Behind the counter: Systemic immunomodulatory treatments for eczema

This is a class of medications that influences the immune system. These drugs can either suppress or enhance the immune system. A systemic medication means that a person either takes it by mouth or receives it as an injection or intravenous (IV) medication. Healthcare professionals usually administer IV medications in a hospital or inpatient setting.

Unlike topical medications, which a person applies directly to their skin, these medications affect the entire body. This means that they can have more side effects than a topical medication because the entire body is involved, not just the area of skin receiving the treatment.

Eczema is a skin condition in which the immune system is too active. Using an immunosuppressive medication can therefore help relieve symptoms in people living with moderate to severe cases of eczema. Systemic immunosuppressive medications are not typically used for mild eczema cases because the risks of treatment do not outweigh the benefits.

Yes, there are a number of different types of immunomodulatory treatments available today. For people with eczema, immunosuppressant drugs are used primarily to counteract the overactive immune response present in these folks.

The main players available are:

• corticosteroids
• immunosuppressants
• biologics
• Janus kinase (JAK) inhibitors

Corticosteroids are anti-inflammatory medications that also suppress the immune system. Prednisone is a common oral corticosteroid used in the treatment of eczema.

Immunosuppressants used to treat moderate to severe eczema include:

• cyclosporine
• methotrexate
• mycophenolate mofetil
• azathioprine

As the name suggests, these drugs work by suppressing different parts of the immune system.

Biologics are new-ish drugs that target specific parts of the immune system. Dupilumab (Dupixent) is the first biologic approved for treating eczema. This drug specifically blocks the interleukin (IL)-4 receptor. Blocking this specific pathway reduces levels of both IL-4 and IL-13.

These two cytokines (a type of protein involved in the immune system) are thought to drive inflammation in people with eczema. When their levels are reduced, there is less inflammation, which means less itching and discomfort.

Tralokinumab-ldrm (Adbry) is the latest approved biologic for eczema, and it targets IL-13, preventing it from binding to its receptor. This helps stop the downstream inflammatory cascade that fuels an eczema flare.

JAK inhibitors are the “new kids on the block.” These drugs target the JAK 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 JAK enzymes and interfering with the signaling pathways that contribute to inflammation.

Abrocitinib (Cibinqo) and upadacitinib (Rinvoq) are both JAK1 inhibitors that a person takes by mouth (orally). Ruxolitinib (Opzelura) blocks both JAK1 and JAK2 and is a cream that a person applies directly to the skin (topically) twice per day.

The newer immunomodulatory drugs for eczema, such as biologics and JAK inhibitors, are more precise in the way that they fight the inflammation that is rampant during an eczema flare.

Newer biologic drugs, such as dupilumab and tralokinumab-ldrm, target more specific parts of the immune system that are primarily involved in eczema, with the goal of reducing unwanted side effects.

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

The immune system is overactive in conditions such as eczema, but it is also responsible for keeping us safe from bacteria, viruses, fungi, and cancer. Older drugs such as methotrexate and prednisone block the immune system more broadly. This means there are more possible side effects and a higher potential for getting an infection or cancer when using these medications.

Prednisone may also have numerous unwanted side effects, such as bone loss, weight gain, diabetes, and blindness, which is why this drug cannot be used long-term even though it is a very effective medication for eczema.

Since biologics and JAK inhibitors are so new to the scene, it is hard to say whether these drugs are safe to use in the long term. Eczema is a chronic, potentially lifelong condition, so having safe medications that are also effective is important in the management of this difficult skin condition.

Topical treatments for eczema, such as steroid ointments and creams, work well in mild cases of eczema. For those living with moderate to severe eczema, especially if it encompasses a large surface area of their body, topical medications are not going to get their symptoms under control.

For more severe eczema, dermatologists tend to add systemic immunomodulatory drugs to a person’s topical regimen in order to get them comfortable as soon as possible. Once an eczema flare has passed, the person can taper off the systemic drug and continue with topical medications alone (maintenance treatment).

Since eczema is a chronic condition, many people need maintenance treatment to “maintain” clear skin and decrease the number of flares they experience.

As mentioned earlier, systemic immunomodulatory medications are typically reserved for people with moderate to severe eczema whose eczema is significantly affecting their quality of life. A doctor would also consider a systemic medication if someone has a large area of involvement, as it would be difficult for them to apply a topical medication all over their body.

Also, if someone has tried a topical medication regimen or light treatment (phototherapy) but has not seen improvement in their condition or has had recurrent flares, then their doctor would consider a systemic drug.

Systemic immunomodulatory medications do come with side effects, however. People who are at higher risk for infections or certain cancers or have liver or kidney disease need careful screening to help determine whether they are candidates for this class of medications.

