Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a real-world analysis from FAERS database

doi:10.21203/rs.3.rs-5171055/v1

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Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a real-world analysis from FAERS database

https://doi.org/10.21203/rs.3.rs-5171055/v1

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The incidence of pediatric inflammatory bowel disease (IBD) has significantly increased over the past few decades. Infliximab (IFX) and adalimumab (ADA) are the only two Tumor necrosis factor-α (TNF-α) inhibitors that have been approved by the FDA for the treatment of IBD in pediatric patients. However, postmarketing pharmacovigilance of the two TNF-α inhibitors in pediatric IBD is not sufficient and requires ongoing vigilant attention. We aimed to evaluate the safety of IFX and ADA in pediatric IBD using data from FAERS database. We filtered the queries within FAERS database to specifically identify indications of IBD among patients under the age of 18 from the first quarter of 2004 to that of 2024. Reporting odds ratio (ROR) and proportional reporting ratio (PRR) algorithnms were used to identify drug-adverse event associtions. A total of 15, 955 reports of adverse events (AEs) caused by IFX and ADA as the primary suspect (PS) for pediatric IBD were extracted from FAERS database. We detected 95 positive signals of IFX involved in 17 system organ classes (SOCs) and 165 positive signals of ADA involved in 20 SOCs. The most commonly reported AEs for IFX were related to infusion reactions, whereas the predominant AEs for ADA involved injection site reactions. The majority of our detected AEs were disclosed on the product labell; however, certain AEs, including attempted suicide, increased weight, and psoriasis for IFX, as well as suicidal depression for ADA, were not listed. The median time to onset of IFX-related AEs was 579 days (interquartile range [IQR] 159.25–1357 days), with the majority occurring after 360 days initiation of IFX. While the median time to onset of ADA-related AEs was 79 days ([IQR] 21.75–295 days), with the majority occurring within 90 days after initiation of ADA. We conducted a comprehensive assessment and comparison of the safety of IFX and ADA for treating pediatric IBD, using real-world data from the FAERS database. Our study emphasizes the importance for medical practitioners to closely monitor AEs that may result in serious outcomes and are not listed in the labeling, thereby ensuring the safety of IFX and ADA treatments for children with IBD.

Health sciences/Gastroenterology

Health sciences/Gastroenterology/Gastrointestinal diseases

Health sciences/Gastroenterology/Gastrointestinal diseases/Inflammatory bowel disease

infliximab

adalimumab

adverse event

pharmacovigilance

children

inflammatory bowel diseases

The incidence of pediatric inflammatory bowel disease (IBD), which includes pediatric Crohn's disease (CD) and ulcerative colitis (UC), has significantly increased over the past few decades¹. Pediatric patients with IBD are characterized by a more severe disease course, which often leads to a high rate of surgery, disability, and various complications, including insufficient growth, delayed pubertal development, and psychosocial issues^2–4. Tumour necrosis factor alpha (TNF-α) inhibitors marked a therapeutic breakthrough as the first biologic therapies for IBD. Infliximab (IFX) and adalimumab (ADA) are currently the only TNF-α inhibitors approved by the FDA or European Medicines Agency for pediatric and adolescent IBD treatment⁵.

TNF-α inhibitors are generally well-tolerated, with infusion reactions (IRs) being the most common side effects. However, it is important to note that there have been reports of various potentially serious adverse events (AEs) associated with their use, such as serious infections, malignancies, central nervous system (CNS) demyelination and peripheral neuropathies^6–9. Some above-mentioned serious AEs have also been reported in children^{10, 11}. What more important, the adverse reactions of paradoxical psoriasiform in children with TNF-α inhibitors have attracted widespread attention^{12, 13}. Serious AEs were the most frequent cause of drug withdrawal. Therefore the safety of anti-Tumour necrosis factor(anti-TNF) therapies for pediatric IBD, demand our utmost attention and ongoing scrutiny.

The FDA Adverse Event Reporting System (FAERS) is a robust and comprehensive database that compiles AE reports submitted by healthcare professionals, patients, and pharmaceutical companies. It plays a pivotal role in supporting the FDA's postmarket surveillance program for drugs and therapeutic biologics by facilitating the identification and assessment of potential safety concerns¹⁴. Subsequently, through a pharmacovigilance analysis of the FAERS, we aimed to assess and compare the safety profiles of IFX and ADA in pediatric IBD treatment, offering a rationale for the clinical application of these TNF-α inhibitors in pediatric patients.

2.1. Data sources and preprocess

The data for this study were obtained from the publicly accessible FAERS database, spanning the period from the first quarter of 2004 to that of 2024. FAERS is a large database that supports the FDA's postmarket surveillance program for drugs and therapeutic biologics (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html). The AEs of TNF-α inhibitors were classified according to the preferred terms (PTs) defined in the Medical Dictionary for Regulatory Activities (MedDRA) version 26.0. Duplicate records were removed in accordance with the FDA's recommended procedure by selecting the latest FDA_DT when the CASEID was the same and the higher PRIMARYID when the CASEID and FDA_DT were the same¹⁵. In order to improve accuracy, we only selected AEs which were judged to be primary suspected (PS) in 'ROLE_COD' and where the indication was inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), among patients under 18 years old.

2.2. Statistical analysis

The analysis of disproportionality was a widely employed methodology in the field of pharmacovigilance. It was used to quantitatively assess the association between drugs and target AEs by calculating the ratio of target AEs to other AEs in a database and providing the putative relevance from a statistical perspective¹⁵. The reporting odds ratio (ROR) and the proportional reporting ratio (PRR) were statistical measures frequently used in pharmacovigilance that can provide insights similar to those of the odds ratio and relative risk, respectively^{16, 17}.. A positive drug signal was indicated when both the ROR and PRR values exceeded the established cut-off values (Supplementary Table S1). A higher ROR and PRR values denote an intensified signal, indicating a greater correlation between the target drug and AEs^{18, 19}. All data operations and statistical analyses were conducted using R software (version 4.3.2) and Microsoft Excel.

