News

OCT: interpretative pearls and pitfalls
In the last decade OCT technology has evolved rapidly, with spectral domain OCT making fast scanning of larger areas and three-dimensional viewing of the macular and optic nerve areas a real option. Technical and clinical differences between time- and spectral domain OCT will be discussed. But, besides an interpretation of clinically relevant issues, a comparison to conservative functional imaging techniques will also be given.

What OCT can offer in the future
Increased scanning speeds using novel approaches promise even more detailed imaging of retinal structures. Increasing the scanning speed will also allow the introduction of averaging algorithms which will reduce the effect of "noise" in the capture system further increasing resolution. The future will also see the use of multimodal mapping - the combination of different data sources to better evaluate the relationship between structure and pathophysiologic changes within the retina and underlying structures.

When and where is OCT useful in uveitis?
Permanent vision loss due to chronic macular edema could be the result of the complications that arise during the chronic-recurrent phase of uveitis, including choroidal neovascular membranes, vitreous traction, macular holes, retinal tears, epiretinal membranes and subretinal fibrosis. Optical coherence tomography (OCT) has become an indispensable tool to the uveitis specialist for the diagnosis of macular disease. OCT may complement FA and can be clinical helpful. In our study, the OCT was helpful to demonstrate the qualitative and quantitative anatomical alterations, having a good correlation with the visual acuity. It revealed additional morphological findings and persistent macular alterations despite of a favorable visual acuity outcome. Thus cross-sectional OCT images may increase understanding of the pathophysiology of uveitis and a better disease monitoring might be achieved with such diagnostic tool.

Uveitic macular Edema: Classification and Outcomes
OCT is effective in detecting macular edema. It allows determination of the distribution of fluid and quantification of retinal thickness. However, a disagreement exists between the significance of these thickness elevations, and the possibility/probability of visual recovery. Furthermore certain structural features such as macular retinal detachments have a different prognostic significance in uveitis as compare to diabetes, where they indicate a poor prognosis for vision recovery. In uveitis, macular detachment has little impact on visual prognosis. Uveitic macular edema is a clear example of the need for clinical studies to determine the role of structural OCT changes in uveitis related entities.

JIA uveitis: epidemiology and screening
Juvenile arthritis is the most common disease associated with uveitis in children. Old and new findings regarding epidemiology and risk factors for JIA associated uveitis are reviewed and opposed to the existing ophthalmologic screening guidelines.

JIA associated uveitis; complications and visual outcome, outcome predictors
JIA associated uveitis can last a long time - complication free remission may occur after 12 years of topical steroids but conversely new sight threatening complications may develop after 20 years. In our cohort study with 25 year follow up in 30% eyes the uveitis remits, in 30% it persists and in 40% complications develop. In 11% eyes visual acuity was less than 6/60. Complications increase with longevity of disease but the majority of patients with complications will have presented late and damage at onset remains a major risk factor. Lack of prolonged remission and persistent flare are risk factors for new complications. The effect of treatment remains questionable. Additional probable factors are ANA positivity, early onset uveitis, male sex and systemic inflammation at onset.

Pathophysiology of JIA
JIA is initially characterized by a chronic inflammation of the synovial tissue and starts with an activation of the endothelial cells. This results in adhesion and migration of different leucocytes, initially with cells of myeloid origin of the innate immune system, monocytes and neutrophils. These activated phagocytes produce and secret high amounts of several cytokines, especially IL-1 and TNF-a, and stimulate the proliferation of lymphocytes and are responsible for the link to the adaptive immune system.

Pathophysiology of JIA associated uveitis
Multiple intraocular cytokines, chemokines and soluble adhesion molecules are increased in the AqH of children with juvenile idiopathic arthritis-associated uveitis. These mediators are present irrespective of active or inactive uveitis and without clear predominance of a Th1 or Th2 associated cytokine profile. However, the level of IL-1 and IL-8 in the aqueous humor might be related to uveitis activity, early or late phase of the course of uveitis or systemic treatment with methotrexate.

Immunosuppression in JIA associated uveitis
As quiescence of JIA associated uveitis often cannot be achieved with topical steroids, one of the classical immunosuppressive drugs, e.g. methotrexate, azathioprine or cyclosporine A, is commonly used as a second-line medication. The respective studies have only been retrospective. The dosages, tapering and length of treatment are not well defined. The role of other DMARDs, e.g., mycofenolat mofetil, rapamycin, tacrolimus and leflunomide, remains to be defined. The current discussion focuses on when on how biologicals may be added to the immunosuppressive management.

TNF-alpha blocking Agents in JIA associated Uveitis
TNF-alpha blocking agents have been shown very effective in the treatment for JIA, but also for the associated uveitis. The presentation summarizes the published data about the use of etanercept, infliximab and adalimumab. It seems that etanercept has the risk of inducing recurrences in this group, and there is growing evidence about some other side effects. Important questions have to be discussed, like the role of induction of autoantibodies and the need for an additional treatment with methotrexate.

Target for Drug Therapy in Uveitis 2008
The introduction of the newer biologic pharmaceuticals for the treatment of systemic autoimmune diseases has provided the uveitis specialist with several new alternatives in the management of patients recalcitrant to the standard treatment paradigms. The targets of these drugs are the soluble mediators of inflammation and involve cytokines and interleukins. However, the clinical utility of these biologics is unknown for several reasons - namely, the absence of controlled, prospective clinical trials; the lack of focus on a single specific uveitis entity so that too few patients are studied; the reliance on visual acuity as a primary outcome rather than the response of CME to treatment.

