C. Michael Samson

Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

A human antibody to interleukin-17A is well tolerated and may be effective in the treatment of psoriasis, rheumatoid arthritis, and noninfectious uveitis. Stopping Inflammation in Its Tracks Inflammation—characterized by redness, swelling, and pain and derived from the Latin word inflammare (to set on fire)—is the body’s principal defense against infection and injury. Once the infection has been squelched by the immune system, the inflammatory response is usually switched off. Sometimes, however, immune cells activated during inflammation elude the “off switch,” resulting in tissue destruction and various diseases—including cancer, rheumatoid arthritis, and skin disorders such as psoriasis. Cytokines that activate immune cells are key drivers of inflammation. To address whether blocking one of these cytokines, interleukin-17A (IL-17A), might be a useful therapeutic strategy for treating inflammatory diseases, Hueber and colleagues used a human monoclonal antibody (AIN457) against IL-17A to treat patients in three small proof-of-concept trials for psoriasis, rheumatoid arthritis, and uveitis (eye inflammation). Their results demonstrate that IL-17A participates in these diseases and that the antibody against this cytokine may be an effective therapeutic agent. The proinflammatory cytokine IL-17A is produced by T helper 17 (TH17) cells and affects many different cell types including macrophages and dendritic cells of the immune system, as well as epithelial, endothelial, and skin cells. IL-17A has been implicated in psoriasis, rheumatoid arthritis, and uveitis, but its exact role is unclear. The etiologies and symptoms of these three diseases are very different. TH17 and TH1 cells have been implicated in both psoriasis (characterized by excessive turnover of skin cells resulting in scaly skin patches) and uveitis (intraocular inflammation that can lead to vision loss). In contrast, in the autoimmune disease rheumatoid arthritis, autoreactive T and B cells together with autoantibodies promote prolonged inflammation, ultimately resulting in the destruction of cartilage and bone. In their three proof-of-concept trials, Hueber and co-workers treated a total of 60 patients with the human monoclonal antibody AIN457 at different doses and observed no major adverse effects. Although the trials were small and the results were preliminary, improvements were seen in all three disease groups. Psoriasis patients receiving AIN457 showed reduced scaly skin patches, decreased production of inflammatory cytokines, and a reduction in T cells infiltrating the skin lesions compared with placebo-treated patients. After receiving infusions of AIN457, rheumatoid arthritis patients exhibited reduced inflammation of the synovial joints as shown by improvements in three different clinical scores compared with placebo-treated patients. Meanwhile, patients with uveitis treated with AIN457 showed improved visual acuity, reduced ocular inflammation, or a reduced need for steroid drugs after 8 weeks. These encouraging results warrant larger clinical trials to assess further the safety and efficacy of AIN457 for treating psoriasis, rheumatoid arthritis, and uveitis and perhaps other inflammatory diseases in which IL-17A has been implicated. Interleukin-17A (IL-17A) is elaborated by the T helper 17 (TH17) subset of TH cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A–producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.

BEVACIZUMAB (AVASTIN) AND RANIBIZUMAB (LUCENTIS) FOR CHOROIDAL NEOVASCULARIZATION IN MULTIFOCAL CHOROIDITIS

Background: Multifocal choroiditis (MFC) is an inflammatory condition, occasionally associated with choroidal neovascularization (CNV). Bevacizumab (Avastin) and ranibizumab (Lucentis) are therapies that target vascular endothelial growth factor. Bevacizumab and ranibizumab have been used successfully to treat CNV in age-related and myopic macular degeneration. Purpose: To describe the treatment of MFC-associated CNV with intravitreal bevacizumab and/or ranibizumab. Design: Retrospective interventional case series. Participants: Six eyes of five patients with MFC-associated CNV were treated with intravitreal bevacizumab and/or ranibizumab. Main Outcome Measures: Visual acuity at 1, 3, and 6 months after the initial injection. Results: Previous therapies (number of eyes treated) included sub-Tenons corticosteroids (2), intravitreal corticosteroids (1), photodynamic therapy (1), and thermal laser (1). The mean number (range) of antivascular endothelial growth factor injections per eye was 2.3 (1–6). The mean duration (range) of follow-up per patient was 41.5 (25–69) weeks. Five of six eyes improved to 20/30 acuity or better at 6 months. One eye suffered a subfoveal rip of the retinal pigment epithelium with 20/400 acuity. There was a qualitative decrease in clinical and angiographic evidence of CNV. Conclusions: Bevacizumab and ranibizumab were effective at improving visual acuity over 6 months in a small series of patients with MFC-associated CNV. Tears of the retinal pigment epithelium may occur after intravitreal antivascular endothelial growth factor therapy in MFC-associated CNV.

CHIKUNGUNYA-ASSOCIATED UVEITIS AND EXUDATIVE RETINAL DETACHMENT: A CASE REPORT.

