Infliximab-associated Gastrointestinal Obstruction: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (2004-2024)

Infliximab-associated Gastrointestinal Obstruction: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (2004-2024) | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 8 December 2025 V1 Latest version Share on Infliximab-associated Gastrointestinal Obstruction: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (2004-2024) Authors : Lili Xu 0000-0003-0254-694X , Yiyi Jin , Zhendong Ding , Qingqing Ye , and Chunyan Chen [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176519174.47477285/v1 190 views 129 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: This study aimed to analyze the reported connection between gastrointestinal obstruction and infliximab (IFX) using data from the FDA Adverse Event Reporting System (FAERS). Methods: Using FAERS data gathered from the first quarter of 2004 (1 January 2004) to the fourth quarter of 2024 (31 December 2024), we conducted a retrospective disproportionality analysis. The standardized MedDRA query (SMQ) restricted scope was used to collect reports that identified IFX as the main suspect medication for gastrointestinal obstruction. Four statistical strategies were used in the investigation to provide robustness in signal detection: multi-item gamma Poisson shrinker (MGPS), Bayesian confidence propagation neural network (BCPNN), proportional reporting ratio (PRR), and reporting odds ratio (ROR). Time-to-onset (TTO) analysis and univariate logistic regression were used to characterize the clinical presentation and identify risk variables for IFX-associated gastrointestinal obstruction. Results: Among 84,592 reports where IFX was the primary suspect drug, 1.94% (n=1,643) were associated with gastrointestinal obstruction. A significant disproportionality signal was detected at the SMQ level (ROR 3.89, 95% CI 3.76–4.02). Key risk factors included age <65 years, female sex, reporting from Canada, and an underlying indication of inflammatory bowel disease (IBD). The median TTO varied among obstruction subtypes but generally exhibited an early failure profile. Sensitivity analysis indicated a random failure profile in certain subtypes. Conclusion: This pharmacovigilance study identifies a significant safety signal linking IFX to gastrointestinal obstruction, particularly in younger female patients with IBD. These findings underscore the necessity for heightened clinical vigilance and further investigation into the underlying mechanisms. 1 Introduction As a chimeric monoclonal antibody directed against tumor necrosis factor-alpha (TNF-α), infliximab (IFX) has served as a fundamental therapeutic option for a spectrum of autoimmune and inflammatory diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, psoriasis, and ankylosing spondylitis[1]. It is highly effective at inducing and maintaining clinical remission in patients with Crohn’s disease (CD) and ulcerative colitis (UC), establishing its role as a fundamental therapy for moderate to severe IBD[2]. However, a paradoxical clinical phenomenon has emerged with expanding IFX use: while the drug is highly effective in controlling inflammatory activity, accumulating reports describe gastrointestinal toxicities, including obstruction, in patients receiving anti-TNF therapy[3,4]. This apparent contradiction is particularly intriguing given that anti-TNF agents, including IFX, are themselves employed successfully in the treatment of symptomatic stricturing Crohn’s disease[5-7], suggesting a complex dual role in both ameliorating and potentially contributing to fibrostenotic complications. Notably, gastrointestinal obstruction is not currently cited in the manufacturer’s prescribing information, highlighting an important gap in safety profiling that merits further investigation. Data mining techniques are widely utilized for the quantitative detection of drug-adverse event associations. Among these, pharmacovigilance analysis utilizing the FAERS database represents a cornerstone method for identifying potential safety signals, including those that are rare[8]. This approach is valuable not only for the early detection of novel adverse events associated with new drugs but also for the continuous safety monitoring of established therapeutics[9]. Therefore, this study was designed to perform a comprehensive retrospective disproportionality analysis of the FAERS database with the primary objective of assessing the potential risk of gastrointestinal obstruction associated with IFX use in a real-world setting. 