2.3 Time to onset analysis

Time to onset (TTO) data for AEs related to IFX and ADA were assessed using median, quartiles and Weibull shape parameter (WPS). We calculated the TTO from the interval between EVENT_DT (date of adverse event) and START_DT (date of drug initiation) in the THER sub-database. Reports with inaccurate dates, missing dates, and input errors (EVENT_DT before START_DT) were excluded. The Weibull distribution can identify and predict the fluctuating increase or decrease in risk incidence over time, using scale α and shape β as key factors to characterise the shape of the Weibull distribution²⁰.

3.1. Overall events and general characteristics

A total of 21,0359,995 reports were recorded in the FAERS database from January 2004 to 2024. After excluding duplicate reports, 17,785,202 reports remained. Following selection for reports that pertain to pediatric patients with IBD, the treatment with IFX and ADA as the primary suspect has been reported in 10,509 and 5,446 cases, respectively. The detailed data processing workflow is shown in Fig. 1. The comparison of clinical characteristics between IFX and ADA was presented in Table 1. In terms of gender, the proportion of male was slightly more than that of female in both IFX and ADA. The AE reports of the two TNF-α inhibitors were concentrated in adolescent group. Concerning the occupation of reporter, IFX was primarily reported by physicians (41.67%), followed by health professionals (21.72%), whereas ADA was predominantly reported by consumers (69.56%), followed by physicians (16.86%). The five most frequently reported regions for IFX and ADA were the United States (US), Germany (DE), Canada (CA), France (FR), and the United Kingdom (GB). In the case of events for which the outcome data were available, serious outcome (including hospitalization, disability, life threatening, and death) were significantly more prevalent in IFX-related events, occurring in 49.37% of cases, compared to 28.03% in ADA-related events. Among them, hospitalization was the most frequently reported serious outcome. Regarding concomitant medications, prednisone, methotrexate, and azathioprine were the top three most frequently reported for both IFX and ADA.

Table 1

Characteristics of IFX and ADA in pediatric inflammatory bowel diseases from the FAERS database.
Characteristics	infliximab (N = 10509)	adalimumab (N = 5446)
Sex
Male	5083 (50.75%)	2826 (51.89%)
Female	5333 (48.37%)	2524 (46.35%)
Unknow	95 (0.9%)	62 (1.14%)
Age
Infant group (0–2)	223 (2.12%)	34 (0.62%)
Preschool group (2–6)	322 (3.06%)	90 (1.65%)
Children group (6–12)	2570 (24.46%)	1202 (22.07%)
Adolescent group (12–18)	7394 (70.36%)	4120 (75.65%)
Reporter
Physician	4379 (41.67%)	918 (16.86%)
Pharmacist	251 (2.39%)	104 (1.91%)
Health Professional	2283 (21.72%)	282 (5.18%)
Other Health Professional	1895 (18.03%)	300 (5.51%)
Consumer	1681 (16%)	3788 (69.56%)
Unknow	18 (0.17%)	54 (0.99%)
Reporter countries(Top5)
US	3593 (34.19%)	2287 (41.99%)
DE	257 (2.45%)	555 (10.19%)
CA	4445 (42.3%)	247 (4.54%)
FR	370 (3.52%)	82 (1.51%)
GB	204 (1.94%)	71 (1.3%)
Outcome of AEs
Congenital Anomaly	12 (0.11%)	2 (0.04%)
Death	65 (0.62%)	34 (0.62%)
Disability	42 (0.4%)	13 (0.24%)
Hospitalization	4917 (46.79%)	1433 (26.31%)
Life-threatening	216 (2.06%)	47 (0.86%)
other serious outcomes	4659 (44.33%)	770 (14.14%)
Unknow	591 (5.72%)	3145 (57.75%)
Concomitant Medications
prednisone	(1108, 10.54%)	(346, 6.3%)
methotrexate	(1094, 10.41%)	(407, 7.47%)
azathioprine	(836, 4.39%)	(239, 4.39%)

3.2. Disproportionality analysis

3.2.1 SOCs of AE signals

The AEs were categorized using the MedDRA based on the affected organs and systems. Using both ROR and PRR algorithms, our research detected 95 positive signals of IFX involved in 17 SOCs and 165 positive signals of ADA involved in 20 SOCs (Fig. 2 and Supplementary Table S2 ). The top 5 common SOCs of IFX and ADA were identical, namely“injury, poisoning and procedural complications”, “gastrointestinal disorders”, “general disorders and administration site conditions”, “infections and infestations”, “investigations”. The general disorders and administration site conditions was identified as the most frequently reported system for AEs associated with ADA (2 540 reports, 34 PTs), exceeding the reports for IFX (986 reports, 8 PTs). ADA demonstrated a higher frequency of AEs in several SOCs compared to IFX, specifically “product issues”, “psychiatric disorders”, and “musculoskeletal and connective tissue disorders”. In contrast to ADA, IFX exhibited a higher incidence of AEs in “injury, poisoning and procedural complications”, “gastrointestinal disorders”, “investigations”, “infections and infestations”, “respiratory, thoracic and mediastinal disorders”, “immune system disorders”, “vascular disorders” and “cardiac disorders”.

3.2.2 The most common signal AEs

At the PT level, we detected 95 positive signals of IFX and 165 positive signals of ADA. After excluding AEs unrelated to the drug, such as those associated with indications, disease progression, and product issues, the number of reports and the signal strength of the top 30 most commonly reported AEs associated with IFX and ADA were presented in Table 2. For IFX, infusion related reaction [N = 823, ROR (95%CI) = 10.8 (8.71–13.39)] was the primary signals among the top 30 most commonly reported AEs. There were also a great many of infusion related reactions(IRs) related AEs, such as dyspnoea, anaphylactic reaction, hypersensitivity, chest discomfort, tachycardia, oxygen saturation decreased, hypotension, anaphylactic shock, throat tightness, and blood pressure decreased. Other significant signals include haematochezia, frequent bowel movements and psoriasis. Additionally, our analysis revealed a range of infection-related AEs, including anal abscess, pneumonia, cellulitis, herpes zoster, lower respiratory tract infection, and pouchitis. Notably, our data mining efforts revealed some unexpected AEs, such as weight increased, nephrolithiasis and fall. In summary, our research indicated that IFX may lead to a range of AEs, some of which were not currently included in the product label.

