AMERICAN UVEITIS SOCIETY MEETING
May 5, 2007
Marriott Harbor Beach Resort and Spa
Ft. Lauderdale, FL
Title of Presentation: IL-17+ interphotoreceptor retinoid-binding protein (IRBP)-specific T cells in experimental autoimmune uveitis (EAU)
Author(s): Hui Shao, Henry J. Kaplan, Deming Sun
Address: Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY
Purpose: To determine the role of IL-17+ T cells in the pathogenesis of EAU and determine the induction and expansion of this T cell subset during the development of autoimmune uveitis.
Methods: Uveitis was induced either by immunization with IRBP peptide or by adoptive transfer of IRBP-specific T cells to EAU-prone (B6 and B10RIII) mice. The T cells from in vivo primed mice were separated and stimulated with the immunizing peptide. Intracellular expression of IFN-g and IL-17 of the T cells was assessed by flow cytometry. In addition, IL-17-producing T cell subset was examined among the eye infiltrating cells and disease severity was also observed after neutralizing IL-17 cytokines by intra-vitreal injection of anti-IL-17 mAbs. Using an in vitro co-culture system, we also determined the induction and expansion of IL-17+ T cells among the IRBP-specific T cells after in vitro activation in the presence and absence of retinal glial and retinal pigmental epithelial (RPE) cells.
Results: IL-17+ T cells appeared in the inflamed eye during the early disease stage (d20 post-injection of IRBP specific T cells) and remained through the late phase of the disease (d50). Intra-vitreal injection of anti-IL-17 mAb significantly reduced disease severity and the antibody-treated mice showed significantly decreased numbers of infiltrating cells in the eye. IL-17+ T cells were readily observed circulating in the periphery of the EAU mice. A subset of autoreactive IRBP-specific CD8+ T cells derived from the spleen of in vivo Ag-primed mice expressed IL-17. IRBP-specific T cells preferentially expressed IL-17 when cultured in IL-23-containing medium, while IFN-g-expressing cells became dominant when the T cells were cultured with IL-2. Importantly, both expanded T cell populations were uveitogenic. IL-23 promoted the expansion of both antigen-specific and non-antigen-specific IL-17+ T cells, while TGF-b and IL-6 acted only on non-antigen-specific IL-17+ T cells. The activation of autoreactive IL-17+ T cells was markedly increased in vivo by the mycobacterial component of CFA and pertussis toxin (PTX) and in vitro by the ligation of Toll-like receptors. Interaction of IRBP-specific T cells with local GFAP+ glial cells, but not RPE cells, produced increased amounts of IL-17. The interaction between local glial cells and IRBP specific T cells was regulated by a distinct pattern of costimulatory molecules.
Conclusion: IL-17+ autoreactive T cells can be readily detected in the periphery and in the inflamed eye during the development of EAU. While IL-17+ T cells contain both antigen-specific and non-specific cells, only the antigen-specific IL-17+ T cells were uveitogenic. The generation and expansion of the IL-17+ T cells is regulated by a number of specific immune conditions.
Title of Presentation: The IL-23/IL-17 axis mediates inflammatory angiogenesis
Author(s): Craig Meagher, Miki Nakanishi, and Erich C. Strauss
Address: Kimura Ocular Immunology Laboratory, Proctor Foundation-UCSF, San Francisco
Angiogenesis, the formation of new from preexisting blood vessels, is a complex, multistep process that involves expression of intracellular adhesion molecules, recruitment of leukocytes, expression of cytokines and growth factors, extracellular matrix remodeling, endothelial cell migration and proliferation, and vessel formation. Pathologic angiogenesis is a critical component of tumorigenesis, chronic systemic inflammatory disorders, and several sight-threatening eye diseases. VEGF-A has emerged as the preeminent growth factor promoting pathologic angiogenesis. Inhibition of pathologic angiogenesis represents a potentially powerful approach to treatment. Insights from cancer investigations suggest the timing of anti-angiogenic therapy appears to be critical as early therapeutic intervention is associated with more favorable outcomes. Moreover, with disease progression, expansion of the spectrum of proangiogenic mediators may elicit treatment resistance thus requiring multiple agents to constrain angiogenesis. A potential alternative or complementary strategy to specific inhibition of growth factors or their receptors may reside in selective targeting of cytokines that regulate inflammation and angiogenesis. Accumulating evidence suggests a major integration and codependence of inflammation with the process of pathologic angiogenesis. However, the underlying mechanisms initiating and promoting inflammatory angiogenesis remain obscure. Interleukin-17 (IL-17) is a CD4 T cell-derived proinflammatory cytokine, and IL-23 serves to expand Th-17 cell populations. In a clinically relevant mouse model of corneal inflammatory angiogenesis, we investigated the role of the IL-23/IL-17 inflammatory axis in angiogenesis. Our results show an essential role for these cytokines in promoting VEGF-A mediated inflammatory angiogenesis; moreover, we have identified a cytokine dependent pathway that promotes the IL-23/IL-17 inflammatory response. Our data suggests that these cytokines may represent novel targets for ocular anti-angiogenic therapeutics.
