Tocilizumab shots: Increasing dose interval may lead to loss of remission in RA
In rheumatoid arthritis (RA) patients in remission, increasing the dose interval of tocilizumab injection from the standard 162 mg once weekly to twice weekly may do more harm than good. Specifically, such a strategy is associated with a lower chance of remission maintenance as well as a lack of improvement in tolerability, as shown in a recent trial.
“To our knowledge, this is the first study to evaluate the efficacy of increasing the dose interval of subcutaneous tocilizumab and the first randomized trial to compare tocilizumab dose reduction with a standard regimen,” the investigators said.
A total of 401 patients with moderate-to-severe RA, who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDS) or tumour necrosis factor inhibitor agents, received 162-mg subcutaneous tocilizumab administered once weekly alone or in combination with a csDMARD for 24 weeks.
Of the patients, 179 (45 percent) achieved clinical remission and were randomized to either continue receiving 162-mg tocilizumab subcutaneously at the same once-weekly dosing schedule (qw; n=89) or switch to a twice-weekly dosing schedule (q2w; n=90) for 24 weeks. Clinical remission was defined as a disease activity score in 28 joints (DAS-28) of <2.6. [Arthritis Rheumatol 2019;doi:10.1002/art.40905]
At week 48, the proportion of patients who maintained clinical remission was significantly higher in the qw group than in the q2w group (90 percent vs 73 percent; p=0.004), regardless of whether tocilizumab was used as monotherapy or combination therapy at the time of randomization. Furthermore, the once-weekly regimen produced a greater reduction in the DAS-28 score (mean change, –4.07 vs –3.65 points; p=0.034).
Results for other efficacy measures (functional disability, various patient-reported outcomes and American College of Rheumatology [ACR] responses) were also more favourable in the qw group, although the differences were not statistically significant relative to the 2qw group.
Body mass index (BMI) and DAS-28 at week 24 emerged as significant predictors of remission at week 48. A one-point increase in BMI correlated with a 12-percent reduction in the likelihood of achieving remission at week 48, while a one-point increase in the 24-week DAS-28 score was associated with a 61-percent reduction.
Tolerability and safety parameters were comparable between the two treatment groups. Infections/infestations were the most commonly reported treatment-emergent adverse events (28 percent with qw vs 30 percent with 2qw), with infections occurring primarily in the upper respiratory tract (10 percent vs 8 percent, respectively).
Despite the marked difference in the proportion of patients who maintained remission between the qw and 2qw groups, the investigators pointed out that “approximately three in four patients in the [2qw] group maintained DAS-28 remission, and no significant differences were found in the rates of remission or low-disease activity using other disease activity indexes such as Simple Disease Activity Index and Clinical Disease Activity Index or using ACR response criteria.”
“Therefore, we consider that this [increased dose interval] strategy may be an interesting option for a substantial proportion of patients under treatment with subcutaneous tocilizumab. In fact, the recommended initial dose from the FDA is 162 mg 2qw, which has demonstrated efficacy in RA, both in combination with csDMARDs or as monotherapy,” they added.
Nevertheless, several issues—including identification of suitable candidates for a dose reduction, and whether patients who relapse after dose reduction can be restarted on full doses and achieve remission, among others—must be addressed before a dose-interval increase may be considered a truly feasible option for those patients who have started with the full weekly dose of subcutaneous tocilizumab.