Pharmacovigilance Insights into Gastrointestinal Adverse Events of JAK Inhibitors: FAERS Signal Detection with Clinical and Pharmacological Implicationse

Pharmacovigilance Insights into Gastrointestinal Adverse Events of JAK Inhibitors: FAERS Signal Detection with Clinical and Pharmacological Implicationse | 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 Pharmacovigilance Insights into Gastrointestinal Adverse Events of JAK Inhibitors: FAERS Signal Detection with Clinical and Pharmacological Implicationse Chenzi Zhao, Zhaochu Wang, Jiumao Lin, Xianmei Li, Jianwei Zeng, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7427805/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 Background: Janus-kinase (JAK) inhibitors are increasingly used across surgical practice for immune-mediated disorders, yet their gastrointestinal (GI) safety profiles remain incompletely defined. Upadacitinib (selective JAK-1) has been linked to severe mucosal complications, whereas ruxolitinib (JAK-1/2) appears better tolerated. Robust real-world comparisons are lacking. Methods: We performed a retrospective, observational pharmacovigilance study of the FDA Adverse Event Reporting System from 1 July 2019 to 31 December 2024. After deduplication, 58 548 upadacitinib and 28 968 ruxolitinib safety reports were retrieved. GI events were coded with MedDRA and grouped into inflammation, ulcer/perforation, bleeding, motility disorders, symptoms and other serious events. Multivariable logistic regression generated adjusted reporting odds ratios (aROR) for ruxolitinib versus upadacitinib, controlling for age, sex, comorbidities and concomitant NSAIDs; sensitivity analyses stratified by age and NSAID use. Results: Compared with upadacitinib, ruxolitinib showed higher reporting of GI motility disorders (803 events; aROR = 1.52, 95% CI 1.05–2.20) but markedly lower reporting of GI inflammation (641 events; aROR = 0.14, 0.07–0.29) and ulcer/perforation (229 events; aROR = 0.27, 0.10–0.68). Upadacitinib-related inflammation was dominated by ulcerative colitis (40.8 %) and Crohn’s disease (28.2 %), while 20.8 % of ulcer/perforation events were frank intestinal perforations. Median onset occurred within the first treatment year for both agents (8 months for upadacitinib ulcers/perforations; 6.5 months for ruxolitinib motility disorders). Age-stratified analyses confirmed an excess of upadacitinib-associated inflammation in adults and children, whereas ruxolitinib-related symptoms were concentrated in patients > 65 years. NSAID co-administration magnified upadacitinib-associated ulcers/perforations but had little effect on ruxolitinib patterns. Conclusions: In real-world practice, upadacitinib carries a substantially higher signal for severe inflammatory and ulcerative GI injury, whereas ruxolitinib is mainly associated with non-serious motility disturbances. Upadacitinib carries a higher signal for severe inflammatory and ulcerative GI injury, whereas ruxolitinib is mainly associated with non-serious motility disturbances. These associations are hypothesis‑generating rather than causal and warrant validation through prospective studies and mechanistic investigations. Health sciences/Diseases Health sciences/Gastroenterology Health sciences/Medical research Upadacitinib Ruxolitinib Gastrointestinal adverse events FAERS Pharmacovigilance Janus-kinase inhibitors Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction The gastrointestinal tract, the largest immune organ and core site for nutrient absorption in the human body, plays a critical role in maintaining systemic immune homeostasis and metabolic balance. The integrity of gastrointestinal function directly impacts these processes. Drug-induced damage to the intestinal mucosa can lead to the depletion of goblet cells, degradation of tight junction proteins, and dysbiosis, which facilitates endotoxemia and triggers systemic inflammatory responses, thereby establishing a vicious cycle of "drug toxicity-barrier disruption-secondary infections" 1 , 2 . Studies have shown that patients undergoing long-term immunomodulatory therapy often experience moderate to severe gastrointestinal symptoms, with drug-related diarrhea, abdominal pain, and gastrointestinal bleeding being the leading causes of treatment discontinuation 3 . A retrospective study further revealed that adverse drug events in elderly patients (≥ 65 years) predominantly affect the digestive system (27.87%) and metabolic/nutritional systems (24.53%). This finding may be related to age-associated decreases in gut microbiota diversity and reduced short-chain fatty acid synthesis capacity, which exacerbates drug-induced intestinal epithelial apoptosis 4 , 5 . Recurrent infections or nutritional depletion often compel clinicians to reduce treatment intensity, indirectly leading to the loss of disease control. Therefore, predicting gastrointestinal adverse events and performing systematic monitoring are key strategies to overcome the vicious cycle of infection and improve long-term disease prognosis. Janus kinase (JAK) inhibitors are a class of novel small-molecule targeted drugs that selectively inhibit the JAK-STAT signaling pathway. They have demonstrated significant efficacy in treating chronic hematologic malignancies and inflammation-mediated autoimmune diseases. However, current research indicates that the gastrointestinal adverse event risk associated with JAK inhibitors requires close attention 6 . Upadacitinib, a highly selective JAK1 inhibitor, has shown rapid symptom relief and mucosal healing advantages in phase III clinical trials for rheumatoid arthritis (RA) and Crohn's disease (CD), with clinical remission rates significantly superior to those of traditional biologic agents. Nonetheless, serious gastrointestinal adverse events, such as gastrointestinal perforation and bleeding, have also been reported 7 , 8 . On the other hand, ruxolitinib, a dual JAK1/2 inhibitor, is primarily used to treat hematologic disorders such as myelofibrosis and polycythemia vera. Recent studies have shown that ruxolitinib can alleviate colonic inflammation by inhibiting STAT1 phosphorylation in animal models, suggesting its potential in treating Th1-type immune dysregulation diseases 9 . However, its gastrointestinal-related adverse effects remain unclear. Existing clinical trials often have limited follow-up periods (usually ≤ 52 weeks) and frequently exclude patients with concomitant gastrointestinal diseases during the screening process, which may lead to underestimation of delayed toxicity in the real world. The FDA Adverse Event Reporting System (FAERS), as the largest post-market surveillance platform globally, integrates cross-population and multi-indication data to identify rare adverse events and high-risk subgroups through large sample sizes. This study examines the FAERS reports of upadacitinib and ruxolitinib and systematically compares their gastrointestinal risk profiles and provide evidence-based insights to optimize treatment decisions. 2. Materials and Methods 2.1 Data Source and Study Design This study was designed as an observational, retrospective pharmacovigilance analysis based on the FDA Adverse Event Reporting System (FAERS). The FAERS database integrates both voluntary and mandatory adverse event reports submitted globally by healthcare professionals, consumers, and pharmaceutical companies 10 . The database includes the following seven core data tables: demographic information (DEMO), drug details (DRUG), adverse event terminology (REAC), patient outcomes (OUTC), report source (RPSR), treatment time window (THER), and indications (INDI). The study included cases reported between July 1, 2019 and December 31, 2024 to cover the post-marketing surveillance period for the target drugs, upadacitinib and ruxolitinib. Data integration was performed using R software (version 4.4.2). The analysis focused on cases related to the main suspect drugs, identified by their generic names (upadacitinib, ruxolitinib) and brand names (RINVOQ, Jakavi), ensuring that the adverse events directly associated with the drugs were included. This study has been reported in accordance with the STROCSS 2025 criteria 11 . Data cleaning was performed using a dual deduplication strategy. First, the latest report version for each case ID was retained according to FDA guidelines. Second, duplicate records across cases were excluded using a tuple-matching algorithm based on four variables: age, sex, event date, and country of occurrence 12 . The adverse events were then standardized and coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 13 . The events were categorized into anatomical systems (e.g., gastrointestinal disorders) based on the System Organ Class (SOC), with specific events (e.g., diarrhea) described using preferred terms (PTs). The events were further classified into Hierarchical Level 2 (HLGT) and Hierarchical Level 3 (HLT) categories, combined with their clinical significance. This classification system enabled systematic categorization and frequency analysis of adverse events, providing a standardized foundation for subsequent risk signal detection. 2.2 Statistical Analysis We performed disproportionality analysis using the reporting odds ratio (ROR), a well-validated method for detecting disproportionate reporting signals in post-marketing passive surveillance databases 14 . The ROR assesses whether the reporting of adverse events associated with a drug is higher than expected, with the expected value being the adverse event incidence rate for any other drug in the reference group. A multivariable logistic regression model was used to calculate adjusted estimates 15 , 16 . First, upadacitinib and ruxolitinib were directly compared according to patient characteristics, report sources, and other relevant information. Second, the regression model was adjusted for factors such as sex, age, hypertension, diabetes, gastritis, hepatitis, cholecystitis, and concomitant NSAID use. In each regression model, the significance of the nonlinear age term and potential interactions between age and the two drugs were evaluated using restricted cubic spline functions; only statistically significant terms were included in the final model. Data on hypertension, diabetes, gastritis, hepatitis, and cholecystitis were derived from the reported indications. Finally, sensitivity analyses were performed, stratified by age groups (minor ( 65 years)) and NSAID use. Regression models were applied to these subgroups. In the sensitivity analysis, some subgroups exhibited complete separation or extreme sparsity of data, preventing model convergence. These variables were excluded from the final multivariable model to ensure result reliability 17 . Adjusted RORs and their 95% confidence intervals (CIs) were used to evaluate differences between the two drugs. A significant increase in the likelihood of gastrointestinal adverse events with ruxolitinib compared with that of upadacitinib was considered when the upper limit of the 95% CI was greater than 1. Data processing and statistical analysis were conducted using R software (R Foundation for Statistical Computing). 