John H. Kempen

Cyclosporine for Ocular Inflammatory Diseases

PURPOSE To evaluate the clinical outcomes of cyclosporine treatment for noninfectious ocular inflammation. DESIGN Retrospective cohort study. PARTICIPANTS A total of 373 patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to use cyclosporine as a single noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007 inclusive. METHODS Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage of cyclosporine and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers. MAIN OUTCOME MEASURES Control of inflammation, sustained control after reducing corticosteroid dosages, and discontinuation of therapy because of toxicity. RESULTS Of the 373 patients (681 eyes) initiating cyclosporine monotherapy, 33.4% by 6 months and 51.9% by 1 year gained sustained, complete control of inflammation over at least 2 visits spanning at least 28 days. Approximately 25% more improved to a level of slight inflammatory activity by each of these time points. Corticosteroid-sparing success (completely controlled inflammation for at least 28 days with prednisone < or = 10 mg/day) was achieved by 22.1% by 6 months and 36.1% within 1 year. Toxicity led to discontinuation of therapy within 1 year by 10.7% of the population. Patients aged more than 55 years were more than 3-fold more likely to discontinue therapy because of toxicity than patients aged 18 to 39 years. Doses of 151 to 250 mg/day tended to be more successful than lower doses and were not associated with a higher discontinuation for toxicity rate; higher doses did not seem to offer a therapeutic advantage. CONCLUSIONS Cyclosporine, with corticosteroid therapy as indicated, was modestly effective for controlling ocular inflammation. Our data support a preference for cyclosporine adult dosing between 151 and 250 mg/day. Although cyclosporine was tolerated by the majority of patients, toxicity was more frequent with increasing age; alternative agents may be preferred for patients aged more than 55 years.

Surgical strategies for coexisting glaucoma and cataract. An evidence-based update

OBJECTIVE To assess short- and long-term control of intraocular pressure (IOP) with different surgical treatment strategies for coexisting cataract and glaucoma. DESIGN Systematic literature review and analysis. METHOD We performed a search of the published literature to identify all eligible articles pertaining to the surgical management of coexisting cataract and glaucoma in adults. One investigator abstracted the content of each article onto a custom-designed form. A second investigator corroborated the findings. The evidence supporting different approaches was graded by consensus as good, fair, weak, or insufficient. MAIN OUTCOME MEASURES Short-term (24 hours or fewer) and long-term (more than 24 hours) IOP control. RESULTS The evidence was good that long-term IOP is lowered more by combined glaucoma and cataract operations than by cataract operations alone. On average, the IOP was 3 to 4 mmHg lower in the combined groups with fewer medications required. The evidence was weak that extracapsular cataract extraction (ECCE) alone results in short-term increase in IOP and was insufficient to determine the short-term impact of phacoemulsification cataract extraction (PECE) on IOP in glaucoma patients. The evidence was weak that short-term IOP control was better with ECCE or PECE combined with an incisional glaucoma procedure compared with ECCE or PECE alone. The evidence was also weak (but consistent) that long-term IOP is lowered by 2 to 4 mmHg after ECCE or PECE. Finally, there was weak evidence that combined PECE and trabeculectomy produces slightly worse long-term IOP control than trabeculectomy alone, and there was fair evidence that the same is true for ECCE combined with trabeculectomy. CONCLUSIONS There is strong evidence for better long-term control of IOP with combined glaucoma and cataract operations compared with cataract surgery alone. For other issues regarding surgical treatment strategies for cataract and glaucoma, the available evidence is limited or conflicting.

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.

Mycophenolate Mofetil for Ocular Inflammation

PURPOSE To evaluate mycophenolate mofetil as a single noncorticosteroid immunosuppressive treatment for noninfectious ocular inflammatory diseases. DESIGN Retrospective cohort study. METHODS Characteristics of patients with noninfectious ocular inflammation treated with mycophenolate mofetil at 4 subspecialty clinics from 1995 to 2007 were abstracted by expert reviewers in a standardized chart review of every eye at every visit. Main outcomes measured were control of inflammation, corticosteroid-sparing effects, and discontinuation of mycophenolate mofetil (including the reasons for discontinuation). Survival analysis was used to estimate the incidence of outcomes, and to identify risk factors for each. RESULTS Among 236 patients (397 eyes) treated with mycophenolate mofetil monotherapy, 20.3%, 11.9%, and 39.8% had anterior uveitis, intermediate uveitis, and posterior uveitis or panuveitis respectively; 14% had scleritis; 7.6% had mucous membrane pemphigoid; and 6.4% had other ocular inflammatory diseases. By Kaplan-Meier estimation, complete control of inflammation--sustained over consecutive visits spanning at least 28 days--was achieved in 53% and 73% of patients within 6 months and 1 year respectively. Systemic corticosteroid dosage was reduced to 10 mg of prednisone or less, while maintaining sustained control of inflammation, in 41% and 55% of patients in 6 months and 1 year respectively. Twelve percent of patients discontinued mycophenolate mofetil within the first year because of side effects of therapy. CONCLUSIONS Given sufficient time, mycophenolate mofetil was effective in managing ocular inflammation in approximately half of the treated patients. Treatment-limiting side effects were observed in 12% of patients and typically were reversible.

Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy

PURPOSE To describe the characteristics of patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy (HAART). METHODS Prospective cohort study. Baseline (enrollment) data were compared between patients with newly diagnosed cytomegalovirus retinitis (incident cases) and those with previously diagnosed cytomegalovirus retinitis (prevalent cases). RESULTS As of December 31, 2000, 45 incident and 200 prevalent cases had been enrolled. Among prevalent cases, the median time from cytomegalovirus retinitis diagnosis was 2.9 years. Incident cases were more likely than prevalent cases to be women (35.4% vs 15.3%, P =.001), African American (45.4% vs 20.4%, P =.002), and uninsured (29.6% vs 7.6%, P <.001). Incident cases were less likely than prevalent cases to be on HAART (51.2% vs 77.6%, P =.001) and to have had an immunologic response to HAART (increase in CD4(+) T-cell count to > 100 cells/microl) (12.2% vs 57.5%, P <.001). The median CD4(+) T-cell count at enrollment among incident cases was 17 cells/microl and among prevalent cases was 159 cells/microl (P <.001). Immune recovery uveitis had been diagnosed in 15.5% of the prevalent cases. Sixty-three percent of prevalent cases were not on anticytomegalovirus therapy. CONCLUSIONS There is a population of patients with previously diagnosed and longstanding cytomegalovirus retinitis who have experienced immune recovery as a consequence of HAART and are no longer receiving anticytomegalovirus therapy. There are demographic differences between incident and prevalent cases that may reflect the evolution of the AIDS epidemic and differences in utilization of health care services.

Azathioprine for Ocular Inflammatory Diseases

PURPOSE To evaluate treatment outcomes of azathioprine for noninfectious ocular inflammatory diseases. DESIGN Retrospective cohort study. METHODS Medical records of 145 patients starting azathioprine as a sole noncorticosteroid immunosuppressant at 4 tertiary uveitis services were reviewed. Main outcome measures included control of ocular inflammation, sustained control after tapering prednisone to </= 10 mg/day, and discontinuation of treatment because of side effects. RESULTS Among 145 patients (255 eyes) treated with azathioprine, 63% had uveitis, 23% had mucous membrane pemphigoid, 11% had scleritis, and 3% had other inflammatory diseases. By Kaplan-Meier analysis, 62% (95% confidence interval [CI], 50% to 74%) of patients with active disease initially gained complete inactivity of inflammation sustained over at least 28 days within 1 year of therapy, and 47% (95% CI, 37% to 58%) tapered systemic corticosteroids to </= 10 mg daily while maintaining control of inflammation within 1 year of therapy. Treatment success was most common for intermediate uveitis (90% with sustained inactivity within 1 year; 95% CI, 64% to 99%). Over the median follow-up of 230 days (interquartile range, 62 to 679 days), azathioprine was discontinued at a rate of 0.45 per person-years (/PY): 0.16/PY because of side effects, 0.10/PY because of ineffectiveness, 0.09/PY because of disease remission, and 0.10/PY because of unspecified causes. CONCLUSIONS Azathioprine was moderately effective as a single corticosteroid-sparing immunosuppressive agent in terms of control of inflammation and corticosteroid-sparing benefits, but required several months to achieve treatment goals; it seems especially useful for patients with intermediate uveitis. Treatment-limiting side effects occurred in approximately one-fourth of patients within 1 year, but typically were reversible.

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.

