IL-17A plays a key role in maintaining intestinal mucosal homeostasis. On the one hand, it contributes to mucosal immunity against intestinal pathogens. Therefore, blocking IL-17A may increase the risk of infectious colitis. On the other hand, it protects against autoimmune and autoinflammatory immune responses, thereby mitigating the development of IBD. However, IL-17A blockade is highly effective against many rheumatic and ** diseases (e.g., PSO, PSA, and AS). Our case observations highlight the risk of colitis, including autoimmune colitis and potentially infectious colitis, in patients receiving IL-17A inhibitors**. The severity of intestinal inflammation can be quite severe and should not be underestimated.
The first patient with a history of Sapho syndrome developed severe colitis 3 months after exposure to IL-17A inhibitors. The patient has no prior history of IBD and lacks known risk factors (e.g., negative family history and no history of smoking). Gastrointestinal symptoms were absent prior to initiation of secukinumab**. Extensive diagnostic evaluation did not reveal any other underlying causes of these clinical symptoms. Associations have been reported between IBD and other autoimmune diseases such as thyroiditis, celiac disease, multiple sclerosis, and psoriasis. In two previous studies, the prevalence of IBD in patients with SAPHO syndrome was estimated to be 5% to 8% to 13%. Thus, with or without exposure to secukinumab, the baseline risk of IBD in this patient may be elevated compared with the general population.
Whether patients taking secuki-numab** have a higher risk of IBD remains controversial. One comparative study showed that patients with PSA AS who started an IL-17A inhibitor** did not have a higher risk of IBD compared with those who started etanercept. However, similar cases of new-onset colitis during IL-17A inhibitors** and data suggesting paradoxical colitis activity in patients with Crohn's disease are of concern. Given the typical overall presentation of this case and the emerging symptoms following recent exposure to secukinumab, drug-induced IBD** appears to be reasonable.
In the second patient, the pathogenesis of colitis appears to be less clear. Possible differential diagnoses include infectious and/or autoimmune colitis, and IL-17A inhibitors** may favor both underlying pathologic mechanisms.
The role of IL-17A in maintaining intestinal mucosal homeostasis is multifaceted. In animal models, blocking IL-17A results in increased intestinal inflammation and impaired epithelial barrier. Several studies have shown that IL-17A is particularly important for immune responses against extracellular pathogenic fungal and bacterial species. In a mouse model, IL-17 receptor E-deficient mice not only exhibited increased colonic pathology and bacterial burden during Citrobacterium infection, but also significantly reduced gene expression encoding antimicrobial peptides and other inflammatory molecules. This results in a significant increase in mortality in IL-17 receptor E-deficient mice. IL-17F and IL-17A also play an important role in immune defense by activating intestinal epithelial cytokines. IL-17A is predominantly produced in T cells, while IL-17F is produced in T cells as well as innate immune system cells and epithelial cells. IL-17F and IL-17A are essential for immune defense against Staphylococcus aureus and rodent citrobacterium. As a result, there may be an increased risk of infectious colitis during IL-17A inhibitors**.
In our patients, macroscopic observations suggest IBD, while microscopic findings on endoscopy suggest predominantly infectious colitis. After discontinuing ixekizumab and using adalimumab**, the patient's symptoms improved. However, due to the persistence of certain symptoms, the patient received antibiotics** (although no enteric pathogens were detected in an extensive diagnostic search). Eventually, the patient's symptoms disappeared. It remains unclear whether the patient is due to antibiotics**. Several studies have shown that antibiotics can not only be the first bacterial infection, but also have significant immunomodulatory effects. Improvement in symptoms after antibiotics** does not rule out an autoimmune cause of symptoms, which may be caused by the switch from secukinumab to ixcolizumab. Another potential cause may be due to impaired barrier function, and infectious causes are causing these symptoms. In IBD, impaired epithelial barrier function and increased opportunities for pathogens to enter the intestinal mucosa are common.
