Tocilizumab for the Treatment of Ocular Inflammatory Disease

Tocilizumab (TCZ; Actemra®; Roche/Genentech in the US; Chugai Pharmaceutical Co. in Japan) is a recombinant, humanized monoclonal antibody directed against the interleukin-6 (IL-6) receptor and currently approved by the Food and Drug Administration (FDA) and the European Commission to treat adults with moderately to severely active rheumatoid arthritis (RA) and pediatric patients with polyarticular Juvenile Idiopathic Arthritis (JIA) or systemic JIA. The FDA has also approved TCZ to treat giant cell (temporal) arteritis and adults and pediatric patients with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome. In Japan, TCZ is approved for the treatment of Castleman’s Disease and Takayasu Arteritis. Sarilumab (Kevzara®; Regeneron in the US; Sanofi outside the US) is a similar fully humanized IL-6 R antagonist indicated for the treatment of adults with moderate to severe rheumatoid arthritis (RA). Common side-effects of IL-6 R inhibition include injection site reaction, upper respiratory symptoms, systemic hypertension, hypercholesterolemia, elevated liver enzymes, neutropenia, and thrombocytopenia. Less common complications include severe, opportunistic infections and intestinal perforation. Siltuximab (Sylvant®; EUSA Pharma) is a chimeric monoclonal antibody targeting IL-6 that is approved in both North America and Europe for the treatment of patients with multicentric Castleman’s disease who are both human immunodeficiency virus and human herpesvirus-8 negative. Additional monoclonal antibodies targeting IL-6, including sirukumab (Johnson and Johnson/Centocor), olokizumab (R-Pharm), and clazakizumab (Bristol Myers Squib/Alder Biopharmaceuticals), are advancing through phase 2/3 clinical development, but have yet to receive regulatory approval in North America or Europe.^1,2

Although not approved specifically for the treatment of ocular inflammatory disease or its complications, a number of studies support the use of TCZ to treat active, noninfectious uveitis or scleritis refractory to conventional immunomodulatory therapies,^3–8 most notably scleritis in the setting of rheumatoid arthritis (RA),⁹ JIA-associated uveitis,^9–12 and uveitic macular edema.^13–18 Silpa-archa et al⁹ reported on the use of intravenous TCZ, 4 to 8 mg/kg monthly, in a mixed cohort of 17 patients with ocular inflammatory disease refractory to conventional immunotherapy, including five subjects with JIA-associated uveitis and four with active RA-associated scleritis. Response rates were generally good, with approximately two-thirds of the patients with uveitis and half of the patients with scleritis followed through 9 months achieving control of inflammation and corticosteroid sparing. Four patients discontinued therapy due to TCZ-associated side effects, including neutropenia, persistent dizziness and nausea, angioedema, and severe abdominal pain. Calvo‐Río et al¹⁰ retrospectively studied 25 subjects with JIA-associated uveitis treated with intravenous TCZ, 8 mg/kg, who were refractory to conventional immunosuppression, including tumor necrosis factor (TNF) inhibitors. The authors noted “rapid and maintained improved in all ocular parameter,” including improvement in vision, anterior chamber cells, and central macular thickness in the vast majority of patients. Complete remission of uveitis was observed in 19 of 25 subjects (74.1%) at 12 months. Adverse events noted in one subject each included thrombocytopenia, combined pneumonia and thrombocytopenia, and combined viral conjunctivitis and bullous impetigo. Tappeiner et al¹¹ retrospectively reviewed 17 patients with active JIA-associated uveitis refractory to conventional immunosuppressive agents, including at least one TNF inhibitor, who were treated with intravenous TCZ, 8 mg/kg. Ten subjects (58.8%) achieved quiescence by 6 months, including seven that remained in remission during follow-up, which ranged from three to 12 months (mean 8.5 months). Of the seven remaining subjects, four showed an improvement in disease activity, two remained stable, and one worsened. Macular edema, present in five eyes at baseline, resolved following initiation of TCZ in all cases. Some lowering of systemic corticosteroids or non-corticosteroid immunosuppressive agents was achieved in 13 subjects (76.4%), including seven (41.2%) in whom these conventional agents were discontinued. Systemic arthritis, present in 11 subjects, resolved in six (54.5%). No adverse events requiring discontinuation of TCZ were noted. Most recently, a prospective, seven-center, UK-based phase II trial protocol of TCZ in anti-TNF refractory patients with JIA-associated uveitis (the APTITUDE trial) treated 21 subjects with subcutaneous TCZ, 162 mg every two to 3 weeks based on weight, for up to 24 weeks.¹² Subject ages ranged from five to 17 years and all had active inflammation despite conventional immunosuppressive therapy, including a TNF inhibitor. Eleven eyes of seven subjects (33.3%) showed either a two-step improvement in or resolution of anterior chamber inflammation at week 12. Of the six subjects who continued beyond week 12, four eventually responded (52.4% at week 24). Four subjects had macular edema at baseline, which resolved in three (75.0%). No serious adverse events were attributed to TCZ. The most common non-serious adverse events included injection site reaction, upper respiratory symptoms, headache, arthralgias, and mildly elevated liver enzymes or triglyceride levels, and decreased neutrophil count. While the response rates in the APTITUDE trial were somewhat lower than those reported in earlier retrospective studies, follow-up was limited to 3 months or less in most subjects and TCZ was delivered subcutaneously – a route suggested to be less effective than intravenous administration in at least some patients with JIA.¹⁹ Similarly, several uveitis referral centers^13–16 and the STOP-Uveitis Study Group^17,18 have each reported on the safety and efficacy of intravenous TCZ, 4 to 8 mg/kg monthly, in mixed cohorts of subjects with uveitis and macular edema. These studies noted consistent, overall improvement in mean vision, central retinal thickness, and/or angiographic leakage at 6 months and beyond in those with active uveitis otherwise refractory to conventional therapy. Recognized TCZ-associated adverse events occurred, but were manageable. Three original articles^20–22 and one letter²³ in this issue of Ocular Immunology & Inflammation address the use of TCZ for the treatment of ocular inflammatory disease.

