Photoclinic

Pemphigus Vulgaris

Christopher C. Brodkin, MD

Volume 56 - Issue 1 - January 2016

A 45-year-old man had been hospitalized previously for a methicillin-resistant Staphylococcus aureus infection, which had been cultured from a boil-type lesion on the left buttock and vesicular lesions on the penis and lips and had been treated as a case of herpes simplex virus (HSV) type 2. He now presented for multiple bullous, burst-type lesions on the head, neck, back, chest, abdomen, groin, and thighs. He had received vancomycin for 5 days at the previous hospital and had been discharged on trimethoprim-sulfamethoxazole and acyclovir for 10 days prior to presentation.

Figure 1. Oral lesions upon presentation.

 

History. The patient had a history of hypertension that was controlled by diet. He denied any surgeries or allergies or a family history of immunocompromised states. Social history showed that he smokes one-third of a pack of cigarettes daily, drinks on binges on weekends, and has snorted cocaine in the past. He had been incarcerated 6 months earlier, but he denied sexual activity or tattooing while in jail. He is married and has had 15 partners in his lifetime. He had been tested for HIV 10 days ago at the other hospital, with negative results.

Physical examination. His vital signs included the following: blood pressure, 123/75 mm Hg; pulse, 92 beats/min; respiratory rate, 18 breath/min; and temperature, 36.7°C. Head and neck examination showed injected conjunctivas and oral thrush. Lymph node examination revealed shotty lymph nodes in the submandibular and tonsillar regions bilaterally. Heart examination showed S1 and S2 in regular rate and rhythm. Lung sounds were clear to auscultation bilaterally. The abdomen was soft, nontender, nondistended, and with normal bowel sounds.

The patient had multiple scattered lesions starting within his mouth (Figure 1) and extending from his neck all the way to his ankles. The most prominent areas of lesions were the left antecubital aspect, as well as the right axilla, flank, and buttocks. He also had these lesions on his penis and scrotum. The affected areas were very tender during the examination. All of the lesions were very crusted and dry, with some new boils developing (Figure 2). The lesions featured periwound cellulitis.

Figure 2. Lesions on torso.

Diagnostic tests. Laboratory evaluation confirmed that he was HIV-negative. Serum protein and urine protein electrophoresis test results were negative. The white blood cell count was mildly elevated at 12,000/µL. A consultant wound care specialist did a punch biopsy of the right posterior arm, the pathology results of which showed a broad zone of suprabasal acantholysis with an overlying separate viable epidermis; at the edge of the vesicle, numerous eosinophils were seen in the epidermis. There was a superficial perivascular infiltrate that included eosinophils.

Direct immunofluorescence testing was performed on fresh and subsequently frozen tissue. Antibodies to immunoglobulin G (IgG) and C3 showed a strong (2+) intracellular staining pattern in the epidermis; antibody to C3 showed only a “shaggy” granular staining pattern focally at the basement membrane zone of the epidermis. Immunoreactants to IgA and IgM were negative. Antibody to fibrin showed nonspecific stromal staining.

These histologic and immunologic findings strongly favored a diagnosis of primary autoimmune pemphigus vulgaris rather than the paraneoplastic variant of pemphigus.

Discussion. Pemphigus vulgaris, although rare, is the most common form of pemphigus in the United States and Europe.1 It usually occurs in persons who are middle-aged or older.2,3

In patients with pemphigus vulgaris, pathogenic autoantibodies (usually IgG) are directed against desmoglein (Dsg), an adhesion molecule.4,5 This interferes with the intercellular cement that holds epidermal cells together and results in intraepidermal blister formation.

Pemphigus vulgaris may be associated with both mucosal and cutaneous lesions. Patients with limited mucosal disease primarily have autoantibodies directed against Dsg 3, while those with more extensive cutaneous disease or with paraneoplastic pemphigus may have both anti-Dsg 3 and anti-Dsg 1 antibodies.6-8 In comparison, patients with pemphigus foliaceus, in which lesions are limited to the skin, have only anti-Dsg 1 antibodies.9,10 The stimulus that leads to autoantibody formation is unknown.

Pemphigus vulgaris is characterized by flaccid bullae that typically begin in the oropharynx and then may spread to involve the skin, with a predilection for the scalp, face, chest, axillae, and groin. The bullae rupture easily, so patients often present with erosions only and no intact bullae. Virtually all patients have oropharyngeal disease at some point in the course of disease. Other mucous membranes also may be involved.11 A positive Nikolsky sign may be present.

Lesions typically are painful, particularly after the blisters rupture. Open, denuded areas can become secondarily infected. Severe oral involvement may impair oral intake. Lesions do not resolve without therapy and often heal with postinflammatory hyperpigmentation. The pigmentary changes generally resolve within 1 to 2 years and do not leave scarring.2

Figure 3. Abdominal CT. Arrow indicates mediastinal mass biopsied.

 

The diagnosis of pemphigus requires biopsy of skin lesions. A deep shave or 4-mm punch biopsy should be performed for routine light microscopy from an early, small bulla or from the edge of a new erosion; histologically, there is evidence of intraepithelial acantholysis without disruption of the basement membrane. Biopsy of a section of normal skin a few millimeters from an involved area also should be obtained for direct immunofluorescence analysis, looking for deposits of IgG between epidermal cells. This second biopsy requires specimen placement in a special medium (not formalin).2

The differential diagnosis of pemphigus vulgaris includes the following: If mouth erosions predominate, consider HSV, aphthae, lichen planus, or erythema multiforme; if widespread erosions predominate, consider pyoderma, impetigo, or other bullous diseases (eg, bullous pemphigoid, bullous drug eruptions).2

Before the introduction of systemic corticosteroids, pemphigus vulgaris had been associated with a high mortality rate.12 The current mortality rate with combination therapy including corticosteroids and immunosuppressive drugs is approximately 5%, with most deaths a result of drug-induced complications, including sepsis.13,14

Management. Patients should be referred to a dermatologist for initial consultation and management of the disease. Long-term follow-up is the rule; some patients require years of or even lifelong suppressive therapy. A minority of patients (approximately 10%) achieve complete remission after initial treatment and do not need continued drug therapy; the majority require maintenance therapy to stay in remission.15

High-dose systemic corticosteroids (eg, prednisone 1 mg/kg/d) are the mainstay of initial therapy in most patients with pemphigus vulgaris.16 Corticosteroids diminish autoantibody production. The duration of treatment is variable; the drugs are tapered as soon as allowed, depending on patient response. Patients with very limited disease may respond to sublesional corticosteroids (triamcinolone acetonide injectable suspension, 5-10 mg/mL), while those with mild to moderate disease may derive benefit from lower doses of systemic corticosteroids.17

Azathioprine (4 mg/kg/d) and cyclophosphamide (2-3 mg/kg/d) are commonly used as corticosteroid-sparing agents.18-20 Reported adverse effects were rare and predominantly related to corticosteroid use.2

Other potential options include methotrexate, dapsone, hydroxychloroquine, gold, mycophenolate, and cyclosporine. Removal of circulating autoantibodies with plasmapheresis has been used in particularly aggressive cases.21 Intravenous immunoglobulin may be useful as monotherapy in patients who do not respond to corticosteroids or who have contraindications to corticosteroid use.22,23

Outcome of the case. The patient was placed on high-dose corticosteroids, and his condition improved. He was discharged on a regimen of prednisone and with instructions to follow up with a dermatologist.

 

References:

  1. Bystryn JC, Rudolph JL. Pemphigus. Lancet. 2005;366(9479):61-73.
  2. Hertl M, Sitaru C. Pathogenesis, clinical manifestations, and diagnosis of pemphigus. UpToDate.http://www.uptodate.com/contents/pathogenesis-clinical-manifestations-and-diagnosis-of-pemphigus. Updated August 4, 2015. Accessed December 9, 2015.
  3. Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJP, West J. Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study. BMJ. 2008;337:a180.
  4. Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell. 1991;67(5):869-877.
  5. Stanley JR, Amagai M. Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N Engl J Med. 2006;355(17):1800-1810.
  6. Harman KE, Gratian MJ, Bhogal BS, Challacombe SJ, Black MM. A study of desmoglein 1 autoantibodies in pemphigus vulgaris: racial differences in frequency and the association with a more severe phenotype. Br J Dermatol. 2000;143(2):343-348.
  7. Ding X, Aoki V, Mascaro JM Jr, Lopez-Swiderski A, Diaz LA, Fairley JA. Mucosal and mucocutaneous (generalized) pemphigus vulgaris show distinct autoantibody profiles. J Invest Dermatol. 1997;109(4):592-596.
  8. Amagai M, Nishikawa T, Nousari HC, Anhalt GJ, Hashimoto T. Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice. J Clin Invest. 1998;102(4):775-782.
  9. Rock B, Labib RS, Diaz LA. Monovalent Fab′ immunoglobulin fragments from endemic pemphigus foliaceus autoantibodies reproduce the human disease in neonatal Balb/c mice. J Clin Invest. 1990;85(1):296-299.
  10. Mahoney MG, Wang Z, Rothenberger K, Koch PJ, Amagai M, Stanley JR. Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest. 1999;103(4):461-468.
  11. Korman N. Pemphigus. J Am Acad Dermatol. 1988;18(6):1219-1238.
  12. Mourellou O, Chaidemenos GC, Koussidou T, Kapetis E. The treatment of pemphigus vulgaris: experience with 48 patients seen over an 11-year period. Br J Dermatol. 1995;133(1):83-87.
  13. Scully, C, Paes De Almeida O, Porter SR, Gilkes JJ. Pemphigus vulgaris: the manifestations and long-term management of 55 patients with oral lesions. Br J Dermatol. 1999;140(1):84-89.
  14. Tehranchi-Nia Z, Qureshi TA, Ahmed AR. Pemphigus vulgaris in older adults. J Am Geriatr Soc. 1998;46(1):92-94.
  15. Bystryn JC, Steinman NM. The adjuvant therapy of pemphigus: an update. Arch Dermatol. 1996;132(2):203-212.
  16. Aberer W, Wolff-Schreiner EC, Stingl G, Wolff K. Azathioprine in the treatment of pemphigus vulgaris: a long-term follow-up. J Am Acad Dermatol. 1987;16(3 pt 1):527-533.
  17. Ahmed AR, Hombal S. Use of cyclophosphamide in azathioprine failures in pemphigus. J Am Acad Dermatol. 1987;17(3):437-442.
  18. Beissert S, Werfel T, Frieling U, et al. A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus. Arch Dermatol. 2006;142(11):1447-1454.
  19. Werth VP, Fivenson D, Pandya AG, et al. Multicenter randomized, double-blind, placebo-controlled, clinical trial of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris. Arch Dermatol. 2008;144(1):25-32.
  20. Herrmann G, Hunzelmann N, Engert A. Treatment of pemphigus vulgaris with anti-CD20 monoclonal antibody (rituximab). Br J Dermatol. 2003;148(3):602-603.
  21. Amagai M, Matsuyoshi N, Wang ZH, Andl C, Stanley JR. Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nat Med. 2000;6(11):1275-1277.
  22. Stern RS, Shear NH. Cutaneous reactions to drugs and biological modifiers. In: Arndt KA, LeBoit PE, Robinson JK, Wintroub BU, eds. Cutaneous Medicine and Surgery: An Integrated Program in Dermatology. Vol 1. Philadelphia, PA: WB Saunders; 1996:412-425.
  23. Heymann AD, Chodick G, Kramer E, Green M, Shalev V. Pemphigus variant associated with penicillin use: a case-cohort study of 363 patients from Israel. Arch Dermatol. 2007;143(6):704-707.