RNA干扰技术在眼科学领域的研究进展

RNA干扰（RNAi）自1998年发现至今，已成为各学科研究基因功能及基因治疗的一种有效方法。虽然RNAi在眼科疾病的发生机制及最终利用其治疗疾病的研究中尚处于起步阶段，但其高特异性和高效性正日益受到重视。而且已经成功地用于抑制病毒复制及肿瘤治疗等的研究中。就RNAi在眼科学领域的应用研究进行综述。     

Biologic therapies for inflammatory eye disease

The era of biologic medical therapies provides new options for patients with treatment-resistant inflammatory eye disease. In this review, the authors summarize current published experience in a rapidly progressing clinical field, including the use of biologics, such as the tumour necrosis factor blockers, daclizumab and rituximab, and related agents, interferons and intravenous immunoglobulin, for the treatment of uveitis, scleritis and orbital inflammation. Reports of dramatic recoveries in patients with recalcitrant ocular inflammation who have received such therapies must be balanced against the high cost of biologics and the potential for serious, and at times unanticipated, complications of this treatment.     

Intravitreal Adalimumab in Active Noninfectious Uveitis: A Pilot Study

Purpose: To evaluate the short-term efficacy of intravitreal adalimumab (IVA) for the treatment of eyes with active noninfectious uveitis.

Methods: Consecutive eyes with active noninfectious uveitis were injected with IVA at 0, 2, then every 4 weeks for total of 26 weeks.

Results: Six out of 7 patients (12 of 13 eyes) completed 26 weeks of treatment. One patient (1 eye) failed treatment. Seven out of 12 eyes had improvement of ≥2 ETDRS lines. Three out of three eyes had resolution of anterior chamber cells. And 9 of 10 eyes with vitreous haze had zero haze at 26 weeks. Five out of 8 eyes with macular edema had complete resolution. Median fluorescein angiography score improved from 14 to 4 on last follow-up.

Conclusions: IVA was effective in controlling the inflammation, decreasing the macular edema, and improving the best corrected visual acuity in the majority of eyes in this series.     

Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA

Osteopontin (OPN) is elevated during the progression of experimental autoimmune uveoretinitis (EAU) in C57BL/6 (B6) mice. Furthermore, EAU symptoms are ameliorated in OPN knockout mice or in B6 mice treated with anti-OPN antibody (M5). Recently, OPN has been shown to promote the Th1 response not only in the extracellular space as a secretory protein but also in cytosol as a signaling component. Thus, we attempted to reduce OPN in both compartments by using a small interfering RNA (siRNA) targeting the OPN coding sequence (OPN-siRNA). EAU was induced in B6 mice by immunization with human interphotoreceptor retinoid-binding protein (hIRBP) peptide sequence 1-20. The OPN- or control-siRNA was administered with hydrodynamic methods 24 h before and simultaneously with immunization (prevention regimen). When plasma OPN levels were quantified following siRNA administration with the prevention regimen, the level in the OPN-siRNA-treated group was significantly lower than that in the control-siRNA-treated group. Accordingly, the clinical and histopathological scores of EAU were significantly reduced in B6 mice when siRNA caused OPN blockade. Furthermore, TNF-α, IFN-γ, IL-2, GM-CSF and IL-17 levels in the culture supernatants were markedly suppressed in the OPN-siRNA-treated group, whereas the proliferative responses of T lymphocytes from regional lymph nodes against immunogenic peptides was not significantly reduced. On the other hand, the protection was not significant if the mice received the OPN-siRNA treatment on day 7 and day 8 after immunization when the clinical symptoms appeared overt (reversal regimen). Our results suggest that OPN blockade with OPN-siRNA can be an alternative choice for the usage of anti-OPN antibody and controlling uveoretinitis in the preventive regimen.     

抗TNF生物制剂在葡萄膜炎临床治疗中的应用进展

目前,葡萄膜炎的治疗主要应用激素和免疫抑制剂,虽然能选择性地作用于免疫细胞亚群,取得较好的临床疗效,但长期应用毒副作用很大。近几年,随着对葡萄膜炎病理机制的深入研究,抗肿瘤坏死因子（ｔｕｍｏｒｎｅｃｒｏｓｉｓｆａｃｔｏｒ,ＴＮＦ）生物制剂等具有明确作用靶点的治疗方法得到极大的发展并应用于临床,在葡萄膜炎的治疗方面具有良好的应用前景,抗ＴＮＦ生物制剂有望成为葡萄膜炎治疗的一线药物。本文将抗ＴＮＦ生物制剂的作用机制、治疗葡萄膜炎的给药方式与剂量、疗效、不良反应及应用前景等方面作一综述。     

儿童非感染性葡萄膜炎的药物治疗

儿童葡萄膜炎占所有葡萄膜炎的5％～10％,多数起病隐匿、病程迁延,常合并多种眼部并发症.儿童葡萄膜炎多为非感染性,其中绝大多数为特发性,最常见的全身病因为幼年特发性关节炎.儿童葡萄膜炎治疗棘手,常用药物为糖皮质激素、抗代谢药、T细胞抑制剂.近年来生物制剂的使用为儿童非感染性葡萄膜炎的治疗提供了新方法.玻璃体腔植入糖皮质激素缓释装置可长时间控制眼内炎症,但在儿童中使用的安全性及有效性仍待进一步研究.     

