Rat models of autoimmune uveitis

Experimental autoimmune uveitis ( EAU) in Lewis rats is a well-established model for human uveitis. During the last years we used this model to demonstrate extraocular induction of uveitis by antigenic mimicry of environmental antigens with retinal autoantigen and investigated the migration and intraocular reactivation of autoreactive green fluorescent protein ( GFP)+ T cells. We could also elaborate several differences between EAU induced with S-antigen peptide PDSAg or R14, a peptide derived from interphotoreceptor retinoid-binding protein, suggesting two differently regulated diseases in the same rat strain. R14-mediated EAU in Lewis rats has been shown to relapse, thus we have a new model to test therapeutic approaches in an ongoing immune response instead of just preventing disease. Finally, we show antigenic mimicry of PDSAg and an HLA-B peptide for oral tolerance induction. After the successful first therapeutic trial this approach will now proceed with international multicenter clinical trials. Copyright (c) 2008 S. Karger AG, Basel

Association between visual function response and reduction of inflammation in noninfectious uveitis of the posterior segment

PURPOSE. To examine the association between visual function response (VFR) and inflammation reduction in active noninfectious uveitis of the posterior segment (NIU-PS). METHODS. Phase 3 SAKURA Study 1 randomized 347 subjects in a double-masked fashion to receive injections of intravitreal sirolimus 44 mu g (n = 117); 440 mu g (n = 114); or 880 mu g (n = 116) every other month. Vitreous haze (VH) response, a measure of inflammation reduction, was defined as a VH score of 0 or 0.5+ at month 5 based on the modified Standardized Uveitis Nomenclature Scale. Visual function was assessed with best-corrected visual acuity (BCVA) and the National Eye Institute (NEI) Visual Function Questionnaire-25 (VFQ-25). In this post-hoc analysis, principal component analysis was used to reduce the information in the multidimensional visual function outcome to a restricted number of independently relevant VFR measures. Minimal clinically important differences (MCID) for the VFQ-25-derived components were based on the standard error of measurements. Overall VFR was defined as either a BCVA improvement of >= 2 lines, or an improvement exceeding the MCID in the VFQ-25 based visual function measures. RESULTS. The VFQ-25 composite score (VFQCS) and mental health subscale score (VFQMHS) were retained as relevant VFRs, with MCIDs of 4.3 and 11.7 points, respectively. A vitreous haze response was significantly associated with each VFR measure: VFQCS (odds ratio [ OR] = 2.23; P = 0.0004); VFQMHS (OR = 2.84; P < 0.0001); BCVA (OR = 2.60; P = 0.0009), and overall VFR (OR = 2.65; P < 0.0001). CONCLUSIONS. Inflammation reduction to a VH score of 0 or 0.5+ was significantly associated with improved visual function. Achieving a VH response of 0 or 0.5+ is a patient-relevant outcome

Fast and Successful Management of Intraocular Inflammation with a Single Intravitreal Dexamethasone Implant

Purpose: To investigate the efficacy and safety of a single dexamethasone intravitreal implant (Ozurdex®, 700 µg). Methods: In this prospective noncomparative case series, 84 patients (54 females) received a dexamethasone intravitreal implant. At weeks 4, 12 and 24 after the injection, vitreous haze, macular thickness and best corrected visual acuity (BCVA) were assessed and adverse events reported. Results: Clearance of vitreous haze could be achieved after 4 weeks in 61% of all eyes (p < 0.001) and remained significant until week 24 (p < 0.001). This was paralleled by a reduction of central retinal thickness after 4 (p < 0.001), 12 (p < 0.001) and 24 weeks (p < 0.006). Significant and fast improvement of BCVA was already achieved after 4 weeks (p < 0.001) but vanished by week 24. Intraocular pressure reached ≥35 mm Hg in 3 eyes and was significantly more frequent in intermediate uveitis compared to posterior uveitis (p < 0.016). Conclusions: The dexamethasone implant is effective in controlling intraocular posterior segment inflammation and reduces central retinal thickness fast and effectively. © 2014 S. Karger AG, Basel

CRALBP is a Highly Prevalent Autoantigen for Human Autoimmune Uveitis

Cellular retinaldehyde binding protein (CRALBP) is an autoantigen in spontaneous equine recurrent uveitis. In order to test whether CRALBP contributes to human autoimmune uveitis, the specificity of antibodies from human uveitis patient's sera was first evaluated in two-dimensional (2D) Western blot analysis. Subsequent identification of the immunoreactive proteins by mass spectrometry resulted in the identification of CRALBP as a putative autoantigen. Additionally, sera from human uveitis and control patients were by Western blot using purified human recombinant CRALBP. Anti-CRALBP autoantibodies occur more frequently (P<.01) in human uveitis patients than in normal controls. Thirty out of 56 tested uveitis patient's sera contained autoantibodies reactive against CRALBP, compared to only four out of 23 normal control subjects. The presence of CRALBP autoantibodies in 54% of tested uveitis patients supports CRALBP as a possible autoantigen in human autoimmune uveitis

Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells

Background: Uveitis is a potentially blinding inflammatory disease of the inner eye with a high unmet need for new therapeutic interventions. Here, we wanted to investigate the suppressive effect of the intraocular application of the small molecule dihydroorotate dehydrogenase (DHODH)-inhibitor PP-001 on experimental relapsing rat uveitis and furthermore determine its effect on proliferation and cytokine secretion of human peripheral blood lymphocytes (PBL) and human retinal pigment epithelial (RPE) cells in vitro. Methods: Spontaneously relapsing uveitis was induced in rats by immunization with interphotoreceptor retinoid-binding protein (IRBP) peptide R14. PP-001 was injected intravitreally after resolution of the primary disease to investigate further relapses. Proliferation and metabolic activity of phytohemagglutinin (PHA)-stimulated human peripheral lymphocytes with and without PP-001 and cytokine secretion were determined by XTT assay and bioplex bead assay. The RPE cell line ARPE-19 as well as primary human RPE cells treated with PP-001 or anti-vascular endothelial growth factor (VEGF) antibody bevacizumab were also investigated for metabolic activity and cytokine/chemokine secretion. Results: Injection of PP-001 into rat eyes reduced the number of relapses by 70%, from 20 relapses (57% of the rats affected) in the control group to 6 relapses (33% of the rats) in the treatment group. In human PBL cultures, PP-001 reduced the proliferation in a dose-dependent manner. The secretion of several cytokines such as IL-17, IFN-gamma, and VEGF was suppressed by PP-001, as previously observed with rat T cells in the experimental autoimmune uveitis (EAU) model. In contrast, human RPE cells were not affected by PP-001, while the anti-VEGF antibody bevacizumab severely impaired the secretion of various cytokines including VEGF. Conclusions: For the first time, intravitreal injection of PP-001 demonstrated an effective, but transient reduction of relapses in the rat EAU model. In vitro PP-001 suppressed proliferation and cytokine/chemokine secretion of human lymphocytes, while neither human RPE cell line ARPE-19 nor primary RPE cells were affected

Inflammatory eye disease:Pre-treatment assessment of patients prior to commencing immunosuppressive and biologic therapy: Recommendations from an expert committee

AIM: To outline recommendations from an expert committee on the assessment and investigation of patients with severe inflammatory eye disease commencing immunosuppressive and/or biologic therapy. METHOD: The approach to assessment is based on the clinical experience of an expert committee and a review of the literature with regard to corticosteroids, immunosuppressive drug and biologic therapy and other adjunct therapy in the management of patients with severe sight-threatening inflammatory eye disease. CONCLUSION: We recommend a careful assessment and consultative approach by ophthalmologists or physicians experienced in the use of immunosuppressive agents for all patients commencing immunosuppressive and/or biologic therapy for sight threatening inflammatory eye disease with the aim of preventing infection, cardiovascular, metabolic and bone disease and reducing iatrogenic side effects

Fluocinolone acetonide 0.19-mg implant for the treatment of noninfectious uveitis with involvement of the posterior segment: a real-world study

Purpose To evaluate the effectiveness of 0.19-mg fluocinolone acetonide implant (FAi) for preventing inflammatory relapses in noninfectious uveitis with posterior segment involvement in standard clinical practice. Further, to assess the value of remission induction therapy with intraocular and periorbital administered high-dose corticosteroids before FAi. Methods A retrospective cohort study in a tertiary referral center specialized in uveitis management. The primary study outcomes were the best-corrected visual acuity (BVCA) and central retinal thickness (CRT) within a 12-month observation period. The secondary outcomes were intraocular pressure (IOP) and intraocular inflammation. The main safety measures were IOP increase and cataract formation. Results In total, 76 eyes of 57 patients received FAi. Locally administered high-dose corticosteroids were applied in 68.4% of all eyes before FAi. BCVA remained stable within the 12-month observation period (63.21 vs. 62.95, difference 0.26 letters;95% CI: - 6.31 to 6.84;p > 0.9). Significant CRT reduction upon FAi was sustained after 12 months (362.7 vs. 309.1 mu m, difference 53.57 mu m;95% CI: 1.55 to 105.6;p = 0.04). Intraocular inflammation was reduced until 9 months of follow-up (0.82 vs. 0.3, difference 0.53;95% CI: 0.11 to 0.95;p = 0.007). A mean IOP increase (13.68 vs. 15.6;difference - 1.92;95% CI: - 3.85 to 0.004;p = 0.0507) and cataract development (20% of all phakic eyes) were noted. Conclusion We observed similar levels of FAi effectiveness for the treatment of noninfectious uveitis in standard clinical practice compared to previous randomized clinical trials. Moreover, remission induction therapy before FAi can benefit patients with increased baseline uveitis activity

Targeted Medical History and Diagnostic Testing in Uveitis.

Uveitis is a collective term for a variety of different intraocular inflammations. The underlying etiologies vary greatly depending on the uveitis subtype, and in particular the anatomical focus. The most common forms of anterior uveitis are acute fibrinous unilateral uveitis, often associated with the HLA-B27 haplotype, and granulomatous inflammation, typically associated with sarcoidosis or herpes infections. Intermediate uveitis is usually idiopathic in nature but can also be associated with multiple sclerosis or sarcoidosis, while vitreoretinal lymphoma must also be considered as a masquerade syndrome in patients aged over 45. Posterior uveitis, on the other hand, as well as retinal vasculitis and panuveitis, have a very broad variety of etiologies; these can, however, be narrowed down through a similar findings-centered approach. Retinitis, for example, is often associated with infections (Toxoplasma gondii and viruses of the herpes group), whereas chorioditis is frequently idiopathic, although infections such as tuberculosis may occur. Therefore, the medical history and laboratory diagnosis should be tailored in patients with uveitis based on the anatomic focus of inflammation (anterior, intermediate, or posterior uveitis, or panuveitis) and the clinical picture (e.g., granulomatous versus nongranulomatous)