Immunology and Uveitis

Agarwal A, Agrawal R, Raje D, Testi I, Mahajan S, Gunasekeran DV, Aggarwal K, Murthy SI, Westcott M, Chee S-P, McCluskey P, Ho SL, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Carreño E, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Herbort CP, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Esposti SD, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Singh R, Sharma A, Sharma K, Zierhut M, Kon OM, Cunningham ET, Kempen JH, Nguyen QD, Pavesio C, Gupta V. Twenty-four Month Outcomes in the Collaborative Ocular Tuberculosis Study (COTS)-1: Defining the "Cure" in Ocular Tuberculosis. Ocul Immunol Inflamm 2020;:1-9.Abstract
PURPOSE: To report the clinical findings, anatomical features, and treatment outcomes in subjects with ocular tuberculosis (OTB) at 24 months in the Collaborative Ocular Tuberculosis Study (COTS)-1. METHODS: Of the 945 subjects included in COTS-1, those who completed a 24-month follow-up after completion of treatment were included. The main outcome measure was a number of patients with treatment failure (TF). RESULTS: 228 subjects (120 males; mean age of 42.82 ± 14.73 years) were included. Most common phenotype of uveitis was posterior ( = 81; 35.53%), and panuveitis ( = 76; 33.33%). Fifty-two patients (22.81%) had TF. On univariable analysis, odds of high TF was observed with bilaterality (OR: 3.46, = .003), vitreous haze (OR: 2.14, = .018), and use of immunosuppressive therapies (OR: 5.45, = .003). However, only bilaterality was significant in the multiple regression model (OR: 2.84; = .02). CONCLUSIONS: Majority of subjects (>75%) achieved cure in the COTS-1 at 24-month follow-up. The concept of "cure" may be a valuable clinical endpoint in trials for OTB.
Maleki A, Ueberroth JA, Walsh M, Foster F, Chang PY, Anesi SD, Foster CS. Combination of Intravenous Methotrexate and Methylprednisolone Therapy in the Treatment of Severe Ocular Inflammatory Diseases. Ocul Immunol Inflamm 2020;:1-5.Abstract
: To evaluate the efficacy of intravenous methotrexate and methylprednisolone in severe, sight-threatening ocular inflammatory conditions.: This was a retrospective observational case series. Patients who had received intravenous methotrexate for ocular inflammation with at least 24 months of follow-up were included in the study.: Ten patients (20 eyes) were included in this study. Mean age of the patients was 47.2 ± 17.7 (range:19-74). At 1-month follow-up visit, nine patients showed improvement and one patient failed treatment. At 12-month follow-up visit, all patients were in remission. Two patients were only on intravenous methotrexate infusions. At twenty-four-month follow-up visit, only one patient, in remission, was on intravenous methotrexate therapy. Leukopenia was the only adverse effect observed.: Intravenous methotrexate and methylprednisolone infusions can be an effective method of treatment in patients with severe, sight-threatening ocular inflammatory conditions.
Peters RPH, Kestelyn PG, Zierhut M, Kempen JH. The Changing Global Epidemic of HIV and Ocular Disease. Ocul Immunol Inflamm 2020;28(7):1007-1014.Abstract
: Overview of the evolving epidemiology of human immunodeficiency virus (HIV)-related ocular disease over time. : Narrative review. : HIV enhances susceptibility to opportunistic eye infections, has direct pathogenic effects, and places patients at risk of immune recovery inflammatory syndromes in previously infected eyes after starting highly-active antiretroviral therapy (HAART). Widespread availability of HAART has resulted in a decrease of infectious ocular conditions such as cytomegalovirus retinitis, toxoplasmic retinitis, squamous cell carcinoma of the conjunctiva, and microvascular retinopathy. However, large coexisting burdens of tuberculosis, herpesvirus infection and syphilis (among others) continue to contribute to the burden of ocular disease, especially in low-resource settings. Growing risks of cataract, retinopathy and retinal nerve fiber thinning can affect patients with chronic HIV on HAART; thought due to chronic inflammation and immune activation. : The changing epidemic of ocular disease in HIV-infected patients warrants close monitoring and identification of interventions that can help reduce the imminent burden of disease.
