Immunology and Uveitis

Immunology and Uveitis Publications

Sobrin L, Yu Y, Han S, Susarla G, Kempen JH, Hubbard RA, VanderBeek BL. Risk of Non-infectious Uveitis with Metformin Therapy in a Large Healthcare Claims Database. Ocul Immunol Inflamm 2021;:1-7.Abstract
PURPOSE: To determine if metformin is associated with noninfectious uveitis (NIU). METHODS: Patients in an insurance claims database who initiated metformin (n = 359,139) or other oral anti-diabetic medications (n = 162,847) were followed for NIU development. Both cohort and case-control analyses were performed to assess differing exposure lengths using Cox and conditional logistic regression, respectively. RESULTS: The hazard ratio (HR) for incident NIU was not significantly different between the metformin and non-metformin cohorts [HR = 1.19, 95% Confidence Interval (CI): 0.92-1.54, = .19]. The case control analysis similarly showed no association between any metformin use 2 years before the outcome date and NIU [odds ratio (OR) = 0.64, 95% CI: 0.39-1.04, = .07]. However, there was a protective 20 association between cumulative metformin duration [(445-729 days) adjusted OR (aOR) = 0.49, 95% CI: 0.27-0.90, = .02] and dosage (>390,000 mg aOR = 0.44, 95% CI: 0.25-0.78, = .001) compared with no metformin use. CONCLUSIONS: Our results suggest metformin use for longer durations may be protective of NIU onset.
Nguyen QD, Anesi SD, Chexal S, Chu DS, Dayani PN, Leng T, Meleth AD, Sallam AA, Sheppard JD, Silverstein SM, Toyos M, Wang RC, Foster CS. Management of repository corticotropin injection therapy for non-infectious uveitis: a Delphi study. Acta Ophthalmol 2021;Abstract
PURPOSE: Diagnosis and management of non-infectious uveitis (NIU), a major cause of blindness worldwide, are challenging. Corticosteroids, the cornerstone of therapy, are not appropriate for long-term use, and while non-biologic and biologic immunomodulators may be used for some patients, data on their efficacy and safety in this population are limited. Repository corticotropin injection (RCI), believed to affect uveitis by multiple mechanisms, has received regulatory approval for treatment of ophthalmic diseases including posterior uveitis, but is not widely used or discussed in guidelines for the management of uveitis and ocular inflammatory diseases. METHODS: The index study employed a modified Delphi process with a panel of 14 US-based ophthalmologists. Consensus recommendations were developed through a series of three questionnaires. Panellists rated statements on a Likert scale from -5 (strongly disagree) to +5 (strongly agree). RESULTS: The Delphi panel provided consensus recommendations on examinations and testing needed for diagnosis, treatment goals, and the use of corticosteroids, as well as the use of non-biologic and biologic immunomodulators. The panel reached consensus that RCI may be considered for posterior and pan-uveitis, and dosing should be individualized for each patient. Dose reduction/discontinuation should be considered for excessive RCI-related toxicity, hyperglycaemia and/or diabetic complications, excessive costs, or remission ≥ 2 years. Patients should be weaned from RCI if uveitis is stable and well controlled. Adverse events during RCI therapy can be managed by appropriate interventions, with dose reduction/discontinuation considered if events are severe or recurrent. CONCLUSIONS: Expert consensus suggests RCI may be an appropriate treatment option for some patients with uveitis when other therapies are ineffective or intolerable.
Maleki A, Garcia CM, Asgari S, Manhapra A, Foster CS. Response to the Second TNF-α Inhibitor (Adalimumab or Infliximab) after Failing the First One in Refractory Idiopathic Inflammatory Retinal Vascular Leakage. Ocul Immunol Inflamm 2021;:1-10.Abstract
: To determine the response to the second TNF-α inhibitor (adalimumab and infliximab) after failing the first agent in idiopathic inflammatory retinal vascular leakage.: This was a retrospective observational case series. Patients with the diagnosis of idiopathic inflammatory retinal vascular leakage who had received both infliximab and adalimumab were included in the study.: Twelve and 15 patients received adalimumab (Group one) and infliximab (Group two) as the first treatment, respectively. The remission rates between Group one (58.3%) and Group two (66.7%) were not statistically significant. ( = .4) As the second agent, adalimumab was more effective in younger patients (27.5 ± 20.6) compared to older patients (48.75 ± 10.2). ( = .03). Moreover, patients with lower vision responded marginally better to infliximab as the second treatment ( = .06).: Either TNF-α inhibitor, adalimumab and infliximab, can be employed in the treatment of the patients with idiopathic inflammatory retinal vascular leakage who fail one of these agents.
