Ulcerative colitis (UC) is a chronic bowel disease. It causes inflammation of the rectum and sometimes the colon. This disease can also affect other parts of the body. It can be very difficult to live with on a daily basis. People with UC may experience frequent diarrhea, rectal bleeding, urgency to defecate, and even incontinence. All of this can significantly reduce their quality of life.

The goal of treatment is twofold:

• To eliminate or reduce symptoms (this is clinical remission),
• To allow the bowel to heal.

When these two goals are achieved, the risk of relapse, hospitalization, surgery, or colorectal cancer decreases.

To monitor the progression of the disease, gastroenterologists use a test called fecal calprotectin: this is a protein measured in stool that helps detect intestinal inflammation.

When conventional treatments like corticosteroids or immunosuppressants are ineffective or poorly tolerated, the investigators use more targeted therapies.

For a long time, doctors have used drugs called anti-TNFs. They block a protein responsible for inflammation (TNF-alpha). These treatments are often injected under the skin, which is generally well-tolerated by patients.

A drug called infliximab, now available as a subcutaneous injection, could be used as a first-line treatment for ulcerative colitis because it appears to be more effective than other injectable anti-TNFs.

Another drug, vedolizumab, works differently from anti-TNFs and can also be used as a first-line treatment.

More recently, new classes of drugs have shown promise:

• JAK inhibitors (such as filgotinib),
• interleukin-12 and interleukin-23 inhibitors (such as ustekinumab).

These new treatments have advantages, such as the oral administration method for filgotinib and the fact that they can be used alone, without any other associated medication, which could simplify patients' lives and improve their quality of life.

Today, there are increasingly more different treatments for ulcerative colitis, and the investigators still don't know clearly what the best strategy is:

Is it better to start with one type of medication rather than another? Does the order in which the investigators try treatments lead to different results?

This is an important question for gastroenterologists, as their goal is to choose the most appropriate treatment for each patient from the outset.

The main objective of this research is to compare four strategies, corresponding to four treatment arms, starting with the use of infliximab, filgotinib, vedolizumab, or ustekinumab, to maintain remission in patients with ulcerative colitis.

The following four arms are therefore proposed:

• Based on efficacy: infliximab - filgotinib - ustekinumab - vedolizumab
• Based on safety: ustekinumab - vedolizumab - infliximab - filgotinib
• Based on current practice: vedolizumab - infliximab - filgotinib - ustekinumab
• Based on convenience and route of administration: filgotinib - ustekinumab - vedolizumab - infliximab

This study will also allow for a comparison of the efficacy, safety, participant acceptability, and quality of life of the four treatment regimens.

This study is intended for adult patients (aged 18 to 65), male or female, with moderate or severe ulcerative colitis (UC) for at least 3 months. Treatment for these patients must require biologic therapy, as determined by the investigator. Participants must be able to provide informed consent to participate in the research and must be covered by a national health insurance plan. Women of childbearing age must be using active contraception for at least the duration of the study (2 years).

Patients will be followed for two years. They will be seen at the initial visit, then every two months during the first year, and then every three months during the second year. At each visit, they will be required to undergo blood and stool tests and complete a questionnaire. Endoscopies will be scheduled for weeks 16, 52, and 104. Patient treatments can be optimized once, and based on the endoscopic score, patients may change treatments according to a predefined sequence.

Inclusion Criteria:

• Male or female patients (using effective contraception and a negative pregnancy test for women of childbearing age) diagnosed with UC for at least 3 months
• Age ≥ 18 years and ≤ 65 years
• Moderate to severe UC according to modified Mayo score (from 5 to 9)
• With endoscopic Mayo score ≥ 2
• With an inadequate response, failure, loss of response, or intolerance to 5-ASA, steroids, or immunosuppressants.
• Patient capable of giving consent
• Patient covered by the French healthcare system
• Women of childbearing age using active contraception (contraceptive implant, oral contraception, female condom or abstinence)) for at least the duration of the study

Exclusion Criteria:

• Usual contra-indication to infliximab, filgotinib, vedolizumab or ustekinumab
• Steroids > 20 mg/day within two weeks before inclusion
• Low proctitis (disease limited to the rectum with an extent < 5 cm)
• Prior history of thromboembolism events
• Prior history of major cardiovascular problems (such as heart attack or stroke)
• Long-standing smokers (> 40 pack years)
• Crohn's disease
• Stoma or colectomy
• Prior exposure to anti-TNF agents, anti-integrins, anti-interleukines 12 and 23 or JAK inhibitor
• Prior exposure to other biologics or experimental drug
• No health insurance
• Pregnant or lactating women : a pregnancy test will be performed for women of childbearing age
• Patients already included in biomedical research other than an observational study (e.g: registry, cohort)
• Concomitant Clostridioides difficile infection
• HIV infection
• Patient who does not master the French language
• Patient under guardianship, curatorship or safeguard of justice
• Minors