Friederike Mackensen

Uveitis Subtypes in a German Interdisciplinary Uveitis Center—Analysis of 1916 Patients

Objective Studies on the epidemiology of uveitis are rare and cohorts are small. We analyzed the frequencies of classified forms of uveitis in all patients at our center. Methods We studied 1916 consecutive patients with inflammatory eye disease. Data were analyzed regarding associated systemic disease, infection, ocular syndromes, anatomic localization, age, and sex. Results In 59.1% of patients, a classified form of uveitis was observed: associated systemic diseases in 43.7%, the most frequent ones sarcoidosis (17.4%) and ankylosing spondylitis (16.8%); ocular syndromes in 34.3%, the most frequent HLA-B27-positive anterior uveitis (AU; 35.1%) and Fuchs uveitis syndrome (FUS; 34.3%); and infections in 22.4%, the most frequent herpetic infections (46.1%) and toxoplasmosis (31.5%). We found AU in 45.4% of patients (15.4% HLA-B27-positive AU and 11.3% FUS), intermediate uveitis in 22.9% (unclassified 53.7% and multiple sclerosis 10.3%), and posterior uveitis in 13.5% (24.7% toxoplasmosis). Panuveitis was diagnosed in 6.2% of cases (Behçet’s disease 12.6%; sarcoidosis 10.9%). The remaining 12.0% of cases showed extrauveal manifestations (scleritis, episcleritis, keratitis, optic neuritis, myositis, and orbital inflammation). Conclusion We describe the largest cohort to date of consecutive patients from a specialized uveitis center. The high frequency of classified disease, nearly 60% in our clinic, shows the usefulness of an interdisciplinary approach, oriented on anatomic presentation.

Epidemiology and Course of Disease in Childhood Uveitis

PURPOSE To describe the disease characteristics and visual outcome of pediatric uveitis. DESIGN Retrospective, longitudinal observation. PARTICIPANTS Five hundred twenty-seven pediatric uveitis patients from the National Eye Institute, University of Illinois, Chicago, and Oregon Health Sciences University. METHODS Retrospective chart review. MAIN OUTCOME MEASURES Demographics, uveitis disease characteristics, complications, treatments, and visual outcomes were determined at baseline and at 1-, 3-, 5-, and 10-year time points. RESULTS The patient population was 54% female; 62.4% white, 12.5% black, 2.7% Asian, 2.1% multiracial, and 14.61% Hispanic. Median age at diagnosis was 9.4 years. The leading diagnoses were idiopathic uveitis (28.8%), juvenile idiopathic arthritis-associated uveitis (20.9%), and pars planitis (17.1%). Insidious onset (58%) and persistent duration (75.3%) were most common. Anterior uveitis was predominant (44.6%). Complications were frequent, and cystoid macular edema (odds ratio [OR] 2.94; P = 0.006) and hypotony (OR, 4.54; P = 0.026) had the most significant visual impact. Ocular surgery was performed in 18.9% of patients. The prevalence of legal blindness was 9.23% at baseline, 6.52% at 1 year, 3.17% at 3 years, 15.15% at 5 years, and 7.69% at 10 years. Posterior uveitis and panuveitis had more severe vision loss. Hispanic ethnicity was associated with a higher prevalence of infectious uveitis and vision loss at baseline. CONCLUSIONS The rate and spectrum of vision threatening complications of pediatric uveitis are significant. Prospective studies using standard outcome measures and including diverse populations are needed to identify children most at risk.

Intravitreal bevacizumab (avastin) as a treatment for refractory macular edema in patients with uveitis: a pilot study.

