Clinical Challenges: Is Recalcitrant Atopic Dermatitis Really Comorbid Disease?

— Dupilumab failure signals the need for extended patch testing to identify a missed diagnosis

by
Kristin Jenkins, Contributing Writer, MedPage Today
November 8, 2023

Recent evidence indicates that a significant percentage of patients with recalcitrant eczematous dermatitis, including those dubbed “treatment-resistant” to dupilumab (Dupixent), may be living with a missed diagnosis of concurrent disease. In the era of targeted therapy, this can have a significant impact on the course of disease and patient quality of life.

The features of atopic dermatitis can mimic, mask, or complicate other inflammatory skin conditions, as well as genetic, immunodeficiency and nutritional diseases; skin infections; infestations; drug eruptions; and malignancy. These conditions and diseases must be excluded before a diagnosis of atopic dermatitis can be confirmed, states the American Academy of Dermatology in its current guidelines for the diagnosis and assessment of atopic dermatitis.

“Up to 20% of patients with atopic dermatitis are misdiagnosed, delaying the onset of care, sometimes for years, leading to increased disease severity and poor quality of life,” said Jonathan Silverberg, MD, PhD, MPH, of George Washington University School of Medicine and Health Sciences in Washington, D.C.

The list of medical conditions that can masquerade as or be masked by atopic dermatitis includes allergic contact dermatitis (ACD), psoriasis, Netherton syndrome, seborrheic dermatitis, scabies, dermatitis herpetiformis, nonbullous pemphigoid, polymorphous light eruption, cutaneous lupus and mixed connective tissue disease, and cutaneous T-cell lymphoma, among others.

“It can be a challenge,” Silverberg acknowledged. “If you see predominantly children, the differential diagnosis is pretty straightforward, but in adults, even those with long-standing disease, the clinical scenario is fraught with misdiagnosis.”

Jenny Murase, MD, of the University of California San Francisco, told MedPage Today that “a differential diagnosis should be considered when there is incomplete response [to dupilumab] or your patient doesn’t say, ‘I’m 80% better’ — because he or she should be.”

“I’ve never seen classic atopic dermatitis fail on dupilumab,” she said. “There’s always been something about the case that’s been unusual in terms of distribution, a systemic contact or a hypersensitivity reaction. It has a different look to it, not like eczema in an adult diagnosed as a child, who has had asthma and hay fever since they were little.”

A retrospective analysis published in the Journal of the American Academy of Dermatology on 233 patients treated with dupilumab for moderate-to-severe atopic dermatitis bears this out.

In 50 patients identified as having an “incomplete” response to dupilumab — defined as less than 80% improvement in the total body surface area affected after 3 to 6 months of therapy — 100% had concomitant conditions or entirely different diagnoses. Diagnosis was delayed by an average of 12.8 months in 38 patients. All told, 18 patients were diagnosed with comorbid ACD and an additional alternative condition, including polymorphous light eruption, cutaneous lupus and mixed connective tissue disease, parapsoriasis or psoriasis, tinea, scabies, Netherton syndrome, and diffuse urticarial and eczematous eruption associated with systemic inflammation.

“Patients diagnosed with atopic dermatitis who fail to respond or respond incompletely to dupilumab should be evaluated for concomitant conditions that may be responsible for residual dermatoses,” the researchers concluded. “Early identification may improve clearance rate, resulting in faster resolution.”

Separately, a subgroup analysis in Dermatitis on 112 patients showed that initiation of treatment prior to patch testing was common. Seventeen patients were started on dupilumab before expanded series patch testing (ESPT) and another 20 were treated with no diagnostic testing.

Notably, a systematic, stepwise approach to the management of recalcitrant atopic dermatitis was shown to be highly effective, clearing disease in 90% of patients. The treatment algorithm, known as CPAT (clear, patch, avoid, treat) includes an initial “soak and smear” routine — consisting of a 20-minute warm-water bath, followed by a 3:1 ratio of moisturizing cream and a mid- to high-strength topical cortisone ointment applied from the neck down — followed by ESPT, 3 to 6 months of allergen avoidance, and finally, treatment.

In 66 patients who underwent just the first three steps of CPAT, 72.7% reported 30% to 60% improvement after an average of 14.8 weeks. In nine patients, 88.9% reported that soak and smear, ESPT, and allergen avoidance alone was sufficient to improve symptoms by 60% or more and that no treatment was required. In patients who also underwent treatment, disease clearance was 80.9% after 11 weeks of dupilumab, and rose to 90.3% after an average of 16.5 months. CPAT also decreased the time it took to diagnose comorbid ACD, from 15 months to 3 months.

ESPT is critical for patients with recalcitrant eczematous dermatoses, said Murase, who has seen upwards of 5,800 patients referred by other dermatologists and allergists. “Under-recognition of the fact that the diagnosis is often multifactorial in an eczematous patient is really concerning to me. One of the things I use most often in my office is my tissue box because patients are so miserable when they come in. Many are just sobbing.”

Murase begins the initial patient visit by talking about the differential diagnosis, and lists the tests needed to clarify diagnosis. Then she discusses therapeutic options. “I think the tendency is to throw a steroid at it, but that doesn’t get to the root of the problem. CPAT is the most effective approach to recalcitrant atopic dermatitis, and delivers the fastest results.”

To refer patients to a local provider of ESPT, Murase recommends the “find a provider” section of the American Contact Dermatitis Society website.