Ocular disease in patients with ANCA-positive vasculitis

ANCA-positive vasculitis is multi-system inflammatory disease that may affect different ocular tissues and/or the orbit. Our study provides a comprehensive review of the clinical aspects of this condition, as documented for 56 patients at five tertiary-referral inflammatory clinics across the United States. Scleritis was the most common ocular diagnosis in our patient cohort, accounting for 75% of the inflammatory eye disease. Non-necrotizing anterior scleritis was the most frequently observed subtype of scleritis, but necrotizing disease affected approximately one quarter of patients. Uveitis, peripheral ulcerative keratitis, and orbital inflammation were other manifestations. Notably, although an association between systemic and retinal vasculitis is commonly assumed, the majority of cases of uveitis were anterior in nature. Moreover, 50% of patients with uveitis also suffered from scleritis, suggesting that uveitis may have been secondary to the scleral inflammation. In many patients, ANCA-positive vasculitis required aggressive therapy. During the study, the majority of our patients were treated with systemic corticosteroids, and over three-quarters of the group were prescribed systemic immunosuppressive medications, including cyclophosphamide in 54% of cases. Patients with ANCA-positive vasculitis were at 2.75-fold increased risk of death in comparison to other patients with ocular inflammation.

Two single-center retrospective studies [10, 12] and one review of published cases [15] have documented the ocular and/or orbital involvement in patients with ANCA-positive vasculitis. All three reports describe a diversity of manifestations, including inflammations of the orbit and nasolacrimal system, conjunctiva, cornea, episclera, sclera, uvea, and retina. Some of these manifestations, such as conjunctivitis (12.5–25%) and nasolacrimal obstruction (up to 25%), were not specifically assessed for the SITE cohort of patients. With regard to the diagnoses that were recorded in the database, these three reports found orbital inflammation to be the most common manifestation (25–45%). Scleritis and episcleritis, the most common group of ocular diagnoses in our patients (75%), were also observed frequently (15–38%). One likely explanation for the different distribution of ocular diagnoses is that the cited reports included all patients presenting to the institution or all patients described in the literature of the day, respectively, whereas the clinical information in the SITE database was collected from tertiary-referral inflammatory eye disease clinics only. A fourth single-center study involved 47 patients who were managed at the Ocular Immunology Service of the Massachusetts Eye and Ear Infirmary (MEEI) [21], which is a tertiary-referral inflammatory eye disease clinic. Interestingly, in that series, 74% of patients with ANCA-positive vasculitis had scleritis, and in 67% of patients this was necrotizing. Some of those patients are included in this report. One notable conclusion from the MEEI-based study was that eye involvement may be the first clinical evidence of ANCA-positive vasculitis.

A comprehensive review of therapy for ANCA-positive vasculitis, published in 2006 by White and Lynch [22], provides recommendations for pharmacologic management. A regimen of daily corticosteroid combined with cyclophosphamide is the treatment of choice to induce remission in patients with severe, life-threatening disease. The effectiveness of cyclophosphamide 2 mg/kg body weight per day and prednisone 1 mg/kg body weight per day was tested by Hoffman et al. [5] in their prospective study conducted at NIAID. Of 133 patients treated with this therapy, 91% experienced improvement and 75% experienced complete resolution of disease. In patients with moderately severe disease, methotrexate or azathioprine may be used to maintain remission [22]. Metzler et al. [23] showed that leflunomide may be superior to methotrexate in the prevention of major relapses. Biologics such as tumor necrosis factor (TNF) antagonists and rituximab, an antibody directed against CD20, have been studied on a smaller scale [22]. Regardless of the chosen therapy, relapses are not uncommon, and complications of treatment can be severe. In one placebo-controlled trial of etanercept, in addition to systemic glucocorticoids plus cyclophosphamide or methotrexate for maintenance of remission, there was a striking difference in toxicity between the groups; solid malignancies developed in six of the 89 patients in the etanercept group but none of the 92 patients in the control group [24].

While trials focusing on the treatment of systemic manifestations of ANCA-positive vasculitis are often large, controlled, clinical studies, reports of therapy for patients with ocular and/or orbital manifestations are more limited in terms of numbers of patients and level of evidence. In 1997, Perry et al. [25] published a series of 13 patients with ANCA-positive vasculitis and orbital involvement. Systemic corticosteroids alone were used in ten patients, but only one of these patients experienced remission of disease. Eventually, the majority of the ten patients were treated with the combination of a systemic immunosuppressive medication or trimethoprim–sulfamethoxazole and corticosteroid. A retrospective series of 29 Australian and New Zealand patients with orbital and adnexal manifestations, published in 2001, included 83% of patients who received prednisone and 62% of patients who took cyclophosphamide [26]. Some subjects in this study were treated with trimethoprim–sulfamethoxazole (24%) or radiotherapy (17%). During the period of study, 86% of our population was treated with oral corticosteroids. Forty-four patients were treated with other systemic immunosuppressive agents; 19 individuals (34%) used methotrexate, and 30 individuals (54%) used cyclophosphamide. Six of the 56 patients received biologic agents. The use of biologic agents in our study alone probably reflects the fact that our clinical data were collected through 2007, i.e., including the period of time when biologic agents have become standard therapy for certain inflammatory diseases, whereas other studies were conducted prior to that time.

Our study has certain limitations that warrant discussion. Foremost are ascertainment bias and the retrospective nature of the data collection. In addition, the SITE database was constructed for the specific purpose of identifying incidence of malignancy in patients receiving systemic immunosuppressive medications for inflammatory eye disease. For this reason, some disease- and treatment-related data were limited in relation to the subject of our investigation. In particular, the clinical or laboratory criteria used to make the diagnosis of ANCA-positive vasculitis were not recorded in the database. Authors of smaller studies have specified their use of clinical features, ANCA positivity, and/or tissue biopsies demonstrating granulomatous inflammation with vasculitis and necrosis [11, 13, 21, 25, 26]. For our multi-centered review, we had to assume that the diagnosis was made appropriately by SITE clinicians, all of whom were academic uveitis specialists and expected to confirm a diagnosis of ANCA-positive vasculitis according to standard criteria, such as the 1990 American College of Rheumatology Criteria for Wegener's granulomatosis [27]. Finally, while some investigators have reported results of medical and surgical therapies by following clinical improvements and remission of different manifestations of ANCA-positive vasculitis [5, 11, 14, 25], our methods did not allow us to track the effectiveness of therapy in specific instances. The sampling procedure conducted at one institution is unlikely to impact our results because patients with ANCA-positive vasculitis are one subgroup that is likely to receive systemic immunosuppression.

Despite the discussed limitations, our description of the ocular manifestations of ANCA-positive vasculitis involves a relatively large group of patients who have been managed at multiple centers. In presenting data from five major tertiary-referral inflammatory eye disease clinics in the United States, our study provides a broad representation of ANCA-positive vasculitis. We observed that ANCA-positive vasculitis involved different ocular tissues and the orbit, but most commonly was manifested as scleritis. Patients with ocular complications of ANCA-positive vasculitis were at increased risk of mortality, despite the frequent systemic use of corticosteroid and immunosuppressive medications.