Anesi SD, Eggenschwiler L, Ferrara M, Artornsombudh P, Walsh M, Foster SC. Reliability of Conjunctival Biopsy for Diagnosis of Ocular Mucous Membrane Pemphigoid: Redetermination of the Standard for Diagnosis and Outcomes of Previously Biopsy-Negative Patients. Ocul Immunol Inflamm 2020;:1-8.Abstract
: To demonstrate the reliability of conjunctival biopsy analyzed by direct immunofluorescence (DIF) and supplemented with avidin-biotin complex immunoperoxidase (ABC) in diagnosing oMMP, and report therapy response in biopsy-positive patients, particularly when previously biopsy-negative elsewhere.: Retrospective outcomes review of 136 consecutive patients after conjunctival biopsy for suspected oMMP.: Among 136 patients, 66% were diagnosed with oMMP by DIF and 13% via supplemental ABC immunoperoxidase. Sensitivity increased from 79.6% with DIF to 95.6% with supplemental ABC. Among 57 biopsy-positive patients, 77% were in remission at 1-year follow-up and 88% after 2 years. Of 34 previous biopsy-negative but now biopsy-positive patients with a 2-year follow-up, 91% achieved remission, including all 16 diagnosed via DIF and ABC.: Conjunctival biopsy analyzed by histopathology and DIF supplemented by ABC has high reliability for diagnosing oMMP and is a useful tool to use before starting long-term immunomodulatory therapy in a patient with suspected oMMP.
Muhammad F, Wang D, McDonald T, Walsh M, Drenen K, Montieth A, Foster SC, Lee DJ. TIGIT A2Ar-Dependent anti-uveitic Treg cells are a novel subset of Tregs associated with resolution of autoimmune uveitis. J Autoimmun 2020;111:102441.Abstract
Regulatory T cells (Tregs) are necessary to prevent autoimmune disease. As such, stable FoxP3 expression is required for the proper function of Tregs in the control of autoimmune disease. Different Treg subsets that utilize different mechanisms of suppression have been identified. The T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif (TIGIT) is a relatively new Treg cell marker that has a suppressive function. We have previously identified the adenosine 2A receptor (A2Ar) as a requirement for the emergence of Tregs following resolution of autoimmune disease. Using a FoxP3-GFP-Cre reporter mouse, we identify FoxP3 and 'exFoxP3' cells, show FoxP3 and not exFoxP3 cells are suppressive. We further show FoxP3 cells express TIGIT, and are induced through A2Ar in healthy volunteers, but not patients with autoimmune disease. Furthermore, we show Tregs emerge in the target tissue at the onset of autoimmune disease in an A2Ar-dependent manner. In summary, we identify a novel subset of TIGIT Tregs that are induced through stimulation of the A2Ar.
McKay MK, Borkar DS, Sevgi DD, Susarla G, Papaliodis GN, Sobrin L. Comparison of Modified Posterior Sub-Tenon's vs. Trans-Septal Triamcinolone Injection for Non-infectious Uveitis. Ocul Immunol Inflamm 2020;:1-8.Abstract
: To compare the safety and efficacy of trans-septal vs. modified posterior sub-Tenon's (PST) corticosteroid injections for noninfectious uveitis.: Retrospective comparison of periocular triamcinolone injection by modified PST (n = 36) vs. traditional trans-septal (n = 79) techniques. Safety and efficacy outcomes were analyzed with regression models.: There was no significant difference in visual acuity improvement between the groups at 6 months. There were higher rates of vitritis resolution in the modified PST group but this was not statistically significant (85.7% vs 62.9%, = .07). Intraocular pressure (IOP) elevation rate trended higher with the modified PST injection (21.9% vs 9.0%, = .06), with no instances of glaucoma surgery in either group. Two modified PST injection patients with refractory IOP rises had IOP normalization after corticosteroid depot removal. One year cataract surgery rates were similar.: Modified PST injection offers clinical efficacy but with possibly higher IOP response rate which could be managed with corticosteroid removal.
