher-like retinopathy, which, although not classic uveitis, reflect ocular involvement during intense systemic inflammation. In all cases, infectious and autoimmune differentials were ruled out, and treatment strategies combined systemic corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), or biologics with local ophthalmic therapies when needed. The overall outcomes were favorable, with good visual recovery in most patients. Case Description A 30-year-old patient presented with a two-week history of general malaise, myalgia, and fever up to 39°C, predominantly in the evenings. An infectious diseases team evaluated the patient, ruling out common and foreign infections, given a history of travel to the Caribbean a few months prior. Respiratory panel filmarray, urine culture, blood cultures, and viral agents such as Epstein-Barr virus, cytomegalovirus, HIV, and herpes were all negative. Also, an interferon gamma release assay was taken with negative result. Imaging studies, including a transthoracic echocardiogram, showed no active infectious focus. Given the absence of an infectious focus and the onset of persistent linear urticarial lesions for at least 48 hours that migrated, a rheumatology consultation was requested during hospitalization. The patient reported a family history of vitiligo and psoriasis vulgaris and noted increased hair loss over recent months, paresthesia in hands and feet without precise distribution, atypical but persistent Raynaud's phenomenon with cold and stress. Acutely, the patient experienced increasing joint pain in recent weeks, accompanying fever, and progressive ocular pain with red eyes. On examination, the patient was in good general condition despite persistent fever. Marked bilateral red eyes with photophobia but no epiphora, linear erythematous urticarial plaques on the chest, back, and extremities not directly associated with scratching were noted. Arthritis was observed in the right middle finger's metacarpophalangeal joint and right knee. Bedside ultrasonography showed synovitis with grade II power Doppler in the described MCP, without synovial hypertrophy. Laboratory results indicated an inflammatory response with a CRP of 6 mg/dl (normal value 0.5 mg/dl), ESR of 34 mm/hr, lymphopenia with an absolute count of 300 cells, elevated liver enzymes seven times the normal value, an absolute platelet count of 605,000 cells, and ferritin of 1100 mg/dl. A rheumatologic study showed ANA at a titer of 1/320 AC-2 pattern, with other autoantibodies negative. Yamaguchi criteria were reviewed, suspecting adult-onset Still's disease, with the patient meeting four major and three minor criteria, lacking only pharyngeal discomfort and negative ANA. A dermatology-rheumatology team evaluated the patient due to persistent erythematous plaques, and a biopsy was performed, suggesting AOSD (Fig. 1 ). An ophthalmology team confirmed acute bilateral anterior non-granulomatous uveitis. Hematology consultation extended the study with a PET-CT scan, showing hypermetabolic reactive lymph nodes in the mediastinum, axillae, and cervical regions without other findings. Further evaluation revealed CD25 levels at 1025 mg/dl (normal up to 625 mg/dl), serum IL-6 at 26 mg/dl (normal up to 2.1 mg/dl), and normal angiotensin-converting enzyme levels. Given these findings, a differential study by hematology demonstrated normal immunophenotyping in peripheral blood and normal beta-2 microglobulin levels. Treatment with methylprednisolone 16 mg daily was initiated, with a significant response within 24 hours. A multidisciplinary meeting, considering elevated IL-6 and sCD25 levels, led to starting tocilizumab 500 mg IV as induction therapy and maintenance with mycophenolate 2 grams daily. The patient remains asymptomatic today, with normal control tests and complete remission of ocular involvement. Case-Based Literature Review Acute bilateral panuveitis after steroid withdrawal was described one of the first reported cases of uveitis in AOSD in a 43-year-old male patient( 7 ). He had previously been diagnosed with AOSD and was being treated with corticosteroids. After self-discontinuation of treatment, he was re-hospitalized with decreased visual acuity in both eyes and sudden vision loss in the left eye. Ophthalmologic evaluation revealed acute bilateral panuveitis (inflammation involving the anterior chamber, vitreous, and retina). Infectious and autoimmune causes were ruled out, and the condition was attributed to AOSD flare following abrupt steroid withdrawal. Reintroduction of corticosteroids led to complete resolution of the inflammation and visual recovery (Table 1). Anterior uveitis with vitritis and refractory scleritis was reported the case of a 19-year-old woman with known AOSD who developed unilateral anterior uveitis with vitritis and nasal scleritis in the left eye( 8 ). Initial treatment with topical and systemic corticosteroids and methotrexate led to partial improvement. However, persistent inflammation and early signs of steroid-induced Cushing syndrome prompted the use of an intravitreal dexamethasone implant. This led to a marked clinical response, with resolution of intraocular inflammation and maintained visual acuity (20/30) without recurrence for at least four months (Table 1). Although true posterior uveitis has not been reported in AOSD, there are rare descriptions of Purtscher-like retinopathy. A case of a 48-year-old woman with bilateral visual disturbance and retinal findings characteristic of Purtscher-like retinopathy in the context of active AOSD( 9 ) and a 29-year-old Japanese woman who developed bilateral Purtscher-like retinopathy during a macrophage activation syndrome (MAS) episode in AOSD( 10 ). Treatment with IV corticosteroids and tocilizumab was effective systemically, but residual visual field defects and retinal nerve fiber layer thinning persisted (Table 1). Discussion Inflammation of the uveal tract requires a detailed diagnostic process to rule out infectious causes, both