Observation

Dupilumab is a human monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 signaling, thereby suppressing type 2 (Th2) inflammation. It is approved by the U.S. Food and Drug Administration for the treatment of moderate-to-severe atopic dermatitis (AD) and has been demonstrated in clinical trials to rapidly improve disease severity, pruritus, and inflammatory biomarkers.1,2 Despite its efficacy, patients with eczematous dermatoses who appear to exhibit “treatment failure” with dupilumab frequently have alternative or concomitant drivers of disease activity, most commonly allergic contact dermatitis (ACD). Given the broad differential diagnosis of AD, conditions such as parapsoriasis, psoriasis, polymorphous light eruption, cutaneous lupus erythematosus and mixed connective tissue disease, or cutaneous T-cell lymphoma (CTCL) must also be considered in these cases.3 Recent literature highlights the importance of comprehensive diagnostic evaluation in refractory cases, as additional investigations including expanded patch testing, biopsy, direct immunofluorescence, skin scrapings, and serologic studies may reveal these alternative or coexisting diagnoses.4 Further, to address cases of apparent nonresponse, the Clear, Patch, Avoid, Treat (CPAT) framework has been proposed. This stepwise approach begins with skin clearance through the “soak-and-smear” method, followed by patch testing and allergen avoidance for at least three months, with escalation to systemic treatment in the event of persistent disease activity.1

To further illustrate the clinical application of these strategies, we present the case of a patient initially labeled as a “dupilumab failure” with presumed “topical steroid withdrawal (TSW),” who achieved disease stabilization through appropriate diagnostic evaluation, targeted interventions, and re-initiation of both topical steroids through a soak and smear regimen followed by dupilumab therapy.

Case Report

A 32-year-old woman with a lifelong history of atopic dermatitis presented with a widespread dermatitis that had dramatically worsened in recent years. She presented with diffuse erythroderma and severe skin pain, describing a burning and “zapping” of her skin throughout the day with disabling pruritus rated as a 10 on the numerical rating scale (NRS). She had a history of asthma, multiple methicillin-resistant Staphylococcus aureus (MRSA) infections, and a strong personal belief that she was experiencing TSW. Her skin condition was so severe she had stopped working as a neonatal intensive care nurse for two years and was eventually bed bound for most of the day in pain. She had not used topical steroid or topical calcineurin inhibitor therapy due to concerns that the topical therapies seemed to “make her skin so much worse.”

Prior systemic therapies included 5 months of dupilumab which “worked initially then stopped working,” that was reinitiated for 10 months three years later; the JAK inhibitors upadacitinib for 20 months and abrocitinib for 2 months, mycophenolate mofetil for 3 months, methotrexate for 16 months, multiple rounds of systemic intramuscular and oral steroids, lebrikizumab for 3 months, narrowband UVB therapy for 7 months (which was noted to make her skin sensitive and painful), and multiple topical therapies including topical steroids and topical calcineurin inhibitors. At the time of initial presentation, she was off all therapy given she felt that nothing that she had used in the past was able to achieve long term remission.

Past diagnostic testing noted a reaction to bacitracin and neomycin in the True test, a positive ANA with a homogenous nucleolar pattern of 1:320 with anti-RNP 2.9 three years prior, a positive ANA 1:1280 and anti-RNP four years prior, and two past biopsies reporting subacute spongiotic dermatitis. The patient did report photosensitivity with extended sun exposure on the face, neck and arms and had been avoiding the sun. A rheumatologic evaluation was performed, and it was felt that the patient did not meet diagnostic criteria for connective tissue disease.

Diagnostic Testing

In view of the refractory and debilitating nature of this patient’s disease, a comprehensive diagnostic evaluation was undertaken. This included expanded patch testing, bacterial cultures, autoimmune serologies, and skin biopsies including direct immunofluorescence. Because of the patient’s conviction regarding TSW, additional laboratory assessments included morning cortisol. Due to the recurrence of skin infection, vitamin D levels were assessed given anti-microbial peptides on the surface of the skin are dependent on vitamin D.

