Hospital Medicine

Pemphigus vulgaris & Bullous Pemphigoid

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Pemphigus Vulgaris and Bullous Pemphigoid

I. What every physician needs to know.

Pemphigus vulgaris (i.e., pemphigus) and bullous pemphigoid (i.e., pemphigoid) are autoimmune disorders in which blistering of the skin is the primary symptom. Autoantibodies against desmoglein (specifically, Dsg 3) cause the intraepidermal blistering seen in pemphigus, while autoantibodies against hemidesmosomes are the reason for the subepidermal blistering seen in pemphigoid. For both of these, exact cause of the formation of autoantibodies is unknown.

Three major types of pemphigus have been defined, of which pemphigus vulgaris is the most common in the United States and Europe ("vulgar" meaning most common). However, pemphigus is still a rare disease. It is also a chronic disease that is potentially fatal. Pemphigus is unique from pemphigoid in that the blistering can involve the mucous membranes as well as skin. In pemphigus, the autoantibody that attacks Dsg is most commonly immunoglobulin G (IgG). Dsg functions as an adhesion molecule that cements together epidermal cells; thus, the effect of IgG's attack is to separate the cells from each other and the epidermis (acantholysis) in order to create the intraepidermal blister seen in this disease. Additionally, this disease can rarely be associated with myasthenia gravis.

Bullous pemphigoid is a more common disease than pemphigus that is less aggressive and, generally, not considered life-threatening. The bullae in pemphigoid are generated when IgG autoantibodies attack bullous pemphigoid antigen 2 (i.e., BPAG2, BP180, or type XVII collagen) and/or bullous pemphigoid antigen 1 (i.e., BPAG1 or BP230 - only found in approximately two-thirds of these patients), which are both components of hemidesmosomes. BP180 acts to anchor hemidesmosomes to the lamina densa of the basement membrane; thus, blisters in pemphigoid occur subepidermally (deeper than in pemphigus).

II. Diagnostic Confirmation: Are you sure your patient has Pemphigus Vulgaris or Bullous Pemphigoid?

The gold standard for diagnosis of pemphigus vulgaris is skin-lesion biopsy. A deep-shave or punch biopsy from the edge of a newly-formed erosion will show histologic evidence of acantholysis. In these erosions, the upper aspect of epidermis sloughs off, leaving a bottom layer described as having a "tombstone" appearance. One of the key features is that there should be no evidence of basement membrane disruption. A second biopsy from an area of "normal" skin nearby an affected area should also show IgG deposits between the epidermal cells. Serologic studies such as Enzyme-linked immunosorbent assay (ELISA) for IgG antibodies to Dsg 1 and Dsg 3 are useful in supporting the diagnosis and aiding with classification; Dsg 3 antibodies will predominate in patients with the mucosal form of the disease, while both Dsg 1 and Dsg 3 are positive in patients with mucosal and cutaneous symptoms. ELISA is over 90% sensitive in the diagnosis of pemphigus vulgaris.

Bullous pemphigoid is also diagnosed by skin biopsy from two sites: one for routine hematoxylin and eosin (H&E) staining and the other for immunofluorescence. The first is taken from the edge of an intact bulla, while the second is, once again, taken from unaffected skin within a few millimeters from an involved area. Immunofluorescence will show linear C3 deposits along the basement membrane; it may also show IgG deposits in 65-96% of cases. The second biopsy can also be performed on "salt-split skin" (can help differentiate between bullous pemphigoid and epidermolysis bullosa acquisita [EBA] - in pemphigoid, IgG is found on the epidermal side of the split as opposed to only on the dermal side, as in EBA). Finally, ELISA can be used to identify antibodies to BP180-NC16A (NC16A is the domain of BP180 that is attacked in pemphigoid), but is a very expensive test.

A. History Part I: Pattern Recognition:

Pemphigus has flaccid, thin-walled bullae that generally originate on the oropharyngeal mucosa. From there, the bullae can spread to involve other parts of the skin, particularly the face/scalp, chest, axilla, and groin areas. The bullae rupture easily secondary to the thin walls, and patients often present with open erosions that are prone to becoming infected. The oropharyngeal involvement can often lead to decreased oral intake. Additionally, the superficial layer of skin in affected individuals can be separated from the deeper layers by mechanical pressure (Nikolsky sign); this can be attempted at the margin of a lesion or on normal skin.