For ADA, the most predominant signals among the top 30 commonly reported AEs were primarily associated with injection site reactions (ISRs), including injection site pain, hemorrhage, erythema, swelling, pruritus, bruising, papule formation, urticaria, and rash. These AEs also demonstrated a stronger ROR value. There was only one PT (sinusitis) related to infection-related AEs. Regarding psychiatric disorders, anxiety, insomnia, and fear of injections were more common AEs. Feeling abnormal and hypoaesthesia were common nervous system disorders AEs which included in the label. Other AEs, such as abdominal pain, intestinal obstruction, gastrointestinal inflammation and hypophagia, may commonly be sequelae of inflammatory bowel disease. Overall, nearly all of the top 30 most frequently reported AEs corresponded to those listed on the product label, and some may be related to the sequelae of inflammatory bowel disease.

After a thorough comparison of the major AEs mentioned or unmentioned in the labels of IFX and ADA, our research revealed that IFX was associated with a significantly higher incidence of AEs related to 'IRs'. Conversely, ADA exhibited a significantly higher rate of 'ISRs' AEs.

Table 2

The top 30 commonly reported AE signals of IFX and ADA in pediatric IBD.
infliximab				adalimumab
PT	N	ROR(95%Cl)	PRR(X²)	PT	N	ROR(95%Cl)	PRR(X²)
infusion related reaction	823	10.8 (8.71–13.39)	10.52 ( 730.38 )	injection site pain	933	77.03 (53.84-110.22)	73.1 ( 2167.48 )
haematochezia	767	2.2 (1.95–2.48)	2.17 ( 173.75 )	injection site haemorrhage	345	94.9 (48.95-183.99)	93.11 ( 803.83 )
dyspnoea	313	3.2 (2.59–3.96)	3.18 ( 128.11 )	injection site erythema	208	127.77 (47.5-343.69)	126.31 ( 489.55 )
frequent bowel movements	302	2.17 (1.8–2.63)	2.16 ( 67.41 )	abdominal pain upper	166	3.12 (2.48–3.93)	3.1 ( 104.32 )
psoriasis	191	2.19 (1.72–2.78)	2.18 ( 43.35 )	injection site swelling	113	25.1 (13.51–46.63)	24.95 ( 230.94 )
anaphylactic reaction	182	4.44 (3.23–6.08)	4.41 ( 102.32 )	injection site pruritus	98	29.91 (14.55–61.51)	29.75 ( 205.88 )
anal abscess	150	2.98 (2.21–4.02)	2.97 ( 56.23 )	intestinal obstruction	95	2.52 (1.89–3.35)	2.51 ( 42.51 )
pneumonia	137	2.33 (1.75–3.11)	2.33 ( 35.13 )	anxiety	94	2.14 (1.62–2.82)	2.13 ( 30.25 )
erythema	121	2.09 (1.55–2.81)	2.08 ( 24.85 )	oropharyngeal pain	93	2.41 (1.81–3.21)	2.4 ( 38.41 )
weight increased	119	2.29 (1.68–3.11)	2.28 ( 29.41 )	injection site bruising	89	54.31 (19.94-147.91)	54.04 ( 199.59 )
flushing	108	4.02 (2.71–5.97)	4.01 ( 55.92 )	injection site papule	82	200.08 (27.85-1437.56)	199.18 ( 195.07 )
hypersensitivity	100	2.09 (1.51–2.89)	2.08 ( 20.55 )	gastrointestinal inflammation	80	2.38 (1.75–3.23)	2.37 ( 32.14 )
chest discomfort	88	2.99 (2.02–4.43)	2.99 ( 33.19 )	injection site reaction	77	31.3 (13.64–71.85)	31.17 ( 162.77 )
tachycardia	79	3.62 (2.32–5.64)	3.61 ( 36.99 )	injection site urticaria	72	87.79 (21.54-357.84)	87.44 ( 166.49 )
oxygen saturation decreased	63	6.82 (3.59–12.94)	6.81 ( 46.44 )	haemoglobin decreased	66	2.29 (1.64–3.21)	2.29 ( 24.74 )
cellulitis	63	3.26 (2.02–5.26)	3.26 ( 26.36 )	pain in extremity	64	2.05 (1.47–2.86)	2.05 ( 18.61 )
hypotension	63	2.78 (1.77–4.36)	2.77 ( 21.46 )	sinusitis	54	2.35 (1.61–3.41)	2.34 ( 21.18 )
fall	57	2.51 (1.59–3.97)	2.51 ( 16.65 )	feeling abnormal	50	3.12 (2.05–4.74)	3.11 ( 31.49 )
herpes zoster	49	2.91 (1.73–4.9)	2.91 ( 17.85 )	inflammation	49	2.09 (1.43–3.06)	2.09 ( 14.96 )
anaphylactic shock	48	9.52 (4.07–22.25)	9.51 ( 40.63 )	insomnia	45	2.81 (1.83–4.31)	2.8 ( 24.26 )
mucous stools	46	2.38 (1.44–3.93)	2.38 ( 12.24 )	fear of injection	44	21.42 (8.49–54.04)	21.37 ( 87.27 )
throat tightness	44	3.08 (1.76–5.39)	3.08 ( 17.2 )	loss of consciousness	44	5.35 (3.16–9.09)	5.34 ( 48.6 )
perirectal abscess	42	3.84 (2.06–7.16)	3.84 ( 20.86 )	inflammatory marker increased	41	6.65 (3.68–12.02)	6.64 ( 52.65 )
subcutaneous abscess	41	3.75 (2.01-7)	3.75 ( 19.9 )	hypophagia	39	10.55 (5.11–21.78)	10.53 ( 63.09 )
blood pressure decreased	39	2.73 (1.54–4.82)	2.73 ( 12.95 )	injection site rash	39	15.82 (6.7-37.37)	15.79 ( 72.08 )
lupus-like syndrome	39	4.64 (2.32–9.3)	4.63 ( 22.71 )	rhinorrhoea	39	2.96 (1.86–4.73)	2.96 ( 22.84 )
nephrolithiasis	36	2.14 (1.24–3.7)	2.14 ( 7.81 )	nasal congestion	38	3.08 (1.91–4.97)	3.08 ( 23.53 )
cyanosis	35	4.63 (2.22–9.63)	4.62 ( 20.33 )	hypoaesthesia	35	2.5 (1.56–4.01)	2.5 ( 15.54 )
lower respiratory tract infection	31	6.15 (2.56–14.73)	6.14 ( 21.64 )	blood iron decreased	34	2.58 (1.59–4.19)	2.58 ( 15.98 )
pouchitis	30	2.38 ( 1.28–4.42 )	2.38 ( 7.98 )	rash papular	31	10.77 (4.74–24.47)	10.76 ( 50.57 )

