An Overview of JAK Inhibitors

Oral Biologics Inhibiting Autoimmune Response to Ease Inflammation

In This Article

Janus kinase (JAK) inhibitors are a kind of medication that inhibits activity and response of one or more of the Janus kinase family of enzymes—JAK1, JAK2, JAK3, and TYK2. JAK inhibitors interfere with the JAK-STAT signaling pathways of these enzymes. These inhibitors have therapeutic properties for treating cancer and inflammatory diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA).

JAK inhibitors
Jiaqi Zhou / Verywell

Usage

In people with RA, cancer, and other inflammatory conditions, their bodies make too many proteins called cytokines. Cytokines play a key role in promoting inflammation.

Generally, inflammation is a good thing because it helps to protect your body from disease. However, when cytokines attach to receptors on immune cells, the cells get the message to produce even more cytokines. Then JAK enzymes add chemical phosphate to the receptor, which attracts STAT proteins. The STAT proteins then further bind and multiply. 

The result of all that is more inflammation, and too much inflammation wreaks havoc on your body. Among the problems is that it makes you susceptible to all kinds of autoimmune diseases, which are conditions in which your immune system attacks healthy, normal tissues in your body.

JAK enzymes are major contributors to the process that creates and sustains autoimmunity. By blocking these enzymes, JAK inhibitors put a stop to the autoimmune process and the messages coming from cytokines.  This, in turn, calms down the immune system, helps ease inflammation, and alleviates other symptoms caused by the misfiring immune system. 

Research published in the January 2019 edition of The Lancet suggests that JAK inhibitors are the safest and most effective treatment for alopecia areata, an autoimmune condition that causes hair to fall out in patches. The drugs are believed to block the key signal pathways responsible for disease activity.

Current Therapies

Only a handful of JAK inhibitor drugs are currently available in the United States. They are:

  • Xeljanz (tofacitinib)
  • Olumiant (baricitinib)
  • Jakafi (ruxolitinib)
  • Rinvoq (upadacitinib)

Several others are currently in the development pipeline.

Xeljanz (tofacitinib)

Approval Status: Xeljanz gained approval from the U.S. Food and Drug Administration in 2012 and is one of the most-often prescribed drugs in its class.

Approved Uses: Xeljanx is approved for the treatment of:

Unapproved Uses: While it's not currently approved for other uses, several studies have suggested that Xeljanz is effective at treating:

Dosage and Formulations: The drug is available in a 5 milligram (mg) pill and an 11 mg extended-release tablet.

Ongoing Research: Research into Xeljanx for psoriasis has yielded positive results.

A 2019 analysis in the British Journal of Dermatology pooled data from one phase II study, four phase III studies, and one long-term extension study composed of psoriasis patients using tofacitinib. Researchers found that those using tofacitinib had reduced symptoms, including skin plaques, which led to an improved quality of life.

The drug was well-tolerated, and safety and side effects were similar to those of disease-modifying anti-rheumatic drug (DMARD) treatments. Further, participants who took 10 mg per day showed greater improvement than those taking 5 mg daily.

The drug's effectiveness was comparable to methotrexate or the biologic Enbrel (etanercept) at a dose of 50 per week. The higher dose was comparable to an Enbrel dose of 100 mg per week. The authors concluded that Xeljanz has a benefit-risk profile similar to other systemic treatments and is a better option for people who prefer oral therapy over injectable biologics.

Olumiant (baricitinib)

Approval Status: The FDA approved Olumiant in 2018.

Approved Uses: Olumiant is for adults with moderately-to-severely active rheumatoid arthritis who did not previously have an adequate response to methotrexate or tumor necrosis factor (TNF) inhibitor therapies. It had been approved in Europe in 2017 as a second-line treatment for moderate to severe active RA in adults, either as a monotherapy or in combination with methotrexate.

Unapproved Uses: A 2020 study suggested that combining baricitinib with direct-acting antivirals could reduce infectivity, viral replication, and inflammation associated with COVID-19.

Baricitinib also has been studied as a psoriasis treatment. A 2016 study reported significant improvement in symptoms.

