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

Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a real-world analysis from FAERS database | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a real-world analysis from FAERS database Yanhong DENG, Shengying Shi, Senling Feng, Xiangping Tan, Yinling Wang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5171055/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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 Figures Figure 1 Figure 2 Figure 3 1. Introduction 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 decades 1 . 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 treatment 5 . 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 concerns 14 . 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. Methods 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 same 15 . 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 perspective 15 . 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 distribution 20 . 3. Results 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(X 2 ) PT N ROR(95%Cl) PRR(X 2 ) 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(X 2 ) PT N ROR (95%Cl) PRR(X 2 ) 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 4. Discussion As the incidence of pediatric-onset IBD is increasing worldwide 21 , 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 IBD 22 . 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 ADA 23 . 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 population 24 . 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 reports 25 . As IFX is administered intravenously, previous studies have demonstrated that there is a well-recognized risk of IRs associated with its use 25 . 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 basophils 25 . 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 edema 29 . 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 trials 30 . 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 intervention 29 . Typically, after adjusting the infusion rate and treating with paracetamol, antihistamines or corticosteroids, the symptoms improve substantially or resolve completely 8 . In addition, the utilization of citrate-free formulations and the implementation of a 29-gauge needle are associated with a reduction in injection site pain 31 . 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 infections 32 . 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 IBD 33 . 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 administration 34 . 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 children 35 . 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 ADA 36 . 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 diagnosis 40 . 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 patients 41 . 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 treatment 42 . 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 lymphomas 5 . 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 therapy 33 . 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 malignancy 43 . In contrast, a larger-scale analysis of adult IBD has shown that anti-TNF monotherapy may be associated with an increased risk of lymphoma 44 . 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 lymphoma 45 . 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 monotherapy 46 . 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 medications 47 . 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 psoriasis 48 . 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 rash 49 . 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 disease 49 . Generally, the paradoxical psoriasis in these patients is typically associated with a state of disease inactivity or mild activity 50 . For most cases, a topical approach is adequate for treatment, with only a minority of patients requiring discontinuation of anti-TNF therapy 51 . 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 inhibitors 53 . 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 treatment 54 . 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 low 58 . 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 AEs 59 . 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 label 60 . 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 screening 61 . 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 adults 62 . A study on pediatric IBD also indicated that excess weight gain was a side effect of anti-TNF treatment 63 . 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 IBD 64 . 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. 5. Conclusions 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. Abbreviations ADA adalimumab AE adverse event AEs adverse events anti-TNF anti-Tumour necrosis factor CA Canada CI confidence interval CNS central nervous system DE Germany FAERS Food and Drug Administration Adverse Event Reporting System FDA Food and Drug Administration FR France GB 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 PS primary suspect PT preferred term ROR reporting odds ratio SOC system organ classes TNF-α Tumor necrosis factor-α TTO Time-to-onset US United States WPS Weibull shape parameter. Declarations 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: References Kuenzig, M. E. et al. Twenty-first century trends in the global epidemiology of pediatric-onset inflammatory bowel disease: systematic review. Gastroenterology, 162 (4), 1147–1159. e4 (2022). Pigneur, B. et al. Natural history of Crohn’s disease: comparison between childhood- and adult-onset disease. Inflamm. Bowel Dis. 16 (6), 953–961 (2010). Chouliaras, G. et al. Disease impact on the quality of life of children with inflammatory bowel disease. World J. Gastroenterol. 23 (6), 1067–1075 (2017). Fumery, M. et al. Long-term outcome of pediatric-onset Crohn’s disease: a population-based cohort study. Dig. Liver Dis. 51 (4), 496–502 (2019). Aardoom, M. A., Veereman, G. & de Ridder, L. 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Bowel Dis. 26 (1), 125–131 (2020). Haas, L. et al. Biologic Agents Are Associated with Excessive Weight Gain in Children with Inflammatory Bowel Disease. Dig. Dis. Sci. 62 (11), 3110–3116 (2017). Torio, M. et al. Nephrolithiasis as an extra-intestinal presentation of pediatric inflammatory bowel disease unclassified. J. Crohns Colitis . 4 (6), 674–678 (2010). Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterials.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5171055","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":365961885,"identity":"606f8f5f-65f3-4d1a-b1a4-4b6158512b1a","order_by":0,"name":"Yanhong DENG","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yanhong","middleName":"","lastName":"DENG","suffix":""},{"id":365961886,"identity":"4c94a5b6-8a9a-41c6-bd65-4a5701abfb79","order_by":1,"name":"Shengying Shi","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shengying","middleName":"","lastName":"Shi","suffix":""},{"id":365961887,"identity":"e5fddb86-324f-4bc8-a28f-556298947c4a","order_by":2,"name":"Senling Feng","email":"","orcid":"","institution":"Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Senling","middleName":"","lastName":"Feng","suffix":""},{"id":365961888,"identity":"788d55a9-bc53-4e97-9ab7-c3f4183c0b8e","order_by":3,"name":"Xiangping Tan","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiangping","middleName":"","lastName":"Tan","suffix":""},{"id":365961889,"identity":"6936f188-7b8e-4dfe-b86b-1b06e0848bfd","order_by":4,"name":"Yinling Wang","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yinling","middleName":"","lastName":"Wang","suffix":""},{"id":365961890,"identity":"a4a793ef-429a-4e9e-aa61-dab999dc3115","order_by":5,"name":"Jinjin Yin","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jinjin","middleName":"","lastName":"Yin","suffix":""},{"id":365961891,"identity":"749f1dd5-5e36-46e8-b3b2-34ac9c34c3ee","order_by":6,"name":"Yuanmei Gao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYFADZuYDBz5UkKaFLfHgjDOkWcNjfJi3hQh18u6Hj0nz1NyJ5mfn+XCAt4FBnl/sAH4thmfS0qR5jj3LndnMu+GA5A4Gw5mzEwhoacgxk+ZhO5y74TBQi+EZhgSD24S09L8Bavl3OHf/YZ4HBxLbiNAiLwG0hbcNaAszD8OBg8RoMZB4lmw5t+9w7ozDbAYHG85IEPaLfH/ywRtvvh3O7e8//PjznwobeX5pQrYcYGCRQOJL4FSJsKWBgfkDYWWjYBSMglEwogEA40xJXstjGFIAAAAASUVORK5CYII=","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yuanmei","middleName":"","lastName":"Gao","suffix":""},{"id":365961892,"identity":"aa0d1bb3-2e04-43f0-961f-ff4864720315","order_by":7,"name":"Shaozhi Liu","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shaozhi","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-09-28 14:53:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5171055/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5171055/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67273545,"identity":"c3d086e7-a670-451f-8024-53955c8fb7a9","added_by":"auto","created_at":"2024-10-23 07:58:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":108447,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of data processing in our study. A detailed description of the selection process of adverse events for IFX and ADA in pediatric inflammatory bowel diseases from the FAERS database.