Uwe Pleyer

Understanding uveitis: the impact of research on visual outcomes.

The term uveitis encompasses a very diverse group of inflammatory ocular diseases that cause a significant burden of legal and economic blindness. Indeed, the socioeconomic impact of uveitis is at least as significant as that of diabetic retinopathy and, in the majority of cases, those affected are young individuals of working age. Significant progress has been made in our understanding of the mechanisms underlying the inflammatory process through the use of animal models, but correlation with human disease has proved elusive and many scientific approaches which appear highly effective in animal models prove to be less effective in patients. Nevertheless, effective, targeted treatments are needed in uveitis as current treatment is based on corticosteroids and immunosuppressive drugs whose usefulness is limited by their many side-effects. The aims of this review are to summarize the state of clinical research in uveitis, to identify gaps in our knowledge, and to propose new opportunities and methodologies for future developments in all aspects of uveitis research, including epidemiology, economic impact analysis, diagnosis, therapeutics, and clinical study design. Optimal patient management and efficient drug development depend on validated structured tools, such as those that have helped to drive a rapid acceleration in the means and methods available to assess and treat patients with rheumatoid arthritis and cancer. Uveitis care should witness a similar boom as the issues discussed are resolved.

Ocular toxoplasmosis past, present and new aspects of an old disease

Ocular toxoplasmosis (OT) is considered the most frequent form of infectious posterior uveitis and is caused by the protozoan parasite Toxoplasma gondii. The resulting vision loss frequently incapacitates patients and places a considerable socio-economic burden on societies in particular in developing countries. Although, toxoplasmic retinochoroiditis is a world-wide phenomenon stark regional differences with regard to prevalence and presumably route of infection exist. This review will discuss our current clinical understanding of OT including typical and atypical manifestations, patient characteristics which influence the course of disease and treatment options. Even though, congenital and acquired OT are not regarded as separate entities, certain differences exist, which will be assessed and evaluated in detail. A strong focus is laid on the disease causing parasite T. gondii, since solving the mystery of OT aetiology and the development of improved therapies will not be possibly with clinical science alone, but rather requires a precise understanding of parasitological and immunological pathomechanisms. Additionally, the biology and genetics of T. gondii form the foundation for novel and sophisticated diagnostic methods. Scientific advances in the recent years have shed some light on the different role of T. gondii strains with regard to OT manifestation and severity of disease. Genetic and environmental factors influencing OT will be presented and commonalities between OT and toxoplasmic encephalitis will be briefly discussed. Furthermore, the laboratory tools to study OT are crucial in our understanding of OT. In vivo and in vitro experimental approaches will be summarised and evaluated extensively. Finally, a brief outlook is given in which direction OT research should be headed in the future.

Delayed mustard gas keratopathy: clinical findings and confocal microscopy

PURPOSE To describe the clinical manifestations and confocal microscopic findings in a patient with delayed mustard gas keratopathy. METHOD Case report. A 32-year-old veteran who had participated in the Iran Iraq conflict was exposed to mustard gas in 1988. Ocular abnormalities in 1996 and 1998 and corneal confocal microscopic findings in 1998 are presented. RESULTS In 1996, slit-lamp examination disclosed bilateral limbal changes with tortuous blood vessels and full-thickness corneal alterations. In 1998, the right eye had porcelain-white episcleral changes and adjacent peripheral ulcerative keratopathy. Confocal microscopy demonstrated irregular-appearing epithelial and basal epithelial cells. The anterior stroma was remarkable for spindle-like keratocytes, diffuse fibrillar inhomogeneities and the presence of highly reflective material. CONCLUSIONS Mustard gas keratopathy is a uncommon cause of ocular damage, but it may lead to delayed ocular damage.

Dependence of regulatory volume decrease on transient receptor potential vanilloid 4 (TRPV4) expression in human corneal epithelial cells

TRPV4 is a non-selective cation channel with moderate calcium permeability, which is activated by exposure to hypotonicity. Such a stress induces regulatory volume decrease (RVD) behavior in human corneal epithelial cells (HCEC). We hypothesize that TRPV4 channel mediates RVD in HCEC. Immunohistochemistry revealed centrally and superficially concentrated TRPV4 localization in the corneal tissue. Immunocytochemical and fluorescence activated cell sorter (FACS) analyses identified TRPV4 membrane surface and cytosolic expression. RT-PCR and Western blot analyses identified TRPV4 gene and protein expression in HCEC, respectively. In addition, 4alpha-PDD or a 50% hypotonic medium induced up to threefold transient intracellular Ca2+ ([Ca2+]i) increases. Following TRPV4 siRNA HCEC transfection, its protein expression level declined by 64%, which abrogated these [Ca2+]i transients. Similarly, exposure to either ruthenium red or Ca(2+)-free Ringers solution also eliminated this response. In these transfected cells, RVD declined by 51% whereas in the non-transfected counterpart, ruthenium red and Ca(2+)-free solution inhibited RVD by 54 and 64%, respectively. In contrast, capsazepine, a TRPV1 antagonist, failed to suppress [Ca2+]i transients and RVD. TRPV4 activation contributes to RVD since declines in TRPV4 expression and activity are associated with suppression of this response. In conclusion, there is TRPV4 functional expression in HCEC.

