Some dermatologists might be inclined to simply refer patients with blistering skin diseases, which are relatively rare, to an expert center, but they should not waive the effort to reach a diagnosis before referral, according to Donna Culton, MD, PhD, who said that new urgency has been created by more effective therapies that work better when started early.

As a practical matter, a referral for a workup as opposed to a referral for therapy is likely to delay the time to therapy, said Culton, professor of dermatology at the University of North Carolina at Chapel Hill, speaking at Maui Derm Hawaii 2026.

Whether treatment is initiated by the clinician making the diagnosis or by the expert center once the patient is referred, clinical management will be set in motion more quickly, she explained. When referred, patients with a diagnosis are more likely to be given a timely appointment, meaning faster time to therapy.

Referrals With a Diagnosis Might Get Seen Quicker

“It is just easier to squeeze in a patient if you already have the diagnosis,” said Culton, referring to how triage often functions at many expert centers.

The heterogenous clinical presentations of the many variants of pemphigus and pemphigoid can be confusing, Culton acknowledged, but she said there is a reliable pathway to a definitive diagnosis. Once one of these blistering diseases is included among suspected etiologies, direct immunofluorescence (DIF) provides a definitive diagnosis in most cases.

This is particularly helpful in atypical cases. While a diagnosis of pemphigus or pemphigoid is often reached efficiently on the basis of the clinical examination, along with a biopsy and hematoxylin and eosin staining in patients with a classic presentation, DIF will work even in atypical variants, she said. These are common.

As examples, she said that acanthosis, although characteristic of pemphigus, is not present or cannot be detected in all patients. Tense itchy bullae are characteristic of pemphigoid, but non-bullous pemphigoid is not uncommon. In either case, DIF can help make the diagnosis when in doubt.

Because of the wide clinical disparities across the many atypical variants, “it is important to keep in mind that pemphigus that does not look like pemphigus can still be pemphigus,” said Culton, who made the same point about pemphigoid. She suggested that perhaps her most important clinical tip for accelerating the time to treatment and diagnosis is to consider these blistering diseases, even when the puzzle pieces do not fit together, and then order a DIF to rule the diseases in or out.

The reason to increase the pressure on early diagnosis, Culton said, is that there are now targeted therapies for both pemphigus, which is a B-cell mediated disease that involves autoantibodies binding around keratinocytes on the epidermal side of the intraepidermal split, and pemphigoid, which is associated with far greater inflammation now understood to be driven by type 2 inflammatory cytokines, such as interleukin-4 (IL-4) and IL-13.

Relative to the nonspecific anti-inflammatory drugs that have been used first-line for decades in both diseases, the anti-CD20 monoclonal antibody rituximab is now widely regarded as the first-line therapy in patients with moderate to severe pemphigus. When approved in 2018 by the FDA, it became the first treatment with an approved indication for this blistering disorder.

Dupilumab Now Used First-Line for Pemphigoid

Dupilumab, a monoclonal antibody that inhibits interleukin IL-4 and IL-13 signaling, was approved by the FDA for pemphigoid in 2025; it was the first treatment and remains the only one with an approved indication for this disease. Culton reported that it has been moving up in the treatment algorithm, particularly for patients with comorbidities that complicate treatment with other options. When members of the US Immunobullous Disease Consortium were surveyed, 67% reported that they now use dupilumab first-line, and the proportion rose to 87% in patients with comorbidities, according to Culton.

A 2021 randomized trial that favored rituximab over mycophenolate mofetil was influential in moving it forward in the treatment of pemphigus, Culton said. But she cited a study showing that early treatment (started within 6 months of symptom onset) vs delayed treatment (started later than 6 months) provided a numerically higher rate of complete remission off therapy (92.9% vs 66.6%; P = .047), statistically significant faster median time to remission (3.0 vs 8.1 months; P < .001), and longer median duration of remission (17.5 vs 8.8 months; P = .006).

Several recent studies, including one published in 2025, suggested that a lower dose of rituximab, such as 100 mg or 500 mg, might be just as effective as the standard 1000-mg dose, but Culton expressed caution. She noted that some studies suggest a faster time to relapse with a low dose, even if this question is not yet fully settled.

“I think the full dose gives us the best chance at long-term control, but we will see,” she said.

Culton warned that the pemphigus response to rituximab depends on both B-cell depletion and death of plasmablasts, a process that takes about 2 months, so benefit is not seen immediately. Conversely, relapse rates begin climbing as B cells begin repletion about 6 months after treatment, even if some patients go on to have a durable response.

Like rituximab for pemphigus, dupilumab offers greater efficacy if initiated early, according to Culton, who noted that the highly targeted effect of this drug on key cytokines that drive this disease provides the rationale for prompt therapy.

However, she pointed out that pemphigoid can be drug-induced, so immune modulation might not always be necessary.

In particular, she pointed out that gliptin-class antidiabetic drugs, such as sitagliptin, is a known cause of pemphigoid that can be reversed simply by switching patients to an alternative therapy. This is not as easy for pemphigoid induced by immune checkpoint inhibitors.

Pemphigus and pemphigoid are rare, and Culton said some dermatologists will only see a few cases in their career. Yet these devastating diseases can now be controlled at a level that was rarely achieved with nonspecific immunomodulators. Therefore, Culton called on those on the frontlines of dermatologic care to consider these diseases even when clinical findings are atypical.

The concept that dermatologists outside of academic centers should consider and pursue the diagnosis of pemphigus and pemphigoid, rather than refer cases, was seconded by Jonas Adalsteinsson, MD, PhD, a dermatologist specializing in autoimmune blistering diseases in the department of dermatology, Icahn School of Medicine at Mount Sinai, New York City.

Referring to Culton’s major points, such as the importance of early diagnosis to accelerate the time to the effective treatments that are now available, “I totally agree,” said Adalsteinsson, senior author of a recent review article on the diagnosis of bullous pemphigoid in the Journal of the American Academy of Dermatology. 

“I would like to add that I think both ELISA and IIF [indirect immunofluorescence] are underused,” he told Medscape Medical News. ELISA is helpful to track disease severity and to screen elderly patients with itch,” he said, whereas IFF is helpful for visualizing the characteristic intraepidermal split.

Colton reported financial relationships with Argenx, Cabaletta, Incyte, Janssen, Lilly, Novartis, Pfizer, Priovant, Regeneron, Sanofi, and Sitala. Adalsteinsson reported no potential conflicts of interest.