The New Calcineurin Inhibitors
The LUMINATE studies have been designed as pivotal clinical trials to evaluate the safety and efficacy of LX211, a novel, next-generation calcineurin inhibitor, for the management of non-infectious uveitis. Three global, prospective, double-masked, parallel-group, dose-ranging, placebo-controlled, randomized multi-centre studies are currently in progress in 56 sites across North America, Europe and India. Pooled masked data from the studies to date on anatomic diagnoses, age and gender distribution will be reported. The LUMINATE Program is the first randomized placebo-controlled set of trials ever conducted for a corticosteroid-sparing immunomodulatory agent in different types of sight-threatening non-infectious uveitis. The wide range of uveitic disease types and subject demographics allow future efficacy should permit their results to be applied widely across disease categories and patient populations.

Posurdex and Uveitis - What do we know
Posurdex consists of dexamethasone in a vicryl pellet which slowly releases the steroid over a period of 3-6 months as it breaks up. It is injected into the vitreous using a specially designed applicator which is quick and easy to do. The first clinical trials with this drug were in patients with a variety of causes of macular edema - diabetes, vascular occlusions, post-cataract surgery and uveitis. More recently these disorders have been separated out and separate clinical trials run. The main trial in uveitis with posurdex is for the management of vitreous haze and hence active posterior segment inflammation. Currently available data from this trial will be discussed.

New Drugs for the Future
We continue to see a movement away from the systemic steroid era. Animal models of uveitis have provided us with further insight into the underlying mechanisms leading to human disease. These observations help in our constant desire to develop more specific therapies that carry less toxicity. Many approaches to this end are or will be tried, sometimes first in the uveitis animal models. These include the use of biologics, gene therapy, cellular therapy, vaccines, and the induction of peripheral immune tolerance. One major question still to be fully answered is whether local ocular therapy will be as effective as systemic therapy. Pharmacogenetics will certainly become increasingly important. Recognizing which medications are ideally suited for individual patients will alter our therapeutic approach dramatically. In principal therapies will be chosen specifically for the patient rather than the illness. Randomized studies in the future may choose subjects on the basis of their genetic background's ability to respond to a medication and how it is metabolized.

Role of APC in Uveitis
Dendritic cells (DC) are the most potent antigen presenting cells in the body, with the capability of presenting foreign (and self) antigen to T cells. DC are present throughout the tissues including the eye but their major role is to present self-antigen in a tolerising role ie to promote homeostasis. When challenged, however, DC act as the first llne of defence and can activate adaptive immune responses with specific T and B cell memory via a panel of broad spectrum innate immune receptors which recognise foreign antigen. The central role of DC in uveitis will be described in this presentation.

Role of RPE in regional immunity in the eye
Ocular pigment epitherial cells, including RPE, greatly participate in the regional immunity of the eye by direct suppression of activated T cells as well as indirect suppression through regulatory T cells (Treg) induced by ocular pigment epithelial cells. The molecular mechanisms involved are different between iris, ciliary and retinal pigment epitherial cells depending upon where they are located. In the symposium, we focus on molecular mechanisms of immunosuppressive activity of RPE.

Autoinflammation versus Autoimmunity
Genes which have been shown to be contributory to autoimmunity have been designated as genetic masterswitches. These genes include HLA, PTPN22, CTLA-4, FoxP3 and AIRE. We have analysed samples from patients with acute anterior uveitis, posterior uveitis and behcet's disease for polymorphisms in PTPN22 and CTLA-4. There was no association between SNP in either gene and these uveitic conditions. It should be considered that these diseases are classified as autoinflammtory rather than autoimmune.

Role of Th17 Cells
Experimental autoimmune uveitis (EAU) induced by immunization with retinal antigen in adjuvant, as well as some types of human uveitis, are associated with a Th17 response. Nevertheless, either Th17 or Th1 cells are able to induce EAU, depending on the specific model. The data to be discussed indicate that ocular autoimmunity can develop in the context of either a Th17 or a Th1 effector response. The response is affected by the conditions present during initial exposure to antigen, including the quality/quantity of innate receptor stimulation and/or type of APC. These data also help to shed light on the heterogeneity of human uveitis, which occurs in the face of responses to the same ocular antigen(s).

Homing in Uveitis
Our lab uses the intravital imaging technique of epifluorescent microscopy as a sensitive measure of the ocular immune response. The technique is non-invasive and not only captures cell dynamics in real-time, but also can deliver time-lapse video and allows visualization of cells or cell populations with transgenic technology or in vivo immunohistology. We have used intravital imaging to characterize cells in the iris vasculature and tissue using various models of ocular inflammation. This technique provides dynamic and quantifiable data for studying fundamental processes of the ocular immune response. Live, sensitive, non-invasive imaging can be extrapolated to studies in patients.

What is new in HLA-B27 associated Uveitis?
Acute anterior uveitis (AAU) is the most common type of uveitis and 50% of these cases are associated with HLA-B27. Half of these patients will develop an associated seronegative spondyloarthropathy (SpA), whilst approximately 25% of the patients initially diagnosed with HLA-B27 associated systemic disease will develop AAU. Gram negative bacterial and Chlamydia trachomatis infections have been strongly implicated in the development of AAU. Whilst subtypes of HLA B27 (05, 02, 04) are linked to AU SNP's of TLR 2 & 4 are not associated with AAU or with the pattern of immune responses to PAMPS.

Pathophysiology of HLA-B27 associated Disorders
The HLA B 27 molecule is interesting because of several aspects:
1. HLA B27 has a unique B pocket among the HLA class B molecules which determines the antigen binding cleft and which is likely to influence the peptide repertoire,
2. there are more than 30 subtypes of HLA-B27 which differ in part only by single amino acids, and which, importantly, are not all associated with AS,
3. intracellular misfolding of HLA B27 may lead to aberrant expression of B27 homodimers on the cell surface with possible influence on antigen presentation,
4. HLA-B27 itself can be presented by HLA-class II as an autoantigen and could be recognized by CD4+ T cells,
5. HLA B27 transgenic rats develop an SpA like disease,
6. intracellular handling of microbes seems to be altered, at least in HLA B27 transfected cell lines.
Very much in that context is based on current hypotheses. The possibility of an HLA B27 restricted immune response to self or foreign antigens has been addressed experimentally, the evidence for that mechanism is rather limited so far.
Several other non-genetic factors are likely to be involved in the pathogenesis of AS, especially if one assumes a role for causative immune responses and triggering microbes such as Chlamydia and Yersinia in ReA.

