- Bullous pemphigoid is an autoimmune blistering disease characterized by autoantibodies against basement membrane zone proteins.
- Bullous pemphigoid generally presents in elderly patients as urticarial plaques and tense bullae, with eosinophilic spongiosis, edema, and subepidermal blister formation on biopsy.
- Bullous pemphigoid often requires systemic immunosuppression to adequately control the disease, usually with corticosteroids followed by a steroid-sparing agent; chronic, longterm treatment is generally required.
Bullous pemphigoid (BP) 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. BP 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 certain other autoimmune blistering conditions (such as pemphigus vulgaris (PV) and pemphigus foliaceus [PF]).
BP may initially present with pruritic urticarial plaques without bulla. Pruritus is a common feature at all stages of the disease. Classic BP 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 BP.
Cicatricial pemphigoid, or “scarring” pemphigoid, may present without tense blisters, more frequently involving the head and neck, and may have a different antigenic target. Cicatricial pemphigoid patients have higher rates of mucosal involvement, and assessing for ocular disease is essential. Patients with pemphigoid affecting the eye warrant rapid evaluation and very aggressive systemic management.
The diagnosis of BP is generally made based on the clinical finding of urticarial plaques and tense bullae, supplemented by histologic features. Skin biopsy will reveal eosinophilic spongiosis, or edema between the keratinocytes. The eosinophils may be found in the epidermis itself, between keratinocytes, or lining up at the dermal/epidermal junction. When there is a blister cavity it will be subepidermal, with basal keratinocytes lifted up, and eosinophils are often seen within the serous fluid of the blister cavity. Direct immunofluorescence may be performed by biopsying uninvolved (non-blistered, non-urticarial, clinically non-inflamed skin) perilesional skin with special processing, wherein pathologists can identify antibodies along the dermal/epidermal junction. Often a linear band of IgG and C3 will be seen. Indirect immunofluorescence can be performed to identify circulating autoantibodies in the patients’ serum. Finally, enzyme linked immunoabsorbent assays (ELISA) are available to confirm the presence of specific antibodies (BP180 and BP230) which can confirm the diagnosis of BP.
The etiopathogenesis of BP is due to IgG autoantibodies binding to epidermal antigenic targets and activating inflammatory cascades, including fixing complement, which attracts inflammatory cells and 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 BP.
Clinically, BP should be distinguished from other autoimmune blistering diseases. 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 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 (DIF) (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 to distinguish from BP, and clinicians should remain alert to the possibility.
While BP is generally idiopathic, there exist forms of drug-induced BP, and careful review of the patient’s medication history and exposures is important. The most common medications include psoralen+UVA phototherapy, antibiotics (penicillins, cephalosporins, and quinolones), loop diuretics, and penicillamine. Other causes of pruritus should be excluded, particularly other blistering diseases (pemphigus, epidermolysis bullosa acquisita). Notably, scabies infestation can present with both urticarial and bullous lesions, and biopsy specimens can reveal eosinophilic spongiosis. Scabies is relatively common, particularly among the elderly, as they may be exposed to both hospitals and nursing home settings, and consideration should be given to whether patients with presumed BP may in fact have an arthropod infestation.
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 (tetracycline-class antibiotics, dapsone, intravenous immunoglobulins) or in some cases high potency topical steroids may adequately control the disease (clobetasol). Rituximab treatment has shown great promise in BP and can induce remission in some patients. Patients with ocular pemphigoid warrant early, aggressive treatment (often with cyclophosphamide or rituximab).
Allergic contact dermatitis
Porphyria cutanea tarda
First-line therapy: Most patients require systemic corticosteroids for adequate disease control (prednisone). In settings where that is contraindicated, non-immunosuppressive anti-inflammatory treatment may be attempted (tetracycline, nicotinamide), or aggressive topical therapy (high potency topical steroids, twice daily, sometimes with occlusion). If there is severe ocular involvement, more aggressive therapy is indicated first-line (cyclophosphamide, rituximab).
- Systemic prednisone (0.5-1 mg/kg; severe disease may require higher dosages) with slow, gradual taper.
- Supplement with spot-treatment of new lesions with high potency topical corticosteroids (short course of clobetasol 0.05% to individual lesions on extremities).
- 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 (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.
- 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.
- Patients may rarely have drug-induced bullous pemphigoid, and careful evaluation of medication history is essential.
- Scabies infestation may mimic BP and clinicians should consider ruling out an arthropod infestation.
- Epidermolysis bullosa acquisita (EBA) can be challenging to distinguish from BP; patients with suspected BP who are treatment refractory should undergo further testing (usually salt-split skin immunofluorescence) to exclude EBA.
- Patients with ocular disease warrant early aggressive therapy and should be referred to an ophthalmologist; potent systemic therapy should be initiated immediately (usually cyclophosphamide or rituximab) as blindness is a risk.
- Patients with BP will generally require prolonged therapy, which can mean chronic immunosuppression. Patients should carefully be evaluated for comorbid conditions and undergo age appropriate evaluation (malignancy, vaccinations) and monitoring for treatment related side effects.
- 68-year-old man
- No significant past medical history
- Review of systems reveals no systemic complaints, including no joint pain, fevers, arthritis, eye symptoms, or recent illness
- Social history is unremarkable
- Presents for evaluation of diffuse pruritic eruption, which started on his thighs and abdomen 2-3 months prior and then progressed to involve his trunk and proximal extremities. Blisters started appearing 1-2 weeks prior to presentation
- Healthy appearing male
- Diffuse urticarial patches on the trunk, abdomen, and proximal extremities
- Numerous tense intact bullae and scattered erosions with some dried adherent serous crust
Diagnosis: Bullous pemphigoid
- If dermatology consultation is available, given presence of bulla and the widespread nature of the disease, consider referral to dermatology
- Initially, testing should include both biopsy of a representative skin lesion for confirmation and a biopsy of perilesional normal appearing skin for immunofluorescence
- Perform a thorough history including any recent medications or exposures (such as visits to a nursing home, wherein patient could have been exposed to scabies)
- Perform routine blood work in anticipation of initiating systemic immunosuppression
- Conduct age appropriate screening and ensure he is up to date with vaccinations; plan to closely follow the patient for medication-induced side effects
- Initiate treatment with either systemic corticosteroids or, while waiting the biopsy results, start with high potency topical corticosteroids
- The biopsy demonstrates eosinophils at the basement membrane with epidermal spongiosis adjacent to a subepidermal blister filled with eosinophils; this is consistent with bullous pemphigoid
- The immunofluorescence studies show IgG and C3 at the dermal/epidermal junction consistent with bullous pemphigoid
- The patient reports no improvement with topical corticosteroids
- Initiate therapy with systemic corticosteroids (prednisone, 1 mg/kg) with plan for close follow-up and likely a steroid-sparing immunosuppressive agent (such as mycophenolate mofetil)
- If the patient fails to respond, consider sending ELISA testing to confirm the presence of bullous pemphigoid pathogenic antibodies, or consider salt-split skin to exclude epidermolysis bullosa acquisita
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