High-Dose Etanercept Can Improve JIA, Increase Risk of Non-Severe Events

Use of high-dose etanercept could help children with juvenile idiopathic arthritis (JIA) reduce disease activity and achieve remission, according to a new analysis.

A post-hoc analysis of the BeSt for Kids trials, results of the trial provide insight into the effects of off-label dose escalation with etanercept as well as the potential risk of safety events relative to using the recommended dose on the agent’s labeling.

“Although high-dose etanercept is used off-label in JIA-patients in clinical practice, supporting evidence is lacking,” wrote investigators. “Therefore, we conducted a post-hoc analysis of the BeSt for Kids trial describing the clinical course of JIA-patients who received high-dose etanercept and of those who did not receive high-dose etanercept despite eligibility according to trial protocol.”

In the US, the approval history of etanercept dates back decades, with the first approval from the US Food and Drug Administration coming in November 1998 for rheumatoid arthritis. The TNF inhibitor would go on to receive approvals for polyarticular JIA, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and pediatric plaque psoriasis in 1999, 2002, 2003, 2004, and 2016, respectively. As outlined by investigators, the dosing for etanercept used in clinical trials for patients with JIA can sometimes prove to be inadequate for achieving desired clinical response. Despite a lack of clinical trial evidence, off-label use at elevated doses occurs in real-world settings.^1,2

With this in mind, investigators designed the current study as an analysis of data from the BeSt for Kids trial. Launched in 2008, the BeSt for Kids trial was aimed at assessing treat-to-target approaches for JIA using sequential DMARD monotherapy, combination-therapy with methotrexate plus 6 weeks of prednisolone, and combination therapy with methotrexate plus etanercept. Among the 92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis included in the trial were 32 patients who received high-dose etanercept.¹

Of note, investigators defined high-dose etanercept as regular dose to a higher dose in line with this trial protocol. Per trial protocol, patients could eventually escalate to etanercept 1.6 mg/kg per week, with a maximum 50 mg per week. The comparator group for the trial were those who did not escalate to high-dose etanercept despite eligibility according to trial-protocol.¹

Among the 32 patients included in the high-dose group, the median age at inclusion was 6 (IQR, 4 to 10) years and 69% were girls. In the comparator group, the median age at inclusion was 8 (IQR, 6 to 9) and 73% were girls. Investigators pointed out the median follow-up time was 24.6 months and clinical parameters were generally similar in both groups, except for number of actively inflamed joints at inclusion (median, 11; IQR, 8 to 18 vs 7; IQR, 5 to 11) among the high-dose group (P = .022).¹

Upon analysis, results indicated most clinical parameters improved within 3 months of the dose increase. Specific improvements are highlighted below:¹

• Median JADAS10 from 7.2 to 2.8 (P = .008)
• VAS-physician from 12 to 4 (P = .022)
• VAS-patient/parent from 38.5 to 13 (P = .003)
• Number of active joints from 2 to 0.5 (P = .12)
• VAS-pain from 35.5 to 15 (P = .030)

Further analysis revealed function impairments, which were assessed using the CHAQ-score (0.63 to 0.50; P = .047), were improved more gradually and erythrocyte sedimentation rate remained stable (6 to 6; P = .32) after initiating therapy. Additionally, results of the investigators’’ analyses revealed both groups achieved the same percentage of patients with inactive disease 6 months after legibility for dose-increase (56%) and loss of disease activity was observed among 25% in the high-dose group and 27% in the comparator group.¹

Analysis of safety outcomes suggested there were no severe adverse events recorded following dose increase. When assessing non-severe adverse events, investigators found 81% of the high-dose group experienced an adverse event of any sort and 55% of the comparator group experienced an adverse event of any sort.¹

Investigators called attention to multiple limitations, including small group size, descriptive nature, unblinded escalation of etanercept, and administration of etanercept alongside a fixed dose regimen of methotrexate. Before concluding, investigators called for additional studies on use of high-dose etanercept.¹

“Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement,” investigators wrote.¹ “However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept.”

References:

1. van Dijk BT, Bergstra SA, van den Berg JM, et al. Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis: does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial. Pediatr Rheumatol Online J. 2024;22(1):53. Published 2024 May 10. doi:10.1186/s12969-024-00989-x
2. Stewart J. Enbrel (Etanercept) FDA Approval history. Drugs.com. Accessed May 21, 2024. https://www.drugs.com/history/enbrel.html.