Juvenile Arthritis: Adverse Events Common With Biologics

Jenni Laidman

December 31, 2014

Although 1 in 3 children with juvenile idiopathic arthritis (JIA) experienced serious adverse events (SAEs) when treated with biologics, the events rarely led to the cessation of treatment, according to a study of 348 patients in Finland, published online December 10 in Rheumatology.

Maarit Tarkiainen, MD, from Children's Hospital, Helsinki University Central Hospital, Finland, and colleagues reviewed the equivalent of 1515 patient-years (py) of treatment, including 710 py receiving etanercept, 591 py receiving infliximab, 188 py receiving adalimumab, 8 py receiving rituximab, 5 py receiving anakinra, 6 py receiving tocilizumab, 6 py receiving abatacept, and 1 py receiving golimumab.

The research provides additional support for the use of biologics, Dr Tarkiainen said in an email to Medscape Medical News. "Even though fears of SAEs during treatment with biologics in juvenile patients still exist to some extent, they can mostly be controlled in the hands of experienced pediatric rheumatologists," she noted.

The lack of malignancies was the most positive result from the trial, Ronald Laxer, MD, professor of pediatric medicine at the University of Toronto, and staff Rheumatologist at the Hospital for Sick Children, Toronto, Ontario, Canada, told Medscape Medical News.

"That is the really concerning long-term side effect from these drugs," said Dr Laxer, who was not involved in the study. "It often prevents people from choosing biologics, so the most important message was the lack of the malignancy piece.

"The other important issue was that despite the frequency of [SAEs], most did not lead to drug switching or discontinuation. So physicians and families really had the sense that the drugs were working and that, despite the event, they were willing to continue."

SAEs occurred in 35% (121) of treated patients, for a total of 173 events (11.4/100 py). Rituximab was associated with the highest rate of SAEs, at 87.5/100 py, followed by 31.2/100 py when receiving tocilizumab, 15.7/100 py when receiving abatacept, 11.8/100 py when receiving infliximab, 11.4/100 py when receiving etanercept, and 10.1/100 py when receiving adalimumab. The rate of serious infections was higher with rituximab treatment than with other antitumor necrosis factor treatments (37.5/100 py; relative risk, 6.16; 95% confidence interval, 1.59 - 23.8; P = .008).

Despite the AEs, biologic therapy continued for 87% (150) of patients, although sometimes with a short pause.

There were no instances of malignant neoplasms or tuberculosis in the study patients. Mild infections, infusion- or injection-site reactions, and alanine aminotransferase elevations were the most common of the 2902 AEs (191/100 py) reported. Ninety-two percent of all patients (319) reported at least one AE.

New-onset uveitis occurred in nine patients, psoriasis or psoriasiform lesions in 13 patients, and inflammatory bowel disease in six patients.

Other national registries for biologic treatment of JIA underestimate mild or moderate AEs, Dr Tarkiainen told Medscape Medical News. However, she noted, comparisons between registries can be problematic, as some are based on surveys or physician reports; this registry was based on the records of patients in primary or tertiary care. In addition, many registries cover a single biologic only, even though 39% of the patients in this study were exposed to more than one biologic, which could account for the twofold increase in SAEs in this study, she said.

Still, other national registries are larger, noted Daniel Lovell, MD, MPH, professor of pediatrics, University of Cincinnati Medical Center, and associate director, Division of Rheumatology, Cincinnati Children's Hospital, Ohio. Dr Lovell is also chairman of the Pediatric Rheumatology Collaborative Study Group, Cincinnati Children's Hospital Medical Center. "In comparison to some of the other registries, this [one] is only of moderate size, and the duration of follow-up was shorter than many of the others. Other, larger, registries have more comprehensive results, and also longer duration of follow-up," he told Medscape Medical News.

Although this Finland registry has adequate data from etanercept, infliximab, and adalimumab, with 150 or more patient years of experience on each of drug, data are thinner on the other compounds, Dr Lovell said. "Your ability to say much of meaning on those other drugs is very limited in this registry, because they just don't have as much exposure. It doesn't give you enough exposure to understand the safety signal for rare or late events."

Dr Tarkiainen agreed. "We wanted to report the follow-up on these drugs despite the short experience, since the safety of these drugs in patients with JIA has a not been evaluated in long-term studies," she wrote. "We cannot say anything of the true frequency of AEs/SAEs based on this study. For rituximab, the rate of SAEs is high mostly due of the severity of the disease in these patients," she added. Most had poorly controlled inflammation and systemic-onset disease and had been previously treated with several biologics before rituximab.

Further, this study cannot distinguish whether an AE is caused by the drug or by something else, Dr Lovell told Medscape Medical News. "Many of these patients are on other drugs, and people get [AEs] just by being around. Take healthy kids, follow a group of them for a year, and 50% of them will have an infection, because that is just what happens with kids. So it's hard to sort out in a registry how much...side effects are due to normal events that are going to happen anyway. "

Although some registries attempt to address that with a comparison group, this study lacks any such control, and even comparison groups cannot completely solve the problem. "Patients treated with biologics are oftentimes different in meaningful ways," Dr Lovell said. "It makes a comparison not quite as homogenous as you would like."

The fact that a third of the patients in this study develop a SAE "underlines the importance that children with JIA be followed closely by their physician," Dr Lovell said.

One coauthor reports receiving personal fees from Pfizer, Roche, and AbbVie unrelated to this work; another coauthor received speakers' honoraria from AbbVie, Pfizer, and MSDl; and another coauthor received speakers' fees from AbbVie, Roche, and Pfizer. The other authors, Dr Lovell, and Dr Laxer have disclosed no relevant financial relationships.

Rheumatology. Published online December 10, 2014. Abstract

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