Anthony Fernandez, MD, PhD: The most challenging aspect of treating moderate to severe refractory AD is balancing aggressiveness of therapy with potential adverse events. Patients with moderate to severe AD typically require systemic therapy to adequately control their disease. Traditionally, this has meant using steroid-sparing immunosuppressive agents such as methotrexate, azathioprine, and mycophenolate mofetil, in addition to TCSs. All of these medications are associated with potential adverse events and require routine lab monitoring to ensure patients are safe regardless of the disease being treated.

What sets patients with moderate to severe AD apart from patients with numerous other diseases requiring steroid-sparing immunosuppressive agents is a significant increased risk for secondary infection. These medications inherently increase the risk for infection, but this risk is magnified in patients with AD. Unlike patients with diseases like psoriasis and cutaneous lupus, disruptions of the epidermal barrier in patients with AD significantly increases the risk for secondary infection. We have seen numerous patients on these medications end up hospitalized with bacteremia or sepsis due to the significant risk for infection, so the challenge is obviously aimed at avoiding this situation.  

Annie Grossberg, MD: There are several challenges in treating moderate-to-severe AD. We find in our practice that establishing a good topical regimen is often the biggest challenge. Whether or not adjuvant treatments such as systemic medications or phototherapy are needed and utilized, the importance of barrier repair and consistent use of regular moisturizers can be challenging for patients and their families. More specifically, the associated time and expense can be a barrier to establishing an effective topical regimen as the cornerstone of their treatment plan.

Other than establishing a solid topical regimen, the decision of when and which systemic medication to initiate when indicated, or consideration of initiation of phototherapy, represents another common challenge. Often we as clinicians recognize that a patient may benefit tremendously from escalation of therapy, but patients and their families may have be hesitatant about systemic medications and their potential adverse effects, and a lot of education is needed.

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Dermatology Advisor: How is treatment of these patients typically approached?

Dr Johnson: A systematic approach is important when treating patients with moderate to severe AD. Initial treatment in these patients includes the use of TCSs for the body — usually class I or II for an acute flare and class III to IV for maintenance therapy — and TCIs for sensitive areas such as the face. It is important to reinforce the need for strict compliance with good skin care practices such as regular emollient use and gentle skin cleansers, as well as avoidance of allergens/irritants. For patients who show improvement in their disease severity with this approach, proactive therapy is then recommended via the use of a TCS (class IV or V) or a TCI on affected or previously affected areas twice a day for 2 consecutive days per week.

For patients who do not respond to this treatment regimen, dupilumab and phototherapy are next in line, but as I mentioned, they both have their respective challenges despite being great treatment modalities. If neither are an option or patients do not respond to these therapis, the off-label use of other systemic therapies — such as methotrexate, mycophenolate mofetil, cyclosporine, or azathioprine — are typically offered.

Dr Fernandez: Typically, we try to assess all aspects of the disease and start with the most conservative treatment regimen we believe would control the disease. For example, how severe is the patient’s disease? What is the history surrounding the patient’s disease? What treatments have already been tried and for how long? Does the patient feel there are certain triggers that cause disease activity? Flares? What is the patient’s routine skin hygiene regimen?

Based on the collective information about the patient’s AD, we develop a treatment regimen and administer a trial of the regimen for several months. Eventually we reassess the patient and then decide based on their response whether we need to escalate the aggressiveness of the regimen to adequately control the disease.

Dr Grossberg: A topical regimen, including a soak-and-smear routine, remains the mainstay of treatment for almost all patients with moderate to severe AD. Appropriate strength TCSs should be selected for various sites of involvement, and steroid-sparing topicals such as TCIs or PDE4 inhibitors may also be utilized, particularly for facial involvement or other areas in which avoidance of TCSs is desirable or necessary.

The importance of consistent and liberal moisturizer use must also be emphasized to the patient. We recommend a detailed regimen for when the AD is flaring and a precise plan and regimen for maintenance once the flare-up improves, so that patients and families know how best to keep the AD controlled.

Once the appropriate topical regimen is established, some children with AD still do not achieve clearance or satisfactory control. In such cases, consideration of staph colonization or other secondary infection should be considered, and measures such as diluted bleach baths may be considered. When moderate to severe AD proves to be refractory to an aggressive topical approach, systemic medications and/or phototherapy may be considered as next steps in therapy.

Dermatology Advisor: What are other key considerations for clinicians treating these patients?

Dr Johnson: If a patient seems to be treatment-resistant, consider external factors such as treatment compliance, incorrect use of prescribed therapies, and hypersensitivity reactions to components of topical treatments, and evaluate the patient for concomitant allergic contact dermatitis, skin infections, and other environmental triggers. If none of these seem to be contributing factors to treatment resistance, consider other AD mimickers. In addition, serial biopsies may be necessary to rule out cutaneous T-cell lymphoma (CTCL).

Dr Fernandez: It is important for clinicians to consider allergic contact dermatitis as a contributing component to the severity of the patient’s disease. Patients with AD have an increased propensity for developing allergies to products they use, even those they may have tolerated without problems for years. Considering allergic contact dermatitis, especially in patients who suddenly develop moderate to severe disease that was previously relatively well-controlled, can be critical to the future control of their disease. When we are suspicious about the presence of allergic contact dermatitis, we consider evaluating for contact allergies with comprehensive patch testing. Sometimes patch test results and subsequent avoidance of detected allergens are all the patient needs to regain excellent control of their disease.

In addition, it is important to remember to keep the amounts of bacteria on the skin controlled. Clinicians can sometimes be fooled into only prescribing immunosuppressive agents due to their knowledge that AD is a chronic inflammatory disease. But it is known that the impaired skin barrier can lead to overgrowth of commensal bacteria, especially Staphylococcus aureus. Overabundance of bacteria then stimulates an inflammatory response and drives increased cutaneous inflammation. Keeping bacterial levels in the skin relatively low with products like chlorhexidine 4% washes a few times a week can considerably lessen the amount of inflammation and severity of AD. This, in turn, can help minimize medication dosages or the need for systemic immunosuppressive agents.