Inflammatory bowel disease (IBD) is a chronic recurrent gastrointestinal disease caused by immune dysregulation, including Crohn’s disease (CD) and ulcerative colitis (UC). Typical clinical manifestations include abdominal pain, diarrhea, mucus and blood in the stool and weight loss, usually accompanied by various parenteral symptoms. These symptoms seriously affect the quality of life of patients and usually require lifelong treatment and management. IBD affects about 4.9 million people worldwide, with the highest number of cases in China and the United States in 2019. The global age-standardized incidence increased slightly from 4.22 cases per 100,000 people in 1990 to 4.45 cases per 100,000 people in 2021, with a prevalence rate of 59.3 cases per 100,000 people, and the crude prevalence rate increased by 47%. In newly industrialized countries, such as Asian and Latin American countries, especially China and India, the incidence rate has increased significantly (1). Traditional therapies mainly include aminosalicylate, corticosteroids and immunomodulators; Biotherapy, especially anti-tumor necrosis factor-α (TNF-α) preparation, has become the cornerstone of treatment for moderate and severe cases or patients who do not respond to standard treatment (2).

Infliximab is a chimeric monoclonal antibody targeting TNF-α, which was approved by FDA in 1998 for the treatment of moderate and severe active Crohn’s disease, and in 2005 for the treatment of moderate and severe ulcerative colitis, becoming the first biological agent widely used in the treatment of IBD (3). Infliximab inhibits the interaction between TNF-α and its receptor by specifically binding to it, thus inhibiting the inflammatory cascade, alleviating intestinal inflammation and promoting mucosal repair (4). A large number of randomized controlled trials (RCT) confirmed its efficacy in inducing and maintaining remission of IBD (3–8). However, infliximab can also cause some adverse reactions. Common adverse reactions include infusion-related reactions (such as fever, chills and rash), upper respiratory tract infection, headache, joint pain and gastrointestinal discomfort, and the incidence rate is about 10-20% (3, 4, 6, 9). In addition, due to its immunosuppression, patients may face an increased risk of serious infections (such as tuberculosis, invasive fungal infections and viral infections) and malignant tumors (such as non-Hodgkin’s lymphoma). Therefore, comprehensive screening is needed before treatment and regular monitoring is needed during treatment (10). With the expansion of clinical application, real-world studies have reported new or rare adverse reactions related to infliximab, including demyelination of the central nervous system, lupus-like syndrome and heart failure (11). In addition, the incidence of delayed hypersensitivity and immune complex-mediated adverse events (AE) (such as serum sickness-like reaction and rheumatoid arthritis) has also increased, so clinicians and patients need to be vigilant (12). Despite these safety problems, infliximab is still the key drug to treat IBD, especially for patients with hormone dependence or refractory hormone. Compared with other anti-TNF-α drugs (such as adalimumab and golimumab), its efficacy is relatively stable (13).

In clinical trials, rare or emerging adverse reactions are often difficult to identify comprehensively, which highlights the urgent need for large-scale and systematic pharmacovigilance data for in-depth investigation. This study leverages the U.S. FDA Adverse Event Reporting System (FAERS), a well-established spontaneous reporting database widely utilized for post-marketing drug safety assessments (14). We aim to employ non-proportional analysis techniques for detecting infliximab-related adverse event signals, utilizing established frequency-based metrics, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN). The aim is to systematically identify common and rare adverse reaction signals potentially associated with IBD patients, in order to provide evidence-based guidance for clinical drug use and enhance the early warning capability for drug safety risks (15).

We analyzed 80,138 reports of infliximab-related AEs in IBD patients from the FAERS database. The results showed a heavy burden of AEs. Women reported a higher proportion (50.7%), and people aged 18–64 accounted for 52.5%. The higher incidence of AEs in women is consistent with the known pattern of IBD-women are usually more susceptible (27). Most reports came from Canada (48.7%) and the United States (45.8%). This may reflect the higher use rate of infliximab or the better reporting system in these countries. The number of AEs showed an overall upward trend. Although it fluctuated, it reached a peak of 8788 cases in 2023. This indicates that infliximab has been widely used in clinic, and it also suggests that its safety needs to be continuously monitored. Clinicians should be aware of this trend and consider close monitoring for AEs, particularly among high-risk groups such as females and middle-aged patients. However, the signals we identified do not prove that infliximab causes these events.

