Effect of first-line biologic initiation on glucocorticoid exposure in children hospitalized with new-onset systemic juvenile idiopathic arthritis: emulation of a pragmatic trial using observational data

Abstract

Background Glucocorticoid exposure is a significant driver of morbidity in children with systemic juvenile idiopathic arthritis (sJIA). We determined the effect of early initiation of biologic therapy (IL-1 or IL-6 inhibition) on glucocorticoid exposure in hospitalized patients with new-onset sJIA. Methods We emulated a pragmatic sequence of trials (“pseudo-trials”) of biologic initiation in children (≤ 18 years) hospitalized with new-onset sJIA utilizing retrospective data from an administrative database from 52 tertiary care children’s hospitals from 2008 to 2019. Eligibility window, treatment assignment and start of follow-up between biologic and non-biologic study arms were aligned for each pseudo-trial. Patients in the source population could meet eligibility criteria at several timepoints. Mixed-effects logistic regression was used to determine the effect of biologic initiation on in-hospital glucocorticoid exposure. Results Four hundred sixty-eight children met eligibility criteria, of which 19% received biologic therapy without preceding or concomitant initiation of immunomodulatory medications. This proportion significantly increased over time during the study period (p < 0.01). 1451 trial subjects were included across 4 pseudo-trials with 71 assigned to the biologic arm and 1380 assigned to the non-biologic arm. After adjustment, there was a trend toward decreased odds of glucocorticoid initiation in the biologic arm compared to the non-biologic arm (OR 0.39, 95% CI [0.13, 1.15]). Conclusion Biologic initiation in children hospitalized with new-onset sJIA significantly increased over time and may be associated with reduced glucocorticoid exposure. The increasing use of first-line biologic therapy may lead to clinically relevant reductions in treatment-related adverse effects of glucocorticoid-reliant therapeutic approaches.

Reporting of Observational Studies Explicitly Aiming to Emulate Randomized Trials

“…We retrieved 3133 unique records, of which 200 were included in the review (Figure 1). All reasons for excluding records after full-text review are given in eAppendix 6 in Supplement 1.…”

“… The included studies spanned 26 fields of medicine, predominately infectious disease (43 [22%]; 27 [14%] on COVID-19), cardiology (30 [15%]), and oncology (30 [15%]) . One hundred and thirty-one studies (66%)…”

“…One-hundred and fifteen studies (58%) completely reported how the target trial protocol was emulated. Eighty-seven studies (44%) provided both the protocol of the target trial and described how it was emulated (Table 2).…”

“…Seventy studies (35%) reported in the title that the study aimed to emulate a target trial; 180 (90%) did so in the Methods section. Twenty studies (10%) reported the study was prospectively registered, 16 of these 20 (80%)…”

Systemic Juvenile Idiopathic Arthritis/Pediatric Still’s Disease, a Syndrome but Several Clinical Forms: Recent Therapeutic Approaches

“…In the author’s, and many experts’, opinion, in patients with a provisional diagnosis of SJIA, early IL-1 blockade is an interesting approach. It certainly reduces the use of steroids [ 27 , 38 ]. It allows clinicians to meet more easily the most recent treat-to-target objectives [ 37 ].…”