3. Results A total of 58,548 safety reports for upadacitinib and 28,968 safety reports for ruxolitinib were included in the analysis. The mean age was 57.8 years (± 16 years) for upadacitinib and 49.8 years (± 26 years) for ruxolitinib, with male proportions of 71.9% and 45.0%, respectively. We observed that patients treated with upadacitinib had a higher mean age and male proportion compared with those treated with ruxolitinib. Additionally, the proportions of individuals with diabetes (0.67% vs. 0.09%) and hypertension (0.82% vs. 0.20%) were greater among upadacitinib users. In contrast, a greater proportion of patients receiving ruxolitinib were also treated with NSAIDs compared with those receiving upadacitinib (11.8% vs. 4.24%). The majority of the reports for both drugs were from the Americas, with the United States accounting for 68.6% of the upadacitinib reports and 81.3% of the ruxolitinib reports. Most of the reports for both drugs were submitted by healthcare professionals (97.0% for upadacitinib and 70.1% for ruxolitinib). The distribution of report years differed between the two drugs, corresponding to their respective approval years (Table 1 ). Table 1 Demographic and clinical characteristics of safety reports of Upadacitinib and Ruxolitinib. Upadacitinib (n = 58,548) Ruxolitinib (n = 28,968) Reporting region US 40185/58548(68.63%) 23538/28965(81.26%) CA 4060/58548(6.93%) 464/28965(1.60%) DE 1909/58548(3.26%) 463/28965(1.59%) JP 1707/58548(2.91%) 360/28965(1.24%) FR 434/58548(0.74%) 574/28965(1.98%) Reporter Health-professional 3374/3479(97.01%) 200/285(70.18%) Consumer/Lawyer/Other 105/3479(3.02%) 85/285(29.82%) Reporting year 2019–2020 60/58547(0.10%) 1696/28966(5.86%) 2020–2021 1518/58547(2.59%) 3467/28966(12.00%) 2021–2022 4080/58547(6.97%) 3843/28966(13.27%) 2022–2023 17574/58547(29.98%) 6982/28966(24.10%) 2023–2024 17640/58547(30.13%) 6742/28966(23.28%) 2024–2025 17673/58547(30.19%) 6231/28966(21.51%) Age, years Mean (± SD) 57.8(± 15.9) 49.8(± 26.3) Sex Female 39561/55001(71.93%) 2172/4848(44.80%) Male 15440/55001(28.07%) 2676/4848(55.20%) Concomitant medications NSAIDs 2483/58548(4.24%) 3419/28968(11.80%) Diabetes 391/58548(0.67%) 27/28965(0.09%) Hypertension 479/58548(0.82%) 57/28965(0.20%) Hepatitis 55/58548(0.09%) 7/28965(0.02%) Cholecystitis 1/58548(0.00%) 0/28965(0.00%) Gastritis 17/58548(0.03%) 4/28965(0.01%) Based on HLGT and HLT classifications and the clinical significance of specific events (PTs), the selected PTs were categorized into the following groups: gastrointestinal inflammation-related events, gastrointestinal bleeding-related events, gastrointestinal ulcer and perforation-related events, gastrointestinal motility disorder-related events, other serious events (such as gastrointestinal stricture and obstruction), and gastrointestinal symptom-related events. First, to detect disproportionate reporting signals, we compared the reports of gastrointestinal adverse events following upadacitinib and ruxolitinib treatment. Compared with upadacitinib, ruxolitinib was associated with increased reporting of gastrointestinal motility disorder-related events [n = 803, adj. ROR = 1.52 (1.05, 2.20)], whereas upadacitinib was associated with a greater incidence of gastrointestinal inflammation-related events [n = 641, adj. ROR = 0.14 (0.07, 0.29)] and gastrointestinal ulcers and perforation-related events [n = 229, adj. ROR = 0.27 (0.10, 0.68)]. Although no statistically significant differences between the two drugs in gastrointestinal bleeding-related events [n = 346, adj. ROR = 0.52 (0.27, 1.02)] and gastrointestinal symptom-related events [n = 2956, adj. ROR = 1.21 (0.99, 1.48)] were observed, the upper limit of the confidence interval for bleeding events and the lower limit for symptom events were close to 1. These findings suggest that upadacitinib may have a greater tendency to cause bleeding events, whereas ruxolitinib might pose a greater potential risk for gastrointestinal discomfort. Statistical significance was not observed for other serious events, such as gastrointestinal stricture and obstruction [n = 346, adj. ROR = 0.76 (0.44, 1.31)], which requires further data or research to confirm (Fig. 1 ). Among the 305 patients receiving ruxolitinib who experienced gastrointestinal motility disorder-related events, 203 (62.1%) experienced diarrhea, and 89 (29.2%) developed constipation (Fig. 2 A). Among the 211 gastrointestinal ulcers and perforation-related events resulting from upadacitinib treatment, 44 (20.8%) were intestinal perforation, and 32 (15.2%) were gastrointestinal perforation. Among the 617 gastrointestinal inflammation-related events, 252 (40.8%) were ulcerative colitis, and 174 (28.2%) were Crohn’s disease (Fig. 2 B). The median time to gastrointestinal motility disorder, gastrointestinal bleeding, gastrointestinal ulcer and perforation, gastrointestinal symptoms, gastrointestinal inflammation, and other serious adverse events after ruxolitinib treatment was 30 days (9–502), 279 days (57–591), 188 days (155–612), 63 days (16–357), 42.5 days (10.8–266), and 103 days (22–189), respectively. In contrast, the median time from the start of upadacitinib treatment to the onset of these gastrointestinal adverse events was 64.5 days (12–228), 91 days (30–344), 126 days (34.8–322), 102 days (30–306), 122 days (27.5–276), and 145 days (73.5–478), respectively (Fig. 3 ). Overall, the distribution patterns of onset times across different gastrointestinal adverse event categories were broadly similar between the two drugs, with most events occurring within the first year of treatment. Additionally, we performed sensitivity analyses stratified by age group and NSAID use. In the age group stratification, upadacitinib significantly increased gastrointestinal inflammation in both the minor subgroup (adj. ROR = 0.08 [0.02–0.37]) and the adult subgroup (adj. ROR = 0.03 [0.13–0.69]). Ruxolitinib, on the other hand, significantly increased gastrointestinal symptoms in the elderly subgroup (adj. ROR = 1.15 [1.10–2.20]), with no gastrointestinal ulcer and perforation events in the minor subgroup or other serious events in the elderly subgroup. In the adult subgroup, ruxolitinib tended to reduce the incidence of gastrointestinal ulcer and perforation risk (adj. ROR = 0.08 [0.02-1.00]), although the upper limit of the confidence interval reached the null value of 1, suggesting a potential clinical difference (Fig. 4 ). In the NSAID use stratification, upadacitinib was associated with statistically significant increases in reports of gastrointestinal inflammation (adj. ROR = 0.15 [0.07–0.30]) and gastrointestinal ulcer and perforation (adj. ROR = 0.29 [0.11–0.74]) in the non-NSAID use subgroup, and a trend toward increased gastrointestinal bleeding risk (adj. ROR = 0.5 [0.25–1.03]). For ruxolitinib, in the non-NSAID use subgroup, an increase in gastrointestinal motility disorder reports (adj. ROR = 1.52 [1.04–2.23]) was observed, whereas in the NSAID use subgroup, gastrointestinal symptom reports (adj. ROR = 2.23 [1.10–4.52]) were significantly higher (Fig. 5 ). 4. Discussion In this contemporary global post-marketing surveillance study, we selected upadacitinib as the reference group for comparison. Upadacitinib has demonstrated robust efficacy in several phase III clinical trials, particularly for ulcerative colitis (UC) and other forms of inflammatory bowel disease (IBD). Given its prominent clinical position in disease treatment, evaluating the gastrointestinal safety profile of ruxolitinib relative to that of upadacitinib could provide valuable insights for potential treatment options. We performed a multivariable logistic regression analysis to calculate adjusted reporting odds ratios (RORs), considering confounding factors such as age, sex, and concomitant medications. Compared with ruxolitinib, upadacitinib was associated with increased reporting of gastrointestinal inflammation-related events and gastrointestinal ulcer and perforation-related events during treatment, with a high likelihood of gastrointestinal bleeding, particularly in more severe preferred terms (PTs), such as intestinal perforation, gastrointestinal bleeding, and colitis. In contrast, adverse events related to ruxolitinib were primarily focused on gastrointestinal motility disorders and gastrointestinal discomfort, with common adverse events including constipation, diarrhea, nausea, and abdominal pain. Most events for both drugs occurred within the first year of treatment, whereas ruxolitinib did not reach a median time for several gastrointestinal adverse events, suggesting a lower incidence or later onset of these events during the observation period, which may reflect a relative advantage in gastrointestinal tolerability. A five-year study reported four cases of gastrointestinal perforation in the upadacitinib group, all of which were severe adverse events 18 . Similarly, gastrointestinal adverse events such as diarrhea and constipation were reported during ruxolitinib treatment 19 , 20 . These findings highlight the need for close monitoring of gastrointestinal symptoms during the use of both drugs, which is consistent with our study results. In the age-stratified sensitivity analysis, gastrointestinal inflammation-related adverse events associated with upadacitinib were statistically significant in both adult and pediatric patients, with the adult group particularly suggesting a risk of gastrointestinal ulcer and perforation. In the gastrointestinal inflammation subgroup, 56.3% of pediatric patients and 27.6% of adult patients developed ulcerative colitis (colitis ulcerative), whereas 23.7% of adult patients with gastrointestinal ulcer and perforation events experienced intestinal perforation, a severe complication. Existing studies have shown that upadacitinib, a selective JAK1 inhibitor, significantly suppresses the downstream signaling of various pro-inflammatory cytokines, including IL-6, IFN-γ, and GM-CSF, by blocking the JAK-STAT pathway. While this inhibition helps alleviate symptoms of inflammatory diseases, it also reduces the body’s normal immune defense capabilities, making it easier for potential pathogenic microorganisms in the gut to become activated, leading to mucosal immune imbalance and inflammation. This, in turn, may result in persistent damage to the intestinal wall and the occurrence of perforation 21 . Local infections or loss of barrier function may also promote the formation of necrosis, which is one of the important mechanisms for perforation. In the age subgroup analysis, the proportion of pediatric patients with ulcerative colitis was greater than that of adults. Considering the incomplete development of the gastrointestinal mucosa and immune defense capabilities in children, they are more prone to drug-induced gastrointestinal adverse events. Close monitoring during treatment is required, particularly regarding dosage, treatment duration, and the choice of concomitant therapies 22 . In contrast, ruxolitinib primarily induces gastrointestinal motility disorders and gastrointestinal