At the SOC level, we found the strongest signals in investigations (mainly positive human antichimeric antibody tests), metabolic and nutritional disorders, and renal and urinary disorders. The prominent signal for renal and urinary disorders does not appear well covered in the current infliximab drug label. This points to a possible new safety concern that needs more study. These associations are hypothesis-generating and cannot be interpreted as confirmed drug-related effects (28, 29). High-frequency SOCs such as musculoskeletal and connective tissue disorders (N = 1,531) and infections and infestations (N = 1,082) are consistent with known risks of infliximab, including lupus-like syndrome and opportunistic infections (30). However, despite their high frequency, the signal strength for infections and infestations was relatively low (ROR = 9.06), which may be confounded by the progression of IBD or concomitant immunosuppressive therapy. Clinicians should regularly monitor for signs of infection and musculoskeletal symptoms, particularly in patients receiving long-term infliximab therapy.

At the PT level, a total of 57 infliximab-related AE signals were identified from the FAERS database. Common signals were mainly related to infections and immune-mediated events, such as pulmonary tuberculosis, disseminated tuberculosis, lupus-like syndrome, and serum sickness, which align with the mechanism whereby infliximab suppresses TNF-α, thereby increasing susceptibility to infections and immune-mediated responses (31). Most of these events have been documented in the drug label and are consistent with findings from previous literature (30).

However, several rare but strong-signal PTs—such as horner’s syndrome, henoch–schonlein purpura nephritis, mesothelioma, lip Tumor, morbid thoughts, and SAPHO syndrome—are not mentioned in the current drug label, indicating potential emerging safety concerns. Unlike the commonly reported infectious and immune events, these signals involve the nervous, renal, neoplastic, psychiatric, and skeletal systems, potentially linked to off-target effects of TNF-α inhibition (32). Among these, henoch–schonlein purpura nephritis represents a key PT with a relatively strong signal under the renal and urinary disorders SOC and is not included in the current prescribing information for infliximab, warranting particular attention. However, it should be emphasized that IBD itself is associated with a spectrum of renal manifestations, with an estimated incidence of 4%-23%. Common presentations include nephrolithiasis (the most frequent), IgA nephropathy/mesangial proliferative glomerulonephritis, tubulointerstitial nephritis, and secondary amyloidosis, with nephrolithiasis and IgA-related nephropathy being especially prominent (33). Therefore, the renal signal found in this analysis may partly reflect the inherent extraintestinal renal involvement of IBD. However, the relatively strong correlation observed in the case of infliximab exposure indicates that inhibition may further undermine immune homeostasis on the basis of disease-related baseline susceptibility. From the mechanism point of view, TNF-α blocking may interfere with mucosal immune regulation and immune complex clearance, which may promote IgA1 glycosylation abnormality or increase glomerular immune complex deposition, and further aggravate renal injury (28, 29). This finding is not an isolated phenomenon, but may reflect a broader immune imbalance model induced by cytokine inhibition. In addition to renal manifestations, some rare but biologically reasonable signals are also worthy of careful interpretation. Horner syndrome is rare, but considering the role of inflammatory mediators in autonomic nerve regulation, it may suggest that TNF-α regulation has a subtle influence on sympathetic ganglion function (34). Similarly, reports on morbid thinking suggest that changes in TNF-α-dependent neuroinflammatory pathways may affect neuropsychiatric homeostasis (35). SAPHO syndrome is characterized by inflammation of bone joints and abnormal bone remodeling, which may represent another manifestation of immune imbalance caused by cytokine blocking in bone and matrix tissue (36, 37). Although the number of cases is still limited, the mechanism consistency of these signals shows that it should not be regarded as pure accidental discovery. At the clinical level, it is recommended to be highly vigilant against these rare AEs. When the patient has atypical nervous system, psychosis, kidney (for example, elevated serum creatinine, abnormal urine routine, proteinuria), tumor or bone performance, it should be evaluated immediately, and the use of infliximab should be temporarily suspended or stopped according to careful risk-benefit assessment.