Purpose: Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) which has been successfully used for the treatment of age-related macular degeneration with choroidal neovascularization. As VEGF is involved in the pathomechanisms of inflammation and endothelial dysfunction the authors used bevacizumab as a last resort treatment in patients with persistent uveitic cystoid macular edema (CME). Patients and Methods: Persistent uveitic CME was defined by optical coherence tomography (OCT) measurements >250 &mgr;m despite previous treatments. The authors reviewed patients with persistent CME who subsequently had been treated with intravitreous bevacizumab 1.25 or 2.5 mg. Improvement was judged by visual acuity (VA) gain ≥2 lines and thickness reduction in OCT. Results: Eleven eyes of 10 patients were injected since February 2006. Median follow-up was 70 days. Reduction in central retinal thickness could be seen as early as 2 weeks with a mean foveal thickness reduction of 127.2 &mgr;m at 4 weeks. Concurrent improvement in VA was seen in 4 of 10 patients, and was unchanged in the others. Four patients received two injections and five patients received three injections. Except for progression of cataract in one eye no ocular or systemic adverse events were recorded. Conclusions: Intravitreal bevacizumab seems to be an effective and safe treatment in the management of refractory inflammatory CME. The effect is transient, and reinjections may be necessary, although the time until reinjection is needed differs individually.

QuantiFERON TB-Gold—A New Test Strengthening Long-Suspected Tuberculous Involvement in Serpiginous-like Choroiditis

PURPOSE To obtain a diagnosis of tuberculosis in patients with a specific subset of uveitis, serpiginous-like choroiditis. This subset has been suspicious for tuberculous etiology in single case reports and old textbooks. DESIGN Retrospective evaluation of a diagnostic test in a specific uveitis cohort. METHODS QuantiFERON is an approved, antigen-specific test that utilizes synthetic peptides representing Mycobacterium tuberculosis proteins. After incubation, interferon gamma secreted by T lymphocytes in response to these antigens is measured. We used the test in 21 of 26 patients identified from our database with serpiginous-like choroiditis. Rates of QuantiFERON positivity were compared to a group of healthy hospital employees (n = 208), another group of healthy hospital workers after tuberculosis contact (n = 117), and a group of randomly tested patients with other uveitis forms (n = 45). RESULTS Eleven of 21 serpiginous-like choroiditis patients (52%) were tested positive. The rate of QuantiFERON positivity in the healthy control groups was 8.7% and 0.9%, and 13% in the other uveitis subsets. Four of the QuantiFERON-positive serpiginous-like choroiditis patients were treated with standard anti-tuberculostatic therapy; three finished the course and improved. Seven patients are either stable without therapy (n = 4) or on low-dose prednisone (n = 3). CONCLUSIONS QuantiFERON testing revealed a high number of positive patients, which indicates a tuberculous etiology in this uveitis subset. Whether bacterial activity or secondary immunologic processes are causative remains a matter of speculation.

CFH, C3 and ARMS2 are significant risk loci for susceptibility but not for disease progression of geographic atrophy due to AMD

Background Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown. Methodology/Principal Findings Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6×10−9, 3.2×10−3, and P = 2.6×10−12, respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm2/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13). Conclusions/Significance This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression.

Intravitreal Bevacizumab in Inflammatory Ocular Neovascularization

PURPOSE To assess the role of bevacizumab in inflammatory ocular neovascularization. DESIGN Retrospective, multicenter, consecutive case series of inflammatory ocular neovascularization. METHODS Patients with inflammatory ocular neovascularization of varying causes for whom standard therapy failed were treated with intravitreal injection of bevacizumab. Main outcome measures included improvement of best-corrected visual acuity (BCVA) expressed in logarithm of minimum angle of resolution units, response of inflammatory ocular neovascularization by funduscopy and angiography, and decrease in central foveal thickness as measured by optical coherence tomography at the three-month follow-up. RESULTS At the three-month follow-up, 84 eyes of 79 patients had been treated with a mean of 1.3 injections (range, one to three). Thirty-four eyes showed juxtafoveal choroidal neovascularization (CNV), 34 eyes showed subfoveal CNV, eight eyes showed peripapillary CNV, and 11 eyes showed neovascularization of the disc (NVD) or neovascularization elsewhere (NVE). BCVA improved 2.4 lines from 0.68 (6/28 or 20/94) to 0.44 (6/17 or 20/55) (P < .001). BCVA improved by one to three lines in 34.5% of the eyes, by four to six lines in 16.7% of the eyes, and by more than six lines in 14.2% of the eyes. Function was unchanged in 23.8% of the eyes. BCVA worsened in 10.7% (zero to three lines in 7.1%, more than four lines in 3.6%). Central foveal thickness decreased from baseline 346 to 252 microm (P < .001). For CNV, 32 eyes (43.2%) had complete regression after the injection, 27 (36.5%) had partial regression, five (6.8%) had no response, and 10 eyes (13.5%) were not evaluated by the contributors. For NVD or NVE, seven eyes (63.6%) had complete regression of new vessels and four eyes (36.4%) had partial regression after the injection. CONCLUSIONS Intravitreal bevacizumab led to short-term significant visual improvement and regression of inflammatory ocular neovascularization in a wide variety of inflammatory ocular diseases.

