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An 81 year old man with a blistering rash

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f522 (Published 31 January 2013) Cite this as: BMJ 2013;346:f522

This article has a correction. Please see:

  1. Sophie Noel, foundation year 2 trainee,
  2. Janet Dua, specialist registrar,
  3. Ghazia Kaushal, consultant
  1. 1Department of Dermatology, Royal Berkshire Hospital, Reading RG1 5AN, UK
  1. Correspondence to: J Dua Janetdua3000{at}yahoo.co.uk

An 81 year old man presented with a 10 day history of an extensive blistering rash that was profoundly itchy. He had a history of hypothyroidism and a deep vein thrombosis. He was receiving carbimazole and warfarin and denied any recent changes in medication.

On examination he had more than 100 blisters over his whole body, although his face was spared (fig 1). Some of the blisters formed a circinate pattern. Nikolsky’s sign was negative. The mucous membranes were not affected.

Figure1

Fig 1 Rash on patient’s torso

Blood tests including full blood count, urea and electrolytes, and liver function tests were within normal ranges. He had a C reactive protein of 28.8 mg/L (reference range 0-4.9; 1 mg/L=9.52 nmol/L).

Questions

  • 1 What are the possible causes of this man’s blisters?

  • 2 Which investigations would you do to confirm your diagnosis?

  • 3 What comorbidities are associated with this condition?

  • 4 What is the best treatment for this condition?

Answers

1 What are the possible causes of this man’s blisters?

Short answer

The main differential diagnoses are bullous pemphigoid, linear IgA disease, and epidermolysis bullosa acquisita.1 This patient had bullous pemphigoid, the most common autoimmune subepidermal blistering disorder. It mainly affects older patients and presents with tense fluid filled blisters that can appear anywhere on the body, including the mucous membranes. It typically occurs over the limbs, groin, and abdomen.1 2

Long answer

Differential diagnoses for skin blistering disorders include bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, and a bullous drug reaction.1 Localised blisters, particularly those on the feet, may be caused by infections such as bullous tinea pedis. Superficial pemphigus vulgaris can usually be discounted because it rarely leaves more than erosions.3

Linear IgA disease typically produces symmetrical annular collections of papules and bullae on the extensor surfaces.2 It is a rare autoimmune condition. Linear depositions of IgA are seen along the basement membrane zone on direct immunofluorescence.4 It affects men and women equally and most commonly occurs in people over 70 years of age.2

Another differential diagnosis is the rare autoimmune disorder epidermolysis bullosa acquisita.5 Around 50% of cases present in a similar manner to bullous pemphigoid, so it is difficult to tell the two conditions apart.6 However epidermolysis bullosa acquisita is much more rare, making it a much less likely diagnosis.1 Clinical features that may help point to a diagnosis of epidermolysis bullosa acquisita include presence at sites of trauma and healing with scarring and milia formation.7

This case is a classic presentation of the most common autoimmune subepidermal blistering disorder: bullous pemphigoid.1 2

To help narrow down the diagnosis, four criteria have been shown to be strongly associated with bullous pemphigoid. These are age over 70 years, non-atrophic scars, fewer (or no) bullae on the head and neck, and no mucosal involvement.1 6

Bullous pemphigoid typically affects older people. In people over 80 years, the incidence is 150-180 patients per year per one million. Patients over 90 years have almost a 300-fold higher risk of developing the condition than those aged 60.8

A typical history will include pruritus, which can take a protracted course. This phase is known as the non-bullous phase and rarely it remains the only expression of bullous pemphigoid.9 During this phase some patients present with an eczematous rash. In others bullous pemphigoid presents as urticated or papular lesions. Urticated lesions are the second most common clinical presentation of bullous pemphigoid and are often dismissed as an allergic urticarial reaction.10

In the bullous stage, multiple tense vesicles and bullae can arise in combination with urticated or eczematous papules and plaques. Blisters develop predominantly on the limbs, groin, and abdomen on normal or erythematous skin. They are filled with clear or occasionally blood stained fluid (fig 1).1 5 These classic bullae are absent in superficial pemphigus vulgaris. Sometimes they form annular or figurate patterns. Bullous pemphigoid affects the mucous membranes in around half of patients1 and can occasionally be localised, with cases reported around stoma sites and at sites of irradiation.11 12

