Updates in Autoimmune Blistering Disease: Established and Emerging Therapies

Dr. Cory Simpson presented information about the autoimmune blistering diseases pemphigus and pemphigoid, including their pathogenesis, varied clinical presentations, diagnostic work-up, and available and emerging treatment options.

Cory Simpson, MD/PhD, is an associate professor in the Department of Dermatology at the University of Washington. He created Simpson Lab in 2021.

First, Simpson described the pathogenesis and clinical presentation of pemphigus and pemphigoid. Both are autoimmune diseases caused by the immune system attacking certain proteins present in the skin and mucous membranes. In pemphigus, the targeted antibodies are desmoglein proteins, which are essential to hold epidermal keratinocytes together; in pemphigoid, the targeted antibodies anchor keratinocytes to their foundation called the basement membrane at the dermal-epidermal junction. 

Pemphigus vulgaris (PV) typically presents with skin blisters and mucosal erosions, most often in the mouth. The blisters may not last long because they easily rupture from normal body movements or rubbing of clothing, leaving behind crusted erosions. PV usually affects the oral cavity first, so patients may have initially seen a dentist, oral surgeon, or otolaryngologist (ENT), but often struggle to get a clear diagnosis due to the rarity of this disorder. 

Simpson also described the clinical presentation of other subtypes of pemphigus, including vegetative PV and pemphigus foliaceus. Vegetative PV presents with thickened adherent scaling and crusting overlying painful erosions that are often in body-folds. Pemphigus foliaceus (PF) often affects the scalp, face, and upper trunk; its blistering is more superficial, and it does not affect the mucous membranes, but it can cause widespread skin redness and peeling, termed exfoliative erythroderma. Given their overlap in appearance and distribution, dermatologists should consider PF in patients thought to have recalcitrant or severe seborrheic dermatitis. 

Pemphigoid more often appears with intact fluid-filled blisters along with erosions where blisters have rupture. Simpson pointed out that the pigmentary changes left behind after blisters heal can take months to years to resolve and can be quite disturbing to patients. While it mostly causes skin blistering, oral erosions may be present in bullous pemphigoid (BP); dermatologists should ask patients about oral symptoms, pain with swallowing, and look in their mouths, as they may not always report oral issues. Urticarial pemphigoid presents without blisters, but rather with hive-like lesions. Dermatologists should consider urticarial pemphigoid in older patients with new onset urticaria, especially if not responding to typical antihistamines. 

The rare mucous membrane pemphigoid (MMP) subtype primarily affects mucosal surfaces instead of the skin, including the linings of the eyes, nose, mouth, throat, larynx, and anogenital regions. Simpson encouraged dermatologists to ask patients about pain with swallowing, urination, defecation, and sexual activity. Patients do not usually mention these symptoms because they are not aware of their association with skin disease. 

Dermatologists should make sure these mucosal structures are not involved. In ocular pemphigoid, the disease targets the eyes and can cause blindness, requiring aggressive treatment to prevent scarring. Simpson always asks pemphigoid patients about eye symptoms and refers patients for annual visits to an ophthalmologist to monitor for early signs of ocular disease.

Drug-induced pemphigus and pemphigoid occur as new-onset or disease exacerbation most often caused by diuretics or antihypertensives, but newer drugs including immune checkpoint inhibitors (cancer treatment) and dipeptidyl peptidase-4 inhibitors (diabetes treatment), have more recently been implicated.

Second, Simpson discussed the diagnostic workup for suspected autoimmune blistering diseases. Pemphigoid mimickers include tinea, scabies, and insect bites, which should be ruled out. A diagnosis of pemphigus or pemphigoid requires a biopsy and ≥1 immunologic test, including direct immunofluorescence (DIF), indirect immunofluorescence (IIF), or enzyme-linked immunosorbent assay (ELISA). 

A biopsy will help to differentiate between pemphigus and pemphigoid; adding DIF, IIF, and ELISA can confirm the diagnosis and subtype. Salt-split skin IIF helps differentiate between rare subtypes of pemphigoid that may have serious comorbidities and even malignancy risk. Recently, the Mayo Clinic and other specialty labs have developed a new test to distinguish rare subtypes of pemphigoid. 

Third, Simpson described available and emerging treatment options for pemphigus and pemphigoid. The traditional treatment approach involves short-term prednisone to control disease while steroid-sparing agents begin to work. Dermatologists should also test for latent infections, including HIV, hepatitis B, hepatitis C, and tuberculosis before beginning immunosuppressive treatment. Rituximab is FDA-approved as first-line treatment for pemphigus; up to 90% of patients can achieve remission. Rituximab has superior sustained clinical remission and reduction in steroid use compared with mycophenolate but may have increased side effects, mostly infections. For patients who are allergic to rituximab, humanized monoclonal antibodies like ocrelizumab (anti-CD20) can be used off label. 

Typical treatment options for pemphigoid include mycophenolate and methotrexate, but dupilumab was recently FDA-approved. Methotrexate can be used in patients with mild impairment of kidney function with close monitoring of blood counts as well as liver and kidney function. A recent trial of dupilumab for pemphigoid showed positive results for some patients; Simpson predicts dupilumab will be most effective for patients with milder disease but is a good first-line therapy due its safety. Rituximab works less well for pemphigoid and should be used with caution in older patients. Non-immunosuppressive therapies include doxycycline, dapsone, and IV immunoglobulin. Topical steroids can be a useful adjunctive therapy but can be challenging for older patients to apply with widespread disease. 

Additional agents under investigation include cellular therapies targeting regulatory T cells and biologics such as omalizumab (anti-immunoglobulin E), bertilimumab (anti-Eotaxin-1), lebrikizumab (anti-interleukin 13), and Janus kinase (JAK) inhibitors. There is limited evidence to support the use of these agents for pemphigus or pemphigoid, but they offer potential options for challenging cases. 

Finally, Simpson emphasized that autoimmune blistering disorders are managed by a multidisciplinary team, including ophthalmologists, dentists, periodontists, oral surgeons, ENTs, gastroenterologists, pulmonologists, urologists, and gynecologists. As well, Simpson always refers patients to the International Pemphigus and Pemphigoid Foundation (www.pemphigus.org) for community and peer support.

Mark your calendar: The DF Clinical Symposium returns January 27–31, 2027.