Pemphigus, Emergency Medicine

Basics

Description

Autoantibody (IgG)-mediated blistering disease of the skin and mucous membrane:
- Characterized by loss of cell-to-cell adhesion called acantholysis
Median age 71 yr
- Reports of disease occurring in neonates through elderly
Rare; worldwide incidence 0.7/100,000
Females > males, 66 vs. 34%
Pemphix is Greek for bubble or blister
Pemphigus, specific term for autoantibody disease against some portion of epidermis
Pemphigoid: A term describing the group of syndromes that cause a separation of the epidermis from the dermis, typically more benign course
Mortality is highest in those with mucocutaneous involvement
- If untreated, mortality rates average 60 " 90%, with treatment this nears 5%
3 major subtypes exist:
- Vulgaris; typically more serious with deeper mucocutaneous involvement:
  - Accounts for 70 " 80% of all pemphigus
  - Up to 70% with vulgaris present with oral lesions, which is often the presenting complaint
  - Autoantibodies to Dsg 1 and 3
  - Affects most races in middle age and elderly Ashkenazi Jews
- Foliaceus; milder and more superficial cutaneous lesions:
  - Oral lesions and better prognosis
  - Autoantibodies to Dsg 1 only
- Paraneoplastic pemphigus; often with severe mucocutaneous involvement
  - Most commonly seen in lymphoreticular malignancies

Pemphigus is rare in neonates and children but may occur in adolescents
Early diagnosis and treatment significantly impact growth, psychological, social, and cultural development
Histopathology is identical to adult disease
Neonates may develop the disease secondary to transplacental transfer of IgG
Neonatal pemphigus spontaneously resolves in several weeks as the maternal antibodies are catabolized

Effective treatment of maternal disease prior to conception lowers the risk of neonatal transmission and gestational complications

Etiology

IgG autoantibodies are directed against desmosomal cadherins desmoglein 1 and desmoglein 3 found in all keratinocytes
Autoantibodies cause histopathologic acantholysis, cytoskeletal derangements, and apoptosis
Bullae formation is caused by the loss of cell " cell adhesion and separation of the keratinocytes
Immunogenetic predisposition secondary to higher frequencies of specific human leukocyte antigen HLA haplotypes including DR4 and DRw6
Drugs such as penicillamine, captopril, rifampin, piroxicam, and phenobarbital can trigger pemphigoid reactions
Endemic pemphigus foliaceus (fogo selvagem), most common in South America, may be triggered or transmitted by bites from flying insects
Pemphigoid reactions may occur in association with a neoplasm, usually lymphoma (paraneoplastic pemphigus)

Diagnosis

Signs and Symptoms

Generalized or focal flaccid bullae (blisters) of the skin and mucosa
Painful skin erosions with shreds of detached epithelium
Painful nonhealing oral, vaginal, or mucosal erosions
Crusting, partially healing skin erosions from ruptured bullae
Hypertrophic, hyperplastic erosive plaques with pustules in intertriginous areas (pemphigus vegetans)
Moist, edematous, exfoliative erosions in seborrheic areas (pemphigus foliaceus)
Erythematous, scaly, crusting skin lesions in a malar distribution (pemphigus erythematosus)
Lesions usually persist without treatment:
- May heal with post inflammatory hyperpigmentation

History

Typically features mucocutaneous blisters followed by erosions
Often appear 1st in mucous membranes with spread to cutaneous involvement; most commonly to scalp, chest, axillae, and groin
Skin lesions are painful flaccid blisters that may appear anywhere

Physical Exam
Nikolsky sign (separation of the epidermis with lateral pressure) is characteristic but not diagnostic:

Poor sensitivity

Essential Workup

Suspected based on clinical presentation
Biopsy with histologic and immunofluorescence testing is essential for definitive diagnosis (arrange with a dermatologist)

Diagnosis Tests & Interpretation

Lab

Serum antibody titers, detected by indirect immunofluorescence, are often used as a marker of disease activity; however, the ED physician usually does not order these titers
ELISA may be used to identify subtypes

Imaging
No diagnostic imaging test exists
Diagnostic Procedures/Surgery
Deep shave or punch biopsy

Differential Diagnosis

Bullous pemphigoid
Contact dermatitis
Dermatitis herpetiformis
Erythema multiforme
Erysipelas
Erythroderma
Toxic epidermal necrolysis
Epidermolysis bullosa
Hand, foot, and mouth disease
Systemic lupus erythematosus
Systemic vasculitis
Oral candidiasis
Herpes simplex gingivostomatitis
Erosive lichen planus
Seborrheic dermatitis

Treatment

Pre-Hospital

If severe disease:
- IV access, pulse oximetry monitor, and cardiac monitor

Initial Stabilization/Therapy

If symptoms of hypotension or sepsis are present, IV fluid resuscitation should be guided by the Parkland burn formula
If signs or symptoms of sepsis are present, initiate broad-spectrum antibiotic coverage
In steroid-dependent patients, administer stress-dose steroids