Bullous pemphigoid usually involves pruritic bullae and/or urticarial plaques that occur most commonly in the groin, axillae, and flexural areas. Unlike pemphigus, involvement of the oropharyngeal mucosa occurs in only 1/3 of cases. It generally occurs as a more sudden widespread eruption, compared to pemphigus. In taking the history, it is also imperative to identify whether the bullae are due to classic (or idiopathic) bullous pemphigoid or due to drug-induced bullous pemphigoid (DIBP). A detailed medication history and temporal onset of the rash should alert one to the possibility of DIBP. Over 50 medications such as antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics, have been reported to cause DIBP.

B. History Part 2: Prevalence:

Pemphigus vulgaris is a rare condition that occurs more commonly with increasing age, with a median age of 71. It occurs in women nearly twice as much as in men (2:1) and has a high risk of death when compared to controls.

Bullous pemphigoid is a less rare condition that also occurs more commonly with increasing age, with a median age of 80. The ratio of occurrence in women to men is approximately the same (2:1), but the risk of death is significantly less than that of pemphigus.

C. History Part 3: Competing diagnoses that can mimic Pemphigus Vulgaris/Bullous Pemphigoid.

Alternative diagnoses for bullous pemphigoid and pemphigus vulgaris are similar. If ulcers of the oropharyngeal mucosa predominate, herpes simplex virus (HSV), aphthae, lichen planus, cicatricial pemphigoid, or erythema multiforme may be the cause. If widespread erosions exist, dermatitis herpetiformis (lesions are generally grouped together and tend to exist on extensor surfaces), pyoderma, impetigo, bullous lupus erythematosus (very rare; associated with other signs of SLE), linear IgA bullous dermatosis, bullous drug eruptions (generally has a history of recent infection or drug ingestion), pemphigoid gestationis, and epidermolysis bullosa acquisita (very rare; can be differentiated from bullous pemphigoid via immunofluorescence of salt-split skin) are all possibilities.

D. Physical Examination Findings.

Lesions of pemphigus vulgaris generally begin in the oropharynx and can spread to other areas; the lesions themselves are flaccid and rupture easily. On physical exam, erosions may be more common than the bullous lesions themselves and are generally very painful. Bullous pemphigoid lesions are more tense and can also have urticarial plaques. Pruritic lesions can be located in flexural areas such as the groin and axilla.

Nikolsky’s sign will be present in pemphigus vulgaris and generally absent in bullous pemphigoid.

E. What diagnostic tests should be performed?

Definitive diagnosis for either of the two diagnoses requires two punch biopsies of the skin lesions. Pemphigus requires one from the edge of a bullae for direct immunofluorescence and one from a few millimeters adjacent to a lesion. Pemphigoid also requires two similar biopsies, the one involving the edge of an intact vesicle for H&E staining and the second from an adjacent area for immunofluorescence. An alternate for bullous pemphigoid is a deep shave biopsy starting adjacent to a blister that is bisected to have two samples: one with blister and one without.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

ELISA can also be useful to identify both diagnoses; pemphigus will have autoantibodies for Dsg 1 and Dsg 3, while pemphigoid will have antibodies for BP180. Additionally, performing immunofluorescence studies on salt-split skin can help solidify the diagnosis of bullous pemphigoid.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

N/A

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

ELISA testing is very expensive and not often available in all clinical settings. Biopsy is significantly cheaper and often sufficient for diagnosis.

III. Default Management.

The mainstay of treatment with either of these diseases is oral glucocorticoid therapy, which works by reducing autoantibody production. However, alternative therapies vary between the two.

For pemphigus vulgaris, prednisone is started at 1 milligram/kilogram/day (mg/kg/day) and tapered once the patient begins to respond.

Patients who cannot be controlled on corticosteroids within 6 months or who have secondary complications due to steroidal therapy should have their treatments modified with "glucocorticoid-sparing agents." Immunosuppressive agents such as azathioprine (2 - 2.5 mg/kg/day), cyclophosphamide (2 - 3 mg/kg/day) and mycophenylate mofetil (2 grams[g]/day) can be used in conjunction with prednisone or methylprednisolone. For refractory cases of pemphigus, rituximab (with or without intravenous immunoglobulin [IVIG]) or IVIG as a monotherapy have shown effectiveness. Highly aggressive cases can also be treated with plasmapharesis to remove circulating antibodies.

For bullous pemphigoid, topical therapy is first-line. Clobetasol cream, 10 - 40 g/day, has proven to be as effective or even superior to oral glucocorticoid therapy in patients with moderate to severe/extensive disease. Oral glucocorticoids are reserved for patients with disease extending to the mucous membranes that hasn't responded to topical therapy or if a patient’s ability to apply on affected areas is not feasible. Doses of oral prednisone range from 0.5 - 1 mg/kg/day and can be tapered within 1 - 2 years. The same glucocorticoid-sparing agents used for pemphigus vulgaris can also be used with bullous pemphigoid. Azathioprine 2 - 3 mg/kg/day has also been used as monotherapy in patients with mild to moderate disease who are unable to tolerate steroid therapy.

A. Immediate management.

N/A

B. Physical Examination Tips to Guide Management.

For pemphigus vulgaris, sublesional steroid treatment with triamcinolone acetonide can be attempted in patients with very limited disease.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Antibodies to Dsg 1 have proven useful in monitoring response to therapy for pemphigus vulgaris and detecting relapse.

D. Long-term management.

Long-term follow-up is critical for patients with either of these diseases as recurrence is very possible and maintenance therapies may be required to keep patients in remission. Referral to a dermatologist for long-term care is highly recommended.

E. Common Pitfalls and Side-Effects of Management.

Fluid management is a commonly forgotten aspect of management in patients with both pemphigus vulgaris and bullous pemphigoid. Hydration should be managed similarly to burn patients.

IV. Management with Co-Morbidities.

No significant changes need to be made for management of either of these diseases unless there is a contraindication to using the recommended medications.

A. Renal Insufficiency.

N/A

B. Liver Insufficiency.

N/A

C. Systolic and Diastolic Heart Failure.

N/A

D. Coronary Artery Disease or Peripheral Vascular Disease.

N/A

E. Diabetes or other Endocrine issues.

N/A

F. Malignancy.

N/A

G. Immunosuppression (HIV, chronic steroids, etc).

N/A

H. Primary Lung Disease (COPD, Asthma, ILD).

N/A

I. Gastrointestinal or Nutrition Issues.

N/A

J. Hematologic or Coagulation Issues.

N/A

K. Dementia or Psychiatric Illness/Treatment.

N/A

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

N/A

B. Anticipated Length of Stay.

Variable.

C. When is the Patient Ready for Discharge?

Patients diagnosed with pemphigus vulgaris can be discharged once they are weaned off their intravenous medications. Patients with bullous pemphigoid can most likely be treated as an outpatient.

D. Arranging for Clinic Follow-up.

Long-term follow-up with dermatology should be arranged as soon as diagnosis of pemphigus vulgaris or bullous pemphigoid is made. Follow-up appointments should be continued until steroids are weaned completely or until continuous management is arranged.

1. When should clinic follow up be arranged and with whom.

N/A

2. What tests should be conducted prior to discharge to enable best clinic first visit.

N/A

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

N/A

E. Placement Considerations.

N/A

F. Prognosis and Patient Counseling.

Pemphigus is a chronic and potentially fatal disease and patients should be counseled accordingly.

Bullous pemphigoid is usually less severe and can resolve in 1 - 2 years.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Hospitalized patients should be given DVT prophylaxis until completely ambulatory.

VII. What's the evidence?

Stanley, JR, Wolff, K, Goldsmith, LA, Katz, SI, Gilchrest, BA, Paller, AS, Leffell, DJ. "Bullous Pemphigoid". Fitzpatrick's Dermatology in General Medicine. 2008.

Langan, SM, Smeeth, L, Hubbard, R, Fleming, KM, Smith, CJ, West, J. "Bullous pemphigoid and pemphigus vulgaris -incidence and mortality in the UK: population based cohort study". BMJ. vol. 337. 2008. pp. a180.

Tsuruta, D, Ishii, N, Hashimoto, T. "Diagnosis and treatment of pemphigus". Immunotherapy. vol. 4. pp. 735-45.

Naldi, L, Cazzaniga, S, Borradori, L. "Bullous pemphigoid: simple measures for a complex disease". J Invest Dermatol. vol. 132. pp. 1948-50.

Stavropoulos, PG, Soura, E, Antoniou, C. "Drug-induced pemphigoid: a review of the literature". J Eur Acad Dermatol Venereol. vol. 28. 2014. pp. 1133-40.

(This is a great review on how to delineate classic BP from drug-induced BP.)

Venning, VA, Taghipour, K, Mohd Mustapa, MF, Highet, AS, Kirtschig, G. "British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012". Br J Dermatol. vol. 167. 2012. pp. 1200-1214.

(The most recent [and excellent] evidence based review of treatment for BP.)

Gregoriou, S, Efthymiou, O, Stefanaki, C, Rigopoulos, D. "Management of pemphigus vulgaris: challenges and solutions". Clin Cosmet Investig Dermatol.. vol. 8. 2015 Oct 21. pp. 521-7.

(This review article provides very detailed, step by step management of PV; easy to read and from 2015.)

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