Neuro-ophthalmology

Recent high-powered trials have propelled neuro-ophthalmology towards the domain of modern immunology. Corticosteroids have long been considered the potent immunosuppressive that will smother all inflammation, but we are fully aware of their dangers and their inadequacy in conditions like giant cell arteritis (GCA) and neuromyelitis optica spectrum disorder (NMOSD).

GCA is most common form of vasculitis that occurs in adults, typically over the age of 50, and commonly causes headaches, joint pain, facial pain, fever, difficulties with vision, and sometimes permanent visual loss in one or both eyes.

NMOSD are inflammatory disorders of the central nervous system characterised by severe, immune-mediated demyelination and axonal damage, predominantly targeting the optic nerves and spinal cord, but also the brain and brainstem. With the introduction of modern biologic agents that have disease-specific targets, we hope to minimise morbidity from side effects and uncontrolled inflammation.

Tocilizumab in giant-cell arteritis trial

Stone JH, Tuckwell K, Dimonaco S, et al.

New Eng J Med 2017;377:317

Design: Tocilizumab blocks interleukin-6 (IL-6). This randomised trial had 251 patients with GCA divided into four groups: 1) standard 12 months tapering prednisone + placebo, 2) rapid six-month taper of prednisone + placebo, 3) rapid six-month taper + tocilizumab subcutaneous injections every week; 4) rapid six-month taper + tocilizumab fortnightly.

Outcomes: Sustained remission at 12 months occurred in 56% of patients receiving weekly tocilizumab, 53% receiving fortnightly tocilizumab, 16% receiving placebo + 6 months prednisone and 18% receiving placebo + 12 months prednisone (P<0.001 tocilizumab vs placebo). Tocilizumab groups had lower total steroid dose (1.9 g) than placebo groups (3.3 and 3.8 g), and the rate of serious adverse events was lower in tocilizumab groups (15%) than placebo groups (22% and 25%).

Limitations: Half the patients were diagnosed using imaging, without a positive temporal artery biopsy. One patient on fortnightly tocilizumab lost vision from ischaemic optic neuropathy. The risk of neutropenia in the tocilizumab groups was around 4%.

Comment: Tocilizumab achieved what all other immunosuppressants had failed to achieve for patients with GCA: reducing steroid dose, disease morbidity and total side effect risk. PHARMAC requires multiple other immunosuppressants to be tried before funding tocilizumab, which is neither justified nor safe treatment. We must continue to advocate for access: tocilizumab should become a first line treatment with prednisone. Around half relapsed on tocilizumab, so there remains room for future treatment developments.

A newer IL-6 receptor-blocker called satralizumab has less frequent dosing and was recently shown to reduce relapse rates in NMOSD patients on stable immunosuppressant treatments, particularly in seropositive cases (Yamamura et al, New Engl J Med 2019;381:2114).

 

Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder

Pittock SJ, Berthele A, Fujihara K, et al.

New Engl J Med. 2019;381:614

Design: Eculizumab is a terminal complement inhibitor. This randomised trial had 143 patients with seropositive NMOSD divided 2:1 into two groups: intravenous eculizumab weekly for four weeks then fortnightly, or placebo. Both groups continued standard stable dose immunosuppressants.

Outcomes: The annualised relapse rate in two years before enrolment was 2.0, it then dropped to 0.02 in the eculizumab group and 0.35 in the placebo group during the trial. That is, 3% of eculizumab and 43% of placebo group had relapse in the 12-month trial (P<0.001). A small improvement in disability with eculizumab and small worsening with placebo was of borderline statistical significance.

Limitations: Only seropositive patients were included. Immunosuppressant treatment continued but rituximab was not permitted. The decrease in relapse rate from baseline with placebo was not explained. Serious side effects in the eculizumab group included upper respiratory infections, headaches, and one fatal empyema. Quality of life measures could have been improved to highlight treatment group differences.

Comment: Eculizumab performed very well, which highlights the importance of complement damage to glial cells in the pathology of this antibody mediated condition.

 

Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial

Cree BAC, Bennett JL, Kim HJ, et al.

Lancet 2019;394:1352

Design: Inebilizumab is an anti-CD19, B cell-depleting antibody. Compared to rituximab (anti-CD20), inebilizumab depletes a broader range of B cells and does not deplete any CD20+ T cells. In this randomised trial, 230 patients with NMOSD and at least one relapse/year in the last two years, were divided 3:1 into two groups: 300 mg intravenous inebilizumab or placebo on days one and 15.

Outcomes: Relapse occurred in 12% of participants receiving inebilizumab versus 39% participants receiving placebo, at around six months follow up (hazard ratio 0·272; p<0·0001). Fewer patients receiving inebilizumab had worsening of disability scores. Adverse events were very similar between groups. There was robust suppression of B cells by inebilizumab, but serious neutropenia occurred in only 2% of the treatment group.

Limitations: Low contrast visual acuity outcomes did not differ (but optic neuritis appeared to be less frequent after inebilizumab). There was no comparison to rituximab, although the evidence that rituximab is beneficial in NMOSD is based on far fewer patients in multiple small uncontrolled case series. The seronegative cases were too few for any efficacy conclusions in that group.

 

Comment: Inebilizumab is a new and evidence-based treatment paradigm for NMOSD, with the advantage of only two intravenous treatments. A comparison with rituximab in terms of overall cost, safety and efficacy would be very interesting.

 

Dr Jesse Gale is a consultant ophthalmologist with subspecialist training in glaucoma and neuro-ophthalmology. He works at Capital and Coast DHB, in private at Capital Eye Specialists, and is a senior clinical lecturer at University of Otago. Current projects include new medical device development, advocating for national electronic records, and electrophysiology in optic nerve diseases.

 

Bottom Banner Advert