Intravitreal bevacizumab as first local treatment for uveitis‐related choroidal neovascularization: long‐term results

Purpose: To report long‐term results of intravitreal (IVT) bevacizumab as first local treatment for choroidal neovascularization (CNV) secondary to uveitis. Methods: Files of patients receiving 1.25 mg/0.05 ml bevacizumab as primary local treatment for CNV were retrospectively reviewed. Main outcomes were change in best‐corrected visual acuity (BCVA) and central foveolar thickness (CFT), treatment‐related adverse events, and number and frequency of injections. Results: Fifteen eyes from fifteen patients were included. Multifocal choroiditis and panuveitis were the diagnosis in seven, ampiginous choroiditis in two, and for six remaining, serpiginous choroiditis, sympathetic ophthalmia, Vogt–Koyanagi–Harada syndrome, punctuate inner choroidopathy, tuberculosis and idiopathic inflammation. In 13 eyes, neovascularization was subfoveal, and peripapillary in two. Intraocular inflammation was strictly controlled in all cases by the time of injections. BCVA improved from logMar 0.53 to logMar 0.29 in 12 eyes (80%), while CFT decreased from 239.06 to 195.2 μm in 13 (87%). Twelve eyes received more than one injection; mean number in this group was 4.25 (2–8), and frequency 1 every 12.97 weeks. There were no adverse events related to bevacizumab or the procedure. Median follow‐up was 17.6 months (8–25). Conclusions: First‐intention IVT bevacizumab for inflammatory CNV showed transient improvement in BCVA and CFT, in eyes under controlled inflammation. Reinjection was needed in most cases. Further work should conclude about safety related to repeated injections.     

Fluocinolone Acetonide Intravitreal Implants in Vogt-Koyanagi-Harada Disease

Purpose: To describe the use of fluocinolone acetonide implants (Retisert) in Vogt-Koyanagi-Harada disease (VKH).

Design: Interventional case series.

Methods: Retrospective review of medical records.

Results: Two patients with VKH requiring high-dose systemic corticosteroid therapy to control their inflammation and bilateral serous retinal detachments received bilateral fluocinolone acetonide implants. Upon tapering of systemic corticosteroids, one patient had recurrent serous retinal detachments and the other patient’s anterior chamber and vitreous inflammation returned.

Conclusions: The authors’ experience with fluocinolone acetonide implants in VKH has been mixed with an inability to fully taper off of systemic corticosteroids.     

Intraoperative Intravitreal Injection of Triamcinolone Acetonide for Cataract Extraction in Patients with Uveitis

Purpose: To evaluate the efficacy of intravitreal triamcinolone injection in controlling postoperative inflammation after cataract extraction in patients with uveitis.

Methods: This retrospective study included 30 eyes with uveitis that had phacoemulsification or extracapsular cataract extraction with intraocular lens implantation. Intravitreal triamcinolone acetonide (4?mg) was injected at the end of surgery. No systemic steroids were given after surgery.

Results: Visual acuity improvement of 2 lines or more occurred in 26 eyes (86.7%). Six eyes (20%) had a best-corrected visual acuity of 6/60 or better before surgery, which increased to 22 eyes (73.3%) after surgery. Five eyes (16.7%) had a visual acuity of 6/12 or better after surgery. Intravitreal triamcinolone injection controlled the postoperative inflammation in all eyes for at least 3 months following surgery.

Conclusion: Intravitreal triamcinolone injection was effective in controlling postoperative inflammation after cataract extraction in patients with uveitis sparing the use of systemic steroids.     

地塞米松玻璃体内植入剂在非感染性葡萄膜炎继发黄斑水肿患者治疗中的作用

目的　观察地塞米松玻璃体内植入剂在治疗非感染性葡萄膜炎继发黄斑水肿中的安全性和临床疗效。方法　回顾性分析我院2019年12月至2021年12月临床确诊的非感染性葡萄膜炎继发黄斑水肿患者30例（30眼）,给予玻璃体内注射地塞米松玻璃体内植入剂治疗。所有患眼均行最佳矫正视力(BCVA)及眼压测量,并采用OCT测量黄斑中心视网膜厚度(CMT)。术后随访6个月,所有患者均于术前,术后1个月、3个月及6个月重复检测并比较BCVA、CMT。随访期间观察患者眼压变化,监测白内障进展、结膜下出血等眼部不良反应。结果　患者术前及术后1个月、3个月及6个月BCVA(logMAR)分别为0.74±0.37、0.47±0.29、0.28±0.14、0.37±0.17。患者术前,术后1个月、3个月及6个月CMT分别为(372.12± 99.42)μm、(298.14±82.44)μm、(278.45±62.43)μm、(289.31±56.34)μm。患者各时间点BCVA、CMT差异均有统计学意义（均为P<0.05)。与术前相比,患者术后1个月、3个月及6个月BCVA和CMT差异均有统计学意义（均为P<0.05）。术后各时间点两两比较结果显示,患者BCVA和CMT差异均无统计学意义（均为P>0.05)。随访期间有6例患者出现眼压升高（≥25 mmHg,1 kPa=7.5 mmHg）,经局部降眼压药物应用后降至正常水平。4例患者出现白内障进展,均无需手术治疗。结论　玻璃体内注射地塞米松玻璃体内植入剂能够提高患者视力及降低CMT,有效治疗非感染性葡萄膜炎继发黄斑水肿。     

