Feasibility Pilot Sequential Multiple Assignment Randomized Trial (SMART) for Acute Severe Ulcerative Colitis

Inclusion Criteria for Clinical trial patients: 1. Patient ≥ 18 to 75 years of age at baseline 2. Diagnosis of ulcerative colitis (verified by a typical clinical history as well as characteristic appearance on endoscopy and histology) 3. Current hospital admission for ulcerative colitis treatment (expecting IV corticosteroid initiation). Note this includes patients seen in emergency room who are expected to be admitted for UC treatment 4. Meeting the following definition of acute severe ulcerative colitis as defined as having ≥ 4 bowel movements per day with visible blood and one of the following: a. Temperature \> 37.8 Celsius b. Pulse \> 90 Beats per minute (BPM) c. Hemoglobin \< 10.5g/dL d. Erythrocyte sedimentation rate ≥ 30mm/h e. Weight loss \> 5 lbs over 3 months f. C-reactive protein ≥ 3.0mg/dL g. Fecal calprotectin \>782 mg/kg (within 4 weeks) h. Oral corticosteroid use for ≥ 14 days at a dose equivalent to ≥ 30mg/day 5. Prior history of receiving at least one dose of adalimumab, certolizumab, infliximab, or golimumab originator or biosimilars or a prior history of receiving at least one approved systemic therapy in the event tumor necrosis factors blockers are clinically inadvisable 6. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, daily bowel movement symptoms surveys, and other study procedures 7. Evidence of a personally signed and dated informed consent document indicating that the participant (or a legal representative) has been informed of all pertinent aspects of the study 8. Ability to take oral medication and be willing to adhere to the study intervention regimen 9. For females of reproductive potential (i.e., females \<55 years of age with intact ovaries and fallopian tubes): A negative pregnancy test on admission and intent to use highly effective contraception during 3-month follow-up period which include the following. 1. Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal, injectable) associated with the inhibition of ovulation, initiated at least 30 days prior to study baseline 2. Progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, initiated at least 30 days prior to study baseline 3. Bilateral tubal occlusion/ligation (could be via hysteroscopy, provided a hysterosalpingogram confirmed success of the procedure) 4. Vasectomized partner(s) provided the vasectomized partner had received medical confirmation of the surgical success and was the sole sexual partner of the trial participant 5. Intrauterine device or intrauterine hormone-releasing system 6. Lifestyle abstinence (refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the patient) 7. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) 8. Consistent use of barrier contraception Exclusion Criteria for Clinical trial patients: 1. Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or clinical findings suggestive of Crohn's disease 2. On IV corticosteroids for ≥ 72 hours prior to enrollment continuously (at any institution) 3. Currently pregnant or breastfeeding 4. Patients who meet diagnostic criteria for toxic megacolon during this current admission. This will be determined by the study team and inpatient treatment team according to the following supportive criteria: Having dilation of the colon \> 6m and three of the following (Temperature\>38 Celsius, Heart Rate \>120 BPM, white blood cells (WBC) \>10500/µL, Hemoglobin \< 10.5mg/dL) and one of the following (dehydration, altered mental status, severe electrolyte disturbances, and hypotension) 5. Known hypersensitivity to any of the following drugs or constituents: methylprednisolone, cyclosporine, tofacitinib, or upadacitinib 6. Patients who had previous exposure to upadacitinib. Previous exposure to other Janus kinase (JAK) inhibitors (e.g., tofacitinib, baricitinib, or filgotinib) are permissible. 7. Patients with ongoing severe infection (as determined by the study team), including untreated or inadequately treated latent or active tuberculosis (TB) a. Active Cytomegalovirus (CMV) colitis is defined as having \> 5 CMV inclusion bodies per high powered field in any one ulcer at baseline. If CMV colitis is confirmed, the patient can remain in the trial if permissible by the infectious disease and primary treatment team and if concomitant anti-viral therapy is initiated. b. Patients with a positive stool exam for enteric pathogens can remain in the trial. Initiation of treatment at the discretion of the treatment team and infectious disease team if needed. 8. Patients who have received any investigational pharmacological agent or invasive investigational procedure within 30 days or five half-lives of study initiation with potential efficacy for UC or that could interact with study medications, as determined by the Principal Investigator. Participation in studies with non-invasive investigational procedures or standard-of-care invasive procedures are permitted. 