Cheung CSY, Mireskandari K, Ali A, Silverman E, Tehrani N. Earlier use of systemic immunosuppression is associated with fewer ophthalmic surgeries in paediatric non-infectious uveitis. Br J Ophthalmol 2020;104(7):938-942.Abstract
BACKGROUND/AIMS: There is a paucity of large trials investigating the effect of management strategies for paediatric non-infectious uveitis on complications requiring surgery. The purpose of our study is to investigate whether earlier initiation of systemic immunosuppression in paediatric non-infectious uveitis is associated with fewer ophthalmic surgeries. METHODS: A retrospective review was conducted on 48 children with non-infectious uveitis assessed in 1998-2013. Patients were divided into uveitis diagnosed before December 2008 (group 1) and after January 2009 (group 2). Duration from uveitis onset to methotrexate initiation (U-MTX) and biological addition (U-Biologic) were reviewed. Follow-up visits with topical corticosteroids >3 times daily and active uveitis (≥1+ cells) during 3.5 years were documented. The main outcome measure was the need for ≥1 ophthalmic surgery at 3.5 years. RESULTS: In group 1, 69.5% of patients required ≥1 ophthalmic surgery at 3.5 years versus 26.9% in group 2 (p=0.005). U-MTX was 28.9±11.8 weeks and 14.2±10.0 weeks for groups 1 and 2 (p=0.028). U-Biologic was 134.6±46.0 weeks and 82.3±43.3 weeks for groups 1 and 2 (p=0.0016). Corticosteroid use >3 times daily was 85.9±52.7 weeks and 14.6±11.1 weeks for groups 1 and 2. Multivariate regression showed methotrexate initiation within 6 months of uveitis onset lowered the likelihood of needing ophthalmic surgery at 3.5 years (OR=6.2, 95% CI 1.2 to 33.4; p=0.033). Univariate regression demonstrated biological addition within 18 months of uveitis onset reduced the likelihood of requiring ophthalmic surgery (OR 12.57, 95% CI 1.28 to 123.48; p=0.030). CONCLUSION: Earlier control of uveitis by addition of immunosuppressive therapy reduced the need for ophthalmic surgery.
Tolesa K, Abateneh A, Kempen JH, Gelaw Y. Patterns of Uveitis among Patients Attending Jimma University Department of Ophthalmology, Jimma, Ethiopia. Ocul Immunol Inflamm 2020;28(7):1109-1115.Abstract
: Uveitis is an important cause of blindness and ocular morbidity in the world. The patterns of uveitis have not been well characterized in sub-Saharan Africa. : To describe the characteristics of uveitis among patients presenting to Jimma University Department of Ophthalmology (JUDO) from July 2013 to December 2014. : This hospital-based prospective cross-sectional study included all new uveitis patients visiting JUDO outpatient department during the study period. : Among 98 patients diagnosed with uveitis, anterior uveitis was found in 74.5% of patients. Majority of the patients, 83.7%, had unilateral uveitis. A uveitis syndrome was identified in 22.5% of cases; of these 15 (68.2%) were infectious. Herpes simplex uveitis was the commonest infectious cause (53.3%) while Toxoplasmosis was the most common cause of posterior uveitis (60%). : Anterior uveitis was the most common pattern found among uveitis patients. Herpes simplex and toxoplasmic chorioretinitis were the most common-identified infectious causes.
