ABSTRACT
New-onset inflammatory bowel disease following Interleukin (IL)-17 inhibitor therapy is a rare iatrogenic complication occurring in 0.5%–1.5% of treated patients, reflecting IL-17's dual role as a systemic pro-inflammatory mediator and intestinal barrier protector. We report 2 cases: a 40-year-old woman who developed secukinumab-associated Crohn's disease and a 25-year-old woman who developed bimekizumab-associated ulcerative colitis, both without previous gastrointestinal history. IL-17 blockade disrupts intestinal homeostasis, triggering dysbiosis and paradoxical Th1/Th2-driven inflammation. Both patients achieved rapid remission following IL-17 inhibitor discontinuation and transition to IL-23 inhibitors. Clinicians should maintain heightened awareness of this complication.
KEYWORDS: IL-17 inhibitors, inflammatory bowel disease, secukinumab, bimekizumab, paradoxical inflammation
INTRODUCTION
IL-17 is a proinflammatory cytokine central to immune-mediated inflammatory diseases. Anti-IL-17 agents (secukinumab, ixekizumab, bimekizumab, and brodalumab) are used for psoriasis, spondyloarthropathies, and other dermatologic/rheumatologic conditions. While paradoxical worsening of established inflammatory bowel disease (IBD) is recognized,1 new-onset-IBD without previous gastrointestinal history is rare (∼0.5%–1.5%).2 Pathophysiology remains incompletely understood, with no clear management guidelines.3 Secukinumab-associated-IBD is documented since 2015, but reports linking bimekizumab are limited.4 We present 2 patients emphasizing diagnostic challenges and management.
CASE REPORTS
Case-1
A 40-year-old woman with hidradenitis suppurativa (HS) and systemic lupus erythematosus (SLE) in remission, no family history of IBD presented with 6 months of abdominal discomfort, bloating, early satiety, episodic diarrhea, and ∼40 lbs weight loss. She started secukinumab for HS 8 months before, with symptoms beginning ∼1 month after initiation and progressively worsened. Pretreatment laboratory test results (low-normal hemoglobin, normal erythrocyte sedimentation rate [ESR]/C-reactive protein [CRP]) and gastrointestinal history were unremarkable. Diarrhea was treated as infectious gastroenteritis without improvement. Esophagogastroduodenoscopy (EGD) revealed atrophic, cobblestoned mucosa, and serpiginous antral and duodenal bulb ulcers (Figure 1). Biopsies demonstrated chronic active gastritis with mild duodenitis without granulomas. Helicobacter pylori was positive and treated with quadruple therapy.
Figure 1.
Esophagogastroduodenoscopy (EGD) findings demonstrating extensive gastroduodenal involvement. (A) Deep, irregular ulceration with surrounding mucosal erythema noted in the prepyloric region. (B) Confluent ulcerations extending across the gastric antrum and prepyloric region, causing mild luminal narrowing. (C, D) Representative views of the gastric body and antrum displaying severe ulcerations interspersed with a distinct cobble-stoning appearance of the surrounding gastric mucosa. (E) A longitudinal, serpiginous ulcer tracking through the duodenal bulb, accompanied by mucosal edema. (F) High-magnification, close-up view of the duodenal mucosal architecture highlighting the ulcer borders and localized inflammatory changes.
Persistent symptoms and atypical ulcers, raised suspicion for upper gastrointestinal Crohn's. Further evaluation revealed hemoglobin-8.8 g/dL, mean corpuscular volume 76.0 fL, CRP51.91 mg/L, and fecal calprotectin (FCP)1120 mcg/g. Clostridioides difficile was negative. Computed tomography (CT) showed transverse, descending, and rectosigmoid colonic wall thickening. Prometheus IBD Serology global interpretive was triple positive. Colonoscopy revealed diffuse rectosigmoid inflammation, distal descending mucosal erosions, excavated transverse colon and rectal ulcers with proximal sparing and normal terminal ileum (simple endoscopic score for Crohn's disease [SES-CD]:11; Figure 2).
Figure 2.
