Thomas Ness

Human recombinant interferon alfa-2a for the treatment of Behçet's disease with sight threatening posterior or panuveitis

Background: Behçets disease is a multisystem vasculitis of unknown origin. Standard treatment mainly comprises systemic immunosuppressive agents. Ocular involvement, mostly posterior uveitis with retinal vasculitis, leads to blindness in 20–50% of the involved eyes within 5 years. The efficacy of interferon alfa-2a was studied in patients with sight threatening posterior uveitis or retinal vasculitis. Methods: 50 patients were included in this open, non-randomised, uncontrolled prospective study. Recombinant human interferon alfa-2a (rhIFNα-2a) was applied at a dose of 6 million units subcutaneously daily. Dose reduction was performed according to a decision tree until discontinuation. Disease activity was evaluated every 2 weeks by the Behçets disease activity scoring system and the uveitis scoring system. Results: Response rate of the ocular manifestations was 92% (three non-responder, one incomplete response). Mean visual acuity rose significantly from 0.56 to 0.84 at week 24 (p<0.0001). Posterior uveitis score of the affected eyes fell by 46% every week (p<0.001). Remission of retinal inflammation was achieved by week 24. Mean Behçets disease activity score fell from 5.8 to 3.3 at week 24 and further to 2.8 at week 52. After a mean observation period of 36.4 months (range 12–72), 20 patients (40%) are off treatment and disease free for 7–58 months (mean 29.5). In the other patients maintenance IFN dosage is three million units three times weekly. Conclusions: rhIFNα-2a is effective in ocular Behçets disease, leading to significant improvement of vision and complete remission of ocular vasculitis in the majority of the patients.

Giant Cell Arteritis: Diagnostic Accuracy of MR Imaging of Superficial Cranial Arteries in Initial Diagnosis—Results from a Multicenter Trial

PURPOSE To assess the diagnostic accuracy of contrast material-enhanced magnetic resonance (MR) imaging of superficial cranial arteries in the initial diagnosis of giant cell arteritis ( GCA giant cell arteritis ). MATERIALS AND METHODS Following institutional review board approval and informed consent, 185 patients suspected of having GCA giant cell arteritis were included in a prospective three-university medical center trial. GCA giant cell arteritis was diagnosed or excluded clinically in all patients (reference standard [final clinical diagnosis]). In 53.0% of patients (98 of 185), temporal artery biopsy ( TAB temporal artery biopsy ) was performed (diagnostic standard [ TAB temporal artery biopsy ]). Two observers independently evaluated contrast-enhanced T1-weighted MR images of superficial cranial arteries by using a four-point scale. Diagnostic accuracy, involvement pattern, and systemic corticosteroid ( sCS systemic corticosteroid ) therapy effects were assessed in comparison with the reference standard (total study cohort) and separately in comparison with the diagnostic standard TAB temporal artery biopsy ( TAB temporal artery biopsy subcohort). Statistical analysis included diagnostic accuracy parameters, interobserver agreement, and receiver operating characteristic analysis. RESULTS Sensitivity of MR imaging was 78.4% and specificity was 90.4% for the total study cohort, and sensitivity was 88.7% and specificity was 75.0% for the TAB temporal artery biopsy subcohort (first observer). Diagnostic accuracy was comparable for both observers, with good interobserver agreement ( TAB temporal artery biopsy subcohort, κ = 0.718; total study cohort, κ = 0.676). MR imaging scores were significantly higher in patients with GCA giant cell arteritis -positive results than in patients with GCA giant cell arteritis -negative results ( TAB temporal artery biopsy subcohort and total study cohort, P < .001). Diagnostic accuracy of MR imaging was high in patients without and with sCS systemic corticosteroid therapy for 5 days or fewer (area under the curve, ≥0.9) and was decreased in patients receiving sCS systemic corticosteroid therapy for 6-14 days. In 56.5% of patients with TAB temporal artery biopsy -positive results (35 of 62), MR imaging displayed symmetrical and simultaneous inflammation of arterial segments. CONCLUSION MR imaging of superficial cranial arteries is accurate in the initial diagnosis of GCA giant cell arteritis . Sensitivity probably decreases after more than 5 days of sCS systemic corticosteroid therapy; thus, imaging should not be delayed. Clinical trial registration no. DRKS00000594 .

