Kuniaki Hijioka

Evaluation of the Long-Term Efficacy and Safety of Infliximab Treatment for Uveitis in Behçet's Disease: A Multicenter Study

PURPOSE To evaluate the long-term efficacy and safety of infliximab for the treatment of uveitis in Behçets disease (BD). DESIGN Retrospective multicenter study using a questionnaire. PARTICIPANTS A total of 164 consecutive patients with BD treated with infliximab for more than 1 year were studied. The mean age at initiation of infliximab treatment was 42.6±11.7 years, and the mean treatment duration was 32.9±14.4 months. METHODS Data before and at the last visit during infliximab treatment were analyzed in 4 groups divided by duration of treatment: group A (n = 43, 12-<24 months), group B (n = 62, 24-<36 months), group C (n = 42, 36-<48 months), and group D (n = 17, ≥48 months). MAIN OUTCOME MEASURES Best-corrected visual acuity (BCVA), relapse of ocular inflammation, numbers of ocular inflammatory attacks per year, and adverse effects of infliximab therapy. RESULTS The frequency of ocular attacks decreased in all groups (from 5.3±3.0 to 1.0±0.3 in group A, 4.8±4.6 to 1.4±0.3 in group B, 4.1±2.9 to 0.9±0.3 in group C, and 9.5±5.8 to 1.6±0.5 in group D; all P < 0.05). The BCVA was improved in approximately 55% of the eyes after treatment. Mean BCVA converted to logarithm of the minimum angle of resolution was improved after treatment with infliximab in groups A to C (from 0.79±1.04 to 0.59±0.94 in group A, 0.59±1.07 to 0.41±1.04 in group B, and 1.15±1.77 to 0.92±1.73 in group C; all P < 0.05) but not in group D. Uveitis relapsed in 59.1% of all patients after infliximab treatment, and no difference in duration until relapse was observed between individual groups. Approximately 80% of relapses occurred within 1 year after the initiation of infliximab treatment in all groups, 90% of which were controlled by increasing doses of topical corticosteroids and shortening the interval of infliximab infusion. Adverse effects were observed in 65 cases or 35% of all subjects. Infliximab treatment was continued in 85% of the patients, but 15% of the patients discontinued infliximab treatment because of adverse effects or insufficient efficacy. CONCLUSIONS Infliximab reduced the frequency of ocular attacks and improved visual acuity in patients with BD-related uveitis and was generally well tolerated with few serious adverse events.

Choroidal Neovascularization Enhanced by Chlamydia pneumoniae via Toll-like Receptor 2 in the Retinal Pigment Epithelium

PURPOSE Choroidal neovascularization (CNV) is directly related to visual loss in persons with age-related macular degeneration (AMD) and other macular disorders. Chlamydia pneumoniae, a prokaryotic pathogen that causes chronic inflammation, is recognized as a risk factor for cardiovascular diseases. In this study, the authors investigated the association between C. pneumoniae infection and AMD using a laser-induced CNV model in mice. METHODS C57BL/6 mice, myeloid differentiation factor (MyD) 88 knockout (KO) mice, Toll-like receptor (TLR) 2 KO mice, and TLR4 KO mice were used. Experimental CNV was induced by rupturing the Bruchs membrane by laser photocoagulation (PC). Seven days after PC, the eyes were enucleated and the areas of CNV were measured in choroidal flat mounts. Cytokine gene expression by quantitative real-time PCR in the primary cultured retinal pigment epithelium (RPE) cells was also examined. RESULTS Vitreous injection of the C. pneumoniae antigen increased the size of CNV. Although lipopolysaccharide stimulation can induce multiple cytokines, cultured mouse RPE cells from C57BL/6 mice expressed IL-6 and VEGF, but not TNF-alpha mRNA, in response to C. pneumoniae antigen. RPE cells from either MyD88 KO mice or TLR2 KO mice did not respond to the C. pneumoniae antigen. TLR2 KO mice did not augment the size increase of experimental CNV by C. pneumoniae antigen in vivo. CONCLUSIONS C. pneumoniae can trigger inflammatory responses in the eye and promote experimental CNV in a TLR2-dependent manner. These data provide experimental evidence to imply persistent C. pneumoniae infection is a risk factor for AMD.

