Clinical features, treatment, and prognosis of secukinumab-induced inflammatory bowel disease

Abstract

Background

Inflammatory bowel disease (IBD) is a rare adverse effect linked to secukinumab, with limited clinical data available. This study aimed to analyze the clinical features of secukinumab-induced IBD and to offer recommendations for the careful administration of secukinumab.

Methods

We conducted a retrospective analysis by gathering case reports and case series of secukinumab-induced IBD through a database search, with data collected until September 30, 2024.

Results

A total of forty patients (21 males and 19 females) fulfilled the inclusion criteria, with a median age of 42 years (range 19, 70). The median time to IBD onset was 4 months following the initial dose (range 0.25, 53). The most common symptoms reported were abdominal pain (60.0%), diarrhea (37.5%), bloody diarrhea (32.5%), and fever (30.0%). Colonoscopy findings predominantly showed ulcers (62.5%) and inflammation (27.5%). Biopsy results revealed crypt microabscesses (22.5%), cryptitis (20.0%), inflammatory cellular infiltrates (20.0%), and both acute and chronic inflammation (22.5%). After discontinuation of secukinumab, patients reported symptom relief following treatment with systemic steroids (60.0%), targeted therapies (52.5%), and mesalamine (22.5%).

Conclusions

Comprehensive screenings are essential for patients prior to initiating secukinumab therapy. Gastrointestinal symptoms necessitate close monitoring during secukinumab treatment. Upon the diagnosis of IBD, secukinumab should be discontinued, and systemic steroid therapy should be initiated. Patients who do not respond or experience a relapse should be considered for immunosuppressive therapy.

Introduction

Secukinumab, a selective interleukin-17 inhibitor, binds specifically to IL-17A and obstructs its interaction with the IL-17 receptor [1]. It has received approval for treating ankylosing spondylitis, psoriasis, and psoriatic arthritis [2]. The safety data from Phase III studies (ERASURE, FIXTURE, FEATURE, and JUNCTURE) indicate that common adverse reactions include nasopharyngitis, headaches, upper respiratory tract infections, diarrhea, and hypercholesterolemia [2,3,4]. Large-scale randomized controlled trials have identified a potential link between secukinumab and inflammatory bowel disease (IBD), which remains a rare side effect [5, 6]. Current understanding primarily stems from case reports, leaving the specifics of incidence and progression ambiguous. A retrospective analysis in real-world settings is essential to gain insight into this IBD side effect. This study aims to analyze the clinical characteristics, treatment approaches, and outcomes associated with secukinumab-induced IBD, ensuring that patients are adequately screened and monitored for the safe administration of secukinumab.

Methods

Data source

Patients with secukinumab induced IBD were identified from the analyzed case reports and case series by searching the database. The databases utilized include Wanfang, the Chinese Biomedical Literature Database, and China National Knowledge Infrastructure, as well as PubMed, Web of Science, Embase, and the Cochrane Library. We conducted a database search utilizing subject terms and free words, which required the integration of Boolean operators "AND" and "OR". The specific search strategies employed included: interleukin-17 inhibitor OR secukinumab AND inflammatory bowel disease OR Crohn's Disease OR ulcerative colitis OR indeterminate colitis. The research articles selected for review were published between December 1, 2014, and September 30, 2024.

Inclusion and exclusion criteria

Secukinumab-induced IBD case reports and case series from the database were included. Reviews, replicated reports, animal studies, and non-secukinumab induced IBD were excluded.

Data extraction

Two researchers conducted independent literature screening and data extraction in accordance with the established inclusion and exclusion criteria. In cases of disagreement, a third researcher intervenes to facilitate consensus. The authors developed a custom form for the extraction of patient data, encompassing variables such as gender, age, country of origin, medical history, drug combinations, indications, onset time, clinical symptoms, type of IBD, computed tomography (CT), colonoscopy, tissue biopsy, white blood cell count, procalcitonin, C-reactive protein (CRP), erythrocyte sedimentation rate, fecal calprotectin, hemoglobin, serum albumin and stool routine, treatment, and outcomes.

Data statistics

We performed a descriptive analysis of the extracted parameters. SPSS 22.0 was used for statistical analysis of the clinical data. Median values (range, minimum, maximum) are used for continuous data. The count data is expressed as n (%).

Results

Epidemiological characteristics

According to the inclusion and exclusion criteria, a total of 40 IBD patients met the requirements, including 21 (52.5%) male patients and 19 (47.5%) female patients. The clinical characteristics of these forty patients are presented in Table 1. The median age of the cohort was 42 years, ranging from 19 to 70, with the majority of patients originating from the United States (13 cases, 32.5%). The primary indications for secukinumab treatment included psoriasis (17 cases, 42.5%), ankylosing spondylitis (7 cases, 17.5%), and psoriatic arthritis (7 cases, 17.5%). The median interval for the onset of IBD post-treatment was 4 months (range 0.25, 53), with 67.5% of patients experiencing onset within one year following drug administration. Six patients (15.0%) reported a history of smoking, two patients (5.0%) had a family history of IBD, and one patient (2.5%) had a history of colitis. Additionally, five patients (12.5%) received other medications, including pantoprazole, meloxicam, and etoricoxib.

