Patients were enrolled if they were aged of 18 years or older, with a diagnosis of TAK (according to the ACR criteria and/or Ishikawa criteria modified by Sharma) established between October 2014 and July 2017. All patients were treatment-naive or free from any immunosuppressive therapy (DMARDs and biological-targeted therapies) for at least 4 months. If previously initiated, steroids must have been started within the month preceding inclusion.
The trial is registered on ClinicalTrials (NCT02101333), and could be find at https://clinicaltrials.gov/ct2/show/NCT02101333?cond=takayasu&draw=2&rank=8; registration date 02/04/2014, registration number NCT02101333). All patients gave written informed consent and also consent for publication. The trial conformed the ethical guidelines of the Declaration of Helsinki and was approved by the Institutional Review Boards of the Ethic committee of “Cochin Hospital University” (CPP Ile de France, Cochin Hospital, 02/02/2014)(N° ID-RCB 2017-AO3380-53).
This prospective open-labelled trial was designed to evaluate the effect of tocilizumab to discontinue steroids after 6 months of tocilizumab therapy, among treatment-naïve patients with TAK. Induction therapy consisted of corticosteroids at a dose of 0.7 mg/kg/day and 7 infusions of tocilizumab at a dose of 8 mg/kg/month. Steroids were decreased using a predefined regimen schedule over the first 6 months of tocilizumab therapy (Supplementary Table 1).
Assessment and definitions
The primary endpoint was the number of patients that achieved steroid discontinuation after 7 infusions of tocilizumab.
Secondary endpoints included disease activity, clinical, biological and radiological responses at 3, 6, 9, 12, 15 and 18 months, rates of sustained remission, number of relapses, time with sustained remission, cumulative steroid doses, frequency of ischemic vascular complications and interventions, and safety.
Clinical response was defined as the absence of new symptoms and/or disappearance of all previous symptoms. Biological response was defined as normalization of all acute-phase reactants, including erythrocyte sediment rate (ESR), C-reactive protein (CRP) and fibrinogen, or a minimum 50% decrease of at least 2 of these markers. Radiological response was defined as the absence of arterial progression at repeated imaging at 6 months after tocilizumab initiation as compared to baseline. Disease activity was defined using NIH and ITAS-2010 scales. Briefly, disease was considered as active if NIH score was of 2 or more, and inactive otherwise; sustained remission was defined as a NIH <2 with a prednisone dosage <10 mg/day. Disease activity was also subjectively evaluated as active, stable or remission, using practitioner’s judgment, independently from NIH scale and other objective laboratory markers. Relapse was defined as the occurrence, among patients that achieved remission, of disease activity requiring a change in treatment regimen. Ischemic vascular events and/or the need for a vascular intervention were recorded during the 18 months follow-up.
Safety was assessed as the incidence and severity of adverse events (AEs), drug reactions and alterations of laboratory findings.
Response rates were of 70% using tocilizumab in patients with refractory TAK. We hypothesized that remission would be achieved among 50% of patients after 6 months of tocilizumab therapy, with an estimated precision of ± 25%.
Data are presented as medians with ranges for continuous variables and frequencies with percentages for qualitative variables. Fisher’s exact test was used to compare qualitative variables and the Wilcoxon rank test to compare continuous variables. All tests were two-sided and a p-value < 0.05 was considered as statistically significant. Statistical analyses were performed using R software (version 3.1.0).