Polymyalgia rheumatic
Table 2 Secondary endpoints in the intention-to-treat population Testing hierarchy Secondary endpoints*
Tocilizumab
Placebo
P value
1 2 3 4 5 6
Proportion of patients in glucocorticoid-free remission at week 12 Proportion of patients in glucocorticoid-free remission at week 24
57.9% 57.9%
17.6% 0.02 17.6% 0.02
Time to first relapse (days; mean±SE)
130 (±13)
82 (±11)
0.007 0.003 0.001
Cumulative prednisone dose at week 16 (mg) Cumulative prednisone dose at week 24 (mg)
727 (721–842) 781 (721–972)
935 (861–1244) 1290 (1106–1809)
Proportion of subjects with increased ESR (>20 mm/hour) at week 24 o r Proportion of subjects with increased CRP (>5 mg/L) at week 24
21.1% 42.1%
47.1% 52.9%
n.r. n.r.
7 8 9
Pain by Visual Analogue Scale (mm) at week 16
12.0 (4.0–29.0) 8.0 (3.0–25.0)
15.0 (1.5–45.5) 16.0 (3.0–50.0) 5.0 (1.0–30.0) 46.9 (42.2–49.8) 0.88 (0.13–1.13)
n.d. n.d. n.d. n.d. n.d.
Patient global assessment of disease activity by Visual Analogue Scale (mm) at week 16
Evaluator global assessment by Visual Analogue Scale (mm) at week 16
2.0 (0–6.0)
10 11
Short Form-36 (Physical Component Score) at week 16 Health Assessment Questionnaire (0–3) at week 16
56.3 (48.8–61.0)
0.0 (0.0–0.5)
n.d., not done; n.r., not reported. *Data shown are medians and IQRs, unless stated otherwise. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
rates of remission were observed in tocilizumab as compared with placebo arms, 25 ultimately leading to breakthrough therapy designation for tocilizumab by the US Food and Drug Administration and the European Medicines Agency for giant cell arteritis. We observed a lower proportion of patients achieving the primary endpoint in the treatment group (63% achieved glucocorticoid-free remission) as compared with previous open-label studies, where responses to tocilizumab were seen in 100%. 19 20 Aside from differences in populations, trial design and outcome measures, this indicates the importance of randomised controlled trials in quantifying and establishing the efficacy of new therapies. Beside a potential additional placebo effect, the rapid tapering of glucocorticoids and the thereby generated lower cumulative glucocorticoid dose may have contributed to the reduced efficacy as compared with previous open-label studies. Post-hoc sample size calculations using the actually observed responses rates in our trial, would have led to 33 patients per group, and therefore would have still been smaller than the recruited number of 36 patients. The present trial was not designed to compare tocilizumab to glucocorticoids or another drug (eg, methotrexate), nor to test rapid tapering of glucocorticoids against another tapering scheme. Also, PMR-SPARE did not aim to investigate refrac- tory or glucocorticoid resistant disease. Rather, the underlying assumptions were that fast and effective induction therapy with glucocorticoids should not be withheld from patients with polymyalgia rheumatica, and that a shorter course of glucocor- ticoids is safer than their prolonged use. 26 27 The full clinical effect of tocilizumab was further expected to require several weeks as observed in previous open-label studies with tocili- zumab monotherapy. 19 Tocilizumab was superior to placebo not only concerning the primary endpoint, but also regarding all those secondary endpoints, which considered the need for glucocorticoids as treatment failure (ie, proportion of patients in glucocorticoid-free remission, time to first relapse and cumu- lative glucocorticoid dose). One implicit conclusion from the significantly lower doses of glucocorticoids required in the tocilizumab compared with the placebo-treated patients would be that the risk of glucocorticoid associated adverse effects was also lower, 8 28 however, our study by its design, the low number of patients and the short observational time cannot confirm such assumption.
ESR by the study drug; vice versa, clinical flares in the tocili- zumab treated group were not accompanied by elevated CRP or ESR levels. DISCUSSION The PMR-SPARE trial showed that tocilizumab at the standard dose of single weekly injections of 162 mg is superior to placebo in achieving glucocorticoid-free remission at 16 and 24 weeks in patients with new-onset polymyalgia rheumatica subjected to an 11 weeks tapering regime of oral glucocorticoids. Tocilizumab also reduced the occurrence of relapses and reduced the cumula- tive glucocorticoid dose by almost 40% by week 24. The observation that glucocorticoid-free remission rates were up to 50% higher in tocilizumab-treated patients compared with those receiving placebo, are in line with results of the Giant-Cell Arteritis Actemra (GiACTA) trial. In that randomised study on tocilizumab in giant cell arteritis about 40% higher
Table 3 Safety over the 24-week trial period Variable
Tocilizumab (n=19) Placebo (n=17)
Duration in trial patient-years Patients with >1 adverse event (AE)—no. (%)
8.2
6.3
16 (84)
14 (82)
No. of events
40
35
Rate per 100 patient-years (95% Cl)
490.6 (468.9 to 523.2) 555.0 (531.9 to 579.0)
Patient with AE according to system organ class—no. (%) Infection 12 (63)
6 (35)
Musculoskeletal or connective- tissue disorder
0
7 (41)*
Gastrointestinal disorder
3 (16)
4 (24)
Malignancy
0 0
0
Patients who withdrew from trial because of AE—no. (%) Patients with serious AE—no. (%)
3 (18)
1† (5)
5† (29)
Serious infections 0 *Musculoskeletal reports not related to polymyalgia rheumatica disease activity by discretion of investigator. 0 †One patient in the tocilizumab group had a serious AE (retinal detachment) and five patients in the placebo group developed serious AEs leading to hospital admission (one pancreatitis, one duodenal ulcer, one diarrhoea (not related to an infection), one heat stroke, one suspected giant cell arteritis).
Bonelli M, et al . Ann Rheum Dis 2022; 81 :838–844. doi:10.1136/annrheumdis-2021-221126
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