Use of Immunosuppression and the Risk of Subsequent Overall or Cancer Mortality.

PURPOSE: To determine the incidence of all-cause and cancer mortality (CM) in association with immunosuppression. DESIGN: Retrospective cohort study at ocular inflammatory disease (OID) subspecialty centers. We harvested exposure and covariate data retrospectively from clinic inception (earliest in 1979) through 2010 inclusive. Then we ascertained overall and cancer-specific mortalities by National Death Index linkage. We constructed separate Cox models to evaluate overall and CM for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression. PARTICIPANTS: Patients with noninfectious OID, excluding those with human immunodeficiency infection or preexisting cancer. METHODS: Tumor necrosis factor (TNF) inhibitors (mostly infliximab, adalimumab, and etanercept); antimetabolites (methotrexate, mycophenolate mofetil, azathioprine); calcineurin inhibitors (cyclosporine); and alkylating agents (cyclophosphamide) were given when clinically indicated in this noninterventional cohort study. MAIN OUTCOME MEASURES: Overall mortality and CM. RESULTS: Over 187 151 person-years (median follow-up 10.0 years), during which 15 938 patients were at risk for mortality, we observed 1970 deaths, 435 due to cancer. Both patients unexposed to immunosuppressants (standardized mortality ratio [SMR] = 0.95, 95% confidence interval [CI], 0.90-1.01) and those exposed to immunosuppressants but free of systemic inflammatory diseases (SIDs) (SMR = 1.04, 95% CI, 0.95-1.14) had similar mortality risk to the US population. Comparing patients exposed to TNF inhibitors, antimetabolites, calcineurin inhibitors, and alkylating agents with patients not exposed to any of these, we found that overall mortality (adjusted hazard ratio [aHR] = 0.88, 0.89, 0.90, 1.11) and CM (aHR = 1.25, 0.89, 0.86, 1.23) were not significantly increased. These results were stable in sensitivity analyses whether excluding or including patients with SID, across 0-, 3-, or 5-year lags and across quartiles of immunosuppressant dose and duration. CONCLUSIONS: Our results, in a cohort where the indication for treatment was proven unassociated with mortality risk, found that commonly used immunosuppressants-especially the antimetabolites methotrexate, mycophenolate mofetil, and azathioprine; the TNF inhibitors adalimumab and infliximab, and cyclosporine-were not associated with increased overall and CM over a median cohort follow-up of 10.0 years. These results suggest the safety of these agents with respect to overall and CM for patients treated with immunosuppression for a wide range of inflammatory diseases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Corneal Endothelial Transplantation in Uveitis: Incidence and Risk Factors.

PURPOSE: To estimate the incidence of corneal endothelial transplantation (CET) and identify risk factors among patients with noninfectious ocular inflammation. DESIGN: Retrospective cohort study. METHODS: Adult patients attending United States tertiary uveitis care facilities diagnosed with noninfectious ocular inflammation were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Time-to-event analysis was used to estimate the incidence of CET, including penetrating keratoplasty, Descemet stripping endothelial keratoplasty, or Descemet membrane endothelial keratoplasty procedures. The incidence of CET was calculated. Potential risk factors for CET were also evaluated using Cox regression, accounting for correlation between eyes of the same patient. RESULTS: Overall, 14,264 eyes met eligibility criteria for this analysis, with a median follow-up of 1.8 eye-years. The Kaplan-Meier estimated incidence of CET within 10 years was 1.10% (95% CI, 0.68%-1.53%). Risk factors for CET included age >60 years vs <40 years (adjusted hazard ratio [aHR], 16.5; 95% CI, 4.70-57.9), anterior uveitis and scleritis vs other types (aHR, 2.97; 95% CI, 1.46-6.05; and aHR, 4.14; 95% CI,1.28-13.4, respectively), topical corticosteroid treatment (aHR, 2.84; 95% CI, 1.32-6.13), cataract surgery (aHR, 4.44; 95% CI, 1.73-11.4), tube shunt surgery (aHR, 11.9; 95% CI, 5.30-26.8), band keratopathy (aHR, 5.12; 95% CI, 2.34-11.2), and hypotony (aHR, 7.38; 95% CI, 3.14-17.4). Duration of uveitis, trabeculectomy, peripheral anterior synechia, and ocular hypertension had no significant association after multivariate adjustment. CONCLUSIONS: In patients with ocular inflammation, CET occurred infrequently. Tube shunt surgery, hypotony, band keratopathy, cataract surgery, and anterior segment inflammation were associated with increased risk of undergoing CET; these factors likely are associated with endothelial cell damage.

