Abstract
Background
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).
Objectives
To assess the effectiveness and safety of tocilizumab, given alone or with corticosteroids, compared with therapy without tocilizumab for treatment of GCA.
Search methods
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.
Selection criteria
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.
Data collection and analysis
We used standard Cochrane methodology.
Main results
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.
Authors' conclusions
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.
Keywords: Aged; Female; Humans; Male; Adrenal Cortex Hormones; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Humanized/adverse effects; Giant Cell Arteritis; Giant Cell Arteritis/drug therapy; Recurrence
Plain language summary
What are the benefits and risks of tocilizumab (a medicine that reduces inflammation) for treating giant cell arteritis (a disease of the blood vessels)?
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.
Summary of findings
Summary of findings 1. Tocilizumab every 4 weeks compared to placebo for giant cell arteritis.
| Tocilizumab every 4 weeks compared to placebo for giant cell arteritis | ||||||
| Patient or population: adults aged over 50 years with giant cell arteritis Setting: hospital Intervention: tocilizumab every 4 weeks Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo | Risk with tocilizumab every 4 weeks | |||||
| Proportion of participants with sustained remission (as defined by study investigators) at ≥ 12 months | 20 per 100 | 85 per 100 (24 to 100) | RR 4.25 (1.21 to 14.88) | 30 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Proportion of participants with relapse‐free survival at ≥ 12 months | 20 per 100 | 85 per 100 (24 to 100) | RR 4.25 (1.21 to 14.88) | 30 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Proportion of all‐cause mortality at ≥ 12 months | 10 per 100 | 0 per 100 (0 to 39) | RR 0.17 (0.01 to 3.94) | 30 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR < 1 favoring tocilizumab |
| Mean time to first relapse after induction of remission (weeks) at ≥ 12 months | 25 weeks (SD 21) | 50 weeks (36.4 to 63.6) | MD 25 (11.4 to 38.6) | 30 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | MD > 0 favoring tocilizumab |
| Cumulative mean dose of corticosteroids at ≥ 12 months | See comment | ‐ | ‐ | 30 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | Median rather than mean cumulative dose of corticosteroids was reported. Investigators reported that median dose of corticosteroid was lower in the tocilizumab compared with the placebo group. |
| Proportion of participants who did not need escape therapy (as defined by study investigators) | Outcome not reported. | |||||
| Mean change in quality of life at ≥ 12 months using the 36‐Item Short Form Health Survey physical component score (SF‐36 PCS) | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Mean change in quality of life at ≥ 12 months using the 36‐Item Short Form Health Survey mental component score (SF‐36 MCS) | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Mean change in VAS (higher scores suggest greater disease activity and worse quality of life) at ≥ 12 months | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Adverse events at ≥ 12 months | 70 per 100 | 75 per 100 (46 to 100) | RR 1.07 (0.66 to 1.73) | 30 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR < 1 favoring tocilizumab |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio; SD: standard deviation; VAS: visual analogue scale | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
1Downgraded one level for imprecision.
Summary of findings 2. Tocilizumab weekly compared to placebo + 52‐week taper for giant cell arteritis.
| Tocilizumab weekly compared to placebo + 52‐week taper for giant cell arteritis | ||||||
| Patient or population: adults aged over 50 years with giant cell arteritis Setting: hospital Intervention: tocilizumab weekly Comparison: placebo + 52‐week taper | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo + 52‐week taper | Risk with tocilizumab weekly | |||||
| Proportion of participants with sustained remission (as defined by study investigators) at ≥ 12 months | 18 per 100 | 56 per 100 (36 to 74) | RR 3.17 (1.71 to 5.89) | 151 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Proportion of participants with relapse‐free survival at ≥ 12 months | 51 per 100 | 77 per 100 (58 to 100) | RR 1.51 (1.13 to 2.02) | 151 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Proportion of all‐cause mortality at ≥ 12 months | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Mean time to first relapse after induction of remission (weeks) at ≥ 12 months | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Cumulative mean dose of corticosteroids at ≥ 12 months | See comment | ‐ | ‐ | ‐ | ‐ | Median rather than mean cumulative dose of corticosteroids was reported. Investigators reported that median dose of corticosteroid was lower in the tocilizumab compared with the placebo group. |
| Proportion of participants who did not need escape therapy (as defined by study investigators) | 45 per 100 | 77 per 100 (56 to 100) | RR 1.71 (1.24 to 2.35) | 151 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Mean change in quality of life at ≥ 12 months using the 36‐Item Short Form Health Survey physical component score (SF‐36 PCS) | ‐2.8 (SD 6.98) | 5.38 (1.64 to 9.1) | MD 8.18 (4.44 to 11.90) | 77 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | MD > 0 favoring tocilizumab |
| Mean change in quality of life at ≥ 12 months using the 36‐Item Short Form Health Survey mental component score (SF‐36 MCS) | 2.6 (SD 10.56) | 8.21 (2.66 to 13.76) | MD 5.61 (0.06 to 11.16) | 77 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | |
| Mean change in VAS (higher scores suggest greater disease activity and worse quality of life) at ≥ 12 months | ‐10 (SD 35.12) | ‐19.68 (‐38 to ‐1.36) | MD ‐9.68 (‐28.0 to 8.64) | 78 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | MD < 0 favoring tocilizumab |
| Adverse events at ≥ 12 months | 92 per 100 | 98 per 100 (90 to 100) | RR 1.06 (0.98 to 1.16) | 151 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR < 1 favoring tocilizumab |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio; SD: standard deviation; VAS: visual analogue scale | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
1Downgraded one level for imprecision.
Summary of findings 3. Tocilizumab weekly compared to placebo + 26‐week taper for giant cell arteritis.
| Tocilizumab weekly compared to placebo + 26‐week taper for giant cell arteritis | ||||||
| Patient or population: adults aged over 50 years with giant cell arteritis Setting: hospital Intervention: tocilizumab weekly Comparison: placebo + 26‐week taper | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo + 26‐week taper | Risk with tocilizumab weekly | |||||
| Proportion of participants with sustained remission (as defined by study investigators) at ≥ 12 months | 14 per 100 | 56 per 100 (28 to 100) | RR 4.00 (1.97 to 8.12) | 150 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Proportion of participants with relapse‐free survival at ≥ 12 months | 32 per 100 | 77 per 100 (51 to 100) | RR 2.41 (1.58 to 3.65) | 150 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Proportion of all‐cause mortality at ≥ 12 months | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Mean time to first relapse after induction of remission (weeks) at ≥ 12 months | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Cumulative mean dose of corticosteroids at ≥ 12 months | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Proportion of participants who did not need escape therapy (as defined by study investigators) | 26 per 100 | 77 per 100 (48 to 100) | RR 2.96 (1.83 to 4.78) | 150 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Mean change in quality of life at ≥ 12 months using the 36‐Item Short Form Health Survey physical component score (SF‐36 PCS) | 2.08 (SD 12.11) | 5.37 (‐2.76 to 13.5) | MD 3.29 (‐4.84 to 11.42) | 68 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | MD > 0 favoring tocilizumab |
| Mean change in quality of life at ≥ 12 months using the 36‐Item Short Form Health Survey mental component score (SF‐36 MCS) | 4.99 (SD 7.54) |
8.21 (2.62 to 13.8) | MD 3.22 (‐2.37 to 8.81) | 68 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | |
| Mean change in VAS (higher scores suggest greater disease activity and worse quality of life) at ≥ 12 months | ‐8.45 (SD 24.81) | ‐19.68 (‐36.18 to ‐2.73) | MD ‐11.23 (‐28.18 to 5.72) | 71 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | MD < 0 favoring tocilizumab |
| Adverse events at ≥ 12 months | 96 per 100 | 98 per 100 (92 to 100) | RR 1.02 (0.96 to 1.09) | 150 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR < 1 favoring tocilizumab |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio; SD: standard deviation; VAS: visual analogue scale | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
1Downgraded one level for imprecision.
Summary of findings 4. Tocilizumab every other week compared to placebo + 52‐week taper for giant cell arteritis.
| Tocilizumab every other week compared to placebo + 52‐week taper for giant cell arteritis | ||||||
| Patient or population: adults aged over 50 years with giant cell arteritis Setting: hospital Intervention: tocilizumab every other week Comparison: placebo + 52‐week taper | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo + 52‐week taper | Risk with tocilizumab every other week | |||||
| Proportion of participants with sustained remission (as defined by study investigators) at ≥ 12 months | 18 per 100 | 53 per 100 (28 to 100) | RR 3.01 (1.57 to 5.75) | 100 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Proportion of participants with relapse‐free survival at ≥ 12 months | 51 per 100 | 75 per 100 (55 to 100) | RR 1.48 (1.08 to 2.03) | 100 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Proportion of all‐cause mortality at ≥ 12 months | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Mean time to first relapse after induction of remission (weeks) at ≥ 12 months | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Cumulative mean dose of corticosteroids at ≥ 12 months | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Proportion of participants who did not need escape therapy (as defined by study investigators) | 45 per 100 | 67 per 100 (47 to 96) | RR 1.49 (1.04 to 2.14) | 100 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Mean change in quality of life at ≥ 12 months using the 36‐Item Short Form Health Survey physical component score (SF‐36 PCS) | ‐ 2.8 (SD 6.98) | 2.71 (‐1.98 to 7.4) | MD 5.51 (0.82 to 10.2) | 44 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | MD > 0 favoring tocilizumab |
| Mean change in quality of life at ≥ 12 months using the 36‐Item Short Form Health Survey mental component score (SF‐36 MCS) | 2.6 (SD 10.56) | 1.98 (‐3.62 to 7.58) | MD ‐0.62 (‐6.22 to 4.98) | 44 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | |
| Mean change in VAS (higher scores suggest greater disease activity and worse quality of life) at ≥ 12 months | ‐10 (SD 35.12) | ‐22.69 (‐42.06 to 4.32) | MD ‐12.69 (‐31.06 to 5.68) | 44 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | MD < 0 favoring tocilizumab |
| Adverse events at ≥ 12 months | 92 per 100 | 96 per 100 (86 to 100) | RR 1.04 (0.94 to 1.15) | 100 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR< 1 favoring tocilizumab |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio; SD: standard deviation; VAS: visual analogue scale | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
1Downgraded one level for imprecision.
Summary of findings 5. Tocilizumab every other week compared to placebo + 26‐week taper for giant cell arteritis.
| Tocilizumab every other week compared to placebo + 26‐week taper for giant cell arteritis | ||||||
| Patient or population: adults aged over 50 years with giant cell arteritis Setting: hospital Intervention: tocilizumab every other week Comparison: placebo + 26‐week taper | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo + 26‐week taper | Risk with tocilizumab every other week | |||||
| Proportion of participants with sustained remission (as defined by study investigators) at ≥ 12 months | 14 per 100 | 53 per 100 (25 to 100) | RR 3.79 (1.82 to 7.91) | 99 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Proportion of participants with relapse‐free survival at ≥ 12 months | 32 per 100 | 76 per 100 (49 to 100) | RR 2.36 (1.53 to 3.64) | 99 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Proportion of all‐cause mortality at ≥ 12 months | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Mean time to first relapse after induction of remission (weeks) at ≥ 12 months | Outcome not reported. | ‐ | ‐ | ‐ | ‐ | |
| Cumulative mean dose of corticosteroids at ≥ 12 months | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Proportion of participants who did not need escape therapy (as defined by study investigators) | 2 2 per 100 | 14 per 100 (6 to 34) | RR 0.65 (0.27 to 1.54) | 99 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR > 1 favoring tocilizumab |
| Mean change in quality of life at ≥ 12 months using the 36‐Item Short Form Health Survey physical component score (SF‐36 PCS) | 26 (SD 2.08) | 26.63 (18.02 to 35.24) | MD 0.63 (‐7.98 to 9.24) | 35 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | MD > 0 favoring tocilizumab Investigators reported an improvement in quality of life in favor of the tocilizumab group. |
| Mean change in quality of life at ≥ 12 months using the 36‐Item Short Form Health Survey mental component score (SF‐36 MCS) | 26 (SD 4.99) | 22.99 (17.35 to 28.63) | MD ‐3.01 (‐8.65 to 2.63) | 35 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | |
| Mean change in VAS (higher scores suggest greater disease activity and worse quality of life) at ≥ 12 months | ‐8.45 (SD 24.81) | ‐22.69 (‐39.69 to ‐5.69) | MD ‐14.24 (‐31.24 to 2.76) | 37 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | MD < 0 favoring tocilizumab |
| Adverse events at ≥ 12 months | 96 per 100 | 96 per 100 (88 to 100) | RR 1.00 (0.92 to 1.08) | 99 (1 RCT) | ⊕⊕⊕⊝ MODERATE 1 | RR < 1 favoring tocilizumab |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio; SD: standard deviation; VAS: visual analogue scale | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
1Downgraded one level for imprecision.