A Subgroup of Age-Related Macular Degeneration is Associated With Mono-Allelic Sequence Variants in the ABCA4 Gene

Purpose. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. Methods. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. Results. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to population-based control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. Conclusions. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.

Therapy Insight: scleritis and its relationship to systemic autoimmune disease

The term scleritis describes a chronic inflammation that involves the outermost coat and skeleton of the eye. Disease can be isolated to the eye, but in up to half of affected individuals it occurs in the context of an immune-mediated systemic inflammatory condition, such as rheumatoid arthritis or Wegeners granulomatosis. Although uncommon, scleritis is often extremely painful, can lead to vision-threatening complications (and involvement of other ocular tissues), and is considered to confer an increased risk of mortality in patients with rheumatoid arthritis. Pathogenic mechanisms in scleritis are poorly understood, but enzymatic degradation of collagen fibrils by resident cells and infiltrating leukocytes seems to be a key feature. Several forms of inflammation can be distinguished histologically; interestingly, although the disease typically presents with engorgement of scleral vessels, vasculitis is not universally present at the microscopic level. Although some patients with scleritis respond well to treatment with NSAIDs, aggressive systemic therapy is often required to obtain a favorable outcome, particularly when systemic disease coexists. The mainstay of treatment is oral prednisone, but this agent is usually combined with a steroid-sparing immunosuppressive drug. New therapies presently under investigation for scleritis include local corticosteroid injections and various biologic agents.

A three-centre experience with adalimumab for the treatment of non-infectious uveitis

Objective The aim of this study was to assess the efficacy of adalimumab in patients with active non-infectious uveitis in three different centres. Methods In a retrospective study we identified patients from our databases who were treated with adalimumab. The composite outcome measure for efficacy included reduction of macular oedema by optic coherence tomography, visual acuity, anterior chamber cells, reduction of frequency of flares and reduction of prednisone dose during the treatment. At least one of the criteria had to be improved and none worsened to declare treatment as effective. Results 60 patients with an average age of 37.3 years (range 4–71 years) were treated with adalimumab over an average follow-up period of 87.9 weeks (range 12–222 weeks). The indication for treatment was in 41 (68.3%) patients the activity of both uveitis and systemic disease and in 19 (31.7%) patients uveitis activity only. 15 (25%) patients were treated before with etanercept and 10 (16.7%) patients with infliximab. 49 out of 60 (81.7%) patients improved, while the other 11 (18.3%) patients did not meet improvement criteria and were given additional or alternative immunosuppressive treatment. At the last follow-up, 47 (78.3%) patients were still on adalimumab treatment. 13 (21.6%) patients stopped adalimumab treatment, due to inefficacy in eight, another three patients due to side effects (liver enzyme elevation and furunculosis), one patient due to pregnancy and one patient died. Conclusions This large retrospective case series showed that adalimumab is effective in up to 80% of patients with uveitis.

Proposed Outcome Measures for Prospective Clinical Trials in Juvenile Idiopathic Arthritis- Associated Uveitis: A Consensus Effort From the Multinational Interdisciplinary Working Group for Uveitis in Childhood

To develop a set of core outcome measures for use in randomized controlled trials (RCTs) and longitudinal observational studies in juvenile idiopathic arthritis (JIA)–associated uveitis.