Key messages
· People with giant cell arteritis who have an injection of tocilizumab every week or two weeks have an improved chance of being symptom-free after a year. People treated with tocilizumab every four weeks probably have an improved chance of being symptom-free after a year.
· Tocilizumab probably causes similar numbers of adverse (unwanted) effects to a placebo (dummy treatment).
· More studies are needed to strengthen the body of evidence and investigate whether duration of treatment affects the success of tocilizumab.
What is giant cell arteritis?
Giant cell arteritis (GCA) is an inflammation (swelling) of the vessels that carry blood from the heart to the rest of the body (arteries). It usually affects people aged over 50 and can cause:
· vision problems (such as double vision or vision loss in one or both eye(s));
· jaw pain while eating or talking;
· pain and tenderness over the temples (sides of the head);
· frequent and severe headaches; and
· weight loss.
If untreated, GCA can cause permanent loss of vision or a stroke.
How is GCA treated?
GCA is usually treated with anti-inflammation medicines called steroids. People typically need to take steroids for several years, which can cause adverse effects such as diabetes, osteoporosis (bone loss), hypertension (raised blood pressure), and infection.
A possible alternative treatment is an injectable medicine called tocilizumab, which aims to stop the body’s defense system (immune system) from mistakenly attacking its healthy tissues and causing inflammation.
What did we want to find out?
We wanted to compare the benefits and risks of tocilizumab against those of other treatments for GCA.
What did we do?
We searched for studies that compared tocilizumab against other treatments for GCA. We compared and summarized the results of these studies and rated our confidence in the evidence, based on factors such as study methods and sizes of participant groups.
What did we find?
We found two studies, conducted in the USA, Canada, and Europe, involving a total of 281 people with GCA. Everyone taking part in the study was aged over 50 (average age: 70), and 74% were women. Tocilizumab was given every four weeks in one study (30 people) and every week or every two weeks in the other study (251 people). Both studies lasted one year, and compared tocilizumab against a placebo. Both studies were funded by the manufacturer of tocilizumab.
Tocilizumab given every four weeks compared to placebo
The evidence suggests that after a year of treatment, compared to placebo, tocilizumab given every four weeks probably:
· improves the chances of successful GCA treatment (absence of symptoms);
· delays the return of GCA; and
· reduces the need to use steroids to treat GCA.
Tocilizumab given every one or two weeks compared to placebo
Tocilizumab given either every week or every two weeks for a year:
· improves the chances of successful GCA treatment;
· probably improves the chances of not needing escape therapy;
· probably improves physical and mental quality of life (well-being); but
· probably makes little or no difference to changes in vision.
Adverse effects
The most common adverse effect experienced by people taking part in the study was infection. The evidence suggests that tocilizumab probably decreases the number of serious adverse effects compared to placebo.
What are the limitations of the evidence?
The evidence is only based on two studies, which limits our confidence in the findings.
How up-to-date is the evidence?
The evidence is current to January 2020.
This review indicates that tocilizumab therapy may be beneficial in terms of proportion of participants with sustained remission, relapse-free survival, and the need for escape therapy. While the evidence was of moderate certainty, only two studies were included in the review, suggesting that further research is required to corroborate these findings. Future trials should address issues related to the required duration of therapy, patient-reported outcomes such as quality of life and economic outcomes, as well as the clinical outcomes evaluated in this review.
Giant cell arteritis (GCA) is the most common form of systemic vasculitis in people older than 50 years of age. It causes granulomatous inflammation of medium- to large-sized vessels. Tocilizumab is a recombinant monoclonal antibody directed against interleukin-6 receptors (IL-6R).
To assess the effectiveness and safety of tocilizumab, given alone or with corticosteroids, compared with therapy without tocilizumab for treatment of GCA.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Science Information database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). There were no date or language restrictions in the electronic search for trials. We last searched the electronic databases on 3 January 2020.