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5171055/v1/b292c097ad7d35ce7a33e8db.png"},{"id":67271971,"identity":"96b3579e-4199-4e08-a954-e215b463a17f","added_by":"auto","created_at":"2024-10-23 07:42:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":18983,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of SOC with IFX-related and ADA-related AEs.\u003c/p\u003e","description":"","filename":"Onlinedrawingimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5171055/v1/6fd68069fbb343a9b574a84b.png"},{"id":67272410,"identity":"0518d1a1-7444-498c-885b-d0c6e1f38762","added_by":"auto","created_at":"2024-10-23 07:50:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":37317,"visible":true,"origin":"","legend":"\u003cp\u003eThe TTO of IFX-related (A) and ADA-related (B) AEs.\u003c/p\u003e","description":"","filename":"Onlinedrawingimage23.png","url":"https://assets-eu.researchsquare.com/files/rs-5171055/v1/951de06a4cffab913fa1daa5.png"},{"id":73937908,"identity":"9bf156c2-33c5-44c0-aaa6-f9a21f86d76c","added_by":"auto","created_at":"2025-01-16 07:24:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1671301,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5171055/v1/78bced7e-05da-4a80-a23a-2c696cc2497b.pdf"},{"id":67271969,"identity":"e0c8e080-3a23-4648-9c5d-a2e35dd83d9d","added_by":"auto","created_at":"2024-10-23 07:42:58","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":53037,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5171055/v1/90c0a56015aff024ae1afc72.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a real-world analysis from FAERS database","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe 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 decades\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. 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\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. 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 treatment\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTNF-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\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Some above-mentioned serious AEs have also been reported in children\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. What more important, the adverse reactions of paradoxical psoriasiform in children with TNF-α inhibitors have attracted widespread attention\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e \u003cp\u003eThe 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 concerns\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Data sources and preprocess\u003c/h2\u003e \u003cp\u003eThe 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 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html\u003c/span\u003e\u003cspan address=\"https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). 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 same\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Statistical analysis\u003c/h2\u003e \u003cp\u003eThe 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 perspective\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. 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\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.. A positive drug signal was indicated when both the ROR and PRR values exceeded the established cut-off values (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). A higher ROR and PRR values denote an intensified signal, indicating a greater correlation between the target drug and AEs\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. All data operations and statistical analyses were conducted using R software (version 4.3.2) and Microsoft Excel.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Time to onset analysis\u003c/h2\u003e \u003cp\u003eTime 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 distribution\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Overall events and general characteristics\u003c/h2\u003e \u003cp\u003eA 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.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The comparison of clinical characteristics between IFX and ADA was presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. 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.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of IFX and ADA in pediatric inflammatory bowel diseases from the FAERS database.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003einfliximab\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;10509)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eadalimumab\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;5446)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5083 (50.75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2826 (51.89%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5333 (48.37%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2524 (46.35%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 (1.14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfant group (0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e223 (2.12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (0.62%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreschool group (2\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e322 (3.06%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90 (1.65%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChildren group (6\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2570 (24.46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1202 (22.07%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdolescent group (12\u0026ndash;18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7394 (70.36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4120 (75.65%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eReporter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysician\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4379 (41.67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e918 (16.86%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePharmacist\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e251 (2.39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e104 (1.91%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHealth Professional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2283 (21.72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e282 (5.18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther Health Professional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1895 (18.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e300 (5.51%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsumer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1681 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3788 (69.56%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (0.17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (0.99%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eReporter countries(Top5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3593 (34.19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2287 (41.99%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e257 (2.45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e555 (10.19%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4445 (42.