Biologics in the treatment of uveitis

PURPOSE OF REVIEW: This review summarizes the current evidence for biologic therapies in the treatment of uveitis. The review emphasizes published research in this field since 2005. RECENT FINDINGS: The anti-tumour necrosis factor-alpha infliximab and adalimumab have demonstrated significant efficacy in controlling uveitis associated with seronegative spondyloarthropathies and juvenile idiopathic arthritis; however, etanercept has failed to show a similar treatment effect in uveitis associated with these conditions. The majority of reports of biologic therapies in posterior uveitis have been uncontrolled trials, or retrospective studies, of uveitis resistant to immunosuppression. Encouragingly, successful control of such refractory intraocular inflammation has been consistently reported with infliximab and interferon alpha, particularly Behcet's disease-associated uveitis. A limited number of reports of anti-interleukin therapies, daclizumab and anakinra, have supported a role for these therapies in some types of uveitis. SUMMARY: Biologic therapies have increased the treatment options for sight-threatening uveitis. Despite experimental rationale, the lack of evidence from randomized controlled studies limits our understanding of when to commence therapy, which agent to choose and how long to continue treatment. Additionally, the high cost and potential side effects of all biologic agents have limited their current use to uveitis refractory to immunosuppression.     

How in vitro techniques have increased our understanding of uveal melanoma cellular biology

The past decade has seen a rapid increase in powerful in vitro techniques allowing for the specific study of the biologic properties of tumours. In this review we discuss the role of in vitro studies in providing insight into the biologic mechanisms involved in uveal melanoma. We also review the basis of these studies for the development of adjuvant therapies to aid in the treatment of systemic disease in patients with uveal melanoma.     

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.     

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。     

Nonsteroidal drugs for the treatment of noninfectious posterior and intermediate uveitis

PURPOSE OF REVIEW: This review summarizes current nonsteroidal drug therapies for noninfectious posterior and intermediate uveitis. RECENT FINDINGS: Continuing evidence shows that second-line agents including antimetabolites, T-cell inhibitors and alkylating agents, are effective in many patients, allowing reduction in steroid dose and preservation of visual function. There is an increased use of mycophenolate mofetil. Biologic therapies, including the antitumour necrosis factor-alpha agents and interferons, have demonstrated a high degree of efficacy in controlling uveitis refractory to immunosuppressants. SUMMARY: There are an increasing number of treatment options. As the vast majority of published studies in uveitis are case series or nonrandomized trials, there remains a lack of level 1 evidence to guide the choice and duration of therapy. Standard initial treatment for steroid-resistant disease is to add a single immunosuppressant to the regime, with additional agents being substituted or added as required. Combination of two immunosuppressants in addition to steroids may be indicated especially in chronic uveitis. High cost and limited long-term experience with biologic agents have restricted their use to uveitis refractory to immunosuppressants, but evidence suggests a potential therapeutic role earlier in Bechet's disease.     

Current and future treatments for Behçet’s uveitis: road to remission

Behçet’s disease (BD) is a multisystem inflammatory disorder of uncertain origin, although it remains defined within the spectrum of systemic immune-mediated vasculitic disorders and also represents a spectrum of putative autoimmune disease. Major symptoms include oral aphthous ulcers, genital ulcerations, skin lesions, and ocular lesions. Despite afflicting many systems, ocular complications of BD are some of the more devastating for the patient and their quality of life. Eye involvement, which affects 60–80 % of BD patients, is characterized in its more severe form by posterior or panuveitis including occlusive retinal vasculitis. While pathogenesis of BD remains complex, association with Class I MHC (HLA-B*51) predisposing to inflammation with engagement of the innate-immune system (neutrophils, NK cells), and perpetuated by the adaptive T cell responses against infectious- and/or auto-antigens. Despite the choice of conventional immunosuppressive therapies available, only recently with the advent of biologic therapy has visual prognosis and outcomes been substantially and favorably altered. For example, both interferon-α (IFN-α) and tumour necrosis factor (TNF)-α antagonists deliver promising results and for the first time improve prognosis. With IFN-α therapy, durable remissions of uveitis can be achieved and lead to drug-free remission. Similarly, anti-TNF therapy with infliximab is reported to be rapidly effective in inducing and maintaining remission. Most recently, rising evidence reports on the use of adalimumab, etanercept, and golimumab, while use of anti-interleukin (IL)-1 agents (anakinra, canakinumab, gevokizumab), IL-6 blockers (tocilizumab), and rituximab (depleting anti-CD20 antibody) is also increasing. The aim of this review is to provide evidence for the role of conventional therapies combined with evidence for advantages and disadvantages of biologic therapies in the treatment of ocular BD. Although randomized controlled trials remain sparse, evidence remains strong and enticing that biologic agents are invaluable for the treatment of sight-threatening Behçet’s uveitis and makes it an exciting time for Behçet’s specialists worldwide.     

