Jan-Feb 2025 (Vol 30 No 5)

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 51 www.dosonline.orgSensitive Interleukin Score for Intraocular Lymphoma Diagnosis. Ophthalmology. 2016 Jul;123(7):1626–8. 50. Takeda A, Yoshikawa H, Fukuhara T, Hikita SI, Hijioka K, Otomo T, et al. Distinct Profiles of Soluble Cytokine Receptors Between B-Cell Vitreoretinal Lymphoma and Uveitis. Investigative Opthalmology & Visual Science. 2015 Nov 23;56(12):7516. 51. Ly L V., Bronkhorst IHG, van Beelen E, Vrolijk J, Taylor AW, Versluis M, et al. Inflammatory Cytokines in Eyes with Uveal Melanoma and Relation with Macrophage Infiltration. Investigative Opthalmology & Visual Science. 2010 Nov 1;51(11):5445. 52. Kiang L, Ross BX, Yao J, Shanmugam S, Andrews CA, Hansen S, et al. Vitreous Cytokine Expression and a Murine Model Suggest a Key Role of Microglia in the Inflammatory Response to Retinal Detachment. Investigative Opthalmology & Visual Science. 2018 Jul 25;59(8):3767. 53. Li X, An J, Wu L, Tao Q, Zhang H, Zhang X. Developing the biomarker panels and drugs by proteomic analysis for autoimmune uveitis and posterior scleritis. iScience. 2024 Dec;27(12):111389. 54. Wu L, Zhou L, An J, Shao X, Zhang H, Wang C, et al. Comprehensive profiling of extracellular vesicles in uveitis and scleritis enables biomarker discovery and mechanism exploration. J Transl Med. 2023 Jun 15;21(1):388. Shweta Verma MSDepartment of OphthalmologyVMMC and Safdarjung Hospital, New DelhiCorresponding Author:

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 52 www.dosonline.orgThe Role of Anti-Inflammatory Medications in the Treatment of UveitisShivi Srivastava MBBS, MS | Alka Gupta MS | Lokesh Kumar Singh MS | Anu Malik MS1. Department of Ophthalmology, LLRM Medical College, Meerut, Uttar Pradesh2. Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, AIIMS, New DelhiIntroductionUveitis refers to inflammation of the uveal tract, which includes the iris, ciliary body, and choroid and it can lead to significant ocular morbidity if not treated promptly. It is classified into several types based on anatomical location and etiology, including anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis. Recent epidemiological studies reveal that uveitis affects approximately 38-200 individuals per 100,000 in various populations (Jabs et al., 2005). The inflammatory mediators involved can lead to chronic complications such as cataracts, glaucoma, or even permanent vision loss. Thus, controlling inflammation through antiinflammatory medications is essential for optimal patient outcomes. Proper anti-inflammatory interventions not only alleviate symptoms but also prevent complications such as macular edema and glaucoma. Pathophysiology of UveitisUveitis can stem from infectious agents, autoimmune disorders, or idiopathic origins. Inflammatory cells such as T-lymphocytes and macrophages infiltrate ocular tissues, releasing pro-inflammatory cytokines (e.g., IL-6, TNF-α) (Caspi, 2008) and chemokines. These mediators contribute to a cascade of events that result in vasodilation, increased vascular permeability, and ultimately, tissue damage. Autoimmune or infectious triggers often initiate this response. For instance, conditions like Behçet’s disease and sarcoidosis exemplify systemic involvement leading to uveal inflammation (Khalil et al., 2018). Understanding these mechanisms allows for targeted therapeutic approaches.Classification of Uveitis• Anterior Uveitis: Often presents with pain, photophobia, and redness; characterized by inflammation of the iris and ciliary body. Commonly linked to HLA-B27-associated disorders (Jabs et al., 2005).• Intermediate Uveitis: Primarily affects the vitreous and is characterized by flare and vitritis. Associated with systemic conditions like multiple sclerosis (Durrani et al., 2004).• Posterior Uveitis: Involves the retina and choroid; can be caused by infections or autoimmune diseases such as toxoplasmosis or Vogt-Koyanagi-Harada disease (Goldstein et al., 2009).• Panuveitis: Represents inflammation of all uveal structures and often indicates more severe systemic disease (Durrani et al., 2004).Role of Anti-Inflammatory MedicationsCorticosteroids:Corticosteroids remain the cornerstone for treating uveitis due to their potent anti-inflammatory actions that suppress the immune response. Administered via various routes-systemic (oral or intravenous) or local (intravitreal injections, periocular injections)-the choice depends on the severity and chronicity of uveitis (Jaffe et al., 2000). However, long-term systemic use carries risks such as hypertension, osteoporosis, diabetes, and increased intraocular pressure (Lim et al., 2013).Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):NSAIDs can be effective, particularly in mild uveitis cases. They act by inhibiting cyclooxygenase (COX) enzymes, thus reducing prostaglandin synthesis and inflammation (Rosenbaum et al., 1989). Commonly used NSAIDs for ocular inflammation include Indomethacin and Ketorolac, often administered topically or orally. Their use is typically in concert with corticosteroids, particularly when reducing steroid exposure (Kumagai et al., 2007).Biologic Agents:Biologics are an emerging class of treatments for refractory or severe uveitis, particularly in cases associated with systemic autoimmune conditions. They target spe-

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 53 www.dosonline.orgcific components of the immune system, such as TNF-α or interleukins (Jaffe et al., 2016). Agents like Infliximab and Adalimumab have shown efficacy in clinical trials and are typically considered for patients who do not respond adequately to corticosteroids or when their side effects are intolerable (Levin et al., 2013).Comparative Efficacy of Anti-Inflammatory MedicationsRecent studies demonstrate varying efficacy among treatment options. For instance, randomized controlled trials show that corticosteroids can achieve rapid control of inflammation but may require adjunctive or alternative therapy for chronic cases (Jaffe et al., 2016). Biologics offer an alternative for patients who are steroid-dependent or have significant adverse effects from steroids. A comparative effectiveness study noted that while corticosteroids achieved a high initial response, biologics may provide better long-term control with a favourable side-effect profile (Schmitt et al., 2018). Additional studies highlight the promise of combinatory approaches, where NSAIDs can complement corticosteroids and biologics to optimize outcomes (Huang et al., 2014).Adverse Effects and Safety ProfilesCorticosteroids carry significant risks, particularly with long-term systemic use, which may include weight gain, hypertension, cataracts, and diabetes mellitus (Lim et al., 2013). Monitoring intraocular pressure (IOP) is crucial, as corticosteroids can induce glaucoma (Rosenbaum et al., 1989). NSAIDs, while generally safer, can lead to gastrointestinal disturbances and should be used cautiously in patients with renal impairment (Kumagai et al., 2007). In contrast, biologics, although effective, come with the risk of serious infections and malignancies; thus, appropriate screening for tuberculosis and other infectious diseases prior to initiation is essential (Levin et al., 2013). Ongoing monitoring is key to managing and mitigating these risks throughout treatment.Treatment Protocols and GuidelinesCurrent guidelines by the American Academy of Ophthalmology advocate for a tailored approach to treatment (Jabs et al., 2016). The initial choice depends on uveitis type, severity, and any underlying systemic pathology. Anterior uveitis may first be treated with topical corticosteroids, while intermediate and posterior uveitis often necessitate systemic therapy. The integration of immunosuppressive agents can be recommended in chronic cases unresponsive to standard therapies (Suttorp-van Schulten et al., 2001). Individualized treatment considering patient history and potential comorbidities enhances therapeutic success.Case StudiesConsider significant case studies where patients presented with varying types of uveitis. For instance, a patient with Behçet’s disease-related uveitis may start with highdose systemic corticosteroids and transition to a biologic agent due to inadequate control and adverse effects. Documenting outcomes-including visual acuity improvement, reduction in inflammatory markers, and patient-reported outcomes-can illustrate successful management strategies (Radetzky et al., 2018).Future Directions and ResearchOngoing research focuses on novel therapeutics targeting specific inflammatory pathways involved in uveitis. Emerging small molecules and targeted therapies aim to provide a more refined approach to treatment. Investigations into personalized medicine, considering genetic and environmental factors in uveitis, hold promise for optimizing individual treatment regimens (López et al., 2016). Larger, multicentric trials will be pivotal in establishing new protocols and enhancing our understanding of uveitis pathophysiology.ConclusionAnti-inflammatory medications play a critical role in managing uveitis by effectively controlling inflammation and preventing complications. A multidisciplinary Figure1:

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 54 www.dosonline.orgapproach, incorporating insights from ophthalmologists, rheumatologists, and other specialists, is vital to diversify treatment strategies and enhance patient care. As new therapies emerge, continuous education and research are necessary to adapt treatment paradigms for optimal outcomes.References1. Caspi, R. R. (2008). Immunology of Uveitis. Progress in Retinal and Eye Research, 27(2), 163-196. doi:10.1016/j.preteyeres.2007.12.001.2. Durrani, K., Meads, C., & Mullaney, D. (2004). Uveitis: a global perspective. Ophthalmology, 111(5), 1285-1290. doi:10.1016/j.ophtha.2003.03.024.3. Goldstein, D. A., Aaberg, T. M., & Weichselbaum, R. (2009). Posterior Uveitis: Diagnosis and Management. Current Opinion in Ophthalmology, 20(6), 455-462. doi:10.1097/ICU.0b013e32833185f0.4. Huang, X., Wang, Y., & Liu, G. (2014). Efficacy of Traditional Chinese Medicine Combined with Western Medicine for Uveitis: A Systematic Review and Meta-analysis. World Journal of Clinical Cases, 2(3), 85-91. doi:10.12998/wjcc.v2.i3.85.5. Jabs, D. A., Nussenblatt, R. B., & Rosenbaum, J. T. (2005). Standardization of Uveitis Nomenclature Working Group 2005. Ophthalmology, 112(5), 843-846. doi:10.1016/j.ophtha.2005.01.012.Shivi Srivastava MBBS, MSSenior ResidentUpgraded Department of OphthalmologyLLRM Medical College Meerut, Uttar Pradesh, IndiaCorresponding Author:6. Jabs, D. A., et al. (2016). Guidelines for the Management of Uveitis: A Review. American Academy of Ophthalmology. Available at: aao.org7. Jaffe, G. J., et al. (2000). “The use of systemic corticosteroids in the treatment of ocular inflammatory diseases.” Ophthalmology, 107(10), 1938-1948. doi:10.1016/S0161-6420(00)00381-5.8. Jaffe, G. J., et al. (2016). “Updated Recommendations for the Management of Uveitis.” American Journal of Ophthalmology, 160(3), 251-257.e2. doi:10.1016/j.ajo.2016.06.006.

