Uses, Types, Side Effects, and More

Janus kinase (JAK) inhibitors are a group of medications that can treat various types of arthritis, including rheumatoid arthritis (RA), cancer, dermatological conditions like atopic dermatitis and alopecia areata, and some bowel conditions like ulcerative colitis and inflammatory bowel disease.

These medications inhibit the activity of one or more of the Janus kinase enzymes (JAK1, JAK2, JAK3, and TYK2). These enzymes promote inflammation, and they are involved in some diseases. Inflammation is limited when the enzyme signaling pathways are interrupted, which can help some autoimmune diseases.

In this article, learn about the dosage, uses, and ongoing research underway for JAK inhibitors available in the United States, as well as common side effects, contraindications, and warnings. It will also discuss promising JAK inhibitors coming down the pipeline.

JAK Inhibitor Drugs

JAK inhibitors come in oral and topical forms. JAK inhibitor drugs currently available in the United States:

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

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.

Uses of JAK Inhibitors

Excess inflammation can be problematic in conditions such as RA, cancer, and immune conditions. JAK inhibitors can help reduce inflammation.

Cytokines are inflammatory proteins that attach to receptors on immune cells. This signals JAK enzymes to add chemical phosphate to their receptors, which attracts another type of protein called 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.

JAk inhibitors interrupt this process so that STAT proteins can’t lead to increased inflammation.

Biologic Drugs vs. JAK Inhibitors

Another class of drugs called biologics are also commonly used to treat arthritis and other autoimmune conditions. Both types of drugs belong to the disease-modifying antirheumatic drugs (DMARDs) family. Biologics are made from animal or plant cells, and JAK inhibitors are synthetic.

Biologics are older and, therefore, have more data backing their use. Biologics are administered via an infusion or intramuscular injection. Biologics are also generally less expensive. However, JAK inhibitors are in pill form or a topical application, which makes them more convenient. Some patients will do best with a combination of both biologics and JAK inhibitors.

Xeljanz (tofacitinib)

Xeljanz was approved by the Food and Drug Administration (FDA) in 2012 and is among 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 some other JAK 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 the treatment of:

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

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.

Rinvoq, Rinvoq LQ (upadacitinib)

Ongoing Research

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

In one analysis of psoriasis patients using tofacitinib, researchers found that those using tofacitinib experienced 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 other disease-modifying anti-rheumatic drugs (DMARDs). Further, participants who took 10 mg per day showed greater improvement than those taking 5 mg daily.

The authors concluded that Xeljanz has a benefit-risk profile similar to other 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 boxed warning for cardiovascular issues, malignancy, and thrombosis.

Uses

Olumiant is FDA-approved for the treatment of some adults with moderately to severely active rheumatoid arthritis, alopecia areata, and COVID-19 in certain hospitalized adults.

One 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 to treat COVID-19.

Olumiant has also been studied as a psoriasis treatment. In one study, patients reported significant symptom improvement, but more research is needed. Use for psoriasis is considered off-label.

Formulations and Dosage

Olumiant is available as a 1 mg, 2 mg, and 4 mg tablet taken once daily. Studies have shown that upper respiratory infections and high cholesterol levels were rare but more frequent with Olumiant at higher doses.

Ongoing Research

According to a 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 thrombocythemia myelofibrosis
• Polycythemia vera in adults who either did not respond to or have an intolerance for hydroxyurea
• 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; Rinvoq LQ (upadacitinib)

Rinvoq was initially approved by the FDA in 2019.

Uses

Rinvoq is approved for the treatment of:

• Rheumatoid Arthritis
•  Atopic Dermatitis 
• Crohn’s Disease
• Psoriatic Arthritis (after other biologics have failed)
• Ankylosing Spondylitis
• Ulcerative Colitis
• Polyarticular Juvenile Idiopathic Arthritis (after other biologics have failed)

Rinvoq LQ is approved for the treatment of:

• Polyarticular Juvenile Idiopathic Arthritis (after other biologics have failed)
• Psoriatic Arthritis (after other biologics have failed)

Studies are ongoing for Rinvoq as a treatment for:

• Psoriasis
• Inflammatory bowel disease

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

Formulations and Dosage

Rinvoq is available in 15 mg, 30 mg, and 45 mg extended-release tablet forms, to be taken once daily. Rinvoq LQ is available as a 1mg/mL solution, which is taken twice daily.

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 spondyloarthritis types.

Cibinqo (abrocitinib) 

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

Uses

Cibinqo is approved for treating refractory, moderate-to-severe atopic dermatitis in adults and children 12 years and older whose disease is poorly 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.

Litfulo (ritlecitinib)

Litfulo was approved by the FDA in 2023.

Uses

Litfulo is approved by the FDA for the treatment of severe alopecia areata in people ages 12 and older.

Formulations and Dosage

This drug is available in a 50 mg capsule form to be taken once a day.

Liflulo comes with a boxed warning from the FDA because it may cause serious side effects like other oral JAK inhibitors. Side effects include:

• Serious infections
• Increased risk of death
• Cancer and immune system problems
• Increased risk of major cardiovascular events
• Blood clots

Opzelura (ruxolitinib) cream

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

Uses

Opzelura is approved for treating 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 two weeks. 

What’s in the Pipeline?

Pipeline drugs are currently being developed and tested but aren’t FDA-approved for any use. These drugs must go through three phases of clinical trials before they can be brought to the FDA for approval.

Several JAK inhibitors are making their way through the pipeline, undergoing clinical trials to determine their safety and effectiveness in treating various 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) and a priority review application, sometimes speeding 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.
• A year-long phase 3 trial found results 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 phase-2 trial demonstrated that filgotinib significantly improved health-related quality of life in 131 participants.
• For Crohn’s disease, a phase-2 study showed that filgotinib led to remission of symptoms significantly more than placebo in people with active disease.
• According to a different 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 treating 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 treating rheumatoid arthritis in Japan under the brand name Smyraf.

Research Highlights

• The drug has improved 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-tolerated and had positive results that remained consistent for 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, although clinical trials have not yet begun.

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.

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 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 British Association of Dermatologists study finds that abrocitinib was well-tolerated and effective in improving symptoms of moderate-to-severe plaque psoriasis.
• A 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 for ankylosing spondylitis began.

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

BMS-986165

BMS-986165 is currently 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 effectively relieves symptoms in people with plaque psoriasis, taking 3 mg or less per day over 12 weeks. 
• A study states that BMS-986165 is unique among JAK inhibitors and may have properties that make it especially effective against autoimmune diseases.

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

Immune-System Suppression

Similar to biologics and traditional DMARDs, JAK inhibitors suppress the immune system. While that makes them beneficial, it increases vulnerability to severe 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. 

Contraindications and Warnings

JAK inhibitors can also cause anemia in some people. This is due to how 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 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. 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.

Summary

JAK inhibitors are another line of defense in treating autoimmune conditions like arthritis, cancer, autoimmune skin conditions, and irritable bowel disease. They work by interrupting a chain of reactions that lead to inflammation. While they have a similar result as biologics, they are taken orally rather than through an injection or infusion. However, these medications are relatively new, and researchers are still learning more about their long-term safety.