A combination of tocilizumab plus prednisone-tapered therapy was superior to placebo plus steroid taper for achieving glucocorticoid-free remission in giant-cell arteritis (GCA), the phase 3 Giant-Cell Arteritis Actemra (GiACTA) trial shows.
John H. Stone, MD, from Harvard Medical School, Boston, Massachusetts, and colleagues published the results of their study in the July 27 issue of the New England Journal of Medicine.
“This trial of tocilizumab for the treatment of [GCA] showed that the two regimens of tocilizumab weekly and of tocilizumab every other week, in combination with a prednisone taper over a period of 26 weeks, were superior to placebo plus a prednisone taper of 26 weeks and to placebo plus a prednisone taper of 52 weeks with regard to sustained remission,” the authors write.
Case series and a phase 2 trial have suggested that the interleukin 6 (IL-6) inhibitor tocilizumab allows for tapering of the glucocorticoid doses that control GCA while still maintaining disease remission, the researchers write.
They therefore conducted the 1-year trial to determine whether subcutaneous tocilizumab resulted in higher rates of sustained glucocorticoid-free remission of GCA compared with placebo.
The researchers randomly assigned 251 patients with GCA in a 2:1:1:1 ratio to receive tocilizumab (162 mg) weekly with a 26-week prednisone taper, tocilizumab (162 mg) every other week with a 26-week prednisone taper, placebo with a 26-week prednisone taper, or placebo with a 52-week prednisone taper.
At week 52, 56% of patients receiving weekly tocilizumab had achieved sustained remission, as had 53% of those receiving tocilizumab every other week. In contrast, only 14% of patients receiving placebo plus a 26-week prednisone taper, and only 18% of those receiving placebo plus a 52-week taper, had achieved sustained remission (P < .0001 for all comparisons of tocilizumab with placebo).
Tocilizumab also had a powerful steroid-sparing effect. Cumulative steroid dose during the 52 weeks was significantly lower in the tocilizumab groups than in the 52-week prednisone taper group. In both tocilizumab groups, the cumulative median steroid dose was 1862 mg compared with 3818 mg in the 52-week taper group and 3296 mg in the 26-week taper group (P < .001 for all comparisons of tocilizumab with placebo).
Adverse events occurred with similar frequency in all groups. However, serious adverse events occurred in 15% and 14% of the weekly and every-other-week tocilizumab groups, respectively, compared with in 22% and 25% of the 26-week and 52-week steroid taper groups, respectively.
“Infection was the most frequently reported adverse event and serious adverse event,” the authors say.
No patients died during the 52-week study.
GCA is a systemic inflammatory vasculitis that typically occurs in adults older than 50 years and that frequently manifests with symptoms such as headache and vision loss. Serum levels of IL-6 are also elevated in patients with GCA and induce production of acute-phase proteins such as C-reactive protein. The concentrations of these acute-phase reactants also correlate with GCA disease activity.
Glucocorticoids are the mainstay of treatment for GCA, with many patients needing long or repeated treatment courses to prevent disease flares. As a result of the adverse effects associated with chronic glucocorticoid use, alternative treatments that maintain disease remission after glucocorticoid discontinuation are needed.
Despite the promising results of the GiACTA trial, the authors emphasize the need for further studies to determine the longer-term efficacy and safety of tocilizumab.
“A 2-year, open-label, follow-up phase of this trial may provide additional information pertaining to the safety and efficacy of tocilizumab beyond 52 weeks,” they conclude.
Both clinicians and patients will welcome the results of this study, David B. Hellman, MD, from the Johns Hopkins University School of Medicine, Baltimore, Maryland, stresses in an accompanying editorial.
However, he agrees that the long-term effect of tocilizumab cannot be determined in just 1 year. In particular, he highlights that as other studies have shown that IL-6 might also stimulate angiogenesis and protect against blindness in those with GCA, larger studies are needed to assess the long-term risk for visual loss or stroke.
He also notes that although tocilizumab treatment resulted in fewer serious adverse events than placebo did, the drug carries black box warnings about the risk for infections caused by opportunistic pathogens.
As a consequence, Dr Hellman indicates that until longer-term data become available, he will “reserve tocilizumab for patients who are at high risk for serious side effects from prednisone and for patients who have repeated flares that are not manageable with low doses of prednisone.”
This study was supported by F. Hoffmann-La Roche. Dr Aringer has reported that the Division of Rheumatology, Medicine III, TU Dresden acted as the study site for the GiACTA trial. Several authors have reported receiving personal fees from AbbVie, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Chugai, Genentech, GlaxoSmithKline, Lilly, Novartis, Roche, Roche Products Ltd, Sanofi, UCB, Roche Genentech, and Xencor. Several authors also reported receiving grant support from the Dutch Arthritis Association, Instituto de Salud Carlos III, Ministerio EconomÃa y Competitividad/FEDER, and Roche-Genentech outside the submitted work. The remaining authors and Dr Hellman have disclosed no relevant financial relationships.
New Engl J Med. 2017;377:317-328. Article abstract, Editorial extract
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