In our patient cases, the switch from secukinumab to ixekizumab is noteworthy. In this case, the drug was not switched to ixekizumab due to ***, but due to a secondary loss of efficacy. The patient has been receiving secukinumab** for several years and has no gastrointestinal symptoms. However, about 6-7 weeks after the start of ixekizumab**, severe symptoms of colitis appeared. To the best of our knowledge, there have been no case reports of colitis in patients who switch from one IL-17A inhibitor to another (e.g., from secukinumab to ixekizumab or vice versa). In contrast, several studies have demonstrated the safety of switching from secukinumab to ixekizumab.
This appears to be particularly useful for difficult** patients who have not previously responded to secukinumab**. The cause of colitis after switching from secukinumab to ixekizumab is unknown. Although secukinumab and ixekizumab are both IL-17A inhibitors, some studies have tried to demonstrate the difference between the two drugs. Seukinumab has a longer half-life and is administered at a dose 3-4 times higher than ixekizumab, reaching peak efficacy approximately 16 weeks after initiation**. This results in a significant increase in systemic exposure. Ixekizumab has a significantly higher affinity for IL-17A and IL-17A F. The increased affinity compared to secuki-numab may explain the lower dose required. Ixekizumab reaches peak efficacy approximately 12 weeks after initiation**. It is clear that although secukinumab and ixekizumab are both IL-17A inhibitors, they have different pharmacokinetic profiles. These differences in affinity, specificity, and systemic exposure may significantly affect *** and efficacy.
In our case, the different affinities for IL-17A and IL-17A F are particularly interesting considering that IL-17A F heterodimers and IL-17A homodimers signal through the same IL-17 receptor A receptor C complex. Ixekizumab has a high affinity for both IL-17A and IL-17A F. IL-17A F heterodimer is a cytokine that mimics IL-17A as well as IL-17F. IL-17A and IL-17F are pro-inflammatory cytokines that are elevated in patients with IBD. This pharmacological profile may contribute to the efficacy of ixekizumab in patients who respond to secukinumab[29]. In addition, these affinity differences may also explain the severe gastrointestinal symptoms experienced by our patients after switching from secukinumab to icokinumab. However, a recent database analysis found that the number of IBD cases observed after secukinumab** was 10 times higher than the number of IBD cases observed after ixekizumab**.
It is mentioned that the number of IBD cases in patients receiving secukinumab and ixekizumab** can be traced in part back to different marketing dates (January 2015, April 2016).
The neutralization of secukinumab by anti-drug antibodies may explain the absence of gastrointestinal symptoms during secukinumab** and the presence of gastrointestinal symptoms with ixcolizumab. Due to secondary loss of efficacy, the patient** changed from secukinumab to ixcolizumab. Anti-secukinumab antibodies can neutralize the effects of secukinumab and prevent IBD.
In clinical practice, patients with IL-17 inhibitor-induced IBD often experience symptoms such as diarrhea, bloody stools, abdominal pain, and fever. These symptoms are usually accompanied by elevated white blood cell count, erythrocyte sedimentation rate, C-reactive protein levels, and fecal calprotectin concentrations. Most new cases of IBD are detected within three months of initiation of anti-IL-17**. Individuals with gastrointestinal symptoms or a history of previous colitis flares, regardless of the underlying autoimmune disease, may be at higher risk. Screening measures such as assessment of past gastrointestinal symptoms and family history of IBD are beneficial, and non-invasive biomarkers such as fecal calprotectin may enhance IBD risk assessment.
Currently, there are no clinical guidelines for patients with post-IL-17 inhibitor disease or new-onset IBD. However, discontinuation of IL-17 inhibitors has been reported to result in significant improvement in symptoms in patients with IL-17A inhibitor-associated colitis. In most cases, symptoms can be relieved within 4 weeks with proper management.
While IL-17 inhibitors are generally considered safe and have demonstrated high potency in PSO, PSA, and AS, it is important to note that rare adverse effects have been documented. These may include new or worsening IBD, although a clear causal relationship has not been established. Larger, prospective studies could help better understand the link between IBD and IL-17 inhibition and the frequency of this rare adverse event.