3.3. The important AE signals of infliximab and adalimumab

Other safety concerns encompass infections, dermatological issues, nervous system disorders, psychiatric disorders, and the rare, yet serious, neoplasms. Consequently, we have identified additional significant AE signals for both IFX and ADA that were not included in the top 30 AEs (Table 3 ).

In the infections and infestations system, our analysis detected 9 additional AEs signal for IFX, which included pilonidal disease, osteomyelitis, wound infection, abscess limb, salmonellosis, pelvic abscess, and tuberculosis. Comparatively, ADA exhibited only 2 additional AE signals, which were rash pustular and enteritis infectious. In the skin and subcutaneous tissue disorders system, our analysis revealed a higher number of reported cases of psoriasis associated with IFX compared to ADA. In the nervous system disorders system, demyelination [N = 8, ROR(95%CI) = 9.51 (1.19–76.04)]was a strong signal for IFX, which was not detected in ADA. In the psychiatric disorders system, suicide attempt was the only AE signal for IFX, which was not listed on the product label. In comparison, there were 9 additional AEs signal for ADA, such as depressed mood, nervousness, mood altered, panic attack, aggression, and depression suicidal. Among them, we need to be particularly alert to the depression suicidal, as it is associated with a high ROR value of 14.58, which is not indicated on the product label. In the neoplasms system, we did not detect any malignancy-related AE signals for both IFX and ADA. Nevertheless, attention should also be given to the top 3 reported AEs associated with malignancy(Supplementary Table S3). The top 3 reported AEs for IFX were B-cell lymphoma [n = 8, ROR(95%CI) = 3.17 (0.84–11.95)], hepatosplenic T-cell lymphoma [(N = 7, ROR(95%CI) = 0.38 (0.16–0.88)], and leukemia [(N = 7, ROR(95%CI) = 0.69 (0.27–1.76)]. In contrast, for ADA, the top 3 reported AEs were Hodgkin's disease[(N = 8, ROR(95%CI) = 2.43 (0.91–6.47)], hepatosplenic T-cell lymphoma [(N = 5, ROR(95%CI) = 0.51 (0.19–1.33)], and unspecified lymphoma [(N = 4, ROR(95%CI) = 0.65 (0.21–1.95)].

Table 3

The important AE signals of IFX and ADA which were not in the top 30 AEs
	infliximab				adalimumab
SOC system	PT	N	ROR (95%Cl)	PRR(X²)	PT	N	ROR (95%Cl)	PRR(X²)
infections and infestations	pilonidal disease	20	5.95 (2.03–17.4)	5.94 ( 13.71 )	abscess intestinal	20	2.11 (1.16–3.85)	2.11 ( 6.27 )
	osteomyelitis	19	3.23 (1.36–7.68)	3.23 ( 7.86 )	rash pustular	15	2.6 (1.26–5.4)	2.6 ( 7.15 )
	wound infection	17	2.89 (1.2–6.96)	2.89 ( 6.11 )	enteritis infectious	5	12.15 (1.42-103.99)	12.14 ( 8.52 )
	abscess limb	17	2.53 (1.09–5.85)	2.53 ( 5.01 )	-	-	-
	salmonellosis	16	6.34 (1.85–21.76)	6.34 ( 11.36 )	-	-	-
	pelvic abscess	15	2.55 (1.04–6.25)	2.55 ( 4.48 )	-	-	-
	tuberculosis	14	5.55 (1.59–19.31)	5.55 ( 9.21 )	-	-	-
	oral herpes	13	3.86 (1.26–11.85)	3.86 ( 6.49 )	-	-	-
	pulmonary tuberculosis	11	3.27 (1.04–10.27)	3.27 ( 4.62 )	-	-	-
skin and subcutaneous tissue disorders	dermatitis psoriasiform	15	3.57 (1.3–9.81)	3.57 ( 6.92 )	rash pruritic	24	2.16 (1.25–3.75)	2.16 ( 7.91 )
	ingrowing nail	12	7.13 (1.6-31.87)	7.13 ( 9.04 )	skin disorder	15	5.21 (2.12–12.78)	5.2 ( 16.22 )
	pustular psoriasis	10	3.96 (1.09–14.4)	3.96 ( 5.11 )	dry skin	14	3.78 (1.64–8.74)	3.78 ( 11.2 )
	dermatitis atopic	8	9.51 (1.19–76.04)	9.51 ( 6.77 )	rash macular	14	3.09 (1.4–6.81)	3.09 ( 8.72 )
	-	-	-		night sweats	8	3.89 (1.27–11.89)	3.89 ( 6.6 )
	-	-	-		pain of skin	7	17.01 (2.09-138.26)	17 ( 13.18 )
	-	-	-		acne fulminans	5	12.15 (1.42-103.99)	12.14 ( 8.52 )
nervous system disorders	presyncope	17	3.37 (1.33–8.54)	3.37 ( 7.38 )	somnolence	23	2.24 (1.27–3.94)	2.23 ( 8.18 )
	demyelination	8	9.51 (1.19–76.04)	9.51 ( 6.77 )	hypersomnia	10	2.43 (1.01–5.84)	2.43 ( 4.2 )
	hyperaesthesia	8	4.75 (1.01–22.39)	4.75 ( 4.74 )	psychomoto rhyperactivity	5	12.15 (1.42-103.99)	12.14 ( 8.52 )
	-	-	-		monoplegia	4	9.72 (1.09–86.95)	9.72 ( 6.26 )
psychiatric disorders	suicide attempt	22	2.18 (1.08–4.4)	2.18 ( 4.95 )	depressed mood	24	5.84 (2.79–12.21)	5.83 ( 28.26 )
	-	-	-		fear	21	10.21 (3.85–27.09)	10.2 ( 33.53 )
	-	-	-		nervousness	20	6.95 (2.94–16.43)	6.94 ( 26.37 )
	-	-	-		anger	13	15.8 (3.56–70.02)	15.79 ( 24.02 )
	-	-	-		mood altered	11	2.97 (1.23–7.17)	2.97 ( 6.46 )
	-	-	-		panic attack	11	2.97 (1.23–7.17)	2.97 ( 6.46 )
	-	-	-		aggression	10	3.47 (1.32–9.12)	3.47 ( 7.24 )
	-	-	-		abnormal behaviour	9	3.12 (1.16–8.39)	3.12 ( 5.68 )
	-	-	-		depression suicidal	6	14.58 (1.75–121.1)	14.57 ( 10.84 )