Genes and anterior Uveitis: are there more associations than HLA-B27?
Acute anterior uveitis (AAU) is closely associated withHLA-B27. In addition, MICA-A4 gene seems to play an important role, both in HLA-B27 positive and negative Caucasian population. A locus at chromosome 9p21-9p24 which uniquely associates with AAU has also been revealed by recent genome wide scan studies. Other studies include TLR signalling network in the genetic mechanisms of AAU. In this lecture, molecular genetic mechanisms involved in the development of AAU, in addition to HLA-B27 will be discussed.

Update in Therapy
First-line therapy for HLA-B27--associated acute anterior uveitis remains topically applied corticosteroids. In severe anterior chamber inflammation a cycloplegic/mydriatic drop may be required to reduce pain and break or prevent posterior synechiae. Noncompliant patients can be treated with a subconjunctival or sub-Tenon injections of corticosteroid.
Systemic immunosuppression is indicated for severe or chronic HLA-B27 uveitis that fails to respond to conventional steroid treatment or/and involvement of posterior segment and cystoid macular edema. The last several years have been widely used TNF blockade. Several studies suggest that the anti-TNF treatment has beneficial effects in HLA-B27 associated uveitis reducing recurrences and that infliximab may be more effective than etanercept in controlling ocular inflammation.

How to best handle uveitic cataract
Cataract represents the most common complication of uveitis. Cataract surgery requires a careful preparation of the patients to avoid important complications. A quiet or well-controlled eye is necessary for at least 3 months before surgery can be contemplated. Pre-operative prophylaxis should be used to prevent significant post-op inflammatory reaction and technically the procedure will be more demanding depending on the severity of the complications induced by the inflammation. Post-op care requires more prolonged use of therapy and close monitoring. The results are usually good with over 75% of cases reaching visual acuity of 6/12 or better. All the different steps in the preparation of the patient for surgery as well as surgical techniques and post-op care will be discussed.

Role of Vitrectomy in the Therapy of Uveitis
Vitreoretinal complications in patients with uveitis can be represented by structural changes that may be out of range for medical therapy. Vitreous opacities, epiretinal membranes causing vitreoretinal traction syndromes, tractional retinal detachements or detachements by retinal necrosis are common indications for surgical interventions. Besides therapeutic aspects, vitrectomy and subretinal aspiration biopsy can be used for diagnostic purposes, especially in patients with endophthalmitis, infectious uveitis or intraocular lymphoma. The diagnosis of infectious uveitis has made recent progress by the use of eubacterial PCR techniques. The perioperative medical management will be discussed as well as the use of intravitreal dyes and drugs.

Role of anti-VEGF Treatment in CNV in Uveitis
After intravitreal bevacizumab injection had shown good response in choroidal neovascularization (CNV) associated with age-related macular degeneration, anti-VEGF treatment also was tested in the CNV secondary to inflammatory diseases. The potential anti-inflammatory mechanisms of VEGF-inhibitors will be discussed in detail. Data of published case series have been reviewed to analyze the level of evidence.

Laser in Uveitis
A. For diagnosis purpose: laser flare-cell photometry to quantify intraocular inflammation
B. To treat uveitis
1. Argon laser: to prevent retinal detachment in cases of retinal tear, retinal necroses or to prevent/treat retinal neovascularisation in retinal occlusive vasculitis. in pars planitis.
2. Nd-YAG laser: iridotomy in case of papillary seclusion but a surgical iridectomy is safer.
3. Transscleral red krypton or Diode laser: to treat neovascular glaucoma in occlusive vasculitis or open angle glaucoma or therapy-resistant inflammatory glaucoma in adults (not in children: high failure rate as primary surgical treatment for secondary glaucoma in juvenile idiopathic arthritis
Complications of lasers in uveitis:
1. Clinically, inflammation can be observed after treating uveitis with different type of lasers but it is usually an effective and well-tolerated procedure.
2. Experimentally argon laser to one retina seems to increase the blood aqueous barrier of both eyes.
3. LASIK does not appear to increase the risk for uveitis after LASIK in HLA-B27 positive patients.

Update on Antiviral Therapy
Major therapeutic progress has been recently achieved in different types of viral eye disorders. Systemic antivirals are not necessary in all cases, especially in non complicated situations. Topical ganciclovir gel or acyclovir ointment may be proposed with a good tolerance. In all other cases, systemic antivirals are mandatory. The introduction of corticosteroids is another major issue that must be considered only under an antiviral shield. Finally, control of viral loads by molecular analysis of ocular fluids may be proposed in selected cases, in order to evaluate treatment efficacy. Maintenance therapy based on low dose antivirals can reduce the rate of recurrence and should be considered but duration of treatment depends on each clinical situation.

Laboratory Diagnosis of viral Uveitis
Discrimination between infectious and non-infectious uveitis is of great importance as it influences the prognosis and patient management. Microbiological diagnostics on peripheral blood is not indicative for the cause of the intraocular inflammation. Therefore, examination of intraocular fluid is of great importance. The application of PCR analysis on ocular fluids and determination of intraocular antibody production in immunocompetent and immunocompromised patients will be presented.

Fuchs Uveitis: Rubella versus other Viruses
In the past 4 years several articles have established the Rubella virus as a cause of many or most cases of Fuchs' heterochromic iridocyclitis (FHI). Evidence for Rubella has been made by the demonstration of intraocular antibody synthesis. FHI has become less common in USA-born patients since the introduction of Rubella vaccination in 1969. Recently positive PCR for CMV in 5 of 16 immunocompetent patients with FHI is reported. Since FHI, is a clinical diagnosis, it is not surprising that more than one etiology may cause this picture.