symptoms, with a predominant occurrence in the elderly population aged 65 years and older. In this group, 60.9% of patients experienced diarrhea, 30.4% developed constipation, and abdominal pain (upper) was the most frequently reported gastrointestinal symptom. The mechanisms underlying gastrointestinal motility disorders and symptoms induced by ruxolitinib remain unclear. However, notably, there have been no clinical reports of ruxolitinib-induced gastrointestinal ulcers or perforations in pediatric patients, and no significant severe gastrointestinal complications have been reported in elderly patients. Overall, the incidence of severe adverse events with ruxolitinib was lower than that with upadacitinib, suggesting that ruxolitinib may improve patient adherence. In the NSAID stratified sensitivity analysis, upadacitinib was associated with a significant increase in reports of gastrointestinal inflammation and ulcer perforation events in the non-NSAID use subgroup, indicating that its gastrointestinal toxicity may be independent of NSAID use. The three most common adverse events were ulcerative colitis, intestinal perforation, and lower gastrointestinal bleeding (hematochezia), all of which are severe adverse events. Notably, the combination of upadacitinib with NSAIDs may lead to dual impairment of the mucosal barrier, suppression of epithelial repair and stem cell renewal, and exacerbation of dysbiosis, which synergistically increases the risk of gastrointestinal inflammation, ulceration, and perforation 23 . In phase III trials of upadacitinib for ulcerative colitis, the use of concomitant NSAIDs was highlighted as further increasing the risk of gastrointestinal perforation 24 . FDA-related studies also indicate a significantly higher reporting rate of gastrointestinal perforation when upadacitinib and NSAIDs are used together 25 . Our study revealed a statistically significant difference between upadacitinib and ruxolitinib in the non-NSAID subgroup, indicating that upadacitinib is associated with greater gastrointestinal toxicity. This suggests that even without the concomitant use of NSAIDs, careful monitoring for gastrointestinal inflammation and ulceration perforation events is warranted. Ruxolitinib, in this subgroup, is primarily associated with gastrointestinal motility disorders, with 67.6% of patients experiencing diarrhea. Gastrointestinal symptoms were predominantly abdominal pain, whereas abdominal discomfort was more frequently reported in patients who used NSAIDs. Importantly, the reporting odds ratio (ROR), as a relative reporting odds ratio, can be influenced by baseline reporting rates and prescribing biases. Specifically, if the baseline reporting rate in this population is low or if clinicians may be more inclined to avoid using NSAIDs in patients with a history of gastrointestinal disorders or in high-risk populations, the risk profile could be artificially lowered due to the co-administration of gastroprotective drugs such as proton pump inhibitors (PPIs). Additionally, gastrointestinal perforation events in the pediatric subgroup, NSAID use subgroup, and other severe events in the elderly subgroup, as well as gastrointestinal inflammation events in the NSAID use subgroup, were not reliable for calculating effect sizes due to sparse data (event rates < 1%). These limitations suggest that the current findings need further validation through multicenter collaboration and larger sample sizes. Upadacitinib, a highly effective and widely used small-molecule targeted oral immunomodulator, has demonstrated significant efficacy in moderate-to-severe inflammatory bowel diseases (IBD), particularly ulcerative colitis, in several phase III trials. However, its gastrointestinal-related adverse event profile requires careful monitoring, especially in patients with a history of gastrointestinal diseases. In phase III clinical trials of upadacitinib, patients treated with upadacitinib had a higher incidence and severity of gastrointestinal adverse events, including serious reactions such as gastrointestinal perforation, compared with those receiving TNF inhibitors or placebo 8 . Furthermore, concerns regarding gastrointestinal adverse events were raised in clinical trials even before phase III studies 26 . Initially approved for the treatment of myelofibrosis (MF) and polycythemia vera (PV), ruxolitinib has recently shown potential in treating immune-related diseases in PV patients, with case reports indicating improvement in their immune conditions following ruxolitinib treatment 27 , 28 . In a study involving patients with very early-onset IBD (VEO-IBD) under 6 years of age, ruxolitinib demonstrated good clinical improvement, including reduced diarrhea, lower inflammation markers, and improved nutritional status 29 . Animal experiments have also shown that ruxolitinib alleviates colitis symptoms in mouse models by inhibiting NF-κB-related inflammation and apoptotic responses while restoring STAT3-mediated epithelial barrier function 30 . Further in-depth analysis of the data in this study revealed that the adverse events associated with upadacitinib are primarily gastrointestinal inflammatory injuries, such as colitis, intestinal perforation, and gastrointestinal bleeding, which are of significant clinical severity. These adverse events occur relatively early during treatment and are reported at a higher frequency across multiple subgroups. Particularly in the non-NSAID use subgroup, gastrointestinal inflammatory injuries related to upadacitinib were significantly more frequent, suggesting a substantial impact on the integrity of the mucosal barrier. In contrast, adverse reactions caused by ruxolitinib are more concentrated in gastrointestinal motility or functional abnormalities, such as diarrhea, constipation, and nausea. Although the frequency of these events is not low, they are mostly mild to moderate and require relatively less clinical intervention. Moreover, ruxolitinib did not reach the median onset time for several adverse event categories, including gastrointestinal inflammation and gastrointestinal ulcer and perforation, which may indicate that its adverse events develop more slowly or have a lower overall incidence. This difference may arise from the differing JAK inhibition profiles of the two drugs: upadacitinib, a selective JAK1 inhibitor, is more likely to affect inflammatory signaling 31 , whereas ruxolitinib, a JAK1/2 inhibitor, may cause less damage to the gastrointestinal mucosa while modulating immune responses 32 . This characteristic may provide a theoretical basis for the potential expansion of the use of ruxolitinib in immune-related indications that rely on gastrointestinal tolerance, such as IBD, and warrants further validation through prospective studies. Although this study reveals the differences in gastrointestinal adverse events between upadacitinib and ruxolitinib using real-world pharmacovigilance data and suggests that ruxolitinib has good tolerability in specific populations and potential therapeutic value in immune indications, such as IBD, that rely on gastrointestinal tolerance, further research is required for validation. Future studies should include prospective, multi-center, real-world cohort studies that integrate electronic medical records and follow-up data to systematically evaluate the efficacy and safety of ruxolitinib in relevant patient populations, particularly in those with a history of gastrointestinal diseases or high-risk backgrounds, such as the use of NSAIDs. Additionally, the differential effects of ruxolitinib compared with those of other JAK inhibitors in different patient subtypes should be explored, with a focus on identifying the risk factors and potential mechanisms for gastrointestinal adverse events. In terms of mechanistic studies, combining animal models or histological experiments to verify the impact of ruxolitinib on intestinal epithelial barrier function is recommended, thereby providing theoretical support and clinical evidence for its expanded indications in diseases such as IBD. 5. Limitations This study was based on the FAERS database, which, while providing many real-world adverse event reports and aiding in the detection of potential safety signals, has several inherent limitations. First, the FAERS is a spontaneous reporting system that is subject to reporting bias, missing information, duplicate cases, and severity-driven reporting, and it cannot provide actual incidence rates or establish causality. Second, the two drugs compared in this study have different indications. Although multivariable regression controlled for some confounding factors, indication bias and prescribing preferences may still influence the results 33 . Furthermore, the lack of critical variables such as drug duration, dosage, specific indications, and laboratory markers in the FAERS limits further refinement of the risk model. Therefore, the results of this study should be considered hypothesis-generating signals that require validation through prospective clinical studies. Nevertheless, FAERS reflects the real-world environment and provides opportunities for early signal detection, investigation of rare adverse events, and comparisons between similar drugs. Drug sensitivity research continues to play a key role in adverse event prediction and clinical individualized medication decision making 34 – 36 . 6. Conclusion In conclusion, based on the FAERS pharmacovigilance database, this study compared and analyzed the gastrointestinal adverse event profiles of upadacitinib and ruxolitinib from multiple dimensions. The results show that upadacitinib is more likely to induce gastrointestinal inflammatory injuries, particularly severe events such as intestinal perforation, bleeding, and colitis, with significant risks observed across multiple subgroups. In contrast, ruxolitinib’s adverse reactions primarily manifest as gastrointestinal motility disturbances and mild to moderate discomfort, with overall better tolerability. Additionally, ruxolitinib did not reach the median onset time for several preferred terms (PTs), suggesting a broader safety margin. Given the inherent limitations of spontaneous reporting systems, these observations should be interpreted as hypothesis-generating rather than establishing causality. Although these findings require further validation through prospective studies, combined with the positive effects of ruxolitinib in IBD animal models and a few clinical cases reported in the existing literature, they suggest that ruxolitinib may have potential therapeutic advantages in gastrointestinal-sensitive populations. This warrants further exploration of its potential for expanding indications in autoimmune diseases, such as inflammatory bowel disease (IBD). Declarations Data Availability Statement The data that support the findings of this study are publicly available from the FDA Adverse Event Reporting System (FAERS) at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. All data used in this study were obtained from this open-access resource and processed using standard pharmacovigilance methods. Additional processed data or analysis scripts are available from the corresponding author upon reasonable request. Ethics statement Ethical approval was not required for this study in accordance with the local legislation and institutional requirements because the data were obtained from the publicly accessible U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Author contribution ZCZ and ZCW conceptualized and designed the study. ZCZ drafted and wrote the manuscript. ZCZ and ZCW performed the data analysis. JML and XML curated the data. YTC and YL contributed to analysis. JWZ, XXW and YMX visualized the data. JH and WHZ reviewed the manuscript. RS supervised the data processing. JW supervised the study and approved the final version. Funding The study was supported by the Clinical Research Center for Traditional Chinese Medicineon Anorectal and Perianal Wound Repair of Fujian Province (2022Y2011). Conflict of Interest Statement The authors declare that they have no financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work submitted to the journal. Generative AI statement Artificial Intelligence (AI) tools were used solely to improve the readability of certain paragraphs. No AI tools were employed in data collection, analysis, or interpretation. All data were generated and verified by the authors, who affirm their authenticity. The authors carefully reviewed and edited the manuscript and take full responsibility for its content. References Berkes, J., Viswanathan, V. K., Savkovic, S. D. & Hecht, G. Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation. Gut 52 , 439–451 (2003). Hamdeh, S., Micic, D. & Hanauer, S. Review article: drug-induced small bowel injury. Aliment. Pharmacol. Ther. 54 , 1370–1388 (2021). Abu-Sbeih, H. & Wang, Y. 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Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease. N Engl. J. Med. 388 , 1966–1980 (2023). Overstreet, A. M. et al. The JAK inhibitor ruxolitinib reduces inflammation in an ILC3-independent model of innate immune colitis. Mucosal Immunol. 11 , 1454–1465 (2018). Research, C. for D. E. and. FDA Adverse Event Reporting System (FAERS) Public Dashboard. FDA (2023). Agha, R. A. et al. Revised Strengthening the reporting of​ cohort, cross-sectional and case-control studies in surgery (STROCSS) Guideline: An update for the age of Artificial Intelligence. Premier J. Science 2025 :10100081 . Poluzzi, E. et al. IntechOpen,. Data Mining Techniques in Pharmacovigilance: Analysis of the Publicly Accessible FDA Adverse Event Reporting System (AERS). in Data Mining Applications in Engineering and Medicine (2012). 10.5772/50095 Mozzicato, P. M. D. R. A. Pharm. Med. 23 , 65–75 (2009). Bate, A. et al. A Bayesian neural network method for adverse drug reaction signal generation. E J. Clin. Pharmacol. 54 , 315–321 (1998). Bate, A. & Evans, S. J. W. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol. Drug Saf. 18 , 427–436 (2009). Li, X. et al. Recent status and trends of innate immunity and the gut-kidney aixs in IgAN: A systematic review and bibliometric analysis. Int. Immunopharmacol. 143 , 113335 (2024). Greenland, S., Mansournia, M. A. & Altman, D. G. Sparse data bias: a problem hiding in plain sight. BMJ 352, i (2016). (1981). van Vollenhoven, R. et al. Upadacitinib monotherapy versus methotrexate monotherapy in patients with rheumatoid arthritis: efficacy and safety through 5 years in the SELECT-EARLY randomized controlled trial. Arthritis Res. Ther. 26 , 143 (2024). Zeiser, R. et al. Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease. N. Engl. J. Med. 385 , 228–238 (2021). Verstovsek, S. et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J. Hematol. Oncol. 10 , 55 (2017). Schwartz, D. M. et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov . 16 , 843–862 (2017). Huang, H., Jiang, J., Wang, X., Jiang, K. & Cao, H. Exposure to prescribed medication in early life and impacts on gut microbiota and disease development. EClinicalMedicine 68 , 102428 (2024). Panchal, N. K. Prince Sabina, E. Non-steroidal anti-inflammatory drugs (NSAIDs): A current insight into its molecular mechanism eliciting organ toxicities. Food Chem. Toxicol. 172 , 113598 (2023). Danese, S. et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet 399 , 2113–2128 (2022). Goldman, A. et al. Gastrointestinal Perforations Associated With JAK Inhibitors: A Disproportionality Analysis of the FDA Adverse Event Reporting System. United European Gastroenterology Journal n/a. Cohen, S. B. et al. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme. Ann. Rheum. Dis. 80 , 304–311 (2021). Swei, E. C., Fox, C. M., Bowles, D. W., Rizeq, M. N. & Onyiah, J. C. Use of Ruxolitinib for the Simultaneous Treatment of Severe Refractory Ulcerative Colitis and Polycythemia Vera. ACG Case Rep. J. 9 , e00741 (2022). Marquès-Camí, M. et al. A 61-year-old patient with Crohn’s disease and severe postoperative recurrence responding to JAK inhibitor ruxolitinib for polycythemia vera treatment. Gastroenterol. Hepatol. 45 (Suppl 1), 16–17 (2022). Rudra, S. et al. Ruxolitinib: Targeted Approach for Treatment of Autoinflammatory Very Early Onset Inflammatory Bowel Disease. Clin. Gastroenterol. Hepatol. 20 , 1408–1410e2 (2022). Li, C. et al. Ruxolitinib Alleviates Inflammation, Apoptosis, and Intestinal Barrier Leakage in Ulcerative Colitis via STAT3. Nes Nutr. Ws . 29 , 1191–1201 (2023). Nielsen, O. H. et al. Selective JAK1 inhibitors for the treatment of inflammatory bowel disease. Pharmacol. Ther. 245 , 108402 (2023). Poto, R. et al. The JAK1/JAK2 inhibitor ruxolitinib inhibits mediator release from human basophils and mast cells. Front Immunol 15 , (2024). Raschi, E. et al. Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance. Targ Oncol. 15 , 449–466 (2020). Harpaz, R. et al. Performance of Pharmacovigilance Signal-Detection Algorithms for the FDA Adverse Event Reporting System. Clin. Pharmacol. Ther. 93 , 539–546 (2013). Goldman, A. et al. The real-world safety profile of sodium-glucose co-transporter-2 inhibitors among older adults (≥ 75 years): a retrospective, pharmacovigilance study. Cardiovasc. Diabetol. 22 , 16 (2023). Khouri, C. et al. Adverse drug reaction risks obtained from meta-analyses and pharmacovigilance disproportionality analyses are correlated in most cases. J. Clin. Epidemiol. 134 , 14–21 (2021). Additional Declarations No competing interests reported. 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7427805","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":510412516,"identity":"b23aa2f5-2ca3-4ab2-915f-6858b562700d","order_by":0,"name":"Chenzi Zhao","email":"","orcid":"","institution":"The Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chenzi","middleName":"","lastName":"Zhao","suffix":""},{"id":510412517,"identity":"fa31cecd-71a6-4e3c-82b8-d9e05830ccf6","order_by":1,"name":"Zhaochu Wang","email":"","orcid":"","institution":"The Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Zhaochu","middleName":"","lastName":"Wang","suffix":""},{"id":510412518,"identity":"51013532-8bd6-47a0-a982-19b4396c3aec","order_by":2,"name":"Jiumao Lin","email":"","orcid":"","institution":"Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jiumao","middleName":"","lastName":"Lin","suffix":""},{"id":510412519,"identity":"7d247dd2-f4cf-4eac-8da0-9910adefb281","order_by":3,"name":"Xianmei Li","email":"","orcid":"","institution":"Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xianmei","middleName":"","lastName":"Li","suffix":""},{"id":510412520,"identity":"f67c3ed2-34e5-41e0-80cf-ed4fb333d33a","order_by":4,"name":"Jianwei Zeng","email":"","orcid":"","institution":"Fujian University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jianwei","middleName":"","lastName":"Zeng","suffix":""},{"id":510412521,"identity":"8ec2597c-22b3-46e2-a628-fb532969aa6f","order_by":5,"name":"Yun Liu","email":"","orcid":"","institution":"Fujian University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Liu","suffix":""},{"id":510412522,"identity":"dcbd121f-8da1-48c5-8201-a9b4db18faaa","order_by":6,"name":"Yangtao Chen","email":"","orcid":"","institution":"The Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yangtao","middleName":"","lastName":"Chen","suffix":""},{"id":510412523,"identity":"71902100-0a5e-4c8b-84b1-2ee46adfc2fa","order_by":7,"name":"Wenhong Zhang","email":"","orcid":"","institution":"Fujian University of Traditional Chinese Medicine Affiliated Rehabilitation 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xuxiong","middleName":"","lastName":"Wu","suffix":""},{"id":510412529,"identity":"aacd882c-72be-46f2-a600-d86d1c0957dd","order_by":11,"name":"Rong Shi","email":"","orcid":"","institution":"The Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Rong","middleName":"","lastName":"Shi","suffix":""},{"id":510412532,"identity":"8604b395-7a6e-4393-817e-173e61c5512b","order_by":12,"name":"Jing Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtElEQVRIiWNgGAWjYLCCBAYGOTb25gPEqmcGaklgMObjOZZAghagNYnzJHIUiNPAP7v/4IeHPw6ntzHkMDD8qNhGWIvEncPMEgkJh3PbGM4eYOw5c5sIa24kszGAtTD2JTAzthGhRR6qJZ2NmceAOC0GUC0JbGzEajG8kWwskZCWbtjGw5ZwkCi/yN1IfPjxh421vPz8xwcf/KggxvsQ0AwmDxCtHgjqSFE8CkbBKBgFIw0AAAEdOh997UUfAAAAAElFTkSuQmCC","orcid":"","institution":"The Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jing","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-08-21 15:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7427805/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7427805/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91189945,"identity":"050872f0-8989-4f2e-8aae-2bf9fcb358ca","added_by":"auto","created_at":"2025-09-12 14:33:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":7826310,"visible":true,"origin":"","legend":"\u003cp\u003eGastrointestinal adverse events of Upadacitinib compared to Ruxolitinib.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-7427805/v1/8d40156ed6040cc91555786e.png"},{"id":91189942,"identity":"bab740ee-0dbd-4234-956d-a3d762237e0f","added_by":"auto","created_at":"2025-09-12 14:33:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":659572,"visible":true,"origin":"","legend":"\u003cp\u003eA. Major sub-categories of Ruxolitinib gastrointestinal adverse event reports. B. Major sub-categories of Upadacitinib gastrointestinal adverse event reports.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-7427805/v1/28d13c242231e2759ff9e4ce.png"},{"id":91189944,"identity":"aef0423d-f79f-40c4-853c-76cd2df7cda3","added_by":"auto","created_at":"2025-09-12 14:33:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":773503,"visible":true,"origin":"","legend":"\u003cp\u003eTime from drug initiation to onset of gastrointestinal adverse events in patients treated with ruxolitinib or upadacitinib. Each panel represents a specific AE category. Boxplots show the median, interquartile range, and outliers; individual dots indicate patient-level data..