Bullous pemphigoid and pemphigus vulgarisBMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2169 (Published 08 June 2017) Cite this as: BMJ 2017;357:j2169
- 1Lancashire Teaching Hospitals NHS Foundation Trust, Royal Preston Hospital, Fulwood, Preston PR2 9HT, UK
- 2St Helens and Knowsley Teaching Hospitals NHS Trust, St Helens WA9 3DA, UK
- Corresponding author: A Aslam
What you need to know
Bullous pemphigoid and pemphigus vulgaris are diseases of an ageing population
Both are associated with high morbidity and mortality, with the commonest cause of death being opportunistic infections from prolonged immunosuppression
Topical and systemic corticosteroids are first line treatment for most patients
Steroid-sparing regimens are used where steroid treatment fails or if there are adverse effects
Non-specialists have important roles in both early detection and ongoing management of these diseases because of their chronic nature and the systemic effects of treatment
Autoimmune bullous diseases are characterised by blistering of the skin or mucous membranes.1 Blisters form due to the antibodies against structural skin components. The two most common bullous diseases are bullous pemphigoid and pemphigus vulgaris. Most of our epidemiological data comes from European studies. Estimates of the incidence of bullous pemphigoid range from 2.8 per 100 000 person years in the US2 to 4.28 per 100 000 person years in the UK3 most commonly presenting in people over 80 years old. Pemphigus vulgaris is rarer and its geographic distribution more variable: whereas in Israel the incidence has been estimated at 5.3 per 100 000 person years, in the UK it was only 0.7.4
To the generalist these may seem to be niche diseases and are often overlooked or misdiagnosed, leading to poor patient outcomes. Because of their chronic nature, high morbidity and mortality, and the systemic effects from treatment, affected people require intensive management. In the past few decades great strides have been made in understanding these diseases but and the development of novel treatments, however these treatments themselves are associated with substantial disease burden. This article highlights the pathophysiology, investigations, and management of bullous pemphigoid and pemphigus vulgaris.
What causes bullous pemphigoid and pemphigus vulgaris?
The aetiology of bullous pemphigoid and pemphigus vulgaris is poorly understood. Possible triggers for bullous pemphigoid include trauma as well as administration of drugs such as furosemide, non-steroidal anti-inflammatory drugs (NSAIDs), or antimicrobials.5 Recently, an association with neurological conditions such as multiple sclerosis, dementia, and parkinsonism has also been demonstrated in case-control studies.6
There is some evidence to suggest that the incidence of pemphigus vulgaris has a genetic component as there is variation between ethnic groups, with a higher prevalence having been reported in Ashkenazi Jews and in those of Mediterranean descent.7
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, which are responsible for dermal-epidermal adhesion (fig 1). The subsequent inflammatory response associated with eosinophil infiltration results in dermal-epidermal splitting.8
In pemphigus vulgaris, autoantibodies are directed against proteins desmoglein 1 and 3 (fig 1) that are involved in the function of desmosomes (cellular structures responsible for intercellular adhesion). Subsequent dysfunction of the desmosomes causes loss of cell adhesion in the epidermis, leading to intraepidermal lesions.9
How do pemphigus vulgaris and bullous pemphigoid present?
The peak age of presentation for patients with bullous pemphigoid is over 80 years, and it is rarely seen in those under 50 years old. Patients with bullous pemphigoid may complain of highly pruritic lesions initially. These lesions may last for several weeks to months, and often the lesions mimic eczema, delaying the diagnosis. In some patients, the disease may not progress beyond this stage.
Patients with pemphigus vulgaris tend to be aged between 40 and 60 years. They may complain of painful swallowing, oral pain, sore throat, or hoarseness, and they often first present to a dentist or oral surgeon.1
These two diseases are both characterised by blister-like skin lesions (bullae), which are tense in bullous pemphigoid and flaccid in pemphigus vulgaris. Figure 2 highlights the differentiating features on examination.
How is the diagnosis confirmed?
No formal diagnostic criteria exist for either of these diseases. Instead the diagnosis is confirmed by the combination of clinical findings, direct immunofluorescence, and, on occasion, autoantibody testing. Direct immunofluorescence involving a perilesional biopsy taken from around 1 cm from the lesion is currently the gold standard for diagnosis of both bullous pemphigoid and pemphigus vulgaris (fig 3).10
Refer patients urgentlyto a dermatologist if you suspect a diagnosis of bullous pemphigoid or pemphigus vulgaris and consider contacting your local dermatology department by telephone if a patient presents with widespread disease. Although histology can support the diagnosis, it does not provide a definitive diagnosis. Serum ELISA kits, though not widely available in the UK, may become more common because of their high sensitivity, possible correlation with disease activity, and prognostic value.1112
How are bullous pemphigoid and pemphigus vulgaris managed?