Dosage and Formulation: Olumiant is available as a 2 mg tablet taken once daily. The FDA did not approve the 4 mg dose, citing serious adverse reactions. Studies had shown that upper respiratory infections and high cholesterol levels were rare but more frequent with baricitinib at higher doses. 

Ongoing Research: According a 2019 report published in Arthritis & Care Research, Olumiant monotherapy (single drug treatment) of 4 mg per day provides effective disease control in people with rheumatoid arthritis. The patients in the study who didn't respond well to baricitinib alone showed improved disease control when methotrexate was added.

Jakafi (ruxolitinib)

Approval Status: Jakafi first became FDA approved in 2011.

Approved Uses: Jakifi is approved for treating:

  • Intermediate or high-risk myelofibrosis, including primary myelofibrosis
  • Post-polycythemia vera myelofibrosis
  • Post-essential thrombrocythemia myelofibrosis

Upapproved Uses: Ruxolitinib also is being studied as a potential treatment for graft-versus-host disease. Thus far, results have been promising in people with this disease who don't have severe diarrhea or who didn't respond well to other available therapies.

It's also under investigation for:

  • Plaque psoriasis
  • Alopecia areata
  • Relapsed diffuse large B-cell lymphoma
  • Peripheral T-cell lymphoma

Dosage and Formulation: This drug is available in tablet form in dosages ranging from 5 mg up to 25 mg. Platelet counts must be monitored before starting Jakafi and while taking it due to a risk of thrombocytopenia, anemia, and neutropenia.

Ongoing Research: Ruxolitinib (INCB18424) was developed for the treatment of intermediate or high-risk myelofibrosis that affects bone marrow, and for polycythemia vera when other treatments have failed. It is designed to inhibit JAK1 and JAK2. Phase III studies have showed significant benefits in relieving myelofibrosis symptoms. 

Topical Ruxolitinib was approved in late 2011 for treating myelofibrosis and in 2014, for the treatment of polycythemia vera. Ruxolitinib clinical trials are currently underway for treating plaque psoriasis, alopecia areata, pancreatic cancer, and two types of lymphoma.

Rinvoq (upadacitinib)

Approval Status: Rinvoq is a new drug, having received FDA approval in 2019.

Approved Uses: Rinvoq is approved for treating adults with moderately-to-severely active rheumatoid arthritis who didn't respond well or couldn't tolerate methotrexate.

Unapproved Uses: Studies are ongoing for Rinvoq as a treatment for:

  • Crohn's disease
  • Ulcerative colitis
  • Atopic dermatitis
  • Ankylosing spondylitis
  • Psoriasis
  • Psoriatic arthritis
  • Inflammatory bowel disease

Dosage and Formulation: This drug is available in a 15-mg tablet form to be taken once a day.

Ongoing Research: Results have generally been positive for Rinvoq as a treatment for the unapproved uses listed above.

Research published in late 2019 reported that upadacitinib was effective and well tolerated in people with active ankylosing spondylitis who didn't tolerate or respond well to non-steroidal anti-inflammatory drugs (NSAIDs). The authors recommended further investigation of the drug for axial sponyloarthritis types.

What’s in the Pipeline?

Pipeline drugs currently are being developed and tested but aren't yet FDA approved for any use. Every one of these drugs must go through three phases of clinical trials before it can be brought to the FDA for approval.

Several JAK inhibitors are making their way through the pipeline, undergoing clinical trials that aim to determine their safety and effectiveness in treating a variety of autoimmune conditions.

Naming New Drugs

In its earliest stages, a new drug is given an alpha-numeric name. Later on, it's assigned a generic name. Once it's FDA approved, the manufacturer gives it a brand name. Typically, drug names are written with the brand name first and the generic name in parentheses.

Filgotinib (GLPG0634)

Potential Uses: Filgotinib is a highly selective JAK1 inhibitor being tested as a treatment for:

  • Rheumatoid arthritis
  • Psoriatic arthritis
  • Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
  • HIV disease

"Highly selective" means that it targets only certain JAK enzymes rather than a large group of them. Researchers hypothesize this could mean higher doses with fewer side effects.