PURPOSE To report the first known case of bilateral granulomatous panuveitis secondary to chikungunya fever in the United States, acquired by a U.S. citizen traveling from an endemic region. METHODS Case report. RESULTS A 47-year-old woman presented with 10 days of bilateral decreased vision and photophobia concurrent with a febrile illness contracted while visiting the Dominican Republic. She presented with bilateral granulomatous panuveitis and exudative retinal detachments. Extensive workup was negative with the exception of positive chikungunya virus immunoglobulin G and immunoglobulin M titers. Initially, she responded to corticosteroid treatment but developed recurrent inflammation 3 months after completing the initial treatment. Immunomodulatory therapy was initiated at the time of recurrence, and with immunomodulatory therapy alone her inflammation has been controlled for 6 months. CONCLUSION The prevalence of chikungunya fever-related uveitis is increasing with the recent epidemics throughout the Americas. Inflammation can occur during the febrile illness or months later and can manifest in a variety of ways. Posterior segment inflammation is more commonly a delayed presentation. Previous reports suggest that chikungunya fever-related uveitis responds well to corticosteroid therapy. This is the first reported case of recurrent inflammation. Given the wide variety of presentations, chikungunya fever-related uveitis should be included in the differential diagnosis of all at-risk patients presenting with acute ocular inflammation, particularly those traveling from endemic regions.

Fundus image diagnostic agreement in uveitis utilizing free and open source software

OBJECTIVE To assess the adequacy of image agreement regarding uveitis based on color fundus and fluorescein angiography images alone, and to use free and open source applications to conduct an image agreement study. DESIGN Cross-sectional agreement study. PARTICIPANTS Baseline fundus and fluorescein images of patients with panuveitis, posterior, or intermediate uveitis enrolled in the Multi-center Uveitis Steroid Treatment (MUST) trial. METHODS Three fellowship-trained specialists in uveitis independently reviewed patient images using ClearCanvas™ and responded using Epi Info™. The diagnoses of the 3 reviewers were compared with the MUST clinician as a gold standard. A rank transformation adjusted for the possible variation in number of responses per patient. Chance-corrected interobserver agreement among the 3 reviewers was estimated with the ι coefficient. Confidence interval (CI) and SE were bootstrapped. RESULTS Agreement between the diagnoses of the respondents and the baseline MUST clinicians diagnosis was poor across all diagnostic categories, ι = 0.09 (95% CI, 0.07-0.11). The agreement among respondents alone also was poor, ι = 0.11 ± 0.02 (95% CI, 0.08-0.13). The specialists requested more patient historical and clinical information to make a diagnosis on all patients. CONCLUSIONS The role in distinguishing the multiple conditions in uveitis appears to be limited when based on fundus imaging alone. Future studies should investigate different categories of clinical data to supplement image data. Freely available applications have excellent utility in ophthalmic imaging agreement studies.

Giant sarcoid tumor of the iris and ciliary body.

Purpose: To report the occurrence of a giant iridociliary sarcoid tumor. Methods: The patient was evaluated by medical history, ophthalmoscopic examination (including photography and ultrasonography) as well as systemic, hematologic, and radiographic examinations. Tumor biopsies allowed for cytopathologic, histopathologic, and immunohistochemical analysis. Results: The 39-year-old black male was found to have a right iris and ciliary body tumor. Ultrasonography revealed a 10×12-mm base, 5.6-mm height, low internal reflectivity, and vitreous debris. Radiographic imaging revealed mediastinal and bilateral hilar lymphadenopathy. A purified protein derivative (PPD) and a hematologic survey were negative. Pathology evaluations of the surgical specimens revealed features of non-caseating granulomata consistent with sarcoidosis. A combination of topical and systemic steroid therapy was locally curative. Conclusions: We describe a giant iridociliary sarcoid tumor in a patient with no lacrimal gland enlargement, conjunctival nodules, or skin lesions. A biopsy was required to establish the diagnosis.

Polychromatic angiography for the assessment of VEGF-induced BRB dysfunction in the rabbit retina.

PURPOSE To determine the utility of polychromatic angiography (PCA) in the assessment of VEGF-induced blood retinal barrier (BRB) dysfunction in rabbits. METHODS Twenty-six eyes of 24 Dutch Belted rabbits were injected intravitreally with 1.25 μg (group A, n = 5), 10 μg (group C, n = 7), or 4 μg (group B, n = 6; group D, n = 4; and group E, n = 4) of VEGF on day 0. Groups D and E were also injected intravitreally with 1.25 μg and 12.5 μg bevacizumab, respectively, on day 2. On days 0, 2, 4, 7, 11, and 14, PCA was performed using a contrast agent mixture composed of fluorescein sodium, indocyanine green, PCM102, and PCM107 and imaged with a modified fundus camera. PCA scores were based on detected leaking fluorophores. RESULTS On day 7, there was a statistically significant difference between PCA scores of group A (0.6 ± 0.89) and both groups B (2.67 ± 1.37, P = 0.0154) and C (3.33 ± 0.52, P = 0.00085). There was also a statistically significant difference between groups B and E (PCA score 0.75 ± 0.96, P = 0.032) on day 7. On day 11, there was statistically significant difference between group C (1.80 ± 1.1) and both groups A (0, P = 0.021) and B (0.33 ± 0.52, P = 0.037). CONCLUSIONS A differential response to both increasing VEGF dose and administration of bevacizumab could be discerned using the PCA. PCA allowed stratification of VEGF-induced BRB dysfunction and inhibitory effects of bevacizumab therapy in the rabbit retina.