Maleki et al²⁰ retrospectively studied the 12-week response rates of 14 eyes of eight patients who had JIA-associated uveitis refractory to conventional care and who then received intravenous TCZ seen at a tertiary referral center in Boston. Age at first visit ranged from seven to 40 years (mean 16.8 years). The number of medications tried prior to intravenous TCZ ranged from three to six (mean four), with methotrexate and a TNF inhibitor utilized most commonly. Two patients were switched from subcutaneous to intravenous TCZ. By week 12, intravenous TCZ induced and maintained remission in five subjects (eight eyes), including one patient previously incompletely responsive to subcutaneous TCZ, and produced no improvement in three. Among the five patients who responded, anterior chamber inflammation, vitreous haze, and secondary papillitis all resolved completely by month 3, whereas active retinal vasculitis resolved between eight and 15 months. Both mean central foveal thickness (320 vs 280 microns) and vision (20/100 vs 20/60) showed improvement between initiation of intravenous TCZ and last visit, which ranged from nine to 70 months (mean 28.6 months). One patient was switched from monthly intravenous TCZ to weekly subcutaneous TCZ after 18 months of quiescence and remained quiet. No TCZ-associated side effects were noted. The authors concluded that intravenous TCZ can be a safe and effective treatment for patients with refractory JIA-associated uveitis and that selected patients may be successfully switched from monthly intravenous to weekly subcutaneous TCZ following a prolonged period of control.