Autoantibodies target “adhesion complexes” in the skin’s basement membrane: BP230 and BP180 antigens. This leads to disordered adhesion within the subepidermis and subsequent blister formation.1

The incidence of bullous pemphigoid has been reported as 6-7 cases per year per one million population8 13 to 42.8 cases per year per one million population.3 Incidence is thought to be rising, although the reason for this is not clear.3

Bullous pemphigoid is potentially fatal, with a one year mortality rate after initiation of treatment of 19-41% in Europe.14 A common cause of death is septicaemia as a result of immunosuppression caused by high dose steroids and loss of the skin’s natural barrier to infection. Other factors include illnesses associated with comorbidities and advanced age.15 In addition, patients can have serious protein loss, and serum albumin should be monitored closely. Referral to a dietitian may be considered.16 The reported rate of relapse is high. One prospective multicentre cohort study of 118 patients reported a 53% relapse rate within the first year of stopping treatment. High titre anti-BP180 enzyme linked immunosorbent assay (ELISA) scores and, to a lesser degree, a positive finding on direct immunofluorescence microscopy are good indicators of relapse.17

2 Which investigations would you do to confirm your diagnosis?

Short answer

Diagnosis of bullous pemphigoid is based on clinical presentation. It is confirmed by histology and direct and indirect immunofluorescence.1 5

Long answer

Diagnosis of bullous pemphigoid is based on clinical presentation, biopsy, and direct and indirect immunofluorescence.1 C reactive protein and erythrocyte sedimentation rate are often raised.

Biopsy of new blisters shows subepidermal clefts (fig 2) containing eosinophil-rich inflammatory infiltrates (fig 3).

Figure2

Fig 2 Subepidermal blister seen in our patient (haematoxylin and eosin stain; original magnification ×25)

Figure3

Fig 3 Eosinophil-rich infiltrate (arrows) seen within the blister (haematoxylin and eosin stain; original magnification ×200)

Direct immunofluorescence is performed on biopsies of perilesional skin.1 It shows linear deposits of both IgG and C3 along the basement membrane.

Serum or blister fluid can be used in indirect immunofluorescence. This typically shows circulating IgG and C3, which binds in a linear fashion to the basement membrane. Less commonly IgE, IgM, and IgA are also found.1

Traditionally, bullous pemphigoid and epidermolysis bullosa acquisita have been distinguished by indirect immunofluorescence on sodium split skin. Bullous pemphigoid autoantibodies are typically found on the epidermis, whereas epidermolysis bullosa acquisita autoantibodies bind to the dermis. A recent study showed that epidermal binding correlated well with a diagnosis of bullous pemphigoid, but dermal binding was not conclusive for epidermolysis bullosa acquisita. The authors suggested that when in doubt immunoblotting analysis should be used to confirm the diagnosis.5

A retrospective study has shown that a positive result on direct immunofluorescence has the highest sensitivity (90.5%) for bullous pemphigoid histology, whereas a positive result on indirect immunofluorescence has the highest specificity (99%). A combination of clinical data and one positive immunopathological test provides the best combination of sensitivity and specificity (98%).18

A few centres offer ELISA, which analyses serum IgG autoantibodies using recombinant proteins encoded by BP180 and BP230. A recent meta-analysis of 17 studies showed that ELISAs for anti-BP180 had a pooled sensitivity of 0.87 (95% confidence interval 0.85 to 0.89) and a pooled specificity of 0.98 (0.98 to 0.99).19

Medical photography can help document the course of the disease.