Subgroup analysis by gender showed that there were significant gender differences in AEs related to infliximab among IBD patients, which highlighted the key role of gender in drug safety evaluation. In the female subgroup, AEs were mainly concentrated in the fields of immune mediation, infection and tumor. Immune-related events, such as lupus-like syndrome, are particularly prominent, accompanied by infections including streptococcal tonsillitis. It is worth noting that rare AEs, such as SAPHO syndrome and vaginal squamous cell carcinoma, have occurred in the female subgroup, and these events have not been fully recorded in the existing drug instructions or previous literature. In contrast, AEs in the male subgroup are mainly related to cardiovascular system, nervous system and tumor. Common events include bradycardia, arrhythmia and infection, such as tuberculosis. Rare AEs include male breast cancer, radial nerve paralysis and proliferative glomerulonephritis. Further gender sensitivity analysis shows that women are more prone to immune-related signals (for example, lupus-like syndrome), while men are more prone to infection and hemodynamic abnormalities (for example, tuberculosis and bradycardia). Compared with previous reports, women’s immune-related events are consistent with existing research results (30); However, SAPHO syndrome and vaginal squamous cell carcinoma have not been recorded in the drug instructions or literature, which highlights the novelty of this study. From the perspective of mechanism, gender differences may be related to hormone regulation and immune dimorphism. Estrogen enhances B cell activation and promotes autoimmune response (38), while testosterone has a relative immunosuppressive effect, which may partly explain the phenomenon that women have higher frequency of immune-related signals and men are more prone to infection. In addition, the gender difference of TNF-α expression and its downstream inflammatory cascade may further affect the pedigree of treatment response and AEs (39). At the same time, differences in burden of complications and treatment patterns may also lead to observed differences; For example, a higher prevalence of cardiovascular risk factors in men may amplify cardiovascular signals, while a higher baseline prevalence of autoimmune diseases in women may increase the risk of immune-related events. In addition, gender differences in medical treatment behavior and adverse event reporting may introduce reporting or testing bias. Therefore, the interpretation of signal detection results from spontaneous reporting system should consider both biological mechanism and potential confounding factors.

Although cardiovascular signals and male breast cancer are rare, they may be related to the unique physiological response of men to TNF-α inhibition. Rare signals such as vaginal squamous cell carcinoma may reflect the local immune monitoring changes related to TNF-α inhibition, but this is still speculation (31). Radial nerve paralysis may represent a signal worthy of further mechanism exploration, rather than a confirmed adverse reaction (34). It is worth noting that this study is based on the database of spontaneous reports, which cannot fully adjust for potential confounding factors, such as age distribution, concomitant medication (such as corticosteroids or immunosuppressants), disease phenotype or disease severity. Therefore, the observed gender differences may reflect the combined effects of biological mechanism and residual confounding factors or reporting bias. In the future, real-world research with multivariate adjustment is needed to further verify these findings. Clinicians should adopt gender-specific monitoring strategies, focus on the immune and tumor AEs of female patients, and strengthen the assessment of cardiovascular, infection and nervous system of male patients. It should be noted that these suggestions are based on signal detection and need to be further verified in clinical research. Special attention should be paid to the atypical manifestations of rare signals to ensure early identification.