Brill D, Papaliodis G. Uveitis Specialists Harnessing Disruptive Technology during the COVID-19 Pandemic and Beyond. Semin Ophthalmol 2021;:1-8.Abstract
Spurred by the coronavirus disease pandemic and shortage of eye care providers, telemedicine is transforming the way ophthalmologists care for their patients. Video conferencing, ophthalmic imaging, hybrid visits, intraocular inflammation quantification, and portable technology are evolving areas that may allow more uveitis patients to be evaluated via telemedicine. Despite these promising disruptive technologies, there remain significant technological limitations, legal barriers, variable insurance coverage for virtual visits, and lack of clinical trials for uveitis specialists to embrace telemedicine.
Minkus CL, Pistilli M, Dreger KA, Fitzgerald TD, Payal AR, Begum H, Kaçmaz OR, Jabs DA, Nussenblatt RB, Rosenbaum JT, Levy-Clarke GA, Sen NH, Suhler EB, Thorne JE, Bhatt NP, Foster SC, Buchanich JM, Kempen JH, for Group SITED (SITE) CSR. Risk of Cataract in Intermediate Uveitis. Am J Ophthalmol 2021;Abstract
PURPOSE: To determine the incidence of and predictive factors for cataract in intermediate uveitis. DESIGN: Retrospective cohort study METHODS: Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study, in which medical records were reviewed to determine demographic and clinical data of every eye/patient at every visit at five participating United States tertiary care uveitis centers. The primary outcome was development of vision-compromising cataract as defined by a decrease in visual acuity to 20/40 or less, or requiring cataract surgery. Survival analysis assessed visually defined cataract to avoid bias due to timing of surgery vis-à-vis inflammatory status. RESULTS: Among 2,190 eyes of 1,302 patients with intermediate uveitis the cumulative incidence of cataract formation was 7.6% by one year (95% CI=6.2-9.1%), increasing to 36.6% by ten years (95% CI=31.2-41.6%). Increased cataract risk was observed in eyes with concurrent anterior uveitis causing posterior synechiae (HR=2.68, 95% CI=2.00-3.59, p<0.001), and in eyes with epiretinal membrane formation (HR=1.54, 95% CI=1.15-2.07, p=0.004). Higher dose corticosteroid therapy was associated with significantly higher incidence of cataract, especially time-updated use of topical corticosteroids ≥2 times/day or ≥4 periocular corticosteroid injections. Low dose corticosteroid medications (oral prednisone 7.5mg daily or less, or topical corticosteroid drops <2 times/day) were not associated with increased cataract risk. CONCLUSIONS: Our study found that the incidence of clinically important cataract in intermediate uveitis is moderate. The risk is higher with markers of severity, and with higher doses of corticosteroid medications, the latter being potentially modifiable.