Contemporaneous Risk Factors for Visual Acuity in Non-Infectious Uveitis.

INTRODUCTION: We evaluated the associations of clinical and demographic characteristics with visual acuity (VA) with over 5 years in a subspecialty noninfectious uveitis population. METHODS: Retrospective data from 5,530 noninfectious uveitis patients were abstracted by expert reviewers, and contemporaneous associations of VA with demographic and clinical factors were modeled. RESULTS: Patients were a median of 41 years old, 65% female, and 73% white. Eyes diagnosed ≥5 years prior to cohort entry had worse VA (-1.2 lines) than those diagnosed <6 months prior, and eyes with cataract surgery performed prior to entry had worse VA (-5.9 lines) than those performed during follow-up. Vitreous haze (-4.2 lines for 3+ vs quiet), hypotony (-2.5 lines for ≤5 mm Hg vs 6-23 mm Hg), and CNV (-1.8 lines) all were strongly associated with reduced VA. CONCLUSION: Factors associated with reduced VA included well-known structural complications, and lack of subspecialty care during cataract surgery.

Visual Acuity Outcome over Time in Non-Infectious Uveitis.

Introduction: We evaluated visual acuity (VA) over 5 years in a subspecialty noninfectious uveitis population.Methods: Retrospective data from 5,530 noninfectious uveitis patients with anterior, intermediate, posterior or panuveitis were abstracted by expert reviewers. Mean VA was calculated using inverse probability of censoring weighting to account for losses to follow-up.Results: Patients were a median of 41 years old, 65% female, and 73% white. Initial mean VA was worse among panuveitis (20/84) than posterior (20/64), intermediate (20/47), and anterior (20/37) uveitides. On average, mean VA improved by 0.62, 0.51, 0.37, and 0.26 logMAR-equivalent lines over 2 years, respectively (each P < .001), then remained stable, except posterior uveitis mean VA worsened to initial levels.Conclusion: Mean VA of uveitic eyes improved and, typically, improvement was sustained under uveitis subspecialty care. Because VA tends to improve under tertiary care, mean VA change appears a better outcome for clinical studies than time-to-loss of VA.

Factors Predictive of Remission of Chronic Anterior Uveitis.