Given evidence from both pediatric and adult cohorts demonstrating that previously unrecognized dietary or topical exposures may underlie cases of treatment-resistant AD, patch testing and allergen avoidance were prioritized.5,6 Patch testing with the North American Contact Dermatitis Society screening series and four additional expanded series trays (Corticosteroid, Emulsifier/External Agents, Fragrance and Sunscreen trays through Allergeaze ®) revealed multiple clinically relevant contact allergies to ingredients contained in the patient’s daily topical products. Allergies to a cleanser (Neo Green) and toner (Thayer) the patient used 3-5 times daily were identified, as well as fragrance mix (the patient used multiple fragranced products), potassium dichromate, and cobalt. The patient was switched off all products that contained fragrance after these allergens were identified.

Bacterial cultures confirmed MRSA colonization, consistent with prior culture results. Although the patient had previously received a few previous 2–3-week courses of doxycycline for treatment of MRSA and Group B Streptococcus, she had never performed a decolonization protocol.

Therapeutic Trials

A two-phase approach was implemented for management of this severe, recalcitrant case. Initially, a rescue regimen consisting of bleach baths followed by the soak-and-smear method with desoximetasone ointment mixed in an over-the-counter emollient was implemented. This was prescribed twice daily for one week, followed by once daily for one week, and then three times weekly.

Decolonization measures were concurrently instituted, beginning with a short course of rifampin 600 mg daily, followed by one month of doxycycline 100 mg daily, in combination with adjunctive measures including chlorhexidine gluconate oral rinse and intranasal mupirocin twice daily for 2 weeks. During this time, environmental interventions included laundering linens every three days and regularly disinfecting household surfaces with diluted bleach. Additionally, topical ruxolitinib cream was prescribed for facial involvement. Together, these measures achieved disease stabilization.

After completing the decolonization regimen to remove the bacterial component of the dermatitis flare and completing patch testing to remove the allergenic component of the dermatitis flare, dupilumab was reintroduced and resulted in a marked improvement in dermatitis, pruritus, and pain. After 6 months on dupilumab, the anti-IL-31 agent nemolizumab was concomitantly initiated with the dupilumab for 5 months to provide further improvement of the pruritus associated with atopic dermatitis, and this was stopped when the patient became pregnant.7 Her disease was well controlled on dupilumab alone throughout her pregnancy.

Discussion

This case underscores that apparent dupilumab “failure” in patients with chronic, refractory AD often reflects incomplete diagnostic evaluation rather than true therapeutic inefficacy. Concomitant allergic contact dermatitis, microbial colonization or infection, and less common mimickers of AD can obscure treatment outcomes. Pediatric and adult studies alike demonstrate that uncommon contact allergens may masquerade as AD for years, contributing to prolonged morbidity and delayed diagnosis.5,6 Without comprehensive diagnostic assessment or appropriate diagnostic testing for secondary causes such as bacterial, fungal or scabietic infection, patients risk being mislabeled as “treatment resistant,” leading to unnecessary therapeutic cycling or withdrawal of effective agents.

This case also highlights confounding factors in patients who describe TSW with the use of topical therapy. Bacterial infection will worsen with the use of topical steroids due to the local immunosuppression on the skin surface from the effect of the topical steroid; although there may be initial improvement, this immunosuppression allows the bacterial infection to flourish and cause worsening of the underlying skin disease. Similarly, those with allergy to elements of the topical steroid, including propylene glycol or the topical steroid molecule, will notice initial improvement with application given the anti-inflammatory effect of the medication, followed by a flare as the allergic reaction from the medication ensues. Therefore, flaring resulting from both overgrowth of bacteria or reactions to allergens in topical steroids clinically mimic the clinical pattern seen when patients describe TSW.

Furthermore, therapies dismissed as ineffective in one clinical context may demonstrate robust efficacy once confounding factors are identified and addressed. This case highlights the critical importance of diagnostic precision, validation of patient concerns, and persistence with evidence-based therapy. In this patient case of TSW and “dupilumab failure,” the patient was treated with initial topical steroids in a soak and smear regimen followed by dupilumab. The therapies used to treat her successfully such that she was no longer bed bound and stricken with debilitating pain and pruritus were identical to the therapies that had been used in the past. However, it was the identification of the bacterial infection through culture and removal of the bacteria through the decolonization, as well as the identification of and removal of her allergens in her skin care products, that resulted in the improvement of her debilitating erythroderma. The initial failure of the therapeutics was due to the lack of diagnostic testing and not the failure of the therapeutics themselves. Development of standardized diagnostic guidelines for refractory dermatitis is essential to minimize harm, optimize outcomes, and ensure delivery of individualized care.