Agrawal R, Testi I, Bodaghi B, Barisani-Asenbauer T, McCluskey P, Agarwal A, Kempen JH, Gupta A, Smith JR, De Smet MD, Yuen YS, Mahajan S, Kon OM, Nguyen QD, Pavesio C, Gupta V, Gupta V. Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 2: Guidelines for Initiating Antitubercular Therapy in Anterior Uveitis, Intermediate Uveitis, Panuveitis, and Retinal Vasculitis. Ophthalmology 2021;128(2):277-287.Abstract
TOPIC: The Collaborative Ocular Tuberculosis Study (COTS), supported by the International Ocular Inflammation Society, International Uveitis Study Group, and Foster Ocular Immunological Society, set up an international, expert-led consensus project to develop evidence- and experience-based guidelines for the management of tubercular uveitis (TBU). CLINICAL RELEVANCE: The absence of international agreement on the use of antitubercular therapy (ATT) in patients with TBU contributes to a significant heterogeneity in the approach to the management of this condition. METHODS: Consensus statements for the initiation of ATT in TBU were generated using a 2-step modified Delphi technique. In Delphi step 1, a smart web-based survey based on background evidence from published literature was prepared to collect the opinion of 81 international experts on the use of ATT in different clinical scenarios. The survey included 324 questions related to tubercular anterior uveitis (TAU), tubercular intermediate uveitis (TIU), tubercular panuveitis (TPU), and tubercular retinal vasculitis (TRV) administered by the experts, after which the COTS group met in November 2019 for a systematic and critical discussion of the statements in accordance with the second round of the modified Delphi process. RESULTS: Forty-four consensus statements on the initiation of ATT in TAU, TIU, TPU, and TRV were obtained, based on ocular phenotypes suggestive of TBU and corroborative evidence of tuberculosis, provided by several combinations of immunologic and radiologic test results. Experts agreed on initiating ATT in recurrent TAU, TIU, TPU, and active TRV depending on the TB endemicity. In the presence of positive results for any 1 of the immunologic tests along with radiologic features suggestive of past evidence of tuberculosis infection. In patients with a first episode of TAU, consensus to initiate ATT was reached only if both immunologic and radiologic test results were positive. DISCUSSION: The COTS consensus guidelines were generated based on the evidence from published literature, specialists' opinions, and logic construction to address the initiation of ATT in TBU. The guidelines also should inform public policy by adding specific types of TBU to the list of conditions that should be treated as tuberculosis.
Sobrin L, Yu Y, Li A, Kempen JH, Hubbard RA, VanderBeek BL. Angiotensin Converting Enzyme-Inhibitors and Incidence of Non-infectious Uveitis in a Large Healthcare Claims Database. Ophthalmic Epidemiol 2021;:1-6.Abstract
: To determine if angiotensin converting enzyme-inhibitors (ACE-I) alter the incidence of non-infectious uveitis (NIU). Patients in a large healthcare claims database who initiated ACE-I (n = 695,557) were compared to patients who initiated angiotensin receptor blockers (ARB, n = 354,295). A second comparison was also made between patients who initiated ACE-I (n = 505,958) and those who initiated beta-blockers (BB, n = 538,109). The primary outcome was incident NIU defined as a first diagnosis code for NIU followed by a second instance of a NIU code within 120 days. For the secondary outcome, a corticosteroid prescription or code for an ocular corticosteroid injection within 120 days of the NIU diagnosis code was used instead of the second NIU diagnosis code. Data were analyzed using Cox regression modeling with inverse probability of treatment weighting (IPTW). Sub-analyses were performed by anatomic subtype. When comparing ACE-I to ARB initiators, the hazard ratio (HR) for incident NIU was not significantly different for the primary outcome [HR = 0.95, 95% Confidence Interval (CI): 0.85-1.07, = .41] or secondary outcome [HR = 0.96, 95% CI: 0.86-1.07, = .44]. Similarly, in the ACE-I and BB initiators comparison, the HR for incident NIU was not significantly different comparing ACE-I and BB initiators for either outcome definition or any of the NIU anatomical subtypes. Our results suggest there is no evidence that ACE-I have a protective effect on NIU.
Pistilli M, 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, Kempen JH. Contemporaneous Risk Factors for Visual Acuity in Non-Infectious Uveitis. Ocul Immunol Inflamm 2021;:1-8.Abstract
INTRODUCTION: We evaluated the associations of clinical and demographic characteristics with visual acuity (VA) with over 5 years in a subspecialty noninfectious uveitis population. METHODS: Retrospective data from 5,530 noninfectious uveitis patients were abstracted by expert reviewers, and contemporaneous associations of VA with demographic and clinical factors were modeled. RESULTS: Patients were a median of 41 years old, 65% female, and 73% white. Eyes diagnosed ≥5 years prior to cohort entry had worse VA (-1.2 lines) than those diagnosed <6 months prior, and eyes with cataract surgery performed prior to entry had worse VA (-5.9 lines) than those performed during follow-up. Vitreous haze (-4.2 lines for 3+ vs quiet), hypotony (-2.5 lines for ≤5 mm Hg vs 6-23 mm Hg), and CNV (-1.8 lines) all were strongly associated with reduced VA. CONCLUSION: Factors associated with reduced VA included well-known structural complications, and lack of subspecialty care during cataract surgery.