PURPOSE: To estimate the incidence of medication-free remission of chronic anterior uveitis and identify predictors thereof. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients diagnosed with anterior uveitis of longer than 3 months' duration followed up at United States tertiary uveitis care facilities. METHODS: Estimation of remission incidence and identification of associated predictors used survival analysis. MAIN OUTCOME MEASURES: Incidence of medication-free remission. For the primary analysis, remission was defined as inactive uveitis while off treatment at all visits spanning an interval of at least 90 days or-for patients who did not return for follow-up after 90 days-remaining inactive without receiving suppressive medications at all of the last visits. Association of factors potentially predictive of medication-free remission was also studied. RESULTS: Two thousand seven hundred ninety-five eyes of 1634 patients with chronic anterior uveitis were followed up over 7936 eye-years (4676 person-years). The cumulative medication-free, person-year remission incidence within 5 years was 32.7% (95% confidence interval [CI], 30.4%-35.2%). Baseline clinical factors predictive of reduced remission incidence included longer duration of uveitis at presentation (for 2 to 5 years vs. less than 6 months: adjusted hazard ratio [aHR], 0.61; 95% CI, 0.44-0.83), bilateral uveitis (aHR, 0.75; 95% CI, 0.59-0.96), prior cataract surgery (aHR, 0.70; 95% CI 0.56-0.88), and glaucoma surgery (aHR, 0.63; 95% CI, 0.45-0.90). Two time-updated characteristics were also predictive of reduced remission incidence: keratic precipitates (aHR, 0.36; 95% CI, 0.21-0.60) and synechiae (aHR, 0.62; 95% CI, 0.41-0.93). Systemic diagnosis with juvenile idiopathic arthritis and spondyloarthropathy were also associated with reduced remission incidence. Older age at presentation was associated with higher incidence of remission (for age ≥40 years vs. <40 years: aHR, 1.29; 95% CI, 1.02-1.63). CONCLUSIONS: Approximately one third of patients with chronic anterior uveitis remit within 5 years. Longer duration of uveitis, younger age, bilateral uveitis, prior cataract surgery, glaucoma surgery, presence of keratic precipitates and synechiae, and systemic diagnoses of juvenile idiopathic arthritis and spondyloarthropathy predict reduced remission incidence; patients with these factors should be managed taking into account the higher probability of a longer disease course.

Comparison Between Methotrexate and Mycophenolate Mofetil Monotherapy for the Control of Noninfectious Ocular Inflammatory Diseases.

PURPOSE: To compare mycophenolate mofetil (MMF) to methotrexate (MTX) as corticosteroid-sparing therapy for ocular inflammatory diseases. DESIGN: Retrospective analysis of cohort study data. METHODS: Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained via medical record review. The study included 352 patients who were taking single-agent immunosuppression with MTX or MMF at 4 tertiary uveitis clinics. Marginal structural models (MSM)-derived statistical weighting created a virtual population with covariates and censoring patterns balanced across alternative treatments. With this methodological approach, the results estimate what would have happened had none of the patients stopped their treatment. Survival analysis with stabilized MSM-derived weights simulated a clinical trial comparing MMF vs MTX for noninfectious inflammatory eye disorders. The primary outcome was complete control of inflammation on prednisone ≤10 mg/day, sustained for ≥30 days. RESULTS: The time to success was shorter (more favorable) for MMF than MTX (hazard ratio = 0.68, 95% confidence interval: 0.46-0.99). Adjusting for covariates, the proportion achieving success was higher at every point in time for MMF than MTX from 2 to 8 months, then converges at 9 months. The onset of corticosteroid-sparing success took more than 3 months for most patients in both groups. Outcomes of treatment (MMF vs MTX) were similar across all anatomic sites of inflammation. The incidence of stopping therapy for toxicity was similar in both groups. CONCLUSIONS: Our results suggest that, on average, MMF may be faster than MTX in achieving corticosteroid-sparing success in ocular inflammatory diseases.

Risk of Retinal Neovascularization in Cases of Uveitis.