Background
Description of the condition
Giant cell arteritis (GCA) is the most common systemic vasculitis affecting people older than 50 years of age (Borchers 2012), with an age‐ and sex‐adjusted prevalence of 204 per 100,000 population aged 50 and over on 1 January 2005 (Crowson 2017). GCA prevalence was 304 per 100,000 population in women, and 91 per 100,000 population in men (Crowson 2017). The disease has a predilection for people of Scandivanian descent (González‐Gay 2009). GCA usually causes granulomatous inflammation of medium‐sized to large vessels (Bongartz 2006).
Common GCA symptoms include vision loss, double vision, jaw and tongue claudication, scalp tenderness, headaches, anorexia, fever, and weight loss (Dejaco 2017). Approximately half of individuals with GCA also have symptoms of polymyalgia rheumatica, such as morning stiffness lasting at least 45 minutes, hip pain or limited range of motion, and bilateral shoulder pain (Salvarani 1995). Large‐vessel GCA can cause upper extremity claudication and asymmetric blood pressures (Muratore 2015). GCA may lead to vision loss, stroke, arterial dissection, aortic aneurysm, and aortic rupture (González‐Gay 2000; Kermani 2012; Nuenninghoff 2003).
Suspicion of a diagnosis of GCA is based on careful history and clinical evaluation, in association with elevated erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP) (Parikh 2006). Although computed tomography–positron emission tomography (CT‐PET), magnetic resonance imaging (MRI), computed tomography (CT), angiography, and ultrasound may aid in GCA diagnosis (Dejaco 2018), a positive temporal artery biopsy is still the gold standard diagnostic test. The 1990 American College of Rheumatology criteria for GCA classification (Table 6), which were originally created to help differentiate GCA from other vasculitides, may guide its diagnosis, with sensitivity of 95.3% and specificity of 90.7% (Hunder 1990). Studies are under way with the goal of developing and validating criteria for GCA diagnosis (Craven 2013).
1. The American College of Rheumatology 1990 Giant Cell Arteritis (GCA) classification criteria.
| Score | Criteria (3 of 5 points is required for the clinical diagnosis of GCA from other forms of vasculitis) |
| 1 | Age at onset ≥ 50 years |
| 2 | A new headache |
| 3 | Temporal artery abnormality such as tenderness to palpation or decreased pulsation |
| 4 | Erythrocyte sedimentation rate ≥ 50 mm/h |
| 5 | Abnormal artery biopsy showing vasculitis with mononuclear cell or granulomatous inflammation, usually with giant cell infiltrates |
Description of the intervention
Tocilizumab is a recombinant humanized anti–human monoclonal antibody directed against soluble and membrane‐bound interleukin‐6 receptors (IL‐6R) of the immunoglobulin IgG1 subclass (EMA 2008). Tocilizumab was initially approved in Japan in 2005 as an orphan drug for the treatment of Castleman’s disease, a rare lymphoproliferative disease that causes plasmacytosis (Higuchi 2010). Intravenous or subcutaneous tocilizumab has been used as monotherapy or in combination with disease‐modifying antirheumatic drugs (DMARDs) in adults with moderate to severe active rheumatoid arthritis, systemic juvenile idiopathic arthritis, juvenile idiopathic polyarthritis, or cytokine release syndrome (EMA 2008).
Interleukin‐6 (IL‐6) has been shown to be involved in the pathophysiology of GCA (Martinez‐Taboada 2008). Because tocilizumab targets the IL‐6 receptor, it has been studied as a steroid‐sparing agent for subcutaneous use in GCA (EMA 2017; FDA 2017).
How the intervention might work
IL‐6, a pleiotropic cytokine produced by cells of various types, has diverse biological functions. It is involved in T‐cell activation, stimulation of hematopoiesis, and in particular, induction of acute phase proteins; these acute phase proteins (e.g. ESR, CRP) are markedly high in individuals with GCA and are monitored clinically for disease activity (Dasgupta 1990; Weyand 2000). IL‐6 is locally produced in granulomatous lesions in the vasculitic arteries (Weyand 1994), as well as by circulating monocytes in GCA patients (Wagner 1994).
Why it is important to do this review
Suspicion of GCA is a medical emergency, wherein diagnosis and initiation of treatment to control vascular inflammation are immediately facilitated. High‐dose glucocorticoids have served as first‐line treatment for GCA, but relapses may occur once steroids are tapered. Patients usually need prolonged steroid therapy, leading to numerous adverse effects, including diabetes mellitus, osteoporosis, hypertension, and infection (Proven 2003). Several studies have therefore been conducted to look at possible steroid‐sparing or biologic agents, one of which is tocilizumab.
Objectives
To assess the effectiveness and safety of tocilizumab, given alone or with corticosteroids, compared to therapy without tocilizumab for treatment of GCA.
Methods
Criteria for considering studies for this review
Types of studies
We included only randomized controlled trials in the review.
Types of participants
We included trials that enrolled individuals at least 50 years of age who met the American College of Rheumatology 1990 guidelines for GCA and active disease as described by study authors with regard to outcome measures (Hunder 1990). GCA should have been proven by a positive temporal artery biopsy or by large‐vessel vasculitis by angiography (MRI, CT, or CT‐PET).
Types of interventions
We included trials of tocilizumab, administered subcutaneously or by intravenous infusion, via any dosage regimen, alone or with corticosteroids, compared with therapy without tocilizumab, with a minimum trial duration of six months. Eligible comparisons include, for example, tocilizumab plus corticosteroids versus corticosteroids alone, and tocilizumab plus corticosteroids versus corticosteroids plus placebo.
Types of outcome measures
We categorized time points at which outcomes were assessed as short term (follow‐up time point of less than 12 months) or long term (follow‐up time point of 12 months or more). When there were multiple time points within each time window, we picked the outcome measurement at the longest follow‐up time point. We did not consider outcomes as inclusion criteria when determining study eligibility.
Primary outcomes
Proportion of participants with sustained remission (as defined by the study investigators) at short term and long term.
Secondary outcomes
The following outcomes were also reviewed at short and long term.
Proportion of participants with relapse‐free survival.
Proportion of all‐cause mortality.
Mean time to first relapse after induction of remission.
Cumulative mean dose of corticosteroids (e.g. prednisolone, prednisone).
Proportion of participants who did not need escape therapy (as defined by study investigators).
Vision changes or general quality of life changes, as reported by the study authors.
Adverse outcomes
Adverse events, as reported by the study authors (e.g. incidence, nature, and severity of complications; laboratory abnormalities; withdrawal).
Search methods for identification of studies
Electronic searches
The Cochrane Eyes and Vision Information Specialist searched the following electronic databases for randomized controlled trials and controlled clinical trials. There were no language or publication year restrictions. We last searched the electronic databases on 3 January 2020.
Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 3 January 2020) (Appendix 1).
MEDLINE Ovid (1946 to 3 January 2020) (Appendix 2).
Embase.com (1947 to 3 January 2020) (Appendix 3).
PubMed (1946 to 3 January 2020) (Appendix 4).
Latin American and Caribbean Health Science Information database (LILACS) (1982 to 3 January 2020) (Appendix 5).
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 3 January 2020) (Appendix 6).
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 3 January 2020) (Appendix 7).
Searching other resources
We contacted experts in the field regarding information about any ongoing trials. We also searched the websites of regulatory agencies such as the US Food and Drug Administration and the European Medicines Agency for additional trials.
We searched the references of reports from included studies for additional relevant studies, with no restrictions on language or date of publication.
Data collection and analysis
Selection of studies
After removing duplicate records, two review authors independently screened the titles and abstracts of studies identified by the search for potentially eligibility using Covidence (Covidence), a web‐based review management software. The two review authors classified each study record as relevant (a vote of “Yes”) or not relevant (a vote of “No”) for full‐text review. We retrieved the full‐text articles of those studies marked relevant, which the two review authors independently reviewed to determine eligibility for inclusion in the review. Any disagreements between review authors were resolved by discussion and consensus.
Data extraction and management
Two review authors independently extracted data from the included trials, including study population, numbers of centers, types of interventions, primary and secondary outcomes, and analyses performed in the original studies. We used Covidence for data extraction (Covidence). We contacted trial investigators to request missing information or clarification; we proceeded with the available information if we did not receive a response within two weeks. Any disagreements between review authors were resolved by discussion and consensus. We presented the characteristics of included studies in 'Characteristics of included studies' tables.
Assessment of risk of bias in included studies
Two review authors independently assessed risk of bias of the included trials according to the methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2017). We considered the following parameters when assessing risk of bias.
Random sequence generation (selection bias).
Allocation concealment (selection bias).
Masking of participants, study personnel, and outcome assessors (performance bias and detection bias).
Incomplete outcome data (attrition bias).
Selective outcome reporting (reporting bias).
Other sources of bias.
We assessed each parameter as at low, high, or unclear risk of bias. Any discrepancies between review authors were resolved through discussion and consensus.
Measures of treatment effect
We used the risk ratio (RR) with 95% confidence intervals (CIs) to express dichotomous data. For continuous outcomes measured on the same scale (e.g. cumulative dose of corticosteroids per body weight), we calculated the mean difference (MD) with 95% CIs. For continuous outcomes that measured the same underlying concept (e.g. health‐related quality of life) but used different measurement scales, we used the standardized mean difference (SMD). We expressed time‐to‐event data as a hazard ratio (HR) with 95% CIs.
Unit of analysis issues
The unit of analysis was the individual participant, therefore accounting for the dependence of eyes was not necessary. For future updates of this review, included studies with multiple arms will be combined into multiple eligible groups for a single pair‐wise comparison when possible.
Dealing with missing data
When possible, we collected data on proportions and reasons for loss to follow‐up and used the estimates that accounted for missing data (e.g. trial investigators' imputed missing data); we did not impute missing data on our own for the purposes of this review.
Assessment of heterogeneity
We planned to evaluate any substantial clinical or methodological heterogeneity across studies before conducting meta‐analysis; however, we did not perform this analysis because we included only two studies, and no meta‐analysis was performed. We planned to quantify any inconsistencies across studies using the I2 statistic, with a value of 50% or more indicating significant statistical heterogeneity; however, we did not perform this analysis because we did not conduct any meta‐analysis, as described above.
Assessment of reporting biases
We compared outcomes mentioned in the study protocol or trial registry against those presented in the published report to assess reporting bias. We planned to construct and inspect a funnel plot for asymmetry for evidence of small‐study effect; however, we did not perform this analysis since there were only two included studies.
Data synthesis
We planned to use a fixed‐effect model for meta‐analysis when fewer than three studies were combined in a meta‐analysis. We described clinical and methodological characteristics of the included studies, including size, inclusion or exclusion of relevant subgroups, timelines, and other important factors. We also noted the strengths and limitations of individual studies and patterns across studies. When possible, we explained how design or study execution flaws created bias. We discussed the relationships between characteristics, reported findings, and patterns across studies. We also discussed the relevance of individual studies to populations, comparisons, settings, and outcomes.
Subgroup analysis and investigation of heterogeneity
We planned to perform a subgroup analysis if multiple interventions were reported (e.g. high‐dose and low‐dose tocilizumab, varying times of corticosteroid taper); however, we did not perform any subgroup analysis because there were only two studies in the review, therefore subgroup analysis was not possible.
Sensitivity analysis
We planned to perform sensitivity analyses to determine the impact on treatment effects of studies judged to have a high risk of bias for at least two domains (e.g., incomplete outcome data and selective outcome reporting), industry‐funded studies, and unpublished studies (conference abstracts). We did not perform sensitivity analyses because there were only two studies in the review, rendering it impossible to perform any meaningful sensitivity analysis.
