Rituximab for non-infectious Uveitis and Scleritis

Purpose To provide a comprehensive review of rituximab use for the treatment of non-infectious uveitis and scleritis. Methods Review of literature through December 2020. Results Individual data was available for 229 patients with refractory non-infectious uveitis (n = 108) or scleritis (n = 121) who received treatment with rituximab (RTX). Rituximab was generally utilized as third-line or later treatment (uveitis: 67/90, 74.4%; scleritis: 90/96, 93.8%) at a mean of 33.5 months following the diagnosis of uveitis (range = 0 to 168.0 months; median = 24.0 months) and 39.4 months after diagnosis of scleritis (range = 1.0 to 168.0 months; median = 21.0 months). Patients with non-infectious uveitis and scleritis either received prior treatment with corticosteroids only (uveitis: 18/90, 20%; scleritis: 4/94, 4.3%), or with one (uveitis: 19/90, 21.1%; scleritis: 30/94, 31.9%), two (uveitis: 11/90, 12.2%; scleritis 27/94, 28.7%), or three or more (uveitis: 37/90, 41.1%; scleritis: 31/94, 33.0%) corticosteroid-sparing immunosuppressive agents with or without corticosteroids before initiation of RTX treatment. The rheumatologic protocol (two infusions of 1 gram of RTX separated by 14 days) was utilized most frequently (uveitis: 45/87, 51.7%; scleritis: 87/114, 76.3%), followed by the Foster protocol (eight weekly infusions of 375 mg/m2 RTX; uveitis: 18/87, 20.7%; scleritis: 10/114, 8.8%), and the oncologic protocol (four weekly infusions of 375 mg/m2 RTX; uveitis: 5/87, 5.7%; scleritis: 6/114, 5.3%). Various other off-label regimens were used infrequently (uveitis: 19/87, 21.8%; scleritis 11/114, 9.6%). Rituximab treatments resulted in a positive therapeutic response for the majority of patients with non-infectious uveitis (81/97, 83.5%). Commonly treated uveitic diagnoses included non-paraneoplastic autoimmune retinopathy (30/107, 28.0%), juvenile idiopathic arthritis (21/107, 19.6%), Vogt-Koyanagi-Harada disease (12/107, 11.2%), and Behçet disease (11/107, 10.3%). Cases of non-infectious scleritis were most commonly attributed to granulomatosis with polyangiitis (75/121, 62.0%) and rheumatoid arthritis (15/121, 12.4%), and showed an even greater rate of positive therapeutic response (112/120, 93.3%) following RTX treatment. No side effects were reported in 76.3% (74/97) of uveitis and 85.5% (71/83) scleritis cases. Of those cases associated with RTX-induced adverse events, the most common were infusion reactions of various severity (11/35, 31.4%). Conclusions Overall, RTX appeared to be both effective and well-tolerated as second or third-line therapy for patients with non-infectious uveitis and scleritis.


Introduction
While corticosteroids are the first-line therapy for noninfectious uveitis and scleritis, their prolonged use is limited by common side effects [1][2][3]. Patients requiring long-term immunosuppression for severe disease have been traditionally treated with non-corticosteroid immunosuppressive agents such as methotrexate or azathioprine, leukocyte inhibitors such as cyclosporine or tacrolimus, or with alkylating agents such as cyclophosphamide or chlorambucil [1,2,4,5]. For ocular inflammation refractory to these more traditional therapies, practitioners have increasingly turned to use of biologic agents such as intravenous immunoglobulin, interferons, and tumor necrosis factor (TNF) antagonists [5,6]. Rituximab (RTX; Rituxan®, Genentech, South San Francisco, CA, USA), a fully humanized anti-CD20 antibody, has gained increasing use and acceptance for the treatment noninfectious ocular inflammation refractory to corticosteroids and traditional immunotherapies. Rituximab causes a depletion of B cells for up to 6 months and is approved by the Food and Drug Administration (FDA) for treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA), and granulomatosis with polyangiitis (GPA, formerly Wegener's Granulomatosis) and microscopic polyangiitis [6][7][8]. Use of RTX has been described in over 100 cases each of refractory non-infectious uveitis and scleritis, as summarized below.