\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-7427805/v1/e65da2b74d507cc400fe0283.png"},{"id":91194000,"identity":"c8c4f46f-c7ee-46dd-b963-c8333c2ea6b0","added_by":"auto","created_at":"2025-09-12 14:49:30","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":555742,"visible":true,"origin":"","legend":"\u003cp\u003eGastrointestinal adverse events of upadacitinib compared with ruxolitinib in pediatric (\u0026lt; 18 years), adult (18 – 65 years) and older-adult (\u0026gt; 65 years) populations.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-7427805/v1/4b91efe4ab78ee320f507ef3.png"},{"id":91194003,"identity":"ab428cd3-6dd0-402e-8322-392ae850d376","added_by":"auto","created_at":"2025-09-12 14:49:30","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":487440,"visible":true,"origin":"","legend":"\u003cp\u003eGastrointestinal adverse events of upadacitinib compared with ruxolitinib in NSAID users and non-users.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-7427805/v1/b87c6523aa56f64e19838e1e.png"},{"id":100422125,"identity":"edbad006-d123-4f7e-855d-ca9a1e83fca7","added_by":"auto","created_at":"2026-01-16 14:06:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9332370,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7427805/v1/8f9f7416-47eb-496c-8bbc-44fe72cebf1f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pharmacovigilance Insights into Gastrointestinal Adverse Events of JAK Inhibitors: FAERS Signal Detection with Clinical and Pharmacological Implicationse","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe gastrointestinal tract, the largest immune organ and core site for nutrient absorption in the human body, plays a critical role in maintaining systemic immune homeostasis and metabolic balance. The integrity of gastrointestinal function directly impacts these processes. Drug-induced damage to the intestinal mucosa can lead to the depletion of goblet cells, degradation of tight junction proteins, and dysbiosis, which facilitates endotoxemia and triggers systemic inflammatory responses, thereby establishing a vicious cycle of \"drug toxicity-barrier disruption-secondary infections\"\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Studies have shown that patients undergoing long-term immunomodulatory therapy often experience moderate to severe gastrointestinal symptoms, with drug-related diarrhea, abdominal pain, and gastrointestinal bleeding being the leading causes of treatment discontinuation\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. A retrospective study further revealed that adverse drug events in elderly patients (\u0026ge;\u0026thinsp;65 years) predominantly affect the digestive system (27.87%) and metabolic/nutritional systems (24.53%). This finding may be related to age-associated decreases in gut microbiota diversity and reduced short-chain fatty acid synthesis capacity, which exacerbates drug-induced intestinal epithelial apoptosis\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Recurrent infections or nutritional depletion often compel clinicians to reduce treatment intensity, indirectly leading to the loss of disease control. Therefore, predicting gastrointestinal adverse events and performing systematic monitoring are key strategies to overcome the vicious cycle of infection and improve long-term disease prognosis.\u003c/p\u003e\u003cp\u003eJanus kinase (JAK) inhibitors are a class of novel small-molecule targeted drugs that selectively inhibit the JAK-STAT signaling pathway. They have demonstrated significant efficacy in treating chronic hematologic malignancies and inflammation-mediated autoimmune diseases. However, current research indicates that the gastrointestinal adverse event risk associated with JAK inhibitors requires close attention\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Upadacitinib, a highly selective JAK1 inhibitor, has shown rapid symptom relief and mucosal healing advantages in phase III clinical trials for rheumatoid arthritis (RA) and Crohn's disease (CD), with clinical remission rates significantly superior to those of traditional biologic agents. Nonetheless, serious gastrointestinal adverse events, such as gastrointestinal perforation and bleeding, have also been reported\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. On the other hand, ruxolitinib, a dual JAK1/2 inhibitor, is primarily used to treat hematologic disorders such as myelofibrosis and polycythemia vera. Recent studies have shown that ruxolitinib can alleviate colonic inflammation by inhibiting STAT1 phosphorylation in animal models, suggesting its potential in treating Th1-type immune dysregulation diseases\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. However, its gastrointestinal-related adverse effects remain unclear. Existing clinical trials often have limited follow-up periods (usually\u0026thinsp;\u0026le;\u0026thinsp;52 weeks) and frequently exclude patients with concomitant gastrointestinal diseases during the screening process, which may lead to underestimation of delayed toxicity in the real world. The FDA Adverse Event Reporting System (FAERS), as the largest post-market surveillance platform globally, integrates cross-population and multi-indication data to identify rare adverse events and high-risk subgroups through large sample sizes. This study examines the FAERS reports of upadacitinib and ruxolitinib and systematically compares their gastrointestinal risk profiles and provide evidence-based insights to optimize treatment decisions.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Data Source and Study Design\u003c/h2\u003e\u003cp\u003eThis study was designed as an observational, retrospective pharmacovigilance analysis based on the FDA Adverse Event Reporting System (FAERS). The FAERS database integrates both voluntary and mandatory adverse event reports submitted globally by healthcare professionals, consumers, and pharmaceutical companies\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The database includes the following seven core data tables: demographic information (DEMO), drug details (DRUG), adverse event terminology (REAC), patient outcomes (OUTC), report source (RPSR), treatment time window (THER), and indications (INDI). The study included cases reported between July 1, 2019 and December 31, 2024 to cover the post-marketing surveillance period for the target drugs, upadacitinib and ruxolitinib. Data integration was performed using R software (version 4.4.2). The analysis focused on cases related to the main suspect drugs, identified by their generic names (upadacitinib, ruxolitinib) and brand names (RINVOQ, Jakavi), ensuring that the adverse events directly associated with the drugs were included. This study has been reported in accordance with the STROCSS 2025 criteria\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eData cleaning was performed using a dual deduplication strategy. First, the latest report version for each case ID was retained according to FDA guidelines. Second, duplicate records across cases were excluded using a tuple-matching algorithm based on four variables: age, sex, event date, and country of occurrence\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. The adverse events were then standardized and coded according to the \u003cb\u003eMedical Dictionary for Regulatory Activities\u003c/b\u003e (MedDRA)\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. The events were categorized into anatomical systems (e.g., gastrointestinal disorders) based on the System Organ Class (SOC), with specific events (e.g., diarrhea) described using preferred terms (PTs). The events were further classified into Hierarchical Level 2 (HLGT) and Hierarchical Level 3 (HLT) categories, combined with their clinical significance. This classification system enabled systematic categorization and frequency analysis of adverse events, providing a standardized foundation for subsequent risk signal detection.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Statistical Analysis\u003c/h2\u003e\u003cp\u003eWe performed disproportionality analysis using the reporting odds ratio (ROR), a well-validated method for detecting disproportionate reporting signals in post-marketing passive surveillance databases\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. The ROR assesses whether the reporting of adverse events associated with a drug is higher than expected, with the expected value being the adverse event incidence rate for any other drug in the reference group. A multivariable logistic regression model was used to calculate adjusted estimates\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. First, upadacitinib and ruxolitinib were directly compared according to patient characteristics, report sources, and other relevant information. Second, the regression model was adjusted for factors such as sex, age, hypertension, diabetes, gastritis, hepatitis, cholecystitis, and concomitant NSAID use. In each regression model, the significance of the nonlinear age term and potential interactions between age and the two drugs were evaluated using restricted cubic spline functions; only statistically significant terms were included in the final model. Data on hypertension, diabetes, gastritis, hepatitis, and cholecystitis were derived from the reported indications. Finally, sensitivity analyses were performed, stratified by age groups (minor (\u0026lt;\u0026thinsp;18 years), adult (\u0026ge;\u0026thinsp;18 and \u0026le;\u0026thinsp;65 years), and elderly (\u0026gt;\u0026thinsp;65 years)) and NSAID use. Regression models were applied to these subgroups. In the sensitivity analysis, some subgroups exhibited complete separation or extreme sparsity of data, preventing model convergence. These variables were excluded from the final multivariable model to ensure result reliability\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAdjusted RORs and their 95% confidence intervals (CIs) were used to evaluate differences between the two drugs. A significant increase in the likelihood of gastrointestinal adverse events with ruxolitinib compared with that of upadacitinib was considered when the upper limit of the 95% CI was greater than 1. Data processing and statistical analysis were conducted using R software (R Foundation for Statistical Computing).\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eA total of 58,548 safety reports for upadacitinib and 28,968 safety reports for ruxolitinib were included in the analysis. The mean age was 57.8 years (\u0026plusmn;\u0026thinsp;16 years) for upadacitinib and 49.8 years (\u0026plusmn;\u0026thinsp;26 years) for ruxolitinib, with male proportions of 71.9% and 45.0%, respectively. We observed that patients treated with upadacitinib had a higher mean age and male proportion compared with those treated with ruxolitinib. Additionally, the proportions of individuals with diabetes (0.67% vs. 0.09%) and hypertension (0.82% vs. 0.20%) were greater among upadacitinib users. In contrast, a greater proportion of patients receiving ruxolitinib were also treated with NSAIDs compared with those receiving upadacitinib (11.8% vs. 4.24%). The majority of the reports for both drugs were from the Americas, with the United States accounting for 68.6% of the upadacitinib reports and 81.3% of the ruxolitinib reports. Most of the reports for both drugs were submitted by healthcare professionals (97.0% for upadacitinib and 70.1% for ruxolitinib). The distribution of report years differed between the two drugs, corresponding to their respective approval years (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\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\u003eDemographic and clinical characteristics of safety reports of Upadacitinib and Ruxolitinib.