Pemphigus Erythematosus

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Background

The various types of pemphigus include pemphigus erythematosus, pemphigoid, pemphigus vegetans, pemphigus vulgaris, 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 (see the image below).



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Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G ....

Pérez-Pérez et al recently hypothesized that pemphigus erythematosus is a multiple autoimmune disease.[1]

High doses of UV light are suggested to be the cause of cleavage of the desmoglein-1 ectodomain. As in cases of pemphigus foliaceus the circulating anti–desmoglein-1 antibodies precipitate this cleaved off ectodomain along with the basement membrane zone, resulting in a lupus band–like appearance.

The lupus component of pemphigus erythematosus is demonstrated by circulating antinuclear antibodies (ANA) and sometimes by immunoglobulin and complement deposits at the dermoepidermal junction

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.[2]

Pathophysiology

Patients with pemphigus erythematosus 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.

Etiology

Patients with pemphigus develop an autoimmune response directed against desmosomes.[3] 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. Additionally, certain HLA haplotypes (A10 or A26, DRW6) are thought to be associated, suggesting a genetic predisposition.

Relapse of pemphigus erythematosus has been associated with atorvastatin intake.[4]

Epidemiology

Frequency

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. Kumar from India, in a 2008 article, reported a high prevalence (4.4 cases per million population).[5]

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 of pemphigus erythematosus between the 2 sexes.

Age

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

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. Some patients may ultimately develop symptoms classified as criteria for systemic lupus erythematosus (SLE) by the American College of Rheumatology (ACR).

Patient Education

Patient education about possible triggers for the pemphigus erythematosus 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.

History

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

Physical Examination

Pemphigus erythematosus lesions typically involve the scalp, the face, the upper part of the chest, and the back.[6] Patients with classic pemphigus erythematosus present with small, flaccid bullae with scaling and crusting. Occasionally, the appearance may suggest a papulosquamous disorder. 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.

Secondary infection may occur, resulting in impetiginization, in healing with pigment changes, and in scarring.

With extensive involvement, pemphigus erythematosus patients may present with an exfoliative erythroderma. The skin may be tender. Patients with pemphigus erythematosus do not typically develop mucous membrane involvement. Electrolyte imbalance and loss of temperature control can occur with extensive skin involvement.

Laboratory Studies

With direct immunofluorescence (see the image below) in pemphigus erythematosus, 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.[7]



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Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G ....

With immunoelectron microscopy in pemphigus erythematosus, 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 systemic lupus erythematosus (SLE); these include anemia, lymphopenia, thrombocytopenia, renal abnormalities, proteinuria, or a positive rheumatoid factor.

Procedures

In pemphigus erythematosus, 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. See the images below.



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Biopsy shows moderate epithelial hyperplasia with a suprabasal cleft that shows suprabasal acantholysis. The rest of the epithelium shows spongiosis w....



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Biopsy shows upper epidermal acantholytic blistering dermatitis involving the granular and upper spinous layer. The blister contains plasma, RBCs, and....



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Biopsy shows upper epidermal acantholytic blistering dermatitis involving the granular and upper spinous layer with absence of roof of blister. The ep....



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Biopsy shows sparse superficial and deep perivascular infiltrate of lymphocytes. The papillary dermis is edematous and there is extravasation of RBCs.....

Medical Care

Topical therapy

Topical corticosteroids are useful for pemphigus erythematosus patients with limited disease 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.[8] Use of daily sunscreen and sun protection is necessary. Griffies et al reported promising results in treating discoid lupus and pemphigus erythematosus in dogs with topical application of 0.1% tacrolimus, an immunomodulator produced by a fungus.[9] Remission with tacrolimus occurred alone in some dogs, whereas steroid use was decreased or discontinued in other dogs.

Systemic therapy

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

Dapsone is effective in some patients with pemphigus erythematosus.[10, 11] 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 0.5 -2.5 mg/kg/d, based on results of thiopurine methyltransferase activity. Those who are deficient are at an increased risk of bone marrow toxicity with this agent, as are patients who are taking allopurinol.

Other useful drugs in pemphigus erythematosus treatment are as follows:

Dexamethasone-cyclophosphamide combination therapy has recently been studied. In 2009, Kandan and Thappa reported good outcomes in 65 cases of pemphigus treated with dexamethasone-cyclophosphamide pulse therapy.[22]

Pasricha and Poonam reported the effects of a few modifications in the regimen in 123 patients treated with the dexamethasone-cyclophosphamide pulse/dexamethasone pulse (DCP/DP) regimen over a period of 5 years (1998-2002). The 3 modifications introduced into the regimen were: (1) an additional daily dose of oral betamethasone sufficient to control the disease activity during phase I, which was progressively tapered completely as the patient recovered; (2) use of systemic antibiotics, if the patient had skin lesions, and oral anticandidal drugs, if the patient had oral ulcers, until complete healing; and (3) insistence on thorough cleaning of the skin and scalp, with a normal soap and shampoo, and proper maintenance of oral hygiene in spite of skin/mucosal lesions. The regimen consisted of DCP/DP repeated in exactly 28-day cycles, along with cyclophosphamide at 50 mg/d, insistence on completing treatment, and avoidance of irregular pulses in all patients.[23]

Cyclophosphamide is contraindicated in patients who wish to have children.[24]

Consultations

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

Diet

Patients on long-term glucocorticoid therapy should increase their intake of calcium and vitamin D, as well as engaging in weight-bearing activity. Dual-energy x-ray absorptiometry (DEXA) scanning and bisphosphates should be discussed with a rheumatologist.