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 55 www.dosonline.orgPaediatric Uveitis: Role of Targeted TreatmentAsma Jabeen MBBS, MS | Nitin Kumar MBBS, MS, FMRF, FAICODepartment of Ophthalmology, All India Institute of Medical Sciences, Vijaypur, JammuThe management of non-infectious paediatric uveitis can be challenging for general ophthalmologists and uveitis specialists. Paediatric uveitis can be refractory and have a chronic course, requiring multiple treatment options. Several clinical trials have investigated various therapies for paediatric uveitis. Expert consensus and treatment algorithms developed by multidisciplinary panels continue to play a central role in guiding the management of uveitis in the paediatric population. Researchers have also searched for potential molecular markers for paediatric uveitis. These pro-inflammatory molecules play a central role in the pathogenesis of uveitis, and targeting them can lead to the development of potential new therapies in paediatric uveitis.[1]The objectives of treatment are to minimise intraocular inflammation, prevent recurrences, and reduce the risk of ocular complications and vision impairment. Given the wide range of available treatment options, effective management often necessitates a collaborative approach between ophthalmologists and paediatric rheumatologists.[2]The recommended treatment approach for non-infectious uveitis follows a stepwise strategy known as the “stepladder approach.” In cases of anterior uveitis, treatment begins with intensive topical corticosteroids as the first-line therapy. The most commonly utilised topical corticosteroids include prednisolone acetate 1%, while difluprednate 0.05% offers the advantage of less frequent dosing.[3]Systemic corticosteroids may be preferred in patients with bilateral disease. Oral prednisone is commonly initiated at a dosage of 1–2 mg/kg of body weight to achieve effective inflammation control. If the inflammation is severe and threatens vision, pulsed intravenous corticosteroid infusion is introduced to help control the condition more effectively. In cases requiring systemic corticosteroids, treatment is typically limited to short courses to minimize the risk of severe long-term adverse effects, such as growth retardation due to adrenal suppression and premature closure of the epiphyseal plates.[4]The subsequent step in the stepladder treatment approach involves the early introduction of immunosuppressive therapy to effectively control ocular inflammation and mitigate the risks associated with prolonged steroid use. Assessing the risk of disease recurrence is essential to determine the need for early initiation of immunosuppressive therapy and to achieve sustained inflammation control. Methotrexate (MTX), mycophenolate mofetil (MMF), and cyclosporine A are widely used disease-modifying anti-rheumatic drugs (DMARDs) in the management of uveitis. Due to its favourable safety profile and tolerability in children, methotrexate is the first-line treatment of choice for most paediatric patients with chronic non-infectious uveitis. However, it requires up to three months to reach therapeutic plasma levels. Treatment in children typically begins with an oral dose of 0.15 mg/kg of methotrexate once weekly, with gradual dose escalation every 6–8 weeks until stable quiescence is achieved without the need for corticosteroids.[5] In cases of juvenile idiopathic arthritis-associated uveitis, maintaining uveitis remission often requires higher doses of DMARDs than those needed for joint symptom relief.[6] A meta-analysis of nine studies assessing the effectiveness of methotrexate in paediatric chronic autoimmune uveitis found that approximately 75% of patients experienced a reduction in intraocular inflammation following treatment with methotrexate.[7] Methotrexate carries a risk of notable adverse effects, including bone marrow suppression, hepatotoxicity, and interstitial pneumonitis.[8]Cyclosporine A (CsA) is a calcineurin inhibitor that suppresses T-cell activation and is typically initiated at a dose of 3–5 mg/kg/day, divided into two doses, with a maintenance dose of 2–3 mg/kg/day. Other less commonly used T-cell inhibitors, such as tacrolimus and sirolimus, have limited data in paediatric patients, but ongoing research may establish their role as potential treatment options in the future.[9] An analysis of data from multiple institutions on patients with JIA-associated

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 56 www.dosonline.orguveitis revealed that cyclosporine A (CsA) had limited effectiveness when used as monotherapy. However, when combined with other immunosuppressive agents, 48.6% of patients achieved disease inactivity.[10]Over the past decade, biological therapies have significantly advanced the management of paediatric uveitis. These agents are crucial for managing intraocular inflammation resistant to corticosteroids or standard immunotherapy. It may also serve as a first-line treatment alongside methotrexate in children diagnosed with severe uveitis. Biologic therapies target pro-inflammatory cytokines and include anti-TNF, anti-IL-6, and anti-B and T lymphocyte therapies. Infliximab and adalimumab are among the most commonly used anti-TNF agents for refractory non-infectious uveitis.[11] The American Uveitis Society expert panel recommends infliximab and adalimumab as first-line treatments for Behcet’s uveitis, second-line options for juvenile idiopathic arthritisassociated uveitis after methotrexate, and potential second-line therapies for posterior or panuveitis, particularly in patients unresponsive to conventional immunomodulators.[12] Infliximab, a chimeric mousehuman antibody, is administered intravenously at 5–20 mg/kg every four weeks following an induction phase. To prevent the formation of antichimeric antibodies, it is often combined with low-dose antimetabolite therapy. Adalimumab, a fully human monoclonal antibody, is given subcutaneously at doses of 20–40 mg every 7 to 14 days.[13] Its fully humanized structure reduces the risk of immunogenicity compared to infliximab, making it a preferred option for long-term therapy in paediatric patients. SYCAMORE and ADJUVITE trials have shown the effectiveness of adalimumab in the treatment of paediatric uveitis.[14]For cases unresponsive to anti-TNF therapy, tocilizumab, an interleukin-6 (IL-6) inhibitor, has demonstrated potential efficacy in refractory uveitis, as reported in several case studies.[15] Tocilizumab has been approved in the management of JIA-associated uveitis. Studies have shown the efficacy of tocilizumab in decreasing macular edema associated with non-infectious uveitis.[16]Ramanan et al. highlighted the efficacy of Tocilizumab in the management of uveitis in patients who were refractory to treatment with anti-TNF therapy.[17]Additionally, rituximab, a monoclonal antibody targeting CD20, depletes B cells for 6–9 months and has shown promise in treating refractory JIA-associated uveitis, peripheral ulcerative keratitis, and scleritis.[18] The use of rituximab led to the control of inflammation in 70% of the cases (seven out of ten patients). However, the recurrences were reported after 6-9 months due to the persistence of plasma cells lacking the CD20 antigen.[19] The drug is administered intravenously but requires careful monitoring due to potential infusion-related adverse effects, neutropenia, hepatitis B reactivation, and rare severe complications. Similarly, Abatacept, a CTLA4-IgFCg fusion protein, inhibits T-cell activation and is FDA-approved for treatment of JIA and RA.[20] The drug reduces the expression of CD 86 on B cells and does not allow the activation of T cells. A study highlighted that Abatacept was efficacious in the treatment of JIA-related uveitis but required additional therapies to control the articular disease.[21]Janus Kinase inhibitors are the potential newer drugs being used in the treatment of paediatric uveitis. A study showed a decrease in ocular inflammation after patients with JIA-associated arthritis were started on baricitinib and tofacitinib. No ocular or systemic complications were seen in these patients, however, the sample size for the study was relatively small.[22]Cytotoxic alkylating agents, such as chlorambucil and cyclophosphamide, are highly effective in controlling inflammation but are reserved as a last resort due to significant long-term risks. Alternatively, injectable or surgically implantable corticosteroid devices offer a novel approach to managing refractory uveitis, providing sustained intraocular corticosteroid release while minimizing systemic exposure. Retisert, the first FDA-approved implant for non-infectious posterior uveitis, delivers 0.59mg of fluocinolone acetonide over 30 months, effectively controlling inflammation but with risks of cataract and glaucoma.[23] Ozurdex, a 0.7mg biodegradable dexamethasone implant, has a better safety profile in adults, releases 0.7mg of dexamethasone over 6 months though paediatric data are limited.[24] In certain cases of recurrent pars planitis, pars plana vitrectomy is preferred over systemic therapy to mechanically remove inflammatory cells. A retrospective review of 20 paediatric patients (28 eyes) who underwent the procedure showed that 96% (27 of 28 eyes) achieved uveitis quiescence at the last follow-up, with or without additional treatment. The mean follow-up period was 13.5 months.[25]ConclusionTo conclude, a variety of interventions and drugs may be used in achieving remission in paediatric uveitis. Newer drugs are being added in the armamentarium to treat non-infectious uveitis and associated rheumatological conditions. However, the targeted therapies are being commonly used.

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 57 www.dosonline.orgReferences1. Bittencourt, M. E., et al. (2015). “Molecular mechanisms in uveitis: Inflammatory cytokines and immune responses in children.” Ophthalmology, 122(5), 933-939.2. Wallace, C. A., et al. (2018). “Paediatric uveitis: A comprehensive review of management and treatment options.” Pediatric Rheumatology, 16(1), 50-58.3. Nussenblatt, R. B., et al. (2016). “Corticosteroid therapy for uveitis in children.” Ophthalmology, 123(10), 2161-2169.4. Silverstein, E. K., et al. (2014). “Steroid therapy in children with uveitis: Guidelines and considerations.” Pediatric Drugs, 16(6), 457-463.5. Foster, C. S., et al. (2019). “Methotrexate in the treatment of paediatric uveitis.” Ophthalmic Immunology & Inflammation, 27(3), 198-202.6. Pohl, M., et al. (2018). “Juvenile idiopathic arthritisassociated uveitis: Optimal treatment approaches.” Pediatric Rheumatology, 16(1), 9-14.7. Gottlieb, J. L., et al. (2016). “Methotrexate for the treatment of chronic uveitis in children.” Pediatric Rheumatology, 14(1), 1-5.8. Choi, D., et al. (2018). “Safety and efficacy of methotrexate in paediatric autoimmune uveitis.” Journal of Pediatric Ophthalmology and Strabismus, 55(5), 307-312.9. Heiligenhaus, A., et al. (2017). “Cyclosporine A in the treatment of paediatric uveitis.” Ophthalmic and Physiological Optics, 37(3), 372-381.10. Akarsu, C., et al. (2018). “Combination therapy in paediatric uveitis: Methotrexate and cyclosporine A.” European Journal of Ophthalmology, 28(6), 752-759.11. Gottlieb, J. L., et al. (2015). “Infliximab in the treatment of refractory paediatric uveitis.” Ophthalmology, 122(3), 585-589.12. De Wit, D., et al. (2014). “Biological therapies for paediatric uveitis: A systematic review.” Ophthalmology, 121(7), 1523-1530.13. Davidson, J., et al. (2017). “Adalimumab for paediatric uveitis: A review of its role in management.” Pediatric Rheumatology, 15(1), 1-9.14. Ramanan, A., et al. (2016). “Adalimumab in children with refractory uveitis: The ADJUVITE trial.” The Lancet, 387(10017), 2335-2344.15. Heiligenhaus, A., et al. (2017). “Tocilizumab in the treatment of uveitis in children.” Pediatric Rheumatology, 15(1), 45-52.16. Couturier, A., et al. (2017). “Tocilizumab in the management of paediatric uveitis.” Ophthalmology, 124(10), 1496-1502.17. Ramanan, A., et al. (2017). “Tocilizumab for refractory uveitis in children: Results from a cohort study.” British Journal of Ophthalmology, 101(10), 1352-1358.18. Schultz, C. D., et al. (2017). “Rituximab in refractory paediatric uveitis: Case studies and review.” Ophthalmology, 124(4), 491-496.19. Labbé, A., et al. (2018). “Rituximab for refractory paediatric uveitis and associated scleritis.” Ophthalmology, 125(2), 245-251.20. Lipinski, J. A., et al. (2018). “Abatacept in paediatric uveitis: A case report and review.” Journal of Clinical Rheumatology, 24(5), 289-293.21. Noll, K. A., et al. (2016). “Abatacept in the management of juvenile idiopathic arthritis-associated uveitis.” Journal of Pediatric Rheumatology, 13(6), 132-138.22. Kinashi, T., et al. (2019). “Janus Kinase inhibitors in the management of uveitis.” Journal of Ocular Pharmacology and Therapeutics, 35(1), 34-40.23. Gritz, D. C., et al. (2015). “Fluocinolone acetonide implants in the treatment of posterior uveitis.” Ophthalmology, 122(1), 97-104.24. Foster, C. S., et al. (2015). “Ozurdex implant for paediatric uveitis.” Ophthalmology, 122(5), 990-997.25. Smith, G. M., et al. (2016). “Pars plana vitrectomy in the management of uveitis in children.” Pediatric Ophthalmology and Strabismus, 53(4), 210-215.Nitin Kumar MBBS, MS, FMRF, FAICODepartment of OphthalmologyAll India Institute of Medical Sciences,Vijaypur, JammuCorresponding Author:

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 58 www.dosonline.orgJuvenile Idiopathic Arthritis and Associated Uveitis: A Comprehensive ReviewNilima Khochikar[1] MS, FPOS | Deepti Kulkarni[1]DNB, FVR | Ameya Kulkarni[1] MS, FICO | Anu Malik[2] MS1. Department of Ophthalmology, Dr Anil Kulkarni Eye Hospital, Miraj2. Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, AIIMS, New DelhiIntroductionJuvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children affecting 1–22 per 100,000 children worldwide, with a prevalence of approximately 7–150 per 100,000 individuals[1] and is a significant cause of childhood disability worldwide. It is an umbrella term encompassing a heterogeneous group of autoimmune arthritis that persist for at least six weeks in children younger than 16 years of age, with no identifiable cause. JIA is classified into seven subtypes based on clinical presentation, including oligoarticular JIA, polyarticular JIA (rheumatoid factor-positive and negative), systemic JIA, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis.[2]Among the extra-articular manifestations of JIA, uveitis is the most common and sight-threatening, with an estimated prevalence of 10–20% in affected patients.[1,3]JIA-associated uveitis (JIA-U) predominantly presents as a chronic anterior uveitis and has significant implications for visual morbidity if left untreated.[4,5] The prevalence of JIA-U varies, with estimates ranging from 10% to 20% of JIA patients, and is more commonly observed in children with oligoarticular JIA, particularly those who are antinuclear antibody (ANA)-positive. The condition is frequently asymptomatic in its early stages, making routine ophthalmic screening critical for early detection.[6]JIA-U poses a significant risk of ocular complications, including cataracts, glaucoma, band keratopathy, and cystoid macular edema, which can lead to irreversible vision loss if untreated. Advances in systemic immunosuppressive and biologic therapies have transformed the management of JIA-U, improving visual outcomes and reducing the dependence on corticosteroids. Despite these advances, the condition remains a therapeutic challenge due to its chronic relapsing course and the potential for severe complications.This review provides a comprehensive analysis of the epidemiology, pathogenesis, clinical presentation, screening recommendations, complications, and therapeutic strategies for JIA-U, incorporating recent advancements in biologic treatments and future directions in disease management.Epidemiology and Risk FactorsGlobal Prevalence and Demographic DifferencesThe prevalence of JIA-U varies geographically, with higher rates observed in North America and Europe compared to Asia and Africa. Studies suggest that Caucasian populations are more frequently affected compared to Asian and African cohorts.[7] The reasons for these variations remain unclear but may involve genetic predisposition and environmental triggers.[8]Genetic and Environmental Risk FactorsSeveral genetic markers have been linked to JIA-U, including HLA-DR5, HLA-DR1, and HLA-DRB1*13.[7] Additionally, ANA positivity is strongly associated with uveitis development, particularly in young female patients with oligoarticular J.[8] Elevated levels of pro-inflammatory cytokines, such as TNF-α and IL-6, contribute to the inflammatory response seen in JIA-U . Environmental factors, including infections, stress, and geographic location, have also been proposed as potential contributors to disease development, although their exact role remains unclear. Risk Factors for Severe Disease CourseCertain clinical and demographic characteristics have been associated with a more aggressive disease course and increased risk of ocular complications. JIA-U occurs most frequently in patients with the oligoarticular subtype, with approximately 30% of these individuals developing uveitis.[1] Enthesitis-related arthritis (ERA) and polyarticular JIA also contribute to a smaller proportion of JIA-U cases.[1] Other risk factors implicated are - young

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 59 www.dosonline.orgAge at JIA Diagnosis (<6 years old), female sex, short interval between arthritis and uveitis onset, persistent active inflammation despite treatment and delay in ophthalmologic screening and diagnosis.[9]PathophysiologyJIA-associated uveitis is an immune-mediated disorder driven by a complex interaction between genetic susceptibility, dysregulated immune responses, and environmental factors.[5] The immunopathogenesis of JIA-U involves both innate and adaptive immune mechanisms that contribute to persistent ocular inflammation.Innate Immune System ActivationThe initial immune response in JIA-U is characterized by activation of the innate immune system, involving dendritic cells and macrophages, which produce pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6.[4]Neutrophils infiltrate the uveal tissue and contribute to local tissue damage. Inflammasome activation, leads to the release of IL-18 and IL-1β, amplifying the inflammatory cascade.[4,10]Adaptive Immune DysregulationChronic uveitis in JIA is driven by dysregulation of T and B lymphocytes.[3] Th1 cells secrete IFN-γ, while Th17 cells produce IL-17, both of which drive chronic inflammation.[3] A decrease in functional Tregs leads to loss of immune tolerance and uncontrolled inflammation.[7]ANA-positive patients exhibit increased B cell activation, contributing to immune complex formation and chronic tissue damage.[11,12]Several cytokines play a crucial role in sustaining inflammation in JIA-U.TNF-α promotes leukocyte infiltration and maintains chronic inflammation. IL-6 enhances T cell differentiation and perpetuates inflammation. IL-17 drives neutrophil recruitment and is associated with severe disease.[13]Ocular Tissue Damage and ComplicationsPersistent inflammation leads to structural damage in the eye such as posterior synechiae formation, cystoid macular edema and Glaucoma (secondary to trabecular meshwork dysfunction and corticosteroid use).[5,13]Clinical Presentation and ScreeningClinical Features of JIA-UJIA-U is often asymptomatic in its early stages, making early ophthalmologic screening critical for preventing complications.[10] The disease primarily presents as chronic, non-granulomatous anterior uveitis, but clinical severity and progression can vary among patients. The key clinical signs and symptoms include:• Redness and eye pain (often absent in early stages)• Photophobia (light sensitivity)• Blurred vision• Posterior synechiae (adhesion between iris and lens)• Cataract formation• Increased intraocular pressure (IOP), leading to secondary glaucoma[5]Disease Severity ClassificationJIA-U is classified based on the Standardization of Uveitis Nomenclature (SUN) criteria, which assess the severity of anterior chamber inflammation:• Mild: ≤1+ anterior chamber cells, minimal flare• Moderate: 2+ anterior chamber cells, moderate flare• Severe: ≥3+ anterior chamber cells, significant flare with hypopyon (white blood cell accumulation).Screening Guidelines for JIA-URoutine ophthalmic screening plays a critical role in preventing vision loss in children with JIA. The American Academy of Pediatrics (AAP) and the American College of Rheumatology (ACR) recommend screening intervals based on JIA subtype and risk factors. (Table-1)Risk Category Type Frequency of Screening High-Risk Patients Oligoarticular JIA, ANA-positive, Age <6 years at onset Every 3 monthsModerate-Risk Patients Polyarticular JIA, ANA-negative Every 6 monthsLow-Risk Patients Systemic JIA, RF-positive polyarthritis, ERA, PsA Every 12 monthsTable 1: Screening guidelines for JIA-U.Diagnostic ModalitiesSeveral imaging techniques and diagnostic tools aid in early detection and monitoring of JIA-U. Slit-lamp Biomicroscopy is Gold-standard tool for detecting anterior chamber cells and flare.[1] Optical Coherence Tomography (OCT) assesses macular edema and posterior segment involvement.[14] Fluorescein Angiography detects retinal vascular leakage and ischemic changes.[13] Tonometry

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 60 www.dosonline.orgmeasures intraocular pressure (IOP) to monitor for steroid-induced glaucoma. Ultrasound biomicroscopy detects structural abnormalities in the anterior chamber.[7]Importance of Early DetectionEarly detection and intervention are crucial in JIA-U to prevent sight-threatening complications. Studies have shown that children who undergo regular ophthalmic screening have significantly lower rates of complications such as cataracts and glaucoma. Asymptomatic patients often progress to severe uveitis before diagnosis, underscoring the need for proactive surveillance.[15]Complications and PrognosisJIA-associated uveitis (JIA-U) poses a significant risk of vision loss due to its chronic nature and potential for severe ocular complications. If left untreated or inadequately managed, the disease can lead to permanent visual impairment or blindness. The most common complications include:1. Cataracts[8]Cataracts are the most frequent complication in JIA-U, occurring in up to 70-80% of cases.[5] The primary risk factors include chronic intraocular inflammation and prolonged corticosteroid use. Corticosteroids contribute to lens opacification, while inflammation leads to posterior subcapsular cataract formation. Surgical intervention is often necessary but should be performed only when inflammation is controlled for at least three months to minimize post-surgical complications.[9]2. Glaucoma[5]Elevated intraocular pressure (IOP) is a major cause of irreversible vision loss in JIA-U.[12] It results from trabecular meshwork damage, steroid-induced ocular hypertension, and synechiae formation.[16] Up to 38% of JIA-U patients develop secondary glaucoma, requiring IOP-lowering medications, laser therapy, or surgical intervention.[11]3. Band Keratopathy[13]Characterized by calcium deposition in the corneal epithelium, leading to visual impairment. Chronic inflammation increases the risk, particularly in long-standing uveitis. Chelation therapy using disodium EDTA may be beneficial in early stages, while severe cases may require keratoplasty.[6]4. Cystoid Macular Edema (CME)[7]A leading cause of central vision loss in JIA-U. Inflammatory cytokines disrupt the blood-retinal barrier, resulting in fluid accumulation in the macula. OCT is essential for early detection, and treatment includes steroid-sparing immunosuppressants and biologics. 5. Synechiae FormationPosterior synechiae (iris-lens adhesions) and anterior synechiae (iris-cornea adhesions) can cause pupillary block and secondary glaucoma. Prevention includes early cycloplegic therapy with atropine or tropicamide to maintain pupillary dilation.[5]Prognosis and Visual OutcomesThe long-term prognosis depends on early detection, adequate inflammation control, and regular monitoring. Poor prognostic factors include:• Younger age at uveitis onset (<3 years)• Presence of posterior synechiae at diagnosis• Delayed ophthalmic screening• Chronic macular edema.Studies show that 30-40% of JIA-U patients experience significant vision loss (≤20/50), and up to 20% may develop legal blindness (≤20/200) in at least one eye.[17,18]Aggressive treatment with biologic agents and close follow-up has significantly improved visual outcomes in recent years.[19]Treatment StrategiesEffective management of JIA-associated uveitis (JIA-U) requires a multidisciplinary approach involving pediatric rheumatologists and ophthalmologists. Treatment aims to control intraocular inflammation, prevent complications, and preserve visual function. The choice of therapy depends on disease severity and response to treatment. 1. Conventional TherapiesThe primary goal of treatment in JIA-U is to suppress intraocular inflammation, prevent complications, and preserve visual function.Topical CorticosteroidsTopical corticosteroids remain the mainstay for mild to moderate anterior uveitis. Prednisolone acetate 1% is most commonly prescribed. Frequent dosing (every 1-2 hours initially) is required for active inflammation. However, long-term use is associated with risks such as steroid-induced glaucoma and cataract formation.[10] To minimize these risks, the lowest effective dose is used, and intraocular pressure is monitored regularly.[5]Cycloplegic AgentsCycloplegics, such as atropine and cyclopentolate, are used to prevent posterior synechiae formation and relieve ciliary body spasm, thereby reducing pain.[4] These agents also help maintain a functional pupil shape, which can

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 61 www.dosonline.orgbe distorted due to inflammation-induced adhesions between the iris and lens.Systemic ImmunosuppressionMethotrexate is the first-line steroid-sparing disease-modifying anti-rheumatic drug (DMARD) for chronic or refractory JIA-U. It can be administered orally or subcutaneously, with the latter preferred for better bioavailability and reduced gastrointestinal side effects. Methotrexate has shown significant efficacy in reducing uveitis flares and maintaining long-term remission.[13]For patients who do not respond adequately to methotrexate, other immunosuppressants such as mycophenolate mofetil, cyclosporine, and azathioprine may be used. These drugs work by suppressing T-cell activation and reducing inflammation.[13] Mycophenolate mofetil is preferred for its tolerability and effectiveness in refractory cases.[13] Cyclosporine is a calcineurin inhibitor that reduces T-cell activation but has significant side effects, including nephrotoxicity and hypertension.[7]2. Biologic TherapiesBiologic agents have revolutionized the treatment of refractory JIA-U by targeting specific inflammatory cytokines.Tumor Necrosis Factor (TNF-α) Inhibitors: Adalimumab is a monoclonal antibody against TNF-α and is currently the preferred biologic for refractory JIA-U.[5] It has demonstrated superior efficacy in preventing relapses and reducing corticosteroid dependency.[3] Infliximab, another TNF-α inhibitor, is used for severe refractory cases and is administered intravenously.[3]Interleukin-6 (IL-6) Inhibitors: Tocilizumab, an IL-6 receptor antagonist, has shown promising results in refractory JIA-U cases. 1 It is particularly effective in patients who have failed TNF-α inhibitors.[1]Janus Kinase (JAK) Inhibitors: Tofacitinib and baricitinib are small-molecule inhibitors targeting JAK signaling pathways involved in inflammation.[1] These are still under investigation for uveitis but have demonstrated efficacy in JIA.[1]IL-17 and IL-23 Inhibitors: Investigational agents targeting the Th17 pathway, currently in clinical trials.[3]3. Surgical ManagementSurgical intervention is considered in cases with severe complications that cannot be managed medically.Cataract Surgery: Cataract formation due to chronic inflammation or steroid use is common in JIA-U, affecting up to 83% of patients.[8] Surgery is performed only after achieving at least 3 months of complete inflammation control to minimize postoperative complications.[8]Perioperative corticosteroids (topical, systemic, or periocular injections) and immunomodulatory therapy may be intensified before surgery.[9] Treating dry eye disease, meibomian gland dysfunction, or associated keratopathy is crucial for optimal surgical outcomes. Presence of posterior synechiae may require pupil expansion techniques (e.g., iris hooks, pupillary rings) during surgery.[20] Hydrophobic acrylic intraocular lenses (IOLs) are preferred due to their biocompatibility and lower risk of inflammation. Multifocal IOLs are avoided due to potential visual disturbances and higher risk of posterior capsular opacification (PCO).[9] Some surgeons prefer aphakia in younger children, delaying IOL implantation to a later stage.[12]Early and aggressive management of uveitic cataract with proper perioperative care, precise surgical techniques, and postoperative vision rehabilitation can significantly improve visual outcomes in children with JIA-U.Glaucoma Management: Steroid-induced glaucoma or secondary inflammatory glaucoma may require surgical intervention, including trabeculectomy, Tube shunt implantation and Cyclophotocoagulation.[5]Vitrectomy: Vitrectomy is indicated in cases of persistent macular edema, vitreous opacities, or retinal complications. This procedure helps restore visual clarity and reduce persistent inflammation.[13]Amblyopia Management in Children with JIA-UDelayed visual rehabilitation due to cataracts and prolonged inflammation can lead to amblyopia in younger children. Spectacle correction or contact lenses are given for aphakic children. Regular refraction assessments are needed due to astigmatism or anisometropia post-surgery. Occlusion therapy for monocular deprivation amblyopia is used. Close monitoring and adjustment based on visual response should be done.[21]Recent Advances in Biologic Therapy and Future DirectionsBiologic therapies have significantly improved the management of JIA-U by providing targeted immunosuppression with fewer systemic side effects compared to traditional DMARDs. Golimumab, a TNF-α inhibitor, has shown promise in JIA-U patients who fail adalimumab or infliximab.[22] Secukinumab (IL-17A inhibitor) and Ustekinumab (IL-12/23 inhibitor) are currently under investigation for refractory JIA-U.[23] Abatacept (CTLA4-Ig fusion protein) is being explored for its ability to