Agrawal R, Testi I, Mahajan S, Yuen YS, Agarwal A, Kon OM, Barisani-Asenbauer T, Kempen JH, Gupta A, Jabs DA, Smith JR, Nguyen QD, Pavesio C, Gupta V, Gupta V. Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 1: Guidelines for Initiating Antitubercular Therapy in Tubercular Choroiditis. Ophthalmology 2021;128(2):266-276.Abstract
TOPIC: An international, expert-led consensus initiative organized by the Collaborative Ocular Tuberculosis Study (COTS), along with the International Ocular Inflammation Society and the International Uveitis Study Group, systematically developed evidence- and experience-based recommendations for the treatment of tubercular choroiditis. CLINICAL RELEVANCE: The diagnosis and management of tubercular uveitis (TBU) pose a significant challenge. Current guidelines and literature are insufficient to guide physicians regarding the initiation of antitubercular therapy (ATT) in patients with TBU. METHODS: An international expert steering subcommittee of the COTS group identified clinical questions and conducted a systematic review of the published literature on the use of ATT for tubercular choroiditis. Using an interactive online questionnaire, guided by background knowledge from published literature, 81 global experts (including ophthalmologists, pulmonologists, and infectious disease physicians) generated preliminary consensus statements for initiating ATT in tubercular choroiditis, using Oxford levels of medical evidence. In total, 162 statements were identified regarding when to initiate ATT in patients with tubercular serpiginous-like choroiditis, tuberculoma, and tubercular focal or multifocal choroiditis. The COTS group members met in November 2018 to refine these statements by a 2-step modified Delphi process. RESULTS: Seventy consensus statements addressed the initiation of ATT in the 3 subtypes of tubercular choroiditis, and in addition, 10 consensus statements were developed regarding the use of adjunctive therapy in tubercular choroiditis. Experts agreed on initiating ATT in tubercular choroiditis in the presence of positive results for any 1 of the positive immunologic tests along with radiologic features suggestive of tuberculosis. For tubercular serpiginous-like choroiditis and tuberculoma, positive results from even 1 positive immunologic test were considered sufficient to recommend ATT, even if there were no radiologic features suggestive of tuberculosis. DISCUSSION: Consensus guidelines were developed to guide the initiation of ATT in patients with tubercular choroiditis, based on the published literature, expert opinion, and practical experience, to bridge the gap between clinical need and available medical evidence.
Ruiz-Lozano RE, Garza-Garza LA, Cavazos-Davila O, Foster SC, Rodriguez-Garcia A. The Clinical and Pathogenic Spectrum of Surgically-Induced Scleral Necrosis. A Review. Surv Ophthalmol 2021;Abstract
The onset of scleral necrosis after ocular surgery can have catastrophic ocular and systemic consequences. The two most frequent surgeries causing surgically-induced scleral necrosis (SISN) are pterygium excision and cataract extraction. Several pathogenic mechanisms are involved in SISN. All of them are poorly understood. Ocular trauma increasing lytic action of collagenases with subsequent collagen degradation, vascular disruption leading to local ischemia, and immune complex deposition activating the complement system represents some of the events that lead to scleral necrosis. The complex cascade of events involving different pathogenic mechanisms and the patient's abnormal immune response frequently leads to delayed wound healing that predisposes the development of scleral necrosis. The management of SISN ranges from short-term systemic anti-inflammatory drugs to aggressive immunosuppressive therapy and surgical repair. Therefore, before performing any ocular surgery involving the sclera, a thorough ophthalmic and systemic evaluation must be done to identify high-risk patients that may develop SISN.
