Reviewed by Dr. Jennifer Wagner
Stone J, et al. N Engl J Med. 2017 July 27;377(4):317-28
Giant cell arteritis (GCA) is a large vessel vasculitis resulting in systemic inflammation with potentially severe consequences of vision loss. GCA often requires frequent prolonged steroid tapers, predisposing to the multiple consequences of long term steroid use. There is urgent need to identify and evaluate steroid sparing agents in these systemic inflammatory diseases requiring such high cumulative doses of steroids. This 1-year randomized, double blind, placebo controlled phase 3 trial (Giant-Cell Arteritis Actemra (GiACTA) trial) evaluated tocilizumab, an IL-6 receptor alpha inhibitor, in the treatment of GCA (either newly diagnosed or relapsing) to achieve higher rates of sustained remission versus placebo. Patients >50 years old with proven GCA (through temporal artery biopsy or imaging plus elevated ESR) were assigned to either weekly subcutaneous tocilizumab 162 mg + 26 week prednisone taper (100 patients), every other week tocilizumab + 26 week prednisone taper (50 patients), weekly subcutaneous placebo + 26 week prednisone taper (50 patients), or weekly subcutaneous placebo + 52 week prednisone taper (51 patients). The primary outcome was sustained prednisone-free remission at week 52 in each of the tocilizumab arms vs placebo + 26 week prednisone taper. Patients who experienced a flare or were not in remission by week 12 or had two consecutive increases in CRP levels were considered not to have responded to the therapy.
At the 52-week trial completion, 56% of weekly tocilizumab patients and 53% with every other week tocilizumab had sustained remission versus 14% of the 26 week taper placebo and 18% of the 52 week taper placebo (p<0.001). The percentage of patients with flares were 23% with weekly tocilizumab, 26% biweekly tocilizumab, 68% placebo with 26-week taper and 49% placebo with 52-week taper. Patients with newly diagnosed GCA did not experience significantly different outcomes between the two dosing frequencies of the tocilizumab; however patients with relapsing disease at baseline had a lower risk of flare with weekly tocilizumab whereas biweekly dosing was not significantly different from placebo. Patients’ global assessment of disease activity using visual analogue scale (VAS) score decreased with tocilizumab therapy (indicating improvement) by -19 with weekly dosing and -25 with biweekly versus -3.4 and -7.2 in the placebo groups (26 week and 52 week taper respectively). Adverse events were similar in all trial groups, with infection being the most frequent. One patient on tocilizumab had an episode of anterior ischemic optic neuropathy that resolved with steroids. Other tocilizumab reactions included injection site reactions and neutropenia.
Overall, tocilizumab treatment was superior to placebo + prednisone taper in achieving sustained prednisone-free remission in GCA and adverse reactions were similar. Weekly treatment with tocilizumab resulted in greater disease control (as compared with every other week dosing, in relapsing, presumably more severe/recalcitrant, GCA). Tocilizumab groups required essentially half the dose of prednisone, which should reduce long term consequences of steroids, such as loss of bone density and risk for infection. Limitations of trials in GCA include a lack of validated outcome measures, although strict parameters for flare and remission were used. Future research is warranted to assess long term efficacy and safety of tocilizumab, as well as cost effectiveness. In conclusion, subcutaneous tocilizumab for GCA appears promising in reducing flares and sustaining remission while requiring lower prednisone dosing.