9. Current malignancy with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin. 10. Patients who had a history of colectomy (total or subtotal), ileoanal pouch, Kock pouch, or ileostomy or were planning bowel surgery 11. Moderate or severe renal, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, neurological, or psychiatric condition including the following: 1. Neutropenia - Absolute Neutrophil Count (ANC) \<1200 cells/mm3 or Total white blood cell count \<2500/µL 2. Hemoglobin \< 7mg/dL without plans for a transfusion 3. Platelet count \<80,000/µL 4. Moderate/severe renal impairment with estimated glomerular filtration rate (eGFR) \<30milliliter (mL)/min/1.73m2 (by simplified four-variable Modification of Diet in Renal) 5. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) liver biochemistry levels that are ≥ 2 times the patient's baseline (as determined based on the principal investigator's judgement) 12. Cirrhosis with mild to severe hepatic impairment (defined as a Child-Pugh score ≥5) 13. History of uncontrolled hypertension (systolic blood pressure \>160 millimeters of mercury (mmHg) or diastolic blood pressure \> 100 millimeters of mercury (mmHg) despite anti-hypertensives) 14. Any of the following cardiovascular conditions: a. Recent (within previous 6 months) cerebrovascular accident, myocardial infarction, or coronary stenting b. Recent (within previous 6 months) moderate-to-severe congestive heart failure (New York Heart Association class III or IV) 15. History of inherited or acquired conditions that predispose to hypercoagulability including the following. Please note, that patients with a remote history of provoked thrombotic event or recent thrombotic event on systemic anticoagulation are NOT exclusionary. a. Antiphospholipid syndrome b. Factor V Leiden mutation c. Prothrombin G20210A mutations d. Deficiencies of antithrombin f. Deficiency of protein C g. Deficiency of protein S h. Heparin cofactor II deficiency i. Plasminogen and plasminogen activator inhibitor-1 j. Dysfibrinogenemia k. Factor XII deficiency 16. Patients with total cholesterol \<80 mg/dL at baseline 17. Patients who had a history of an allergic reaction or significant sensitivity to constituents of the treatment (and its excipients) and/or other products in the same class of medication (ex., tofacitinib) 18. Patients who had hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection defined as: a. HBV: hepatitis B surface antigen (HBsAg) positive with detectable deoxyribonucleic acid (DNA) not on therapy. Patients with serologic evidence of a resolved prior HBV infection (i.e., HBsAg-negative and anti-HB Core-positive) or patients with HBsAg positive on suppressive HBV therapy with low DNA (\<105 copies/mL or \<104 IU/mL negative) are not exclusionary b. HCV: HCV ribonucleic acid detectable in any patient with anti-HCV antibody c. HIV: Confirmed positive anti-HIV antibody with Cluster of Differentiation 4 (CD4) counts \<350 cells/microliter (uL) or acquired immunodeficiency syndrome (AIDS)- defining opportunist infection 19. Solid organ or bone marrow transplant within 1 year or expected transplant within 6 months 20. History of more than one episode of herpes zoster, a history of disseminated herpes zoster or disseminated herpes simplex 21. Current use of medications which significantly increase the risk of venous thromboembolic event as determined by the investigator including: 1. Hormone replacement therapy 2. Testosterone 3. Tamoxifen 22. Vaccination with live or attenuated live vaccines within 6 weeks of baseline or scheduled to receive these vaccines during study period or within 140 days (20 weeks) after last dose of study medication. 23. History of any lymphoproliferative disorder (such as Epstein-Barr Virus (EBV)-related lymphoproliferative disorder), history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current hematologic disease. 24. Patients who had a history of spontaneous GI perforation (other than appendicitis or mechanical injury), diverticulitis, or significantly increased risk of GI perforation per investigator's judgement 25. Actively receiving strong CYP3A4 inducers or inhibitors prior to the first dose of study drug or are expected to receive any of these medications during the study period. This includes grapefruit and grapefruit juice. 26. The presence of any condition significantly affecting oral drug absorption (e.g., gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass), as determined by the Principal Investigator. Procedures such as gastric banding that simply divide the stomach into separate chambers are NOT exclusionary. 27. Patients who had a history of a clinically significant medical condition or any other reason which, in the opinion of the investigator, would have interfered with the patient's participation in this study, would have made the patient an unsuitable candidate to receive treatment, or would have put the patient at risk by participating in the protocol Inclusion criteria for Physicians: 1\. Clinicians (Internal medicine residents, gastroenterology fellows, and attending gastroenterologists or colorectal surgeons) caring for the patients enrolled in the clinical trial Exclusion criteria for Physicians: 1\. Non-clinicians not caring for the enrolled patient