Fifty-eight children were included, of whom 39 (67.2%) were diagnosed with UC and 19 (32.8%) with IBDU. Their median [IQR] age was 14.5 [11.5–16.5] years at the initiation of ustekinumab therapy (Table 1). The median [IQR] duration of the follow-up was 12.8 [5.1–26.3] months. Before having undergone ustekinumab therapy, 50 (86.2%) children had been treated with immunomodulators. All 58 patients were treated with biologic agents: 20 (34.5%) failed one biologic agent, 28 (48.3%) failed two biologic agents, and 10 (17.2%) failed three biologic agents. The median PUCAI at the initiation of ustekinumab therapy was 45 [31.3–55].

The induction and maintenance doses of ustekinumab are presented in Supplementary Table 1 (see electronic supplementary material [ESM]). Ustekinumab was provided in combination therapy in 47 (81%) children, as follows: corticosteroids (31 children, 53.4%), 5-aminosalicylic acid (5-ASA) (26 children, 44.8%), thiopurines (16 children, 27.6%), methotrexate (3 children, 5.2%), and others (adalimumab, golimumab, vedolizumab, cyclosporin, and tacrolimus).

Twenty-three (39.7%) of the patients underwent escalation of ustekinumab dosage during the follow-up period: 18 (78.3%) underwent interval shortening, one underwent dose elevation, three underwent both interval shortening and dose elevation, and one underwent re-induction. Thirteen patients (57%) had clinical or biomarker response to dose escalation.

Twenty-four (41.4%) children discontinued ustekinumab therapy at a median duration of 5 [3.4–10.3] months after initiation. The reasons for discontinuation were non-response in 21 (87.5%) and adverse events in three (12.5%). Following discontinuation, 10 (41.7%) patients underwent colectomy.

CFR was observed in 27 (46.6%), 33 (56.9%), and 37 (63.8%) children, at 16, 26, and 52 weeks, respectively (Fig. 1). Clinical remission was observed in 29 (50%), 33 (56.9%), and 37 (63.8%) children at 16, 26, and 52 weeks, respectively, and clinical response in 39 (67.2%) children at 16 weeks (Fig. 1). The decrease in PUCAI during the follow-up is presented in Supplementary Table 2 (see ESM). Of the 31 children treated with corticosteroids at the initiation of ustekinumab therapy, 26 (83.9%) were weaned within a median of 3 [2–4] months. None of them needed re-treatment with corticosteroids during the follow-up. The rates of CFR in patients treated with corticosteroids at baseline were 39%, 52%, and 61% at weeks 16, 26, and 52 compared with 56%, 63%, and 67% among those that were not treated with steroids (p = 0.199, p = 0.384, p = 0.671, respectively). Overall, 19/31 (57.6%) children that were under corticosteroid therapy at baseline and 18/27 (66.7%) that were not treated with corticosteroids achieved CFR (p = 0.671).

Time to clinical response, corticosteroid-free clinical remission, and laboratory remission

CRP and FC levels at 52 weeks were available in 32 (55%) and 25 (43%) children, respectively. Normal CRP and FC <150 μg/g were achieved at 52 weeks in 45 (77.6%) and 36 (62%) children, respectively. Among 33 children with elevated CRP and 46 with elevated FC at baseline, these rates were 60.1% and 52.2%, respectively. Laboratory remission was achieved in 11 (19%), 16 (36.2%), and 25 (51.7%) children at 16, 26, and 52 weeks, respectively. The longitudinal changes in CRP, FC, serum hemoglobin, albumin, and erythrocyte sedimentation rate (ESR) are presented in Supplementary Table 2 (see ESM). Six children (10.3%) underwent colectomy at a median duration of 3 [1–9] months while on ustekinumab therapy, three of them had severe UC at the initiation of ustekinumab. Eleven children (19%) had IBD-related hospitalization. Disease exacerbation among remitters was observed in 13 (37.1%) children after a median of 5 [4–9] months during follow-up. Endoscopic and radiologic remission were observed in 3/16 (19%) and 7/10 (70%) children that underwent endoscopic or radiologic evaluation, respectively. Endoscopic and radiologic remission were reached in 8.1% and 23.3%, respectively, among the ITT group, using non-response imputation for children that failed therapy. Eight patients had a Mayo score of 1 at endoscopic follow-up.

The variables associated with the achievement of CFR were diagnosis of UC compared with IBDU (HR 2.24, 95% CI 1.03–4.85; p = 0.041), lack of previous vedolizumab therapy (HR 2.18, 95% CI 1.11–4.27; p = 0.023), and a history of corticosteroid-resistant disease (HR 4.29, 95% CI 1.58–11.65; p = 0.004). Other variables, such as age, sex, disease duration and phenotype, clinical and endoscopic severity, extra-intestinal manifestations, past therapies (except vedolizumab), dosing regimen, and combination therapy were not associated with clinical and laboratory remission. While the six patients that received an induction dose of 130 mg were not prone to failure (5/6 responded to ustekinumab), all these patients required dose escalation of ustekinumab. The clinical response rate at week 16 was correlated with the CFR rate at week 52: 17 of 19 (89%) non-responders did not achieve CFR, and 35 of 39 (90%) responders achieved CFR (p < 0.001). A multivariate analysis adjusted to age, disease type, previous therapy with vedolizumab, and steroid resistance revealed that none served as an independent predictor of CFR.

Ustekinumab levels were available for 22 (38%) patients (49 measurements altogether). The median [IQR] levels were 4.1 [1.9–5.1], 2.7 [1.6–6.8], and 2.6 [2.1–5.4] μg/mL at weeks 16, 26, and 52, respectively. None of the patients had evidence of anti-drug antibodies. No difference was observed between 4-week and 8-week dose intervals (3.4 [2.4–4.5] vs 2.6 [1.4–6], p = 0.435). All four patients with measurements below 1 μg/mL had active disease. However, serum levels of patients in clinical remission were not different from those of patients with active disease (3.7 [2.6–5.7] vs 5.1 [0.4–6.2] μg/mL, respectively; p = 0.872). Among the nine patients that underwent dose escalation and had available repeated measurements of drug levels before and after dose escalation, 6 (67%) had an increase in drug levels post-escalation (from 4.7 [2.3–5.1] to 8.9 [4.8–9.7] μg/mL). Of these six patients, four responded to dose escalation. The serum levels at week 16 were not predictive of CFR at 52 weeks.

Adverse events that were potentially related to ustekinumab therapy were reported in 6 (10.3%) children (Table 2), leading to discontinuation of therapy in three. The adverse events included interstitial nephritis, hypersensitivity reaction, breast abscess, injection-site reaction, cytomegalovirus infection, and one death due to an acute episode of severe diarrhea in an adolescent male. No further details were provided on the last adverse event due to privacy policy.