Methods
The authors conducted a literature search using the National Library of Medicine's PubMed database for all English language articles published through December 2020 with the following search terms: "rituximab AND eye", "rituximab AND uveitis," and "rituximab AND scleritis." Use of RTX for orbital inflammation was summarized in a separate companion review [9]. Relevant references within these articles were also reviewed. Included here were all cases of non-infectious scleritis and uveitis for which individual case data was available. Articles describing large series of patients in which individual case data was not provided were not included in the current analysis, but were read for content and referenced when appropriate. Individual information on patient age, sex, anatomical localization and cause of disease, treatment prior to initiation of RTX, time from diagnosis to initiation of RTX, visual acuity before RTX treatment began, visual acuity at last visit, RTX treatment regimen, total number of RTX cycles and interval between cycles, therapeutic response, treatments following initiation of RTX therapy, duration of follow-up and whether disease recurrence occurred, and adverse events attributed to RTX were collected when available. Therapeutic response varied from study to study. In this review, a patient was considered to have had a positive therapeutic response to RTX if they achieved disease quiescence, showed a two-step or more improvement in inflammation as graded by Standardization of Uveitis Nomenclature group [10], showed relative or absolute sparing of corticosteroids or non-corticosteroid medications, or if the authors subjectively documented improvement. Line of therapy was tallied according to the following criteria: first-line -RTX initiated before or at same time as corticosteroids; second-line -RTX initiated after corticosteroidseither alone or with a second more traditional immunosuppressive agent; third-line or greater -RTX initiated after a non-corticosteroid immunosuppressive agent, such as nonbiologic or biologic disease modifying antirheumatic drug, alkylating agents, or intravenous immunoglobulins, with or without corticosteroids. Treatment regimens were classified into either the rheumatologic protocol (two doses of 1000 mg separated by 14 days) [11], the oncologic protocol (four doses of 375 mg/m 2 weekly) [12], the Foster protocol (eight doses of 375 mg/m 2 weekly) [13], or other category for the less commonly utilized dosing protocols. Univariate comparisons were made with two-tailed Ttest and nomimal, uncorrected p-values were reported.
Cancer-associated retinopathy (CAR) and melanomaassociated retinopathy (MAR) In total, 10.3% of patients (11/107; 10 CAR, 1 MAR) with non-infectious uveitis were treated with RTX for paraneoplastic retinopathy. These patients had a male to female ratio of 0.38 to 1 and mean age of 63.3 years (range = 46.0 to 86.0 years; median 61.0 years) when RTX treatment began. The mean interval from diagnosis of CAR or MAR to initiation of RTX treatment was 19.1 months (range = 0 to 75.0 months; median = 12.5 months). A total of 81.8% (9/11) of patients received treatment with either the rheumatologic or oncologic protocol, while the dose and frequency was unspecified in 18.2% (2/11). Following RTX treatment, 54.5% (6/11) of cases were assessed to have a positive therapeutic response based on improvement in vision, visual fields, and/or ERG. Overall, 75.0% (6/8) reported no adverse events following RTX treatments, but unspecified infusion reactions were reported in two patients (2/8, 25.0%) [14].

Vogt-Koyanagi-Harada (VKH) disease
Patients with VKH disease accounted for 11.2% (12/107) of patients with non-infectious uveitis who were treated RTX. All patients were female and possessed a mean age of 23.4 years (range = 8.0 to 41.0 years; median = 21.0 years) at time of RTX therapy. The mean interval from initial diagnoses of uveitis to RTX treatment was 49.5 months (range = 10.0 to 156.0 months; median = 36.0 months). In total, 72.7% (8/ 11) of patients were diagnosed with anterior uveitis and 27.3% (3/11) with panuveitis. A total of 66.7% (8/12) were treated according to the rheumatologic protocol, and the remaining 33.3% (4/12) with a variety of uncommon offlabel regimens. All subjects received two or more doses without any reported adverse events and were described to achieve disease remission without relapse at mean follow up of 19.8 months (range = 9.0 to 36.0 months; median = 17.0 months).