Title of Presentation: Comparison of Antimetabolite Therapies for Noninfectious Ocular Inflammation
Author(s): Anat Galor MD, Henry A Leder MD, Douglas A Jabs MD, MBA, Sanjay D Kedhar MD, James P Dunn MD, George Peters III MD, Jennifer E Thorne MD, PhD
Address: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD
Purpose: To compare the effectiveness and side effect profile of methotrexate, azathioprine and mycophenolate mofetil in the treatment of noninfectious ocular inflammation
Design: Retrospective case series.
Participants: 315 patients with inflammatory eye disease treated with methotrexate, azathioprine or mycophenolate at an academic referral center
Methods: Retrospective review of patients who were treated in the Division of Ocular Immunology at the Wilmer Eye Institute with antimetabolite therapy. Data recorded included patient demographics, dose of antimetabolite, dose of prednisone, use of other immunosuppressive drugs, response to therapy, and side effects associated with drug use. Only data on the first antimetabolite agent used by our department was included for patients with a treatment history of multiple immunosuppressive agents. Patients with a diagnosis of anterior uveitis were excluded from the effectiveness analysis. All patients were included in the analysis of treated-related side effects.
Main Outcome Measures: Ability to control ocular inflammation with an antimetabolite and to taper prednisone to ≤ 10 mg daily (“treatment success”) and incidence of treatment-related side effects.
Results: One hundred twenty-eight patients with inflammatory eye disease were treated with methotrexate, 44 with azathioprine, and 143 with mycophenolate. Uveitis accounted for the majority of the diagnoses, followed by scleritis. Treatment success at the initial starting dose of the antimetabolite was achieved by 30% in the methotrexate group, 54% in the azathioprine group and 51% in the mycophenolate group (P=0.003). After dose escalation or addition of second immunosuppressive agents, the percentage of patients achieving treatment success was higher in the mycophenolate group than in the methotrexate and azathioprine groups (P=0.05). The incidence of side effects was higher in the azathioprine group (0.32/PY) compared to methotrexate (0.13/PY) and mycophenolate (0.21/PY) with more patients discontinuing the drug due to side effects in the azathioprine group as well (0.21/PY versus 0.08/PY for methotrexate and 0.10/PY for mycophenolate).
Conclusions: These data suggest that more patients on mychophenolate achieved “treatment success” compared to methotrexate and azathioprine. Methotrexate was often initiated at a subtherapeutic dose and required dose escalation. Azathioprine therapy had a higher incidence of treatment-related side effects compared to methotrexate and mycophenolate.
Title of Presentation: Risk factors for cystoid macular edema complicating intermediate uveitis. Jennifer E. Thorne, MD, PhD; Ebenezer Daniel, MBBS; Douglas A. Jabs, MD, MBA; Sanjay R. Kedhar, MD; George B. Peters, MD, MBA; James P. Dunn, MD
Address: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD
Purpose: To describe risk factors for the presence of cystoid macular edema (CME) among patients presenting with intermediate uveitis.
Design: Cross-sectional study.
