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Case Note

Case Note:Pruritic Eruption on the Trunk and Proximal Extremities

History

A 68-year-old male with no significant past medical history presents for management of urticarial plaques and blisters on the trunk, abdomen and proximal extremities.

Initial evaluation

  • Healthy-appearing male
  • Review of systems reveals no systemic complaints, including no joint pain, fevers, arthritis, eye symptoms, or recent illness
  • Social history is unremarkable
    • No recent visits to a nursing home, wherein the patient could have been exposed to scabies
  • Presents for evaluation of diffuse urticarial patches, which started on the thighs and abdomen 2-3 months prior to presentation and then progressed to involve his trunk and proximal extremities
    • Numerous tense, intact bullae and scattered erosions with some dried adherent crust
    • Blisters started appearing 1-2 weeks prior to presentation
  • Image 1
    Image 1

Enter your diagnosis

Diagnosis

  • A diagnosis of bullous pemphigoid is rendered

Initial Treatment

  • Biopsy of representative skin lesion is performed to confirm diagnosis
  • Biopsy of perilesional normal appearing skin is performed for immunofluorescence
  • Routine blood work is performed in anticipation of initiating systemic immunosuppression
  • Patient is referred for age-appropriate screening and it is confirmed that they are up-to-date with vaccinations
  • Patient is initiated on topical corticosteroids whilst awaiting biopsy results

Follow-up evaluation strategy

Follow-up evaluation:

  • The biopsy demonstrated eosinophils at the basement membrane with epidermal spongiosis adjacent to a subepidermal blister filled with eosinophils
    • Consistent with bullous pemphigoid
  • The immunofluorescence studies showed immunoglobin G (IgG) and complement C3 at the dermal/epidermal junction
    • Again, consistent with bullous pemphigoid
  • The patient reported no improvement with topical corticosteroids
  • Therapy with systemic corticosteroids (prednisone, 1 mg/kg) is initiated, with plan for close follow-up and likely a steroid-sparing immunosuppressive agent (such as mycophenolate mofetil)
    • If the patient fails to respond, either enzyme-linked immunosorbent assay (ELISA) testing to confirm the presence of bullous pemphigoid pathogenic antibodies, or salt-split skin to exclude epidermolysis bullosa acquisita can be considered

 
Further recommendations:

  • Patients with mild disease may be treated with tetracycline (with or without nicotinamide) or sometimes with high-potency topical steroids
    • Dapsone and intravenous immunoglobulin are also considerations if systemic immunosuppression is not possible
  • Management of new lesions may be supplemented with spot treatment with high-potency topical corticosteroids
    • Short course of clobetasol 0.05% to individual lesions on extremities

 
Subsequent treatment steps:

  • As was considered in this present case, patients initiated on systemic corticosteroids will often require transition to a steroid-sparing agent
    • The agent should be selected by taking into account patient comorbidities and patient-specific factors (e.g. reliability, compliance, underlying disease)
    • Appropriate steroid-sparing options to initiate in order to taper systemic corticosteroids include: mycophenolate mofetil, azathioprine, and methotrexate
    • Rituximab is very effective in new, emerging data, and clinicians are encouraged to consult the most up-to-date literature

General discussion

Bullous pemphigoid is an uncommon autoimmune blistering disease, which tends to affect elderly patients in or after the fifth decade of life, with an average age of onset of 65. The precise incidence is unknown, with some studies suggesting a rate of approximately 4-5 per 100,000 person-years, with men and women equally affected. Bullous pemphigoid is an autoimmune condition wherein antibodies attack the hemidesmosome, the region of the epidermis where the basement keratinocytes adhere to the basement membrane zone and the underlying dermis. As such, antibodies and inflammation in that region lead to epidermal detachment and a subepidermal blister. Because the entire epidermis is above the antigenic target of the autoantibodies, there is a full layer of epidermis overlying the blister. This leads to 'tense' blisters, which are frequently intact and do not necessarily spontaneously rupture, as can happen in other autoimmune blistering conditions (such as pemphigus vulgaris [PV] and pemphigus foliaceus [PF]).
 