3.4. Time to onset of infliximab and adalimumab associated AEs

Reports with inaccurate, missing, or unknown onset times were excluded from the analysis. Subsequently, we analyzed 3 990 IFX-related and 1 548 ADA-related AE cases that reported their onset times and end times, with detailed results presented in Fig. 3. As depicted in Fig. 3, the majority of IFX-related AEs occurred between 361 to 1080 days (N = 1152, 28.87%), followed by within 30 days (N = 704, 17.65%). Conversely, most of ADA-related AEs occurred within 90 days (N = 818, 52.84%), with a small proportion of AEs occurring beyond 1081 days. The median TTO for IFX-related AEs was 579 days (interquartile range [IQR], 159.25 to 1357 days), with the WSP test’s β and its 95% CI being 0.84 (0.82–0.86), indicating an early failure-type profile. The median TTO for ADA-related AEs, was significantly shorter at 79 days (interquartile range [IQR], 21 to 293 days), with the WSP test’s β and its 95% CI being 0.62 (0.60–0.65), indicating an early failure-type profile (see at Table 4).

Table 4 Weibull shape parameter test for AEs associated with IFX and ADA. CI:confidence interval.

Drug	Case reports	Median (d) (25%-75%)	Scale parameter: α (95%CI)	Shape parameter: β (95%CI)	Type
IFX	3990	579 (159.25–1357)	809.48 (778.01-840.96)	0.84 (0.82–0.86)	Early failure
ADA	1548	79 (21–293)	182.20 (166.81–197.60)	0.62 (0.60–0.65)	Early failure

As the incidence of pediatric-onset IBD is increasing worldwide²¹, the choice of therapeutic strategies in pediatrics presents a significant challenge to physicians. TNF-α inhibitors such as IFX and ADA are the mainstay treatment for severe or complicated pediatric IBD²². Therefore, clinician awareness of both common and serious AEs associated with IFX and ADA is important for quality improvement in paediatric care. We were using real-world public database to assess and compare the safety of two TNF-α inhibitor(IFX and ADA) in pediatric patients with IBD. The total annual number of reported AEs for IFX was higher than for ADA, possibly because IFX received approval for use in children earlier than ADA²³. Our report indicated that the proportion of male is slightly more than that of female in pediatric IBD, and adolescents constitute the demographic with the highest number of reported AEs, which might be related to the higher IBD incidence in this population²⁴. Given that IFX was delivered via intravenous infusion, the majority of its AEs were reported by healthcare providers. Conversely, ADA allowed for patient self-administration via subcutaneous injection, with the majority of AEs being self-reported. The most frequently reported regions for IFX and ADA were the same, primarily in Europe and the United States. IFX-related AEs had a higher incidence of serious outcomes, reaching 49.37%, compared with 28.03% for ADA-related AEs, with hospitalization being the predominant serious outcome reported. Prednisone, methotrexate, and azathioprine were identified as the most prevalent co-medications among patients receiving IFX and ADA treatments, which may potentially influence the incidence of AEs.

4.1. The prevalent signal AEs of infliximab and adalimumab

Our study found that the most frequently reported signal AEs of IFX and ADA were involved in the same SOC, mainly focusing on “injury, poisoning and procedural complications”, “gastrointestinal disorders”, “general disorders and administration site conditions”, “infections and infestations”, “investigations”. The majority of these AEs, such as IRs, ISRs, infections, and neurological disorders, were documented in the product label, which corroborates the reliability of this study.

IFX exhibited a higher incidence of signal AEs in “injury, poisoning and procedural complications” system, with infusion related reaction being the most frequently reported AEs. Furthermore, there were other eleven IR-related AEs among the top 30 reports, such as dyspnoea, anaphylactic reaction, flushing, hypersensitivity, chest discomfort and so on, which were consistent with literature reports²⁵. As IFX is administered intravenously, previous studies have demonstrated that there is a well-recognized risk of IRs associated with its use²⁵. IRs are usually classified into two main types: acute and delayed IRs. Acute IRs usually occur during or within 2 hours of infusion and include a variety of symptoms such as anaphylaxis, fever, chills, dyspnoea, headache, nausea, vomiting and rash. Among them, anaphylaxis is the most serious infusion reaction, potentially presenting with symptoms such as bronchospasm, laryngeal edema, hypotension, and shock. Immediate medical intervention is necessary. Delayed IRs usually occur within 24 hours to 14 days after infusion, with symptoms being relatively mild, such as fever, joint pain, myalgia, fatigue. These symptoms often resolve spontaneously, although medication may be required in some instances. While the exact pathogenesis of IRs is not yet understood, potential mechanisms encompass cytokine release syndrome, anaphylactic reactions, complement activation by anti-IFX antibodies, or degranulation of mast cells and basophils²⁵. The current research concludes that prophylactic premedication with corticosteroids or antihistamines before IFX infusions does not decrease the overall incidence of IRs, including acute IR, but it can reduce the symptoms of mild IR^26–28. Therefore, close monitoring of IRs is imperative when administering infliximab to pediatric IBD patients to ensure timely intervention in case of AEs occurred.