Methods: Setting: Single-center, academic practice. Study population: 208 patients (363 eyes) with intermediate uveitis were evaluated from July 1984 through September 2006. Procedures: Data on patients diagnosed with intermediate uveitis were analyzed. Main outcome measures: Presence of CME at the time of presentation to our clinic; risk factors for presenting with CME.
Results: Of the 208 patients, the median age at presentation was 37 years. 66% were women; 91% were Caucasian; 74% had bilateral intermediate uveitis, yielding 363 affected eyes. Of these 363 eyes, 155 eyes (43%) had CME at the time of presentation to our clinic. After controlling for potentially confounding variables including demographics, duration of disease, active inflammation, history of diabetes or hypertension, and presence of epiretinal membrane, a history of CME prior to presentation was associated with a 4-fold increased risk of CME at presentation (odds ratio [OR] = 4.28, 95% confidence interval [CI]: 1.97, 9.29, P < 0.001) and smoking was associated with a 2.5-fold increased risk of CME at presentation (OR = 2.60, 95% CI: 1.33, 5.09, P = 0.005). Patients who were actively smoking at the time of presentation were more likely to have CME (OR = 4.90, P = 0.008) than were patients who had previously smoked but had quit by the time they presented to our clinic (OR = 1.97, P = 0.055). After adjusting for confounding, there was a 4% increased risk of CME at presentation for every additional cigarette smoked per day (OR = 1.04, 95%CI: 1.01, 10.7, P = 0.005).
Conclusions: Among our patients with intermediate uveitis, smoking was associated with an increased risk of CME at the time of presentation in a dose-dependent fashion. Active smoking at the time of presentation was more strongly associated with CME at presentation than was former smoking.
In-vivo confocal microscopy as a new diagnostic tool in Fuchs Uveitis syndrome
Mackensen F. 1, Dali N. 1, Setiobudi C. 1, Rosenbaum J.T. 2, Lim L.L. 2, Becker, M.D. 1
1 Interdisciplinary Uveitis Center, University of Heidelberg, Germany
2 Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
Introduction:
Fuchs Uveitis Syndrome (FUS) is a diagnosis made by a variety of clinical signs, the main ones being diffusely distributed keratic precipitates (KP), heterochromy and/or diffuse iris defects seen on retroillumination. In patients where the latter two signs are not present, it is more difficult to state the diagnosis. As the prognosis of FUS is good and the only treatment required is for complications such as cataracts or glaucoma, the correct diagnosis at an early time point is essential for the further management of the patient.
The Heidelberg Confocal Laser microscope (HRT II, Heidelberg Engineering, Germany) with the Rostock Cornea Module attachment (RCM) is a new generation confocal microscope that allows high resolution imaging of cellular details on the corneal level, such as KP. Here we describe a distinctive KP morphology that appears to be specific for FUS.
Methods:
Patients diagnosed with either definite or probable FUS according to clinical criteria (n = 31) were examined clinically and with the HRT RCM from January 2006 to April 2007. KPs imaged by the HRT RCM were graded by one un-masked and one masked grader using strict grading criteria and were compared to a cohort of other subjects with different forms of uveitis (n = 70). Institutional Review Board permission was granted. Diagnostic certainty for FUS was determined with clinical criteria (definite if heterochromia or transillumination defects were present or probable if absent), and correlated to the HRT RCM findings. Anatomic localization was determined by SUN workshop criteria.
Results:
Two of the examined patients did not yield gradable images with the HRT RCM. The majority (20/29 = 69%) of the FUS patients were found to have stellate KP on the HRT RCM. Of the remaining patients, three showed no KPs at all and seven had either ink blot (n=2), granular (n=2) or stringy KPs (n=3). The HRT appreciates stellate KP even in patients where the KP seen by slitlamp exam were not stellate, or the patients showed no KPs on slitlamp exam.
Of the patients with a definite diagnosis of FUS and KP on HRT at the time of examination (n=15), 80% showed stellate KP with the HRT RCM. The patients with a probable diagnosis, (n=11), showed stellate KP with the HRT in 72%. Interestingly, 11 patients showed predominantly intermediate inflammation; 8 with a probable and 3 with a definite diagnosis of FUS. In 81% (9/11) stellate KP were found on HRT RCM exam. In contrast, stellate KP were found in only 10 subjects (14%) within the group of other uveitis subsets.