PURPOSE: To evaluate the risk of and risk factors for retinal neovascularization (NV) in cases of uveitis. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with uveitis at 4 US academic ocular inflammation subspecialty practices. METHODS: Data were ascertained by standardized chart review. Prevalence data analysis used logistic regression. Incidence data analysis used survival analysis with time-updated covariates where appropriate. MAIN OUTCOME MEASURES: Prevalence and incidence of NV. RESULTS: Among uveitic eyes of 8931 patients presenting for initial evaluation, 106 of 13,810 eyes had NV (prevalence = 0.77%, 95% confidence interval [CI], 0.60-0.90). Eighty-eight more eyes developed NV over 26,465 eye-years (incidence, 0.33%/eye-year; 95% CI, 0.27-0.41). Factors associated with incident NV include age <35 years compared with >35 years (adjusted hazard ratio [aHR], 2.4; 95% CI, 1.5-3.9), current cigarette smoking (aHR, 1.9; 95% CI, 1.1-3.4), and systemic lupus erythematosus (aHR, 3.5, 95% CI, 1.1-11). Recent diagnosis of uveitis was associated with an increased incidence of NV (compared with patients diagnosed >5 years ago, aHR, 2.4 [95% CI, 1.1-5.0] and aHR, 2.6 [95% CI, 1.2-6.0] for diagnosis within <1 year vs. 1-5 years, respectively). Compared with anterior uveitis, intermediate uveitis (aHR, 3.1; 95% CI, 1.5-6.6), posterior uveitis (aHR, 5.2; 95% CI, 2.5-11), and panuveitis (aHR, 4.3; 95% CI, 2.0-9.3) were associated with a similar degree of increased NV incidence. Active (aHR, 2.1, 95% CI, 1.2-3.7) and slightly active (aHR, 2.4, 95% CI, 1.3-4.4) inflammation were associated with an increased incidence of NV compared with inactive inflammation. Neovascularization incidence also was increased with retinal vascular occlusions (aHR, 10, 95% CI, 3.0-33), retinal vascular sheathing (aHR, 2.6, 95% CI, 1.4-4.9), and exudative retinal detachment (aHR, 4.1, 95% CI, 1.3-13). Diabetes mellitus was associated with a somewhat increased incidence of retinal NV (aHR, 2.3, 95% CI, 1.1-4.9), and systemic hypertension (aHR 1.5, 95% CI, 0.89-2.4) was associated with nonsignificantly increased NV incidence. Results were similar in sensitivity analyses excluding the small minority of patients with diabetes mellitus. CONCLUSIONS: Retinal NV is a rare complication of uveitis, which occurs more frequently in younger patients, smokers, and those with intermediate/posterior/panuveitis, systemic vasculopathy, retinal vascular disease, or active inflammation. Inflammation and retinal NV likely are linked; additional studies are needed to further elucidate this connection.

Factors predictive of remission of new-onset anterior uveitis.

PURPOSE: To identify factors predictive of remission of inflammation in new-onset anterior uveitis cases treated at tertiary uveitis care facilities. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients seeking treatment at participating academic uveitis clinics within 90 days of initial diagnosis of anterior uveitis. METHODS: Retrospective cohort study based on standardized chart review. MAIN OUTCOME MEASURES: Factors predictive of remission (no disease activity without corticosteroid or immunosuppressive treatments at all visits during a 90-day period). RESULTS: Nine hundred ninety eyes (687 patients) had a first-ever diagnosis of anterior uveitis within 90 days before initial presentation and had follow-up visits thereafter. The median follow-up time was 160 days. Systemic diagnoses with juvenile idiopathic arthritis (JIA; adjusted hazard ratio [aHR], 0.38; 95% confidence interval [CI], 0.19-0.74) and Behçet's disease (aHR, 0.10; 95% CI, 0.01-0.85) were associated with a lower incidence of uveitis remission. Cases of bilateral uveitis (aHR, 0.68; 95% CI, 0.54-0.87) and those with a history of cataract surgery before presentation (aHR, 0.51; 95% CI, 0.29-0.87) also had a lower incidence of remission. Regarding clinical findings at the initial visit, a high degree of vitreous cells at initial presentation was associated with a lower incidence of remission (for 1+ or more vs. none: aHR, 0.72; 95% CI, 0.55-0.95). An initial visual acuity of 20/200 or worse, with respect to 20/40 or better, also was predictive of a lower incidence of remission (aHR, 0.52; 95% CI, 0.32-0.86). CONCLUSIONS: Factors associated with a lower incidence of remission among new-onset anterior uveitis cases included diagnosis with JIA, Behçet's disease, bilateral uveitis, history of cataract surgery, findings of 1+ or more vitreous cells at presentation, and an initial visual acuity of 20/200 or worse. Patients with these risk factors seem to be at higher risk of persistent inflammation; reciprocally, patients lacking these factors would be more likely to experience remission. Patients with risk factors for nonremission of uveitis should be managed taking into account the higher probability of a chronic inflammatory course.

