Adverse reactions associated with the use of ustekinumab in Crohn's disease treatment：an analysis based on the FAERS database

doi:10.21203/rs.3.rs-4880247/v1

Background: Approved in 2016 for Crohn’s disease(CD), ustekinumab’s adverse reaction signals(ADRs) remain largely unclear. This study aims to enhance clinical safety by identifying ADRs through mining the FAERS database.

Methods: We collected adverse drug event (ADE) data for ustekinumab used in the treatment of CD, reported in the FDA’s Adverse Event Reporting System from the fourth quarter of 2016 to 2023. For signal mining, we employed the Reported Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Belief Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). Additionally, we conducted a statistical classification of ADRs according to the System Organ Class (SOC).

Results: The timeframe was limited to Q4 2016 to Q4 2023. For CD, 17,187 ADRs were identified, resulting in 44,232 signals affecting 24 SOCs and 258 PTs. The most numerous reports were for injury, poisoning, and procedural complications. Infections and infestations had the highest ROR signals. Among PTs, congenital pulmonary airway malformation had the strongest ROR signal and the highest off-label use instances.

Conclusion: When administering ustekinumab for CD, in addition to monitoring common AEs like infections and tumors, vigilance is crucial for potential AEs involving the heart, hepatobiliary system, and emerging genetic diseases.

Biological sciences/Drug discovery/Drug safety

Health sciences/Gastroenterology/Gastrointestinal system

Crohn's disease

adverse reactions

FAERS

Ustumumab

treatment

Crohn’s disease is a chronic inflammatory bowel disease affecting the gastrointestinal tract, with a rising incidence worldwide. In many countries across North America, Oceania, and Europe, the prevalence of inflammatory bowel disease exceeds 0.3%. In newly industrialized countries in Africa, Asia, and South America, the incidence is continually increasing, contributing to a significant disease burden. The pathogenesis of Crohn’s disease is believed to involve immune and microbial dysregulation, among other mechanisms, though the exact details remain unclear. Current treatments include hormonal therapy, immunotherapy,and biologic therapies ^{[1, 2]}. Ustekinumab is an anti-IL-12/23p40 monoclonal antibody that works by binding to the p40 subunit shared by both IL-12 and IL-23. This binding prevents the interaction of these cytokines with the IL-12 receptor β1 subunit of the IL-12 and IL-23 receptor complexes^[3]. Ustekinumab was approved by the FDA in 2009, with its primary indications being moderate to severe plaque psoriasis and psoriatic arthritis. In September 2016, the US FDA extended its approval to include the treatment of Crohn’s disease.Clinicaltrials demonstrated that ustekinumab was superior to placebo in achieving and maintaining clinical remission in Crohn’s disease^[4], offering a new therapeutic strategy for this condition.

Because the use of ustekinumab for the treatment of Crohn’s disease is relatively recent, many adverse reactions remain unclear. Current research primarily focuses on its efficacy and safety, positioning ustekinumab as an alternative treatment option for Crohn’s disease following the failure of traditional immunosuppressive therapy or TNF-α antagonist treatment^[5]. The US Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) is an open database that compiles reports of adverse drug reactions from healthcare professionals, patients, and drug manufacturers. This data can be utilized to identify potential adverse reaction signals caused by drugs and to assess their associated risks^[6]. In this study, the FAERS database was extensively mined and analyzed using four statistical methods: reported odds ratio (ROR), proportional reporting ratio (PRR), Bayesian belief propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM)^[7]. The aim was to reveal the pharmacovigilance signals of ustekinumab in the treatment of Crohn’s disease and to enrich the content of drug labeling.

2.1. Data source and analysis

2.1.1 Source of Data

This study utilized adverse event (AE) data from the FAERS database in the United States, which has been open since 2004 and contains reports submitted by medical professionals, drug companies, patients, and others. The database is updated quarterly and is known for its large scale and high standardization. It is an internationally recognized and globally accessible reporting system. Given that ustekinumab was approved by the FDA for the treatment of Crohn’s disease on September 23, 2016, this study retrieved the report files and adverse reaction data related to ustekinumab from the FAERS database, covering the period from the fourth quarter of 2016 to the fourth quarter of 2023. The data were processed using R language version 4.40 software.

2.1.2 Standardization of drug names and adverse drug reactions

In this study, ustekinumab was designated as the suspected drug type, and its name was uniformly coded using Medex_UIMA_1.3.8. The data from the FAERS database was pre-processed using R language version 4.40 software, which involved removing duplicate reports to obtain standardized data. The latest version 26.1 of the Medical Dictionary for Regulatory Activities (MedDRA 26.1) ^[8] was employed to match the preferred terms (PT) for adverse reactions associated with ustekinumab, focusing specifically on the indication for Crohn’s disease. Additionally, the system organ class (SOC) related to these PTs was recorded. Information on the reporting year, gender, age, reporting country, reporter type, occurrence time, and clinical outcome of patients with Crohn’s diseasewho experienced adverse events due to ustekinumab treatment was extracted from the database.