As ADA is administered via subcutaneous injection, literature reported that the most prevalent AE were injection site reactions (ISRs), encompassing a range of symptoms such as pain, erythema, pruritus, inflammation, rash, induration, and edema²⁹. Our study results were consistent with the literature. Among the top 30 reported AEs for adalimumab, there were 9 AEs being related to ISRs, which included injection site pain, hemorrhage, erythema, swelling, pruritus, bruising, papule formation, urticaria, and rash. Usually, the prevalence of ISRs have been reported as ranging from 12–37% in clinical trials³⁰. The majority of ISRs manifest within the initial month of therapy, with a typical duration of 3 to 5 days, and often resolve spontaneously without necessitating additional medical intervention²⁹. Typically, after adjusting the infusion rate and treating with paracetamol, antihistamines or corticosteroids, the symptoms improve substantially or resolve completely⁸. In addition, the utilization of citrate-free formulations and the implementation of a 29-gauge needle are associated with a reduction in injection site pain³¹.

4.2. Infections and infestations

TNF-α inhibitors, which can alter the immune response, potentially increase the risk of infectious complications or opportunistic infections. Safety evidence from adults with IBD indicates that TNF-α inhibitors were associated with an increased risk of serious infections³². Whereas, a research by Dulai et al. indicated that the risk of serious infections in pediatric patients with IBD on anti-TNF therapy was significantly lower than that observed in pediatric patients using steroids or in adults receiving anti-TNF treatment for IBD³³. Further research indicated TNF-α inhibitors were associated with a higher risk of serious infections in children and young adults with IBD compared to immunomodulators, and this risk varied depending on the individual TNF-α inhibitors and the route of administration³⁴. Nonetheless, a recent nationwide cohort study of 2817 paediatric patients with IBD from Denmark indicated that the utilization of TNF-α inhibitors did not significantly increase the risk of serious infections among these children³⁵.

In our study, among the 30 most common adverse events (AEs), the total number of infection-related signal AEs for both IFX and ADA was not high. Particularly for ADA, there were only 94 cases of infection-related reports, while IFX had more, with 644 cases. This was differed from a network meta-analysis of adult CD studied by Singh S and Murad MH et al, indirectly comparing IFX with ADA indicated that IFX presented a lower risk of infections than ADA³⁶. Given that serious infections are the most common reason for discontinuing treatment, clinicians must maintain heightened vigilance when prescribing the two TNF-α inhibitors for children with IBD. For IFX, we should pay attention to the top 3 most frequently reported infection-related adverse events (AEs): anal abscess [N = 150, ROR (95%CI) = 2.98 (2.21–4.02)], pneumonia [N = 137, ROR (95%CI) = 2.33 (1.75–3.11)], and cellulitis [N = 63, ROR (95%CI) = 3.26 (2.02–5.26)]. Additionally, the top 4 AEs with the highest signal strength also required attention, such as salmonellosis [N = 16, ROR (95%CI) = 6.34 (1.85–21.76)], lower respiratory tract infection [N = 31, ROR (95%CI) = 6.15 (2.56–14.73)], pilonidal disease [N = 20, ROR (95%CI) = 5.95 (2.03–17.4)], and tuberculosis [N = 14, ROR (95%CI) = 5.55 (1.59–19.31)]. Comparatively, for ADA, we should pay attention to the infection-related AEs related, including sinusitis[(N = 54, ROR(95%CI) = 2.35 (1.61–3.41)], rash pustular[(N = 15, ROR(95%CI) = 2.6 (1.26–5.4)], abscess intestinal[(N = 20, ROR(95%CI) = 2.11 (1.16–3.85)], enteritis infectious[(N = 5, ROR(95%CI) = 12.15 (1.42-103.99)].

An increasing number of studies found that except for anti-TNF and immunomodulating agents, disease activity, the use of corticosteroid, malnutrition, comorbidity, age and other factors are all potential confounders that may predispose to infection^{32, 37–39}. The same maybe true for the children's population. Recent studies have shown that children with IBD have an increased risk of serious infections requiring hospitalization compared to the general population, especially within the first year after diagnosis⁴⁰. Evidence of histologic inflammation in IBD has been pinpointed as an independent risk factor for serious infections, including sepsis, suggesting that attaining histologic remission could mitigate the risk of infections in IBD patients⁴¹. Meanwhile, a recently retrospective cohort study of 980 patients with IBD from Sweden indicated that the incidence rate of serious infection did not increase with anti-TNF therapy and seemed to decrease more than 1 year after initiation of anti-TNF treatment⁴². Consequently, our primary concern should be the management of inflammatory diseases, not the potential side effects associated with TNF inhibitors. Nonetheless, we must remain alert to the possibility of infections and ensure ongoing surveillance.

4.3. Neoplasms, benign, malignant, and unspecified

IBD, characterized as a chronic inflammatory disorder, is generally associated with a greater risk of cancer. In pediatric IBD, the most commonly reported malignancies are colorectal cancers, cholangiocarcinomas, and lymphomas⁵. In our research, although we did not detect any malignancy-related AE signals for both IFX and ADA, we found the top 3 most reported AEs in neoplasms system were related to lymphoma. For IFX, we should pay attention to B-cell lymphoma (8 cases), hepatosplenic T-cell lymphoma (7 cases) and leukemia (7 cases). In contrast, Hodgkin's disease (7 cases), hepatosplenic T-cell lymphoma (5 cases) and lymphoma (4 cases) were the top 3 AEs for ADA, which should attract our attention.