PURPOSE: To report the novel application of nontreponemal and treponemal antibody to confirm diagnosis of ocular syphilis from vitreous samples. METHODS: Two distinct case reports emphasizing the importance of confirmatory vitreous treponemal antibody. Multimodal imaging of patients was also applied. RESULTS: We report two distinct cases with positive serum treponemal antibody but opposing vitreous treponemal antibody results. One case with a positive vitreous test responded well to antisyphilitic treatment. By contrast, a case with a negative vitreous result was changed to serpiginous choroiditis, eventually cured by immunomodulatory treatment. CONCLUSION: Intraocular fluid analysis of nontreponemal and treponemal antibody may play an important role in ruling out suspected ocular syphilis in settings without a polymerase chain reaction facility, especially immunocompromised patients who are at risk of multiple infections. Further studies are needed to establish the sensitivity and specificity of nontreponemal and treponemal antibody test on vitreous samples.
Pistilli M, Joffe MM, Gangaputra SS, Pujari SS, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Sen NH, Suhler EB, Thorne JE, Bhatt NP, Foster SC, Begum H, Fitzgerald TD, Dreger KA, Altaweel MM, Holbrook JT, Kempen JH, for Group SITED (SITE) R. Visual Acuity Outcome over Time in Non-Infectious Uveitis. Ocul Immunol Inflamm 2019;:1-8.Abstract
: We evaluated visual acuity (VA) over 5 years in a subspecialty noninfectious uveitis population.: Retrospective data from 5,530 noninfectious uveitis patients with anterior, intermediate, posterior or panuveitis were abstracted by expert reviewers. Mean VA was calculated using inverse probability of censoring weighting to account for losses to follow-up.: Patients were a median of 41 years old, 65% female, and 73% white. Initial mean VA was worse among panuveitis (20/84) than posterior (20/64), intermediate (20/47), and anterior (20/37) uveitides. On average, mean VA improved by 0.62, 0.51, 0.37, and 0.26 logMAR-equivalent lines over 2 years, respectively (each < .001), then remained stable, except posterior uveitis mean VA worsened to initial levels.: Mean VA of uveitic eyes improved and, typically, improvement was sustained under uveitis subspecialty care. Because VA tends to improve under tertiary care, mean VA change appears a better outcome for clinical studies than time-to-loss of VA.
Agrawal R, Agarwal A, Jabs DA, Kee A, Testi I, Mahajan S, McCluskey PJ, Gupta A, Palestine A, Denniston A, Banker A, Invernizzi A, Fonollosa A, Sharma A, Kumar A, Curi A, Okada A, Schlaen A, Heiligenhaus A, Kumar A, Gurbaxani A, Bodaghi B, Islam Shah B, Lowder C, Tappeiner C, Muccioli C, Vasconcelos-Santos DV, Goldstein D, Behra D, Das D, Makhoul D, Baglivo E, Denisova E, Miserocchi E, Carreno E, Asyari F, Pichi F, Sen NH, Uy H, Nascimento H, Tugal-Tutkun I, Arevalo FJ, Davis J, Thorne J, Hisae Yamamoto J, Smith J, Garweg JG, Biswas J, Babu K, Aggarwal K, Cimino L, Kuffova L, Agarwal M, Zierhut M, Agarwal M, DeSmet M, Tognon MS, Errera M-H, Munk M, Westcott M, Soheilian M, Accorinti M, Khairallah M, Nguyen M, Kon OM, Mahendradas P, Yang P, Neri P, Ozdal P, Amer R, Lee R, Distia Nora RL, Chhabra R, Belfort R, Mehta S, Shoughy S, Luthra S, Mohamed SO, Chee S-P, Basu S, Teoh S, Ganesh S, Barisani-Asenbauer T, Guex-Crosier Y, Ozyazgan Y, Akova Y, Habot-Wilner Z, Kempen J, Nguyen QD, Pavesio C, Gupta V, Gupta V. Standardization of Nomenclature for Ocular Tuberculosis - Results of Collaborative Ocular Tuberculosis Study (COTS) Workshop. Ocul Immunol Inflamm 2019;:1-11.Abstract
: To standardize a nomenclature system for defining clinical phenotypes, and outcome measures for reporting clinical and research data in patients with ocular tuberculosis (OTB).: Uveitis experts initially administered and further deliberated the survey in an open meeting to determine and propose the preferred nomenclature for terms related to the OTB, terms describing the clinical phenotypes and treatment and reporting outcomes.: The group of experts reached a consensus on terming uveitis attributable to tuberculosis (TB) as tubercular uveitis. The working group introduced a SUN-compatible nomenclature that also defines disease "remission" and "cure", both of which are relevant for reporting treatment outcomes.: A consensus nomenclature system has been adopted by a large group of international uveitis experts for OTB. The working group recommends the use of standardized nomenclature to prevent ambiguity in communication and to achieve the goal of spreading awareness of this blinding uveitis entity.