2.2 Data signal analysis

In this study, we employed a commonly used asymmetric measurement in pharmacovigilance research to identify potential signals between adverse events (ADEs) and the treatment of Crohn’s disease with ustekinumab. This method, awidely recognized data mining technique, analyzes the correlation between drugs and adverse events by comparing the observed frequencies in exposed and non-exposed populations using the four-fold table method (Table 1).

Table 1

Fourfold table of disproportionality method.
	Drug-related ADEs	Non-drug-related ADEs	Total
Drug	a	b	a + b
Non-drug	c	d	c + d
Total	a + c	b + d	N = a + b + c + d

In this study, we used the following four methods: reporting odds ratio (ROR)^[9]、proportional reporting ratio (PRR)^[10]、Bayesian belief propagation neuralnetwork (BCPNN)(BCPNN)^[11] and empirical Bayesian geometric mean (ebgm) ^[12]。The BCPNN algorithm primarily utilizes the information component (IC) and its confidence interval (CI) to evaluate the strength of the association between drugs and adverse reactions. Based on the classical four-fold table and Bayesian discrimination principles, this model excels at early-stage detection ofadverse event signals. An adverse event signal may be indicated when the lower limit of the 95% confidence interval of IC is greater than 0 and the number of reports (a) is greater than or equal to 3. In this study, we combined the ROR, PRR, BCPNN, and MGPS algorithms. The objective was to leverage the strengths of each method, broaden the detection scope, verify results from multiple perspectives, and effectively integrate the unique characteristics of different algorithms to identify more comprehensive and reliable safety signals. The specific formulas for the four algorithms are provided in (Table 2).

Table 2 Four algorithms

Effective ADR results should meet the positive signal selection criteria of the fouralgorithms mentioned above. All data on adverse reactions related to the treatment of Crohn’s disease with ustekinumab were processed and statistically analyzed using software such as R Studio 4.40. The overall flowchart of this study is illustrated in (Fig. 1).

3.1 Basic information of patients with adverse events related to the treatment of Crohn's disease with ustekinumab

A total of 10,573,648 adverse event (AE) reports from 2004 to 2024 were extracted from FAERS, and 47,494 adverse event reports related to ustekinumab were identified. Refer to Fig. 1. When restricting the indication to Crohn’s disease and the period from Q4 2016 to Q4 2023, the number of adverse event reports (AER) was 17,187, involving 44,232 AEs across 24 SOC categories. Among these, 258 PTS exhibited positive signals across ROR, PRR, BCPNN, and EBGM algorithms (see Annex). The year 2020 saw 4,851 reports, the highest among all years. Of all AERs, 58.14% included gender information, with 34.96% being male. The age group with the highest incidence of adverse events was 30–39 years (12.31%). The United States reported the most cases (54.87%), followed by Canada (22.35%), the UK (8.14%), Australia (2.16%), Japan (1.79%), and Germany (1.71%). The primary reporters were patients (41.68%), pharmacists (34.32%), and doctors (15.13%), with subcutaneous injection being the predominant method of drug administration (80.35%).Database analysis revealed that serious adverse outcomes associated with ustekinumab treatment for Crohn’s disease primarily included hospitalization, disability, life-threatening events, death, and unknown outcomes. Apart from unknown serious medical events (63.82%), hospitalization was the most common serious adverse outcome, with 3,965 cases (31.48%), followed by death (232 cases, 1.84%) and life-threatening events (206 cases, 1.64%). The duration of adverse reactions was over 60 days (18.59%)(Table 3). From 2016 to 2020, AER reports increased, peaking in 2020, as illustrated in(Fig. 2).

Table 3

Basic information table of patients with Crohn's disease treated with ulinumab in faers database from the fourth quarter of 2016 to the fourth quarter of 2023
variable	Case Number	Case Proportion
Number of events	17187
Year
2016	59	0.34%
2017	895	5.21%
2018	1962	11.42%
2019	2319	13.49%
2020	4851	28.22%
2021	2298	13.37%
2022	2406	14.00%
2023	2397	13.95%
sex
female	9993	58.14%
male	6008	34.96%
unknown	1186	6.90%
age_yr	45.00(31.00,59.00)
age_yrQ
< 20	629	3.83%
20–29	1663	10.12%
30–39	2023	12.31%
40–49	1998	12.16%
50–59	1966	11.97%
60–69	1571	9.56%
>=80	218	1.33%
unknow	6362	38.72%
wt	70.37(58.97,86.00)
Reporter
Consumer	7163	41.68%
Pharmacist	5898	34.32%
Physician	2601	15.13%
Other health-professional	1320	7.68%
Reported countries
United States	9430	54.87%
Canada	3841	22.35%
United Kingdom	1399	8.14%
other	1330	7.74%
Australia	372	2.16%
Japan	307	1.79%
Germany	294	1.71%
France	214	1.25%
route
subcutaneous	13810	80.35%
intravenous	2352	13.68%
Outcomes
other serious	8040	63.82%
hospitalization	3965	31.48%
death	232	1.84%
life threatening	206	1.64%
tto	80.00(0.00,347.00)
ttoQ
< 7	1194	10.87%
7 ~ 28	233	2.12%
28 ~ 60	370	3.37%
>=60	2043	18.59%
unknow	7147	65.05%