Not everyone is a suitable candidate for this class of medications. People can safely manage mild eczema with topical treatments rather than systemic therapy, as mentioned earlier. Young children and older adults have more vulnerable immune systems and are usually not considered good candidates for systemic treatment.

People who are pregnant or nursing cannot take medications such as methotrexate (pregnancy category X) due to the risk to the developing baby and the risk of miscarriage and stillbirth.

Methotrexate can damage the liver, so people with liver disease should not take this drug. Those with a history of severe infections, hepatitis, and tuberculosis should also refrain from using these medications.

People with diabetes should be careful when considering a drug such as prednisone, as it can increase their blood sugar levels.

Drug allergies are possible with this class of medications, so people with a history of drug allergy to the drug itself or part of the drug should strictly avoid further use in order to prevent anaphylaxis, which can be life threatening (deadly).

Those with a history of cancer should be careful when considering a systemic immunomodulatory medication, as these drugs can increase the risk of cancer or lead to a recurrence of previous cancer.

Systemic immunomodulatory medications can affect the entire body, not just the skin. This is why this class of medications incurs more risks and side effects than topical medications.

The only way to reduce this risk is by avoiding this class of medication altogether. Limiting its use to treating acute flares rather than long-term maintenance therapy will also reduce the risks but not eliminate them.

If someone does decide to pursue systemic treatment, good hand hygiene and staying up to date on age-appropriate vaccinations will help keep them safe from acquiring certain infections. Seeing a doctor regularly for routine evaluations and blood tests can help monitor for the presence of potential side effects so that a doctor can treat them swiftly and appropriately.

Systemic medications may cause allergic reactions, so it is important that people familiarize themselves with the symptoms of an allergic drug reaction so that they know what to look out for (i.e., difficulty breathing or swallowing or rashes). People should stop taking their medications immediately if they notice any of these symptoms.

Older drugs such as prednisone can cause side effects such as:

• weight gain
• diabetes
• blindness
• bone loss
• thinning skin
• Cushing syndrome

Methotrexate can cause:

• hair loss
• diarrhea
• vomiting
• stomach pain
• mouth sores
• damage to the liver and kidneys
• miscarriage and stillbirths among pregnant people

Mycophenolate mofetil can cause:

• headaches
• dizziness
• stomach upset
• diarrhea
• vomiting
• colitis

Cyclosporine can cause high blood pressure and kidney damage.

Azathioprine can cause:

• hair loss
• nausea
• diarrhea
• skin cancer
• drug hypersensitivity reactions
• Stevens-Johnson syndrome/toxic epidermal necrolysis

All of these older drugs pose a higher risk of infections and cancer.

The newer immunomodulatory drugs, such as biologics and JAK inhibitors, have fewer side effects because of their targeted mechanism of action. The main side effects of dupilumab are:

• conjunctivitis (pink eye)
• cold sores
• local skin reactions where the medication is injected into the skin (injection site reaction)

In clinical trials, common side effects of tralokinumab-ldrm include:

• upper respiratory infections
• pink eye
• injection site reactions
• increased levels of blood eosinophils (a marker of an allergic reaction)

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 fighting infections)

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

Since systemic immunomodulatory drugs have the potential for so many side effects, it is not wise to take these medications long term. Most dermatologists use these medications to quickly quiet a flare down, and then they transition their patients off of them.

If long-term dosing is needed, a dermatologist will schedule regular checkups to monitor the person for any potential side effects. This includes a physical exam and blood tests, as well as imaging studies as needed.

If a systemic immunomodulatory treatment is not effective in managing someone’s eczema, there are several other options available.

Sometimes a person may not respond to one type of immunomodulatory drug, such as azathioprine, but will respond beautifully to another type, such as a biologic. In other cases, their doctor may only need to change the dose of the medication.

Combination therapy is also an option. This is when someone uses a systemic immunomodulatory drug along with topical treatments or phototherapy.

Stress can be an eczema trigger. Stress reduction techniques such as meditation, yoga, talk therapy, and exercising in nature can all help improve symptoms and reduce flares.

Finally, if a person and their dermatologist have exhausted all treatment options, it might be possible for the person to participate in a clinical trial to try a new medication.

Human beings are complex, and not every treatment is going to work the same for everyone. This is where the “art” of medicine takes place and people’s medications are tailored to their specific needs.

This might mean there is some trial and error before someone finds the right medication and treatment plan that will help clear up their eczema and prevent or reduce future flares.

This is an exciting time to treat eczema, as there are more drugs currently available and in the pipeline to treat this difficult and challenging skin condition.

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.