There is hope on the horizon for this painful and deadly disease that particularly affects older patients.
Bullous pemphigoid is a chronic subepidermal autoimmune blistering skin disease that mostly affecting older people from the age of 70 years.
According to an article published Nature Reviews Disease Primers last month, the number of BP cases is rising due to an ageing population and better tic techniques – although diagnosis is still tricky. The condition is known to be influenced by genetics, environmental factors and other autoimmune diseases.
Co-lead author, Sydney dermatologist Professor Dedee Murrell, head of the Department of Dermatology at St George Hospital and the University of NSW, has had a special interest in BP for many years.
She says many elderly patients – particularly those in nursing homes – could potentially be going undiagnosed as the condition was often mistaken for drug reactions, eczema, hives, unexplained rash and even scabies.
“They don’t think of it until it gets so bad that the blisters come and then people are stuck in nursing homes with itching. They’re just giving them steroids. They’re not investigating them,” says Professor Murrell.
“The itch is terrible and not only is this about quality of life. It leads to infections, horrible blisters and worse. The mortality rate is about 20% in one year with this disease.”
BP is the most common autoimmune blistering disorder and occurs when the body’s immune system mistakenly produces antibodies against specific proteins in the skin, particularly those involved in the attachment between the epidermis and dermis.
The two primary targets of these autoantibodies are BP180 (also called type XVII collagen) and BP230 (a plakin protein). These proteins are crucial for maintaining the adhesion between the epidermis and dermis, which keeps the skin intact and resistant to damage.
“The onset of BP is often insidious, with prodromal non-bullous symptoms, such as pruritus and erythematous, eczematous or urticarial lesions, that precede blister development by months to years,” the authors write in Nature.
“These blisters, filled with clear fluid, can appear anywhere on the body but are most common in the trunk, limbs and flexural areas. Ten to twenty per cent of mucous membranes, mainly in the oral cavity, can additionally be involved.
“BP is distinguished from other subepidermal autoimmune bullous diseases by its chronic course, with periods of exacerbation and remission. Although BP may spontaneously remit, it usually persists for years if untreated.”
WHAT IS KNOWN ABOUT PREVALENCE AND TRENDS
The prevalence and incidence of are not widely studied, and available data are relatively limited. However, some trends and figures have been observed. Australian figures were not provided in the article, although the authors pointed to the rarity of the condition and a variation of prevalence by country.
By way of example, they pointed to Romania, where the prevalence is 1.46 cases per 100,000 population; and the UK, where the prevalence is much higher, at 4.80 cases per 100,000 population.
When it came to incidence, which represents the number of new cases in 100,000 people over one year, studies have shown the country with the lowest incidence is in Finland, at 1.80 cases per 100,000 person-years, and the highest incidence in the UK, with 7.63 cases per 100,000 person-years.
A meta-analysis reported that the cumulative incidence of BP varies widely between 0.12 and 6.60 cases per 100,000 person-years globally. The global average incidence of BP is 0.82 cases per 100,000 person-years.
According to the Australasian Blistering Diseases Foundation, about one to four people per 100,000 individuals per year are diagnosed each year, making BP a rare condition.
In recent decades, the incidence of BP has increased significantly in several countries, including Germany, France, Finland, Israel, and the UK. Several factors likely explain this rise in BP incidence, including ageing populations.
RISK FACTORS AND COMORBIDITIES
Increased risk factors are also believed to play a role in the rising number of BP cases. Conditions like dementia and the use of certain medications such as diuretics, ACE inhibitors and antibiotics are linked to an increased risk of developing BP.
Over time, awareness and diagnostic techniques for BP have also improved, leading to more cases being identified.
“Ageing is the most important risk factor for BP: individuals older than 90 years of age have an almost 300-fold higher risk of developing BP than those who are under 60 years of age,” the authors write.
“Multiple studies indicate a higher prevalence of BP in women than in men, probably owing to the over-representation of women in older age groups.
“Owing to their advanced age, patients with BP have many comorbidities, of which the most frequently reported are cardiovascular diseases, neurological diseases, type 2 diabetes mellitus and venous thromboembolism.
“Epidemiological data show that the concomitant presence of neurological and neurogenerative diseases, such as stroke, multiple sclerosis, Parkinson disease and dementia, increases the risk of developing BP.
“Although some patients with these diseases have autoantibodies to BP180, confirming a causal association between neurological diseases and BP requires further evidence.”
When it comes to malignancies in patients with BP, some studies have reported an elevated risk of haematological malignancies and skin cancers, whereas others have found no association between BP and malignancies.
Numerous medications have been suggested to predispose people to BP; however the authors write that the risk is most evident for dipeptidyl peptidase inhibitors (gliptins), which are used for the treatment of T2DM.
A French study comparing the intake frequency of gliptins in 1787 patients with BP and 225,412 individuals from the general population found that the observed intake of gliptins, particularly vildagliptin, was significantly higher in those with BP (observed-to-expected ratio 4.4; 95% CI 3.5–5.7; p < 0.0001).
Another study involving 82 patients with BP and 328 matched controls demonstrated that gliptin use was associated with a threefold increased risk of BP (adjusted OR 3.2; 95% CI 1.9–5.4), with vildagliptin and linagliptin showing even higher risks.
A population-based study using Korean insurance data also confirmed that gliptin use significantly increased the risk of BP (adjusted OR 1.58; 95% CI 1.25–2.00; p < 0.001), with vildagliptin posing the highest risk, particularly in males.
“Currently, it is not known why particularly vildagliptin and linagliptin carry the highest risk, why there is a long latency of several months or even years between the initiation of gliptin use and the onset of BP, and what the immuno-patho-mechanism is behind gliptin-associated BP,” the authors wrote.