Conclusion:
Our findings suggest that the HRT RCM may have a role in the early diagnosis of FUS even when heterochromia or iris transillumination defects are not present. The HRT seems to be more sensitive to detect stellate appearing KP than slitlamp exam.
Title of Presentation: Phase 2/3 Clinical Trial of a Novel Calcineurin Inhibitor, LX211 for the Treatment of Non-Infectious Uveitis
Author(s): Quan Dong Nguyen for the LUMINATE (Lux Uveitis Multicenter Investigation of a New Approach to Treatment) Uveitis Program Investigator Group
Address: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD
LX211 is a novel calcineurin inhibitor (CNi) possessing four-fold greater potency, an altered metabolic and PK/PD profile and potentially improved safety compared to the prototypical CNi, cyclosporine A. Three pivotal dose-ranging clinical trials have been designed to evaluate the safety and efficacy of LX211 as a steroid-sparing agent for the treatment, control and maintenance of sight-threatening, non-infectious posterior, intermediate, panuveitis and anterior uveitis. These global, prospective, double-masked, parallel-group, dose-ranging, placebo-controlled, randomized multicenter studies comprise the LUMINATE Uveitis Program, which is currently in progress. In all studies, patients are randomized (2:2:2:1) either to one of three doses of LX211 (0.2 mg/kg, 0.4 mg/kg or 0.6 mg/kg b.i.d taken as capsules orally) or placebo. Study LX211-01-UV (LUMINATE Active) will evaluate 210 patients with active predominantly posterior manifestations of their condition. Study LX211-03-UV (LUMINATE Anterior) will evaluate 100 patients with active predominantly anterior manifestation of inflammatory disease. A third study, LX211-02-UV (LUMINATE Maintenance) will evaluate LX211 in 220 patients whose disease is controlled and will be used to spare the use of systemic corticosteroid and, if applicable, to replace the patient’s current poorly-tolerated corticosteroid-sparing agent. Primary endpoint: assessment of ocular inflammation according to the specifications of each study. The primary endpoints in Protocol LX211-01-UV (LUMINATE Active) are mean change from baseline in graded vitreous haze after 16 weeks of therapy or at the time of rescue if earlier and mean change from baseline in graded vitreous haze after 24 weeks of therapy or at time of rescue, if earlier. Protocol LX211-02-UV (LUMINATE Maintenance) will assess the proportion of subjects experiencing inflammatory exacerbation during 26 weeks of treatment. This is defined by a clinically significant deterioration in either eye for one or more of the following: graded vitreous haze, graded anterior chamber cells or visual acuity (Best Corrected Visual Acuity, BCVA). Protocol LX211-03-UV (LUMINATE Anterior) will assess mean change in graded anterior chamber cells after 16 weeks of therapy or at the time of rescue, if earlier. Secondary endpoints: Assessment of corticosteroid utilization, rates of exacerbation, quality of life, anterior segment inflammation, macular edema, and visual acuity and its relevance to support the indication sought. Safety: Assessments will include the incidence and severity of adverse events, change from baseline in intraocular pressure and changes in laboratory values. Conclusions: The LUMINATE uveitis program is the first clinical development program for regulatory approval of a corticosteroid-sparing immunosuppressive agent in different types of sight-threatening non-infectious uveitis.
Title of Presentation: Autoimmune hepatitis and uveitis: A case series
Author(s): Lyndell Lim, Johnathon Scarborough, Jennifer Thorne, Friederike Mackensen, Tisha Prabriputaloong, Justine Smith
AIM: Autoimmune hepatitis is a chronic progressive hepatitis of unknown cause. Although it has been associated with the presence of other autoimmune diseases such as thyroiditis, ulcerative colitis and rheumatoid arthritis, a clear association with uveitis has yet to be described. Here we report four cases of autoimmune hepatitis and uveitis.
METHODS: One index case was identified from the Uveitis Clinic of the Casey Eye Institute of the Oregon Health & Science University. Further cases were identified by a web-based survey of members of the American Uveitis Society and the International Uveitis Study Group.