To date, the association between TNF-α inhibitors and the risk of malignancy remains controversial. A early systematic review indicated that there was no increased risk of lymphoma in children with IBD treated with anti-TNF drugs, as compared to those receiving other IBD treatments or to adults who received anti-TNF therapy³³. Moreover, a study of 5,776 pediatric patients with IBD found that IFX exposure was not associated with a higher risk of developing malignancy, while thiopurine exposure was an important factor preceding the onset of malignancy⁴³. In contrast, a larger-scale analysis of adult IBD has shown that anti-TNF monotherapy may be associated with an increased risk of lymphoma⁴⁴. Additionally, in 2021, a case series review has revealed that five pediatric IBD patients, treated only with IFX and not exposed to thiopurines, were subsequently diagnosed with lymphoma⁴⁵. Concurrently, a recently cohort study of 10,777 pediatric IBD patients found that the overall incidence of lymphoma was low, and the risk of lymphoma was more associated with exposure to thiopurines, rather than with anti-TNF monotherapy⁴⁶. Even though the association between the use of TNF-α inhibitors and malignancy risk lacks robust evidence, a cohort study of pediatric IBD patients from Swedish indicated that childhood-onset IBD patients have a persistently higher risk of developing various cancers, regardless of exposure to medications⁴⁷. Consequently, necessitating intensified clinical monitoring for IBD patients who received TNF-α inhibitors.

4.4. Skin and subcutaneous tissue disorders

Recent literature has reported that paradoxical psoriasiform eruptions induced by TNF inhibitors have been observed in children treated with TNF inhibitors for any indication ¹³. Our research indicated a significant association between IFX and an increased rate of psoriasis cases [N = 191, ROR (95%CI) = 2.19 (1.72–2.78)]. Conversely, ADA was linked to fewer reported cases of psoriasis [N = 68, ROR (95%CI) = 0.73 (0.55–0.95)] and did not trigger the AE signal. Our finding was consistent with Cyrenne's research, indicating that IFX is associated with the highest likelihood of inducing psoriasis⁴⁸. In contrast, a meta-analysis found that patients treated with ADA have a higher statistical risk for the development of psoriasis or psoriasiform skin conditions. However, there was no plausible mechanistic evidence to explicitly explain the difference between different types of anti-TNF-associated psoriasis or psoriasiform rash⁴⁹. Usually, the incidence of psoriasiform dermatitis in the pediatric IBD population receiving TNF-α inhibitors was generally reported to be between 5.8% and 10.5%⁵⁰. The other higher statistical risk for the development of psoriasis or psoriasiform skin conditions has been associated with females, patients who initiate anti-TNF treatment at a younger age, smokers, those with ileocolonic Crohn's disease⁴⁹. Generally, the paradoxical psoriasis in these patients is typically associated with a state of disease inactivity or mild activity⁵⁰. For most cases, a topical approach is adequate for treatment, with only a minority of patients requiring discontinuation of anti-TNF therapy⁵¹. In addition, ustekinumab has demonstrated efficacy in managing psoriasis and psoriasiform alopecia triggered by anti-TNF therapies^{51, 52}.

We also found significant signals associated with a lupus-like syndrome [N = 39, ROR (95%CI) = 4.64 (2.32–9.3)] for IFX, whereas ADA did not trigger such signal. These findings were consistent with a meta-analysis by Dai C et al, indicating a higher incidence of lupus symptoms in patients treated with IFX compared to those treated with other TNF-α inhibitors⁵³. Moreover, several risk factors for lupus-like syndrome were also closely related to the type of disease (with more frequently in CD than in UC patients), older age, being female, family history of SLE, and the presence of elevated levels of anti-dsDNA antibodies prior to anti-TNF-α treatment⁵⁴. Therefore, increasing clinical surveillance for skin-related symptoms in pediatric IBD patients treated with TNF-α inhibitors is essential.

4.5. Nervous system disorders

Following the introduction of TNF-α inhibitors, previous studies have reported associations with neurological disorders, particularly CNS demyelination, and have suggested that the peripheral nervous system may also be involved^55–57. In our study, we detected three signal AEs related to CNS disorders for IFX, which were presyncope [(N = 17, ROR(95%CI) = 3.37 (1.33–8.54)], demyelination [N = 8, ROR(95%CI) = 9.51 (1.19–76.04)], and hyperaesthesia [N = 8, ROR(95%CI) = 4.75 (1.01–22.39)]. In contrast, the signal AEs for ADA included loss of consciousness, hypoaesthesia, somnolence, hypersomnia, psychomotor hyperactivity, and monoplegia, with a strong signal of psychomotor hyperactivity [N = 4, ROR(95%CI) = 12.15 (1.42-103.99)]. Among these neurological disorders, demyelination draws great attention. The true prevalence of demyelinating diseases in patients treated with TNF-α inhibitors was not yet known due to conflicting data, but it appeard to be very low⁵⁸. Nevertheless, close monitoring of neurological disorders, especially demyelination, is required when children use TNF-α inhibitors.

4.6. Psychiatric disorders

In the psychiatric disorders, our research identified that suicide attempt was a significant signal AE for patients treated with IFX. This finding aligned with the results of a recent retrospective observational study, which confirmed that IFX treatment was associated with an increased risk of psychiatric AEs⁵⁹. Comparatively, ADA has shown a greater number of AE signals in psychiatric disorders system, including anxiety, insomnia, depressed mood, nervousness, and so on. Among them, suicidal depression being of particular concern due to its high ROR value of 14.58. A systematic review of drug-induced suicide revealed that both IFX and ADA were associated with a risk of suicide, which was not mentioned on the approved label⁶⁰. Indeed, given the increased prevalence of depression and anxiety in individuals with IBD, the American College of Gastroenterology advises that all such patients undergo psychiatric screening⁶¹. Consequently, physicians must remain alert to the possibility of psychiatric disorders, especially suicidal behaviors, in pediatric IBD patients receiving anti-TNF therapy.

