Effect of Tocilizumab on Disease Activity in Patients With Active Polymyalgia Rheumatica Receiving Glucocorticoid Therapy: A Randomized Clinical Trial

Abstract

Importance: Few treatments are available for patients with glucocorticoid-dependent polymyalgia rheumatica. IL-6 antagonists may reduce disease activity in patients with active glucocorticoid-dependent polymyalgia rheumatica.

Objective: To compare the efficacy of tocilizumab vs placebo in patients with glucocorticoid-dependent polymyalgia rheumatica.

Design, setting, and participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial enrolled 101 patients with polymyalgia rheumatica at 17 hospitals in France from February 2017 to October 2019. Final follow-up occurred in November 2020. Inclusion criteria were persistent disease activity (polymyalgia rheumatica activity score computed using the C-reactive protein level [CRP PMR-AS] >10) and prednisone dose greater than or equal to 10 mg per day.

Interventions: Patients were randomly assigned to receive intravenous tocilizumab (8 mg/kg; n = 51) or placebo (n = 50) every 4 weeks for 24 weeks, combined with predefined standardized tapering of oral prednisone.

Main outcomes and measures: The primary efficacy end point was CRP PMR-AS less than 10 (range, 0-100; higher values indicate greater activity; no minimal clinically important difference defined) combined with either prednisone dose less than or equal to 5 mg per day or a decrease in prednisone dose greater than or equal to 10 mg from baseline at week 24. There were 11 secondary outcomes assessed at week 24 included in this report, including disease activity (measured by CRP PMR-AS) and the proportion of patients no longer taking prednisone.

Results: Of the 101 randomized patients (mean age, 67.2 years; 68 [67.3%] women), 100 (99%) received at least 1 infusion and 100 completed the trial. The primary end point was achieved in 67.3% of patients in the tocilizumab group and 31.4% of patients in the placebo group (adjusted difference, 36.0% [95% CI, 19.4%-52.6%]; adjusted relative risk, 2.3 [95% CI, 1.5-3.6]; P < .001). Of 11 reported secondary end points at 24 weeks, 7 showed significant differences favoring tocilizumab, including mean CRP PMR-AS score (7.5 [95% CI, 5.4-9.6] vs 14.9 [95% CI, 11.4-18.4]; adjusted difference, -7.5 [95% CI, -11.2 to -3.8]; P < .001) and the percentage of patients no longer receiving prednisone (49.0% vs 19.6%; adjusted difference, 29.3% [95% CI, 18.9%-39.7%]; adjusted relative risk, 2.5 [95% CI, 1.8-3.5]; P < .001). The most frequent adverse events were infections, experienced by 23 patients (46.9%) in the tocilizumab group and 20 (39.2%) in the placebo group.

Conclusions and relevance: Among patients with active polymyalgia rheumatica despite prednisone therapy, tocilizumab, compared with placebo, resulted in a significantly greater percentage of patients with a CRP PMR-AS less than 10 with reduced prednisone requirements at week 24. Further research is needed to confirm efficacy and to determine the balance of potential benefits and harms.

Trial registration: ClinicalTrials.gov Identifier: NCT02908217.

Figure 1.. Flow of Patients in a Trial of Tocilizumab vs Placebo in Polymyalgia Rheumatica

^aRandomization was stratified by hospital and baseline polymyalgia rheumatica activity score calculated using the C-reactive protein level (CRP PMR-AS) (>17 or ≤17). The CRP PMR-AS is the algebraic sum of morning stiffness in minutes multiplied by 0.1, ability to elevate the upper limbs on a scale of 0 to 3, physician's global assessment on a 10-point visual analog scale (VAS), patient-assessed pain intensity on a 10-point VAS, and CRP level in mg/dL. ^bThe patients in the tocilizumab group with missing outcomes due to not undergoing the week 24 assessment were classified as having failed the study treatment. ^cAt week 24, a total of 42 patients in the tocilizumab group and 45 in the placebo group had received all 6 infusions; in the remaining patients, the numbers of infusions were 5 for 5 tocilizumab patients and 1 placebo patient, 4 for 1 tocilizumab patient and 3 placebo patients, 3 for no tocilizumab patients and 2 placebo patients, and 2 for 1 tocilizumab patient and no placebo patients.

Figure 2.. Disease Activity and Prednisone Dosing From Baseline to Week 24 in a Trial of Tocilizumab vs Placebo in Polymyalgia Rheumatica

The horizonal lines indicate the median value (equal to the lowest quartile if not visible), the squares indicate the mean, edges of boxes indicate the IQR, the ends of the whiskers indicate the highest and lowest values within 1.5 times the IQR beyond the upper and lower quartiles, and the dots indicate more extreme data. A, The CRP PMR-AS is the algebraic sum of morning stiffness in minutes multiplied by 0.1, ability to elevate the upper limbs on a scale of 0 to 3, physician's global assessment on a 10-point visual analog scale (VAS), patient-assessed pain intensity on a 10-point VAS, and C-reactive protein level in mg/dL. Low disease activity is defined as CRP PMR-AS <7; high disease activity, CRP PMR-AS >17; and remission, CRP PMR-AS <1.5. CRP PMR-AS ≥10 indicates a need for treatment escalation. Patients were included if their CRP PMR-AS was >10 as soon as prednisone was decreased below 10 mg/d.