Summary of findings and assessment of the certainty of the evidence
We created a summary of findings table in which we presented a summary of the evidence, providing key information about the best estimate of the magnitude of effect when possible, in relative terms and as absolute differences, for comparisons of alternative management strategies, numbers of participants, and trials. Each important outcome was addressed, and a rating of overall confidence in effect estimates for each outcome was included. We created the summary of findings table based on the methods described in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Schunemann 2019), using Review Manager 5 table editor (Review Manager 2020). To keep the table simple, we only presented outcomes for one time point (short or long term) when there was no variation of the results across the two time points assessed; otherwise, we presented outcomes at both time points in separate summary of findings tables (Schunemann 2019).
We included the following seven outcomes.
Proportion of participants with sustained remission
Proportion of participants with relapse‐free survival
Proportion of all‐cause mortality
Mean time to first relapse after induction of remission
Cumulative mean dose of corticosteroids (e.g. prednisolone, prednisone)
Vision changes or general quality of life changes, as reported by the study authors
Adverse events, as reported by the study authors (e.g. incidence, nature, and severity of complications; laboratory abnormalities; withdrawal)
Results
Description of studies
Results of the search
The electronic database search conducted on 3 January 2020 yielded 1712 records (Figure 1). After removal of duplicates, we screened 1409 records based on title and abstract and excluded 1387 records. We retrieved 22 full‐text reports for further screening, included 13 reports from two studies (Characteristics of included studies), and excluded nine reports (Characteristics of excluded studies). We did not identify any ongoing studies potentially meeting our inclusion criteria. We searched two databases (Appendix 4, Appendix 6) on 10 August 2021 and found no additional studies meeting our inclusion criteria.
1.
Study flow diagram.
Included studies
For details of the included studies, see Characteristics of included studies.
Types of studies
We included 13 reports from two studies (Stone 2017; Villiger 2016). One study recruited participants from 76 sites across 14 countries including the USA, Canada, and Europe (Belgium, Denmark, France, Germany, Italy, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, and the UK) (Stone 2017). The other study recruited participants from Switzerland (Villiger 2016).
Type of participants
The two studies included a total of 281 participants (of which 74% were women) with GCA. One study recruited 30 participants (70% women) with a mean age of 71 years (Villiger 2016). The other study included 251 participants (75% women) with a mean age of 69 years (Stone 2017). Follow‐up period for both studies was 52 weeks. Both studies included participants that were older than 50 years of age, with new‐onset or relapsing GCA who fulfilled the 1990 American College of Rheumatology criteria. GCA was diagnosed by positive temporal artery biopsy or assessed as large vessel vasculitis by magnetic resonance angiography (MRA) and had to be humorally active at inclusion (ESR ≥ 40 mm in the first hour and CRP level of ≥ 20 mg/L). Villiger 2016 excluded individuals with uncontrolled comorbidities, such as active infection, or any disease requiring systemic glucocorticoid treatment, previous treatment with tocilizumab or any other biological agent. Stone 2017 excluded individuals receiving intravenous methylprednisolone at doses greater than 100 mg daily within six weeks before baseline, or treatment with changes in methotrexate doses more than six weeks of study enrollment. Individuals receiving other immunosuppressive medications were also excluded.
Type of interventions
Tocilizumab doses and route of administration differed between the two studies. Tocilizumab was given via infusion in the Villiger 2016 study and subcutaneously in the Stone 2017 study. Comparators also differed between studies, wherein the corticosteroid used with placebo was prednisolone for the Villiger 2016 study and prednisone for the Stone 2017 study. Treatment duration was 52 weeks. In the Villiger 2016 study, participants were randomized into two groups, the intervention and the comparator groups at a ratio of 2:1. The intervention group comprising 20 participants received intravenous tocilizumab, given as 13 infusions at 8 mg/kg bodyweight every four weeks for 52 weeks. The comparator group (10 participants) received placebo. "Participants in both groups also received prednisolone at a dose of 1 mg/kg per day and tapered weekly by 0·1 mg/kg per day until week 8, then weekly by 0·05 mg/kg, reached 0.1 mg/kg by week 12." Afterwards, the prednisolone dose was reduced every month by 1 mg per day to 0 mg. All participants also received aspirin (100 mg per day), pantoprazole (40 mg per day), calcium (1000 mg per day), cholecalciferol (800 U per day), and ibandronate 3 mg intravenously every three months. The Stone 2017 study randomized 251 participants in a 2:1:1:1 ratio into two intervention and two comparator groups, as follows: tocilizumab weekly (100 participants), placebo with tocilizumab every other week (50 participants), placebo with prednisone that was tapered over 26 weeks (50 participants), and placebo with prednisone that was tapered over a 52 weeks (51 participants). The intervention groups received subcutaneous tocilizumab at either a dose of 162 mg weekly plus a 26‐week prednisone taper (tocilizumab weekly), or 162 mg every other week plus a 26‐week prednisone taper (tocilizumab every other week). The comparator groups received either a weekly subcutaneous placebo plus a 26‐week prednisone taper (placebo + 26‐week taper) or a weekly subcutaneous placebo plus a 52‐week prednisone taper (placebo + 52‐week taper). Randomization was stratified according to the baseline prednisone dose of ≤ 30 mg per day versus > 30 mg per day.
Type of outcomes
Proportion of participants with sustained remission
Sustained remission was measured by both Villiger 2016 and Stone 2017. Villiger 2016 assessed complete remission at week 12, defined as absence of clinical signs or symptoms of GCA, normal ESR and CRP at a prednisolone dose of 0.1 mg/kg per day. Stone 2017 also assessed sustained prednisone‐free remission at week 52 between each tocilizumab group and the placebo group that underwent the 26‐week taper. Sustained prednisone‐free remission was defined as remission from week 12 through week 52 and adherence to the prednisone taper.
Proportion of participants with relapse‐free survival
Villiger 2016 assessed relapse‐free survival at week 52, defined as time to first relapse after induction of remission. Relapse was defined as a re‐increase in ESR from less than 20 mm in the first hour to ≥ 40, CRP ≥ 10 mg/L, and at least one sign or symptom of GCA. Major relapse was defined as the presence of cranial symptoms; otherwise, relapse was considered minor. Stone 2017 did not report this outcome.
Proportion of all‐cause mortality
Villiger 2016 reported the proportion of all‐cause mortality at week 52. Stone 2017 did not assess this outcome.
Mean time to first relapse after induction of remission
Stone 2017 defined flare as the recurrence of symptoms attributable to active GCA, with or without elevation of ESR or CRP, or both. This was reported as the incidence of the first flare after remission in a time‐to‐event analysis by means of Kaplan‐Meier curves. Trial groups were compared with the use of Cox proportional‐hazards models, adjusted for the baseline prednisone dose. For participants who withdrew from the trial, data censoring was used. Villiger 2016 did not report this outcome.
Cumulative mean dose of corticosteroids
Both Stone 2017 and Villiger 2016 reported median cumulative prednisone dose over the follow‐up period. Villiger 2016 also reported the proportion of participants with prednisolone tapered to 0 mg/day during the follow‐up period.
Proportion of participants who did not need escape therapy (as defined by study investigators)
Escape therapy was defined in Unizony 2013 (the published protocol of the Stone 2017 study) as "the inability to follow the protocol‐defined prednisone taper by participants who had a disease flare". Stone 2017 analyzed the absence of the need for escape therapy at any time during the 52 weeks after randomization.
Vision changes
Stone 2017 reported various vision changes. Villiger 2016 did not assess this outcome.
Quality of life
Stone 2017 assessed health‐related quality of life using the physical and mental component summary score of the Medical Outcomes Study 36‐Item Short‐Form Health Survey (SF‐36). Each assessment score ranged from 0 to 100, with higher scores representing better function. This study also evaluated the patient’s global assessment of disease activity on the basis of a visual analogue scale (VAS; scores range from 0 to 100 mm, with higher scores indicating greater disease activity). Villiger 2016 did not assess this outcome.
Adverse outcomes
Both Stone 2017 and Villiger 2016 assessed the incidence, nature, and severity of adverse events. Stone 2017 assessed adverse events among participants who had received at least one dose of tocilizumab or placebo.
Excluded studies
Details of the excluded studies along with reasons for their exclusion are provided in Characteristics of excluded studies.
Risk of bias in included studies
See Figure 2 and Figure 3 for a summary of the risk of bias assessment.
2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Random sequence generation
Both studies used appropriate methods for random sequence generation and were judged to be at low risk of bias.
Allocation concealment
We judged both studies to be at low risk of bias for allocation concealment as the method used to conceal treatment allocation was adequate.
Blinding
Investigators, participants of both studies, and outcome assessors were masked to treatment, therefore both studies were assessed as at low risk of performance and detection bias.
Incomplete outcome data
Of the 251 participants enrolled in Stone 2017, 216 (86%) completed the trial through week 52. Intention‐to‐treat (ITT) and safety populations included only 250 participants because one participant assigned to receive tocilizumab every other week did not receive the trial drug. In the Villiger 2016 study, two participants in the tocilizumab group and three participants in the placebo group withdrew before week 12. Two participants withdrew due to lost of interest in the trial and wanted to be given tocilizumab. The rate of attrition was considered minimal, and data were analyzed in an ITT manner. We therefore judged both studies to be at low risk for attrition bias.
Selective reporting
In both studies, review‐specific outcomes outlined in the trial registry were reported in the published report, therefore both studies were assessed as at low risk for reporting bias.
Other potential sources of bias
Both Stone 2017 and Villiger 2016 were industry‐funded; industry sources provided the intervention under investigation (tocilizumab), and both studies were therefore assessed as at high risk for other potential sources of bias.
Effects of interventions
See: Table 1; Table 2; Table 3; Table 4; Table 5
We have presented five "Summary of findings" tables that compare: (1) tocilizumab every 4 weeks compared to placebo (Table 1); (2) tocilizumab weekly compared to placebo with a 52‐week taper (Table 2); (3) tocilizumab weekly compared to placebo with a 26‐week taper (Table 3); (4) tocilizumab every other week compared to placebo with a 52‐week taper (Table 4); and (5) tocilizumab every other week compared to placebo with a 26‐week taper (Table 5).
Primary outcomes
Proportion of participants with sustained remission
Villiger 2016 reported that complete remission from GCA was higher in the tocilizumab group compared with placebo after 52 weeks: tocilizumab 17 (85%) versus placebo 2 (20%). Participants in Villiger 2016 who received tocilizumab 8 mg/kg bodyweight every 4 weeks were more than 4 times likely to experience sustained remission beyond 12 months compared with placebo (risk ratio (RR) 4.25, 95% confidence interval (CI) 1.21 to 14.88) (Analysis 1.1).
1.1. Analysis.
Comparison 1: Tocilizumab every 4 weeks versus placebo, Outcome 1: Proportion of participants with sustained remission (as defined by study investigators)
At 12 months, point estimates from Stone 2017 favored participants who received tocilizumab compared with those that received placebo: tocilizumab weekly versus placebo + 52‐week taper (RR 3.17, 95% CI 1.71 to 5.89) (Analysis 2.1); tocilizumab weekly versus placebo + 26‐week taper (RR 4.00, 95% CI 1.97 to 8.12) (Analysis 3.1); tocilizumab every other week versus placebo + 52‐week taper (RR 3.01, 95% CI 1.57 to 5.75) (Analysis 4.1); ; tocilizumab every other week versus placebo + 26‐week taper (RR 3.79, 95% CI 1.82 to 7.91) (Analysis 5.1). Villiger 2016 also reported that among participants whose prednisolone dose was successfully tapered to 0 mg per day, 16 (80%) participants receiving tocilizumab versus 2 (20%) participants receiving placebo experienced complete remission. We did not calculate overall estimates for the estimates of Villiger 2016 (tocilizumab every four weeks) and either estimates from Stone 2017 (tocilizumab weekly or every other week) because of high statistical heterogeneity (I2 > 70%).
2.1. Analysis.
Comparison 2: Tocilizumab weekly versus placebo + 52‐week taper, Outcome 1: Proportion of participants with sustained remission (as defined by study investigators)
3.1. Analysis.
Comparison 3: Tocilizumab weekly versus placebo + 26‐week taper, Outcome 1: Proportion of participants with sustained remission (as defined by study investigators)
4.1. Analysis.
Comparison 4: Tocilizumab every other week versus placebo + 52‐week taper, Outcome 1: Proportion of participants with sustained remission (as defined by study investigators)
5.1. Analysis.
Comparison 5: Tocilizumab every other week versus placebo + 26‐week taper, Outcome 1: Proportion of participants with sustained remission (as defined by study investigators)
We rated the certainty of evidence for sustained remission at 12 months or greater for the comparison of tocilizumab versus placebo as moderate‐certainty, downgrading for imprecision.