\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=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUpadacitinib (n\u0026thinsp;=\u0026thinsp;58,548)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRuxolitinib (n\u0026thinsp;=\u0026thinsp;28,968)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReporting region\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\u003eUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40185/58548(68.63%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e23538/28965(81.26%)\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=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4060/58548(6.93%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e464/28965(1.60%)\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=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1909/58548(3.26%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e463/28965(1.59%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1707/58548(2.91%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e360/28965(1.24%)\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=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e434/58548(0.74%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e574/28965(1.98%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReporter\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\u003eHealth-professional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3374/3479(97.01%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e200/285(70.18%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConsumer/Lawyer/Other\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e105/3479(3.02%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e85/285(29.82%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReporting year\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\u003e2019\u0026ndash;2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e60/58547(0.10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1696/28966(5.86%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2020\u0026ndash;2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1518/58547(2.59%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3467/28966(12.00%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2021\u0026ndash;2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4080/58547(6.97%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3843/28966(13.27%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u0026ndash;2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e17574/58547(29.98%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6982/28966(24.10%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2023\u0026ndash;2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e17640/58547(30.13%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6742/28966(23.28%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2024\u0026ndash;2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e17673/58547(30.19%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6231/28966(21.51%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years\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\u003eMean (\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e57.8(\u0026plusmn;\u0026thinsp;15.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e49.8(\u0026plusmn;\u0026thinsp;26.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\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\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e39561/55001(71.93%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2172/4848(44.80%)\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=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15440/55001(28.07%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2676/4848(55.20%)\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\u003eNSAIDs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2483/58548(4.24%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3419/28968(11.80%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e391/58548(0.67%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27/28965(0.09%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e479/58548(0.82%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e57/28965(0.20%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e55/58548(0.09%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7/28965(0.02%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCholecystitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1/58548(0.00%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0/28965(0.00%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastritis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e17/58548(0.03%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4/28965(0.01%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eBased on HLGT and HLT classifications and the clinical significance of specific events (PTs), the selected PTs were categorized into the following groups: gastrointestinal inflammation-related events, gastrointestinal bleeding-related events, gastrointestinal ulcer and perforation-related events, gastrointestinal motility disorder-related events, other serious events (such as gastrointestinal stricture and obstruction), and gastrointestinal symptom-related events.\u003c/p\u003e\u003cp\u003eFirst, to detect disproportionate reporting signals, we compared the reports of gastrointestinal adverse events following upadacitinib and ruxolitinib treatment. Compared with upadacitinib, ruxolitinib was associated with increased reporting of gastrointestinal motility disorder-related events [n\u0026thinsp;=\u0026thinsp;803, adj. ROR\u0026thinsp;=\u0026thinsp;1.52 (1.05, 2.20)], whereas upadacitinib was associated with a greater incidence of gastrointestinal inflammation-related events [n\u0026thinsp;=\u0026thinsp;641, adj. ROR\u0026thinsp;=\u0026thinsp;0.14 (0.07, 0.29)] and gastrointestinal ulcers and perforation-related events [n\u0026thinsp;=\u0026thinsp;229, adj. ROR\u0026thinsp;=\u0026thinsp;0.27 (0.10, 0.68)]. Although no statistically significant differences between the two drugs in gastrointestinal bleeding-related events [n\u0026thinsp;=\u0026thinsp;346, adj. ROR\u0026thinsp;=\u0026thinsp;0.52 (0.27, 1.02)] and gastrointestinal symptom-related events [n\u0026thinsp;=\u0026thinsp;2956, adj. ROR\u0026thinsp;=\u0026thinsp;1.21 (0.99, 1.48)] were observed, the upper limit of the confidence interval for bleeding events and the lower limit for symptom events were close to 1. These findings suggest that upadacitinib may have a greater tendency to cause bleeding events, whereas ruxolitinib might pose a greater potential risk for gastrointestinal discomfort. Statistical significance was not observed for other serious events, such as gastrointestinal stricture and obstruction [n\u0026thinsp;=\u0026thinsp;346, adj. ROR\u0026thinsp;=\u0026thinsp;0.76 (0.44, 1.31)], which requires further data or research to confirm (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAmong the 305 patients receiving ruxolitinib who experienced gastrointestinal motility disorder-related events, 203 (62.1%) experienced diarrhea, and 89 (29.2%) developed constipation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Among the 211 gastrointestinal ulcers and perforation-related events resulting from upadacitinib treatment, 44 (20.8%) were intestinal perforation, and 32 (15.2%) were gastrointestinal perforation. Among the 617 gastrointestinal inflammation-related events, 252 (40.8%) were ulcerative colitis, and 174 (28.2%) were Crohn\u0026rsquo;s disease (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe median time to gastrointestinal motility disorder, gastrointestinal bleeding, gastrointestinal ulcer and perforation, gastrointestinal symptoms, gastrointestinal inflammation, and other serious adverse events after ruxolitinib treatment was 30 days (9\u0026ndash;502), 279 days (57\u0026ndash;591), 188 days (155\u0026ndash;612), 63 days (16\u0026ndash;357), 42.5 days (10.8\u0026ndash;266), and 103 days (22\u0026ndash;189), respectively. In contrast, the median time from the start of upadacitinib treatment to the onset of these gastrointestinal adverse events was 64.5 days (12\u0026ndash;228), 91 days (30\u0026ndash;344), 126 days (34.8\u0026ndash;322), 102 days (30\u0026ndash;306), 122 days (27.5\u0026ndash;276), and 145 days (73.5\u0026ndash;478), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Overall, the distribution patterns of onset times across different gastrointestinal adverse event categories were broadly similar between the two drugs, with most events occurring within the first year of treatment.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAdditionally, we performed sensitivity analyses stratified by age group and NSAID use. In the age group stratification, upadacitinib significantly increased gastrointestinal inflammation in both the minor subgroup (adj. ROR\u0026thinsp;=\u0026thinsp;0.08 [0.02\u0026ndash;0.37]) and the adult subgroup (adj. ROR\u0026thinsp;=\u0026thinsp;0.03 [0.13\u0026ndash;0.69]). Ruxolitinib, on the other hand, significantly increased gastrointestinal symptoms in the elderly subgroup (adj. ROR\u0026thinsp;=\u0026thinsp;1.15 [1.10\u0026ndash;2.20]), with no gastrointestinal ulcer and perforation events in the minor subgroup or other serious events in the elderly subgroup. In the adult subgroup, ruxolitinib tended to reduce the incidence of gastrointestinal ulcer and perforation risk (adj. ROR\u0026thinsp;=\u0026thinsp;0.08 [0.02-1.00]), although the upper limit of the confidence interval reached the null value of 1, suggesting a potential clinical difference (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn the NSAID use stratification, upadacitinib was associated with statistically significant increases in reports of gastrointestinal inflammation (adj. ROR\u0026thinsp;=\u0026thinsp;0.15 [0.07\u0026ndash;0.30]) and gastrointestinal ulcer and perforation (adj. ROR\u0026thinsp;=\u0026thinsp;0.29 [0.11\u0026ndash;0.74]) in the non-NSAID use subgroup, and a trend toward increased gastrointestinal bleeding risk (adj. ROR\u0026thinsp;=\u0026thinsp;0.5 [0.25\u0026ndash;1.03]). For ruxolitinib, in the non-NSAID use subgroup, an increase in gastrointestinal motility disorder reports (adj. ROR\u0026thinsp;=\u0026thinsp;1.52 [1.04\u0026ndash;2.23]) was observed, whereas in the NSAID use subgroup, gastrointestinal symptom reports (adj. ROR\u0026thinsp;=\u0026thinsp;2.23 [1.10\u0026ndash;4.52]) were significantly higher (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this contemporary global post-marketing surveillance study, we