Wennink et al²¹ described their results using monthly TCZ, 8 mg/kg, to treat seven children with intermediate or panuveitis and severe, vision-threatening leakage of fluorescein angiography (FA) seen at a tertiary referral center in the Netherlands. Ages ranged from three to 11 years, all had active, refractory uveitis despite treatment with combined systemic corticosteroids and one or more non-corticosteroid immunosuppressive agent, including a tumor necrosis factor (TNF) inhibitor (n = 5), unless otherwise contraindicated (two excluded for suspicion of demyelinating disease based on the presence of white matter changes seen on screening magnetic resonance imaging). The cause of the uveitis in all subjects was indeterminant (idiopathic). Uveitis was graded according to the Standardization of Uveitis Nomenclature (SUN) classification, whereas leakage on FA was graded according to the Angiography Scoring for Uveitis Working Group (ASUWOG). Ages ranged from three to 11 years. All subjects showed a dramatic reduction in both overall leakage on FA (14 to 8; nominal p = .018) and in central macular thickness (CMT) on optical coherence tomography (OCT; 321 to 295; nominal p = .043) over the first 6 months of therapy. Best-corrected visual acuity was either stable or improved in all but one affected eye, which developed cataract during the period of the study. Three of five subjects who were receiving systemic corticosteroids at the initiation of TCZ were able to taper off corticosteroids completely. No ocular or systemic side effects were attributed to TCZ use. The authors cited a number of studies that support the efficacy and tolerability of intravenous TCZ in JIA-associated uveitis,^10,11,24 and both intravenous TCZ^{9,13,15,16,25–27} and subcutaneous sarilumab²⁸ in adults with various forms of ocular inflammation and concluded that TCZ can also show rapid and significant improvements in disease activity in children with noninfectious, indeterminant intermediate and panuveitis.

Farhat et al²² described their experience with intravenous TCZ, 8 mg/kg monthly, to treat three patients with refractory relapsing polychondritis (RP) associated ocular inflammation at a tertiary referral center in Paris, France. All three subjects had scleritis and two had secondary uveitis. Intravenous TCZ was used following 6 months of methotrexate and infliximab in one patient, after 2 months of azathioprine in a second, and at presentation in a third. All three subjects showed complete and sustained remission for one to two-years of follow-up, with two requiring the addition of low-dose prednisone, 5 mg/day, and one on intravenous TCZ alone. One patient had transient neutropenia. The authors cited three previous reports of RP-associated ocular inflammation successfully treated with intravenous TCZ^29–31 and suggested that therapeutic IL-6 receptor blockade should be considered in this setting. Others have reported success with intravenous TCZ to treat various forms of scleritis refractory to other therapies.^9,32

Adán et al²³ described a 26-year-old woman with long-standing, bilateral JIA-associated uveitis and macular edema unresponsive to conventional immunotherapy, including prednisone, methotrexate, and successive TNF inhibitors (infliximab followed by adalimumab). Intravenous TCZ, 8 mg/kg monthly, was initiated and following six monthly infusions the patient’s uveitis and macular edema resolved, but she developed neutropenia and lymphadenopathy requiring discontinuation of TCZ at which point both the inflammation and macular edema recurred. Following informed consent, subcutaneous TCZ, 162 mg, was initiated, and after six weekly administrations, the uveitis and macular edema again resolved. The authors noted no recurrence of her neutropenia after 8 months of follow-up and suggested that subcutaneous TCZ might be considered in selected patients who show a good response to intravenous TCZ, but who develop dose-limiting side effects.

Together, these studies highlight both past and potential uses of TCZ to treat ocular inflammatory disease refractory to conventional immunosuppressive therapies, including TNF inhibitors. Existing evidence would seem to support the use of intravenous TCZ as second or third-line therapy, particularly in patients with RA-associated scleritis, JIA-associated uveitis, and uveitic macular edema – although other forms of scleritis and uveitis have shown a clear response to intravenous TCZ in selected subjects. Limited data suggest that subcutaneous administration of TCZ may be less effective than intravenous dosing in patients with ocular inflammatory disease, although several patients have experienced control of their inflammation with subcutaneous delivery and this route may be better tolerated. Tocilizumab is contraindicated in patients with a history of cancer, tuberculosis, invasive fungal infection such as candidiasis, aspergillosis, and pneumocystis, or active bacterial, viral, or parasitic infections. Those treated with TCZ should have their blood pressure, lipid profile, liver enzyme levels, and neutrophil and platelet counts monitored regularly. Patients on TCZ should not receive live, attenuated vaccines.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

Acknowledgements

The authors have no relevant financial conflicts.