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Pemphigus Vulgaris
Byron M. Ingram, DO
Robert M. Hasty, DO, FACOI, FACP
image BASICS
Pemphigus is derived from the Greek word pemphix meaning “bubble” or “blister.” Pemphigus vulgaris is the most common form of pemphigus.
DESCRIPTION
  • Rare, potentially fatal autoimmune mucocutaneous blistering disease due to loss of keratinocyte to keratinocyte adhesion that involves the skin and the mucous membranes
  • Flaccid, painful, nonhealing bullae, pustules, or ulcerations that appear spontaneously on the skin and mucosal surfaces, typically begin in the oropharynx, and then may spread to the skin, having a predilection for the scalp, face, chest, axillae, groin, and pressure points.
  • Patient often presents with erosions and no intact bullae.
  • System(s) affected: skin, GI, genitourinary
EPIDEMIOLOGY
Incidence
  • Disease of the middle-aged population, typically occurring after the age of 50 years, although some cases have been reported in younger adults and children
  • Affects both sexes equally
  • 0.1 to 3.2 cases per 100,000 individuals annually worldwide
Prevalence
  • Uncommon, affects <200,000 people in the United States
  • Seen more frequently in people of Mediterranean decent and Ashkenazi Jew
ETIOLOGY AND PATHOPHYSIOLOGY
  • Autoantibodies (IgG) are directed against desmoglein (Dsg) 1 and 3 adhesion molecules. Dsgs interact with desmosomes, which hold epidermal cells together. The antibodies against Dsg molecules cause intraepidermal blister formation and acantholysis.
  • Dsg 3 is predominantly expressed in oral epithelium, whereas both Dsg 1 and Dsg 3 are expressed in the skin.
  • Dsg 1 is expressed more intensely in the superficial layer, whereas Dsg 3 is found more abundantly in basal and suprabasal layers.
  • Additionally, autoantibodies against Dsg 4, the acetylcholine receptor, and pemphaxin have been identified in patients with pemphigus vulgaris (PV). The exact pathogenesis of pemphigus has yet to be fully explained and is likely a “multiple hit” process. Autoimmune; stimulus is unknown.
  • Inducing factors include physical trauma, such as thermal burns, UV light, and ionizing radiation; neoplasm, emotional stress, drugs, and infections. Most patients lack a recognized inducing factor.
Genetics
Strong association with certain human leukocyte antigens (HLA), especially HLA DR4, DR14, DRB1, DQB1, DQ1, and DQ3, although the susceptibility gene differs depending on ethnic origin.
COMMONLY ASSOCIATED CONDITIONS
  • Thymoma
  • Myasthenia gravis
  • Paraneoplastic pemphigus is a type of pemphigus defined by the fact that the patient has a malignancy at the time the pemphigus is diagnosed.
  • Gastric adenocarcinoma
image DIAGNOSIS
PHYSICAL EXAM
  • Mucosal lesions: Intact bullae are rare; commonly are ill-defined, irregularly shaped gingival, buccal, or palatine erosions that are painful and slow-healing; most often affected area is the oral cavity; may involve conjunctiva, oropharynx esophagus, labia, vagina, cervix, penis, urethra, and anus (1)[C].
  • Cutaneous lesions: painful, flaccid blisters with clear fluid found on normal skin or on erythematous base; fragile bullae rupture easily, forming painful, superficial, coin-sized, sharply demarcated erosions (1)[C]. Pruritus is usually absent. Palms and soles are usually spared (2)[C]. Nails: Acute or chronic paronychia, onychomadesis, subungual hematomas, and nail dystrophies may be present.
  • Nikolsky sign: involves application of pressure to skin causing intraepidermal cleavage that allows the superficial skin to slip free from the deeper layers, producing an erosion; can be elicited on normal skin or at the margin of a blister (1)[C]
  • Asboe-Hansen sign: Lateral pressure on the edge of a blister may spread the blister into clinically unaffected skin.
DIFFERENTIAL DIAGNOSIS
  • Predominance of oral mucous lesions: herpes simplex virus (HSV), aphthous ulcers, lichen planus, erythema multiforme
  • Predominance of widespread cutaneous lesions: bullous pemphigoid, cicatricial pemphigoid, bullous drug eruptions, pemphigus erythematosus, pemphigus foliaceus, paraneoplastic pemphigus, impetigo, contact dermatitis, dermatitis herpetiformis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigoid gestationis, and linear IgA dermatosis
DIAGNOSTIC TESTS & INTERPRETATION
Diagnosis is achieved via different parameters: perilesional tissue biopsy, clinical, histologic, and immunologic examinations along with serologic findings. The clinical assessment should include a review of the patient's medications since clinical and laboratory studies cannot reliably distinguish between idiopathic pemphigus and drug-induced pemphigus.
Initial Tests (lab, imaging)
  • Shave or 4-mm punch biopsy of edge of fresh bullous lesion
  • A second 4-mm punch biopsy of the perilesional skin is sent for direct immunofluorescence (DIF).