3.2. Signal detection related to the treatment of Crohn's disease with ustekinumab

3.2.1. Signal detection based on system organ

The statistical results (Fig. 3) indicated that 24 System Organ Classes (SOCs) were primarily involved in the occurrence of adverse events (AER) in Crohn’s disease treatment with ustekinumab. The most frequently reported SOCs were injuries, poisoning, and procedural complications (n = 10,338, 23.37%), followed by gastrointestinal disorders (7,611, 17.21%), infections and infestations(6,941, 15.69%), general disorders and administration site conditions (5,831, 13.18%), and nervous system disorders (2,459, 5.56%). Notably, infections and infestations were identified as positive signals by all four methods, aligning with the drug’s instructions, and the remaining SOCs were also consistent with the instructions, suggesting a high reliability of this study. However, some SOCs not listed in the drug manual—such as vascular disorders (553, 1.25%), eye disorders (413, 0.93%), cardiac disorders (320, 0.72%), and metabolism and nutrition disorders (384, 0.87%)—warrant attention and preventive measures.

3.2.2. Signals detection based on preferred term levels

At the Preferred Term (PT) level, this study employed four algorithms to analyze adverse drug reactions and evaluate their compliance with various screening criteria, resulting in the identification of 258 PTs. The top 50 signals, sorted by Reporting Odds Ratio (ROR) and number of reports, are presented in (Tables 4 and 5). Among these, the ROR signal for congenital pulmonary airway malformation was the strongest, indicating a new adverse reaction not mentioned in the drug’s instructions. Other strong signals included transitional cell carcinoma recurrent, spirochete infection, and fecal calprotectin abnormalities. Based on the number of reports, the top 10 signals were off-label use, Crohn’s disease, product dose omission issue, product useissue, inappropriate schedule of product administration, abdominal pain, lower respiratory tract infection, infusion-related reaction, accidental exposure to product, and product storage error.