Cyclophosphamide for ocular inflammatory diseases

PURPOSE To evaluate the outcomes of cyclophosphamide therapy for noninfectious ocular inflammation. DESIGN Retrospective cohort study. PARTICIPANTS Two hundred fifteen patients with noninfectious ocular inflammation observed from initiation of cyclophosphamide. METHODS Patients initiating cyclophosphamide, without other immunosuppressive drugs (other than corticosteroids), were identified at 4 centers. Dose of cyclophosphamide, response to therapy, corticosteroid-sparing effects, frequency of discontinuation, and reasons for discontinuation were obtained by medical record review of every visit. MAIN OUTCOME MEASURES Control of inflammation, corticosteroid-sparing effects, and discontinuation of therapy. RESULTS The 215 patients (381 involved eyes) meeting eligibility criteria carried diagnoses of uveitis (20.4%), scleritis (22.3%), ocular mucous membrane pemphigoid (45.6%), or other forms of ocular inflammation (11.6%). Overall, approximately 49.2% (95% confidence interval [CI], 41.7%-57.2%) gained sustained control of inflammation (for at least 28 days) within 6 months, and 76% (95% CI, 68.3%-83.7%) gained sustained control of inflammation within 12 months. Corticosteroid-sparing success (sustained control of inflammation while tapering prednisone to 10 mg or less among those not meeting success criteria initially) was gained by 30.0% and 61.2% by 6 and 12 months, respectively. Disease remission leading to discontinuation of cyclophosphamide occurred at the rate of 0.32/person-year (95% CI, 0.24-0.41), and the estimated proportion with remission at or before 2 years was 63.1% (95% CI, 51.5%-74.8%). Cyclophosphamide was discontinued by 33.5% of patients within 1 year because of side effects, usually of a reversible nature. CONCLUSIONS The data suggest that cyclophosphamide is effective for most patients for controlling inflammation and allowing tapering of systemic corticosteroids to 10 mg prednisone or less, although 1 year of therapy may be needed to achieve these goals. Unlike with most other immunosuppressive drugs, disease remission was induced by treatment in most patients who were able to tolerate therapy. To titrate therapy properly and to minimize the risk of serious potential side effects, a systematic program of laboratory monitoring is required. Judicious use of cyclophosphamide seems to be beneficial for severe ocular inflammation cases where the potentially vision-saving benefits outweigh the substantial potential side effects of therapy, or when indicated for associated systemic inflammatory diseases.

The multicenter uveitis steroid treatment trial: rationale, design, and baseline characteristics.

PURPOSE To describe the design and methods of the Multicenter Uveitis Steroid Treatment (MUST) trial and the baseline characteristics of enrolled patients. DESIGN Baseline data from a 1:1 randomized, parallel treatment design clinical trial at 23 clinical centers comparing systemic corticosteroid therapy (and immunosuppression when indicated) with fluocinolone acetonide implant placement. METHODS Eligible patients had active or recently active noninfectious intermediate uveitis, posterior uveitis, or panuveitis. The study design had 90% power (2-sided type I error rate, 0.05) to detect a 7.5-letter (1.5-line) difference between groups in the mean visual acuity change between baseline and 2 years. Secondary outcomes include ocular and systemic complications of therapy and quality of life. Baseline characteristics include demographic and clinical characteristics, quality of life, and reading center gradings of lens and fundus photographs, optical coherence tomography images, and fluorescein angiograms. RESULTS Over 3 years, 255 patients were enrolled (481 eyes with uveitis). At baseline, 50% of eyes with uveitis had best-corrected visual acuity worse than 20/40 (16% worse than 20/200). Lens opacities (39% of gradeable phakic eyes), macular edema (36%), and epiretinal membrane (48%) were common. Mean health utility was 74.1. CONCLUSIONS The MUST trial will compare fluocinolone acetonide implant versus systemic therapy for management of intermediate uveitis, posterior uveitis, and panuveitis. Patients with intermediate uveitis, posterior uveitis, or panuveitis enrolled in the trial had a high burden of reduced visual acuity, cataract, macular edema, and epiretinal membrane; overall quality of life was lower than expected based on visual acuity.

Effect of technique on intraocular pressure after combined cataract and glaucoma surgery: An evidence-based review

TOPIC To analyze the literature pertaining to the techniques used in combined cataract and glaucoma surgery, including the technique of cataract extraction, the timing of the surgery (staged procedure versus combined procedure), the anatomic location of the operation, and the use of antifibrosis agents. CLINICAL RELEVANCE Cataract and glaucoma are both common conditions and are often present in the same patient. There is no agreement concerning the optimal surgical management of these disorders when they coexist. METHODS/LITERATURE REVIEWED Electronic searches of English language articles published since 1964 were conducted in Pub MED and CENTRAL, the Cochrane Collaborations database. These were augmented by a hand search of six ophthalmology journals and the reference lists of a sample of studies included in the literature review. Evidence grades (A, strong; B, moderate; C, weak; I, insufficient) were assigned to the evidence that involved a direct comparison of alternative techniques. RESULTS The preponderance of evidence from the literature suggests a small (2-4 mmHg) benefit from the use of mitomycin-C (MMC), but not 5-fluorouracil (5-FU), in combined cataract and glaucoma surgery (evidence grade B). Two-site surgery provides slightly lower (1-3 mmHg) intraocular pressure (IOP) than one-site surgery (evidence grade C), and IOP is lowered more (1-3 mmHg) by phacoemulsification than by nuclear expression in combined procedures (evidence grade C). There is insufficient evidence to conclude either that staged or combined procedures give better results or that alternative glaucoma procedures are superior to trabeculectomy in combined procedures. CONCLUSIONS In the literature on surgical techniques and adjuvants used in the management of coexisting cataract and glaucoma, the strongest evidence of efficacy exists for using MMC, separating the incisions for cataract and glaucoma surgery, and removing the nucleus by phacoemulsification.