Risk of choroidal neovascularization among the uveitides.

PURPOSE: To evaluate the risk, risk factors, and visual impact of choroidal neovascularization (CNV) in uveitis cases. DESIGN: Retrospective cohort study. METHODS: Standardized medical record review at 5 tertiary centers. RESULTS: Among 15,137 uveitic eyes (8868 patients), CNV was rare in the cases of anterior or intermediate uveitis. Among the 4041 eyes (2307 patients) with posterior uveitis or panuveitis, 81 (2.0%) had CNV at presentation. Risk factors included posterior uveitis in general and specific uveitis syndromes affecting the outer retina-retinal pigment epithelium-choroid interface. Among the 2364 eyes (1357 patients) with posterior uveitis or panuveitis and free of CNV at the time of cohort entry, the cumulative 2-year incidence of CNV was 2.7% (95% confidence interval [CI], 1.8% to 3.5%). Risk factors for incident CNV included currently active inflammation (adjusted hazard ratio [aHR], 2.13; 95% CI, 1.26 to 3.60), preretinal neovascularization (aHR, 3.19; 95% CI, 1.30 to 7.80), and prior diagnosis of CNV in the contralateral eye (aHR, 5.79; 95% CI, 2.77 to 12.09). Among specific syndromes, the incidence was greater in Vogt-Koyanagi-Harada syndrome (aHR, 3.37; 95% CI, 1.52 to 7.46) and punctate inner choroiditis (aHR, 8.67; 95% CI, 2.83 to 26.54). Incident CNV was associated with a 2-line loss of visual acuity (+0.19 logarithm of the minimal angle of resolution units; 95% CI, 0.079 to 0.29) from the preceding visit. CONCLUSIONS: CNV is an uncommon complication of uveitis associated with visual impairment that occurs more commonly in forms affecting the outer retina-retinal pigment epithelium-choroid interface, during periods of inflammatory activity, in association with preretinal neovascularization, and in second eyes of patients with unilateral CNV. Because CNV is treatable, a systematic approach to early detection in high-risk patients may be appropriate.

Risk of hypotony in noninfectious uveitis.

OBJECTIVE: We sought to describe the risk and risk factors for hypotony in a noninfectious uveitis cohort. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with noninfectious uveitis seen between 1979 and 2007 at 4 academic ocular inflammation specialty clinics. METHODS: Data were collected from medical records by trained, certified, expert reviewers. MAIN OUTCOME MEASURES: Hypotony (<5 mmHg) and low intraocular pressure (<8 mmHg), each sustained for ≥ 2 visits spanning ≥ 30 days. RESULTS: During follow-up, 126 of 6785 patients (1.86%) developed hypotony at the rate of 0.61% (95% confidence interval [CI], 0.50-0.75%) per eye-year. Cataract surgery was associated with a 7.5-fold risk (adjusted hazard ratio [aHR], 7.51; 95% CI, 3.97-14.23) of incident hypotony. Phacoemulsification, the type of cataract surgery associated with the least hypotony risk still was associated with nearly 5-fold higher hypotony incidence (aHR, 4.87; 95% CI, 2.25-10.55). Increased risk was observed in children (aHR, 2.92; 95% CI, 1.20-7.10) with respect to young adults, and duration of uveitis of >5 years (aHR, 3.08; 95% CI, 1.30-7.31) with respect to uveitis of <6 month duration. Band keratopathy, ≥ 3+ vitreous cells, exudative retinal detachment, posterior synechia, and a history of pars plana vitrectomy also were associated with greater hypotony incidence. With respect to anterior uveitis, intermediate uveitis (aHR, 0.17; 95% CI, 0.05-0.56) and posterior uveitis (aHR, 0.11; 95% CI, 0.03-0.45) were associated with lower hypotony risk, whereas panuveitis (aHR, 1.25; 95% CI, 0.67-2.35) was similar. Approximately five-sixths (84.1%) of eyes presenting with hypotony had a visual acuity of ≤ 20/200 (aOR for visual acuity ≤ 20/200, 13.85; 95% CI, 7.23-26.53). Risk factors for prevalent hypotony were similar. CONCLUSIONS: The risk of hypotony is low among eyes with noninfectious uveitis, but is more frequently observed in cases with anterior segment inflammation. Signs of present or past inflammation were associated with greater risk, suggesting excellent inflammatory control may reduce the risk of hypotony. Prior ocular surgery also was associated with higher risk; cataract surgery in particular was associated with much higher risk of hypotony. Lower risk of hypotony with phacoemulsification than with alternative cataract surgery approaches suggests the phacoemulsification approach is preferable.

