How Do JAK Inhibitors Work? (2023)

Janus kinase (JAK) inhibitors are a group of medications that inhibit the activity of one or more of the Janus kinase enzymes (JAK1, JAK2, JAK3, and TYK2). These enzymes normally promote inflammation, and they are involved in some diseases. By interfering with the enzyme signaling pathways, JAK inhibitors can be used to help treat cancer and inflammatory diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA).

JAK inhibitors come in pill and topical forms.

How Do JAK Inhibitors Work? (1)

JAK inhibitor drugs currently available in the United States:

  • Xeljanz (tofacitinib)
  • Olumiant (baricitinib)
  • Jakafi (ruxolitinib)
  • Rinvoq (upadacitinib)
  • Inrebic (fedratinib)
  • Cibinqo(abrocitinib)
  • Opzelura (ruxolitinib)

All of the approved JAK inhibitors target all of the JAK enzymes. Several others currently in the development pipeline are selective for certain JAK enzymes.

What They Do

Excess inflammation can be a problem in conditions such as RA, cancer, and immune-mediated conditions.

Cytokines are inflammatory proteins that attach to receptors on immune cells. This signals JAK enzymes to add chemical phosphate to their receptors, whichattracts signal transducer and activator of transcription(STAT) proteins. The STAT proteins further increase inflammation.

Overactivity of this process can make you susceptible to autoimmune diseases—conditions in which your immune system attacks healthy, normal tissues in your body.

Xeljanz (tofacitinib)

Xeljanz was approved by the Food and Drug Administration (FDA) in 2012 and is one of the most often prescribed drugs in its class.

The newest FDA warnings on Xeljanz state that there is a higher rate of all-cause mortality, including sudden cardiovascular death with Xeljanz versus TNF inhibitors. Additionally. there are higher rates of lymphomas and lung cancers; MACE (cardiovascular death, myocardial infarction, and stroke); and thrombosis (pulmonary embolism, venous and arterial thrombosis).

Uses

Xeljanz is approved for treatment of:

  • Rheumatoid arthritis (after other biologic treatments have failed)
  • Psoriatic arthritis
  • Ulcerative colitis
  • Ankylosing spondylosis
  • Juvenile idiopathic arthritis

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

  • Crohn’s disease
  • Alopecia areata
  • Vitiligo
  • Psoriasis
  • Atopic dermatitis

The drug is sometimes used off-label for treating these and other conditions.

Formulations and Dosage

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

Ongoing Research

Research about the effect of Xeljanz on psoriasis has yielded positive results.

A 2019 analysis in the British Journal of Dermatology pooled data from one phase 2 study, four phase 3 studies, and one long-term extension study composed of psoriasis patients using tofacitinib. Researchers found that those using tofacitinib experienced a reduction of 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 drugs (DMARDs).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)

The FDA approved Olumiant in 2018. It carries an FDA black box warning for cardiovascular issues malignancy, and thrombosis.

Uses

Olumiant is approved 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.

A 2020 study suggested that combining baricitinib with direct-acting antivirals could reduce infectivity, viral replication, and inflammation associated with COVID-19. While it's not approved, it has been issued in Europe for the treatment of COVID-19.

Baricitinib has also been studied as a psoriasis treatment. A 2016 study reported significant improvement in symptoms, but more research is needed. Use for psoriasis is considered off-label.

Formulations and Dosage

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 to a 2019 report published in Arthritis & Care Research, Olumiant monotherapy 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)

Jakafi was FDA-approved in 2011. It is designed to inhibit JAK1 and JAK2.

Uses

Jakifi is approved to treat:

  • Intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombrocythemia myelofibrosis
  • Polycythemia vera in adults who either did not respond to or have an intolerance for hydroxyuremia
  • Acute graft-versus-host in adults and children aged 12 and older who did not respond to steroid treatment
  • Graft-versus-host-disease

Ruxolitinib may be used off-label for several other indications, such as alopecia and plaque psoriasis, and is under investigation for other conditions, including certain cancers.

Formulations and Dosage

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 (low red blood cells), and neutropenia.

Ongoing Research

Ruxolitinib clinical trials are currently underway for treating plaque psoriasis, alopecia areata, pancreatic cancer, and two types of lymphoma.

Rinvoq (upadacitinib)

Rinvoq was initially approved by the FDA in 2019.

Uses

Rinvoq is approved for treating adults with moderately to severely active rheumatoid arthritis who didn't respond well or couldn't tolerate methotrexate. It is also approved for treating ulcerative colitis, atopic dermatitis, and psoriatic arthritis.

Studies are ongoing for Rinvoq as a treatment for:

  • Crohn's disease
  • Ankylosing spondylitis
  • Psoriasis
  • Inflammatory bowel disease

These uses haven't been FDA approved and are thus considered off-label.

Formulations and Dosage

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.

Cibinqo(abrocitinib)

Cibinqo is a newer drug in this group, having received FDA approval in 2022.