Ebrahimiadib N, Maleki A, Fadakar K, Manhapra A, Ghassemi F, Foster SC. Vascular Abnormalities in Uveitis. Surv Ophthalmol 2021;Abstract
Inflammation can involve several ocular structures, including the sclera, retina, uvea, and cause vascular changes in these tissues. Although retinal vasculitis is the most common finding associated with uveitis involving the posterior segment, other vascular abnormalities may be seen in the retina. These include capillary non perfusion and ischemia, vascular occlusions, pre-retinal neovascularization, micro- and macro-aneurysms, and telangiectasia. Moreover, vasoproliferative tumors and subsequent Coat-like response can develop secondary to uveitis. Fluorescein angiography is ideal for the investigation of retinal vascular leakage and neovascularization, while optical coherence tomography angiography (OCTA) can provide depth resolved images from the superficial and deep capillary plexus and can demonstrate vascular remodeling. Choroidal vascular abnormalities primarily develop in the choriocapillaris or in the choroidal stroma, and can appear as flow void in OCTA and filling defect and vascular leakage in indocyanine green angiography. Extensive choriocapillaris non-perfusion in the presence of choroidal inflammation can increase the risk of choroidal neovascular membrane development. Iris vascular changes may manifest as dilation of vessels in stroma due to inflammation or rubeosis that is usually from ischemia in retinal periphery secondary to chronic inflammation. More severe forms of scleral inflammation, such as necrotizing scleritis, are associated with vascular occlusion in the deep episcleral plexus, which can lead to necrosis of sclera layer and uveal exposure.
Fan N-W, Li J, Mittal SK, Foulsham W, Elbasiony E, Huckfeldt RM, Chauhan SK, Chen Y. Characterization of Clinical and Immune Responses in an Experimental Chronic Autoimmune Uveitis Model. Am J Pathol 2021;191(3):425-437.Abstract
Autoimmune uveitis is a sight-threatening intraocular inflammatory disease. For >30 years, the mouse model of experimental autoimmune uveitis has been employed to investigate disease mechanisms and test immunotherapeutic approaches. However, inflammation in this model is self-limited, and does not replicate the chronic, insidious nature prevalent in the human disease. Herein, a robust and reliable model of chronic autoimmune uveitis was developed and characterized in two strains of wild-type mice by modifying interphotoreceptor retinoid-binding protein dose and peptide fragments from conventional experimental autoimmune uveitis models. In both of these murine strains, immunization with our modified protocols resulted in a slowly progressive uveitis, with retinal scars and atrophy observed in the chronic stage by fundoscopy. Optical coherence tomography demonstrated decreased retinal thickness in chronic autoimmune uveitis mice, and electroretinography showed significantly reduced amplitudes of dark-adapted a- and b-waves and light-adapted b-waves. Histologic examination revealed prominent choroiditis with extensive retinal damage. Flow cytometry analysis showed substantially increased numbers of CD44IL-17IFN-γ memory T-helper 17 (Th17) cells in the retina, cervical lymph nodes, inguinal lymph nodes, and spleen. These data establish new modified protocols for inducing chronic uveitis in wild-type mice, and demonstrate a predominant memory Th17 cell response, suggesting an important role for memory Th17 cells in driving chronic inflammation in autoimmune uveitis.
