What are JAK inhibitors and how do they work?

Janus kinase (JAK) inhibitors are a group of medicines that help block immune system signals in the body that can lead to swelling (inflammation) and pain in conditions like rheumatoid arthritis, ulcerative colitis, and psoriatic arthritis. They work by blocking enzymes that lead to overactivity of the immune system.

When used for the treatment of rheumatoid arthritis, Janus kinase (JAK) inhibitors are part of a wider group of drugs called DMARDs (Disease-Modifying Anti-Rheumatic Drugs). DMARDs help to slow down ongoing joint damage in rheumatoid arthritis.

JAK inhibitors come in oral and topical (skin) formulations.

How do they work?

Janus kinase (JAK) inhibitors work by slowing down the overactivity of the immune system that can lead to inflammation and pain. They do this by inhibiting the activity of one or more JAK enzymes (JAK1, JAK2, JAK3, and TYK2) found in the cell.

The immune system is the body’s natural defense against infection and other diseases. But sometimes the immune system can become overactive and cause medical problems. By blocking JAK enzymes, JAK inhibitors help to decrease the immune system reaction that can lead to inflammation, pain and other symptoms.

Enzymes are proteins in the body that help to facilitate processes in the body, like chemical reactions. JAK enzymes promote inflammatory signals in the body which are associated with cytokine (interleukin, interferon) release. Cytokines are small proteins that affect the growth of cells that are involved in inflammation and the immune response. JAK-dependent cytokines have been shown to lead to a number of inflammatory and autoimmune diseases.

List of JAK Inhibitors

JAK inhibitors approved in the United States include:

• Cibinqo (abrocitinib)
• Inrebic (fedratinib)
• Jakafi (ruxolitinib)
• Litfulo (ritlecitinib)
• Ojjaara (momelotinib)
• Olumiant (baricitinib)
• Opzelura (ruxolitinib)
• Rinvoq (upadacitinib)
• Vonjo (pacritinib)
• Xeljanz (tofacitinib)

What are JAK inhibitors used for?

JAK inhibitors are approved by the FDA to treat a variety of medical conditions involving the skin, joints, gastrointestinal tract and other systems. Further descriptions of these conditions can be found in the approved uses section below.

• Acute graft versus host disease (aGVHD)
• Alopecia areata
• Ankylosing spondylitis
• Atopic dermatitis (eczema)
• COVID-19 (in certain patients with breathing problems)
• Crohn’s disease
• Myelofibrosis
• Non-radiographic axial spondyloarthritis
• Polyarticular juvenile idiopathic arthritis
• Polycythemia vera
• Psoriatic arthritis
• Rheumatoid arthritis
• Ulcerative colitis
• Vitiligo

FDA approved uses for JAK inhibitors

Cibinqo (abrocitinib) - In January 2022, the FDA approved Pfizer’s Cibinqo (abrocitinib), an oral Janus kinase 1 (JAK1) inhibitor.

• Cibinqo is used to treat patients with refractory, moderate-to-severe atopic dermatitis (eczema) when other products, including biologics, are not effective or advisable. Atopic dermatitis (eczema) is one of the most common inflammatory skin diseases.
• Cibinqo is given by mouth once a day and can be used by adults and children 12 years of age and older.

Inrebic (fedratinib) - Inrebic, an oral JAK2 inhibitor, was approved in August 2019 for the treatment of adult patients with myelofibrosis. Inrebic is given by mouth once a day.

• Myelofibrosis is a rare bone marrow cancer in which the marrow is replaced by fibrous scar tissue which disrupts the normal production of blood cells.
• Symptoms include night sweats, itching, stomach discomfort, and bone or muscle pain, among others.

Jakafi (ruxolitinib) - Jakafi is a JAK1/JAK2 inhibitor used for the treatment of myelofibrosis and polycythemia vera in adults; and graft-versus-host disease in patients 12 years of age and older. Jakafi tablets are administered twice daily.

• Myelofibrosis is a rare cancer in which bone marrow is replaced by scar tissue, resulting in an enlarged spleen and reduced production of white blood cells and platelets.
• Polycythemia vera is a rare blood cancer caused by a mutation in the bone marrow stem cells. This leads to an increase of red and white blood cells and platelets, leading to life-threatening blood clots, stroke and heart attack.
• Graft-versus-host disease is a serious or deadly complication that can occur after a stem cell or bone marrow transplant when newly transplanted donor cells attack the transplant recipient's body.

Litfulo (ritlecitinib) - In June 2023 the FDA cleared Pfizer’s Litfulo for treatment of severe alopecia areata in adults and adolescents 12 years and older. It is given as an oral, once-daily treatment.

• Litfulo inhibits Janus kinase 3 (JAK3) and tyrosine kinases expressed in the hepatocellular carcinoma (TEC) family of kinases (TEC).
• Alopecia areata, an autoimmune disease, results in patchy or complete hair loss, often on the scalp, face, or body. It is caused by an immune attack on the hair follicles which causes the hair to fall out.

Ojjaara (momelotinib) - In September 2023, the FDA approved GSK’s Ojjaara, a JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor for the treatment of myelofibrosis in adult patients with anemia. Ojjaara tablets are administered orally once daily.