CMV induced anterior Uveitis
CMV anterior uveitis presents either as acute recurrent anterior uveitis with ocular hypertension consistent with Posner Schlossman syndrome (PSS), or chronic anterior uveitis consistent with Fuchs heterochromic iridocyclitis (FHI). Their keratic precipitates differ, but both groups may develop stromal iris atrophy, cataracts and glaucoma. CMV positive and negative PSS eyes are clinically indistinguishable. CMV positive FHI eyes are more likely to be male, >57years at diagnosis, with nodular corneal endothelial lesions. Systemic valganciclovir produces short term benefit.

Viral induced posterior Uveitis
Significant quantities of information regarding the pathogenesis and behaviour of cytomegalovirus retinitis and necrotizing herpetic retinitis have accumulated during the last 25 years, in part because of the explosion of CMV retinitis in HIV-infected patients in the 1990s. Knowledge is evolving of non-classical infections such as Epstein-Barr virus associated retinitis, non-necrotizing herpetic retinal vasculitis, and occlusive CMV infection in the immunocompetent and invoke the interplay between infection and inflammation in creating clinical features of disease.

Uveitis: Autoimmunity and Infection
A number of theories have been proposed to explain the potential link between infection and the development of an autoimmune disease. This link is less well explored with regard to ocular immune diseases; nevertheless there is evidence to support the concept that certain infections may trigger autoimmune eye disease and uveitis. This is exemplified by studies in Multiple Sclerosis, Behçet's syndrome and acute anterior uveitis, for example where there is data to support the concept that microbial infection may lead to the development of uveitis. The immunopathogenesis of infection-triggered autoimmunity can be divided into several groups including: cross reactive immune response due to molecular mimicry and peptide spreading, altered antigenic epitopes or antigen presentation, immune complex induced inflammation and PAMP induced Toll receptor activation. Understanding the way in which microbial infection may initiate or perpetuate ocular inflammation has implications for the treatment and prevention of these potentially blinding diseases.

Update on Uveitis by Toxoplasmosis
The mechanisms underlying ocular toxoplasmosis and its recurrences are not understood, and we are thus not in a position to prevent these events. New pathophysiological insight in the host-parasite interrelation and local immunoregulatory factors has been gathered from strain typing and cytokine profiling studies. Ongoing experimental research now has begun to apply this knowledge in developing new treatment directions and strategies going far beyond the use of antiparasitic drugs. Further efforts have been made in order to define new parameters for the quantification of a possible treatment effect. A correct diagnosis of the disease and recognition of visual function and recurrence behaviour are prerequisite to estimating its clinical burden and functional consequences, tailoring affected individuals as well as for designing and conducting clinical studies to test treatment strategies.

Ocular Infections Following Solid Organ Transplantation
Failing vital organs is a major indication for solid organ transplantation. A central issue in organ transplantation remains suppression of allograft rejection. Increasingly potent immunosuppressive agents have dramatically reduced the incidence of rejection while increasing the patient's susceptibility to opportunistic infections. Both preemptive and preventive protocols have been established for the prevention of infections following solid organ transplantation.
The main purpose is to present an overview and assess the ocular infections following organ transplantation.
Despite the preventive and preemptive protocols, 10 (5%) of 187 patients with solid organ transplantation developed ocular infections. The most common ocular infections include CMV retinitis, recurrence of toxoplasmic retinochoroiditis, ocular toxoplasmosis and CMV retinitis, endogenous bacterial endophthalmitis, and reactivation of M. tuberculosis chorioretinitis.
Following solid organ transplantation, ocular infections occurred in 5% of the patients. The sources of infection were donor, recipient, nosocomial or community acquired. A thin line is maintained between immunosuppression and the potential opportunistic ocular infections. Patients undergoing solid organ transplantation should have ophthalmologic examination at 1 month, 6 months and two years following transplantation.

Problems with Uveitis in Developing Countries
Uveitis includes a large group of diverse inflammatory diseases; the causes vary considerably by geographic location around the world depending upon the population studied. Infectious uveitis accounted for 11.9% to 50% of cases in different countries of developing world while it was relatively a minority of cases in developed world. This could probably due to environmental factors such as tropical climate, prevailing pathogens, availability of the vectors and reservoir hosts and host factors including racial, nutritional and socioeconomic variations. The most common infectious forms of uveitis seen in developing countries include onchocerciasis, toxoplasmosis, herpetic uveitis, tuberculosis, leprosy, leptospirosis and other parasitic diseases. In a study from south India, infectious uveitis accounted for nearly one-third of all cases of uveitis and included leptospiral uveitis, tuberculous uveitis, and herpetic anterior uveitis. Lack of screening programs, socioeconomic constraints, and non availability of laboratory facilities in many ophthalmic set up further challenges the uveitis work up and treatment.

Inflammatory pathways in the aging retina and in age-related retinal degeneration
Inflammation is involved in the pathogenesis of age-related macular degeneration (AMD). The precise inflammatory pathways involved remain to be clarified. Using microarray technique, we have identified a number of genes that are involved in retinal aging. Among them 24 genes are involved in various inflammatory pathways, including the complement activation pathway, cytokine/chemokine secretion pathway and phagocytosis pathway. Further immunohistology study revealed age-dependent complement activation at the retina/choroidal interface and subretinal microglia migration/activation. Our results suggest that under normal physiological conditions, a number of inflammatory pathways are involved in retinal aging and may be important for retinal homeostasis. Dysregulation of the inflammatory pathways is likely to contribute to the pathogenesis of AMD.

