A randomized trial of tacrolimus versus tacrolimus and prednisone for the maintenance of disease remission in noninfectious uveitis.

PURPOSE: To compare tacrolimus monotherapy with tacrolimus and prednisone therapy for the maintenance of disease remission in subjects with noninfectious posterior segment intraocular inflammation (PSII). DESIGN: Randomized, controlled, phase 2b, open-label, dual-center noninferiority trial. PARTICIPANTS: Fifty-eight patients with sight-threatening PSII. METHODS: Patients requiring a second-line systemic immunosuppressive agent to control their PSII were treated with therapeutic doses of oral tacrolimus. Those subjects who subsequently were able to taper their prednisone dose to 10 mg daily without disease reactivation were assigned randomly either to stop prednisone or to continue 7.5 to 10 mg prednisone daily for 9 months. MAIN OUTCOME MEASURES: Change in logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) and rate of patient withdrawal resulting from treatment inefficacy or intolerance. RESULTS: Thirty-five patients successfully tapered their prednisone to 10 mg daily. Of these, 16 were allocated randomly to receive tacrolimus monotherapy and 19 to continue taking prednisone and tacrolimus dual therapy. The difference in the mean change in VA for monotherapy compared with the dual therapy group was less than 1 logMAR letter (logMAR, -0.008; 95% confidence interval, -0.108 to 0.092; P = 0.870). The proportion of patients who tolerated treatment and maintained disease remission for 9 months after randomization also was similar in both groups (monotherapy, 62.5%; dual therapy, 68.4%; P = 0.694). All monotherapy treatment failures were the result of disease reactivation, whereas 50% of dual-therapy failures were the result of drug intolerance. CONCLUSIONS: This study provides preliminary evidence that corticosteroids can be withdrawn in tacrolimus-treated patients who are able to achieve control of PSII with 10 mg prednisone daily, and any advantage of dual therapy in the prevention of disease reactivation was offset by its greater treatment intolerance. These findings support the further evaluation of corticosteroid-free treatment in future phase 3 trials (International Standard Randomised Controlled Trial Number Register identification, ISRCTN46576063). FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Adalimumab in the therapy of uveitis in childhood.

PURPOSE: Chronic anterior uveitis in children often takes a serious course. Despite various immunosuppressive drugs some children do not respond sufficiently and there is a high risk of them becoming seriously disabled. Anti-TNF alpha therapy has been shown by our group and others to be mostly ineffective (Etanercept) or partly effective (Infliximab) with the risk of anaphylactic reactions. Here we report on 18 young patients treated with Adalimumab (Humira), a complete humanised anti-TNF alpha antibody. METHODS: We retrospectively analysed 18 patients, who were treated with Adalimumab (20-40 mg, every 2 weeks, when ineffective every week); 17 had juvenile idiopathic arthritis, one was without detectable underlying disease. The age at onset of arthritis varied from 0.5-15 years and for uveitis from 2-19 years. Patients were included when the previous anti-inflammatory therapy had been ineffective. It consisted of systemic steroids (n = 18), Cyclosporin A (n = 18), Methotrexate (n = 18), Azathioprine (n = 12), Mycophenolate mofetil (n = 4), Cyclophosphamide (n = 2), Leflunomide (n = 3), Etanercept (n = 8) and Infliximab (n = 5). The grading for uveitis was: (a) effective: no relapse or more than two relapses less than before treatment, (b) mild: one relapse less than before treatment, (c) no response: no change in relapse rate and (d) worsening: more relapses under treatment than before. The grading for arthritis (depending on the clinical findings), using three out of six parameters of the ACR PED Criteria, was: effective, mild, no response, worsening. RESULTS: For arthritis (n = 16) the response to Adalimumab was effective in 10 of 16 patients, mild in three patients, three did not respond. For uveitis (n = 18) Adalimumab was effective in 16, mild in one child, and one patient did not show any effect. After a very good response initially a shorter application time had to be used to maintain the good anti-inflammatory effect in one child. Additional immunosuppressive treatment was used in seven of the effectively treated children. Due to elevation of liver enzymes in one patient, who also took MTX, Adalimumab had to be discontinued. No anaphylactic reactions or increased frequency of infections since start of Adalimumab treatment was reported. CONCLUSIONS: For our group of children with long lasting disease our results show that Adalimumab was effective or mildly effective against the arthritis in 81%, but in uveitis in 88%. While these results regarding arthritis are comparable with other TNF-alpha blocking drugs (Etanercept), Adalimumab seems to be much more effective against uveitis than Etanercept. Anaphylactic reactions, found in a previous study from our group after Infliximab treatment, were not seen with Adalimumab. The necessary dosage and the treatment period, which probably have to be defined individually for each patient, remain unclear.