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e247 (4.54%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e370 (3.52%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82 (1.51%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e204 (1.94%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 (1.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eOutcome of AEs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital Anomaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (0.11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.04%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (0.62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (0.62%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (0.24%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4917 (46.79%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1433 (26.31%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife-threatening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e216 (2.06%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (0.86%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eother serious outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4659 (44.33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e770 (14.14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e591 (5.72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3145 (57.75%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant Medications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eprednisone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1108, 10.54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(346, 6.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emethotrexate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(1094, 10.41%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(407, 7.47%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eazathioprine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(836, 4.39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(239, 4.39%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Disproportionality analysis\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e3.2.1 SOCs of AE signals\u003c/h2\u003e \u003cp\u003eThe 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.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Supplementary Table S2 ). The top 5 common SOCs of IFX and ADA were identical, namely\u0026ldquo;injury, poisoning and procedural complications\u0026rdquo;, \u0026ldquo;gastrointestinal disorders\u0026rdquo;, \u0026ldquo;general disorders and administration site conditions\u0026rdquo;, \u0026ldquo;infections and infestations\u0026rdquo;, \u0026ldquo;investigations\u0026rdquo;. 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 \u0026ldquo;product issues\u0026rdquo;, \u0026ldquo;psychiatric disorders\u0026rdquo;, and \u0026ldquo;musculoskeletal and connective tissue disorders\u0026rdquo;. In contrast to ADA, IFX exhibited a higher incidence of AEs in \u0026ldquo;injury, poisoning and procedural complications\u0026rdquo;, \u0026ldquo;gastrointestinal disorders\u0026rdquo;, \u0026ldquo;investigations\u0026rdquo;, \u0026ldquo;infections and infestations\u0026rdquo;, \u0026ldquo;respiratory, thoracic and mediastinal disorders\u0026rdquo;, \u0026ldquo;immune system disorders\u0026rdquo;, \u0026ldquo;vascular disorders\u0026rdquo; and \u0026ldquo;cardiac disorders\u0026rdquo;.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e3.2.2 The most common signal AEs\u003c/h2\u003e \u003cp\u003eAt 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 \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. For IFX, infusion related reaction [N\u0026thinsp;=\u0026thinsp;823, ROR (95%CI)\u0026thinsp;=\u0026thinsp;10.8 (8.71\u0026ndash;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.\u003c/p\u003e \u003cp\u003eFor 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.\u003c/p\u003e \u003cp\u003eAfter 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.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe top 30 commonly reported AE signals of IFX and ADA in pediatric IBD.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003einfliximab\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c8\" namest=\"c5\"\u003e \u003cp\u003eadalimumab\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eROR(95%Cl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePRR(X\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eROR(95%Cl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePRR(X\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003einfusion related reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e823\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.8 (8.71\u0026ndash;13.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.52 ( 730.38 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einjection site pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e933\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e77.03 (53.84-110.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e73.1 ( 2167.48 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehaematochezia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e767\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2 (1.95\u0026ndash;2.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.17 ( 173.75 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einjection site haemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e94.9 (48.95-183.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e93.11 ( 803.83 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edyspnoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e313\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.2 (2.59\u0026ndash;3.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.18 ( 128.11 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einjection site erythema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e127.77 (47.5-343.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e126.31 ( 489.55 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efrequent bowel movements\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.17 (1.8\u0026ndash;2.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.16 ( 67.41 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eabdominal pain upper\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e166\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.12 (2.48\u0026ndash;3.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.1 ( 104.32 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epsoriasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e191\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.19 (1.72\u0026ndash;2.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.18 ( 43.35 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einjection site swelling\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25.1 (13.51\u0026ndash;46.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e24.95 ( 230.94 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eanaphylactic reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.44 (3.23\u0026ndash;6.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.41 ( 102.32 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einjection site pruritus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e29.91 (14.55\u0026ndash;61.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29.75 ( 205.88 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eanal abscess\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.98 (2.21\u0026ndash;4.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.97 ( 56.23 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eintestinal obstruction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.52 (1.89\u0026ndash;3.