Amniotic membrane use in ophthalmology

PURPOSE OF REVIEW: The purpose of this review is to describe the most recent and relevant clinical and experimental data about the use of amniotic membrane in ophthalmology. RECENT FINDINGS: The amniotic membrane is a biologic tissue that has been used as a graft for corneal and conjunctival reconstruction in a variety of ocular surface diseases. It is avascular and possesses anti-angiogenetic, anti-scarring and antiinflammatory properties. It is not a substitute but rather a substrate upon which cells can migrate and regenerate, forming new and healthy tissue. The amniotic membrane can also be used as a biologic patch, as a bandage, to treat acute inflammatory disorders. With the development of cell therapy, amniotic membrane can be also used as a carrier of limbal stem cells or their progeny, cultivated in vitro. SUMMARY: Amniotic membrane use in ophthalmic surgery has been shown to provide an alternative for corneal and conjunctival reconstruction in many clinically challenging situations; however, there is still a lack of scientific evidence based on randomized comparative studies to prove that its use is better than other alternative therapies for ocular surface reconstruction.     

Biologic Therapy for HLA-B27-associated Ocular Disorders

The treatment of articular and extra-articular manifestations associated with HLA-B27 has undergone dramatic changes over the past two decades, mainly as a consequence of the introduction of biologic agents and in particular anti-tumor necrosis factor α (anti-TNFα) agents. Uveitis is known to be the most frequent extra-articular feature in HLA-B27-associated spondyloarthritides. Topical corticosteroids and cycloplegic agents remain the cornerstones of treatment. However, biologic therapy may be effective in the management of refractory or recurrent forms of uveitis. This review gives an update on the management of HLA-B27-associated ocular disorders with biologics, including anti-TNFα agents and non-anti-TNFα biologic modifier drugs. There is an emerging role for newer biologics targeting interleukin-12/23 and interleukin-17 for the treatment of spondyloarthritides but data on their efficacy on anterior uveitis are sparse.     

影像学技术在眼前节相关生物学参数测量中的应用

角膜厚度、房角宽度等眼前节生物学参数是眼前节疾病诊断和手术的重要依据,以往的测量方法简单直接、主观性强、不能定量研究,无法满足现代眼科临床的需要。最近几年临床上出现了许多可用于眼前节生物学测量的新的影像学新技术如Scheimpflug技术、超声生物显微镜技术、光学相干断层扫描技术、Orbscan角膜地形图技术以及共聚焦显微镜技术等,它们使眼前节生物学参数的测量变得更加方便、准确、客观,极大地提高了眼前节医生的诊疗水平,本文就这些可进行眼前节生物学参数测量的技术设备进行综述,并对它们在临床上的应用进行回顾,以期为这些技术在眼科临床获得更好的应用提供参考。     

The Use of Biologic Agents in the Treatment of Ocular Manifestations of Behcet’s Disease

Behçet’s Disease (BD) is a multisystem inflammatory disorder of uncertain etiology with a variety of potential manifestations throughout the body, and its ocular complications are some of its most devastating. Treatment with immunosuppressive agents has improved outcomes, but many patients suffer from disease that responds poorly to conventional therapies. Because of this, therapy with a variety of biological response modifiers has been employed. The earliest was interferon-α, and a multitude of reports have described its benefits for the uveitis associated with Behçet’s Disease. Many patients enjoy durable remissions of their ocular inflammatory disease even after discontinuation of therapy, but side-effects are almost universal and some can be dangerous. Of the newer biological response modifiers, infliximab, a monoclonal antibody to TNF-α, has been most extensively studied. It is reported to be rapidly effective in many cases of Behçet’s Disease uveitis, though with conflicting data as to the ability to induce durable remission after cessation of treatment. Side-effects are relatively rare, but may be serious. Several reports have been published on the use of other biologic agents, including adalimumab (a humanized antibody to TNF-α), etanercept (a molecule that resembles the TNF-α receptor), and rituximab (an antibody to CD20 that depletes the body of CD20-positive B cells). Of the three of these, adalimumab has the most promising initial evidence, etanercept has very few positive reports in patients with BD uveitis (and is likely ineffective in uveitis in general), and rituximab is lacking data. Although randomized controlled trials are almost completely lacking, currently available evidence is promising that biologic agents can prove an invaluable addition to the armamentarium of the practitioner treating patients with BD uveitis.     

