James P. Dunn

Fluocinolone acetonide sustained drug delivery device to treat severe uveitis.

PURPOSE Uveitis is often a chronic disease requiring long-term medical therapy. In this report, we describe a pilot safety and efficacy trial of a novel sustained drug delivery system containing fluocinolone acetonide to treat patients with severe uveitis. DESIGN Prospective, noncomparative, interventional case series PARTICIPANTS Patients with severe uveitis. METHODS Sustained drug delivery devices designed to release fluocinolone acetonide for at least 2.5 years were implanted through the pars plana into the vitreous cavity of seven eyes of five patients. All patients had severe uveitis not well controlled with, or intolerant to, repeated periocular corticosteroid injections, systemic corticosteroids, nonsteroidal immunosuppressive agents, or a combination thereof at the time of device implantation. Before device implantation, patients underwent complete evaluation including history, ophthalmologic examination, fluorescein angiography, visual field testing, and electroretinography. After surgery, patients were reexamined at 1 week, 2 weeks, 4 weeks, and at 1- to 3-month intervals. Visual fields, electroretinograms, and fluorescein angiography were repeated at 3- to 6-month intervals. MAIN OUTCOME MEASURES Preoperative and postoperative visual acuity, ocular inflammation, anti-inflammatory medication use, and intraocular pressure. RESULTS Patients had a diagnosis of Behçets syndrome (two eyes), or idiopathic panuveitis (five eyes, including two with necrotizing retinitis, two with progressive chorioretinitis, and one with iridocyclitis and intermediate uveitis). Patients were observed an average of 10 months (range, 5-19 months). All eyes had stabilized or improved visual acuity after device implantation, and four of seven eyes had an improvement of three lines or more. The mean initial visual acuity, measured by Snellen chart, was 20/207, and the mean final visual acuity was 20/57 (P = 0.02). After surgery, at the final visit, no eye had clinically detectable inflammation, and all seven eyes had a marked reduction in systemic, topical, and periocular anti-inflammatory medication use. Four eyes had increased intraocular pressure 6 weeks to 6 months after device implantation. Intraocular pressure has been controlled on topical medications. No patient experienced intraoperative complications. CONCLUSIONS A fluocinolone acetonide sustained drug delivery device is a promising new therapy for the treatment of severe uveitis. Intraocular pressure must be carefully monitored long after device implantation. Based on these data, a randomized study of a larger group of patients is warranted.

Episcleritis and scleritis: clinical features and treatment results.

PURPOSE To evaluate the clinical experience with episcleritis and scleritis at a tertiary care eye center. METHODS Retrospective chart review. RESULTS One hundred thirty-four patients with scleral inflammation were seen over a 12-year period. Thirty-seven patients had episcleritis, and 97 patients had scleritis. Ocular complications occurred in only 13.5% of patients with episcleritis but in 58.8% of patients with scleritis (P <.0001). No patient with episcleritis had a decrease in visual acuity, whereas 15.9% of patients with scleritis did. Only 16.7% of patients with episcleritis required more than topical corticosteroids for treatment, and these patients required oral nonsteroidal anti-inflammatory drugs. Conversely, 30.4% of patients with scleritis required nonsteroidal anti-inflammatory drugs, 31.9% oral prednisone, and 26.1% systemic immunosuppressive drugs (P <.0001). Necrotizing scleritis and posterior scleritis more often were associated with ocular complications, occurring in 91.7% and 85.7%, respectively, than were diffuse anterior scleritis and nodular anterior scleritis (P =.020). Patients with necrotizing scleritis and posterior scleritis were more likely to be treated with oral corticosteroids or immunosuppressive drugs (90% and 100%, respectively) than were patients with diffuse anterior scleritis and nodular anterior scleritis (56.4% and 21.4%, respectively, P =.002). CONCLUSIONS Scleritis is a severe ocular inflammation, often associated with ocular complications, and nearly always treated with systemic medications. Nearly 60% of these patients will need oral corticosteroids or immunosuppressive drugs to control the disease.

Cytomegalovirus Retinitis and Viral Resistance: Ganciclovir Resistance

Cytomegalovirus (CMV) retinitis is among the most common opportunistic infections in patients with AIDS and a substantial cause of visual loss. With long-term therapy, resistant CMV may develop. In a prospective study of 108 patients with CMV retinitis, 80.6% of patients were found to have either a positive blood culture or positive urine culture for CMV at the diagnosis of retinitis. At diagnosis of retinitis, 0.9% and 2.7% of patients had a ganciclovir-resistant blood culture isolate and urine culture isolate, respectively. Of 76 patients initially treated with ganciclovir, 11.4% had a resistant blood or urine culture isolate by 6 months of treatment and 27.5% by 9 months. The development of ganciclovir resistance during follow-up correlated with the occurrence of CMV retinitis in the contralateral eye (odds ratio = 9.06, P = .003).

Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy

PURPOSE To estimate the incidence and describe the characteristics of immune recovery uveitis in patients with acquired immunodeficiency syndrome (AIDS) and cytomegalovirus retinitis treated with highly active antiretroviral therapy. METHODS The records of all patients with AIDS and cytomegalovirus retinitis from 1995 to 1998 seen at the AIDS Ophthalmology Service of the Johns Hopkins Medical Institutions were reviewed. Eighty-two patients with cytomegalovirus retinitis treated with highly active antiretroviral therapy were identified. Thirty-three patients (40.2%) were classified as responders to highly active antiretroviral therapy, defined as an increase in CD4+ T-cell count by 50 cells/microL or more to a level of 100 cells/microL or more. RESULTS Immune recovery uveitis occurred in six patients. Among the 33 patients with an immunologic response to highly active antiretroviral therapy, the incidence rate of immune recovery uveitis was 0.109/person-year. Ocular complications associated with immune recovery uveitis included cystoid macular edema (four patients), epiretinal membranes (two patients), and optic disk neovascularization (one patient). CONCLUSIONS Immune recovery uveitis was uncommon in our population but may have vision-impairing complications.

Discontinuing anticytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy

PURPOSE To describe our experience with discontinuation of anticytomegalovirus maintenance therapy in patients who have had immune reconstitution after initiation of highly active antiretroviral therapy. METHODS Fifteen patients with treated cytomegalovirus retinitis, who had immune reconstitution after initiation of highly active retroviral therapy, had anticytomegalovirus maintenance therapy discontinued. Patients were followed closely for relapse of retinitis. RESULTS Median nadir CD4+ T-cell count, before institution of highly active antiretroviral therapy, was 20 cells/microl. At the time of discontinuation of anticytomegalovirus therapy, median CD4+ T-cell count was 297 cells/microl. Patients were followed for a median of 8 months off anticytomegalovirus therapy (range, 3 to 16 months). The median CD4+ T-cell count at last follow-up was 267 cells/microl. No patient off anticytomegalovirus therapy relapsed. CONCLUSION In selected patients with immune reconstitution after initiation of highly active antiretroviral therapy, anticytomegalovirus therapy may be safely discontinued, at least temporarily. Longer follow-up of these patients is needed to determine how long such therapy may be interrupted, and when anticytomegalovirus therapy should be reinstituted.

Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs: retrospective cohort study.

Context Whether immunosuppressive treatment adversely affects survival is unclear. Objective To assess whether immunosuppressive drugs increase mortality. Design Retrospective cohort study evaluating overall and cancer mortality in relation to immunosuppressive drug exposure among patients with ocular inflammatory diseases. Demographic, clinical, and treatment data derived from medical records, and mortality results from United States National Death Index linkage. The cohort’s mortality risk was compared with US vital statistics using standardised mortality ratios. Overall and cancer mortality in relation to use or non-use of immunosuppressive drugs within the cohort was studied with survival analysis. Setting Five tertiary ocular inflammation clinics. Patients 7957 US residents with non-infectious ocular inflammation, 2340 of whom received immunosuppressive drugs during follow up. Exposures Use of antimetabolites, T cell inhibitors, alkylating agents, and tumour necrosis factor inhibitors. Main outcome measures Overall mortality, cancer mortality. Results Over 66 802 person years (17 316 after exposure to immunosuppressive drugs), 936 patients died (1.4/100 person years), 230 (24.6%) from cancer. For patients unexposed to immunosuppressive treatment, risks of death overall (standardised mortality ratio 1.02, 95% confidence interval [CI] 0.94 to 1.11) and from cancer (1.10, 0.93 to 1.29) were similar to those of the US population. Patients who used azathioprine, methotrexate, mycophenolate mofetil, ciclosporin, systemic corticosteroids, or dapsone had overall and cancer mortality similar to that of patients who never took immunosuppressive drugs. In patients who used cyclophosphamide, overall mortality was not increased and cancer mortality was non-significantly increased. Tumour necrosis factor inhibitors were associated with increased overall (adjusted hazard ratio [HR] 1.99, 95% CI 1.00 to 3.98) and cancer mortality (adjusted HR 3.83, 1.13 to 13.01). Conclusions Most commonly used immunosuppressive drugs do not seem to increase overall or cancer mortality. Our results suggesting that tumour necrosis factor inhibitors might increase mortality are less robust than the other findings; additional evidence is needed.

