An Overview of JAK Inhibitors

Oral Biologics Inhibiting Autoimmune Response to Ease Inflammation

JAK inhibitors

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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).

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 more cytokines. After cytokines bind to receptors, JAK adds chemical phosphate to the receptor. This attracts STAT proteins which further bind and multiply. The result is more inflammation, and too much inflammation wreaks havoc on your body. It makes you susceptible to all kinds of autoimmune diseases, conditions where the body’s immune system, that ordinarily would attack viruses and bacteria, attacks itself. This response is called autoimmunity.

JAK enzymes are major contributors to 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 and helps to ease inflammation and other disease symptoms caused by the immune system overacting.

In addition to application in treating systemic (affecting the entire body) autoimmune diseases, JAK inhibitors are also being researched for the treatment of skin and hair disorders. Research reported in the January 2019 publication of The Lancet finds JAK inhibitors are the safest and most effective treatment for blocking the key signal pathways responsible for triggering alopecia areata, an autoimmune condition that causes hair to fall out in patches. Further, the most preferable treatment method is monotherapy (one type of treatment), which would exclude immunosuppressant drugs (drugs that suppress the immune system), including glucocorticosteroids

The researchers concluded that would make sense to look further into the development of topical JAK inhibitors for the treatment of alopecia areata and other autoimmune skin conditions.

Current Therapies

There are only a handful of JAK inhibitor medicines available in the United States at this time, with Xeljanz (tofacitinib) and Olumiant (baricitinib) being the most commonly prescribed. Many more are being developed and tested. Xeljanz was approved in 2012 for the treatment of RA and in mid-2018, the Food and Drug Administration (FDA) approved the 2-milligram (mg) dose of Olumiant (baricitinib) to be taken once daily for adults with moderate-to-severe RA who did not previously have an adequate response to methotrexate or tumor necrosis factor (TNF) inhibitor therapies. 

Xaljanz

Xaljanz is currently approved for the treatment of RA, PsA, and ulcerative colitis (UC). Xaljanz is available in a 5 milligram (mg) pill and an 11 mg extended-release tablet. Several studies have demonstrated that Xaljanz is effective in treating Crohn’s disease, alopecia areata, vitiligo, psoriasis, and atopic dermatitis.

One 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 comprised of psoriasis patients using tofacitinib. The researchers found that those using tofacitinib were experiencing an improved quality of life, as their skin plaques and other psoriasis symptoms were improved. The drug was well-tolerated, and safety and side effects were similar to those of disease-modifying anti-rheumatic drug (DMARD) treatments. Further, patients that took 10 mg per day showed greater improvement than those taking 5 mg daily.

The report’s authors noted the efficiency was comparable to methotrexate or biologic Enbrel (etanercept) 25 mg twice weekly. The higher dose was comparable to Enbrel 50 mg twice a week. The authors concluded that Xaljanz has a benefit-risk profile similar to other systemic treatments. It is a better option for people who prefer oral therapy over injectable biologics.

Olumiant

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

Baricitinib was developed to block JAK1 and JAK2 enzymes. It had previously 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.

In April 2018, the FDA recommended the approval of baricitinib in 2 mg but did not recommend the 4 mg dose, citing serious adverse reactions. Previous studies showed that upper respiratory infections and high cholesterol levels were rare but more frequent with baricitinib at higher doses. 

Ruxolitinib

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.

What’s in the Pipeline?

Pipeline drugs are drugs that are being developed and tested currently. Every one of these drugs must go through three phases of clinical trials before it can be brought to the FDA for approval. A number of JAK inhibitors are currently in the drug pipeline undergoing clinical trials. These trials aim to determine the safety of drugs and address their effectiveness in treating variety of autoimmune conditions.

Peficitinib

Peficitinib (ASP015K) is a JAK 1 and JAK 3 inhibitor currently being investigated for the treatment of RA. The drug has been shown to improve RA outcomes in two phase IIB studies. 

Filgotinib

Filgotinib (GLPG0634), a selective JAK1 inhibitor, is being investigated for the treatment of RA. Results of two phase IIb have shown it to be effective both in combination with methotrexate and as a monotherapy. Filgotinib is also being tested for the treatment of PsA and UC. 

Itacitinib

Phase II trials are currently underway for testing the efficacy and safety of Itacitinib (INCB039110) for treating plaque psoriasis. 

SHR0302

SHR0302, a highly potential selective JAK1, JAK2, and JAK2 inhibitor, is currently being evaluated in phase II trials for treating rheumatoid arthritis by researchers in China.  

Upadacitinib

Upadacitinib (ABT-494) is a JAK inhibitor currently being investigated for the treatment of RA, UC, Crohn’s disease, PsA, and atopic dermatitis. One study reported in the May 2019 issue of the journal, The Lancet, finds that Upadacitinib monotherapy is “statistically significant” in improving symptoms and function in people with RA in people who previously did not respond to methotrexate.

PF-04965842        

PF-04965842 is an oral JAK1 inhibitor currently being investigated for the treatment of plaque psoriasis. Research from a 2017 British Association of Dermatologists study finds that PF-04965842 was effective in improving symptoms of moderate to severe psoriasis.  Additionally, the drug was well-tolerated.

BMS-986165

BMS-986165 is a TKY2 inhibitor currently being studied for treating moderate to severe plaque psoriasis. Data from phase II studies show the drug has effective in relieving symptoms in people with psoriasis taking 3 or less mg per day over a period of 12 weeks. BMS-986165 is also being studied for the treatment of PsA.

Possible Side Effects

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, there have been instances of people coming 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. The good news is the effects of these drugs wear off as soon as you stop taking them, and your body will get back its full ability to fight infections.

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.

Some people may have an increased risk for cancer because JAK inhibitor drugs block the immune processes responsible for preventing tumors. 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 reported to your doctor. Some can managed with lifestyle and medication, while others require a medication change.

A Word From Verywell

If you are someone who has been benefited from using older drugs, such as biologics or methotrexate, for treating your autoimmune condition, you probably don’t need a JAK inhibitor. But the older treatments don’t work for everyone and a JAK inhibitor might offer needed relief. Studies have shown that at least half of the people who didn’t improve using biologics and traditional DMARDs were able to see symptom improvement with JAK inhibitor use.

Another advantage of JAK inhibitors is that they can be taken by mouth. If you take a biologic, you would have either inject the medicine under the skin or go to your doctor’s office for an infusion through an IV. But you can take JAK inhibitors in pill form.

Just remember these medications are fairly new and researchers are keeping track of 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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