JAK Inhibitors

JAK inhibitors are a newer group of oral medicines for moderate to severe inflammatory bowel disease. In the United States, tofacitinib and upadacitinib are used mainly for ulcerative colitis, and upadacitinib is also used for Crohn’s disease in adults who failed tumor necrosis factor (TNF) blockers. They can act within days, but carry important risks, including serious infections, blood clots, heart problems, and some cancers that require careful monitoring. (fda.gov)

Key Takeaways

• Tofacitinib and upadacitinib are oral Janus kinase (JAK) inhibitors used for moderate to severe ulcerative colitis, and upadacitinib is also approved for Crohn’s disease in adults after TNF blocker failure. (fda.gov)

• These medicines often improve ulcerative colitis symptoms within the first few days of treatment, faster than many biologics. (pubmed.ncbi.nlm.nih.gov)

• Because of increased risks of serious heart events, blood clots, some cancers, and serious infections, the FDA requires strong boxed warnings for JAK inhibitors and limits their use to people who have not responded to TNF blockers. (fda.gov)

• Common monitoring includes blood counts, liver tests, and cholesterol levels, along with infection screening for tuberculosis and hepatitis before starting therapy. (pfizermedical.com)

• Vaccination, especially against shingles and pneumonia, and a review of heart and clotting risk factors are important parts of deciding whether a JAK inhibitor is appropriate. (pubmed.ncbi.nlm.nih.gov)

What are JAK inhibitors?

Janus kinase (JAK) inhibitors are small‑molecule medicines that block enzymes inside immune cells called JAKs. These enzymes help pass along signals from inflammatory cytokines. By blocking JAKs, these drugs turn down many inflammatory signals at once. (fda.gov)

Unlike biologics, which are large proteins given by infusion or injection, JAK inhibitors are pills. They are called “targeted synthetic” drugs because they are made chemically but act in a focused way on specific immune pathways.

In the United States:

• Tofacitinib (Xeljanz) is approved for adults with moderate to severe ulcerative colitis who did not respond to or could not tolerate TNF blockers. (fda.gov)

• Upadacitinib (Rinvoq) is approved for adults with moderate to severe ulcerative colitis and Crohn’s disease, also after an inadequate response or intolerance to at least one TNF blocker. (fda.gov)

Where do JAK inhibitors fit in IBD treatment?

Most people with ulcerative colitis or Crohn’s disease start with other medicines such as 5‑ASA, steroids, or biologics. JAK inhibitors are part of the “advanced therapy” group used for moderate to severe disease.

Because of safety concerns from a large rheumatoid arthritis trial, the FDA instructs that JAK inhibitors be reserved for people who failed or cannot tolerate TNF blockers. (fda.gov)

Recent American Gastroenterological Association (AGA) guidelines list both tofacitinib and upadacitinib among effective options for moderate to severe ulcerative colitis, but note that in the United States JAK inhibitors are labeled for use only after TNF failure. (gastro.org)

A care team may consider a JAK inhibitor when:

• Several biologics have not worked or lost effect

• Very rapid symptom control is important

• A person prefers an oral medicine and is a lower‑risk candidate for blood clots and heart disease

How fast do they work and how are they taken?

JAK inhibitors have a short half‑life and reach steady levels quickly, which helps explain their rapid effect.

• In ulcerative colitis trials, tofacitinib reduced rectal bleeding and stool frequency compared with placebo within about 3 days of starting treatment. (pubmed.ncbi.nlm.nih.gov)

• Upadacitinib improved stool frequency, bleeding, urgency, and abdominal pain between day 1 and day 3, with benefits continuing through the first weeks. (pubmed.ncbi.nlm.nih.gov)

Typical patterns (details may vary by country and person):

*Exact dose and schedule are individualized by the prescribing clinician.

Because these drugs clear from the body within days, they can usually be stopped without tapering if a serious side effect or infection occurs, although disease symptoms may return.

Benefits and practical advantages

Key advantages of JAK inhibitors include:

• Oral dosing with no infusions or injections

• Very rapid symptom relief in many people, which can be important for quality of life and work or school participation (pubmed.ncbi.nlm.nih.gov)

• Effectiveness in some people who already failed several biologics

• No formation of anti‑drug antibodies, which can limit some biologics over time

• Short washout period if pregnancy is planned or another therapy must be started

For some people with both IBD and joint or skin inflammation, JAK inhibitors may also help arthritis or psoriasis, since they are used for those conditions as well.

Risks and safety monitoring

Because JAK inhibitors affect many immune pathways, they carry several class‑wide safety warnings.