2 Methods 2.1 Data Sources and Extraction Data were extracted from the FAERS database for the period spanning from the first quarter (Q1) of 2004 (1 January 2004) to the fourth quarter (Q4) of 2024 (31 December 2024). The OpenVigil 2.1 tool, a publicly accessible pharmacovigilance platform that interfaces directly with the FDA’s database, was utilized to extract, clean, and process adverse event (AE) reports[10,11]. Two independent investigators extracted the clinical characteristics of AE reports involving IFX. These included but were not limited to: individual safety report (ISR) identifiers, patient outcomes, drug names (both trade and generic, queried via Medical Subject Headings [MeSH]), drug role codes, dosages, event terms, case identifiers, patient gender and age, and reporter country. All reports were systematically screened, and only those listing IFX as the ’primary suspect’ drug were retained for subsequent analysis. In accordance with FDA guidelines, only the most recent version of each case was retained to eliminate duplicate reports[12]. 2.2 Definition of Adverse Events All AEs within the FAERS database are coded using Preferred Terms (PTs) based on the Medical Dictionary for Regulatory Activities (MedDRA, version 27.0) terminology. Reports were identified using the narrow scope of the standardized MedDRA query (SMQ) ’gastrointestinal obstruction’. PTs with less than 3 cases reported with infliximab as the primary suspect drug were excluded. In this research, the narrow scope of the SMQ for gastrointestinal obstruction encompassed 90 PTs (Supplementary Table 1). 2.3 Disproportionality Analysis Disproportionality analysis was performed using a standard 2x2 contingency table (Supplementary Table 2) to investigate potential associations between IFX and gastrointestinal obstruction-related AEs. Analyses were conducted at both the PT and SMQ levels. Signal detection was carried out using four distinct computational algorithms: the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). This multi-method approach was adopted to strengthen the robustness of the findings and mitigate the risk of false-positive signals inherent to any single method [13,14]. A positive signal was defined as one that met the predetermined threshold criteria for at least two of these four algorithms, indicating a statistically significant association between IFX and the target AE. The mathematical formulas and specific thresholds for each algorithm are detailed in Supplementary Table 3. 2.4 Time-to-onset Analysis The time-to-onset (TTO) was defined as the interval between the initiation of IFX therapy (START_DT) and the occurrence of a gastrointestinal obstruction event (EVENT_DT). Reports with inconsistent dates, missing data, or evident entry errors were excluded to ensure reliability. TTO was summarized using median and interquartile range (IQR), and the Weibull shape parameter (β) was employed to characterize the hazard profile over time. When β is <1 and its 95% CI is <1, the hazard of ADR occurrence is considered to have decreased over time (early failure‐type profile); when β is equal to or close to 1 and its 95% CI includes the value 1, the hazard is estimated to occur constantly over time (random failure‐ type profile). Finally, when β is >1 and its 95% CI excludes the value 1, the hazard is considered to increase over time (wear‐out failure‐type profile)[15,16]. The median TTO and β parameter were calculated for adverse events with at least 50 reported cases. 