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.

The Diagnosis and Treatment of Giant Cell Arteritis

BACKGROUND Giant cell arteritis (GCA) is the most common systemic vasculitis in persons aged 50 and above (incidence, 3.5 per 100,000 per year). It affects cranial arteries, the aorta, and arteries elsewhere in the body, e.g., in the limbs. METHODS We selectively review the pertinent literature, including guidelines and recommendations from Germany and abroad. RESULTS The typical symptoms of new-onset GCA are bitemporal headaches, jaw claudiacation, scalp tenderness, visual disturbances, systemic symptoms such as fever and weight loss, and polymyalgia. The diagnostic assessment comprises laboratory testing (erythrocyte sedimentation rate, C-reactive protein), imaging studies (duplex sonography, high-resolution magnetic resonance imaging, positron-emission tomography), and temporal artery biopsy. The standard treatment is with corticosteroids (adverse effects: diabetes mellitus, osteoporosis, cataract, arterial hypertension). A meta-analysis of three randomized controlled trials led to a recommendation for treatment with methotrexate to lower the recurrence rate and spare steroids. Patients for whom methotrexate is contraindicated or who cannot tolerate the drug can be treated with azathioprine instead. CONCLUSION Giant cell arteritis, if untreated, progresses to involve the aorta and its collateral branches, leading to various complications. Late diagnosis and treatment can have serious consequences, including irreversible loss of visual function.

Long-term Visual Outcomes of Intravitreal Bevacizumab in Inflammatory Ocular Neovascularization

PURPOSE To assess the long-term role of bevacizumab (Avastin; Genentech Inc, South San Francisco, California, USA) in inflammatory ocular neovascularization. DESIGN Retrospective multicenter consecutive case series of inflammatory ocular neovascularization. METHODS settings: Multicenter institutional and private practices. STUDY POPULATION Patients with inflammatory ocular neovascularization in one or both eyes of varying etiologies who failed standard therapy. intervention: Intravitreal injection of bevacizumab. MAIN OUTCOME MEASURES Improvement of best-corrected visual acuity (BCVA) expressed as logarithm of minimal angle of resolution (logMAR), and decrease in central foveal thickness as measured by optical coherence tomography at 6, 12, 18, and 24 months of follow-up. RESULTS Mean logMAR BCVA (central foveal thickness) following intravitreal bevacizumab was as follows: baseline, 0.65 (6/27 or 20/90) (338 microm; 99 eyes of 96 patients); 6 months, 0.42 (6/16 or 20/53) (239 microm; 2.0 injections; 81 eyes); 12 months, 0.39 (6/15 or 20/49) (241 microm; 2.3 injections; 95 eyes); 18 months, 0.40 (6/15 or 20/50) (261 microm; 3.0 injections; 46 eyes); and 24 months, 0.34 (6/13 or 20/44) (265 microm; 3.6 injections; 27 eyes). Paired comparisons revealed significant visual improvement at 6 months of 2.4 lines (P = .000), at 12 months of 2.5 lines (P = .000), at 18 months of 2.5 lines (P = .001), and at 24 months of 2.2 lines (P = .013). Paired comparisons revealed significant central foveal flattening at 6 months of 78 microm (P = .000), at 12 months of 85 microm (P = .000), at 18 months of 90 microm (P = .003), and at 24 months of 77 microm (P = .022). Three eyes developed submacular fibrosis and 1 eye submacular hemorrhage. CONCLUSION Intravitreal bevacizumab led in the long-term to significant mean visual improvement of > or =2.2 lines and significant foveal flattening in a wide variety of inflammatory ocular diseases without major complications.

