Are You Confident of the Diagnosis?
In 1926, Francis Senear and Barney Usher described 11 patients with features of a pemphigus-lupus erythematosus overlap, which they named “pemphigus erythematosus,” later to be known as Senear-Usher syndrome. Subsequently, Walter Lever observed that some patients previously diagnosed as having pemphigus erythematosus in fact had systemic lupus erythematosus, or went on to develop more widespread pemphigus foliaceus (PF), or even pemphigus vulgaris, in many cases due to an incorrect initial diagnosis. Rather than lump these different diseases under one term, he proposed that pemphigus erythematosus be used to describe a localized form of PF with a better prognosis.
What you should be alert for in the history
Determine the scope of cutaneous disease (only on the face or elsewhere on the scalp and body?). Ask about recent changes in medications. Ask about aggravating factors, which can include stress, ultraviolet radiation, menses, recent vaccinations, or cessation of smoking. Ask about possible signs of systemic lupus, including oral ulcers, photosensitivity, arthritis, seizures or psychosis, and/or chest pain indicating possible serositis.
Characteristic features on physical examination
Classically, pemphigus erythematosus affects only the face, similar in distribution to the malar rash of systemic lupus erythematosus. Skin blisters are rarely intact, more often presenting with confluent crusted erosions that can be mistaken for impetigo, seborrheic dermatitis, rosacea, or eczema (Figure 1).
In patients with widespread disease, the Nikolsky sign may be present, where blisters can be extended into normal-appearing skin by fingertip pressure lateral to the edge of a blister, or induced in normal-appearing skin distant from areas of blistering by mechanical shear force, indicating the loss of cell adhesion throughout the epidermis. The Nikolsky sign is not specific for pemphigus and may also be observed in staphylococcal scalded skin syndrome and toxic epidermal necrolysis.
Expected results of diagnostic studies
Skin or mucosal biopsy for histology. A punch or shave biopsy for histology should be obtained at the lateral edge of a fresh blister. Biopsy of an old blister can confuse the diagnosis due to necrosis of the roof of the blister and/or re-epithelialization of the base. Pemphigus erythematosus will show acantholysis (loss of intercellular adhesion between intact keratinocytes) in the granular or subcorneal layer of the epidermis, identical to the blister of pemphigus foliaceus (Figure 2).
Blisters are usually noninflammatory, but neutrophils and/or eosinophils can be present within and around the blister cavity. In some early lesions, eosinophilic spongiosis may be the only histologic finding. Autoantibodies to the keratinocyte cell surface should be documented, either by direct immunofluorescence, indirect immunofluorescence, or ELISA. By definition, all pemphigus erythematosus patients will have the cell surface immunofluorescence staining pattern characteristic of pemphigus foliaceus.
Skin biopsy for direct immunofluorescence (DIF). A punch or shave biopsy should be obtained from normal-appearing perilesional skin and submitted in Michel’s or other appropriate fixative for direct immunofluorescence analysis. Like PF, pemphigus erythematosus will demonstrate IgG cell surface staining of keratinocytes. IgA may also be positive. C3 is rarely positive. Additionally, shaggy IgM, fibrinogen, +/- IgG staining of the basement membrane zone may be observed, representing a positive lupus band test (Figure 3). Even if all skin lesions have healed because of recent therapy, DIF should remain positive for at least several weeks. Cell surface-bound IgG is typically internalized by keratinocytes within the blister cavity, leading to false negative results if samples for DIF are taken from blistered skin.
Serum sample for indirect immunofluorescence (IIF). Serum is incubated with epithelial substrates (typically guinea pig esophagus or normal human skin). Incubation of pemphigus erythematosus sera with monkey esophagus (a common substrate for pemphigus vulgaris testing) is often negative. Similar to DIF, IIF for pemphigus erythematosus will demonstrate IgG cell surface staining, and less often IgA or C3, and will remain positive for at least several weeks after skin lesions have healed. Indirect immunofluorescence is a semi-quantitative test, with titer roughly correlating with disease activity.
