Introduction

The treatment of complex perianal fistulas (cPAF) in Crohn’s disease remains challenging. Diversion stoma is typically reserved for patients with advanced disease and for palliation. However, data regarding its contribution to radiological remission (RR) in the era of biologic therapies are limited. This study aimed to evaluate effects of diversion stoma on RR.

Aims & Methods

After identifying RR-associated factors in entire cPAF cohort(n:236), a control group was generated using propensity score matching(PSM), accounting for these variables. Stoma(n:60) and control(n:59) groups were assessed for demographic and treatment-related characteristics. In the study group (n:60+59) univariate time-dependent anlayses were conducted for RR. Than, RR-related factors (p<0.1 in univariate analyses) were evaluated in multivariate Cox regression analysis. Cinical remission (CR) was defined as the absence of fistula drainage ≥3 months, confirmed by gentle compression. RR was defined as fibrotic closure of all fistula tracts in MRI. MRI assessments were reevaluated and confirmed by two radiologists.

Results

Among 236 patients with cPAF, factors associated with RR included multiple fistulas, branched morphology, trans-sphincteric fistulas (TSF), frequent need for antibiotics, and use of multiple anti-TNF agents. A total of 60 patients who underwent stoma formation were matched via PSM to 59 patients in the control cPAF group.
Stoma creation occurred at a relatively late stage, with a median fistula duration of 29 months (IQR: 69). The median stoma duration was 24 months (IQR:46). With stoma, CR was achieved in 77% and RR in 60% of patients. The median time to CR was 20 months (range: 3–196; IQR:13), and the median time to RR was 29 months (range: 6–208; IQR:28). The stoma was reversed in 45.8% of cases (n:27).
While multiple fistulas, TSF, and a history of multiple anti-TNF use were associated with RR in the entire cohort, their distribution was similar between stoma and control groups. However, the stoma group had a higher proportion of females (51.7% vs. 32.2%), more frequent history of seton use (53.3% vs. 35.6%), and longer IBD duration at the time of fistula development (30 vs. 5 months). These factors may be considered negative influencers in IBD and could compromise the success of the stoma group from the beginning. Both radiologic response and RR rates were significantly higher in the stoma group. In Kaplan-Meier analysis, diversion stoma was significantly associated with RR (log-rank: 0.02) (Table 1). Cox regression analysis showed that the presence of multiple fistulas and TSF were independently associated with poor RR, while diversion stoma was independently associated with achieving RR (Table 1). Among patients with a stoma, only multiple fistulas (p = 0.03) and TSF (p = 0.004) were associated with poor RR.

Conclusion

Diversion stoma in patients with cPAF, after adjusting for key prognostic factors, was independently associated with RR. Despite having unfavorable prognostic features such as TSF, multiple fistula tracts, and other negative influencers, the success of even relatively late-stage stoma formation may encourage consideration of earlier stoma creation to achieve RR.

Clinical Case Summary

27-year-old male with penetrating Crohn's disease (CD; A1, L2, pB3), diagnosed at the age of 9, with multiple hospitalizations. The patient was treated with infliximab + azathioprine for three years. Colonoscopy at 16 years showed pancolitis and was complicated with perforation, being submitted to total colectomy with rectal preservation and ileostomy. Therapy was switched to adalimumab+methotrexate, with partial clinical response. After seven years, due to severe complex fistulizing perianal disease, adalimumab was switched to ustekinumab. After 2 years of Ustekinumab monotherapy, he presented disabling symptoms and developed an enterocutaneous fistula peri-ileostomy. Combination therapy with ustekinumab+vedolizumab was started. The patient still maintained discharge from the enterocutaneous and perianal fistulas. After 1 year, a painful circumferential penile ulcer with swelling and seropurulent discharge was noted. Other causes, namely infections were excluded. Biopsies were performed and revealed non-caseous granulomatous inflammation with lymphocytic and eosinophilic infiltrates, compatible with CD. Topical therapy with tacrolimus ointment was applied, with no response. Ustekinumab+vedolizumab was switched to upadacitinib. There was a substantial improvement of the penile lesion, the enterocutaneous fistula discharge reduced, and perianal symptoms resolved on maintenance therapy with Upadacitinib.
Genital metastatic CD is uncommon and mainly occurs in the setting of colonic involvement and perianal disease. Treatment options for MCD remain underwhelming due to the limited available evidence and varying responses of reported therapeutic methods. Optimization of biologic therapy is mandatory.

References

For this case we'll include:
- Pictures ​of the penile ulcers before and during maintenance therapy with upadacitinib
- Endoscopic evaluation during follow-up
- Histological specimen of colectomy and from multiple endoscopic evaluations performed
- Radiological evidence of perianal and peri-ileostomy enterocutaneous fistula

Introduction

Short bowel syndrome (SBS) is a malabsorptive condition mostly caused by massive surgical resection of the small intestine and is associated with significant morbidity and mortality, reduced quality of life, and high healthcare costs¹. Crohn’s disease (CD) represents a potential cause leading to an increased risk of SBS with considerable clinical consequences². Human microbiota-associated (HMA) mice represent a model to establish human fecal microbiota in preclinical models^3-4. Here, for the first time, we tried to conduct a “humanized” model of SBS, using faeces from patients affected by this disease.

Aims & Methods

The aim of the current study is to determine the functional role of the gut microbiota of CD patients with or without SBS. A dextran sodium sulphate model of colitis on C57BL/6 mice was employed to assess immune and metabolic signatures following faecal transplantation from patients affected by SBS/IF, CD with high or low risk for SBS/IF. Lymph node samples were collected to examine differences in T cell populations, and disease activity index and bronchoscopy were used to evaluate the activity of the disease.

Results

Fecal microbiota transplantation (FMT) from CD patient with a low risk of SBS/IF was associated with worse disease activity and endoscopic scores in colitis mice. Additionally, an increase in the percentages of Treg, Tnaive, Th1, and Th17 cells was observed in mice that received FMT from CD patient with a low risk of SBS/IF, compared to controls and those that received FMT from patient with SBS/IF or from CD patient with a high risk of SBS/IF.

Conclusion

Our data underscore the complex interactions between gut microbiota and host immunity and highlight the importance of careful donor selection in FMT applications, particularly for inflammatory conditions. Further research is warranted to characterize specific microbial and immunological factors that drive these effects and to identify microbiota profiles that could potentially confer therapeutic benefits.

References

1. Massironi S, Cavalcoli F, Rausa E, Invernizzi P, Braga M, Vecchi M. Understanding short bowel syndrome: current status and future perspectives. Dig Liver Dis. 2020;52(3):253-261. doi:10.1016/j.dld.2019.11.013
2. Aksan A, Farrag K, Blumenstein I, Schröder O, Dignass AU, Stein J. Chronic intestinal failure and short bowel syndrome in Crohn's disease. World J Gastroenterol. 2021;27(24):3440-3465. doi: 10.3748/wjg.v27.i24.3440.
3. Staley C, Kaiser T, Beura LK, Hamilton MJ, Weingarden AR, Bobr A, Kang J, Masopust D, Sadowsky MJ, Khoruts A. Stable engraftment of human microbiota into mice with a single oral gavage following antibiotic conditioning. Microbiome. 2017;5(1):87. doi: 10.1186/s40168-017-0306-2.
4. Zhu Z, Kaiser T, Staley C. Antibiotic Conditioning and Single Gavage Allows Stable Engraftment of Human Microbiota in Mice. Methods Mol Biol. 2021;2327:281-291. doi: 10.1007/978-1-0716-1518-8_17.