Scleritis (Tables 1, 3)
There have been a total of 36 reports describing 121 patients who received treatment with RTX for noninfectious scleritis [11, 12, 24, 37- [48,61,68,70]. However, the rationale of designated treatment intervals and indications for retreatment in other reports were unclear. Of note, three patients developed disease recurrence despite receiving RTX treatment cycles every 4 to 6 months [55,57], and two patients experienced relapse while receiving repeat infusions of unreported interval [47].

Granulomatosis with Polyangiitis
In total, 62.0% (75/121) of patients with non-infectious scleritis who received RTX treatment possessed an underlying diagnosis of GPA. These patients had a male to female ratio of 0.80 to 1 and a mean age of 48.  [58,62], and one patient each (1/45, 2.2%) developed herpes zoster [56], ocular hypertension [57], and the nonspecific constellation of dry eyes, weight loss, fatigue, and joint pain [63] attributed to RTX treatment.

Discussion
Rituximab, a fully humanized monoclonal anti-CD20 antibody, has increasingly been utilized as a safe and efficacious treatment of refractory, non-infectious uveitis or scleritis arising from npAIR, JIA, VKH disease, Behçet disease, GPA, and RA. Rituximab was used as a third-line or later treatment in nearly three-quarters of patients with non-infectious uveitis who had been unresponsive to corticosteroid or other corticosteroid-sparing immunosuppressants, with treatment generally initiated 2 to 3 years following initial diagnosis. Half of these patients received the rheumatologic protocol, one fifth the Foster protocol, another fifth various off-label dosing regimens, and the remaining tenth the oncologic protocol. Nearly all patients with non-infectious scleritis refractory to corticosteroid or other corticosteroid sparing immunosuppressants received RTX as a third-line or later agent, with treatment generally initiated 2 to 3 years following initial diagnosis. Three quarters of these patients received the rheumatologic protocol, a tenth various uncommon off-label regimens, another tenth the Foster protocol, and the remaining with the oncologic protocol. Patients with uveitis experienced a positive therapeutic response in more than eight out of 10 cases, with less than a quarter reporting generally mild adverse events that were most commonly injection site reactions. Similarly, patients with scleritis reported disease remission in nearly nine out of 10 cases, with slightly more than a seventh of patients reporting generally mild side effects.
Maintenance of disease remission in patients with refractory non-infectious uveitis and scleritis appeared to be more likely following multiple cycles of RTX treatment or other forms of ongoing systemic immunosuppression. The majority of patients who maintained disease remission following RTX treatment either required other forms of systemic immunosuppression (uveitis: 44.4%; scleritis: 40.3%) or ongoing RTX infusions (uveitis: 29.3%; scleritis: 35.5%). A minority of patients were able to attain sustained drug free remission (uveitis: 17.8%; scleritis: 24.2%). Following the first cycle of RTX treatment, just under one-third of patients (uveitis: 29.6%; scleritis: 30.8%) developed disease recurrence.
Given that the patients in this review tended to possess either intractable non-infectious uveitis or scleritis despite treatments with corticosteroid and traditional non-corticosteroid immunosuppressive agents, it was unsurprising that RTX was generally used as a third-line or later medication. Other possible contributing factors could have been the cost of RTX, a relatively more difficult route of administering RTX, and/or the unfamiliarity to providers with RTX as a treatment choice in such patients. From 2005 to 2020, authors consistently used RTX as a third-line (90/95, 94.7%) medication to treat scleritis. While RTX was also used as predominantly a third-line medication (67/90, 74.4%) for treatment of refractory uveitis, some authors began to utilize RTX as a second-line (18/90, 20.0%) agent to treat VKH disease, npAIR, and CAR beginning in 2017 [14,29]. Of note, RTX was used as a first line-drug for three patients with npAIR and two with CAR [14,17,20,35,36]. Three of these patients were each part of a larger series wherein other patients received RTX as a third-line agent, and no explanation was provided as to why these patients differed in their treatment approach [14,17,20]. Sen et al. and Or et al. both initiated early treatment with RTX in hopes of targeting the B lymphocytes responsible for production of serum antibodies directed against a retinal antigen in the photoreceptor layer [35,36]. The generally positive outcomes noted here suggest, however, that RTX might be considered earlier in the course of therapy in some patients.
