If you have moderate to severe atopic dermatitis, or AD, first-line treatment — meaning the treatment providers usually prescribe first, such as topical corticosteroids — might not be enough to get your AD under control. But breakthroughs over the past decade have launched many new second- and third-line treatments. These include phototherapy, which uses UV (ultraviolet) light, and systemic treatments taken by mouth or given by injection that treat the whole body and not just the AD site. Let's take a look at second- and third-line options for treating your atopic dermatitis.
Second-Line Treatments for AD
Topical calcineurin inhibitors
Topical calcineurin inhibitors, or TCIs, are a type of immunosuppressant, a medication that limits or stops your body’s immune system from reacting. (See more about immunosuppressants under third-line treatments below.)
You put them directly on your skin to block a protein called calcineurin, which fuels inflammation in AD.
There are two types:
- Elidel cream (pimecrolimus) may be prescribed if your AD is mild to moderate.
- Protopic ointment (tacrolimus) comes in different strengths to treat moderate to severe AD.
TCIs are often used as an alternative to first-line corticosteroids, including for people of color, who might choose them over stronger topical corticosteroids that cause hypopigmentation, or lightening of the skin. People who use TCIs are counseled to wear sunscreen and protective clothing when outdoors.
Side effects. A common side effect of TCIs is a burning or stinging feeling, though it usually goes away within a week or so.
Topical PDE4 inhibitors
In 2016, the FDA approved a topical drug as an alternative to corticosteroids or calcineurin inhibitors for mild to moderate AD. Crisaborole (Eucrisa), which is made as a 2% ointment, targets PDE4 (phosphodiesterase 4) enzymes deep in your skin to ease inflammation. It’s been approved for people ages 3 months and up.
Studies show it’s a good long-term treatment choice. One study found crisaborole did not discolor skin. It’s also been shown to improve AD symptoms such as lichenification, which happens when scratching or rubbing your skin too much makes scaly, dry patches on your skin.
Another option, called roflumilast (Zoryve) cream, is approved for mild to moderate atopic dermatitis. It’s available in a 0.15% concentration for adults and kids 6 and up and a 0.05% concentration for kids aged 2-5.
The newest PDE4 inhibitor is difamilast (Adquey). It comes in a 1% ointment approved for use in adults and children age 2 and older.
Side effects. Some people have reported mild temporary pain or a sting when crisaborole (Eucrisa) is applied.
Roflumilast cream (Zoryve) side effects may include:
- Headache
- Diarrhea
- Nausea or throwing up
- Pain where you put it on
- Pink eye
- Upper respiratory tract infection or rhinitis
The most common side effects of Adquey include:
- Infection in the nose or throat, sore throat, or common cold symptoms
- Inflamed hair follicles or rash on the skin area where you apply Adquey
- A skin infection called molluscum contagiosum
Biologics
A biologic is made in a laboratory but uses human DNA from proteins from living cells or tissues to treat some diseases. Approved in 2017, dupilumab (Dupixent) is a biologic drug that’s injected into your skin. It's a second-line treatment for AD. Dupilumab is a monoclonal antibody, meaning it contains exact copies, or clones, of proteins that are part of your immune system. You can sometimes spot this kind of drug because of “mab” at the end of the name.
Dupilumab blocks chemical signals that act up during an AD episode, which quiets down the reaction. Sometimes it can be used with crisaborole.
Another new player in the game is nemolizumab (Nemluvio). The FDA approved it in 2024. It blocks the Interleukin-31 receptor (IL-31) from triggering the protein that makes you itch. It is given as a shot.
Side effects. The most common side effects of dupilumab are ocular, meaning it has to do with your eyes. Some people have reported dry eye, eyelid swelling, and conjunctivitis that isn’t infectious. For nemolizumab, you could get headaches, hives, a rash, or skin redness.
JAK inhibitors
The FDA approved the first Janus kinase — aka JAK — inhibitor to treat AD in 2021. The meds abrocitinib (Cibinqo) and upadacitinib (Rinvoq) in this treatment family have gotten the go-ahead for AD treatment. They can be taken by mouth. Ruxolitinib (Opzelura) is a topical JAK inhibitor cream applied to skin.
JAK inhibitors are synthetic, or man-made, small molecules that hinder signals in your body that cause inflammation. This calms down your immune system.