Table 1 Epidemiological characteristics of 40 patients with IBD

Clinical signs

The clinical manifestations of 40 patients appear in Table 2. Thirty-six patients reported symptoms, with abdominal pain (24 cases, 60.0%), diarrhea (15 cases, 37.5%), bloody diarrhea (13 cases, 32.5%), and fever (12 cases, 30.0%) being the most prevalent. Additional symptoms included hematochezia (8 cases, 20.0%), weight loss (7 cases, 17.5%), vomiting (5 cases, 12.5%), and nausea (4 cases, 10.0%).

Table 2 Clinical symptoms and related examinations of 40 patients with IBD

Imaging examination

A CT examination of 15 patients primarily revealed colitis (6 cases, 15.0%) and thickening (5 cases, 12.5%). Colonoscopy was conducted on 34 patients, predominantly identifying ulcers in 25 cases (62.5%) and inflammation in 11 cases (27.5%). A small number of patients exhibited edema (7 cases, 17.5%), erythema (5 cases, 12.5%), and congestion (3 cases, 7.5%). Among the 34 patients who underwent colonoscopy, the findings predominantly included ulcers (25 cases, 62.5%) and mucosal inflammation (11 cases, 27.5%). Classification indicated that 18 patients had Crohn's Disease, 13 patients (32.5%) had ulcerative colitis, and 4 patients (10.0%) had indeterminate colitis.

Biopsy

Twenty-eight patients underwent biopsy, which showed crypt microabscesse (9 cases, 22.5%), cryptitis (8 cases, 20.0%), inflammatory cellular infiltrates (8 cases, 20.0%), acute and chronic inflammation (9 cases, 22.5%). These inflammatory cells consisted of lymphocyte (3 cases, 7.5%), neutrophil (1 case, 2.5%) and plasma cell (1 case, 2.5%).

Laboratory examination

Sixteen patients reported white blood cell counts with a median of 13990/μL (range 8360, 17500). CRP levels were reported in 19 patients, showing a median of 128 mg/L (range 17, 463). Fecal calprotectin measurements were available for 6 patients; 5 (12.5%) exhibited elevated levels while 1 (2.5%) was considered normal.

Treatment and outcomes

The treatment and results for 40 patients are outlined in Table 3. Secukinumab was discontinued in 36 patients (90.0%) and not reported in 4 patients (10.0%). The primary treatment regimens consisted of systemic steroids (24 cases, 60.0%), antibiotics (615.0%), sulfasalazine (1 case, 2.5%), mesalamine (9 cases, 22.5%), and targeted therapies (21 cases, 52.5%). These targeted therapies included TNFα inhibitors (infliximab, adalimumab, certolizumab, golimumab), an IL-12/23 antagonist (ustekinumab), interleukin 23 inhibitors (guselkumab, tildrakizumab), and JAK1 inhibitors (upadacitinib, tofacitinib). Thirty-one patients (77.5%) experienced symptom improvement, while 9 patients (22.5%) did not report any outcome. In one instance, secukinumab was re-administered, leading to a relapse of IBD.

Table 3 Treatment and outcomes of 40 patients with IBD

Discussion

In clinical trials, secukinumab was associated with an increased risk of IBD, although the incidence remained low. A thorough analysis of clinical trials and post-marketing surveillance regarding the long-term safety of secukinumab revealed IBD incidences of 0.01 and 0.05, respectively [7]. Patients with psoriasis exhibit a higher propensity for developing IBD, with many potentially harboring subclinical forms of the disease [8, 9]. Additionally, individuals with a familial predisposition to IBD are at an elevated risk [10]. It is postulated that secukinumab-induced IBD in psoriasis patients may be linked to a pre-existing heightened baseline risk [8]. Smoking further exacerbates the likelihood of IBD [11]. A comprehensive evaluation of both personal and familial IBD histories is crucial. Given the increasing reports of IBD associated with secukinumab, healthcare providers are urged to assess IBD risk prior to the commencement of secukinumab therapy. As a result, many clinicians are now advised to refrain from prescribing secukinumab to patients with a history of IBD and to closely monitor gastrointestinal health [12]. Nevertheless, the majority of patients affected do not have a prior history of IBD, familial connections, or a smoking history. Therefore, additional clinical data is required to elucidate the risk factors and severity associated with secukinumab-induced IBD.