地塞米松玻璃体内植入剂治疗非感染性葡萄膜炎继发黄斑水肿的研究进展

葡萄膜炎继发的黄斑水肿(macular edema,ME)是一种葡萄膜炎常见的并发症,可导致非感染性葡萄膜炎(noninfectious uveitis,NIU)患者的视功能障碍。临床上,葡萄膜炎继发ME的治疗仍然非常棘手。目前有多种药物用于治疗葡萄膜炎继发ME,例如皮质类固醇、抗血管内皮生长因子和免疫调节剂等。但是,临床效果报告不一致。近些年来,地塞米松玻璃体内植入剂(intravitreal dexamethasone implant,IDI)是一种广泛应用的皮质类固醇药物。最近的研究表明,IDI有效地改善了葡萄膜炎相关的ME,根据需要通过密切监测和再治疗,这种效应可持续至少6mo。本文就目前国内外关于IDI治疗NIU继发ME进行汇总,并概述相关结果,以期为未来NIU继发ME的诊治提供依据。     

Intraocular Pressure Monitoring Post Intravitreal Steroids: A Systematic Review

The use of intravitreal (IVT) corticosteroids for treatment of posterior segment diseases has increased significantly over the last decade. A commonly recognized complication of IVT steroids is secondary ocular hypertension (OHT) that can occur immediately secondary to direct intraocular volume increase or weeks to months later as a result of increased outflow resistance. We performed a meta-analysis and found 32% (95% confidence interval, 28.2–36.3) of individuals developed OHT following 4 mg IVT triamcinolone, 66% (50.2–78.8) and 79% (72.2–84.5) following 0.59 and 2.1 mg fluocinolone implant, respectively, and 11% (6.4–17.9) and 15% (9.2–24.3) following 0.35 and 0.7 mg dexamethasone implant, respectively. Risk factors included pre-existing glaucoma, higher baseline intraocular pressure (IOP), younger age, OHT following previous injection, uveitis, higher steroid dosage, and fluocinolone implant. Most cases of OHT can be controlled medically; up to 45% following fluocinolone implant require surgery, however. We suggest a protocol to monitor IOP after IVT steroid injection/implantation that includes checking IOP within 30 minutes after injection, followed by 1 week after IVT triamcinolone and 2 weeks after implant insertion, then every 2 weeks for the first month and monthly for up to 6 months after IVT triamcinolone and dexamethasone implantation and 9 months after fluocinolone implantation.     

Drug Delivery Options for the Treatment of Ocular Inflammation

Treatments available for ocular inflammatory diseases and their associated complications have expanded significantly over the course of the last ten years. While corticosteroids are a mainstay of therapy for uveitis and macular edema, the methods of delivering corticosteroids have evolved. Intravitreal triamcinolone acetonide provides a local therapy for persistent cystoid macular edema (CME) and posterior uveitis. Other intravitreal therapies, such as bevacizumab and methotrexate, have also been used successfully in uveitic CME. Sustained release intravitreal implants, including the fluocinolone acetonide implant and the dexamethasone drug delivery system, offer an alternative therapy for chronic, recalcitrant posterior uveitis and CME. Their design was inspired by the ganciclovir implant, which prevented the progression of CMV retinitis in AIDS patients. Technological advances in drug delivery have supplied new treatments for patients with ocular inflammatory disease.     

Long-Term Intravitreal Dexamethasone Implant Outcomes in Uveitis

ABSTRACT

Purpose: To describe the long-term clinical outcomes in a cohort of uveitic eyes treated with the intravitreal dexamethasone implant (Ozurdex; Allergan, Inc).

Methods: Seventy-nine (63 patients) receiving 134 implant injections over 82 months were included. Indication, visual acuity (VA), intraocular pressure (IOP), vitreous haze score (VHS), central retinal thickness (CRT), time to reinjection, systemic treatments, and complications data were recorded.

Results: The cumulative probability of VA improvement was 80% at 1 month and 90% at 12 months, and it was maintained until 60 months. Eyes with baseline vitritis (VHS >0.5; 68%) had a probability of VHS improvement of 33% at 1 month, 75% at 12 months, and 85% at 60 months. The probability of CRT improvement was 33% at 1 month, 75% at 12 months, and 85% at 60 months. The most frequent adverse event was moderate IOP elevation (≥25 mmHg) in 30.3%, no cases of retinal detachment or endophthalmitis were observed.

Conclusions: The dexamethasone implant provides favorable VA, CRT, and VHS long-term outcomes in uveitis with a reduced rate of severe adverse events.