托珠单抗治疗巨细胞动脉炎的临床试验。

Trial of Tocilizumab in Giant-Cell Arteritis.

机构信息

From the Massachusetts General Hospital Rheumatology Unit, Harvard Medical School, Boston (J.H.S., S.H.U.); Roche Products, Welwyn Garden City (K.T., S.D., N.C.), and Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea (B.D.) - both in the United Kingdom; Genentech, South San Francisco, CA (M.K.); the Department of Rheumatology, Medicine III, University Medical Center and Faculty of Medicine Technische Universität Dresden, Dresden (M.A.), Friedrich-Alexander-University Erlangen-Nürnberg, Department of Internal Medicine 3-Rheumatology and Immunology (J.R.), and Institute of Clinical Immunology (G.S.), Universitätsklinikum Erlangen, Erlangen, and the Division of Rheumatology and Clinical Immunology, Department of Medicine IV, University of Munich, Munich (H.S.-K.) - all in Germany; the Department of General Internal Medicine, University Hospitals Gasthuisberg, Leuven, Belgium (D.B.); the Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center, Groningen, the Netherlands (E.B.); the Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona (M.C.C.); the Division of Internal Medicine, Azienda Ospedaliera-Istituto di Ricovero e Cura a Carattere Scientifico di Reggio Emilia and Università di Modena e Reggio Emilia, Reggio Emilia, Italy (C.S.); and Hospital for Special Surgery, New York (R.S.).

出版信息

N Engl J Med. 2017 Jul 27;377(4):317-328. doi: 10.1056/NEJMoa1613849.

DOI:10.1056/NEJMoa1613849

PMID:28745999

Abstract

BACKGROUND

Giant-cell arteritis commonly relapses when glucocorticoids are tapered, and the prolonged use of glucocorticoids is associated with side effects. The effect of the interleukin-6 receptor alpha inhibitor tocilizumab on the rates of relapse during glucocorticoid tapering was studied in patients with giant-cell arteritis.

METHODS

In this 1-year trial, we randomly assigned 251 patients, in a 2:1:1:1 ratio, to receive subcutaneous tocilizumab (at a dose of 162 mg) weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. The primary outcome was the rate of sustained glucocorticoid-free remission at week 52 in each tocilizumab group as compared with the rate in the placebo group that underwent the 26-week prednisone taper. The key secondary outcome was the rate of remission in each tocilizumab group as compared with the placebo group that underwent the 52-week prednisone taper. Dosing of prednisone and safety were also assessed.

RESULTS

Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26-week prednisone taper and 18% of those in the placebo group that underwent the 52-week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52-week period was 1862 mg in each tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26-week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52-week taper (P<0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26-week taper, and 25% of those in the placebo group that underwent the 52-week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week.

CONCLUSIONS

Tocilizumab, received weekly or every other week, combined with a 26-week prednisone taper was superior to either 26-week or 52-week prednisone tapering plus placebo with regard to sustained glucocorticoid-free remission in patients with giant-cell arteritis. Longer follow-up is necessary to determine the durability of remission and safety of tocilizumab. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01791153 .).

摘要

背景

在糖皮质激素减量时，巨细胞动脉炎常复发，长期使用糖皮质激素与副作用有关。白细胞介素-6 受体拮抗剂托珠单抗在巨细胞动脉炎患者糖皮质激素减量过程中对复发率的影响。

方法

在这项为期 1 年的试验中，我们将 251 名患者随机分为 2:1:1:1 的比例，接受每周或每两周皮下注射托珠单抗（剂量为 162mg），联合 26 周泼尼松减量，或安慰剂联合 26 周或 52 周泼尼松减量。主要结局是每个托珠单抗组在第 52 周时持续无糖皮质激素缓解的比率与接受 26 周泼尼松减量的安慰剂组的比率。次要关键结局是每个托珠单抗组与接受 52 周泼尼松减量的安慰剂组的缓解率。还评估了泼尼松的剂量和安全性。

结果

每周接受托珠单抗治疗的患者中有 56%在第 52 周时持续缓解，每两周接受托珠单抗治疗的患者中有 53%持续缓解，而接受 26 周泼尼松减量的安慰剂组患者有 14%持续缓解，接受 52 周泼尼松减量的安慰剂组患者有 18%持续缓解（与安慰剂相比，每种活性治疗均为 P<0.001）。在 52 周期间，每个托珠单抗组的累积中位泼尼松剂量为 1862mg，而接受 26 周减量的安慰剂组为 3296mg（均为 P<0.001），接受 52 周减量的安慰剂组为 3818mg（均为 P<0.001）。每周接受托珠单抗治疗的患者中有 15%、每两周接受托珠单抗治疗的患者中有 14%、接受 26 周泼尼松减量的安慰剂组患者中有 22%、接受 52 周泼尼松减量的安慰剂组患者中有 25%发生严重不良事件。每周接受托珠单抗治疗的患者中有 1 例发生缺血性前部视神经病变。

结论

托珠单抗每周或每两周一次联合 26 周泼尼松减量治疗优于 26 周或 52 周泼尼松减量加安慰剂治疗，可使巨细胞动脉炎患者持续无糖皮质激素缓解。需要更长时间的随访来确定托珠单抗的缓解持久性和安全性。（由 F. Hoffmann-La Roche 资助；临床试验.gov 编号，NCT01791153）。