Endophthalmitis prophylaxis in cataract surgery: overview of current practice patterns in 9 European countries.

Data on practice patterns for prophylaxis against infectious postoperative endophthalmitis (IPOE) during cataract surgery in 9 European countries were searched in national registers and reviews of published surveys. Summary reports assessed each nations IPOE rates, nonantibiotic prophylactic routines, topical and intracameral antibiotic use, and coherence to the European Society of Cataract & Refractive Surgeons (ESCRS) 2007 guidelines. Although the reliability and completeness of available data vary between countries, the results show that IPOE rates differ significantly. Asepsis routines with povidone-iodine and postoperative topical antibiotics are generally adopted. Use of preoperative and perioperative topical antibiotics as well as intracameral cefuroxime varies widely between and within countries. Five years after publication of the ESCRS guidelines, there is no consensus on intracameral cefuroxime use. Major obstacles include legal barriers or persisting controversy about the scientific rationale for systematic intracameral cefuroxime use in some countries and, until recently, lack of a commercially available preparation.

Anti-TNF-α Treatment: A Possible Promoter in Endogenous Uveitis? Observational Report on Six Patients: Occurrence of Uveitis Following Etanercept Treatment

Background: TNF-α inhibitory drugs are widely used with beneficial effect in the treatment of rheumatic diseases, such as juvenile idiopathic arthritis and ankylosing spondylitis. Due to the complex immune regulatory function of TNF-α, induction of inflammation in several organs including the eye, skin, and gastrointestinal tract has been reported. This report describes the occurrence of intraocular inflammation after treatment with the TNF-α antagonist etanercept. Methods: In this observational case series, we followed and examined six patients receiving etanercept for juvenile idiopathic arthritis, ankylosing spondylitis, adult Still’s disease, or psoriasis. Result: All patients responded well to their joint affliction, but developed endogenous uveitis for the first time after application of etanercept. Following acute intervention with corticosteroids, etanercept was discontinued and instead an antibody-based anti-TNF treatment using infliximab was instituted. We documented visual acuity before and after change from etanercept to treatment with the anti-TNF-α antibody infliximab. Interestingly, prompt long-term remission (mean 34 months) of uveitis without recurrence could be induced in all patients. Conclusions: Our observations may indicate that immunodysregulatory and even proinflammatory effects of etanercept are of relevance in clinical practice. Further randomized controlled clinical trials are necessary to investigate possible side effects of anti-TNF therapy using etanercept and infliximab.

Detection and Localization of the Hydrophobic Surfactant Proteins B and C in Human Tear Fluid and the Human Lacrimal System

Purpose: To evaluate the expression and presence of the surfactant proteins (SP) B and C in the lacrimal apparatus at the ocular surface and in tear fluid. Methods: Expression of SP-B and SP-C was analyzed by RT-PCR in healthy lacrimal gland, conjunctiva, meibomian gland, accessory lacrimal glands, cornea, and nasolacrimal ducts. The deposition of the hydrophobic proteins SP-B and SP-C was determined by Western blot and immunohistochemistry in healthy tissues, tear fluid, and aqueous humor. Results: The presence of both SP-B and SP-C on mRNA and protein level was evidenced in healthy human lacrimal gland, conjunctiva, cornea, and nasolacrimal ducts. Moreover, both proteins were present in tear fluid but were absent in aqueous humor. Immunohistochemical investigations revealed production of both peptides by acinar epithelial cells of the lacrimal gland and additionally by accessory lacrimal glands of the eyelid as well as epithelial cells of the conjunctiva and nasolacrimal ducts. Immunohistochemically, healthy cornea and goblet cells revealed no reactivity. Conclusions: Besides the recently detected surfactant-associated proteins SP-A and SP-D, our results show that SP-B and SP-C are also peptides of the tear film, the ocular surface, and the lacrimal apparatus. Based on the current knowledge of lowering surface tension in alveolar lung cells, a similar effect of SP-B and SP-C may be assumed concerning the tear film.

Immunomodulatory therapy in ophthalmology - is there a place for topical application?