Table 4

The number of adverse events of ustekinumab in Crohn's disease ranked top 50 in PTS in faers database.
pt_english	Case Reports	ROR(95% CI)	PRR(95% CI)	chisq	IC(IC025)	EBGM(EBGM05)
off label use	3110	4.11(3.96, 4.26)	3.89(3.74, 4.05)	6764.34	1.95(1.9)	3.87(3.76)
crohn's disease	2743	64.06(61.53, 66.69)	60.15(57.84, 62.55)	146391.23	5.79(5.73)	55.21(53.38)
product dose omission issue	1721	7.26(6.92, 7.62)	7.02(6.75, 7.3)	8837.24	2.8(2.73)	6.95(6.68)
product use issue	1394	8.68(8.23, 9.16)	8.44(7.96, 8.95)	9060.55	3.06(2.98)	8.35(7.98)
inappropriate schedule of product administration	917	5.26(4.92, 5.61)	5.17(4.87, 5.48)	3072.23	2.36(2.27)	5.14(4.86)
abdominal pain	694	4.42(4.1, 4.77)	4.37(4.04, 4.73)	1797.68	2.12(2.01)	4.35(4.08)
lower respiratory tract infection	479	13.54(12.37, 14.83)	13.41(12.16, 14.79)	5394.55	3.72(3.59)	13.16(12.2)
infusion related reaction	453	8.99(8.19, 9.87)	8.91(8.08, 9.83)	3142.4	3.14(3)	8.8(8.14)
accidental exposure to product	353	4.11(3.7, 4.57)	4.09(3.71, 4.51)	819.95	2.02(1.87)	4.07(3.73)
product storage error	327	3.99(3.58, 4.45)	3.97(3.53, 4.47)	722.77	1.98(1.82)	3.95(3.61)
therapeutic response decreased	289	7.26(6.46, 8.15)	7.22(6.42, 8.12)	1532.44	2.84(2.67)	7.15(6.49)
abscess	282	25.36(22.51, 28.58)	25.21(22.41, 28.36)	6316.8	4.6(4.43)	24.32(22.01)
intestinal obstruction	269	10.01(8.87, 11.29)	9.95(8.85, 11.19)	2135.49	3.3(3.12)	9.82(8.88)
exposure during pregnancy	266	5.01(4.44, 5.66)	4.99(4.44, 5.61)	842.53	2.31(2.14)	4.96(4.48)
clostridium difficile infection	264	14.37(12.72, 16.24)	14.29(12.7, 16.07)	3195.48	3.81(3.63)	14.01(12.65)
underdose	227	3.53(3.09, 4.02)	3.51(3.06, 4.03)	406.41	1.81(1.62)	3.5(3.14)
therapeutic product effect decreased	207	4.12(3.59, 4.72)	4.1(3.57, 4.7)	483.68	2.03(1.83)	4.09(3.64)
fistula	199	25.69(22.29, 29.6)	25.58(22.3, 29.34)	4525.16	4.62(4.42)	24.66(21.9)
haematochezia	193	4.41(3.82, 5.08)	4.39(3.83, 5.04)	502.92	2.13(1.92)	4.37(3.88)
anal abscess	174	40.66(34.88, 47.4)	40.5(34.62, 47.38)	6317.21	5.26(5.04)	38.22(33.62)
frequent bowel movements	160	7.6(6.5, 8.88)	7.57(6.47, 8.86)	902.84	2.91(2.68)	7.5(6.58)
drug level decreased	147	16.71(14.18, 19.68)	16.65(14.23, 19.48)	2110.25	4.02(3.79)	16.27(14.18)
cellulitis	132	3.59(3.03, 4.27)	3.59(3.01, 4.28)	245.04	1.84(1.59)	3.57(3.1)
kidney infection	124	7.97(6.68, 9.52)	7.95(6.66, 9.48)	744.98	2.98(2.72)	7.87(6.78)
nephrolithiasis	114	3.36(2.8, 4.04)	3.36(2.82, 4.01)	187.95	1.74(1.48)	3.35(2.87)
intestinal stenosis	102	35.43(29.03, 43.25)	35.35(29.06, 43)	3232.17	5.07(4.78)	33.61(28.44)
abdominal abscess	84	28.58(22.97, 35.57)	28.53(23, 35.39)	2139.28	4.78(4.46)	27.39(22.81)
gastrointestinal infection	79	11.95(9.57, 14.93)	11.93(9.62, 14.8)	777.3	3.55(3.23)	11.74(9.74)
skin cancer	78	3.77(3.02, 4.71)	3.77(3.04, 4.68)	157.68	1.91(1.59)	3.75(3.11)
postoperative wound infection	76	13.73(10.94, 17.23)	13.71(10.84, 17.35)	877.16	3.75(3.42)	13.45(11.12)
tooth abscess	76	10.96(8.74, 13.75)	10.94(8.65, 13.84)	675.54	3.43(3.11)	10.78(8.92)
ear infection	76	3.79(3.02, 4.75)	3.78(3.05, 4.69)	154.92	1.91(1.59)	3.77(3.12)
drug level below therapeutic	76	14.88(11.85, 18.68)	14.86(11.75, 18.8)	960.87	3.86(3.54)	14.55(12.03)
cholelithiasis	74	4.28(3.4, 5.38)	4.27(3.38, 5.4)	184.47	2.09(1.76)	4.25(3.51)
anal fistula	73	18.06(14.31, 22.79)	18.03(14.25, 22.81)	1143.02	4.14(3.8)	17.58(14.47)
abscess intestinal	70	49.38(38.72, 62.96)	49.3(38.97, 62.37)	3082.49	5.52(5.17)	45.95(37.49)
respiratory tract infection	69	3.52(2.78, 4.46)	3.52(2.78, 4.45)	123.73	1.81(1.47)	3.5(2.87)
post procedural infection	68	10.57(8.32, 13.44)	10.56(8.35, 13.36)	579.34	3.38(3.04)	10.41(8.52)
rectal abscess	67	54.32(42.34, 69.7)	54.24(42.04, 69.98)	3235.86	5.65(5.29)	50.2(40.75)
small intestinal obstruction	60	7.13(5.53, 9.19)	7.12(5.52, 9.19)	312.32	2.82(2.45)	7.05(5.7)
hernia	56	3.84(2.95, 4.99)	3.83(2.97, 4.94)	116.61	1.93(1.56)	3.82(3.06)
gastrointestinal inflammation	54	8.62(6.59, 11.28)	8.61(6.54, 11.33)	358.73	3.09(2.71)	8.51(6.8)
intestinal perforation	51	6.74(5.11, 8.88)	6.73(5.11, 8.85)	246.35	2.74(2.34)	6.67(5.3)
wound infection	50	7.34(5.56, 9.71)	7.34(5.58, 9.66)	270.7	2.86(2.46)	7.27(5.75)
basal cell carcinoma	40	3.21(2.35, 4.38)	3.21(2.35, 4.39)	60.51	1.68(1.23)	3.2(2.47)
gastroenteritis	40	4.08(2.99, 5.56)	4.07(2.97, 5.57)	92.26	2.02(1.58)	4.06(3.13)
skin infection	40	4.52(3.31, 6.16)	4.51(3.3, 6.17)	108.67	2.17(1.72)	4.49(3.46)
malignant melanoma	37	3.29(2.38, 4.55)	3.29(2.4, 4.5)	58.74	1.71(1.25)	3.28(2.5)
abscess limb	36	10.67(7.68, 14.84)	10.66(7.64, 14.88)	310.32	3.39(2.93)	10.51(7.98)
infected fistula	36	80.14(56.7, 113.27)	80.08(56.27, 113.96)	2507.27	6.16(5.67)	71.53(53.55)
tooth infection	35	3.46(2.48, 4.82)	3.46(2.48, 4.83)	60.79	1.78(1.31)	3.44(2.61)
squamous cell carcinoma	34	4.82(3.44, 6.75)	4.81(3.45, 6.71)	102	2.26(1.78)	4.79(3.61)
pyoderma gangrenosum	33	11.97(8.48, 16.89)	11.96(8.4, 17.02)	325.52	3.56(3.07)	11.76(8.82)
tonsillitis	33	8.28(5.87, 11.67)	8.27(5.81, 11.77)	208.32	3.03(2.54)	8.18(6.14)
subcutaneous abscess	33	9.59(6.8, 13.52)	9.58(6.73, 13.63)	250.06	3.24(2.75)	9.46(7.1)
pharyngitis	30	3.22(2.25, 4.61)	3.22(2.26, 4.58)	45.73	1.68(1.17)	3.21(2.38)
blood iron decreased	30	3.12(2.18, 4.46)	3.12(2.19, 4.44)	42.93	1.64(1.13)	3.11(2.3)
poor quality product administered	30	3.25(2.27, 4.65)	3.24(2.28, 4.61)	46.35	1.69(1.18)	3.23(2.39)
defaecation urgency	28	5.39(3.72, 7.82)	5.39(3.71, 7.82)	99.31	2.42(1.89)	5.35(3.92)
appendicitis	27	4.05(2.78, 5.92)	4.05(2.79, 5.88)	61.72	2.01(1.48)	4.03(2.94)
injection related reaction	27	18.14(12.37, 26.59)	18.13(12.25, 26.83)	425.26	4.14(3.6)	17.67(12.83)

