Psoriasis is a chronic, recurrent, inflammatory, and systemic immune-mediated disease triggered by the interaction between genetic and environmental factors. Its typical clinical manifestations include scaly erythema or plaques, which may be localized or widespread. The etiology of psoriasis involves various factors, including genetics, immunity, and environmental influences (1). The global prevalence of psoriasis among adults ranges from 0.51% to 11.43%, with the highest prevalence in children at 1.37% (2, 3). Currently, biologic agents have been chosen as the primary systemic treatment for psoriasis, playing a significant and effective role in managing severe, refractory, and special types of psoriasis (4). In addition, biologics are employed as either standalone treatments or in conjunction with other systemic or topical medications for psoriasis management, according to the psoriasis management guidelines of the dermatology societies in Singapore, the United States, and Canada (5–7). Interleukin (IL) inhibitors are commonly used biological agents for the treatment of psoriasis, including the IL-12/23 (P40 subunit) inhibitor Ustekinumab, the IL-23 (P19 subunit) inhibitor Guselkumab, and IL-17A inhibitors such as Secukinumab, Ixekizumab, Bimekizumab, Brodalumab, and others. IBD is a chronic inflammatory condition with a prevalence of approximately 0.3%, affecting the small intestine, colon, and rectum. It includes two subtypes: Ulcerative colitis (UC) and Crohn’s disease (CD) (8). There has been demonstrated to be a higher expression of IL-17 in the intestinal mucosa of patients with CD and UC (9), but it has been found that anti-IL-17 agents fail to show clinical efficacy and may cause exacerbations of symptoms (10–12) and clinical relapses in patients with IBD (13, 14). On the other hand, there had been a central role played by IL-23 regulation in the pathogenesis of IBD, with there being a key link in the disease process. It had been suggested by studies that there was a promising therapeutic target in IL-23 for suppressing intestinal inflammation (15). However, the study indicated that IL-23 is produced in response to microbial colonization, and blocking IL-23 may disrupt the microbiota composition, increasing susceptibility to intestinal infections and exacerbate intestinal inflammation (16).

Given that it remains unclear whether the new-onset IBD in psoriasis patients is attributable to the disease itself or the treatment with interleukin inhibitors, therefore, the objective of this study is to perform a meta-analysis of RCTs to clarify the risk of new-onset IBD in psoriasis patients following treatment with five interleukin inhibitors(including Bimekizumab, Ixekizumab, Secukinumab, Brodalumab, and Ustekinumab), as well as the differences between them.

This systematic review and meta-analysis integrated data from 17 RCTs, encompassing a total of 16,557 psoriasis patients, to evaluate and compare the risk of new-onset IBD in patients treated with five distinct interleukin inhibitors, thereby providing scientific evidence for clinical practice. The research findings indicated that although the use of interleukin inhibitors was associated with a risk of new-onset IBD, the overall risk remained low. In most cases, the administration of these drugs did not significantly increase the incidence of IBD. The meta-analysis revealed no significant differences in the risk of new-onset IBD between Bimekizumab, Secukinumab, Brodalumab, Ustekinumab group and their control groups. However, compared to the control group, Ixekizumab was significantly associated with an increased risk of new-onset IBD in psoriasis patients (MH RD 0.0027, 95% CI 0.0001-0.0054, I² = 0%, P = 0.04). Compared with the meta-analysis by Yamada et al. (40), our study identified a significant association between Ixekizumab and the risk of new-onset IBD—an observation that was not clearly emphasized in earlier analyses. First, given the low heterogeneity across studies and the rarity of new-onset IBD events in psoriasis patients treated with interleukin inhibitors, we adopted a fixed-effects model combined with the Mantel-Haenszel method to estimate risk differences. This approach enhances the clinical interpretability of absolute risk estimates, mitigates the potential overestimation associated with odds ratios in sparse-event settings, and allows for the inclusion of studies reporting zero events. Second, by incorporating recently published randomized controlled trials and expanding the overall sample size, our study improves the precision of statistical estimates and the reliability of the findings.