  • Serum for indirect immunofluorescence (IDIF) is positive for circulating autoantibodies against Dsgs in 80-90% if DIF is positive.
  • ELISA testing can be used to distinguish pemphigus from the other blistering disorders. The sensitivity of ELISA exceeds 90% (3)[C]. In order to distinguish PV from BP, immunoblot assay is needed. These tests are not widely available so may not be accessible by all institutions.
Follow-Up Tests & Special Considerations
IDIF corresponds loosely to disease activity and may be useful to gauge disease activity.
Test Interpretation
  • Light microscopy: intradermal blister; loss of cohesion between epidermal cells (acantholysis) with an intact basement membrane; “row of tombstones appearance”
  • DIF looking for deposits of IgG between epidermal cells
  • In women with cervical involvement, the histologic findings of pemphigus vulgaris may be mistaken for cervical dysplasia in Papanicolaou smears.
image TREATMENT
Reduce inflammatory response and autoantibody production by suppression of the immune system to decrease blister formation and promote healing of blisters and erosions.
GENERAL MEASURES
  • Minimize activities that may cause trauma to skin and precipitate blisters.
  • Avoid use of dental plates, dental bridges, dental floss or contact lenses that may precipitate or exacerbate mucosal disease.
  • Wound care: Daily gentle cleaning, topical agents to promote wound healing, and use of nonadhesive dressings. Clobetasol propionate 0.05% ointment 2 times daily in conjunction with systemic steroids for hard-to-treat lesions
  • Oral analgesics: Use before eating for painful oral lesions (viscous lidocaine, Benadryl).
MEDICATION
First Line
  • High-dose systemic glucocorticoids (e.g., prednisone 1 to 2 mg/kg/day) are the mainstay of treatment (4)[B],(5)[C],(6)[A].
  • Glucocorticoids can be used alone; however, combination with other steroid-sparing immunosuppressive drugs is most effective (azathioprine—most commonly used [starting at 1 mg/kg/day and increasing by 0.5 mg/kg/day every 2 to 3 weeks to reach a maintenance dose of 2.5 mg/kg/day]; other nonsteroidal adjunctive therapies include dapsone [50 to 200 mg/day] or mycophenolate mofetil [MMF] [2 to 3 g/day]) (6)[A].
  • Rituximab is becoming a first-line treatment and may be a safer alternative to steroids. Dosing: 4 weekly infusions 375 mg/m2 or 1,000 mg ×2 separated by 2 weeks (5)[C]
  • For mild to moderate disease: Combination therapy of nonsteroidal adjunctive treatment and prednisone is an effective treatment regimen to achieve rapid and complete control of PV. For those patients who fail treatment, rituximab is an efficacious alternative therapy (7)[C].
  • Rapidly progressive lesions necessitate high prednisone dose (1.5 to 2.5 mg/kg/day) for early and adequate control of the disease. Patients with impaired physical status, especially those with
    P.779

    relatively stable lesions at baseline, might safely and effectively be treated with low-dose oral prednisone on alternate days plus azathioprine every day (Lever's minitreatment [LMT]) for oral pemphigus (4)[B].
  • For oropharyngeal disease: Perilesional/intralesional triamcinolone acetonide injections combined with conventional immunosuppressive therapy shortened the time of complete clinical remission and reduced the total amount of corticosteroids used.
Second Line
For refractory disease
  • Rituximab alone or in combination with intravenous immunoglobulin (IVIG) is an effective therapy for patients with refractory PV (8)[A].
  • Other options: methotrexate (10 to 20 mg/week), hydroxychloroquine, gold, plasmapheresis (5)[C]
  • Cyclosporine (2.5 to 5 mg/kg/day) may be ineffective as a steroid-sparing agent (6)[A].
  • Tumor necrosis factor (TNF)-&agr; antagonist, etanercept, may be an effective therapeutic agent and may reduce healing time of skin lesions in PV and for patients presenting with recalcitrant disease (6)[A].
  • IVIG is a recommended and effective treatment for patients who are not able to tolerate the standard treatment (9)[A].
  • For persistent lesions: intralesional triamcinolone acetonide (20 mg/mL)
ISSUES FOR REFERRAL
  • Ophthalmologist referral in suspected ocular involvement and prolonged use of high-dose steroids
  • Referral to a dentist and/or otolaryngologist for patients with extensive oral disease
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Secondary infections requiring IV antibiotics
  • Severe oral lesions leading to dehydration requiring fluid resuscitation
image ONGOING CARE
A minority of (10%) achieve complete remission after initial treatment and do not need continued drug therapy; most require maintenance therapy to stay in remission.
FOLLOW-UP RECOMMENDATIONS
  • Patients taking steroids long-term should be screened for osteopenia/osteoporosis, avascular necrosis, HPA-axis suppression, cataract, cushingoid features, hyperlipoproteinemia, myopathy, mood changes, and immunosuppression. Patients on systemic steroids should maintain adequate vitamin D and calcium intake through diet and supplements.