Endogenous endophthalmitis caused by methicillin-resistant Staphylococcus aureus (MRSA).

Purpose: To report clinical features, diagnostic features, and outcome in three patients presenting with fulminant endogenous endophthalmitis caused by methicillin-resistant Staphylococcus aureus. Methods: Retrospective review of clinical data and microbiological findings in three cases. Results: All three patients had predisposing conditions for endogenous endophthalmitis (B-cell lymphoma, diabetes mellitus, steroid therapy, or gastrointestinal symptoms, such as vomiting and diarrhea). Two patients were colonized by methicillin-resistant Staphylococcus aureus in typical sites (nose, groin, throat, and conjunctiva), whereas one patient who developed phlebitis at the infusion puncture site followed by bacteremia presented no typical colonization. Despite adequate therapy, two patients lost visual function in the infected eye, one of which had to be enucleated. The other patients eye regained adequate function. Conclusion: Endogenous endophthalmitis by methicillin-resistant Staphylococcus aureus is a rare but serious condition. Early and specific therapy based on reliable detection of the underlying microorganism may help in preventing loss of visual function.

Interleukin-2 Receptor and Angiotensin-Converting Enzyme as Markers for Ocular Sarcoidosis.

Purpose To study the impact of soluble IL2 receptor (sIL2R), chest x-ray (CxR), and angiotensin-converting enzyme (ACE) as markers for sarcoidosis in uveitis patients. Design Retrospective study. Methods Serum concentrations of sIL2R and ACE were measured in patients with active uveitis. Those with elevated sIL2R and /or ACE values were examined for suspected systemic sarcoidosis. Main Outcome Measure Our main outcome parameters were the specificity and sensitivity of sIL2R, CxR and ACE in screening for ocular sarcoidosis. Results We measured 261 patients with uveitis for sarcoidosis using sIL2R and ACE between January 2008 and November 2011; sarcoidosis was been diagnosed using other tests (e.g. computer tomography, brochoalveolar lavage, biopsy) in 41 of 53 patients with elevated sIL2R values (>639 U/ml) and in one patient with normal sIL2R (582 U/ml). Their mean sIL2R value was 1310 U/ml, extending from 582 to 8659 U/ml. Only 9 patients, however, presented elevated ACE (>82 U/l). Their mean ACE value was 116.4 U/l, ranging from 84.1 to 175.5 U/l. IL2R specificity was 94% with 98% sensitivity. In contrast, ACE had a specificity of 99.5%, but a sensitivity of only 22%; the chest x-ray had a specificity of 100% with 50% sensitivity in detecting sarcoidosis. We observed the entire spectrum of uveitis: sixteen patients suffered from anterior, 8 from intermediate, 16 from posterior, and 2 from panuveitis. Conclusions An elevated level of soluble IL2R suggests sarcoidosis with uveitis more convincingly than ACE, making sIL2R a more effective marker parameter for sarcoidosis than ACE or chest x-ray in uveitis patients.

Three-year visual and anatomic results of administrating intravitreal bevacizumab in inflammatory ocular neovascularization