Activity

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

Complications

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

Prevention

Sun avoidance and sun protection are recommended for pemphigus erythematosus patients.

Medication Summary

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

Plasmapheresis and immunoadsorption have been shown to be effective in the treatment of pemphigus erythematosus. Plasmapheresis[25, 26, 27, 28] and, more recently, immunoadsorption,[29, 30, 31] are extracorporeal treatments that act rapidly on disease activity by lowering the load of the causative autoantibodies in the patient's circulation, causing a rebound of the plasma cell clone. During rebound, the plasma cells are more sensitive to chemotherapy.

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,[32] immunoadsorption was effective and safe in treating resistant and severe pemphigus. However, more studies are needed to support these data.

Steroid therapy

Concomitant calcium supplements and antacid drugs (eg, proton pump inhibitors) are recommended throughout therapy. A study[33] of patients with pemphigus vulgaris showed intravenous pulse combined with low-dose oral steroid therapy to be 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.[34] Topical steroids were more effective than oral therapy and were associated with far fewer severe complications. However, a 2003 report warns of the development of steroid-induced skin atrophy and striae after this regimen, and it has not been validated in other immunobullous diseases.[35]

Antineoplastic therapy

These agents inhibit cell growth and proliferation and serve as steroid-sparing agents. 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).[27]

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.[36, 37, 38]

Immunosuppressant therapy

These agents are effective in the treatment of autoimmune diseases. See Glied and Rico[39] and Tan et al[40] for references regarding adverse effects (eg, abnormal LFT results) related to thiopurine-methyltransferase (TPMT).

Also see the clinical guideline summary from the British Association of Dermatologists, Guidelines for prescribing azathioprine in dermatology.[41]

Intravenous immunoglobulins

IVIGs have proven beneficial in achieving rapid disease control in patients with immunobullous diseases.[42, 43, 44, 45, 46, 47, 48]

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.[49]

Rituximab targets a cell-specific protein and may represent a promising novel therapeutic option for refractory immunobullous diseases.[50, 51, 52, 53]

 

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Clinical Context:  Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. It stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Class Summary

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.

Cyclophosphamide (Cytoxan, Neosar)

Clinical Context:  Several regimens with cyclophosphamide have been described in the treatment of immunobullous disorders. Cyclophosphamide is a potent cytotoxic agent that can cause severe cytopenia and hemorrhagic cystitis (bladder inflammation).

Oral low-dose cyclophosphamide is usually used as a steroid-sparing agent.

Intravenous cyclophosphamide (500 mg qd for 1 d) plus low-dose oral (50 mg qd) has been combined with intravenous pulse dexamethasone (100 mg qd for 3 d) to achieve rapid disease control.

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).

More recently, 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.

More studies are needed to outline the risk of adverse effects vs benefits of this regimen.

Class Summary

These agents inhibit cell growth and proliferation and serve as steroid-sparing agents.

Dapsone (Avlosulfon)

Clinical Context:  Dapsone is bactericidal and bacteriostatic against mycobacteria; its mechanism of action is similar to that of sulfonamides, where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth.

Class Summary

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.

Azathioprine (Imuran)

Clinical Context:  Among the slowly acting adjuvant therapies, azathioprine is a useful and safe steroid-sparing agent, provided TPMT assay is performed prior to treatment. TPMT is an enzyme that converts azathioprine into its inactive metabolites.

If TPMT is lacking or present in a much lower concentration, patient is at high risk for bone marrow suppression and thus anemia, thrombocytopenia, and leukopenia. Therefore, analysis of TPMT levels is recommended before starting treatment.

Other adverse effects (eg, abnormal LFT results) are not reflected by this enzyme level.

Class Summary

These agents are effective in the treatment of autoimmune diseases.

Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin)

Clinical Context:  Immune globulin intravenous consists of IgG collected from a pool of thousands of blood donors (virus-free), thus providing a wide range of immunologically different IgG. Theoretically, they bind and neutralize pathogenic autoantibodies.

It is administered IV, with each cycle lasting 3-5 days, at a dose of 1-2 g/kg/cycle. Several cycles are usually required.

