Update of the evidence based, interdisciplinary guideline for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

BACKGROUND: Uveitis in juvenile idiopathic arthritis (JIAU) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first line therapy, and disease modifying anti-rheumatic drugs (DMARDs) are commonly used. However, treatment has not been standardized. METHODS: Interdisciplinary guideline were developed with representatives from the German Ophthalmological Society, Society for Paediatric Rheumatology, Professional Association of Ophthalmologists, German Society for Rheumatology, parents' group, moderated by the Association of the Scientific Medical Societies in Germany. A systematic literature analysis in MEDLINE was performed, evidence and recommendations were graded, an algorithm for anti-inflammatory treatment and final statements were discussed in a consensus meeting (Nominal Group Technique), a preliminary draft was fine-tuned and discussed thereafter by all participants (Delphi procedure). RESULTS: Consensus was reached on recommendations, including a standardized treatment strategy according to uveitis severity in the individual patient. Thus, methotrexate shall be introduced for uveitis not responding to low-dose (≤ 2 applications/day) topical corticosteroids, and a TNFalpha antibody (preferably adalimumab) used, if uveitis inactivity is not achieved. In very severe active uveitis with uveitis-related deterioration of vision, systemic corticosteroids should be considered for bridging until DMARDs take effect. If TNFalpha antibodies fail to take effect or lose effect, another biological should be selected (tocilizumab, abatacept or rituximab). De-escalation of DMARDs should be preceded by a period of  ≥ 2 years of uveitis inactivity. CONCLUSIONS: An interdisciplinary, evidence-based treatment guideline for JIAU is presented.

[Management of anticoagulants in ophthalmic surgery-a survey among ophthalmic surgeons in Germany]. / Umgang mit gerinnungshemmenden Substanzen in der Ophthalmochirurgie ­ eine Umfrage unter Ophthalmochirurgen in Deutschland.

INTRODUCTION: As our population ages and comorbidities rise, ophthalmic surgeons are increasingly faced with patients on anticoagulant therapy or with clotting disorders. The ophthalmic surgeon has to weigh the perioperative risk of haemorrhage when anticoagulation continues against the risk of thromboembolism caused by discontinuation or changing the patient's medication (bridging, switching, cessation). There are currently no guidelines or recommendations. METHODS: A survey was sent to the DOG (German Ophthalmologic Society) divisions and associated surgical organizations to determine the status quo. A questionnaire was sent out and filled out by the different groups of specialists. RESULTS: All four divisions of the DOG and four associated organizations returned completed questionnaires. Surgical interventions were listed that are carried out during anticoagulant therapy without exceptions, as well as interventions that were classified to require medical adjustment. Although the assessments varied, general consensus was achieved regarding interventions not requiring adjustments due to anticoagulants (i. e., intravitreal injection, cataract surgery, laser and corneal operations, simple muscle surgery), and those interventions requiring adjustments in medications (glaucoma operations, complex retina surgery, eye socket surgery, complex surgery of the lid). CONCLUSION: Main result of this survey was the specification of serious bleeding complications which are permanent vision loss and re-operation. They could serve as endpoint parameters for essential future investigations. Nevertheless, this survey makes clear that the decision about an adjustment of anticoagulant medication in ophthalmic surgery is currently made individually and not based on established standards.

[Differential diagnosis of anterior uveitis]. / Differenzialdiagnose der anterioren intraokularen Entzündung.

Anterior uveitis is a potentially sight-threatening disease, which affects either one or both eyes. Although the etiology is not fully understood, important associations with systemic diseases and infections have been established. A thorough clinical investigation with the slit lamp may reveal important findings leading to diagnosis and therapy. Additional diagnostic procedures are usually required only with the occurrence of relapses. Most anterior uveitis cases with an underlying autoimmune etiology respond very well to topical steroids and mydriasis while systemic treatment is rarely needed. In contrast, infectious causes typically require systemic medication. Anterior uveitis has a good prognosis if treated adequately despite some complications like cataract, macular edema, or increase of intraocular pressure, which cannot be prevented in all cases.

Fate of late complications in type I diabetic patients after successful pancreas-kidney transplantation.