Colonoscopy findings showing patchy, multisegmental colonic ulceration and mucosal injury. (A) View of the distal descending colon demonstrating diffuse erythema, loss of normal vascular pattern, and multiple superficial mucosal erosions with overlying exudate. (B) Segment of the transverse colon showing a deep, well-demarcated ulceration surrounded by relatively spared, edematous mucosa. (C) Retroflexed or direct view of the rectum revealing a large, discrete ulcer with irregular borders and localized mucosal friability.
Histology showed mild ileal villous blunting, rare cecal/ascending colon microgranulomas, and moderately active chronic colitis in the rectum. Given the complete absence of predrug symptoms, she was diagnosed with secukinumab-associated CD. Concurrent photophobia and arthalgias attributed to SLE overlap with CD extraintestinal manifestations but cannot be definitively attributed to either.
Secukinumab was discontinued; prednisone 40 mg was initiated and tapered 5 mg/wk over 6 weeks. She improved within 1 week and transitioned to guselkumab. At 8 months, CRP <3 mg/L, FCP173 mcg/g, colonoscopy revealed normal mucosa throughout (SES-CD:0) with healed ulcerations on EGD (Figure 3), and concurrent HS improvement.
Figure 3.
Follow-up endoscopy and colonoscopy findings following discontinuation of secukinumab, demonstrating significant mucosal healing. (A) View of the gastric antrum and pylorus showing complete resolution of active ulcerations, replaced by areas of quiescent mucosa and chronic cicatricial scarring. (B) The duodenal bulb displaying a completely healed, linear scar at the site of the previous serpiginous ulcer, with normalization of the surrounding tissue. (C) Retrograde evaluation of the terminal ileum revealing normal, intact villous architecture and absence of inflammatory changes. (D) Examination of the transverse colon showing complete endoscopic remission, characterized by a smooth, normally appearing colonic mucosa with a restored, distinct vascular pattern. (E) Rectal retroflexion/view demonstrating a fully epithelialized, healed ulcer bed with healthy-appearing surrounding rectal mucosa.
Case-2
A 25-year-old woman with plaque psoriasis and no family history of IBD presented with 2-weeks of acute nonbloody diarrhea (5-6 episodes daily, Bristol VI/VII), colicky lower abdominal pain and 15 lbs weight loss over 4 weeks. Infectious workup (gastrointestinal polymerase chain reaction [GI PCR], stool ova/parasites, and C. difficile) was negative. Loperamide and dicyclomine provided partial relief before worsening with fecal incontinence, urgency, dehydration, and fatigue. Laboratory test results revealed CRP 12.8 mg/L, FCP 1,000 mcg/g, thyroid stimulating harmone (TSH) 4.78 mIU/L with normal fT4, and negative celiac serologies. Notably, bimekizumab was initiated 3 months earlier, transitioned from guselkumab for persistent scalp psoriasis. She had no gastrointestinal symptoms before bimekizumab or while on guselkumab with unremarkable baseline laboratory test results. EGD was unremarkable with negative celiac and H. pylori biopsies (Figure 4).
Figure 4.
Normal esophagogastroduodenoscopy (EGD) findings. (A) Endoscopic evaluation of the second part of the duodenum displaying normal, healthy mucosa with well-defined, intact circular folds (plicae circulares) and no evidence of inflammation, villous blunting, or ulceration. (B) Representative view of the stomach demonstrating healthy gastric mucosa with a preserved, normal rugal pattern, adequate distensibility, and an absence of erythema, erosions, or lesions.
Colonoscopy revealed pancolitis (ascending Mayo:2; descending Mayo:1-2; rectosigmoid Mayo:1) with a sigmoid pseudopolyp and normal terminal ileum (Figure 5). Histology confirmed cryptitis, crypt abscesses, and lymphoplasmacytic infiltration consistent with UC. She was diagnosed with bimekizumab-associated UC. Bimekizumab was discontinued, prednisone 40 mg was initiated, tapered 10-mg/week, and transitioned to risankizumab. At 6 months, she achieved clinical remission (SCCAI:2), CRP <3 mg/L with concurrent psoriasis improvement.
Figure 5.