“In some studies, specific immunological or phenotypic properties have been reported in gliptin-associated BP. Although the effect of cessation of gliptin treatment on the clinical outcome of BP is currently not known, replacement of gliptins with other anti-diabetes drugs should be considered, as they do not increase the risk of BP.”
Immune checkpoint inhibitors such as anti-PD1, anti-PDL1 and anti-cytotoxic T lymphocyte antigen 4 therapies, which are used for the treatment of advanced cancer, are an emerging group of medications also predisposing to BP, but more research needs to be done to examine this risk.
BP AND THE MICROBIOME
The relationship between BP and the microbiome is an emerging area of research. The evidence suggests that the microbiome, both in the gut and on the skin, plays an important role in the development and progression of BP.
Alterations in the microbiota, such as reduced microbial diversity in the gut and an increase in harmful bacteria on the skin, may contribute to the disease’s pathogenesis, the authors say.
Research into these microbiome changes could lead to new diagnostic and therapeutic approaches that focus on restoring balance to the microbiome and potentially improving BP outcomes.
“Additionally, dynamic profiling of the gut microbiota in patients with various BP stages showed microbiota shifts that align with disease activity, emphasizing the potential role of microbial changes in BP onset and remission,” the authors write.
“Collectively, these findings highlight the importance of microbiome research in understanding BP with the potential for new diagnostic and therapeutic approaches that target the gut–skin axis.”
DIAGNOSIS
The diagnosis of BP is made through a combination of clinical evaluation, laboratory tests, and specialised procedures. The presentation usually includes:
• Blisters: These are fluid-filled sacs that form beneath the outer skin layer (epidermis). They are often tense and can occur on areas like the abdomen, thighs, groin, or arms.
• Erythema: The skin around the blisters may become red and inflamed.
• Pruritus: BP often causes intense itching before and during the blistering process.
Direct Immunofluorescence (DIF) is a specialised laboratory technique used to identify immune deposits in the skin. A skin biopsy is taken from the affected area and the sample is then treated with a fluorescent antibody that binds to any immune deposits present in the skin. Under a microscope, the doctor can see fluorescent patterns that confirm the presence of IgG antibodies binding to the BMZ, which is characteristic of BP.
This test is critical in confirming the diagnosis of BP because it provides direct evidence of the immune response that causes the disease.
In addition to the skin biopsy and DIF, another diagnostic tool is the detection of autoantibodies in the blood (serum). These autoantibodies specifically target BP180 (type XVII collagen) and BP230 (a plakin protein), which are involved in skin adhesion.
Blood tests are done to check for the presence of IgG autoantibodies. These autoantibodies are often elevated in BP patients and are a hallmark of the disease. The detection of these serum autoantibodies is helpful in confirming BP, especially when the clinical signs and DIF findings are suggestive but not definitive.
TREATMENT
Professor Murrell says one of the biggest challenges to treating the disease currently was that it is limited to supportive care and oral corticosteroids, which are not ideal for frail or elderly patients.
“There are so many horrible side effects. And even if you get on it, you’re on it for four to six weeks at high doses to get the disease under control, and then a minimum of four months to taper down the dose,” she says.
“And then, typically, at least, at least half the patients relapse. Many patients can’t cope with the itch and the weepy wounds, and they get infections and that brings more challenges.”
But the treatment landscape is about to change. Professor Murrell has been involved in the design and conduct of an international trial into the use of dupilumab to treat BP.
The drug is currently listed on the Pharmaceutical Benefits Scheme (PBS) in Australia for the treatment of patients aged 12 years and above with severe atopic dermatitis who have failed to respond to optimally prescribed topical treatments.
“We already know that this is such a safe treatment that’s approved for basically young children, six months and up with bad eczema,” Dr Murrell tells DR.
Dupilumab significantly improved symptoms and disease activity in patients with bullous pemphigoid, according to late-breaking pivotal data presented at the 2025 American Academy of Dermatology’s annual meeting in Florida.
Five times more adults using the monoclonal antibody achieved sustained disease remission at 36 weeks compared to placebo, with significant reductions were also seen in disease severity and itch.
Dupilumab also significantly lowered the use of oral corticosteroids and rescue medications compared to placebo, the pivotal ADEPT phase 2/3 study evaluating the investigational use dupilumab in adults with moderate-to-severe bullous pemphigoid has found.
In the ADEPT study, 106 adults with moderate-to-severe BP were randomized to receive dupilumab 300 mg (n=53) every two weeks after an initial loading dose or placebo (n=53), along with standard-of-care oral corticosteroids (OCS). During treatment, all patients underwent a protocol-defined OCS tapering regimen if control of disease activity was maintained.
Regulatory submissions for the drug are currently under review in both the US and the EU to expand approvals for its use in BP. Dupilumab was previously granted orphan drug designation by the FDA for BP, which applies to investigational medicines intended for the treatment of rare diseases that affect fewer than 200,000 people in the US.
Sanofi, which markets the drug in Australia under the brand name Dupixent, says it can’t reveal when it plans to apply for TGA approval.
“The incidence of BP is increasing along with the increase in life expectancy and attendant chronic neurological diseases and polypharmacy in this population,” the authors conclude.
“Conventional treatments of BP, in particular, corticosteroids and immunosuppressive drugs, are effective but can have considerable adverse effects and increase mortality.
“Available mouse models may be helpful in identifying and targeting key inflammatory molecules and pathways in the pathophysiology of BP.
“It is important to assess in RCTs whether new targeted therapies that are currently being developed, such as dupilumab, omalizumab, IL-17 inhibitors, complement inhibitors, efgartigimod and JAK inhibitors, are effective in patients with BP.”