3 Results 3.1 Descriptive Analysis Between Q1 2004 and Q4 2024, a total of 84,592 individual case safety reports (ICSRs) listing IFX as the primary suspect drug were recorded in the FAERS database. Among these, gastrointestinal obstruction-related events accounted for 1.94% (n=1,643) of all reports. The clinical characteristics of these patients are summarized in Table 1. A slight predominance of gastrointestinal obstruction reports was observed in females (51.67%) compared to males (48.33%). The majority of cases (91.71%) occurred in patients under 65 years of age, with the 41–64 year age group representing the largest subset (40.81%). The median age was 40 years (IQR: 24–54). Geographically, the highest number of reports originated from Canada (52.53%, n=840). Crohn’s disease was documented as the primary indication for IFX use in 76.92% (n=1,130) of cases with available data. Serious outcomes were reported in the vast majority of gastrointestinal obstruction cases (99.94%), including fatalities in 3.05% (n=50). The most recent reporting period (2020-2024) contributed the largest proportion of cases (57.15%). Table1 Clinical characteristics of patients with IFX-associated gastrointestinal obstruction Available number Value Available number Value Sex 1291 (78.58) 63459 (75.02) Male 624 (48.33) 26485 (41.74) Female 667 (51.67) 36974 (58.26) Age 1061 (64.58) 44969 (53.16) ＜18 183 (17.25) 5020 (11.16) 18-40 357 (33.65) 13662 (30.38) 41-64 433 (40.81) 18031 (40.10) ≥65 88 (8.29) 8256 (18.36) Median (IQR) 40 (24-54) 46 (30-60) Serious outcomes 1642 (99.94) 76822 (90.81) Death 50 (3.05) 3990 (5.19) Life-threatening 26 (1.58) 2018 (2.63) Hospitalization 969 (59.01) 21030 (27.37) Disability 1 (0.06) 582 (0.76) Other outcomes 596 (36.30) 49202 (64.05) Indications 1469 (89.41) 77844 (92.02) Crohn’s disease 1130 (76.92) 27645 (35.51) Indeterminate colitis 86 (5.85) 1302 (1.67) Colitis ulcerative 82 (5.58) 11954 (15.36) Rheumatoid arthritis 52 (3.54) 13706 (17.61) Other indications 119 (8.10) 23237 (29.85) Reported countries 1599 (97.32) 80941 (95.68) Canada 840 (52.53) 32358 (39.98) the United States 337 (21.08) 24876 (30.73) Brazil 77 (4.82) 3000 (3.71) Japan 75 (4.69) 2211 (2.73) Germany 41 (2.56) 883 (1.09) Other countries 229 (14.32) 17613 (21.76) Reporting year 1643 (100) 84592 (100) 2020-2024 939 (57.15) 39547 (46.75) 2015-2019 37 (2.25) 3674 (4.34) 2010-2014 491 (29.88) 24582 (29.06) 2004-2009 176 (10.71) 16789 (19.85) IFX infliximab, AEs adverse events, n number of cases, IQR interquartile range. 3.2 Disproportionality Analysis ROR, PRR, IC and EBGM were calculated to find the signal values of gastrointestinal obstruction associated with IFX in the FAERS database. Compared to the overall AEs in the database, IFX-associated “gastrointestinal obstruction” based on SMQ term [ROR 3.89 (3.76-4.02); PRR 3.82 (3711.42); IC 0.80 (0.60–0.99)], had significantly higher reporting rates (Table 2). Subsequent analysis at the PT level identified 30 PTs that satisfied the thresholds of two methodologies (Table 3). The most frequently reported PTs included intestinal obstruction (n=600), intestinal stenosis (n=303), small intestinal obstruction (n=193), ileal stenosis (n=113), large intestinal stenosis (n=101), ileus (n=63), and small intestinal stenosis (n=53). Univariate logistic regression analysis was performed to identify potential risk factors (Figure 1). The results showed that age (<65 years: OR =2.399 [1.9918–3.001], p < 0.001), sex (male: OR =0.756 [0.675–0.846], p < 0.001), country (Canada: OR =1.748 [1.580–1.935], p < 0.001) and indication (IBD: OR =7.384 [6.251–8.723], p < 0.001) were associated with the occurrence of IFX induced gastrointestinal obstruction-related AEs. Table 2 Signal strength of reports of IFX-associated gastrointestinal obstruction based on Standardized MedDRA Query (SMQ) level in the FAERS database Gastrointestinal obstruction 1810 *3.89 (3.76-4.02) *3.82 (3711.42) *3.76 (3.65) 1.91 (1.85) *Indicates statistically significant signals in algorithm Abbreviations: SMQ, the standardized meddra query; ROR, reporting odds ratio; CI, confidence interval; PRR, proportional reporting ratio; χ2,chi-squared; IC, information component; IC025, the lower limit of 95% CI, of the IC; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of 95% CI, of EBGM Table 3 Signal strength of reports of IFX-associated gastrointestinal obstruction based on Preferred Term (PT) level in the FAERS database Intestinal obstruction 600 *5.19 (4.90-5.50) *5.16 (1950.52) *2.33 (2.20) *5.03 (4.77) Intestinal stenosis 303 *33.13 (30.32-36.20) *33.02 (7760.19) *4.78 (4.37) *27.41 (25.27) Small intestinal obstruction 193 *5.32 (4.80-5.89) *5.31 (652.57) *2.37 (2.14) *5.16 (4.70) Ileal stenosis 113 *26.78 (23.22-30.88) *26.74 (2389.36) *4.52 (3.92) *22.96 (20.16) Large intestinal stenosis 101 *17.05 (14.72-19.75) *17.03 (1373.85) *3.95 (3.41) *15.45 (13.51) Ileus 63 *1.61 (1.35-1.92) *1.611(14.47) *0.68 (0.57) 1.61 (1.36) Small intestinal stenosis 53 *19.82 (16.16-24.31) *19.81 (839.64) *4.14 (3.38) 17.68 (14.67) Anal stenosis 41 *28.86 (22.74-36.62) *28.85 (929.65) *4.61 (3.64) *24.49 (19.70) Gastrointestinal obstruction 36 *4.87 (3.84-6.18) *4.87 (107.41) *2.25 (1.77) *4.75 (3.83) Gastrointestinal motility disorder 28 *1.72 (1.32-2.24) 1.72 (8.31) *0.77 (0.59) 1.71 (1.34) Volvulus 26 *3.59 (2.72-4.73) *3.58 (47.35) *1.82 (1.38) *3.53 (2.73) Gastrointestinal stenosis 22 *17.91 (13.07-24.55) *17.91 (314.96) *4.01 (2.93) *16.16 (12.11) Subileus 22 *3.93 (2.90-5.31) *3.93 (46.82) *1.95 (1.44) *3.86 (2.92) Rectal stenosis 18 *22.04 (15.49-31.36) *22.04 (316.62) *4.28 (3.01) *19.43 (14.07) Large intestinal obstruction 17 *2.24 (1.59-3.15) *2.24 (11.45) *1.15 (0.82) 2.22 (1.62) Oesophageal stenosis 15 *1.51 (1.05-2.18) 1.51 (2.59) *0.59 (0.41) 1.51 (1.08) Anastomotic stenosis 13 *13.85 (9.23-20.77) *13.85 (142.25) *3.68 (2.45) *12.79 (8.83) Gastrointestinal scarring 13 *6.11 (4.11-9.07) *6.11 (53.42) *2.56 (1.73) *5.91 (4.12) Obstruction gastric 8 *1.75 (1.06-2.88) 1.75 (2.54) *0.80 (0.49) 1.74 (1.10) Oesophageal obstruction 8 *2.58 (1.56-4.24) *2.58 (7.58) *1.35 (0.82) 2.55 (1.62) Duodenal stenosis 7 *4.48 (2.62-7.66) *4.48 (18.39) *2.13 (1.25) *4.38 (2.68) Jejunal stenosis 7 *24.19 (13.70-42.72) *24.19 (134.65) *4.40 (2.49) *21.07 (12.52) Postoperative ileus 7 *3.85 (2.25-6.57) *3.85 (14.39) *1.92 (1.12) *3.78 (2.31) Gastrointestinal anastomotic leak 6 *5.65 (3.16-10.12) *5.65 (22.18) *2.46 (1.37) *5.49 (3.22) Mechanical ileus 6 *3.31 (1.86-5.89) *3.31 (9.46) *1.70 (0.96) 3.26 (1.92) Stricturoplasty 6 *93.30 (45.28-192.25) *93.29 (342.38) *5.87 (2.85) *58.68 (30.29) Intestinal fibrosis 4 *7.78 (3.79-15.93) *7.77 (22.49) *2.90 (1.41) *7.45 (3.87) Anal dilation procedure 3 *93.30 (33.56-259.35) *93.29(171.19) *5.87 (2.11) *58.68 (23.03) Distal intestinal obstruction syndrome 3 *3.15 (1.39-7.13) *3.15(4.32) *1.64 (0.72) 3.11 (1.47) Gastrointestinal anastomotic stenosis 3 *14.14 (6.08-32.88) *14.14 (33.57) *3.70 (1.59) *13.04 (6.02) *Indicates statistically significant signals in the algorithm Abbreviations: PT, preferred term; ROR, reporting odds ratio; CI, confidence interval; PRR, proportional reporting ratio; χ2,chi-squared; IC, information component; IC025, the lower limit of 95% CI, of the IC; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of 95% CI, of EBGM Figure 1 Univariate logistic regression analysis of factors associated with IFX-associated gastrointestinal obstruction IBD: inflammatory bowel disease; CD: Crohn’s disease; UC: ulcerative colitis; IC: indeterminate colitis 3.3 Time-to-onset analysis Of 1643 IFX‐associated reports of gastrointestinal obstruction, 412 reports contained TTO data. Table 4 summarizes the results of the TTO and WSP analyses performed on seven major PTs (≥50 cases). Intestinal obstruction, intestinal stenosis, small intestinal obstruction, ileal stenosis, large intestinal stenosis, ileus, and small intestinal stenosis associated with IFX had median time to death (TTO) of 268 days (IQR 45-1347), 497 days (IQR 63-1609), 616 days (IQR 100-1558), 483 days (IQR 142-1095), 628 days (IQR 62-3731), 423 days (IQR 66-844), and 314 days (IQR 2-760), respectively. The shape parameter β and its 95% CI upper limit were both less than 1, according to the WSP test findings for those PTs. This suggests an early failure pattern with a diminishing hazard of AEs over time. Although the majority of events (30.8%; n=163) occurred after 1080 days, a notable proportion (20.0%) arose within 30 days of IFX initiation (Figure 2). Given that gastrointestinal obstruction is typically a subacute or chronic adverse event rather than an immediate reaction, we performed a sensitivity analysis by excluding cases with a recorded TTO of 0 days (n=73). After exclusion, 339 reports remained for TTO analysis. As detailed in Supplementary Table 4, the median TTO for all PTs increased compared to the primary analysis, except for large