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.51 ( 42.51 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.33 (1.75\u0026ndash;3.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.33 ( 35.13 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eanxiety\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.14 (1.62\u0026ndash;2.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.13 ( 30.25 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eerythema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.09 (1.55\u0026ndash;2.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.08 ( 24.85 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eoropharyngeal pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.41 (1.81\u0026ndash;3.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.4 ( 38.41 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eweight increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.29 (1.68\u0026ndash;3.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.28 ( 29.41 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einjection site bruising\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e54.31 (19.94-147.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e54.04 ( 199.59 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eflushing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.02 (2.71\u0026ndash;5.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.01 ( 55.92 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einjection site papule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e200.08 (27.85-1437.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e199.18 ( 195.07 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehypersensitivity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.09 (1.51\u0026ndash;2.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.08 ( 20.55 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003egastrointestinal inflammation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.38 (1.75\u0026ndash;3.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.37 ( 32.14 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003echest discomfort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.99 (2.02\u0026ndash;4.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.99 ( 33.19 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einjection site reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e31.3 (13.64\u0026ndash;71.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e31.17 ( 162.77 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003etachycardia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.62 (2.32\u0026ndash;5.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.61 ( 36.99 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einjection site urticaria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e87.79 (21.54-357.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e87.44 ( 166.49 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eoxygen saturation decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.82 (3.59\u0026ndash;12.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.81 ( 46.44 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehaemoglobin decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.29 (1.64\u0026ndash;3.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.29 ( 24.74 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecellulitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.26 (2.02\u0026ndash;5.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.26 ( 26.36 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003epain in extremity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.05 (1.47\u0026ndash;2.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.05 ( 18.61 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehypotension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.78 (1.77\u0026ndash;4.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.77 ( 21.46 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esinusitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.35 (1.61\u0026ndash;3.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.34 ( 21.18 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.51 (1.59\u0026ndash;3.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.51 ( 16.65 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003efeeling abnormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.12 (2.05\u0026ndash;4.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.11 ( 31.49 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eherpes zoster\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.91 (1.73\u0026ndash;4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.91 ( 17.85 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einflammation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.09 (1.43\u0026ndash;3.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.09 ( 14.96 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eanaphylactic shock\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.52 (4.07\u0026ndash;22.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.51 ( 40.63 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einsomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.81 (1.83\u0026ndash;4.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.8 ( 24.26 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emucous stools\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.38 (1.44\u0026ndash;3.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.38 ( 12.24 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003efear of injection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21.42 (8.49\u0026ndash;54.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e21.37 ( 87.27 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ethroat tightness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.08 (1.76\u0026ndash;5.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.08 ( 17.2 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eloss of consciousness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.35 (3.16\u0026ndash;9.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.34 ( 48.6 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eperirectal abscess\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.84 (2.06\u0026ndash;7.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.84 ( 20.86 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einflammatory marker increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.65 (3.68\u0026ndash;12.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6.64 ( 52.65 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esubcutaneous abscess\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.75 (2.01-7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.75 ( 19.9 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehypophagia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.55 (5.11\u0026ndash;21.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10.53 ( 63.09 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eblood pressure decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.73 (1.54\u0026ndash;4.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.73 ( 12.95 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einjection site rash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15.82 (6.7-37.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15.79 ( 72.08 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elupus-like syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.64 (2.32\u0026ndash;9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.63 ( 22.71 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003erhinorrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.96 (1.86\u0026ndash;4.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.96 ( 22.84 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enephrolithiasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.14 (1.24\u0026ndash;3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.14 ( 7.81 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enasal congestion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.08 (1.91\u0026ndash;4.