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.

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.

The Risk of Intraocular Pressure Elevation in Pediatric Noninfectious Uveitis.

PURPOSE: To characterize the risk and risk factors for intraocular pressure (IOP) elevation in pediatric noninfectious uveitis. DESIGN: Multicenter retrospective cohort study. PARTICIPANTS: Nine hundred sixteen children (1593 eyes) younger than 18 years at presentation with noninfectious uveitis followed up between January 1978 and December 2007 at 5 academic uveitis centers in the United States. METHODS: Medical records review by trained, certified experts. MAIN OUTCOME MEASURES: Prevalence and incidence of IOP of 21 mmHg or more and 30 mmHg or more and incidence of a rise in IOP by 10 mmHg or more. To avoid underascertainment, outcomes were counted as present when IOP-lowering therapies were in use. RESULTS: Initially, 251 (15.8%) and 46 eyes (2.9%) had IOP ≥21 mmHg and ≥30 mmHg, respectively. Factors significantly associated with presenting IOP elevation included age of 6 to 12 years (versus other pediatric ages), prior cataract surgery, pars plana vitrectomy, duration of uveitis ≥6 months, contralateral IOP elevation, presenting visual acuity worse than 20/40, and topical corticosteroid use (in a dose-response relationship). The median follow-up was 1.25 years (interquartile range, 0.4-3.66). The estimated incidence of any observed IOP elevation to ≥21 mmHg, to ≥30 mmHg, and increase in IOP by ≥10 mmHg was 33.4%, 14.8%, and 24.4%, respectively, within 2 years. Factors associated with IOP elevation included pars plana vitrectomy, contralateral IOP elevation (adjusted hazard ratio [aHR], up to 9.54; P < 0.001), and the use of topical (aHR, up to 8.77 that followed a dose-response relationship; P < 0.001), periocular (aHR, up to 7.96; P < 0.001), and intraocular (aHR, up to 19.7; P < 0.001) corticosteroids. CONCLUSIONS: Intraocular pressure elevation affects a large minority of children with noninfectious uveitis. Statistically significant risk factors include IOP elevation or use of IOP-lowering treatment in the contralateral eye and local corticosteroid use that demonstrated a dose-and route of administration-dependent relationship. In contrast, use of immunosuppressive drug therapy did not increase such risk. Pediatric eyes with noninfectious uveitis should be followed up closely for IOP elevation, especially when strong risk factors such as the use of local corticosteroids and contralateral IOP elevation are present.

Periocular corticosteroid injections in uveitis: effects and complications.

PURPOSE: To evaluate the benefits and complications of periocular depot corticosteroid injections in patients with ocular inflammatory disorders. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: A total of 914 patients (1192 eyes) who had received ≥ 1 periocular corticosteroid injection at 5 tertiary uveitis clinics in the United States. METHODS: Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained at every visit via medical record review by trained reviewers. MAIN OUTCOME MEASURES: Control of inflammation, improvement of visual acuity (VA) to ≥ 20/40, improvement of VA loss attributed to macular edema (ME), incident cataract affecting VA, cataract surgery, ocular hypertension, and glaucoma surgery. RESULTS: Among 914 patients (1192 eyes) who received ≥ 1 periocular injection during follow-up, 286 (31.3%) were classified as having anterior uveitis, 303 (33.3%) as intermediate uveitis, and 324 (35.4%) as posterior or panuveitis. Cumulatively by ≤ 6 months, 72.7% (95% CI, 69.1-76.3) of the eyes achieved complete control of inflammation and 49.7% (95% CI, 45.5-54.1) showed an improvement in VA from <20/40 to ≥ 20/40. Among the subset with VA <20/40 attributed to ME, 33.1% (95% CI, 25.2-42.7) improved to ≥ 20/40. By 12 months, the cumulative incidence of ≥ 1 visits with an intraocular pressure of ≥ 24 mmHg and ≥ 30 mmHg was 34.0% (95% CI, 24.8-45.4) and 15.0% (95% CI, 11.8-19.1) respectively; glaucoma surgery was performed in 2.4% of eyes (95% CI, 1.4-3.9). Within 12 months, among phakic eyes initially ≥ 20/40, the incidence of a reduction in VA to <20/40 attributed to cataract was 20.2% (95% CI, 15.9-25.6); cataract surgery was performed within 12 months in 13.8% of the initially phakic eyes (95% CI, 11.1-17.2). CONCLUSIONS: Periocular injections were effective in treating active intraocular inflammation and in improving reduced VA attributed to ME in a majority of patients. The response pattern was similar across anatomic locations of uveitis. Overall, VA improved in one half of the patients at some point within 6 months. However, cataract and ocular hypertension occurred in a substantial minority.