Olumiant (baricitinib) - In June 2018, the FDA first approved Eli Lilly’s Olumiant tablets to be used for the treatment of rheumatoid arthritis in adults. It is now also approved in adults to treat severe alopecia areata and COVID-19 in certain hospitalized patients with breathing trouble.

• Olumiant is a JAK inhibitor administered once daily by mouth.
• In COVID-19, treatment for adults is administered for up to 14 days or until hospital discharge, whichever is first.
• In July 2021, the FDA expanded the Emergency Use Authorization (EUA) for Olumiant to allow the emergency use of this drug, with or without remdesivir, for treatment of suspected or laboratory confirmed COVID-19 in hospitalized children 2 years of age or older with certain breathing problems. Olumiant is not authorized for patients younger than 2 years.

Related: COVID-19: Prevention, Treatment and Vaccines

Opzelura (ruxolitinib cream) - Opzelura from Incyte is a JAK inhibitor approved for the treatment of atopic dermatitis (eczema) and for repigmentation in nonsegmental vitiligo in adults and children 12 years of age and older. Over-activity of the JAK signaling pathway has been shown to drive inflammation in atopic dermatitis and vitiligo.

• Opzelura was the first topical JAK inhibitor approved for use in the United States. It is applied as a cream formulation. The oral formulation of ruxolitinib is approved under the brand name Jakafi.
• Nonsegmental vitiligo is a chronic autoimmune disease caused by loss of pigment-producing melanocytes leading to loss of skin pigment. Patients can develop white patches of skin on both sides of the body, such as face, hands, feet, upper and lower extremities, and trunk body areas.
• Opzelura is administered topically to the affected skin area. Patients should not use more than one 60 gram tube per week or one 100 gram tube per 2 weeks.

Rinvoq (upadacitinib) - AbbVie's Rinvoq was first approved in August 2019 for the treatment of adults with moderate-to-severe rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate.

• Rheumatoid arthritis is an autoimmune inflammatory condition in which the body attacks its own joints, often in areas like the hands, feet or wrist, causing pain, swelling, and loss of function of the joint.
• Since that time, Rinvoq has also been approved to treat psoriatic arthritis, atopic dermatitis (eczema), ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spondyloarthritis.
• Psoriatic arthritis is a type of rheumatoid arthritis that tends to affect the joints of the hands and feet. Symptoms can include swelling of the ankles, toe joints, hands, and knees. Psoriasis of the nail may occur.
• Ulcerative colitis (UC) is an autoimmune, chronic inflammatory bowel disease. In UC, ulcers and swelling occur on the lining of the colon (large intestine) and the rectum. Common symptoms of UC include stomach pain, stomach cramping, bloody or pus-filled diarrhea, rectal pain or bleeding, blood in the stool, an urgent need to defecate, weight loss, and fatigue, among other symptoms.
• Crohn's disease is also a type of chronic inflammatory bowel disease (IBD) that gets worse over time. It occurs as inflammation in the gastrointestinal (digestive) tract and leads to diarrhea and stomach area pain, and may require surgery.
• Ankylosing spondylitis (AS) is a type of inflammatory arthritis that primarily affects the spine, although other joints in the body may be involved. The most common complaint is pain and stiffness in the lower back, especially in the morning, buttock or hip pain, and difficulties with sleeping or walking. The condition can drastically affect quality of life. It can be seen and diagnosed with an x-ray.
• Non-radiographic axial spondyloarthritis is a type of inflammatory arthritis of the spine and sacroiliac joints (the joints that connect the lower spine and pelvis). It causes joint inflammation, leading to chronic back pain and stiffness, but it cannot be detected by an x-ray.

Vonjo (pacritinib) - Vonjo, from CTI BioPharma, is a JAK2/FLT3 multikinase inhibitor for the treatment of adult patients with myelofibrosis with severe thrombocytopenia (low platelet counts). It was first approved by the FDA in February 2022. Vonjo capsules are administered orally twice daily with or without food.

• Vonjo has activity against wild type JAK2 and the JAK2V617F mutation, and FMS-like tyrosine kinase 3 (FLT3).
• At clinically relevant concentrations, Vonjo does not inhibit JAK1, and has higher inhibitory activity for JAK2 compared to JAK3 and TYK2. Inhibiting JAK1 can worsen thrombocytopenia and immunosuppression in myelofibrosis.

Xeljanz (tofacitinib) - Xeljanz, from Pfizer, is an oral JAK inhibitor used to treat rheumatoid arthritis, ulcerative colitis, psoriatic arthritis, and ankylosing spondylitis in adults; and polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. It was first approved by the FDA in November 2012.

In lab studies, Xeljanz has been shown to inhibit JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2, but how these combinations contribute to the therapeutic effect is not fully known.

Xeljanz XR, the extended-release form of Xeljanz, is approved to be used in adults for the treatment of rheumatoid arthritis, ulcerative colitis, psoriatic arthritis, and ankylosing spondylitis.

• Xeljanz is given as an oral tablet twice a day
• Xeljanz XR is given as an oral tablet once daily
• Xeljanz oral solution is given by mouth twice daily.

This list may not be all-inclusive of all approved products. This is not all the information you need to know about JAK inhibitors for safe and effective use and does not take the place of your doctor’s directions. Review the full product information and discuss this information and any questions you have with your doctor or other health care provider.

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