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.08 ( 23.53 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecyanosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.63 (2.22\u0026ndash;9.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.62 ( 20.33 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehypoaesthesia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.5 (1.56\u0026ndash;4.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.5 ( 15.54 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elower respiratory tract infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.15 (2.56\u0026ndash;14.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.14 ( 21.64 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eblood iron decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.58 (1.59\u0026ndash;4.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.58 ( 15.98 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epouchitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.38 ( 1.28\u0026ndash;4.42 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.38 ( 7.98 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003erash papular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.77 (4.74\u0026ndash;24.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10.76 ( 50.57 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3. The important AE signals of infliximab and adalimumab\u003c/h2\u003e \u003cp\u003eOther 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\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e ).\u003c/p\u003e \u003cp\u003eIn 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\u0026thinsp;=\u0026thinsp;8, ROR(95%CI)\u0026thinsp;=\u0026thinsp;9.51 (1.19\u0026ndash;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\u0026thinsp;=\u0026thinsp;8, ROR(95%CI)\u0026thinsp;=\u0026thinsp;3.17 (0.84\u0026ndash;11.95)], hepatosplenic T-cell lymphoma [(N\u0026thinsp;=\u0026thinsp;7, ROR(95%CI)\u0026thinsp;=\u0026thinsp;0.38 (0.16\u0026ndash;0.88)], and leukemia [(N\u0026thinsp;=\u0026thinsp;7, ROR(95%CI)\u0026thinsp;=\u0026thinsp;0.69 (0.27\u0026ndash;1.76)]. In contrast, for ADA, the top 3 reported AEs were Hodgkin's disease[(N\u0026thinsp;=\u0026thinsp;8, ROR(95%CI)\u0026thinsp;=\u0026thinsp;2.43 (0.91\u0026ndash;6.47)], hepatosplenic T-cell lymphoma [(N\u0026thinsp;=\u0026thinsp;5, ROR(95%CI)\u0026thinsp;=\u0026thinsp;0.51 (0.19\u0026ndash;1.33)], and unspecified lymphoma [(N\u0026thinsp;=\u0026thinsp;4, ROR(95%CI)\u0026thinsp;=\u0026thinsp;0.65 (0.21\u0026ndash;1.95)].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe important AE signals of IFX and ADA which were not in the top 30 AEs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003einfliximab\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eadalimumab\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOC system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR (95%Cl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRR(X\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eROR (95%Cl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePRR(X\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"8\" rowspan=\"9\"\u003e \u003cp\u003einfections and infestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epilonidal disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.95 (2.03\u0026ndash;17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.94 ( 13.71 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eabscess intestinal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.11 (1.16\u0026ndash;3.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.11 ( 6.27 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eosteomyelitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.23 (1.36\u0026ndash;7.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.23 ( 7.86 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003erash pustular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.6 (1.26\u0026ndash;5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.6 ( 7.15 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ewound infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.89 (1.2\u0026ndash;6.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.89 ( 6.11 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eenteritis infectious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.15 (1.42-103.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.14 ( 8.52 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eabscess limb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.53 (1.09\u0026ndash;5.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.53 ( 5.01 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003esalmonellosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.34 (1.85\u0026ndash;21.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.34 ( 11.36 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epelvic abscess\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.55 (1.04\u0026ndash;6.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.55 ( 4.48 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etuberculosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.55 (1.59\u0026ndash;19.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.55 ( 9.21 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eoral herpes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.86 (1.26\u0026ndash;11.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.86 ( 6.49 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epulmonary tuberculosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.27 (1.04\u0026ndash;10.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.27 ( 4.62 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003eskin and subcutaneous tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003edermatitis psoriasiform\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.57 (1.3\u0026ndash;9.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.57 ( 6.92 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003erash pruritic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.16 (1.25\u0026ndash;3.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.16 ( 7.91 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eingrowing nail\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.13 (1.6-31.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.13 ( 9.04 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eskin disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.21 (2.12\u0026ndash;12.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5.2 ( 16.22 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epustular psoriasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.96 (1.09\u0026ndash;14.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.96 ( 5.11 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003edry skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.78 (1.64\u0026ndash;8.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.78 ( 11.2 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003edermatitis atopic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.51 (1.19\u0026ndash;76.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.51 ( 6.77 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003erash macular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.09 (1.4\u0026ndash;6.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.09 ( 8.72 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003enight sweats\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.89 (1.27\u0026ndash;11.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.89 ( 6.6 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003epain of skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17.01 (2.09-138.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e17 ( 13.18 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eacne fulminans\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.15 (1.42-103.