Secondary outcomes
Proportion of participants with relapse‐free survival
Villiger 2016 (30 participants) reported that relapse‐free survival was higher in favor of participants who received tocilizumab versus placebo: 85% versus 10% at 12 months follow‐up. Participants in the tocilizumab group were more likely to experience relapse‐free survival at 12 months compared with the placebo group (RR 4.25, 95% CI 1.21 to 14.88) (Analysis 1.2). We rated the certainty of evidence as moderate, downgrading for imprecision.
1.2. Analysis.
Comparison 1: Tocilizumab every 4 weeks versus placebo, Outcome 2: Proportion of participants with relapse‐free survival
At the end of the 52‐week period, Stone 2017 reported percentages of patients who had a flare. According to the numbers of participants included in the ITT analysis (250 participants), participants receiving weekly tocilizumab were more likely to be flare‐free than those in the placebo + 52‐week taper (RR 1.51, 95% CI 1.13 to 2.02; N = 151) (Analysis 2.2) or the placebo + 26‐week taper group (RR 2.41, 95% CI 1.58 to 3.65; N = 150) (Analysis 3.2). Participants receiving tocilizumab every other week were also more likely to be relapse‐free at 52 week than those in the placebo + 52‐week taper (RR 1.48, 95% CI 1.08 to 2.03; N = 100) (Analysis 4.2) or the placebo + 26‐week taper group (RR 2.36, 95% CI 1.53 to 3.64; N = 99) (Analysis 5.2).
2.2. Analysis.
Comparison 2: Tocilizumab weekly versus placebo + 52‐week taper, Outcome 2: Proportion of participants with relapse‐free survival
3.2. Analysis.
Comparison 3: Tocilizumab weekly versus placebo + 26‐week taper, Outcome 2: Proportion of participants with relapse‐free survival
4.2. Analysis.
Comparison 4: Tocilizumab every other week versus placebo + 52‐week taper, Outcome 2: Proportion of participants with relapse‐free survival
5.2. Analysis.
Comparison 5: Tocilizumab every other week versus placebo + 26‐week taper, Outcome 2: Proportion of participants with relapse‐free survival
We rated the certainty of evidence as moderate, downgrading for imprecision.
Proportion of all‐cause mortality
Villiger 2016 (30 participants) provided information on all‐cause mortality, reporting that all‐cause mortality was 0% in the tocilizumab group versus 10% in the placebo group. Point estimates suggest no evidence of a difference between the two groups for all‐cause mortality at 12 months (RR 0.17, 95% CI 0.01 to 3.94) ( Analysis 1.3) . Stone 2017 did not report on all‐cause mortality, but stated that no participant had died during the one‐year follow‐up period. We rated the certainty of evidence for this outcome at 12 months as moderate, downgrading for imprecision.
1.3. Analysis.
Comparison 1: Tocilizumab every 4 weeks versus placebo, Outcome 3: Proportion of all‐cause mortality
Mean time to first relapse after induction of remission
Investigators in Villiger 2016 (30 participants) reported that one participant in the tocilizumab group had a major relapse at week 11, compared to five participants in the placebo group (at weeks 6, 10, 12, 17, and 20). The mean time to first relapse after 12 months was 50 weeks and 25 weeks for the tocilizumab and placebo groups, respectively. At 12 months, point estimates indicate that the mean time to relapse was longer in participants who received tocilizumab compared with those who received placebo (mean difference (MD) 25.00 weeks, 95% CI 11.40 weeks to 38.60 weeks) (Analysis 1.4). Stone 2017 did not report on this outcome. We rated the certainty of evidence at 12 months to be moderate, downgrading for imprecision.
1.4. Analysis.
Comparison 1: Tocilizumab every 4 weeks versus placebo, Outcome 4: Mean time to first relapse after induction of remission (weeks)
Cumulative mean dose of corticosteroids
Villiger 2016 and Stone 2017 did not report cumulative mean dose of corticosteroid, but rather cumulative median doses. Villiger 2016 (30 participants) reported that the cumulative median prednisolone dose was lower after 12 weeks in favor of the tocilizumab group (34 mg/kg, interquartile range (IQR) 32 to 35) compared to the placebo group (36 mg/kg, IQR 34 to 39; P = 0.048). The high cumulative prednisolone dose persisted at 26 weeks for the placebo group (66 mg/kg, IQR 52 to 75) compared to the tocilizumab group (41 mg/kg, IQR 39 to 46; P = 0.002); this was even higher at 52 weeks: placebo group (110 mg/kg, IQR 88 to 150) versus tocilizumab group (43 mg/kg, IQR 39 to 52; P < 0.001). We rated the certainty of evidence at all three time points at moderate, downgrading for imprecision. At 12 months, 80% participants in the tocilizumab group had tapered prednisolone to 0 mg/day, compared to 20% of participants in the placebo group. The mean follow‐up time to stopping corticosteroids in the tocilizumab group was 38 weeks (95% CI 35 to 42) compared to 50 weeks (95% CI 46 to 54) in the placebo group. This suggests that participants in the tocilizumab group were more likely to have a lower mean follow‐up time to stopping corticosteroids: MD 12 weeks, 95% CI 7 to 17; P < 0.001.
Stone 2017 reported that over the 52‐week period, the total median cumulative prednisone dose was lower in favor of the groups that received tocilizumab weekly (1862 mg, 95% CI 1582 to 1942) or every other week (1862 mg, 95% CI 1568 to 2240) compared with either the placebo + 26‐week taper (3296 mg, 95% CI 2730 to 4024) or the placebo + 52‐week taper (3818 mg, 95% CI 2818 to 4426); P < 0.001, for all comparisons of tocilizumab with placebo.
Proportion of participants who did not need escape therapy (as defined by study investigators)
Stone 2017 was the only study that reported this outcome. Of those participants who received tocilizumab weekly, 77% did not need escape therapy by 12 months. Stone 2017 also reported the proportion of participants who did not need escape therapy by 12 months in the following groups: tocilizumab every other week (67%), placebo + 52‐week taper (26%), and placebo + 26‐week taper (45%).
Point estimates at 12 months favored participants who received tocilizumab weekly compared with those receiving placebo + 52‐week taper (RR 1.71, 95% CI 1.24 to 2.35); 151 participants) (Analysis 2.3); tocilizumab weekly compared to placebo + 26‐week taper (RR 2.96, 95% CI 1.83 to 4.78; 150 participants) (Analysis 3.3) ; tocilizumab every other week compared with placebo + 52‐week taper (RR 1.49, 95% CI 1.04 to 2.14; 100 participants) (Analysis 4.3) . Results of the same trial (Stone 2017) did not favor but not every other week tocilizumab (RR 0.65, 95% CI 0.27 to 1.54; 99 participants) compared with placebo + 26‐week taper (Analysis 5.3) (moderate‐certainty due to imprecision).
2.3. Analysis.
Comparison 2: Tocilizumab weekly versus placebo + 52‐week taper, Outcome 3: Proportion of participants who did not need escape therapy (as defined by study investigators)
3.3. Analysis.
Comparison 3: Tocilizumab weekly versus placebo + 26‐week taper, Outcome 3: Proportion of participants who did not need escape therapy (as defined by study investigators)
4.3. Analysis.
Comparison 4: Tocilizumab every other week versus placebo + 52‐week taper, Outcome 3: Proportion of participants who did not need escape therapy (as defined by study investigators)
5.3. Analysis.
Comparison 5: Tocilizumab every other week versus placebo + 26‐week taper, Outcome 3: Proportion of participants who did not need escape therapy (as defined by study investigators)
Vision changes or general quality of life changes, as reported by the study authors
Vision changes
Stone 2017 reported that one participant who received tocilizumab every other week had a GCA flare that manifested as an anterior ischemic optic neuropathy. The visual loss resolved with escape therapy using open‐label glucocorticoid treatment. Another participant in this group had an episode of blurred vision. Investigators also reported participants who presented with vision symptoms as their flare symptoms in the placebo groups: five events in the placebo group + 26‐week taper (amaurosis fugax, blurred vision in two, and diplopia), and five participants in the placebo group + 52‐week taper (four with blurred vision and one with diplopia).
General quality of life changes
Stone 2017 assessed quality of life using the 36‐Item Short Form Health Survey (SF‐36) physical component score (PCS) at 52 weeks follow‐up. Investigators reported an improvement in quality of life in favor of the tocilizumab group. The mean increase in the SF‐36 PCS from baseline to week 52 was 4.10 in the weekly tocilizumab group and 2.76 in the bi‐weekly tocilizumab group, which indicate clinical improvement. In the two placebo groups, SF‐36 PCS showed a decrease, indicating a worse quality of life: −0.28 for the placebo group + 26‐week taper and −1.49 for the placebo group + 52‐week taper. Stone 2017 also reported that participants in the weekly tocilizumab group experienced an increase in overall quality of life scores by 5.59 points compared to the placebo group + 52‐week taper (MD 5.59, 95% CI 0.86 to 10.32) .
While point estimates for SF‐36 PCS at 12 months favored participants who received weekly tocilizumab compared to those receiving placebo + 52‐week taper (MD 8.17, 95% CI 4.44 to 11.90; 77 participants) (Analysis 2.4), there was no evidence of a difference in SF‐36 PCS scores between tocilizumab weekly versus placebo + 26‐week taper (MD 3.29, 95% CI −4.84 to 11.42; 68 participants) (Analysis 3.4) . Likewise, point estimates favored tocilizumab every other week as compared with placebo + 52‐week taper (MD 5.51, 95% CI 0.82 to 10.20; 44 participants) (Analysis 4.4) but not as compared with placebo + 26‐week taper (MD 0.63, 95% CI −7.98 to 9.24; 35 participants) (Analysis 5.4) (moderate‐certainty due to imprecision).
2.4. Analysis.
Comparison 2: Tocilizumab weekly versus placebo + 52‐week taper, Outcome 4: Quality of life: 36‐Item Short Form Health Survey (SF‐36)
3.4. Analysis.
Comparison 3: Tocilizumab weekly versus placebo + 26‐week taper, Outcome 4: Quality of life: 36‐Item Short Form Health Survey (SF‐36)
4.4. Analysis.
Comparison 4: Tocilizumab every other week versus placebo + 52‐week taper, Outcome 4: Quality of life: 36‐Item Short Form Health Survey (SF‐36)
5.4. Analysis.
Comparison 5: Tocilizumab every other week versus placebo + 26‐week taper, Outcome 4: Quality of life: 36‐Item Short Form Health Survey (SF‐36)
At 12 months follow‐up, point estimates indicate evidence of a difference in the SF‐36 mental component score (SF‐36 MCS) between the group that received tocilizumab weekly versus placebo + 52‐week taper (MD 5.61, 95% CI 0.06 to 11.16; 77 participants) (Analysis 2.4) but not versus placebo + 26‐week taper (MD 3.22, 95% CI −2.37 to 8.81; 68 participants) (Analysis 3.4). Comparing tocilizumab every other week versus placebo + 52‐week taper (MD −0.62, 95% CI −6.22 to 4.98; 44 participants) (Analysis 4.4) or versus placebo + 26‐week taper (MD −3.01, 95% CI −8.65 to 2.63; 35 participants) (Analysis 5.4) shows no evidence of differences in the MCS. We rated the certainty of evidence for the SF‐36 PCS and MCS quality of life for all comparisons at 12 months as moderate, downgrading for imprecision.
Stone 2017 also reported the patient's global assessment of disease activity on the basis of a visual analogue scale (VAS; scores range from 0 to 100 mm, where higher scores suggest greater disease activity and worse quality of life). At 12 months, within‐group mean VAS score decreased from baseline to 12 months, indicating improvement of −19.0 in the group that received weekly tocilizumab and −25.3 in the group that received biweekly tocilizumab; these were greater than the decrease observed in either placebo group (−3.4 in placebo + 26‐week taper and −7.2 in placebo + 52‐week taper). However, point estimates suggest no evidence of a difference in VAS scores for the following comparisons: tocilizumab weekly versus placebo + 52‐week taper (MD −9.68, 95% CI −28.00 to 8.64; 78 participants) (Analysis 2.5); tocilizumab weekly versus placebo + 26‐week taper (MD −11.23, 95% CI −28.18 to 5.72; 71 participants) (Analysis 3.5); tocilizumab every other week versus placebo + 52‐week taper (MD −12.69, 95% CI −31.06 to 5.68; 44 participants) (Analysis 4.5); and tocilizumab every other week versus placebo + 26‐week taper (MD −14.24, 95% CI −31.24 to 2.76; 37 participants) (Analysis 5.5). We rated the certainty of evidence for the SF‐36 PCS and MCS quality of life for all comparisons at 12 months as moderate, downgrading for imprecision.