OBJECTIVE To assess the 3-year visual outcome of intravitreal bevacizumab in inflammatory ocular neovascularization. DESIGN Experimental study. METHODS Retrospective multicenter consecutive case series in 81 patients with inflammatory ocular neovascularization refractory to standard therapy and treated with intravitreal bevacizumab. The outcome measures included improvement of best corrected visual acuity expressed as logarithm of minimum angle of resolution (logMAR) and paired comparison decrease in central foveal thickness by optical coherence tomography. RESULTS Mean best corrected visual acuity improved from baseline 0.699 (6/30 or 20/101) (SD 0.434) to 0.426 (6/16 or 20/53) (SD 0.428) (n = 81; p < 0.001), a gain of 2.7 lines (median 3 injections; 81 eyes; 81 patients). Paired comparisons revealed significant central foveal flattening at 3 years of 97.9 μm (n = 51; p < 0.001). In a subgroup analysis, visual improvement was significant for ocular histoplasmosis (p = 0.026); multifocal choroiditis (p = 0.05); serpiginous choroiditis (p = 0.028); ocular toxoplasmosis (p = 0.042); and punctate inner choroidopathy (p = 0.015). In a subgroup analysis, foveal flattening was significant for ocular histoplasmosis (p = 0.004); multifocal choroiditis (p = 0.007); serpiginous choroiditis (p = 0.011); and punctate inner choroidopathy (p = 0.001). Of the group, 5 eyes developed submacular fibrosis, 1 eye retinal pigment epithelial tear, and 1 eye macular ischemia in the context of vasculitis. CONCLUSION At 3 years, intravitreal bevacizumab sustained significant visual improvement of 2.7 lines and significant foveal flattening of 98 μm in a wide variety of inflammatory ocular diseases without major complications after a median of 3 injections.

DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas

Granulomas are immune cell aggregates formed in response to persistent inflammatory stimuli. Granuloma macrophage subsets are diverse and carry varying copy numbers of their genomic information. The molecular programs that control the differentiation of such macrophage populations in response to a chronic stimulus, though critical for disease outcome, have not been defined. Here, we delineate a macrophage differentiation pathway by which a persistent Toll-like receptor (TLR) 2 signal instructs polyploid macrophage fate by inducing replication stress and activating the DNA damage response. Polyploid granuloma-resident macrophages formed via modified cell divisions and mitotic defects and not, as previously thought, by cell-to-cell fusion. TLR2 signaling promoted macrophage polyploidy and suppressed genomic instability by regulating Myc and ATR. We propose that, in the presence of persistent inflammatory stimuli, pathways previously linked to oncogene-initiated carcinogenesis instruct a long-lived granuloma-resident macrophage differentiation program that regulates granulomatous tissue remodeling.

NKG2D stimulated T-cell autoreactivity in giant cell arteritis and polymyalgia rheumatica

Objective To investigate functional expression of NKG2D on CD4 and CD8 T-cells in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). Methods Peripheral blood was drawn from patients with GCA (n=16), PMR (n=78) and healthy controls (HC, n=64). Tissue samples were obtained from GCA patients and controls. Proliferation and cytokine production assays were performed using CFSE and intracellular IFN-γ or TNF-α staining, respectively, and flow cytometry analysis. Immunofluorescence and immunohistology were applied to analyse the presence of NKG2D-expressing T-cells and NKG2D-ligands in temporal arteries, respectively. mRNA levels of NKG2D-ligands were determined by RT-PCR. Results In both GCA and PMR patients, NKG2D was preferentially expressed on senescent CD4CD28− and CD8CD28−, as well as on CD8CD28 T-cells. Frequencies of senescent T-cells were increased in GCA and PMR patients compared to HC. In GCA tissue samples, infiltrating T-cells were predominately CD28−. NKG2D expressing T-cells concentrated around the vasa vasorum of the adventitia. Antigenic stimulation induced rapid up-regulation of NKG2D on CD4CD28− and CD4CD28 T-cells, whereas TNF-α and interleukin-15 enhanced NKG2D expression on senescent CD4 and CD8 T-cells only. NKG2D cross-linkage augmented anti-CD3 triggered proliferation, IFN-γ and TNF-α production of CD8 T-cells. In CD4CD28− T-cells, NKG2D ligation resulted in increased IFN-γ production only. NKG2D ligands were expressed in temporal arteries from GCA patients, particularly in the adventitial and medial layers of affected vessels. Conclusions NKG2D is functionally expressed on CD4CD28− and CD8 T-cells in GCA and PMR. NKG2D-ligands are present in temporal arteries and may co-stimulate NKG2D expressing T-cells.