Intracameral bevacizumab for iris rubeosis.

PURPOSE: To determine whether intracameral bevacizumab decreases vascular leakage from iris rubeosis in patients with neovascular glaucoma. DESIGN: Interventional case series. METHODS: The study included six eyes of three patients with secondary neovascular glaucoma due to proliferative diabetic retinopathy (n = 2) or ischemic central retinal vein occlusion (n = 1). All patients received an intracameral injection of 1.0 mg bevacizumab. Morphologic changes and vascular leakage were investigated prospectively by iris fluorescein angiography. RESULTS: Decrease in leakage was detected as early as one day after injection. No inflammation was observed. No relapse was seen within the follow-up of four weeks. CONCLUSION: Intraocular injection of bevacizumab may provide an additional strategy for the treatment of iris rubeosis in neovascular glaucoma.

Tubulointerstitial nephritis and uveitis in siblings.

PURPOSE: To report on the occurrence of tubulointerstitial nephritis and uveitis (TINU) and HLA typing in two siblings. DESIGN: Retrospective case study. METHODS: HLA typing from two siblings with TINU syndrome and their parents was performed on DNA from peripheral blood mononuclear cells (PBMC). RESULTS: The boy developed TINU syndrome in 2001, his sister 5 years later. Both siblings inherited the HLA alleles HLA-DRB1*1401 and HLA-DQB1*0503 on the maternal haplotype, a haplotype that had rarely been observed in patients with TINU. CONCLUSIONS: The observations support inheritance of HLA-linked risk factors of TINU, but indicate heterogeneity of the risk phenotype due to linkage with different reported haplotypes.

Retinal pigment epithelial tear after subretinal rtpa and intravitreal air for the displacement of a large submacular hemorrhage.

PURPOSE: The authors report a case of retinal pigment epithelial (RPE) tear following pars plana vitrectomy (PPV), subretinal recombinant tissue plasminogen activator (rt-PA), and intravitreal gas administration for the displacement of large submacular hemorrhage. METHODS: A patient with a large submacular hemorrhage secondary to neovascular age-related macular degeneration (AMD) received a subretinal rt-PA injection and intravitreal air installation after PPV. Ophthalmic examination included standardized visual acuity testing and fluorescein angiography. PATIENTS: One patient from the authors' outpatient clinic. RESULTS: Baseline visual acuity of the eye was 20/160. Ophthalmoscopy showed a predominantly hemorrhagic lesion in the macula. Ophthalmoscopy and fluorescein angiography 2 weeks after the surgery revealed a RPE tear. Postoperative visual acuity was 20/1000. CONCLUSIONS: This case demonstrates that a RPE tear is a possible complication of the procedure of subretinal rt-PA and intravitreal air tamponade after PPV for the displacement of a large submacular hemorrhage secondary to neovascular AMD. The surgeon has to be aware about this complication and should inform the patient before surgery.

An unusual case of central serous chorioretinopathy in a patient with acute retinal necrosis.

PURPOSE: In acute retinal necrosis, which is caused by herpes virus, urgent treatment is essential. DESIGN AND METHODS: Here we present a 47 years old male patient, who developed an acute retinal necrosis in his left eye. Therapy was initiated with systemic aciclovir and corticosteroids. RESULTS: During the course of disease our patient achieved improvement of acute retinal necrosis but he developed central serous chorioretinopathy. CONCLUSIONS: The development of central serous chorioretinopathy in our patient was most probably due to the systemic corticosteroids he received. Especially in patients with an intraocular inflammation this diagnosis may lead to severe differential diagnostic problems.

