> Table of Contents > Pemphigoid, Bullous
Pemphigoid, Bullous
John P. Fardal, DO
Lisa Clemons, MD
image BASICS
DESCRIPTION
  • Bullous pemphigoid (BP) is a chronic, acquired autoimmune subepidermal blistering skin disorder caused by linear deposition of autoantibodies against the epithelial basal membrane zone.
  • Pruritic, tense, symmetric, localized, widespread bullae, or urticarial plaques
  • Flexural surface (80%), axillary, inguinal folds, and abdomen (20%)
  • Oral lesions develop in 10-20% of cases, rarely affecting mucosae of eyes, nose, pharynx, and anogenital zones.
EPIDEMIOLOGY
  • Most common autoimmune blistering disease
  • Typical between 60 and 80 years old, but juvenile bullous pemphigoid can occur
  • Affects both females and males, possibly with higher incidence in females
  • No association with race or geographic location
Incidence
  • BP incidence increases with age (1).
  • 6 to 13 new cases/million per year
ETIOLOGY AND PATHOPHYSIOLOGY
  • Autoantibodies react against hemidesmosomal proteins: the 230-kDa BP antigen (BPAg1) within basal keratinocytes and 180-kDa (BPAg2 or type XVII collagen) in the basement membrane zone (BMZ).
  • IgG is usually the predominant autoantibody leading to C3 complement activation, recruitment of inflammatory cells, and liberation of proteolytic enzymes that break down the dermoepidermal junction.
  • The noncollagenous 16A domain (NC16A) located at the membrane proximal region of BP180 is considered the major target epitope and is recognized in 80-90% of BP patients.
  • It has recently been shown that IgE antibodies correlate with a severe form of BP, and those who test positive for IgE anti-BP180 antibodies required longer duration for remission and therapy.
Genetics
  • Certain class II antigens of the major histocompatibility complex (MHC) alleles DQB1*0301 predominate in the United States.
  • Expression of this allele on antigen-presenting cells is thought to be involved in the presentation to autoreactive T cells in patients with BP.
  • Molecular mimicry has been proposed as a mechanism by which exogenous agents may trigger the immune response.
RISK FACTORS
  • Advanced age
  • No clear precipitating factors but can be related to infections such as hepatitis B, hepatitis C, Helicobacter pylori, Toxoplasma gondii, cytomegalovirus (CMV)
  • Associated with autoimmune disorders and inflammatory dermatoses like lichen planus, psoriasis, and other forms of bullous disease
  • Increased risk in patients with neurologic disorders such as multiple sclerosis, dementia, stroke, Parkinson disease, and psychiatric disorders
  • Although drug-induced BP is rare, chronic intake of neuroleptics, aldosterone antagonists, furosemide, dopaminergic drugs, opioids, salicylates, NSAIDs, and phenacetin have been associated.
  • Less frequent: trauma, burns, surgical scars, UV radiation, and x-ray therapy
COMMONLY ASSOCIATED CONDITIONS
  • Underlying malignancy can be found in patients with BP, but it may be age related, and the correlation is marginal.
  • Several autoimmune disorders such as rheumatoid arthritis, Hashimoto thyroiditis, dermatomyositis, lupus erythematosus, inflammatory dermatoses-like psoriasis, and lichen planus have been reported but are rare.
image DIAGNOSIS
PHYSICAL EXAM
  • Lesions usually are 1 to 3 cm round or oval, tense blisters localized on either normal or inflamed skin.
  • 80-90% appear in the lower trunk, axilla, and groin, and 10-20% in oral and intertriginous spaces.
  • Blister rupture leads to painful erosions that may become crusted and occasionally invaded by organisms.
  • Fluid is clear but sometimes presents with hemorrhagic exudates.
  • Negative active acantholysis (Nikolsky sign) and no extension of bullae into the surrounding, unblistered skin when vertical pressure is applied to the top of the bulla (Asboe-Hansen sign) support the diagnosis.
DIFFERENTIAL DIAGNOSIS
  • Blistering diseases with antibodies: pemphigus, cicatricial pemphigoid, pemphigoid gestationis, epidermolysis bullosa acquisita, linear IgA dermatosis, dermatitis herpetiformis, bullous erythema multiforme
  • Blistering diseases without antibodies: erythema multiforme, toxic epidermal necrolysis, porphyria, epidermolysis bullosa, allergic contact dermatitis, bullous impetigo, staphylococcal scaled-skin syndrome, friction blisters
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Diagnosis of BP is based on a combination of clinical features, and the key is immunopathologic findings on skin biopsy.