acute and chronic, as the first step in establishing a therapeutic approach( 6 ). Once infections are excluded, the clinical presentation—including laterality (unilateral or bilateral), anatomical classification (anterior, posterior, or panuveitis), and the speed of onset—helps narrow down the diagnostic possibilities. In adults, acute unilateral anterior uveitis with extraocular manifestations often points to spondyloarthropathies, inflammatory bowel disease, or sarcoidosis, while bilateral acute presentations are primarily associated with these conditions, as well as Behçet’s disease. Published case reports have shown that timely treatment with systemic corticosteroids, sometimes supplemented with methotrexate, biologics like tocilizumab, or local steroid implants; led to favorable outcomes, including full resolution of uveitis and preservation of vision in most patients. While ocular involvement is common in Crohn’s disease or systemic lupus erythematosus, it is rarely described in AOSD. When it does occur, it is typically associated with chronic forms of the disease. This case represents a unique presentation of AOSD with acute bilateral anterior uveitis as the predominant clinical feature, a finding not previously reported. The diagnostic process for this patient was particularly challenging due to the need to exclude traditional autoimmune diseases and infections comprehensively. Extensive laboratory evaluation, including repeated testing for autoantibodies and B-cell activation markers, consistently yielded negative results( 1 ). Despite these challenges, the elevated levels of inflammatory markers and innate immunity activation provided strong evidence for AOSD. A skin biopsy of slightly more persistent urticarial lesions than expected surprisingly revealed findings consistent with Still’s disease, further solidifying the diagnosis. In addition to elevated inflammatory markers, this patient exhibited significantly high levels of IL-6 and soluble IL-2 receptor (sCD25), which are associated with innate immune activation. Elevated IL-6 levels likely played a central role in the clinical manifestations observed. The development of acute bilateral anterior uveitis can be attributed to IL-6-mediated disruption of the blood-ocular barrier, promoting endothelial dysfunction and increasing vascular permeability, which facilitated macrophage and neutrophil infiltration and perpetuated localized inflammation. Similarly, the persistent fever and arthritis align with the systemic effects of IL-6 overproduction, which drives the activation of synoviocytes and systemic inflammatory responses. Elevated sCD25 levels further indicate enhanced T-cell activation, a hallmark of the cytokine milieu characteristic of AOSD. These findings supported the diagnosis of AOSD by integrating clinical manifestations, exclusion of alternative diagnoses, and the contribution of elevated inflammatory markers, underscoring the systemic and ocular impact of cytokine dysregulation. Histopathological analysis of a skin biopsy revealed an inflammatory reaction at least, compatible with AOSD, further solidifying the diagnosis. In juvenile idiopathic arthritis (JIA), another condition associated with uveitis, studies suggest that increased disease activity correlates with a higher risk of ocular involvement( 11 , 12 ). In AOSD, IL-6 overproduction likely contributes to blood-ocular barrier disruption, facilitating leukocyte infiltration and perpetuating local inflammation( 3 , 4 ) In Behçet’s disease, macrophages and dendritic cells play critical roles in antigen presentation, with pro-inflammatory M1 macrophages releasing cytokines through NF-κB and inflammasome pathways, including IL-1β. This triggers secondary recruitment of T cells, including Th1 and Th17 subsets, which release cytokines such as IL-6, IL-17, and IL-23, perpetuating the inflammatory cycle( 13 , 14 ) In AOSD, elevated IL-6 levels play a critical role in driving organ-specific manifestations. By upregulating vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1), IL-6 enhances endothelial activation and promotes leukocyte adhesion and migration, contributing to significant infiltration of inflammatory cells into ocular tissues. Macrophages recruited to the site likely polarize to a pro-inflammatory M1 phenotype as described in Behcet's disease, further amplifying local cytokine production, including IL-6 itself, and perpetuating inflammation in ocular structures. This mechanism plausibly explains the acute bilateral anterior uveitis observed in this patient, integrating systemic cytokine dysregulation with localized ocular pathology. In diseases like Behçet’s, local macrophages and dendritic cells play critical roles in antigen presentation, with M1-type macrophages releasing cytokines such as IL-1β through NF-κB and inflammasome pathways, leading to secondary recruitment of Th1 and Th17 lymphocytes. Similarly, in this patient, macrophages are likely polarized to a pro-inflammatory M1 phenotype, perpetuating inflammation through local IL-6 production and other cytokines such as IL-17 and IL-23. The rapid resolution of ocular and systemic symptoms following corticosteroid and tocilizumab treatment underscores the pivotal role of IL-6 in the pathophysiology of this disease and its potential as a therapeutic target (Fig. 2 ). This case highlights the potential for tocilizumab, an IL-6 receptor antagonist, as an effective therapy in managing atypical AOSD presentations involving organ-specific inflammation( 5 , 15 ). Other IL-6 inhibitors, such as sarilumab, or alternative biologics targeting cytokines like IL-1 (e.g., anakinra or canakinumab), may also be considered in similar cases, particularly in patients with incomplete response to tocilizumab or specific contraindications( 16 ). Elevated sCD25 levels, indicative of T-cell activation, decreased markedly after tocilizumab administration, further supporting its efficacy. In conclusion, this case documents acute bilateral