Cost and availability limit its use. IVIG is expensive. It is generally used in resistant and severe bullous diseases in addition to immunosuppressive therapy or as monotherapy in patients with contraindications for immunosuppressive drugs.

Class Summary

IVIGs have proven beneficial in achieving rapid disease control in patients with immunobullous diseases.

Rituximab (Rituxan)

Clinical Context:  Rituximab is a monoclonal anti-CD20 antibody (CD20 is a protein on the surface of lymphocytes), reported to be effective in treating resistant pemphigus foliaceous and vulgaris. It may deplete B lymphocytes (antibody-producing cells) and rapidly removes desmoglein antibodies (antibodies causing pemphigus) from circulation.

Class Summary

Anti-inflammatory agents (eg, dapsone, gold, tetracyclines) are also being used to treat certain immunobullous disorders. Rituximab targets a cell-specific protein and may represent a promising novel therapeutic option for refractory immunobullous diseases.

Author

Rakesh Bharti, MD, MBBS, Consultant Dermatologist and HIV Specialist, BDC Research Centre, India

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Julia R Nunley, MD, Professor, Program Director, Dermatology Residency, Department of Dermatology, Virginia Commonwealth University Medical Center

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Board of Dermatology<br/>Co-Editor for the text Dermatological Manifestations of Kidney Disease .

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.

Additional Contributors

Ponciano D Cruz, Jr, MD, Professor and Vice-Chair, Paul R Bergstresser Chair, Department of Dermatology, University of Texas Southwestern Medical Center

Disclosure: Received consulting fee from RCTS for independent contractor; Received honoraria from Mary Kay Cosmetics for consulting; Received grant/research funds from Galderma for principal investigator.

Acknowledgements

The author acknowledges the patience of his wife Prabha Bharti while carrying out work on this article and the constant pushing of his learned sons Aseem and Anshul.

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Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.

Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.

Biopsy shows moderate epithelial hyperplasia with a suprabasal cleft that shows suprabasal acantholysis. The rest of the epithelium shows spongiosis with neutrophils. The submucosa has a moderately dense mixed perivascular infiltrate of lymphocytes and neutrophils. At places, the epithelium is missing, and the surface is covered by fibrin and necrotic inflammatory cells. Photo courtesy of Dr. Uday Khopkar.

Biopsy shows upper epidermal acantholytic blistering dermatitis involving the granular and upper spinous layer. The blister contains plasma, RBCs, and few acute inflammatory cells. The epidermis at the periphery of the blister shows mild spongiosis with neutrophils. In the roof of the blister, a few elongated acantholytic cells can be seen. Underlying dermis shows superficial and mid perivascular mixed infiltrate of neutrophils and lymphocytes. Photo courtesy of Dr. Uday Khopkar.

Biopsy shows upper epidermal acantholytic blistering dermatitis involving the granular and upper spinous layer with absence of roof of blister. The epidermis shows mild spongiosis with neutrophils. Underlying dermis shows superficial and mid perivascular mixed infiltrate of neutrophils and lymphocytes. Photo courtesy of Dr. Uday Khopkar.

Biopsy shows sparse superficial and deep perivascular infiltrate of lymphocytes. The papillary dermis is edematous and there is extravasation of RBCs. Basal layer shows vacuolization and interface infiltration by lymphocytes. Reticular dermis shows small amount of mucin. Photo courtesy of Dr. Uday Khopkar.

Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.

Biopsy shows moderate epithelial hyperplasia with a suprabasal cleft that shows suprabasal acantholysis. The rest of the epithelium shows spongiosis with neutrophils. The submucosa has a moderately dense mixed perivascular infiltrate of lymphocytes and neutrophils. At places, the epithelium is missing, and the surface is covered by fibrin and necrotic inflammatory cells. Photo courtesy of Dr. Uday Khopkar.

Biopsy shows upper epidermal acantholytic blistering dermatitis involving the granular and upper spinous layer. The blister contains plasma, RBCs, and few acute inflammatory cells. The epidermis at the periphery of the blister shows mild spongiosis with neutrophils. In the roof of the blister, a few elongated acantholytic cells can be seen. Underlying dermis shows superficial and mid perivascular mixed infiltrate of neutrophils and lymphocytes. Photo courtesy of Dr. Uday Khopkar.

Biopsy shows upper epidermal acantholytic blistering dermatitis involving the granular and upper spinous layer with absence of roof of blister. The epidermis shows mild spongiosis with neutrophils. Underlying dermis shows superficial and mid perivascular mixed infiltrate of neutrophils and lymphocytes. Photo courtesy of Dr. Uday Khopkar.

Biopsy shows sparse superficial and deep perivascular infiltrate of lymphocytes. The papillary dermis is edematous and there is extravasation of RBCs. Basal layer shows vacuolization and interface infiltration by lymphocytes. Reticular dermis shows small amount of mucin. Photo courtesy of Dr. Uday Khopkar.