Introduction to JAK Inhibitors
Introduction to JAK InhibitorsIf you’ve been asking about treatment options for chronic conditions like rheumatoid arthritis, psoriasis, or ulcerative colitis, you may have come across the term JAK inhibitors. These medications represent a newer class of therapies that target specific enzymes involved in the body’s immune response. To understand how they work, it’s helpful first to grasp the basics of autoimmune and inflammatory processes.
Understanding autoimmune diseases
The body’s immune system is designed to protect itself from harmful invaders like bacteria and viruses. It does this by recognizing foreign substances and attacking them. When someone gets a cut or catches a cold, the immune system sends white blood cells to the affected area to fight off invaders and start the healing process. This response often results in inflammation, with its characteristic signs of redness, swelling, heat, and pain. Inflammation is the body’s natural response to injury or infection and is not in itself a bad sign. Often, the response is strong enough to completely eliminate the invaders, and healing follows. The short-term effects (acute inflammation) clear up, and things return to normal. However, if the body can’t respond quickly enough or the injury or infection persists (chronic inflammation), it can potentially lead to other diseases.
In autoimmune diseases, this normal system malfunctions and mistakenly targets the body’s own healthy cells and tissues. There is no “invader” that the immune system can fight off. The inflammation is chronic and can cause ongoing damage to the body.
There are more than 80 different autoimmune diseases. They can affect various parts of the body, including: 
- Joints (e.g., rheumatoid arthritis)
- Skin (e.g., psoriasis)
- Digestive system (e.g., UCI and Crohn’s disease)
- Endocrine system (e.g., Type 1 diabetes)
- Nervous system (e.g., multiple sclerosis)
- Kidneys (e.g., Lupus disease)
- Blood (e.g., Giant cell arteritis, polycythemia vera)
The exact causes of autoimmune diseases are unknown. Possible factors include:
- Genetics: Some autoimmune diseases tend to run in families.
- Environmental factors: Viruses, some chemicals, and other environmental factors may trigger the disease in susceptible individuals.
- Gender: Autoimmune diseases are more common in women.
There is no cure for most autoimmune diseases. Current treatments aim to:
- Control the immune system’s overactivity
- Reduce inflammation and pain
- Manage symptoms
Janus kinase (JAK) inhibitors – a new way to manage inflammation
JAK inhibitors include a class of medications that target specific enzymes in the body known as Janus kinases (JAKs.) These enzymes play a crucial role in the signaling pathways that regulate immune responses and inflammation.
In autoimmune diseases, the immune system mistakenly attacks the body’s own tissues, leading to inflammation and damage. JAK inhibitors work by blocking the activity of JAK enzymes, thereby disrupting the signaling pathways that promote inflammation. This helps reduce symptoms and prevent further tissue damage.
There are four main types of JAK enzymes:
- JAK1 i involved in signaling for the cytokines that regulate immune responses.
- JAK2 plays a role in blood cell production and immune function.
- JAK3 is primarily found in immune cells and is crucial for lymphocyte development.
- TYK2 participates in signaling for various cytokines involved in inflammation.
Cytokines are tiny protein messengers that act as messengers in the body, especially for the immune system. Cytokine receptors help cells communicate with each other, telling them what to do, like activating immune responses, causing inflammation, or even helping fight cancer.
Conditions treated with JAK inhibitors
JAK inhibitors are not a cure for autoimmune diseases. Their main function is to control inflammation and reduce the swelling and pain that inflammation causes.
JAK inhibitors have been FDA-approved for the treatment of a number of autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PA), ulcerative colitis (UC), Crohn’s Disease, atopic dermatitis (eczema), alopecia areata, various blood disorders, and myelofibrosis.
| Brand | Conditions treated | Pros and cons |
| Xeljanz
tofacitinib Inhibits JAK1+ JAK3 |
FDA-approved for adults with:
FDA-approved for patients ages 2 and older with active polyarticular course juvenile idiopathic arthritis. Prescribed off-label for patients with:
|
Effective oral drug, with relatively rapid effect. Can be used alone or in combination with DMARDs.
_____________________________ Increased risk of infections, risk of serious side effects. Needs regular blood tests. |
| Olumiant baricitinib
Inhibits JAK1 + JAK2 |
FDA-approved for adults with:
Prescribed off-label for other conditions in dermatology, including treatment of atopic dermatitis, psoriasis, and vitiligo. |
Only drug FDA-approved for severe alopecia areata.