The success rate of pancreas transplantation allows us to study in more detail the potential beneficial effects of normoglycemia on secondary complications in diabetes mellitus. We report a prospective follow-up (mean 26 mo) of metabolic control, neuropathy, retinopathy, and peripheral microcirculation in 31 patients with type I (insulin-dependent) diabetes (mean age 33 +/- 1 yr; mean duration of diabetes 21 +/- 1 yr) after combined kidney and segmental pancreas grafting. All patients had normal HbA1 levels. Glucose tolerance (GT), insulin, C-peptide, and glucagon were normal in 22 patients, and impaired oral GT with reduced insulin secretory capacity was seen in 9 patients. During follow-up, there was no deterioration of GT and insulin release. Vascular risk factors, e.g., hypertension, cholesterol, and triglycerides, decreased after grafting. Autonomic neuropathy improved clinically, and R-R variation increased significantly in 3 of 18 patients. Peripheral neuropathy improved clinically in 46% of patients and did not deteriorate in the others. Motor nerve conduction velocity increased greater than 20% in 8, less than 20% in 12, and was unchanged in 8 of 28 recipients. Most of the patients (n = 30) had pretransplant laser treatment of their advanced retinopathy. Posttransplant visual acuity improved at least more than one line in 56%, stabilized in 32%, and deteriorated in 12% of patients. Patients with functioning grafts for greater than 1 yr had no further deterioration of visual acuity. Vitreous hemorrhage frequency and severity dropped markedly from pretransplant (from 69 to 24%) 10 mo after grafting. Retinal morphology remained stable in all eyes except two.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cystoid macular edema in uveitis]. / Zystoides Makulaödem bei Uveitis.

Cystoid macular edema (CME) is the most frequent cause of visual deterioration in uveitis patients. Intraocular inflammation disturbs the blood-retina barrier and leads to retinal edema. The basis of successful treatment is the anti-inflammatory and immunosuppressive therapy of uveitis. Restoration of the blood-retina barrier is mediated by corticosteroids and nonsteroidal anti-inflammatory agents. Resorption of extracellular fluid is improved by systemic carboanhydrase inhibitors. Despite aggressive therapy loss of visual acuity is frequent. Therefore, early diagnosis of CME and initiation of treatment, even if visual acuity is not yet impeded, is mandatory.

Immune responses to retinal autoantigens and peptides in equine recurrent uveitis.

PURPOSE: To test the hypothesis that autoimmune mechanisms are involved in horses in which equine recurrent uveitis (ERU) develops spontaneously. METHODS: Material obtained from horses treated for spontaneous disease by therapeutic routine vitrectomy was analyzed for total IgG content and IgG specific for S-Antigen (S-Ag) and interphotoreceptor retinoid-binding protein (IRBP). The cellular infiltrate of the vitreous was analyzed by differential counts of cytospin preparations and flow cytometry using equine lymphocyte-specific antibodies. Antigen-specific proliferation assays were performed comparing peripheral blood lymphocytes (PBLs) with vitreal lymphocytes by stimulation with S-Ag and several S-Ag- and IRBP-derived peptides. RESULTS: The total IgG content of specimens from horses with ERU was very high with great variability among the investigated samples (11.5 +/- 8.0 mg). Autoantibodies to S-Ag or IRBP or both were found in 72% of vitreous specimens from horses with uveitis. The leukocyte infiltrates (up to 2 x 10(8) cells per sample) were dominated by lymphocytes (>90%) in most cases (22/32). Flow cytometry showed that more than 50% of these cells were CD4(+) T cells. In vitro stimulation of vitreal lymphocytes, but not of PBL, showed a strong proliferative response to peptides derived from S-Ag or IRBP in 9 of 12 patients. CONCLUSIONS: In the eyes of horses with ERU, IgG antibodies and autoreactive T cells specific for retinal antigens were detected. These results strongly support the hypothesis that ERU is an autoimmune-mediated disease and is highly similar to recurrent uveitis in humans in both clinical and immunologic parameters.

Ocular inflammation stimulated by intravitreal interleukin-8 and interleukin-1.