Interleukin‐18 regulates pathological intraocular neovascularization

Recently, the proinflammatory cytokine IL‐18 has been shown to have a role in angiogenesis. This study aimed to elucidate its role in abnormal neovascularization (NV) in an oxygen‐induced retinopathy (OIR) mouse model of the retinopathy seen in human premature newborns. IL‐18 was constitutively expressed in the retina in C57BL/6 mice, but expression transiently dropped on Day 17 after birth in mice exposed to 75% oxygen for 5 days between Days 7 and 12. Coincident with the IL‐18 reduction in oxygen‐treated mice, vascular endothelial growth factor was expressed in the retina, and OIR developed. By Day 24, NV in the retina had regressed to normal levels. By contrast, IL‐18 knockout mice, exposed to elevated oxygen concentrations, developed more severe OIR on Day 17, and it is important that this persisted until Day 24. This suggested that IL‐18 negatively regulated retinal NV. To investigate this further, we administrated recombinant IL‐18 to C57BL/6 mice during the development of OIR but found no significant inhibition of retinopathy. However, when IL‐18‐binding protein was administered during the OIR recovery phase to neutralize endogenous IL‐18, OIR was still apparent on Day 24. We therefore concluded that IL‐18 regulates pathogenic retinal NV by promoting its regression rather than inhibiting its development. This suggests some useful, new approaches to treating retinopathy in humans.

Acquired resistance to infliximab against uveitis due to Behçet's disease after one year of administration

most likely cause of the late-onset haptic disinsertion from the IOL. Even if fatigue of the haptic–optic junction led to the haptic disinsertion, the supportive capsular bag surrounding the IOL should have prevented the IOL from dislocating into the anterior chamber, as in one of the two cases reported by Solano et al. Several causes of the anterior dislocation of the IOL in our patient are possible. First, progressive fatigue in the haptic–optic junction or haptic disinsertion from the optic may have existed before the episode we observed. Second, the anterior capsulotomy during ECCE surgery may have been performed by the can-opener method, which can result in a larger and less intact anterior capsular rim than with the currently used continuous circular capsulorhexis method. Third, this episode apparently occurred when the patient bent forward to wash his face in the dark. An acute rise in intraocular pressure (IOP) caused by physiological changes, including increases in aqueous infl ow, in resistance to aqueous outfl ow, and in episcleral venous pressure after the body position is altered, can induce anterior movement of the lens–iris diaphragm. Along with haptic–optic junction fatigue or existing haptic disinsertion from the optic, an immediate rise in IOP when the patient bent forward may also have caused a posterior pressure gradient leading to the anterior dislocation of the IOL in our patient with incomplete optic fi xation in the capsular bag and a dilated pupil in the dark. In theory, haptic disinsertion as a complication in the case of a one-piece IOL is impossible. However, intraoperative or postoperative traumatic fractures of one-piece IOLs have been reported, but without any ill effects of the fracture in the periphery of the one-piece silicon IOL at the 3-month follow-up. On the basis of our case of late-onset spontaneous IOL dislocation, we do not think it advisable to keep a fractured one-piece IOL in the bag in certain circumstances, especially when the anterior capsular rim is not intact or when it is larger than the size of the optic. Late-onset nontraumatic optic dislocation with haptic disinsertion from a three-piece IOL is a rare long-term complication after cataract surgery. Progressive fatigue of the haptic–optic junction may cause haptic disinsertion, and a head-down position with pupil dilatation in the dark may result in subsequent spontaneous IOL dislocation. Delicate surgical techniques and careful selection of IOL products are important to prevent such a complication.

Investigation of the role of CD1d-restricted invariant NKT cells in experimental choroidal neovascularization.