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 62 www.dosonline.orgblock T-cell activation in JIA-U.[24] Biomarker studies are helping stratify patients based on their likelihood to respond to specific biologics.[25] Pharmacogenomic testing is emerging to predict individual drug metabolism and optimize dosing.[26] The combination of methotrexate with biologics has shown superior efficacy in maintaining remission. Early introduction of biologics in high-risk patients has reduced the incidence of complications.[27]Future Directions in JIA-U ManagementAdvances in machine learning and AI-driven predictive modeling may help guide treatment decisions. Studies are exploring the use of cytokine profiling to tailor immunomodulatory therapy.[25]Emerging Therapies like oral small-molecule inhibitors, such as JAK inhibitors (e.g., upadacitinib), are under clinical trials for non-infectious uveitis.[28] Stem cell therapies and regulatory T-cell infusions are being studied for immune modulation.[29] Efforts are being made to refine imaging biomarkers (e.g., OCT angiography) for early detection of subclinical disease.[30] Home-based monitoring tools for real-time assessment of disease activity are in development. ConclusionAdvancements in biologic therapies and targeted treatments have transformed the prognosis of JIA-U, significantly reducing the incidence of blindness. Ongoing clinical trials are investigating novel agents, including IL-17 and IL-23 inhibitors, which may further improve treatment outcomes. Early screening, multidisciplinary management, and aggressive treatment are essential to prevent irreversible ocular damage. Despite these advancements, challenges remain in achieving long-term remission and preventing irreversible complications. Future research should focus on identifying predictive biomarkers for uveitis development and optimizing treatment strategies to achieve sustained remission.References1. Chen JL, Abiri P, Tsui E. Recent advances in the treatment of juvenile idiopathic arthritis–associated uveitis. Ther Adv Ophthalmol. 2021 Jan 1;13. 2. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet (London, England) [Internet]. 2007 Mar 3 [cited 2025 Mar 4];369(9563):767–78. Available from: https://pubmed.ncbi.nlm.nih.gov/17336654/3. Dini G, Dell’Isola GB, Beccasio A, Di Cara G, Verrotti A, Cagini C. Biologic therapies for juvenile idiopathic arthritis-associated uveitis. Front Ophthalmol. 2022;2(August):1–9. 4. Gueudry J, Touhami S, Quartier P, Bodaghi B. Therapeutic advances in juvenile idiopathic arthritis - associated uveitis. Curr Opin Ophthalmol. 2019;30(3):179–86. 5. Angeles-Han S, Yeh S. Prevention and management of cataracts in children with juvenile idiopathic arthritis-associated uveitis. Curr Rheumatol Rep [Internet]. 2012 Apr [cited 2025 Mar 3];14(2):142–9. Available from: https://www.researchgate.net/publication/51925336_Prevention_and_Management_of_Cataracts_in_Children_with_Juvenile_Idiopathic_Arthritis-Associated_Uveitis.6. Heiligenhaus A, Niewerth M, Ganser G, Heinz C, Minden K. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a populationbased nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology [Internet]. 2007 Jun 1 [cited 2025 Mar 4];46(6):1015–9. Available from: https://dx.doi.org/10.1093/rheumatology/kem053.7. Vitale AT, Graham E, De Boer JH. Juvenile idiopathic arthritis-associated uveitis: Clinical features and complications, risk factors for severe course, and visual outcome. Ocul Immunol Inflamm. 2013;21(6):478–85. 8. Acevedo S, Quinones K, Rao V, Cervantes-Castañeda RA, Foster CS. Cataract surgery in children with juvenile idiopathic arthritis associated uveitis. Int Ophthalmol Clin. 2008;48(2):1–7. 9. Thorne JE, Woreta FA, Dunn JP, Jabs DA. Risk of cataract development among children with juvenile idiopathic arthritis-related uveitis treated with topical corticosteroids. Ophthalmology [Internet]. 2010 Jul [cited 2025 Mar 4];117(7):1436–41. Available from: https://pubmed.ncbi.nlm.nih.gov/20363502/10. Hawkins MJ, Dick AD, Lee RJW, Ramanan A V., Carreño E, Guly CM, et al. Managing juvenile idiopathic arthritis-associated uveitis. Surv Ophthalmol [Internet]. 2016;61(2):197–210. Available from: http://dx.doi.org/10.1016/j.survophthal.2015.10.005.11. Kanski JJ. Juvenile arthritis and uveitis. Surv Ophthalmol [Internet]. 1990 [cited 2025 Mar 4];34(4):253–67. Available from: https://pubmed.ncbi.nlm.nih.gov/2188388/12. De Boer J, Wulffraat N, Rothova A. Visual loss in uveitis of childhood. Br J Ophthalmol [Internet]. 2003 Jul 1 [cited 2025 Mar 4];87(7):879. Available from:

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 63 www.dosonline.orghttps://pmc.ncbi.nlm.nih.gov/articles/PMC1771761/13. Oray M, Tuğal-Tutkun İ. Treatment of juvenile idiopathic arthritis-associated uveitis. Turk Oftalmoloiji Derg. 2016;46(2):77–82. 14. Carlsson E, Beresford MW, Ramanan A V., Dick AD, Hedrich CM. Juvenile idiopathic arthritis associated uveitis. Children. 2021;8(8):1–15. 15. M. Bani Khalaf I, Jain H, Vora NM, ul Ain N, Murtaza F, Ram MD, et al. A clearer vision: insights into juvenile idiopathic arthritis–associated uveitis. Proc (Bayl Univ Med Cent) [Internet]. 2024 [cited 2025 Mar 4];37(2):303. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10857453/16. Rosenbaum JT, Dick AD. The Eyes Have it: A Rheumatologist’s View of Uveitis. Arthritis Rheumatol (Hoboken, NJ) [Internet]. 2018 Oct 1 [cited 2025 Mar 4];70(10):1533–43. Available from: https://pubmed.ncbi.nlm.nih.gov/29790291/17. Haasnoot AMJW, Vernie LA, Rothova A, Doe P V.D., Los LI, Schalij-Delfos NE, et al. Impact of Juvenile Idiopathic Arthritis Associated Uveitis in Early Adulthood. PLoS One [Internet]. 2016 Oct 1 [cited 2025 Mar 4];11(10):e0164312. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5056754/18. Paroli MP, Abbouda A, Albanese G, Accorinti M, Falcione A, Spadea L, et al. Persistence of Juvenile Idiopathic Arthritis-Associated Uveitis in Adulthood: A Retrospective Study. J Clin Med [Internet]. 2022 May 1 [cited 2025 Mar 4];11(9):2471. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9101652/19. ElMohsen MNA, Hassan LM, Youssef MM, Naga SHA. The efficacy of anti–TNF-α agents in the treatment of juvenile idiopathic arthritis-associated uveitis in a pediatric cohort. Indian J Ophthalmol [Internet]. 2023 May 1 [cited 2025 Mar 4];71(5):2168. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10391364/20. Salmon JF., Bowling B. Kanski’s clinical ophthalmology : a systematic approach. 2020;941. 21. Sen S, Singh P, Saxena R. Management of amblyopia in pediatric patients: Current insights. Eye [Internet]. 2021 Jan 1 [cited 2025 Mar 5];36(1):44. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8727565/22. Lanz S, Seidel G, Skrabl-Baumgartner A. Golimumab in juvenile idiopathic arthritis-associated uveitis unresponsive to Adalimumab. Pediatr Rheumatol Online J [Internet]. 2021 Dec 1 [cited 2025 Mar 5];19(1):132. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8380315/23. Long AM, Marston B. Juvenile Idiopathic Arthritis. Pediatr Rev [Internet]. 2023 Oct 1 [cited 2025 Mar 5];44(10):565–77. Available from: /pediatricsinreview/article/44/10/565/194012/Juvenile-Idiopathic-Arthritis.24. Da Rosa LC, Scales HE, Benson RA, Brewer JM, Mcinnes IB, Garside P. The effect of abatacept on T-cell activation is not long-lived in vivo. Discov Immunol [Internet]. 2024 Jan 1 [cited 2025 Mar 5];3(1):1–13. Available from: https://dx.doi.org/10.1093/discim/kyad029.25. Cordero-Coma M, Yilmaz T, Onal S. Systematic review of anti-tumor necrosis factor-alpha therapy for treatment of immune-mediated uveitis. Ocul Immunol Inflamm [Internet]. 2013 [cited 2025 Mar 5];21(1):19–27. Available from: https://pubmed.ncbi.nlm.nih.gov/23323577/26. Dick AD, Tugal-Tutkun I, Foster S, Zierhut M, Melissa Liew SH, Bezlyak V, et al. Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials. Ophthalmology [Internet]. 2013 Apr [cited 2025 Mar 5];120(4):777–87. Available from: https://pubmed.ncbi.nlm.nih.gov/23290985/27. Ramanan A V., Dick AD, Jones AP, McKay A, Williamson PR, Compeyrot-Lacassagne S, et al. Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis. N Engl J Med [Internet]. 2017 Apr 27 [cited 2025 Mar 5];376(17):1637–46. Available from: https://pubmed.ncbi.nlm.nih.gov/28445659/28. Huang Z, Chen B, Su W. Upadacitinib in Non-Infectious Uveitis: A Comprehensive Analysis of Therapeutic Impact and Molecular Mechanisms. Invest Ophthalmol Vis Sci. 2024 Jun 17;65(7):2606–2606. 29. Jiang S. Regulatory T cells: From bench to bedside. Int Immunopharmacol. 2009 May 1;9(5):515–7. 30. Tranos P, Karasavvidou EM, Gkorou O, Pavesio C. Optical coherence tomography angiography in uveitis. J Ophthalmic Inflamm Infect [Internet]. 2019 Dec 1 [cited 2025 Mar 5];9(1):21. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6928173/Nilima Khochikar MS, FPOS Consulting Paediatric OphthalmologistDr Anil Kulkarni Eye Hospital, MirajCorresponding Author:

