AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The various types of pemphigus include pemphigoid, pemphigus vegetans, Hailey-Hailey disease, and pemphigus foliaceus.

Pemphigus erythematosus, also known as Senear-Usher syndrome, is an overlap syndrome with features of lupus erythematosus (LE) and pemphigus foliaceus. Pemphigus is demonstrated by acantholysis and immunoglobulin deposits in the interkeratinocyte substance. The lupus component is demonstrated by circulating antinuclear antibodies (ANA) and sometimes by immunoglobulin and complement deposits at the dermoepidermal junction. The disease has a better prognosis than pemphigus foliaceus, but it can be chronic.

For a thorough description and introduction to the possible causes of pemphigus, see the article "Pemphigus: An Acronym for a Disease with Multiple Causes", published by the International Pemphigus Society.

Pathophysiology

Patients present with vesiculobullae or superficially eroded lesions, which may ooze and crust, particularly in sun-exposed areas, such as the face, the upper part of the chest, and the back. Pemphigus may be photoactivated. LE is the classic autoimmune disease that demonstrates photosensitivity. It appears that a genetic predisposition to autoimmunity combines with a sensitivity to ultraviolet light leading to an overlap of these 2 diseases in rare cases. Now these are called immunobullous disease.

Frequency

United States

The incidence in the United States is estimated to be similar to that internationally.

International

The incidence of pemphigus is 0.5-3.2 cases per 100,000 population per year. Patients with pemphigus erythematosus comprise only a small subgroup of those with pemphigus.

Mortality/Morbidity

With timely diagnosis and treatment, the disease typically has a good prognosis. Some patients may ultimately develop symptoms classified as criteria for systemic lupus erythematosus (SLE) by the American Rheumatism Association (ARA).

Race

Pemphigus erythematosus, like other variants of pemphigus erythematosus and LE, may be increased in patients who express specific human leukocyte antigen (HLA) haplotypes. Those identified to have pemphigus erythematosus are positive for human leukocyte antigen A10 (HLA-A10) or human leukocyte antigen A26 (HLA-A26) and human leukocyte antigen DRW6 (HLA-DRW6).

Sex

Reports generally find no difference in occurrence between the 2 sexes, although some studies from India suggest a male preponderance.

Age

Pemphigus erythematosus may occur at any age, but it is unusual in children.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Onset and progression are typically slow.
• Although the distribution of the lesions should suggest induction by sunlight, the patient may be completely unaware of the photosensitive nature of the disorder.

Physical

• Lesions typically involve the scalp, the face, the upper part of the chest, and the back.
• Patients with pemphigus erythematosus classically present with small, flaccid bullae with scaling and crusting. Occasionally, the appearance may suggest a papulosquamous disorder.
• Secondary infection may occur, resulting in impetiginization, in healing with pigment changes, and in scarring.
• On the face, pemphigus erythematosus presents on the bridge of the nose and on the malar areas as in the butterfly distribution seen in LE.
• With extensive involvement, patients may present with an exfoliative erythroderma.
• The skin may be tender.
• Patients with pemphigus erythematosus do not typically develop mucous membrane involvement, which can be seen in some other variants of pemphigus.
• Electrolyte imbalance and loss of temperature control can occur with extensive skin involvement.

Causes

• Patients with pemphigus develop an autoimmune response directed against desmosomes. In patients with pemphigus foliaceus and its variant, pemphigus erythematosus, the target antigen is desmoglein 1. Desmogleins are desmosomal proteins important in keratinocyte adhesion. The binding of autoantibodies is postulated to result in a cascade of biochemical intracellular events that eventuates in the loss of desmosome function.
• Certain HLA haplotypes (A10 or A26, DRW6) are thought to be associated, suggesting a genetic predisposition.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Direct immunofluorescence
• • Linear deposits of immunoglobulin G (IgG) and C3 are present in the intercellular space of the epidermis.
  • Granular deposits of C3 and IgG at the dermoepidermal junction are present in 80% of patients, particularly in biopsy specimens from the face or other sun-exposed areas.
• Immunoelectron microscopy: IgG and C3 deposits are localized to the epidermal cell membranes and the upper dermis.
• Patients with pemphigus erythematosus may have other laboratory abnormalities suggestive of SLE; these include anemia, lymphopenia, thrombocytopenia, renal abnormalities, proteinuria, or a positive rheumatoid factor.

