A Trial of Upadacitinib for Non-responsive Eosinophilic Esophagitis

The goal of this study is to find out if a medication called upadacitinib can help treat a condition called Eosinophilic Esophagitis (EoE). The main question it aims to answer are: \- Does upadacitinib in addition to topical corticosteroids help reduce EoE disease activity? Participants will: * Take upadacitinib or placebo every day for 12 weeks, followed by 12 weeks of upadacitinib * Fill out surveys and answer health questions * Visit the clinic every 4 weeks for checkups and tests

Inclusion Criteria: 1. Age 18-65 years. 2. Diagnosis of EoE per 2018 AGREE consensus guidelines. 3. Currently using topical corticosteroids (TCS) for EoE treatment (either swallowed budesonide, ≥2mg total daily dose or swallowed fluticasone, ≥1760 mcg total daily dose) for at least 8 weeks (prior to the screening endoscopy) and willing to remain on the same TCS treatment with no changes to regimen throughout the study. 4. Have active esophageal eosinophilia (peak eosinophil count ≥15 eos/hpf \[eosinophils per high power field\]) as measured during the screening endoscopy despite ongoing therapy with TCS. 5. Have active symptoms of esophageal dysfunction attributed to EoE (such as trouble swallowing, heartburn, reflux, vomiting, chest pain, painful swallowing, abdominal pain, malnutrition, etc.) in the 4 weeks prior to the screening endoscopy. 6. Willing to continue all current EoE treatments (including medications such as proton pump inhibitors (PPIs), diet elimination, etc.) throughout participation in the study. 7. Able to read, comprehend, and sign consent form. 8. Ability to take oral medication (swallow a pill) and be willing to adhere to the study regimen (follow dosing instructions and complete study procedures). Exclusion Criteria: 1. Use of systemic corticosteroids (such as prednisone or methylprednisolone) within 4 weeks of the screening endoscopy. 2. Use of dupilumab (dupixent) within 3 months of the screening endoscopy. 3. Use of estrogen (including estrogen-containing contraceptives and other hormonal treatments) within 30 days of screening. 4. Previous esophageal resection. 5. Medical instability making it unsafe to perform an upper endoscopy. 6. At the Screening / Baseline or Enrollment Visit, meeting any of the following conditions: 6.1. Two or more prior episodes of herpes zoster (shingles), or one or more episodes of disseminated herpes zoster; 6.2. One or more prior episodes of disseminated herpes simplex (including eczema herpeticum); 6.3. Human immunodeficiency virus (HIV) infection, defined as confirmed positive anti-HIV antibody (HIV Ab) test or a positive HIV Ab/Ag test; 6.4. Active tuberculosis (TB) or latent TB, or meet TB exclusionary parameters; 6.5. Active infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days, or oral/intramuscular anti-infectives within 14 days prior to the visit; 6.6. Active diverticulitis within the past 3 months; 6.7. Chronic recurring infection and/or active viral infection that, based on the investigator's clinical assessment, makes the participant an unsuitable candidate for the study; 6.8. COVID-19 infection: In participants who tested positive for COVID-19, at least 5 days must have passed between a COVID-19 positive test result and the visit of asymptomatic participants. Participants with mild/moderate COVID-19 infection can be enrolled if fever is resolved without use of antipyretics (fever reducers such as ibuprofen, aspirin, and paracetamol) for 24 hours and other symptoms improved, or if 5 days have passed since the COVID-19 positive test result (whichever comes last). Participants may be rescreened if deemed appropriate by the investigator based upon the participant's health status. 6.9. Hepatitis B (HBV) and Hepatitis C (HCV) screening values that meet the following criteria at the most recent testing prior to the first dose of study drug: 6.9.1. HBV: hepatitis B surface antigen (HBs Ag) positive (+) test or detectable HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for participants who are hepatitis B core antibody (HBc Ab) positive (+); 6.9.2. HCV: detectable HCV ribonucleic acid (RNA) in any participant with anti-HCV antibody (HCV Ab). 7. At the Screening / Baseline or Enrollment visit, any of the following medical diseases or disorders: 7.1. Prior history of * cerebrovascular accident (stroke), * myocardial infarction (heart attack), * coronary stenting, * coronary bypass surgery (heart bypass surgery), * or thrombotic events including deep venous thrombosis (DVT) and pulmonary embolism (PE); 7.2. History of an organ transplant which requires continued immunosuppression; 7.3. History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same class; 7.4. History of GI perforation (other than due to appendicitis or mechanical injury), diverticulitis, or significantly increased risk for GI perforation per investigator judgment; 7.5. Conditions that could interfere with drug absorption including but not limited to short bowel syndrome or gastric bypass surgery; participants with a history of gastric banding/segmentation (such as Lap Band or Realize Band) are not excluded; 7.6. History of malignancy except for successfully treated non-melanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix; 7.7. Current uncontrolled hypertension defined as a confirmed systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg; 7.8. Known inherited or acquired conditions that predispose to hypercoagulability; 7.9. Current or past smokers; 7.10. In patients 50 years of age and older: * High-density lipoprotein (HDL) cholesterol level of \ 2 × upper limit of normal (ULN); 13.2. Serum alanine transaminase (ALT) \> 2 × ULN; 13.3. Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula \< 30 mL/min/1.73 m2; 13.4. Total white blood cell (WBC) count \< 2,500/µL; 13.5. Absolute neutrophil count (ANC) \< 1,200/µL; 13.6. Platelet count \< 100,000/µL; 13.7. Absolute lymphocyte count \< 750/µL; 13.8. Hemoglobin \< 9 g/dL. 14. Known allergic reaction, significant sensitivity, or intolerance to Janus kinase (JAK) inhibitors or their components 15. History of or current clinically significant medical or psychiatric conditions or any other reason that in the opinion of the Investigator would interfere with the participant's participation in this study, would place the participant at risk by participating in the study or would make the participant an unsuitable candidate to receive study drug. 16. Inability to read or understand English.