4.7. Other unexpected AEs

In our study, we found some unexpected AEs for IFX which were not list in product label, such as weight increased [(N = 119, ROR(95%CI) = 2.14 (1.24–3.7))], fall[(N = 57, ROR(95%CI) = 2.51 (1.59–3.97))], and nephrolithiasis [(N = 36, ROR(95%CI) = 2.29 (1.68–3.11)]. Indeed, weight increased has been reported in numerous literatures in adults⁶². A study on pediatric IBD also indicated that excess weight gain was a side effect of anti-TNF treatment⁶³. The reason for weight gain may be related to the control of inflammation caused by anti-TNF-α treatment and the subsequent improvement in appetite. Regarding nephrolithiasis, previous studies suggested it was a rare but notable extra-intestinal complication in children with IBD⁶⁴. Nevertheless, vigilant observation of these side effect is essential.

4.8. Time to onset of infliximab and adalimumab associated AEs

We found that the median TTO of ADA-related AEs was shorter than that of IFX-related AEs (79 vs. 398 days). Moreover, the majority of ADA-related AEs occurred within 90 days (N = 818, 52.84%). This may be due to the fact that ADA was self-administered via subcutaneous injection, and the most common AEs were related to ISRs. In addition, the number of ADA-related AEs in the 'general disorders and administration site conditions' SOC was significantly higher than that of IFX-related AEs, with 2,540 versus 986 reports, respectively. According to our data, there is a slow but steady decrease in the risk of AEs happening over an extended period for both IFX and ADA. For ADA, it's important to take note that the majority of AEs were seen shortly after administration, typically within the first three months. As for IFX, it has been observed that a significant 61.47% of AEs occurred after the first year of treatment.

4.9. Limitations

Our research has several limitations. First, the FAERS database is derived from spontaneous reporting, and the sources are relatively complex, some data lack much information, and some AE reports may be arbitrary and biased, potentially leading to reporting bias and underreporting. Second, although ROR and PRR methods are frequently utilized and easily understood data mining techniques in pharmacovigilance, they may inevitably generate some false positive signals. Third, data mining techniques cannot confirm the causal relationship between the target drug and the target AE. Furthermore, incidence cannot be accurately calculated using spontaneous reporting data. Additionally, controlling for confounding factors is challenging, such as a patient's clinical condition, comorbidities, concomitant medications, and other potential factors, all of which can influence the occurrence of AEs. Despite these limitations, our study thoroughly documented and assessed the safety of post-marketing use of IFX and ADA for pediatric IBD patients, based on the largest sample from a real-world database so far.

In summary, we conducted a pharmacovigilance analysis to assess the safety of IFX and ADA in pediatric IBD using the FAERS database. The most commonly reported AEs for IFX were related to infusion reactions, whereas the predominant AEs for ADA involved injection site reactions. Focus should be placed on AEs with serious outcome, such as infectious diseases, oncological diseases (lymphomas), central nervous system diseases (demyelination), and mental disorders. Furthermore, other unexpected AEs, such as increased weight and the occurrence of paradoxical psoriasis for IFX, and the risk of suicide for both IFX and ADA, should be taken into account as they were not indicated on the product label. Consequently, the real-world analysis of AEs in pediatric IBD patients treated with TNF-α inhibitors highlighted the necessity for more rigorous clinical monitoring and the prompt implementation of intervention measures upon the occurrence of AEs, thereby reducing the risk of negative outcomes.

ADA

adalimumab

adverse event

AEs

adverse events

anti-TNF

anti-Tumour necrosis factor

Canada

confidence interval

CNS

central nervous system

Germany

FAERS

Food and Drug Administration Adverse Event Reporting System

FDA

Food and Drug Administration

France

the United Kingdom

IBD

inflammatory bowel disease

IFX

infliximab

IRs

infusion reactions

ISRs

injection site reactions

IQR

interquartile range

MedDRA

Medical Dictionary for Regulatory Activities

primary suspect

preferred term

ROR

reporting odds ratio

SOC

system organ classes

TNF-α

Tumor necrosis factor-α

TTO

Time-to-onset

United States

WPS

Weibull shape parameter.

Acknowledgments

We express our gratitude to the FDA in the United States for supplying a complimentary data source for our study.

Funding statement

This paper was not funded.

Conflict of interest

The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

Author contributions

Yanhong Deng and Shengying Shi designed the research, analyzed the data, and wrote the manuscript draft; Senling Feng, Xiangping Tan, and Jinjin Yin contributed to the data collection and analysis; Yinling Wang, prepared the tables and figures; Shaozhi Liu and Yuanmei Gao directed the research, reviewed and edited the manuscript.

Ethics approval

Anonymized data were collected from a publicly available database and did not require approval from the ethics committee.

Data availability statement

The data are available in the FDA Adverse Event Reporting System (FAERS): https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

Supplementary material

The Supplementary Material for this article can be found online at:

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No competing interests reported.

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Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a real-world analysis from FAERS database

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Abstract

Figures

1. Introduction

2. Methods

2.1. Data sources and preprocess

2.2. Statistical analysis

2.3 Time to onset analysis

3. Results

3.1. Overall events and general characteristics

3.2. Disproportionality analysis

3.2.1 SOCs of AE signals

3.2.2 The most common signal AEs

3.3. The important AE signals of infliximab and adalimumab

3.4. Time to onset of infliximab and adalimumab associated AEs

4. Discussion

4.1. The prevalent signal AEs of infliximab and adalimumab

4.2. Infections and infestations

4.3. Neoplasms, benign, malignant, and unspecified

4.4. Skin and subcutaneous tissue disorders

4.5. Nervous system disorders

4.6. Psychiatric disorders

4.7. Other unexpected AEs

4.8. Time to onset of infliximab and adalimumab associated AEs

4.9. Limitations

5. Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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