RESULTS: A total of 12 cases were identified by the web-based survey, with detailed information available for four. Of these four cases, there were 3 females and one male (age range 20-70 years). All four had chronic, persistent, bilateral non-granulomatous uveitis. Two had panuveitis, one had intermediate uveitis and one had anterior uveitis. In all but one the onset was insidious and all four had complications arising from their uveitis, ranging from glaucoma and cataract to band keratopathy and pthisis.
CONCLUSION: Despite the small numbers in this study, it would appear that there may be an association between autoimmune hepatitis and uveitis.
Title of Presentation: Infliximab Therapy for Vogt-Koyanagi-Harada Disease
Author(s): Yue Wang MD PhD, Paul A. Gaudio MD
Address: Department of Ophthalmology, Yale University School of Medicine, New Haven, CT
Purpose: To report our experience using infliximab to treat two patients with Vogt-Koyanagi-Harada disease (VKH).
Design: Interventional case report
Methods: Records review
Results: Case 1: A 30-year-old Hispanic woman with incomplete VKH had been poorly controlled by corticosteroids, cyclosporine, cyclophosphamide, and azathioprine for 14 months. After initiation of infliximab infusion of 5mg/kg, her ocular inflammation was brought under excellent control and her neurological symptoms completely resolved. Case 2: A 32-year-old Korean man with incomplete VKH was treated with prednisone 1mg/kg and infliximab infusion of 5mg/kg. Prednisone was tapered successfully and his ocular inflammation remains under excellent control four weeks after initiation of infliximab therapy.
Conclusions: Our limited experience suggests that VKH may be quite effective in the treatment of VKH.
Title of Presentation: Unusual ocular involvement in granulomatous common variable immune deficiency
Author(s):NPatel,GLarkin
Address:_ Dept of Ophthalmology, Kings College Hospital, Denmark Hill, London, UK
Introduction: Common Variable Immunodeficiency (CVID) is the most common cause of significant antibody deficiency in adults. CVID represents a heterogeneous group of disorders that can be sporadic or familial with various modes of inheritance resulting in defects of B-cell function, regulatory T-cells and macrophage function. Granulomatous lesions are occasionally found in the lymphoid or solid organs of patients diagnosed with this condition.
Purpose: To describe the previously unreported complication of scleritis in a patient with choroidal granulomas secondary to granulomatous common variable immune deficiency.
Method: Retrospective case study
Results: Active granulomatous common variable immune deficiency (CVID) in this patient presented with enlargement of a choroidal granuloma with an overlying serous retinal detachment involving the macula in the right eye. An episode of scleritis was suspected clinically. This was confirmed by Ultrasound and MRI imaging in the same eye. The scleritis responded oral corticosteroids.
Conclusion: Ocular involvement in granulomatous CVID may includes uveitis, scleritis and choroidal granulomas.
Title of Presentation: Persistent Syphilitic Uveitis in an AIDS patient
Author(s): Matilda Chan MD, PhD, Nisha Acharya, MS, MD
Address: F.I. Proctor Foundation, University of California, San Francisco; San Francisco, CA
Purpose: To describe a case of an AIDS patient with ocular syphilis who did not respond to two courses of IV penicillin but whose inflammation completely resolved after starting HAART.
Methods: Case report
Results: A 40 year old man with a history of AIDS and a CD4 count of 23 cells/ml presented to our service with decreased vision, high intraocular pressure, panuveitis and chorioretinitis OU. Systemic evaluation was consistent with ocular syphilis, including an abnormal RPR, FTA-ABS and LP. The patient was treated with topical prednisolone acetate and a 3 week course of IV penicillin with continued inflammation OU. Four months later, the inflammation remained and new chorioretinal lesions were present. The patient was re-treated with another course of IV penicillin, but the anterior and posterior inflammation persisted. Finally, the patient started HAART. Three months later, his CD4 count had increased to 123 cells/ml and his inflammation had completely resolved. At a recent exam 12 months after starting HAART, he remains stable.
Conclusions: Ocular syphilis may not respond to the standard treatment for neurosyphilis. Immune reconstitution following onset of HAART may lead to resolution of inflammation.