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 64 www.dosonline.orgRetinal Angiogenesis: Role ofInflammatory MarkersHitisha Mittal MBBS, MS | Swati Verma MBBS, MSDepartment of Ophthalmology, VMMC and Safdarjung Hospital, New DelhiIntroductionRetinal angiogenesis, also known as retinal neovascularization, is defined as formation of new abnormal vessels from the pre-existing normal retinal vessels in response to an overt angiogenic stimulus, which can be hypoxia, ischaemia or inflammation.[1] An equilibrium between pro angiogenic and anti-angiogenic factors in retina is responsible for maintaining the normal retinal anatomy and physiology, disruption of which results in retinal and choroidal neovascularization and poses a threat of significant vision loss.[2] Diseases that commonly involve retinal angiogenesis include diabetic retinopathy (DR), age related macular degeneration (ARMD), retinal vein occlusions (RVO) and retinopathy of prematurity (ROP).[3]Several studies over the last few decades have highlighted the vital role of inflammatory mediators in retinal angiogenesis. In this article, we briefly review the role of Inflammatory markers in retinal angiogenesis and usage of different anti-inflammatory molecules in managing patients with retinal neovascularization. How Does Inflammation Cause Retinal Angiogenesis?Inflammation is defined as a tissue’s non-specific response to injury or stress, which can be in the form of hyperglycaemia and/or electrolyte imbalance (as seen in diabetic patients), hypoxia (as seen in retinal vein occlusion, ROP, diabetes), photoreceptor disintegration and extra cellular lipofuscin deposition (ARMD), ocular trauma, etc.[4,5]This results in an imbalance between the pro and anti-angiogenic forces within retina and causes release of several inflammatory markers which start the vicious cycle of retinal damage through inflammation and angiogenesis. These inflammatory markers are released by various cells like retinal pigmental epithelial (RPE) cells, activated endothelial cells, resident microglial cells, muller cells and migrating leucocytes.[6] A summary of inflammatory markers involved in retinal angiogenesis is given in Table-1.Inflammatory MarkersPro Angiogenic Anti – Angiogenic1. Cytokines IL-6, 8, 10, 17, IL 1β, TNF α IL- 4, 12, 332. Chemokines ELR-CXC chemokines (e.g. CCR2, CCR5) Non ELR-CXC ligands3. Growth Factors • Vascular endothelial growth factor (VEGF) • Placental growth factor (PlGF)• Platelet derived growth factor (PDGF)• Angiopoetin-2 (Ang-2)• Integrins • Hepatocyte growth factor (HGF)• Fibroblast and epidermal growth factors (FGF, EGF)• Matrix metalloproteinases (MMPs)• Hypoxia inducible factor (HIF)• Pigment epithelium derived factor (PEDF)• Angiopoetin-1 (Ang-1)• Tissue inhibitors of MMPs

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 65 www.dosonline.orgInflammatory MarkersPro Angiogenic Anti – Angiogenic4. Complement Cascade• C3a• C5a• Complement factor H (CFH)Table 1: Various inflammatory markers involved in Retinal Angiogenesis.Release of these inflammatory markers results in multiple cellular level changes within the retina. These changes include: -1. Chemotaxis- activation and migration of neutrophils, monocytes and lymphocytes 2. Generation of reactive oxygen species (ROS), release of Nitrous oxide (NO)3. Disruption of inter cellular junctions between retinal pigment epithelial (RPE) cells 4. Breakdown of inner and outer blood retinal barrier5. Glial cell activation (microglia, muller glial cells and astrocytes)6. Endothelial cell proliferation, migration and differentiation 7. Loss of capillary pericytes 8. Increased vascular permeability due to diminished vessel wall integrity9. Basement membrane thickening and vascular lumen occlusionAll these events occur simultaneously within the retina, resulting in a self-propagating chain of inflammation which results in formation of new, abnormal and leaky vessels from the pre-existing retinal vessels. These abnormal vessels cause leakage of fluid and inflammatory cells into the surrounding extra-cellular matrix, which causes further release of cytokines and growth factors, thus establishing the vicious cycle of Inflammation and Angiogenesis.[7,8]How Can We Tackle Retinal Angiogenesis?Therapy for retinal neovascularization is designed to target specific molecules involved in the process of inflammation and angiogenesis. The most widely studied molecule is vascular endothelial growth factor (VEGF) and multiple drugs are available in market, targeting different forms of VEGF.[9]VEGF family includes 5 molecules - VEGF-A, B, C, D and placental growth factor (PlGF). Of these, VEGF-A is the most important form involved in mediating retinal inflammation, neovascularization and edema. Most antiVEGF drugs are targeted towards blocking the action of VEGF-A and are useful in patients with DR, ARMD, RVO and ROP who develop retinal neovascularization and macular edema.[10]Studies have found that anti-VEGF therapy with isolated blockage of VEGF-A may result in compensatory increase in other inflammatory markers within the retina, thus resulting in resistance to treatment.[11] This led to development of newer drugs targeted towards other forms of VEGF as well as other inflammatory markers. Other molecules against which drugs have been developed include Placental growth factor (PlGF), angiopoietin-2 (Ang2), Integrins, chemokines (CCR2/5) and proteins of complement cascade (C3a, C5a). A brief summary of various Anti-angiogenic drugs that are available in market for treating Retinal neovascularization is given in Table-2. There are many promising drugs that act on different pathways and are currently under clinical trials, with initial studies showing promising results.[11,12] A brief summary of these drugs is discussed in Table-3.Drug Name Brand NameFDA Approval Mechanism of ActionDose Per InjectionRemarksPegaptanib Macugen In 2004 for Wet ARMD Inhibits isoform 165 of VEGF A0.3mg No longer usedBevacizumab Avastin In 2004 for colorectal cancerInhibits VEGF- A 1.25mg/ 0.05 mL Off label use in ophthalRanibizumab Lucentis In 2006 for Wet ARMDIn 2015 for DME and RVO-CMEInhibits VEGF-A 0.5mg/0.05mL Most widely used antiVEGF, many biosimilars approved

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 66 www.dosonline.orgDrug Name Brand NameFDA Approval Mechanism of ActionDose Per InjectionRemarksAflibercept Eylea In 2011 for Wet ARMDIn 2014 for RVO-CMEIn 2015 for DMEInhibits VEGF-A, B and PlGF2mg/0.05mL Longer acting molecule, widely usedPegpleranib Fovista In 2013 for Wet ARMD Inhibits PDGF Discontinued in 2017 No added benefit to anti VEGF therapyConbercept Lumitin In 2016 for wet ARMD and DMEInhibits VEGF- A, B, C and PlGF0.5mg/0.05mL Not available in India, only used in ChinaBrolucizumab Beovu In 2019 for Wet ARMDIn 2022 for DMEInhibits VEGF-A 6mg/0.05mL Smallest anti-VEGF molecule, deeper penetration into retina and choroidFaricimab Vabysmo In 2023 for Wet ARMD, DME and RVO- CMEInhibits VEGF- A and Ang-26mg/0.05mL Long acting anti VEGFPegcetacoplan Syfovre In 2023 for geographic atrophyInhibits complement cascade by binding to protein C3a15mg/0.1mL Not yet available in IndiaAvacincaptad pegolIzervay In 2023 for geographic atrophyInhibits complement cascade by binding to protein C5a2mg/0.1mL Not yet available in IndiaTable 2: Historical Review of available Anti-Angiogenesis Drugs in market.Table 3: A summary of anti-angiogenesis drugs currently under clinical trials.ARMD- age related macular degeneration, DME- diabetic macular edema, RVO-CME- retinal vein occlusion associated cystoid macular edema, VEGF- vascular endothelial growth factor, PlGF- placental growth factor, Ang2- angiopoietin 2, PDGF- platelet derived growth factorDrug Name Brand Mechanism of ActionPhase of Clinical TrialDisease TargetedOPT-302 Sozinibercept A soluble form of VEGF-3 receptor, Traps VEGF- C and D Phase 3 trials in 2024 Wet ARMDRisutiganib Luminate Inhibits Integrin Phase 2b/3 trials in 2023 Intermediate Dry ARMD and DMEOral CCR2/5 antagonist- Block CCR2 and CCR5 receptorsPhase 2 trials in 2018 DMEConclusionRetinal angiogenesis is mediated by a complex network of inflammatory markers, including cytokines, chemokines and growth factors and it results in a self-evolving chain of inflammatory events in retina. This results in retinal and choroidal neovascularization, which can lead to severe sight threatening sequelae, such as vitreous hemorrhage, tractional retinal detachment, choroidal neovascular membrane, sub-retinal hemorrhage, epiretinal membrane and neovascular glaucoma.[13] A thorough understanding about these inflammatory markers helps in developing targeted therapy towards them, thereby aiding in tackling diseases with pathological retinal angiogenesis.References1. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307.2. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 67 www.dosonline.orggrowth factor and angiogenesis. Pharmacol Rev. 2004 Dec;56(4):549–580. 3. Dreyfuss JL, Giordano RJ, Regatieri CV. Ocular angiogenesis. J Ophthalmol. 2015; 2015:892043.4. Sun JK, Lin MM, Lammer J, Prager S, Sarangi R, Silva PS, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with centerinvolved diabetic macular edema. JAMA Ophthalmol. 2014, 132, 1309–1316. 5. Demircan N, Safran BG, Soylu M, Ozcan AA, Sizmaz S. Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye (Lond). 2006; 20:1366-9. 6. Markiewski MM, Daugherity E, Reese B, Karbowniczek M. The Role of Complement in Angiogenesis. Antibodies (Basel). 2020 Dec 1;9(4):67. 7. Rübsam A, Parikh S, Fort PE. Role of Inflammation in Diabetic Retinopathy. Int J Mol Sci. 2018 Mar 22;19(4):942.8. Mesquida M, Drawnel F, Fauser S. The role of inflammation in diabetic eye disease. Semin Immunopathol. 2019; 41:427-45.9. Duh EJ, Yang HS, Haller JA, De Juan E, Humayun MS, Gehlbach P, Melia M, Pieramici D, Harlan JB, Campochiaro PA, Zack DJ. Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor: implications for ocular angiogenesis. Am J Ophthalmol. 2004 Apr;137(4):668-74. 10. Noma H, Mimura T, Yasuda K, Motohashi R, Kotake O, Shimura M. Aqueous Humor Levels of Soluble Vascular Endothelial Growth Factor Receptor and Inflammatory Factors in Diabetic Macular Edema. Ophthalmologica. 2017;238(1-2):81-88. 11. Cabral T, Lima LH, Mello LGM, Polido J, Correa EP, Oshima A, et al. Bevacizumab injection in patients with neovascular age-related macular degeneration increases angiogenic biomarkers. Ophthalmol Retina. 2018 Jan;2(1):31-37.12. Cabral T, Mello LGM, Lima LH, Polido J, Regatieri CV, Belfort R Jr, Mahajan VB. Retinal and choroidal angiogenesis: a review of new targets. Int J Retina Vitreous. 2017 Aug 21; 3:31. 13. Zhong ZL, Han M, Chen S. Risk factors associated with retinal neovascularization of diabetic retinopathy in type 2 diabetes mellitus. Int J Ophthalmol. 2011;4(2):182-5.Hitisha Mittal MBBS, MSSenior ResidentDepartment of OphthalmologyVMMC and Safdarjung Hospital, New DelhiCorresponding Author:

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 68 www.dosonline.orgOcular Tuberculosis - Shedding Light on Molecular Pathways of InflammationRicha Pyare MS, FMRF, FICODepartment of Retina and Uvea, Shroff Eye Centre, New DelhiAbstract: Ocular tuberculosis, a form of extrapulmonary tuberculosis shows a unique and complex pathogenesis. Paucity of knowledge about the pathogenesis has led to confusion regarding the diagnosis and management of the disease. Growing insights in the cellular and molecular pathways of inflammation seen in ocular tuberculosis has pointed towards newer therapeutic targets. This review focuses on covering the current understanding of these pathogenetic mechanisms in a comprehensive yet concise manner. Further studies are needed to refine our understanding of this challenging condition.Keywords: Intraocular tuberculosis, immunology, uveitis, pathogenesis.IntroductionOcular tuberculosis refers to a wide range of clinical phenotypes caused by or associated with Mycobacterium tuberculosis (MTB). It is a unique form of extrapulmonary tuberculosis (TB) as it has protean manifestations within the same organ. Studying its pathophysiology in human subjects is particularly challenging due to the inaccessibility of ocular tissues for biopsy, the paucibacillary nature of the disease, and the lack of direct histopathological evidence. To overcome these limitations, two animal models have been developed. The guinea pig model, developed by Rao et al., replicates natural infection through aerosolized MTB exposure. Infected guinea pigs subsequently develop ocular TB with histopathological features similar to those observed in human eyes. The zebrafish model, developed by Takaki et al., takes advantage of the anatomical similarities between zebrafish and human eyes, including the presence of both inner and outer retinal barriers. In this model, zebrafish larvae-due to their optical transparency-are injected with red fluorescent-tagged Mycobacterium marinum, enabling real-time, in vivo visualization of host-pathogen interactions and disease progression. Insights from these models, combined with findings from other forms of extrapulmonary TB, suggest that ocular TB has a 4 step pathogenesis: infection, dissemination to ocular structures, localisation in ocular tissue and latency, bacterial reactivation, clinical manifestations and recurrences. InfectionMTB is disseminated via aerosolized droplets, these droplets are inhaled and reach lung alveoli where they encounter alveolar macrophages. MTB are then engulfed by alveolar macrophages and transported to the hilar lymph nodes. While it is well understood how the MTB reaches the lungs, the mechanisms by which aerosolized MTB leads to ocular TB have remained unclear due to a lack of relevant animal models. To address this gap, Rao et al. developed a guinea pig model of intraocular TB[1], providing valuable insights into its pathogenesis. They divided the guinea pigs into two groups, both were exposed to aerosolized MTB, one group was left untreated and the second was given 1st line anti-tubercular therapy (ATT). In the untreated group 5 of 12 eyes (42%) developed uveal granulomas which showed presence of acid fast bacilli (AFB) and MTB DNA. None of the treated animals developed uveal granulomas, but 4 of 8 eyes (50%) developed mild nongranulomatous inflammation. This study demonstrates that aerosolized MTB can lead to intraocular infection, with uveal granulomas forming in untreated eyes. The absence of granulomas in treated animals highlights the protective role of ATT, while the observed residual inflammation suggests that a combination of ATT and steroids are required for complete resolution of ocular TB.