Autoimmune bullous diseases are best managed by a dermatologist in secondary care. The British Association of Dermatologists (BAD) produced guidelines for the management of bullous pemphigoid in 2012.13 The European Dermatology Forum also produced two separate guides in 2015 for the management of bullous pemphigoid and pemphigus vulgaris, but the evidence base for treatment of pemphigus vulgaris is less established, reflecting its rarity.14
Advise patients who have bullous pemphigoid secondary to a particular drug to stop the suspected agent as this can reduce the risk of relapse.15
In both conditions, the mainstay of treatment has been systemic or topical steroids, supported by strong evidence. The first studies to show benefit from steroids in treating bullous pemphigoid were undertaken in the 1950s, though these were uncontrolled. Later randomised controlled trials and meta-analyses confirmed their effectiveness.16 In one multicentre randomised controlled trial, 341 newly diagnosed patients with bullous pemphigoid received either systemic or topical steroids. In both groups over 90% of patients achieved disease control at 21 days.17 However, as these treatments may be associated with considerable adverse effects, the focus of attention has now moved towards steroid-sparing drugs and biological therapies. Box 1 outlines practical considerations before starting treatment with steroids.
Practical considerations before starting treatment with corticosteroids
Baseline blood tests, including full blood count, urea and electrolytes, and liver function tests
A proton pump inhibitor for gastric protection
Osteoporosis baseline screening and bone protection
Mycobacterium tuberculosis screening in high risk populations because of the risk of reactivation of latent tuberculosis
The aim of treatment 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 two weeks of treatment. This is followed by a consolidation phase, when the optimum dose of the medication should be continued until most lesions have healed. During the maintenance period, medication doses are titrated down to a level sufficient to prevent disease recurrence with minimal side effects. In a few cases, it may be possible to stop treatment altogether if disease remission occurs, although the risk of relapse remains.
Serum antibody testing may be useful at this stage (for antibodies to BP 180 and BP 230 in bullous pemphigoid and antidesmoglein 3 in pemphigus vulgaris) when considering stopping treatment, as immunological remission has been reported to be associated closely with clinical remission.18
The use of both topical and systemic corticosteroids is supported by a strong evidence base, including a recent Cochrane review.16 In general, steroid creams such as clobetasol propionate are used first when disease is confined to a small area, as they have similar efficacy to systemic steroids.17 They are applied directly to the lesions and may be associated with cutaneous side effects, including the formation of striae and skin atrophy. In more widespread disease, application over the whole body is advised, excluding the face. However, the practical considerations of applying a cream in this way may limit this approach.19
Where disease is more widespread systemic treatment is preferred and effective.20 Usually oral prednisolone is preferred. Use of systemic steroids is limited by immunosuppressive and metabolic effects, which can lead to diabetes, osteoporosis, severe infections, and ischaemic heart disease. As these side effects are dose dependant, it is important to achieve remission with the lowest possible dose.
Prednisolone 0.75-1.0 mg/kg is effective in most patients within two to four weeks of initiation. At this point, the dose of steroid can be reduced. If, at four weeks, new lesions are still forming then an adjunct (see below) should be considered. Adjuvants may also be considered if the steroids are poorly tolerated.
Antibiotics and nicotinamide
Tetracycline antibiotics have long been used in the treatment of bullous pemphigoid and pemphigus vulgaris because of their anti-inflammatory effect, with little evidence to support their use until recently. In 2017 in a multicentre trial with 278 patients, after six weeks of treatment, doxycycline was shown to be non-inferior to oral prednisolone. Furthermore, the group treated with doxycycline had a lower incidence of adverse effects.21 Tetracyclines may therefore offer an alternative first line treatment in bullous pemphigoid: for example, in patients with pre-existing diabetes or hypertension. Trials on a similar scale have not looked at tetracycline use in pemphigus vulgaris, and no guidelines for pemphigus vulgaris routinely recommend using antibiotics. The current British Association of Dermatologists guidelines for the management of pemphigus vulgaris are from 2003, and an update is in progress.
Nicotinamide (also known as niacinamide or nicotinic acid amide) is the water soluble, active form of vitamin B3, 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 three times a day.