anterior uveitis as a rare manifestation of AOSD, treated successfully with corticosteroids and tocilizumab. The absence of ocular or systemic relapses during follow-up suggests that IL-6 inhibition could be a cornerstone in the management of similar cases. Further investigations are warranted to delineate the mechanisms underlying ocular involvement in AOSD and to evaluate the efficacy of IL-6 inhibitors and other biologic agents as potential first-line therapies for atypical presentations. Additionally, understanding the shared pathways between systemic inflammation in AOSD and localized ocular involvement could provide insights into targeted therapeutic strategies. Declarations Conflict of interests: The authors have declared that no conflict of interest exists Funding: None Data availability statement: All data generated or analyzed during this study are included in this published article and its supplementary information. Acknowledgments: None Author Contributions: Conceptualization: CK, LH, CU, AC; Data Curation: CK, LH, CU, AC; Formal Analysis: CK, LH, CU; Funding Acquisition: CK, LH, CU; Investigation: CK, LH, CU; Resources: CK, LH, CU; Supervision: CK, LH, CU; Writing - Original Draft Preparation: CK, LH, CU, AC; Writing - Review and Editing: CK, LH, CU, AC Ethics approval and consent to participate: Written informed consent was obtained from the patient for participation in this case report, including awareness of the purpose, risks, and benefits of publication. This case report was conducted in accordance with institutional guidelines. The case was approved by the Institutional Review Board of Clínica Alemana de Santiago/Universidad del Desarrollo – Comite de Etica de la Investigacion V1.1-2013 Consent for publication: Informed consent to publish identifying clinical details and images was obtained from the patients Clinical trial number : Not applicable. References Gerfaud-Valentin M, Maucort-Boulch D, Hot A, Iwaz J, Ninet J, Durieu I, et al. Adult-Onset Still Disease. Medicine. 2014; Castañeda S, Atienza-Mateo B, Martín-Varillas JL, Serra López-Matencio JM. Anakinra for the Treatment of Adult-Onset Still’s Disease. Expert Rev Clin Immunol. 2018; Nordström D, Knight A, Luukkainen R, Vollenhoven R van, Rantalaiho V, Kajalainen A, et al. Beneficial Effect of Interleukin 1 Inhibition With Anakinra in Adult-Onset Still’s Disease. An Open, Randomized, Multicenter Study. J Rheumatol. 2012; Kaneko Y, Kameda H, Ikeda K, Ishii T, Murakami K, Takamatsu H, et al. Tocilizumab in Patients With Adult-Onset Still’s Disease Refractory to Glucocorticoid Treatment: A Randomised, Double-Blind, Placebo-Controlled Phase III Trial. Ann Rheum Dis. 2018; Lee YH. Tocilizumab in Patients With Adult-Onset Still’s Disease Refractory to Glucocorticoid Treatment. Ann Rheum Dis. 2019; Xie JS, Ocampo V, Kaplan AJ. Anterior uveitis for the comprehensive ophthalmologist. Canadian Journal of Ophthalmology. 2024; Jiang W, Tang L, Duan X, Jiang B. A case of uveitis in adult-onset Still’s disease with ophthalmologic symptoms. Rheumatol Int. 2013;33(7):1867–72. Ahn SJ, Hwang SJ, Lee BR. Intravitreal dexamethasone implants for the treatment of refractory scleritis combined with uveitis in adult-onset Still’s disease: a case report. BMC Ophthalmol. 2016;16(1):196. Buyukavsar C, Karagoz E, Sonmez M, Kar T, Kaya A, Düzgun E, et al. A rare ocular manifestation of adult onset Still’s disease: Purtscher’s-like retinopathy. Ocul Immunol Inflamm. 2018;26(2):286–91. Akiyama K, Iwasaki Y, Tanaka R. Severe adult Still’s disease complicated by Purtscher-like retinopathy treated with intravenous pulse methylprednisolone and tocilizumab. Case Rep Ophthalmol. 2021;12(2):531–7. Tappeiner C, Schenck S, Niewerth M, Heiligenhaus A, Minden K, Klotsche J. Impact of Antiinflammatory Treatment on the Onset of Uveitis in Juvenile Idiopathic Arthritis: Longitudinal Analysis From a Nationwide Pediatric Rheumatology Database. Arthritis Care Res (Hoboken). 2015; Liebling EJ, Faig W, Chang J, Mendoza E, Moore N, Vicioso NL, et al. Temporal Relationship Between Juvenile Idiopathic Arthritis Disease Activity and Uveitis Disease Activity. Arthritis Care Res (Hoboken). 2022; Tekgöz N, Çelikel E, Aydın F, Tekin ZE, Kurt T, Sezer M, et al. The Other Side of the Coin: Uveitis in Patients With Juvenile Idiopathic Arthritis. Turkish Journal of Pediatric Disease. 2023; Hosseini SM, Shoeibi N, Ebrahimi R, Ghasemi M. Patterns of Uveitis at a Tertiary Referral Center in Northeastern Iran. J Ophthalmic Vis Res. 2018; Puéchal X, Debandt M, Berthelot J, Bréban M, Dubost J, Fain O, et al. Tocilizumab in Refractory Adult Still’s Disease. Arthritis Care Res (Hoboken). 2010; Al-Homood IA. Biologic Treatments for Adult-Onset Still’s Disease. Rheumatology. 2013; Tables Table 1 Ocular Manifestation Ref. Year Treatment Outcome Bilateral acute panuveitis (7) 2013 Reintroduction of systemic corticosteroids Complete resolution, visual improvement Anterior uveitis + vitritis + scleritis (8) 2016 Systemic corticosteroids, MTX, intravitreal dexamethasone Remission of ocular inflammation, no recurrence Purtscher-like retinopathy (9) 2018 Systemic corticosteroids Not fully detailed Purtscher-like retinopathy with MAS (10) 2021 IV corticosteroids + tocilizumab Systemic remission, visual field defects persisted Additional Declarations No competing interests reported. 