Lipopolysaccharide-activated IL-10-secreting dendritic cells suppress experimental autoimmune uveoretinitis by MHCII-dependent activation of CD62L-expressing regulatory T cells.

Dendritic cells (DC) are key regulators of immune responses. Mature DC are traditionally considered to be immunogenic, although there is accumulating evidence that they can also be tolerogenic and induce Ag-specific regulatory T cells (Tregs). However, the mechanism of this Treg induction and the site of Treg action in vivo are yet to be defined. In this study, using the experimental model of interphotoreceptor retinoid-binding protein peptide (1-20)-induced experimental autoimmune uveoretinitis, we show that s.c. inoculation of IRBP-peptide-pulsed IL-10-producing LPS-activated mature DC (IL-10-DC) at one site (the cervical region) suppresses autoimmunity induced at a separate site (the inguinal region). Our data show that s.c. IL-10-DC correlates with an increase in the number of CD4(+)CD25(+)Foxp3(+) Tregs at the DC-draining lymph nodes (DC-dLN). However, although MHCII(-/-) IL-10-DC also induces Treg expansion at this DC-dLN, they failed to suppress experimental autoimmune uveoretinitis. Furthermore, unlike wild-type IL-10-DC, MHCII(-/-) IL-10-DC did not correlate with an increase in the percentage of Tregs expressing CD62L at the DC-dLN, nor did they associate with an increase in Treg number at a distal site. Similar effects were also observed after s.c. hen egg lysozyme-pulsed IL-10-DC, which produced a strong reduction in the number and activation of proliferating Ag-specific CD4(+) 3A9 T effector cells. We therefore propose that IL-10-DC require MHCII-dependent Ag presentation, and hence TCR ligation, to promote CD62L-mediated trafficking of Tregs to the site of T effector cell priming, where they suppress autoimmunity.

CD4+CD25+ T regulatory cells induced by LPS-activated bone marrow dendritic cells suppress experimental autoimmune uveoretinitis in vivo.

BACKGROUND: Tolerance-inducing DC are considered to be less mature than immunogenic DC, but the conditions promoting a less mature DC phenotype are not clear. We have previously shown that lipopolysaccharide (LPS) can have differential effects on DC function depending on the timing of DC exposure to LPS. Here, we show that early LPS-activated bone marrow derived DC (early DC, eDC), when administered subcutaneously to mice in vivo, promote tolerance to EAU induced via immunisation with interphotoreceptor retinol binding protein (IRBP) peptide 161-180. The effect correlates with the failure of eDC to secrete IL-12, and appears to be mediated in part via expansion of naturally occurring CD4+ CD25+ T regulatory cells (Tregs), which also mediate suppression of EAU on adoptive transfer to naive mice followed by immunization with autoantigen. METHODS: Immature DC were prepared from BMDC cultures. Early DC (eDC) and late DC (lDC) for tolerance experiments were obtained by differential timing of LPS addition and their cytokine secretion profile was analyzed. eDC and lDC were subcutaneously injected into mice. From the dLN CD4+ CD25+ GITR+ T regulatory cells found to express FoxP3 were isolated and transferred into mice prior to immunisation with IRBP. The immune response was scored by histopathology. Tregs were characterized in vitro by intracellular staining, cytokine secretion assay and transwell experiments. RESULTS: eDC secrete IL-10 but no IL-12 or IFNgamma. When injected subcutaneously into naive mice, they expand the population of CD4+ CD25(+high) GITR+ T cells expressing FoxP3 in the dLN, thus increasing the total number of IL-10 producing cells. eDC induced Tregs inhibit CD4+ CD25- T effector cell proliferation by a contact dependent process, and both eDC and Tregs suppress retinal damage when adoptively transferred. CONCLUSIONS: We suggest that DC maturation may be necessary for both tolerance and immunity, but differential levels of activation and/or cytokine production direct the outcome of DC-T cell interaction and this is determined by IL-12 production. T regulatory cells induced in vivo by contact with eDC are able to suppress disease in the EAU model by adoptive transfer.