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10-10-2017 | Juvenile idiopathic arthritis | Feature | Article

Talking point: Are biologics over-used in the treatment of JIA?

Timothy Beukelman, MD, MSCE, Associate Professor of Pediatrics in the Division of Pediatric Rheumatology at the University of Alabama at Birmingham, USA, speaks to medwireNews about the differing viewpoints on whether biologic treatments are over-used for the treatment of children with juvenile idiopathic arthritis (JIA).

Biologic treatments – including etanercept, adalimumab, abatacept, and tocilizumab – “have completely transformed the lives of many children with arthritis,” and “no-one disputes their effectiveness,” says Beukelman. However, some pediatric rheumatologists believe that biologics are currently overprescribed for children with JIA, and are reluctant to prescribe these drugs as first-line therapy.

The pros and cons of biologics

“The biologic agents are remarkably effective for most patients who take them,” says Beukelman, noting that “the short- and intermediate-term effectiveness of these medications is better than could ever have been hoped for 30 years ago.” Furthermore, “there is frequently a more rapid clinical response [with biologics] compared with methotrexate,” and “in general, biologics are better tolerated than methotrexate with respect to common minor adverse effects, such as nausea and vomiting, oral ulcers, and fatigue,” he continues.

Beukelman acknowledges, however, that “there are still some uncertainties about the long-term safety” associated with biologic use in children with JIA, particularly regarding infections and malignancy. The US labels for the tumor necrosis factor (TNF) inhibitors adalimumab and etanercept carry a black box warning for both serious infection and malignancy risk, while the label for the interleukin-6 inhibitor tocilizumab includes a boxed warning for serious infection risk.

Although “one perceived disadvantage [of treatment with biologics] is an increased risk for infection,” Beukelman says that “most studies in children have shown that the risk of infection with biologics is mostly similar to, or only slightly higher than, that seen with nonbiologics such as methotrexate.”

For example, a German registry study of 3350 children with JIA demonstrated that infection rates were higher among those who were treated with etanercept or adalimumab compared with methotrexate, with rates of 8.1 and 9.7 versus 1.6 per 1000 patient–years, but the authors concluded that “[t]he total rate of serious infections […] seems low,” and treatment with biologic agents “increases the risk for serious infection slightly” compared with methotrexate.

And a prospective cohort study of 58 JIA patients from the USA found no significant difference in the rates of infection between patients who were treated with TNF inhibitors versus those who were not over 12 months of follow-up, with corresponding infection rates of 0.29 and 0.24 per month.

Furthermore, “nearly all studies have shown that the risk of infection with biologics is lower than that with systemic glucocorticoids,” Beukelman adds.

There are limited data available on the long-term risk for malignancy among pediatric rheumatology patients who are treated with biologics. The boxed warning was added to the labels for TNF inhibitors following a report submitted to the US FDA in 2010 of 48 cases of malignancy among children treated with TNF inhibitors. Half of the malignancies reported were lymphomas, and the other half comprised a variety of cancer types, including leukemia, melanoma, and solid organ tumors. The authors of the report noted, however, that the results were confounded by the potential risk for malignancy associated with underlying diseases and the concomitant use of immunosuppressants, meaning that “a clear causal relationship could not be established.”

Subsequently, an Italian study of 1038 children with JIA who were treated with etanercept reported that two participants were diagnosed with cancer during treatment. One patient developed thyroid carcinoma 1 year after commencing etanercept, while the second had a bladder carcinoma after 9.5 years of treatment, leading the researchers to underscore “the need to follow carefully JIA patients exposed to biologics and to continue long-term observation in adulthood.” However, in a Finnish study of 348 children with JIA who were treated with etanercept, infliximab, adalimumab, rituximab, anakinra, tocilizumab, abatacept, or golimumab, there were no cases of malignancy over a median follow-up of 51 months. And an analysis of 7,812 children with JIA by Beukelman and colleagues found that although children with JIA had an increased risk for malignancy than those without JIA over a total follow-up of 12,614 person–years, treatment with methotrexate, TNF inhibitors, or other immunomodulatory agents was not associated with a significantly increased risk.

Moreover, in a long-term safety investigation of German JIA patients who were treated with either biologics or methotrexate over a mean observation period of 5.5 years, the study authors found no significant difference in the risk for malignancy among those who were treated with etanercept or adalimumab compared with methotrexate, with rates of 0.09, 0.27 and 0.07 per 100 person–years, respectively.

Beukelman emphasizes that, in contrast to the limited information currently available on malignancy risk, “the devastating effects of undertreated juvenile arthritis are well known and documented.”

He says: “The very small potential long-term risk of malignancy pales in comparison, in my opinion.”