Posterior capsular opacification and YAG laser capsulotomy in uveitis patients following cataract surgery.

OBJECTIVE: To evaluate the incidence of visually significant posterior capsule opacification (PCO with visual acuity ≤20/50) and the incidence of Nd:YAG laser capsulotomy in the year following cataract surgery for uveitic eyes. METHOD: Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study using a standardized chart review process. RESULTS: Among 1,855 uveitic eyes of 1,370 patients who had undergone cataract surgery, visually significant PCO occurred in 297 eyes (16%), and YAG laser capsulotomy was done in 407 eyes (22%) within the first year following surgery. Higher odds of developing 20/50 visual acuity attributed to PCO were noted in children and young adults compared with adults older than 65 years of age (overall p = 0.03). Poorer preoperative visual acuity (overall p = 0.0069) and postoperative inflammation (odds ratio [OR] = 1.83; 95% CI, 1.37-2.45; p < 0.0001) were associated with PCO incidence. In multivariable analysis, risk factors for YAG laser capsulotomy were younger age groups compared with those older than 65 years of age at the time of surgery (adjusted OR [aOR] = 1.90-2.24; 95% CI, 1.90-2.24; overall p = 0.0007), female sex (aOR = 1.37; 95% CI, 1.03-1.82; p = 0.03), postoperative active inflammation (aOR = 165; 95% CI, 1.27-2.16; overall p < 0.0001), extracapsular cataract extraction compared with phacoemulsification (aOR = 1.70; 95% CI, 1.17-2.47; overall p < 0.0001), and insertion of an intraocular lens (aOR = 4.60; 95% CI, -2.29-9.25; p < 0.0001). Black race was associated with lower YAG laser capsulotomy incidence than Whites (aOR = 0.36; 95% CI, 0.24-0.52; overall p < 0.0001). CONCLUSIONS: Vision-reducing (≤20/50) PCO is common, occurring in about one sixth of uveitic eyes within 1 year of cataract surgery; a higher number (22%) of eyes underwent YAG laser capsulotomy within the first year. Age and postoperative inflammation following cataract surgery are the variables most associated with the incidence of visually significant PCO and YAG laser capsulotomy.

Remission of Non-Infectious Anterior Scleritis: Incidence and Predictive Factors.

PURPOSE: To assess how often non-infectious anterior scleritis remits and identify predictive factors. METHODS: Our retrospective cohort study at four ocular inflammation subspecialty centers collected data for each affected eye/patient at every visit from center inception (1978, 1978, 1984, 2005) until 2010. Remission was defined as inactivity of disease off all suppressive medications at all visits spanning at least three consecutive months or at all visits up to the last visit (to avoid censoring patients stopping follow-up after remission). Factors potentially predictive of remission were assessed using Cox regression models. RESULTS: During 1,906 years' aggregate follow-up of 832 affected eyes, remission occurred in 214 (170 of 584 patients). Median time-to-remission of scleritis = 7.8 years (95% confidence interval [CI]: 5.7, 9.5). More remissions occurred earlier than later during follow-up. Factors predictive of less scleritis remission included scleritis bilaterality (adjusted hazard ratio [aHR] = 0.46, 95% CI: 0.32-0.65); and diagnosis with any systemic inflammatory disease (aHR = 0.36, 95% CI: 0.23-0.58), or specifically with Rheumatoid Arthritis (aHR = 0.22), or Granulomatosis with Polyangiitis (aHR = 0.08). Statin treatment (aHR = 1.53, 95% CI: 1.03-2.26) within ≤90 days was associated with more remission incidence. CONCLUSIONS: Our results suggest scleritis remission occurs more slowly in anterior scleritis than in newly diagnosed anterior uveitis or chronic anterior uveitis, suggesting that attempts at tapering suppressive medications is warranted after long intervals of suppression. Remission is less frequently achieved when systemic inflammatory diseases are present. Confirmatory studies of whether adjunctive statin treatment truly can enhance scleritis remission (as suggested here) are needed.

Methotrexate for ocular inflammatory diseases.