Choroidal neovascularization (CNV) is directly related to visual loss in age-related macular degeneration and other macular disorders. We have investigated the role of CD1d-restricted invariant natural killer T (NKT) cells in laser-induced experimental CNV. Quantitative real-time PCR detected increased expression of NKT cell-related genes (Valpha14 and CXCL16) in whole eyes undergoing CNV, indicating local accumulation of NKT cells. We found a significant reduction of CNV and lower concentrations of vascular endothelial growth factor (VEGF) in ocular fluid in two different NKT cell-deficient mice, CD1d knockout (KO) and Jalpha18 KO mice. We also established in vitro co-cultures of retinal pigment epithelial cells and splenic NKT cells, and confirmed NKT cells could produce VEGF in the dish. Moreover, inoculating alpha-galactosylceramide, the ligand for NKT cells, into the vitreous cavity of C57BL/6 mice promoted CNV. We concluded that NKT cells play an important role in CNV as an inducer of VEGF.

Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization

Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8+ T cells reduced pathological preretinal NV, with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8+ T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.

Distinct Profiles of Soluble Cytokine Receptors Between B-Cell Vitreoretinal Lymphoma and Uveitis.

PURPOSE To determine the profiles of soluble cytokine receptors and cytokines, including mostly their ligands, in the vitreous humor of patients with B-cell vitreoretinal lymphoma (VRL) and uveitis. METHODS Vitreous samples were collected from immunocompetent patients with VRL (n = 21), uveitis (n = 20), and idiopathic epiretinal membrane (n = 21) as controls. Cytometric beads assay were used to determine the vitreous concentrations of soluble receptors and cytokines. RESULTS Vitreous levels of soluble IL-2 receptor α (sIL-2Rα), sIL-6R, soluble tumor necrosis factor receptor (TNFR) 1, sTNFR2, soluble vascular endothelial growth factor receptor (sVEGFR) 1, sVEGFR2, and IL-10 were higher in patients with VRL than in those with uveitis and controls, whereas those of sIL-1R1, sIL-1R2, and sIL-4R were higher in patients with uveitis than those with VRL and controls. In analyses in patients with VRL, elevation of sVEGFR1 and sVEGFR2 levels was more prominent in patients with systemic metastatic retinal lymphoma (SMRL) than in those with primary VRL/primary central nervous system lymphoma (PVRL/PCNSL). Furthermore, sIL-2Rα levels were increased in patients with VRL who developed subretinal lesions compared with in those who mainly had vitreous cavity opacity, positively correlated with the density of CD3+ cells in the vitrectomy cell blocks. CONCLUSIONS The profiles of soluble cytokine receptors and cytokines in patients with VRL were different from those with uveitis. In addition, sVEGFR1 and sVEGFR2 levels may be differential diagnostic markers between PVRL/PCNSL and SMRL, and sIL-2Rα levels can anticipate infiltration of VRL cells into the subretina and/or retina.

Protective Role for CD1d-Reactive Invariant Natural Killer T Cells in Cauterization-Induced Corneal Inflammation

PURPOSE Corneal inflammation can be induced by various stimuli, such as chemical burns, trauma, and acute bacterial infection, and directly impairs visual acuity. Natural killer T (NKT) cells belong to a specialized population of leukocytes that coexpress the T-cell receptor and NK markers. This study examined the role of CD1d-reactive invariant NKT cells in cauterization-induced acute corneal inflammation. METHODS The corneas of CD1d-knockout (KO) mice and Jalpha18-KO mice (both of which are NKT cell deficient) and control mice were cauterized with silver nitrate. Corneal edema and opacity were examined, and the phenotypes of the corneal-infiltrating cells were analyzed histologically at 24 hours and by flow cytometry at 96 hours. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expression of vascular endothelial growth factor (VEGF), interferon (IFN)gamma, and tumor necrosis factor (TNF)alpha in the cauterized corneas. RESULTS The CD1d-KO and Jalpha18-KO mice had significantly greater levels of corneal edema and opacity than did the control mice. Although the number of infiltrating cells was not significantly different at 96 hours, both groups of NKT cell-deficient mice demonstrated increased early neutrophil accumulation at 24 hours and early expression of VEGF, IFNgamma, and TNFalpha. There was no difference in the level of VEGF-induced corneal neovascularization. CONCLUSIONS NKT cells appear to regulate the early accumulation of neutrophils, protect the cornea from excessive inflammation, and maintain corneal clarity. However, in this study, they did not affect the corneal revascularization process induced by VEGF.