Uses

Cibinqo(abrocitinib)is approved for the treatment of refractory, moderate-to-severe atopic dermatitis in adults whose disease is not well controlled with other systemic medications—including biologics.

Formulations and Dosage

This drug is available as 50 mg, 100 mg, and 200 mg tablets for oral administration.

Opzelura (ruxolitinb) cream

Ruxolitinib cream was FDA-approved in 2022, whileoral ruxolitinib was FDA approved in 2011.

Uses

Opzelura is approved for the treatment of nonsegmental vitiligo in adult and pediatric patients 12 years of age and older. It is also approved to treat mild to moderate atopic dermatitis.

Formulations and Dosage

Opzelura is available as a 1.5% cream applied twice daily. The maximum dose is 60 g per week or 100 g every 2 weeks.

How Rheumatoid Arthritis Is Treated

What’s in the Pipeline?

Pipeline drugs are currently being developed and tested but aren't 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.

Filgotinib (GLPG0634)

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 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.

In August 2020, the FDA rejected the drug due to toxicity. It was approved for medical use in both the European Union and Japan in September 2020.

Research Highlights

Here's a sample of takeaways from research on filgotinib thus far.

Use for RA:

  • 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.

Use for other diseases:

  • 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 significantly more than placebo in people with active disease.
  • According to a different 2020 study, filgotinib appears to make beneficial changes that may reduce immune-system activation in HIV disease.

Peficitinib (ASP015K)

Peficitinib inhibits two specific enzymes, JAK 1 and JAK 3, and is currently 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 the treatment of rheumatoid arthritis in Japan under the brand name Smyraf.

Research Highlights

  • 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.
  • It was well-tolerate and had positive results that remained consistent for the full-duration of a year-long study.

Itacitinib (INCB039110)

Itacitinib is under investigation as a treatment for:

  • Plaque psoriasis
  • Chronic graft-vs-host disease

It has 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 Highlight

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

Abrocitinib (PF-04965842)

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

In June of 2020, phase 2, phase 2b, and phase 3 clinical trials began for abrocitinib as a treatment for atopic dermatitis. It has been approved for the treatment of atopic dermatitis. Other potential uses are in earlier stages of study.

Research Highlights

  • Abrocitinib has completed at least one phase 2 study that 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. Another paper from that year cites evidence from animal studies suggesting abrocitinib be studied for autoimmune diseases.

SHR0302

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 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 began 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 Highlights

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 hepatic stellate cell function.
  • A 2016 study showed the drug made numerous potentially beneficial changes to the immune function in rats with drug-induced arthritis.

BMS-986165

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 was 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 Highlights

  • Data from phase II studies show the drug was effective in relieving symptoms in people with plaque psoriasis taking 3 mg or less 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.

Psoriatic Disease Drugs in the Pipeline

Why Do Pipeline Drugs Have Code-Like Names?

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

Possible Side Effects

There are side effects common to all JAK inhibitors, and each JAK inhibitor has its own list of potential adverse events.

Some common ones may go away once your body gets used to the medication. Others may persist and have serious effects.

Common

Common side effects that may go away with use include:

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

Tell your healthcare provider if you have shortness of breath or other serious or ongoing side effects. Some can be managed through lifestyle and medication, while others require a medication change.

Immune-System Suppression

Similar to biologics and traditional DMARDs, JAK inhibitors suppress the immune system. While that's what makes them beneficial, this increases vulnerability to serious infections—especially upper respiratory and urinary tract infections.

In clinical studies, some people have developed tuberculosis (TB), a serious bacterial lung infection.People who take JAK inhibitors also have an increased risk of shingles, a painful rash caused by viral reactivation.

If you stop using these drugs, your immune system should return to normal and begin preventing infections again.

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

Other

JAK inhibitors can also cause anemia 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 levels.Your healthcare provider may need to prescribe a statin drug, such as Lipitor (atorvastatin), to regulate your cholesterol.

Blood clots can occur, resulting in an increased risk of cardiovascular events, deep vein thrombosis, and pulmonary embolism.

Liver damage is a possible adverse reaction of JAK inhibitor use. And these drugs are contraindicated in patients with diverticulitis, as they can lead to viscous perforation.

There's also an increased risk of heart-related events, like heart attack or stroke, as well as cancer and death with the use of Xeljanz, Olumiant, and Rinvoq. And there is an increased risk of lymphomas and lung cancer when compared to TNF inhibitors.

A Word From Verywell

If you have an autoimmune condition and are doing well on biologics or methotrexate, you might not need a JAK inhibitor.However, if you haven't had success with these treatments, a JAK inhibitor might offer needed relief.

These medications are fairly new, though, and researchers are just learning about their long-term safety.You can talk to your healthcare provider to see if you can take them alongside other medications and supplements (interactions are possible) and report any concerning or ongoing side effects.

Rheumatoid Arthritis Drugs in the Pipeline

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