Status: Phase 3 trials have been concluded. In late 2019, the manufacturer submitted a new drug application (NDA) along with a priority review application, which sometimes speeds up the approval process. As of mid-2020, the FDA has not issued a decision on the NDA. Applications also have been submitted to regulatory agencies in Europe and Japan.

RA Research:

  • Two phase 2b trials for RA have shown this drug to be effective both in combination with methotrexate and as a monotherapy.
  • Phase 3 trials have shown filgotinib to be effective for people with active RA who didn't respond to or couldn't tolerate biological DMARDs and for those who've never taken methotrexate.
  • One year-long phase 3 trial found results to be consistent for the study's full duration.
  • An analysis comparing filgotinib at different doses and in combination with different RA drugs found that a daily dosage of either 100 mg or 200 mg plus methotrexate was the most effective treatment regimen for RA. The authors report no significant risk of severe side effects.

Other Research:

  • For psoriatic arthritis, a 2020 phase-2 trial demonstrated that filgotinib significantly improved health-related quality of life in 131 participants.
  • For Crohn's disease, a 2017 phase-2 study showed that filgotinib led to remission of symptoms in significantly more than placebo in people with active disease.
  • According to a 2020 study, filgotinib appears to make beneficial changes that may reduce immune-system activation in HIV disease.

Peficitinib (ASP015K)

Potential Uses: Peficitinib inhibits two specfic enzymes, JAK 1 and JAK 3, and currently is being investigated for the treatment of rheumatoid arthritis.

Status: Phase 3 trials are concluded and the manufacturer has submitted a new drug application to the FDA. This drug is approved for rheumatoid arthritis in Japan under the brand name Smyraf.

Research:

  • The drug has been shown to improve RA outcomes in two phase-2b studies.
  • Two phase-3 trials have demonstrated that peficitinib can improve outcomes in people with RA who didn't respond well to other drugs and have moderately-to-severely active disease.
  • Studies suggest peficitinib is superior to placebo at reducing symptoms and suppressing joint damage, was well tolerated, and had positive results that remained consistent for the full-duration of a year-long study.

Itacitinib (INCB039110)

Potential Uses: Itacitinib is under investigation as a treatment for:

  • Plaque psoriasis
  • Chronic graft-vs-host disease

It's also been suggested as a possible therapy for COVID-19 because of specific effects it has on the immune system.

Status: Phase-2 trials are currently underway for testing the efficacy and safety of Itacitinib for treating plaque psoriasis. The drug has moved on to phase 3 for chronic graft-versus-host disease despite failing in trials for the acute form of the condition. As of mid-2020, research had not yet begun for COVID-19.

Research:

  • A phase-2 study published in 2016 demonstrated significant improvement in an assessment of plaque psoriasis symptoms.

Abrocitinib (PF-04965842)        

Potential Uses: Abrocitinib is an oral selective JAK1 inhibitor currently being investigated for the treatment of:

  • Plaque psoriasis
  • Atopic dermatitis, moderate-to-severe, in adults and adolescents
  • Vitiligo
  • Alopecia Areata
  • Autoimmune diseases with JAK1 involvement

Status: This drug is not yet approved for any use. In June of 2020, phase-2, phase-2b, and phase-3 clinical trials began for abrocitinib as a treatment for atopic dermatitis. At least one phase-2 trial for plaque psoriasis has been completed. Other potential uses are in earlier stages of study.

Research:

  • Abrocitinib has completed at least one phase-2 study the demonstrated it improved symptoms and was well tolerated.
  • Research from a 2017 British Association of Dermatologists study finds that abrocitinib was well tolerated and effective in improving symptoms of moderate-to-severe plaque psoriasis.
  • A 2018 study suggested the drug could be beneficial in inflammatory diseases in general, and another paper from that year cites evidence from animal studies suggesting abrocitinib be studied for autoimmune diseases.

SHR0302

Potential Uses: SHR0302 is believed to be a highly selective JAK1, JAK2, and JAK3 inhibitor. It's being investigated as a possible treatment for:

  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Lupus
  • Crohn's disease
  • Ulcerative colitis
  • Alopecia areata
  • Atopic dermatitis
  • Myoproliferative neoplasms (a type of blood cancer)
  • Hepatic fibrosis (a liver disease)

Status: This drug is not yet approved for any use. In May 2020, researchers in the U.S. and China launched phase-2 clinical trials for alopecia areata, and Chinese researchers initiated a phase-1 trial for liver impairment. In June 2020, phase-2 and 3 trials began for ankylosing spondylitis.