selected upadacitinib as the reference group for comparison. Upadacitinib has demonstrated robust efficacy in several phase III clinical trials, particularly for ulcerative colitis (UC) and other forms of inflammatory bowel disease (IBD). Given its prominent clinical position in disease treatment, evaluating the gastrointestinal safety profile of ruxolitinib relative to that of upadacitinib could provide valuable insights for potential treatment options. We performed a multivariable logistic regression analysis to calculate adjusted reporting odds ratios (RORs), considering confounding factors such as age, sex, and concomitant medications. Compared with ruxolitinib, upadacitinib was associated with increased reporting of gastrointestinal inflammation-related events and gastrointestinal ulcer and perforation-related events during treatment, with a high likelihood of gastrointestinal bleeding, particularly in more severe preferred terms (PTs), such as intestinal perforation, gastrointestinal bleeding, and colitis. In contrast, adverse events related to ruxolitinib were primarily focused on gastrointestinal motility disorders and gastrointestinal discomfort, with common adverse events including constipation, diarrhea, nausea, and abdominal pain. Most events for both drugs occurred within the first year of treatment, whereas ruxolitinib did not reach a median time for several gastrointestinal adverse events, suggesting a lower incidence or later onset of these events during the observation period, which may reflect a relative advantage in gastrointestinal tolerability. A five-year study reported four cases of gastrointestinal perforation in the upadacitinib group, all of which were severe adverse events\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Similarly, gastrointestinal adverse events such as diarrhea and constipation were reported during ruxolitinib treatment\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. These findings highlight the need for close monitoring of gastrointestinal symptoms during the use of both drugs, which is consistent with our study results.\u003c/p\u003e\u003cp\u003eIn the age-stratified sensitivity analysis, gastrointestinal inflammation-related adverse events associated with upadacitinib were statistically significant in both adult and pediatric patients, with the adult group particularly suggesting a risk of gastrointestinal ulcer and perforation. In the gastrointestinal inflammation subgroup, 56.3% of pediatric patients and 27.6% of adult patients developed ulcerative colitis (colitis ulcerative), whereas 23.7% of adult patients with gastrointestinal ulcer and perforation events experienced intestinal perforation, a severe complication.\u003c/p\u003e\u003cp\u003eExisting studies have shown that upadacitinib, a selective JAK1 inhibitor, significantly suppresses the downstream signaling of various pro-inflammatory cytokines, including IL-6, IFN-γ, and GM-CSF, by blocking the JAK-STAT pathway. While this inhibition helps alleviate symptoms of inflammatory diseases, it also reduces the body\u0026rsquo;s normal immune defense capabilities, making it easier for potential pathogenic microorganisms in the gut to become activated, leading to mucosal immune imbalance and inflammation. This, in turn, may result in persistent damage to the intestinal wall and the occurrence of perforation\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Local infections or loss of barrier function may also promote the formation of necrosis, which is one of the important mechanisms for perforation. In the age subgroup analysis, the proportion of pediatric patients with ulcerative colitis was greater than that of adults. Considering the incomplete development of the gastrointestinal mucosa and immune defense capabilities in children, they are more prone to drug-induced gastrointestinal adverse events. Close monitoring during treatment is required, particularly regarding dosage, treatment duration, and the choice of concomitant therapies\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn contrast, ruxolitinib primarily induces gastrointestinal motility disorders and gastrointestinal symptoms, with a predominant occurrence in the elderly population aged 65 years and older. In this group, 60.9% of patients experienced diarrhea, 30.4% developed constipation, and abdominal pain (upper) was the most frequently reported gastrointestinal symptom. The mechanisms underlying gastrointestinal motility disorders and symptoms induced by ruxolitinib remain unclear. However, notably, there have been no clinical reports of ruxolitinib-induced gastrointestinal ulcers or perforations in pediatric patients, and no significant severe gastrointestinal complications have been reported in elderly patients. Overall, the incidence of severe adverse events with ruxolitinib was lower than that with upadacitinib, suggesting that ruxolitinib may improve patient adherence.\u003c/p\u003e\u003cp\u003eIn the NSAID stratified sensitivity analysis, upadacitinib was associated with a significant increase in reports of gastrointestinal inflammation and ulcer perforation events in the non-NSAID use subgroup, indicating that its gastrointestinal toxicity may be independent of NSAID use. The three most common adverse events were ulcerative colitis, intestinal perforation, and lower gastrointestinal bleeding (hematochezia), all of which are severe adverse events. Notably, the combination of upadacitinib with NSAIDs may lead to dual impairment of the mucosal barrier, suppression of epithelial repair and stem cell renewal, and exacerbation of dysbiosis, which synergistically increases the risk of gastrointestinal inflammation, ulceration, and perforation\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. In phase III trials of upadacitinib for ulcerative colitis, the use of concomitant NSAIDs was highlighted as further increasing the risk of gastrointestinal perforation\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. FDA-related studies also indicate a significantly higher reporting rate of gastrointestinal perforation when upadacitinib and NSAIDs are used together\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Our study revealed a statistically significant difference between upadacitinib and ruxolitinib in the non-NSAID subgroup, indicating that upadacitinib is associated with greater gastrointestinal toxicity. This suggests that even without the concomitant use of NSAIDs, careful monitoring for gastrointestinal inflammation and ulceration perforation events is warranted.\u003c/p\u003e\u003cp\u003eRuxolitinib, in this subgroup, is primarily associated with gastrointestinal motility disorders, with 67.6% of patients experiencing diarrhea. Gastrointestinal symptoms were predominantly abdominal pain, whereas abdominal discomfort was more frequently reported in patients who used NSAIDs. Importantly, the reporting odds ratio (ROR), as a relative reporting odds ratio, can be influenced by baseline reporting rates and prescribing biases. Specifically, if the baseline reporting rate in this population is low or if clinicians may be more inclined to avoid using NSAIDs in patients with a history of gastrointestinal disorders or in high-risk populations, the risk profile could be artificially lowered due to the co-administration of gastroprotective drugs such as proton pump inhibitors (PPIs). Additionally, gastrointestinal perforation events in the pediatric subgroup, NSAID use subgroup, and other severe events in the elderly subgroup, as well as gastrointestinal inflammation events in the NSAID use subgroup, were not reliable for calculating effect sizes due to sparse data (event rates\u0026thinsp;\u0026lt;\u0026thinsp;1%). These limitations suggest that the current findings need further validation through multicenter collaboration and larger sample sizes.\u003c/p\u003e\u003cp\u003eUpadacitinib, a highly effective and widely used small-molecule targeted oral immunomodulator, has demonstrated significant efficacy in moderate-to-severe inflammatory bowel diseases (IBD), particularly ulcerative colitis, in several phase III trials. However, its gastrointestinal-related adverse event profile requires careful monitoring, especially in patients with a history of gastrointestinal diseases. In phase III clinical trials of upadacitinib, patients treated with upadacitinib had a higher incidence and severity of gastrointestinal adverse events, including serious reactions such as gastrointestinal perforation, compared with those receiving TNF inhibitors or placebo\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Furthermore, concerns regarding gastrointestinal adverse events were raised in clinical trials even before phase III studies\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Initially approved for the treatment of myelofibrosis (MF) and polycythemia vera (PV), ruxolitinib has recently shown potential in treating immune-related diseases in PV patients, with case reports indicating improvement in their immune conditions following ruxolitinib treatment\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In a study involving patients with very early-onset IBD (VEO-IBD) under 6 years of age, ruxolitinib demonstrated good clinical improvement, including reduced diarrhea, lower inflammation markers, and improved nutritional status\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Animal experiments have also shown that ruxolitinib alleviates colitis symptoms in mouse models by inhibiting NF-κB-related inflammation and apoptotic responses while restoring STAT3-mediated epithelial barrier function\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFurther in-depth analysis of the data in this study revealed that the adverse events associated with upadacitinib are primarily gastrointestinal inflammatory injuries, such as colitis, intestinal perforation, and gastrointestinal bleeding, which are of significant clinical severity. These adverse events occur relatively early during treatment and are reported at a higher frequency across multiple subgroups. Particularly in the non-NSAID use subgroup, gastrointestinal inflammatory injuries related to upadacitinib were significantly more frequent, suggesting a substantial impact on the integrity of the mucosal barrier. In contrast, adverse reactions caused by ruxolitinib are more concentrated in gastrointestinal motility or functional abnormalities, such as diarrhea, constipation, and nausea. Although the frequency of these events is not low, they are mostly mild to moderate and require relatively less clinical intervention. Moreover, ruxolitinib did not reach the median onset time for several adverse event categories, including gastrointestinal inflammation and gastrointestinal ulcer and perforation, which may indicate that its adverse events develop more slowly or have a lower overall incidence. This difference may arise from the differing JAK inhibition profiles of the two drugs: upadacitinib, a selective JAK1 inhibitor, is more likely to affect inflammatory signaling\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e, whereas ruxolitinib, a JAK1/2 inhibitor, may cause less damage to the gastrointestinal mucosa while modulating immune responses\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. This characteristic may provide a theoretical basis for the potential expansion of the use of ruxolitinib in immune-related indications that rely on gastrointestinal tolerance, such as IBD, and warrants further validation through prospective studies.