Serum sample for desmoglein ELISA. Desmoglein 1 ELISA is more sensitive and specific (100% and 96%, respectively) for PF than indirect immunofluorescence and may replace the latter as the preferred diagnostic test. However, desmoglein ELISA is not always available from major national reference laboratories. Desmoglein ELISA index values roughly correlate with disease activity. However, because the desmoglein ELISA measures both pathogenic as well as nonpathogenic antibodies (see “Pathophysiology” below), positive desmoglein ELISA index values may still be observed in patients in remission.
Immunologic testing for lupus should be performed. Thirty percent of pemphigus erythematosus patients have positive antinuclear antibody titers. Eighty percent have positive lupus band tests (IgM and fibrinogen at the basement membrane zone) on sun-exposed skin; 20-40% of biopsies from non-sun-exposed skin will show a positive lupus band test.
The clinical differential diagnosis for pemphigus erythematosus, or localized PF, can include bullous impetigo, seborrheic dermatitis, rosacea, herpes simplex, or eczema.
The differential diagnosis for more widespread cases of PF include Staphylococcal scalded skin syndrome, necrolytic migratory erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and other rare autoimmune blistering diseases.
Who is at Risk for Developing this Disease?
The epidemiology of pemphigus erythematosus is unknown, although it is a rare subset of pemphigus foliaceus, which itself is a rare disease (estimates of PF incidence in Western Europe are approximately 0.5-1.0 per million per year).
Penicillamine and captopril have been associated with PF onset. The prevalence of pemphigus (including vulgaris and foliaceus) in penicillamine users is estimated at 7 percent, with the majority having PF. Although angiotensin-converting enzyme inhibitors other than captopril are not as strongly associated with pemphigus, it is reasonable to change these medications. Diet has also been proposed as a risk factor for pemphigus (eg, garlic, onions). However, discontinuation of penicillamine or other medications and modification of diet rarely result in disease remission.
What is the Cause of the Disease?
Superficial skin blisters in pemphigus erythematosus, as in pemphigus foliaceus, are caused by autoantibodies against desmoglein 1. Desmoglein 1 is a transmembrane protein of the desmosome, which is the major cell adhesive junction in keratinocytes. Anti-desmoglein antibodies are necessary and sufficient for blister formation in animal and human skin models; complement or other immune mediators are not required for blister formation.
The immune mechanisms causing the loss of tolerance to desmoglein 1 in pemphigus erythematosus are unknown, as are the reasons for the simultaneous occurrence of desmoglein 1 autoantibodies with a positive lupus band test.
Most pathogenic anti-desmoglein 1 antibodies target the desmoglein extracellular domain that is predicted to form the transadhesive interface between cells, while nonpathogenic antibodies more often target other extracellular domains. These studies suggest that pathogenic autoantibodies may cause disease by steric hindrance of desmoglein adhesive interactions.
In addition, keratinocyte signaling pathways such as p38 mitogen activated protein kinase regulate the cell surface internalization of desmogleins, which may also contribute to disease pathology. Corticosteroids upregulate desmoglein expression in keratinocytes, which may account for their rapid therapeutic effect (within days, even when circulating antibody titers have not yet changed), as well as their efficacy when used topically.
Systemic Implications and Complications
Most patients with pemphigus erythematosus do not develop systemic signs or symptoms of lupus, and conversely, most patients with systemic lupus do not develop pemphigus. Nevertheless, the possibility of systemic autoimmunity from lupus should be considered and screened for in patients with PF that is predominantly localized in a malar distribution.
Treatment options are summarized in Table I.
|Topical corticosteroids or macrolides|
|Tetracyclines plus niacinamide|
Optimal Therapeutic Approach for this Disease
Class IV-VI steroids, such as triamcinolone acetonide 0.1%, triamcinolone acetonide 0.025%, or aclometasone ointment, can be applied twice daily to new blisters and erosions on the face, although chronic use should be avoided. Topical tacrolimus may be preferable for chronic use on facial erosions. For mild disease (transient lesions that heal within 1 week), monotherapy with topical agents may be sufficient. Mild disease may also respond to tetracyclines plus niacinamide (doxycycline 100mg twice daily plus niacinamide 500mg three times daily).