And he calls for “continued studies of the long-term risks of rare adverse events such as malignancy.”

Indeed, Pharmachild, the ongoing observational study of several national registries, aims to evaluate the long-term safety of biologic agents and methotrexate in children with JIA. An analysis of baseline characteristics demonstrated that approximately 63% of the registry participants have been treated with biologics, either alone or together with methotrexate, and around 29% have received methotrexate alone. When complete, this analysis “will provide a powerful tool for the future analysis of safety events coming from different registries,” say the study authors.

Outstanding concerns

Although more data are needed from ongoing safety studies such as Pharmachild, the evidence to date supports a positive risk-to-benefit ratio for the use of biologics in pediatric rheumatology.

“For nearly any child with significant juvenile arthritis, the benefits of biologics outweigh the potential risks,” believes Beukelman.

However, some rheumatologists still prefer to start with methotrexate. Beukelman notes that “the two competing current approaches are starting with methotrexate and assessing for ineffectiveness before starting a biologic, versus starting the biologic very near the time of diagnosis,” and sees three main factors that deter rheumatologists from the latter strategy: financial cost; fear of overtreatment; and uncertainties surrounding the long-term effects.

Financial cost

“In my mind, the primary barrier to earlier use of biologics is the economic cost,” says Beukelman.

He points out that “biologics are incredibly expensive and place a major strain on the healthcare system.” For example, a decision modeling study found that compared with methotrexate, treatment with etanercept, adalimumab, abatacept, and infliximab was associated with an additional cost of US$ 26,061 (€ 22,175), US$ 46,711 (€ 39,748), US$ 16,204 (€ 13,787), and US$ 31,209 (€ 26,557), respectively, for each additional patient who achieved a treatment response at 1 year according to the ACR Pediatric 30 criteria.

“There is hope that biosimilars will begin to address the problem” of the high costs associated with biologics, says Beukelman, but he feels that “in the United States at least, the cost saving from biosimilars is unlikely to be a major factor” in addressing these issues.


Another factor that may prevent some rheumatologists from recommending early treatment with biologics is fear of overtreatment.

“Methotrexate can be highly effective for a significant minority of patients with juvenile arthritis,” explains Beukelman, meaning that some rheumatologists “have difficulty justifying ‘overtreatment’ with biologics prior to assessing the response to methotrexate.”

“They feel that the uncertainty surrounding the long-term safety of biologics is sufficiently concerning that they would rather take a stepwise approach.”

Long-term uncertainties

Many physicians feel that the prescribing decision “should be based more on the families’ risk tolerance than the physician’s risk tolerance,” says Beukelman. This can be particularly challenging, however. “These families have just been diagnosed with something they’ve never heard of before, and any mention of the word ‘malignancy’ can be overwhelmingly scary.”

Although healthcare providers may be “a little more nervous about long-term safety” when prescribing biologic therapies in children than they would be with adult patients, Beukelman points out that “in my estimation, kids can tolerate medications much better than adults, because they’re otherwise healthy,” with fewer comorbid conditions than adult patients with arthritis.

Looking to the future, Beukelman says that “we need to better understand the benefits of early use of biologic therapy” versus starting with methotrexate.

Two published studies sought to address this question. The ACUTE-JIA open-label trial of 60 children with JIA found that patients who were treated with first-line infliximab plus methotrexate were significantly more likely to achieve at least a 75% improvement in ACR pediatric criteria than those who were treated with either methotrexate alone or methotrexate in combination with sulfasalazine and hydroxychloroquine. And in the second study, researchers from the Childhood Arthritis and Rheumatology Research Alliance found that early aggressive therapy gave rise to “substantial proportions of patients” having clinically inactive disease (CID) at 6 months among 85 children with JIA, but there was no significant difference in the rates of CID between patients who were treated with a combination of methotrexate, etanercept, and prednisolone versus those who were given methotrexate plus placebo.

The ongoing STOP-JIA study aims to compare three treatment strategies in patients with JIA: first-line DMARD followed by biologic therapy as needed; DMARD plus biologic combination therapy from treatment onset; and biologic first-line therapy. The study plans to enroll 400 children with JIA, and is expected to be completed in September 2018.

“Many people believe there is a “window of opportunity near the time of diagnosis,” in which “biologics can actually be more effective” than if they are used later, “and even alter the whole disease course,” Beukelman says. However, he notes that at present “there is not sufficient evidence to fully support that theory,” and “without that evidence, there are people who are reasonably reluctant to prescribe biologics as part of their initial therapy.”

By Claire Barnard

medwireNews is an independent medical news service provided by Springer Healthcare. © 2017 Springer Healthcare part of the Springer Nature group

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