\u003c/p\u003e\u003cp\u003eAlthough this study reveals the differences in gastrointestinal adverse events between upadacitinib and ruxolitinib using real-world pharmacovigilance data and suggests that ruxolitinib has good tolerability in specific populations and potential therapeutic value in immune indications, such as IBD, that rely on gastrointestinal tolerance, further research is required for validation. Future studies should include prospective, multi-center, real-world cohort studies that integrate electronic medical records and follow-up data to systematically evaluate the efficacy and safety of ruxolitinib in relevant patient populations, particularly in those with a history of gastrointestinal diseases or high-risk backgrounds, such as the use of NSAIDs. Additionally, the differential effects of ruxolitinib compared with those of other JAK inhibitors in different patient subtypes should be explored, with a focus on identifying the risk factors and potential mechanisms for gastrointestinal adverse events. In terms of mechanistic studies, combining animal models or histological experiments to verify the impact of ruxolitinib on intestinal epithelial barrier function is recommended, thereby providing theoretical support and clinical evidence for its expanded indications in diseases such as IBD.\u003c/p\u003e"},{"header":"5. Limitations","content":"\u003cp\u003eThis study was based on the FAERS database, which, while providing many real-world adverse event reports and aiding in the detection of potential safety signals, has several inherent limitations. First, the FAERS is a spontaneous reporting system that is subject to reporting bias, missing information, duplicate cases, and severity-driven reporting, and it cannot provide actual incidence rates or establish causality. Second, the two drugs compared in this study have different indications. Although multivariable regression controlled for some confounding factors, indication bias and prescribing preferences may still influence the results\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Furthermore, the lack of critical variables such as drug duration, dosage, specific indications, and laboratory markers in the FAERS limits further refinement of the risk model. Therefore, the results of this study should be considered hypothesis-generating signals that require validation through prospective clinical studies. Nevertheless, FAERS reflects the real-world environment and provides opportunities for early signal detection, investigation of rare adverse events, and comparisons between similar drugs. Drug sensitivity research continues to play a key role in adverse event prediction and clinical individualized medication decision making\u003csup\u003e\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eIn conclusion, based on the FAERS pharmacovigilance database, this study compared and analyzed the gastrointestinal adverse event profiles of upadacitinib and ruxolitinib from multiple dimensions. The results show that upadacitinib is more likely to induce gastrointestinal inflammatory injuries, particularly severe events such as intestinal perforation, bleeding, and colitis, with significant risks observed across multiple subgroups. In contrast, ruxolitinib\u0026rsquo;s adverse reactions primarily manifest as gastrointestinal motility disturbances and mild to moderate discomfort, with overall better tolerability. Additionally, ruxolitinib did not reach the median onset time for several preferred terms (PTs), suggesting a broader safety margin. Given the inherent limitations of spontaneous reporting systems, these observations should be interpreted as hypothesis-generating rather than establishing causality. Although these findings require further validation through prospective studies, combined with the positive effects of ruxolitinib in IBD animal models and a few clinical cases reported in the existing literature, they suggest that ruxolitinib may have potential therapeutic advantages in gastrointestinal-sensitive populations. This warrants further exploration of its potential for expanding indications in autoimmune diseases, such as inflammatory bowel disease (IBD).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are publicly available from the FDA Adverse Event Reporting System (FAERS) at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.\u003c/p\u003e\n\u003cp\u003eAll data used in this study were obtained from this open-access resource and processed using standard pharmacovigilance methods.\u003c/p\u003e\n\u003cp\u003eAdditional processed data or analysis scripts are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was not required for this study in accordance with the local legislation and institutional requirements because the data were obtained from the publicly accessible U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZCZ and ZCW conceptualized and designed the study. ZCZ drafted and wrote the manuscript. ZCZ and ZCW performed the data analysis. JML and XML curated the data. YTC and YL contributed to analysis. JWZ, XXW and YMX visualized the data. JH and WHZ reviewed the manuscript. RS supervised the data processing. JW supervised the study and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by the Clinical Research Center for Traditional Chinese Medicineon Anorectal and Perianal Wound Repair of Fujian Province (2022Y2011).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work submitted to the journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenerative AI statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eArtificial Intelligence (AI) tools were used solely to improve the readability of certain paragraphs. No AI tools were employed in data collection, analysis, or interpretation. All data were generated and verified by the authors, who affirm their authenticity. The authors carefully reviewed and edited the manuscript and take full responsibility for its content.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBerkes, J., Viswanathan, V. K., Savkovic, S. D. \u0026amp; Hecht, G. Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation. \u003cem\u003eGut\u003c/em\u003e \u003cb\u003e52\u003c/b\u003e, 439\u0026ndash;451 (2003).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHamdeh, S., Micic, D. \u0026amp; Hanauer, S. Review article: drug-induced small bowel injury. \u003cem\u003eAliment. Pharmacol. Ther.\u003c/em\u003e \u003cb\u003e54\u003c/b\u003e, 1370\u0026ndash;1388 (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbu-Sbeih, H. \u0026amp; Wang, Y. 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Adverse drug reaction risks obtained from meta-analyses and pharmacovigilance disproportionality analyses are correlated in most cases. \u003cem\u003eJ. Clin. Epidemiol.\u003c/em\u003e \u003cb\u003e134\u003c/b\u003e, 14\u0026ndash;21 (2021).\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":"Upadacitinib, Ruxolitinib, Gastrointestinal adverse events, FAERS, Pharmacovigilance, Janus-kinase inhibitors","lastPublishedDoi":"10.21203/rs.3.rs-7427805/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7427805/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eJanus-kinase (JAK) inhibitors are increasingly used across surgical practice for immune-mediated disorders, yet their gastrointestinal (GI) safety profiles remain incompletely defined. Upadacitinib (selective JAK-1) has been linked to severe mucosal complications, whereas ruxolitinib (JAK-1/2) appears better tolerated. Robust real-world comparisons are lacking.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We performed a retrospective, observational pharmacovigilance study of the FDA Adverse Event Reporting System from 1 July 2019 to 31 December 2024. After deduplication, 58 548 upadacitinib and 28 968 ruxolitinib safety reports were retrieved. GI events were coded with MedDRA and grouped into inflammation, ulcer/perforation, bleeding, motility disorders, symptoms and other serious events. Multivariable logistic regression generated adjusted reporting odds ratios (aROR) for ruxolitinib versus upadacitinib, controlling for age, sex, comorbidities and concomitant NSAIDs; sensitivity analyses stratified by age and NSAID use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eCompared with upadacitinib, ruxolitinib showed higher reporting of GI motility disorders (803 events; aROR = 1.52, 95% CI 1.05–2.20) but markedly lower reporting of GI inflammation (641 events; aROR = 0.14, 0.07–0.29) and ulcer/perforation (229 events; aROR = 0.27, 0.10–0.68). Upadacitinib-related inflammation was dominated by ulcerative colitis (40.8 %) and Crohn’s disease (28.2 %), while 20.8 % of ulcer/perforation events were frank intestinal perforations. Median onset occurred within the first treatment year for both agents (8 months for upadacitinib ulcers/perforations; 6.5 months for ruxolitinib motility disorders). Age-stratified analyses confirmed an excess of upadacitinib-associated inflammation in adults and children, whereas ruxolitinib-related symptoms were concentrated in patients \u0026gt; 65 years. NSAID co-administration magnified upadacitinib-associated ulcers/perforations but had little effect on ruxolitinib patterns.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eIn real-world practice, upadacitinib carries a substantially higher signal for severe inflammatory and ulcerative GI injury, whereas ruxolitinib is mainly associated with non-serious motility disturbances. Upadacitinib carries a higher signal for severe inflammatory and ulcerative GI injury, whereas ruxolitinib is mainly associated with non-serious motility disturbances. These associations are hypothesis‑generating rather than causal and warrant validation through prospective studies and mechanistic investigations.\u003c/p\u003e","manuscriptTitle":"Pharmacovigilance Insights into Gastrointestinal Adverse Events of JAK Inhibitors: FAERS Signal Detection with Clinical and Pharmacological Implicationse","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-12 14:33:25","doi":"10.21203/rs.3.rs-7427805/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":"cbbb636e-220c-4414-ab43-a2d235a24454","owner":[],"postedDate":"September 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54217718,"name":"Health sciences/Diseases"},{"id":54217719,"name":"Health sciences/Gastroenterology"},{"id":54217720,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-01-16T13:13:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-12 14:33:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7427805","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7427805","identity":"rs-7427805","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}