Rituximab for Ocular Inflammatory Disease

Rituximab (RTX) is a recombinant, chimeric monoclonal antibody directed against the cell surface protein CD20, which is present predominantly on more mature B-cells^1,2 and to a much lesser extent on a small subset of CD3 + T-cells.³ Targeting of CD20 by RTX results in depletion of circulating B-cells,⁴ an approach used initially to treat B-cell malignancies and more recently for an increasing number of autoimmune conditions. Federal Drug Administration (FDA)-approved uses of RTX in adults include non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA) in combination with methotrexate in patients with moderately-to severely-active RA who have inadequate response to one or more tumor necrosis factor antagonist therapies, granulomatosis with polyangiitis (previously known as Wegener’s granulomatosis), microscopic polyangiitis in combination with glucocorticoids, and pemphigus vulgaris, whereas RTX is approved for pediatric patients with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, and mature B-cell acute leukemia. Off-label use of RTX to treat other inflammatory conditions is common,^5,6 however, particularly for demyelinating and autoimmune disorders – including uveitis,⁷ scleritis,^7,8 and orbital inflammation.^9–11 This issue of Ocular Immunology and Inflammation contains two research articles^12,13 and two letters^14,15 related to the role of RTX in the management of ocular inflammatory diseases.

Bolletta et al¹² retrospectively reviewed the efficacy of intravenous RTX in the treatment of five patients with recurrent Vogt-Koyanagi-Harada (VKH) disease whose uveitis was incompletely controlled with traditional immunotherapy. Subjects were seen between January 2019 and November 2020 at a tertiary referral center in Reggio-Emilia, Italy. Each received 1000 mg of intravenous RTX on days 1 and 15 of treatment, followed by repeat infusions as required for reactivation at six-month intervals or greater. Infusions were accompanied by treatment with intravenous methylprednisolone followed by oral prednisone (1 mg/kg to a maximum of 50 mg) with taper, as well as oral paracetamol and antihistamines to minimize infusion reactions. Prior immunosuppressive treatments were discontinued one month prior to initiating RTX in each patient. Outcome metrics included best-corrected visual acuity (BCVA) and disease activity as assessed both clinically and using multimodal imaging (MMI). Effective corticosteroid-sparing was defined as the ability to reduce and maintain a patient’s systemic corticosteroid dose to 10 mg/day or less. The cohort included one man and four women who ranged in age from 40 to 66 years. The interval from onset of VKH disease to treatment with RTX ranged from 9 to 73 months, with a median of 16 months. Prior to RTX, all patients were on systemic corticosteroids and mycophenolate mofetil and two were on a second immunosuppressive agent – one on cyclosporin and a seond on adalimumab. Follow-up ranged from 12 to 21 months, during which three subjects received a total of four cycles of RTX infusion, whereas two received three rounds. Although anterior segment inflammation was controlled in each subject at the time of first RTX infusion, all showed evidence of active posterior segment inflammation, including four with marked choroidal thickening and one with papillitis. While baseline BCVA was 20/50 or better in eight of the ten affected eyes, one 43-year-old female subject with myopic degeneration developed bilateral choroidal neovascularization (CNV) treated with three serial intravitreal injections of ranibizumab prior to initiating RTX therapy and her vision at baseline was 20/250 in each eye. Baseline choroidal thickness as measured using enhanced depth imaging (EDI) optical coherence tomography (OCT) ranged from 274 to 763 microns, with a median of 466.0 microns. Following either three or four cycles of RTX, BCVA in the right and left eyes with myopic CNV improved to 20/66 and 20/100, respectively, whereas BCVA in the remaining eyes remained stable at 20/50 or better. Moreover, choroidal thickness improved in all eyes resulting in a new range of 101 to 520 microns with a median of 254.5 microns. Cumulative corticosteroid dose for the year prior to initiation of RTX therapy ranged from 5.04 to 10.00 grams with a median of 7.49 grams, whereas the dose for the year following initiation ranged from 0.79 to 3.23 grams with a median of 2.78 grams. At final follow-up, four of the five subjects had been weaned off systemic corticosteroids completely, whereas one required 10 mg/day to maintain quiescence. No RTX-associated adverse events were reported. While the interpretation of BCVA response was limited by generally good baseline visions and the potentially confounding effect of myopic CNV in two of the ten affected eyes, RTX-associated reduction in choroidal thickness in all eyes together with corticosteroid sparing in each subject would seem to support the assertion by the authors and others^716–21 that systemic RTX should be considered in the management of VKH disease that remains refractory to conventional immunosuppressive therapy, and that MMI, especially EDI OCT, can be useful for monitoring disease activity. The authors acknowledged the limitations of their study given that it was small, retrospective, uncontrolled, and from a single tertiary referral center.²²