2.5. Analysis.
Comparison 2: Tocilizumab weekly versus placebo + 52‐week taper, Outcome 5: Quality of life: visual analogue scale
3.5. Analysis.
Comparison 3: Tocilizumab weekly versus placebo + 26‐week taper, Outcome 5: Quality of life: visual analogue scale
4.5. Analysis.
Comparison 4: Tocilizumab every other week versus placebo + 52‐week taper, Outcome 5: Quality of life: visual analogue scale
5.5. Analysis.
Comparison 5: Tocilizumab every other week versus placebo + 26‐week taper, Outcome 5: Quality of life: visual analogue scale
Villiger 2016 did not report on vision changes or quality of life.
Adverse outcomes
In Villiger 2016, there was no difference in terms of the number of participants who experienced any adverse event between the tocilizumab group (15 participants [75%]) and the placebo group (7 participants [70%]) (RR 1.07, 95% CI 0.66 to 1.73; 30 participants) (Analysis 1.5); however, fewer participants experienced any serious adverse event in the tocilizumab group (7 participants [35%]) versus the placebo group (5 participants [50%]). Investigators in Villiger 2016 recorded 26 adverse events in 15 participants in the tocilizumab group, compared with 23 recorded in seven participants in the placebo group. Investigators reported that there were seven serious adverse events in seven participants in the tocilizumab group (one had a severe headache with tinnitus needing hospitalization unrelated to GCA; three with gastrointestinal complications; one did not take the prescribed pantoprazole and developed a prepyloric ulcer perforation; a second had a hepatopathy due to an undefined viral infection; and a third underwent gastrointestinal endoscopy due to gastrointestinal bleeding 12 days after treatment initiation). The others were: severe psychosis, eye infection due to Moraxella catarrhalis, herpes infection necessitating admission, and Stevens‐Johnson syndrome three days after the third infusion. Ten adverse events were reported in five participants in the placebo group (three were serious cardiovascular adverse events: one had a syncope; another underwent percutaneous coronary intervention for coronary artery disease and later suffered a fatal myocardial infarction; a sigmoid perforation with a previously undiagnosed diverticulosis). Serious adverse events in the tocilizumab versus the placebo group were as follows: cardiovascular (1 versus 3); gastrointestinal (3 versus 1); osteoporotic fracture (0 versus 2), back pain (0 versus 2); glucocorticoid‐related hyperglycemia and myopathia (1 versus 2), infection disease (1 versus 0); and skin disease (1 versus 0). There were no infusion‐related adverse events. We rated the certainty of evidence for adverse events as moderate, downgrading for imprecision.
1.5. Analysis.
Comparison 1: Tocilizumab every 4 weeks versus placebo, Outcome 5: Adverse events at 12 months or more
In Stone 2017, investigators noted that the proportion of participants with adverse events was similar between groups (Analysis 2.6; Analysis 3.6; Analysis 4.6; Analysis 5.6). Investigators also observed that “fewer patients reported serious adverse events in the group that received tocilizumab weekly (15%) or every other week (14%) than in the placebo group that underwent the 26‐week taper (22%) or the placebo group that underwent the 52‐week taper (25%).” Infection was the most frequently reported adverse event, with serious infections observed among participants that received weekly tocilizumab (7%), tocilizumab every other week (4%), placebo group + 26‐week taper (4%), and placebo group + 52‐week taper (12%). Stone 2017 reported that injection‐site reactions were as follows: weekly tocilizumab (7%), tocilizumab every other week (14%), placebo + 26‐week taper (10%), and placebo + 52‐week taper (2%). Investigators did not observe gastrointestinal perforations, myocardial infarctions, demyelinating disorders, or anaphylaxis. One participant who received tocilizumab every other week experienced a thrombotic stroke on day 254 of the study, which investigators considered unrelated to tocilizumab, attributing it to warfarin discontinuation for a surgery unrelated to GCA.
2.6. Analysis.
Comparison 2: Tocilizumab weekly versus placebo + 52‐week taper, Outcome 6: Adverse events
3.6. Analysis.
Comparison 3: Tocilizumab weekly versus placebo + 26‐week taper, Outcome 6: Adverse events
4.6. Analysis.
Comparison 4: Tocilizumab every other week versus placebo + 52‐week taper, Outcome 6: Adverse events
5.6. Analysis.
Comparison 5: Tocilizumab every other week versus placebo + 26‐week taper, Outcome 6: Adverse events
Laboratory abnormalities
Villiger 2016 reported that laboratory abnormalities were similar between groups at the end of the follow‐up period. They were as follows: ([number of episodes (patients) − % of tests]): abnormal transaminase levels (alanine transaminase > 70 U/L [women] or > 100 U/L [men]: tocilizumab 5 (2) − 2% versus placebo 3 (2) − 2%); (aspartate transaminase > 70 U/L [women] or > 100 U/L [men] tocilizumab 2 (2) − 1% 1 versus placebo 0 (0) − 0%); (leucopenia [leucocytes < 3.5*109/L]: tocilizumab 15 (6) − 5% versus placebo 1 (1) − 1%); (neutropenia [neutrophils < 1.6*109/L]: tocilizumab 9 (4) − 3% versus placebo 0 (0) − 0%); (thrombocytopenia [thrombocytes < 140*109/L] tocilizumab: 15 (5) − 5% versus placebo 4 (2) − 5%); (cholesterol > 5.2 mmol/L tocilizumab: 37 (18) − 84% versus placebo 8 (5) − 48%); (triglycerides > 1.7 mmol/L tocilizumab: 20 (9) − 47% versus placebo 7 (5) − 58%). Stone 2017 observed grade 3 neutropenia in 4 (4%) participants who received weekly tocilizumab and in 2 (4%) participants who received tocilizumab every other week. Two (2%) participants in the weekly tocilizumab group, one (2%) participant in the bi‐weekly tocilizumab group, and one (2%) participant in the placebo group experienced a grade 3 elevation of alanine aminotransferase levels. One (2%) participant in the placebo group + 52‐week taper experienced a grade 3 elevation of alanine aminotransferase levels.
Withdrawals
In Villiger 2016, five participants withdrew from the study before week 12 (tocilizumab [n = 2] versus placebo [n = 3]). In the placebo group, two participants lost interest in the study and asked to be given tocilizumab, and one participant withdrew before week 12 due to a serious adverse effect. In the tocilizumab group, one participant withdrew due to a serious adverse event, and a second participant withdrew due to an adverse event. Stone 2017 reported that 6% of participants in each tocilizumab group and 4% of participants in the placebo + 26‐week taper group withdrew due to an adverse event; no participants in the placebo + 52‐week taper group withdrew due to an adverse event. Among the total sample of 251, frequently cited reasons for withdrawal from the study were adverse events, 11 (4%); participant’s decision, 11 (4%); and lack of efficacy, 8 (3%).
Discussion
Summary of main results
We identified two randomized controlled trials that evaluated the efficacy and safety of tocilizumab for GCA. Tocilizumab was given via infusion every four weeks in one study, and subcutaneously every week or every other week in the other study. In both studies, both arms received a predetermined corticosteroid taper and were followed up for 52 weeks. Overall, both studies favored tocilizumab in terms of proportion of participants with new or relapsing GCA that achieved sustained remission at long term (12 months or more) (moderate‐certainty evidence). The mean time to first relapse after induction of remission and proportion of participants with relapse‐free survival were higher at 12 months or longer in favor of tocilizumab compared with placebo (moderate‐certainty evidence). We found no evidence of a difference in all‐cause mortality between the two groups (moderate‐certainty evidence).
Cumulative median rather than mean dose of corticosteroids was reported in both studies, and findings suggest that the median cumulative dose of corticosteroids was lower in favor of tocilizumab compared to placebo (moderate‐certainty evidence). One study assessed proportion of participants who did not need escape therapy (defined by investigators as the inability to keep to the protocol‐defined prednisone taper) at 12 months or longer, which was in favor of participants receiving weekly tocilizumab versus placebo + 52‐week taper; participants receiving tocilizumab every other week versus placebo + 52‐week taper; and participants receiving tocilizumab weekly versus placebo +26‐week taper (moderate‐certainty evidence). There was no evidence of a difference between participants receiving tocilizumab every other week versus placebo + 26‐week taper (moderate‐certainty evidence).
One study that assessed vision changes and quality of life reported no evidence of a difference between groups in terms of vision changes. Both changes in the SF‐36 PCS and MCS consistently favored participants who received weekly tocilizumab compared to those receiving placebo + 52‐week taper at 12 months ; evidence was less consistent in other comparisons. There was no evidence of a benefit in patient's global assessment of disease activity based on VAS scales (moderate‐certainty evidence). Both included studies reported various adverse events; one study reported fewer serious adverse events in favor of tocilizumab compared to placebo (moderate‐certainty evidence).
Overall completeness and applicability of evidence
One of the two included studies was conducted in 76 sites, including 15 sites in the USA and Canada, and 61 sites across Europe. Participants were mostly women, and the majority were white. The lack of diversity among included participants therefore suggests that specific racial or ethnic groups may be underrepresented, and so our conclusions may not translate to other populations. Individuals with other concomitant health issues or prior use of other biologics were excluded, thereby decreasing the generalizability of findings.
There was variability in the dose as well as the frequency of dosing across the two included studies. For example, while one study compared tocilizumab administered every four weeks versus placebo, the other study compared tocilizumab weekly or every other week versus various placebo regimens (placebo plus prednisolone taper at 52 weeks or placebo plus prednisolone taper at 26 weeks).
Quality of the evidence
We elected to include outcome data only from randomized controlled trials. At least two review authors reviewed studies for eligibility according to Cochrane guidelines. The quality of reporting on methods used in both studies was quite good, with both studies complying with CONSORT guidelines. Both studies adequately described all risk of bias domains and were therefore judged to be at low risk for selection, performance, detection, attrition, and reporting bias. The certainty of evidence for the outcomes assessed was mostly moderate to high owing to imprecision.
Potential biases in the review process
The Cochrane Eyes and Vision Information Specialist performed a comprehensive search of electronic bibliographic databases for studies using prespecified criteria with no publication date or language restrictions. We also searched references and citation lists in the reports from included studies to identify any further relevant studies. Title and abstract screening of studies identified from the electronic database search and full‐text article review were conducted by two review authors (AA and SAA) working independently. Both review authors (AA and SAA) independently extracted data from the included studies into a web‐based review management software, assessed risk of bias for each study, and uploaded the data into Review Manager 5 (Review Manager 2020). The two review authors double‐checked the data entered into Review Manager 5 for possible errors. We assessed information regarding declaration of interest and funding source of studies as a potential source of bias. Both studies were funded by Roche (the manufacturer of the tocilizumab intervention evaluated in this review). Although the investigators of Villiger 2016 indicated they have no competing interest, many investigators in Stone 2017 had financial relationships with industry sponsors that marketed tocilizumab and reported receiving other grant support and personal fees from Roche while conducting the study.
Agreements and disagreements with other studies or reviews
Participants who received tocilizumab in the Villiger 2016 and Stone 2017 studies were prospectively followed after tocilizumab was discontinued at week 52. Adler 2019 prospectively followed 17 of 20 participants in the Villiger 2016 study who received their last dose of tocilizumab at week 52 and were in lasting remission without any co‐medication, such as corticosteroids or methotrexate. Mean follow‐up time for Adler 2019 was 28.1 months after the last tocilizumab infusion. Investigators observed that improvement in clinical and serological remission in nine participants lasted for a mean of 29.3 months. Mean time to relapse was also lower in eight participants, with six of eight relapses occurring within five months after the last tocilizumab infusion. Relapsing participants were younger than those without relapse, and none of the relapsing participants developed blindness.