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.14 ( 8.52 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003enervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epresyncope\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.37 (1.33\u0026ndash;8.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.37 ( 7.38 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003esomnolence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.24 (1.27\u0026ndash;3.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.23 ( 8.18 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003edemyelination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.51 (1.19\u0026ndash;76.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.51 ( 6.77 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ehypersomnia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.43 (1.01\u0026ndash;5.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.43 ( 4.2 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ehyperaesthesia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.75 (1.01\u0026ndash;22.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.75 ( 4.74 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003epsychomoto rhyperactivity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.15 (1.42-103.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12.14 ( 8.52 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003emonoplegia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9.72 (1.09\u0026ndash;86.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9.72 ( 6.26 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"8\" rowspan=\"9\"\u003e \u003cp\u003epsychiatric disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003esuicide attempt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.18 (1.08\u0026ndash;4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.18 ( 4.95 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003edepressed mood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.84 (2.79\u0026ndash;12.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5.83 ( 28.26 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003efear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10.21 (3.85\u0026ndash;27.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10.2 ( 33.53 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003enervousness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6.95 (2.94\u0026ndash;16.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.94 ( 26.37 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eanger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15.8 (3.56\u0026ndash;70.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e15.79 ( 24.02 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003emood altered\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.97 (1.23\u0026ndash;7.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.97 ( 6.46 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003epanic attack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.97 (1.23\u0026ndash;7.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.97 ( 6.46 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eaggression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.47 (1.32\u0026ndash;9.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.47 ( 7.24 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eabnormal behaviour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.12 (1.16\u0026ndash;8.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.12 ( 5.68 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003edepression suicidal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14.58 (1.75\u0026ndash;121.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14.57 ( 10.84 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Time to onset of infliximab and adalimumab associated AEs\u003c/h2\u003e \u003cp\u003eReports 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.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. As depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the majority of IFX-related AEs occurred between 361 to 1080 days (N\u0026thinsp;=\u0026thinsp;1152, 28.87%), followed by within 30 days (N\u0026thinsp;=\u0026thinsp;704, 17.65%). Conversely, most of ADA-related AEs occurred within 90 days (N\u0026thinsp;=\u0026thinsp;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\u0026rsquo;s β and its 95% CI being 0.84 (0.82\u0026ndash;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\u0026rsquo;s β and its 95% CI being 0.62 (0.60\u0026ndash;0.65), indicating an early failure-type profile (see at Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"6\"\u003e \u003cp\u003eTable 4 Weibull shape parameter test for AEs associated with IFX and ADA. CI:confidence interval.\u003c/p\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase reports\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian (d) (25%-75%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eScale parameter: α (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eShape parameter: β (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eType\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIFX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3990\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e579 (159.25\u0026ndash;1357)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e809.48 (778.01-840.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.84 (0.82\u0026ndash;0.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEarly failure\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1548\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79 (21\u0026ndash;293)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e182.20 (166.81\u0026ndash;197.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.62 (0.60\u0026ndash;0.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEarly failure\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":" \u003cp\u003eAs the incidence of pediatric-onset IBD is increasing worldwide\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, 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 IBD\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. 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 ADA\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. 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 population\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.1. The prevalent signal AEs of infliximab and adalimumab\u003c/h2\u003e \u003cp\u003eOur study found that the most frequently reported signal AEs of IFX and ADA were involved in the same SOC, mainly focusing on \u0026ldquo;injury, poisoning and procedural complications\u0026rdquo;, \u0026ldquo;gastrointestinal disorders\u0026rdquo;, \u0026ldquo;general disorders and administration site conditions\u0026rdquo;, \u0026ldquo;infections and infestations\u0026rdquo;, \u0026ldquo;investigations\u0026rdquo;. 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.\u003c/p\u003e \u003cp\u003eIFX exhibited a higher incidence of signal AEs in \u0026ldquo;injury, poisoning and procedural complications\u0026rdquo; 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 reports\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. As IFX is administered intravenously, previous studies have demonstrated that there is a well-recognized risk of IRs associated with its use\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. 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 basophils\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. 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\u003csup\u003e\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Therefore, close monitoring of IRs is imperative when administering infliximab to pediatric IBD patients to ensure timely intervention in case of AEs occurred.\u003c/p\u003e \u003cp\u003eAs 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 edema\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. 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\u0026ndash;37% in clinical trials\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. 