Albert T. Vitale

Expert Panel Recommendations for the Use of Anti–Tumor Necrosis Factor Biologic Agents in Patients with Ocular Inflammatory Disorders

TOPIC To provide recommendations for the use of anti-tumor necrosis factor α (TNF-α) biologic agents in patients with ocular inflammatory disorders. CLINICAL RELEVANCE Ocular inflammatory diseases remain a leading cause of vision loss worldwide. Anti-TNF-α agents are used widely in treatment of rheumatologic diseases. A committee of the American Uveitis Society performed a systematic review of literature to generate guidelines for use of these agents in ocular inflammatory conditions. METHODS A systematic review of published studies was performed. Recommendations were generated using the Grading of Recommendations Assessment, Development, and Evaluation group criteria. RESULTS Numerous studies including controlled clinical trials have demonstrated that anti-TNF-α biologic agents (in particular infliximab and adalimumab) are effective in the treatment of severe ocular inflammatory disease. Based on these studies, the expert panel makes the following recommendations. CONCLUSIONS Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçets disease. Infliximab and adalimumab can be considered as second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis. Infliximab and adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy, and scleritis in patients requiring immunomodulation in patients who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. Infliximab and adalimumab can be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success.

Low-dose Cyclosporine Therapy in the Treatment of Birdshot Retinochoroidopathy

INTRODUCTION Birdshot retinochoroidopathy is an uncommon uveitic syndrome of presumed autoimmune etiology. Therapy with systemic and periocular steroids is of inconsistent efficacy, attendant with numerous potential long-term side effects. Steroid-sparing strategies with more specific agents such as cyclosporine (Cyclosporin A, CSA) have been suggested as the first line treatment for this disease. PATIENTS AND METHODS The records of 19 patients (35 eyes) with the clinical diagnosis of birdshot retinochoroidopathy were examined. Age at onset ranged from 33 to 69 years (mean, 46.1 years) in nine men and ten women. The median follow-up from disease onset was 36 months. Eight patients were treated with low-dose (2.5-5 mg/kg daily) CSA alone, six required the addition of azathioprine (1.5-2 mg/kg daily), and six received no systemic immunosuppressive therapy. RESULTS HLA-A29 was positive in 94% (16 of 17) of patients tested. Vitreous inflammation was controlled in 23 (88.5%) treated eyes, with fewer bouts of recurrent inflammation, and a corresponding improvement or stabilization of visual acuity in 20 (83.3%) eyes. In contrast, intraocular inflammation never was controlled fully in untreated eyes, and visual acuity decreased in six (54.5%) eyes by an average of 2.5 Snellen lines. Nephrotoxic side effects of low-dose CSA therapy were not observed, but hypertension developed in two patients. CONCLUSION Although the definitive strategy for the management of birdshot retinochoroidopathy is unknown, control of intraocular inflammation with a favorable visual outcome, together with a lack of demonstrable CSA-associated nephrotoxicity and secondary side effects in these patients with birdshot retinochoroidopathy indicate that vision preservation is possible with low-dose CSA alone or in combination with other steroid-sparing immunosuppressive agents as an alternative to the long-term use of corticosteroids.

Identifying a Clinically Meaningful Threshold for Change in Uveitic Macular Edema Evaluated by Optical Coherence Tomography

PURPOSE To identify a clinically meaningful threshold for change in retinal thickness measured by optical coherence tomography for patients with uveitic macular edema using correlation with change in visual acuity. DESIGN Cross-sectional and longitudinal study. METHODS One hundred twenty-eight eyes (101 individuals) with macular edema enrolled in the Multicenter Uveitis Steroid Treatment (MUST) trial. At enrollment and after 6 months of follow-up, retinal thickness was measured at the central subfield with time-domain optical coherence tomography and visual acuity was measured with logarithmic (Early Treatment Diabetic Retinopathy Study) visual acuity charts. Participants were classified as having macular edema if the retinal thickness was 260 μm or more. RESULTS A threshold for change in retinal center subfield thickness of 20% balanced the percentage of false positives and false negatives for predicting more than a 10-letter change in visual acuity with a sensitivity of 77% and a specificity of 75%. The results were similar for more than 5-letter changes and for 15-letter or more changes. Those with a 20% or more reduction in retinal thickness had a mean 11.0-letter improvement (95% confidence interval, 7.7 to 14.3) as compared with a -0.4-letter change (95% confidence interval, -4.1 to 3.3) in visual acuity for those without a 20% reduction (P < .01). CONCLUSIONS In addition to being above the level of measurement uncertainty, a 20% change in retinal thickness in patients with macular edema seems to be optimal for clinically important changes in visual acuity and may be considered as an outcome for clinical trials of treatments for uveitic macular edema.