Table 5

The reported odds ratio of ustekinumab in Crohn's disease ranked top 50 in PTS in faers database.
pt_english	Case Reports	ROR(95% CI)	PRR(95% CI)	chisq	IC(IC025)	EBGM(EBGM05)
congenital pulmonary airway malformation	3	116.59(34.17, 397.85)	116.58(33.91, 400.77)	292.2	6.63(5.09)	99.24(35.54)
transitional cell carcinoma recurrent	3	99.1(29.45, 333.51)	99.09(29.4, 334.03)	253.31	6.43(4.9)	86.3(31.26)
spirochaetal infection	3	90.09(26.96, 301.01)	90.08(26.72, 303.66)	232.57	6.31(4.79)	79.39(28.93)
faecal calprotectin	4	82.58(29.2, 233.53)	82.58(29.22, 233.36)	286.54	6.2(4.85)	73.51(30.81)
infected fistula	36	80.14(56.7, 113.27)	80.08(56.27, 113.96)	2507.27	6.16(5.67)	71.53(53.55)
external ear cellulitis	6	66.07(28.54, 152.93)	66.06(28.44, 153.45)	349.51	5.91(4.79)	60.15(29.8)
crohn's disease	2743	64.06(61.53, 66.69)	60.15(57.84, 62.55)	146391.2	5.79(5.73)	55.21(53.38)
periumbilical abscess	3	61.94(18.97, 202.27)	61.93(19.11, 200.74)	164.43	5.83(4.34)	56.71(21.07)
anal fistula infection	8	56.84(27.6, 117.03)	56.83(27.52, 117.36)	404.01	5.71(4.73)	52.41(28.64)
small intestine adenocarcinoma	7	55.06(25.47, 119.05)	55.05(25.63, 118.23)	342.91	5.67(4.63)	50.89(26.7)
rectal abscess	67	54.32(42.34, 69.7)	54.24(42.04, 69.98)	3235.86	5.65(5.29)	50.2(40.75)
abscess intestinal	70	49.38(38.72, 62.96)	49.3(38.97, 62.37)	3082.49	5.52(5.17)	45.95(37.49)
incision site abscess	7	48.68(22.59, 104.9)	48.68(22.67, 104.55)	304.45	5.5(4.47)	45.41(23.89)
bartholin's abscess	3	47.19(14.63, 152.25)	47.19(14.56, 152.96)	126.58	5.46(3.99)	44.11(16.55)
jejunal stenosis	3	46.09(14.3, 148.58)	46.09(14.22, 149.4)	123.7	5.43(3.96)	43.15(16.2)
postoperative abscess	21	44.34(28.5, 68.98)	44.32(28.24, 69.56)	833.35	5.38(4.76)	41.6(28.74)
anastomotic stenosis	10	44.05(23.22, 83.56)	44.04(23.06, 84.09)	394.35	5.37(4.49)	41.35(24.2)
anal abscess	174	40.66(34.88, 47.4)	40.5(34.62, 47.38)	6317.21	5.26(5.04)	38.22(33.62)
vaginal fistula	10	37.54(19.85, 71)	37.54(19.66, 71.68)	336.5	5.15(4.28)	35.57(20.87)
omphalitis	9	36.71(18.76, 71.83)	36.7(18.85, 71.46)	296.11	5.12(4.2)	34.82(19.86)
perineal abscess	14	36(21.02, 61.65)	35.99(21.2, 61.1)	451.61	5.1(4.34)	34.18(21.79)
intestinal stenosis	102	35.43(29.03, 43.25)	35.35(29.06, 43)	3232.17	5.07(4.78)	33.61(28.44)
choroid melanoma	3	35.39(11.08, 113.08)	35.39(11.13, 112.49)	95.16	5.07(3.61)	33.64(12.73)
pyoderma	14	35.31(20.62, 60.46)	35.3(20.79, 59.92)	442.94	5.07(4.32)	33.56(21.4)
abscess rupture	8	34.32(16.86, 69.87)	34.32(16.95, 69.5)	246	5.03(4.06)	32.67(18.03)
abdominal wall abscess	13	32.66(18.71, 57.01)	32.65(18.86, 56.52)	380.12	4.96(4.19)	31.16(19.55)
vaginal abscess	6	31.21(13.76, 70.79)	31.21(13.7, 71.09)	167.54	4.9(3.8)	29.85(15.04)
arthritis enteropathic	7	30.03(14.08, 64.06)	30.03(13.98, 64.5)	187.89	4.85(3.82)	28.77(15.26)
abdominal abscess	84	28.58(22.97, 35.57)	28.53(23, 35.39)	2139.28	4.78(4.46)	27.39(22.81)
stoma site abscess	6	26.43(11.69, 59.77)	26.42(11.6, 60.18)	141.13	4.67(3.58)	25.45(12.86)
fistula	199	25.69(22.29, 29.6)	25.58(22.3, 29.34)	4525.16	4.62(4.42)	24.66(21.9)
abscess	282	25.36(22.51, 28.58)	25.21(22.41, 28.36)	6316.8	4.6(4.43)	24.32(22.01)
overgrowth bacterial	4	24.7(9.1, 67.02)	24.7(9.09, 67.11)	87.67	4.58(3.28)	23.84(10.34)
blood zinc decreased	3	23.32(7.37, 73.75)	23.32(7.34, 74.12)	61.89	4.5(3.05)	22.56(8.61)
incision site discharge	5	22.78(9.34, 55.57)	22.78(9.43, 55.03)	100.65	4.46(3.29)	22.05(10.46)
anastomotic haemorrhage	3	22.78(7.21, 72.02)	22.78(7.17, 72.41)	60.39	4.46(3.02)	22.05(8.42)
intestinal fistula	21	22.68(14.68, 35.04)	22.67(14.73, 34.89)	420.54	4.46(3.84)	21.95(15.25)
perirectal abscess	13	22.49(12.94, 39.09)	22.48(12.99, 38.92)	258.06	4.44(3.68)	21.77(13.71)
anal squamous cell carcinoma	5	21.88(8.98, 53.33)	21.87(9.05, 52.83)	96.41	4.41(3.23)	21.21(10.06)
gastrointestinal stenosis	7	21.12(9.95, 44.83)	21.12(10.03, 44.48)	129.99	4.36(3.34)	20.49(10.92)
ileal stenosis	22	20.51(13.42, 31.35)	20.5(13.32, 31.55)	395.78	4.32(3.72)	19.91(13.96)
short-bowel syndrome	10	20.33(10.84, 38.15)	20.33(10.86, 38.07)	178.28	4.3(3.44)	19.75(11.66)
vesical fistula	3	20.22(6.41, 63.8)	20.22(6.36, 64.27)	53.19	4.3(2.86)	19.65(7.52)
anal infection	4	19.15(7.09, 51.75)	19.15(7.05, 52.03)	66.86	4.22(2.93)	18.64(8.11)
infected cyst	17	18.42(11.37, 29.82)	18.41(11.28, 30.05)	272.32	4.16(3.49)	17.94(11.98)
enterocutaneous fistula	11	18.4(10.11, 33.5)	18.4(10.02, 33.78)	176.06	4.16(3.34)	17.93(10.86)
intestinal anastomosis complication	3	18.35(5.83, 57.8)	18.35(5.77, 58.32)	47.89	4.16(2.72)	17.88(6.85)
chlamydial infection	9	18.19(9.38, 35.27)	18.18(9.34, 35.4)	142.22	4.15(3.24)	17.72(10.18)
injection related reaction	27	18.14(12.37, 26.59)	18.13(12.25, 26.83)	425.26	4.14(3.6)	17.67(12.83)
anal fistula	73	18.06(14.31, 22.79)	18.03(14.25, 22.81)	1143.02	4.14(3.8)	17.58(14.47)