________________________ Increased risk of infections, risk of serious side effects. |
| Rinvoq
upadacitinib Inhibits JAK1 |
FDA-approved for adults with:
FDA-approved for children aged 2 and older with active Juvenile Idiopathic Arthritis and in children aged 2-18 with active psoriatic arthritis when TNF blockers did not work well or could not be tolerated. Prescribed off-label for patients with alopecia areata, hidradenitis suppurativa, and lichen planus. |
Has a better safety profile than older JAKi drugs
_____________________________ Increased risk of infections, risk of serious side effects like sudden allergic reaction (anaphylaxis). Has a possible increased risk of cancers like lymphoma and lung cancer. Needs regular blood tests. |
| Jakafi
ruxolitinib Inhibits JAK1 and JAK2 |
FDA-approved for adults with myelofibrosis or polycythemia vera (myeloproliferative neoplasms) after treatment with hydroxyurea did not work well enough or they could not tolerate it.
Prescribed off-label for patients with lichenoid and granulomatous dermatoses, as well as alopecia areata. |
Jakafi is the only drug that treats myeloproliferative neoplasms.
_____________________________ Increased risk of infections and skin cancers. Needs regular blood tests. |
| Sotyktu
deucravacitinib Targets TYK2 |
FDA-approved for the treatment of adults with moderate to severe plaque psoriasis.
Prescribed off-label for patients with: systemic sclerosis, Sjögren syndrome, and various skin and joint conditions. |
Oral medication is more convenient for some patients than injectable biologics. Sotyktu is the first TYK2 inhibitor for psoriasis. Has fewer side effects.
_____________________________ May not be suitable for people with pre-existing conditions such as active infections or severe liver problems. |
| Opzelura
ruxolitinib Inhibits JAK1 and JAK2 |
FDA-approved for children aged 12 and older as well as adults with:
|
Unlike systemic JAK inhibitors taken by mouth, Opzelura is a topical cream that delivers targeted therapy, making it suitable for short-term and non-continuous chronic use
_____________________________ Increased risk of blood clots in legs or lungs, which can be dangerous, particularly in older adults with cardiovascular risk factors. |
Prescribing JAKi medications off-label is at the sole discretion of the patient’s doctor.
Potential side effects of JAKi medications
While JAK inhibitors can be effective, they may also cause side effects. Common ones include:
- Infections: Increased risk of bacterial, viral, and fungal infections.
- Blood clots: Elevated risk of deep vein thrombosis and pulmonary embolism.
- Cardiovascular events: Potential for heart-related issues, especially in older adults.
- Cancer: Slightly increased risk of some cancers.
- Elevated cholesterol: Changes in lipid profiles.
- Gastrointestinal issues: Nausea, diarrhea, or abdominal pain.
Drug Interactions
JAK inhibitors can interact with other medications, potentially altering their effectiveness or increasing side effects. Notable interactions include:
- Immunosuppressants: Combining with other immune-modulating drugs can amplify immunosuppression.
- Live Vaccines: Should be avoided during treatment due to increased infection risk.
- CYP3A4 Inhibitors: Drugs that inhibit this liver enzyme can increase JAK inhibitor levels in the blood.
People with pre-existing conditions or current drug regimens should make sure that the prescribing doctor is aware of these and any other issues that may affect the effectiveness and safety of the medications.
Frequently asked questions about JAK inhibitors
Are JAK inhibitors safer than steroids?
JAK inhibitors and steroids both suppress the immune system, but in different ways. Steroids are effective for short-term relief but can have significant side effects with long-term use, such as osteoporosis and weight gain. JAK inhibitors may offer a more targeted approach with potentially fewer long-term risks, but they still carry their own set of side effects.
Are JAK inhibitors safer than biologics?
Both JAK inhibitors and biologics are used to treat autoimmune conditions. Biologics are protein-based therapies administered via injection or infusion, while JAK inhibitors are oral medications. The safety profiles differ; some studies suggest similar efficacy, but JAK inhibitors may have a higher risk of side effects like blood clots and infections.
Who should not take JAK inhibitors?
Individuals with a history of serious infections, blood clotting disorders, cancers, or liver disease should exercise caution. Additionally, older adults and those with cardiovascular risk factors should discuss potential risks with their healthcare provider.
Do JAK inhibitors cause weight gain?
Weight gain has been reported in some patients taking JAK inhibitors, though it’s not a universal side effect. The exact mechanism isn’t fully understood, and more research is needed to determine the prevalence and causes.
What is the cardiovascular risk of JAK inhibitors?
There is evidence suggesting an increased risk of cardiovascular events, such as heart attacks and strokes, particularly in older adults or those with existing risk factors. The government’s Food and Drug Administration has issued warnings regarding these risks, emphasizing the importance of evaluating individual patient profiles before initiating therapy.