Desmoglein 1 is cleaved by exfoliative toxins elaborated by certain strains of Staphylococcus aureus. Because S.aureus is a normal part of the resident cutaneous flora, anti-staphylococcal antibiotics (including tetracyclines) can help to improve mild flares of disease in otherwise stable patients.
With persistent or widespread disease, oral the corticosteroids such as prednisone may be necessary. For moderate disease, 0.5 mg/kg/day of prednisone or equivalent may be sufficient. Doses generally do not need to exceed 1 mg/kg/day of prednisone. If patients flare on 1 mg/kg/day of prednisone, the dose can be split to twice daily or three times daily dosing, which increases the therapeutic efficacy without increasing the total daily dose.
Before starting high-dose steroids, tuberculosis screening should be performed (via tuberculin skin testing or Quantiferon-gold blood assay). If patients will be on chronic corticosteroids (at least 5mg daily prednisone equivalent for at least 3 months), osteoporosis counseling and prevention is indicated. Additionally, Pneumocystis prophylaxis should be considered for patients on chronic prednisone, particularly with daily prednisone doses of 15mg or higher. Patients should remain on high-dose steroids until new lesions cease to form, and then the dose can be gradually tapered to the minimum required to control disease. If patients can be managed with 10mg (or ideally 5mg) daily prednisone or less, corticosteroid monotherapy is feasible.
Dapsone (100-200mg daily) can sometimes be effective to lower the daily corticosteroid dose in patients with stable disease. Dapsone can be used in addition to mycophenolate mofetil or azathioprine. As an advantage, dapsone 100mg daily provides Pneumocystis prophylaxis. Glucose-6-phosphate dehydrogenase (G6PD) activity should ideally be measured before starting therapy, particularly in men of African-American and Middle Eastern descent. Most patients will experience a 1-2 g/dL drop in hemoglobin due to hemolysis, although some patients can experience a severe pancytopenia with or without systemic hypersensitivity reaction. Laboratory monitoring should be performed at least every other week for the first 8 weeks.
In patients requiring greater than 10mg daily prednisone for control of disease activity, or in patients with contraindications to systemic corticosteroid therapy, other immunosuppressants are necessary to reduce or replace systemic corticosteroids. Mycophenolate mofetil and azathioprine have shown approximately equal efficacy and safety in clinical trials for pemphigus, although there is a trend toward both greater efficacy and safety with mycophenolate mofetil. Mycophenolate mofetil (30-40 mg/kg/day divided twice daily) is generally well tolerated, although side effects of fatigue, gastrointestinal upset, and tremor are not uncommon, particularly at higher doses. Reduction of corticosteroid dose can be initiated as early as one month after starting mycophenolate mofetil, although the maximal effects of mycophenolate mofetil is not achieved until 2-3 months.
Azathioprine can be started at 50mg daily and titrated upward by 50mg every 1-2 weeks until side effect, therapeutic effect, or the target dose of 2.5mg/kg/day occurs. Measurement of the serum thiopurine methyltransferase (TPMT) level prior to the start of azathioprine therapy can be performed, although some studies suggest that TPMT levels do not correlate with the incidence of adverse effects or the efficacy of azathioprine therapy. Nevertheless, if serum TPMT levels are very low or very high, azathioprine may not be a good choice for therapy, due to an increased likelihood for adverse effects or lack of therapeutic effect, respectively. The active metabolites for azathioprine do not significantly accumulate until 6-8 weeks after initiation of therapy, leading to a delayed therapeutic effect.
More severe cases with generalized erosions on the face and body may require more aggressive therapy. These cases are better diagnosed as pemphigus foliaceus.
