Behind the counter: JAK inhibitors as second-line treatment for Crohn’s disease

JAK inhibitors, or janus kinase inhibitors, are a class of anti-inflammatory medications to help treat the following conditions:

• inflammatory bowel disease (IBD) — Crohn’s disease and ulcerative colitis
• rheumatological diseases
• certain dermatological diseases such as:
  • atopic dermatitis
  • psoriasis
  • eczema

The medication currently comes in both oral and topical formulations.

Several JAK inhibitors have approval in the United States, but only two of these have approval to help treat IBD:

• Xeljanz (tofacitinib) for ulcerative colitis
• Rinvoq (upadacitinib) for both ulcerative colitis and Crohn’s disease

Doctors also use JAK inhibitors as a second-line therapy for people who do not respond well or have an intolerance to one or more first-line or conventional therapies.

JAK inhibitors work by inhibiting a pro-inflammatory pathway called the JAK-STAT pathway. By binding to JAK molecules, they block pro-inflammatory molecules called cytokines from activating genes that ramp up the immune system.

Rinvoq works primarily by blocking the JAK1 molecule, which inhibits the immune response that may cause Crohn’s disease.

However, as JAK inhibitors have more potential side effects and safety concerns than biologics, doctors use them as a second-line treatment for Crohn’s disease. They fill a potential gap in people whose condition is difficult to manage.

Biologics such as anti-tumor necrosis factor-alphas (anti-TNFs) are a different class of medication than JAK inhibitors and inhibit the immune system using a different pathway. Therefore, a person with Crohn’s disease who has not responded or is intolerant to anti-TNF medications may be able to take JAK inhibitors as a second therapy.

Anti-TNFs are generally safer than JAK inhibitors. However, they may be inconvenient to administer as doctors usually give them as injectables or infusions. JAK inhibitors for IBD come in the form of a daily pill, which may be easier to take.

JAK inhibitors are used for moderate to severe IBD and are comparable to biological therapy. However, there are several benefits of JAK inhibitors over biologics:

• Unlike most biologics, JAK inhibitors come in oral formulations, which can be more convenient to administer.
• JAK inhibitors work by a different mechanism than biologics, offering a feasible alternative for those who do not respond or cannot tolerate biological therapy.
• JAK inhibitors are more selective in targeting specific cytokines in the immune system and, therefore, more precise in treating certain disorders.
• Due to their small molecule size, JAK inhibitors do not cause a person to develop antibodies to them. This means that, unlike anti-TNFs, a person can start and stop the medication without the risk of developing resistance.

A doctor may recommend JAK inhibitors to people with moderate to severe Crohn’s and who do not respond or are intolerant to a first-line treatment, usually a biological therapy.

Before starting the medication, people living with other conditions and taking medications should speak with a doctor about contraindications to avoid serious side effects.

It is also important to discuss with a doctor the need to obtain vaccinations for herpes and varicella-zoster before starting the medication. People should avoid live vaccines right before or during the use of JAK inhibitors.

Some people may experience relief from their Crohn’s symptoms within 2 weeks.

While taking the medication, a person can expect regular blood work. A doctor will also monitor them for infection, abdominal pain, blood clots, and cardiovascular disease. People receiving other forms of treatment, such as steroids, may need to taper off their previous medication regimen once they start the medication.

There are several risks and side effects to consider when taking JAK inhibitors:

• Infections: JAK inhibitors may increase the risk of developing and reactivating infections such as latent tuberculosis or hepatitis B and C. They may also increase the risks of elevated liver tests, a drop in blood cell counts, and increased cholesterol levels. Screening lab tests before starting the medication is recommended.
• Heart health: People ages 50 years or above who have at least one cardiovascular risk factor may have a higher risk of adverse cardiovascular events and of developing blood clots. Anyone who smokes should consider stopping, and those with blood clots should discontinue the medication.
• Cancer: There is a higher risk of lymphoma and other malignancies and nonmelanoma skin cancer (NMSC) compared with those taking anti-TNF medications. An annual skin exam for NMSC is advisable for those taking JAK inhibitors.
• Bowel perforation: People with worsened abdominal pain while taking the medication should consult a doctor.
• Infection after surgery: There can be an increased risk of infection after major surgeries. Anyone taking this medication should consult their surgeon about whether they can have it before surgery.
• Risk to pregnancy: People should avoid the medication during pregnancy or while breastfeeding.

On average, 40–50% of people who take JAK inhibitors enter remission.

When it comes to Crohn’s disease, there are three types of remission:

• Clinical: When a person has no symptoms.
• Endoscopic: When there is no sign of inflammatory damage on an endoscopic exam.
• Histologic: When there is no sign of active inflammation under the microscope.

With regards to clinical remission based on studies, 36–46% of individuals enter remission at 12 weeks and, in those who respond, 42% on 15 milligrams (mg) and 55% on 30 mg of the medication maintained clinical remission at 52 weeks.

With regards to endoscopic remission, 34–46% of people entered remission at 12 weeks, and 28% on 15 mg and 41% on 30 mg entered remission at 52 weeks.

There is currently no data for histologic remission rates among those who take JAK inhibitors for Crohn’s disease.

A person should not stop taking the medication without consulting with a doctor first. Stopping the medication might cause Crohn’s symptoms to reoccur, although how soon this happens is unclear.

If a JAK inhibitor stops working for someone, a doctor may ask them to stop taking it and switch them to a different class of medications for their Crohn’s disease.

Dr. Qin Rao is an ABMS board certified internal medicine physician specializing in gastroenterology and hepatology. He is currently a practicing physician at Manhattan Gastroenterology in New York City, specializing in irritable bowel syndrome, inflammatory bowel disease, dyspepsia, and hemorrhoid treatment.