Dermatologist Dr. Joan Paul answers common questions about JAK inhibitors for eczema.

Janus kinase (JAK) inhibitors are a newer class of medications that target the Janus kinase family of enzymes. There are four types of these enzymes in humans: JAK1, JAK2, JAK3, and Tyrosine kinase 2 (Tyk2). These enzymes play a crucial role in a person’s immune response and promote inflammation.

JAK inhibitors work by blocking specific Janus kinase enzymes and interfering with the signaling pathways that contribute to inflammation.

If you have eczema, JAK inhibitors can be helpful because eczema is often associated with an overactive immune system and increased inflammation in the skin. By reducing inflammation, people living with eczema experience less redness and itching with the help of JAK inhibitors.

The three available JAK inhibitors used to treat eczema in the United States are:

  • upadacitinib (Rinvoq)
  • abrocitinib (Cibinqo)
  • ruxolitinib (Opzelura)

Upadacitinib and abrocitinib are taken by mouth (orally) once a day, and ruxolitinib is a cream that is applied directly onto the skin twice a day (topically).

Yes, JAK inhibitors work differently than steroids and biologics.

Steroids work by:

  • suppressing the immune system
  • constricting blood vessels
  • decreasing mitosis (cell splitting/division, which leads to anti-proliferative effects)
  • reducing inflammation

Steroids can be applied directly onto the skin, injected into the skin or muscle, or taken by mouth.

Biologics are large molecules derived from living cells. They target specific components of the immune system, which typically results in reduced inflammation. The two biologics available in the United States to treat eczema are:

  • dupilumab (Dupixent)
  • tralokinumab-ldrm (Adbry)

These drugs are injected into the skin (subcutaneous injection). Dupilumab is a fully human monoclonal antibody that binds to interleukin (IL)-4Rα and inhibits the signaling of both IL-4 and IL-13. Tralokinumab-ldrm is a fully human monoclonal antibody that specifically binds to IL-13.

Both IL-4 and IL-13 are abnormally increased in eczema, which is why both of these drugs work so well in reducing eczema symptoms.

Whereas biologic medications target a specific part of the immune system, JAK inhibitors block the Janus kinase family of enzymes, as mentioned earlier.

All three types of medication work to reduce inflammation but by different pathways.

JAK inhibitors are not typically considered a first-line treatment for eczema. Usually, we try topical corticosteroids, topical calcineurin inhibitors (i.e., tacrolimus ointment), light therapy, or conventional oral medications like prednisone (an oral steroid) before considering a JAK inhibitor.

If these more typical medications and treatments fail or are not tolerable, then we consider prescribing a JAK inhibitor.

JAK inhibitors, especially the oral versions, are considered more often among patients with moderate to severe eczema, not for those with only mild symptoms. This is because JAK inhibitors can have more side effects than the typical first-line treatment options.

Also, this class of medication is newer, so we are still learning about its effectiveness and potential side effects.

Dermatologists want their eczema patients to get better as quickly as possible, but we also want our patients to remain safe. This is why we normally try safer treatment options before considering a medication with more possible side effects and limited clinical trial data.

Since eczema is not a curable condition, people sometimes need long-term treatment, what we call “maintenance therapy.” If someone is doing really well on a JAK inhibitor, we may consider continuing the patient on it as long as there are no side effects, with some drug holidays interspersed whenever they have clear skin and no eczema symptoms.

In clinical trials, however, dermatology patients typically take an oral JAK inhibitor like upadacitinib or abrocitinib for 12–16 weeks at a time, not long-term.

JAK inhibitors are one of the newer classes of medications to treat eczema. This means not a lot of research has been done on this drug class compared to older medications like topical steroids. We are still learning about JAK inhibitors, and the ongoing research results are exciting.

For example, the oral JAK inhibitors upadacitinib and abrocitinib reduced itching in research patients in a matter of days. Eczema is commonly known as the “itch that rashes,” where itching is the primary uncomfortable symptom that keeps people up at night and impairs their ability to live their life to the fullest. Having a drug that can reduce or eliminate itching so quickly is really a wonderful breakthrough in the treatment of eczema.

The topical formulation of a JAK inhibitor, ruxolitinib, has also shown promising results in clinical trials. In one study, itching was reduced in some patients within 12 hours of taking the drug. At the end of the 8-week treatment period, subjects reported an 80% reduction in itching compared to 48% of those receiving the placebo cream.

This drug also helped more than 50% of the subjects get clear or almost clear skin at the end of the study. That is truly remarkable.

But a word of caution: Not everyone will respond as well as these research patients to a JAK inhibitor. This is why it is important to make treatment decisions regarding your eczema with a board certified dermatologist who can help tailor your treatment(s) to your personal needs.

As mentioned earlier, JAK inhibitors are one of the “new kids on the block” when it comes to the treatment of eczema, which means we are still learning about its potential side effects.

This class of medication has a black box warning associated with it, informing potential patients about the risk of serious infections, death, cancer, cardiovascular events, and clotting (thrombosis) while taking these drugs. These side effects are thankfully rare, which is why dermatologists still prescribe these medications to their eczema patients.

Steroids, on the other hand, do not carry a black box warning, but these drugs cannot be used long-term.