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 intervention\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Typically, after adjusting the infusion rate and treating with paracetamol, antihistamines or corticosteroids, the symptoms improve substantially or resolve completely\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. In addition, the utilization of citrate-free formulations and the implementation of a 29-gauge needle are associated with a reduction in injection site pain\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.2. Infections and infestations\u003c/h2\u003e \u003cp\u003eTNF-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 infections\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. 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 IBD\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. 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 administration\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. 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 children\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn 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 ADA\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. 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\u0026thinsp;=\u0026thinsp;150, ROR (95%CI)\u0026thinsp;=\u0026thinsp;2.98 (2.21\u0026ndash;4.02)], pneumonia [N\u0026thinsp;=\u0026thinsp;137, ROR (95%CI)\u0026thinsp;=\u0026thinsp;2.33 (1.75\u0026ndash;3.11)], and cellulitis [N\u0026thinsp;=\u0026thinsp;63, ROR (95%CI)\u0026thinsp;=\u0026thinsp;3.26 (2.02\u0026ndash;5.26)]. Additionally, the top 4 AEs with the highest signal strength also required attention, such as salmonellosis [N\u0026thinsp;=\u0026thinsp;16, ROR (95%CI)\u0026thinsp;=\u0026thinsp;6.34 (1.85\u0026ndash;21.76)], lower respiratory tract infection [N\u0026thinsp;=\u0026thinsp;31, ROR (95%CI)\u0026thinsp;=\u0026thinsp;6.15 (2.56\u0026ndash;14.73)], pilonidal disease [N\u0026thinsp;=\u0026thinsp;20, ROR (95%CI)\u0026thinsp;=\u0026thinsp;5.95 (2.03\u0026ndash;17.4)], and tuberculosis [N\u0026thinsp;=\u0026thinsp;14, ROR (95%CI)\u0026thinsp;=\u0026thinsp;5.55 (1.59\u0026ndash;19.31)]. Comparatively, for ADA, we should pay attention to the infection-related AEs related, including sinusitis[(N\u0026thinsp;=\u0026thinsp;54, ROR(95%CI)\u0026thinsp;=\u0026thinsp;2.35 (1.61\u0026ndash;3.41)], rash pustular[(N\u0026thinsp;=\u0026thinsp;15, ROR(95%CI)\u0026thinsp;=\u0026thinsp;2.6 (1.26\u0026ndash;5.4)], abscess intestinal[(N\u0026thinsp;=\u0026thinsp;20, ROR(95%CI)\u0026thinsp;=\u0026thinsp;2.11 (1.16\u0026ndash;3.85)], enteritis infectious[(N\u0026thinsp;=\u0026thinsp;5, ROR(95%CI)\u0026thinsp;=\u0026thinsp;12.15 (1.42-103.99)].\u003c/p\u003e \u003cp\u003eAn 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\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. 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 diagnosis\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. 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 patients\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. 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 treatment\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.3. Neoplasms, benign, malignant, and unspecified\u003c/h2\u003e \u003cp\u003eIBD, 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 lymphomas\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e \u003cp\u003eTo 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 therapy\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. 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 malignancy\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. In contrast, a larger-scale analysis of adult IBD has shown that anti-TNF monotherapy may be associated with an increased risk of lymphoma\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. 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 lymphoma\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. 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 monotherapy\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. 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 medications\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Consequently, necessitating intensified clinical monitoring for IBD patients who received TNF-α inhibitors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.4. Skin and subcutaneous tissue disorders\u003c/h2\u003e \u003cp\u003eRecent literature has reported that paradoxical psoriasiform eruptions induced by TNF inhibitors have been observed in children treated with TNF inhibitors for any indication \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Our research indicated a significant association between IFX and an increased rate of psoriasis cases [N\u0026thinsp;=\u0026thinsp;191, ROR (95%CI)\u0026thinsp;=\u0026thinsp;2.19 (1.72\u0026ndash;2.78)]. Conversely, ADA was linked to fewer reported cases of psoriasis [N\u0026thinsp;=\u0026thinsp;68, ROR (95%CI)\u0026thinsp;=\u0026thinsp;0.73 (0.55\u0026ndash;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 psoriasis\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. 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 rash\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. 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%\u003csup\u003e50\u003c/sup\u003e. 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 disease\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. Generally, the paradoxical psoriasis in these patients is typically associated with a state of disease inactivity or mild activity\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. For most cases, a topical approach is adequate for treatment, with only a minority of patients requiring discontinuation of anti-TNF therapy\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. In addition, ustekinumab has demonstrated efficacy in managing psoriasis and psoriasiform alopecia triggered by anti-TNF therapies\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe also found significant signals associated with a lupus-like syndrome [N\u0026thinsp;=\u0026thinsp;39, ROR (95%CI)\u0026thinsp;=\u0026thinsp;4.64 (2.32\u0026ndash;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 inhibitors\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. 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 treatment\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. Therefore, increasing clinical surveillance for skin-related symptoms in pediatric IBD patients treated with TNF-α inhibitors is essential.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.5. Nervous system disorders\u003c/h2\u003e \u003cp\u003eFollowing 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\u003csup\u003e\u003cspan additionalcitationids=\"CR56\" citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e. In our study, we detected three signal AEs related to CNS disorders for IFX, which were presyncope [(N\u0026thinsp;=\u0026thinsp;17, ROR(95%CI)\u0026thinsp;=\u0026thinsp;3.37 (1.33\u0026ndash;8.54)], demyelination [N\u0026thinsp;=\u0026thinsp;8, ROR(95%CI)\u0026thinsp;=\u0026thinsp;9.51 (1.19\u0026ndash;76.04)], and hyperaesthesia [N\u0026thinsp;=\u0026thinsp;8, ROR(95%CI)\u0026thinsp;=\u0026thinsp;4.75 (1.01\u0026ndash;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\u0026thinsp;=\u0026thinsp;4, ROR(95%CI)\u0026thinsp;=\u0026thinsp;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 low\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e. Nevertheless, close monitoring of neurological disorders, especially demyelination, is required when children use TNF-α inhibitors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e4.6. Psychiatric disorders\u003c/h2\u003e \u003cp\u003eIn 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 AEs\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e. 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 label\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e. 