Overall, continued long-term immunosuppression appeared to be more important than selecting a particular treatment protocol given the comparable efficacy of the various treatment regimens, and the proclivity for disease relapse in RTX-treated patients with non-infectious uveitis and scleritis. The rheumatologic protocol (132/ 201, 65.7%) was by far the most commonly utilized treatment regimen. Other established treatment regimens such as the Foster and oncologic protocols were utilized to treat a minority of patients. Roughly one in six subjects received various other off-label dosing regimens. Following RTX treatment according to the rheumatologic regimen, more than 90% of those with both uveitis and scleritis experienced a positive therapeutic response. Given limited sample sizes and lack of standardization across the studies, the collected data was insufficient to allow for comparison of treatment efficacy between the various regimens. For those cases with individualized dosing data, about one-third were treated with only 1 cycle of RTX leading to disease remission in more than eight out of 10although roughly one-quarter of those with initial positive therapeutic response eventually relapsed despite subsequent treatment with other forms of systemic immunomodulatory therapy. Nearly one quarter of cases reported using rituximab for 2 cycles, with half receiving a second cycle in response to disease recurrence. The remaining patients received more than 2 cycles of RTX not for specifically for disease relapse, but also for further disease control, scheduled re-treatments to maintain disease remission, or reasons not otherwise specified.
Clinical trials investigating RTX treatment for rheumatologic diseases have found it to be relatively welltolerated with mild to moderate infusion-related reactions as the most common adverse response [76][77][78]. Severe adverse reactions are uncommon, but can include tumor lysis syndrome, severe mucocutaneous reactions, progressive multifocal leukoencephalopathy, hepatitis B reactivation, infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation [79]. Roughly one-fifth (35/180, 19.4%) of RTX-treated patients with non-infectious uveitis and scleritis were reported to have an adverse event. According to the common terminology criteria for adverse events, 40.0% (14/35) were Grade 1 reactions, 37.1% (13/35) were Grade 2 reactions, and 22.8% (8/35) were Grade 3 or 4 reactions; no deaths (Grade 5) were reported. The most common adverse event was an infusion reaction (11/35, 31.4%). Overall, the rate of reported adverse events did not differ significantly from rates reported in the literature [76][77][78].
Our retrospective analysis had limitations as it relied heavily on case descriptions that varied greatly in detail regarding definition of positive therapeutic response, treatment protocols, rationale for retreatment, and total number of RTX cycles, duration of follow-up and whether disease relapse occurred, and presence of adverse events. Reports with individual case data were included, but several larger series provide only statistics rather than case descriptions and could not be incorporated into our calculations. Finally, the efficacy of the studies reviewed here may not reflect a broader population-based sample of refractory non-infectious uveitis and scleritis due to referral, selection, treatment, evaluator, and/or publication bias [80].

Conclusions
Rituximab appears to be an effective and welltolerated option for immunosuppression in patients with non-infectious uveitis and scleritis. Authors generally favored utilizing the rheumatologic protocol and tended to report mild adverse events in about one-fifth of treated patients, with infusion reactions being most common. Uveitis associated with npAIR, JIA, VKH disease, and Behçet disease, and scleritis arising from GPA and RA all appear to be well-suited for use of RTX. In contrast, roughly half of treated patients with CAR showed a positive response. Overall, the current ophthalmologic literature strongly supports RTX use for non-infectious uveitis and scleritis refractory to corticosteroid and traditional non-corticosteroid immunosuppressive agents.