Colonoscopy findings demonstrating variable-grade colitis. (A) Segmental view of the ascending colon demonstrating localized mucosal erythema and superficial erosions. (B) High-magnification view of the ascending colon displaying marked diffuse erythema, complete loss of the normal vascular pattern, and distinct mucosal granularity, characteristic of moderate endoscopic disease activity (Mayo endoscopic subscore 2). (C) Endoscopic evaluation of the descending colon showing mild erythema and a blunt or decreased vascular marking pattern consistent with mild disease activity (Mayo endoscopic subscore 1). (D) Representative view of the rectosigmoid region similarly demonstrating an absence of normal vascular markings and localized, mild mucosal hyperemia (Mayo endoscopic subscore 1).
DISCUSSION
New onset-IBD following IL-17 inhibitor therapy is increasingly recognized paradoxical adverse event. A meta-analysis reported 2.4 new-onset-IBD cases per 1,000 patient-years with anti-IL-17 agents vs none with placebo.2 Pharmacovigilance data identified cases emerging within 6 months of initiation (median 2.9 months).5
The mechanism lies in IL-17A's tissue-dependent duality.6 In inflamed skin and joints, it drives neutrophilic inflammation via NF-κB/MAPK. In the gut, IL-17A maintains homeostasis through a double-shield, by upregulating tight junction proteins (claudin-3, ZO-1) via ERK/MAPK, stimulating antimicrobial peptide production (RegIIIγ, lipocalin-2, beta-defensins) and sustaining secretory IgA via epithelial polymeric immunoglobulin receptor expression.6,7 Blockade compromises barrier integrity, permits dysbiosis, bacterial translocation, and provokes compensatory Th1-skewed inflammatory response resembling IBD, as demonstrated in IL-17A/IL-17RA deficient murine models.5,7 Critically, lamina propria γδ T cells produce gut-protective IL-17A independently of IL-23, explaining why upstream IL-23 blockade preserves the barrier unlike IL-17 blockade. In the Abcb1a-deficient colitis model, IL-17A/IL-17RA blockade accelerated mortality, whereas IL-23 inhibition attenuated colitis and expanded regulatory T cells.7
In our cases, the upstream biology differed by disease: IL-1β-T17 axis in HS and IL-23-dependent dermal γδ Th17 cells in psoriasis.8,9 Secukinumab and bimekizumab controlled skin disease but collaterally removed gut-protective IL-17A signaling.
Case 1 illustrates how anchoring to H. pylori gastritis and SLE–CD symptom overlaps delayed diagnosis. Case 2 is among the earliest bimekizumab-associated UC reports. Pooled phase 2/3 psoriasis data documented rare IBD events with bimekizumab.10 The temporal correlation, with a Naranjo score of +6 (probable) in both, supported a drug-associated etiology11 (Table 1).
Table 1.
Naranjo Adverse Drug Reaction Probability Scale applied to both cases
| Clinical question | Case 1 | Case 2 |
| 1. Are there previous conclusive reports of this reaction? | Yes (+1) | Yes (+1) |
| 2. Did the adverse event appear after the suspected drug was given? | Yes (+2) | Yes (+2) |
| 3. Did the adverse event improve when the drug was discontinued or a specific antagonist was given? | Yes (+1) | Yes (+1) |
| 4. Did the adverse event reappear when the drug was readministered? | Not performed (0) | Not performed (0) |
| 5. Are there alternative causes that could have caused the reaction? | Yes (+1) | Yes (+1) |
| 6. Did the reaction reappear when a placebo was given? | N/A (0) | N/A (0) |
| 7. Was the drug detected in any body fluids in toxic concentrations? | N/A (0) | N/A (0) |
| 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? | Not performed (0) | Not performed (0) |
| 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? | No (0) | No (0) |
| 10. Was the adverse event confirmed by any objective evidence? | Yes (+1) | Yes (+1) |
| Total score | +6 (probable) | +6 (probable) |
Although the absolute risk is low, vigilance is warranted in patients with personal/family IBD history, preexisting gastrointestinal symptoms, age older than 60 years, and spondyloarthritis with subclinical gut inflammation.2,5,12,13 Confirmation requires exclusion of mimics via FCP, inflammatory markers, stool studies, and ileocolonoscopy with biopsies. Management involves prompt discontinuation; corticosteroid induction, and transition to an alternative biologic with efficacy towards dermatologic disease and new-onset IBD.3,5 Obtaining a baseline FCP before initiation and monitoring during treatment is reasonable.