Pars planitis ☆: Clinical features and class II HLA associations

OBJECTIVE To describe a cohort of patients with pars planitis followed at a single tertiary care institution, determine the frequency of multiple sclerosis and/or optic neuritis in patients with this disorder, and calculate gene frequencies of human leukocyte antigen (HLA) class II alleles in these patients. DESIGN Fifty-three patients with the diagnosis of pars planitis underwent clinical record review or telephone interview for follow-up or both; 32 of these underwent phlebotomy for analysis of HLA class II alleles. MAIN OUTCOME MEASURES Outcomes included visual acuity, occurrence of multiple sclerosis and/or optic neuritis, and HLA class II gene frequencies. RESULTS With a mean follow-up of 2 years, approximately 90% of patients maintained a visual acuity better than 20/40 in at least one eye. The most frequently encountered ophthalmic complications included cystoid macular edema, cataract, and epiretinal membrane formation. Of 37 patients with pars planitis who had medical or neurologic follow-up evaluations, 6 (16.2%) developed multiple sclerosis. The HLA-DR15 allele, coding for one of the two HLA-DR2 subtypes, was associated with pars planitis (odds ratio = 2.86, 95% confidence interval = 1.42-5.78, P = 0.004). CONCLUSIONS A common immunogenetic predisposition to multiple sclerosis and pars planitis may be associated with the HLA-DR15 allele. This association may represent genetic linkage to the HLA-DR locus or a role for the HLA-DR15 gene product in the pathogenesis of both of these diseases.

Mutations Conferring Ganciclovir Resistance in a Cohort of Patients with Acquired Immunodeficiency Syndrome and Cytomegalovirus Retinitis

Cytomegalovirus (CMV) retinitis is among the most common opportunistic infections in patients with acquired immunodeficiency syndrome. In a prospective study of 210 patients with CMV retinitis, 26 were identified as having either a phenotypic or a genotypic ganciclovir-resistant isolate from either blood or urine cultures. For blood culture isolates with an IC(50) >6.0 microm for ganciclovir, the sensitivity and specificity for detecting a UL97 mutation were 95% and 98%, respectively, whereas for an IC(50) >8.0 microM they were 79% and 99%, respectively. Although there were trade-offs between the 2 thresholds for blood culture isolates, for urine culture isolates an IC(50) >8.0 microM appeared to be better at identifying genotypic resistance. UL97 mutations identified in both the blood and urine cultures of individual patients were identical in 87.5% of cases. High-level ganciclovir resistance (IC(50), >30 microM) typically, but not invariably, was associated with a mutation in both the UL97 and UL54 genes.

Incidence of Foscarnet Resistance and Cidofovir Resistance in Patients Treated for Cytomegalovirus Retinitis

ABSTRACT Cytomegalovirus (CMV) retinitis is a common opportunistic infection in patients with AIDS. With long-term therapy for CMV retinitis, resistant CMV may develop. In a prospective study of 122 patients with CMV retinitis, 2.4 and 0.8% of patients had foscarnet-resistant blood culture isolates (50% inhibitory concentration [IC50], >400 μM) and urine culture isolates, respectively, at diagnosis of CMV retinitis prior to treatment, whereas 4.1 and 6.6% had cidofovir-resistant (IC50, >2 μM) blood and urine culture isolates, respectively. Patients were treated according to best medical judgement. Of 44 foscarnet-treated patients, 26% had a resistant blood or urine culture isolate by 6 months of treatment and 37% had a resistant isolate by 9 months; of 13 cidofovir-treated patients, 29% had a resistant blood or urine culture isolate by 3 months of therapy. The probabilities of developing foscarnet resistance while on foscarnet and developing cidofovir resistance while on cidofovir were not significantly different from that for developing ganciclovir resistance while on ganciclovir (odds ratios, 1.87 [P = 0.19] and 2.28 [P = 0.15], respectively).

Clinical features and associated systemic diseases of HLA-B27 uveitis

PURPOSE To delineate the clinical features, course, complications, and associated systemic diseases in patients with HLA-B27-associated uveitis. METHODS We reviewed the records of 148 patients with HLA-B27-associated uveitis from two large uveitis practices. RESULTS There were 127 (86%) white and 21 (14%) nonwhite patients, and a male-to-female ratio of 1.5:1. The median age at onset of uveitis was 32 years; eight patients (5%) had their first attack after age 55 years. Acute anterior uveitis was noted in 129 patients (87%), and nonacute inflammation was noted in 19 (13%). Ocular involvement was categorized as unilateral or unilateral alternating in 138 patients (93%), but ten patients (7%) had bilateral, concurrent disease. The median duration of an attack was six weeks, and the median number of recurrences for patients with more than 12 months of follow-up was three. Cataracts were associated with posterior synechiae (P = .03), increased intraocular pressure (P = .003), and cystoid macular edema (P = .04). An HLA-B27-associated systemic disorder was present in 83 patients (58%), 30 of whom were women, and it was diagnosed in 43 of the 83 patients as a result of the ophthalmologic consultation. Thirty-four (30%) of 112 patients had a family history of a spondyloarthropathy. CONCLUSIONS Although HLA-B27-associated uveitis is usually described as a disease of young white men, women and nonwhites may also be affected. A subgroup of patients have severe disease and consequently more complications. Most patients have an associated systemic disease, including women, who appear to have more atypical spondyloarthropathies. The systemic diseases were frequently undiagnosed before the onset of the ocular disease and before the uveitis consultation.