Interleukin-8 (IL-8), a cytokine with neutrophil chemotactic and activating properties, is known to be stimulated by IL-1. Fischer rats are more resistant to inflammation than Lewis rats probably due to a higher corticosteroid stress response. To determine the role of IL-8 in ocular inflammation, the effect of intravitreal injection of IL-8 was compared with that of IL-1 in both Lewis and Fischer rats. The IL-8, IL-1 alpha, or sterile balanced salt solution (control) was injected into one eye of each animal. Both IL-8 and IL-1 alpha caused inflammation in the eye of both strains, as detected by leukocyte counts of the anterior chamber and histopathologic examination. The eyes of animals injected with a cytokine had significantly higher numbers of leukocytes compared with eyes of control animals. Histopathologic examination confirmed these findings. The IL-1 alpha induced inflammation more consistently and more severely than the most effective dose of IL-8. This finding agreed with the concept of IL-1 initiating a cascade of inflammatory mediators including IL-8, which acts more specifically on a smaller population of leukocytes. A contralateral response was observed in the uninjected eye of experimental and control animals. The contralateral response in animals receiving the cytokines was significantly greater than that in controls. Lewis rats show a higher inflammatory response to the injections than do the Fischer rats. These data suggest that IL-8 may be active as one component in neutrophil-mediated ocular inflammation.

Molecular mimicry as a therapeutic approach for an autoimmune disease: oral treatment of uveitis-patients with an MHC-peptide crossreactive with autoantigen--first results.

In the rat model of experimental autoimmune uveitis (EAU) we have demonstrated that a peptide from the sequence of human disease-associated MHC-class I antigens can induce uveitis upon immunization. Moreover, oral administration of this MHC-peptide tolerized Lewis rats to the disease induced with two different retinal autoantigens, retinal S-antigen (S-Ag) and IRBP. In uveitis patients T cells responding to S-Ag peptide also respond to the MHC-peptide, which shows crossreactivity with the major epitope from S-Ag due to some shared discontinuous amino acid homologies. The 14-mer peptide B27PD is derived from the sequence of all HLA-B antigens that are statistically associated with uveitis (including HLA-B27). Patients with long-lasting endogenous uveitis, suffering from side effects of conventional immuno-suppressive therapy or being therapy-refractive, were orally tolerized with peptide B27PD in this first open therapeutic trial. Patients received peptide three times a week over a 12 weeks period, while only low dose steroids were allowed as concomitant medication. The aims were (1) to investigate whether immunosuppressive therapy could be discontinued and steroids reduced while relapses of ocular inflammation reside and (2) to search for side effects. The Helsinki Declaration was strictly observed and the study design approved by the local ethical committee. The first patients orally tolerized with the HLA-peptide (two had stopped azathioprine immediately prior to onset of oral peptide treatment) could discontinue their steroids because of reduced intraocular inflammation. No side effects of therapy were observed. Oral tolerance induction with a peptide derived from the patients' own HLA-antigens and crossreactive with the organ-specific autoantigen seems to be a potent therapeutic approach.

Oral tolerance with an HLA-peptide mimicking retinal autoantigen as a treatment of autoimmune uveitis.

Endogenous uveitis is a T cell mediated autoimmune disease leading to impairment of visual acuity. The association of different uveitis entities with HLA-class I antigens and the discovery of antigenic mimicry between a peptide of uveitis-associated HLA-class I antigens and a peptide of retinal autoantigen led to a new hypothesis for the pathogenesis of uveitis. On the basis of this mechanism an open trial of oral tolerance induction with the HLA-peptide B27PD was initiated for nine patients with long lasting, therapy-refractive uveitis. Within 6 weeks of oral peptide treatment all patients responded with a marked decrease of intraocular inflammation, which allowed a reduction of systemic corticosteroids in seven patients. One patient, who suffered from an acute relapse, responded within 2 weeks, followed by an increase of visual acuity. In addition, two patients discontinued azathioprine immediately prior to oral tolerance induction without the occurrence of relapses. Visual acuity remained unchanged or increased in 14 of 16 eyes. One patient did not finish oral peptide treatment. None of these patients experienced any adverse events. It was concluded that the oral application of highly tolerogenic peptides might be a potent approach for the treatment of autoimmune diseases.

