“Trial of Tocilizumab in Giant-Cell Arteritis.“
Stone JH, Tuckwell K, Dimonaco S, et al.
N Engl J Med. 2017 Jul 27;377(4):317-328. [Full text]
Summary by Spandana Thenkabail
Giant Cell Arteritis (GCA) is a chronic inflammatory disease involving large and medium sized arteries, affecting individuals older than 50 years. It is characterized by headaches, vision loss, and jaw claudication, and can result in fatal complications such as aortic aneurysms and myocardial infarctions. High dose glucocorticoids with slow tapers have been the mainstay of treatment for flares, as they effectively control inflammation and alleviate symptoms. However, glucocorticoids are not without risk. High and prolonged courses can cause many complications, such as increased risk for infection, fractures, cataracts, diabetes, hypertension and weight gain.
Glucocorticoid risk has prompted investigators to study the role of other agents in treating GCA. Previous phase 2 trials have shown success with Tocilizumab (TCZ), an IL 6 inhibitor, in reducing total glucocorticoid burden and maintaining remission. As such, the authors of this study conducted a large, randomized, double-blinded, placebo-controlled phase 3 trial to investigate whether TCZ resulted in higher rates of glucocorticoid-free remission in patient with GCA compared to placebo at 52 weeks.
Due to the outcomes of this study, TCZ was approved by the FDA for use in GCA. It is reserved for the management of patients who are at high risk for glucocorticoid toxicity or develop glucocorticoid-related side effects during the course of treatment, or who experience frequent, relapsing disease .
251 patients included were those who were: 50 years or older with active GCA within the past 6 weeks, and who have a history of elevated ESR secondary to GCA. The diagnosis of GCA in these patients had to be confirmed by biopsy or evidence of large-vessel vasculitis on angiography, CTA, MRA or PET.
Exclusion criteria: Use of methylprednisolone >100 mg within the past 6 weeks.
Patients were randomized in a 2:1:1:1 ratio to the following groups:
- Treatment 1: Weekly subcutaneous TCZ (162 mg) plus a 26-week prednisone taper
- Treatment 2: Every other week subcutaneous TCZ (162 mg) plus a 26-week prednisone taper
- Placebo 1: Weekly subcutaneous placebo plus a 26-week prednisone taper
- Placebo 2: Weekly subcutaneous placebo plus a 52-week prednisone taper
The primary outcome was the rate of glucocorticoid-free sustained remission at 52 weeks in each tocilizumab group vs the placebo group that underwent the 26 week taper.
“Remission” was defined as absence of a flare and normalization of CRP.
“Sustained remission” was defined as remission from weeks 12 to 52.
Key secondary outcomes include:
- Rate of glucocorticoid-free sustained remission at 52 weeks in each of the tocilizumab groups vs the placebo group that underwent the 52 week taper
- Incidence of first flare after remission
- Cumulative prednisone dose over 52 weeks
- Quality of life changes from baseline to 52 weeks [measured by the 36 item Short Form Survey (SF-36) and Visual Analog Scale (VAS)].
There were significant differences in sustained remission at 52 weeks noted. 56% of the patients in the group that received TCZ weekly and 53% of those in the group that received TCZ every other week had sustained remission at 52 weeks (primary outcome), as compared with 14% of the patients in the placebo group that underwent the 26-week taper (P<0.001 for the comparison of each TCZ group with placebo) and 18% of those in the placebo group that underwent the 52-week taper (key secondary outcome; P<0.001 for the comparison of each TCZ group with placebo).
Other secondary outcomes:
- Rate of flares were significantly less in the groups that received TCZ compared to the placebo group that underwent the 26-week taper. [Hazard ratio 0.23 (99% CI, 0.11 to 0.46) in the group that received TCZ weekly and 0.28 (99% CI, 0.12 to 0.66) in the group that received TCZ every other week]. P<0.001 for both comparisons.
- Total median cumulative prednisone dose over the 52-week period was significantly less in the TCZ groups (1862 mg for TCZ weekly and 1862 mg for TCZ every other week groups), as compared with the placebo groups (3296 mg in the 26-week taper and 3818 mg in the 52-week taper groups). P<0.001 for all comparisons.
- There was also a statistically significant increase in SF-36 survey scores (indicating clinical improvement) in the weekly TCZ group as compared to the placebo groups (99% CI, 0.86 to 10.32; P = 0.002). There was an increase in score for the patients receiving TCZ every other week, but there was no so statistical significance achieved when compared with placebo groups.
- There was a statistically significant mean decrease (indicating improvement) from baseline in global assessment using the VAS questionnaire in both TCZ groups vs placebo.
The authors concluded there were no differences in the number and severity of the adverse events between the two groups.
In light of the serious side effects associated with high dose, long-term glucocorticoid use, this study provides an effective adjunctive therapy to circumvent those toxicities in patients with GCA. Tocilizumab administered weekly and every other week with 26-week steroid taper resulted in a significant increase in sustained remission rates, decrease in cumulative steroid use, decrease in flares, as well improvements in patient-reported clinical outcomes when compared to a steroid-taper alone.
However, it is important to note that medications are not without risk. The study resulted in one significant safety issue with a patient in the TCZ every other week group who developed ischemic optic neuropathy. He was ultimately treated with steroids with resolution of symptoms. This highlights that close monitoring is required, as there are still unknowns with regards to TCZ. Of note, TCZ currently carries a black box warning about the risk of opportunistic infection.
One limitation of this study was the relatively short time period that outcomes were studied (over 1 year), which may not be enough time to appropriately evaluate for long-term remission. To address this, the authors went on to publish a study that was a 2-year extension of the original trial and assessed long-term remission with TCZ vs placebo . The study found that among patients who maintained clinical remission in part 2, higher proportions of those originally assigned to TCZ were treatment-free compared with those originally assigned to placebo (TCZ qweekly patients remained flare-free the longest). Also, cumulative steroid doses over 3 years were lower in patients originally assigned to TCZ vs placebo.
While TCZ is not currently first-line treatment of GCA, it is an appropriate adjunct in patients with significant toxicities from steroids, or those who experience frequent flares.
- UpToDate, “Treatment of giant cell arteritis”
- Stone J, Bao M, Han J, Aringer M, Blockmans D, Brouwer E, Cid M, Dasgupta B, Rech J, Salvarani C, Spiera R, Unizony S. Long-Term Outcome of Tocilizumab for Patients with Giant Cell Arteritis: Results from Part 2 of a Randomized Controlled Phase 3 Trial [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10)