3.2.3 Signal analysis of PTS death adverse events

This study extracted data on fatal adverse reaction events, encompassing a total of 17 System Organ Classes (SOCs). The top three causes of death were infectious diseases (136 cases), systemic diseases (121 cases), and various injuries (60 cases). The highest mortality rates were observed in heart disease (7.5%), tumors (5.76%), and hepatobiliary system diseases (2.24%). Among these, only tumors were mentioned in the drug’s instructions, while heart disease and hepatobiliary system diseases were not, indicating a need for increased attention and monitoringof these adverse events (Table 6).

Table 6

Total number and percentage of adverse events of death
soc_english	Death Case Reports	Total Case Reports	Death proportion
injury, poisoning and procedural complications	60	10338	0.58%
investigations	10	1442	0.69%
gastrointestinal disorders	59	7611	0.78%
musculoskeletal and connective tissue disorders	16	1802	0.89%
nervous system disorders	24	2459	0.98%
psychiatric disorders	7	714	0.98%
immune system disorders	4	317	1.26%
respiratory, thoracic and mediastinal disorders	17	1098	1.55%
metabolism and nutrition disorders	6	384	1.56%
vascular disorders	9	553	1.63%
renal and urinary disorders	7	370	1.89%
infections and infestations	136	6941	1.96%
general disorders and administration site conditions	121	5831	2.08%
blood and lymphatic system disorders	5	231	2.17%
hepatobiliary disorders	8	357	2.24%
neoplasms benign, malignant and unspecified (incl cysts and polyps)	52	903	5.76%
cardiac disorders	24	320	7.50%