Procedures

• Select an early vesicle or bulla for skin biopsy. Perilesional skin is tested on immunofluorescence studies.

Histologic Findings

Intraepidermal superficial bullae are usually within the granular layer or just below it. Acantholysis may occur in the blister floor or roof. Old lesions may have follicular hyperkeratosis with acantholysis and dyskeratosis of the granular layer.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Topical therapy

Topical corticosteroids are useful for patients with limited diseases or as an adjunct to systemic therapy. Selection of the appropriate topical steroid strength and vehicle depends on the body site, the age of the patient, and the potential for steroid adverse effects. Use of daily sunscreen and sun protection is necessary.

Systemic therapy

Systemic steroids have been the mainstay of therapy for widespread pemphigus since their first use in 1950. Prednisone 1-2 mg/kg/d as a single morning dose or as intravenous pulses may control the disease. Appropriate monitoring and follow-up care to avoid steroid adverse effects is critical.

Dapsone is effective in some patients with pemphigus erythematosus. Patients tend to respond relatively quickly, with improvement within several weeks. It can be a steroid-sparing drug. The possible mode of action is stabilization of lysosomal membranes and inhibition of polymorphonuclear leukocyte (PMN) toxicity. The recommended dose is 100-200 mg/d. Hemolytic jaundice may result in people with G-6-PD deficiency. Other adverse effects include agranulocytosis, leading to death, headaches, malaise, hepatitis, hypersensitivity reactions, and neuropathy. Caution is required.

Azathioprine is a potent immunosuppressive agent that has been used as a steroid-sparing agent. The usual doses are 75-150 mg (2-3 mg/kg/d) combined with 40-80 mg of prednisone. After initial control of the disease is obtained, tapering to maintenance doses of azathioprine is recommended. Patients who are thiopurine methyltransferase activity deficient (11% of the population) are at an increased risk of bone marrow toxicity with this agent.

Other useful drugs

• Tetracycline and niacinamide
• Cyclophosphamide
• Methotrexate
• Parenteral gold
• Hydroxychloroquine
• Plasmapheresis
• Mycophenolate mofetil
• Extracorporeal photochemotherapy

Consultations

A dermatologist with expertise in using and in monitoring of these agents is recommended.

Diet

Patients on long-term glucocorticoids should increase their intake of calcium and vitamin D as well as bisphosphates in an effort to prevent osteoporosis.

Activity

Patients should use appropriate sun-smart behaviors and protective clothing to minimize sun exposure that may exacerbate disease activity.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goal of pharmacotherapy is to reduce morbidity and to prevent complications.

Plasmapheresis and immunoadsorption have been shown to be effective in the treatment of pemphigus erythematosus. Plasmapheresis^{1, 2, 3} and, more recently, immunoadsorption,^{4, 5, 6} are extracorporeal treatments that act rapidly on disease activity by lowering the load of the causative autoantibodies in the patient's circulation.

In immunoadsorption, the immunoglobulins are selectively removed from the patient's plasma by adsorbing the antibodies to the matrix in a column of the immunoadsorption apparatus, after which the "cleansed" plasma is returned to the patient. Reportedly, immunoadsorption has higher efficacy and fewer adverse effects compared with plasmapheresis. In one German study,⁷ immunoadsorption was effective and safe in treating resistant and severe pemphigus. However, more studies are needed to support these data.

Drug Category: Corticosteroids

The mainstay of treatment of immunobullous diseases is steroids. Generally, high-dose steroids (ie, prednisolone, prednisone, methylprednisolone, dexamethasone), PO or IV, are effective in obtaining rapid disease control. However, high-dose and prolonged treatment with steroids often causes significant adverse effects. Screening and risk assessment of possible adverse effects (eg, diabetes, glaucoma, osteoporosis, blood pressure, history of GI bleeding) are required prior to and during treatment.

