When Blisters Don't Look Like Blisters: Diagnosing Pemphigus, Pemphigoid

Autoimmune blistering diseases are among the most diagnostically challenging conditions in dermatology, and not just because they are rare. At Maui Derm NP+PA Summer 2026 in Colorado Springs, Donna Culton, MD, PhD, professor of dermatology and director of the Immunofluorescence Service at the University of North Carolina School of Medicine, led an interactive case-based session titled “Blistering Diseases: What's the Diagnosis?”1 The session addressed conditions that do not frequently present the way textbooks suggest they will.

Chronicity and Oral Involvement as Early Clues

For clinicians encountering a patient with suspected autoimmune blistering disease, Culton emphasized that the clinical picture is often more nuanced than the classic tense blister of bullous pemphigoid or the flaccid erosions of pemphigus vulgaris. Chronicity is a key historical feature, as is the distribution of involvement, particularly oral disease in pemphigus.

"For a pemphigus patient, a lot of times it's the chronicity of the disease, accompanying not only cutaneous features but also, and sometimes only, oral disease, so oral ulcers, sores, erosions, [and] bleeding,” Culton said. “That should tip you off to maybe this [being] pemphigus.”

For pemphigoid, the diagnostic challenge is somewhat different. Clinicians should be aware that many patients experience a prodromal phase that may resemble urticaria, eczematous dermatitis, or prurigo nodularis, none of which immediately suggest a blistering disease. For some patients, this non-bullous phenotype is not a prodrome at all. It is simply how their disease manifests.

While blisters and erosions are the classic hallmarks of autoimmune blistering diseases, lesions may present in highly variable forms, including erythematous, urticarial, prurigo-like, or eczematous manifestations.2 This heterogeneity is a primary reason these diagnoses are missed or delayed.

Culton offered a practical rule of thumb for NPs and PAs working in general dermatology: any patient > 65 years old presenting with a pruritic disorder that is not responding to topical steroids or other first-line treatment should prompt consideration of a non-bullous form of pemphigoid.

The Cases That Stump Clinicians Most

During the meeting, Culton presented 2 cases chosen specifically to illustrate atypical presentations. The first involved a younger-than-expected patient with pemphigus herpetiformis: a clinical variant with an annular morphology that does not resemble the flaccid blisters most clinicians associate with pemphigus.

"It just trips people up because they're not expecting pemphigus in a younger patient, and they're not expecting it to look more classic in the flaccid blisters," Culton said.

The diagnostic stakes here are high. Culton noted that data increasingly support earlier initiation of B cell depletion therapy in pemphigus, with earlier treatment correlating with better odds of achieving clinical remission. A delayed or missed diagnosis translates directly into a delayed start on rituximab and a worse long-term prognosis.

The second common pitfall she addressed involves serological testing. Indirect immunofluorescence and ELISA can return low-titer or negative results even in pathologically confirmed disease, particularly in atypical presentations. Newer forms of pemphigoid, including anti-p200 pemphigoid, do not produce antibodies to BP180 or BP230, the targets of standard ELISA panels. When the serology is negative but the clinical picture fits, Culton said that clinicians should not abandon the diagnosis.

Biopsy Site and Lab Relationship Matter

For NPs and PAs considering how to work up a suspected case before or alongside referral, Culton underscored 2 practical prerequisites: knowing where to biopsy and having a reliable lab capable of processing specimens for direct immunofluorescence. Perilesional tissue, not the lesion itself, is the appropriate site for direct immunofluorescence biopsy, Culton explained.

Referral Thresholds and the Role of Dupilumab

For pemphigus, Culton recommended prompt specialist referral once a diagnosis is biopsy-confirmed, given that rituximab initiation typically requires specialist involvement and that earlier B cell depletion confers a durable benefit.

For pemphigoid, the treatment calculus has shifted considerably following the June 2025 FDA approval of dupilumab (Dupixent), the first targeted therapy to receive approval for bullous pemphigoid and the 8th indication for the biologic in diseases driven by type 2 inflammation.3 Because many NPs and PAs are already experienced prescribers of dupilumab, Culton suggested this approval creates an opportunity for earlier intervention without immediate specialist escalation. Referral becomes most pressing when a patient is failing dupilumab or when the diagnosis remains uncertain.

"A referral is more necessary if the patient is failing [dupilumab]," she said. "[That would be a reason] to prompt a referral to a specialist."

Editor’s note: Reported disclosures for Culton include GENZYME CORPORATION, ARGENX US, and Regeneron Pharmaceuticals.

References

1. Culton D. Blistering Diseases: What's the Diagnosis? – Interactive Format. Session presented at Maui Derm Summer 2026 in Colorado Springs on June 27.

2. van Beek N, Holtsche MM, Atefi I, et al. State-of-the-art diagnosis of autoimmune blistering diseases. Front Immunol. 2024;15:1363032. https://doi.org/10.3389/fimmu.2024.1363032

3. Smith T. FDA Approves Dupilumab (Dupixent) for Bullous Pemphigoid in Adult Patients. HCPLive. Published June 20, 2025. Accessed June 25, 2026. https://www.hcplive.com/view/fda-approves-dupilumab-dupixent-for-bullous-pemphigoid-in-adult-patients