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6497504","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":477809844,"identity":"7b325866-af99-4c37-8145-3702c62b9aaf","order_by":0,"name":"Claudio Karsulovic","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYDACHjBpwcDAzMD4gKEAJlyAUwNMiwRIC7MBgwFM2ACnBiQtDAxsEkRp4e85/OzjzzYJOYPjzM8qfhjYRPPPbn7A8AOPFomzbcazedskjA0Os5nd7DFIy51x55gBYw8eLQb8DMbMjG0SiTObedhu8Bgczm24kWDAjM9hBvzsnxl/QrUU/jH4nzv/RvoH/Fp4e4wZgA5L7GfmYWPmMTiQu+FGDn5bJM6cKWbmOSdhzM/MZiwtY5Ccu/FGTsFBfH7h70nfzPijzEaOjf/ww49vKuxy591I3/jgRwVuLdjBAVI1jIJRMApGwShABQCD6UfPuUXzRAAAAABJRU5ErkJggg==","orcid":"","institution":"Clínica Alemana","correspondingAuthor":true,"prefix":"","firstName":"Claudio","middleName":"","lastName":"Karsulovic","suffix":""},{"id":477809845,"identity":"b5c56535-7fc1-42b8-a2a0-fc28c52d59c9","order_by":1,"name":"Cristhian Urzua","email":"","orcid":"","institution":"Clínica Alemana","correspondingAuthor":false,"prefix":"","firstName":"Cristhian","middleName":"","lastName":"Urzua","suffix":""},{"id":477809846,"identity":"d7646452-38c4-4552-b8bc-cda4161cbcac","order_by":2,"name":"Lia Hojman","email":"","orcid":"","institution":"Clínica Alemana","correspondingAuthor":false,"prefix":"","firstName":"Lia","middleName":"","lastName":"Hojman","suffix":""},{"id":477809847,"identity":"0dcc8621-662f-414a-84c9-f308ce47c74b","order_by":3,"name":"Alex Castro","email":"","orcid":"","institution":"Clínica Alemana","correspondingAuthor":false,"prefix":"","firstName":"Alex","middleName":"","lastName":"Castro","suffix":""}],"badges":[],"createdAt":"2025-04-21 15:53:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6497504/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6497504/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85848941,"identity":"e98237e4-9266-4e23-a961-df2b40dca826","added_by":"auto","created_at":"2025-07-02 10:06:06","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":103803,"visible":true,"origin":"","legend":"\u003cp\u003eHematoxylin and eosin (H\u0026amp;E), 20× magnification. A predominantly perivascular dermal inflammatory infiltrate, with a minor interstitial component. No epidermal changes are present. In panel 2, H\u0026amp;E, 40× magnification. The infiltrate is composed of lymphocytes, neutrophils, and eosinophils. Leukocyte margination and neutrophilic infiltration of the venular-capillary vessel walls are noted, without fibrinoid necrosis.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6497504/v1/77d76179e759187dd385a56d.jpg"},{"id":85848504,"identity":"8a2f5602-7800-4d87-8ee5-abb1fb700404","added_by":"auto","created_at":"2025-07-02 09:58:06","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":30306,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation of the proposed pathophysiological mechanism linking systemic cytokine dysregulation in adult-onset Still’s disease to acute bilateral anterior uveitis.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6497504/v1/5afc0cda16e5606c94a37654.jpg"},{"id":91627723,"identity":"6704478a-82b4-40b9-a022-bf078655d55d","added_by":"auto","created_at":"2025-09-18 12:24:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":570403,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6497504/v1/e234f09b-ba4e-4c78-a07b-c24450392f8d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ocular Manifestations in Adult-Onset Still’s Disease: A Rare Case of Bilateral Uveitis and Updated Literature Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAdult-onset Still\u0026rsquo;s disease (AOSD) is a rare autoinflammatory disorder characterized by systemic inflammation, including spiking fever, arthralgia or arthritis, evanescent rash, and elevated inflammatory markers(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Although its pathogenesis remains poorly understood, AOSD is believed to result from dysregulated innate immune responses, leading to overproduction of cytokines such as interleukin (IL)-1, IL-6, and IL-18(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eOcular involvement in AOSD is exceptionally rare, with uveitis being infrequently reported and primarily associated with chronic disease forms. Previous reports suggest that when uveitis occurs in AOSD, it is often chronic and secondary to the underlying inflammatory state rather than an acute presentation(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Acute anterior uveitis, particularly bilateral presentations, has not been documented as a clinical manifestation of AOSD to date. This case not only provides a novel perspective on the potential ocular complications of AOSD but also emphasizes its clinical significance by highlighting the need for heightened awareness of atypical presentations that could influence diagnostic strategies and therapeutic approaches. This case describes a patient with acute bilateral anterior uveitis as a unique and previously unreported presenting feature of AOSD, broadening the clinical spectrum of this disease. The potential link between the inflammatory cytokine milieu characteristic of AOSD and uveitis has been suggested, with IL-6 overproduction playing a central role in both systemic and ocular inflammation (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe presence of acute bilateral anterior uveitis poses significant diagnostic challenges, as it requires exclusion of infectious, autoimmune, and systemic inflammatory conditions(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In this case, extensive evaluations ruled out potential infectious causes such as tuberculosis, syphilis, and viral etiologies, including herpes simplex virus and cytomegalovirus. Autoimmune conditions such as sarcoidosis, Beh\u0026ccedil;et\u0026rsquo;s disease, and spondyloarthropathies were also excluded through targeted laboratory and imaging studies. This thorough exclusion process ultimately guided the diagnosis towards adult-onset Still\u0026rsquo;s disease (AOSD) as the underlying cause. In adults, bilateral anterior uveitis is more commonly associated with Beh\u0026ccedil;et\u0026rsquo;s disease, sarcoidosis, or inflammatory bowel disease. This case demonstrates how elevated inflammatory markers and cytokines, alongside the exclusion of traditional autoimmune or infectious causes, can guide the diagnosis toward AOSD. Moreover, the rapid response to corticosteroids and IL-6 inhibition underscores the potential for targeted therapies in managing such atypical presentations.