intestinal stenosis. The Weibull distribution parameters indicated that the early failure profile (β <1) remained for most PTs. However, for ileal stenosis, ileus, and small intestinal stenosis, a random failure profile was observed (Supplementary Table 4). Supplementary Figure 1 illustrates the updated TTO distribution after excluding TTO = 0 cases. Table 4 Distribution of time-to-onset for infliximab-associated gastrointestinal obstruction adverse events Case - Scale parameter Shanpe parameter n Median (IQR) Min-max α 95%CI β 95%CI Intestinal obstruction 146 268 (45-1347) 0-5713 401.73 259.11-622.85 0.38 0.33-0.44 Early failure Intestinal stenosis 101 497 (63-1609) 0-6531 589.87 366.15-976.97 0.40 0.33-0.47 Early failure Small intestinal obstruction 67 616 (100-1558) 0-6304 742.28 435.54-1265.05 0.46 0.38-0.57 Early failure Ileal stenosis 34 483 (142-1095) 0-3536 672.25 418.86-1078.93 0.74 0.56-0.97 Early failure Large intestinal stenosis 15 628 (62-3731) 14-5030 1033.42 445.79-2395.67 0.63 0.42-0.96 Early failure Ileus 36 423 (66-844) 0-3697 400.68 221.82-723.75 0.57 0.43-0.75 Early failure Small intestinal stenosis 13 314 (2-760) 0-4549 221.87 27.78-1771.73 0.27 0.17-0.44 Early failure Figure 2 Time to onset of IFX-related gastrointestinal obstruction Supplementary Table 1 The PT codes and names included in the narrow scope of the SMQ of gastrointestinal obstruction 10089056 Abdominal adhesiolysis 10021335 Ileus spastic 10057204 Anal dilation procedure 10021518 Impaired gastric emptying 10002176 Anal stenosis 10068577 Intestinal atony 10051268 Anastomotic stenosis 10072877 Intestinal fibrosis 10002250 Anastomotic ulcer, obstructive 10074168 Intestinal malrotation repair 10002581 Anorectal stenosis 10022687 Intestinal obstruction 10074458 Appendicolith 10084261 Intestinal plication surgery 10069083 Barium impaction 10022698 Intestinal pseudo-obstruction 10087251 Bauhin’s valve syndrome 10022699 Intestinal stenosis 10086417 Bowel obstruction surgery 10022863 Intussusception 10088625 Delayed passage of meconium 10023176 Jejunal stenosis 10056361 Distal intestinal obstruction syndrome 10062062 Large intestinal obstruction 10084561 Duodenal bulb deformity 10023794 Large intestinal obstruction reduction 10013830 Duodenal obstruction 10074061 Large intestinal stenosis 10088983 Duodenal stasis 10081592 Malignant gastrointestinal obstruction 10050094 Duodenal stenosis 10051399 Mechanical ileus 10013850 Duodenal ulcer perforation, obstructive 10027058 Meconium ileus 10013855 Duodenal ulcer, obstructive 10051606 Necrotising colitis 10075012 Encapsulating peritoneal sclerosis 10049150 Necrotising gastritis 10052072 Fibrosing colonopathy 10055668 Necrotising oesophagitis 10074216 Fixed bowel loop 10028951 Neonatal intestinal obstruction 10017649 Gallstone ileus 10029957 Obstruction gastric 10082102 Gastric electrical stimulation 10076953 Obstructive defaecation 10058035 Gastric ileus 10082992 Oesophageal bypass 10081549 Gastric pacemaker insertion 10074074 Oesophageal compression 10081547 Gastric pacemaker removal 10057305 Oesophageal dilation procedure 10061970 Gastric stenosis 10030178 Oesophageal obstruction 10075799 Gastric stent insertion 10030194 Oesophageal stenosis 10089497 Gastric stent removal 10081525 Oesophageal stent stenosis 10017829 Gastric ulcer haemorrhage, obstructive 10034358 Peptic ulcer perforation, obstructive 10017836 Gastric ulcer perforation, obstructive 10034365 Peptic ulcer, obstructive 10017840 Gastric ulcer, obstructive 10054048 Postoperative ileus 10052541 Gastric volvulus 10050173 Prepyloric stenosis 10065879 Gastrointestinal anastomotic leak 10057206 Pylorus dilation procedure 10078817 Gastrointestinal anastomotic stenosis 10065707 Rectal obstruction 10082064 Gastrointestinal decompression 10038079 Rectal stenosis 10073232 Gastrointestinal dilation procedure 10041101 Small intestinal obstruction 10052105 Gastrointestinal hypomotility 10077307 Small intestinal obstruction reduction 10061173 Gastrointestinal motility disorder 10062263 Small intestinal stenosis 10061974 Gastrointestinal obstruction 10058795 Stomach dilation procedure 10081656 Gastrointestinal scarring 10074183 Stricturoplasty 10018007 Gastrointestinal stenosis 10050396 Subileus 10021307 Ileal stenosis 10054156 