Participants in the Stone 2017 study who were in clinical remission stopped the double‐blind tocilizumab treatment, and 215 of the original 251 participants entered a 2‐year long‐term extension (part 2) of the trial (Stone 2019), while 197 participants completed 3 years in the trial. Clinical remission was maintained over two years by participants in the weekly and bi‐weekly tocilizumab groups. Participants receiving tocilizumab were also treatment‐free (no tocilizumab or glucocorticoid treatment), which was higher than those in the placebo group who maintained clinical remission. Median time to first flare without tocilizumab was also longer for participants in the original tocilizumab groups compared to the placebo groups. Stone 2019 reported that tocilizumab retreatment, with or without glucocorticoid, was effective for restoring clinical remission. Cumulative steroid dose over the 3‐year study was lowest in the weekly tocilizumab group. In agreement with our findings, the rates of serious adverse events per 100 patient‐years over two years were comparable for those who never received tocilizumab versus those who received ≥ 1 dose of tocilizumab.
Berti 2018 performed a meta‐analysis on relapse‐free maintenance for glucocorticoid‐sparing strategies (not just tocilizumab) in GCA and reported the robustness or precision of the evidence using the fragility index (FI). They defined fragility index according to Walsh 2014 "as the minimum number of subjects in a randomized controlled trial whose status would have to change (e.g., from having the outcome to not) to render a statistically significant result non significant, or vice‐versa." The Villiger 2016 trial had an FI of 4, while the Stone 2017 trial had an FI of 28; both had a positive outcome. Berti 2018 further stated that the strongest evidence for GCA relapse prevention strategy supports tocilizumab (over abatacept, adalimumab, etanercept, infliximab, intravenous glucocorticoid pulse, and methotrexate). Berti 2018 also underscored the difference of the FI between the Villiger 2016 and Stone 2017 studies of 4 and 28, respectively, but with similar P values; reporting that the fragility index reflects the robustness of randomized controlled trials better than the P values.
Authors' conclusions
Implications for practice.
Tocilizumab is an effective and safe steroid‐sparing therapy in patients with newly diagnosed and relapsing giant cell arteritis (GCA). Tocilizumab was approved in Europe in September 2017 and in the US by the Food and Drug Administration in May 2017 for GCA. It remains unknown how long tocilizumab should be given; however, the Swedish Society of Rheumatology issued its 2018 guidelines that tocilizumab with glucocorticoid taper is recommended as an addition to treatment with glucocorticoids for patients who have relapsed during or after completion of glucocorticoid treatment for large vessel arteritis, clinically active GCA, elevated C‐reactive protein and erythrocyte sedimentation rate, obvious side effect, or greater risk of future treatment with glucocorticoids (Turesson 2019). They further stated that tocilizumab should be stopped after one year for patients who have achieved sustained remission, who should be followed by a specialist for at least six months after treatment completion.
Our findings indicate that compared to glucocorticoids, tocilizumab therapy in people with GCA may be beneficial in terms of proportion of participants with sustained remission, relapse‐free survival, lower cumulative median dose of glucocorticoids, as well as the need for no escape therapy. However, we found no clear benefit of tocilizumab therapy compared with glucocorticoids in quality of life. Although the most frequently occurring adverse event of tocilizumab was infection, and the frequency of adverse events was similar among participants in both the tocilizumab and placebo groups, the paucity of data rendered it impossible to rule out significant adverse events of tocilizumab. Additionally, while the trials included in this review did not find a significant increase in infection from tocilizumab compared to glucocorticoid treatment, the primary concern regarding tocilizumab has always been opportunistic infection, which has been shown in large clinical studies for rheumatoid arthritis (Campbell 2011; Jones 2010).
The evidence in this review was derived from participants who were mostly white, without concomitant health issues or prior use of other biologics. The use of tocilizumab therapy in other racial groups or patients with other comorbidities, as well as those with prior exposure to other biologic agents, should therefore be considered carefully, since this population was either underrepresented or excluded from studies that contributed data for current review.
Implications for research.
The criteria for diagnosing GCA has not changed since the 1990 American College of Rheumatology GCA classification (Table 6), which was originally created to help differentiate GCA from other vasculitides (Hunder 1990). Studies are under way with the goal of developing and validating criteria for GCA diagnosis (Craven 2013), which may further hone therapeutic studies. Tocilizumab targets interleukin‐6 (IL‐6) receptors which, in turn affects the usual inflammatory acute phase reactants (e.g. erythrocyte sedimentation rate, C‐reactive protein, fibrinogen) that clinicians would monitor for disease activity. Given the interest in this agent for GCA, future studies looking at tocilizumab for GCA should look at other possible cost‐effective laboratory (biomarkers) and neuroimaging parameters to monitor disease activity.
Future research should also look into the duration of treatment with tocilizumab and evaluate its effect on outcomes that are meaningful to care providers, patients, and regulators. The effect of tocilizumab on health‐related quality of life was inconclusive, and economic outcomes were not an objective of this review. Future reviews or updates to this review should consider addressing these outcomes along with outcomes that are important to providers, patients, regulatory agents, and payers, to better inform decision‐making in terms of provider and patient choice as well as policy changes.
In the open‐label observational studies of Adler 2019 and Stone 2019, it was shown that half of patients relapsed after tocilizumab was discontinued after remission had been achieved. Longer follow‐up is also needed to provide better safety data for tocilizumab in GCA. It is also unclear whether tocilizumab has a more fundamental role in the pathogenesis of GCA. Unizony 2012 reported a GCA case that was in clinical remission with tocilizumab, but upon autopsy was found to have active disease in almost all of the arterial branches of the aorta. Stone 2017 also reported one case in the bi‐weekly tocilizumab group that had a flare with an anterior ischemic optic neuropathy, which resolved with glucocorticoid treatment. This improvement suggests that steroids may have a more critical role in the control (thus pathogenesis) of GCA.
Other studies are looking at other biologics targeting other areas in the immune cascade (T cells, interleukin‐1, interleukin‐23, B‐cells, tumor necrosis factor‐alpha, interleukin‐1 beta, etc.) in GCA patients with relapsing disease. Additionally, future studies should also look at reporting fragility index to measure the defined minimum number of participants whose status would have to change (from having the outcome to not, or vice‐versa). Schirmer 2018 stated that future randomized controlled trials will be performed to study the effect of tocilizumab monotherapy and whether polymyalgia rheumatica and GCA can be considered as distinct low‐ and high‐activity types of the same disease. Furthermore, looking at real‐world data of those patients treated with tocilizumab and their course of GCA‐related visual loss and stroke is recommended, given that Cid 1998 showed that GCA patients with ischemic complications had lower tissue expression and circulating levels of IL‐6 compared to those without ischemic events.
What's new
| Date | Event | Description |
|---|---|---|
| 12 April 2022 | New citation required but conclusions have not changed | Analysis 2.2; Analysis 3.2; Analysis 4.2 and Analysis 5.2 added; Summary of Finding tables updated; Results and Discussion section corrected and updated. Abstract and PLS updated. |
| 12 April 2022 | Amended | Changes have been made to some sections. |
History
Protocol first published: Issue 11, 2019 Review first published: Issue 8, 2021
Acknowledgements
We thank Lori Rosman, Information Specialist for Cochrane Eyes and Vision (CEV), who created and executed the electronic search strategies. We thank Genie Han, Senior Research Coordinator, for support in preparation of this review.
We also thank Anupa Shah, Managing Editor for CEV, for support and guidance in preparation of this review.
We would also like to thank the following peer reviewers for their comments: Nikisha Richards (Virginia Commonwealth University Medical Center) and Avnish Deobhakta (Mount Sinai).
This review was managed by CEV@US and was signed off for publication by Tianjing Li and Gianni Virgili.
Appendices
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor: [Giant Cell Arteritis] explode all trees #2 MeSH descriptor: [Polymyalgia Rheumatica] explode all trees #3 giant NEAR/2 cell NEAR/2 arteritis #4 (temporal* OR cranial* OR Horton* OR granulomatous* OR "giant cell") NEAR/2 (arteriti* OR disease* OR syndrome* OR aoriti*) #5 GCA #6 (polymyalgia OR myalgia*) NEAR/2 (rheumatic* OR arteritica*) #7 ("forestier certonciny" NEAR/2 syndrome*) OR (pseudopolyarthriti* NEAR/2 rhizomelic*) OR "Peri Extra Articular Rheumatism" #8 {OR #1‐#7} #9 MeSH descriptor: [Antibodies, Monoclonal] explode all trees #10 MeSH descriptor: [Interleukin‐6] explode all trees #11 MeSH descriptor: [Receptors, Interleukin‐6] explode all trees #12 Tocilizumab* OR actemra* OR atlizumab* OR lusinex* OR "r 1569" OR r1569 OR roactemra* #13 ("IL 6" NEXT receptor*) OR ("interleukin 6" NEXT receptor*) #14 (monoclonal NEAR/4 antibod*) OR MRA #15 (lymphocyte* OR cell*) NEAR/4 agent* #16 {OR #9‐#15} #17 #8 AND #16
Appendix 2. MEDLINE Ovid search strategy
1. Randomized Controlled Trial.pt. 2. Controlled Clinical Trial.pt. 3. (randomized or randomised).ab,ti. 4. placebo.ab,ti. 5. drug therapy.fs. 6. randomly.ab,ti. 7. trial.ab,ti. 8. groups.ab,ti. 9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 10. exp animals/ not humans.sh. 11. 9 not 10 12. exp Giant Cell Arteritis/ 13. exp Polymyalgia Rheumatica/ 14. (giant adj2 cell adj2 arteritis).tw. 15. ((temporal* or cranial* or Horton* or granulomatous* or "giant cell") adj2 (arteriti* or disease* or syndrome* or aoriti*)).tw. 16. GCA.tw. 17. ((polymyalgia or myalgia*) adj2 (rheumatic* or arteritica*)).tw. 18. (("forestier certonciny" adj2 syndrome*) or (pseudopolyarthriti* adj2 rhizomelic*) or "Peri Extra Articular Rheumatism").tw. 19. or/12‐18 20. exp Antibodies, Monoclonal/ 21. exp Interleukin‐6/ 22. exp Receptors, Interleukin‐6/ 23. (Tocilizumab* or actemra* or atlizumab* or lusinex* or "r 1569" or r1569 or roactemra*).tw,rn,nm. 24. (("IL 6" adj receptor*) or ("interleukin 6" adj receptor*)).tw,rn. 25. ((monoclonal adj4 antibod*) or MRA).tw,rn. 26. ((lymphocyte* or cell*) adj4 agent*).tw. 27. or/20‐26 28. 11 and 19 and 27
The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville et al (Glanville 2006).