Genetics update of macular diseases

Significant progress has been made in recent years in the discovery of genes causing early-onset inherited macular diseases [54]. The identification of these genes and their disease-causing mutations can aid in the diagnosis of patients who are genetically affected but have not yet developed the clinical phenotype. By understanding the primary defect in the pathophysiology of these diseases, treatment can be directed to the earlier stages in disease pathways, perhaps delaying or preventing the onset of vision loss. Furthermore, the disease gene could be replaced with a normal copy, allowing expression of the normal protein and potentially avoiding the disease phenotype altogether. Much work remains to elucidate the biologic mechanisms by which these genetic mutations result in disease phenotypes. Understanding the interaction of the disease genes with genetic background resulting in a normal phenotype, as in Best disease, or a completely different clinical entity, as in RDS-associated pattern dystrophy, could lead to useful therapies for these and other macular diseases. Animal models created by removing the normal genes, similar to what was performed with ABCA4, can assist in the development of therapeutic interventions. Further insight into the biochemical processes that cause macular dystrophies, including AMD, will contribute to our ability to develop treatments that will become increasingly vital in the years to come.     

The use of biologic agents in the treatment of ocular manifestations of Behcet's disease

Beh?et's Disease (BD) is a multisystem inflammatory disorder of uncertain etiology with a variety of potential manifestations throughout the body, and its ocular complications are some of its most devastating. Treatment with immunosuppressive agents has improved outcomes, but many patients suffer from disease that responds poorly to conventional therapies. Because of this, therapy with a variety of biological response modifiers has been employed. The earliest was interferon-α, and a multitude of reports have described its benefits for the uveitis associated with Beh?et's Disease. Many patients enjoy durable remissions of their ocular inflammatory disease even after discontinuation of therapy, but side-effects are almost universal and some can be dangerous. Of the newer biological response modifiers, infliximab, a monoclonal antibody to TNF-α, has been most extensively studied. It is reported to be rapidly effective in many cases of Beh?et's Disease uveitis, though with conflicting data as to the ability to induce durable remission after cessation of treatment. Side-effects are relatively rare, but may be serious. Several reports have been published on the use of other biologic agents, including adalimumab (a humanized antibody to TNF-α), etanercept (a molecule that resembles the TNF-α receptor), and rituximab (an antibody to CD20 that depletes the body of CD20-positive B cells). Of the three of these, adalimumab has the most promising initial evidence, etanercept has very few positive reports in patients with BD uveitis (and is likely ineffective in uveitis in general), and rituximab is lacking data. Although randomized controlled trials are almost completely lacking, currently available evidence is promising that biologic agents can prove an invaluable addition to the armamentarium of the practitioner treating patients with BD uveitis.     

重视葡萄膜炎药物治疗研究,提高葡萄膜炎药物治疗效果

各类非感染性葡萄膜炎的治疗,糖皮质激素是首选药物.但单一药物治疗对慢性或复发性葡萄膜炎的疗效欠佳,长期应用又具有明显的毒副作用,因此部分患者需辅助以免疫抑制剂或生物制剂治疗.不同类型免疫抑制剂和生物制剂的作用机制不完全相同,因此各自的适应证、疗效和毒副作用也不尽一样.在临床实践中,应根据葡萄膜炎的类型选择敏感的免疫抑制剂或生物制剂治疗,同时密切观察其疗效和毒副作用.葡萄膜炎治疗中的常用药物类型、疗效以及存在的问题值得我们进一步关注和深入研究,以提高葡萄膜炎药物治疗的效果.     

Biologic Therapy for the Treatment of Giant Cell Arteritis

Giant cell arteritis (GCA), a vasculitis of the medium and large arteries, is traditionally managed with glucocorticoids. However, the side effects of chronic glucocorticoid use and the occurrence of refractory cases warrant the consideration of steroid-sparing agents, including biologic agents. Interleukin-6 (IL-6) inhibition shows the most promise as biologic therapy for refractory cases of GCA, but data to support the use of other existing biologic agents are currently lacking. A better understanding of the pathogenesis of GCA as well as clinical trials investigating both existing and emerging biologic agents is needed to expand therapeutic options for the treatment of GCA.     

Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives

Retinitis Pigmentosa (RP) is a hereditary retinopathy that affects about 2.5 million people worldwide. It is characterized with progressive loss of rods and cones and causes severe visual dysfunction and eventual blindness in bilateral eyes. In addition to more than 3000 genetic mutations from about 70 genes, a wide genetic overlap with other types of retinal dystrophies has been reported with RP. This diversity of genetic pathophysiology makes treatment extremely challenging. Although therapeutic attempts have been made using various pharmacologic agents (neurotrophic factors, antioxidants, and anti-apoptotic agents), most are not targeted to the fundamental cause of RP, and their clinical efficacy has not been clearly proven. Current therapies for RP in ongoing or completed clinical trials include gene therapy, cell therapy, and retinal prostheses. Gene therapy, a strategy to correct the genetic defects using viral or non-viral vectors, has the potential to achieve definitive treatment by replacing or silencing a causative gene. Among many clinical trials of gene therapy for hereditary retinal diseases, a phase 3 clinical trial of voretigene neparvovec (AAV2-hRPE65v2, Luxturna) recently showed significant efficacy for RPE65-mediated inherited retinal dystrophy including Leber congenital amaurosis and RP. It is about to be approved as the first ocular gene therapy biologic product. Despite current limitations such as limited target genes and indicated patients, modest efficacy, and the invasive administration method, development in gene editing technology and novel gene delivery carriers make gene therapy a promising therapeutic modality for RP and other hereditary retinal dystrophies in the future.     

Biologic Therapy for the Treatment of Giant Cell Arteritis

Abstract

Giant cell arteritis (GCA), a vasculitis of the medium and large arteries, is traditionally managed with glucocorticoids. However, the side effects of chronic glucocorticoid use and the occurrence of refractory cases warrant the consideration of steroid-sparing agents, including biologic agents. Interleukin-6 (IL-6) inhibition shows the most promise as biologic therapy for refractory cases of GCA, but data to support the use of other existing biologic agents are currently lacking. A better understanding of the pathogenesis of GCA as well as clinical trials investigating both existing and emerging biologic agents is needed to expand therapeutic options for the treatment of GCA.     

Anti-macular degeneration agents

Anti-VEGF therapy is a promising new avenue for the treatment of ocular neovascular diseases. Early preclinical data and recent clinical data support the efficacy and safety of several novel anti-VEGF for NVAMD. Whether these novel biologics are used on their own, in combination with previously available therapies, or with newly developing therapies, they represent a new avenue in treatment. These agents are highly selective in their targeted approaches, and when administered appropriately , offer treatment with minimal damage to retinal tissue. In the future, biotherapeutic agents will certainly play a powerful role in the treatment of human choroidal neovascular membrane formation.     

New options for uveitis treatment

Simulation can be defined as malingering, or sometimes functional visual loss (FVL). It manifests as either simulating an ophthalmic disease (positive simulation), or denial of ophthalmic disease (negative simulation). Conscious behavior and compensation or indemnity claims are prominent features of simulation. Since some authors suggest that this is a manifestation of underlying psychopathology, even conversion is included in this context. In today’s world, every ophthalmologist can face with simulation of ophthalmic disease or disorder. In case of simulation suspect, the physician’s responsibility is to prove the simulation considering the disease/disorder first, and simulation as an exclusion. In simulation examinations, the physician should be firm and smart to select appropriate test(s) to convince not only the subject, but also the judge in case of indemnity or compensation trials. Almost all ophthalmic sensory and motor functions including visual acuity, visual field, color vision and night vision can be the subject of simulation. Examiner must be skillful in selecting the most appropriate test. Apart from those in the literature, we included all kinds of simulation in ophthalmology. In addition, simulation examination techniques, such as, use of optical coherence tomography, frequency doubling perimetry (FDP), and modified polarization tests were also included. In this review, we made a thorough literature search, and added our experiences to give the readers up-to-date information on malingering or simulation in ophthalmology.     

Association between lumican gene -1554 T/C polymorphism and high myopia in Asian population:a meta-analysis

Uveitis is one of the most important causes of blindness worldwide. Its etiology and pathogenesis are complicated and have not been well understood. The treatment for uveitis is predominantly based on steroids and immunosuppressants. However, systemic side effects limit their clinical application. With the advancement of molecular biology, some intravitreal implants and biologic agents have been used for the treatment of uveitis. Additionally, novel techniques such as gene therapy and RNA interference are being studied for using as uveitis therapy. This paper reviews recent advances in uveitis treatment.     

Non-pharmaceutical treatment options for meibomian gland dysfunction

This review examines currently available non-pharmaceutical treatment modalities for meibomian gland dysfunction. A detailed search of the PubMed and MEDLINE databases was performed to identify original articles in English that have evaluated such nonpharmaceutical therapies in patients with this condition. Conventional therapies such as application of a warming compress, the practice of lid hygiene, and manual expression of meibomian glands as well as more technologically advanced approaches such as intraductal probing, thermal pulsation, and intense pulsed light therapy are included in the review. These non-pharmaceutical treatment options may each have a role to play in the management of meibomian gland dysfunction, but more studies are necessary to compare treatments directly under identical experimental conditions in order to determine their relative efficacy. Additional large-scale, randomised, controlled trials are also required to provide more information such as the specific indications best suited to each treatment modality, the efficacy of such approaches in combination with pharmaceutical-based therapy, and the mechanisms of action of some of the more technologically advanced systems.