Current challenges facing the clinical treatment for HTLV-1 ocular manifestations

ABSTRACTIntroduction Human T-lymphotropic virus type 1 (HTLV-1) is a lifelong persistent retrovirus associated with numerous systemic and ocular diseases, presenting significant clinical challenges.Areas covered A detailed overview of HTLV-1 associated ocular diseases is provided, along with the highlighting of recent findings challenging traditional views on transmission routes and the role of proviral load in HTLV-1 disease onset. The focus is on pathogenesis, clinical presentation, diagnostic approaches, current therapeutic strategies, recent advancements, and potential future directions in treatment.Expert opinion Recent discoveries emphasize the crucial role of horizontal transmission in HTLV-1 associated diseases, highlighting the need for heightened global awareness and effective screening practices. It’s revealed that HTLV-1 uveitis onset can be accelerated patients with Graves’ disease, despite a low proviral load and short latency period. Understanding such interplay and the pathogenesis of HTLV-1-associated ocular diseases is important in developing effective treatment strategies. Given the complexities of HTLV-1 ocular diseases, interdisciplinary collaboration is of the essence.KEYWORDS: Human T-lymphotropic virus type 1HTLV-1Horizontal transmissionHTLV-1 uveitisGraves’ diseaseKeratoconjunctivitis SiccaScleritisOptic neuritisAdult T-cell leukemia/lymphomaATLL-related ocular manifestationsOpportunistic infectionsHematopoietic stem cell transplantationDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsThe Human T-Cell Leukemia Virus-1 (HTLV-1) is associated with a wide range of ocular conditions, including HTLV-1 uveitis, keratoconjunctivitis sicca, interstitial keratitis, optic neuritis, overlap syndrome, and Adult T-cell leukemia/lymphoma (ATLL)-related ocular conditions. Each condition presents unique clinical challenges that necessitate an in-depth understanding and tailored treatment strategies for effective management.Therapeutic strategies for ocular inflammatory diseases related to HTLV-1, including HTLV-1 uveitis, currently focus on suppressing inflammation and controlling symptoms, largely through the use of steroids. This reliance on steroids punctuates the crucial need for new, targeted, and less invasive treatments. While potential solutions such as targeted drugs and biologics offer promising advances, it’s necessary to conduct further research to confirm their effectiveness, assess safety, and validate their use.The growing recognition of horizontal transmission as a significant route for HTLV-1-associated disease could drive changes in public health interventions. Clinical procedures might also evolve, potentially to include HTLV-1 infection screening for patients with Graves’ disease, and improved guidelines on the use of biologics in HTLV-1 carriers.ATLL, a severe malignancy caused by HTLV-1, often presents with ocular manifestations. Early detection and appropriate management of ATLL-related ocular symptoms, including those related to leukemia eye infiltration, are critical to improving patient outcomes.The introduction of allogeneic hematopoietic stem-cell transplantation has improved ATLL treatment and survival, yet it can cause ocular complications such as frosted branch angiitis. Careful monitoring and frequent comprehensive ocular examinations post-transplant are crucial for early detection and treatment.The importance of robust, context-specific evidence and the need for interdisciplinary collaboration to translate research findings into clinical practice are highlighted. Despite the inherent challenges, continued efforts in research, innovation, and collaboration are essential to bring about substantial improvements in the clinical management of HTLV-1 ocular manifestations.Declaration of interestThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Figure 1. Pathogenesis of HTLV-1 Uveitis. The illustration depicts the role of HTLV-1-infected CD4+ T cells in triggering uveitis through cytokine and chemokine production. These cells not only accumulate in the eyes of affected patients but also infect human ocular cells, causing common clinical features such as vitreous opacity and retinal vasculitis.Display full sizeFigure 2. HU following methimazole treatment in Graves’ disease. HU development is depicted post-methimazole treatment for Graves’ disease. (A) Exophthalmos accompanied by Graves’ disease. (B) Vitreous opacity is observable in the right eye. (C) Retinal vasculitis is identified by fluorescein angiography. (Image reproduced with permission from Kamoi et al., Lancet, 2022 [Citation26]).Display full sizeFigure 3. (A) Traditional understanding of HTLV-1 associated diseases development. A high provirus load following a long latency period is seen as a crucial factor in the onset of ATLL, HAM/TSP, and HU.”Display full size(B) Our recent discovery. Despite a low provirus load and a short latency period, severe HU can occur in young HTLV-1 carriers post the onset of Graves’ disease and subsequent methimazole treatment. This suggests an accelerated development of HU under these conditions.Figure 4. Depiction of Ocular Infiltration. illustration demonstrates the infiltration of leukemic cells into various regions of the eye, highlighting their impact on ocular structures and vision.Display full sizeFigure 5. Clinical pictures of the Knob-like ATLL cell Multiple Ocular Infiltration (KAMOI)sign.Display full sizeThe KAMOI sign, marked by white arrows, can be observed at the bulbar conjunctiva surrounding the corneal limbus and the palpebral conjunctiva around the lacrimal punctum (A), as well as in the retina (B). ATLL cells infiltrating the vitreous tend to aggregate into multiple clusters (C). (Image reproduced with permission from Kamoi et al., Cornea 2016 [Citation92]; Kamoi et al.,Viruses. 2022 [Citation18]).Additional informationFundingThis paper was funded by JSPS KAKENHI (grant no. JP 20K09824), a Grant on Rare and Intractable Diseases from the Ministry of Health, Labour, and Welfare of Japan (grant no. 22FC0201), and a Research Program on Emerging and Re-emerging Infectious Diseases grant from the Japan Agency for Medical Research and Development, AMED (grant no. 23fk0108671h0001,23fk0108672h0001).