For pemphigus vulgaris, immunosuppressants such as azathioprine, mycophenolate, dapsone, methotrexate, chlorambucil, and cyclophosphamide are often used off-label in conjunction with steroids for their steroid-sparing effect as first line treatment.2223 However, in a Cochrane review, there was no clear benefit from using combination therapy of corticosteroid and immunosuppressive agents compared with corticosteroid alone.24 In bullous pemphigoid these agents are used as second line therapy after treatment with steroids has failed or the side effects were not tolerated. There is no conclusive evidence of superiority of any one of these agents over another. Adverse effects differ between drugs but can include myelosuppression and hepatotoxicity, and so full blood count and liver function need to be monitored.
Useful information and support is available for patients (box 2)
Information resources for patients
International Pemphigus and Pemphigoid Foundation (www.pemphigus.org/)—Provides free and up to date information about blistering diseases as well as hosting an online chat
Pemphigus Vulgaris Network (http://pemphigus.org.uk/)—A similar support group for the UK
PEM Friends (http://pemfriends.co.uk/)—UK based support organisation, affiliated with the International Pemphigus and Pemphigoid Foundation
What newer treatments are available?
Recent research has focused on the use of use of biological therapies in the treatment of bullous pemphigoid and pemphigus vulgaris, as in other autoimmune conditions. Several randomised controlled trials have demonstrated the effectiveness of the monoclonal antibody rituximab in comparison with steroids in both diseases. Currently no formal consensus exists on which patients would qualify for treatment, but rituximab may be used as an adjunct to corticosteroids or equally potent as a monotherapy.2526 The main side effects are infection, neutropenia, and increased risk of thromboembolic disease.
Intravenous immunoglobulins, plasmapheresis, and immunoadsorption are novel therapies that are reserved for patients with more severe disease where rapid control is required or other therapies have failed.27 While their use has not been studied as extensively as the other treatments available, 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 often self limiting but may last from months to years.8 During its active stage, bullous pemphigoid can lead to considerable morbidity, and older age and use of high dose steroids have been identified as risk factors for increased mortality.28
Before the introduction of corticosteroids, pemphigus vulgaris was also almost universally fatal, but there has been a subsequent decline in mortality.2930 Though the duration of disease duration varies, pemphigus vulgaris is thought to have a more chronic course than bullous pemphigoid, with few patients achieving complete remission.
Sources and selection criteria
We searched PubMed using keywords “bullous pemphigoid” and “pemphigus vulgaris”, targeting recent studies and review articles in the past 10 years. We consulted the British Association of Dermatology guidelines as well as the European Society of Dermatology and Venereology guidelines. In appraising the strength of the evidence, we referred to the Cochrane Library.
Education into practice
Would you consider autoimmune diseases when confronted with a blistering rash?
When should the generalist refer urgently to a dermatology clinic?
What is the role for shared care between specialists and GPs for long term stable patients on systemic immunosuppressant therapy?
How the non-specialist can help
Refer patients with widespread blistering suspected of having bullous pemphigoid or pemphigus vulgaris urgently to the dermatologist. Consider calling your local dermatology department to discuss the possibility of hospital admission
After discussion with a dermatologist, be prepared to initiate oral corticosteroids in those strongly suspected to have either bullous pemphigoid or pemphigus vulgaris while awaiting a formal review
Prescribe adequate quantities of potent topical corticosteroids on an ongoing basis for those with limited skin disease. Their use in extensive disease may be limited by practical factors (such as ability of patient or availability of carer to apply the treatment), and they may be associated with systemic absorption and adverse events
Monitor patients taking oral corticosteroids long term for side effects by checking weight, blood pressure, and urine dipstick (for glucose) and review the risks of bone density loss
Report any adverse events to the dermatologist where appropriate and any process for reporting adverse drug reactions (such as the MHRA yellow card scheme)
Ensure compatibility with other concomitant medication and highlight any systemic medication on the patient’s electronic medical record in order to avoid any drug interactions
Ensure patients taking immunosuppressants are offered annual flu vaccination and a once-only pneumoccoal vaccination
Ensure female patients taking immunosuppressants are up to date with their cervical screening
How patients were involved with the creation of this article
No patients were involved in the creation of this article.
Contributors: MK and AMA both contributed to the concept and design of the review. MK created the first draft and AMA revised the content and approved the final version to be published. Both authors act as guarantors
Competing interests: We have read and understood the BMJ Group policy on declaration of interests and we have nothing to declare.
Provenance and peer review: Not commissioned; externally peer reviewed.