A randomized controlled trial has demonstrated a viable contender for maintaining corticosteroid remission in GCA: the interleukin-6 (IL-6) receptor inhibitor, tocilizumab (TCZ).
Giant cell arteritis (GCA) is a systemic vasculitis that produces a granulomatous inflammation of large- and medium-sized-arteries, most commonly involving the aorta and extracranial branches of the carotid arteries.1,2,3,4
Classically affecting patients over the age of 50 years, GCA is known to be the most common primary vasculitis affecting Western countries.2,3,4
While headaches, myocardial infarction, stroke, and claudication of the jaw are important clinical manifestations of GCA5, those relevant to an ophthalmological perspective include transient ischemic visual symptoms and permanent blindness (e.g., ischemic optic neuropathy or central retinal artery occlusion).1,3
Complications of the vasculitis can result from ischemia secondary to arterial occlusion, systemic inflammation, and aneurysm formation and rupture due to persistent arterial wall injury1 ; therefore, prompt and effective control of inflammation is essential. High-dose corticosteroids (e.g., 1–1.5 mg/kg of oral prednisone per day or intravenous (IV) methylprednisolone) should be considered urgently in the treatment of GCA. Earlier treatment may lead to more rapid symptomatic relief of headache, normalization of inflammatory markers, and reduction or prevention of vision loss after initiation.1,5,6
While corticosteroids have significantly decreased the incidence of blindness in patients with GCA, studies have shown that vascular inflammation persists even after corticosteroid therapy, allowing for progressive occlusion of the affected vessels.1
In addition, since the majority of patients tend to flare as corticosteroid dosage is reduced, long-term treatment with a slow reduction of steroids is thereby necessary.3
Unfortunately, long-term corticosteroid use can lead to significant comorbidities such as infection, fractures, cataracts, diabetes, and even psychosis.3
Consultation with the primary-care provider and/or rheumatologist may be necessary to help with treatment and management of side effects.
For this reason, the search for corticosteroid-sparing treatment regimens in GCA has been under way. Prior randomized controlled trials evaluating corticosteroid-sparing agents such as methotrexate and tumor necrosis factor inhibitors have failed or shown inconclusive or conflicting results.3,6
However, a randomized controlled trial has finally demonstrated a viable contender for maintaining corticosteroid remission in patients with GCA: the interleukin-6 (IL-6) receptor inhibitor, tocilizumab (TCZ).5
The rationale for blocking the receptor for IL-6 is based on the cytokine’s central role in regulating both innate and acquired immunities.3 Produced by T-cells, B-cells, endothelial cells, fibroblasts, and macrophages, IL-6 has been shown to be increased in inflamed arteries, potentiating the inflammatory responses of GCA.3
A study by Weyand et al (2000) suggested that disease activity in GCA correlates with serum levels of IL-6, and that compared to erythrocyte sedimentation rate (ESR), IL-6 may be a more sensitive biological marker for disease activity in GCA patients who were untreated and treated with corticosteroids.1
Consequently, numerous studies (including a phase II trial) examining TCZ were performed, and results suggested the high efficacy of the IL-6 receptor inhibitor in inducing and maintaining remission in GCA.2,4
More recently, the results of the much awaited GiACTA trial, a 1-year, multicenter, randomized, controlled, double blind trial, show significant promise in the use of TCS for inducing and maintaining remission in GCA.3,5
In the GiACTA trial, 251 patients were randomly assigned to one of four treatment groups3:
> 162 mg of subcutaneous TCZ weekly + 26- week prednisone taper (cumulative prednisone dose = 1,862 mg)
> 162 mg of subcutaneous TCZ every two weeks + 26-week prednisone taper (cumulative prednisone dose = 1,862 mg)
> Placebo + 26-week prednisone taper (cumulative prednisone dose = 3,296 mg)
> Placebo + 52-week prednisone taper (cumulative prednisone dose = 3818 mg)
Sustained remission was defined as normalization of C-reactive protein (30 mm/hour) from week 12 to week 52 while adhering to prednisone taper.5
Outcomes were measured at 52 weeks and included rates of corticosteroid-free remission maintained by each TCZ group compared with those of the placebo group treated with a 26-week prednisone taper and a 52-week taper prednisone taper.5
Results of the GiACTA trial showed that by 52 weeks, 56% of patients receiving TCZ weekly and 53% of those receiving it biweekly had achieved and sustained remission, compared to 14% of the placebo group on the 26-week prednisone taper, and 18% of those on the 52-week prednisone taper.5
Furthermore, 23% and 26% of those on TCZ weekly and biweekly had a flare, respectively, compared to 68% of those on the 26-week prednisone taper, and 49% of those on the 52-week taper.5
Safety of TCZ was also evaluated: 15% and 14% of the weekly and biweekly TCZ groups respectively reported serious adverse events, while those in the placebo 26-week taper and 52-week taper reported 22% and 25% adverse events respectively.5
Infection was the most common adverse event in all groups, and occurred in 7% of those on weekly TCZ, 4% on biweekly TCZ, 4% of those on placebo and 26-week taper, and 12% of those on placebo and 52- week taper.5
In conclusion, GiACTA trial has demonstrated with a 1-year, randomized, placebo controlled design that TCZ was more effective in sustaining corticosteroid-free remission than both placebo groups with 26- week and 52-week prednisone taper.5
Furthermore, weekly treatment with TCZ resulted in better control of disease activity than biweekly TCZ.5 Some criticisms have arisen since publication of the GiACTA trial,7,8 and while further studies may be needed to characterize its long-term safety profile and efficacy, TCZ shows significant promise in the treatment of GCA.
Ophthalmologists should be aware of these newer agents including TCZ and should refer selected GCA patients for consideration of treatment in the appropriate clinical situation.
Iyza F. Baig
Baig is affiliated with McGovern Medical School at The University of Texas Health Science Center in Houston (UTHealth), Houston.
Pascoe is affiliated with McGovern Medical School at The University of Texas Health Science Center in Houston (UTHealth), Houston.
Andrew G. Lee, MD
Dr. Lee is affiliated with Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston; Baylor College of Medicine, Houston; adjunct professor of ophthalmology; Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medical College, Houston; clinical professor, UTMB Galveston, TX and the UT M.D. Anderson Cancer Center, Houston; and adjunct professor of ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, IA. The authors did not indicate any proprietary interests relevant to the subject matter.
1. Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ. Treatment of giant cell arteritis: Interleukin-6 as a biologic marker of disease activity. Arthritis and Rheumatism. 2000;43:1041-1048.
2. Villiger PM, Prof, Adler S, MD, Kuchen S, MD, et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387:1921-1927.
3. Unizony SH, Dasgupta B, Fisheleva E, et al. Design of the tocilizumab in giant cell arteritis trial. International Journal of Rheumatology. 2013;2013:1–10.
4. Loricera J, Blanco R, HernÃ¡ndez JL, et al. Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients. Seminars in Arthritis and Rheumatism. 2015;44:717-723.
5. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of Tocilizumab in Giant-Cell Arteritis. New England Journal of Medicine. 2017;377:317-328.
6. Ferfar Y, Mirault T, Desbois AC, et al. Biotherapies in large vessel vasculitis. Autoimmunity Reviews. 2016;15:544-551.
7. GonzÃ¡lez-Gay MA, Loricera J, Blanco R. Trial of Tocilizumab in Giant-Cell Arteritis. New England Journal of Medicine. 2017;377:1493.
8. Walker UA. Trial of Tocilizumab in Giant-Cell Arteritis. New England Journal of Medicine. 2017;377:1493- 1495