Summary
Autoimmune blistering diseases are characterized by the formation of skin or mucous membrane blisters. The blisters are due to the action of antibodies against the structural components of the skin. The two most common blistering diseases are bullous pemphigoid and pemphigus vulgaris. Most epidemiological data arise from European studies. The incidence of pemphigoid is estimated to range from 2.8 per 100,000 person-years in the US to 4.28 per 100,000 person-years in the UK, occurring most commonly in people >80 years of age. Pemphigus vulgaris is rarer and its geographical distribution more variable: while in Israel, the incidence is estimated to be 5.3 per 100,000 person-years, in the United Kingdom it was only 0.7. To the general practitioner these diseases may seem niche and are often overlooked or misdiagnosed, leading to poor patient outcomes. Due to its chronic nature, high morbidity and mortality, and systemic effects of treatment, affected individuals require intensive management. In recent decades, great advances have been made in the understanding of these diseases and the development of new treatments, however, these are associated with a substantial disease burden.
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► What causes bullous pemphigoid and pemphigus vulgaris?
The etiology of bullous pemphigoid and pemphigus vulgaris is poorly understood. Possible triggers for bullous pemphigoid are trauma as well as the administration of drugs such as furosemide, non-steroidal anti-inflammatory drugs or antimicrobials. Recently, an association with neurological disorders such as multiple sclerosis, dementia and parkinsonism has also been demonstrated in case-control studies.
There is some evidence to suggest that the incidence of pemphigus vulgaris has a genetic component, as there are variants between ethnic groups, with a higher prevalence in Ashkenazi Jews and those descended from the Mediterranean area.
► What is the pathophysiology of pemphigus vulgaris and bullous pemphigoid?
In bullous pemphigoid, antibodies are directed against two basement membrane antigens, BP 180 and BP 230, responsible for dermal-epidermal adhesion. The subsequent inflammatory response associated with eosinophil infiltration results in dermal-epidermal separation. In pemphigus vulgaris, autoantibodies are directed against the proteins desmoglein 1 and 3 that participate in the function of desmosomes (cellular structures responsible for intercellular adhesion). Subsequent dysfunction of desmosomes causes loss of cell adhesion in the epidermis causing intraepidermal lesions.
► How do pemphigus vulgaris and bullous pemphigoid present?
They are associated with high morbidity and mortality; the most common cause of death is opportunistic infections due to prolonged immunosuppression.
The maximum age of presentation for patients with pemphigoid is >80 years, and it is rarely seen in people <50 years. Patients with bullous pemphigoid may initially have highly pruritic lesions. These injuries can last several weeks to months; Often, the lesions mimic eczema, delaying diagnosis. In some patients, the disease does not progress beyond this stage. Patients with pemphigus vulgaris tend to be between 40 and 60 years old. They may complain of odynophagia, oral pain, sore throat or hoarseness, and often consult the dentist or oral surgeon first.
These two diseases are characterized by skin with bullae lesions (bullae), which are tight in bullous pemphigoid and flaccid in pemphigus vulgaris.
What you need to know • Bullous pemphigoid and pemphigus vulgaris are diseases of the elderly • Both are associated with high morbidity and mortality, with the most common cause of death being opportunistic infections due to prolonged immunosuppression. • First-line treatments for most patients are topical and systemic corticosteroids. • Steroid-sparing regimens are used when steroid treatment fails or if there are adverse effects. • Non-specialists have an important role in both the early detection and ongoing management of these diseases due to the nature and systemic effects of the treatment. |
►How is the diagnosis confirmed?
There are no formal diagnostic criteria for any of these diseases. Instead, the diagnosis is confirmed by the combination of findings, direct immunofluorescence, and sometimes autoantibody testing. Currently, the gold standard for the diagnosis of both pemphigoid and pemphigus vulgaris is direct immunofluorescence with perilesional biopsy taken about 1 cm from the lesion.
Patients with a presumptive diagnosis of bullous pemphigoid or pemphigus vulgaris should be urgently referred to a dermatologist and, if the patient presents with generalized disease, consider contacting their local dermatology department by telephone. Although histology can support the diagnosis, it does not provide a definitive diagnosis. Serum ELISA kits may be more sensitive due to their correlation with disease activity and prognostic value.
► How are bullous pemphigoid and pemphigus vulgaris managed?
Autoimmune blistering diseases are best managed by a dermatologist in secondary care. In 2012, the British Association of Dermatologists produced guidelines for the management of bullous pemphigoid. In 2015, the European Dermatology Forum also produced 2 separate guidelines for the management of bullous pemphigoid and pemphigus vulgaris, but the evidence base for the treatment of pemphigus vulgaris is less established, reflecting its rarity.
It is recommended that patients with bullous pemphigoid secondary to medication discontinue the suspected agent as this may reduce the risk of relapse.
In both conditions, the mainstay of treatment has been the use of topical or systemic steroids, based on strong evidence. The first study demonstrating the benefit of steroids in the treatment of pemphigoid was carried out in the 1950s, although without control. Subsequent randomized controlled trials and meta-analyses confirmed its effectiveness.
In a multicenter randomized controlled study, 341 patients newly diagnosed with bullous pemphigoid received systemic or topical steroids. In both groups, at 21 days, more than 90% of the patients achieved disease control. However, as these treatments can be associated with considerable adverse effects, the focus is now directed towards steroid-sparing drugs and during biological therapies.