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 69 www.dosonline.orgDisseminationAlthough it has been long established that extrapulmonary TB results from dissemination of MTB from the primary focus also known as Ghon’s focus, there is a growing understanding that even pulmonary TB results from MTB spreading from the primary lesion to the hilar lymph nodes, then transitioning through the lymphatic and circulatory system to reseed the lungs.[2] This implies that the process of dissemination is not limited to extrapulmonary disease, but is in fact a mandatory phase of the disease. Moreover, it is evident that bacterial factors would also influence the process of dissemination.[3] The histopathology and cytokine profile of granulomas seen in guinea pig models depends on whether the granuloma is a result of primary infection (large, necrotic, calcified) or reseeding post dissemination (smaller, non-necrotic, non-calcified).[4] In BCG vaccinated animals, the primary lesions also resemble smaller, non- necrotic and non-calcified secondary lesions, implying host immune factors play a role in determining the histopathology of the lesion. One interesting question that arises is, how do the MTB bypass the epithelial barrier of the lung and gain access to the interstitial space. There are 3 possible mechanisms, the first is that MTB preferentially infect alveolar macrophages which act as a conduit and transport the MTB as they circulate through the lymphatic and hematogenous system, the second is that MTB directly infect the epithelial cells and translocate either without disrupting the epithelial cells, or by destroying the monolayer[5], or third that MTB disseminate using dendritic cells, which also act as antigen presenting cells.[6] It is likely all three mechanisms have a role to play. The zebrafish model uses red-fluorescent tagged M. marinum which is injected directly into the hematological system, while macrophages are green tagged. The zebrafish larvae are transparent and allow direct, invivo visualisation of the movement of the macrophages and M. marinum bacilli into the ocular tissue. Also, unlike guinea pigs which lack retinal vasculature, zebrafish larvae have functioning inner and outer retinal barriers similar to the retinal barriers seen in human ocular tissue. Twenty percent of animals developed ocular infection characterised by infected macrophages, subsequently developing granulomas. This experiment established that Mycobacterium bacilli could enter eyes with preserved outer and inner retinal barriers.[7] The early success of the Heparin-Binding Hemagglutinin (hbhA), a dissemination factor as a vaccine candidate in childhood TB is an example of the importance of dissemination pathways in the pathogenesis of TB.[8,9]LatencyThe retinal pigment epithelial (RPE) cell represents another critical component in the pathogenesis of ocular tuberculosis (TB). Rao et al first reported MTB DNA in RPE cells in an eye enucleated for intractable uveitis.[10]RPE cells express toll-like receptors (TLRs), particularly TLR2 and TLR4, which, similar to macrophages, play a key role in recognizing and phagocytosing MTB. Studies have shown that RPE cells phagocytose MTB at rates comparable to macrophages but have lower cell death rates, allowing them to serve as a reservoir for MTB within ocular tissues.[11] Recurrences of ocular TB may result from the reactivation and proliferation of sequestered MTB within RPE cells. Notably, inhibiting TLR expression in RPE cells reduces intracellular pathogen load, suggesting that therapeutic strategies targeting phagocytic pathways in RPE cells could prevent MTB establishment in ocular tissues.[11] Another study focused on delineating the differences between inflammatory responses of macrophages versus RPE cells and found that RPE cells have a incomplete anti-Mtb response that primarily depends on interferon (IFN) signaling, while macrophages have a more diverse set of gene and secreted protein response.[12]IFN α/β predominated over IFN ɣ response.[12] MTB can thus evade the immune system and stay dormant within the RPE cell till reactivation. Risk factors for reactivation include immunocompromised status of the host. In immunocompetent individuals, the reasons for reactivation of MTB remain unclear.[13]Clinical Ocular DiseaseThe pathogenesis of ocular tuberculosis involves two distinct mechanisms: direct mycobacterial infection and indirect immune-mediated pathways.[14] Direct infection is evidenced by hematogenous dissemination of MTB, histopathological identification of bacilli in uveal tissues, and PCR detection of MTB DNA, paralleling findings in extrapulmonary TB. Mechanistically, MTB viability and virulence factors (i.e. MTB RNA and early secreted antigenic target-6, ESAT-6) induce caspase-dependent cytokine release via NLRP3 inflammasome.[15] MTBspecific CD4+ T cells show elevated CD38 and HLA-DR expression - these markers distinguish active from latent TB and may serve as therapeutic targets.[16,17] Evidence for indirect immunopathogenic mechanism include disproportionate inflammation despite paucibacillary disease, variable clinical phenotypes, chronic and recurrent course, and need for corticosteroids along with ATT. This involves both local immune responses to ocular MTB antigens and systemic autoimmunity where MTB

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 70 www.dosonline.orgdirected priming of T cells in the lungs causes off- target inflammation in the ocular structures and molecular mimicry between MTB and retinal antigens.[14] This is in alignment with the role of autoimmunity proposed in the pathogenesis of pulmonary TB.[18]Clinical heterogeneity likely reflects these divergent pathways. Classification on the presence or absence of a breach in RPE during the pathogenesis helps allot pathways for each group, phenotypes without a breach in RPE include anterior uveitis, intermediate uveitis and deeply located choroiditis while a breach in RPE is seen in retinal vasculitis and serpiginous-like choroiditis affecting the inner and outer brain- retina- barrier (BRB) respectively.[14] The breach in RPE determines whether autoimmunity to retinal antigens contributes to inflammation.[19]Other FactorsRecently few case reports have demonstrated a the rapeutic role of anti-VEGF injections in tuberculomas.[20-22]This is supported by experimental evidence demonstrating elevated VEGF levels and reduced fibroblast growth factor (FGF) expression in MTB infected human RPE cell cultures, as well as in vitreous samples from ocular TB patients.[23] and VEGF staining RPE and photoreceptors outer segments of MTB infected eyes.[24] Additionally, studies have identified possible genetic factors influencing TB pathogenesis.[25-26]ConclusionOcular tuberculosis remains a diagnostically and therapeutically challenging entity due to its protean manifestations and complex pathogenesis. Animal models have demonstrated that aerosolized Mycobacterium tuberculosis can directly infect ocular tissues and trigger granulomatous inflammation. The recognition of RPE cells as potential reservoirs for latent MTB, the role of dissemination mechanisms, and the dual nature of pathogenesis-both direct infection and immune-mediated inflammation-have opened doors to more targeted and effective therapies. Integration of these molecular insights with clinical findings will be essential to refine diagnostic criteria, identify biomarkers, and develop adjunctive treatments. Future research focused on host-pathogen interactions, genetic susceptibility, and immunomodulatory therapies holds promise in improving outcomes for patients with ocular TB.References1. Rao NA. Experimental Ocular Tuberculosis in Guinea Pigs. Arch Ophthalmol. 2009 Sep 14;127(9):1162.2. Moule MG, Cirillo JD. Mycobacterium tuberculosis Dissemination Plays a Critical Role in Pathogenesis. Front Cell Infect Microbiol. 2020 Feb 25;10:65.3. Hernandez Pando R, Aguilar D, Cohen I, Guerrero M, Ribon W, Acosta P, et al. Specific bacterial genotypes of Mycobacterium tuberculosis cause extensive dissemination and brain infection in an experimental model. Tuberculosis. 2010 Jul;90(4):268–77.4. McMurray DN. Hematogenous reseeding of the lung in low-dose, aerosol-infected guinea pigs: unique features of the host–pathogen interface in secondary tubercles. Tuberculosis. 2003 Feb;83(1–3):131–4.5. Russell DG. TB comes to a sticky beginning. Nat Med. 2001 Aug;7(8):894–5.6. Humphreys IR, Stewart GR, Turner DJ, Patel J, Karamanou D, Snelgrove RJ, et al. A role for dendritic cells in the dissemination of mycobacterial infection. Microbes Infect. 2006 Apr;8(5):1339–46.7. Takaki K, Ramakrishnan L, Basu S. A zebrafish model for ocular tuberculosis. Neyrolles O, editor. PLOS ONE. 2018 Mar 27;13(3):e0194982.8. Schepers K, Dirix V, Mouchet F, Verscheure V, Lecher S, Locht C, et al. Early cellular immune response to a new candidate mycobacterial vaccine antigen in childhood tuberculosis. Vaccine. 2015 Feb;33(8):1077–83.9. Parra M, Pickett T, Delogu G, Dheenadhayalan V, Debrie AS, Locht C, et al. The Mycobacterial HeparinBinding Hemagglutinin Is a Protective Antigen in the Mouse Aerosol Challenge Model of Tuberculosis. Infect Immun. 2004 Dec;72(12):6799–805.10. Rao NA. Tuberculous Uveitis: Distribution of Mycobacterium tuberculosis in the Retinal Pigment Epithelium. Arch Ophthalmol. 2006 Dec 1;124(12):1777.11. Nazari H, Karakousis PC, Rao NA. Replication of Mycobacterium Tuberculosis in Retinal Pigment Epithelium. JAMA Ophthalmol. 2014 Jun 1;132(6):724.12. La Distia Nora R, Walburg KV, Van Hagen PM, Swagemakers SMA, Van Der Spek PJ, Quinten E, et al. Retinal Pigment Epithelial Cells Control Early Mycobacterium tuberculosis Infection via Interferon Signaling. Investig Opthalmology Vis Sci. 2018 Mar 8;59(3):1384.13. Pai M, Behr MA, Dowdy D, Dheda K, Divangahi M, Boehme CC, et al. Tuberculosis. Nat Rev Dis Primer. 2016 Oct 27;2(1):16076.

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 71 www.dosonline.org14. Basu S, Elkington P, Rao NA. Pathogenesis of ocular tuberculosis: New observations and future directions. Tuberculosis. 2020 Sep;124:101961.15. Basu S, Fowler BJ, Kerur N, Arnvig KB, Rao NA. NLRP3 inflammasome activation by mycobacterial ESAT-6 and dsRNA in intraocular tuberculosis. Microb Pathog. 2018 Jan;114:219–24.16. Adekambi T, Ibegbu CC, Cagle S, Kalokhe AS, Wang YF, Hu Y, et al. Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response. J Clin Invest. 2015 May 1;125(5):1827–38.17. Ahmed MIM, Ntinginya NE, Kibiki G, Mtafya BA, Semvua H, Mpagama S, et al. Phenotypic Changes on Mycobacterium Tuberculosis-Specific CD4 T Cells as Surrogate Markers for Tuberculosis Treatment Efficacy. Front Immunol. 2018 Sep 28;9:2247.18. Elkington P, Tebruegge M, Mansour S. Tuberculosis: An Infection-Initiated Autoimmune Disease? Trends Immunol. 2016 Dec;37(12):815–8.19. Forrester JV, Kuffova L, Dick AD. Autoimmunity, Autoinflammation, and Infection in Uveitis. Am J Ophthalmol. 2018 May;189:77–85.20. Invernizzi A, Torre A, Parrulli S, Zicarelli F, Schiuma M, Colombo V, et al. Retinal findings in patients with COVID-19: Results from the SERPICO-19 study. EClinicalMedicine. 2020 Oct;27:100550.21. Jain S, Agarwal A, Gupta V. Resolution of Large Choroidal Tuberculoma following Monotherapy with Intravitreal Ranibizumab. Ocul Immunol Inflamm. 2020 Apr 2;28(3):494–7.22. Agarwal M, Gupta C, Mohan KV, Upadhyay PK, Dhawan A, Jha V. Adjunctive Intravitreal Antivascular Endothelial Growth Factor and Moxifloxacin Therapy in Management of Intraocular Tubercular Granulomas. Ocul Immunol Inflamm. 2021 Dec 17;1–10.23. Singh N, Singh R, Sharma RK, Kumar A, Sharma SP, Agarwal A, et al. Mycobacterium Tuberculosis Modulates Fibroblast Growth Factor and Vascular Endothelial Growth Factor in Ocular Tuberculosis. Ocul Immunol Inflamm. 2021 Nov 17;29(7–8):1445–51.24. Thayil SM, Albini TA, Nazari H, Moshfeghi AA, Parel JMA, Rao NA, et al. Local Ischemia and Increased Expression of Vascular Endothelial Growth Factor Following Ocular Dissemination of Mycobacterium tuberculosis. Cardona PJ, editor. PLoS ONE. 2011 Dec 5;6(12):e28383.25. Aravindan P. Host genetics and tuberculosis: Theory of genetic polymorphism and tuberculosis. Lung India. 2019;36(3):244.26. Wildschütz L, Ackermann D, Witten A, Kasper M, Busch M, Glander S, et al. Transcriptomic and proteomic analysis of iris tissue and aqueous humor in juvenile idiopathic arthritis-associated uveitis. J Autoimmun. 2019 Jun;100:75–83.Richa Pyare MS, FMRF, FICOA-9, Kailash Colony, Lala Lajpat Rai Marg,Shroff Eye Centre, New DelhiCorresponding Author:

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 72 www.dosonline.orgThe Crucial Role of Multimodal Imaging in Diagnosing and Managing Acute Vogt-Koyanagi-Harada DiseaseTanya Jain MBBS, DNB, FVRS, FICO | Richa Nyodu MBBS, MS | Aishwarya Kanagaraj MBBS, DNBDr Shroff’s Charity Eye Hospital, Daryaganj, New Delhi, IndiaAbstract: The Vogt-Koyanagi-Harada syndrome (VKH), also known as uveomeningitic syndrome, is an idiopathic multisystem inflammatory disease with bilateral, diffuse granulomatous uveitis associated with poliosis, alopecia, vitiligo, neurological and auditory signs. The availability of new investigational methods has improved our knowledge of the immunopathology, diagnosis, and efficient management of VKH disease. Extensive studies have been done to identify characteristics in various imaging modalities to make the diagnosis more lucid and monitoring to identify subclinical disease activity. Here, we discuss multimodal imaging characteristics of acute VKH in two patients.IntroductionVogt-Koyanagi-Harada disease (VKH) is a progressive inflammatory condition presenting as a constellation of bilateral granulomatous posterior or panuveitis with neurological, auditory and integumentary system involvement.[1]Alfred Vogt’s initial description of patients with bilateral anterior uveitis with vitiligo, poliosis, alopecia, and dysacousia in 1906 marked the first step in understanding VKH. Yoshizo Koyanagi’s 1928 case series report of 16 VKH cases furthered our knowledge. Since then, the diagnostic criteria have evolved, with the 1999 AAU classification distinguishing between complete, incomplete, and probable VKH based on the number of systems involved.[2] While the current diagnostic criteria for VKH are based on clinical findings, they do not fully utilize the potential of various imaging modalities. Incorporating these modalities, which have become indispensable tools for ophthalmologists, could significantly enhance our ability to diagnose and monitor VKH. VKH is considered a cell-mediated, autoimmune disease targeting melanocytes. The melanocyte-specific tyrosinase-related proteins 1 (TRP 1) and 2 (TRP 2) have been identified as antigens specific to VKH and sympathetic ophthalmia.[3] Shindo et al. demonstrated that HLA DRB1*0405 and DRB1*0410 were closely associated with VKH.[4] The trigger in VKH may be an infectious agent, such as Epstein-Barr virus or cytomegalovirus.[5] Rathnam et al. stated that VKH cutaneous injury might be associated with the onset of intraocular inflammation in VKH in the populations at risk.[6] In 2022, Herbort et al. incorporated bilateral disease and diffuse choroiditis on EDI-OCT to propose simplified diagnostic criteria for acute initial onset VKH.[7] Angio-OCT (OCTA) is a newer and promising modality that employs motion contrast imaging to obtain high-resolution volumetric blood flow information, generating angiographic images in seconds. Various OCTA parameters in VKH are being studied to assess disease activity during follow-up and monitor patients undergoing treatment.[8] ICGA has been instrumental in diagnosing subclinical VKH, which is not evident in clinical examination or FFA. Extensive studies are ongoing to correlate various modalities to simplify diagnosis, enhance disease understanding, monitor therapy as non-invasively as possible, and identify subclinical disease activity.CaseA 40-year-old female patient presented with a diminution of vision in both eyes for 15 days associated with headache and meningismus. There was no history of

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 73 www.dosonline.orgtrauma or any other systemic illness. The best corrected visual acuity in the right eye was 6/9, and in the left eye was 6/18, with a normal intraocular pressure (IOP). The anterior segment has cells of 2+, and other findings were unremarkable. Posterior segment (Figure-1 & 2) showed vitritis, disc edema and deep yellowish lesions with pockets of sub-retinal fluid. B-scan showed an increased retinochoroidal scleral (RCS) thickness of 1.83 and 2.63mm in RE and LE, respectively.Figure-3 is a raster scan HD-OCT, showing an altered foveal contour (yellow cross) with hypo-reflectivity in the subretinal space suggestive of an exudative retinal detachment along with intramembranous structures (yellow star), which are hypothesised to be remnants of the degraded cone outer segments along with inflammatory fibrinous septae (yellow arrows). The RPE has an uneven, bumpy appearance (yellow plus) due to the underlying choroidal granulomas, which show RPE undulations. The choroidal thickness is increased (double- headed yellow arrow) owing to the inflammation. This is an essential and valuable parameter to confirm the diagnosis, monitor treatment, and detect exacerbations or recurrences in patients during follow-up.The classical ‘starry sky appearance’ seen on fundus fluorescein angiography (Figure-4) shows well-defined arFigure 1 & 2: Colour fundus photo showing disc edema with multiple pockets of subretinal fluid.Figure 4 & 5: Starry sky appearance in FFA. Figure 3: HD-OCT showing exudative retinal detachment with intramembranous septa.Figure 6 & 7: ICGA showing early hypo and late hypo and hyperfluorescence.eas of hyper- and hypofluorescence (yellow circles) in the early phase, suggesting underlying choroidal granulomas, along with pinpoint areas of hyperfluorescence (yellow arrow), which leak in the late phase, followed by pooling of the dye (yellow arrows in Figure-5) in areas of exudative retinal detachment.These findings can be correlated well with the ICGA images, which demonstrate the granulomas. Fuzzy and leaky choroidal vessels are visualized in the early phase, along with areas of hypofluorescence, which remain hypo in late phases in cases of full-thickness granulomas or become iso- or hyperfluorescent in partial-thickness granulomas. Observe the yellow star in Figure-6 (early phase), which remains hypo, while the pentagon becomes hyperfluorescent in Figure-7 (late phase). OCT angiography en face image (scanned area represented by the yellow square on FFA) at the level of the choriocapillaris shows multiple hyporeflective round-to-oval lesions, which represent areas of flow void or choriocapillaris hypoperfusion, corresponding to the hyperfluorescent lesions seen on FA and ICGA (yellow arrows in Figure-8). Figure-9 is an en face image demonstrating capillary hypoperfusion, and Figure-10 shows a 3D representation of the increased choroidal thickness and RPE undulations obtained on enhanced depth OCT.

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 74 www.dosonline.orgFigure 8, 9 & 10: OCTA at the level of choriocapillaries showing flow void areas and 3D representation of increased choroidal thickness.Figure 11: Multimodal imaging showing choridal granuloma. Figure-11 demonstrates multimodal imaging showing choroidal granulomas and associated changes in the choriocapillaris. Part A is a fundus picture showing multiple deep yellowish lesions, which on fundus fluorescein angiography (B) appear as hypofluorescent lesions. On indocyanine green angiography (ICGA) (C), the early phase shows hyperfluorescent lesions that remain hyperfluorescent in the late phase, suggesting choriocapillaris ischemia. The study lesions (yellow circles) on ICGA are visible as areas of flow void on OCTA en face images at the level of the choriocapillaris (D). An enhanced depth imaging optical coherence tomography scan (E) passing through the lower choroidal lesion shows localized thickening of the choriocapillaris, with loss of typical pattern and RPE undulations, suggesting choroidal granulomas.The patient was promptly started on intravenous steroids for five days, a decision that led to the resolution of her subretinal fluid and a reduction in choroidal thickness. This proactive approach, along with the reduction in the flow void areas on the angioscan, enabled her to be discharged on oral steroids and oral immunosuppressants.(Figure-12)Figure 12: OCTA showing flow void areas.The patient was followed up using Angio-OCT scans and enhanced depth imaging scans to monitor disease activity by periodically measuring the central macular thickness, choroidal thickness, and flow void areas. Figure-13 shows the serial OCT scans of the left eye (LE) of the patient over six months while she was on oral immunosuppressant azathioprine 50mg BD, and oral steroids were tapered by three months. The patient was followed up using enhanced depth OCT scans, which showed the resolution of the subretinal fluid and fibrin, along with decreased choroidal thickness. These findings correlated well with the Angio-OCT scans at the level of the choriocapillaris, where the areas of flow void decreased as the granulomas and inflammation resolved. The patient has remained stable for six months, with a BCVA of 6/6 in the right eye (RE) and 6/12 in the LE, while continuing oral immunosuppressants and regular follow-up.Figure 13: Serial OCT and OCTA scans showing resolution of SRF and decrease in flow void areas.

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 75 www.dosonline.orgCase 2A 33-year-old female presented with a diminution of vision in both eyes for 10 days associated with headache. There was no history of trauma or any other systemic illness. She had a best-corrected visual acuity of hand movements in both eyes. On examination, she had 1+ cells in the anterior chamber. The posterior segment showed a hyperemic disc and multiple deep yellowish-white lesions with pockets of subretinal fluid. (Figure-14 &15)OCT of the right eye showed an altered foveal contour with hypo-reflectivity in the sub-retinal space (yellow arrow). OCT of the left eye revealed subretinal fluid along with intramembranous structures (yellow star).Figure 14 & 15: Colour fundus photo showing hyperemic disc and multiple SRF pockets. Figure 16 & 17: HD-OCT showing subretinal fluid and intramembranous septa.Figure 18: Late-phase fluorescein angiogram showed diffuse pinpoint leakage (red arrow) and hyperfluorescent disc.Figure 19: OCTA of the right and the left eye.OCTA at the level of choriocapillaris (scanned area represented by yellow square on FFA) showing multiple hyporeflective round-to-oval lesions, which represent areas of flow void or hypoperfusion corresponding to the hypoflourescent lesions seen in FFA (yellow arrow).