Rosenbaum JT, Bodaghi B, Couto C, Zierhut M, Acharya N, Pavesio C, Tay-Kearney M-L, Neri P, Douglas K, Pathai S, Song AP, Kron M, Foster SC. New observations and emerging ideas in diagnosis and management of non-infectious uveitis: A review. Semin Arthritis Rheum 2019;49(3):438-445.Abstract
BACKGROUND: Non-infectious uveitis (NIU) is an immune-mediated disease with clinical symptoms such as eye pain, redness, floaters, and light sensitivity. NIU is one of the leading causes of preventable blindness. OBJECTIVE: This review describes current and emerging therapies for NIU. METHODS: PubMed searches were conducted using the terms uveitis, therapy, corticosteroids, immunomodulators, biologics, intravitreal injections, intraocular implants, and adverse events deemed relevant if they presented data relating to prevalence, diagnosis, and treatment of uveitis. RESULTS: Diagnosis and management of NIU may require collaboration among different healthcare providers, including ophthalmologists and rheumatologists. Although many patients with NIU respond to corticosteroid (CS) therapy, long-term CS use can be associated with potentially severe adverse events. Localized CS therapies have been developed to reduce adverse events; however, some intravitreal injections and intraocular implants were linked to elevated intraocular pressure and cataracts. CS-sparing therapies such as biologics have demonstrated efficacy and safety while reducing CS burden. Biologics targeting tumor necrosis factor provide CS-sparing options for patients with NIU. Additional studies are needed to address long-term efficacy and safety of biologics targeting IL-6 and inhibitors of JAK/STAT. CONCLUSION: Biologics, JAK/STAT inhibitors, and improved localized therapies may provide additional options for patients with NIU.
Testi I, Agrawal R, Mahajan S, Agarwal A, Gunasekeran DV, Raje D, Aggarwal K, Murthy SI, Westcott M, Chee SP, McCluskey P, Ho SL, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Carreño E, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Herbort CP, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Esposti SD, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Singh R, Sharma A, Sharma K, Zierhut M, Rousselot A, Grant R, Kon OM, Cunningham ET, Kempen J, Nguyen QD, Pavesio C, Gupta V. Tubercular Uveitis: Nuggets from Collaborative Ocular Tuberculosis Study (COTS)-1. Ocul Immunol Inflamm 2019;:1-9.Abstract
Tuberculosis (TB) is a major infection that can affect the eye as first and sole presentation without features of systemic disease. Controversy exists regarding diagnosis and management of tubercular uveitis (TBU), further compounded by regional variations in disease expression. Collaborative Ocular Tuberculosis Study (COTS)-1 aims to address knowledge deficits through collaboration amongst uveitis specialists across the globe by sharing the data of patients with TBU presented at participating centers from January 2004 to December 2014. Data collection was facilitated by a novel method of real-time encrypted web-based data entry allowing regular updates as new data and recommendations become available. Information on clinical features, investigation findings, management, and treatment outcomes were reviewed to get an idea about real world scenario. The current review aims to focus on methodology and briefing of published reports from COTS group in COTS-1 study to highlight key messages from this large data.