SAN FRANCISCO, CA—Introducing one or more sequential biologic agents increases the rate of adverse events and infection when compared to treatment with methotrexate alone in children with juvenile idiopathic arthritis (JIA),research presented at the 2015 ACR/ARHP Annual Meeting has found.

During the past 15 years, many biologic agents have been introduced for the treatment of JIA. What’s unknown, however, is whether adding one biologic agent to methotrexate adds risk for serious adverse events or serious infections, and “is this risk different for second or further biologics?” asked Joost Swart, MD, from Pediatric Rheumatology, Wilhelmina Children’s Hospital/UMC Utrecht, Utrecht, The Netherlands.

Dr. Joost and colleagues used data from Pharmachild, an ongoing, multi-center, non-interventional, retrospective/prospective registry of patients with JIA given either methotrexate alone or in combination with 1 or more biologics as part of their standard care. The Pharmachild registry, the largest international pharmacovigilance JIA database, includes 93 centers from more than 30 countries worldwide.

A total of 5,862 patients who had received methotrexate for JIA (81% of the database) were divided into three treatment groups, and drug exposure was divided into three phases based on the start date of each drug: methotrexate alone (11,239 patient-years), methotrexate and one biologic (9,158 patient-years), and methotrexate and two or more biologic agents (2,814 patient-years).

At baseline, the methotrexate and 2 or more biologics group was significantly different for age at onset of JIA (P<0.0001), age at JIA diagnosis (P=0.0004), and disease duration at baseline (P<0.0001).

The study found that 23% of children (n=1,674) were treated primarily with methotrexate and no biologics; in this group, 37.3% had a JIA category of oligo persistent.

Of the 52% (n=3,025) who received methotrexate and 1 biologic, 32.9% of whom were JIA category polyarticular RF-negative, the majority were exposed to etanercept (66.1%), followed by adalimumab (18.5)%, infliximab (5.5%), tocilizumab (5.3%), and abatacept (1.3%); biologic exposures of less than 1% occurred with anakinra, golimumab, rituximab, canakinumab, certolizumab, and others.

Of the 16% (n=1,163) treated with methotrexate and 2 or more biologics, 29.0% of whom were JIA category polyarticular RF-negative and 19.2%, systemic, approximately one-third were exposed to etanercept (30.2%), followed by adalimumab (27.0%), infliximab (14.3%), tocilizumab (9.0%), abatacept (7.0%), anakinra (4.0%), golimumab (3.5%), rituximab (2.4%), and canakinumab (1.8%); exposure to certolizumab and other biologic agents was less than 1%.

Study authors calculated the incidence rate events multiplied by 100 patient-years for events of special interest or at least moderate other adverse events (AEs) for all Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class.

“The addition of a biologic agent significantly increases the rate of AEs and infections,” Dr. Joost said. “This risk is even around 3 times higher during the use of a second or further biological,” he added. At least 1 biologic increased incidence rates of all AEs (10.7, 13.9, 19.5); similarly, increases were seen for serious AEs (3.0, 4.7, 9.2), infections (2.9, 4.6, 4.8), and serious infections (0.7, 1.4, 2.0).

He concluded by noting that “real benefit-risk ratios of drugs can be found by close monitoring of AEs in large registries.”