Eric B. Suhler

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.

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.

Mycobacterial diseases and antitumour necrosis factor therapy in USA

Objective In North America, tuberculosis and nontuberculous mycobacterial (NTM) disease rates associated with antitumour necrosis factor α (anti-TNFα) therapy are unknown. Methods At Kaiser Permanente Northern California, the authors searched automated pharmacy records to identify inflammatory disease patients who received anti-TNF therapy during 2000–2008 and used validated electronic search algorithms to identify NTM and tuberculosis cases occurring during anti-TNF drug exposure. Results Of 8418 anti-TNF users identified, 60% had rheumatoid arthritis (RA). Among anti-TNF users, 18 developed NTM and 16 tuberculosis after drug start. Anti-TNF associated rates of NTM and tuberculosis were 74 (95% CI: 37 to 111) and 49 (95% CI: 18 to 79) per 100 000 person-years, respectively. Rates (per 100, 000 person-years) for NTM and tuberculosis respectively for etanercept were 35 (95% CI: 1 to 69) and 17 (95% CI: 0 to 41); infliximab, 116 (95% CI: 30 to 203) and 83 (95% CI: 10 to 156); and adalimumab, 122 (95% CI: 3 to 241) and 91 (95% CI: 19 to 267). Background rates for NTM and tuberculosis in unexposed RA-patients were 19.2 (14.2 to 25.0) and 8.7 (5.3 to 13.2), and in the general population were 4.1 (95% CI 3.9 to 4.4) and 2.8 (95% CI 2.6 to 3.0) per 100, 000 person-years. Among anti-TNF users, compared with uninfected individuals, NTM case-patients were older (median age 68 vs 50 years, p<0.01) and more likely to have RA (100% vs 60%, p<0.01); whereas, tuberculosis case-patients were more likely to have diabetes (37% vs 16%, p=0.02) or chronic renal disease (25% vs 6%, p=0.02). Conclusions Among anti-TNF users in USA, mycobacterial disease rates are elevated, and NTM is associated with RA.

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.

Biologic therapies for inflammatory eye disease

The era of biologic medical therapies provides new options for patients with treatment‐resistant inflammatory eye disease. In this review, the authors summarize current published experience in a rapidly progressing clinical field, including the use of biologics, such as the tumour necrosis factor blockers, daclizumab and rituximab, and related agents, interferons and intravenous immunoglobulin, for the treatment of uveitis, scleritis and orbital inflammation. Reports of dramatic recoveries in patients with recalcitrant ocular inflammation who have received such therapies must be balanced against the high cost of biologics and the potential for serious, and at times unanticipated, complications of this treatment.

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.

Incidence and prevalence of uveitis in Veterans Affairs Medical Centers of the Pacific Northwest.

PURPOSE To ascertain the frequency of uveitis in Veterans Affairs (VA) patients in the Pacific Northwest and to compare disease rates with those in previously published epidemiologic studies. DESIGN Cross-sectional, population based-study. METHODS The medical records of 152,267 patients seen at six VA Medical Centers in Oregon and Washington during fiscal year 2004 were searched for uveitis-related International Classification of Diseases 9th edition codes. Cases were reviewed and classified anatomically, by associated systemic disease, and as incident or prevalent. Only definite cases were used for disease rate calculations. RESULTS This study found a crude incidence of 25.6 cases/100,000 person-years and a crude prevalence of 69 cases/100,000 persons. The most common anatomic location for uveitis was anterior. Approximately half of cases were idiopathic, with human leukocyte antigen-B27-related diseases being the most common identified cause. There was no statistical evidence of increased or decreased incidence with age, although uveitis seemed to be more prevalent in the younger age groups. CONCLUSIONS Our data are consistent with those of most published population-based studies on the epidemiologic features of uveitis, but we detected significantly lower incidence and prevalence than those reported in a recently published study from Kaiser Permanente. The significance of and possible explanations for the differences between our data and that published by the Kaiser group are discussed.

Prevalence of serologic evidence of cat scratch disease in patients with neuroretinitis

OBJECTIVE To determine the prevalence of Bartonella henselae seropositivity in patients with a clinical diagnosis of neuroretinitis. DESIGN Retrospective, clinic-based, cross-sectional study. PARTICIPANTS Eighteen consecutive patients seeking treatment at the Casey Eye Institute from November 1993 through November 1998 who had neuroretinitis. METHODS The billing and photographic records of the Casey Eye Institute were searched for patients with a primary or secondary diagnosis of neuroretinitis or Lebers idiopathic stellate neuroretinitis. Charts were then reviewed to determine the results of B. henselae antibody titers and other pertinent clinical information. MAIN OUTCOME MEASURES Results of B. henselae serologic testing. RESULTS Fourteen of 18 patients with neuroretinitis had serologic studies. Nine of the 14 tested patients (64.3%) were found to have elevated IgM or IgG for B. henselae, suggesting current or past infection. Patients with positive serologic analysis results tended to have worse vision at presentation. There were no other obvious differences between seropositive and seronegative groups in this study, including duration or quality of recovery. CONCLUSIONS At our tertiary care ophthalmology institution, most tested patients with neuroretinitis had evidence of past or present cat-scratch disease based on positive serologic analysis for B. henselae, a much greater prevalence than is expected to be found in the general population or in patients with idiopathic uveitis. Further study is indicated to clarify the prevalence of cat-scratch disease in neuroretinitis and the role and efficacy of antibiotics in treatment.

Adalimumab in Patients with Active Noninfectious Uveitis.

BACKGROUND Patients with noninfectious uveitis are at risk for long-term complications of uncontrolled inflammation, as well as for the adverse effects of long-term glucocorticoid therapy. We conducted a trial to assess the efficacy and safety of adalimumab as a glucocorticoid-sparing agent for the treatment of noninfectious uveitis. METHODS This multinational phase 3 trial involved adults who had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite having received prednisone treatment for 2 or more weeks. Investigators and patients were unaware of the study-group assignments. Patients were randomly assigned in a 1:1 ratio to receive adalimumab (a loading dose of 80 mg followed by a dose of 40 mg every 2 weeks) or matched placebo. All patients received a mandatory prednisone burst followed by tapering of prednisone over the course of 15 weeks. The primary efficacy end point was the time to treatment failure occurring at or after week 6. Treatment failure was a multicomponent outcome that was based on assessment of new inflammatory lesions, best corrected visual acuity, anterior chamber cell grade, and vitreous haze grade. Nine ranked secondary efficacy end points were assessed, and adverse events were reported. RESULTS The median time to treatment failure was 24 weeks in the adalimumab group and 13 weeks in the placebo group. Among the 217 patients in the intention-to-treat population, those receiving adalimumab were less likely than those in the placebo group to have treatment failure (hazard ratio, 0.50; 95% confidence interval, 0.36 to 0.70; P<0.001). Outcomes with regard to three secondary end points (change in anterior chamber cell grade, change in vitreous haze grade, and change in best corrected visual acuity) were significantly better in the adalimumab group than in the placebo group. Adverse events and serious adverse events were reported more frequently among patients who received adalimumab (1052.4 vs. 971.7 adverse events and 28.8 vs. 13.6 serious adverse events per 100 person-years). CONCLUSIONS In our trial, adalimumab was found to be associated with a lower risk of uveitic flare or visual impairment and with more adverse events and serious adverse events than was placebo. (Funded by AbbVie; VISUAL I ClinicalTrials.gov number, NCT01138657 .).