\u003c/p\u003e \u003cp\u003eWe identified and analyzed four key publications that reported ocular involvement in AOSD, specifically uveitis or related posterior segment complications. These include two cases of bilateral or unilateral anterior/panuveitis, and two additional cases involving Purtscher-like retinopathy, which, although not classic uveitis, reflect ocular involvement during intense systemic inflammation. In all cases, infectious and autoimmune differentials were ruled out, and treatment strategies combined systemic corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), or biologics with local ophthalmic therapies when needed. The overall outcomes were favorable, with good visual recovery in most patients.\u003c/p\u003e"},{"header":"Case Description","content":"\u003cp\u003eA 30-year-old patient presented with a two-week history of general malaise, myalgia, and fever up to 39\u0026deg;C, predominantly in the evenings. An infectious diseases team evaluated the patient, ruling out common and foreign infections, given a history of travel to the Caribbean a few months prior. Respiratory panel filmarray, urine culture, blood cultures, and viral agents such as Epstein-Barr virus, cytomegalovirus, HIV, and herpes were all negative. Also, an interferon gamma release assay was taken with negative result. Imaging studies, including a transthoracic echocardiogram, showed no active infectious focus.\u003c/p\u003e \u003cp\u003eGiven the absence of an infectious focus and the onset of persistent linear urticarial lesions for at least 48 hours that migrated, a rheumatology consultation was requested during hospitalization. The patient reported a family history of vitiligo and psoriasis vulgaris and noted increased hair loss over recent months, paresthesia in hands and feet without precise distribution, atypical but persistent Raynaud's phenomenon with cold and stress. Acutely, the patient experienced increasing joint pain in recent weeks, accompanying fever, and progressive ocular pain with red eyes.\u003c/p\u003e \u003cp\u003eOn examination, the patient was in good general condition despite persistent fever. Marked bilateral red eyes with photophobia but no epiphora, linear erythematous urticarial plaques on the chest, back, and extremities not directly associated with scratching were noted. Arthritis was observed in the right middle finger's metacarpophalangeal joint and right knee. Bedside ultrasonography showed synovitis with grade II power Doppler in the described MCP, without synovial hypertrophy.\u003c/p\u003e \u003cp\u003eLaboratory results indicated an inflammatory response with a CRP of 6 mg/dl (normal value 0.5 mg/dl), ESR of 34 mm/hr, lymphopenia with an absolute count of 300 cells, elevated liver enzymes seven times the normal value, an absolute platelet count of 605,000 cells, and ferritin of 1100 mg/dl. A rheumatologic study showed ANA at a titer of 1/320 AC-2 pattern, with other autoantibodies negative. Yamaguchi criteria were reviewed, suspecting adult-onset Still's disease, with the patient meeting four major and three minor criteria, lacking only pharyngeal discomfort and negative ANA.\u003c/p\u003e \u003cp\u003eA dermatology-rheumatology team evaluated the patient due to persistent erythematous plaques, and a biopsy was performed, suggesting AOSD (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). An ophthalmology team confirmed acute bilateral anterior non-granulomatous uveitis. Hematology consultation extended the study with a PET-CT scan, showing hypermetabolic reactive lymph nodes in the mediastinum, axillae, and cervical regions without other findings. Further evaluation revealed CD25 levels at 1025 mg/dl (normal up to 625 mg/dl), serum IL-6 at 26 mg/dl (normal up to 2.1 mg/dl), and normal angiotensin-converting enzyme levels.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGiven these findings, a differential study by hematology demonstrated normal immunophenotyping in peripheral blood and normal beta-2 microglobulin levels. Treatment with methylprednisolone 16 mg daily was initiated, with a significant response within 24 hours. A multidisciplinary meeting, considering elevated IL-6 and sCD25 levels, led to starting tocilizumab 500 mg IV as induction therapy and maintenance with mycophenolate 2 grams daily. The patient remains asymptomatic today, with normal control tests and complete remission of ocular involvement.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCase-Based Literature Review\u003c/h2\u003e \u003cp\u003eAcute bilateral panuveitis after steroid withdrawal was described one of the first reported cases of uveitis in AOSD in a 43-year-old male patient(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). He had previously been diagnosed with AOSD and was being treated with corticosteroids. After self-discontinuation of treatment, he was re-hospitalized with decreased visual acuity in both eyes and sudden vision loss in the left eye. Ophthalmologic evaluation revealed acute bilateral panuveitis (inflammation involving the anterior chamber, vitreous, and retina). Infectious and autoimmune causes were ruled out, and the condition was attributed to AOSD flare following abrupt steroid withdrawal. Reintroduction of corticosteroids led to complete resolution of the inflammation and visual recovery (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eAnterior uveitis with vitritis and refractory scleritis was reported the case of a 19-year-old woman with known AOSD who developed unilateral anterior uveitis with vitritis and nasal scleritis in the left eye(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Initial treatment with topical and systemic corticosteroids and methotrexate led to partial improvement. However, persistent inflammation and early signs of steroid-induced Cushing syndrome prompted the use of an intravitreal dexamethasone implant. This led to a marked clinical response, with resolution of intraocular inflammation and maintained visual acuity (20/30) without recurrence for at least four months (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eAlthough true posterior uveitis has not been reported in AOSD, there are rare descriptions of Purtscher-like retinopathy. A case of a 48-year-old woman with bilateral visual disturbance and retinal findings characteristic of Purtscher-like retinopathy in the context of active AOSD(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) and a 29-year-old Japanese woman who developed bilateral Purtscher-like retinopathy during a macrophage activation syndrome (MAS) episode in AOSD(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Treatment with IV corticosteroids and tocilizumab was effective systemically, but residual visual field defects and retinal nerve fiber layer thinning persisted (Table\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eInflammation of the uveal tract requires a detailed diagnostic process to rule out infectious causes, both acute and chronic, as the first step in establishing a therapeutic approach(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Once infections are excluded, the clinical presentation\u0026mdash;including laterality (unilateral or bilateral), anatomical classification (anterior, posterior, or panuveitis), and the speed of onset\u0026mdash;helps narrow down the diagnostic possibilities. In adults, acute unilateral anterior uveitis with extraocular manifestations often points to spondyloarthropathies, inflammatory bowel disease, or sarcoidosis, while bilateral acute presentations are primarily associated with these conditions, as well as Beh\u0026ccedil;et\u0026rsquo;s disease.\u003c/p\u003e \u003cp\u003ePublished case reports have shown that timely treatment with systemic corticosteroids, sometimes supplemented with methotrexate, biologics like tocilizumab, or local steroid implants; led to favorable outcomes, including full resolution of uveitis and preservation of vision in most patients.\u003c/p\u003e \u003cp\u003eWhile ocular involvement is common in Crohn\u0026rsquo;s disease or systemic lupus erythematosus, it is rarely described in AOSD. When it does occur, it is typically associated with chronic forms of the disease. This case represents a unique presentation of AOSD with acute bilateral anterior uveitis as the predominant clinical feature, a finding not previously reported. The diagnostic process for this patient was particularly challenging due to the need to exclude traditional autoimmune diseases and infections comprehensively. Extensive laboratory evaluation, including repeated testing for autoantibodies and B-cell activation markers, consistently yielded negative results(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Despite these challenges, the elevated levels of inflammatory markers and innate immunity activation provided strong evidence for AOSD. A skin biopsy of slightly more persistent urticarial lesions than expected surprisingly revealed findings consistent with Still\u0026rsquo;s disease, further solidifying the diagnosis.\u003c/p\u003e \u003cp\u003eIn addition to elevated inflammatory markers, this patient exhibited significantly high levels of IL-6 and soluble IL-2 receptor (sCD25), which are associated with innate immune activation. Elevated IL-6 levels likely played a central role in the clinical manifestations observed. The development of acute bilateral anterior uveitis can be attributed to IL-6-mediated disruption of the blood-ocular barrier, promoting endothelial dysfunction and increasing vascular permeability, which facilitated macrophage and neutrophil infiltration and perpetuated localized inflammation. Similarly, the persistent fever and arthritis align with the systemic effects of IL-6 overproduction, which drives the activation of synoviocytes and systemic inflammatory responses. Elevated sCD25 levels further indicate enhanced T-cell activation, a hallmark of the cytokine milieu characteristic of AOSD. These findings supported the diagnosis of AOSD by integrating clinical manifestations, exclusion of alternative diagnoses, and the contribution of elevated inflammatory markers, underscoring the systemic and ocular impact of cytokine dysregulation. Histopathological analysis of a skin biopsy revealed an inflammatory reaction at least, compatible with AOSD, further solidifying the diagnosis.\u003c/p\u003e \u003cp\u003eIn juvenile idiopathic arthritis (JIA), another condition associated with uveitis, studies suggest that increased disease activity correlates with a higher risk of ocular involvement(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In AOSD, IL-6 overproduction likely contributes to blood-ocular barrier disruption, facilitating leukocyte infiltration and perpetuating local inflammation(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn Beh\u0026ccedil;et\u0026rsquo;s disease, macrophages and dendritic cells play critical roles in antigen presentation, with pro-inflammatory M1 macrophages releasing cytokines through NF-κB and inflammasome pathways, including IL-1β. This triggers secondary recruitment of T cells, including Th1 and Th17 subsets, which release cytokines such as IL-6, IL-17, and IL-23, perpetuating the inflammatory cycle(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn AOSD, elevated IL-6 levels play a critical role in driving organ-specific manifestations. By upregulating vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1), IL-6 enhances endothelial activation and promotes leukocyte adhesion and migration, contributing to significant infiltration of inflammatory cells into ocular tissues. Macrophages recruited to the site likely polarize to a pro-inflammatory M1 phenotype as described in Behcet's disease, further amplifying local cytokine production, including IL-6 itself, and perpetuating inflammation in ocular structures. This mechanism plausibly explains the acute bilateral anterior uveitis observed in this patient, integrating systemic cytokine dysregulation with localized ocular pathology. In diseases like Beh\u0026ccedil;et\u0026rsquo;s, local macrophages and dendritic cells play critical roles in antigen presentation, with M1-type macrophages releasing cytokines such as IL-1β through NF-κB and inflammasome pathways, leading to secondary recruitment of Th1 and Th17 lymphocytes. Similarly, in this patient, macrophages are likely polarized to a pro-inflammatory M1 phenotype, perpetuating inflammation through local IL-6 production and other cytokines such as IL-17 and IL-23. The rapid resolution of ocular and systemic symptoms following corticosteroid and tocilizumab treatment underscores the pivotal role of IL-6 in the pathophysiology of this disease and its potential as a therapeutic target (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThis case highlights the potential for tocilizumab, an IL-6 receptor antagonist, as an effective therapy in managing atypical AOSD presentations involving organ-specific inflammation(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Other IL-6 inhibitors, such as sarilumab, or alternative biologics targeting cytokines like IL-1 (e.g., anakinra or canakinumab), may also be considered in similar cases, particularly in patients with incomplete response to tocilizumab or specific contraindications(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Elevated sCD25 levels, indicative of T-cell activation, decreased markedly after tocilizumab administration, further supporting its efficacy.\u003c/p\u003e \u003cp\u003eIn conclusion, this case documents acute bilateral anterior uveitis as a rare manifestation of AOSD, treated successfully with corticosteroids and tocilizumab. The absence of ocular or systemic relapses during follow-up suggests that IL-6 inhibition could be a cornerstone in the management of similar cases. Further investigations are warranted to delineate the mechanisms underlying ocular involvement in AOSD and to evaluate the efficacy of IL-6 inhibitors and other biologic agents as potential first-line therapies for atypical presentations. Additionally, understanding the shared pathways between systemic inflammation in AOSD and localized ocular involvement could provide insights into targeted therapeutic strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interests:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have declared that no conflict of interest exists\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article and its supplementary information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: CK, LH, CU, AC; Data Curation: CK, LH, CU, AC; Formal Analysis: CK, LH, CU; Funding Acquisition: CK, LH, CU; Investigation: CK, LH, CU; Resources: CK, LH, CU; Supervision: CK, LH, CU; Writing - Original Draft Preparation: CK, LH, CU, AC; Writing - Review and Editing: CK, LH, CU, AC\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for participation in this case report, including awareness of the purpose, risks, and benefits of publication.\u003cbr\u003e\u0026nbsp;This case report was conducted in accordance with institutional guidelines. The case was approved by the Institutional Review Board of Cl\u0026iacute;nica Alemana de Santiago/Universidad del Desarrollo \u0026ndash; Comite de Etica de la Investigacion V1.1-2013\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent to publish identifying clinical details and images was obtained from\u0026nbsp;the\u0026nbsp;patients\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGerfaud-Valentin M, Maucort-Boulch D, Hot A, Iwaz J, Ninet J, Durieu I, et al. Adult-Onset Still Disease. Medicine. 2014;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCasta\u0026ntilde;eda S, Atienza-Mateo B, Mart\u0026iacute;n-Varillas JL, Serra L\u0026oacute;pez-Matencio JM. Anakinra for the Treatment of Adult-Onset Still\u0026rsquo;s Disease. Expert Rev Clin Immunol. 2018;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNordstr\u0026ouml;m D, Knight A, Luukkainen R, Vollenhoven R van, Rantalaiho V, Kajalainen A, et al. Beneficial Effect of Interleukin 1 Inhibition With Anakinra in Adult-Onset Still\u0026rsquo;s Disease. An Open, Randomized, Multicenter Study. J Rheumatol. 2012;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaneko Y, Kameda H, Ikeda K, Ishii T, Murakami K, Takamatsu H, et al. Tocilizumab in Patients With Adult-Onset Still\u0026rsquo;s Disease Refractory to Glucocorticoid Treatment: A Randomised, Double-Blind, Placebo-Controlled Phase III Trial. Ann Rheum Dis. 2018;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee YH. Tocilizumab in Patients With Adult-Onset Still\u0026rsquo;s Disease Refractory to Glucocorticoid Treatment. Ann Rheum Dis. 2019;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXie JS, Ocampo V, Kaplan AJ. Anterior uveitis for the comprehensive ophthalmologist. Canadian Journal of Ophthalmology. 2024;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang W, Tang L, Duan X, Jiang B. A case of uveitis in adult-onset Still\u0026rsquo;s disease with ophthalmologic symptoms. Rheumatol Int. 2013;33(7):1867\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhn SJ, Hwang SJ, Lee BR. Intravitreal dexamethasone implants for the treatment of refractory scleritis combined with uveitis in adult-onset Still\u0026rsquo;s disease: a case report. BMC Ophthalmol. 2016;16(1):196.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuyukavsar C, Karagoz E, Sonmez M, Kar T, Kaya A, D\u0026uuml;zgun E, et al. A rare ocular manifestation of adult onset Still\u0026rsquo;s disease: Purtscher\u0026rsquo;s-like retinopathy. Ocul Immunol Inflamm. 2018;26(2):286\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAkiyama K, Iwasaki Y, Tanaka R. Severe adult Still\u0026rsquo;s disease complicated by Purtscher-like retinopathy treated with intravenous pulse methylprednisolone and tocilizumab. Case Rep Ophthalmol. 2021;12(2):531\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTappeiner C, Schenck S, Niewerth M, Heiligenhaus A, Minden K, Klotsche J. Impact of Antiinflammatory Treatment on the Onset of Uveitis in Juvenile Idiopathic Arthritis: Longitudinal Analysis From a Nationwide Pediatric Rheumatology Database. Arthritis Care Res (Hoboken). 