Superior mesenteric artery syndrome 10021328 Ileus 10047697 Volvulus 10021333 Ileus paralytic 10074224 Volvulus repair This table shows 90 relevant PT codes and names for gastrointestinal obstruction according to the narrow scope of the SMQ. Abbreviations: PT, preferred term; SMQ, Standardized MedDRA Queries Supplementary Table 2 Two-by-two contingency table for disproportionality analyses Target drug a b a+b All other drugs c d c+d Total a+c b+d N=a+b+c+d Abbreviations: AEs; adverse events Supplementary Table 3 Four different types of disproportionality analysis ROR ROR = (a/c)/(b/d) 95%CI=eln (ROR)±1.96(1/a+1/b+1/c+1/d)^0.5 a≥3, 95% CI (lower limit) >1 PRR PRR=[a/(a+b)]/[c/(c+d)] χ 2 =[(ad-bc) 2 (a+b + c + d)] / [(a+b) (c + d) (a+c) (b + d)] a≥3, PRR≥2 and χ 2 ≥4 BCPNN IC=log 2 a(a+b+c+d)/((a+c) (a+b)) IC025=e ln(IC)−1.96(1/a+1/b+1/c+1/d)^0.5 a≥3, IC 025 >0 MGPS EBGM=a(a+b+c+d)/((a+c) (a+b)) EBGM05=e ln(EBGM)−1.64(1/a+1/b+1/c+1/d)^0.5 a > 0, EBGM 05 > 2 ROR, reporting odds ratio; CI, confidence interval; χ2, chi-squared. PRR, proportional reporting ratio; BCPNN, Bayesian confidence propagation neural network; IC, information component; IC025, the lower limit of the 95% CI of the IC; MGPS, multiple gamma Poisson shrinkage; EBGM, empirical Bayesian geometric mean; EBGM05, empirical Bayesian geometric mean lower 95% CI for the posterior distribution. Supplementary Table 4 Distribution of time-to-onset for infliximab-associated gastrointestinal obstruction adverse events (Eliminate cases in which TTO=0) Case - Scale parameter Shape parameter n Median (IQR) Min-max α 95%CI β 95%CI Intestinal obstruction 127 365 (131-1604) 5-5713 790.25 605.50-1031.36 0.69 0.60-0.79 Early failure Intestinal stenosis 88 644 (263-1875) 3-6531 1126.06 851.48-1489.19 0.79 0.66-0.93 Early failure Small intestinal obstruction 61 715 (162-1757) 2-6304 1151.43 808.95-1638.90 0.75 0.61-0.91 Early failure Ileal stenosis 33 487 (184-1112) 13-3536 765.48 514.17-1139.61 0.90 0.68-1.18 Random failure Large intestinal stenosis 15 628 (62-3731) 14-5030 1033.42 445.79-2395.67 0.63 0.42-0.96 Early failure Ileus 34 460 (106-917) 3-3697 515.22 32.86-809.64 0.78 0.59-1.02 Random failure Small intestinal stenosis 10 489 (134-1772) 3-4549 878.14 322.10-2394.09 0.65 0.40-1.06 Random failure Supplementary Figure 1 Time to onset of IFX-related gastrointestinal obstruction (Eliminate cases in which TTO=0) 4 Discussion This study represents, to our knowledge, the first large-scale pharmacovigilance investigation to systematically establish a significant association between IFX and gastrointestinal obstruction, thereby identifying a novel and clinically relevant safety signal not currently described in its prescribing information. By analyzing real-world data from the FAERS database spanning 2004 Q1 to 2024 Q4, a robust association between IFX therapy and gastrointestinal obstructive events was confirmed, and key risk factors along with characteristic time-to-onset profiles were further identified. Although the incidence of IFX-related gastrointestinal obstruction was low (1.94%), the overwhelming proportion of serious cases (99.94%) underscores the necessity for heightened clinical vigilance. This finding reinforces the critical role of post-marketing surveillance in detecting rare yet severe adverse events associated with widely used therapeutics. To minimize spurious associations, a multi-algorithmic disproportionality analysis was employed, through which consistent and robust safety signals were detected at both SMQ and PT levels. Notably, significantly elevated reporting rates were observed at the SMQ level, and thirty preferred terms met the signal detection criteria. Among these, intestinal obstruction, intestinal stenosis, and small intestinal obstruction were the most frequent and represented the core clinical manifestations of this adverse effect. This analysis revealed that gastrointestinal obstruction reports were predominantly documented in patients with IBD, particularly CD. This finding aligns with the primary therapeutic application of IFX[17]. The underlying pathophysiology is hypothesized to involve multiple mechanisms, including disease-related strictures and potential treatment-induced fibrotic changes. Although IFX is