Topical steroids can cause skin thinning, open wounds, and stretch marks if used continuously. Oral steroids can cause weight gain, infections, bone fractures, skin thinning, high blood pressure, high blood sugar levels, Cushing’s syndrome, and adrenal insufficiency when used for a long period of time.

Steroids work extremely well in reducing inflammation and helping eczema patients get clear skin, but the side effects associated with their long-term use limit their utility for eczema patients. JAK inhibitors don’t have the same dose-dependent risk of side effects as steroids do, as their side effects can occur at any time.

Both JAK inhibitors and steroids have their place in the treatment of eczema, but it is important to understand their respective side effects so people can make an informed decision about their eczema treatment plan.

JAK inhibitors and biologics increase a person’s risk of getting an infection because both of these drugs work to suppress the immune system but in different ways. The immune system is overactive in conditions like eczema, but it is also responsible for keeping us safe from bacteria, viruses, fungi, and cancer.

Older biologic medications like adalimumab (Humira) block the immune system more broadly and, therefore, have more side effects associated with it. Newer biologic drugs like dupilumab and tralokinumab-ldrm are targeting more specific parts of the immune system that are primarily involved in eczema with the goal of reducing unwanted side effects.

The main side effects of dupilumab are conjunctivitis (pink eye), cold sores, and local skin reactions where the medication is injected into the skin (injection site reaction). In clinical trials, upper respiratory infections, pink eye, injection site reactions, and increased levels of blood eosinophils (a marker of an allergic reaction) were common side effects of tralokinumab-ldrm.

The potential side effects of JAK inhibitors include:

  • infections (shingles, upper respiratory infections, flu-like illness, folliculitis, cold sores)
  • tiredness
  • headaches
  • acne
  • nausea
  • vomiting
  • abdominal pain
  • fever
  • muscle aches
  • high blood pressure
  • increased blood creatine phosphokinase
  • low platelet count
  • decreased blood neutrophils (a type of white blood cell focused on combating infections)

JAK inhibitors seem to have a much broader and more serious variety of potential side effects when compared to biologics. However, research is still ongoing with both of these drugs, so we may discover more or less side effects in the future.

The Food and Drug Administration (FDA) applied a black box warning for JAK inhibitors due to the increased risk of thrombosis (clotting) and cardiovascular events (i.e., heart attack) seen among patients treated with an oral JAK inhibitor tofacitinib (Xeljanz or Xeljanz XR) for arthritis or ulcerative colitis.

However, a recent review article analyzed the data from 20,651 patients from 35 phase-3 dermatology-specific randomized clinical trials and discovered no statistically significant difference between JAK inhibitors and placebo/comparison drug with respect to MACE, death, or venous thromboembolic event (i.e., blood clots in the legs [deep venous thrombosis] or lungs [pulmonary embolism]).

The study authors noted that the majority of the patients in these trials were young (the mean age of the research subjects was 38.5 years old) and that the follow-up time period was short (mean follow-up time was 4.9 months). Since it can take several months to years for a cardiac or venous thromboembolic event to develop, it is hard to say whether these studies properly captured the actual risk of MACE in these patients with such a short follow-up time.

In clinical trials, dermatology patients typically take an oral JAK inhibitor like upadacitinib or abrocitinib for 12–16 weeks at a time, not long-term. This short time frame when compared to the more long-term dosing required to treat psoriatic or rheumatoid arthritis is probably what led to less concerning cardiovascular side effects than expected.

Research is ongoing regarding the risk of MACE with JAK inhibitors for dermatology patients, but this recent study’s result was reassuring.

JAK inhibitors are not a good treatment option for everyone with eczema. Certain people should avoid taking a JAK inhibitor, such as those with:

  • a history of active infections (shingles, tuberculosis, HIV, hepatitis B and C)
  • clotting problems (stroke, pulmonary embolism)
  • liver disease
  • cancers (leukemia, lymphoma, melanoma, non-melanoma skin cancer, lung cancer)
  • stomach and intestinal perforations
  • prior allergic reactions to JAK inhibitors or a component of the medication
  • women who are currently pregnant or breastfeeding

JAK inhibitors have a black box warning associated with them, informing patients about the risk of “serious infections, mortality, cancer, cardiovascular events and clotting (thrombosis).” It is important for people to discuss these risks with their dermatologist before deciding to try a JAK inhibitor to treat their eczema.

This is a tough question to answer, as most people will use their health insurance to cover the expense of their medications. The cost of a JAK inhibitor versus a brand name biologic really depends on a person’s health insurance coverage and things like their deductible and coinsurance.

Typically, generic medications will be more economical than brand-name drugs. Newer drugs will also be more expensive than drugs that have been around for a while.

It is always best to look at websites that compare prescription drug prices or to speak with your pharmacist or health insurance company about the cost of your medications.

Also, certain drug manufacturers offer patient assistance programs to help offset the cost of their medications, which can be extremely helpful to those with limited financial means.

Dr. Joan Paul is an ABMS board certified dermatologist who specializes in psoriasis, skin cancer, skin of color, and global health. She has also completed seven medical missions in the countries of Haiti, Trinidad & Tobago, Mexico, Malawi, Uganda, India, and Botswana.