In 2019, phase-2 clinical trials got underway for ulcerative colitis and Crohn's disease. The drug has also reached phase-2 trials for atopic dermatitis. Phase-3 trials for rheumatoid arthritis are expected to conclude in 2022. Preliminary research has begun for lupus.

Research:

So far, very little research on this drug has been concluded and published.

  • A 2019 study out of China suggested that SHR0302 can inhibit the growth of myoproliferative neoplasms and lower inflammation by altering the JAK-STAT signaling pathway. However, these effects were weaker than those of Jakafi.
  • A 2016 study demonstrated that SHR0302 may alleviate hepatic fibrosis by targeting functions of hepatic stellate cells.
  • A 2016 study showed the drug made numerous potentially beneficial changes to the immune function in rats with drug-induced arthritis.

BMS-986165

Potential Uses: BMS-986165 currently is being studied for treating:

  • Plaque psoriasis, moderate-to-severe
  • Crohn's disease
  • Ulcerative colitis
  • Psoriatic arthritis
  • Lupus
  • Autoimmune disease

Status: As of mid-2020, this drug is in phase-3 trials for plaque psoriasis; phase-2 trials for Crohn's disease, psoriatic arthritis, lupus, and ulcerative colitis; and phase-1 trials for autoimmune diseases in general.

Research:

  • Data from phase II studies show the drug was effective in relieving symptoms in people with plaque psoriasis taking 3 or less mg per day over a period of 12 weeks. 
  • A 2019 study states that BMS-986165 is unique among JAK inhibitors and may have properties making it especially effective against autoimmune diseases.

Possible Side Effects

All drugs have possible side effects. Each JAK inhibitor has its own unique list of potential adverse events and it's important that you become familiar with it. However, the drugs in this class do share a risk of certain side effects.

Immune-System Suppression

Similarly to biologics and traditional DMARDs, JAK inhibitors suppress the immune system, which means people who take them are more vulnerable to serious infections, especially upper respiratory and urinary tract infections.

In clinical studies, some people have come down with tuberculosis (TB), a very serious bacterial lung infection. People who take JAK inhibitors also have an increased for shingles, a viral infection that causes a painful rash. If you go off of these drugs due to infection(s), your immune system should return to normal and begin preventing infections again.

Some people may have an increased risk for cancer because JAK inhibitor drugs block the immune processes responsible for preventing tumors. 

Other Side Effects

JAK inhibitors can also cause anemia (low red cell counts) in some people. This is due to the way they affect proteins the body needs to make red blood cells. JAK inhibitors are also known for lowering white blood cell counts, a condition called lymphopenia.

These drugs may affect cholesterol numbers. Your doctor may need to prescribe a statin drug, such as Lipitor (atorvastatin), to regulate your numbers.

Blood clots and liver damage are also possible adverse reactions with JAK inhibitor use. Additionally, JAK inhibitors may interact with other medications used to treat autoimmune diseases. 

Common side effects that may go away once your body has gotten used to a JAK inhibitor drug include:

  • Diarrhea
  • Headache
  • Cold symptoms, such as sore throat or a runny or stuffy nose
  • Dizziness
  • Easy bruising
  • Weight gain
  • Bloating and gas
  • Fatigue

Shortness of breath and other serious and ongoing side effects should be reported to your doctor. Some can be managed with lifestyle and medication, while others require a medication change.

A Word From Verywell

If you're doing well on older drugs (such as biologics or methotrexate) for treating your autoimmune condition, you probably don’t need a JAK inhibitor. However, if you haven't had success with the older treatments, a JAK inhibitor might offer needed relief.

Another advantage of JAK inhibitors is that they come in pill form, while biologics require injection or infusion. 

These medications are fairly new, though, and researchers are just learning about their long-term safety. You should check with your doctor to make you can take them alongside other medications and supplements and report any concerning or ongoing side effects. 

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