Concomitant calcium supplements and antacid drugs (eg, proton pump inhibitors) are recommended throughout therapy. A study⁸ of patients with pemphigus vulgaris showed intravenous pulse combined with low-dose oral steroid therapy to be more effective and associated with fewer severe adverse effects than oral high-dose steroid therapy.

To reduce the adverse effects of systemic steroids, French researchers compared the efficacy and adverse effect profile of topical steroids with that of systemic steroids in the treatment of moderate-to-severe bullous pemphigoid.⁹ Topical steroids were more effective than oral therapy and were associated with far fewer severe complications. However, a recent report warns of the development of steroid-induced skin atrophy and striae after this regimen.¹⁰

Drug Category: Antineoplastic agents

These agents inhibit cell growth and proliferation. Intravenous pulse cyclophosphamide (500 mg qd) has also been suggested as adjunctive therapy after plasmapheresis to prevent "rebound" (marked increase of antibodies compensating for the antibodies depleted by plasmapheresis).³
High-dose immunoablative cyclophosphamide without stem cell rescue was effective in 2 patients with resistant pemphigus. However, considering the serious adverse effects of this high-dose regimen, it should be reserved for patients who are resistant to other treatments.^{11, 12, 13}

Drug Category: Sulfone antibiotics

Dapsone's anti-inflammatory mechanism of action differs from the antibacterial mechanism of action. Suppression of neutrophils by inhibiting the halide-myeloperoxidase system is the most likely mechanism of action for anti-inflammatory effects.

Drug Category: Immunosuppressants

These agents are effective in the treatment of autoimmune diseases. See Glied and Rico¹⁴ and Tan et al¹⁵ for references regardings adverse effects (eg, abnormal LFT results) related to triphosphate-methyltransferase (TPMT).

Drug Category: Intravenous immunoglobulins

Latest development in the armamentarium for treating immunobullous disorders. IVIGs have proven beneficial in achieving rapid disease control in patients with immunobullous diseases.^{16, 17, 18, 19, 20, 21}

Drug Category: Anti-inflammatory agents

Anti-inflammatory agents (eg, dapsone, gold, tetracyclines) are also being used to treat certain immunobullous disorders. However, they are generally used in patients with mild-to-moderate disease, with the exception of those with dermatitis herpetiformis and linear IgA disease, in whom dapsone is still first-line treatment. Dapsone can be started after glucose-6-P-dehydrogenase screening. Low levels are associated with a high risk of methemoglobinemia. When using tetracyclines, some authors have reported minocycline-induced pigmentation in patients with pemphigus and pemphigoid, with a prevalence that appears to be much higher than in persons with acne or rheumatoid arthritis.²²
Targets a cell-specific protein and may represent a promising novel therapeutic option for refractory immunobullous diseases.^{23, 24, 25, 26}

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

Sun avoidance and sun protection are recommended.

Complications

The types of medications used to control severe pemphigus erythematosus may lead to serious iatrogenic disorders.

Prognosis

The prognosis of pemphigus erythematosus is better than that of pemphigus vulgaris. With good dermatologic care, patients with pemphigus erythematosus are often able to live normal lives.

Patient Education

Patient education about possible triggers for the disease is important. Patients should minimize sun exposure. Additionally, as in all photosensitive disorders, patient education on the use of sunscreens, protective clothing, and sun-smart behaviors is a cornerstone of therapy.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to explain the toxicity and adverse effects of steroids, cyclophosphamide, or other drugs
• Failure to explain the disease's prognosis before treatment

Special Concerns

• A delay of pregnancy is recommended during treatment and for a minimum of 2 years after stopping treatment with immunosuppressants.
• Wound healing may be delayed in patients on glucocorticoids.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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3. Turner MS, Sutton D, Sauder DN. The use of plasmapheresis and immunosuppression in the treatment of pemphigus vulgaris. J Am Acad Dermatol. Dec 2000;43(6):1058-64. [Medline].
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Article Last Updated: Oct 2, 2006