2015;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiebling EJ, Faig W, Chang J, Mendoza E, Moore N, Vicioso NL, et al. Temporal Relationship Between Juvenile Idiopathic Arthritis Disease Activity and Uveitis Disease Activity. Arthritis Care Res (Hoboken). 2022;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTekg\u0026ouml;z N, \u0026Ccedil;elikel E, Aydın F, Tekin ZE, Kurt T, Sezer M, et al. The Other Side of the Coin: Uveitis in Patients With Juvenile Idiopathic Arthritis. Turkish Journal of Pediatric Disease. 2023;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHosseini SM, Shoeibi N, Ebrahimi R, Ghasemi M. Patterns of Uveitis at a Tertiary Referral Center in Northeastern Iran. J Ophthalmic Vis Res. 2018;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePu\u0026eacute;chal X, Debandt M, Berthelot J, Br\u0026eacute;ban M, Dubost J, Fain O, et al. Tocilizumab in Refractory Adult Still\u0026rsquo;s Disease. Arthritis Care Res (Hoboken). 2010;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Homood IA. Biologic Treatments for Adult-Onset Still\u0026rsquo;s Disease. Rheumatology. 2013;\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 251px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOcular Manifestation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRef.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYear\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 215px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 251px;\"\u003e\n \u003cp\u003eBilateral acute panuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp class=\"MsoNormal\" align=\"center\"\u003e(7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 227px;\"\u003e\n \u003cp\u003eReintroduction of systemic corticosteroids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 215px;\"\u003e\n \u003cp\u003eComplete resolution, visual improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 251px;\"\u003e\n \u003cp\u003eAnterior uveitis + vitritis + scleritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp class=\"MsoNormal\" align=\"center\"\u003e(8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 227px;\"\u003e\n \u003cp\u003eSystemic corticosteroids, MTX, intravitreal dexamethasone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 215px;\"\u003e\n \u003cp\u003eRemission of ocular inflammation, no recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 251px;\"\u003e\n \u003cp\u003ePurtscher-like retinopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp class=\"MsoNormal\" align=\"center\"\u003e(9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 227px;\"\u003e\n \u003cp\u003eSystemic corticosteroids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 215px;\"\u003e\n \u003cp\u003eNot fully detailed\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 251px;\"\u003e\n \u003cp\u003ePurtscher-like retinopathy with MAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp class=\"MsoNormal\" align=\"center\"\u003e(10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 227px;\"\u003e\n \u003cp\u003eIV corticosteroids + tocilizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 215px;\"\u003e\n \u003cp\u003eSystemic remission, visual field defects persisted\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":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":"","lastPublishedDoi":"10.21203/rs.3.rs-6497504/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6497504/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdult-onset Still’s disease (AOSD) is a systemic autoinflammatory disorder with a broad clinical spectrum. Ocular involvement is extremely rare and typically associated with chronic disease or posterior segment inflammation. To date, acute bilateral anterior uveitis has not been reported as an initial manifestation of AOSD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe report the case of a 30-year-old patient who presented with fever, urticarial rash, arthralgia, and acute bilateral ocular pain and photophobia. Comprehensive infectious and autoimmune workups were negative. Dermatologic and histopathologic findings, elevated inflammatory markers, and markedly increased IL-6 and sCD25 levels supported the diagnosis of AOSD. The patient responded rapidly to systemic corticosteroids and IL-6 blockade with tocilizumab, achieving full clinical and ophthalmologic remission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case represents the first report of acute bilateral anterior uveitis as the initial clinical manifestation of AOSD. The ocular inflammation was likely driven by cytokine dysregulation, particularly IL-6, which may compromise the blood-ocular barrier. The favorable response to tocilizumab further supports IL-6 as a key pathogenic factor. Considering this, we conducted a focused literature review, identifying four additional cases of ocular involvement in AOSD. These cases underline the importance of prompt diagnosis and immunomodulatory treatment to preserve vision and control systemic disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case expands the known clinical spectrum of AOSD and underscores the need to consider it in patients presenting with bilateral anterior uveitis and systemic inflammatory signs. IL-6 inhibition may be an effective therapeutic approach in such atypical presentations.\u003c/p\u003e","manuscriptTitle":"Ocular Manifestations in Adult-Onset Still’s Disease: A Rare Case of Bilateral Uveitis and Updated Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 09:58:01","doi":"10.21203/rs.3.rs-6497504/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":"fd76a9c4-ce0b-487a-83a3-2f52565367fc","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-18T12:23:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-02 09:58:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6497504","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6497504","identity":"rs-6497504","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}