3 What comorbidities are associated with this condition?

Short answer

Bullous pemphigoid is mainly associated with conditions of ageing: Parkinson’s disease, cerebrovascular disease,20 and some neurological disorders.6 Bullous pemphigoid often coexists with other autoimmune disorders, but studies have shown there is no significant association.21 Drugs such as diuretics and neuroleptics have been found to be more commonly used in patients with bullous pemphigoid.22

Long answer

Diseases typically associated with old age such as cerebrovascular disease and Parkinson’s disease are more common in patients with bullous pemphigoid.20 Neurological disorders, such as epilepsy and schizophrenia, are associated with a higher rate of bullous pemphigoid, as are skin disease, specifically psoriasis.6

Bullous pemphigoid has been reported to coexist with other autoimmune disorders. A case-control study found that although this was not uncommon, there was no direct link between the two.23

The increased rate of cancer in patients with bullous pemphigoid is thought to be coincidental and to reflect the increased prevalence of the two conditions in old age.23 It has been suggested that there may be an association with cancer in people with atypical presentations, such as onset in middle age, and the presence of cancer should investigated in such patients.24

Certain drugs, such as diuretics and neuroleptics, have been associated with the development of bullous pemphigoid.22 There have also been several case reports of patients taking furosemide and developing the condition.1 21

4 What is the best treatment for this condition?

Short answer

Mild, moderate, or localised bullous pemphigoid may be treated with highly potent topical steroids. Tetracyclines used alone or in combination with nicotinamide can be useful in mild to moderate disease. Oral steroids are the mainstay of treatment for moderate to severe disease. Immunosuppressants should be considered in severe or unresponsive disease.1 25

Long answer

Treatment has changed considerably over the past decade.26 Management should be based on the extent of the disease and the comorbidities present. Treatment can be split into topical and systemic therapy.

Highly potent topical steroids (clobetasol propionate) are recommended, particularly in mild, moderate, and localised disease.25 One large case-control study also highlighted the role of potent topical corticosteroids in controlling generalised disease as effectively as oral corticosteroids, with increased survival rates and fewer severe side effects.27

The gold standard treatment is oral corticosteroids. The dose is tapered gradually over six to nine months. The British Association of Dermatologists’ guidance recommends varying doses for mild and localised disease (0.3 mg/kg/day), moderate disease (0.5 mg/kg/day), and severe (0.75 mg to 1 g/kg/day) disease.1 A recent Cochrane review showed that doses of more than 0.75 mg/kg/day are associated with a greater incidence of side effects and no improvement in outcome.25

Tetracycline antibiotics (minocycline or tetracycline) alone, or combined with nicotinamide, are useful first line agents in mild to moderate disease. This may spare some patients from immunosuppressant therapy and has shown some benefit in small studies.25 In moderate disease, tetracyclines combined with prednisolone may have a steroid sparing action. One multicentre controlled non-inferiority trial is currently recruiting patients to determine whether doxycycline is as effective and safe as prednisolone.28

Immunosuppressants such as azathioprine, mycophenolate mofetil, methotrexate, and, rarely, chlorambucil, cyclophosphamide, and ciclosporin should be considered when disease is not controlled by corticosteroids alone, or if corticosteroids are contraindicated. Recommendations for patients with severe bullous pemphigoid and psoriasis state that methotrexate should be considered.1

Dapsone is also a beneficial corticosteroid sparing agent, especially in mucous membrane pemphigoid, where it can be combined with corticosteroids.26

Other treatments that case reports have deemed successful include topical tacrolimus, intravenous immunoglobulin, anti-CD20 monoclonal antibody, and anti-IgE monoclonal antibody.25 28 29

Skin care should include the use of regular antiseptic soaks such as potassium permanganate or aluminium acetate solution to dry eroded areas and to reduce the risk of infection. Non-adhesive dressings may prevent clothing from adhering to eroded areas of skin. Blisters should be left intact to prevent the risk of secondary bacterial infection. However, if they interfere with function, they can be pierced with a sterile needle to drain the fluid; the roof of the blister should be left intact.1 Given the propensity towards infection it is prudent to swab lesions for culture.

An important aspect of good clinical management of bullous pemphigoid is regular medical observation, so that problems that influence further morbidity or mortality can be detected early and prevented.

Patient outcome

Our patient was started on prednisolone at a dose of 0.5 mg/kg. He improved clinically and was blister free after two weeks. He is currently on a slowly tapering dose of prednisolone and remains well.

Notes

Cite this as: BMJ 2013;346: f522

Footnotes

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References