Practical considerations before starting corticosteroid treatment • Baseline blood tests, including complete blood count, urea and electrolytes, and liver function tests • Indicate a proton pump inhibitor for gastric protection • Assess baseline osteoporosis and bone protection • Detection of Mycobacterium tuberculosis in high-risk populations due to the risk of reactivation of latent tuberculosis. |
The therapeutic goal is to suppress disease activity to the point where new lesions stop forming and existing lesions begin to heal. Typically, the disease begins to improve after 2 weeks of treatment. This is followed by a consolidation phase, when the optimal dose of medication should be continued until the majority of the lesions have healed. During the maintenance period, medication doses are reduced to a level sufficient for disease recurrence to occur with minimal side effects. In some cases, if the disease subsides it may be possible to stop treatment completely, although the risk of relapse remains.
When considering the optimal treatment, at this stage antibody testing may be useful (against BP 180 and BP 230 for bullous pemphigoid and antidesmoglein 3 for pemphigus vulgaris), since immunological remission has been closely related to clinical remission.
► Topical corticosteroids
The use of topical and systemic corticosteroids is based on strong evidence, including a recent Cochrane review. In general, steroid creams such as clobetasol propionate are the first choice when the disease is limited to a small area, as their effectiveness is similar to that of systemic steroids.
They are applied directly to lesions and can be associated with cutaneous side effects, such as the formation of stretch marks and skin atrophy. In the most generalized disease, application on the entire body, excluding the face, is recommended. However, considerations for applying a cream in this way may limit this approach.
► Systemic corticosteroids
When the disease is more widespread, systemic treatment is preferable as it is more effective. Oral prednisolone is usually preferred. The use of systemic steroids is limited by immunosuppression and metabolic effects that can lead to diabetes, osteoporosis, serious infections, and ischemic heart disease. As these side effects are dose dependent, it is important to achieve remission with the lowest possible dose.
Prednisolone 0.75-1.0 mg/kg is effective in most patients within 2 to 4 weeks of initiation. At this point, the steroid dose may be reduced. If new lesions continue to form after 4 weeks then an adjunct should be considered. If steroids are poorly tolerated, adjuvants may also be considered.
► Antibiotics and nicotinamide
Tetracycline antibiotics have long been used in the treatment of bullous pemphigoid and pemphigus vulgaris due to their anti-inflammatory effect, with little evidence to support their use until recently. But in 2017, a multicenter trial with 278 patients showed that treatment with doxycycline for 6 weeks was noninferior to oral prednisolone. On the other hand, the group treated with doxycycline had a lower incidence of adverse effects.
Tetracyclines may therefore offer an alternative as a first-line treatment for bullous pemphigoid: for example, in patients with pre-existing diabetes or hypertension. Trials on a similar scale have not aimed to look at the action of tetracycline in pemphigus vulgaris and there are no guidelines for pemphigus vulgaris that recommend routine use of antibiotics. The current British Association of Dermatologists guideline for the management of pemphigus vulgaris is from 2003, but an update is underway.
Nicotinamide (also known as niacinamide or nicotinic acid amide) is the active form of vitamin B3, soluble in water, and its anti-inflammatory properties are used for the treatment of blistering diseases. It is always combined with a tetracycline and the dose is 500 mg, 3 times/day.
► Immunosuppressants
For pemphigus vulgaris, immunosuppressants such as azathioprine, mycophenolate, dapsone, methotrexate, chlorambucil, and cyclophosphamide are often used off-label in combination with steroids due to their steroid-sparing effect. However, a Cochrane review found no clear benefit of combined therapy of corticosteroids and immunosuppressive agents compared with corticosteroids.
In bullous pemphigoid, these agents used as second-line therapy after steroid treatment failed or were not tolerated because of their side effects. There is no conclusive evidence of the superiority of any of these agents over another. Adverse effects differ between drugs and include myelosuppression and hepatotoxicity, so monitoring complete blood count and liver function is necessary.
► What are the newest treatments available?
Recent research has focused on the use of biological therapies for the treatment of bullous pemphigoid and pemphigus vulgaris, as well as other autoimmune diseases. Several patients randomized in controlled trials have demonstrated the efficacy of the monoclonal antibody rituximab compared to steroids for the treatment of both diseases.
There is currently no formal consensus on which patients would qualify for treatment, but rituximab can be used as an adjunct to corticosteroids, although it is equally potent as monotherapy. The main side effects are infection, neutropenia, and an increased risk of thromboembolic disease.
Intravenous immunoglobulins, plasmapheresis, and immunoadsorption are newer therapies that are reserved for patients with more severe disease in whom rapid management is required or in whom other therapies have failed. Although their use has not been studied as extensively as other available treatments, they may play an increasing role in the management of blistering diseases in the future.
► What is the prognosis of bullous pemphigoid and pemphigus vulgaris?
Bullous pemphigoid is usually self-limiting but can last months to years. During its active phase, bullous pemphigoid can cause considerable morbidity. Older age and high doses of steroids have been identified as risk factors for increased mortality. Before the introduction of corticosteroids, pemphigus vulgaris was also almost universally fatal, but mortality has subsequently decreased. Although the duration of the disease varies, pemphigus vulgaris is believed to follow a more chronic course than bullous pemphigoid, with few patients achieving complete remission.