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 screening\u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e. Consequently, physicians must remain alert to the possibility of psychiatric disorders, especially suicidal behaviors, in pediatric IBD patients receiving anti-TNF therapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e4.7. Other unexpected AEs\u003c/h2\u003e \u003cp\u003eIn our study, we found some unexpected AEs for IFX which were not list in product label, such as weight increased [(N\u0026thinsp;=\u0026thinsp;119, ROR(95%CI)\u0026thinsp;=\u0026thinsp;2.14 (1.24\u0026ndash;3.7))], fall[(N\u0026thinsp;=\u0026thinsp;57, ROR(95%CI)\u0026thinsp;=\u0026thinsp;2.51 (1.59\u0026ndash;3.97))], and nephrolithiasis [(N\u0026thinsp;=\u0026thinsp;36, ROR(95%CI)\u0026thinsp;=\u0026thinsp;2.29 (1.68\u0026ndash;3.11)]. Indeed, weight increased has been reported in numerous literatures in adults\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e. A study on pediatric IBD also indicated that excess weight gain was a side effect of anti-TNF treatment\u003csup\u003e\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e. 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 IBD\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e. Nevertheless, vigilant observation of these side effect is essential.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e4.8. Time to onset of infliximab and adalimumab associated AEs\u003c/h2\u003e \u003cp\u003eWe 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\u0026thinsp;=\u0026thinsp;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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e4.9. Limitations\u003c/h2\u003e \u003cp\u003eOur 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.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eIn 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.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eADA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eadalimumab\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eadverse event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eadverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eanti-TNF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eanti-Tumour necrosis factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecentral nervous system\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFAERS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFood and Drug Administration Adverse Event Reporting System\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFDA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFood and Drug Administration\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe United Kingdom\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIBD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einflammatory bowel disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIFX\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einfliximab\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIRs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einfusion reactions\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eISRs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einjection site reactions\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMedDRA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMedical Dictionary for Regulatory Activities\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprimary suspect\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epreferred term\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ereporting odds ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSOC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esystem organ classes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTNF-α\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTumor necrosis factor-α\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTTO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTime-to-onset\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUnited States\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWPS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWeibull shape parameter.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe express our gratitude to the FDA in the United States for supplying a complimentary data source for our study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis paper was not funded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYanhong 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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnonymized data were collected from a publicly available database and did not require approval from the ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe data are available in the FDA Adverse Event Reporting System (FAERS): https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Supplementary Material for this article can be found online at:\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKuenzig, M. E. et al. Twenty-first century trends in the global epidemiology of pediatric-onset inflammatory bowel disease: systematic review. \u003cem\u003eGastroenterology, 162\u003c/em\u003e (4), 1147\u0026ndash;1159. e4 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePigneur, B. et al. Natural history of Crohn\u0026rsquo;s disease: comparison between childhood- and adult-onset disease. \u003cem\u003eInflamm. Bowel Dis.\u003c/em\u003e \u003cb\u003e16\u003c/b\u003e (6), 953\u0026ndash;961 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChouliaras, G. et al. Disease impact on the quality of life of children with inflammatory bowel disease. \u003cem\u003eWorld J. Gastroenterol.\u003c/em\u003e \u003cb\u003e23\u003c/b\u003e (6), 1067\u0026ndash;1075 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFumery, M. et al. Long-term outcome of pediatric-onset Crohn\u0026rsquo;s disease: a population-based cohort study. \u003cem\u003eDig. Liver Dis.\u003c/em\u003e \u003cb\u003e51\u003c/b\u003e (4), 496\u0026ndash;502 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAardoom, M. A., Veereman, G. \u0026amp; de Ridder, L. A Review on the Use of Anti-TNF in Children and Adolescents with Inflammatory Bowel Disease. \u003cem\u003eInt. J. Mol. Sci.\u003c/em\u003e \u003cb\u003e20\u003c/b\u003e (10), 2529 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKroesen, S., Widmer, A. F., Tyndall, A. \u0026amp; Hasler, P. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. \u003cem\u003eRheumatol. (Oxford)\u003c/em\u003e. \u003cb\u003e42\u003c/b\u003e (5), 617\u0026ndash;621 (2003).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohan, N. et al. 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Crohns Colitis\u003c/em\u003e. \u003cb\u003e4\u003c/b\u003e (6), 674\u0026ndash;678 (2010).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"infliximab, adalimumab, adverse event, pharmacovigilance, children, inflammatory bowel diseases","lastPublishedDoi":"10.21203/rs.3.rs-5171055/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5171055/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe 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\u0026ndash;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\u0026ndash;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.\u003c/p\u003e","manuscriptTitle":"Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a real-world analysis from FAERS database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-23 07:42:53","doi":"10.21203/rs.3.rs-5171055/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"26274650-f876-4a5d-b7e9-d236def13b34","owner":[],"postedDate":"October 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":38931934,"name":"Health sciences/Gastroenterology"},{"id":38931935,"name":"Health sciences/Gastroenterology/Gastrointestinal diseases"},{"id":38931936,"name":"Health sciences/Gastroenterology/Gastrointestinal diseases/Inflammatory bowel disease"}],"tags":[],"updatedAt":"2025-02-21T03:53:21+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-23 07:42:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5171055","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5171055","identity":"rs-5171055","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}