Side effects. JAK inhibitors can make you more likely to catch colds, lead to an infection in your urinary tract or upper respiratory system, and can cause headaches, nausea, acne, inflamed hair follicles, or diarrhea.
Phototherapy
Also known as light therapy, phototherapy uses ultraviolet (UV) light to treat AD. The UV light is used directly on your skin and mimics sunlight, which helps generate nourishing vitamin D.
UV light decreases bacteria on your skin, improves your skin barrier function, reduces swelling, and eases itching. Many providers use narrowband light, aka narrow UVB, which draws on a slimmer band on the UV spectrum that strengthens the dosage and blocks out rays that can burn your skin. It works well with a low, building number of treatments per week and seems to clear up AD faster than other UV wavelengths.
You’ll go to your provider’s office for treatments at regular times so the light strength and time length can be carefully controlled.
Side effects. Most people don’t have problems with phototherapy. But some effects can include xerosis, or dry skin; itching or burning; or a skin rash.
Third-Line Treatments
Many third-line treatments — meaning your provider will turn to them when first- and second-line treatments haven’t worked — are immunosuppressive medications. These include azathioprine, cyclosporine, methotrexate, and mycophenolate mofetil. These four meds are considered traditional systemic medications, which means they’re taken orally or injected and affect your whole body. They’re also considered “off-label,” meaning they’re not FDA-approved for the purpose of treating AD. But they can be effective and your provider might still prescribe them.
Because your immune system guards your body from infections, it’s key to remember you have more chance of getting a bacterial, viral, or fungal infection while your meds hold your immune system’s protective agents at bay.
Cyclosporine
Cyclosporine is a calcineurin inhibitor you take by mouth. It’s made of amino acids that come from a fungus. Though it doesn’t cure AD, it works well to control it.
Cyclosporine offers a few advantages over other treatments. It works quickly, within one to two weeks. You might still see more improvements in your AD within three to four months, too. The downside is the effects don’t last for most people, though some report their symptoms quiet down for a few months after they finish a course of the drug.
Side effects. Cyclosporine’s side effects limit the number of people who can safely take it, as well as how long it’s safe to do so. Some effects may include:
- High blood pressure
- Less kidney efficiency
- An increase in cholesterol
Your provider will regularly check your levels while you are taking cyclosporine.
Methotrexate
Methotrexate zeroes in on cells in your immune system, calming them down, regulating them, and altering signals they send. You’ll take it as a shot, which you can give yourself, or tablets, once a week on the same day and time. It can take a few months for it to start working, but it’s key to stick with it, because it can work well enough for you to drop back on your use of topical meds.
If methotrexate works for you, you can take it for up to a year, and possibly continue on lower doses under your doctor’s supervision.
Side effects. Methotrexate isn’t known to cause many side effects, and if there are any, they clear up soon. The main side effect of methotrexate is nausea in some people. Your doctor might advise you to take folate acid, anti-nausea meds, or, if you’ve been taking it as a tablet, switch to shots.
Bear in mind that because it’s an immunosuppressant, it cuts your white blood cells, which fight infection. So you might be more likely to get one, such as a chest infection or a viral infection on your skin. Your doctor may order blood tests when you first start methotrexate to make sure your body tolerates the drug.
Mycophenolate mofetil (MMF)
Mycophenolate was first made as an immunosuppressive drug for people who were having organ transplants. It works a little differently than many other immunosuppressive meds, in that it targets white blood cells by slowing them down.
MMF has been shown to be effective for skin conditions like AD. It can take about three months for it to take effect. The good news is, if it works for you, you can take it longer-term than other drugs. It can be used by itself or along with other immunosuppressant drugs, such cyclosporine.
Side effects. Side effects of mycophenolate include nausea, constipation, and vomiting; sleep problems; burning or tingling in your skin; swelling in your extremities; or muscle or joint pain.
Azathioprine
Also known as an antimetabolite, azathioprine is an immunosuppressant, meaning it hampers growth of white blood cells that trigger AD inflammation. Like mycophenolate and methotrexate, it can take several months before positive effects kick in. You might see improvements for several months after you finish your course of the drug.
Side effects. Most people don’t have marked side effects from taking azathioprine. Because of its immunosuppressive qualities, though, it can affect your bone marrow, which can lead to anemia and infection risk.
Your provider will do a blood test to see if you’re likely to have negative effects.
Show Sources
SOURCES:
Photo Credit: Tetra images/Getty Images
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