Based on data mining of adverse events (AEs) related to the treatment of Crohn’s disease with ustekinumab from the FAERS database, this study aims to provide new insights for the use of ustekinumab in Crohn’s disease treatment through real-world data. Ustekinumab is an antagonistic antibody against IL-12 and IL-23, cytokines closely associated with cancer, infections, and inflammatory diseases. Consequently, treatment with ustekinumab may lead to adverse events such as infections and cancer, warranting careful monitoring and management ^{[4, 13, 14]}. This consistency with the highest signal of the four statistical methods for the infection system in our research results supports the reliability of this research method to a certain extent. However, some systems not mentioned in the drug instructions and clinical trials, such as congenital inheritance, injury, poisoning and procedural complications, metabolism and nutrition disorders, and cardiac disorders, have emerged. Additionally, new adverse reactions, such as congenital pulmonary airway malformation, recurrent transitional cell carcinoma, spirochete infection, and fecal calprotectin abnormalities, were identified. In the following sections, we will discuss the medical characteristics and adverse events related to the treatment of Crohn’s disease with ustekinumab based on statistical data, followed by a comprehensive summary and analysis.

4.1 Demographic characteristics of adverse reactions related to the treatment of Crohn's disease with ustekinumab

Based on the statistical data from this study, the incidence of Crohn’s disease was higher in women (58.14%) compared to men (34.96%). Epidemiological data indicate that the prevalence of Crohn’s disease is higher in women in the United States, while it is more common in men in Japan ^[15], Given that the reports from the United States (54.87%) in the database are significantly higher than those from Japan (1.79%) and other countries, the adverse reactions related to ustekinumab treatment for Crohn’s disease may not be associated with gender. Additionally, only 3.83% of the reports are from individuals younger than 18 years old, indicating a paucity of studies on adolescents and children. Retrospective studies have shown that ustekinumab is effective and safe for pediatric and adolescent patients with Crohn’s disease, suggesting that these populations can benefit from ustekinumab treatment ^{[16, 17]}, In this study, 10.89% of the participants were older than 60 years. Some studies have shown that ustekinumab is also effective and safe for treating Crohn’s disease in older adults ^[18]. However, the sample size in this study is insufficient, necessitating further large-scale studies to validate our findings. Of the reports, 49.45% were submitted by pharmacists or doctors, indicating relatively reliable data sources. The top five countries in terms of the number of reports are all developed countries. In contrast to the stable and relatively high hospitalization rates for Crohn’s disease patients in developed countries in North America and Western Europe, other countries, especially less developed ones, are experiencing rapidly increasing rates ^[19]. These less developed countries need to be particularly vigilant regarding the adverse reactions related to ustekinumab treatment for Crohn’s disease.

4.2 Known systemic adverse reactions and their new signals

In terms of infections, nasopharyngitis and upper respiratory tract infections are common. Other reported infections include Clostridium difficile infection, herpes zoster, gastrointestinal abscess, pneumonia, gastroenteritis, viral gastroenteritis, pyelonephritis, cytomegalovirus (CMV) colitis, and cholecystitis. Regarding the tumor system, non-melanoma skin cancer (NMSC) is predominant ^[20]. In addition to NMSC, the incidence of other malignant tumors is low. Reported cases include intestinal cancer, renal cancer, testicular cancer, prostate cancer, endometrial adenocarcinoma, melanoma, breast cancer, and pancreatic cancer. Common digestive system symptoms are vomiting, abdominal pain, and diarrhea ^[21–23], These observations are consistent with existing guidelines and instructions. Crohn’s disease has also been reported in patients. This occurrence is considered a phenomenon of efficacy attenuation of biological agent treatment rather than a true adverse event of the drug. Studies have shown that increasing the maintenance dose of ulinumab is effective in more than 50% of patients. For patients who do not respond to the standard maintenance dose of ulinumab, dose adjustment can be considered ^[24]. In this study, new adverse reaction signals were observed in the infection system, including lower respiratory tract infections, spirochete infections, mycoplasma and other bacterial and viral infections, and oral infections. Regarding the digestive system, new signals such as ulcers, stenosis, and obstruction were noted. In the context of tumors, new signals of lymphoma and neuroendocrine cancer were detected. Additionally, a large retrospective study reported a case of lymphoma as an adverse reaction during the treatment of Crohn’s disease with ustekinumab ^[25], which warrants attention. Additionally, the number of reports of various injuries, poisoning, and operation complications is the highest, accounting for 23.37% of all reports. This may be due to the improper use of drugs by patients. To mitigate these issues, standardized procedures, attention to detail, and efforts to reduce adverse events during drug administration are essential. Doctors and pharmacists need to enhance their guidance and education on proper drug use for patients.