Complement, complement regulators and eye disease.
The recent demonstration that a common polymorphism in the gene encoding the complement regulator factor H is a risk factor for AMD has ignited an explosion of interest in the relevance of this unfashionable arm of innate immunity to diverse eye diseases. The growing body of evidence implicating complement and its regulation in eye diseases makes a persuasive case for exploring the use of anti-complement therapies.

The molecular Link between oxidative Damage and Inflammation in age-related macular Degeneration
Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). To test the hypothesis that an oxidation fragment of docosanexaenoic acid (DHA) found adducted to proteins present in drusen and plasma of AMD patients is involved in the AMD inflammatory response we immunized C57BL/6J mice with mouse serum albumin adducted with carboxyethylpyrrole (CEP), a unique hapten that can only be derived from DHA. Immunized mice develop antibodies to CEP, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, show decreased a- and b-wave amplitudes in response to light, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD.
We hypothesize that these CEP-immunized mice are sensitized to the ongoing generation of CEP-adducts in the outer retina, where DHA is abundant and the conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD as well as animal model that can be used to test therapeutics designed to prevent oxidative damage or slow the immune systems response to this outer retina inflammatory signal.

Molecular Pathology of AMD: CFH, CX3CR1, and "Epitheliitis"
AMD is a complex disease triggered by environmental factors in genetically predisposed individuals. AMD pathology illustrates degeneration of photoreceptors, RPE, Bruch's membrane, and choroidal capillaries in the macula. Macrophages and microglia were found in the AMD lesions of archived sections, which suggest a mild inflammation in RPE ('epitheliitis'). The frequencies of the CFH or CX3CR1 risk allele were higher in AMD (77% or 28%) than non-AMD (38% or 11%, respectively) eyes. CX3CR1 expression was lower in the AMD macula. Molecular pathology validates the association between CX3CR1 or CFH and AMD. These risk alleles might link to 'epitheliitis' and AMD development.

The Comparison of AMD Treatments Trial (CATT): Lucentis - Avastin Trial
To evaluate the relative efficacy and safety of treating neovascular AMD with Lucentis on a fixed schedule, Avastin on a fixed schedule, Lucentis on a variable schedule, and Avastin on a variable schedule.
Eligible patients must have an eye with a choroidal neovascularization secondary to age-related macular degeneration and visual acuity 20/25 to 20/320. Patients will be assigned by randomization to one of four treatment groups: Lucentis or Avastin on either a fixed (every 28 days) or variable (re-treatment based on signs of lesion activity) schedule. A total of 1200 patients will be recruited. The primary outcome measure for comparison of the treatment groups is the mean change in visual acuity score. Secondary outcomes include number of treatments, change in subretinal and intraretinal fluid on OCT, change in lesion size on fluorescein angiography, incidence of side effects, and cost.
During the first year of funding, extensive work with CMS prompted the Revised Medicare Clinical Trial Policy. Patient enrollment of the trial began in February, 2008. An update of the current status will be presented. Obstacles encountered in designing and orchestrating support will be discussed.

Decrease of Behçet's Disease in Japan
Behçet's disease used to be the most frequent etiology of uveitis and intraocular inflammation in Japan. However, it seems to be decreasing in recent years. Our study showed that sarcoidosis was the most frequent cause of uveitis and intraocular inflammation in Japan, followed by Vogt-Koyanagi-Harada disease and Behçet's disease. Sarcoidosis was gradually increasing and Vogt-Koyanagi-Harada disease showed almost no change. However, frequency of Behçet's disease was shown to be constantly decreasing in Japan. The exact cause of this change is unknown, and further epidemiological studies are needed to clarify this.

Recent Progress in understanding the etiopathogenesis of Behçet's Disease
Behçet's disease is characterized by recurrent and self-limited inflammatory attacks affecting mucocutaneous tissues, eyes, joints, blood vessels, lungs and central nervous system. Enhanced or dysregulated inflammatory response mainly in innate immune system can be triggered by various environmental or endogenous stimuli, and a perivascular mixed cellular infiltrate with a thrombotic tendency has been regarded as the main pathological finding in BD lesions. Etiopathogenesis of BD is yet unknown. However, many findings support a strong role for genetic factors in the disease pathogenesis. Association of HLA-B51 with BD has been known for 35 years, without any clues about its functional significance. HLA-B51 molecules have probably several different mechanisms of action. Recent studies suggest that one of the possible mechanisms may be its interaction with KIR3DL1 receptors, which are expressed on NK cells, CD8+ cells and ??T cells. On the other hand, whole genome linkage analysis suggests that there may be several other genetic variations other than HLA-B51 contributing to BD susceptibility. We do expect that new genetic analysis methods will result in the identification of novel genetic associations, which may enable us to further our understanding of the disease pathogenesis as well as to develop better diagnostic and therapeutic approaches for BD.

What is Behçet's Disease? Could we diagnose the disease in the absence of extraocular manifestations?
The diagnosis of Behçet disease is based on a combination of clinical findings. Ocular lesions defined in the current sets of diagnostic or classification criteria are nonspecific. Behçet uveitis is a distinct entity that can be differentiated from other uveitic entities. It is important to recognize characteristic features of Behçet uveitis because there are patients with Behçet disease but other forms of uveitis by coincidence, and patients with typical ocular involvement but without systemic manifestations of the disease. Pathognomonic ocular findings will be outlined that may help the diagnosis of Behçet uveitis in patients without systemic manifestations.