Kempen JH, Pistilli M, Begum H, Fitzgerald TD, Liesegang TL, Payal A, Zebardast N, Bhatt NP, Foster SC, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Sen NH, Suhler EB, Thorne JE, for Group SITED (SITE) CSR. Remission of Non-Infectious Anterior Scleritis: Incidence and Predictive Factors. Am J Ophthalmol 2021;223:377-395.Abstract
PURPOSE: To assess how often non-infectious anterior scleritis remits and identify predictive factors. METHODS: Our retrospective cohort study at four ocular inflammation subspecialty centers collected data for each affected eye/patient at every visit from center inception (1978, 1978, 1984, 2005) until 2010. Remission was defined as inactivity of disease off all suppressive medications at all visits spanning at least three consecutive months or at all visits up to the last visit (to avoid censoring patients stopping follow-up after remission). Factors potentially predictive of remission were assessed using Cox regression models. RESULTS: During 1,906 years' aggregate follow-up of 832 affected eyes, remission occurred in 214 (170 of 584 patients). Median time-to-remission of scleritis = 7.8 years (95% confidence interval [CI]: 5.7, 9.5). More remissions occurred earlier than later during follow-up. Factors predictive of less scleritis remission included scleritis bilaterality (adjusted hazard ratio [aHR] = 0.46, 95% CI: 0.32-0.65); and diagnosis with any systemic inflammatory disease (aHR = 0.36, 95% CI: 0.23-0.58), or specifically with Rheumatoid Arthritis (aHR = 0.22), or Granulomatosis with Polyangiitis (aHR = 0.08). Statin treatment (aHR = 1.53, 95% CI: 1.03-2.26) within ≤90 days was associated with more remission incidence. CONCLUSIONS: Our results suggest scleritis remission occurs more slowly in anterior scleritis than in newly diagnosed anterior uveitis or chronic anterior uveitis, suggesting that attempts at tapering suppressive medications is warranted after long intervals of suppression. Remission is less frequently achieved when systemic inflammatory diseases are present. Confirmatory studies of whether adjunctive statin treatment truly can enhance scleritis remission (as suggested here) are needed.
Tripathy K, Ying H, Maldonado Cerda A, Filipowicz A, Kaya M, Seymen Z, Anesi SD, Chang PY, Foster CS. Widefield Fundus Fluorescein Angiography Features of Uveitis Associated with Juvenile Idiopathic Arthritis. Ocul Immunol Inflamm 2020;:1-10.Abstract
PURPOSE: To evaluate the wide-field fundus fluorescein angiography (WFA) characteristics of uveitis associated with juvenile idiopathic arthritis (JIA-uveitis). METHODS: Retrospective review of records. WFA with Spectralis (Heidelberg) of JIA-uveitis patients were analyzed using the scoring system by Angiography Scoring for Uveitis Nomenclature. RESULTS: Thirty-seven eyes of 20 patients were studied. A total score of at least 1 was noted in 27 eyes (72.97%). WFA features included optic disc hyperfluorescence (51.35%), macular leakage (27.03%), retinal vascular staining/leakage at posterior pole (27.03%) and peripheral retina (64.86%), capillary leakage at the posterior pole (37.84%), and peripheral retina (59.46%). A decision to change the management plan was made in 8 of 9 patients with bilateral quiet anterior chambers after WFA results. CONCLUSION: More than 70% of JIA-uveitis eyes showed some WFA-evidence of posterior segment inflammation, which changed the course of therapy for a major proportion of patients with no clinically active anterior chamber inflammation.
Silpa-Archa S, Dejkong A, Kumsiang K, Chotcomwongse P, Preble JM, Foster SC. Poor prognostic factors in post-traumatic endophthalmitis following open globe injury. Int J Ophthalmol 2020;13(12):1968-1975.Abstract
AIM: To demonstrate prognostic factors for poor visual outcome in patients with post-traumatic endophthalmitis (PTE) following open globe injury. METHODS: A retrospective study was conducted on 66 patients (66 eyes) with PTE following open globe injury from 2005 to 2015. Potential factors accounting for good and poor visual outcome were statistically analyzed by Chi-square test and Logistic regression model. RESULTS: In 66 cases, 39 cases (59%) had a poor visual outcome. Univariate and multivariate Logistic regression analysis identified retained intraocular foreign body (IOFB) as the only factor significantly associated with poor visual outcome [adjusted odds ratio, 4.62; 95% confidence interval (1.04-20.53); =0.04]. The most common causative agents were gram-positive organisms (83%), of which (33%), was the most common pathogen. All cases received intravitreal antibiotic injections. Oral ciprofloxacin was the most used systemic antibiotic (33%). Pars plana vitrectomy was performed in 83% (55/66) of cases. At 6mo follow-up, mean BCVA was 1.74±0.72 logMAR units. CONCLUSION: In patients with PTE following open globe injury, the only predictor of poor visual outcome is the presence of IOFB. is the most isolated microorganism.

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