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How do Janus kinase inhibitors work? Studio Firma/Stocksy
  • Recently, the Food and Drug Administration (FDA) has approved Rinvoq for some people with atopic dermatitis.
  • Rinvoq is a Janus kinase (JAK) inhibitor.
  • These drugs work by blocking an important pathway called the signal transducer and activator of transcription (STAT) pathway.
  • In this article, we explain how JAK inhibitors work.

Efficient communication between the cells of the human body is crucial for proper development, maintenance, and defense. The JAK-STAT pathway forms an important part of this communication. It helps regulate many processes related to growth, blood cell formation, immune response, and cell death.

Cytokines are small proteins that coordinate the body’s immune response by binding to JAK receptor proteins embedded in cell membranes. This binding activates the JAK receptors.

Once activated, JAK proteins trigger STAT proteins to move into the nucleus of the cell, which houses the DNA. The STAT proteins bind to DNA and regulate gene transcription, which directs the creation of new proteins.

Atopic dermatitis, the most common type of eczema, is a chronic skin condition in which the immune system mistakenly attacks the body.

The JAK-STAT pathway plays a pivotal role in the overactive immune responses typical of atopic dermatitis.

The resulting inflammation damages the skin barrier, making it dry and itchy. Damage to the skin from scratching can also make people with eczema more susceptible to skin infections.

Dr. Eric Simpson, M.C.R., a professor of dermatology and director of clinical research in the Department of Dermatology at Oregon Health & Science University in Portland, outlines the role of cytokines in atopic dermatitis during a National Eczema Association webinar.

“Cytokines […] are chemical messengers that your immune system uses […] to tell other cells to coordinate a response to an invader, and, unfortunately, in eczema, your immune system thinks you’re being invaded […] all the time.”

JAK inhibitors limit the production of cytokines by blocking one or more of the four JAK family proteins: JAK1, JAK2, JAK3, and TYK2.

Dr. Simpson explains, “JAK inhibitors [are] small molecules [that go] straight through a cell membrane. [They] will only bind to a JAK protein that’s specific for that inhibitor.”

He adds: “Each receptor has two JAK proteins, sometimes even three […]. If you block one, all the cytokines cannot signal through. Since each receptor for a cytokine uses a different pairing of JAKs, this […] allows a drug developer to be very, very specific and, hopefully, just block one or two cytokines.”

Dr. Tien Nguyen MD, is a dermatologist at MemorialCare Orange Coast Medical Center in Fountain Valley, CA. In an interview with Medical News Today, he explained:

“The only way for the receptor to send a signal to the nucleus is via the JAK-STAT pathway. So by blocking the JAK-STAT pathway, the pro-inflammatory cytokines cannot send the signals to the nucleus anymore, dampening down the loop and the pro-inflammatory magnification of the inflammation.”

In other words, when a JAK inhibitor, such as Rinvoq, blocks the JAK-STAT pathway, cytokines cannot trigger inflammation.

Clinical trials have shown that JAK inhibitors reduce skin redness, itching, skin thickness, and scaling. Different JAK inhibitors have their unique safety and effectiveness profiles.

The FDA has approved three JAK inhibitors to treat atopic dermatitis:

The FDA approved Opzelura for treatment of mild to moderate atopic dermatitis for short-term, occasional use in people who do not have a weakened immune system and do not respond to other prescriptions for topical application.

Rinvoq and Cibinqo received the FDA approval to treat moderate to severe atopic dermatitis with inadequate response to other systemic medications, which are drugs that work throughout the body, or when these therapies are not suitable for a person.

To summarize, Rinvoq and other JAK inhibitors interfere with the way in which cytokines work, reducing inflammation and, consequently, the symptoms of eczema.