How Do JAK Inhibitors (DMARDs) Work?

Janus kinase (JAK) inhibitors are synthetic small molecule drugs that inhibit the activity and response of enzymes known as Janus kinases, and their signaling pathways. JAK inhibitors belong to a family of drugs known as disease-modifying anti-rheumatic drugs (DMARDs), which constitute the primary treatment for rheumatoid arthritis (RA).

Janus kinases are enzymes known as tyrosine kinases that transmit signals from the cell membrane, downstream within the cell. Janus kinases are involved in cellular processes such as immune response, blood cell formation (hematopoiesis), and cell cycle which is the process of cell growth, division, differentiation into specialized cells, and programmed death.

The JAK signals stimulate immune cells to produce inflammatory proteins (cytokines), resulting in persistent inflammation in autoimmune conditions. Unregulated JAK signaling leads to certain types of bone marrow and blood cancers. JAK inhibitors slow down the progression of these diseases by interrupting the transmission of intracellular signals.

JAK inhibitors are useful in treating conditions that result from overactive JAK signaling pathways. JAK inhibitors are used in the treatment of autoimmune conditions, and blood and bone marrow cancers. JAK inhibitors are in clinical trials for use in many other conditions as well.

Topical JAK inhibitors are being investigated for use in several skin conditions.

Autoimmune conditions

Currently, JAK inhibitors are approved by FDA for use in the following autoimmune conditions:

• Rheumatoid arthritis
• Psoriatic arthritis
• Ulcerative colitis
• Blood disorders

Blood disorders

JAK inhibitors are also approved by FDA for use in the treatment of blood disorders such as:

• Myelofibrosis: A bone marrow cancer in which fibrous scar tissue replaces the normally soft, spongy tissue that produces blood cells.
• Polycythemia vera: A condition in which the bone marrow produces too many red cells.
• Graft-versus-host disease (GVHD): A condition that occurs after bone marrow or stem cell transplant, in which the transplanted cells attack the host cells.

COVID-19

On November 19, 2020, the FDA granted a JAK inhibitor (baricitinib) Emergency Use Authorization (EUA) for use in hospitalized COVID-19 patients.

JAK inhibitors are small molecule drugs with extremely low molecular weight, which enables them to enter right into a cell and alter its function. Another advantage of JAK inhibitors is that you can take them as oral pills, unlike treatments with biologic medications such as monoclonal antibodies which have to be injected or infused into the bloodstream.

JAK inhibitors suppress the immune system and their primary side effect is susceptibility to infections. Upper respiratory tract and nasal infections are the most common infections, which occur in more than 10% of patients.

Less common infections include:

• Tuberculosis
• Herpes simplex
• Herpes zoster
• Oral candidiasis

Other side effects include:

• Nausea
• Indigestion
• Diarrhea
• Headaches
• Increased cholesterol levels
• Hypertension
• Abnormal blood counts
• Abnormal liver function tests
• Increased blood creatinine
• Increased risk of bowel perforation
• Decrease in kidney function

• Baricitinib (Olumiant)
• Tofacitinib (Xeljanz, Xeljanz XR)
• Upadacitinib (Rinvoq)
• Ruxolitinib (Jakafi)
• Fedratinib (Inrebic)