  • Half of patients will have elevated total serum IgE.
  • ˜50% of patients have peripheral blood eosinophilia that does not correlate with serum IgE levels.
  • Diagnosis of atypical and nonbullous variants relies on findings of direct and indirect immunofluorescence from specific circulating antibodies.
  • Considerations
    • BP has a waxing and waning course with spontaneous remission in the absence of treatment.
    • ELISA for the NC16A domain of BP180 is available at some centers, reported sensitivity 82-94%; specificity 93-99.9%
    • Old age and poor general health along with presence of anti-BP180 have been related with poor prognosis.
Diagnostic Procedures/Other
  • Diagnosis is made by skin biopsy with direct immunofluorescence exam.
  • Histopathology: 4-mm punch biopsy from the edge of an intact bulla (perilesional skin). Staining shows subepidermal blister and multiple eosinophils.
  • Immunohistochemistry: Studies have suggested that the detection of C3d deposits at the dermoepidermal junction in formalin-fixed tissue is helpful for the diagnosis and is the most consistent finding.
  • Direct immunofluorescence (DIF): Second 4-mm perilesional punch biopsy will show linear deposition of IgG and/or C3 along BMZ.
  • Serologic studies: Indirect immunofluorescence (IIF) and ELISA are done when DIF is negative, there is a strong suspicion of BP, and when the skin biopsy cannot be performed. Both detect circulating IgG antibodies against 230BP (specificity 96%) and 180BP (specificity 90%).
image TREATMENT
GENERAL MEASURES
  • Discontinue trigger factors.
  • In oral lesions: Avoid hard consistency, spicy, and hot food. Soft and liquid meals should be given instead.
  • Strict control of wounds to avoid complications.
MEDICATION
First Line
  • Primary objectives are to control the skin eruption and minimize serious side effects of treatments, particularly in the elderly (2)[C].
  • Potent topical corticosteroids are considered first line.
    • Topical clobetasol propionate 0.05% cream: 40 g/day used twice daily, noted to be as effective as 0.5 mg/kg prednisone (3)[B]
    • Side effects: skin atrophy, striae, hypertrichosis, acne, and ecchymosis
  • P.777

  • Systemic therapy—has more side effects than topical
    • Oral prednisolone: 0.5 mg/kg/day for disease control. Goal is to achieve the lowest maintenance dosage that will prevent new lesion formation and reduce adverse reactions.
    • Clinical response is usually obtained within 1 to 2 weeks and is indicated by healing of existing lesions and cessation of new blister formation.
    • Evidence shows that higher doses >0.75 mg/kg/day do not improve healing rate but do increase mortality.
    • Taper the dose gradually within 1 to 2 years to avoid relapse; consider transition to steroidsparing agent.
    • Side effects: cutaneous atrophy, osteoporosis, GI ulcers, Cushing syndrome, diabetes mellitus, hypertension
    • Tetracycline and nicotinamide may be beneficial in disease control and longer remission period (4)[C].
Second Line
  • Although evidence is limited, immunosuppressive agents like azathioprine, mycophenolate mofetil, and methotrexate may be used in severe cases; especially in conjunction with systemic corticosteroids.
    • Addition of azathioprine to prednisone regimen reduces the total maintenance dose of prednisone by 45% without increasing serious side effects or mortality.
    • Azathioprine: 0.5 to 2.5 mg/kg/day, most common side effect: myelosuppression; caution for lethal hypersensitivity syndrome
    • Mycophenolate mofetil: 1.5 to 2 g/day, most common side effect: GI disturbance
  • Methotrexate: 5 to 20 mg/week, low dose usually initiated (5 mg/week) plus folic acid replacement. Adverse effects: myelosuppression, hepatotoxicity. Higher rate of remission with the use of prednisone
  • Dapsone: 25 to 50 mg daily, most common side effect: hemolytic anemia; watch for agranulocytosis.
Third Line
  • Cyclosporine: caution with renal disease
  • Plasmapheresis: Reduce the amount of prednisolone required to achieve disease control.
  • Omalizumab: used in patients who have high levels of IgE antibodies
  • IVIG: for patients who did not respond to first-line therapy or at risk of potentially fatal side effects from conventional therapy. The recommended dose is 1 to 2 g/kg divided over a 3- or 5-day cycle every 3 to 4 weeks.
  • Rituximab has limited data (5)[C].
ISSUES FOR REFERRAL
  • Dermatology for systemic management and/or scarring, which may suggest mucous membrane pemphigoid
  • Gastroenterology, otorhinolaryngology referral in patients who have esophageal, pharyngeal, laryngeal involvement
  • Ophthalmologic consult when patient complains of burning sensation, itching, visual changes, and in those patients who require high doses of steroids
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Extensive denuding of skin, dehydration, and electrolyte imbalance requiring IV fluid reposition
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Taper medication when disease is stable and control side effects.
  • Perform periodic skin examination for new lesions.
  • Frequent bacterial cultures of cutaneous erosions are essential to identify early infections.
DIET
  • Liquid or soft diet with active oral lesions
  • After lesions are resolved, advance diet. Avoid hard or crunchy foods, as they may cause flare ups.
  • Supplement with calcium and vitamin D for patients on systemic corticosteroids
PATIENT EDUCATION
  • Symptoms of infection, worsening lesions
  • Education in good skin hygiene and wound care
  • Wash clothing and linens if they come in contact with oozing, crusting, or infected skin.
  • Protect from sun exposure and physical trauma to the skin.
PROGNOSIS
  • Disease length can persist from weeks to years even under treatment.
  • Around 47% of patients experience relapse within 1 year of therapy, and ˜50% of patients can achieve remission within 2.5 to 6 years.
  • Yearly mortality varies from 6% to 40%.
  • Poor prognosis and high mortality: old age, poor general condition, and the presence of antibodies in serum
  • Other factors that may be included are age >80 years, prednisolone dose >37 mg/day after hospitalization, serum albumin levels of <3.6 g/dL, ESR >100 mm/hr.
REFERENCES
1. Marazza G, Pham HC, Schärer L, et al. Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study. Br J Dermatol. 2009; 161(4):861-868.
2. Feliciani C, Joly P, Jonkman MF, et al. Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. Br J Dermatol. 2015;172(4) 867-877.
3. Joly P, Roujeau JC, Benichou J, et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med. 2002;346(5):321-327.
4. Fivenson DP, Breneman DL, Rosen GB, et al. Nicotinamide and tetracycline therapy of bullous pemphigoid. Arch Dermatol. 1994;130(6):753-758.
5. Saouli Z, Papadopoulos A, Kaiafa G, et al. A new approach on bullous pemphigoid therapy. Ann Oncol. 2008;19(4):825-826.
Additional Reading
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  • García-Romero MT, Werth VP. Randomized controlled trials needed for bullous pemphigoid interventions. Arch Dermatol. 2012;148(2):243-246.
  • Gürcan HM, Ahmed AR. Analysis of current data on the use of methotrexate in the treatment of pemphigus and pemphigoid. Br J Dermatol. 2009;161(4):723-731.
  • Kirtschig G, Middleton P, Bennett C, et al. Interventions for bullous pemphigoid. Cochrane Database Syst Rev. 2010;(10):CD002292.
  • Marzano AV, Tedeschi A, Berti E, et al. Activation of coagulation in bullous pemphigoid and other eosinophil-related inflammatory skin diseases. Clin Exp Immunol. 2011;165(1):44-50.
  • Mutasim DF. Autoimmune bullous dermatoses in the elderly: an update on pathophysiology, diagnosis and management. Drugs Aging. 2010;27(1):1-19.
  • Schmidt E, della Torre R, Borradori L. Clinical features and practical diagnosis of bullous pemphigoid. Dermatol Clin. 2011;29(3):427-438.
  • Ujiie H, Nishie W, Shimizu H. Pathogenesis of bullous pemphigoid. Dermatol Clin. 2011;29(3):439-446.
  • Venning VA, Taghipour K, Mohd Mustapa MF, et al. British Association of Dermatologists' guidelines for the management of bullous pemphigoid 2012. Br J Dermatol. 2012;167(6):1200-1214.
Codes
&NA;
ICD10
L12.0 Bullous pemphigoid
Clinical Pearls
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  • Tense bullae differentiates the lesions of bullous pemphigoid from the flaccid bullae of pemphigus vulgaris.
  • Low doses of potent topical steroid have been shown to be just as effective as larger amounts in the initial therapy of BP.