Bullous pemphigoid may initially present with pruritic urticarial plaques without bulla. Pruritus is a common feature at all stages of the disease. Classic bullous pemphigoid presents with urticarial plaques with bullae, usually on the abdomen and proximal thighs, and can involve the rest of the trunk or extend to the extremities as well. Oral involvement is uncommon, with 10-25% of patients having oral erosions due to bullous pemphigoid.
 

The etiopathogenesis of bullous pemphigoid is due to IgG autoantibodies binding to epidermal antigenic targets and activating inflammatory cascades, including fixing complement, which attracts inflammatory cells. The resultant inflammatory response leads to the characteristic subepidermal inflammation, clefting, and bulla formation. The target antigens (BP180 and BP230) are components of the hemidesmosome, which binds the basement keratinocytes to the dermis. Eosinophils are typically present in the affected skin and at the bullae (and urticarial plaques) in patients with bullous pemphigoid.
 

Clinically, bullous pemphigoid should be distinguished from other autoimmune blistering diseases. Epidermolysis bullosa acquisita (EBA) can look very similar to bullous pemphigoid; patients with EBA are more likely to have scarring, milia formation, and be recalcitrant to therapy. Patients with PF will often have transient, fragile, self-rupturing bullae and present with adherent crusts. Patients with PV may have more oral involvement, flaccid bullae, and lack urticarial lesions. Patients with dermatitis herpetiformis may have small vesicles, but they are often so pruritic that the lesions are excoriated crusts and are concentrated on the elbows, knees, and buttocks. Patients with linear immunoglobin A (IgA) bullous dermatosis may have tense bullae and sometimes urticarial lesions; linear IgA can be distinguished by biopsy (neutrophils instead of eosinophils) or direct immunofluorescence (which will show IgA linearly along the basement membrane). Scabies infestation may display characteristic crusting in the web spaces, and patients may be more pruritic at night; however, severe scabies infestation can be a challenge and clinicians should remain alert to the possibility.
 

Treatment is aimed at stopping new blister formation with anti-inflammatory or immunosuppressive agents, preventing secondary infection through open or crusted sores at sites of prior blister formation, and promoting healing of blisters and erosions. Most patients will require long-term or chronic therapy. First-line treatment is generally with immunosuppressive agents to control disease (systemic prednisone), followed by steroid-sparing agents (mycophenolate mofetil, azathioprine, or sometimes methotrexate), depending on the individual patient's comorbid conditions and extent of disease. Some elderly patients or those with contraindications to systemic suppression may be managed with anti-inflammatory agents (e.g. tetracycline-class antibiotics, dapsone, intravenous immunoglobulins), or in some cases high-potency topical steroids (e.g. clobetasol) may adequately control the disease. Rituximab treatment has shown great promise in bullous pemphigoid and can induce remission in some patients. Patients with ocular pemphigoid warrant early, aggressive treatment (often with cyclophosphamide or rituximab).

Further reading

Cozzani E, Gasparini G, Burlando M, et al. Atypical presentations of bullous pemphigoid: clinical and immunopathological aspects. Autoimmun Rev 2015;14:438-45.

Kershenovich R, Hodak E, Mimouni D. Diagnosis and classification of pemphigus and bullous pemphigoid. Autoimmun Rev 2014;13:477-81.

Lo Schiavo A, Ruocco E, Brancaccio G, et al. Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversis. Clin Dermatol 2013;31:391-9.

Ruocco E, Wolf R, Caccavale S, et al. Bullous pemphigoid: associations and management guidelines: facts and controversies. Clin Dermatol 2013;31:400-12.

Schmidt E, Zillikens D. Pemphigoid diseases. Lancet 2013;381:320-32.

Shetty S, Ahmed AR. Treatment of bullous pemphigoid with rituximab: critical analysis of the current literature. J Drugs Dermatol 2013;12:672-7. 

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