highly effective in reducing acute inflammation, its association with exacerbated fibrosis in stricturing disease has been paradoxically observed[18,19]. We propose that a disruption of the homeostatic balance between TNF-α and TGF-β may underlie this phenomenon. Specifically, it is suggested that IFX binding to transmembrane TNF-α on macrophages may trigger reverse signalling, activating pathways that induce TGF-β secretion[19,20]. This could lead to the subsequent activation of Smad-dependent pathways and transcriptional upregulation of profibrotic genes[21,22]. While short-term TGF-β elevation might contribute to immunoregulation, chronic exposure is postulated to promote ECM deposition and myofibroblast activation, thereby directly accelerating fibrogenesis[23]. Furthermore, IFX might independently disrupt ECM homeostasis via suppression of matrix metalloproteinase (MMP) activity[24-26]. A marked downregulation of multiple MMPs has been documented in the serum and intestinal tissues of CD patients following TNF-α neutralization, whereas a commensurate reduction in tissue inhibitors of metalloproteinases (TIMPs) was not observed[25,27]. This altered MMP/TIMP ratio compromises collagen degradation, which synergizes with TGF-β–mediated fibrogenesis to accelerate ECM accumulation[28,29]. The ileum may be particularly vulnerable to this process due to its inherently narrow lumen and lower baseline MMP activity, which could explain the predominance of IFX-associated strictures in this segment[30,31]. This analysis identified younger age, female sex, and Canadian origin as factors associated with reports of IFX-related gastrointestinal obstruction. Younger age, particularly below 40 years, is a well-established independent risk factor for stricturing complications in Crohn’s disease[32]. Although female sex is not directly associated with higher rates of stricturing, women more frequently exhibit inflammatory behavior[33]. We hypothesize that while IFX effectively suppresses mucosal inflammation and induces endoscopic healing, its limited tissue penetration as a large antibody may fail to resolve chronic inflammation in deeper intestinal layers such as the muscularis propria and myenteric plexus. These persistent transmural inflammatory signals, potentially mediated through pathways like TGF-β1, could continue to activate myofibroblasts, leading to excessive extracellular matrix deposition, smooth muscle hyperplasia, and ultimately the development of fibrotic strictures. The notably high proportion of reports originating from Canada is more likely attributable to the nation’s unique epidemiological context and advanced pharmacovigilance infrastructure rather than a truly elevated biological risk. Canada’s high IBD incidence rates result in greater absolute IFX exposure[34], and its centralized healthcare system coupled with structured monitoring programs enhances detection capacity[35]. Furthermore, the mandatory non-medical switch policy implemented in Canada in 2019 (requiring stable patients to switch from the original drug to a biosimilar drug) also temporarily enhanced monitoring and reporting activities, which is consistent with the significant increase in reporting observed in this study from 2020 to 2024. The initial time-to-onset analysis suggested an early failure profile across all evaluated Preferred Terms. However, a substantial number of reports with TTO values of 0 days were observed, a finding inconsistent with the expected subacute or chronic nature of this adverse event and likely indicative of misattribution or reporting inaccuracies. A sensitivity analysis excluding these implausible cases was therefore conducted. Following exclusion, the hazard profile for specific obstruction subtypes, particularly ileal stenosis, ileus, and small intestinal stenosis, shifted from an early to a random failure pattern. This shift indicates that the original analysis was compromised by spurious TTO entries, particularly those with a value of zero. The remaining early-onset cases may reflect rapid unmasking of pre-existing subclinical strictures or pharmacodynamic interactions with concomitant medications. Furthermore, a substantial proportion of cases exhibited onset beyond 1080 days, a pattern