Ed Treatment/Procedures

Systemic corticosteroids are the mainstay of therapy
Mild-to-moderate disease should receive PO prednisone, and intralesional triamcinolone acetonide may be used
Severe disease: Conventional high-dose corticosteroids:
- If severe symptoms are unresponsive to high-dose PO corticosteroids, consider pulse IV corticosteroids and admission for plasmapheresis
Adjuvant immunosuppressive therapy may also be added to decrease the symptoms associated with high-dose systemic corticosteroids or in patients with contraindications to steroid therapy:
- Dapsone, gold, azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate, and IV immunoglobulins

Medication

First Line

Immune suppression:
- Hydrocortisone: 100 " 300 mg/d IV stress-dose steroids adjusted based on patients known dosage and use habits
- Methylprednisolone (pulse IV therapy; adults): 1 g IV over 3 hr daily
- Prednisone: 1 mg/kg/d PO daily (adults); moderate-to-severe disease PO daily for 5 " 10 wk, then taper
- Triamcinolone acetonide for
  limited intraoral involvement " 10 mg/mL 0.1-mL injection into each superficial lesion
Pain:
- Opiates, anti-inflammatory agents, acetaminophen
- Biobrane synthetic dressing
- Diphenhydramine and Maalox or Xylocaine oral wash

Second Line

Usually performed as an inpatient for severe, refractory cases
Immune suppression:
- IVIG: single cycle 400 mg/kg per day for
- 5 days
- Rituximab
- Triamcinolone acetonide: 10 mg/mL 0.1-mL injection into each superficial lesion
Pain:
- Gabapentin 300 mg daily titrated up to 300 mg TID over a month
Other considerations: Patients on high-dose steroids should have diets high in vitamin D and calcium and may benefit from a proton-pump inhibitor or bisphosphonates.

Follow-Up

Disposition

Admission Criteria

Most acute flares are minor and can be managed with PO glucocorticoids and dermatology follow-up
Admit 1st-time presentations of disease to facilitate treatment and definitive diagnosis with biopsy and rule out of high morbidity blistering skin disease
Admit patients with extensive mucocutaneous involvement, intractable pain, coexisting bacterial skin infection, or signs of sepsis
Admit to a floor bed if pulse parenteral steroid therapy or plasmapheresis is indicated
Admit to the ICU or burn unit if any signs and symptoms of shock or sepsis are present because aggressive fluid resuscitation, wound care, and multiple medications will be required

Discharge Criteria

Discharge if mild-to-moderate disease will not require aggressive steroid management, plasmapheresis, or aggressive pain control

Follow-Up Recommendations

A follow-up evaluation with dermatology is essential to monitor the course of the disease and to adjust treatment
Rheumatology follow-up may be advantageous to assess risk of osteoporosis via bone scan if on high-dose steroids

Pearls and Pitfalls

Mucocutaneous lesions often begin on face, head/scalp, or oral cavity
Long-term management is the rule; ensure proper dermatology follow-up
Glucocorticoids are the mainstay of therapy
Paraneoplastic type often with severe oral mucosal involvement, consider associated lymphoproliferative disorder
Patients on immunosuppressive treatment including steroids and immunomodulating agents are at very high risk of complications and may present in adrenal crisis, severe sepsis, or hyperosmolar nonketotic acidosis secondary to new-onset type 2 diabetes
Patients with hypotension require aggressive fluid resuscitation

Additional Reading

Amagai M,
Ikeda S, Shimizu
H, et al. A randomized double-blind trial of intravenous immunoglobulin
for pemphigus. J Am Acad Dermatol.
2009;60:595 " 603.
Kasperkiewicz M, Schmidt E, Zillikens D. Current therapy of the pemphigus group. Clin Dermatol. 2012;30:84 " 94.
Kavusi S, Daneshpazhooh M, Farahani F, et al. Outcome of pemphigus vulgaris. J Eur Acad Dermatol Venereol. 2008;22:580 " 584.
Langan SM, Smeeth L, Hubbard R, et al. Bullous pemphigoid and pemphigus vulgaris " incidence and mortality in the UK: Population based cohort study. BMJ. 2008;337:a180.
Martin LK, Werth VP, Villaneuva EV, et al. A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol. 2011;64:903 " 908.
Rashid RM, Candido KD. Pemphigus pain: A review on management. Clin J Pain. 2008;24:734 " 735.
Schmidt E, Waschke J. Apoptosis in pemphigus. Autoimmun Rev. 2009;8:533 " 537.

Codes

ICD9

684 Impetigo
694.4 Pemphigus
694.6 Benign mucous membrane pemphigoid

ICD10

L10.0 Pemphigus vulgaris
L10.2 Pemphigus foliaceous
L10.9 Pemphigus, unspecified
L10.81 Paraneoplastic pemphigus
L01.03 Bullous impetigo
L10.1 Pemphigus vegetans
L10.3 Brazilian pemphigus [fogo selvagem]
L10.4 Pemphigus erythematosus
L10.5 Drug-induced pemphigus
L10.89 Other pemphigus
L10.8 Other pemphigus
L10 Pemphigus

SNOMED

65172003 Pemphigus (disorder)
49420001 Pemphigus vulgaris (disorder)
35154004 pemphigus foliaceus (disorder)
402718003 Pemphigus paraneoplastica (disorder)
200907003 Drug-induced pemphigus (disorder)
402717008 Immunoglobulin A pemphigus (disorder)

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