Meds & Escalation
If your gastroenterologist has brought up tofacitinib, upadacitinib, ozanimod, or etrasimod, you are looking at the newest generation of oral treatments for ulcerative colitis. These medications fall into two distinct drug classes: JAK inhibitors and S1P receptor modulators. Both are taken as daily pills, which makes them appealing alternatives to the injections and infusions required by biologics. But "oral" does not automatically mean "simpler." Each class works through a different mechanism, carries its own set of risks, and requires specific monitoring. Understanding these differences gives you a stronger foundation for conversations with your care team about which treatment fits your situation.
How JAK Inhibitors Work in Ulcerative Colitis
JAK inhibitors block Janus kinase enzymes inside immune cells. These enzymes act as intracellular signaling switches that relay inflammatory signals from cytokines on the cell surface to the cell nucleus. By interrupting this signaling cascade, JAK inhibitors reduce the overactive immune response that drives UC inflammation. Two JAK inhibitors are currently FDA-approved for moderate-to-severe ulcerative colitis: tofacitinib (Xeljanz), which was the first oral advanced therapy approved for UC, and upadacitinib (Rinvoq), a more selective JAK1 inhibitor approved for both UC and Crohn's disease.
One of the standout features of this drug class is speed. Compared to biologics, JAK inhibitors have a rapid onset of action and a short half-life, meaning they start working quickly and also clear the body faster if discontinued. Real-world data from an Australian multicenter study found clinical remission rates of 79% at week 8 and 84% at week 16 with upadacitinib in biologic-experienced patients, numbers that surpass those reported in phase 3 trials. Another advantage: because these are synthetic small molecules rather than proteins, they do not trigger the formation of anti-drug antibodies, a common reason biologics lose effectiveness over time.
JAK Inhibitor Risks and Monitoring Requirements
JAK inhibitors carry a boxed warning from the FDA, and patients need to understand the specific risks involved. Tofacitinib was associated with an elevated risk of herpes zoster (shingles) at an incidence rate of 3.38 per 100 patient-years, though over 90% of cases were nonserious and mild to moderate. Risk factors for shingles include older age, lower body weight, and prior TNF inhibitor failure. Your doctor will likely recommend the Shingrix vaccine before starting treatment.
The broader safety concerns stem from a post-marketing trial of tofacitinib in rheumatoid arthritis patients over age 50 with cardiovascular risk factors. That study identified increased rates of blood clots, major cardiovascular events, and malignancy at higher doses. While these findings led to dose restrictions and the boxed warning across the JAK inhibitor class, the UC-specific safety data with upadacitinib has been more reassuring, with no serious thromboembolic events or malignancy reported during 16-week follow-up periods, though longer-term data collection continues. Routine monitoring typically includes:
Complete blood counts to watch for neutropenia and lymphocytopenia
Lipid panels, since JAK inhibitors can raise cholesterol levels
Liver function tests, particularly during the induction phase
How S1P Receptor Modulators Target UC Differently
S1P receptor modulators work through an entirely different mechanism. Rather than blocking inflammatory signaling inside cells, they prevent lymphocytes from leaving lymph nodes and entering the bloodstream. By trapping these immune cells at the source, fewer inflammatory lymphocytes travel to the colon and less gut damage occurs. Two S1P modulators are FDA-approved for moderate-to-severe UC: ozanimod (Zeposia), approved in 2021, and etrasimod (Velsipity), approved in 2023.
Both drugs are once-daily pills, but they differ in practical ways. Ozanimod requires a dose titration over the first week, gradually increasing from a lower starting dose. Etrasimod starts at its full 2 mg dose on day one with no up-titration required. The two drugs also differ in how quickly the immune system recovers after stopping them. Lymphocyte counts typically recover within about 7 days after stopping etrasimod, compared to one to two months after stopping ozanimod, a meaningful difference if you need to switch therapies or if surgery becomes necessary.
S1P Modulator Side Effects and Cardiac Considerations
The most distinctive monitoring requirement for S1P modulators involves the heart. Because S1P receptors are present on cardiac cells, these drugs can cause a temporary decrease in heart rate (bradycardia) and atrioventricular conduction delays when treatment begins. Before starting ozanimod or etrasimod, your doctor will order an ECG to check for pre-existing conduction abnormalities. Patients with a history of certain heart conditions, resting heart rate below 50 bpm, or those taking specific anti-arrhythmic medications may need evaluation by a cardiologist before beginning treatment.
S1P modulators have also been associated with an increased risk of macular edema, a condition where fluid accumulates in the central part of the retina. A baseline eye examination including the macula is recommended near the start of treatment, with periodic follow-up assessments. In clinical trials, macular edema was rare, occurring in only one patient (0.3%) in the etrasimod group during the 52-week ELEVATE UC trial. The most commonly reported side effects in the pivotal etrasimod trials were anemia, headache, and nausea.
How These Oral Treatments Compare to Biologics
For patients weighing oral medications against biologics, several practical differences stand out. Biologics require either infusions at a treatment center or self-administered injections at home, while both JAK inhibitors and S1P modulators are daily pills. JAK inhibitors and S1P modulators are also synthetic small molecules with no risk of immunogenicity, whereas biologic proteins can trigger anti-drug antibodies that reduce effectiveness over time.
However, current guideline positioning matters. The AGA's living guideline classifies several biologics (infliximab, vedolizumab, risankizumab, guselkumab) as higher-efficacy for biologic-naive patients, while JAK inhibitors and S1P modulators may be positioned differently depending on treatment history. In patients who have already lost response to a biologic, upadacitinib moves into a higher-efficacy position, and research shows it can be effective even after prior tofacitinib failure. S1P modulators, with their distinct mechanism and generally favorable safety profile, offer yet another option for patients who need a new approach.
The right choice depends on your complete treatment history, risk factors, lifestyle priorities, and insurance coverage. Some patients prefer the convenience of a pill; others prioritize the long-term safety track record of certain biologics. Neither preference is wrong. What matters is that you and your gastroenterologist make a fully informed decision together.
New medications need close monitoring. Track your daily symptoms with Aidy from the start so you and your GI can evaluate whether your new oral treatment is working.