4.3 Emerging system and adverse reaction signals

In this study, new System Organ Classes (SOCs) such as congenital diseases, as well as those affecting blood vessels, the eyes, the heart, metabolism, reproduction, and the liver and gallbladder, have emerged. This indicates that beyond the commonly reported systems like infection, the gastrointestinal tract, and tumors in drug instructions, adverse reactions from other systems are also surfacing and warrant attention. Among these, the genetic system’s congenital pulmonary airway malformation, ranking first in the ROR analysis, deserves particular attention. The study demonstrates that in pregnant patients with Crohn’s disease treated with ulinumab, thelevel of ust in the umbilical cord blood is significantly higher than the measured maternal serum drug level ^[26]. A study reported a case of a patient who became pregnant and subsequentlymiscarried during the treatment of refractory Crohn’s disease with ulinumab ^[27], Conversely, recent studies suggest that using ulinumab during pregnancy is safe, with favorable outcomes forinfants during pregnancy and postpartum^[28]. Currently, there is a lack of sufficient samples andcases, but the strong signals of adverse reactions in the genetic system highlighted in the database warrant attention to improve the treatment of Crohn’s disease during pregnancy. Additionally, fecal calprotectin levels correlate with the severity of Crohn’s disease colitis symptoms ^[29], The abnormal fecal calprotectin levels identified in the new signal may be related to the efficacy of ustekinumab in treating Crohn’s disease ^[30].

4.4 Death signal

This study incorporated an analysis of death signals. Deaths accounted for 1.84% of seriousadverse events, with the highest number of deaths arising from infections. However, the highest mortality rate was associated with cardiovascular system diseases, including myocardial infarction and heart failure. A clinical study on ulinumab for the treatment of inflammatory bowel disease suggested a potential risk of cardiovascular adverse events^[22], One case analysis reported a male patient with Crohn’s disease who was diagnosed with heart failure after 10 months of ulinumab treatment. Following discontinuation of the drug, the patient’s symptoms improved and cardiac function was restored ^[31]. Conversely, a meta-analysis of major adverse cardiovascular events in patients with inflammatory bowel disease indicated that the risk of cardiovascular events during the induction or maintenance phase of ulinumab treatment for Crohn’s disease was not higher than that of a placebo^[32]. These findings differ from the results of this study, highlighting the need for further research to confirm these risks. Despite the weak cardiac system disease signal in the four statistical methods, the high risk necessitates efforts to avoid this adverse event to reduce mortality. Additionally, adverse events related to the tumor and hepatobiliary systems are also on the rise. Ulinumab is associated with several hepatobiliary adverse reaction signals, such as cholangitis and cholelithiasis, ranking third in mortality. However, relevant clinical trial data are lacking ^[33].

4.5 limitation

This study provides robust scientific evidence for the safety evaluation of ulinumab in the treatment of Crohn’s disease from multiple perspectives. However, some limitations exist. The FAERS database is a “self-reporting system,” which carries the risk of missing, repeated, and inaccurate reports, potentially introducing bias into the research results. Reporting bias and incomplete information are concerns, as reports from laypersons such as consumers may not be as reliable and comprehensive as those from medical professionals. Additionally, the reporting countries are not comprehensive, leading to regional bias. The database also lacks phase-specific safety evaluations of the drug, covering only the adverse event data reported since the drug’s launch, without assessing the severity of these events. This limits the ability to perform only qualitative evaluations of adverse events. Future research should consider more rigorous prospectiveclinical studies, combining clinical trials and epidemiological studies, to address these limitations.

This study, utilizing the FAERS system, has identified new adverse reaction signals in established systems, such as oral infections and lymphomas, as well as in new systems, including the genetic, cardiovascular, metabolic, and reproductive systems, since the introduction of ulinumab for the treatment of Crohn’s disease. Notably, the newly emerging cardiac system signals exhibit a high mortality rate, necessitating attention. It highlights the importance for patients and healthcare professionals to closely monitor not only common infectious diseases but also adverse reactions related to the heart and tumors. Furthermore, it is crucial to fully recognize the risks associated with medication, particularly its impact on various congenital familial genetic diseases, and to regulate drug use appropriately to minimize the occurrence of adverse events.

Funding

This paper was not funded.

Declaration of interest

The authors declare no relevant financial relationships or involvement with any organization orentity with financial interests or conflicts related to the manuscript’s topics. This includes employment, consulting, remuneration, stock ownership or options, expert testimony, grants, patents,or royalties.

Reviewer disclosures

Peer reviewers for this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

CWG and QLK conceptualized the study. DL, XJM, QLK and XMW processed, analyzed,and interpreted the FAERS data. CWG drafted the manuscript, which was reviewed and edited by YFS and NRW.

Ethics statement

Ethical approval was not needed as the FAERS database contains anonymized patient data.

Availability of data and materiak

The datasets generated and/or analyzed during the current study are available in the US FAERS database.

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No competing interests reported.

UlinumabFDAinstruction2024.pdf

Adverse reactions associated with the use of ustekinumab in Crohn's disease treatment：an analysis based on the FAERS database

Status:

Version 1

Abstract

Figures

1. Introduction

2. Methods

2.1. Data source and analysis

2.1.1 Source of Data

2.1.2 Standardization of drug names and adverse drug reactions

2.2 Data signal analysis

3. Results

3.2. Signal detection related to the treatment of Crohn's disease with ustekinumab

3.2.1. Signal detection based on system organ

3.2.2. Signals detection based on preferred term levels

3.2.3 Signal analysis of PTS death adverse events

4. Discussion

4.1 Demographic characteristics of adverse reactions related to the treatment of Crohn's disease with ustekinumab

4.2 Known systemic adverse reactions and their new signals

4.3 Emerging system and adverse reaction signals

4.4 Death signal

4.5 limitation

5. Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1