Appendix 3. Embase.com search strategy
#1 'randomized controlled trial'/exp #2 'randomization'/exp #3 'double blind procedure'/exp #4 'single blind procedure'/exp #5 random*:ab,ti #6 #1 OR #2 OR #3 OR #4 OR #5 #7 'animal'/exp OR 'animal experiment'/exp #8 'human'/exp #9 #7 AND #8 #10 #7 NOT #9 #11 #6 NOT #10 #12 'clinical trial'/exp #13 (clin* NEAR/3 trial*):ab,ti #14 ((singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*)):ab,ti #15 'placebo'/exp #16 placebo*:ab,ti #17 random*:ab,ti #18 'experimental design'/exp #19 'crossover procedure'/exp #20 'control group'/exp #21 'latin square design'/exp #22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 #23 #22 NOT #10 #24 #23 NOT #11 #25 'comparative study'/exp #26 'evaluation'/exp #27 'prospective study'/exp #28 control*:ab,ti OR prospectiv*:ab,ti OR volunteer*:ab,ti #29 #25 OR #26 OR #27 OR #28 #30 #29 NOT #10 #31 #30 NOT (#11 OR #23) #32 #11 OR #24 OR #31 #33 'giant cell arteritis'/exp #34 'temporal arteritis'/exp #35 'rheumatic polymyalgia'/exp #36 (giant NEAR/2 cell NEAR/2 arteritis):ab,ti,kw #37 ((temporal* OR cranial* OR horton* OR granulomatous* OR 'giant cell') NEAR/2 (arteriti* OR disease* OR syndrome* OR aoriti*)):ab,ti,kw #38 gca:ab,ti,kw #39 ((polymyalgia OR myalgia*) NEAR/2 (rheumatic* OR arteritica*)):ab,ti,kw #40 (('forestier certonciny' NEAR/2 syndrome*):ab,ti,kw) OR ((pseudopolyarthriti* NEAR/2 rhizomelic*):ab,ti,kw) OR 'peri extra articular rheumatism':ab,ti,kw #41 #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 #42 'monoclonal antibody'/exp #43 'interleukin 6'/exp #44 'interleukin 6 receptor'/exp #45 tocilizumab*:ab,ti,kw,tn OR actemra*:ab,ti,kw,tn OR atlizumab*:ab,ti,kw,tn OR lusinex*:ab,ti,kw,tn OR 'r 1569':ab,ti,kw,tn OR r1569:ab,ti,kw,tn OR roactemra*:ab,ti,kw,tn #46 ('il 6 receptor*'):ab,ti,kw,tn OR ('interleukin 6 receptor*'):ab,ti,kw,tn #47 ((monoclonal NEAR/4 antibod*):ab,ti,kw,tn) OR mra:ab,ti,kw,tn #48 ((lymphocyte* OR cell*) NEAR/4 agent*):ab,ti,kw #49 #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 #50 #32 AND #41 AND #49
Appendix 4. PubMed search strategy
1. ((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomised[tiab] OR randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT (animals[mh] NOT humans[mh]) 2. ((temporal*[tw] OR cranial*[tw] OR horton*[tw] OR granulomatous*[tw] OR "giant cell"[tw]) AND (arteriti*[tw] OR disease*[tw] OR syndrome*[tw] OR aoriti*[tw])) 3. GCA[tw] 4. ((polymyalgia[tw] OR myalgia*[tw]) AND (rheumatic*[tw] OR arteritica*[tw])) 5. ((forestier certonciny syndrome*[tw]) OR ((pseudopolyarthriti*[tw] AND rhizomelic*[tw]) OR "peri extra articular rheumatism"[tw]) 6. #2 OR #3 OR #4 OR #5 7. tocilizumab*[tw] OR actemra*[tw] OR atlizumab*[tw] OR lusinex*[tw] OR 'r 1569'[tw] OR r1569[tw] OR roactemra*[tw] 8. (il 6 receptor*[tw] OR interleukin 6 receptor*[tw]) 9. (monoclonal antibod*[tw] OR mra[tw]) 10. ((lymphocyte*[tw] OR cell*[tw]) AND agent*[tw]) 11. #7 OR #8 OR #9 OR #10 12. #1 AND #6 AND #11 13. Medline[sb] 14. #12 NOT #13
Appendix 5. LILACS search strategy
((Giant Cell Arteriti$) OR "Arteritis de Células Gigantes" OR "Arterite de Células Gigantes" OR MH:C10.114.875.700$ OR MH:C10.228.140.300.850.500$ OR MH:C14.907.253.946.700$ OR MH:C14.907.940.090.530$ OR MH:C14.907.940.907.700$ OR MH:C17.800.862.252 OR MH:C20.111.258.962.800 OR (temporal arteritis$) OR (cranial arteritis$) OR (Horton$ disease$) OR (granulomatous arteritis$) OR GCA OR (Polymyalgia Rheumatic$) OR "Polimialgia Reumática" OR MH:C05.651.742$ OR MH:C05.799.720$ OR MH:C17.300.775.720$ OR (polymyalgia rheumatic$) OR (polymyalgia arteritica$) OR (myalgia$ rheumatic$) OR (myalgia$ arteritica$) OR (Forestier Certonciny Syndrome$) OR (pseudopolyarthriti$ rhizomelic$) OR "Peri Extra Articular Rheumatism") AND ((monoclonal antibod$) OR MH:D12.776.124.486.485.114.224$ OR MH:D12.776.124.790.651.114.224$ OR MH:D12.776.377.715.548.114.224$ OR MH:D12.644.276.374.465.224$ OR MH:D12.776.467.374.465.202$ OR MH:D23.529.374.465.224$ OR MH:D12.776.543.750.705.852.420.400$ OR Tocilizumab$ OR actemra$ OR atlizumab$ OR lusinex$ OR "r 1569" OR r1569 OR roactemra$ OR "IL 6 receptor" OR "interleukin 6 receptor" OR MRA OR (lymphocyte$ agent$) OR (cell$ agent$))
Appendix 6. ClinicalTrials.gov search strategy
Giant Cell Arteritis AND (Tocilizumab OR actemra OR atlizumab OR lusinex OR "r 1569" OR r1569 OR roactemra OR "il 6 receptor" OR "interleukin 6 receptor" OR "monoclonal antibodies")
Appendix 7. WHO ICTRP search strategy
Giant Cell Arteritis AND Tocilizumab OR Giant Cell Arteritis AND actemra OR Giant Cell Arteritis AND atlizumab OR Giant Cell Arteritis AND lusinex OR Giant Cell Arteritis AND "r 1569" OR Giant Cell Arteritis AND r1569 OR Giant Cell Arteritis AND roactemra OR Giant Cell Arteritis AND "il 6 receptor" OR Giant Cell Arteritis AND "interleukin 6 receptor" OR Giant Cell Arteritis AND monoclonal antibodies
Data and analyses
Comparison 1. Tocilizumab every 4 weeks versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Proportion of participants with sustained remission (as defined by study investigators) | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 1.1.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 1.2 Proportion of participants with relapse‐free survival | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 1.2.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 1.3 Proportion of all‐cause mortality | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 1.3.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 1.4 Mean time to first relapse after induction of remission (weeks) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.4.1 12 months or more | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.5 Adverse events at 12 months or more | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5.1 12 months or more | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected |
Comparison 2. Tocilizumab weekly versus placebo + 52‐week taper.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 2.1 Proportion of participants with sustained remission (as defined by study investigators) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.2 Proportion of participants with relapse‐free survival | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 2.2.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 2.3 Proportion of participants who did not need escape therapy (as defined by study investigators) | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 2.3.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 2.4 Quality of life: 36‐Item Short Form Health Survey (SF‐36) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.4.1 Physical component score (PCS) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.4.2 Mental component score (MCS) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.5 Quality of life: visual analogue scale | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.6 Adverse events | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected |
Comparison 3. Tocilizumab weekly versus placebo + 26‐week taper.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 3.1 Proportion of participants with sustained remission (as defined by study investigators) | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 3.2 Proportion of participants with relapse‐free survival | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 3.2.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 3.3 Proportion of participants who did not need escape therapy (as defined by study investigators) | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 3.3.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 3.4 Quality of life: 36‐Item Short Form Health Survey (SF‐36) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.4.1 Physical component score (PCS) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.4.2 Mental component score (MCS) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.5 Quality of life: visual analogue scale | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.6 Adverse events | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected |
Comparison 4. Tocilizumab every other week versus placebo + 52‐week taper.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 4.1 Proportion of participants with sustained remission (as defined by study investigators) | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 4.1.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 4.2 Proportion of participants with relapse‐free survival | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 4.2.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 4.3 Proportion of participants who did not need escape therapy (as defined by study investigators) | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 4.3.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 4.4 Quality of life: 36‐Item Short Form Health Survey (SF‐36) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.4.1 Physical component score (PCS) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.4.2 Mental component score (MCS) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.5 Quality of life: visual analogue scale | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.6 Adverse events | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected |
Comparison 5. Tocilizumab every other week versus placebo + 26‐week taper.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 5.1 Proportion of participants with sustained remission (as defined by study investigators) | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 5.1.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 5.2 Proportion of participants with relapse‐free survival | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 5.2.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 5.3 Proportion of participants who did not need escape therapy (as defined by study investigators) | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 5.3.1 12 months or more | 1 | Risk Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 5.4 Quality of life: 36‐Item Short Form Health Survey (SF‐36) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.4.1 Physical component score (PCS) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.4.2 Mental component score (MCS) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.5 Quality of life: visual analogue scale | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.6 Adverse events | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Stone 2017.
| Study characteristics | ||
| Methods |
Study design: parallel‐group 4‐arm randomized controlled trial. Participants were "randomly assigned in a 2:1:1:1 ratio to one of four groups... randomization was stratified according to the baseline prednisone dose (≤30 mg per day vs. >30 mg per day)." Number randomized (total and number per group): 353 screened, 251 enrolled. Group 1: tocilizumab weekly plus a 26‐week prednisone taper (n = 100) Group 2: tocilizumab every other week plus a 26‐week prednisone taper (n = 50) Group 3: placebo plus a 26‐week prednisone taper (n = 50) Group 4: placebo plus a 52‐week prednisone taper (n = 51) Unit of randomization and analysis: individual Number analyzed: 251 Analyses performed in the original studies:
Length of follow‐up: 52 weeks double‐blind (2017 NEJM), followed by 104‐week open‐label extension of tocilizumab 162 mg weekly (separately reported in 2019 at ACR) Number of centers: "76 sites across the USA, Canada, and Europe" Sample size calculations: a sample of 100 patients in the group that received tocilizumab weekly and 50 patients in both the group that received tocilizumab every other week and the placebo group that underwent the 26‐week taper would provide the trial with more than 90% power to detect a difference in the percentage of patients with sustained remission at week 52 in each tocilizumab group vs the placebo group that underwent the 26‐week taper, assuming an effect size of 40 percentage points (i.e. a difference of 40 percentage points in the percentage of patients with the primary outcome). It was explained in Lancet 2016: a sample size of 30 patients would yield a power of more than 80% to detect a risk difference of 60% at a conventional α level of 0.05, assuming complete remission to be 90% in the tocilizumab group and 30% in the placebo group. We expected a dropout rate of 10%. An interim analysis was not planned or done. Unit of analysis: participant |
|
| Participants |
Country: 76 sites, 14 countries across the USA, Canada, and Europe (Belgium, Denmark, France, Germany, Italy, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, and the UK). Europe (61 sites) and North America (15 sites) Setting: hospital Enrollment start and end year: July 2013 to April 2015 Tocilizumab weekly (N = 100)
Tocilizumab every other week (N = 49)
Placebo + 26‐week taper (N = 50)
Placebo + 52‐week taper (N = 51)
Overall
Inclusion criteria: patients 50 years or older with new‐onset or relapsing giant cell arteritis who fulfilled the 1990 American College of Rheumatology criteria 21 were eligible for study participation. Giant cell arteritis had to be proven by positive temporal artery biopsy or assessed as large vessel vasculitis by magnetic resonance angiography and had to be humorally active at inclusion (ESR of ≥ 40 mm in the first hour and CRP level of ≥ 20 mg/L). Exclusion criteria: the use of intravenous methylprednisolone at doses greater than 100 mg daily within 6 weeks before baseline; concomitant treatment with changes in methotrexate doses within > 6 weeks of study enrollment, or if increased throughout screening and 52‐week treatment period; concomitant use of other immunosuppressive medications Pretreatment: no demographic and baseline characteristic differences Study group differences: "The demographic characteristics and clinical features of the patients were similar among the four groups" |
|
| Interventions |
Intervention 1: tocilizumab weekly: subcutaneous tocilizumab, at a dose of 162 mg, weekly, plus a 26‐week prednisone taper Intervention 2: tocilizumab every other week: subcutaneous tocilizumab, at a dose of 162 mg, every other week, plus a 26‐week prednisone taper Comparator 1: placebo + 26‐week taper: subcutaneous placebo weekly plus a 26‐week prednisone taper Comparator 2: placebo + 52‐week taper: subcutaneous placebo weekly plus a 52‐week prednisone taper |
|
| Outcomes |
Primary outcomes: sustained prednisone‐free remission at week 52 between each tocilizumab group and the placebo group that underwent 26‐week taper Secondary outcomes: comparison of percentages of participants with sustained remission at week 52 between each tocilizumab group vs the placebo group that underwent the 52‐week taper; cumulative prednisone dose over 52‐week trial period; incidence of the first flare after remission in a time‐to‐event analysis; quality of life (physical and mental component summary scores of the Medical Outcomes Study 36‐Item Short‐Form Health Survey and a patient's global assessment of disease activity (higher score indicating greater disease activity)) from baseline to week 52; safety (incidence, nature, severity of adverse events and lab abnormalities in the safety populations, which included participants who had received at least 1 dose of tocilizumab or placebo) Adverse events, as reported by study authors: infection (which was the most frequently reported adverse event and serious adverse event), cardiovascular events, vision disturbance, injection‐site reaction |
|
| Identification |
Sponsorship source: F. Hoffmann‐La Roche, Ltd (Switzerland). Mechanistic studies are supported in part through a grant from the Arthritis Foundation. Comments: median rather than mean cumulative prednisone dose was reported. Author's name: John H Stone Institution: Massachusetts General Hospital and Harvard Medical School Email: jhstone@mgh.harvard.edu Address: Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 Declarations of interest: authors declared various forms of conflicts of interest, including, but not limited to, speaking and consultation fees, research support, and stock or stock option ownership with various industries. Trial registration number: NCT01791153 |
|
| Notes |
Cumulative prednisone dose: "The total median cumulative prednisone dose over the 52‐week period" Prednisone as escape therapy: "escape therapy we 52‐week taper." Management of prednisone taper: at baseline, the initial prednisone dose taken orally had to be between 20 mg and 60 mg per day. The prednisone dose was tapered weekly in all the trial groups as determined by the protocol. Doses of 20 mg or more per day were administered in an open‐label manner, but when the prednisone dose was less than 20 mg per day, participants and all trial personnel were unaware of the dose. Once prednisone was tapered from 1 mg per day to 0 mg per day, placebo tablets were used to maintain the blinding. Disease (GCA) assessment during the study: a laboratory assessor monitored all other laboratory variables independently of the efficacy assessor and notified the efficacy assessor of any verified ESR of 30 mm or more per hour. The efficacy assessor evaluated clinical activity of GCA and managed the prednisone taper. Both the laboratory assessor and the efficacy assessor were unaware of the group assignments. Disease assessment was performed at each visit to determine whether the participant’s disease was in remission and whether the participant could safely continue the prednisone taper. Definition of GCA/disease flare: determined by the efficacy assessor. Defined as the recurrence of signs or symptoms of GCA or an elevation of the ESR to 30 mm or more per hour that was attributable to GCA. The definition of disease flare included the necessity for an increase in the prednisone dose. Participants who had a flare or who could not adhere to the prednisone taper switched to open‐label escape therapy with prednisone, but continued to receive the assigned trial regimen (tocilizumab or placebo). Such participants were considered to have treatment failure with regard to the primary outcome. Definition of GCA/disease remission: absence of flare and the normalization of the CRP concentration to less than 1 mg/dL. Sustained remission was defined as remission from week 12 through week 52 and adherence to the prednisone taper. Management of GCA/disease flare: not clearly stated in their protocol Definition of NO response/failed primary outcome: participants who had a flare, received glucocorticoid treatment beyond that permitted by the protocol, withdrew from the trial, or did not have remission by week 12 were considered to not have had a response. Participants who had 2 consecutive elevations in CRP concentration above 1 mg/dL, or 1 elevation in CRP concentration followed by a missing value from week 12 |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Participants were randomly assigned in a 2:1:1:1 ratio to 1 of 4 groups. |
| Allocation concealment (selection bias) | Low risk | Participants were randomized through an interactive voice response system, therefore allocation was concealed de facto. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Authors indicated that this was a randomized, double‐blind, placebo‐controlled, phase 3 trial, masking of participants and study personnel de facto. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | "A laboratory assessor monitored all other laboratory variables independently of the efficacy assessor and notified the efficacy assessor of any verified ESR of 30 mm or more per hour. The efficacy assessor evaluated clinical activity of giant‐cell arteritis and managed the prednisone taper. Both the laboratory assessor and the efficacy assessor were unaware of the group assignments." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 251 patients were enrolled, but intention‐to‐treat and safety populations included 250 patients because 1 patient who had been assigned to receive tocilizumab every other week did not receive the trial drug. A total of 216 patients (86%) completed the trial through week 52 |
| Selective reporting (reporting bias) | Low risk | Review‐specific outcomes specified in the trial registry were reported in the results. |
| Other bias | High risk | The trial is funded by F. Hoffmann‐La Roche, Ltd (Switzerland). |
Villiger 2016.
