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Renal involvement is frequently present in patients with rheumatoid arthritis (RA). Approximately 15–25% of patients with RA have renal insufficiency, defined as a glomerular filtration rate (GFR) <60 mL/min.1 Although concomitant use of methotrexate (MTX) has been proven to be more effective than administration of biological agents alone,2 MTX elimination is delayed in patients with renal insufficiency, which can increase the risk of adverse events.3 ,4 Therefore we often use MTX at reduced dosage for these patients in daily practice, which may result in inadequate responses.
The ACTRA-RI (Actemra for RA patients with renal insufficiency) study was designed to evaluate the efficacy and safety of tocilizumab (TCZ) therapy in the real-life registry of patients with RA and renal insufficiency. For this study, we registered all patients with RA who had begun TCZ therapy in participating hospitals as of January 2014 (total 405 patients with RA: 102 with renal insufficiency and 303 without). An estimated GFR (eGFR) was first calculated using an equation that had been officially approved by the Japanese Society of Nephrology.5 The calculated value was corrected for each patient's body surface area to arrive at an absolute eGFR value for patients with RA.6
As shown in table 1, approximately 60% of the registered patients switched from another biological therapy because of inadequate responses or adverse events. Patients with renal insufficiency were significantly older and had RA for a longer duration. Mean serum levels of haemoglobin were significantly lower in the renal insufficiency group. Hypertension and diabetes, which are traditional risk factors for chronic renal disease, were more frequently complicated in this patient group. Sixty-eight per cent of patients with renal insufficiency received TCZ therapy without MTX because of concerns of MTX-related adverse effects. Nine patients (8.8%) with renal insufficiency and 25 (8.3%) without this complication discontinued TCZ therapy within the first 24 weeks. In both patient groups, the most frequent reason for withdrawal was adverse events. Regardless of MTX use, there were no significant differences in rates of dropout, adverse events, or severe adverse events between the groups with and without renal insufficiency. In addition, these rates were not significantly different between MTX users and non-users, even in patients with renal insufficiency.
A total of 371 patients (91.6%) completed the 24-week TCZ therapy. We divided these patients into four groups according to the status of MTX use and renal insufficiency. As shown in table 2, significant improvements in mean clinical disease activity index values were observed at week 24 in all groups. Although the differences observed between these groups at baseline remained at week 24, mean haemoglobin levels were significantly increased over time during TCZ therapy, even in patients with renal insufficiency. There were no significant differences in efficacy among the four groups. Efficacy parameters in the renal insufficiency group were comparable with those in the group without this complication whether patients received MTX concomitantly or not.
In this multicentre study, the 24-week TCZ therapy had good efficacy parameters as well as stable safety and tolerability profiles in patients with RA and renal insufficiency, regardless of MTX use. A recent randomised, double-blind clinical trial (ACT-RAY) indicated that there is no clinically relevant superiority of TCZ plus MTX therapy over TCZ monotherapy in patients with MTX-resistant RA even if some end points after 1 year favoured the combination treatment.7 ,8 Accompanying the increased number of elderly patients with RA and significant comorbidities such as hypertension and diabetes, renal insufficiency has been seen more commonly in this patient population.9 ,10 TCZ is considered one of the promising options for treatment of patients with RA and renal insufficiency in a real-life medical practice. To evaluate long-term efficacy and safety issues, a further follow-up survey is required for the patients registered in the ACTRA-RI study.
Contributors All authors contributed to the study conception and design, acquisition of data, analysis and interpretation of data, and drafting of the manuscript with regard to important intellectual content.
Funding This study was supported by research funds from the National Hospital Organization (NHO), Japan.
Competing interests SM has received lecture fees from Chugai Pharmaceutical Co and Eisai Co, and a research grant from Chugai Pharmaceutical Co. YU has received a lecture fee from Chugai Pharmaceutical Co.
Patient consent Obtained.
Ethics approval This study is registered with the University Hospital Medical Information Network-Clinical Trials Registry (UMIN000014934). In addition, the ethics committees of participating hospitals approved the protocol for this study.
Provenance and peer review Not commissioned; externally peer reviewed.