Pemphigus erythematosus is typically localized and has a good prognosis; ideally topical therapies will be sufficient to control disease. However, facial erosions are often disfiguring and may not respond to topical therapies. When starting patients on systemic therapy, risks of medications should be discussed. There is no systemic medication for pemphigus that is 100% safe. Patients should be educated on the signs and symptoms of systemic lupus so that any potential systemic involvement can be identified and treated early. Broad spectrum sunscreens should be used regularly.
Open erosions can become superinfected with S.aureus or herpesviruses; culture of refractory or worsening lesions should be considered. Remind patients that their skin during active disease is fragile, so crusted blisters should not be scrubbed.
The Centers for Disease Control recommends that all patients on immunosuppressive therapy receive influenza and other regularly scheduled vaccinations. While on immunosuppressive therapy, patients should be reminded that they should not receive live vaccines (eg, nasal influenza or zoster.)
Unusual Clinical Scenarios to Consider in Patient Management
Pregnant patients with pemphigus erythematosus should be referred for high-risk obstetrical care. Pregnant patients who cannot be managed with topical therapy are usually treated with prednisone monotherapy, as most other immunosuppressive agents are pregnancy category D, including mycophenolate mofetil, azathioprine, tetracyclines, and cyclophosphamide. Dapsone is pregnancy category C.
There are sparse data regarding the safety of immunosuppressives in men whose pregnant wives can be exposed to drugs in seminal fluid. Rare cases of birth defects with azathioprine use by fathers has been reported. An ongoing registry of male transplant patients receiving mycophenolate mofetil has shown no significant increase in birth defects.
What is the Evidence?
Senear, FE, Usher, B. “An unusual type of pemphigus combining features of lupus erythematosus”. Arch Dermatol Syphilol. vol. 13. 1925. pp. 761-81. (The original description of the disease.)
Senear, FE, Kingery, LB. “Pemphigus erythematosus”. Arch Dermatol Syphilol. vol. 60. 1949. pp. 238-52. (Senear reinforces pemphigus erythematosus as a variant of pemphigus.)
Lever, WF, Springfield, IL, Charles, C. “Pemphigus and pemphigoid”. 1965. (Lever identifies many cases previously diagnosed as pemphigus erythematosus as misdiagnoses of systemic lupus erythematosus, pemphigus foliaceus, or pemphigus vulgaris. He proposes that pemphigus erythematosus be used to describe a localized form of pemphigus foliaceus with good prognosis.)
Jablonska, S, Chorzelski, T, Blaszczyk, M, Maciejewski, W. “Pathogenesis of pemphigus erythematosus”. arch Dermatol Res. vol. 258. 1977. pp. 135-40. (Defines the immunologic characteristics of pemphigus erythematosus sera by immunofluorescence and anti-nuclear antibody testing.)
Payne, AS, Stanley, JR, Wolff, K, Goldsmith, LA, Katz, SI, Gilchrest, B, Paller, AS, Leffell, DJ. “Dermatology in general medicine”. McGraw Hill. 2011. (A more complete review of the clinical presentation and management of pemphigus.)
Murrell, DF, Dick, S, Ahmed, AR, Amagai, M, Barnadas, MA, Borradori, L. “Consensus statement on definitions of disease endpoints and therapeutic response for pemphigus”. J Amer Acad Dermatol. vol. 58. 2008. pp. 1043-6. (An international consensus of definitions for disease endpoints (such as remission, relapse, and treatment failure).
Amagai, M, Komai, A, Hashimoto, T, Shirakata, Y, Hashimoto, K, Yamada, T. “Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus”. Br J Dermatol. vol. 130. 1999. pp. 351-7. (Describes the development of the desmoglein ELISA, including sensitivity and specificity.)
Beissert, S, Werfel, T, Frieling, U, Bohm, M, Sticherling, M, Stadler, R. “A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus”. Arch. Dermatol. vol. 142. 2006. pp. 1447-54. (This prospective randomized trial of 40 pemphigus patients [including 7 PF] demonstrated equal efficacy and safety between mycophenolate mofetil (2 g daily) and azathioprine (2mg/kg/day) as steroid-sparing agents in pemphigus, with a trend toward greater efficacy and safety for mycophenolate mofetil.)
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