Multiple case reports and clinical studies support the findings of this research, indicating that psoriasis patients may be associated with developing new-onset IBD following treatment with Ixekizumab (41, 42). However, reports of new-onset IBD associated with Secukinumab, Bimekizumab, Brodalumab, and Ustekinumab were relatively rare. Notably, existing research suggested that Ustekinumab is not only effective in treating IBD but can also alleviate new-onset IBD induced by Ixekizumab (43, 44). Schreiber analyzed data from 21 clinical trials and found that the exposure-adjusted incidence rates of new-onset IBD among psoriasis patients treated with Secukinumab ranged between 0.01 and 0.13, indicating that such events were uncommon (45). Furthermore, Wang conducted data mining and analysis on interleukin-17A inhibitor-associated IBD adverse events based on the FAERS database and noted that Ixekizumab is associated with a risk of new-onset IBD (46). IL-17 is a crucial inflammatory cytokine in the Th17/IL-23 pathway and is highly expressed in the intestinal mucosa of patients with UC and CD. Although the interleukin-17 inhibitor Ixekizumab is considered to have therapeutic potential for IBD, its critical role in maintaining epithelial barrier integrity and gut microbiota balance may explain the risk of IBD development during its treatment. In contrast, interleukin-23 inhibitors (such as Ustekinumab) selectively reduce IL-17 produced through the IL-23-dependent pathway, thereby alleviating inflammation and achieving remission in IBD, while IL-23-independent IL-17 remains capable of maintaining epithelial barrier integrity and preserving microbial balance (47). It is worth noting that a previous study by Yamada et al (40). explored the association between IL-17 inhibitors and the risk of new-onset IBD, reporting no significant increase in IBD incidence associated with IL-17 inhibitors. Compared with that study, we incorporated more recent RCTs, thereby expanding the temporal scope and data coverage and enhancing the currency and representativeness of the findings. Moreover, our study not only examined three IL-17 inhibitors (Ixekizumab, Secukinumab, and Brodalumab), but also included an IL-12/23 inhibitor (Ustekinumab) and a dual IL-17A/IL-17F inhibitor (Bimekizumab), enabling a more comprehensive comparative analysis across different types of IL inhibitors. Notably, we observed a statistically significant association between Ixekizumab use and an increased risk of new-onset IBD in patients with psoriasis compared with the control group—an observation not clearly identified in previous studies (40). In addition, we included diarrhea as a secondary endpoint, considering it a potential early symptom of IBD, thereby complementing the understanding of gastrointestinal adverse events associated with interleukin inhibitors. Overall, while our results are consistent with prior studies in suggesting a low incidence of new-onset IBD among psoriasis patients treated with IL inhibitors, this study contributes novel insights by updating the evidence base, broadening the range of therapeutic agents evaluated, and incorporating additional clinically relevant outcomes. These findings provide more comprehensive evidence to support clinical decision-making in the management of psoriasis with IL inhibitors.

This meta-analysis of RCTs included 16,557 psoriasis patients from 21 published trials, allowing for risk estimation. Overall, among 12,185 psoriasis patients treated with interleukin inhibitors, 22 new-onset IBD cases were reported as adverse events, compared to 1 case among 4,372 controls. The incidence rate of new-onset IBD in patients treated with interleukin inhibitors was 2.4 per 1,000 patient-years. The low incidence rate reported in the current meta-analysis is consistent with a rate of 2.4 per 1,000 patient-years, as reported in a previous meta-analysis that investigated the risk of IBD associated with interleukin-17A inhibitors in RCTs (40). The low incidence rate reported in the current meta-analysis is consistent with the findings of a 5-year safety study on Ixekizumab in patients with psoriasis, which reported an IBD incidence rate of 0.2 per 100 patient-years, including both UC and CD (48). A similar incidence rate was also observed in a longitudinal observational study of Secukinumab in patients with plaque psoriasis (49). The incidence rate of 2.4 cases per 1000 patient-years observed in our study falls within the range reported in observational studies assessing IBD risk in psoriasis patients. However, this rate appears significantly higher compared to the incidence rate of 0.109 cases per 1000 person-years reported in the general US population (50).

Diarrhea is one of the common clinical symptoms of CD and UC. As the diagnosis of IBD is primarily confirmed through colonoscopy, patients with mild symptoms may not undergo the procedure, resulting in them remaining undiagnosed. However, most studies included in this analysis reported diarrhea as an adverse event. Since diarrhea was not reported as an adverse event in RCTs involving Ixekizumab and Ustekinumab, this study focused on 13 RCTs related to Bimekizumab (23, 26, 29, 33–35, 37), Secukinumab (22, 27, 28), and Brodalumab (18, 30). A fixed-effect model analysis revealed no significant increase in the risk of diarrhea among psoriasis patients treated with these three interleukin inhibitors. Notably, interleukin inhibitors reshape the gut microbiota through immunoregulation and microenvironmental remodeling. IL-17 and IL-23 play critical roles in structuring the intestinal microbial ecosystem and maintaining immune homeostasis. Inhibition of these cytokines may diminish pro-inflammatory microbes, compromise antimicrobial defenses, and disrupt epithelial integrity, together promoting dysbiosis and contributing to the gastrointestinal adverse effects observed during treatment (51). Further studies are needed to clarify the causal links between microbiota alterations and gastrointestinal outcomes.

In the sensitivity analysis, we employed both random-effects models and a leave-one-out approach to assess the risk of new-onset IBD in psoriasis patients treated with Ixekizumab compared to the control group, further validating the robustness of these findings. The results demonstrated that the data remained consistent and robust.

Although this study is drawn from data from a substantial number of RCTs, several limitations should be acknowledged. Despite the relatively large sample size, the rarity of IBD as a complication and the reporting of zero events in some studies may introduce bias into the statistical results. While this study provides preliminary evidence regarding the association between five interleukin inhibitors and the risk of new-onset IBD, further prospective studies and long-term follow-up researches are necessary to confirm the safety of these drugs in psoriasis patients, particularly their long-term effects on intestinal health. Although a fixed-effect model was employed in this study, significant heterogeneity may still exist due to variations in study designs and patient populations. Factors such as the type of psoriasis and study duration could influence IBD risk, yet these variables were not adequately controlled for in the included studies.

In summary, no significant difference in the risk of new-onset IBD was observed between the Bimekizumab, Secukinumab, Brodalumab, Ustekinumab group and control group(placebo or non-interleukin inhibitors) for the treatment of psoriasis patients. A significant difference in the risk of new-onset IBD was observed between the Ixekizumab group and the control group in the treatment of psoriasis patients(MH RD 0.0027, 95% Cl 0.0001-0.0054, I² = 0%, P=0.04). Therefore, psoriasis patients undergoing Ixekizumab treatment should remain vigilant regarding gastrointestinal symptoms, particularly in high-risk individuals, to facilitate early identification and management of potential IBD.