| Study characteristics | ||
| Methods |
Study design: randomized controlled trial Study grouping: parallel group Unit of analysis: participants Number randomized (total and number per group): 30 total; intervention group: 20; comparator intervention: 10 Number analyzed: 30 participants in total (intention‐to‐treat analysis); 20 in tocilizumab group and 10 in placebo group Number of arms: 2 arms: 1) tocilizumab (8 mg/kg every 4 weeks until week 52) + glucocorticoids (GCs); 2) placebo + GCs Enrollment start and end year: September 2011 to December 2014 Length of follow‐up: 52 weeks Number of centers: 1 Sample size calculations: "we calculated that a sample size of 30 patients would yield a power of more than 80% to detect a risk difference of 60% at a conventional α level of 0·05, assuming complete remission to be 90% in the tocilizumab group and 30% in the placebo group" Analyses performed in the original studies: intention‐to‐treat analysis |
|
| Participants |
Country: Switzerland Setting: single center: University Hospital Bern Intervention: Tocilizumab (any dosage intravenously or subcutaneously) alone or with corticosteroids
Corticosteroids (alone or placebo)
Overall
Inclusion criteria: "patients older than 50 years of age with new‐onset or relapsing giant cell arteritis who fulfilled the 1990 American College of Rheumatology criteria. Giant cell arteritis had to be proven by positive temporal artery biopsy or assessed as large vessel vasculitis by MR angiography, and had to be humorally active at inclusion (erythrocyte sedimentation rate of ≥40 mm in the first hour, and C‐reactive protein level of ≥20 mg/L)" Exclusion criteria: "uncontrolled concomitant health problems, active infection, or any disease requiring systemic glucocorticoid treatment, previous treatment with tocilizumab, or any other biological agent was not allowed. Participants were permitted to receive prednisolone up to 1 mg/kg body weight for a maximum of 10 days between inclusion in the trial and the first infusion. All patients gave written informed consent before study enrolment." Pretreatment: baseline comparability was not reported Study group differences: not reported, but appears balanced at baseline |
|
| Interventions |
Intervention: "patients received 13 infusions every 4 weeks until week 52. Prednisolone was started at 1 mg/kg per day and tapered weekly by 0.1 mg/kg per day until week 8, then weekly by 0.05 mg/kg, reaching 0.1 mg/kg by week 12. Thereafter, the dose was reduced every month by 1 mg per day to 0 mg. Concomitant drugs in all patients consisted of 100 mg aspirin per day, 40 mg pantoprazole per day, 1000 mg calcium per day, 800 U cholecalciferol per day, and 3 mg ibandronate intravenously every 3 months" Comparison intervention: "prednisolone was started at 1 mg/kg per day and tapered weekly by 0·1 mg/kg per day until week 8, then weekly by 0.05 mg/kg, reaching 0.1 mg/kg by week 12. Thereafter, the dose was reduced every month by 1 mg per day to 0 mg. Concomitant drugs in all patients consisted of 100 mg aspirin per day, 40 mg pantoprazole per day, 1000 mg calcium per day, 800 U cholecalciferol per day, and 3 mg ibandronate intravenously every 3 months" |
|
| Outcomes |
Primary outcome: complete remission at week 12 without clinical signs or symptoms of GCA, and normal ESR and CRP at a prednisolone dose of 0.1 mg/kg per day Secondary outcomes: relapse‐free survival at week 52, time to first relapse after induction of remission, and cumulative dose of prednisolone Adverse events: various adverse events have been reported including discontinuation from the study due to adverse events, cardiovascular serious adverse events (lethal myocardial infarction), severe headache with tinnitus leading to admittance to hospital, gastrointestinal complications including undiagnosed diverticulosis and sigmoid perforation; glucocorticoid‐related problems were severe psychosis, immobilizing steroid‐induced myopathy and hyperglycemia, lumbar fractures and vertebroplasty, as well as infection due to Moraxella catarrhalis. The rest were herpes infection and a case of Stevens‐Johnson syndrome. |
|
| Identification |
Sponsorship source: Roche and the University of Bern Country: Switzerland Setting: single center: University Hospital Bern Comments: none Author's name: Peter M Villiger Institution: Department of Rheumatology, Immunology and Allergology, University Hospital, University of Bern, Bern, Switzerland Email: peter.villiger@insel.ch Address: Department of Rheumatology, Immunology and Allergology, University Hospital and University of Bern, CH3010 Bern, Switzerland Declarations of interest: the authors declare no competing interests. Trial registration number: NCT01450137 |
|
| Notes |
Cumulative dose of prednisolone: cumulative prednisolone dose (mg/kg) (median IQR) Tocilizumab plus prednisolone (N = 20) vs placebo plus prednisolone (N = 10):
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Patients were randomly assigned (2:1) to receive oral glucocorticoids and either tocilizumab at 8 mg/kg bodyweight or placebo, both intravenously. Allocation to treatment groups was done using a central computerized randomization procedure with a permuted block design and a block size of three, and concealed using central randomization generated by the clinical trials unit." |
| Allocation concealment (selection bias) | Low risk | "Allocation to treatment groups was done using a central computerized randomization procedure with a permuted block design and a block size of three and concealed using central randomization generated by the clinical trials unit... we used subsequently opened sealed, opaque, sequentially numbered envelopes containing the allocation information." |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | "Patients, investigators, and study personnel were masked to treatment assignments during the study; we used subsequently opened sealed, opaque, sequentially numbered envelopes containing the allocation information." |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | "The responsible senior statistician was not involved in study conduct or monitoring. Patients, investigators, and study personnel were masked to treatment assignments during the study... The site oncology nurse who prepared the study drug was not masked to this information but had no contact with patients or health professionals involved in their care... All MRA images, as well as image quality, were assessed independently by two experienced radiologists who were blinded regarding treatment allocation and serological parameters. Interrater agreement was substantial for the vasculitis score" |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 2 participants in the tocilizumab group withdrew before week 12 (1 due to a serious adverse event, 1 due to an adverse event), and 3 participants in the placebo group withdrew before week 12 (1 due to a serious adverse event, 2 lost interest). However, the rate of attrition was minimal, and data were analyzed in an intention‐to‐treat manner. |
| Selective reporting (reporting bias) | Low risk | "All pre‐specified outcomes in clinical trial register were reported" |
| Other bias | High risk | This study was funded by industry, and "tocilizumab was provided by Roche." |
CRP: C‐reactive protein ESR: erythrocyte sedimentation rate GCA: giant cell arteritis IQR: interquartile range MR: magnetic resonance SD: standard deviation
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Calderón‐Goercke 2019 | Not the intervention of interest |
| Gloor 2017 | Not an RCT, post hoc exploratory analysis of risk factors for treatment failure in an already included study |
| Goercke 2018 | Not the study design of interest |
| Goercke 2018a | Not the study design of interest |
| NCT03892785 | Not the intervention of interest |
| Unizony 2019 | Not an RCT, post hoc exploratory analysis of risk factors for treatment failure in an already included study |
| Vegas‐Revenga 2017 | Not the study design of interest |
RCT: randomized controlled trial
Differences between protocol and review
New author SAA added to the review author team.
Contributions of authors
Conception and study design: AA, RS
Drafting of the review: AA, RS, SAA
Commenting on it critically for intellectual content: AA, RS, SAA
Final approval of the document to be published: AA, RS, SAA
Sources of support
Internal sources
No sources of support provided
External sources
-
National Eye Institute, National Institutes of Health, USA
Cochrane Eyes and Vision US Project, supported by grant 1 U01 EY020522‐01 (PI: Tianjing Li, MD, MHS, PhD)
-
Queen’s University Belfast, UK
Gianni Virgili, Co‐ordinating Editor for Cochrane Eyes and Vision’s work is funded by the Centre for Public Health, Queen’s University of Belfast, Northern Ireland
-
National Institute for Health Research (NIHR), UK
The NIHR funded the CEV Editorial Base in London during the time this review was being written
Declarations of interest
AA: None known. RS: None known. SAA: None known.
Edited (no change to conclusions)
References
References to studies included in this review
Stone 2017 {published data only}
- Birchwood C, Tuckwell K, Dimonaco S, Klearman M, Collinson N, Stone JH.Tocilizumab in patients with giant cell arteritis: analysis of new-onset and relapsing subgroups from a randomized, double-blind, placebo-controlled, phase 3 trial. Investigative Ophthalmology & Visual Science 2017;58(8).
- Haskova Z, Strand V, Dimonaco S, Tuckwell K, Klearman M, Collinson N, et al.Health-related quality of life in patients with giant cell arteritis treated with tocilizumab in a phase 3 randomized controlled trial. Investigative Ophthalmology & Visual Science 2018;59(9).
- Mollan SP, Tuckwell K, Dimonaco S, Klearman M, Collinson N, Stone JH.Tocilizumab in patients with giant cell arteritis: results from a Phase 3 randomized controlled trial. Journal of Headache and Pain 2018;19. [DOI: 10.1186/s10194-018-0900-0] [DOI]
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