IL-23p19 inhibitors were selected as they block upstream Th17 differentiation, reducing pathogenic IL-17A/F.6,14 Guselkumab (case 1) is FDA approved for moderate-to-severe Crohn's disease (GRAVITI), not for HS (NOVA), but real-world data suggest benefit in certain patients providing dual-coverage rationale.15,16 Risankizumab (case 2) is FDA-approved for both moderate-to-severe UC (INSPIRE) and plaque psoriasis (UltIMMa-1/2), the best single-agent choice.17,18 Although, IL-23 blockade lowers IL-22, this tracks with declining inflammation while IL-23 independent signaling sustains the barrier as confirmed in IBD trials.7,14,15,17
Host genetics likely determine susceptibility. NOD2, IL23R, and ATG16L1 loci impair the same barrier functions that intestinal IL-17A maintains, potentially predisposing IL-17–inhibitor–associated IBD, though this remains unproven.19,20 Prospective genotype-stratified cohorts are needed for validation.
Neither patient had pretreatment endoscopies. A shared limitation across literature as endoscopic screening before IL-17 inhibitor initiation is not routinely performed to exclude subclinical IBD.
IL-17-inhibitor-associated IBD is rare but demands prompt recognition. Clinicians should counsel patients on red-flag gastrointestinal symptoms, pursue timely evaluation, and transition to alternate therapies. Further research is needed to identify at-risk populations and establish management guidelines.
DISCLOSURES
Author contributions: USA Vankayala: Data collection, literature review, and manuscript writing. A. Khouri and IS Alcala: manuscript writing and editing. A. Gonzalez: manuscript revision, work supervision, and guidance. All authors approved the final version of the manuscript. The authors declare no conflicts of interest. USA Vankayala is the article guarantor.
Acknowledgments: The completion of this research paper could not have been possible without the participation and assistance of my co-authors, and their contributions are sincerely appreciated and gratefully acknowledged. I express my deep appreciation to all my team members for their proactive hard work on this series. A special thanks to Dr. Gonzalez Adalberto for his supervision and guidance.
Financial disclosure: None to report.
Informed consent was obtained for the case reports.
ABBREVIATIONS:
- ATG16L1
autophagy-related 16-like protein 1
- CD
Crohn's disease
- CRP
C-reactive protein
- CSC
colonoscopy
- CT
computed tomography
- EGD
esophagogastroduodenoscopy
- ERK
extracellular signal-regulated kinase
- FAERS
FDA adverse event reporting system
- FCP
fecal calprotectin
- FDA
Food and Drug Administration
- fT4
free thyroxine
- GI
gastrointestinal
- H. pylori
Helicobacter pylori
- HS
hidradenitis suppurativa
- IBD
inflammatory bowel disease
- IFN-γ
interferon-gamma
- IgA
immunoglobulin A
- IL
interleukin
- IL-17RA
interleukin-17 receptor A
- IL23R
Interleukin-23 receptor
- MAPK
mitogen-activated protein kinase
- NF-κB
nuclear factor kappa-light-chain-enhancer of activated B cells
- NOD2
Nucleotide-binding oligomerization domain-containing protein 2
- PNCR
polymerase chain reaction
- SCCAI
Simple Clinical Colitis Activity Index
- SES-CD
simple endoscopic score for Crohn's disease
- SLE
systemic lupus erythematosus
- Th1
T-helper type 1
- Th2
T-helper type 2
- Th17
T-helper type 17
- TSH
thyroid-stimulating hormone
- UC
ulcerative colitis
- ZO-1
zonula occludens-1
Contributor Information
Anas Khouri, Email: khouria2@ccf.org.
Isabella Suarez Alcala, Email: isasuareza95@gmail.com.
Adalberto Gonzalez, Email: gonzala6@ccf.org.
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