Management of Behçet Uveitis
During the last decade, major progress has been achieved to control ocular inflammation in nearly all presentations of the disease, whatever their severity. It can be difficult to predict the course in an individual patient. There is no definitive cure for BD and the aims of treatment are to prevent irreversible damage, which mostly occurs early during the course of disease, especially in high risk populations such as young men.
The use of conventional immunosuppressives such as azathioprine or cyclosporine A in combination with corticosteroids was the gold standard for the management of BD. More recently, large case series have shown the efficacy of immunomodulatory agents such as interferon alpha and/or anti-TNF alpha agents.
Recently, the European League Against Rheumatism (EULAR) commissioned a task force to prepare recommendations for the management of BD. Two recommendations were adopted for patients with ocular involvement:
* Azathioprine and corticosteroids are proposed in all patients with posterior segment involvement (category of evidence : Ib)
* In all severe cases of uveitis, it is recommended that either cyclosporine A or infliximab be used in combination with azathioprine and corticosteroids; alternatively interferon-alpha with or without corticosteroids could be used (Ib/IIb).
Like all recommendations, they have to be validated in different countries and different settings, taking patient preferences also into consideration, and they have to be expanded and updated as new treatment modalities are developed.
Management of BD has been dramatically improved due to new therapeutic strategies. However, the importance of prospective RCTs in the evaluation of the management options of Behçet's disease should be emphasized.

Progress in the Nomenclature of ocular sarcoidosis
Sarcoidosis is a preponderant condition among uveitis entities throughout most of the world. It can occur as a systemic disease including the eye but it can also exclusively involve the eye. In the latter situation, diagnosis is difficult as no criteria exist so far for such an isolated intraocular involvement. In order to propose diagnostic criteria for intraocular disease, an International workshop on ocular sarcoidosis (IWOS) convened in Tokyo end of 2006. The result of the Tokyo concensus workshop will be presented by the organizer of the workshop putting forward criteria susceptible to help establishing the diagnosis of ocular sarcoidosis.

Diagnosis and assessment of choroidal inflammation using appropriate investigational technology
The choroidal space was not readily acccessible to imaging in the same fashion as the superficial fundus structures were visualized. Therefore choroiditis entities were lumped together by descriptive terms such as "white dot syndromes", a potpourri of choroidal (and non choroidal) conditions becoming apparent once choroidal inflammatory reaction was visible to fundus examination. Inflammatory mechanisms could only be understood with the help of imaging methods giving direct access to the choroidal stroma and the choriocapillaris. Indocyanine green angiography (ICGA) allowed to explore choroidal inflammation before it is accessible to conventional fundus examination by spill-over mechanism. Thanks to this technology it became possible to determine at least two inflammatory mechanisms involving the choroid. Either inflammation is prepondeant in the choroidal stroma or the inflammatory mechanism is principally involving the choriocapillaris. By identifying the structure who is primarily touched, ICGA made it possible to classify choroiditis not based on a descriptive all encompassing terminology but on the basis of the the inflammatory mechanism involved. This more appropriate appraisal of choroiditis will be further developed during the symposium.

Non invasive assessment and follow-up of inflammatory activity in Behçet's uveitis using laser flare photometry
More precise and often less invasive investigational methods allow more appropriate assessment and follow-up of uveitis. Laser flare photometry (LFP), established for the assessment of uveitis at the end of last century, is one such technology clearly outweighing traditional slit-lamp methods to measure intraocular inflammation. To date LFP is the only quantitative parameter to measure intraocular inflammation. Because of its exquisite sensitivity, LFP is a very useful modality to monitor inflammatory activity and hence to follow-up uveitis. The application of LFP to Behçet's disease has been explored lately on large series and will be presented during the symposium.

Developments in diagnosing the Tubulointerstitial nephritis and uveitis (TINU) syndrome
Tubulointerstitial nephritis and uveitis (TINU) syndrome is rare even in specialized clinics. Urinary beta-2 microglobulin showed subclinical nephritis in up to 2/3 of pediatric patients with bilateral, sudden onset anterior uveitis. The HLA DRB1*0102 formerly strongly associated to proven TINU syndrome was shown to be present in 12.5% of patients with this uveitis subset. Both tests indicate that TINU is underdiagnosed.

Diagnosis of infectious uveitis caused by emerging agents
To conclude the workshop an update will be given on the numerous emerging infectious agents causing uveitis.

Pathophysiology of Glaucoma in Uveitis
My talk will emphasize that elevated intra-ocular pressure (IOP) appears to be a rising complication of uveitis, and an increasingly difficult management problem. I will mention those uveitis entities that are frequently associated with raised IOP. The mechanisms responsible for IOP rise will be addressed, and using case scenarios I will highlight the difficulty in establishing a precise mechanism of IOP rise and management plan in every patient. Other management issues, including compliance, will also be covered.

Keynote Lecture: Steroid induced Glaucoma
In the normal population a small proportion of patients develop a marked elevation of intraocular pressure (IOP) and glaucoma after long term treatment with corticosteroids ("steroid responder"). Ultrathin sections through the trabecular meshwork of eyes with steroid glaucoma showed an accumulation of extracellular material (ECM) distinct from the "plaques" typical for primary open angle glaucoma (POAG). In vitro trabecular cells respond to steroid treatment with increased expression of ECM components. The high percentage of steroid responder among POAG patients will be discussed.

Prostaglandines in the Therapy of uveitic Glaucoma
Prostaglandin analogues (PAs) are widely used as first or second line drugs to treat primary open angle glaucoma. Prostaglandins, and perhaps ocular hypotensive PAs as well, have pro-inflammatory effects. Secondly, PAs have been reported to increase cystoid macula oedema (CMO) incidence. CMO is a critical complication in uveitis patients, associated with poor outcome. Use of PAs in uveitic glaucoma or IOP rise associated with uveitis is therefore controversial. Current literature however suggests that PAs are potent topical medications for lowering raised IOP in patients with uveitis and are not associated with an increased risk of CMO or anterior uveitis.