consistent with cumulative drug-induced fibrotic processes mediated by extracellular matrix remodelling. To mitigate the risk of IFX-associated intestinal fibrosis and obstruction, a multimodal strategy is recommended, incorporating vigilant monitoring, advanced imaging techniques such as magnetization transfer MRI and ultrasound elastography [36], and the prospective use of antifibrotic agents in high-risk patients. Emerging preclinical evidence suggests that drugs such as sunitinib and pirfenidone inhibit TGF-β signalling and reduce procollagen secretion and ECM deposition[37,38]. Future clinical trials should evaluate whether combination therapy with anti-TNF and antifibrotic agents can delay fibrotic progression while maintaining control of inflammation. This study has several limitations inherent to the use of spontaneous reporting systems, which can be categorized into three main aspects. First, data quality issues include unavoidable reporting biases and incomplete demographic and clinical information, which may affect the accuracy and completeness of the analyses. Second, methodological constraints comprise the inability to calculate incidence rates due to unknown exposure denominators, potential geographic bias resulting from uneven reporting across countries, and confounding factors such as concomitant medications and comorbidities that hinder causal inference. Third, interpretative limitations must be acknowledged; disproportionality metrics like the information component and reporting odds ratio reflect increased reporting frequency rather than definitively established elevated risk[39]. Despite these limitations, the FAERS database remains a valuable source of real-world evidence on rare and delayed adverse events not commonly observed in clinical trials. 5 Conclusion This large-scale pharmacovigilance study identifies a significant and robust association between IFX therapy and gastrointestinal obstruction, a serious adverse event not currently described in its official prescribing information. The signal was particularly pronounced in specific patient subgroups, including those with inflammatory bowel disease, females, and individuals under 65 years of age. These findings underscore the necessity for heightened clinical vigilance and proactive monitoring of at-risk patients receiving IFX. Further epidemiological studies are required to confirm causality, while mechanistic investigations are warranted to elucidate the underlying pathogenic processes and inform optimal clinical management strategies. Compliance with ethical standards Funding No funding was received in the preparation of this manuscript. Conflict of interest Lili Xu, Yiyi Jin, Qingqing Ye, and Chunyan Chen have no conflicts of interest directly relevant to the content of this article. Ethical approval Ethical approval was not required for this study. Data Source The data used in this study were derived from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, a public, spontaneous adverse event (AE) reporting database maintained by the FDA. FAERS is accessible to all researchers free of charge and supports post-marketing pharmacovigilance research by providing real-world AE data for drugs and therapeutic products. 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Keywords fda adverse event reporting system gastrointestinal obstruction， infliximab， Authors Affiliations Lili Xu 0000-0003-0254-694X The First Affiliated Hospital of Ningbo University View all articles by this author Yiyi Jin The First Affiliated Hospital of Ningbo University View all articles by this author Zhendong Ding The First Affiliated Hospital of Ningbo University View all articles by this author Qingqing Ye The First Affiliated Hospital of Ningbo University View all articles by this author Chunyan Chen [email protected] The First Affiliated Hospital of Ningbo University View all articles by this author Metrics & Citations Metrics Article Usage 190 views 129 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Lili Xu, Yiyi Jin, Zhendong Ding, et al. Infliximab-associated Gastrointestinal Obstruction: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (2004-2024). Authorea . 08 December 2025. 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