  • Patients taking azathioprine should have CBC, Cr, and LFT checked at baseline and every 2 weeks, the first 3 months, then every 3 months after.
  • PV can be exacerbated by sun exposure, dental work, trauma, stress, and radiographs. Patients undergoing dental work should be treated prophylactically with 20 mg of prednisone per day for 5 to 7 days in addition to their regular treatment regimen.
  • Minimizing sun exposure, use of broad-spectrum sunscreen, and wearing protective clothing is recommended.
Patient Monitoring
Seek medical care for any unexplained blisters and if treated for PV and develop any of the following symptoms:
  • Fever, chills
  • General ill feeling
  • Myalgias, joint pain
  • New blisters or ulcers
DIET
  • Patients with active oral lesions may benefit from liquid or soft diet and then advance as tolerated.
  • Avoid spicy and acidic food when oral ulcers are present.
  • Hard food that may cause mechanical trauma to epithelium, such as nuts, chips, and hard vegetables and fruits, may be best avoided in cases of active oral disease.
PATIENT EDUCATION
  • Minimize activities that may cause trauma to skin and precipitate blisters, such as contact sports. Nontraumatic exercises, such as swimming, may be helpful.
  • Explain wound care of erosions: daily gentle cleaning, covering open areas with clean petrolatum and nonadhesive dressings, as it will take longer for you to recover from infections if you are taking corticosteroids or immunosuppressants.
  • Educate patients about the chronicity of the disease and the need for long-term follow up:
    • For oral pemphigus:
      • Soft diets and soft toothbrushes help to minimize local trauma.
      • Explain the need for meticulous oral hygiene to prevent dental decay. Encourage gentle tooth brushing, dental flossing, and visits to the dentist/dental hygienist at least every 6 months.
      • Discuss how dental plates, dental bridges, or contact lenses may precipitate or exacerbate mucosal disease.
      • Topical analgesics or anesthetics (e.g., benzydamine hydrochloride 0.15% or viscous lidocaine) may be useful in alleviating oral pain, particularly prior to eating or tooth brushing.
      • Patients may also contact the International Pemphigus & Pemphigoid Foundation (IPPF) for support groups.
PROGNOSIS
  • Mortality rate with combination therapy is ˜5%, with most deaths due to drug-induced complications, including sepsis.
  • 10% of patients achieve complete remission after initial treatment; most require maintenance therapy to stay in remission.
  • Morbidity and mortality are related to the extent of disease, the maximum dose of oral steroids required to induce remission, and the presence of other diseases. Prognosis is worse in older persons and patients with extensive disease.
  • Most deaths occur during the first few years of the disease; if a patient survives 5 years, prognosis is good.
REFERENCES
1. Bystryn JC, Rudolph JL. Pemphigus. Lancet. 2005;366(9479):61-73.
2. Kavala M, Altintaş S, Kocatürk E, et al. Ear, nose and throat involvement in patients with pemphigus vulgaris: correlation with severity, phenotype and disease activity. J Eur Acad Dermatol Venereol. 2011;25(11):1324-1327.
3. Joly P, Litrowski N. Pemphigus group (vulgaris, vegetans, foliaceus, herpetiformis, brasiliensis). Clin Dermatol. 2011;29(4):432-436.
4. Chaidemenos G, Apalla Z, Koussidou T, et al. High dose oral prednisone vs. prednisone plus azathioprine for the treatment of oral pemphigus: a retrospective, bi-centre, comparative study. J Eur Acad Dermatol Venereol. 2011;25(2):206-210.
5. Santoro FA, Stoopler ET, Werth VP. Pemphigus. Dent Clin North Am. 2013;57(4):597-610.
6. Singh S. Evidence-based treatments for pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid: a systematic review. Indian J Dermatol Venereol Leprol. 2011;77(4):456-469.
7. Strowd LC, Taylor SL, Jorizzo JL, et al. Therapeutic ladder for pemphigus vulgaris: emphasis on achieving complete remission. J Am Acad Dermatol. 2011;64(3):490-494.
8. Zakka LR, Shetty SS, Ahmed AR. Rituximab in the treatment of pemphigus vulgaris. Dermatol Ther (Heidelb). 2012;2(1):17.
9. Ishii N, Hashimoto T, Zillikens D, et al. High-dose intravenous immunoglobulin (IVIG) therapy in autoimmune skin blistering diseases. Clin Rev Allergy Immunol. 2010;38(2-3):186-195.
Additional Reading
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Leshem YA, Gdalevich M, Ziv M, et al. Opportunistic infections in patients with pemphigus. J Am Acad Dermatol. 2014;71(2):284-292.
Codes
&NA;
ICD10
L10.0 Pemphigus vulgaris
Clinical Pearls
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Pemphigus vulgaris is a rare, chronic, potentially fatal autoimmune vesiculobullous disease of the mucous membranes and skin. Biopsy immediately with rush processing. When clinical suspicion is high, initiate therapy without delay using systemic corticosteroids. Minimize activities that may cause trauma to skin and precipitate blisters, such as contact sports.