Trabeculectomy in Uveitis
Patients who develop refractory glaucoma in association with uveitis are at high risk of significant visual loss and represent a considerable therapeutic challenge. The published results of non-augmented trabeculectomy surgery have typically been less successful than in other types of glaucoma. This talk presents current data on the long-term safety and efficacy of trabeculectomy plus mitomycin C from a combined specialist Glaucoma and Uveitis team. The talk will cover the pre-, intra- and post-operative strategies used to ensure optimal long-term success.

Non perforating deep sclerectomy (NPDS) in uveitis patients
Non perforating deep sclerectomy is a filtering procedure characterized by removal of a deep corneoscleral flap without entering the anterior chamber. Aqueous humour percolates through the thin remaining trabeculo-descemetic window, which acts as a safety valve against hyperfiltration, and hence complications such as profound hypotony, flat anterior chamber and ciliochoroidal detachment are avoided with this technique. The fact that no iridectomy is performed adds to a quiet anterior chamber and lessens the risk of intraoperative hemorrhage. Disadvantages of NPDS include: a steep learning curve; more time consuming than trabeculectomy; postoperative pressures in the high teens; added expense if intrascleral implants are used; limited indications (NPDS is contraindicated in patients with goniosynechiae or shallow anterior chamber); the need for a second procedure (goniopuncture) in a substantial number of patients. The presentation will present the results of NPDS in uveitis patients published in the peer-reviewed literature and discuss the pro's and nos of NPDS versus trabeculectomy for this specific patient group.

Pathophysiology of CME
CME develops commonly in the wake of various ocular disorders affecting the inner and/or outer blood-retina barrier and represents a complication with a final pathway common to all these disorders including uveitis. In the introductory lecture, the new insights in pathogenesis of inflammatory CME will be reviewed and the factors determining the potential visual outcome analyzed.

Clinical Importance of CME
Cystoid macular edema (CME) represents a major cause of visual loss in uveitis. The clinical impact of CME in uveitis is tremendous, especially in those with chronic uveitis. CME is also emerging as a major cause of visual loss in HIV-infected patients with immune recovery uveitis. In older patients, CME develops earlier and has a poor visual prognosis.

Recent diagnostic Methods and their Relevance
The development of new imaging techniques has changed significantly our appraisal of CME. The presentation will expand on the anatomical evaluation of CME by OCT and introduce the three main patterns of CME based on the distribution of fluid within the retina. The discrepancies between the OCT and angiographic findings will also be discussed as well as the imaging characteristics important for future visual outcomes.

CME in Children
The occurrence and impact of CME in children with uveitis was so far not systematically studied and this novel topic will be introduced in this topic.

Classical Treatment of CME
So far, there are no official guidelines for the treatment of uveitic CME and the optimal therapy is not identified. The treatment of CME in uveitis includes both medical and surgical interventions depending upon the fundamental disease process and secondary structural problems in the eye. The goal of medical intervention is to suppress intraocular inflammation thereby reducing vascular permeability, while the goal of surgical intervention is to eliminate retinal traction and remove the vitreous body, the latter of which may serve as a reservoir of inflammatory cytokines. An algorithm for considering these interventions in inflammatory CME will be introduced and discussed.

Biologicals and Octreotide in CME
This presentation will focus on the therapeutic use of biologicals and octreotide for inflammatory CME and his experience with these treatment modalities.

Surgery for CME
This lecture will elucidate the surgical possibilities in the treatment of CME including the role of vitrectomy in the treatment of CME and use of steroid implants and discuss their efficacy and adverse effects.

Diagnostic Criteria of intraocular Tuberculosis
Prevalence of tubercular etiology in various series of uveitis patients varies from 0.5 to 10.5% in tertiary care uveitis centers. The diagnosis of intraocular tuberculosis remains presumptive in majority, in the absence of demonstrable AFB or histopathological evidence. In the absence of any diagnostic criteria, the diagnosis is often missed and patients do not receive anti-tubercular therapy, which is highly effective in reducing recurrences of uveitis. We shall be presenting guidelines, validated on large sample size, to make a presumptive or confirmatory diagnosis of intraocular tuberculosis.

Role of gamma-interferon tests for the management of presumed tuberculous intraocular inflammation
Patients with intraocular inflammation of the posterior segment with a reacting Mantoux represented a therapeutical dilemma in the past. Because these patients needed sustained inflammation suppressive therapy, anti-tuberculous drugs had to be given concomitantly in order to avoid potential reactivation of latent tuberculous foci. The new gamma-interferon inducing tuberculous tests, allowing to differenciate between a BCG vaccination induced or tuberculosis induced positive Mantoux came out as very useful for such situations. By establishing clearly tuberculous exposure, whether latent or still active, these test proved to be very useful in these situations. Use and potential insufficience of these tests will be discussed.

Latent Tuberculosis and Uveitis
The etiology of various ocular inflammatory disorders remains unclear in the Western world, which e.g. in India are often associated with TB. Especially serpiginous chorioretinitis and some types of retinal vasculitis belong to this group. Using quantiferon testing and radiological methods like the FDG-PET/CT scan we now have some good evidence that also in the Western world TB may probably induce such disorders, but from the stage of latent, non-infectious TB. This presentation will give an update about the optimal diagnostics and suggest therapy regimen for such situations.

Pathogenesis of Tuberculous Uveitis
Diverse clinical features of intraocular tuberculosis are in part due to the hematogenous spread of the infectious agent primarily from lung by circulating monocytes harboring the infectious agent and the bacterial load. Expression of Toll like and complement receptors on the monocytes is required for recognition, phagocytosis, and initiation of innate and subsequent T cell mediated immunity. The later immune response is required for development of granulomatous inflammation. The lodgment and reactivation of dormant organisms in the eye appears to be main pathogenic mechanism of the ocular tuberculosis.

