Efficacy and Safety of Upatinib in the Treatment of Active Anal Fistulas in Crohn's Disease

Anal fistula is the most common perianal lesion of Crohn's disease (CD), and the incidence of anal fistula in eastern CD population is significantly higher than that in Western population. The treatment of CD active anal fistula is difficult, which seriously affects the quality of life of patients and consumes a lot of medical resources. Injection of biological agents is the most commonly used method for the treatment of CD anal fistula, small molecule drugs can be taken orally, and the curative effect is more lasting. Upadacitinib was the first small molecule drug approved for CD treatment in China on June 30, 2023. At present, there is only one post-subgroup analysis of a global Phase 3 clinical study on Upatinib in the treatment of CD anal fistula, and the number of active anal fistula cases included is small, and the study objects are mostly western populations. This study intends to include CD patients with active anal fistula, and adopts the method of single-center single-arm study to explore the efficacy of Upatinib in the treatment of CD anal fistula, so as to provide more evidence-based medical evidence for the drug selection of CD anal fistula in China.

Crohn's disease (CD) is a chronic non-specific inflammatory disease of the intestine, and anal fistula is the most common perianal lesion in CD. Active anal fistula refers to the infection of the fistula, which causes perianal pain, discharge, redness, swelling, and even fever in patients. Biologics are currently the most widely used drugs for treating CD anal fistula. Studies with fistula healing as the main endpoint of observation show that the clinical remission rate of fistula is about 50% at most. CD anal fistula is difficult to treat, has a high recurrence rate, seriously affects the quality of life of patients, and consumes a large amount of medical resources.

CD anal fistula is a special subtype of CD, and exploring CD anal fistula has very important clinical significance. The incidence of anal fistula in Asian CD patients is significantly higher than that in Western CD patients; the prognosis of CD patients with anal fistula is worse, and the risk of intestinal stenosis or perforation is 3 to 4 times higher than that of patients without anal fistula; approximately 10% of patients present with anal fistula as the first manifestation of CD, and the symptoms of anal fistula most affect the quality of life of patients during the course of the disease; the susceptibility genes of CD anal fistula patients are different from those of other CD patients, and the susceptibility genes of the Asian CD population are different from those of the Western population. Our previous study included Han CD patients from southern China for analysis and found that polymorphisms in the IRGM, AOX1, and NKX2-3 genes are associated with the development of anal fistula.Compared with the widely used biologics for treating CD, small molecule drugs have great prospects. Biologics are complex proteins that require injection for treatment, have immunogenicity, are prone to secondary failure, and are relatively expensive. In contrast, small molecule drugs have a relatively small molecular weight, are easier to pass through cell membranes; have a short half-life and can be taken orally; have no antigenicity or immunogenicity, and have better sustained efficacy; and have lower production costs.

Upadacitinib was approved for the treatment of CD on June 30, 2023, and it is the first small molecule drug approved for CD treatment in China. The New England Journal of Medicine recently published the results of a phase 3 clinical study of upadacitinib for CD \[8\]: In the induction period study, the clinical remission rate of the upadacitinib 45 mg treatment group was higher than that of the placebo group (U-EXCEL study, 49.5% vs. 29.1%; U-EXCEED study, 38.9% vs. 21.1%), and the endoscopic response rate was also higher than that of the placebo group (U-EXCEL study, 45.5% vs. 13.1%; U-EXCEED study, 34.6% vs. 3.5%); in the maintenance period study (U-ENDURE), the clinical remission rates (37.3% and 47.6%) and endoscopic response rates (27.6% and 40.1%) of the upadacitinib 15 mg and 30 mg treatment groups at week 52 were both higher than those of the placebo group (15.1% and 7.3%). The above study results show that upadacitinib is effective in treating CD.However, as a new small molecule drug, the efficacy of upadacitinib for the special subtype of CD anal fistula is not clear.

JAK/STAT is involved in innate and adaptive immunity. After activation, the signal is rapidly transmitted from the membrane to the nucleus, and then cytokines are activated, white blood cell transport is promoted, and cell proliferation is initiated, triggering intestinal inflammation and playing an important role in the pathogenesis of CD. The JAK/STAT signaling pathway may also be an important pathogenic mechanism of CD anal fistula. Manreet et al. found that CD anal fistula patients have gene variations in the JAK/STAT signaling pathway \[9\]. Upadacitinib targets and inhibits JAK1. Mechanistically, it may be effective for CD anal fistula. At present, only post hoc subgroup analysis data from the aforementioned three clinical studies on CD (not yet published) are available. In these studies, the complete remission rates of patients with active fistulas treated with different doses of upadacitinib at week 52 were 25% (3/12) and 10% (1/10), respectively, which were superior to the placebo group (0%, 0/23 and 0/7). However, the number of active fistula cases included in this post hoc subgroup analysis was relatively small, and the study subjects were mostly Western populations. Therefore, more efficacy data on this new small molecule drug for CD fistulas in the Chinese population are needed.

Therefore, this study intends to include CD patients with active fistulas and use a single-arm clinical study approach to explore the efficacy of upadacitinib in treating Chinese CD fistula patients. This will prepare for subsequent randomized controlled trials (RCTs) to further investigate the efficacy of different doses of upadacitinib in treating fistulas and compare the efficacy of upadacitinib with other biological agents in treating fistulas, and also provide more evidence-based medical evidence for the drug selection of CD fistulas.

Our hospital is one of the largest inflammatory bowel disease centers in the country. Additionally, due to the reputation of the anorectal surgery department, it has gathered a large number of fistula patients, providing a guarantee for the number of cases in this study.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥18 years and ≤70 years;
* Make a clear diagnosis of CD according to the "Consensus Opinions on the Diagnosis and Treatment of Inflammatory Bowel Disease (Beijing, 2018)";
* The disease severity of CD was moderate and severe according to Crohn's diseaseactivityindex (CDAI), that is, CDAI score \> 220.
* Complicated with active anal fistula, that is, on the basis of perianal MRI confirmation of anal fistula, the patient has perianal pain, fluid seepage and other symptoms, and the transanal surgeon judges that the symptoms are related to anal fistula activity;
* Patients with previous thrombosis, including deep vein thrombosis, pulmonary thromboembolism, atrial thrombosis, peripheral artery thrombosis and cerebral thrombosis confirmed by imaging;
* Informed consent. The subjects gave barrier-free informed consent, voluntarily participated in the clinical study and signed the informed consent.

Exclusion Criteria:

* History of allergy to the active ingredient of upatinib;
* Severe damage of liver and kidney function; Hemoglobin \< 8g/L;
* History of malignant tumor;
* Patients with previous thrombosis;
* Neutrophil count \< 1×109/L; , or lymphocyte count \< 500×109/L;
* Patients with intestinal complications (including intestinal stricture with proximal intestinal dilation or intestinal fistula). Diagnosis based on CTE/MRE.
* Presence of enterostomy;
* With active severe infection (such as sepsis) or opportunistic infection (such as active tuberculosis, shingles);
* Pregnant or planning pregnancy.
* Patients with vaginal fistula;
* Patients with anorectal stenosis.