Noninfectious uveitis and pregnancy.

PURPOSE To report the course of uveitis disease activity during pregnancy and the postpartum period in women with noninfectious uveitis. DESIGN Observational case series. METHODS The medical records of women with noninfectious uveitis and pregnancy during follow-up at a large eye hospital were retrospectively reviewed. Patients with pregnancy were included in the study if follow-up was adequate to document the presence or absence of flare-ups in uveitis activity during the pregnancy and/or postpartum period. RESULTS Seventy-six pregnancies among 50 women were included in the study. Thirty-three pregnancies were in women with Vogt-Koyanagi-Harada disease, 19 were in women with Behcet disease, and 24 were in women with idiopathic uveitis. A flare-up in uveitis activity occurred within the first 4 months of pregnancy in 49 of 76 cases (64%) and later in pregnancy in 17 cases (22%); no flare-up occurred during pregnancy in 21 cases (28%). An early pregnancy flare-up was typical of Vogt-Koyanagi-Harada disease and idiopathic uveitis. A flare-up within 6 months of delivery occurred in 38 of 59 cases (64%) that had adequate examination data available from the postpartum period. The postpartum flare-up was especially typical of Behcet disease. CONCLUSIONS Many women with noninfectious uveitis will experience a flare-up in disease activity within the first 4 months of pregnancy. Later pregnancy appears to be a time of relative disease inactivity. Many will experience a rebound in activity within 6 months of delivery.

The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management.

Ocular inflammatory disease is a leading cause of vision loss worldwide. Uveitis encompasses a wide spectrum of pathology, both with respect to its etiology and the anatomic location within the eye. Inflammation can be confined to the eye and may also be seen systemically. The cornerstone of management of ocular inflammatory disease historically has been corticosteroids, which are invaluable in the immediate control of inflammation; however, corticosteroids are inappropriate for long-term use as they are associated with a wide array of toxic side effects. As we continue to learn more about the various etiologies and elucidate the basic science pathways and mechanisms of action that cause intraocular inflammation, new therapeutic approaches have evolved. They include employment of immunomodulatory agents (corticosteroid-sparing therapies) that have expanded our treatment options for these vision-threatening diseases. These pharmacologics provide therapy for ocular and systemic inflammation in an individualized, patient-tailored, stepladder approach with the ultimate goal of durable, corticosteroid-free remission. We review the preferred practice patterns of a tertiary care center specializing in ocular inflammatory disease.

Fluorescein Angiography versus Optical Coherence Tomography for Diagnosis of Uveitic Macular Edema

OBJECTIVE To evaluate agreement between fluorescein angiography (FA) and optical coherence tomography (OCT) results for diagnosis of macular edema in patients with uveitis. DESIGN Multicenter cross-sectional study. PARTICIPANTS Four hundred seventy-nine eyes with uveitis from 255 patients. METHODS The macular status of dilated eyes with intermediate uveitis, posterior uveitis, or panuveitis was assessed via Stratus-3 OCT and FA. To evaluate agreement between the diagnostic approaches, κ statistics were used. MAIN OUTCOME MEASURES Macular thickening (MT; center point thickness, ≥ 240 μm per reading center grading of OCT images) and macular leakage (ML; central subfield fluorescein leakage, ≥ 0.44 disc areas per reading center grading of FA images), and agreement between these outcomes in diagnosing macular edema. RESULTS Optical coherence tomography (90.4%) more frequently returned usable information regarding macular edema than FA (77%) or biomicroscopy (76%). Agreement in diagnosis of MT and ML (κ = 0.44) was moderate. Macular leakage was present in 40% of cases free of MT, whereas MT was present in 34% of cases without ML. Biomicroscopic evaluation for macular edema failed to detect 40% and 45% of cases of MT and ML, respectively, and diagnosed 17% and 17% of cases with macular edema that did not have MT or ML, respectively; these results may underestimate biomicroscopic errors (ophthalmologists were not explicitly masked to OCT and FA results). Among eyes free of ML, phakic eyes without cataract rarely (4%) had MT. No factors were found that effectively ruled out ML when MT was absent. CONCLUSIONS Optical coherence tomography and FA offered only moderate agreement regarding macular edema status in uveitis cases, probably because what they measure (MT and ML) are related but nonidentical macular pathologic characteristics. Given its lower cost, greater safety, and greater likelihood of obtaining usable information, OCT may be the best initial test for evaluation of suspected macular edema. However, given that ML cannot be ruled out if MT is absent and vice versa, obtaining the second test after negative results on the first seems justified when detection of ML or MT would alter management. Given that biomicroscopic evaluation for macular edema erred frequently, ancillary testing for macular edema seems indicated when knowledge of ML or MT status would affect management. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

A novel method for screening the multifocal electroretonogram in patients using hydroxychloroquine.