Progress in the Nomenclature of ocular sarcoidosis
Sarcoidosis is a preponderant condition among uveitis entities throughout most of the world. It can occur as a systemic disease including the eye but it can also exclusively involve the eye. In the latter situation, diagnosis is difficult as no criteria exist so far for such an isolated intraocular involvement. In order to propose diagnostic criteria for intraocular disease, an International workshop on ocular sarcoidosis (IWOS) convened in Tokyo end of 2006. The result of the Tokyo concensus workshop will be presented by the organizer of the workshop putting forward criteria susceptible to help establishing the diagnosis of ocular sarcoidosis.

Diagnosis and assessment of choroidal inflammation using appropriate investigational technology
The choroidal space was not readily acccessible to imaging in the same fashion as the superficial fundus structures were visualized. Therefore choroiditis entities were lumped together by descriptive terms such as "white dot syndromes", a potpourri of choroidal (and non choroidal) conditions becoming apparent once choroidal inflammatory reaction was visible to fundus examination. Inflammatory mechanisms could only be understood with the help of imaging methods giving direct access to the choroidal stroma and the choriocapillaris. Indocyanine green angiography (ICGA) allowed to explore choroidal inflammation before it is accessible to conventional fundus examination by spill-over mechanism. Thanks to this technology it became possible to determine at least two inflammatory mechanisms involving the choroid. Either inflammation is prepondeant in the choroidal stroma or the inflammatory mechanism is principally involving the choriocapillaris. By identifying the structure who is primarily touched, ICGA made it possible to classify choroiditis not based on a descriptive all encompassing terminology but on the basis of the the inflammatory mechanism involved. This more appropriate appraisal of choroiditis will be further developed during the symposium.

Non invasive assessment and follow-up of inflammatory activity in Behçet's uveitis using laser flare photometry
More precise and often less invasive investigational methods allow more appropriate assessment and follow-up of uveitis. Laser flare photometry LFP), established for the assessment of uveitis at the end of last century, is one such technology clearly outweighing traditional slit-lamp methods to measure intraocular inflammation. To date LFP is the only quantitative parameter to measure intraocular inflammation. Because of its exquisite sensitivity, LFP is a very useful modality to monitor inflammatory activity and hence to follow-up uveitis. The application of LFP to Behçet's disease has been explored lately on large series and will be presented during the symposium.

Role of gamma-interferon tests for the management of presumed tuberculous intraocular inflammation
Patients with intraocular inflammation of the posterior segment with a reacting Mantoux represented a therapeutical dilemma in the past. Because these patients needed sustained inflammation suppressive therapy, anti-tuberculous drugs had to be given concomitantly in order to avoid potential reactivation of latent tuberculous foci. The new gamma-interferon inducing tuberculous tests, allowing to differenciate between a BCG vaccination induced or tuberculosis induced positive Mantoux came out as very useful for such situations. By establishing clearly tuberculous exposure, whether latent or still active, these test proved to be very useful in these situations. Use and potential insufficience of these tests will be discussed.

Diagnosis of infectious uveitis caused by emerging agents
To conclude the workshop an update will be given on the numerous emerging infectious agents causing uveitis.

Risks of local and systemic therapy of uveitis
Risks of systemic immunosuppressive therapy for uveitis are only partially quantified. Systematic review of patient records spanning several years from large uveitis programs provides estimates of risk that can be used to counsel patients and to compare with risks of ocular interventions to treat uveitis. A large randomized, controlled clinical trial comparing oral therapy to implanted intraocular corticosteroids will provide data regarding the relative merits of a specific type of local therapy versus what is accepted as conventional systemic treatment for intermediate, posterior, and panuveitis.

Histologic predictors of local response
Knowledge of the different infiltrating cell types and predominant anatomic sites of inflammation in different types of uveitis provides a data-supported framework to design optimal strategies for local delivery of disease-modifying drugs to the eye. Drug delivery can be optimized by transcorneal, transcleral, intraocular, or systemic delivery. Drug targeting can be optimized by selecting inhibitors of cytokines (TNF-alpha, interleukin 1) or cell types (CD4+ T-lymphocytes, CD8+ T lymphocytes, macrophages). Presentation of the known histologic features of anterior, intermediate, posterior, and panuveitis will provide a framework for drug selection now and drug development in the future.

Pharmacologic predictors of local response
Review of current immunosuppressive medications helps predict which might be useful for local delivery. Antigen-specific T cells are primed and expanded before entry into the eye and interference with antigen presentation or CD80-CD28 binding intraocularly is likely to be ineffective. Strategies based on complement, cytokines, signaling, and blood ocular barrier function are more likely to be successful. Methotrexate, infliximab, alefacept, and interferon hold promise whereas azathioprine, mycophenolate, leflunomide, cyclosporine, cyclophosphamide, and abatacept have theoretical or practical impediments to intraocular use.

Local therapy for uveitic complications
Strategies to control local uveitic complications such as steroid-induced glaucoma, cystoid macular edema, choroidal neovascularization, retinal and neural degeneration, and preretinal fibrosis would benefit patients by controlling the local ocular events that damage the visual apparatus independent of the degree of uveitic activity. Anti-inflammatory, anti-neoplastic, and anti-proliferative immunosuppressive drugs such as sirolimus may play dual roles in posterior uveitis prone to choroidal neovascularization. Drugs developed for macular degeneration that act on the complement system may be ideal to curtail secondary complications from excess inflammation.

Innovations: Topical TNF inhibitor
Innovations in local therapy for uveitis are rare in this time. The most interesting drug is called ESBA105. This is a topically applicable TNF-alpha inhibitor with a unique local biodistribution pattern. Extensive preclinical experiments in rabbits strongly suggest that this antibody fragment easily reaches therapeutic levels in both the anterior and posterior segment upon eye drop administration. As the potency of ESBA105 is very similar to marketed, systemically applied TNF-alpha inhibitors, it is anticipated that this inhibitor has high potential for treatment of uveitis and other inflammatory ocular conditions. ESBA105 is currently in phase I clinical development.