PURPOSE: To evaluate the outcome of treatment with methotrexate for noninfectious ocular inflammation. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to add methotrexate 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, route of administration of methotrexate, 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, corticosteroid-sparing effects, and incidence of and reason for discontinuation of therapy. RESULTS: Among 384 patients (639 eyes) observed from the point of addition of methotrexate to an anti-inflammatory regimen, 32.8%, 9.9%, 21.4%, 14.6%, 15.1%, and 6.3%, respectively, had anterior uveitis, intermediate uveitis, posterior or panuveitis, scleritis, ocular mucous membrane pemphigoid, and other forms of ocular inflammation. In these groups, complete suppression of inflammation sustained for >or=28 days was achieved within 6 months in 55.6%, 47.4%, 38.6%, 56.4%, 39.5%, and 76.7%, respectively. Corticosteroid-sparing success (sustained suppression of inflammation with prednisone

Remission of Intermediate Uveitis: Incidence and Predictive Factors.

PURPOSE: To evaluate the incidence of remission among patients with intermediate uveitis; to identify factors potentially predictive of remission. DESIGN: Retrospective cohort study. METHODS: Involved eyes of patients with primary noninfectious intermediate uveitis at 4 academic ocular inflammation subspecialty practices, followed sufficiently long to meet the remission outcome definition, were studied retrospectively by standardized chart review data. Remission of intermediate uveitis was defined as a lack of inflammatory activity at ≥2 visits spanning ≥90 days in the absence of any corticosteroid or immunosuppressant medications. Factors potentially predictive of intermediate uveitis remission were evaluated using survival analysis. RESULTS: Among 849 eyes (of 510 patients) with intermediate uveitis followed over 1934 eye-years, the incidence of intermediate uveitis remission was 8.6/100 eye-years (95% confidence interval [CI], 7.4-10.1). Factors predictive of disease remission included prior pars plana vitrectomy (PPV) (hazard ratio [HR] [vs no PPV] = 2.39; 95% CI, 1.42-4.00), diagnosis of intermediate uveitis within the last year (HR [vs diagnosis >5 years ago] =3.82; 95% CI, 1.91-7.63), age ≥45 years (HR [vs age <45 years] = 1.79; 95% CI, 1.03-3.11), female sex (HR = 1.61; 95% CI, 1.04-2.49), and Hispanic race/ethnicity (HR [vs white race] = 2.81; 95% CI, 1.23-6.41). Presence/absence of a systemic inflammatory disease, laterality of uveitis, and smoking status were not associated with differential incidence. CONCLUSIONS: Our results suggest that intermediate uveitis is a chronic disease with an overall low rate of remission. Recently diagnosed patients and older, female, and Hispanic patients were more likely to remit. With regard to management, pars plana vitrectomy was associated with increased probability of remission.

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.

Adverse effects of smoking on patients with ocular inflammation.

BACKGROUND: To evaluate how smoking affects the time to disease quiescence and time to disease recurrence in patients with ocular inflammation. METHODS: A retrospective cohort study of patients with ocular inflammation who were followed longitudinally and had smoking information available in the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study database. RESULTS: Among 2676 patients with active ocular inflammation, smokers were more likely to have bilateral ocular disease and poorer visual acuity on presentation compared with non-smokers and previous smokers. In a multivariate analysis, there was no statistically significant difference in the time to disease quiescence between groups. However, the median time to recurrence of ocular inflammation was statistically significantly longer for non-smokers (9.4 months) and for previous smokers (10.7 months) than for current smokers (7.8 months) (p=0.02). The RR of ocular inflammation recurrence was higher for smokers than for non-smokers (adjusted HR=1.19, 95% CI 1.03 to 1.37) and tended towards significance in previous smokers (adjusted HR=1.11, 95% CI 0.93 to 1.35). CONCLUSIONS: Smoking was associated with an increased likelihood of bilateral ocular inflammation and reduced vision upon presentation, and an increased risk of recurrence compared with not smoking. These results suggest that patients with ocular inflammation should be counselled to stop smoking as part of routine management.

Ocular disease in patients with ANCA-positive vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis-the term recently applied to Wegener's granulomatosis-is a rare multi-system inflammation characterized by necrotizing granulomas and vasculitis. We investigated the ocular manifestations of this disease in a group of patients drawn from five inflammatory eye disease clinics across the United States. Of 8,562 persons with ocular inflammation, 59 individuals were diagnosed with ANCA-positive vasculitis; 35 males and 21 females, aged 16 to 96 years, were included in this study. Ocular diagnoses were scleritis (75.0%), uveitis (17.9%), and other ocular inflammatory conditions (33.9%) including peripheral ulcerative keratitis and orbital pseudotumor. Mean duration of ocular disease was 4.6 years. Oral corticosteroids and other systemic immunosuppressive agents were used by 85.7% and 78.5% of patients, respectively. Over time, patients with ANCA-positive vasculitis experienced 2.75-fold higher mortality than other patients with inflammatory eye disease.

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.