Trials of vaccination against experimental autoimmune uveoretinitis with a T-cell receptor peptide.

T lymphocytes which mediate several experimental autoimmune diseases, including encephalomyelitis (EAE) and uveoretinitis (EAU) in Lewis rats, preferentially utilize V beta 8 gene product in their receptor. Vaccination against a V beta 8.2-derived peptide was reported to inhibit EAE induction and we report here on the effect of vaccination with this peptide on the development of EAU. Experimental rats were pretreated with the V beta 8.2 peptide, emulsified in adjuvant (CFA), whereas control animals were untreated or injected with saline in CFA. Rats of all groups were immunized 30 or 40 days later with the immunopathogenic antigen, emulsified in Mycobacterium-enriched CFA. Vaccination with CFA emulsions containing either the V beta 8.2 peptide or saline, remarkably inhibited the development of the tested diseases, as compared to the untreated controls. Vaccination with the V beta 8.2 peptide had variable effects in this study on disease development: it inhibited the S-antigen-induced EAU more than did treatment with CFA in four out of six experiments, had a similar effect to that of CFA in one experiment and enhanced the disease in another experiment. Conversely, vaccination with the V beta 8.2 peptide slightly enhanced the EAU induced by the interphotoreceptor retinoid-binding protein (IRBP), or its dominant determinant, in three of four experiments and had no apparent effect in the fourth experiment. In addition, we could not reproduce the reported protective effect of vaccination with the V beta 8.2 peptide against induction of EAE. Vaccination with the V beta 8.2 peptide also had no clear effect on the development of humoral or cellular immune responses against S-antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Endotoxin-induced production of inflammatory mediators by cultured ciliary epithelial cells.

Systemic injection of bacterial endotoxin (Lipopolysaccharide, LPS) in experimental animals induces anterior uveitis without major pathological changes in other organs. The present study investigates the effect of LPS on production of inflammatory mediators in cultured bovine pigmented ciliary epithelial cells (CB-cells) by means of radioimmunoassays and bioassays. LPS was found to stimulate CB-cells to secrete prostaglandin E2 and prostacyclin (assayed as its stable metabolite 6-keto-prostaglandin F1a), but not leukotriene B4 or thromboxane A2 (assayed as its stable metabolite thromboxane B2). CB-cells produced membrane-associated interleukin 1-activity in response to LPS, but no tumor necrosis factor-activity was found after challenge of CB-cells with LPS. The direct effect of LPS on production of inflammatory mediators by cells from the anterior uvea could play a role in the pathophysiology of endotoxin-induced uveitis.

[Practical advice for recovery and successful processing of anterior chamber puncture and vitrectomy samples]. / Praktische Hinweise zur Gewinnung und erfolgreichen Aufbereitung von Vorderkammerpunktat und Vitrektomiematerial.

For the diagnosis of unclear intraocular inflammation which threatens visual acuity and does not respond to therapy, the collection of intraocular fluid from the anterior chamber or the vitreous body is sometimes required. After surgery the correct and speedy processing of the rapidly degrading fluid determines the quality and reliability of the laboratory results. This article describes the different steps which are important after surgery to ensure optimal results for the different diagnostic laboratory procedures. If specimens are to be sent to cytology or microbiology laboratories, processing directly after surgery is necessary, while material which has to undergo PCR analysis, should remain untreated.

[Does combined pancreas-kidney transplantation modify diabetic retinopathy in type-1 diabetic patients?]. / Beeinflusst die kombinierte Pankreas-Nieren-Transplantation die diabetische Retinopathie bei Typ-1-Diabetikern?