Serious infections and shingles

JAK inhibitors increase the risk of serious bacterial, viral, and fungal infections, including tuberculosis and opportunistic infections. (pfizermedical.com)

Herpes zoster (shingles) is clearly more common with tofacitinib, and appears increased with other JAK inhibitors as well, especially at higher doses and in older adults or those with prior TNF failure. (pubmed.ncbi.nlm.nih.gov)

Care teams typically:

• Screen for tuberculosis and hepatitis before starting therapy

• Review infection history and exposures

• Encourage staying current on non‑live vaccines, including the recombinant shingles vaccine and pneumococcal vaccine when appropriate

• Avoid live vaccines during treatment

Blood clots and major heart problems

A large safety trial in rheumatoid arthritis found that tofacitinib was linked with higher rates of: (fda.gov)

• Venous thromboembolism (VTE) such as deep vein thrombosis and pulmonary embolism

• Major adverse cardiovascular events (MACE) such as heart attack and stroke

• Higher overall mortality compared with TNF blockers

These findings led the FDA to apply a boxed warning to tofacitinib and to extend similar warnings to upadacitinib and other JAK inhibitors for chronic inflammatory diseases. Clinicians are advised to be especially cautious in people who:

• Are older

• Smoke or formerly smoked

• Have known heart disease, stroke, or many cardiovascular risk factors

• Have a history of blood clots

Cancer risk

The same trial noted higher rates of some cancers, especially lung cancer and lymphoma, with tofacitinib compared with TNF blockers in high‑risk rheumatoid arthritis patients. (fda.gov)

For IBD, long‑term cancer risk with JAK inhibitors is still being studied. Care teams usually consider a person’s age, smoking history, and prior cancers before choosing this class.

Lab changes: blood counts, liver tests, and cholesterol

JAK inhibitors can cause:

• Increases in cholesterol (LDL and HDL)

• Mild to moderate rises in liver enzymes

• Drops in white blood cells, lymphocytes, or hemoglobin (fda.gov)

Because of this, treatment usually includes:

• Baseline labs, then repeat tests after the first few weeks and at regular intervals

• Dose adjustments or temporary holds if counts become too low or liver tests rise significantly

Pregnancy and breastfeeding

Data in pregnancy are limited. Animal studies for both drugs suggest potential harm to the developing fetus, so labels advise avoiding use in pregnancy unless benefits clearly outweigh risks. (drugs.com)

Common approaches include:

• Verifying a negative pregnancy test before starting upadacitinib

• Using reliable contraception while taking either drug and for a period after the last dose

• Planning any pregnancy in coordination with IBD and obstetric specialists

Breastfeeding safety is also uncertain. Manufacturers and expert groups generally do not recommend breastfeeding during upadacitinib therapy, and advise caution or avoidance with tofacitinib, especially for newborn or preterm infants. (drugs.com)

Drug combinations to avoid

To limit infection and cancer risk, JAK inhibitors are not usually combined with:

• Other JAK inhibitors

• Biologic IBD therapies

• Strong additional immunosuppressants such as azathioprine or cyclosporine (fda.gov)

Low‑dose steroids may be used short term, then tapered as the JAK inhibitor takes effect.

Comparing tofacitinib and upadacitinib

Both drugs share most major risks and monitoring needs. Choice between them usually depends on disease type (UC vs Crohn’s), prior therapies, desired dosing schedule, and individual risk factors.

FAQs

Are JAK inhibitors considered biologics?

No. JAK inhibitors like tofacitinib and upadacitinib are small‑molecule pills, not injected proteins. They are often grouped with biologics as “advanced therapies” because they target specific immune pathways and require similar safety monitoring.

Can someone stop a JAK inhibitor suddenly?

These medicines do not need a taper, and they are often stopped abruptly if a serious infection, blood clot, or other major side effect appears. Symptoms of ulcerative colitis or Crohn’s disease can return once the drug is cleared, so long‑term plans are always made with the care team.

How long can someone stay on a JAK inhibitor?

There is no fixed time limit. People may stay on a JAK inhibitor as long as it controls disease and stays safe on monitoring. Because of boxed warnings and evolving long‑term data, clinicians review risk and benefit regularly, especially as a person ages or develops new health conditions.

Do JAK inhibitors cause weight gain?

Weight gain is not a primary known effect. Some people gain weight as inflammation improves and appetite returns, while others notice little change. Any sudden or unexplained weight change should be discussed with the care team, since it can also signal fluid retention, heart issues, or other problems.