Topical corticosteroids, although effective in the treatment of ocular immune-mediated diseases, are well known for their ocular side-effects. Not surprisingly, a variety of alternative immunomodulatory agents have been tested for topical use including cyclosporin A (CsA), mycophenolate mofetil (MMF), tacrolimus (FK506), rapamycin (sirolimus) and leflunomide. Local application bears the possibility to avoid the severe side-effects of systemic therapy. The effect of topical therapy is naturally restricted to local immune response mechanisms, such as antigen presentation by Langerhans and dendritic cells. Moreover, many immunomodulatory agents (e.g. CsA) are lipophilic and thus have low water solubility and penetrate insufficiently intra-ocularly, often being stored in the lipophilic corneal epithelial barrier. Therefore, the therapeutical success is limited for intra-ocular immune-mediated diseases like anterior uveitis. However, a multitude of strategies have been introduced to circumvent these problems including complexing substances such as cyclodextrins (CDs) and liposomes. In the prevention and treatment of transplant rejection after keratoplasty, many attempts to introduce topical immunomodulatory therapy have failed; on the other hand, further therapeutic options not primarily expected are being evaluated today such as treatment of severe keratoconjunctivitis sicca. In our own studies, we investigated the pharmacokinetics of topical treatment with different agents including MMF and evaluated the efficacy of topical treatment in animal models for uveitis and keratoplasty. Taken together, topical immunomodulatory therapy will not replace systemic therapy but further treatment options can be expected.

Ocular absorption of cyclosporine A from liposomes incorporated into collagen shields.

We investigated the ability of liposomes to deliver the immunosuppressive agent cyclosporine A (CsA) to the cornea, anterior sclera, aqueous humor, and vitreous in rabbit eyes. One drop (10 microliters) of liposome-encapsulated CsA (CsA-LIP) or olive oil drops containing an equivalent concentration of CsA (CsA-DR) were administered at 15-minute intervals within the first hour and then one hourly over a 6-hour period. In addition, collagen shields soaked for 30 minutes in the liposome preparation (CsA-LIP-CS) were tested in vitro and in vivo as a new drug delivery approach. CsA levels were measured by fluorescence-immunoassay after 1, 3, or 6 hours of drug administration. CsA levels in this study were highest in cornea and anterior sclera. In animals receiving either CsA-DR or CsA-LIP, CsA levels generally increased from 1 to 6 hours. In animals receiving a single application of CsA-CS-LIP, CsA levels peaked at 3 hours and declined at 6 hours in cornea and sclera. CsA-LIP and CsA-CS-LIP delivered significantly higher levels of CsA to the cornea and sclera at 1 and 3 hours than CsA-DR. In aqueous and vitreous humor, CsA levels increased from 1 to 6 hours in animals receiving either CsA-DR or CsA-LIP. On the other hand, animals receiving a single application of CsA-CS-LIP had lower levels of CsA at 6 hours than at the earlier time points. Animals receiving CsA-LIP or CsA-CS-LIP had significantly higher levels of CsA in aqueous and vitreous humor at 1, 3, and 6 hours than animals receiving CsA-DR.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and Safety of Intravenous Secukinumab in Noninfectious Uveitis Requiring Steroid-Sparing Immunosuppressive Therapy

PURPOSE Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibited promising activity in a proof-of-concept study when administered in intravenous (IV) doses to patients with active, chronic, noninfectious uveitis. This study compared the efficacy and safety of different IV and subcutaneous (SC) doses of secukinumab in patients with noninfectious uveitis. DESIGN Multicenter, randomized, double-masked, dose-ranging, phase 2 clinical trial. PARTICIPANTS Thirty-seven patients with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis who required corticosteroid-sparing immunosuppressive therapy. METHODS Patients were randomized to secukinumab 300 mg SC every 2 weeks for 4 doses, secukinumab 10 mg/kg IV every 2 weeks for 4 doses, or secukinumab 30 mg/kg IV every 4 weeks for 2 doses. Intravenous or SC saline was administered to maintain masking. Efficacy was assessed on day 57 (2-4 weeks after last dose). MAIN OUTCOME MEASURES Percentage of patients with treatment response, defined as (1) at least a 2-grade reduction in vitreous haze score or trace or absent vitreous haze in the study eye without an increase in corticosteroid dose and without uveitis worsening or (2) reduction in corticosteroid dosages to prespecified levels without uveitis worsening. Percentage of patients with remission, defined as anterior chamber cell and vitreous haze scores of 0 or 0.5+ in both eyes without corticosteroid therapy or uveitis worsening. RESULTS Secukinumab 30 mg/kg IV and 10 mg/kg IV, compared with the 300 mg SC dose, produced higher responder rates (72.7% and 61.5% vs. 33.3%, respectively) and remission rates (27.3% and 38.5% vs. 16.7%, respectively). Statistical and clinical superiority for the 30 mg/kg IV dose compared with the 300 mg SC dose was established in a Bayesian probability model. Other measures, including time to response onset, change in visual acuity, and change in vitreous haze score, showed numeric trends favoring IV dosing. Secukinumab, administered in IV or SC formulations, appeared safe and was well tolerated. CONCLUSIONS Intravenous secukinumab was effective and well tolerated in noninfectious uveitis requiring systemic corticosteroid-sparing immunosuppressive therapy. Greater activity with IV dosing suggests that patients may not receive sufficient drug with SC administration. High-dose IV secukinumab may be necessary to deliver secukinumab in therapeutic concentrations.