The study group consisted of 30 patients with a functioning pancreas graft of at least 12 months. Fifty-seven eyes were examined; 26 eyes from 15 patients with a non-functioning pancreas graft made up the control group. Three patients were in both groups because their graft was rejected after a 12-month period. The mean age in the study group was 37 years, the mean observation time 38 months. The mean duration of diabetes before transplantation was 24 years and all patients were on kidney dialysis. Retinal coagulation for diabetic retinopathy had previously been performed in 80.7% of the patients. The mean age (38 years), observation time (36 months), duration of diabetes before transplantation (24 years), and incidence of retinal coagulation (84.6%) were comparable in the control group. All patients had regular ophthalmological examinations every 6 to 12 months. This included best-corrected visual acuity, applanation tonometry, slit-lamp examination and dilated binocular funduscopy. Seven 30 degrees fundus pictures of the posterior pole were taken: The images were graded by comparing them with the ETDRS (Early Treatment Diabetic Retinopathy Study) Group standard photographs. The original Airlie House grading scale was changed because we did not take stereoscopic pictures. Evaluation and grading were done independently by two examiners. The retinopathy score was graded from 0 (no retinopathy) to 11 (no evaluation possible due to opaque media). Visual acuity remained stable in both the study and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

[Allergic conditions of the eye]. / Allergische Erkrankungen des Auges. Wann ist die Sehkraft in Gefahr?

In the doctor's office, seasonal and non-seasonal conjunctivitis must be differentiated from more serious conditions. These include vernal conjunctivitis which, when chronic, represents a risk for corneal complications. In atopic keratoconjunctivitis, too, which manifests in every fourth patient with atopic dermatitis, the patient's vision is in danger. Furthermore, wearers of contact lenses may develop characteristic conjunctival changes or a contact allergy triggered by lens cleansing fluid. When the diagnosis has been established, treatment with local or systemic antihistaminics, H1 blockers or mast cell stabilizers can be initiated. In contrast, the indication for glucocorticoids should be established only by an ophthalmogist.

[Wide-field fundus autofluorescence in non-infectious posterior uveitis]. / Weitwinkelfundusautofluoreszenz bei nichtinfektiöser Uveitis posterior.

BACKGROUND: Posterior uveitis comprises a heterogeneous group of diseases with inflammatory alterations of the posterior fundus and is a common cause of visual impairment and blindness. The goal of this study was to evaluate the diagnostic value of wide-field fundus autofluorescence (FAF) in patients with non-infectious posterior uveitis and chorioretinal alterations. MATERIAL AND METHODS: In this study 73 eyes from 51 patients were included. Best-corrected visual acuity, wide-field color and FAF images achieved by a wide-field scanning laser opththalmoscope (SLO, Optomap P200Tx, Optos PLC, Dunfermline UK) and a full ophthalmological examination were obtained from each patient. A systematic analysis of chorioretinal alterations detected with FAF and color images was conducted followed by the evaluation of the diagnostic information of wide-field FAF compared to the clinical finding and wide-field color images. RESULTS: Of the 73 eyes included in the study 52 showed peripheral alterations. In 32 cases wide-field FAF images revealed a greater number and more extensive chorioretinal alterations than the corresponding wide-field color images of the posterior fundus. CONCLUSIONS: In this study wide-field FAF images showed more chorioretinal alterations than seen in funduscopy or in color SLO images. Therefore, wide-field FAF images offer important additional information for detection and documentation of peripheral and central chorioretinal alterations.

[Unilateral retinal pseudoarteritis after eyeball contusion]. / Unilaterale retinale pseudoarteritis nach contusio bulbi.

This article reports an unusual case of unilateral frosted branch angiitis. Three major groups of this disease are known: secondary frosted branch angiitis due to viral infection or autoimmune diseases, frosted branch-like angiitis related to malignant diseases and the rare entity of idiopathic frosted branch angiitis. A 58-year-old patient presented with strictly unilateral sheathing and partly occluded retinal arteries, vitritis and macular edema and 4 months prior to presentation he suffered a contusion of the eye with traumatic cataract and vitreous hemorrhage followed by cataract extraction and vitrectomy. The general medical history revealed that the contralateral eye and biochemical analyses were unremarkable despite slightly elevated antinuclear antibody (ANA) levels. Under high dose steroid therapy the patient showed slow improvement in all clinical findings. This case does not fit into any of the known groups and can therefore be defined as pseudoarteritis.

[Recurrent uveitis of unknown origin in childhood]. / Kindliche rezidivierende Uveitis unklarer Genese.

This report describes a 12-year-old girl with diffuse infiltrating retinoblastoma. This inflammatory condition belongs to the uveitis masquerade syndromes, which comprise a group of various ocular diseases such as chronic intraocular inflammation and ocular tumors.