Purpose: To evaluate retinal function in patients on hydroxychloroquine using multifocal electroretinography. Methods: A retrospective chart review was performed for 23 patients (46 eyes) on hydroxychloroquine therapy and referred for multifocal electroretinogram (mfERG) testing. Duration of treatment, daily hydroxychloroquine dose, visual acuity, fundus examination, color vision testing, Amsler grid testing, visual field examination, and fluorescein angiography results were obtained when available. Multifocal electroretinogram response amplitudes were calculated for the central and paracentral regions and compared with previously published normal values. The central and paracentral regions of the mfERG color difference plot, which assigns colors to localized areas of the mfERG based on deviation from normal, were assessed using a novel Color Difference Plot Scoring System which relies on the color pattern observed within each region. Results: Ninety-two regions were assessed for response amplitudes, 31 of which showed a depressed response amplitude. Of the 17 eyes which had at least one region with a depressed response amplitude, clinical examination findings were relatively benign. Color difference plot scoring showed strong agreement with response amplitude, with a Color Difference Plot Scoring System score of 2 or 3 showing 93.55% sensitivity and 60% specificity for a depressed response amplitude. Interrater reliability of the scoring system as measured by Kendall’s W coefficient of concordance was 0.6484 (P < 0.00001). Conclusion: The mfERG appears to be able to detect decreased retinal function in hydroxychloroquine patients with normal clinical examinations, and may be useful in identifying patients that require close monitoring for the development of clinically relevant toxicity. The Color Difference Plot Scoring System may be used as a tool to aid in the interpretation of results of the mfERG in the clinic setting.

Lack of Consensus in the Diagnosis and Treatment for Ocular Tuberculosis among Uveitis Specialists

Abstract Purpose: To assess the approach of specialists to ocular tuberculosis (TB). Methods: The American Uveitis Society (AUS) Listserv was surveyed using two clinical cases and general questions. Results: Of 196 members, 87 responded (44.4%), of whom 64 were affiliated with practices in North America, while 23 were outside of North America. The survey provided normative data on how physicians evaluate patients with uveitis as well as opinions about ocular TB. Responses varied widely on such issues as (1) the pretest probability that a patient with granulomatous panuveitis had TB uveitis (range 1–75%) or that a patient with a risk factor for TB had ocular TB (range 0–90%); (2) the optimal duration of anti-TB therapy; and (3) whether therapy should be discontinued after 2 months in nonresponders. Conclusions: Consensus is lacking among uveitis specialists for the diagnosis or management of ocular TB.

Bilateral Acute Iris Transillumination Following Systemic Moxifloxacin for Respiratory Illness: Report of Two Cases and Review of the Literature

Purpose: To describe two cases of bilateral acute iris transillumination following systemic administration of moxifloxacin and review the literature. Methods: Review of clinical records, and review of the literature using the PubMed database. Results: A 75 year-old man and 33 year-old woman presented with bilateral conjunctival injection, photophobia, and atonic, distorted pupils. The symptoms began acutely following a respiratory illness, for which both were treated with moxifloxacin. Both patients demonstrated profound iris transillumination, sectoral posterior bowing of the iris, corneal endothelial pigment dusting, and trabecular meshwork hyperpigmentation. One patient had a cotton-wool spot. A literature review identified 59 previous reports in 5 publications, including 17 patients with no antecedent fluoroquinolone use. Conclusions: Increased awareness of this recently described clinical entity should lead to a decrease in unnecessary diagnostic evaluations. It is currently unclear whether this disease represents an adverse effect of fluoroquinolone use or a sequela of a systemic illness.

Acute multifocal placoid pigment epitheliopathy associated with cavernous sinus thrombosis.

Acute multifocal placoid pigment epitheliopathy (AMPPE) has been associated with disease of the central nervous system. In this case report, we discuss a patient presenting with AMPPE in the setting of a new central nervous system association: cavernous sinus thrombosis.