The comparison between CT group and MT group further illustrates the complexity of TNF-α inhibitors in the real world. In CT group, commonly used combination drugs, such as prednisone and azathioprine, are associated with more obvious cardiovascular and autonomic nervous system-related AEs. These findings may reflect the synergistic effect of pharmacodynamics, that is, combined immunosuppression will enhance systemic inflammatory regulation and vascular dystonia (39). Therefore, the observed signal may represent the drug interaction effect, rather than the single effect of infliximab (40). On the contrary, in MT group, immune mediation and some tumor signals seem to be more significant. Although this may indicate that infliximab monotherapy is enough to disrupt immune homeostasis and thus induce autoimmune or tumor-related events, it still needs to be cautious (30). However, previous studies generally show that the risk of malignant tumor is more common in infliximab combined with azathioprine, especially involving non-melanoma skin cancer, leukemia and lymphoma, while the evidence of monotherapy is still limited (41–43). Therefore, the tumor signals observed in MT group in this study are different from the existing conclusions, which should be interpreted with caution, because these signals may be influenced by confounding factors and inherent reporting bias in real-world data. Overall, the results of CT group may reflect that drug interaction enhances the systemic effect of TNF-α inhibitors, while MT group more directly reflects the immunomodulatory effect of infliximab (31). The cumulative effect of combined immunosuppression should be considered when interpreting the risk of malignant tumor, rather than attributing the risk entirely to a single drug. Clinically, the monitoring strategy should be adjusted according to the treatment methods: for patients receiving CT treatment, special attention should be paid to cardiovascular and malignant tumor risks; For patients receiving MT treatment, immune-related AEs and tumor risk (such as breast cancer) should be evaluated in combination with individual baseline risk factors to achieve individualized management.

AEs related to infliximab often lead to serious clinical consequences, and a considerable part of them require hospitalization or lead to death, which highlights the importance of its safety. The TTO analysis showed that the median occurrence time of AEs was 620 days; However, the shape parameter of Weibull distribution (β = 0.73) is less than 1, which indicates that there is an “early failure” mode, that is, most AEs occur in the early stage of treatment. Importantly, the relatively long median treatment time balance and the existence of β < 1 suggest that the time distribution of risk is heterogeneous, which is characterized by a high risk shortly after the start of treatment, and then gradually decreases with time, rather than most events occurring in the first month. It is worth noting that some serious AEs appeared several years after drug use, which emphasized the need to be vigilant against long-term risks. These results show that it is very important to strengthen monitoring in the first month after starting infliximab treatment, especially for potential target organs such as kidney, cardiovascular system and infection site. For patients who have been treated with infliximab for a long time, regular follow-up is very important to find the delayed serious adverse reactions. The joint analysis of TTO and WSP provides a time-dependent risk assessment framework for pharmacovigilance, which is helpful to optimize individualized monitoring strategies and improve patient safety.

Although the scope of this study is extensive, it is still limited by the inherent limitations of spontaneous reporting system. Underreporting, selective reports and incomplete clinical information may distort signal strength, especially for rare or non-serious events. Limiting the reporting target to medical professionals can improve the reliability, but may reduce the sensitivity to emerging signals. In addition, causal inference cannot be established, and unmeasured confounding factors (including disease severity, concomitant drugs and complications) may affect the results. Nevertheless, FAERS database is still of great value for hypothesis generation and early detection of unexpected safety signals (19). Future research should be included in a well-designed real-world cohort, and multivariate adjustment and mechanism research should be conducted to verify new findings, especially those related to gender differences and rare events.

In conclusion, based on FAERS database, this study analyzed the AE reports related to infliximab use in 80,138 IBD patients. The results showed that the burden of AE was heavy, and the incidence of AE was the highest in women and patients aged 18-64. Common AEs are consistent with known risks, such as lupus-like syndrome, tuberculosis and serum sickness. However, the study also found some rare but closely related AEs, including Horner syndrome, mesothelioma, SAPHO syndrome and vaginal squamous cell carcinoma, suggesting that there may be potential new safety problems that are not covered by the current drug labels. Gender subgroup analysis shows that women are mainly affected by immune and tumor-related events, while men experience cardiovascular and nervous system events more, which highlights the significant gender differences in drug safety. These findings suggest that gender-specific monitoring strategies should be implemented in clinical practice. In addition, corticosteroid combined with azathioprine is associated with an increased risk of autonomic nervous system and cardiovascular AEs, while monotherapy is more likely to cause immune and tumor-related events. These results emphasize the importance of FAERS database in post-marketing drug safety monitoring, and call on clinicians to be alert to emerging or gender-specific AEs. Future research should combine prospective design with molecular mechanism research to further verify these findings and clarify their potential mechanisms.