Mucosal or cutaneous Candida infections and neutropenia may arise during secukinumab therapy [13]. Our study indicated that none of the 40 patients experienced neutropenia or fungal infections. IBD predominantly presents in individuals aged 15–30 and 40–60, with a median age of diagnosis at 42 years, consistent with existing literature [14]. The onset of IBD following secukinumab administration can range from 3 weeks to 53 months, underscoring the necessity for vigilant monitoring throughout treatment. Gender does not significantly affect the onset of secukinumab-induced IBD, although there is a slight male predominance (52.5% male vs. 47.5% female). The majority of these patients are located in the United States. Genetic factors may contribute to the development of IBD in patients receiving secukinumab. Genetic analyses have identified polymorphisms in the TLA1 gene associated with sustained inflammation post-secukinumab treatment [15]. Some patients may concurrently utilize medications such as pantoprazole, which could also trigger IBD [16]. Despite the use of these suspected agents, it frequently results in microscopic colitis, a chronic inflammatory condition of the colon characterized by persistent, watery, non-bloody diarrhea with essentially normal colonoscopic findings [17, 18]. A temporal relationship observed between gastrointestinal symptoms and secukinumab suggests its potential role in the etiology of IBD. Dosage does not seem to be a risk factor for secukinumab-induced IBD, as evidenced by the FIXTURE study, which found no significant dose-related differences in adverse events among the secukinumab groups, aside from mild to moderate Candida infections [3].

Typical manifestations in patients with secukinumab-induced IBD include abdominal pain, diarrhea (including bloody diarrhea), and fever. These symptoms often correlate with elevated white blood cell counts, increased erythrocyte sedimentation rates, elevated C-reactive protein levels, and heightened fecal calprotectin concentrations. It is crucial to remember that a minority of IBD patients may show no overt symptoms and remain undiagnosed until a colonoscopy is performed [19]. The severity of secukinumab-induced IBD can vary significantly, encompassing mild IBD-like lesions to acute fulminant colitis [20]. Diagnosing this condition can prove complex, as secukinumab may induce lymphocytic colitis and microscopic colitis, necessitating differentiation from IBD [21, 22]. Confirmation of IBD diagnosis may require imaging studies, colonoscopy, and serum markers. Fecal calprotectin levels greater than 250 μg/g warrant gastroenterological assessment to exclude active IBD, particularly while secukinumab administration is deferred [23, 24].

The pathophysiological mechanism of secukinumab—induced IBD remains ambiguous. IL-17 plays a crucial role in the intestinal defense system, and the inhibition of either its ligands or IL-17 receptors can disrupt this equilibrium, potentially leading to IBD [25]. Numerous colitis animal models have demonstrated that the blockade of IL-17A results in heightened intestinal inflammation and compromised epithelial integrity [24]. IL-17A is integral to the immune response against extracellular pathogenic fungi and bacteria, and its inhibition may elevate the risk of infectious colitis. [26] Additionally, both IL-17F and IL-17A are vital for immune defense by stimulating cytokine production in the intestinal epithelium [27]. As a pro-inflammatory cytokine, dysregulation of IL-17 can result in an exaggerated inflammatory response and contribute to the onset of autoimmune disorders [28]. The inhibition of IL-17RA has been shown to decrease neutrophil aggregation, disrupt the intestinal epithelial barrier, and reduce the expression of intestinal antimicrobial peptides, thereby facilitating bacterial invasion and increasing intestinal permeability, which ultimately leads to inflammation [29]. Chronic mucocutaneous candidiasis has been linked to defects in the IL17RA and IL17F genes [30]. Furthermore, animal studies indicate that moderate chemically-induced colitis in mice can trigger the proliferation of Candida albicans, significantly exacerbating intestinal inflammation and eliciting antibodies against Saccharomyces cerevisiae [31]. These findings suggest that the inhibition of IL-17 may lead to secondary overgrowth of Candida albicans, potentially instigating or exacerbating gastrointestinal inflammation.

Currently, a clinical guideline for managing secukinumab-induced IBD is lacking. Discontinuing secukinumab is crucial. Systemic steroids may serve as the initial treatment to alleviate symptoms. In cases of steroid resistance, alternative therapeutic options should be explored. Agents like TNF-α inhibitors, IL-12/23 inhibitors, IL-23 inhibitors, and JAK inhibitors have shown effectiveness [32, 33]. Generally, IBD patients experience a favorable prognosis post-treatment. However, re-initiating secukinumab therapy is not advised due to the risk of IBD recurrence.

Conclusion

IBD was a rare and significant adverse event associated with secukinumab. Prior to initiating secukinumab therapy, practitioners must conduct thorough screenings for gastrointestinal inflammation in patients. Those previously treated with secukinumab require vigilant monitoring. If there is suspicion of secukinumab-induced IBD, its use should be avoided. Corticosteroids play a crucial role in treatment, and immunosuppressive therapy must be administered to patients who either fail to respond or experience relapses.