High-dose intravenous corticosteroids for ocular inflammatory diseases.

PURPOSE: To evaluate the effectiveness and risk of complications of high-dose intravenous pulsed corticosteroids for noninfectious ocular inflammatory diseases. METHODS: Retrospective cohort study in which 104 eyes of 70 patients who received high-dose intravenous corticosteroids for treatment of active ocular inflammation were identified from five centers. The main outcome measures were control of inflammation and occurrence of ocular or systemic complications within 1 month after treatment. RESULTS: Within ≤1 month of starting treatment, 57% of eyes achieved complete control of inflammation (95% confidence interval (CI): 33-83%), improving to 82% when near-complete control was included (95% CI: 61-96%). Most eyes (85%; 95% CI: 70-95%) gained clinically significant improvement in anterior chamber inflammation. One patient developed a colon perforation during treatment. No other major complications were recorded. CONCLUSIONS: Treatment of ocular inflammation with high-dose intravenous corticosteroids resulted in substantial clinical improvement for most cases within 1 month. Complications of therapy were infrequent.

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.

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.

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

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.

Methods for identifying long-term adverse effects of treatment in patients with eye diseases: the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study.

PURPOSE: To evaluate potential epidemiologic methods for studying long-term effects of immunosuppression on the risk of mortality and fatal malignancy, and present the methodological details of the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study. METHODS: Advantages and disadvantages of potential study designs for evaluating rare, late-occurring events are reviewed, and the SITE Cohort Study approach is presented. RESULTS: The randomized, controlled trial is the most robust method for evaluating treatment effects, but long study duration, high costs, and ethical concerns when studying toxicity limit its use in this setting. Retrospective cohort studies are potentially more cost-effective and timely, if records exist providing the desired information over sufficient follow-up time in the past. Case-control methods require extremely large sample sizes to evaluate risk associated with rare exposures, and recall bias is problematic when studying mortality. The SITE Cohort Study is a retrospective cohort study. Past use of antimetabolites, T-cell inhibitors, alkylating agents, and other immunosuppressives is ascertained from medical records of approximately 9,250 ocular inflammation patients at five tertiary centers over up to 30 years. Mortality and cause-specific mortality outcomes over approximately 100,000 person-years are ascertained using the National Death Index. Immunosuppressed and non-immunosuppressed groups of patients are compared with each other and general population mortality rates from US vital statistics. Calculated detectable differences for mortality/fatal malignancy with respect to the general population are 22%/49% for antimetabolites, 28%/62% for T-cell inhibitors, and 36%/81% for alkylating agents. CONCLUSIONS: Information from the SITE Cohort Study should clarify whether use of these immunosuppressive drugs for ocular inflammation increases the risk of mortality and fatal cancer. This epidemiologic approach may be useful for evaluating long-term risks of systemic therapies for other ocular diseases.