We included only randomized controlled trials (RCTs) that compared tocilizumab of any dosage regimen (alone or with corticosteroids) with therapy without tocilizumab that had a minimum follow-up of six months. Participants were at least 50 years of age, with biopsy-proven GCA or by large-vessel vasculitis by angiography, and met the American College of Rheumatology 1990 guidelines for GCA.
We used standard Cochrane methodology.
Main results
We included two RCTs in the review. The studies were conducted in the USA, Canada, and Europe and enrolled a total of 281 participants with GCA, of whom 74% were women. The mean age of participants was 70 years, with new-onset or relapsing GCA, and fulfilled the 1990 American College of Rheumatology criteria with no uncontrolled comorbidities. Both studies were funded by F. Hoffmann-La Roche AG, the manufacturer of tocilizumab.
Findings
One RCT (30 participants) compared tocilizumab administered every four weeks versus placebo. Point estimates at 12 months and beyond favored tocilizumab over placebo in terms of sustained remission (risk ratio (RR) 4.25, 95% confidence interval (CI) 1.21 to 14.88; moderate-certainty evidence). Point estimates suggest no evidence of a difference for all-cause mortality at 12 months or more (RR 0.17, 95% CI 0.01 to 3.94; moderate-certainty evidence). At 12 months, mean time to first relapse after induction of remission was 25 weeks in favor of participants receiving tocilizumab compared to placebo (mean difference (MD) 25, 95% CI 11.4 to 38.6; moderate-certainty evidence).
The second RCT (250 participants) randomized participants into two intervention and two comparator groups to receive tocilizumab weekly (100 participants), bi-weekly (49 participants), weekly placebo + 26-week taper (50 participants), or weekly placebo + 52-week taper (51 participants). At 12 months, point estimates from this study on proportion of participants with sustained remission favored participants who received tocilizumab weekly versus placebo + 52-week taper (RR 3.17, 95% CI 1.71 to 5.89; 151 participants); tocilizumab weekly versus placebo + 26-week taper (RR 4.00, 95% CI 1.97 to 8.12; 150 participants); tocilizumab every other week versus placebo + 52-week taper (RR 3.01, 95% CI 1.57 to 5.75; 100 participants); tocilizumab every other week versus placebo + 26-week taper (RR 3.79, 95% CI 1.82 to 7.91; 99 participants) (moderate-certainty evidence). Point estimates on proportion of participants who did not need escape therapy (defined by the study as the inability to keep to the protocol-defined prednisone taper) favored participants who received tocilizumab weekly versus placebo + 52-week taper (RR 1.71, 95% CI 1.24 to 2.35; 151 participants); tocilizumab weekly versus placebo + 26-week taper (RR 2.96, 95% CI 1.83 to 4.78; 150 participants); tocilizumab every other week versus placebo + 52-week taper (RR 1.49, 95% CI 1.04 to 2.14; 100 participants) but not tocilizumab every other week versus placebo + 26-week taper (RR 0.65, 95% CI 0.27 to 1.54; 99 participants) (moderate-certainty evidence). This study did not report mean time to first relapse after induction of remission or all-cause mortality.
Across comparison groups, the same study found no evidence of a difference in vision changes and inconsistent evidence with regard to quality of life. Evidence on quality of life as assessed by the physical (MD 8.17, 95% CI 4.44 to 11.90) and mental (MD 5.61, 95% CI 0.06 to 11.16) component score of the 36-Item Short Form Health Survey (SF-36) favored weekly tocilizumab versus placebo + 52-week taper but not bi-weekly tocillizumab versus placebo + 26-week taper (moderate-certainty evidence).
Adverse events
One RCT reported a lower percentage of participants who experienced serious adverse events when receiving tocilizumab every four weeks versus placebo. The second RCT reported no evidence of a difference among groups with regard to adverse events; however, fewer participants reported serious adverse events in the tocilizumab weekly and tocilizumab biweekly interventions compared with the placebo + 26-week taper and placebo + 52-week taper comparators. Investigators in both studies reported that infection was the most frequently reported adverse event.