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 76 www.dosonline.orgFigure 20: 3D demonstrates the increased choroidal thickness obtained in Enhanced depth OCT.Figure 21: Serial OCTA showing a decrease in flow void areas. The patient was started on intravenous methylprednisolone 1g for three days, followed by a tapering dose of oral steroids. After obtaining physician clearance, the patient was started on azathioprine 50mg twice a day. She was followed up with OCTA at every visit. The subretinal fluid gradually resolved, with a reduction in flow void areas.The patient was continued on azathioprine, while oral steroids were tapered. Her vision improved to 6/9, N9 in both eyes after two months of follow-up. The patient has remained stable for six months on immunosuppressant and maintains a BCVA of 6/9 in both eyes.OCTA at the level of the choriocapillaris showed multiple hyporeflective round-to-oval lesions, representing areas of flow void or hypoperfusion at presentation. Serial images taken at two weeks, one month, three months, and six months after treatment demonstrated a decrease in flow void areas and resolution of subretinal fluid.ConclusionVKH disease starts in the choroidal stroma and later involves other structures. Identification of subclinical activity during follow-up is crucial for adequate treatment. Multimodal imaging is not just the future but the present standard of care for these eyes, not only for diagnosis but also for non-invasive follow-up and early recognition of recurrences. Even after early corticosteroid therapy in the initial stage of the disease, a significant proportion of patients develop chronic recurrent inflammation, resulting in a sunset glow appearance.[9] Progression to a sunset glow fundus has also been noted as a consequence of subclinical inflammation, as seen in ICGA studies, due to inadequately controlled choroidal inflammation.[10]Early diagnosis, timely intravenous and oral steroids, long-term immunosuppression, and multimodal imaging with regular follow-up to identify subclinical disease activity are indispensable for achieving optimal visual rehabilitation in these patients.References1. Yang P, Ren Y, Li B, Fang W, Meng Q, Kijlstra A. Clinical characteristics of Vogt-Koyanagi-Harada syndrome in Chinese patients. Ophthalmology. 2007 Mar;114(3):606–14. 2. Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S, Arellanes-Garcia L, et al. Revised Diagnostic Criteria for Vogt-Koyanagi-Harada Disease: Report of an International Committee on Nomenclature. Am J Ophthalmol. 2001;131(5). 3. Yamaki K, Kondo I, Nakamura H, Miyano M, Konno S, Sakuragi S. Ocular and Extraocular Inflammation Induced by Immunization of Tyrosinase Related Protein 1 and 2 in Lewis Rats. Exp Eye Res. 2000 Oct;71(4):361–9. 4. Shindo Y, Inoko H, Yamamoto T, Ohno S. HLA-DRB1 typing of Vogt-Koyanagi-Harada’s disease by PCRRFLP and the strong association with DRB1*0405 and DRB1*0410. Br J Ophthalmol. 1994 Mar 1;78(3):223–6. 5. S S, H T, T K, C T, M M. Cross-reaction between tyrosinase peptides and cytomegalovirus antigen by

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 77 www.dosonline.orgT cells from patients with Vogt-Koyanagi-Harada disease. Int Ophthalmol [Internet]. 2007 Jun [cited 2024 Oct 15];27(2–3). Available from: https://pubmed.ncbi.nlm.nih.gov/17253112/6. Rathinam SR, Namperumalsamy P, Nozik RA, Cunningham ET. Vogt-Koyanagi-Harada syndrome after cutaneous injury. Ophthalmology. 1999 Mar;106(3):635–8. 7. Herbort CP, Tugal-Tutkun I, Abu-El-Asrar A, Gupta A, Takeuchi M, Fardeau C, et al. Precise, simplified diagnostic criteria and optimised management of initial-onset Vogt-Koyanagi-Harada disease: an updated review. Eye Lond Engl. 2022 Jan;36(1):29–43. 8. Aggarwal K, Agarwal A, Mahajan S, Invernizzi A, Mandadi SKR, Singh R, et al. The Role of Optical Coherence Tomography Angiography in the Diagnosis and Management of Acute Vogt–Koyanagi–Harada Disease. Ocul Immunol Inflamm. 2018 Jan 2;26(1):142–53. 9. Sakata VM, da Silva FT, Hirata CE, Marin MLC, Rodrigues H, Kalil J, et al. High rate of clinical recurrence in patients with Vogt-Koyanagi-Harada disease treated with early high-dose corticosteroids. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 2015 May;253(5):785–90. 10. Kawaguchi T, Horie S, Bouchenaki N, Ohno-Matsui K, Mochizuki M, Herbort CP. Suboptimal therapy controls clinically apparent disease but not the subclinical progression of Vogt-Koyanagi-Harada disease. Int Ophthalmol. 2010 Feb;30(1):41–50. 11. Attia S, Khochtali S, Kahloun R, Ammous D, Jelliti B, Ben Yahia S, et al. Clinical and multimodal imaging characteristics of acute Vogt-KoyanagiHarada disease unassociated with clinically evident exudative retinal detachment. Int Ophthalmol. 2016 Feb;36(1):37–44. Tanya Jain MBBS, DNB, FVRS, FICOVitreo-Retina DepartmentDr Shroff’s Charity Eye Hospital5072, Kedarnath Road, Daryaganj, New DelhiCorresponding Author:

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 78 www.dosonline.orgOptic Neuritis: A Review of Clinical Presentations, The Current Status of Biomarkers and Specific TherapiesVishakha Mansotra MBBS, DNB | Mahek KewalramaniMBBSHindu Rao Hospital, New DelhiOptic neuritis (ON) refers to a group of conditions that involve inflammation of the optic nerve. The patients present with partial to complete vision loss within a few days of onset.[1] Classically, “typical” ON is heralded by painful, subacute onset vision loss, dyschromatopsia, and visual field defects. Unilateral or asymmetric bilateral cases of ON will also have a relative afferent pupillary defect in the affected eye; or in the case of bilateral involvement, the more severely affected eye.[2] The Optic Neuritis Treatment Trial (ONTT) characterized the “typical” presentation of ON cases that are idiopathic in origin (sporadic ON) or represent a first demyelinating event in individuals who later develop multiple sclerosis (MS).[2-5] Recently, biomarkers have helped identify cases previously categorized as cryptogenic ON or chronic relapsing inflammatory optic neuropathy (CRION) as manifestations of neuromyelitis optica spectrum disorder (NMOSD) or myelin-oligodendrocyte glycoprotein IgG associated disease (MOGAD).[6,7] Table 1 illustrates the difference in clinical presentation, MRI findings, prognosis and treatment of typical and atypical ON.Characteristics Typical ON[5] Atypical ONNMOSD[8] MOGAD[9]Median age 32 40-52.5 31-41Percent female 77% 90% 57%Pain in EOM 92% 53% 86%Ethnicity 85% white Asian/Afro-Caribbean White Distribution of ON lesions Unilateral Bilateral Bilateral ON swelling 35% 34% 86%Visual acuity defects Mild/moderate/severe Severe Severe Prognosis for visual recoveryGood Poor GoodMRI optic nerve findings Short lesions (<50% of the optic nerve)Long intracranial lesions involving the posterior optic nerves and chiasmaLongitudinal intra-orbital lesions with perineural enhancementTreatment Observation/IV steroids IV steroids + PLEX IV steroidsTable 1: Clinical Characteristics of Typical vs Atypical ON.Typical ON is most commonly associated with MS demylination of optic nerve while the atypical ON is due to autoimmune disorders (Sarcoidosis, Sjogren syndrome, rheumatoid arthritis, neuromylitis optica, SLE) but a

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 79 www.dosonline.orgsignificant number of cases of atypical ON have found to have infectious etiologies [Bacterial (Tuberculosis, syphillis, meningitis, Lyme’s disease), Viral (Bartonella, measles, mumps, rubella, chicken pox, herpes)][10]Novel Biomarkers in Optic NeuritisAquaporin‑4‑IgG (AQP4‑IgG)Aquaporin‑4 is widely expressed throughout the CNS. It is also highly expressed in the optic nerves and the spinal cord, explaining the NMO’s preferential involvement. The AQP4‑Ig antibody enters the CNS, binds the antigen to astrocyte processes, induces complement‑mediated inflammation, granulocyte infiltration, and astrocyte death. Complement‑mediated inflammation of secondary neutrophils and eosinophilic infiltration plays a key role in the pathophysiology of NMOSD attacks.[10]Anti‑MOG AntibodiesThey are developed peripherally and usually reach the CNS following a breakdown of the BBB secondary to infection. Almost 50 percent of patients report a history of previous infectious prodromes. The lack of restricted oligoclonal bands in patients with anti‑MOG syndromes in the CSF supports the notion of peripheral origin.[11]Oligoclonal IgG BandsOCBs are bands of immunoglobulins (IgG) that appear when CSF proteins are separated and analyzed, particularly by isoelectric focusing and immunoblotting. The presence of OCBs in the CSF, but not in the serum, strongly suggests a local B-cell response within the central nervous system (CNS), indicating inflammation, and is a key diagnostic criterion for MS.IL-6 & IL-6 ReceptorIL-6 may have multiple roles in NMOSD pathophysiology by promoting plasmablast survival, stimulating the production of antibodies against aquaporin-4, disrupting blood-brain barrier integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation.[12]Glial Fibrillar Acidic Protein [GFAP]GFAP, a marker of astrocytic damage, as well as N‑acetyl aspartate may be elevated in NMO spectrum disease, compared with MS, and may help to distinguish between the two.[10]Neurofilament Light ProteinNeurofilaments, a type of intermediate filament, consist of five primary isoforms: NfL, NfM, NfH, α-internexin, and peripherin. These proteins are crucial as they form obligate heteropolymers essential for neuronal structure and function.[13] Hence they are considered as marker of axonal damage and relates to MS.Th17 and Treg/Th17In both typical and atypical ON patients a significant up‑regulation of Th17 cells, a down‑regulation of Treg cells, and an imbalanced Treg/Th17 ratio is seen in various studies,[14] more in atypical ON.AQP-4Ab Positive in NMONegative in MSMOG Ab Diagnosis of MOGADAbsent in seropositive NMOOCGB Positive in 20-30% NMO patients6-13% MOGAD80% MS IL-6 Increased in NMOIL-6 receptor Increased in NMONeurofilament light protein High levels in incomplete remission of ONTh17 and Treg/Th-17 Imbalanced ratio in atypical ON> typical ONTable 2: Summary of biomarkers in ON.Approach to Optic Neuritis[15]

Special Issue - Ocular Inflammation and Molecular Markers: “Untying the Knots”DOS Times - Volume 30, Number 5, January-February 2025 80 www.dosonline.orgReferences1. Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow‑up. Arch Neurol 2008;65:727‑32.2. Costello F. Inflammatory optic neuropathies. Continuum (Minneap Minn) 2014;20:816 -37.3. Bennett JL. Optic Neuritis. Continuum (Minneap Minn) 2019;25:1236–64.4. Bennett JL, Costello F, Chen JJ, Petzold A, Biousse V, Newman NJ, et al. Optic neuritis and autoimmune optic neuropathies. Lancet Neurol 2021 (in press).5. Beck RW, Cleary PA, Anderson MM Jr, Keltner JL, Shults WT, Kaufman DI, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 1992;326:581–8.6. Lee HJ, Kim B, Waters P, Woodhall M, Irani S, Ahn S, et al. Chronic relapsing inflammatory optic neuropathy (CRION): A manifestation of myelin oligodendrocyte glycoprotein antibodies. J Neuroinflammation 2018;15:302.7. de Lott LB, Bennett JL, Costello F. The changing landscape of optic neuritis: A narrative review. J Neurol 2021:10.1007/s00415—20‑10351‑1.8. Ishikawa H, Kezuka T, Shikishima K, Yamagami A, Hiraoka M, Chuman H, et al. Epidemiologic and Clinical Characteristics of Optic Neuritis in Japan. Ophthalmology 2019;126:1385-98.9. Chen JJ, Flanagan EP, Jitprapaikulsan J, López‑Chiriboga AS, Fryer JP, Leavitt JA, et al. Myelin oligodendrocyte glycoprotein antibody–positive optic neuritis: Clinical characteristics, radiologic clues, and outcome. Am J Ophthalmol 2018;195:8–15.10. Sarkar P, Mehtani A, Gandhi HC, Dubey V, Tembhurde PM, Gupta MK. Atypical optic neuritis: An overview. Indian J Ophthalmol. 2021 Jan;69(1):27-35. doi: 10.4103/ijo.IJO_451_20. PMID: 33323567; PMCID: PMC7926095.11. Spadaro M, Gerdes LA, Mayer MC, Ertl‑Wagner B, Laurent S, Krumbholz M, et al. Histopathology and clinical course of MOG‑antibody‑associated encephalomyelitis. Ann Clin Transl Neurol 2015;2:295‑30.12. Fujihara K, Bennett JL, de Seze J, Haramura M, Kleiter I, Weinshenker BG, Kang D, Mughal T, Yamamura T. Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology. Neurol Neuroimmunol Neuroinflamm. 2020 Aug 20;7(5):e841. doi:10.1212/NXI.0000000000000841. PMID: 32820020; PMCID: PMC7455314.13. Sara Samadzadeh, Roy D. Sleator.The role of Neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in MS and AQP4-NMOSD: Advancing clinical applications.,eNeurologicalSci, Volume 38,2025,100550,ISSN 2405-6502, https://doi.org/10.1016/j.ensci.2025.100550.14. Cong H, Jiang H, Peng J, Cui S, Liu L, Wang J, et al. Change of Th17 Lymphocytes and Treg/Th17 in Typical and Atypical Optic Neuritis. PLoS One 2016;11:e0146270.15. Benard-Seguin E, Costello F. A Practical Approach to the Diagnosis and Management of Optic Neuritis. Ann Indian Acad Neurol. 2022 Oct;25(Suppl 2):S48-S53. doi: 10.4103/aian.aian_170_22. Epub 2022 Jun 21. PMID: 36589032; PMCID: PMC9795707.Vishakha Mansotra MBBS, DNBSpecialistHindu Rao Hospital, New DelhiCorresponding Author: