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Contents lists available at ScienceDirect

Digestive and Liver Disease

journal homepage: www.elsevier.com/locate/dld

Alimentary Tract

Single or continuous multiple intravenous re-induction in Crohn’s

disease patients who lost response to ustekinumab: Evidence from
real-world data
Jian Tang a,b,1, Qing Li a,b,1, Zhaopeng Huang a,b, Lishuo Shi c, Qin Guo a,b, Miao Li a,b,
Xiang Gao a,b,∗, Kang Chao a,b,∗
a
Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
b
Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
c
Center for Clinical Research, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China

a r t i c l e i n f o a b s t r a c t

Article history: Background and Aims: Re-induction optimization of ustekinumab is effective in Crohn’s disease (CD) pa-
Received 4 November 2023 tients who experienced a loss of response (LOR) to ustekinumab. However, whether continuous multiple
Accepted 10 January 2024
intravenous optimization is better than single dose re-induction remains unknown. We aimed to compare
Available online xxx
effectiveness of two strategies in CD patients with LOR to ustekinumab.
Keywords: Methods: We retrospectively included CD patients who had LOR to standardized ustekinumab therapy.
Crohn’s disease They were divided into three groups according to different times (one to three) for re-induction.
Intravenous re-induction Results: This study included 50, 26 and 22 of 98 eligible patients in one intravenous re-induction sub-
Loss of response group, double intravenous re-induction subgroup and three intravenous re-induction subgroup, respec-
Ustekinumab tively. At week 24, 67.3%, 75.5%, 56.6%, 69.8% and 61.2% of all achieved steriod free clinical remission,
clinical response, endoscopic remission, endoscopic response and C-reactive protein normalization, re-
spectively. No differences were found in all endpoints between three groups. Ustekinumab trough level
at week 24 but not times of re-induction showed a tendency to predict clinical remission. No serious
adverse events were found in this cohort.
Conclusion: Intravenous re-induction was safe and effective in CD patients who experienced LOR to ustek-
inumab. Trough level of ustekinumab but not times of intravenous re-induction may associated with clin-
ical efficacy.
© 2024 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

1. Introduction
Crohn’s disease (CD), as a chronic inflammatory disease, needs
long-term therapy to control symptoms and progression [1]. Ustek-
inumab (UST), a monoclonal antibody targeting the p40 subunit
of interleukin-12 and interleukin-23, is effective in moderately to
severely active CD [2]. UST has achieved favorable clinical and en-
doscopic remission rates in Chinese patients with CD since it was
approved in China in 2020 [3]. However, consistent with previous
reports, some patients experienced an incomplete response or lose
response to UST over time. Two meta-analyses showed that 55%
– 58% of CD patients with inadequate response or loss of response
∗
These authors are co-corresponding authors, No.26 Yuancun Road II, Tianhe dis-
trict, Guangzhou 510 0 0 0, P. R. China. Tel: +86 15989051165
E-mail addresses: gxiang@mail.sysu.edu.cn (X. Gao), chaokang3@mail.sysu.edu.cn
(K. Chao).
1
These authors contributed equally to this work.
may benefit from UST dose escalation including interval shortening
and intravenous re-induction [4,5]. Therefore, appropriate optimiz-
ing strategies are needed for those having loss of response (LOR)
to UST.
Currently, researches on UST optimization were focused on the
management of patients with LOR to standard UST dosing, which
includes either intensification of UST subcutaneous dosing or re-
induction of intravenous UST [6–12]. The POWER study, a ran-
domized, double-blind, controlled study, reported that single in-
travenous re-induction was sufficient to improve the clinical out-
comes of patients [11,12]. The results from these studies demon-
strated that intravenous re-induction was effective [13,14]. One re-
cent study showed that intravenous re-induction was superior to
merely shortening drug intervals [15]. The STEADY study, an ob-
servational real-world cohort study, reported that UST double in-
travenous loading induction as initial therapy had higher clinical
remission than single intravenous induction at week 52 [16]. A ret-
rospective data showed that optimization of UST by two initial in-

https://doi.org/10.1016/j.dld.2024.01.189
1590-8658/© 2024 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

Please cite this article as: J. Tang, Q. Li, Z. Huang et al., Single or continuous multiple intravenous re-induction in Crohn’s disease patients
who lost response to ustekinumab: Evidence from real-world data, Digestive and Liver Disease, https://doi.org/10.1016/j.dld.2024.01.189
JID: YDLD
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J. Tang, Q. Li, Z. Huang et al.
travenous doses was more effective than standard therapy in re-
fractory CD patients [17]. Whether continuous double or multiple
intravenous UST were effective in patients with LOR remains un-
clear. In addition, the safety issues concerning dose accumulation
need to be taken seriously.
In the present study, we further explored the effectiveness and
safety of the re-induction optimization strategies with different
times of intravenous UST, aiming to find evidence of the best opti-
mizing strategy.
2. Methods
2.1. Study design and patients
This was a retrospective, observational, single-center study. Pa-
tients who received intravenous re-induction therapy of UST due
to a LOR were enrolled at the sixth affiliated hospital of Sun Yet
Sen University between July 1, 2020, and July 1, 2023. The inclu-
sion criteria were: (1) patients with confirmed diagnosis of CD
and prescribed with UST; (2) patients were administered initial in-
travenous weight-based dosage of UST as induction therapy, fol-
lowed by at least one subcutaneous maintenance injection of 90
mg UST as initial UST therapy; (3) patients received intravenous re-
induction with UST due to LOR. Exclusion criteria include patients
with other reasons which would possibly confound the outcomes
(for example, super-imposed infection, short gut syndrome, or any
other manifestation that might be anticipated to require surgery),
concomitant medication with other biological agents and incom-
plete data. The patients were prescribed with different times of in-
travenous UST after a shared decision making between the physi-
cians and patients. The patients were divided into three groups ac-
cording to different times (one to three) of intravenous UST for RI.
Clinical data was collected from the hospital’s electronic medi-
cal record system. Patients characteristics, Crohn’s disease activity
index (CDAI), serum C-reactive protein (CRP), erythrocyte sedimen-
tation rate (ESR), hematocrit, hemoglobin (Hb), albumin (Alb), body
mass index (BMI), simple endoscopic score for CD (SES-CD), serum
UST trough concentration and adverse event were gathered both at
the optimization baseline and after 24 weeks.
Figure 1. Flow chart of the patient cohort.
UST, ustekinumab; RI: re-induction; ORI, one intravenous re-induction; DRI, double intravenous re-induction; TRI, three intravenous re-induction.
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2.2. Definitions and Measures
LOR was defined as the reappearance of CD activity that led to
re-induction, which was evaluated by the clinicians according to
clinical criteria (CDAI ≥150 [11,18,19,26], as well as confirmation
through laboratory findings (elevated CRP and ESR), and/or radi-
ological or endoscopic activity. The endoscopic activity was eval-
uated by SES-CD. Computed tomography enterography (CTE) was
utilized to identify the radiological activity.
The primary outcome was corticosteroid-free clinical remission
(CFCR) at post-optimization week 24. CFCR was defined as having
a CDAI score of less than 150, without the history of having taken
oral or intravenous corticosteroids within the thirty days before
assessment [20]. The secondary outcomes included clinical remis-
sion (CDAI < 150), clinical response (CDAI decrease of more than
70 and/or less than 150), endoscopic remission and response, CRP
normalization, the UST trough level, and the incidence of adverse
events requiring treatment discontinuation at post-optimization
week 24. Endoscopic response was defined as SES-CD reduction of
more than 50% from optimization baseline. Endoscopic remission
was defined as SES-CD < 3 [21]. Normalization for CRP was con-
sidered as CRP level less than 5 mg/L.
2.3. Statistical analysis
Continuous data were reported as mean ± SD or median (in-
terquartile range [IQR]) depending on normality. Categorical data
were described as percentages. Proportions were compared by chi-
squared test, applying Yate correction when appropriate. Compari-
son between the three groups was conducted by one-way ANOVA
or the Kruskal–Wallis test, and comparison between two groups
was analyzed using the Student’s t test or Wilcoxon test. A receiver
operating characteristic (ROC) curve was established to explore the
cut-off value of serum trough concentration of UST for predict-
ing clinical remission and endoscopic remission. Logistic regression
model was used to find variables associated with clinical remission
at week 24. Variables with P < 0.10 on univariable analysis were
included in a multivariable model where P < 0.05 was considered
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Table 1
Baseline characteristics at the time of intravenous ustekinumab re-induction.

Basal Characteristics Total (n = 98) ORI (n = 50) DRI (n=26) TRI (n=22) P value

Weeks from first induction to re-induction, median (IQR) 28 (24, 46) 28 (24, 46) 24 (24, 38) 24 (24, 32) 0.882
Age, median (IQR) 32.0 (24.0, 40.0) 34.0 (23.3, 42.0) 30.0 (23.0, 39.8) 31.5 (28.0, 38.8) 0.846
Male, n (%) 69 (70.4) 36 (72.0) 21 (80.8) 12 (54.5) 0.132
Smoker, n (%) 11 (11.2) 5 (10.0) 4 (15.4) 2 (9.1) 0.731
Disease duration, month, median (IQR) 24 (12.0, 69.0) 24 (12.0, 57.0) 36 (19.5, 90.0) 54 (14.3, 69.0) 0.138
Montreal classification, n (%)
Age 0.093
A1 5 (5.1) 5 (10.0) 0 0
A2 71 (72.4) 31 (62.0) 21 (80.8) 19 (86.4)
A3 22 (22.4) 14 (28.0) 5 (19.2) 3 (13.6)
Location, n (%) 0.264
L1 16 (16.3) 7 (14.0) 5 (19.2) 4 (18.2)
L2 5 (5.1) 5 (10.0) 0 0
L3 77 (78.6) 38 (76.0) 21 (80.8) 18 (81.8)
L4 2 (2.0) 1 (2.0) 0 1 (4.5) 0.540
Behavior, n (%) 0.418
B1 49 (50.0) 29 (58.0) 12 (46.2) 8 (36.4)
B2 29 (20.4) 13 (26.0) 9 (34.6) 7 (31.8)
B3 20 (20.4) 8 (16.0) 5 (19.2) 7 (31.8)
Perianal disease, n (%) 44 (44.9) 26 (52.0) 13 (50.0) 5 (22.7) 0.059
Extraintestinal manifestations, n (%) 17 (17.3) 7 (14.0) 3 (11.5) 7 (31.8) 0.121
Prior surgery, intestinal resection, n (%) 33 (33.7) 14 (28) 10 (38.5) 9 (40.9) 0.472
Prior surgery, perianal, n (%) 39 (39.8) 20 (40) 10 (38.5) 9 (40.9) 0.984
Previous treatment, n (%)
Immunomodulators (AZA, 6-MP, MTX, 6-TGN) 57 (58.2) 28 (56) 14(53.8) 15 (68.2) 0.548
Prior corticosteroids 37 (37.8) 21 (42) 9(34.6) 7 (31.8) 0.663
Prior biological treatments, n (%)
Infliximab 60 (61.2) 24 (48) 17(65.4) 19 (86.4) 0.008
Adalimumab 14 (14.3) 4 (8) 3(11.5) 7 (31.8) 0.026
Prior number of biological agents, n (%) 0.030
0 28 (28.6) 19 (38) 7 (26.9) 2 (9.1)
1 58 (59.2) 29 (58) 14 (53.8) 15 (68.2)
2 12 (12.2) 2 (4) 5 (19.2) 5 (22.7)

Abbreviations: IQR, interquartile range; AZA, azathioprine; 6-MP, 6-Mercaptopurine; MTX, methotrexate; 6-TGN, 6-thioguanine nucleotide; UST, ustek-
inumab; RI: re-induction; ORI, one intravenous re-induction; DRI, double intravenous re-induction; TRI, three intravenous re-induction.

significant. All analyses were conducted using SPSS 27.0. A statisti-
cally significant P value was defined as a two-sided P value < 0.05.
2.4. Ethical considerations
The study protocol conforms to the ethical guidelines of the
1975 Declaration of Helsinki (6th revision, 2008) as reflected in a
priori approval by the institution’s human research committee. The
study protocol was approved by the Ethical Committee of Sun Yat-
Sen University.
3. Results
3.1. Study population
A total of 140 patients receiving intravenous re-induction with
UST were eligible. Of these, 98 patients were included in this anal-
ysis. Among them, 50, 26 and 22 were included in one intravenous
re-induction (ORI), double intravenous re-induction (DRI) and three
intravenous re-induction (TRI) groups, respectively (Figure 1). The
baseline demographic, clinical characteristics and medication his-
tory of patients are listed in Table 1. To adjust for confounding
factors related to past medication history, multiple regression anal-
ysis was performed later in this study. Overall, baseline demo-
graphic and clinical characteristics were comparable among the
three groups.
The median time of exposure to UST before re-induction was
28 (24, 46) weeks. The baseline colonoscopy was performed in 62
patients (25, 21 and 16 in ORI, DRI and TRI, respectively). SES-
CD scores at optimization baseline were comparable among three
groups (P = 0.565). Fifty three patients (22, 17 and 14 in ORI, DRI
and TRI, respectively) underwent paired endoscopy. Among these
patients, the median scores of SES-CD at baseline was 6 (5, 7)
scores, 7 (5, 8) scores and 6 (4, 7) scores in ORI, DRI and TRI,
respectively (P = 0.380). CTE was performed, finding moderate-
severe activity in all these patients. None of these patients received
re-induction therapy together with oral corticosteroids during the
24-week follow-up period. A total of 22, 17 and 14 patients under-
went paired endoscopy in the ORI, DRI and TRI cohort, respectively.
3.2. Efficacy of RI
A significant improvement in CDAI after re-induction [182.1
(160.1, 219.7) vs 122.6 (96.7, 160.0), P < 0.001), as well as ESR
and Alb levels (Table 2). Overall, re-induction of intravenous UST
resulted in clinical remission (corticosteroid-free) and response in
67.3% and 75.5% of patients at week 24. We also evaluated endo-
scopic outcomes. At week 24, the rates of endoscopic remission
and response were 56.6% (30/53) and 69.8% (37/53). In addition,
CRP normalization was achieved in 61.2% of patients at week 24
(Figure 2A).
3.3. Efficacy of RI in different groups
In the ORI group, the rates of clinical remission (corticosteroid-
free) and response were 64.0% and 72.0%, respectively, compared
to 69.2% and 80.8% in the DRI group, and 72.7% and 77.3% in
the TRI group. At week 24, the rate of endoscopic remission were
59.1% (13/22), 47.1% (8/17) and 64.3% (9/14) in ORI, DRI and TRI
group, respectively (P = 0.600). Similarly, the rates of endoscopic
response at week 24 were 68.2% (15/22), 70.6% (12/17) and 71.4%
(10/14) in the ORI, DRI and TRI groups, respectively (P = 0.975).
Additionally, there was no significant difference in CRP normal-
ization among the three groups, with rates of 68.0% in the ORI

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Table 2
Differences in biochemical indicators, BMI and CDAI before and after re-induction.

Variables Week 0 (n=98) Week 24 (n=98) P value

CRP, median (IQR) 5.4 (1.4, 14.6) 3.2 (1.2, 11.8) 0.137
ESR, median (IQR) 12.0 (4.0, 27.0) 8.0 (2.0, 15.0) 0.027
Hematocrit, mean ± SD 0.39 ± 0.06 0.40 ± 0.05 0.059
Hb, median (IQR) 124.0 (113.3, 140.5) 130 (116.3, 139.0) 0.101
Alb, mean ± SD 38.9 ± 4.9 41.7 ± 4.2 <0.001
BMI, median (IQR) 19.4 (17.5, 21.5) 19.6 (18.2, 22.0) 0.158
CDAI, median (IQR) 182.1 (160.1, 219.7) 122.6 (96.7, 160.0) <0.001

Abbreviations: CRP: C-reactive protein; ESR: erythrocyte sedimentation rate;

hemoglobin (Hb); Alb: albumin; BMI: body mass index; CDAI: Crohn’s disease activity
index; IQR, interquartile range.

Figure 2. (A) Clinical, endoscopic and biochemical outcomes of different RI strategies after re-induction therapy; (B) The median UST trough concentration at weeks 0 and
24 in ORI, DRI and TRI group. (ORI, one intravenous re-induction; DRI, double intravenous re-induction; TRI, three intravenous re-induction; CRP, C-reactive protein.)

arm, 46.2% in the DRI arm and 63.6% in the TRI arm (P = 0.173)
(Figure 2A). Furthermore, there were no differences observed in in-
flammatory burden and nutritional state among the three groups
(Table 3).
3.4. Exposure-Response Effect of UST
Overall, 29 patients (9, 9 and 11 in ORI, DRI and TRI cohort, re-
spectively) had UST trough concentration detected before and at
week 24 after optimization of UST. The results showed a signif-
icantly higher UST trough concentration after optimization [0.71
(0.21, 1.49) μg/mL vs 3.81 (2.14, 7.15) μg/mL, P < 0.001], indicat-
ing that re-induction can effectively increase serum trough level
of UST. In the ORI group, the median UST trough concentration at
weeks 0 and 24 was 1.49 (0.5, 2.11) μg/mL and 3.81 (2.72, 7.39)
μg/mL, respectively (P = 0.006). In the DRI group, the median
UST trough concentration at weeks 0 and 24 was 0.38 (0.06, 0.71)
μg/mL and 4.64 (1.72, 7.15) μg/mL, respectively (P = 0.008). For the
TRI group, the median UST trough concentration at weeks 0 and
24 was 0.89 (0.4, 1.2) μg/mL and 3.6 (2.3, 6.15) μg/mL, respectively
(P = 0.013) (Figure 2B). When comparing the different groups, no
statistically differences were found at both week 0 (P = 0.290) and
week 24 (P = 0.811).
The data on UST trough concentrations at week 24 after UST
dose optimization were available for 41 patients (17, 13 and 11 in
ORI, DRI and TRI cohort). The cut-off UST trough concentration for
predicting clinical remission was determined to be 3.3 μg/mL, with
an area under the curve (AUC) of 0.721, a sensitivity of 66.7%, and a
specificity of 72.4%. Similarly, the cut-off UST trough concentration
for predicting endoscopic remission was found to be 4.8 μg/mL,

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Table 3
Differences in biochemical indicators, BMI and CDAI among different re-induction strategy subgroups.

Variables ORI (n = 50) DRI (n=26) TRI (n=22) P value

CRP, median (IQR) 3.0 (1.2, 7.1) 5.9 (1.4, 20.6) 2.6 (0.5, 7.8) 0.170
ESR, median (IQR) 7.5 (2.0, 15.0) 9.5 (3.5, 13.0) 9.0 (2.5, 15.0) 0.680
Hematocrit, mean ± SD 0.40 ± 0.05 0.41 ± 0.05 0.39 ± 0.06 0.469
HGB, median (IQR) 130.0 (116.8, 143.5) 132.5 (116.3, 141.8) 129.0 (118.0, 137.5) 0.836
ALB, median (IQR) 42.0 (39.2, 44.6) 40.3 (38.7, 46.5) 41.8 (38.5, 44.2) 0.920
BMI, median (IQR) 20.4 (18.4, 23.0) 19.1 (18.2, 22.9) 19.4 (18.1, 20.7) 0.234
CDAI, median (IQR) 136 (99.8, 169.0) 123.9 (87.6, 158.3) 106.0 (95.9, 146.2) 0.422

Abbreviations: CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; hemoglobin (Hb); Alb: albumin;
BMI: body mass index; CDAI: Crohn’s disease activity index; IQR, interquartile range; ORI, one intravenous re-
induction; DRI, double intravenous re-induction; TRI, three intravenous re-induction.

Table 4
Results of multivariate analysis related to clinical remission at week 24 after re-induction.

Univariate analysis Multivariate analysis

Characteristics
Odds Ratio (95% CI) P value Odds Ratio (95% CI) P value

Gender (woman) 0.900 (0.354 - 2.287) 0.825

Age 0.978 (0.944 - 1.014) 0.227
Course of disease 1.000 (0.991 - 1.010) 0.985
Smoke (yes) 0.422 (0.086 - 2.080) 0.289
Perianal diseases (no) 1.071 (0.458 - 2.507) 0.874
Extraintestinal manifestations 0.833 (0.266 - 2.608) 0.754
(yes)
Bio-naive (yes) 0.462 (0.166 - 1.286) 0.139
Prior number of biological agents
0 reference
1 1.930 (0.674 - 5.529) 0.221
2 3.667 (0.862 - 15.593) 0.079
Prior biological treatments
Infliximab (yes) 1.621 (0.664 - 3.958) 0.289
Adalimumab (yes) 1.673 (0.527 - 5.311) 0.383
C-reactive protein at baseline 1.026 (1.003 - 1.050) 0.026 1.035 (0.981 - 1.091) 0.204
Albumin (<32) 4.571 (0.791 - 26.426) 0.090 4.334 (0.436 - 43.118) 0.211
Times of intravenous re-induction 0.732 (0.313 - 1.711) 0.471
(≥ 2)
Ustekinumab trough concentration 0.767 (0.596 - 0.987) 0.039 0.776 (0.599 - 1.006) 0.056

with an AUC of 0.759, a sensitivity of 66.7%, and a specificity of
88.9%.
The study found that patients with higher UST trough concen-
trations (above 4.8 ug/mL and 3.3 ug/mL) had higher rates of en-
doscopic remission compared to those with lower concentrations.
Similarly, the rates of endoscopic response were higher for patients
with concentrations above 4.8 ug/mL (100.0% vs 50.0%; P = 0.008)
and 3.3 ug/mL (92.9% vs 45.5%; P = 0.021). However, there was no
significant difference in clinical outcomes based on UST concentra-
tions. On the other hand, patients with higher UST trough concen-
trations (above 4.8 ug/mL and 3.3 ug/mL) had significantly higher
rates of CRP normalization compared to those with lower concen-
trations. The rates of CRP normalization were 85.0% and 75.0% for
patients with concentrations above 4.8 ug/mL and 3.3 ug/mL, and
38.1% and 41.2% for patients below these concentrations (P = 0.002
and P = 0.029) (Supplementary Figure 1A and 1B).
3.5. Factors Associated with Clinical Remission Of RI With UST
The logistic regression analysis involved various factors, such as
gender, age, disease course, smoking, perianal ailments, extrain-
testinal manifestations, bio-naïve status, previous usage of bio-
logical agents, previous biological treatments, baseline CRP levels,
baseline Alb levels, intravenous re-induction frequency, and UST
trough concentration. The findings of the multivariate analysis con-
cerning clinical remission can be seen in Table 4. Baseline con-
founding variables were considered as prior biological treatments,
prior number of biological agents, and CRP levels at baseline. None
of the aforementioned potential risk factors were identified as in-
dependent risk factors in this investigation. Nonetheless, the out-
comes suggested that the UST trough concentration, rather than
the frequency of intravenous UST re-induction, was linked to clini-
cal improvement.
3.6. Safety
No serious adverse events related to UST therapy or drug con-
centrations were reported during follow-up.
4. Discussion
This study was the first to analyze the effects of different times
of intravenous UST re-induction in CD patients with LOR with
UST. The findings of this study confirmed that intravenous UST re-
induction was beneficial for approximately three-quarters of pa-
tients with LOR to UST. However, the study did not find a signifi-
cant difference in efficacy among the different times of intravenous
UST administration.
Previous studies have demonstrated that intravenous UST re-
induction was safe and effective in CD patients who experience
LOR to UST [6,13-15,22-26]. On one meta-analyse, two studies fo-
cused on UST intravenous re-induction [5]. A cohort study con-
ducted by Heron et al. found that the rate of steriod free clin-
ical remission was 31.0% (18/58) after intravenous re-induction
[6]. Sedano et al. observed that 11 of 14 (78.6%) achieved clin-
ical response, and 8 of 14 (57%) achieved remission for UST in-
travenous re-induction in patients with CD with partial response
or LOR who already were on every-4-week subcutaneous dos-

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J. Tang, Q. Li, Z. Huang et al.
ing[13]. The other meta-analyse included three studies which fo-
cused on ustekinumab intravenous re-induction, and pointed that
53% (95%CI, 0.10 - 0.93) patients achieved clinical response [4,22-
24]. A multicenter cohort study found that re-induction with in-
travenous UST after secondary LOR resulted in clinical remission
in 56% at week 20 [14]. A study which evaluated the efficacy of
weight-based UST intravenous re-induction showed that clinical
remission were achieved in 69.6% of patients[15]. In a retrospec-
tive observational study conducted by Bermejo F et al., 53 patients
from 13 centers were included. The study findings showed that the
clinical remission rates at week 8 and 16 after re-induction were
49.0% and 43.3%, respectively [26]. These studies reported vary-
ing clinical remission rates after intravenous re-induction varying
from 31% to 69.6%. The results in our study revealed a slightly
greater rate of clinical remission, reaching 67.3%. This could be in-
terpreted alongside the baseline distributions of these character-
istics within the study population. In our cohort, patients had a
short disease duration (median: 24 months), mild intestinal in-
flammation [median: SES-CD = 6 (5, 8) scores] and timely re-
induction treatment (weight-based UST intravenous re-induction;
median: 28 weeks). The results which was recently reported in the
POWER study indicated patients with disease duration less than 5
years easier benefited from re-induction are consistent with that of
our study. Nevertheless, these outcomes further reinforce the ad-
vantages of administering intravenous UST. Therefore, intravenous
UST re-induction should be considered as a routine option before
switching to alternative therapies in patients who experience sec-
ondary LOR to UST.
Several small-scale studies have indicated that an intensified in-
travenous induction therapy for UST might deliver superior effec-
tiveness [16,17]. The question arose as to whether employing mul-
tiple intravenous re-induction could be a more effective approach.
Insurance policy and bio-similars may infleunce the cost-effective
of different optimizing strategies. In real world setting, patients
in China may prefer intravenous ustekinumab re-induction with-
out interval reduction due to its convenience and less cost. As a
result, some individuals have opted for receiving double or triple
doses of intravenous re-induction following LOR. We conducted a
comparative analysis to assess the effectiveness of various duration
of re-induction. Remarkably, different from the favorable outcomes
noted with UST double intravenous loading as the initial treatment,
our real-world data indicated no noteworthy variances in efficacy
among the single intravenous and continuous double/three intra-
venous re-induction cohorts. There are two possible reasons for
this. Firstly, the sample size of each group was relatively small and
further validation with a larger sample size is needed. Secondly,
it is possible that the drug concentrations, rather than the re-
induction strategies, are the key factors in determining efficacy. In
our study, we found no significant difference in after re-induction
drug concentrations among different subgroups. Additionally, our
logistic analysis showed that UST trough levels at week 24 tended
to predict clinical remission.
Therapeutic drug monitoring (TDM) has proven to be valu-
able in the management of patients with a LOR to anti-TNF α
agents [27]. However, there are limited data on the correlation
between UST drug concentrations and patient outcomes. Various
studies have reported different cut-off values ranging from 1.12
ug/ml to 4.5 ug/ml for predicting clinical or endoscopic remis-
sion [11,12,28-31]. Consequently, the relationship between serum
concentrations of UST and the achievement of clinical/endoscopic
remission remains uncertain. In our study, we also conducted
exposure-response analyses of UST in patients with CD, and we
found a significantly higher UST trough concentration in the after-
optimization group. There was no statistically significant difference
in UST trough concentration at weeks 0 and 24 among three sub-
groups. Among the 41 patients with complete data on serum UST
6
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Digestive and Liver Disease xxx (xxxx) xxx
trough concentration after optimization, our study demonstrated
a high sensitivity in the predicting clinical and endoscopic remis-
sion with a cut-off UST trough concentration of 3.3 ug/ml and 4.8
ug/ml, respectively, which was slightly higher than previously re-
ported values. We speculated that this difference may be attributed
to variations in study populations and laboratory measurement pa-
rameters [32].
Previous studies have mentioned some factors that may influ-
ence the effectiveness of UST dose intensification, but these fac-
tors have not been clearly defined [33,34]. Patient characteris-
tics, including a history of non-response to other biological treat-
ments, smoking, and possible factors associated with a more com-
plicated disease (e.g., perianal diseases, history of extraintesti-
nal manifestation, and hypoalbuminemia), have been reported as
potential factors linked to poorer responses to UST re-induction
[35]. However, our logistic regression model did not find any of
these potential risk factors to be independent risk factors in this
study. Based on these results and our own clinical experience, it
is important not to let these factors restrict the decision to at-
tempt to maximize the effectiveness of treatment before consid-
ering switching medications. Additionally, it is advisable to con-
sider appropriate medical supportive measures, such as drainage
of perianal abscess, treatment of perianal fistula, and albumin
supplementation.
The present study aimed to investigate whether the times of
intravenous re-induction of UST affects its efficacy in CD patients
with LOR to UST. The study provided informative findings that
can contribute to the optimization strategy of UST treatment in
these patients. However, there were some limitations to consider.
Firstly, the sample size was relatively small, with a small num-
ber of participants in each group. Although we performed multi-
variate logistic regression analysis in order to effectively control
for covariates, further study with sufficient power is needed to
further confirm the hypothesis. Secondly, we only included those
patients who underwent paired endoscopy to assess endoscopic
outcomes in 24-week follow-up period, which could have intro-
duced some selection bias. In addition, fecal calprotectin would
be helpful to reflect the mucosal healing. Future prospective stud-
ies should included the fecal calprotectin. Thirdly, the availabil-
ity of trough levels of UST data was limited to only 41.8% of the
patients in this cohort, which may affect the confidence in the
results.
In relation to safety profiles, our investigation indicates that the
approach of enhancing intravenous re-induction of UST exhibits a
satisfactory safety profile. Notably, we did not detect any instances
of infusion reactions when administering the supplementary intra-
venous re-induction.
In conclusion, the study further confirmed that intravenous re-
induction with UST was effective and safe for patients with CD
who have not responded adequately to UST. Notably, it showed
that multiple intravenous re-induction did not show superiority to
one intravenous re-induction, especially in the long-term phase. It
suggested that the trough level of UST but not the times of intra-
venous UST re-induction was associated with the clinical improve-
ment. This real-world evidence may help to guide clinical decision-
making in patients who lost response to UST. However, further
prospective studies with larger sample sizes are needed to validate
these findings.
Funding
Supported by the program of Guangdong Provincial Clinical Re-
search Center for Digestive Diseases (2020B1111170 0 04), the Sixth
Affiliated Hospital of Sun Yat-Sen University Clinical Research-
‘1010’ Program (1010CG(2023)-12) and Key-Area Research and De-
velopment Program of Guangdong Province (2023B1111040 0 03).
JID: YDLD
ARTICLE IN PRESS
J. Tang, Q. Li, Z. Huang et al.
Conflict of interest
No potential conflict of interest was reported by the authors.
Acknowledgments
We would like to thank to Guangzhou Huayin Medical Labora-
tory Center (Guangzhou, China) for the technical support provided
in the detection of ustekinumab trough concentrations.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.dld.2024.01.189.
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