Vergouwen et al¹⁴ described three patients with severe non-infectious scleritis incompletely controlled on conventional immunotherapy and who showed no subjective or clinical improvement following two or more subconjunctival injections of 2.5 to 7.5 mg of RTX. All subjects were treated at a tertiary referral center in Rotterdam, The Netherlands, and follow-up ranged from eight to ten months. The authors concluded that in contrast to systemic RTX,^7,8 subconjunctival RTX appeared to show no therapeutic benefit in their patients with active scleritis. Local or intralesional RTX has been reported to provide therapeutic benefit for patient with conjunctival lymphoma.²³

Mehta et al¹⁵ reported a 40-year-old Asian Indian woman with systemic lupus erythematosus and antiphospholipid antibody seropositivity seen at a tertiary referral center in Bangalore, India, who developed episcleritis in one eye and peripheral ulcerative keratitis (PUK) in the fellow eye three weeks after receiving an initial RTX infusion. In addition, the patient was on systemic methotrexate, 15 mg/week, and prednisone, 8 mg/day. The authors noted that while systemic RTX is generally used with beneficial effect in patients with both PUK,^24,25 and ocular inflammation broadly,^7–9 worsening of both systemic²⁶ and ocular^27,28 inflammation following RTX infusion has been reported. The authors reminded us that it is important to monitor for disease worsening following the initiation of systemic RTX therapy. While it was unclear whether the reported patient received systemic corticosteroid infusion concurrent with RTX treatment to minimize her risk of infusion reaction, it has been our clinical impression that such corticosteroid bridging can lessen the risk of paradoxical worsening of inflammation in this setting.

Daldal and Naziroglu¹³ investigated the protective effect of RTX on lipopolysaccharide (LPS)-induced oxidative cytotoxicity in human adult retinal pigment epithelial (ARPE)-19 cells in vitro. Rituximab is known to alter calcium channel activity through CD20, a constituent of cell surface Ca²⁺ ion channels. Transient receptor potential melastatin 2 (TRPM2) channel is one such Ca²⁺ ion channel, which is known to be activated in ARPE-19 cells in response to various inflammatory stimuli, resulting in turn in the increased local production of inflammatory mediators. Whereas RTX acts to increase cytosolic Ca²⁺ and reactive oxygen species (ROS) in tumor cells, it acts to inhibit TRPM2-related Ca²⁺ cytosolic influx in many normal cells, an effect that appears to be both anti-inflammatory and protective. The authors showed that these TRPM2 mediated inflammatory effects are inhibited by RTX in ARPE-19 cells, and specifically that RTX treatment lowered specific oxidant, apoptotic, and inflammatory cytokine mediators – each of which contribute to LPS-induced ARPE-19 cell death. They concluded that RTX may provide protection against inflammation-induced RPE damage.

Together, these findings support and expand the growing body of evidence promoting the use of systemic RTX to treat ocular inflammatory disease that is refractory to first-line corticosteroid and immunosuppressive therapies. They also remind clinicians of the importance of close, early observation and the potentially important role of bridging corticosteroids to lessen the risk of early, paradoxical post-infusional worsening of inflammation. New and emerging B-cell depletion strategies^{1,27,28,29,30} hold perhaps even greater promise for the management of the most refractory of forms of non-infectious uveitis, scleritis, and orbital inflammation.^7–9

Acknowledgments

The authors have no relevant financial conflicts.